{"_id": "WikiPedia_Pharmacology$$$corpus_1", "text": "Drug resistance  is the reduction in effectiveness of a medication such as an  antimicrobial  or an  antineoplastic  in treating a  disease  or condition. [ 1 ]  The term is used in the context of resistance that  pathogens  or cancers have \"acquired\", that is, resistance has evolved.  Antimicrobial resistance  and  antineoplastic resistance  challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be  multidrug-resistant ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2", "text": "The development of antibiotic resistance in particular stems from the drugs targeting only specific bacterial molecules (almost always proteins). Because the drug is  so  specific, any mutation in these molecules will interfere with or negate its destructive effect, resulting in antibiotic resistance. [ 2 ]  Furthermore, there is mounting concern over the abuse of antibiotics in the farming of livestock, which in the  European Union  alone accounts for three times the volume dispensed to humans \u2013 leading to development of super-resistant bacteria. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3", "text": "Bacteria are capable of not only altering the enzyme targeted by antibiotics, but also by the use of enzymes to modify the antibiotic itself and thus neutralize it. Examples of target-altering pathogens are  Staphylococcus aureus , vancomycin-resistant  enterococci  and macrolide-resistant  Streptococcus , while examples of antibiotic-modifying microbes are  Pseudomonas aeruginosa  and aminoglycoside-resistant  Acinetobacter baumannii . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4", "text": "In short, the lack of concerted effort by governments and the pharmaceutical industry, together with the innate capacity of microbes to develop resistance at a rate that outpaces development of new drugs, suggests that existing strategies for developing viable, long-term anti-microbial therapies are ultimately doomed to failure. Without alternative strategies, the acquisition of drug resistance by pathogenic microorganisms looms as possibly one of the most significant public health threats facing humanity in the 21st century. [ 6 ]  Some of the best alternative sources to reduce the chance of antibiotic resistance are probiotics, prebiotics, dietary fibers, enzymes, organic acids, phytogenics. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5", "text": "Drug, toxin, or chemical resistance is a consequence of  evolution  and is a response to pressures imposed on any living organism. Individual organisms vary in their sensitivity to the drug used and some with greater  fitness  may be capable of surviving drug treatment. Drug-resistant traits are accordingly inherited by subsequent offspring, resulting in a population that is more drug-resistant. Unless the drug used makes sexual reproduction or  cell-division  or  horizontal gene transfer  impossible in the entire target population, resistance to the drug will inevitably follow. This can be seen in  cancerous  tumors where some cells may develop resistance to the drugs used in  chemotherapy . [ 9 ]  Chemotherapy causes  fibroblasts  near  tumors  to produce large amounts of the protein  WNT16 B. This protein stimulates the growth of cancer cells which are drug-resistant. [ 10 ]   MicroRNAs  have also been shown to affect acquired drug resistance in cancer cells and this can be used for therapeutic purposes. [ 11 ]   Malaria  in 2012 has become a resurgent threat in  South East Asia  and  sub-Saharan Africa , and drug-resistant strains of  Plasmodium falciparum  are posing massive problems for health authorities. [ 12 ] [ 13 ]   Leprosy  has shown an increasing resistance to  dapsone ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6", "text": "A rapid process of sharing resistance exists among  single-celled organisms , and is termed horizontal gene transfer in which there is a direct exchange of genes, particularly in the  biofilm  state. [ 14 ]  A similar asexual method is used by  fungi  and is called \" parasexuality \". Examples of drug-resistant strains are to be found in microorganisms [ 15 ]  such as bacteria and viruses, parasites both  endo-  and  ecto- , plants, fungi,  arthropods , [ 16 ] [ 17 ]  mammals, [ 18 ]  birds, [ 19 ]  reptiles, [ 20 ]  fish, and amphibians. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7", "text": "In the domestic environment, drug-resistant strains of organism may arise from seemingly safe activities such as the use of  bleach , [ 21 ]  tooth-brushing and mouthwashing, [ 22 ]  the use of antibiotics, disinfectants and detergents,  shampoos , and soaps, particularly antibacterial soaps, [ 23 ] [ 24 ]  hand-washing, [ 25 ]  surface sprays, application of  deodorants ,  sunblocks  and any cosmetic or health-care product,  insecticides , and dips. [ 26 ]  The chemicals contained in these preparations, besides harming beneficial organisms, may intentionally or inadvertently target organisms that have the potential to develop resistance. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8", "text": "The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are: [ 28 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9", "text": "[ 30 ] \n [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10", "text": "Beta-lactam antibiotics (penicillin and cephalosporin)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11", "text": "Chloramphenicol"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12", "text": "Binds to penicillin-binding proteins, Inhibiting peptidoglycan synthesis"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13", "text": "Bind to 50S ribosome subunit, inhibiting formation of peptide bonds"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14", "text": "Plasmid encode beta-lactamase, which open the beta-lactam ring, inactivating it."}
{"_id": "WikiPedia_Pharmacology$$$corpus_15", "text": "Plasmid encode an enzyme that acetylate the drug, thereby inactivating it."}
{"_id": "WikiPedia_Pharmacology$$$corpus_16", "text": "Erythromycin"}
{"_id": "WikiPedia_Pharmacology$$$corpus_17", "text": "Quinolones"}
{"_id": "WikiPedia_Pharmacology$$$corpus_18", "text": "Rifampin"}
{"_id": "WikiPedia_Pharmacology$$$corpus_19", "text": "Trimethoprim"}
{"_id": "WikiPedia_Pharmacology$$$corpus_20", "text": "Bind to 50S ribosome subunit, inhibiting protein synthesis"}
{"_id": "WikiPedia_Pharmacology$$$corpus_21", "text": "Binds to DNA topoisomerase, an enzyme essential for DNA synthesis"}
{"_id": "WikiPedia_Pharmacology$$$corpus_22", "text": "Binds to the RNA polymerase; inhibiting initiation of RNA synthesis"}
{"_id": "WikiPedia_Pharmacology$$$corpus_23", "text": "Inhibit the enzyme dihydrofolate reduces, blocking the folic acid pathway"}
{"_id": "WikiPedia_Pharmacology$$$corpus_24", "text": "Bacteria make an altered penicillin-binding proteins, that do not bind to the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_25", "text": "Bacteria make a form of 50S ribosome that does not binds to the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_26", "text": "Bacteria make an altered DNA topoisomerase that does not binds to the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_27", "text": "Bacteria make an altered polymerase that does not binds to the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_28", "text": "Bacteria make an altered enzyme that does not binds to the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_29", "text": "Tetracycline"}
{"_id": "WikiPedia_Pharmacology$$$corpus_30", "text": "Binds to 30S Ribosome subunit, inhibiting protein synthesis by blocking tRNA"}
{"_id": "WikiPedia_Pharmacology$$$corpus_31", "text": "New membrane transport system prevent drug from entering cell."}
{"_id": "WikiPedia_Pharmacology$$$corpus_32", "text": "New membrane transport system pumps drug out of cell."}
{"_id": "WikiPedia_Pharmacology$$$corpus_33", "text": "Biological cost  is a measure of the increased  energy metabolism  required to achieve a function. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_34", "text": "Drug resistance has a high metabolic price in pathogens [ 32 ]  for which this concept is relevant (bacteria, [ 33 ]  endoparasites, and tumor cells.) In viruses, an equivalent \"cost\" is genomic complexity. The high metabolic cost means that, in the absence of antibiotics, a resistant pathogen will have decreased evolutionary fitness as compared to susceptible pathogens. [ 34 ]  This is one of the reasons drug resistance adaptations are rarely seen in environments where antibiotics are absent. However, in the presence of antibiotics, the survival advantage conferred off-sets the high metabolic cost and allows resistant strains to proliferate. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_35", "text": "In humans, the gene  ABCB1  encodes  MDR1(p-glycoprotein)  which is a key transporter of medications on the cellular level. If MDR1 is overexpressed, drug resistance increases. [ 35 ]  Therefore, ABCB1 levels can be monitored. [ 35 ]  In patients with high levels of ABCB1 expression, the use of secondary treatments, like metformin, have been used in conjunction with the primary drug treatment with some success. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_36", "text": "For  antibiotic resistance , which represents a widespread problem nowadays, drugs designed to block the mechanisms of bacterial antibiotic resistance are used. For example, bacterial resistance against  beta-lactam antibiotics  (such as  penicillin  and  cephalosporins ) can be circumvented by using antibiotics such as  nafcillin  that are not susceptible to destruction by certain  beta-lactamases  (the group of enzymes responsible for breaking down beta-lactams). [ 36 ]  Beta-lactam bacterial resistance can also be dealt with by administering beta-lactam antibiotics with drugs that block beta-lactamases such as  clavulanic acid  so that the antibiotics can work without getting destroyed by the bacteria first. [ 37 ]  Researchers have recognized the need for new drugs that inhibit  bacterial efflux pumps , which cause resistance to multiple antibiotics such as  beta-lactams ,  quinolones ,  chloramphenicol , and  trimethoprim  by sending molecules of those antibiotics out of the bacterial cell. [ 38 ] [ 39 ]  Sometimes a combination of different classes of antibiotics may be used synergistically; that is, they work together to effectively fight bacteria that may be resistant to one of the antibiotics alone. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_37", "text": "Destruction of the resistant  bacteria  can also be achieved by  phage therapy , in which a specific  bacteriophage  (virus that kills bacteria) is used. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_38", "text": "Antineoplastic resistance , often used interchangeably with  chemotherapy  resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. [ 1 ]  In some cases, cancers can evolve resistance to multiple drugs, called  multiple drug resistance ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_39", "text": "There are two general causes of antineoplastic therapy failure: Inherent genetic characteristics, giving cancer cells their resistance and acquired resistance after drug exposure, which is rooted in the concept of  cancer cell heterogeneity . [ 1 ]  Characteristics of resistant cells include altered  membrane transport , enhanced  DNA repair ,  apoptotic pathway  defects, alteration of target molecules, protein and pathway mechanisms, such as enzymatic deactivation. [ 1 ] \nSince cancer is a genetic disease, two genomic events underlie acquired drug resistance: Genome alterations (e.g. gene amplification and deletion) and  epigenetic modifications .\nCancer cells are constantly using a variety of tools, involving genes, proteins, and altered pathways, to ensure their survival against antineoplastic drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_40", "text": "Antineoplastic resistance, synonymous with  chemotherapy  resistance, is the ability of cancer cells to survive and grow despite different anti-cancer therapies, i.e. their  multiple drug resistance . There are two general causes of antineoplastic therapy failure: [ 2 ] \nInherent resistance, such as genetic characteristics, giving cancer cells their resistance from the beginning, which is rooted in the concept of  cancer cell heterogeneity  and  acquired resistance  after drug exposure. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_41", "text": "Cancer cell heterogeneity, or  tumour heterogeneity , is the idea that tumours are made up of different populations of cancer cells that are morphologically, phenotypically and functionally different. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_42", "text": "Cancer cell heterogeneity can cause disease progression when molecularly  targeted therapy , fails to kill those tumor cells which do not express the marker, then divide and mutate further, creating a new heterogeneous tumour. In breast cancer models of the mouse the immune  microenvironment  affects susceptibility to  neoadjuvant chemotherapy . In breast cancer, particularly in the triple-negative subtype, immune checkpoint blockade has been used successfully in metastatic cases and neoadjuvant therapy. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_43", "text": "Since cancer is a genetic disease, [ 5 ]  two genomic events underlie these mechanisms of acquired drug resistance: Genome alterations (e.g. gene amplification and deletion) and  epigenetic modifications ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_44", "text": "Chromosomal rearrangement  due to  genome instability  can cause gene amplification and deletion.\n Gene amplification  is the increase in copy number of a region of a chromosome. [ 6 ]  which occur frequently in solid tumors, and can contribute to tumor evolution through altered gene expression. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_45", "text": "Hamster cell research in 1993 showed that amplifications in the  DHFR  gene involved in DNA synthesis began with chromosome break in below the gene, and subsequent cycles of  bridge-breakage-fusion  formations result in large intrachromosomal repeats. [ 7 ]  The over amplification of oncogenes can occur in response to chemotherapy, thought to be the underlying mechanism in several classes of resistance. [ 6 ]  For example,  DHFR  amplification occurs in response to  methotrexate , [ 8 ]   TYMS  (involved in DNA synthesis) amplification occurs in response to  5-fluorouracil , [ 9 ]  and  BCR-ABL  amplification occurs in response to  imatinib mesylate . [ 10 ]  Determining areas of gene amplification in cells from cancer patients has huge clinical implications.\n Gene deletion  is the opposite of gene amplification,  where a region of a chromosome is lost and drug resistance occurs by losing tumor suppressor genes such as  TP53 . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_46", "text": "Genomic instability can occur when the  replication fork  is disturbed or stalled in its migration. This can occur with replication fork barriers, proteins such as  PTIP ,  CHD4  and  PARP1 , which are normally cleared by the cell's DNA damage sensors, surveyors, and responders BRCA1 and BRCA2. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_47", "text": "Epigenetic modifications  in antineoplastic drug resistance play a major role in cancer development and drug resistance as they contribute to the regulation of gene expression. [ 12 ]  Two main types of epigenetic control are DNA methylation and histone methylation/acetylation.  DNA methylation  is the process of adding methyl groups to DNA, usually in the upstream  promoter  regions, which stops DNA transcription at the region and effectively silences individual genes.  Histone modifications , such as  deacetylation , alters  chromatin  formation and silence large chromosomal regions. In cancer cells, where normal regulation of gene expression breaks down, the oncogenes are activated via hypomethylation and tumor suppressors are silenced via hypermethylation. Similarly, in drug resistance development, it has been suggested that epigenetic modifications can result in the activation and overexpression of pro-drug resistance genes. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_48", "text": "Studies on cancer cell lines have shown that hypomethylation (loss of methylation) of the  MDR1  gene promoter caused overexpression and the multidrug resistance. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_49", "text": "In a methotrexate resistant breast cancer cell lines without drug uptake and folate carrier expression, giving  DAC , a DNA methylation inhibitor, improved drug uptake and folate carrier expression. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_50", "text": "Acquired resistance to the alkylating drug  fotemustine  in  melanoma  cell showed high MGMT activity related to the  hypermethylation  of the  MGMT  gene exons. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_51", "text": "In Imatinib resistant cell lines, silencing of the  SOCS-3  gene via methylation has been shown to cause  STAT3  protein activation, which caused uncontrolled proliferation. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_52", "text": "Cancer cells can become resistant to multiple drugs by altered  membrane transport , enhanced  DNA repair ,  apoptotic pathway  defects, alteration of target molecules, protein and pathway mechanisms, such as enzymatic deactivation. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_53", "text": "Many classes of antineoplastic drugs act on intracellular components and pathways, like DNA, nuclear components, meaning that they need to enter the cancer cells. The  p-glycoprotein  (P-gp), or the multiple drug resistance protein, is a phosphorylated and glycosylated membrane transporter that can shuttle drugs out of the cell, thereby decreasing or ablating drug efficacy. This transporter protein is encoded by the  MDR1  gene and is also called the  ATP-binding cassette (ABC) protein .  MDR1 has promiscuous substrate specificity, allowing it to transport many structurally diverse compounds across the cell membrane, mainly hydrophobic compounds. Studies have found that the MDR1 gene can be activated and overexpressed in response to pharmaceutical drugs, thus forming the basis for resistance to many drugs. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_54", "text": "For example, the antibiotic  rifampicin  has been found to induce  MDR1  expression. Experiments in different drug resistant cell lines and patient DNA revealed gene rearrangements which had initiated the activation or overexpression of  MDR1. [ 17 ]  A C3435T polymorphism in exon 226 of  MDR1  has also been strongly correlated with p-glycoprotein activities. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_55", "text": "MDR1  is activated through  NF-\u03baB , a protein complex which acts as a transcription factor. [ 19 ] [ 20 ] [ 21 ] [ 22 ]  In the rat, an NF-\u03baB binding site is adjacent to the  mdr1b  gene, [ 23 ]   NF-\u03baB can be active in tumour cells because its mutated  NF-\u03baB  gene or its inhibitory I\u03baB gene mutated under chemotherapy. In  colorectal cancer  cells, inhibition of NF-\u03baB or MDR1 caused increased  apoptosis  in response to a chemotherapeutic agent. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_56", "text": "Enhanced  DNA repair  plays an important role in the ability for cancer cells to overcome drug-induced DNA damages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_57", "text": "Platinum-based chemotherapies, such as  cisplatin , target tumour cells by cross-linking their DNA strands, causing mutation and damage. [ 2 ]  Such damage will trigger  programmed cell death  (e.g.  apoptosis ) in cancer cells. Cisplatin resistance occurs when cancer cells develop an enhanced ability to reverse such damage by removing the cisplatin from DNA and repairing any damage done. [ 2 ] [ 12 ]  The cisplatin-resistant cells upregulate expression of the  excision repair cross-complementing (ERCC1)  gene and protein. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_58", "text": "Some chemotherapies are  alkylating agents  meaning they attach an alkyl group to DNA to stop it from being read.  O6-methylguanine DNA methyltransferase (MGMT)  is a DNA repair enzyme which removes alkyl groups from DNA.  MGMT   expression is upregulated in many cancer cells, which protects them from alkylating agents. [ 12 ]  Increased MGMT expression has been found in colon cancer, lung cancer, non-Hodgkin's lymphoma, breast cancer, gliomas, myeloma and pancreatic cancer. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_59", "text": "TP53  is a  tumor suppressor gene  encoding the p53 protein, which responds to DNA damage either by  DNA repair , cell cycle arrest, or  apoptosis . Losing  TP53  via  gene deletion  can allow cells to continuously replicate despite DNA damage. The tolerance of DNA damage can grant cancer cells a method of resistance to those drugs which normally induce apoptosis through DNA damage. [ 2 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_60", "text": "Other genes involved in the apoptotic pathway related drug resistance include  h-ras  and  bcl-2 /bax. [ 25 ]  Oncogenic  h-ras  has been found to increase expression of ERCC1, resulting in enhanced DNA repair (see above). [ 26 ]  Inhibition of h-ras was found to increase cisplatin sensitivity in  glioblastoma  cells. [ 27 ]  Upregulated expression of  Bcl-2  in leukemic cells ( non-Hodgkin's lymphoma ) resulted in decreased levels of apoptosis in response to chemotherapeutic agents, as  Bcl-2  is a pro-survival  oncogene . [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_61", "text": "During  targeted therapy , oftentimes the target has modified itself and decreased its expression to the point that therapy is no longer effective. One example of this is the loss of  estrogen receptor  (ER) and  progesterone receptor  (PR) upon  anti-estrogen treatment  of breast cancer. [ 29 ]  Tumors with loss of ER and PR no longer respond to  tamoxifen  or other anti-estrogen treatments, and while cancer cells remain somewhat responsive to  estrogen  synthesis inhibitors, they eventually become unresponsive to  endocrine  manipulation and no longer dependent on estrogen for growth. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_62", "text": "Another line of therapeutics used for treating breast cancer is targeting of  kinases  like  human epidermal growth factor receptor 2  (HER2) from the  EGFR family . Mutations often occur in the  HER2  gene upon treatment with an inhibitor, with about 50% of patients with lung cancer found to have an  EGFR-T790M  gatekeeper mutation. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_63", "text": "Treatment of  chronic myeloid leukemia  (CML) involves a  tyrosine kinase inhibitor  that targets the  BCR/ABL  fusion gene called  imatinib . In some people resistant to Imatinib, the  BCR/ABL  gene is reactivated or amplified, or a single  point mutation  has occurred on the gene. These point mutations enhance  autophosphorylation  of the BCR-ABL protein, resulting in the stabilization of the ATP-binding site into its active form, which cannot be bound by imatinib for proper drug activation. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_64", "text": "Topoisomerase  is a lucrative target for cancer therapy due to its critical role as an enzyme in  DNA replication , and many  topoisomerase inhibitors  have been made. [ 31 ]  Resistance can occur when topoisomerase levels are decreased, or when different isoforms of topoisomerase are differentially distributed within the cell. Mutant enzymes have also been reported in patient leukemic cells, as well as mutations in other cancers that confer resistance to topoisomerase inhibitors. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_65", "text": "One of the mechanisms of antineoplastic resistance is over-expression of drug-metabolizing enzymes or carrier molecules. [ 2 ]  By increasing expression of metabolic enzymes, drugs are more rapidly converted to drug conjugates or inactive forms that can then be excreted. For example, increased expression of  glutathione  promotes drug resistance, as the electrophilic properties of glutathione allow it to react with cytotoxic agents, inactivating them. [ 32 ]  In some cases, decreased expression or loss of expression of drug-metabolising enzymes confers resistance, as the enzymes are needed to process a drug from an inactive form to an active form.  Arabinoside , a commonly used chemotherapy for leukemia and lymphomas, is converted into cytosine arabinoside triphosphate by deoxycytidine kinase. Mutation of deoxycytidine kinase or loss of expression results in resistance to arabinoside. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_66", "text": "Growth factor expression levels can also promote resistance to antineoplastic therapies. [ 2 ]  In breast cancer, drug resistant cells were found to express high levels of IL-6, while sensitive cells did not express significant levels of the growth factor. IL-6 activates the CCAAT enhancer-binding protein transcription factors which activate  MDR1  gene expression (see Alteration of Membrane Transport). [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_67", "text": "Pharmacogenetics  play an increasingly important role in antineoplastic treatment. [ 34 ]  Rapid sequencing technologies can identify genetic markers for treatment sensitivity and potential resistance. Certain markers are more representative and more likely to be used clinically. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_68", "text": "When BRCA1 and BRCA2 are missing, as in 5 percent to 10 percent of all breast cancers, a stalled fork remains destabilized and its newly synthesized DNA is degraded. This genomic instability means the cancer cell is actually more sensitive to DNA-damaging chemotherapy drugs. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_69", "text": "MDR proteins are known to be drug-resistance genes, and are highly expressed in various cancers. Inhibition of the  MDR  genes could result in sensitization of cells to therapeutics and a decrease in antineoplastic resistance. Reversin 121 (R121) is a high-affinity peptide for MDR, and  use of R121 as a treatment for pancreatic cancer cells results in increased chemosensitivity and decreased proliferation. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_70", "text": "Aberrant  NF-\u03baB  expression is found in many cancers, and NF-\u03baB has been found to be involved in resistance to platinum-based chemotherapies, such as cisplatin. NF-\u03baB inhibition by genistein in various cancer cell lines (prostate, breast, lung and pancreas) showed increased growth inhibition and an increase in chemosensitivity, seen as an increase in apoptosis induced by therapeutic agents. [ 37 ]  However, targeting the NF-\u03baB pathway can be difficult, as there can be many off-target and non-specific effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_71", "text": "Expression of mutated  TP53  causes defects in the apoptotic pathway, allowing cancerous cells to avoid death. Re-expression of the wild-type gene in cancer cells  in vitro  has been shown to inhibit cell proliferation, induce cell cycle arrest and apoptosis. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_72", "text": "In  ovarian cancer , the  ATP7B  gene encodes for a copper efflux transporter, found to be upregulated in cisplatin-resistant cell lines and tumors. Development of antisense deoxynucleotides against ATP7B mRNA and treatment of an ovarian cancer cell line shows that inhibition of ATP7B increases sensitivity of the cells to cisplatin. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_73", "text": "The  Global Leaders Group on Antimicrobial Resistance  consists of world leaders and experts from across sectors working together to accelerate political action on  antimicrobial resistance (AMR) . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_74", "text": "The Group performs an independent global advisory and advocacy role and works to maintain urgency, public support, political momentum and visibility of the AMR challenge on the global health and development agenda."}
{"_id": "WikiPedia_Pharmacology$$$corpus_75", "text": "\"The Global Leaders Group on Antimicrobial Resistance collaborates globally with governments, agencies, civil society and the private sector through a  One Health  approach to advise on and advocate for prioritized political actions for the mitigation of drug resistant infections through responsible and sustainable access to and use of  antimicrobials .\" [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_76", "text": "The Global Leaders Group on Antimicrobial Resistance was established in November 2020 [ 5 ] [ 6 ] [ 7 ]  following the recommendation of the Interagency Coordination Group on Antimicrobial Resistance to strengthen global political momentum and leadership on AMR. The inaugural meeting of the Group took place in January 2021. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_77", "text": "The Quadripartite Joint Secretariat (QJS) on Antimicrobial Resistance, [ 9 ]  a joint effort by the  Food and Agriculture Organization of the United Nations  (FAO), the  United Nations Environment Programme  (UNEP),the  World Health Organization  (WHO), and the  World Organisation for Animal Health  (WOAH) provide secretariat support for the Group."}
{"_id": "WikiPedia_Pharmacology$$$corpus_78", "text": "The Global Leaders Group on Antimicrobial Resistance is chaired by Her Excellency  Mia Amor Mottley , Prime Minister of  Barbados . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_79", "text": "The Group includes members from across different sectors and countries  [ 11 ]  including heads of state, serving or former ministers and/or senior government officials (acting in their individual capacities), senior representatives of foundations and civil society organizations and leaders from the private sector."}
{"_id": "WikiPedia_Pharmacology$$$corpus_80", "text": "Current Group members: [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_81", "text": "This  molecular  or  cell biology  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_82", "text": "KatG  is an  enzyme  that functions as both  catalase  and  peroxidase . In  Mycobacterium tuberculosis ,  mutations in KatG are commonly associated with resistance to the antibiotic drug  isoniazid , which targets the  mycolic acids  within  M. tuberculosis , and more general  multi-drug resistance . [ 1 ] [ 2 ]  Due to both its catalase and peroxidase activity, this enzyme protects  M. tuberculosis  against  reactive oxygen species .  M. tuberculosis ' survival within macrophages depends on the KatG enzyme. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_83", "text": "Drug-resistant epilepsy  ( DRE ), also known as  refractory epilepsy ,  intractable epilepsy , or  pharmacoresistant epilepsy  refers to a state in which an individual with a diagnosis of epilepsy is unresponsive to multiple first line therapies. Based on the 2010 guidelines from the International League against Epilepsy (ILAE), DRE is officially diagnosed following a lack of therapeutic relief in the form of continued  seizure  burden after trialing at least two  antiepileptic drugs  (AEDs) at the appropriate dosage and duration.  [ 1 ] [ 2 ]  The probability that the next medication will achieve seizure freedom drops with every failed AED. For example, after two failed AEDs, the probability that the third will achieve seizure freedom is around 4%. [ 3 ]  Drug-resistant epilepsy is commonly diagnosed after several years of uncontrolled seizures, however, in most cases, it is evident much earlier. Approximately 30% of people with epilepsy have a drug-resistant form. [ 4 ]  Achieving seizure control in DRE patients is critical as uncontrolled seizures can lead to irreversible damage to the brain, cognitive impairment, and increased risk for sudden unexpected death in epilepsy called  SUDEP . [ 5 ] [ 6 ]  Indirect consequences of DRE include seizure related injuries and/or accidents, impairment in daily life, adverse medication effects, increased co-morbidities especially psychological, and increased economic burden, etc. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_84", "text": "Some clinical factors that are thought to be predictive of DRE include the female sex, focal epilepsy, developmental delay, status epilepticus, earlier age of onset of epilepsy, neurological deficits, having an abnormal EEG and/or imaging findings, genetic predisposition, association with the ABCB1 gene, and  inborn errors of metabolism . [ 7 ] [ 8 ]  Especially among pediatric populations there is a growing association between DRE and genetic conditions or developmental disorders such as  Lennox-Gastaut  or  Dravet Syndrome ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_85", "text": "There are numerous theories regarding the mechanism of action behind DRE many of which have been studied in human and/or animal models. However, it still remains unclear the exact pathogenesis of this condition. [ 7 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_86", "text": "The first step is for physicians to refer their DRE patients to an epilepsy specialist in a comprehensive epilepsy center where further diagnostic work-up can be performed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_87", "text": "One of the first steps in management of drug resistant epilepsy is confirming the diagnosis by  EEG.  Typically patients are admitted to hospital for prolonged EEG monitoring with video technology used to capture clinical events as they occur. [ 10 ]   Typically patients are taken off their anti-seizure medications in order to characterize the evolution of seizure symptoms and their relation with changes in electrical activity of brain. This is done while simultaneously minimizing the adverse consequences of seizures. Additional maneuvers to provoke seizures are also frequently performed, like sleep deprivation, photic stimulation, and hyperventilation. This study can take anywhere from 1\u201314 days. The length of the study depends on factors like baseline seizure frequency, the number and type of seizure medications the patient is taking prior to the study, institutional protocols etc. The goal is to record 3-4 typical seizures, though in some cases more or fewer seizures may need to be recorded. After this evaluation some patients may be determined to have non-epileptic causes of their symptoms, eg.  syncope ,  psychogenic nonepileptic seizures ,  cardiac arrhythmia  etc."}
{"_id": "WikiPedia_Pharmacology$$$corpus_88", "text": "For patients who are confirmed to have epilepsy, this testing helps further elucidate the type of epilepsy (generalized vs focal), type of seizures (atonic, absence, GTC, etc.), and can be used for pre-surgical evaluation or to guide further management. Changes on EEG in relation to clinical seizure symptoms is used to determine the likely area of the brain responsible (symptomatic zone) and by extrapolation the area where seizure activity likely starts (seizure onset zone). In some specific cases, prolonged EEG may be done as an outpatient or ambulatory study where the patient goes home with an EEG set-up. This type of monitoring is usually limited to 2\u20133 days and patients are not taken off their AEDs. [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_89", "text": "MRI of brain  is the most common first-line neuroimaging modality to be used in evaluation of a structural cause of epilepsy. A 3 Tesla MRI is generally recommended, as opposed to scanning on lower magnet strengths. MRI for evaluation of epilepsy often include T1 and T2 images that are optimized to appreciate gray-white matter differentiation and oblique coronal images along the axis of hippocampus. Identification of common lesions associated with epilepsy like focal cortical dysplasia, mesial temporal sclerosis, microencephalocele, and heterotopia require thorough review of images by trained clinicians as the changes can be very subtle and easily missed if not specifically evaluated for. Oftentimes, repeat MRI is required to elucidate an etiology to epilepsy and typically an epilepsy imaging protocol is followed to identify these subtle changes. There is ongoing quantitative analysis of standard MRI images to identify subtle lesions and use of stronger magnetic fields, like 7 Tesla MRI, for better delineation of anatomical details. Additionally, not all structural abnormalities seen on MRI correlate with epilepsy and may represent incidental findings. [ 11 ] [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_90", "text": "Positron emission tomography scan  (PET) using the  18 F-FDG radiotracer can also be used in evaluation of DRE. Its use in epilepsy evaluation is based on the premise that areas of the brain responsible for seizure onset also have persistent metabolic dysfunction and do not use glucose at the same rate as neurotypical areas of the brain. Specifically, during seizure activity (ictal) one would expect a hypermetabolic state with increased radiotracer uptake on PET scan while in between events (interictal) one would expect a hypometabolic state with lower radiotracer uptake on PET scan. Oftentimes findings on PET scan are often correlated with other diagnostic workup that has already/concurrently been obtained to further localize an epileptogenic area of the brain, particularly in the case of focal epilepsy. Other ligands like  11 C-flumazenil, 1 1 C-alpha-methyl-L-tryptophan,  11 C-methionine, have also been used, mostly on research basis to help identify areas of seizure onset. [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_91", "text": "Single-Photon Emission Computerized Tomography ( SPECT scan)  is another radiotracer based imaging technique that uses an oxygen radio-isotope to assess blood flow in the brain. This imaging is performed during inpatient video EEG monitoring in which the tracer is injected into the patient's bloodstream as soon as a seizure start. Areas of the brain associated with seizure onset will have increased blood flow, hence, increased uptake of the tracer if injected at an appropriate time. Imaging is performed after seizure activity is over to assess areas showing a significant increase in blood flow at seizure onset. A major limitation with this technique is the logistics required when injecting the radiotracer and quality of the images produced. [ 16 ] [ 17 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_92", "text": "Magnetoencephalography  (MEG): A newer non-invasive imaging technique that measures the magnetic field associated with neuronal firing in the brain. While each individual neuron's magnetic field is undetectable, when neurons are firing concurrently, such as during a seizure, the magnetic field generated is detected via MEG. This data provides real time brain mapping and has proven to be extremely effective in pre-surgical planning and localization of epilepsy. MEG is particularly useful in detect more superficial abnormalities and is more sensitive than other imaging modalities.  [ 11 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_93", "text": "Neuropsychological testing involves a series of tests aimed at assessing higher order mental functions like memory, executive function, language, overall IQ, etc. in order to establish baseline cognitive function. If there is poor performance in measures of specific cognitive domains like verbal memory, naming, visual-spatial orientation; it may point to areas of brain that are dysfunctional and likely related to seizure onset. This testing could also indicate poor performance on most measures and suggest more widespread dysfunction in the brain. Besides helping assess the likely area of seizure onset, this testing can be informative post surgical intervention and/or epilepsy therapy. [ 11 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_94", "text": "If epilepsy surgery is being considered, testing is often performed to determine the hemisphere of the brain involved in language and memory function. This helps inform about potential risks to language and memory with surgery. There are two main tests available for this objective: the  Wada test  and  fMRI ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_95", "text": "The Wada test has been one of the most commonly used tests around the world since the 1960s. This is an invasive testing technique that requires neurointerventionalists, neuropsychologists, neurophysiologists, EEG technologists, and anesthesiologists. When conducting the wada test, a catheter is threaded from wrist or groin into the carotid artery and finally the middle cerebral artery. [ 20 ]   An injection of sodium amytal is given to temporarily anesthetize 2/3rd of the cerebral hemisphere on one side. Neuropsychological testing is then done to assess language and memory function of the other hemisphere. Once the patient is fully recovered from the injection on the first side, the catheter is withdrawn and threaded up the contralateral middle cerebral artery with neuropsychological testing repeated. This testing informs the \"reserve\" for memory and language function in each hemisphere and the potential for impairment with resective surgery on a given side. In some cases additional testing with selective injection of the posterior cerebral artery (that supplies the mesial temporal region including hippoampus) can be done. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_96", "text": "The Wada test is increasingly being replaced by the noninvasive fMRI imaging technique. Functional MRI (fMRI) measures the change in blood flow and oxygenation in different parts of the brain in response to an activity. Different tasks or paradigms are presented to a patient while they are in an MRI scanner. These tasks are designed to activate areas involved in different language functions and post processing of the images helps identify areas that are activated during different language tasks."}
{"_id": "WikiPedia_Pharmacology$$$corpus_97", "text": "While the term drug resistant epilepsy implies ineffectiveness of pharmacologic therapy, recent advances in the pharmaceutical industry have introduced new drugs that have proven to be effective in the management of DRE patients. Given the novel nature of these drugs, many of the sources utilized are primary/case studies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_98", "text": "Approved by the FDA in 2019 for treatment of epilepsy in adults, Cenobamate is primarily used to treat patients with  focal onset seizures . The mechanism of action of this drug is unclear, but is likely related to the inactivation of Na Channels and action as a  GABA  modulator. The dosing range for this drug is anywhere from 100-400 mg with a half-life of 55 hours. There have been at least three separate clinical trials involving Cenobamate with results showing a reduction in seizure burden by at least 50% in the experimental groups especially at higher doses of the drug. Of note, Cenobamate can interact with other medications especially other AEDs being taken and as such requires medication titration.  [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_99", "text": "This drug was used at high doses as an obesity drug that was later recalled given adverse cardiac effects. Fenfluramine is now approved at lower doses as of 2020 for treatment of seizures in patients 2 years and older with Lennox-Gastaut and Dravet syndrome. Fenfluramine is an amphetamine derivative that acts as a  serotonin agonist  and on GABA and  NMDA receptors . The dosing range is anywhere from 0.2-0.7 mg/kg/day with higher dosing being the most effective for seizure burden. [ 24 ]  Among Dravet and LGS patients, it has been shown to be helpful with most seizure types including atonic, GTC, and tonic. This medication has also been reported to be helpful in behavioral and cognitive symptoms associated with intractable epilepsy. In specific, at higher doses there are reports of patients showing improvement in daily executive functioning and emotional regulation. No adverse cardiac events have been reported with the use of fenfluramine for epilepsy treatment with the main side effects being diarrhea, weight loss, and fatigue. [ 22 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_100", "text": "Cannabidiol has recently been emerging as an effective treatment for epilepsy without the psychoactive effects of the Cannabis Sativa plant it is derived from. It gained approval in 2019 for treatment of DRE associated with Dravet, LGS, and more recently seizures associated with  Tuberous Sclerosis  in patients over the age of 2 years old. The mechanism of action of Cannabidiol is unclear but hypothesized to be related to Ca channels, adenosine signaling, and overall modulation of neuronal hyperexcitability. Cannabidiol is often used concurrently with another AED, especially  clobazam , although there is evidence of the efficacy of Cannabidiol when used on its own. Some studies suggest the efficacy of Cannabidiol for all forms of DRE regardless of the underlying etiology. [ 26 ]  Similar to Fenfluramine, there has been evidence of improvements in cognition, emotional regulation, and communication in addition to seizure control for patients taking Cannabidiol.  [ 22 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_101", "text": "First gained approval in the US in 2012 for the treatment of drug resistant focal epilepsy in patients 12 years and older. It is an antagonist at AMPA receptors with a dosing range from 4-12 mg/day. It is primarily used as an adjunctive treatment option and at higher doses is associated with adverse symptoms like dizziness, ataxias, and withdrawal symptoms. Perampanel has also been studied in the context of sleep and has been shown to help with sleep maintenance and reduction of daytime sleepiness. [ 28 ] [ 29 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_102", "text": "For over 100 years it has been known that a diet with a high fat content and a  low carbohydrate content  can reduce seizures. Radically curbing carbohydrate intake imitates starvation and forces the body to draw energy from ketone bodies that form when fat is metabolized instead of drawing its energy from sugar. This state is called ketosis and it changes several biochemical processes in the brain in a way that inhibits epileptic activity. On this basis there are several diets that are often recommended to children under 12 years old, but are also effective in adults for DRE management. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_103", "text": "The  ketogenic diet  is the diet that is most commonly recommended by doctors for patients with epilepsy. In this diet the ratio of fat to carbohydrates and proteins is 4:1. That means that the fat content of the consumed food must be around 80%, the protein content must be around 15%, and the carbohydrate content must be around 5%. For comparison the average western diet consists of a  carbohydrate  content of over 50%. After one year on the ketogenic diet the success rate (seizure reduction over 50%) is between 30 and 50% and the dropout rate is around 45%.  [ 32 ] [ 33 ]  Although the ketogenic diet can be very effective, some families report that it's not compatible with daily life given its restrictive nature. It can be especially difficult for adolescents to follow as their autonomy increases. For this reason a fat ratio of 3: 1 instead of 4:1 can be recommended to make meals more palatable. Side effects of the ketogenic diet include constipation, fatigue, weight loss, and kidney stones (typically after long-term adherence). [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_104", "text": "In the 1960s, it was discovered that when  medium-chain triglycerides  (MCT) are metabolized more ketone bodies are produced than from metabolizing any other fat. This discovery sparked the introduction of the MCT-ketogenic diet, a modification of the ketogenic diet. In the MCT-ketogenic diet, MCT oil is added to ketogenic meals, [ 35 ]  which allows the carbohydrate content to be increased. The efficacy of the MCT ketogenic diet does not differ significantly from the classic ketogenic diet however not all patients, especially pediatric populations, can tolerate the large amounts of MCT oil required. This diet can also be costly. [ 31 ] [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_105", "text": "A modified Atkins diet was coined after the popular  Atkins diet  with the goal of reducing seizures through ketosis. In this diet, the fat content is slightly lower than in the ketogenic diet at around 60%, the protein content is around 30% and the carbohydrate content is around 10%. Several studies show that the modified Atkins diet is just as effective as the ketogenic diet.  [ 37 ]  Some physicians recommend the modified Atkins diet because they assume that patients will adhere to it on the long-term because it is more compatible with daily life and the meals are more enjoyable. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_106", "text": "The aim of the LGI diet is to keep blood glucose levels at a stable state. Rapid fluctuations in glucose levels both high and low is thought to be a trigger for seizures in some patients with epilepsy. This diet permits 40-60 gram of carbohydrates daily but with the goal of a glycemic index of <50. This diet has been studied among pediatric populations as an effective form of management for DRE. [ 31 ] [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_107", "text": "In epilepsy surgery, a distinction can be made between resective and disconnective procedures. In a resective procedure the area of the brain that causes the seizures is removed. In a disconnective procedure the neural connections in the brain that allow the seizures to spread are disconnected. In most cases epilepsy surgery is only an option when the area of the brain that causes the seizures - the so-called epileptic focus can be clearly identified and is not responsible for critical functions such as language. Several imaging techniques such as magnetic resonance tomography and functional techniques like electrocorticography are used to demarcate the epileptic focus clearly. [ 40 ]  Recording fMRI and EEG simultaneously is a noninvasive method detecting cerebral hemodynamic changes related to interictal epileptic discharges (IEDs) on scalp EEG. This has been shown through different studies to help diagnose different types of epilepsy. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_108", "text": "Temporal lobe epilepsy  (TLE) in which the epileptic focus is in the  temporal lobe , is one of the most common types of epilepsy in adolescents and adults. Hence temporal lobe resection, during which the whole temporal lobe or just a part of the temporal lobe for example the hippocampus or the amygdala is removed, is the most common epilepsy surgery procedure. Between 40 and 60% of patients that undergo temporal lobe resection are continuously seizure free [ 41 ] [ 42 ]  The surgery itself is very safe with a mortality of 0%. [ 43 ] [ 44 ]  The risk for neurologic complications from a temporal lobe resection is around 3 to 7% [ 45 ] [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_109", "text": "If the source of seizures is a lesion, for example a scar tissue from a brain injury a tumor or malformed blood vessels, this lesion can be removed surgically in a lesionectomy. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_110", "text": "Corpus callosotomy is a palliative procedure for specially severe cases of epilepsy. This  corpus callosum  is a large bundle of nerve fibers that connects both brain halves with each other. To prevent the spreading of seizures from one brain hemisphere (brain half) to the other the corpus callosum can be split. This procedure is mostly carried out on patients with so-called drop attacks that come with a very high risk of injury and in which the epileptic focus is not clearly delimitable. It is very rare that a corpus callosotomy causes seizure freedom however in half of the patients the dangerous drop attacks are less severe. [ 47 ]   After a corpus callosotomy among others there is the risk that language is temporarily or permanently impaired. The younger a patient is at the time of the corpus callosotomy, the better the prognosis. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_111", "text": "This procedure is a modern adaptation of the radical hemispherectomy in which one brain hemisphere is removed to prevent the spread of seizures from one brain hemisphere to the other. In the functional version only a part of the hemisphere is removed but the connections to the other brain hemisphere are cut through. This procedure is only performed on a small group of patients under the age of 13 that have severe damage or malformation of one hemisphere, patients with Sturge Weber syndrome or patients with Rasmussen's encephalitis. Surgical intervention is considered a viable option for infants with drug-resistant epilepsy, particularly when anti-seizure medications fail to achieve seizure control. For this population, surgery can lead to favorable outcomes in a substantial number of cases. [ 48 ]  The functional hemispherectomy can achieve long-term seizure freedom in over 80% of patients however often at the price of hemiplegia and hemianopsy. The death rate is around 1 to 2% and 5% of patients develop a hydrocephalus that needs to be treated with a shunt. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_112", "text": "Multiple subpial transection  (MST) is a palliative procedure that is considered when an epileptic focus can be identified but cannot be removed because it is in a functionally relevant brain region- a so-called eloquent region. In an MST nerve fibers are disconnected so that seizures cannot spread from the epileptic focus into the rest of the brain. Between 60 and 70% of patients experienced a seizure reduction of over 95% after an MST and the risk for neurologic deficits is around 19%. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_113", "text": "Vagus nerve stimulation  (VNS) involves implanting  a pacemaker-like generator below the skin in the chest area that intermittently sends electrical impulses to the left  vagus nerve  in the neck. The impulses are mediated to the brain by the vagus nerve and thereby help to inhibit electrical disturbances that cause seizures. The antiepileptic effect of vagus nerve stimulation increases over several months: after two years around half of VNS patients experience a reduction of their seizures by at least 50% [ 51 ] [ 52 ]  and after 10 years the average seizure reduction is around 75% [ 53 ]  Furthermore, in most patients mood (VNS has a significant anti-depressent effect and is approved for depression in some countries), alertness and quality-of-life are increased significantly within the first year of vagus nerve stimulation. [ 54 ] [ 55 ]  VNS patients can induce an extra stimulation themselves with a VNS magnet when they noticed that a seizure is approaching and it has been shown that the majority of seizures can be interrupted this type of on-demand stimulation. [ 56 ] [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_114", "text": "The procedure to implant a vagus nerve stimulator is very safe: no case of death related to VNS implantation surgery has ever occurred. Infection of the tissue pocket in which the generator is located that requires antibiotic treatment occurs in around 3% of patients. [ 58 ] [ 59 ]  The most common side effect is hoarseness or change in voice. Headaches and shortness of breath are less common. In most cases, side effects only occur during activity of the stimulation (mostly every 3 to 5 minutes) and reduce over time. [ 60 ]  In most cases VNS does not replace antiepileptic medication. Patients must continue their antiepileptic medication however in many cases the dose can be reduced over time so that patients experience fewer side effects of the medication. The battery of the VNS generator can, depending on the model and the settings, last between 3 and 10 years. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_115", "text": "In 82% of epilepsy patients the heart rate increases quickly and suddenly upon a seizure [ 61 ]  This is known as  ictal tachycardia .  Ictal   tachycardia  is so characteristic that it can be distinguished from the slow gradual increase of heart rate that occurs during physical activity. This way in the majority of epilepsy patients seizures can be detected in the ECG. In addition to classical VNS, some new VNS generators continuously monitor heart rate and identify fast and sudden heart rate increases associated with seizures with intelligent software. Then an automatic additional stimulation can be triggered to interrupt, prevent or alleviate the seizure. This new generator type was shown to detect and treat at least four out of five seizures and 60% of seizures were shown to be interrupted with this heart-rate triggered stimulation. [ 62 ]  The earlier in the course of the seizure the stimulation occurred the quicker the seizure ended generally seizures were shown to be reduced by around 35% by  stimulation [ 63 ] [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_116", "text": "Deep brain stimulation   of the  anterior nuclei of the thalamus  is approved for DRE in some countries in Europe, but has been and continues to only be used in a very few patients. After 5 years of DBS a seizure reduction of 69% and a 50%-responder rate of 68% was reported in a randomized-double blinded trial. [ 65 ]  The rate of serious device related events was 34% in this study."}
{"_id": "WikiPedia_Pharmacology$$$corpus_117", "text": "Responsive neurostimulation  (RNS) is approved for DRE in the US and involves stimulation directly to 1 or 2 seizure foci when abnormal electrocorticographic activity is detected by the devices software. After 2 years of RNS a seizure reduction of 53% was reported in a randomized-double blinded trial as well as a rate of serious device related events of 2.5%. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_118", "text": "Transcutaneous vagus nerve stimulation  (tVNS) is approved for DRE in some European countries and involves externally stimulating the auricular branch of the vagus nerve in the ear. tVNS failed to demonstrate efficacy in a first randomized-double blinded trial: responder rates did not differ between active and control groups potentially indicating a placebo effect behind the 34% seizure reduction seen in the patients who completed the full follow-up period. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_119", "text": "Multidrug resistance pumps  ( MDR pumps ) also known  Multidrug efflux pumps  are a type of  efflux pump  and  P-glycoprotein . MDR pumps in the  cell membrane  extrudes many foreign substances out of the cells and some pumps can have a broad specificity. [ 1 ]   MDR pumps exist in animals, fungi, and bacteria and likely evolved as a defense mechanism against harmful substances. There are seven families of MDRs and are grouped by homology, energy source, and overall structure. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_120", "text": "There are five major classes of efflux pumps in bacteria: the ATP-binding cassette (ABC) superfamily, the resistance nodulation division (RND) superfamily, the major facilitator superfamily (MFS), the small multidrug resistance (SMR) superfamily, and the multidrug and toxic compound extrusion (MATE) family. There are also two minor classes: the proteobacterial antimicrobial compound efflux (PACE) family, and the p-aminobenzoyl-glutamate transporter (AbgT) family. [ 2 ]  The ABC superfamily uses ATP as an energy source for export while the rest of the efflux pumps use proton motive force. Between them, the efflux pump classes cover a wide range of substrate specificities and are involved in numerous cellular processes including cell-to-cell communication, biofilm formation, virulence, and impart cellular protection through extrusion of toxic metabolic byproducts, toxic compounds, and clinical antibiotics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_121", "text": "Extrusion of compounds by efflux pumps is energy dependent. [ 2 ]  ABC transporters use ATP hydrolysis for efflux. The rest of the characterized pumps use proton motive force. The increased use in antibiotics has resulted in a concomitant increase in antibiotic resistant bacteria. Pathogenic bacterial and fungal species have developed MDR pumps which efflux out many antibiotics and antifugals, increasing the concentration needed for their effect. In bacteria, overexpression of some efflux pumps can result in decreased susceptibility to multiple antibiotics. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_122", "text": "Because of their importance in drug evasion such as in  antibiotic resistance , there is a growing about of research on Efflux pump inhibitors (EPIs). [ 4 ]  Many promising EPIs come from plant  secondary metabolites [ 5 ]  and  small molecule compounds . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_123", "text": "Multiple drug resistance  ( MDR ),  multidrug resistance  or  multiresistance  is  antimicrobial resistance  shown by a species of  microorganism  to at least one  antimicrobial  drug in three or more antimicrobial categories. [ 1 ]  Antimicrobial categories are classifications of antimicrobial agents based on their mode of action and specific to target organisms. [ 1 ]  The MDR types most threatening to  public health  are MDR  bacteria  that resist multiple  antibiotics ; other types include MDR  viruses ,  parasites  (resistant to multiple  antifungal ,  antiviral , and  antiparasitic  drugs of a wide chemical variety). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_124", "text": "Recognizing different degrees of MDR in bacteria, the terms  extensively drug-resistant  ( XDR ) and  pandrug-resistant  ( PDR ) have been introduced.  Extensively drug-resistant (XDR)  is the non-susceptibility of one bacteria species to all antimicrobial agents except in two or less antimicrobial categories. Within XDR,  pandrug-resistant (PDR)  is the non-susceptibility of bacteria to all antimicrobial agents in all antimicrobial categories. [ 1 ]  The definitions were published in 2011 in the journal  Clinical Microbiology and Infection  and are openly accessible. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_125", "text": "Common multidrug-resistant organisms, typically bacteria, include: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_126", "text": "Overlapping with MDRGN, a group of  Gram-positive  and  Gram-negative  bacteria of particular recent importance have been dubbed as the ESKAPE group ( Enterococcus faecium ,  Staphylococcus aureus ,  Klebsiella pneumoniae ,  Acinetobacter baumannii ,  Pseudomonas aeruginosa  and  Enterobacter  species). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_127", "text": "Various microorganisms have survived for thousands of years by their ability to adapt to antimicrobial agents. They do so via  spontaneous mutation  or by  DNA transfer . This process enables some bacteria to oppose the action of certain antibiotics, rendering the antibiotics ineffective. [ 5 ]  These microorganisms employ several mechanisms in attaining multi-drug resistance:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_128", "text": "Many different bacteria now exhibit multi-drug resistance, including  staphylococci ,  enterococci ,  gonococci ,  streptococci ,  salmonella , as well as numerous other Gram-negative bacteria and  Mycobacterium tuberculosis .  Antibiotic resistant bacteria are able to transfer copies of  DNA  that code for a mechanism of resistance to other bacteria even distantly related to them, which then are also able to pass on the resistance genes, resulting in generations of antibiotics resistant bacteria. [ 11 ]  This initial transfer of DNA is called  horizontal gene transfer . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_129", "text": "Phage-resistant bacteria variants have been observed in human studies.  As for antibiotics, horizontal transfer of  phage  resistance can be acquired by  plasmid  acquisition. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_130", "text": "Yeasts such as  Candida species  can become resistant under long-term treatment with  azole  preparations, requiring treatment with a different drug class.\n Lomentospora prolificans  infections are often fatal because of their resistance to multiple antifungal agents. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_131", "text": "HIV  is the prime example of MDR against antivirals, as it mutates rapidly under monotherapy.\n Influenza virus  has become increasingly MDR; first to amantadines, then to  neuraminidase inhibitors  such as  oseltamivir , (2008-2009: 98.5% of Influenza A tested resistant), also more commonly in people with weak immune systems.  Cytomegalovirus  can become resistant to  ganciclovir  and  foscarnet  under treatment, especially in  immunosuppressed  patients.  Herpes simplex virus  rarely becomes resistant to  acyclovir  preparations, mostly in the form of cross-resistance to  famciclovir  and  valacyclovir , usually in immunosuppressed patients. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_132", "text": "The prime example for MDR against antiparasitic drugs is  malaria .  Plasmodium vivax  has become  chloroquine  and  sulfadoxine-pyrimethamine  resistant a few decades ago, and as of 2012  artemisinin -resistant  Plasmodium falciparum   has emerged in western Cambodia and western Thailand. [ 16 ] \n Toxoplasma gondii  can also become resistant to  artemisinin , as well as  atovaquone  and  sulfadiazine , but is not usually MDR [ 17 ] \n Antihelminthic  resistance is mainly reported in the veterinary literature, for example in connection with the practice of livestock drenching [ 18 ]  and has been recent focus of  FDA  regulation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_133", "text": "To limit the development of antimicrobial resistance, it has been suggested to: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_134", "text": "The medical community relies on education of its prescribers, and self-regulation in the form of appeals to voluntary  antimicrobial stewardship , which at hospitals may take the form of an antimicrobial stewardship program. It has been argued that depending on the cultural context government can aid in educating the public on the importance of restrictive use of antibiotics for human clinical use, but unlike  narcotics , there is no regulation of its use anywhere in the world at this time. Antibiotic use has been restricted or regulated for treating animals raised for human consumption with success, in Denmark for example. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_135", "text": "Infection prevention  is the most efficient strategy of prevention of an infection with a MDR organism within a hospital, because there are few alternatives to antibiotics in the case of an extensively resistant or panresistant infection; if an infection is localized, removal or  excision  can be attempted (with MDR-TB the lung for example), but in the case of a systemic infection only generic measures like  boosting the immune system with immunoglobulins  may be possible. The  use of bacteriophages  (viruses which kill bacteria) is a developing area of possible therapeutic treatments. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_136", "text": "It is necessary to develop new antibiotics over time since the  selection  of resistant bacteria cannot be prevented completely. This means with every application of a specific antibiotic, the survival of a few bacteria which already have a resistance gene against the substance is promoted, and the concerning bacterial population amplifies. Therefore, the resistance gene is farther distributed in the organism and the environment, and a higher percentage of bacteria means they no longer respond to a therapy with this specific antibiotic. In addition to developing new antibiotics, new strategies entirely must be implemented in order to keep the public safe from the event of total resistance. New strategies are being tested such as  UV light  treatments and bacteriophage utilization, however more resources must be dedicated to this cause."}
{"_id": "WikiPedia_Pharmacology$$$corpus_137", "text": "Treatment-resistant depression  (TRD) is  major depressive disorder  in which an affected person does not respond adequately to at least two different  antidepressant  medications at an adequate dose and for an adequate duration. [ 1 ]  Inadequate response has most commonly been defined as less than 25% reduction in  depressive symptoms  following treatment with an antidepressant. [ 2 ]  Many clinicians and researchers question the construct validity and clinical utility of treatment-resistant depression as currently conceptualized. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_138", "text": "Other factors that may contribute to inadequate treatment are: a history of repeated or severe  adverse childhood experiences , early  discontinuation of treatment , failure to consider psychotherapy and other psychosocial interventions, patient noncompliance,  misdiagnosis , cognitive impairment, low income and other social determinants, and concurrent medical conditions, including  comorbid   psychiatric disorders . [ 2 ]  Cases of treatment-resistant depression may also be referred to by which medications people are resistant to (e.g.:  SSRI -resistant). [ 5 ]  Adding further treatments such as  aripiprazole  or  quetiapine  is weakly supported as of 2022. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_139", "text": "Comorbid  psychiatric disorders commonly go undetected in the treatment of  depression . If left untreated, the symptoms of these disorders can interfere with both evaluation and treatment. \n Anxiety disorders  are one of the most common disorder types associated with treatment-resistant depression. The two disorders commonly co-exist, and have some similar symptoms. Some studies have shown that patients with both major depressive disorder and  panic disorder  are the most likely to be nonresponsive to treatment. \n Substance abuse  may also be a predictor of treatment-resistant depression. It may cause depressed patients to be noncompliant in their treatment, and the effects of certain substances can worsen the effects of depression. \nOther psychiatric disorders that may predict treatment-resistant depression include  attention deficit hyperactivity disorder , [ 7 ]   personality disorders ,  obsessive compulsive disorder , and  eating disorders . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_140", "text": "Some people who are diagnosed with treatment-resistant depression may have an underlying undiagnosed health condition that is causing or contributing to their depression.  Endocrine disorders  like  hypothyroidism ,  Cushing's disease , and  Addison's disease  are among the most commonly identified as contributing to  depression . Others include  diabetes ,  coronary artery disease ,  cancer ,  HIV , and  Parkinson's disease . \nAnother factor is that medications used to treat comorbid medical disorders may lessen the effectiveness of  antidepressants  or cause  depression symptoms . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_141", "text": "People with depression who also  display psychotic symptoms  such as  delusions  or  hallucinations  are more likely to be treatment resistant. Another depressive feature that has been associated with poor response to treatment is longer duration of  depressive episodes . [ 5 ]  Finally, people with more  severe depression  and those who are  suicidal  are more likely to be nonresponsive to  antidepressant  treatment. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_142", "text": "There are three basic categories of drug treatment that can be used when a medication course is found to be ineffective. One option is to switch the patient to a different  medication . Another option is to add a medication to the patient's current treatment. This can include  combination therapy : the combination of two different types of  antidepressants , or  augmentation therapy : the addition of a non-antidepressant medication that may increase the effectiveness of the  antidepressant . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_143", "text": "Increasing the dosage of an  antidepressant  is a common strategy to treat  depression  that does not respond after adequate treatment duration. Practitioners who use this strategy will usually increase the dose until the person reports intolerable  side effects , symptoms are eliminated, or the dose is increased to the limit of what is considered safe. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_144", "text": "Studies have shown a wide variability in the effectiveness of switching  antidepressants , with anywhere from 25 to 70% of people responding to a different antidepressant. [ 12 ]  There is support for the effectiveness of switching people to a different  SSRI ; 50% of people that were non-responsive after taking one SSRI were responsive after taking a second type. Switching people with treatment-resistant depression to a different class of antidepressants may also be effective. People who are non-responsive after taking an SSRI may respond to  moclobemide  or  tricyclic antidepressants ,  bupropion  or an  MAOI . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_145", "text": "Some off label antidepressants are low dose  ketamine  and highly serotonergic  catecholamines  (including very controlled use of  MDMA  in the treatment of  PTSD  and crippling  depression / anxiety ). [ citation needed ]  For lethargic syndromes,  dysthymia , or caffeine-resistant amotivation, a dopaminergic stimulant such as  methylphenidate , or even  dextroamphetamine  or  methamphetamine  can be helpful. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_146", "text": "Primarily dopaminergic or norepinephrine releasing stimulants, in low doses, have been used especially in the past, or in conjunction with a multidisciplinary therapy approach, although more targeted and \"mild\" agents, including  modafinil  and  atomoxetine  are considered first line [ by whom? ]  for both childhood and adult  lethargy  and inattention disorders, due to their virtually nonexistent abuse potential (limited to one or two cases per 10 000), and higher selectivity, safety, and thus slightly broader therapeutic index. When depression is related or co-morbid to an inattention disorder, often  ADHD , then both can be carefully managed with the same first line stimulant medication, typically both  methylphenidate  and  lisdexamfetamine . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_147", "text": "Medications that have been shown to be effective in people with treatment-resistant depression include  lithium ,  liothyronine ,  benzodiazepines ,  atypical antipsychotics , and  stimulants . Adding lithium may be effective for people taking some types of antidepressants including SSRIs or SNRIs. Lithium augmentation therapy was associated with a 41.2% remission rate of unipolar depression compared to 14.4% with placebo. [ 14 ] [ 15 ]  Liothyronine (synthetic T 3 ) is a type of  thyroid hormone  and has been associated with improvement in mood and depression symptoms. Benzodiazepines may improve treatment-resistant depression by decreasing the adverse side effects caused by some antidepressants and therefore increasing patient compliance. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_148", "text": "Atypical antipsychotics  such as  aripiprazole ,  quetiapine  or  olanzapine  can be added to anti-depressants as part of augmentation of treatment. [ 15 ]  Eli Lilly, the company that sells both olanzapine and fluoxetine individually, has also released a combination formulation which contains olanzapine and fluoxetine in a single capsule.  Some low to moderate quality evidence points to success in the short term (8\u201312 weeks) using  mianserin  (or antipsychotics  cariprazine , olanzapine, quetiapine or  ziprasidone ) to augment antidepressant medications. [ 17 ]  These have shown promise in treating refractory depression but come with serious side effects. [ 18 ]  Stimulants such as  amphetamines  and  methylphenidate  have also been tested with positive results but have potential for  abuse . However, stimulants have been shown to be effective for the unyielding depressed combined lacking  addictive personality  traits or  heart problems . [ 19 ] [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_149", "text": "Ketamine  has been tested as a rapid-acting antidepressant [ 22 ]  for treatment-resistant depression in  bipolar disorder , and  major depressive disorder . [ 23 ]  Spravato, a nasal spray form of  esketamine , was approved by the  FDA  in 2019 for use in treatment-resistant depression when combined with an oral antidepressant. [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_150", "text": "A 2016  placebo   randomized controlled trial  evaluated the  rapid antidepressant  effects of the psychedelic  ayahuasca  in treatment-resistant depression with positive outcome. [ 26 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_151", "text": "In 2018, the United States  Food and Drug Administration  (FDA) granted  breakthrough therapy  designation for psilocybin-assisted therapy for treatment-resistant depression. [ 28 ] [ 29 ]  A systematic review published in 2021 found that the use of psilocybin as a pharmaceutical substance was associated with reduced intensity of depression symptoms. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_152", "text": "Electroconvulsive therapy  is generally only considered as a treatment option in severe cases of treatment-resistant depression. It is used when medication has repeatedly failed to improve symptoms, and usually when the patient's symptoms are so severe that they have been hospitalized. Electroconvulsive therapy has been found to reduce thoughts of  suicide  and relieve depressive symptoms. [ 31 ]  It is associated with an increase in  glial cell line derived neurotrophic factor . [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_153", "text": "rTMS ( repetitive transcranial magnetic stimulation ) is gradually becoming recognised as a valuable therapeutic option in treatment-resistant depression. A number of randomised placebo-controlled trials have compared real versus sham rTMS. These trials have consistently demonstrated the efficacy of this treatment against major depression. There have also been a number of  meta-analyses  of  RCTs [ 33 ]  confirming the efficacy of rTMS in treatment-resistant major depression, as well as naturalistic studies showing its effectiveness in \"real world\" clinical settings. [ 34 ] [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_154", "text": "dTMS ( deep transcranial magnetic stimulation ) is a continuation of the same idea as rTMS, but with the hope that deeper stimulation of subcortical areas of the brain leads to increased effect. [ 36 ]  A 2015  systematic review  and  health technology assessment  found lacking evidence in order to recommend the method over either ECT or rTMS because so few studies had been published. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_155", "text": "Vagus nerve stimulation  has also been used for treatment-resistant depression. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_156", "text": "Deep brain stimulation  has been used in a small number of clinical trials to treat people with severe treatment-resistant depression. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_157", "text": "Magnetic seizure therapy  is currently being investigated for treating refractory depression."}
{"_id": "WikiPedia_Pharmacology$$$corpus_158", "text": "Transcranial direct-current stimulation  is a form of  neuromodulation  that uses constant, low  direct current  delivered via electrodes on the head."}
{"_id": "WikiPedia_Pharmacology$$$corpus_159", "text": "There is sparse evidence on the effectiveness of  psychotherapy  in cases of treatment-resistant depression. [ 9 ]  However, a review of the literature suggests that it may be an effective treatment option. [ 39 ]  Psychotherapy may be effective in people with treatment-resistant depression because it can help relieve  stress  that may contribute to depressive symptoms. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_160", "text": "A  Cochrane   systematic review  has shown that psychological therapies (including  cognitive behavioural therapy ,  dialectical behavior therapy ,  interpersonal therapy  and intensive short-term dynamic psychotherapy) added to usual care (with antidepressants) can be beneficial for depressive symptoms and for response and  remission  rates over the short term (up to six months) for patients with treatment-resistant depression. Medium- (7\u201312 months) and long\u2010term (longer than 12 months) effects seem similarly beneficial. Psychological therapies, including cognitive behavioral therapy, added to usual care (antidepressants) seem as acceptable as usual care alone and may be used as a first line treatment for mild to moderate treatment resistant depression. [ 41 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_161", "text": "Treatment-resistant depression is associated with more instances of  relapse  than depression that is responsive to treatment. One study showed that as many as 80% of people with treatment-resistant depression who needed more than one course of treatment relapsed within a year. Treatment-resistant depression has also been associated with lower long-term quality of life. [ 42 ] [ clarification needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_162", "text": "Another study saw just 8 of 124 patients in remission after two years of standard depression treatment. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_163", "text": "This  pharmacology -related article is a  stub . You can help Wikipedia by  expanding it ."}
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{"_id": "WikiPedia_Pharmacology$$$corpus_165", "text": "Typing  {{Pharma-stub}}  produces the message shown at the beginning, and adds the article to the following category:"}
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{"_id": "WikiPedia_Pharmacology$$$corpus_173", "text": "1DD-LSD  ( N1-dodecanoyl-lysergic acid diethylamide ,  SYN-L-004 ) is an  acylated  derivative of  lysergic acid diethylamide  (LSD). In animal studies it produces a weak  head-twitch response  but with 27x lower potency than LSD itself. It is being researched as a potential slow-onset, long lasting  prodrug  for LSD which is expected to have reduced psychoactive effects. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_174", "text": "Morning glory:  Argyreia nervosa  (Hawaiian Baby Woodrose),  Ipomoea  spp. (Morning Glory, Tlitliltzin, Badoh Negro),  Rivea corymbosa  (Coaxihuitl, Ololi\u00faqui)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_175", "text": "2-Aminoacetophenone , also known as  \u03b2-ketophenethylamine ,  \u03b1-desmethylcathinone , or  phenacylamine , is a  substituted phenethylamine   derivative . [ 1 ] [ 2 ]  It is the phenethylamine homologue of  cathinone  (\u03b2-ketoamphetamine) and hence is a parent compound of a large number of  stimulant  and  entactogen   drugs . [ 1 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_176", "text": "Phenacylamine is also  active  itself; it is a  potent   monoamine releasing agent  of  dopamine  ( EC 50 Tooltip half-maximal effective concentration  = 208 \u00a0 nM)  in vitro , whereas it was inactive for  serotonin  ( EC 50  > 10,000 \u00a0 nM) and the  EC 50  for  norepinephrine  was not assessed but the drug induced 96% release of norepinephrine at a concentration of 10,000 \u00a0 nM. [ 2 ] [ 5 ]  Hence, phenacylamine acts as a  norepinephrine\u2013dopamine releasing agent  (NDRA). [ 2 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_177", "text": "Despite its activity  in vitro  however, phenacylamine failed to substitute for  dextroamphetamine  in animal  drug discrimination  tests at doses several-fold higher than effective doses of cathinone. [ 6 ]  It was concluded that, similarly to  phenethylamine  but in contrast to  amphetamine  and cathinone, phenylacylamine is likely to be rapidly inactivated via  monoamine oxidase  (MAO)-mediated  metabolism   in vivo  and will be inactive without concomitant use of a  monoamine oxidase inhibitor  (MAOI). [ 6 ]  It has also been suggested that phenacylamine may have diminished  blood\u2013brain barrier   permeability  and limited  central  activity due to its decreased  lipophilicity  relative to cathinone. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_178", "text": "2C-B-aminorex  ( 2C-B-AR ) is a recreational  designer drug  with  psychedelic  effects. It is a substituted  aminorex  derivative which was first identified in Sweden in June 2019. [ 1 ]  Structurally, it is a hybrid of  4-bromo-2,5-dimethoxyphenethylamine  (2C-B) and aminorex. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_179", "text": "2CE-5iPrO  ( 5-iPrO-2C-E ) is a  psychedelic   substituted phenethylamine  derivative related to  2C-E , but with the 5- methoxy  group extended to isopropoxy. Similar to related \"tweetio\" compounds such as  2CD-5EtO , it has a longer duration of action than 2C-E but is otherwise similar in activity, although it shows reduced  antiinflammatory  actions. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_180", "text": "2'-Fluoro-4-methylaminorex  ( 2F-MAR ,  2'-F-4-MAR ) is a recreational  designer drug  from the  substituted aminorex  family, with  stimulant  effects, first reported in 2018. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_181", "text": "3-Methyl-PCPy  ( 3-Me-PCPy ) is an  arylcyclohexylamine  derivative with an unusual spectrum of pharmacological effects, acting as both a potent  NMDA antagonist  and also a  triple reuptake inhibitor  which inhibits reuptake of all three monoamine neurotransmitters  serotonin ,  dopamine  and  noradrenaline . It also acts as a high  affinity   sigma receptor  ligand, selective for the  \u03c3 2  subtype. It produces both  stimulant  and  dissociative  effects in animal behavioural studies. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_182", "text": "3-Methyl-PCPy is covered by drug analogue laws in various jurisdictions (UK, Germany, Japan, Australia etc.) as a generic arylcyclohexylamine derivative, and a  structural isomer  of  phencyclidine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_183", "text": "3F-PiHP  ( 3F-\u03b1-PiHP ) is a recreational  designer drug  from the  substituted cathinone  family, with  stimulant  effects. It was first identified in both Sweden and Finland in mid-2019, [ 1 ]  and was made illegal in Finland in August 2019. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_184", "text": "4-Acetyloxy- N,N -diallyltryptamine  (or  4-AcO-DALT ) is a  tryptamine   derivative . It has been sold as a  designer drug , but little other information is available. It was first officially identified in seized drug samples in 2012. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_185", "text": "4-Acetyloxy- N,N -dipropyltryptamine  (or  4-AcO-DPT ) is a  tryptamine   derivative . 4-AcO-DPT has been sold as a  designer drug . [ 1 ]  It is an ester of  4-HO-DPT , a psychedelic tryptamine first synthesized by  Alexander Shulgin . Anecdotal reports indicate that 4-AcO-DPT exerts psychoactive effects in humans, however, the pharmacology of 4-AcO-DPT has not been examined. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_186", "text": "4-HO-DsBT  ( 4-hydroxy- N,N -di- sec -butyltryptamine ) is a  tryptamine  derivative which acts as a  serotonin receptor   agonist . It was first made by  Alexander Shulgin  and is mentioned in his book TiHKAL, but was never tested by him. [ 1 ]  However it has subsequently been tested  in vitro  and unlike the  n -butyl and isobutyl isomers which are much weaker, the  s -butyl derivative retains reasonable potency, with a similar  5-HT 2A  receptor affinity to  MiPT  but better selectivity over the  5-HT 1A  and  5-HT 2B  subtypes. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_187", "text": "4-HO-MALT  ( 4-hydroxy- N -methyl- N -allyltryptamine ) is a  tryptamine  derivative which has been sold as a  designer drug , first being detected in Slovenia in 2021. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_188", "text": "4-HO-McPeT  ( 4-hydroxy- N -methyl- N -cyclopentyltryptamine ) is a  tryptamine  derivative which has  serotonergic  effects. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_189", "text": "4-Hydroxy- N -allyltryptamine  ( 4-HO-NALT ) is a  tryptamine  derivative developed by modification of  norpsilocin  (4-HO-NMT). It produces a  head-twitch response  in mice consistent with psychedelic-like activity, as do the corresponding ethyl, propyl, isopropyl and benzyl derivatives (4-HO-NET, 4-HO-NPT, 4-HO-NiPT and 4-HO-NBnT), but the bulkier t-butyl and cyclohexyl derivatives are inactive. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_190", "text": "4'-Bromo-4-methylaminorex  ( 4B-MAR ,  4'-Br-4-MAR ) is a  designer drug  from the  substituted aminorex  family, first definitively identified in Austria in January 2022. Its pharmacological activity has not been reported, but it is believed to have  stimulant  effects. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_191", "text": "4'-Chloro-4-methylaminorex  ( 4C-MAR ,  4'-Cl-4-MAR ) is a recreational  designer drug  from the  substituted aminorex  family, with  stimulant  effects. It has reportedly been sold since around 2021 and was first definitively identified in Austria in January 2022. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_192", "text": "5-Ethoxy-DMT  ( 5-ethoxy- N , N -dimethyltryptamine ,  5-EtO-DMT ,  O -ethylbufotenine ) is a  tryptamine   derivative  which has been previously synthesized as a chemical intermediate, but has not been studied to determine its pharmacology. [ 1 ] [ unreliable source? ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_193", "text": "The widespread recreational use of  N , N -dialkylated  5-methoxytryptamine  derivatives including  5-MeO-DMT ,  5-MeO-MiPT  and  5-MeO-DiPT  has led to concern that the 5-ethoxy  homologs  of these drugs could emerge as novel  designer drugs , and consequently 5-EtO-DMT and other derivatives including 5-EtO-DET, 5-EtO-DPT, 5-EtO-DiPT, 5-EtO-DALT, 5-EtO-MPT, 5-EtO-MiPT, 5-EtO-EiPT, 5-EtO-MET and 5-EtO-EPT have been synthesized as  analytical standards  in order to facilitate future research into these compounds. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_194", "text": "5-Fluoro-MET  ( 5F-MET ,  5-fluoro- N -methyl- N -ethyltryptamine ) is a  psychedelic   tryptamine  derivative related to drugs such as  5-Fluoro-DMT  and  N -methyl- N -ethyltryptamine  (MET). It acts as an  agonist  at the  5-HT 2A  receptor  with an EC 50  of 20.6 nM and produces a  head-twitch response  in animal studies. Ring fluorination in this case increases efficacy at 5-HT 2A , with 5F-MET having an efficacy of 87.6% vs  5-HT , vs 36.2% for the  partial agonist  MET. It is claimed to have  antidepressant  activity. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_195", "text": "5-MeO-DBT  ( 5-Methoxy-N,N-dibutyltryptamine ,  5-MeO-BET ) is a rare  substituted tryptamine  derivative, which is thought to be a  psychoactive substance  and was identified in a  designer drug  sample by a forensic laboratory in Slovenia in March 2021, [ 1 ]  although only analytical studies have been conducted and no pharmacological data is available. [ 2 ] [ 3 ] [ 4 ]  It is nevertheless controlled under drug analogue legislation in a number of jurisdictions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_196", "text": "5-MeO-DBT was made schedule I at the state level in  Alabama  on September 13th, 2024. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_197", "text": "5-MeO-isoDMT , or  5-OMe-isoDMT , also known as  5-methoxy- N , N -dimethylisotryptamine , is a putatively non- hallucinogenic   serotonin   5-HT 2A  receptor   agonist  and  psychoplastogen  of the  isotryptamine  group. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]  It is the isotryptamine  analogue  of the non-hallucinogenic  6-MeO-DMT  and is a  positional isomer  of the psychedelic  6-MeO-isoDMT . [ 3 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_198", "text": "The drug does not substitute for  serotonergic psychedelics  in animal  drug discrimination  tests and does not produce the  head-twitch response , a behavioral of psychedelic effects, at any dose. [ 1 ] [ 3 ] [ 5 ] [ 7 ] [ 6 ]  Hence, it appears to be non-hallucinogenic. [ 3 ] [ 5 ] [ 6 ]  On the other hand, 5-MeO-isoDMT has comparable psychoplastogenic  potency  and effects compared to the psychedelic  5-MeO-DMT . [ 1 ] [ 2 ] [ 4 ] [ 5 ]  These effects are blocked by the serotonin 5-HT 2A  receptor  antagonist   ketanserin . [ 4 ] [ 5 ]  Certain analogues and  derivatives  of 5-MeO-isoDMT, like  isoDMT  and the \u03b1-methylated  AAZ-A-154  (DLX-001; ( R )-5-MeO-\u03b1-methyl-isoDMT), likewise produce no head-twitch response, whereas 6-MeO-isoDMT produces a reduced head-twitch response. [ 1 ] [ 4 ] [ 5 ] [ 6 ]  Hence, these analogues appear to be less or fully non-hallucinogenic similarly to 5-MeO-isoDMT. [ 1 ] [ 4 ] [ 5 ] [ 6 ]  In addition, like 5-MeO-isoDMT, they retain potent psychoplastogenic effects. [ 1 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_199", "text": "5-MeO-isoDMT was first described in the  scientific literature  by 1984. [ 6 ] [ 7 ]  It was subsequently further characterized in 2020. [ 4 ] [ 5 ]  Confusingly, the drug has been referred to as \"6-MeO-isoDMT\" (or rather \"6-OMe-isoDMT\") in some publications. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_200", "text": "This  drug  article relating to the  nervous system  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_201", "text": "5-Nitro-DMT  ( 5-nitro- N,N -dimethyltryptamine ) is a  substituted tryptamine  derivative which acts as a  serotonin receptor   agonist , [ 1 ]  though its subtype selectivity has not been studied with modern techniques."}
{"_id": "WikiPedia_Pharmacology$$$corpus_202", "text": "[11C]ME@HAPTHI  is a  radiotracer  of the  norepinephrine transporter  for  positron emission tomography . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_203", "text": "25T7-NBOMe  (also known as  2C-T-7-NBOMe  or  NBOMe-2C-T-7 ) is a  substituted phenethylamine  derivative from the  25-NB  family. It acts as an agonist at the  5-HT 2A  and  5-HT 2C   serotonin   receptors , [ 2 ]  has  psychedelic  effects and has been sold as a  designer drug . [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_204", "text": "In November 2020, voters in the  U.S. state  of  Oregon  passed  Ballot Measure 110 , [ 2 ]   \"[ reclassifying] possession/penalties for specified drugs\". [ 3 ]  It reclassifies possession of drugs including  heroin ,  methamphetamine ,  PCP ,  LSD  and  oxycodone  as a Class E civil violation. [ 4 ]  The  Drug Policy Alliance , a New York-based non-profit organization was behind the measure [ 4 ]  and the measure also received financial support from the  Chan-Zuckerberg  Initiative. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_205", "text": "The new law aimed to reverse racial disparities in policing, and was projected to reduce black arrests by 94%. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_206", "text": "The new law came into effect on February 1, 2021. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_207", "text": "In 2024, the measure was significantly amended by House Bill 4002, which repealed the drug decriminalization portion in response to growing public backlash against said component. The bill, however, retains the provision of expanded access to drug addiction treatment using cannabis tax dollars. Starting September 1, 2024, possession of  hard drugs  became classified as a criminal misdemeanor outside of the regular A-E categorization system, carrying a sentence of up to 6 months of jail, which may be waived if the convictee enters into mandatory drug treatment. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_208", "text": "This  Oregon elections -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_209", "text": "This article about a  criminal law  topic is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_210", "text": "A-349,821  is a potent and selective  histamine H 3  receptor   antagonist [ 1 ]  (or possibly an  inverse agonist ). [ 2 ]  It has  nootropic  effects in animal studies, [ 3 ]  although there do not appear to be any plans for clinical development at present and it is currently only used in laboratory research. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_211", "text": "A-967079  is a drug which acts as a potent and selective  antagonist  for the  TRPA1  receptor. It has  analgesic  and  antiinflammatory  effects and is used in scientific research, but has not been developed for medical use. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_212", "text": "A.B.C. Liniment  was a  patent medicine   liniment  sold between approximately 1880 to 1935 as a topical pain relieving agent. [ 1 ] [ 2 ]  It was sold for relief of pain caused by various ailments, including  lumbago  (lower back pain),  sciatica ,  neuralgia ,  rheumatism , and stiffness after exercise. It was named for its three primary ingredients,  aconite ,  belladonna , and  chloroform . [ 1 ]  There were numerous examples of  poisoning  from the mixture, resulting in at least one death. [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_213", "text": "Abarelix , sold under the brand name  Plenaxis , is an injectable  gonadotropin-releasing hormone  antagonist ( GnRH antagonist ) which is marketed in  Germany  and the  Netherlands . It is primarily used in  oncology  to reduce the amount of  testosterone  made in patients with advanced symptomatic  prostate cancer  for which no other treatment options are available. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_214", "text": "It was originally marketed by Praecis Pharmaceuticals as  Plenaxis , [ 2 ]  and is now marketed by Speciality European Pharma in Germany [ 4 ]  after receiving a marketing authorization in 2005. The drug was introduced in the  United States  in 2003, but was discontinued in this country in May 2005 due to poor sales and a higher-than-expected incidence of severe  allergic reactions . [ 5 ]  It remains marketed in  Germany  and the  Netherlands  however. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_215", "text": "Abietatriene  is a  diterpene , C 20 H 30 , that is  abietane  having three  double bonds  located at the positions 8, 11, and 13. It has a role as a plant  metabolite  and derives from a  hydride  of an  abietane . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_216", "text": "This article about an  organic compound  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_217", "text": "The  absorption rate constant   K a  is a value used in  pharmacokinetics  to describe the rate at which a  drug  enters into the system. It is expressed in units of time \u22121 . [ 1 ]  The K a  is related to the  absorption half-life  (t 1/2a ) per the following equation: K a  = ln(2) / t 1/2a . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_218", "text": "K a  values can typically only be found in research articles. [ 2 ]  This is in contrast to parameters like  bioavailability  and  elimination half-life , which can often be found in drug and pharmacology handbooks. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_219", "text": "AC-262536  is a drug developed by  Acadia Pharmaceuticals  which acts as a  selective androgen receptor modulator  (SARM). Chemically it possesses  endo-exo isomerism , with the endo form being the active form. It acts as a  partial agonist  for the  androgen receptor  with a  K i  of 5 \u00a0 nM, and no significant affinity for any other receptors tested. In animal studies it produced a maximal effect of around 66% of the  levator ani   muscle  weight increase of  testosterone , but only around 27% of its maximal effect on  prostate gland  weight. [ 1 ] [ 2 ] [ 3 ]  It is an  aniline  SARM related to  ACP-105  and  vosilasarm  (RAD140). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_220", "text": "AC-90179  is a  piperidine  derivative which acts as an  inverse agonist  at the  5-HT 2A   serotonin   receptor  and an antagonist at  5-HT 2C . It was developed as a potential antipsychotic but was not pursued for medical applications due to poor oral bioavailability; however, it continues to be used as a tool compound in pharmacological research. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_221", "text": "AMCP  ( Academy of Managed Care Pharmacy)  is a  professional organization  representing the interests of  pharmacists  who practice in  managed care  settings. [ 2 ] [ 3 ] [ 4 ]  It publishes the  Journal of Managed Care & Specialty Pharmacy . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_222", "text": "AMCP is a member organization of the Alliance for a Stronger FDA. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_223", "text": "AMCP participated as a member of the COVID-19 Vaccine Education and Equity Project, launched in December 2020 under the leadership of the  Alliance for Aging Research ,  HealthyWomen  and the National Caucus and Center on Black Aging. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_224", "text": "In early 2021, AMCP received a $5,000 grant from  Pfizer  for a project titled \u201cEmerging Patterns in the Adoption of New-to-Market Oncology Biosimilars.\u201d [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_225", "text": "AMCP led the 2022 grassroots effort to pass the  Preapproval Information Exchange (PIE) Act of 2022  (H.R. 9297), which codified Food & Drug Administration (FDA) guidance related to communications between pharmaceutical and health payers, such as insurance plans and pharmacy benefit managers, regarding pipeline drug therapies. [ 9 ]  AMCP originally developed the concept of \"preapproval information exchange\" in 2016. [ 10 ]   The  PIE Act  was passed by the United States Congress on December 23, 2022, as part of the 2022 omnibus spending bill and was signed into law on December 29, 2022. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_226", "text": "Acetic acid/hydrocortisone  is a commonly used combination drug to treat infections of the  outer ear  and  ear canal . Branded as  Vosol HC  and  Acetasol HC , it combines the  antibacterial  and  antifungal  action of  acetic acid  with the  anti-inflammatory  functions of  hydrocortisone ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_227", "text": "Acetrizoic acid  is a pharmaceutical drug that was used as an  iodinated contrast  medium for  X-ray imaging . [ 1 ] [ 2 ]  It was applied in form of its salt, sodium acetrizoate, but is no longer in clinical use. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_228", "text": "The substance has high  osmolality  and is  water-soluble . The three  iodine  atoms in the molecule readily absorb X-rays and are therefore responsible for its usability as a contrast medium. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_229", "text": "Acetrizoate was developed by V.H. Wallingford of  Mallinckrodt , and introduced in 1950; [ 4 ]  it was employed as a contrast agent for several radiographic studies, including  pyelography , [ 5 ] [ 6 ]   angiography  of the  brain ,  carotid  arteries and the  aorta , [ 7 ] [ 8 ]  and  cholecystography . [ 9 ] [ 10 ]  It was soon found to be highly toxic to the  kidneys  and  nervous system \u2014work urging caution in its administration was published as early as 1959, [ 11 ]  after reports of adverse reactions ranging from hypersensitivity to brain damage\u2014and was eventually replaced by other agents with higher efficacy and lower toxicity, such as  sodium diatrizoate , a closely related compound. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_230", "text": "Trade names include Urokon, Triurol and Salpix, as well as Gastrografina and Urografina in Portugal."}
{"_id": "WikiPedia_Pharmacology$$$corpus_231", "text": "N -Acetyl- L -tyrosine  is an  amino acid , an  N - acetyl  derivative of  tyrosine . It is used for  parenteral nutrition  and as a  dietary supplement . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_232", "text": "N -Acetylcysteine amide  (abbrev. NACA, AD4 and also known as  acetylcysteinamide ) is an amide derivative of  N -acetylcysteine  that appears to have better  blood\u2013brain barrier  permeability and  bioavailability  and a similar antioxidant capability. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_233", "text": "ACP-105  is a drug which acts as a  selective androgen receptor modulator  (SARM). It has been investigated for potential use in the treatment of  age-related cognitive decline . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The drug has been found to reduce  anxiety -like behavior in a  mouse model  of  Alzheimer's disease  when administered alone, as well as enhance  spatial memory  when coadministered with the  selective   estrogen receptor \u03b2   agonist   AC-186 . [ 3 ]  ACP-105 is an  aniline  SARM and is related to  AC-262536  and  vosilasarm  (RAD140). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_234", "text": "Activation syndrome  is a form of stimulation (sometimes suicidal) or agitation that has been observed in association with some  psychoactive drugs . [ 1 ]  A causative role has not been established. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_235", "text": "Serotonin reuptake inhibitors (SSRI) have been associated with a state of restlessness, lability, agitation, and anxiety termed \"activation syndrome\". In some people, this state change can increase suicidal tendencies, especially in those under age 25 and during the initial weeks of treatment. [ 2 ]  SSRI-induced activation syndrome is well-accepted by clinicians. [ 3 ] \nIt is unclear whether jitteriness/anxiety syndrome predicts either good or poor prognosis (level D).  [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_236", "text": "Acylsulfonamide  is a  functional group  in  organic chemistry  that is sometimes used in  medicinal chemistry . [ 1 ]  It consists of a  sulfonamide  group (SO 2 NH) linked to an  acyl  group (RCO), forming the structure R 1 -CO-NH-SO 2 -R 2 . This moiety is found in several biologically active molecules and marketed drugs, serving as an useful  pharmacophore . [ 2 ]  Acylsulfonamides are of particular interest due to their ability to act as  bioisosteres  of  carboxylic acids , offering similar  hydrogen bonding  capabilities and comparable  pKa  values (typically between 3.5-4.5). [ 2 ]  They are incorporated in various drugs candidates targeting conditions such as bacterial infections, pain, and cancer. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_237", "text": "The following are approved drugs that contain the acylsulfonamide functional group:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_238", "text": "Several  investigational new drugs  contain also the acylsulfonamide functional group. Examples include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_239", "text": "Adebrelimab  is a drug that is being evaluated for the treatment of solid tumors. Adebrelimab is recombinant humanized IgG4 monoclonal antibody with specificity for  PD-L1 . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_240", "text": "In 2023, adebrelimab was approved for use in China for the treatment of  small cell lung cancer . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_241", "text": "Adiphenine  is an inhibitor of  nicotinic receptors . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_242", "text": "Adipiodone  ( INN , or  iodipamide ; trade names  Cholografin  and  Biligrafin ) is a pharmaceutical drug used as a  radiocontrast agent  in  X-ray imaging . It was introduced in the 1950s. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_243", "text": "Admilparant  is an  investigational new drug  being developed by  Bristol-Myers Squibb  for the treatment of  idiopathic pulmonary fibrosis  (IPF) and progressive pulmonary fibrosis (PPF). It is a first-in-class  lysophosphatidic acid receptor 1  (LPA1) antagonist. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_244", "text": "As of 2024, admilparant is in Phase III clinical trials for both IPF and PPF. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_245", "text": "Administrative Controlled Substances Code Number  ( ACSCN ) is a number assigned to drugs listed on the schedules created by the US  Controlled Substances Act  (CSA). The ACSCN is defined in  21 CFR  \u00a7 1308.03(a)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_246", "text": "Each chemical/drug on one of the schedules is assigned an ACSCN (for example,  heroin  is assigned 9200). The code number is used on various documents used in administration of the system mandated by the CSA."}
{"_id": "WikiPedia_Pharmacology$$$corpus_247", "text": "ACSCN tables include the CSA schedule, common alternative chemical and trade names, and the free base conversion ratio (the  molecular mass  of the substance in question divided by the molecular mass of the  free base ). This is used to make meaningful qualitative comparisons between substances, and labeling of the end product may, as is required in many European countries, list the active substance using both (e.g. \"each tablet contains 120 mg dihydrocodeine bitartrate, representing 80 mg dihydrocodeine base\"). This method of citation is in theory compulsory worldwide for substances in Schedule I of the  Single Convention on Narcotic Drugs  1961, a classification corresponding to  opioids  in US Schedule II with  Narcotic  classification plus  cocaine  (which inherited a narcotic designation from the 1931  Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs  and preceding treaties and national laws including the 1914  Harrison Narcotics Tax Act ) and German  Bet\u00e4ubungsmittelgesetz  (BtMG) Schedule I and so on. [ 1 ] [ 2 ] [ 3 ] [ 4 ]   This is also the case for Single Convention Schedule IV, which roughly corresponds to the United States' CSA Schedule I. [ 5 ]  and CSU Schedule"}
{"_id": "WikiPedia_Pharmacology$$$corpus_248", "text": "For a complete list, see the list of schedules: [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_249", "text": "Advanced Therapy Medicinal Products , or  ATMPs , are advanced therapeutic  drugs  that are based on  cell therapy  or  gene therapy  (sometimes in combination with a  medical device  - where they are then called a tissue engineered product). The criteria to which a drug must conform to be classified as an ATMP, are defined in Article 17 of Regulation (EC) No 1394/2007 by the  European Commission . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_250", "text": "AF-353  is a drug which acts as an antagonist of the P2X3 homotrimeric and P2X2/3 heterotrimeric forms of the  P2X purinoreceptors . It has been found to block  taste  responses and has been proposed as an agent for masking the bitter taste of medications. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_251", "text": "Aganodine  is a  guanidine  that activates presynaptic  imidazoline receptors . [ 1 ]  Through its  agonism  at imidazoline receptors, aganodine inhibits the presynaptic release of  norepinephrine . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_252", "text": "An  agent study  is a part of a  clinical trial  that tests the  chemotherapeutic  properties of a specific substance. More specifically, an agent study is used to detect whether or not a substance can prevent or inhibit  cancer . [ 1 ]  In a clinical trial, researchers perform multiple studies in order to test the potential of new cancer drugs. An agent study helps determine the potential of a substance to inhibit cancer, before more studies are done in order to further knowledge of this potential."}
{"_id": "WikiPedia_Pharmacology$$$corpus_253", "text": "Agent studies are used to determine whether a substance exhibits  cytotoxicity  or  cytostasis .  A cytotoxic agent will shrink a tumor, while, a cytostatic agent slows or stops tumor growth and  metastases . It is important to determine which of these effects an agent poses so that a proper clinical trial can be designed. For example, a study with a cytotoxic agent will look for tumor shrinkage vs. dose. It is much harder to develop a clinical trial for a cytostatic agent. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_254", "text": "Phase I trials are used to determine the  maximum tolerated dose  of an agent. This dose is then used in the Phase II trials. Maximum tolerated dose is based on the measured toxicity in cytotoxic agents. Cytostatic agents have been demonstrated to show biologic effects while also being nontoxic. It is recommended that cytostatic agent trials determine toxicity as well as evaluation of a biologic end point in response to different doses. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_255", "text": "Synonym:\nChemoprevention study"}
{"_id": "WikiPedia_Pharmacology$$$corpus_256", "text": "Ainuovirine  is a  non-nucleoside reverse transcriptase inhibitor  (NNRTI) being developed by  Kainos Medicine  for the treatment of  HIV infections . [ 1 ]  Ainuovirine was approved in China in 2021 for the treatment of HIV-1 infection. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_257", "text": "Air polymer-type A , sold under the brand name  ExEm Foam , is a drug for the detection of  fallopian tube  patency (openness) in people with known or suspected  infertility . [ 1 ] [ 2 ]  It was approved for use in the  United States  in November 2019. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_258", "text": "Air polymer-type A is infused into the  uterus  to allow for visual assessment of fallopian tubes during an  ultrasound  examination called a  sonohysterosalpingography . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_259", "text": "The most common adverse reactions are  pelvic pain  and  abdominal pain ,  nausea  and  faintness  (caused by a nerve and blood vessel reaction called  vasovagal reaction ) and post-procedure spotting. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_260", "text": "The US  Food and Drug Administration  (FDA) approved air polymer-type A based on literature reports. [ 2 ]  To evaluate how well air polymer-type A works, the FDA primarily used data from two trials. [ 2 ]  Trial A [ 4 ]  was conducted at a site in  Italy  and Trial B [ 5 ]  at three sites in  Poland . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_261", "text": "Evaluation of side effects was based on multiple literature reports and collected safety reports from countries where air polymer-type A is already approved. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_262", "text": "Akbarieh  ( Persian :  \u0627\u06a9\u0628\u0631\u06cc\u0647 ), headquarters in  Tehran, Iran , is one of the oldest suppliers of pharmaceuticals and fine chemicals and importers to Iran. [ 1 ] [ 2 ]  Established in 1890, the company is still operated by the Akbarieh family. Akbarieh customers are health professionals, and manufacturers of pharmaceuticals, food, cosmetic and feed industries. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_263", "text": "Akbarieh provides API  (Active Pharmaceutical Ingredient) , animal health and nutrition products, cosmetic raw materials and finished goods, and food additives. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_264", "text": "Akbarieh Company was founded by Ali Akbar Akbarieh MD in 1890 in the city of  Tabriz , Iran to supply pharmaceutical products and modern medicine to the local population. The Company moved from Tabriz to the capital, Tehran in 1944. The business currently provides pharmaceutical products, ingredients, raw materials, laboratory and hospital equipment to the Iranian market."}
{"_id": "WikiPedia_Pharmacology$$$corpus_265", "text": "This  Iranian corporation or company  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_266", "text": "In medicine and pharmacology,  albondin  (gp60) is a cell receptor that binds  serum albumin . [ 1 ]  It seems to be expressed on endothelial cells and binding induces endocytosis. Not much is known about this protein, except for its approximate  molecular mass  of 60\u00a0kDa. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_267", "text": "ALC-0159  is a  PEG /lipid conjugate (i.e.  PEGylated  lipid), specifically, it is the  N,N -di myristyl amide of  2-hydroxyacetic acid , O-pegylated to a PEG chain mass of about 2 kilo daltons  (corresponding to about 45-46 ethylene oxide units per molecule of  N,N -dimyristyl hydroxyacetamide).  It is a  non-ionic surfactant  by its nature. It has been deployed in the  Pfizer - BioNTech   SARS-CoV-2   mRNA vaccine  (0.05 mg per dose) [ 1 ]  that contains the active ingredient  tozinameran . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_268", "text": "Aldafermin  is a  fibroblast growth factor 19  (FGF19) analogue developed for  non-alcoholic steatohepatitis . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_269", "text": "Align Biopharma  is an initiative by six of the largest global  pharmaceutical companies  to create standards for physicians to access information on drugs. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_270", "text": "The companies participating include  Allergan ,  AstraZeneca ,  Biogen ,  GlaxoSmithKline ,  Novartis  and  Pfizer , and the software company Veeva Systems. The group is led by vice presidents and technology officers from each participating company. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_271", "text": "It was created to address the expansion of  personalized medicine  and specialized drugs, which are not frequently prescribed and tailored prescribing information is needed for each patient. The stated goals of Align are to allow physicians to use a single login to access pharmaceutical information for all six companies, and create a standard for consenting to receive information from pharmaceutical companies. [ 3 ]  Currently, companies individually verify the health care credentials of each provider before allowing them access to information. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_272", "text": "Alloclamide  ( Pectex ,  Tuselin ) is an  antitussive  and  antihistamine  drug marketed in Finland and Spain. It has never been marketed in the US."}
{"_id": "WikiPedia_Pharmacology$$$corpus_273", "text": "It is sold as an oral solution, containing 6.25 mg/mL alloclamide. The recommended dosage for adults is 25 mg three to four times daily. Adverse effects include constipation and sedation. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_274", "text": "Allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen , sold under the brand name  Stratagraft , is a medical treatment used for thermal burns containing intact dermal elements. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_275", "text": "Common side effects include pruritus (itching), blisters, hypertrophic scar, and impaired healing (stalled healing process) at the treatment site. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_276", "text": "Stratagraft is produced from two kinds of human skin cells (keratinocytes and dermal fibroblasts) grown together to make a bi-layered construct (a cellularized scaffold). [ 3 ]  Since the human keratinocyte cells were grown with mouse cells during initial stages of product development, Stratagraft is formally considered to be a xenotransplantation product (involving tissues or cells belonging to different species). [ 3 ]  Mouse cells are no longer used in the final manufacturing process. [ 3 ]  It was approved for medical use in the United States in June 2021. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_277", "text": "Stratagraft (allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen-dsat) is  indicated  for the treatment of adults with thermal burns containing intact dermal elements for which surgical intervention is clinically indicated (deep partial-thickness burns). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_278", "text": "The US  Food and Drug Administration  (FDA) evaluated the effectiveness and safety of Stratagraft based on two randomized clinical studies involving a total of 101 adult participants with deep partial thickness thermal burns. [ 3 ]  In both studies, two deep partial-thickness burn wounds of comparable area and depth on each participant were identified and randomized to receive either a single topical application of Stratagraft or autograft. [ 3 ]  The effectiveness is demonstrated by the percentage of Stratagraft treatment sites that achieved a complete wound closure, and the significantly decreased need for autografts at the Stratagraft treatment sites. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_279", "text": "The FDA granted Stratagraft regenerative medicine advanced therapy,  priority review , and  orphan drug  designations for this indication. [ 3 ]  Stratagraft was developed in conjunction with the U.S. Department of Health and Human Services\u2019 Biomedical Advanced Research and Development Authority. [ 3 ]  The FDA granted approval to Stratatech, a  Mallinckrodt  company. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_280", "text": "Allogeneic cultured keratinocytes and fibroblasts in bovine collagen , sold under the brand name  Gintuit , is a  cellular therapy  used for the treatment of mucogingival (the  oral mucosa  and  gingival  (gum) tissues of the mouth) conditions. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_281", "text": "Common adverse reactions observed during clinical trials include sinusitis (sinus inflammation), nasopharyngitis (inflammation of the upper throat, upper respiratory tract infection, aphthous stomatitis (canker sores), and local surgery site reactions such as pain and redness. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_282", "text": "Allogeneic cultured keratinocytes and fibroblasts in bovine collagen is a cellular sheet that consists of two layers, an upper layer composed of living human keratinocytes (the primary cell type in the skin's outer layer) and a lower layer constructed of bovine-derived collagen, human  extracellular matrix proteins  (molecules that support and give structure to cells), and living human dermal fibroblasts (skin cells that generate connective tissues). [ 2 ]  It is the first cell-based product made from allogeneic (cells derived from a donor source that is unrelated to the intended recipient) human cells and bovine collagen approved by the US  Food and Drug Administration  (FDA). [ 2 ]  It was approved for medical use in the United States in March 2012. [ 1 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_283", "text": "Allogeneic cultured keratinocytes and fibroblasts in bovine collagen is  indicated  for topical (non-submerged) application to a surgically created vascular wound bed in the treatment of mucogingival conditions in adults. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_284", "text": "The efficacy of allogeneic cultured keratinocytes and fibroblasts in bovine collagen (Gintuit) was evaluated in two clinical studies in adults with insufficient gingival tissue. [ 2 ]  In each of the two studies, Gintuit was associated with an increase of at least 2 mm of gingival tissue in at least 50% of the study subjects. The overall clinical trial safety data for Gintuit included 121 subjects from both studies. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_285", "text": "The  Allotrope Foundation  is a consortium of pharmaceutical companies, instrument vendors and software companies to simplify the exchange of scientific electronic data. It publishes the Allotrope Foundation Ontology (AFO) which is a  controlled vocabulary  to structure data, the Allotrope Data Models (ADM) and the Allotrope Data Format (ADF) based on  HDF5  which incorporates those for use in practice. Standardization aims at the goal of  FAIR data . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_286", "text": "Aloxistatin  ( loxistatin ,  E-64d ,  EST ) is a drug which acts as a  cysteine protease  inhibitor and has  anticoagulant  effects. It is a synthetic analogue of  E-64 , a natural product derived from fungi. [ 1 ] [ 2 ] [ 3 ]  It was researched for the treatment of  muscular dystrophy  but was not successful in human  clinical trials , [ 4 ]  though it has continued to be investigated for treatment of  spinal cord injury ,  stroke  and  Alzheimer's disease . [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_287", "text": "Aloxistatin also shows  antiviral  effects. [ 10 ] [ 11 ] [ 12 ]  Studies have shown it can inhibit  cathepsin L , a protein believed to play a role in  SARS-CoV-2  cellular entry. In a laboratory study using SARS-CoV-2 pseudovirions, aloxistatin was able to reduce  viral entry  into cells by approximately 92%. [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_288", "text": "ALX-1393  is a  glycine reuptake inhibitor ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_289", "text": "ALX-1393 works by inhibiting the action of  GLYT2 . [ 2 ]  This causes elevated levels of glycine, an inhibitory neurotransmitter."}
{"_id": "WikiPedia_Pharmacology$$$corpus_290", "text": "ALX-1393 has been shown to have potential as an  analgesic . This is thought to be due to the elevated  glycine  levels reducing the transmission of the pain signals. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_291", "text": "Tests have shown that it was able to help reduce cancer pain in a potent way. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_292", "text": "AM-0902  is a drug which acts as a potent and selective  antagonist  for the  TRPA1  receptor, and has  analgesic  and  antiinflammatory  effects. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_293", "text": "Amastatin , also known as  3-amino-2-hydroxy-5-methylhexanoyl- L -valyl- L -valyl- L -aspartic acid , is a  naturally occurring , competitive and reversible  aminopeptidase   inhibitor  that was isolated from  Streptomyces  sp. ME 98-M3 . [ 1 ]  It specifically inhibits  leucyl aminopeptidase ,  alanyl aminopeptidase  (aminopeptidase M/N),  bacterial leucyl aminopeptidase  ( Aeromonas proteolytica  aminopeptidase),  leucyl/cystinyl aminopeptidase  (oxytocinase/vasopressinase), [ 2 ]  and, to a lesser extent,  glutamyl aminopeptidase  (aminopeptidase A), [ 3 ]  as well as other aminopeptidases. [ 4 ]  It does not inhibit  arginyl aminopeptidase  (aminopeptidase B). [ 5 ] [ 6 ]  Amastatin has been found to potentiate the  central nervous system  effects of  oxytocin  and  vasopressin   in vivo . [ 7 ]  It also inhibits the degradation of  met-enkephalin ,  dynorphin A , and other  endogenous   peptides . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_294", "text": "Amcenestrant  is a novel oral  selective estrogen receptor degrader  (SERD) that is being evaluated for the treatment of  estrogen receptor -positive (ER+)  breast cancer . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_295", "text": "Phase III trial for breast cancer in Japan had started, but this trial has been discontinued. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_296", "text": "The  American Association of Colleges of Pharmacy  ( AACP ) is the national organization representing the interests of  pharmacy education . Founded in 1900, AACP comprises all  accredited colleges and schools  with  pharmacy degree  programs, including more than 6,400 faculty, 63,800 students enrolled in professional programs, and 4,800 individuals pursuing graduate study in the field of  pharmacy . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_297", "text": "AACP provides member services \u2013 including meetings and events, webinars, continuing education, publications, reports and searchable directories for faculty, speakers and grants. AACP also works to promote the profession of pharmacy and the value of pharmacy education to audiences beyond the academic community."}
{"_id": "WikiPedia_Pharmacology$$$corpus_298", "text": "The  American College of Clinical Pharmacy  (ACCP) is a  pharmacy   professional association  representing the interests of clinical  pharmacists . [ 1 ] [ 2 ]   [ 3 ]  ACCP is the publisher of  Pharmacotherapy  and JACCP: Journal of the American College of Clinical Pharmacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_299", "text": "According to the ACCP, its purpose is to advance human health by extending the frontiers of clinical pharmacy. [ 1 ]  It has more than 15,000 members."}
{"_id": "WikiPedia_Pharmacology$$$corpus_300", "text": "American Society of Health-System Pharmacists (ASHP)  is a professional organization that represents  pharmacists  who serve as patient care providers in  hospitals ,  health systems ,  ambulatory clinics , and other healthcare settings. The organization's nearly 60,000 members include pharmacists, student pharmacists, and pharmacy technicians. [ 1 ]  ASHP maintains a national database on U.S. drug shortages that is published on their website."}
{"_id": "WikiPedia_Pharmacology$$$corpus_301", "text": "The aim of the society is to support the professional practice of pharmacists in hospitals and health systems. In addition, the society advocates to government agencies, such as the  Food and Drug Administration  (FDA) and the  Centers for Disease Control and Prevention  (CDC) on public policy issues related to  medication  use and  public health ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_302", "text": "The  American Society of Pharmacognosy  ( ASP ) is a scientific society that promotes the growth and development of  pharmacognosy  through presentation of research achievements and publication of meritorious research."}
{"_id": "WikiPedia_Pharmacology$$$corpus_303", "text": "ASP was founded in 1959 as an outgrowth of the Plant Science Seminar established in 1923. ASP has over 1,100 active and associate members. [ 1 ]  Approximately 40 percent of the active members reside outside the U.S. and Canada in more than 60 countries. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_304", "text": "Pharmacognosy includes the study of the physical, chemical, biochemical and biological properties of drugs, drug substances, or potential drugs or drug substances of natural origin as well as the search for new drugs from natural sources. Research problems in pharmacognosy include studies in the areas of  phytochemistry ,  microbial chemistry ,  biosynthesis ,  biotransformation ,  chemotaxonomy  and other biological and chemical sciences."}
{"_id": "WikiPedia_Pharmacology$$$corpus_305", "text": "ASP publishes the quarterly  ASP Newsletter  and co-publishes the  Journal of Natural Products  with the  American Chemical Society . [ 5 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_306", "text": "An ASP Fellow,  Satoshi \u014cmura , was awarded the 2015  Nobel Prize in Physiology or Medicine  along with two other researchers for their work in researching therapies for roundworm parasite and malaria infections. \u014cmura is also a past recipient of the ASP Norman R. Farnsworth Research Achievement Award (2013) for his work on novel bacterial strains, such as  Streptomyces avermitilis , and their bioactive constituents. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_307", "text": "AMG-333  is a drug which acts as a potent and selective blocker of the  TRPM8   ion channel , which is the main receptor responsible for the sensation of  cold . It was developed as a potential treatment for  migraine . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_308", "text": "AMG-517  is a drug which acts as a potent and selective blocker of the  TRPV1   ion channel . [ 1 ] [ 2 ]  It was developed as a potential treatment for  chronic pain , but while it was an effective  analgesic  in animal studies it was dropped from human  clinical trials  at Phase I due to producing  hyperthermia  as a side effect, as well as poor water solubility. It is still used in scientific research into the function of the TRPV1 channel and its role in pain and  inflammation , and has been used as a template for the design of several newer analogues which have improved properties. [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_309", "text": "AMG-9810  is a drug which acts as a potent and selective  antagonist  for the  TRPV1  receptor. [ 1 ]  It has  analgesic  and  antiinflammatory  effects and is used in scientific research, but has not been developed for medical use. It has high antagonist potency and good  bioavailability  and  pharmacokinetics , and so has been used to study the role of TRPV1 in areas other than pain perception, such as its roles in the brain. [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_310", "text": "Aminopeptidase A inhibitors   are a class of antihypertensive drugs that work by inhibiting the conversion of  angiotensin II  to  angiotensin III  by the  aminopeptidase A  enzyme. The first medication in this class is  firibastat . [ 1 ] [ 2 ] [ 3 ]  It is hypothesized that the drugs may be more effective in overweight people and those of African descent. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_311", "text": "Ammonia ( 13 N)  ( ammonia  with  radioisotope   nitrogen-13 ) is a medication for diagnostic  positron emission tomography  (PET) imaging of the  myocardium . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_312", "text": "Amulirafusp alfa  (IMM0306) is a  cancer immunotherapy  that targets  CD20 -positive  B-cell malignancies . It is a fusion protein that combines a CD20  monoclonal antibody  with the  CD47  binding domain of  SIRP\u03b1 , allowing it to simultaneously engage both CD20 and CD47 on cancer cells. [ 1 ]  Amulirafusp alfa has a dual mechanism of action that enhances both  macrophage -mediated  phagocytosis  and  natural killer cell  activation. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_313", "text": "Amurca  is the  Latin  name for the bitter-tasting, dark-colored, watery sediment that settles out of  unfiltered olive oil  over time. It has been known in English as \"olive oil  lees \" [ 1 ]  and recently as \"olive mill waste water (OMWW)\". [ 2 ]  Historically, amurca was used for numerous purposes, as first described by  Cato the Elder  in  De Agri Cultura , and later by  Pliny the Elder . [ 3 ]   Cato mentions its uses as a  building  material (128),  pesticide  (91, 92, 96, 98),   herbicide  (91, 129),  dietary supplement  for  oxen  (103) and trees (36, 93), food  preservative  (99, 101), as a maintenance product for leather (97),  bronze  vessel (98), and  vases  (100), and as a treatment for firewood in order to avoid smoke (130). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_314", "text": "This article incorporates text from a publication now in the  public domain :\u00a0 Chambers, Ephraim , ed. (1728). \"Amurca\".  Cyclop\u00e6dia, or an Universal Dictionary of Arts and Sciences  (1st\u00a0ed.). James and John Knapton, et al."}
{"_id": "WikiPedia_Pharmacology$$$corpus_315", "text": "This  toxicology -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_316", "text": "The  amylin receptors  (AMYRs) are  heterodimers  of the  calcitonin receptor  that are bound to by  amylin  with high affinity and consist of  AMY1 ,  AMY2 , and  AMY3 . [ 1 ] [ 2 ]  Amylin mimetics that are  agonists  at the amylin receptors are being developed as therapies for  diabetes  and  obesity , and one,  pramlintide , has been FDA approved. [ 3 ] [ 4 ]  The AMY1 receptor may be activated by both amylin and the  calcitonin gene-related peptide  (CGRP) and could play a role in the effects of  CGRP receptor antagonists  developed for  migraine . [ 5 ] [ 6 ]  Dual agonists of the amylin and calcitonin receptors (DACRAs) are under development for obesity. [ 7 ]  Amylin and its receptors are believed to play a role in  Alzheimer's disease . [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_317", "text": "Anavip  (stylized as  ANAVIP ) is the trade name of a snake  antivenin  indicated for the management of adult and pediatric patients with  North American rattlesnake   envenomation . [ 1 ] [ 2 ] [ 3 ]  As defined by the  FDA , the proper name is  crotalidae  immune F(ab') 2  (equine) . [ 4 ]   It is manufactured by  Instituto Bioclon  for Rare Disease Therapeutics in the United States."}
{"_id": "WikiPedia_Pharmacology$$$corpus_318", "text": "Anavip is a divalent  fragment antigen-binding  protein, F(ab') 2 , derived from the blood of  horses  immunized with the  venom  of the snakes  Bothrops asper  and  Crotalus durissus . The product is produced by  pepsin  digestion of horse  blood plasma  then purified resulting in a preparation containing >85% F(ab') 2 . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_319", "text": "Angel dusting  is the misleading  marketing  practice of including a minuscule amount of an  active ingredient  in a  cosmetic ,  cosmeceutical ,  dietary supplement ,  food  product, or  nutraceutical , insufficient to give any measurable benefit. The advertising materials may  claim  that the ingredient is helpful and that the ingredient is contained in the product, both of which are true.  However, no claim is made that the product contains enough of the active ingredient to have an effect \u2013 this is just assumed by the purchaser. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_320", "text": "This food  ingredient  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_321", "text": "Annexin Pharmaceuticals  is a Swedish privately held  biotech  company [ 1 ] [ 2 ]  developing new therapeutic approaches for inflammatory  cardiovascular diseases . The concept for the therapy is based on the anti-inflammatory properties of  Annexin A5 , a body own protective protein that acts simultaneously against several key  pathogenic  mechanisms of cardiovascular diseases. The company is currently focusing on treatment of  peripheral artery disease  (PAD)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_322", "text": "An  anti-\u03b1-synuclein drug , or an  \u03b1-synuclein inhibitor , is a  drug  which blocks or inhibits  \u03b1-synuclein . [ 1 ] [ 2 ]  \u03b1-Synuclein is a  protein  which is thought to be involved in the development and progression of  \u03b1-synucleinopathies  including  Parkinson's disease ,  dementia with Lewy bodies , and  multiple system atrophy . [ 1 ] [ 2 ]  Anti-\u03b1-synuclein drugs are under development for treatment of Parkinson's disease and other \u03b1-synuclein-related diseases. [ 1 ] [ 2 ]  Examples include the  monoclonal antibodies   prasinezumab  and  cinpanemab , which both failed to show effectiveness in slowing the progression of Parkinson's disease in  phase 2   clinical trials . [ 1 ]  Other anti-\u03b1-synuclein drugs, like the monoclonal antibody  exidavnemab , the \u03b1-synuclein  vaccines   PD01A  and  PD03A , and the  small-molecule  \u03b1-synuclein misfolding and aggregation inhibitors  minzasolmin  and  emrusolmin , are also under development. [ 1 ] [ 3 ] [ 2 ] [ 4 ]   Memantine  is also being studied as a potential  disease-modifying treatment  for Parkinson's disease by inhibiting cell-to-cell transmission of \u03b1-synuclein and is in a  phase 3  trial for this purpose. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_323", "text": "Antianalgesia  is the ability of some endogenous chemicals (notably  cholecystokinin  and  neuropeptide Y ) to counter the effects of exogenous  analgesics  (such as  morphine ) or endogenous pain inhibiting  neurotransmitters /modulators, such as the endogenous opioids. [ 1 ]  A learned form can be established using methods similar to the learning principle of  conditioned inhibition , and has been demonstrated in rats."}
{"_id": "WikiPedia_Pharmacology$$$corpus_324", "text": "Anticachexia  (AN-tee-kuh-KEK-see-uh)  is a drug or effect that works against  cachexia  (loss of body weight and muscle mass)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_325", "text": "AOH1996  is an experimental  anticancer medication  which acts as a  small molecule   inhibitor  of  proliferating cell nuclear antigen  (PCNA) and is in  Phase I   clinical trials  at  City of Hope  as of August 2023 for the treatment of  solid tumors . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_326", "text": "AOH1996 was created to target a  post-translationally modified  isoform of PCNA, termed caPCNA, which is preferentially found in  cancer cells . PCNA is crucial in the body for  DNA   repair , but targeting it is difficult because of its role in healthy cells. By selectively targeting caPCNA, it may be possible to kill cancer cells without affecting healthy tissues. [ 5 ]   In vitro  testing demonstrated that AOH1996 inhibited the growth and  induced cell cycle arrest  and  apoptotic cell death  in a wide variety of cancer cell lines, but had no effect on several normal, nonmalignant cell types. [ 6 ] [ 7 ]  In mouse and dog animal models, there were no observed side effects or toxicity even at six times the effective dose. [ 3 ]  It could be used either as a monotherapy (single drug regimen) or in combination with one or more other chemotherapy drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_327", "text": "Although the press described it as a \"miracle drug\" that would cure cancer, some experts have expressed skepticism. Prof Dorothy Bennett, Director of the Molecular and Clinical Sciences Research Institute, St George\u2019s, University of London, critiqued the paper's cancer killing claim as actually a modest slowing of growth but, \"there appears to be broad evidence here.... suggesting that this kind of approach deserves further development.\u201d [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_328", "text": "The substance was named after the initials and the birth year of Anna Olivia Healey, who died of  neuroblastoma  in 2006. The funds collected by her parents have helped support the development of the chemical compound. [ 6 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_329", "text": "Apafant  ( WEB-2086 ,  LSM-2613 ) is a drug which acts as a potent and selective inhibitor of the  phospholipid  mediator  platelet-activating factor  (PAF). It was developed by structural modification of the  thienotriazolodiazepine   sedative  drug  brotizolam  and demonstrated that PAF inhibitory actions could be separated from activity at the  benzodiazepine receptor . Apafant was investigated for several applications involving inflammatory responses such as  asthma  and  conjunctivitis  but was never adopted for medical use, however it continues to be used in pharmacology research. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_330", "text": "Approvable letters , and the related  non-approvable letters  (alternately  not-approvable letters ), were notifications sent out by the  Food and Drug Administration  (FDA) to  drug manufacturers  alerting them to the approval prospects of their  drugs  under development. [ 1 ]  The letters were intended to let manufacturers know how much work is needed on their applications. [ 1 ]  Non-approval letters were rejections of a drug's application. [ 2 ]  Approvable and non-approvable letters were covered under  Title 21 of the Code of Federal Regulations , section 314.110. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_331", "text": "In 2018, the FDA replaced approvable letters with  Complete Response Letters  (CRL) to notify applicants when additional information is required before approval. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_332", "text": "Approvable letters were issued to applicants at the end of the FDA's review period to indicate that the application or abbreviated application is basically approvable providing certain issues are resolved. It was an indication that the application substantially met FDA requirements if specific conditions, such as labeling changes, are agreed to. The letter described what was required by the FDA. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_333", "text": "Applicants had 10 days after the date of the approvable letter to amend the application, notify of intent to file for an extension, withdraw the application, request a hearing or notify that they agreed to an extension. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_334", "text": "Aqua omnium florum  or  all-flower water   was water distilled from  cow-dung  in May, when the cows ate fresh grass with meadow flowers.  It was also known less euphemistically as  aqua stercoris vaccini stillatitia  (distilled water of cow dung). [ 1 ]  This was used as a medicine to treat a variety of ailments including  gout ,  rheumatism  and  tuberculosis . [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_335", "text": "The 17th century court physician  George Bate  favoured it and it appeared in the  Pharmacop\u0153ia Bateana  \u2014  Bate's Dispensatory . [ 4 ]   Recipes included: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_336", "text": "cow dung, gathered in May, adding to it a third of white wine and then distilled"}
{"_id": "WikiPedia_Pharmacology$$$corpus_337", "text": "fresh cow-dung and snails with their shells bruised equal parts, mix and distill in a common still"}
{"_id": "WikiPedia_Pharmacology$$$corpus_338", "text": "Rx  Fresh cow dung gathered in the morning; spring or rain water; mix and digest twenty-four hours, let it settle, and then decant the clear brown tincture."}
{"_id": "WikiPedia_Pharmacology$$$corpus_339", "text": "The latter prescription was used as a  panacea  by a female doctor in Bate's time.  Many incurable cases were brought to her which she treated in this way and she made a great fortune of \u00a320,000 from this practice. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_340", "text": "Cow tea  or  urina vaccina  ( cow's urine ) was sometimes called  aqua omnium florum  too. [ 1 ]   This was used as a  purgative  for which the dosage would be \"half a pint drank warm from the cow\". [ 5 ]   It was drunk by women in May to clear their  complexion . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_341", "text": "Cow dung, urine and other bovine products are still used extensively in the traditional Hindu medicine,  Ayurveda . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_342", "text": "Arcarine  ( ORM-11984 ) is a  selective androgen receptor modulator  (SARM) developed by  Orion Corporation , a Finnish pharmaceutical company. [ 1 ] [ 2 ] [ 3 ]  It belongs to a class of drugs designed to have tissue-selective  androgenic  effects, potentially offering the benefits of androgens while minimizing unwanted side effects. [ 1 ]  Arcarine was investigated for the treatment of various conditions, including  benign prostatic hyperplasia ,  hypogonadism , and  osteoporosis . [ 4 ] [ 5 ]  The compound reached  Phase I clinical trials  before development was discontinued. [ 4 ]  Like other SARMs, Arcarine was developed to potentially provide  anabolic  effects in muscle and bone tissue while having reduced androgenic effects in other tissues, such as the  prostate . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_343", "text": "Arpraziquantel  ( ( R )-praziquantel ) is the  eutomer  (the biologically active  enantiomer ) of  praziquantel , and is a  medication  which is currently under investigation for the treatment of  schistosomiasis  in young children since it has less side effects than the usual  racemic mixture   formulation  of praziquantel. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_344", "text": "In December 2023, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  adopted a positive opinion in accordance with Article 58 of Regulation (EC) No 726/20041 for the medicinal product arpraziquantel, intended for the treatment of schistosomiasis in young children. [ 1 ]  The applicant for this medicinal product is Merck Europe B.V. [ 1 ]  It is intended exclusively for markets outside the European Union. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_345", "text": "Arpraziquantel is the  International nonproprietary name . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_346", "text": "Artificial intelligence in pharmacy  is the application of  artificial intelligence  (AI) [ 1 ] [ 2 ] [ 3 ]  to the discovery, development, and the treatment of patients with  medications . [ 4 ]  AI in  pharmacy  practices has the potential to revolutionize all aspects of pharmaceutical research as well as to improve the clinical application of pharmaceuticals to prevent, treat, or cure disease. [ 5 ]  AI, a technology that enables machines to simulate  human intelligence , has found applications in  pharmaceutical research ,  drug manufacturing , drug delivery systems, clinical trial optimization, treatment plans, and patient-centered services. [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_347", "text": "AI  algorithms  analyze vast  datasets  with greater speed and accuracy than traditional methods. [ 9 ] [ 10 ]  This has enabled the identification of potential  drug candidates , prediction of their  interactions , and optimization of formulations. [ 11 ]  AI-driven  simulations  and modeling assist researchers in understanding  molecular interactions , thus expediting the  drug development  timeline. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_348", "text": "AI is revolutionizing the drug delivery systems. AI technology can assist in identifying biological targets for pharmaceuticals, evaluating the pharmacological profiles of potential drugs, and analyzing genetic information; in the future, this could lead to drugs personalized to an individual, targeted cancer treatments, and edible vaccines. [ 14 ] [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_349", "text": "This  artificial intelligence -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_350", "text": "Substituted arylalkylamines , also alternatively known in many cases as  substituted arylethylamines , [ 1 ]  are a group of  chemical compounds . [ 2 ] [ 3 ] [ 4 ]  These compounds are divided into two main categories: indolylalkylamines and phenylalkylamines. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_351", "text": "These compounds are related to  monoamine neurotransmitters , which are chemicals in the brain that transmit signals between nerve cells. Because of this, substituted arylalkylamines can have a wide range of effects on the body and mind. They are used in many medications, including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_352", "text": "This article about an  amine  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_353", "text": "Asandeutertinib  is an  investigational new drug  that is being evaluated for the treatment of cancer. It is an  epidermal growth factor receptor  (EGFR)  tyrosine kinase inhibitor  (TKI) with antineoplastic properties. [ 1 ] [ 2 ]  Developed by TYK Medicines, this small molecule drug is currently being investigated for the treatment of  non-small cell lung cancer  (NSCLC), particularly in patients with EGFR mutations. [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_354", "text": "Asoxime chloride , or more commonly  HI-6 , is a  Hagedorn oxime  used in the treatment of  organophosphate poisoning . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_355", "text": "ASP2535  is an inhibitor of the  type 1 glycine transporter . [ 1 ]  It could potentially be used in treatment of  Alzheimer's disease  and  schizophrenia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_356", "text": "ASP2535 has been investigated for the treatment of Alzheimer's disease and schizophrenia, it is able to inhibit the memory deficit induced by  scopolamine , an anticholinergic agent. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_357", "text": "This article about a biochemical   receptor  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_358", "text": "The  asymmetric membrane capsule  is an example of a single core  osmotic  delivery system, consisting of a drug-containing core surrounded by an asymmetric  membrane  made with a non disintegrating  polymer  ( cellulose acetate ,  ethylcellulose  etc.). [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_359", "text": "ATC code B   Blood and blood forming organs  is a section of the  Anatomical Therapeutic Chemical Classification System , a system of alphanumeric codes developed by the  World Health Organization  (WHO) for the classification of  drugs  and other medical products. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_360", "text": "Codes for  veterinary  use ( ATCvet codes ) can be created by placing the letter Q in front of the human ATC code: for example,  QB . [ 5 ]   National issues of the ATC classification may include additional codes not present in this list, which follows the WHO version."}
{"_id": "WikiPedia_Pharmacology$$$corpus_361", "text": "ATC code H04   Pancreatic hormones  is a therapeutic subgroup of the  Anatomical Therapeutic Chemical Classification System , a system of alphanumeric codes developed by the  World Health Organization  (WHO) for the classification of  drugs  and other medical products. [ 1 ] [ 2 ] [ 3 ]  Subgroup H04 is part of the anatomical group  H  Systemic hormonal preparations, excluding sex hormones and insulins . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_362", "text": "Codes for  veterinary  use ( ATCvet codes ) can be created by placing the letter Q in front of the human ATC code: for example,  QH04 . [ 5 ]   National issues of the ATC classification may include additional codes not present in this list, which follows the WHO version."}
{"_id": "WikiPedia_Pharmacology$$$corpus_363", "text": "ATC code L   Antineoplastic and immunomodulating agents  is a section of the  Anatomical Therapeutic Chemical Classification System , a system of alphanumeric codes developed by the  World Health Organization  (WHO) for the classification of  drugs  and other medical products. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_364", "text": "Codes for  veterinary  use ( ATCvet codes ) can be created by placing the letter Q in front of the human ATC code: for example,  QL . [ 5 ]   National issues of the ATC classification may include additional codes not present in this list, which follows the WHO version."}
{"_id": "WikiPedia_Pharmacology$$$corpus_365", "text": "ATC code M   Musculo-skeletal system  is a section of the  Anatomical Therapeutic Chemical Classification System , a system of alphanumeric codes developed by the  World Health Organization  (WHO) for the classification of  drugs  and other medical products. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_366", "text": "Codes for  veterinary  use ( ATCvet codes ) can be created by placing the letter Q in front of the human ATC code: for example,  QM . [ 5 ]   National issues of the ATC classification may include additional codes not present in this list, which follows the WHO version."}
{"_id": "WikiPedia_Pharmacology$$$corpus_367", "text": "ATC code S   Sensory organs  is a section of the  Anatomical Therapeutic Chemical Classification System , a system of alphanumeric codes developed by the  World Health Organization  (WHO) for the classification of  drugs  and other medical products. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_368", "text": "Codes for  veterinary  use ( ATCvet codes ) can be created by placing the letter Q in front of the human ATC code: for example,  QS . [ 5 ]   National issues of the ATC classification may include additional codes not present in this list, which follows the WHO version."}
{"_id": "WikiPedia_Pharmacology$$$corpus_369", "text": "ATCvet code QI   Immunologicals  is a section of the  Anatomical Therapeutic Chemical Classification System for veterinary medicinal products , a system of alphanumeric codes developed by the  World Health Organization  (WHO) for the classification of  drugs  and other medical products for  veterinary  use. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_370", "text": "National issues of the ATC classification may include additional codes not present in this list, which follows the WHO version."}
{"_id": "WikiPedia_Pharmacology$$$corpus_371", "text": "Ateganosine  is a  telomerase  inhibitor [ 1 ]  and  apoptosis  inducer currently under investigation for the treatment of various cancers, including  non-small cell lung cancer  (NSCLC). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_372", "text": "Atezolizumab/hyaluronidase , sold under the brand name  Tecentriq Hybreza , is a  fixed-dose combination  medication used for the treatment of non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. [ 1 ] [ 2 ]  It contains  atezolizumab , a programmed death-ligand 1 (PD-L1) blocking monoclonal antibody; and  hyaluronidase  (human recombinant), an  endoglycosidase . [ 1 ]  It is taken by  subcutaneous injection . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_373", "text": "The most common adverse reactions include fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_374", "text": "Atezolizumab/hyaluronidase was approved for medical use in the United States in September 2024. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_375", "text": "Atezolizumab/hyaluronidase is a subcutaneous injection version of atezolizumab for all the adult indications as the intravenous formulation of atezolizumab including non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_376", "text": "The subcutaneous injection of atezolizumab and hyaluronidase was evaluated in IMscin001 (NCT03735121), an open-label, multi-center, international, randomized trial in adults with locally advanced or metastatic non-small cell lung cancer who were not previously exposed to cancer immunotherapy and who had disease progression following treatment with platinum-based chemotherapy. [ 2 ]  A total of 371 participants were randomized (2:1) to receive subcutaneous atezolizumab and hyaluronidase or intravenous atezolizumab until disease progression or unacceptable toxicity. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_377", "text": "Atumelnant  (developmental code name  CRN04894 ) is an  investigational new drug  developed by Crinetics Pharmaceuticals for the treatment of  adrenocorticotropic hormone  (ACTH)-dependent  endocrine disorders . It is a  selective   antagonist  of the  melanocortin type 2 receptor  (MC2R), also known as the ACTH receptor, which is primarily expressed in the  adrenal glands . [ 1 ]  Atumelnant is being evaluated to treat conditions such as  congenital adrenal hyperplasia  (CAH) and ACTH-dependent  Cushing's syndrome  caused for example by  pituitary adenomas . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_378", "text": "Aurea Alexandrina  was an ancient  opiate . It is called  Aurea  from the gold which enters its composition, and  Alexandrina  for the physician  Nicolaus Myresus Alexandrinus , who invented it. [ 1 ]  It was considered to be a good preservative against  colic  and  apoplexy . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_379", "text": "Aurolac  is an industrial adhesive sold in  Romania , designed for use in repairing terracotta stoves, which is commonly abused as an  inhalant . [ 1 ]  The law HG 767/2001 applies restrictions on where and how aurolac, which it uses as a generic term for a variety of substances containing  ethers ,  ketones ,  acetates , as well as  methanol  and  toluene , can be sold. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_380", "text": "In 2000, a child who had abused Aurolac was photographed while naked and crying in a tram station in Bucharest's Rahova district. The image was widely published and used to define social problems in Romania.  [ 3 ]  The 2001 documentary  Children Underground  also details the effects of Aurolac abuse amongst Bucharest's homeless children."}
{"_id": "WikiPedia_Pharmacology$$$corpus_381", "text": "This  Romania -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_382", "text": "An  Australian Approved Name  ( AAN ) is a  generic drug  name set by the  Therapeutic Goods Administration  (TGA) for use in Australia. [ 1 ]  In late 2016, the TGA changed several drug names to the corresponding  international nonproprietary name  (INN), or, in cases where an INN was not available (as with  asparaginase ), another established generic name, such as the  United States Adopted Name  (USAN). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_383", "text": "Australian Medicines Handbook  (AMH) is a peer-reviewed medicines prescribing guide for Australian health professionals. The handbook is available in paper and digital formats and is supplemented by the  AMH Aged Care Companion  and the  AMH Children's Dosing Companion ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_384", "text": "It is included in the  Clinical Information Access Portal ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_385", "text": "The AMH was first published in May 1998 driven by the need for a local, independent and up-to-date source of drug information to foster rational prescribing. Reflecting contemporary Australian clinical practice and adhering to the principles of the quality use of medicines, it is generally considered the Australian equivalent to the  British National Formulary  on which it was partly modelled."}
{"_id": "WikiPedia_Pharmacology$$$corpus_386", "text": "AMH Pty Ltd, the publishing company created to develop and maintain the AMH content, is a professional partnership between three organisations: the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, the  Pharmaceutical Society of Australia , and the  Royal Australian College of General Practitioners . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_387", "text": "Automatism , in  toxicology , refers to a tendency to take a drug over and over again, forgetting each time that one has already taken the dose. This can lead to a cumulative overdose. A particular example is  barbiturates  which were once commonly used as  hypnotic  (sleep inducing) drugs. Among the current hypnotics,  benzodiazepines , especially  midazolam  might show marked automatism, possibly through their intrinsic  anterograde amnesia  effect. Barbiturates are known to induce  hyperalgesia , i.e. aggravation of pain and for sleeplessness due to pain, if barbiturates are used, more pain and more disorientation would follow leading to drug automation and finally a \"pseudo\"suicide. Such reports dominated the medical literature of 1960s and 1970s; a reason replacing the barbiturates with benzodiazepines when they became available. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_388", "text": "Avacincaptad pegol , sold under the brand name  Izervay , is a medication used for the treatment of  age-related macular degeneration . [ 1 ]  Avacincaptad pegol is a  complement  inhibitor. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_389", "text": "Avacincaptad pegol was approved for medical use in the United States in August 2023. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_390", "text": "Avacincaptad pegol is  indicated  for the treatment of  geographic atrophy  secondary to age-related macular degeneration. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_391", "text": "Avacincaptad pegol is the  international nonproprietary name . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_392", "text": "Average daily quantity  ( ADQ ) is similar to the World Health Organization's  defined daily dose , but is adjusted to reflect how medications are used in  England . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_393", "text": "Azagly-nafarelin , sold under the brand name  Gonazon , is a  gonadotropin-releasing hormone agonist  (GnRH agonist) medication which is used in  veterinary medicine  in  Europe . [ 1 ] [ 2 ]  It is a  GnRH analogue  and a  synthetic   peptide , specifically a  decapeptide . [ 1 ] [ 2 ] [ 3 ]  The medication has been approved in Europe as a solid  silicone -based matrix  implant  for use as a  contraceptive  in animals such as male dogs, cats, and others, but is no longer or was never commercially available. [ 1 ] [ 2 ] [ 4 ] [ 5 ]  The medication has also been used to treat  benign prostatic hyperplasia  in animals. [ 6 ] [ 7 ]  In addition to its use in mammals, azagly-nafarelin has been approved for use in  aquaculture   fish , specifically to control  ovulation  in  salmonids , and was the first GnRH agonist to be available for use in fish. [ 2 ] [ 8 ]  It was introduced for use by 2005. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_394", "text": "An  azasteroid  is a type of  steroid   derivative  which has one of the  carbon  atoms in the steroid ring system replaced by a  nitrogen  atom. Two azasteroids,  finasteride  and  dutasteride , are used clinically as  5\u03b1-reductase inhibitors . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_395", "text": "Some of the 6-azasteroids may prove to be useful drugs, but have yet to reach the pharmaceutical market. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_396", "text": "AZD2693  is an  antisense therapy  developed by  AstraZeneca  for the treatment of  non-alcoholic fatty liver disease  based on the  PNPLA3  gene, believed to be the largest single genetic risk factor for this condition. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_397", "text": "AZD 9272  is a drug which acts as a selective  antagonist  for the  metabotropic glutamate receptor  subtype  mGluR5 . [ 1 ]  It was unsuccessful in human trials as an analgesic, [ 2 ]  but continues to be widely used in research especially as its  radiolabelled  forms. [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_398", "text": "Azemiglitazone  ( MSDC-0602 ) is a novel  insulin sensitizer  designed to retain the effect of  thiazolidinediones  on  mitochondrial pyruvate carriers  with limited  PPAR-gamma  binding. It is hoped to have fewer adverse effects than the thiazolidinediones and is being developed by Cirius Therapeutics for  type 2 diabetes  and  non-alcoholic fatty liver disease . [ 1 ] [ 2 ] [ 3 ]   It is formulated as its  potassium   salt , azemiglitazone potassium (MSDC-0602K). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_399", "text": "Azficel-T , sold under the brand name  Laviv , is a  cell therapy  product for the improvement of the appearance of moderate to severe  nasolabial fold  wrinkles in adults. [ 1 ] [ 2 ] [ 3 ]  It consists of  fibroblasts  harvested from the patient's own skin. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_400", "text": "It was approved for medical use in the United States in June 2011. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_401", "text": "This  medical treatment \u2013related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_402", "text": "Azumolene  is an experimental drug which is a derivative of  dantrolene . In animal studies, azumolene showed similar efficacy to dantrolene at controlling symptoms of  malignant hyperthermia  but with better water solubility and lower toxicity, albeit with lower potency. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_403", "text": "Baccatin III  is an isolate from the yew tree (Genera  Taxus ).  Baccatin III is a precursor to the anti- cancer  drug  paclitaxel  (Taxol)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_404", "text": "In 2014, researchers reported introduction and expression of the endophytic fungal gene responsible for synthesizing baccatin III ( 10-deacetylbaccatin III 10-O-acetyltransferase ), to the mushroom  Flammulina velutipes . [ 1 ]  Researchers achieved the same accomplishment with   Escherichia coli  in 2000. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_405", "text": "This article about an  ester  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_406", "text": "Batoclimab  (also known as HBM9161 or HL161) is a fully human  monoclonal antibody  administered by subcutaneous injection. It works by inhibiting the  neonatal fragment crystallizable receptor , which leads to a reduction in antibodies of the  thyrotropin receptor . It is being developed to treat  myasthenia gravis  and  thyroid eye disease . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_407", "text": "Baxdrostat  is an  investigational drug  that is being evaluated for the treatment of  hypertension . [ 1 ]   It is an  aldosterone synthase  inhibitor. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_408", "text": "BC-LI-0186  is a compound that acts as an  inhibitor  of the  GTPase   enzyme   leucyl-tRNA synthetase  (LRS). This enzyme acts as part of the  mTOR  complex and acts as a  leucine  sensor which stimulates  mTORC1  in the presence of leucine. BC-LI-0186 blocks the docking site for mTORC1 and thereby prevents the mTOR activation and increased protein synthesis which is usually triggered by  branched-chain amino acids  such as leucine, yet without inhibiting the separate catalytic activity of LRS. [ 1 ]  This may have potential applications in the treatment of  cancer , [ 2 ]  and BC-LI-0186 has also been shown to promote muscle regeneration after injury. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_409", "text": "Belapectin  (also known as GR-MD-02) is a  galectin-3  inhibitor developed by  Galectin Therapeutics  that failed phase 3  clinical trials  for the treatment of  non-alcoholic steatohepatitis . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_410", "text": "Belnacasan  ( VX-765 ) is a drug developed by  Vertex Pharmaceuticals  which acts as a potent and selective inhibitor of the enzyme  caspase 1 . This enzyme is involved in  inflammation  and cell death, and consequently blocking its action may be useful for various medical applications, including treatment of  epilepsy ,  arthritis , aiding recovery from  heart attack  and slowing the progression of  Alzheimer's disease . Belnacasan is an orally active  prodrug , being converted in the body to the active drug VRT-043198 ( O -desethyl-belnacasan). However while belnacasan has proved well tolerated in human  clinical trials , it has not shown sufficient efficacy to be approved for use for any of the applications suggested to date, though research continues into possible future uses of this or similar drugs. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_411", "text": "Bexirestrant  is a  selective estrogen receptor degrader  (SERD) which is being evaluated for the treatment of  breast cancer . This orally bioavailable compound has demonstrated potent activity against both wild-type and mutant forms of the estrogen receptor (ER), addressing a critical need in overcoming resistance to current endocrine therapies. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_412", "text": "It is structurally characterized by an E- alkene  linked to an  azetidine  core."}
{"_id": "WikiPedia_Pharmacology$$$corpus_413", "text": "Bezuclastinib  is an  investigational new drug  that is being evaluated for the treatment of solid tumors and  systemic mastocytosis . [ 1 ] [ 2 ]  It acts as an inhibitor of  KIT  (a specific type of  receptor tyrosine kinase ). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_414", "text": "Bimokalner  is an  investigational new drug  under evaluation for preventing and treating  hearing loss  caused by  cisplatin  treatment. It is a  voltage-gated potassium channel  agonist targeting  Kv7.4  and is being developed by Acousia Therapeutics GmbH. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_415", "text": "In  medicinal chemistry  and  pharmacology , a  binding coefficient  is a quantity representing the extent to which a  chemical compound  will  bind  to a  macromolecule . [ 1 ] [ 2 ]  The preferential binding coefficient can be derived from the  Kirkwood-Buff solution theory  of solutions. Preferential binding is defined as a thermodynamic expression that describes the binding of the cosolvent over the solvent. This is in a system that is open to both the solvent and cosolvent.  [ 3 ]  Consequently, preferential interaction coefficients are measures of interactions that involve \u201csolutes that participate in a reaction in solution.\u201d  [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_416", "text": "This article about  medicinal chemistry  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_417", "text": "In  pharmacology ,  biological activity  or  pharmacological activity  describes the beneficial or adverse effects of a  drug  on  living matter . [ 1 ] [ 2 ]  When a drug is a complex chemical mixture, this activity is exerted by the substance's  active ingredient  or  pharmacophore  but can be modified by the other constituents. Among the various properties of chemical compounds, pharmacological/biological activity plays a crucial role since it suggests uses of the compounds in the medical applications. However, chemical compounds may show some adverse and toxic effects which may prevent their use in medical practice."}
{"_id": "WikiPedia_Pharmacology$$$corpus_418", "text": "Biological activity is usually measured by a  bioassay  and the activity is generally  dosage -dependent, which is investigated via  dose-response curves .  Further, it is common to have effects ranging from beneficial to adverse for one substance when going from low to high doses. Activity depends critically on fulfillment of the  ADME  criteria. To be an effective drug, a compound not only must be active against a target, but also possess the appropriate ADME (Absorption, Distribution, Metabolism, and Excretion) properties necessary to make it suitable for use as a drug. [ 3 ]  Because of the costs of the measurement, biological activities are often predicted with computational methods, so-called  QSAR  models."}
{"_id": "WikiPedia_Pharmacology$$$corpus_419", "text": "Bioactivity is a key property that promotes osseointegration for bonding and better stability of dental implants. [ 4 ]   Bioglass  coatings represent high surface area and reactivity leading to an effective interaction of the coating material and surrounding bone tissues. In the biological environment, the formation of a layer of  carbonated hydroxyapatite  (CHA) initiates bonding to the bone tissues. The bioglass surface coating undergoes  leaching / exchange of ions , dissolution of glass, and formation of the HA layer that promotes cellular response of tissues. [ 5 ]  The high specific surface area of bioactive glasses is likely to induce quicker solubility of the material, availability of ions in the surrounding area, and enhanced protein adsorption ability. These factors altogether contribute toward the bioactivity of bioglass coatings. In addition, tissue mineralization (bone, teeth) is promoted while tissue forming cells are in direct contact with bioglass materials."}
{"_id": "WikiPedia_Pharmacology$$$corpus_420", "text": "Whereas a material is considered bioactive if it has interaction with or effect on any  cell tissue  in the  human body , pharmacological activity is usually taken to describe beneficial effects, i.e. the effects of  drug candidates  as well as a substance's  toxicity ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_421", "text": "In the study of  biomineralisation , bioactivity is often meant to mean the formation of  calcium phosphate  deposits on the surface of objects placed in  simulated body fluid , a  buffer solution  with ion content similar to  blood ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_422", "text": "The  Board of Pharmacy Specialties  ( BPS ) was established in 1976 and is an independent division of the  American Pharmacists Association  that grants recognition within the United States [ 1 ]  to appropriate  pharmacy  practice specialities and establishes standards for certification of  pharmacists  in 14 specialities. [ 2 ]  The specialty examinations are accredited by National Commission for Certifying Agencies (NCCA), the accreditation body of  Institute for Credentialing Excellence  (ICE)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_423", "text": "The Executive Director of the BPS is William M. Ellis. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_424", "text": "The BPS recognizes 14 specialties: [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_425", "text": "A  bone seeker  is an  element , often a  radioisotope , that tends to  accumulate  in the  bones  of humans and other animals when introduced into the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_426", "text": "For example,  strontium  and  radium  are chemically similar to  calcium  and can replace the calcium in bones. [ 1 ] [ 2 ]   Plutonium  is also a bone seeker, though the mechanism by which it accumulates in bone tissue is unknown. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_427", "text": "Radioactive  bone seekers are  particular health risks  as they irradiate surrounding tissue, though this can be useful for  radiotherapy , such as in the case of  radium-223 . [ 2 ] [ 4 ]  Stable bone seekers can also be harmful: excessive strontium absorption has been linked with increased levels of  rickets . [ 5 ] [ 6 ]  The salt  strontium ranelate , however, is a bone seeker which is sometimes used to strengthen bones as a treatment for  osteoporosis . [ 7 ]  Bone seekers have been proposed as a method of delivering  antibiotics  to infected bone tissue. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_428", "text": "This  isotope -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_429", "text": "Alexander A. Borb\u00e9ly  (born 1939 in  Budapest ) is a Hungarian-Swiss  pharmacologist  known for his  sleep  research."}
{"_id": "WikiPedia_Pharmacology$$$corpus_430", "text": "Borb\u00e9ly proposed the two-process model of  sleep regulation  in 1982 which postulates there are two complementary processes (S and C, which stands for Sleep and Circadian, respectively) which together account for one's sleep schedule. [ 1 ]  This model has been widely influential and strongly influenced the field of circadian  neuroscience  for decades. [ 2 ] [ non-primary source needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_431", "text": "This article about a Hungarian scientist is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_432", "text": "This article about a Swiss scientist is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_433", "text": "Bortezomib/dexamethasone  is a  combination drug  against  multiple myeloma . [ 1 ]  When bortezomib is used by the  trade name  Velcade, the combination is called  Vel/Dex  (or  Vel-Dex  or  Veldex ).  Bortezomib  is a  proteasome inhibitor  and  dexamethasone  is a  corticosteroid ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_434", "text": "Boserolimab  \t(MK-5890) is a  monoclonal antibody  in development for  lung cancer . It is developed by  Merck . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_435", "text": "BPI-16350  is a small molecule  CDK4/6 inhibitor  that is being studied for the treatment of cancer. [ 1 ] [ 2 ]  It has a similar structure to  abemaciclib  but is more selective for CDK4/6 over CDK9 according to preclinical research. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_436", "text": "Brainshuttle  or  brain shuttle  is a technology developed by  Roche  to help molecules such as  monoclonal antibodies  to cross the  blood-brain barrier  more than they would otherwise. It has been tested with anti-amyloid monoclonal antibodies such as  trontinemab . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_437", "text": "Brensocatib  is an  investigational new drug  that is being evaluated to treat  bronchiectasis . [ 1 ]  It is a  dipeptidyl-peptidase I  (also known as  cathepsin C ) inhibitor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_438", "text": "Brepocitinib  ( PF-06700841 ) is a drug which acts as a dual  inhibitor  of  JAK1  and  TYK2 , and was developed for the treatment of  plaque psoriasis . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_439", "text": "Brimarafenib  is an  investigational new drug  that is being evaluated for the treatment of cancer.  It targets the proto-oncogene  BRAF  with activating mutations BRAF mutations (such as  V600E ), non-V600 BRAF mutations, and RAF fusions. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_440", "text": "It is being developed by MapKure, LLC, a joint venture between SpringWorks Therapeutics and  BeiGene . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_441", "text": "The  British Society for the History of Pharmacy (BSHP)  is an organisation in the United Kingdom devoted to the  history of pharmacy . [ 1 ]  It was established in 1967, [ 2 ]  although its roots date to 1952, when the Council of the  Pharmaceutical  Society established a history of pharmacy committee. The society has published a  journal ,  Pharmaceutical Historian , from the beginning. Since 2017 [ 3 ]  it has been issued by BSHP on behalf of the International Society for the History of Pharmacy. [ 4 ]  From its foundation, BSHP has been keen to encourage the study of pharmacy history amongst students. This advocacy role has included providing lecturers for history courses at Schools of Pharmacy. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_442", "text": "The organisation is affiliated with the  International Society for the History of Pharmacy  and the  British Society for the History of Medicine . Its president is Chris Duffin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_443", "text": "This article about an organisation in the  United Kingdom  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_444", "text": "This article about a  history -related organization is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_445", "text": "BRL-37344  is a drug which acts as a selective  agonist  of the  \u03b2 3  adrenergic   receptor , [ 1 ]  which has been investigated for various  biomedical research  applications but never developed for clinical use. [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_446", "text": "Bromo-Seltzer  is a brand of  antacid  formulated to  relieve pain  occurring together with  heartburn ,  upset stomach , or  acid indigestion . It originally contained  sodium bromide  and  acetanilide , both toxic substances which were eventually removed. Its current formulation contains the pain reliever  aspirin  and two reactive chemicals\u00a0\u2013  sodium bicarbonate  and  citric acid \u00a0\u2013 which creates effervescence when mixed with water. Sodium bicarbonate is an antacid."}
{"_id": "WikiPedia_Pharmacology$$$corpus_447", "text": "Bromo-Seltzer was invented in 1888 by  Isaac E. Emerson  and produced by the Emerson Drug Company of  Baltimore, Maryland . It was sold in the United States in the form of  effervescent  granules that were mixed with water before  ingestion . [ 1 ]  The product took its name from a component of the original formula,  sodium bromide ; each dose contained 3.2  mEq /teaspoon of it.  Bromides  are a class of tranquilizers that were withdrawn from the U.S. market in 1975 due to their toxicity. Their  sedative  effect probably accounted for Bromo-Seltzer's popularity as a  hangover remedy . Early formulas also used  acetanilide  as the  analgesic  ingredient; it is now known to be toxic. [ 2 ]  Acetanilide was replaced with its metabolite  acetaminophen , and its current formulation uses  aspirin ,  sodium bicarbonate , and  citric acid , the latter two of which provide the  carbonation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_448", "text": "Bromo-Seltzer's main offices and factory were located in downtown Baltimore, Maryland, at the corner of West Lombard and South Eutaw streets. [ 3 ]  The factory's most notable feature was the  Emerson Bromo-Seltzer Tower , built in 1911, whose four clock faces are ringed by letters spelling out the product name. The tower was patterned on the  Palazzo Vecchio  in  Florence, Italy , and is listed on the  National Register of Historic Places . The tower originally held a 51-foot (16m) representation of a Bromo-Seltzer bottle at its top, glowing blue and rotating on a vertical axis. The sign weighed 20 tons (18.1 tonnes), included 314 incandescent light bulbs, and was topped with a crown. The sign was removed in 1936 because of structural concerns. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_449", "text": "Emerson, who traveled widely, said the fizz reminded him of the bubbling action of  Mount Bromo , a volcano in Java. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_450", "text": "Bromo-Seltzer is mentioned in several films and TV shows, including  The Crooked Circle  (1932),  Bed of Roses  (1933),  Topper  (1937),  Wonder Man  (1945),  Somewhere in the Night  (1946),   The Postman Always Rings Twice  (1981),  The Hudsucker Proxy  (1994), [ 5 ]  the 1998  The Simpsons  episode \" Bart Carny \", and in  Golden Girls  (Season 4, Episode 1)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_451", "text": "It is mentioned in  John Steinbeck 's 1939 novel  The Grapes of Wrath ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_452", "text": "Drugstore Bromo-Seltzer dispensers are mentioned in  Georges Simenon 's 1949 detective novel  Maigret chez le coroner  that takes place in Arizona."}
{"_id": "WikiPedia_Pharmacology$$$corpus_453", "text": "It was a sponsor of the old time radio program, \u201cThe Inner Sanctum\u201d."}
{"_id": "WikiPedia_Pharmacology$$$corpus_454", "text": "It is mentioned in several songs, including \" Bewitched, Bothered and Bewildered \" by  Rodgers and Hart , \" Adelaide's Lament \" in the musical  Guys and Dolls , and \" Pachuco Cadaver \" by  Captain Beefheart and his Magic Band . In  Spike Jones ' version of   Laura , the chorus chants \"Bromo-Seltzer, Bromo-Seltzer...\" to evoke the sound of a chugging train."}
{"_id": "WikiPedia_Pharmacology$$$corpus_455", "text": "Brydioside  is any one of several  chemical compounds  isolated from certain plants, notably  Bryonia dioica .  They can be seen as derivatives of the  triterpene   hydrocarbon   cucurbitane  ( C 30 H 54 ), more specifically from  cucurbitacin L  (23,24-dihydrocucurbitacin I). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_456", "text": "They include"}
{"_id": "WikiPedia_Pharmacology$$$corpus_457", "text": "BU08028  is a drug which acts as an extremely potent  partial agonist  at both the  \u03bc-opioid receptor  and  nociceptin receptor . It is a  homologue  of  buprenorphine  extended by just one carbon on the side chain, but has relatively greater activity at the nociceptin receptor, which is thought to reduce the abuse potential without compromising analgesia. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_458", "text": "Buloxibutid  is an  investigational new drug  that is being evaluated to treat  COVID-19  infections. [ 1 ]  It is an  angiotensin II receptor type 2  agonist. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_459", "text": "Butaxamine  ( INN ; also known as  butoxamine ) is a  \u03b2 2 -selective   beta blocker . [ 1 ] [ 2 ]  Its primary use is in experimental situations in which blockade of  \u03b2 2  receptors  is necessary to determine the  activity  of the drug (i.e. if the \u03b2 2  receptor is completely blocked, but the given effect is still present, the given effect is not a characteristic of the \u03b2 2  receptor). It has no clinical use. An alternative name is \u03b1-(1-[ tert -butylamino]ethyl)-2,5-dimethoxybenzyl alcohol."}
{"_id": "WikiPedia_Pharmacology$$$corpus_460", "text": "BW-501C67  is a  peripherally selective   serotonin   5-HT 2A  and  5-HT 2C  receptor   antagonist  which is used in  scientific research . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]  It shows  selectivity  for the serotonin  5-HT 2  receptors  over the  \u03b1 1 -adrenergic receptor . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_461", "text": "The drug antagonizes peripheral but not  central  effects of  serotonin receptor agonists  like serotonin. [ 2 ] [ 3 ] [ 7 ] [ 6 ]  As examples, it has been found to antagonize the  sympathomimetic  effects of serotonin in animals, including  vasoconstriction  and  pressor  effects, but does not block centrally mediated effects like increased  corticosterone   secretion  or  myoclonus . [ 3 ] [ 7 ] [ 8 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_462", "text": "BW-501C67 and  analogues  were  patented  for use in  combination  with serotonin 5-HT 2A  receptor  agonists  like  serotonergic psychedelics  in 2023. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_463", "text": "BW284C51  is a selective  acetylcholinesterase inhibitor . [ 1 ]  It is also a  nicotinic antagonist . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_464", "text": "Bytox Hangover Patch  is a medication used to reduce effects of  hangover . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_465", "text": "Bytox Hangover Patch was first introduced in  New York  2011 by Alex Fleyshmakher and Leonard Grossman. [ 3 ] [ 4 ]  Bytox word is a portmanteau of \"bye\" and \"toxins\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_466", "text": "In 2012, Bytox was banned in the  United Kingdom  by the  Medicines and Healthcare products Regulatory Agency  due to no license. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_467", "text": "Bytox works in the same way as  scopolamine  does. [ 1 ]  It is made using  acai berries  and extract of  green tea . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_468", "text": "CA77.1  ( CA ) is a synthetic compound that activates  chaperone-mediated autophagy  (CMA) by increasing the expression of the lysosomal receptor for this pathway,   LAMP2A , in  lysosomes . CA77.1 is a derivative of earlier compound AR7(HY-101106), which shows potent CMA activation  in vitro  but is not suitable for  in vivo  use. [ 1 ] [ 2 ] [ 3 ]  CA77.1 is able to activate CMA  in vivo , and demonstrates brain penetrance and favorable pharmacokinetics.  It has been shown in animal studies that  in vivo  administration of CA77.1 to enhance  chaperone-mediated autophagy ,  may help to degrade toxic pathogenic protein products  such as  tau proteins  and has potential applications in the treatment of  Alzheimer's disease [ 4 ] [ 5 ]  particularly in improving both behavior and neuropathology in PS19 mice models."}
{"_id": "WikiPedia_Pharmacology$$$corpus_469", "text": "Cadonilimab  is a  PD-1 / CTLA-4  bispecific  monoclonal antibody [ 1 ] [ 2 ]  developed to treat a variety of solid cancer types. In June, 2022 it was approved in China \"for use in patients with relapsed or metastatic  cervical cancer  (r/mCC) who have progressed on or after  platinum-based chemotherapy \". [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_470", "text": "Cagrilintide  is a long-acting analogue of  amylin . It is being tested to treat  obesity  and  type 2 diabetes  by itself and in combination with  semaglutide  as  cagrilintide/semaglutide . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_471", "text": "A systematic review and metanalysis of cagrisema, published in 2024, found that cagrisema may provide weight loss benefits. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_472", "text": "Cagrilintide/semaglutide , marketed as  CagriSema , is a combination of  cagrilintide , a  dual amylin and calcitonin receptor agonist , and  semaglutide , a  GLP-1 agonist . It is injected once weekly and is being tested in  type 2 diabetes  and  obesity . Preliminary trial results found a greater weight loss compared to either medication alone.  HbA1c  was significantly improved compared to cagrilintide alone and non-significantly better than semaglutide alone. [ 1 ] [ 2 ]  In a Phase II trial, weight loss averaged -15.6 percent after 32 weeks, making CagriSema comparable in efficacy to  tirzepatide . [ 3 ] [ 4 ]  A future trial sponsored by Novo Nordisk is comparing tirzepatide and CagriSema head-to-head. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_473", "text": "CagriSema entered  Phase III clinical trials  in 2023. [ 6 ]  In December 2024, Novo Nordisk announced the results of REDEFINE 1, one of their series of Phase III trials, testing weekly cagrilintide 2.4 mg and semaglutide 2.4 mg individually and together versus placebo in obese or overweight subjects with one or more comorbidities. [ 7 ]  In the  intention-to-treat analysis , people treated with CagriSema lost 20.4% of their body weight over 68 weeks, versus 11.5% with cagrilintide 2.4 mg alone, 14.9% with semaglutide 2.4 mg alone, and 3.0% with placebo. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_474", "text": "A  calcium channel opener  is a type of  drug  which facilitates  ion  transmission through  calcium channels ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_475", "text": "An example is  Bay K8644 , which is an  analogue  of  nifedipine  that specifically and directly activates  L-type   voltage-dependent calcium channels . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_476", "text": "In contrast to Bay K8644, which is not for clinical use,  ambroxol  is a frequently used mucolytic drug that triggers lysosomal secretion by mobilizing calcium from acidic calcium stores. [ 2 ]  This effect does most likely not occur by a direct interaction between the drug and a lysosomal calcium channel, but indirectly by neutralizing the acidic pH within lysosomes. Calcium permeable ion channels in lysosomal membranes that may be activated by a luminal pH increase include two pore channels (TPCs), mucolipin TRP channels (TRPMLs) and purinergic receptors of the P2X channel type. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_477", "text": "Calculus bovis , [ 1 ]   niu-huang  ( \u725b\u9ec3 ) or  cattle gallstones  are dried  gallstones  of  cattle  used in  Chinese herbology . In  China  and  Japan  it has been long used to treat various diseases, including  high fever ,  convulsion  and  stroke . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_478", "text": "In Asian countries, calculus bovis are sometimes harvested when  steers  ( Bos taurus domesticus ) are slaughtered. Their  gall bladders  are taken out, the  bile  is filtered, and the stones are cleaned and dried. The bezoars may also be surgically removed by  veterinarians  when working cattle become ill. In Western countries, they are usually discarded. Its equivalent in  Hindu  culture is  Gorochana ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_479", "text": "Calculus bovis have a color varying from golden yellow to brownish yellow.  The shape of a stone is variable and depends on how it was formed, becoming spherical, oval, triangular, tubular, or irregular."}
{"_id": "WikiPedia_Pharmacology$$$corpus_480", "text": "Since natural calculus bovis are scarce, they can be very expensive.  There are artificial calculus bovis or  bovis calculus artifactus  used as substitutes. In China, these are manufactured from  cholic acid  derived from bovine bile [ 3 ]  combined with dry bovine  bile  powder,  porcine   ursodeoxycholic acid ,  taurine ,  bilirubin ,  cholesterol , etc. [ 4 ]  Chinese regulations forbid the use of artificial calculus bovis in 42 drugs. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_481", "text": "Calculus bovis can cultivated (induced)  in vivo  by implanting a foreign object and microbials into bovine biles. [ 6 ] :\u200a478\u200a  It can also be cultivated (precipitated)  in vitro  from bovine bile by adding  ursodeoxycholic acid ,  cholic acid , and calcium bilirubinate, producing  calculus bovis sativus . [ 7 ] [ 8 ]  Unlike artificial calculus bovis, either type of cultivated calculus bovis can fully replace calculus bovis under Chinese regulations. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_482", "text": "Calmurid  was the name of a skin cream manufactured by Galderma (now discontinued due to safety reasons). Calmurid Cream contained the active ingredients  lactic acid  and  urea , [ 1 ]  whereas  Calmurid HC  contained an additional ingredient, the mild  corticosteroid   hydrocortisone ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_483", "text": "Owing to lactic acid's  keratolytic  properties (to break down hard skin cells) and urea's hydrating properties, Calmurid was used primarily in the treatment of dry, scaly skin.  Ichthyosis  and general  dermatitis  in the absence of  inflammation  are some of its indications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_484", "text": "When the extra steroid component is added (as in Calmurid HC), it was used to treat dry, scaly skin that is accompanied by inflammation of the skin. This may include various forms of  eczema . The presence of a corticosteroid, however, means that the cream needed to be used sparingly and only for the shortest time period due to possible side effects that could occur due to systemic absorption of the steroid."}
{"_id": "WikiPedia_Pharmacology$$$corpus_485", "text": "Composition: Urea 100\u00a0mg/g and lactic acid 50\u00a0mg/g in an emulsified base containing betaine monohydrate,  glyceryl monostearate , diethanolamine cetylphosphate complex, hard fat, cholesterol, sodium chloride, purified water."}
{"_id": "WikiPedia_Pharmacology$$$corpus_486", "text": "Camibirstat  is an  investigational new drug  that is being evaluated for the treatment of cancer.  It is a small molecule that acts as a selective inhibitor of  SMARCA2  and  SMARCA4 , which are key components of the  SWI/SNF  chromatin remodeling complex. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_487", "text": "It is being developed by Foghorn Therapeutics. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_488", "text": "Camizestrant  is an  investigational new drug  that is being evaluated to treat  breast cancer . [ 1 ]  It is an  estrogen receptor alpha  antagonist and a  selective estrogen receptor degrader  (SERD). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_489", "text": "Camlipixant  is an  investigational new drug  that is being evaluated for the treatment of chronic  cough . [ 1 ]  It is a  P2X3 receptor  antagonist. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_490", "text": "Camonsertib  is an  investigational new drug  that is being evaluated for the treatment of cancer.  It is a selective oral small molecule inhibitor of ATR ( Ataxia telangiectasia and Rad3 related ), developed by Repare Therapeutics. This drug targets tumors with specific genetic alterations that create vulnerabilities in  DNA damage response  (DDR) pathways, particularly those with  ATM  or  BRCA1 / BRCA2  mutations. [ 1 ]  It is currently in Phase 2 clinical trials both as a monotherapy and in combination with other agents, including  PARP inhibitors ,  gemcitabine , and  lunresertib . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_491", "text": "The  Canadian Society of Hospital Pharmacists  (CSHP) is a  professional organization  representing the interests of  pharmacists  who practice in hospitals and related healthcare settings. [ 1 ] [ 2 ]  It publishes the  Canadian Journal of Hospital Pharmacy . The CSHP has more than 3,000  hospital pharmacists  as members."}
{"_id": "WikiPedia_Pharmacology$$$corpus_492", "text": "Cantharidic acid  is a selective  inhibitor  of PP2A ( protein phosphatase 2 ) and PP1 ( protein phosphatase 1 ). [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_493", "text": "It is the  hydrolysis  product of  cantharidin ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_494", "text": "9-Carboxymethoxymethylguanine  ( CMMG ) is a compound which is known as the principal  metabolite  of the antiviral medication  aciclovir  (and its  prodrug   valaciclovir ), and has been suggested as the causative agent in the neuropsychiatric side effects sometimes associated with these medications. These are mainly suffered by patients with  kidney failure  or otherwise decreased kidney function, and can include psychotic reactions, hallucinations, and rarely more complex disorders such as  Cotard delusion . Patients suffering these symptoms following aciclovir treatment were found to have much higher levels of CMMG than normal, and since this is the first time Cotard delusion has been linked to a drug as a side effect, this discovery may be useful in the study of Cotard delusion and its treatment. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_495", "text": "Cardanolide  is a  steroid  with a  molecular weight  of 344.54 g/mol."}
{"_id": "WikiPedia_Pharmacology$$$corpus_496", "text": "Carmantadine  ( INN Tooltip International Nonproprietary Name ,  USAN Tooltip United States Adopted Name ; developmental code name  SCH-15427 ) is an  antiparkinsonian agent  of the  adamantane  group that was never marketed. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It is  structurally related  to  amantadine  and shares some of its  pharmacological  actions. [ 2 ]  Another related drug is  dopamantine . [ 2 ] [ 3 ] [ 4 ]  Carmantadine was first described by 1972 and is said to have reached early  clinical trials . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_497", "text": "The  Carr index  ( Carr's index [ 1 ]  or  Carr's Compressibility Index [ 2 ] ) is an indicator of the  compressibility  of a  powder . It is named after the scientist Ralph J. Carr, Jr."}
{"_id": "WikiPedia_Pharmacology$$$corpus_498", "text": "The Carr index is calculated by the  formula   \n \n \n \n C \n = \n 100 \n \n \n \n \n \u03c1 \n \n T \n \n \n \u2212 \n \n \u03c1 \n \n B \n \n \n \n \n \u03c1 \n \n T \n \n \n \n \n \n \n {\\displaystyle C=100{\\frac {\\rho _{T}-\\rho _{B}}{\\rho _{T}}}} \n \n , where  \n \n \n \n \n \u03c1 \n \n B \n \n \n \n \n {\\displaystyle \\rho _{B}} \n \n  is the freely settled  bulk density  of the powder, and  \n \n \n \n \n \u03c1 \n \n T \n \n \n \n \n {\\displaystyle \\rho _{T}} \n \n  is the tapped bulk density of the powder after \"tapping down\".  It can also be expressed as  \n \n \n \n C \n = \n 100 \n ( \n 1 \n \u2212 \n \n \u03c1 \n \n B \n \n \n \n / \n \n \n \u03c1 \n \n T \n \n \n ) \n \n \n {\\displaystyle C=100(1-\\rho _{B}/\\rho _{T})} \n \n ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_499", "text": "The Carr index is frequently used in  pharmaceutics  as an indication of the compressibility  of a powder.  In a free-flowing powder, the bulk density and tapped density would be close in value, therefore, the Carr index would be small. On the other hand, in a poor-flowing powder where there are greater interparticle interactions, the difference between the bulk and tapped density observed would be greater, therefore, the Carr index would be larger. [ 3 ]  A Carr index greater than 25 is considered to be an indication of poor flowability, and below 15, of good flowability. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_500", "text": "Another way to measure the flow of a powder is the  Hausner ratio , which can be expressed as  \n \n \n \n H \n = \n \n \u03c1 \n \n T \n \n \n \n / \n \n \n \u03c1 \n \n B \n \n \n \n \n {\\displaystyle H=\\rho _{T}/\\rho _{B}} \n \n ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_501", "text": "Both the Hausner ratio and the Carr index are sometimes criticized, despite their relationships to flowability being established  empirically , as not having a strong theoretical basis. Use of these measures persists, however, because the equipment required to perform the analysis is relatively cheap and the technique is easy to learn."}
{"_id": "WikiPedia_Pharmacology$$$corpus_502", "text": "Mark Gibson (2001).  Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form . Boca Raton: CRC Press.  ISBN \u00a0 1-57491-120-1 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_503", "text": "Robert H. Carter III  (January 12, 1847 - January 13, 1908) was an American pharmacist. He was the first African American certified pharmacist from  Massachusetts . \nBy 1871, Carter worked for druggist and chemist William P. S. Caldwell on 49 Purchase Street. [ 1 ]  He married hairdresser Parthenia M. Harris on July 8, 1869. They had six children. Between 1876 and 1907, he owned and managed pharmacies in  Boston  and  New Bedford, Massachusetts . On January 5, 1896, he was certified as a registered pharmacist. [ 1 ]  He worked as a pharmacist for 37 years. [ 1 ]  He was a member of the  National Negro Business League . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_504", "text": "He died January 13, 1908, in  Brighton, Boston  of tuberculosis. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_505", "text": "This  African American\u2013related  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_506", "text": "C avg  is the average concentration of a drug in the  central circulation  during a dosing interval in  steady state . It is calculated by"}
{"_id": "WikiPedia_Pharmacology$$$corpus_507", "text": "where  \n \n \n \n A \n U \n \n C \n \n \u03c4 \n , \n \n ss \n \n \n \n \n \n {\\displaystyle AUC_{\\tau ,{\\text{ss}}}} \n \n  is the  area under the curve  and  \n \n \n \n \u03c4 \n \n \n {\\displaystyle \\tau } \n \n  the dosing interval."}
{"_id": "WikiPedia_Pharmacology$$$corpus_508", "text": "CCG-4986  is a drug which is the first non-peptide compound discovered that acts as a selective inhibitor of the  regulator of G protein signalling  protein subtype  RGS4 . [ 1 ] [ 2 ]  Regulators of G protein signalling are proteins which act to limit and shorten the response produced inside a cell following activation of a  G protein-coupled receptor . Since different RGS subtypes are expressed in different tissues and are associated with particular receptors, this makes it possible for selective inhibitors of RGS proteins to be developed, which should be able to enhance the activity of a particular receptor in a defined target tissue, but not elsewhere in the body. [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_509", "text": "CD38-IN-78c  is a drug which acts as a potent and selective  inhibitor  of the  glycoprotein  enzyme  CD38 . [ 1 ]  In animal studies it boosts levels of  nicotinamide adenine dinucleotide  (NAD+) in tissues via inhibition of CD38 mediated breakdown of  nicotinamide riboside  (NR) and  nicotinamide mononucleotide  (NMN), and has been shown to ameliorate metabolic dysfunction associated with the aging process. [ 2 ]  It also has potential therapeutic application in the treatment of  asthma . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_510", "text": "CDD-2807  is a chemical compound which acts as a potent and selective inhibitor of  serine/threonine-protein kinase  33 ( STK33 ), with a IC 50  of 9.2 nM. In animal studies it causes production of abnormal sperm with reduced motility, and it has been investigated as a potential  male contraceptive  drug. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_511", "text": "Cefepime/enmetazobactam , sold under the brand name  Exblifep , is a  medication  used for the treatment of  urinary tract infections . [ 1 ] [ 2 ]  It is a  fixed dose combination  containing  cefepime , a  cephalosporin  antibacterial; and  enmetazobactam , a  beta-lactamase inhibitor . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_512", "text": "The combination was approved for medical use in the United States in February 2024, [ 1 ] [ 4 ]  and in the European Union in March 2024. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_513", "text": "In the US, cefepime/enmetazobactam is  indicated  for the treatment of people with complicated urinary tract infections including  pyelonephritis , caused by the following susceptible microorganisms:  Escherichia coli ,  Klebsiella pneumoniae ,  Pseudomonas aeruginosa ,  Proteus mirabilis , and  Enterobacter cloacae  complex. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_514", "text": "In the EU, cefepime/enmetazobactam is indicated for the treatment of complicated urinary tract infections, including pyelonephritis; [ 2 ]   hospital-acquired pneumonia , including  ventilator-associated pneumonia ; [ 2 ]  and the treatment of people with  bacteremia  that occurs in association with, or is suspected to be associated with, any of the infections listed above. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_515", "text": "Enmetazobactam was invented by Orchid Pharma in India and then out-licensed to Allecra Therapeutics for further development. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_516", "text": "The combination was approved for medical use in the United States in February 2024. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_517", "text": "In January 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Exblifep, intended for the treatment of urinary tract infections and pneumonia in adults. [ 2 ]  The applicant for this medicinal product is Advanz Pharma Limited. [ 2 ]  The combination was approved for medical use in the European Union in March 2024. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_518", "text": "The combination cefepime/enmetazobactam is sold under the brand name Exblifep. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_519", "text": "Cendakimab  (RPC4046; ABT 308; CC-93538) is a  monoclonal antibody  against  interleukin 13 . It is developed by  Bristol Myers Squibb [ 1 ]  for  eosinophilic esophagitis . [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_520", "text": "Cenerimod  is an  investigational new drug  that is being evaluated for the treatment of  systemic lupus erythematosus . [ 1 ]   It is a  sphingosine-1-phosphate receptor  modulator. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_521", "text": "The  Center for Pharmaceutical Research and Innovation  ( CPRI ) is a  University of Kentucky -based research center established by the University of Kentucky College of Pharmacy in 2012 to facilitate academic translational research and  drug discovery / drug development . The UK CPRI specializes in  natural product -based drug discovery from microbes found within unique environments including underground and surface  coal mines ,  acid mine drainage  and  mine reclamation  sites, thermal vents associated with underground coal mine fires (see  coal seam fire ) [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ]  and deep-well drilling for  carbon sequestration . CPRI also provides core support for  medicinal chemistry ,  assay  development and screening, rational  drug design ,  computational chemistry , and  ADME T. The Center collaborates with investigators focused on drug discovery or development research in the areas of  cancer , drug and alcohol  addiction ,  cardiovascular disease ,  infectious disease ,  regenerative medicine  and  neurodegenerative disease ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_522", "text": "Central Norway Pharmaceutical Trust  ( Norwegian :  Sykehusapotekene i Midt-Norge HF ) is a  health trust  owned by  Central Norway Regional Health Authority  that operates four hospital  pharmacies  at  St. Olavs Hospital  in  Trondheim ,  Kristiansund Hospital ,  Molde Hospital  and  \u00c5lesund Hospital . The pharmacies are part of the  Ditt Apotek  chain and use  Norsk Medisinaldepot  as  wholesaler . The hospitals in Levanger, Namsos and Orkanger do not use the trust for their pharmacies. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_523", "text": "Ceralasertib  is an  investigational new drug  that is being evaluated for the treatment of cancer. [ 1 ]  It is an  ATR kinase  inhibitor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_524", "text": "Cerdulatinib  is a  small molecule  SYK/ JAK   kinase  inhibitor in development for treatment of  hematological malignancies . [ 1 ]  It has lowest nM  IC50  values against  TYK2 ,  JAK1 ,  JAK2 ,  JAK3 , FMS, and  SYK . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_525", "text": "It is being developed by  Portola Pharmaceuticals ; in September 2018 the  FDA  granted  orphan drug  status to cerdulatinib for the treatment of  peripheral T-cell lymphoma  (PTCL). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_526", "text": "Cetrimide , or  alkyltrimethylammonium bromide , is an  antiseptic  which is a  mixture  of three  quaternary ammonium compounds :  tetradonium bromide  (TTAB or MITMAB),  cetrimonium bromide  (CTAB), and  laurtrimonium bromide  (DTAB or LTAB). [ 1 ]  It was first discovered and developed by  ICI  and introduced under the brand name  Cetavlon . [ 2 ]  It is used as a 1-3\u00a0% solution for cleaning roadside accident wounds. [ 3 ]  ICI also introduced  Savlon , which was a combination of cetrimide and  chlorhexidine . ICI later sold the Savlon brand OTC to  Johnson & Johnson  in May 1992. [ 4 ]  Cetrimide is used in various applications such as antiseptic agents, diagnostic test and analysis, topical formulations, and dental treatment. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_527", "text": "A  channel modulator , or  ion channel modulator , is a type of drug which modulates  ion channels . They include  channel blockers  and  channel openers . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_528", "text": "Ion channels are typically categorised by gating mechanism and by the ion they conduct. Note that an ion channel may overlap between different categories. Some channels conduct multiple ion currents and some are gated by multiple mechanisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_529", "text": "Examples of targets for modulators include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_530", "text": "Voltage-gated ion channels"}
{"_id": "WikiPedia_Pharmacology$$$corpus_531", "text": "Ligand gated ion channels"}
{"_id": "WikiPedia_Pharmacology$$$corpus_532", "text": "Ion channels gated by other mechanisms (e.g. light gated and  mechanosensitive ion channels ). These types of channels can also be pharmacologically modulated. For lists of the substances that pharmacologically modulate them, see their respective articles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_533", "text": "Ion channels can also be modulated indirectly. For example with  G protein coupled receptors  (GPCRs), for  G protein coupled inward rectifier potassium channels  (GIRKs) and M channels. Ion channels can also be modulated by  reuptake inhibitors  and  releasing agents ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_534", "text": "A  channel opener , also known as a  channel activator , is a type of  drug  which facilitates  ion  flow through  ion channels ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_535", "text": "They include the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_536", "text": "Cheng Fong Chemical Co. Ltd  is a Chinese active pharmaceutical ingredient (API) company that exports to the United States of America. [ 1 ]  In September 2016, the US FDA issued a warning letter \"following a five-day inspection in April 2016 that found the company failed to appropriately maintain its facilities and investigate reports of foreign particles in finished batches.\" [ 2 ]  According to the FDA, Cheng Fong officials told investigators \"that the rooms had never been cleaned.\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_537", "text": "This Chinese corporation or company article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_538", "text": "Chiglitazar  (trade name  Bilessglu ) is a drug for the treatment of  type 2 diabetes . [ 1 ]   It is a  peroxisome proliferator-activated receptor  (PPAR)  agonist ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_539", "text": "In China, chiglitazar is approved for  glycemic control  in adult patients with type 2 diabetes when used in combination with diet and exercise. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_540", "text": "A  chloride channel blocker  is a type of  drug  which inhibits the transmission of  ions  (Cl \u2212 ) through  chloride channels ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_541", "text": "Niflumic acid  is a chloride channel blocker that has been used in experimental  scientific research . [ 1 ]  Another example is  anthracene-9-carboxylic acid , a potent blocker of the  CLCN1 -type chloride channel found in skeletal muscle, which is used to study animal models of  myotonia congenita . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_542", "text": "Some antagonists of  glycine receptors  and  GABAA receptors  also act as chloride channel blockers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_543", "text": "3-Chloro-PCP  ( 3'-Cl-PCP ) is a recreational  designer drug  from the  arylcyclohexylamine  family, with  dissociative  effects. It has comparable potency to  phencyclidine  but with a slightly different effects profile, being somewhat more potent as an  NMDA antagonist  but around the same potency as a  dopamine reuptake inhibitor . [ 1 ]  It was first identified in Slovenia in December 2020, [ 2 ]  and was made illegal in Hungary in April 2021. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_544", "text": "6-Chloronicotine  is a drug which acts as an  agonist  at neural  nicotinic acetylcholine receptors . It substitutes for  nicotine  in animal studies with around twice the potency, and shows  antinociceptive  effects. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_545", "text": "3-Chlorophenmetrazine  ( 3-CPM ,  PAL-594 ) is a recreational  designer drug  with  stimulant  effects. It is a  substituted phenylmorpholine  derivative, closely related to better known drugs such as  phenmetrazine  and  3-fluorophenmetrazine . It has been shown to act as a monoamine releaser with some preference for  dopamine  and  noradrenaline  release over  serotonin . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_546", "text": "Chlorosibutramine  is an analogue of the  anorectic  drug  sibutramine , which has been sold as an ingredient in  weight loss  products sold as  dietary supplements , first detected in South Korea in 2013. [ 1 ] [ 2 ] [ 3 ]  It is illegal in South Korea. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_547", "text": "Chlorosipentramine  is an analogue of the  anorectic  drug  sibutramine , which has been sold as an ingredient in  weight loss  products sold as  dietary supplements , first detected in South Korea in 2017. [ 1 ]  It is one of a number of sibutramine derivatives which have been sold in grey-market weight loss products since sibutramine itself was taken off the market due to safety concerns. Others include  desmethylsibutramine ,  didesmethylsibutramine , homosibutramine,  chlorosibutramine , and benzylsibutramine. [ 2 ] [ 3 ]  Chlorosipentramine is illegal in South Korea along with other related compounds. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_548", "text": "3-Chlorostyrylcaffeine  ( CSC ), or  8-(3-chlorostyryl)caffeine  ( 8-CSC ), is a  potent  and  selective   adenosine   A 2A  receptor   antagonist  which is used in  scientific research . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_549", "text": "It has 520-fold selectivity for the adenosine A 2A  receptor over the adenosine  A 1  receptor  (K i  = 54 \u00a0 nM and 28,000 \u00a0 nM for the rat receptors, respectively). [ 1 ] [ 2 ]  Its  affinities  for the adenosine  A 2B  and  A 3  receptors  are similarly low (K i  = 8,200 \u00a0 nM and >10,000 \u00a0 nM, respectively). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_550", "text": "CSC has been found to reverse the  catalepsy  induced by the  dopamine   D 1  receptor   antagonist   SCH-23390  and the dopamine  D 2  receptor  antagonists  raclopride  and  sulpiride  in animals. [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_551", "text": "The drug was one of the first selective adenosine A 2A  receptor antagonists to be developed. [ 1 ]  However, in addition to its adenosine receptor antagonism, CSC was subsequently found to be a potent  monoamine oxidase B  (MAO-B)  inhibitor  (K i  = 80.6 \u00a0 nM for baboon MAO-B). [ 2 ] [ 1 ] [ 3 ] [ 7 ] [ 8 ]  CSC was first described in the  scientific literature  by 1993. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_552", "text": "CHZ868  is a drug which acts as a  Janus kinase inhibitor  selective for the  JAK2  subtype. It was one of the first Janus kinase inhibitors developed, originally for the treatment of  leukemia  and related blood cancers, and while it did not get approved for clinical use, it is still used for research in the area. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_553", "text": "cis -Urocanic acid  ( cis -UCA) is a chemical compound produced by  ultraviolet  irradiation of  trans -urocanic acid , a metabolite naturally formed in the body from  histidine .  cis -Urocanic acid is suspected of involvement in the development of  skin cancer . It acts as an  immunosuppressant  through action as an  agonist  of the  5-HT 2A  receptor , and blocking this receptor has been shown to reduce  cis -UCA mediated photocarcinogenesis. [ 1 ] [ 2 ] [ 3 ]  However the  immunomodulatory  effects of  cis -UCA are complex and also involve other pathways, and at low levels it shows  antiinflammatory  actions and may be protective against UV damage in the  cornea  and  retina . [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_554", "text": "Clark's rule  is a  medical term  referring to a mathematical formula used to calculate the proper dosage of  medicine  for children aged 2\u201317 based on the weight of the patient and the appropriate adult dose. [ 1 ]  The formula was named after  Cecil Belfield Clarke  (1894\u20131970), a  Barbadian  physician who practiced throughout the UK, the West Indies and Ghana. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_555", "text": "The procedure is to take the child's  weight  in  pounds , divide by 150 lb, and multiply the fractional result by the adult dose to find the equivalent child dosage. For example, if an adult dose of medication calls for 30 mg and the child weighs 30 lb, divide the weight by 150 (30/150) to obtain 1/5 and multiply 1/5 times 30 mg to get 6 mg."}
{"_id": "WikiPedia_Pharmacology$$$corpus_556", "text": "Though it is more common for physicians to use medications that have suggested manufacturer's doses for children, familiarity of Clark's rule is used as an additional layer of protection against potentially deadly  medication errors  in clinical practice. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_557", "text": "Similar to Clark's rule is  Fried's rule , by which the formula is modified to be used for infants. [ 6 ]  The formula is nearly identical, except with the child's weight replaced by the infant's age in months."}
{"_id": "WikiPedia_Pharmacology$$$corpus_558", "text": "Fried's rule was named after  Kalman Fried  (1914\u20131999), an Israeli geneticist and pediatrician who developed his own formula while treating and observing children at the  Hebrew University of Jerusalem -affiliated   Hadassah Medical Center  in the 1960s. Fried though was more renowned as a  geneticist  rather than a  pediatrician . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_559", "text": "The earlier  Young's rule [ 1 ]  for calculating the correct dose of medicine for a child is similar: it states that the child dosage is equal to the adult dosage multiplied by the child's age in years, divided by the sum of 12 plus the child's age."}
{"_id": "WikiPedia_Pharmacology$$$corpus_560", "text": "Young's rule was named after  Thomas Young  (1773\u20131829), an English polymath, physician and physicist. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_561", "text": "Claziprotamide  is an  investigational new drug  that is being evaluated for the treatment of rare metabolic disorders such as  pantothenate kinase-associated neurodegeneration  (PKAN) and  neurodegeneration with brain iron accumulation  (NBIA). It acts as a positive allosteric modulator (PAM) of  pantothenate kinases  1 and 3 ( PANK1  and  PANK2 ) which are critical for  coenzyme A  biosynthesis and cellular metabolism. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_562", "text": "Cleaning validation  is the methodology used to assure that a cleaning process removes chemical and microbial residues of the  active, inactive or detergent ingredients  of the product manufactured in a piece of equipment, the cleaning aids utilized in the cleaning process and the  microbial  attributes. [ 1 ] [ 2 ]  All residues are removed to predetermined levels to ensure the quality of the next product manufactured is not compromised by residues from the previous product and  the quality of future products using the equipment, to prevent cross-contamination and as a  good manufacturing practice  requirement."}
{"_id": "WikiPedia_Pharmacology$$$corpus_563", "text": "The U.S.  Food and Drug Administration  (FDA) has strict regulations about cleaning validation. For example, FDA requires firms to have written general procedures on how cleaning processes will be validated. Also, FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required. FDA also require firms to conduct the validation studies in accordance with the protocols and to document the results of studies. The valuation of cleaning validation is also regulated strictly, which usually mainly covers the aspects of equipment design, cleaning process written, analytical methods and sampling. Each of these processes has their related strict rules and requirements. Acceptance criteria for cleaning validation protocols considers limits for chemicals and actives, limits for bio burden, visually cleanliness of surfaces, and the demonstration of consistency when executing the cleaning procedure.   Regarding the establishment of limits, FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. Current expectations for setting cleaning limits include the application of risk management principles and the consideration of Health Based Exposure Limits as the basis for setting cleaning limits for actives. [ 3 ]  Other limits that have been mentioned by industry include analytical detection levels such as 10  PPM ,  biological activity  levels such as 1/1000 of the normal  therapeutic dose  and  organoleptic  levels. [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_564", "text": "This  industry -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_565", "text": "Clesrovimab  (MK-1654) is a fully human  monoclonal antibody  designed to prevent  respiratory syncytial virus  (RSV) infections. Developed by  Merck , it is in a phase III trial as of 2023. It works differently than  nirsevimab . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_566", "text": "Clindamycin/adapalene/benzoyl peroxide , sold under the brand name  Cabtreo , is a  fixed-dose combination  medication used for the treatment of  acne . [ 2 ]  It contains  clindamycin , as the phosphate, a  lincosamide  antibacterial;  adapalene , a synthetic  retinoid ; and  benzoyl peroxide , an  oxidizing agent . [ 2 ]  It is  applied to the skin . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_567", "text": "Clindamycin/adapalene/benzoyl peroxide was approved for medical use in the United States in October 2023. [ 2 ] [ 3 ]  It is the first triple-combination topical acne treatment approved by the US  Food and Drug Administration . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_568", "text": "Clorprenaline  ( INN Tooltip International Nonproprietary Name ,  USAN Tooltip United States Adopted Name ,  BAN Tooltip British Approved Name ), also known as  isoprophenamine  and known as  clorprenaline hydrochloride  ( USAN Tooltip United States Adopted Name ,  JAN Tooltip Japanese Accepted Name ) in the case of the  hydrochloride   salt , is a  sympathomimetic  and  bronchodilator   medication  which is marketed in  Japan . [ 1 ] [ 2 ] [ 3 ]  It acts as a  \u03b2-adrenergic receptor agonist  or as a  \u03b2-sympathomimetic . [ 2 ] [ 3 ]  Brand names of clorprenaline in Japan are numerous and include Asnormal, Bazarl, Bronchon, Clopinerin, Conselt, Cosmoline, Fusca, Kalutein, Pentadoll, Restanolon, and Troberin. [ 2 ] [ 1 ]  The drug was first described in the literature by 1956. [ 1 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_569", "text": "CM-4620  is a drug which acts as a selective inhibitor of the  calcium channel   ORAI1 . It has  antiinflammatory  effects and is being researched for the treatment of  pancreatitis . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_570", "text": "C min  is a term used in  pharmacokinetics  for the minimum  blood plasma  concentration reached by a drug during a  dosing interval , which is the time interval between administration of two  doses . This definition is slightly different from  C trough , the concentration immediately prior to administration of the next dose. [ 1 ]   C min  is the opposite of  C max , the maximum concentration that the drug reaches.  C min  must be above certain thresholds, such as the  minimum inhibitory concentration  (MIC), to achieve a  therapeutic effect . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_571", "text": "In most cases  C min  is directly measurable. At steady state the minimum plasma concentration can also be calculated using the following equation: [ 3 ] \n \n \n \n \n \n C \n \n m \n i \n n \n \n \n = \n \n \n \n S \n F \n D \n \n k \n \n a \n \n \n \n \n \n V \n \n d \n \n \n ( \n \n k \n \n a \n \n \n \u2212 \n \n k \n \n e \n \n \n ) \n \n \n \n \u00d7 \n \n ( \n \n \n \n \n e \n \n \u2212 \n \n k \n \n e \n \n \n \u03c4 \n \n \n \n 1 \n \u2212 \n \n e \n \n \u2212 \n \n k \n \n e \n \n \n \u03c4 \n \n \n \n \n \n \u2212 \n \n \n \n e \n \n \u2212 \n \n k \n \n a \n \n \n \u03c4 \n \n \n \n 1 \n \u2212 \n \n e \n \n \u2212 \n \n k \n \n a \n \n \n \u03c4 \n \n \n \n \n \n \n ) \n \n \n \n {\\displaystyle C_{min}={\\frac {SFDk_{a}}{V_{d}(k_{a}-k_{e})}}\\times \\left({\\frac {e^{-k_{e}\\tau }}{1-e^{-k_{e}\\tau }}}-{\\frac {e^{-k_{a}\\tau }}{1-e^{-k_{a}\\tau }}}\\right)}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_572", "text": "C min  is also an important parameter in  bioavailability  and  bioequivalence  studies, it is part of the pharmacokinetic information recommended for submission of  investigational new drug  applications. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_573", "text": "A  codrug  consists of two drug  moieties , generally \"active against the same disease\", that are joined through one or more  covalent chemical bonds  to create a single  new chemical entity ; [ 1 ]  they can also be described as a  mutual  prodrug , recognising that a  catabolic   biosynthetic  step is most often required to liberate the two drugs. [ 2 ]  While acting against the same disease, the two moities may operate via different  mechanisms of action , and so display differing specific therapeutic effects. [ citation needed ]  The recognised advantages of a codrug approach to small molecule  drug design  include the possibilities of (i) combined efficacies of the two drugs that are therapeutically synergistic, (ii) altered properties that improve the pharmacokinetics (e.g., halflife) of the codrug over its individually administered components (iii) improved modes of  drug delivery , and (iv) masking of reactive functional groups of each component drug, possibly improving shelf life (as well as pharmacokinetics). [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_574", "text": "An effective codrug should be pharmacologically inactive in its own right but should release the constituent drugs upon biochemical breakage of the chemical linkage at the target tissue where their therapeutic effects are needed. As such, the chemical linkage (usually a  covalent bond ) should be subjectable to biodegradation, such as hydrolysis, by an enzymatic or non-enzymatic mechanism. The differential distribution of enzymes capable of catalyzing the breakage of the chemical linkage in different tissues may be exploited to achieve tissue-specific metabolism of the codrug to release the constituent drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_575", "text": "Colforsin daropate  is a carboxylic ester derived from the condensation of  forskolin  (colforsin) with  N , N -dimethyl-\u03b2-alanine. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_576", "text": "Its water-soluble hydrochloride salt ( NKH 477 ) [ 2 ]  is an  adenylyl cyclase  activator which has been studied for its cardiac selectivity. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_577", "text": "Colterol  is a short-acting  \u03b22-adrenoreceptor agonist .    Bitolterol , a  prodrug  for colterol, [ 1 ]  is used in the management of  bronchospasm  in  asthma  and  chronic obstructive pulmonary disease  (COPD)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_578", "text": "Patents: [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_579", "text": "Conessine  is a  steroidal alkaloid  found in a number of plant species from the family  Apocynaceae , including  Holarrhena floribunda , [ 1 ]   Holarrhena antidysenterica [ 2 ]  and  Funtumia elastica . [ 3 ]  It acts as a  histamine antagonist , selective for the  H 3  subtype  (with an affinity of pK i  = 8.27; K i  = ~5 nM). [ 4 ]  It was also found to have long CNS clearance times, high  blood\u2013brain barrier  penetration and high affinity for the adrenergic receptors. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_580", "text": "The  conflict procedure  is an experiment often used in  scientific research  to quantify  anxiety  levels by measuring changes in punished/unpunished responses. It is often used to screen  drugs  for their potential to inhibit anxiety ( anxiolytic  potential)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_581", "text": "Some researchers from France have conducted an experiment on \"Effects of Chronic Antidepressants in an Operant Conflict Procedure of Anxiety in the rat (1998)\", \"the aim of their study was to reveal possible anxiolytic like effects of antidepressants during ongoing treatment. Rats were subjected to a conflict procedure during which lever pressing for food was suppressed by a conditioned signal for punishment and contingent electric foot shocks.\" [ 1 ]  In the preparatory phase of the experiment, researchers increased anxiety using electrical shocks on rats gradually over a several week long training process. They then administered the chosen drug and observed how it altered the responses of the rats. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_582", "text": "Other studies have used conflict procedures to test a variety of drugs, and some have reported that depressants cause an increase in punished responses, while anxiolytic drugs decrease the level of punished responding. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_583", "text": "This  animal rights -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_584", "text": "This  psychology -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_585", "text": "Corey lactone 4-phenylbenzoate  is a synthetic intermediate used in the manufacture of some  prostaglandin  derivatives. [ 1 ]  It has been used as a false name by some  designer drug  manufacturers as a label to sell  substituted cathinone  derivatives after the banning of  mephedrone  and related drugs in some jurisdictions - but there is no evidence to suggest that Corey lactone 4-phenylbenzoate has any stimulant effects in its own right.  [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_586", "text": "Cosibelimab , sold under the brand name  Unloxcyt , is a monoclonal antibody used for the treatment of  cutaneous squamous-cell carcinoma . [ 1 ]  It is a programmed death ligand-1 (PD-L1) blocking antibody. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_587", "text": "The most common adverse reactions include fatigue, musculoskeletal pain, rash, diarrhea, hypothyroidism, constipation, nausea, headache, pruritis, edema, localized infection, and urinary tract infection. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_588", "text": "Cosibelimab was approved for medical use in the United States in December 2024. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_589", "text": "Cosibelimab is  indicated  for the treatment of adults with metastatic  cutaneous squamous-cell carcinoma  or locally advanced cutaneous squamous-cell carcinoma who are not candidates for curative surgery or curative radiation. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_590", "text": "Efficacy was evaluated in study CK-301-101 (NCT03212404), a multicenter, multicohort, open-label trial in 109 participants with metastatic cutaneous squamous-cell carcinoma or locally advanced cutaneous squamous-cell carcinoma who were not candidates for curative surgery or curative radiation. [ 2 ]  Participants were excluded if they had any of the following: active or suspected autoimmune disease, allogeneic transplant within six months prior to treatment, prior treatment with anti-PD-1/PD-L1 blocking antibodies or other immune checkpoint inhibitor therapy, uncontrolled or significant cardiovascular disease, ECOG PS \u2022 2, or infection with HIV, hepatitis B, or hepatitis C. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_591", "text": "Cosibelimab was approved for medical use in the United States in December 2024. [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_592", "text": "Cosibelimab is the  international nonproprietary name . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_593", "text": "Cosibelimab is sold under the brand name Unloxcyt. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_594", "text": "Cost-minimization  is a tool used in  pharmacoeconomics  to compare the cost per course of treatment when alternative therapies have demonstrably equivalent clinical effectiveness. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_595", "text": "Therapeutic equivalence (including adverse reactions, complications and duration of therapy) must be referenced by the author conducting the study and should have been done prior to the cost-minimization work.  Since equal efficacy and equal tolerability is already demonstrated, there is no requirement to find a common efficacy denominator as would be the case when conducting a  cost-effectiveness  study.  The author is not precluded from doing so through the use of \"cost/cure\" or \"cost/year of life gained\".  If efficacy and tolerability is demonstrated, however, then a simple comparison of \"cost/course of treatment\" can suffice for the purpose of comparing two or more therapeutically equivalent treatment alternatives. When conducting a cost-minimization study, the author needs to measure all costs (resource expenditures) inherent to the delivery of the therapeutic intervention and that are relevant to the pharmacoeconomic perspective. The optimal choice is that which can be provided for the lowest cost."}
{"_id": "WikiPedia_Pharmacology$$$corpus_596", "text": "This  economics -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_597", "text": "CPD-1  ( LS-193743 ) is a  drug  with a  benzofuranyl   piperazine  structure, which acts as a  potent  and  selective   agonist  for the  5-HT 2   receptor  family, with highest  affinity  and full agonist efficacy at the  5-HT 2C  subtype, and lower affinity and  partial agonist  action at the  5-HT 2A  and  5-HT 2B  subtypes. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_598", "text": "Crelosidenib  is an  investigational new drug  that is being evaluated for the treatment of cancer.  It acts as a selective inhibitor of  isocitrate dehydrogenase 1  (IDH1), an enzyme that plays a crucial role in cellular metabolism and is frequently mutated in various cancers, including  cholangiocarcinoma . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_599", "text": "Kolliphor EL , formerly known as  Cremophor EL , is the registered trademark of  BASF  Corp. for its version of polyethoxylated castor oil.  It is prepared by reacting 35 moles of  ethylene oxide  with each mole of  castor oil . The resulting product is a mixture ( CAS number  61791-12-6): the major component is the material in which the hydroxyl groups of the castor oil  triglyceride  have been  ethoxylated  with ethylene oxide to form  polyethylene glycol   ethers . Minor components are the polyethyelene glycol  esters  of  ricinoleic acid , polyethylene glycols and polyethylene glycol ethers of  glycerol . [ 1 ]  Kolliphor EL is a synthetic,  nonionic   surfactant  used to stabilize  emulsions  of nonpolar materials in  water ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_600", "text": "Kolliphor EL is an  excipient  or additive in drugs. Therapeutically, modern drugs are rarely given in a pure chemical state, so most active ingredients are combined with excipients or additives such as Kolliphor EL. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_601", "text": "Allergic reactions to  Taxol  are most often allergic reactions to Kolliphor EL; symptoms include tightness in the chest, shortness of breath, and similar reactions consistent with severe anaphylactic reactions.  Although many anti-allergens including corticosteroids and Benadryl may be administered before chemotherapy, they are not always sufficient to prevent the severe reaction to Kolliphor EL."}
{"_id": "WikiPedia_Pharmacology$$$corpus_602", "text": "Allergic reaction should not be confused with the normal side effects of  Taxol .  The allergic reaction is usually immediate, similar to severe allergic reactions typical of other allergens."}
{"_id": "WikiPedia_Pharmacology$$$corpus_603", "text": "BASF offers a purified, injectable version of Kolliphor EL, known as Kolliphor ELP. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_604", "text": "Crisugabalin  ( HSK16149 ) is a selective  GABA  analog in development for the treatment of  chronic pain . It has a wider  therapeutic index  than  pregabalin , which as a similar  mechanism of action . In China, it was approved in 2024 for the treatment of diabetic peripheral  neuropathic pain . [ 1 ]   In the United States, it is in Phase III trials as of 2023. [ 2 ] [ 3 ]  The drug can be administered with or without food. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_605", "text": "CS-27349 , or  L -2-\u03b1-tropinyl benzilate , is an experimental  incapacitating agent . It acts as an  antagonist  to  muscarinic acetylcholine receptors , causing  delirium . It has 37% of the potency of the related compound  3-quinuclidinyl benzilate  (BZ) in producing peripheral effects, but 85% of the potency in producing central effects. The mean dose required to incapacitate subjects was 1.2 times that of BZ. [ 1 ]  It has not been in use since the 1970s, and there have been no publications about its effects or long-term toxicology since then. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_606", "text": "CU-CPT4a  is a drug which acts as a selective antagonist of  Toll-like receptor 3  (TLR3), with an IC 50  of 3.44 \u03bcM. It is used for research into the function of TRL3 and its role in  inflammation ,  autoimmune  disorders and  cancer . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_607", "text": "CU-CPT9a  is a drug which acts as a potent and selective antagonist of  Toll-like receptor 8  (TLR8), with an IC 50  of 0.5nM. Activation of toll-like receptors triggers release of  cytokines  and other signalling factors, leading to  inflammation . This is an essential part of the  immune system 's response to infection, but chronic activation of TLR signalling is thought to be involved in various inflammatory and autoimmune disorders. CU-CPT9a has  immunosuppressant  properties, and may have applications in the treatment of autoimmune disorders, as well as being used in scientific research into the function of TLR8. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_608", "text": "In old  pharmacy , a  cucupha  or  cucufa  was a  cap , or cover for the head, with  cephalic   spices  quilted in it, worn for certain nervous  distempers , particularly those affecting the head."}
{"_id": "WikiPedia_Pharmacology$$$corpus_609", "text": "A  CYP17A1 inhibitor  is a type of  drug  that  inhibits  the  enzyme   CYP17A1 . [ 1 ]  CYP17A1 inhibitors work by blocking specific enzyme functions, impacting androgen biosynthesis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_610", "text": "CYP17A1 inhibitors may inhibit one or both of the enzyme\u2019s functions:  17\u03b1-hydroxylase  and  17,20-lyase . Some inhibitors are selective and target only the 17,20-lyase function, while others inhibit both functions. [ 2 ]  By inhibiting these enzymatic functions, CYP17A1 inhibitors prevent the conversion of  pregnane   steroids  into  androgens  like  testosterone . This action classifies them as  androgen   biosynthesis  inhibitors and functional  antiandrogens ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_611", "text": "Examples of CYP17A1 inhibitors include the older drug  ketoconazole  and the newer drugs  abiraterone acetate ,  orteronel ,  galeterone , and  seviteronel . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_612", "text": "CYP17A1 inhibitors, such as abiraterone acetate, are primarily used in the treatment of  prostate cancer . These drugs reduce androgen levels, which helps to slow the progression of prostate cancer in patients with castration-resistant prostate cancer. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_613", "text": "Non-selective CYP17A1 inhibitors that inhibit both the 17\u03b1-hydroxylase and 17,20-lyase functions must be administered alongside a  glucocorticoid  (e.g.,  prednisone ) to prevent  adrenal insufficiency  and  mineralocorticoid excess . This precaution is necessary because non-selective inhibitors can disrupt  cortisol  production, leading to hormone imbalances. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_614", "text": "Cytoprotection  is a process by which chemical compounds provide protection to  cells  against harmful agents. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_615", "text": "A gastric  cytoprotectant  is any medication that combats  ulcers  not by reducing  gastric acid  but by increasing mucosal protection. [ 2 ]  Examples of gastric cytoprotective agents include  prostaglandins  which protect the stomach mucosa against injury by increasing gastric  mucus  secretion.  Nonsteroidal anti-inflammatory drugs  (NSAIDs) inhibit the synthesis of prostaglandins and thereby make the stomach more susceptible to injury. [ 3 ]   Gastric cytoprotective drugs include  carbenoxolone , deglycyrrhizinised  liquorice ,  sucralfate  (aluminium hydroxide and sulphated  sucrose ),  misoprostol  (a  prostaglandin  analogue),  bismuth chelate  (tri-potassium di-citrato bismuthate) and  zinc  L -carnosine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_616", "text": "This article incorporates text from the  United States National Library of Medicine , which is in the  public domain ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_617", "text": "Cytrel  is a  cellulose -based  tobacco  substitute used in some low-tar  cigarette  brands. It formerly constituted 25% of  Silk Cut  cigarettes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_618", "text": "Development began on a replacement for tobacco in cigarettes in the 1950s, to reduce undesirable tobacco smoke components present in cigarettes. Cytrel was developed by  Celanese  Fiber Marketing Company."}
{"_id": "WikiPedia_Pharmacology$$$corpus_619", "text": "The fiber underwent a challenging development phase, during which scientists faced difficulties in achieving satisfactory smoking characteristics, taste, and manufacturing properties. Despite these challenges, the product proved to be less dense than tobacco and useful as a bulking agent, prompting further development efforts. After undergoing five revisions, the Celanese Fiber Marketing Company finally released Type 308 to the market."}
{"_id": "WikiPedia_Pharmacology$$$corpus_620", "text": "It was one of the  NSM  ( New Smoking Materials ) that came into popularity in the 1970s."}
{"_id": "WikiPedia_Pharmacology$$$corpus_621", "text": "DailyMed  is a website operated by the  U.S. National Library of Medicine  (NLM) to publish up-to-date and accurate drug labels (also called a \" package insert \") to health care providers and the general public. The contents of DailyMed is provided and updated daily by the  U.S. Food and Drug Administration  (FDA). The FDA in turn collects this information from the pharmaceutical industry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_622", "text": "The documents published use the  HL7  version 3  Structured Product Labeling  (SPL) standard, [ 1 ]  which is an  XML  format that combines the human readable text of the product label with structured data elements that describe the composition, form, packaging, and other properties of the drug products in detail according to the  HL7 Reference Information Model  (RIM)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_623", "text": "As of August\u00a021, 2021 [update] , it contained information about 140,232 drug listings. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_624", "text": "It includes an  RSS feed  for updated drug information. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_625", "text": "In 2006 the FDA revised the drug label and also created DailyMed to keep prescription information up to date. [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_626", "text": "Danicopan , sold under the brand name  Voydeya , is a medication used for the treatment of  paroxysmal nocturnal hemoglobinuria . [ 6 ] [ 7 ]  It is a  complement  inhibitor which reversibly binds to factor D to prevent alternative pathway-mediated  hemolysis  and deposition of  complement C3  proteins on red blood cells. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_627", "text": "The most common side effects include fever, headache, increased levels of liver enzymes (a sign of possible liver problems) and pain in the extremities (arms and legs). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_628", "text": "Danicopan was approved for medical use in Japan in January 2024, [ 9 ]  in the United States in March 2024, [ 6 ] [ 10 ]  and in the European Union in April 2024. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_629", "text": "Danicopan is  indicated  as add-on therapy to  ravulizumab  or  eculizumab  for the treatment of extravascular hemolysis in adults with paroxysmal nocturnal hemoglobinuria. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_630", "text": "Danicopan was approved for medical use in Japan, [ 11 ]  the United States, [ 6 ]  and the European Union in 2024. [ 7 ]  The FDA granted the application  breakthrough therapy  designation. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_631", "text": "In February 2024, the  Committee for Medicinal Products for Human Use  of the EMA adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Voydeya, intended as add-on therapy to ravulizumab or eculizumab for the treatment of residual hemolytic anemia in adults with paroxysmal nocturnal hemoglobinuria (PNH). [ 7 ] [ 13 ]  The applicant for this medicinal product is Alexion Europe. [ 7 ]  Danicopan was approved for medical use in the European Union in April 2024. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_632", "text": "In October 2024, the  National Institute for Health and Care Excellence (NICE)  adopted a recommendation for danicopan\u00a0as an add-on therapy for adults with the  paroxysmal nocturnal haemoglobinuria (PNH)  based results from the phase 3 ALPHA trial, which evaluated the efficacy and safety of the drug as an add-on to  ravulizumab  or  eculizumab  in patients with PNH who experienced clinically significant extravascular haemolysis. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_633", "text": "Danicopan is the  international nonproprietary name . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_634", "text": "Dapagliflozin/sitagliptin , sold under the brand name  Sidapvia , is a  fixed-dose combination   anti-diabetic medication  used for the treatment of  type 2 diabetes . [ 1 ]  It contains dapagliflozin, as propanediol monohydrate, a  SGLT-2 inhibitor ; and sitagliptin, as phosphate monohydrate, a  DPP-4 inhibitor . [ 1 ]  It is taken  by mouth . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_635", "text": "Dapolsertib is an  investigational new drug  that is being evaluated for the treatment of cancer.  It is dual inhibitor of  PIM  family of serine/threonine protein kinases and mutant forms of  FMS-related tyrosine kinase 3  (FLT3) that is being developed by Ryvu Therapeutics SA. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_636", "text": "Darbinurad  is a  investigational new drug  that is being evaluated for the treatment of  gout .  It is a selective  urate transporter  1 (URAT1) inhibitor that blocks the reabsorption of  uric acid  within the renal  proximal tubule , thereby reducing serum uric acid concentrations. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_637", "text": "Darovasertib  is an  investigational new drug  that is being evaluated for the treatment of metastatic  uveal melanoma  and other cancers.  It is a first-in-class oral, small molecule inhibitor of  protein kinase C  (PKC). [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_638", "text": "It selectively targets mutant forms of PKC found in tumors with GNAQ or GNA11 mutations, which are present in approximately 90% of uveal melanoma cases. [ 1 ]  The U.S. Food and Drug Administration (FDA) granted orphan drug designation to darovasertib for the treatment of uveal melanoma on May 2, 2022, highlighting its potential to address an unmet medical need in this rare and aggressive form of eye cancer. [ 1 ]  As of 2024, darovasertib is in clinical development, with ongoing phase 1/2 trials evaluating its efficacy both as a monotherapy and in combination with other agents, such as  binimetinib  and  crizotinib . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_639", "text": "10-Deacetylbaccatins  are a series of closely related natural  organic compounds  isolated from the yew tree (Genera  Taxus ).  10-Deacetylbaccatin III is a precursor to the anti-cancer drug  docetaxel  (Taxotere)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_640", "text": "10-deacetylbaccatin III 10- O -acetyltransferase  converts 10-deacetylbaccatin to  baccatin III :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_641", "text": "This article about a  ketone  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_642", "text": "A  demulcent  (derived from the  Latin :  demulcere  \"caress\") is a  mucilaginous  or oleaginous preparation [ 1 ]  that forms a soothing protective film over a  mucous membrane , relieving minor pain and inflammation of the  membrane . [ 2 ]  However, they generally help for less than 30 minutes. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_643", "text": "Demulcents are sometimes referred to as  mucoprotective  agents. Demulcents such as  pectin ,  glycerin ,  honey , and  syrup  are common ingredients in cough mixtures and cough drops. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_644", "text": "Natural demulcents include  slippery elm ,  pectin ,  licorice-root  and  marsh-mallow ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_645", "text": "Synthetic demulcents include  methylcellulose ,  propylene glycol , and  glycerin ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_646", "text": "Tripathi, K. D. (31 October 2018).  Essentials of Medical Pharmacology, 8th Edition . Jaypee Brothers Medical Publishers.  ISBN \u00a0 978-93-5270-499-6 .  OCLC \u00a0 1050280101 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_647", "text": "The  D\u00e9nomination Commune Fran\u00e7aise  ( DCF ), or \"Common French Denomination/Name\" in  English , is the formal  French  name for a  drug . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_648", "text": "This  France -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_649", "text": "The  Denominazione Comune Italiana  ( DCIT ), or \"Common Italian Denomination/Name\" in  English , is the formal  Italian   generic name  for a  drug . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_650", "text": "The  Dermatologic And Ophthalmic Drugs Advisory Committee  (DODAC) receives requests for technical and clinical evaluation of new drugs by the  U.S. Food and Drug Administration  (FDA).  The committee, consisting of members from academic and clinical dermatology, ophthalmology, biostatistics, the general public, and the pharmaceutical industry, makes non-binding recommendations to both the  CDER  and  CBER  divisions of the FDA about the advisability of approving new medications to treat  dermatologic  and  ophthalmic  conditions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_651", "text": "Derwent Drug file , formerly known as Ringdoc, is an  information monitoring ,  abstracting  and  documentation  service, specifically designed to meet the  information  needs of people requiring information on  pharmaceuticals . The Derwent Drug File\nprovides all relevant and important information for the whole life-cycle of a  drug , from  drug design  to use. The Derwent Drug File concentrates information about the drug itself and its use.  Online  file contains over 1.5 million records from 1964 to present. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_652", "text": "Desmethylsibutramine  (also known as  norsibutramine  and  BTS-54354 ) is an  active metabolite  of the  anorectic  drug  sibutramine . It is a more potent  monoamine   reuptake inhibitor  than sibutramine and has been sold as an ingredient in  weight loss  products sold as  dietary supplements , along with related compounds such as the  N -ethyl and 3,4-dichloro derivatives. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_653", "text": "Deterenol  (also known as  Isopropylnorsynephrine  and  Isopropyloctopamine ; trade name  Betaphrine ) is a  stimulant  drug which acts as a  beta agonist . It has been found as an ingredient of  dietary supplement  products, but is banned in most countries due to risk of  cardiac arrest . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_654", "text": "Deuruxolitinib , sold under the brand name  Leqselvi , is a medication used for the treatment of  alopecia areata . [ 1 ]  It is a  Janus kinase inhibitor  selective for  JAK1  and  JAK2 . [ 2 ]  Although the relative effectiveness of deuruxolitinib and another Janus kinase inhibitor\u2014 baricitinib \u2014for alopecia areata may vary depending on the population studied, both drugs are more effective than alternative treatments. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_655", "text": "Deuruxolitinib was approved for medical use in the United States in July 2024. [ 1 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_656", "text": "Deuruxolitinib is  indicated  for the treatment of adults with severe alopecia areata. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_657", "text": "The FDA prescribing label for deuruxolitinib contains a  boxed warning  for serious infections; malignancies; cardiovascular death, myocardial infarction, and stroke; and thrombosis. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_658", "text": "Deuruxolitinib is the  international nonproprietary name [ 7 ]  and the  United States Adopted Name . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_659", "text": "Dexamethasone/levofloxacin , sold under the brand name  Levodexa , is a  fixed-dose combination  medication used for the prevention and treatment of inflammation, and the prevention of infection, associated with  cataract surgery . [ 1 ] [ 3 ]  It contains  dexamethasone , a  corticosteroid ; and  levofloxacin , an  anti-infective . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_660", "text": "It was approved for medical use in Canada in December 2023. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_661", "text": "Dexamethasone/levofloxacin is  indicated  for the prevention and treatment of inflammation, and the prevention of infection, associated with cataract surgery in adults. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_662", "text": "In pre-modern medicine,  diascordium  (medical  Lat.   diascordium , for  diascordi\u014dn , from  Gr.   \u03b4\u03b9\u1f70 \u03c3\u03ba\u03bf\u03c1\u03b4\u03af\u03c9\u03bd , [a preparation] of scordium,  \u03c3\u03ba\u03cc\u03c1\u03b4\u03b9\u03bf\u03bd , \"a strong-smelling plant mentioned by  Dioscorides \", possibly  Teucrium scordium [ 1 ] ), or  diascord , is a kind of  electuary , or  opiate , first described by Jerome Frascata, and denominated from the dried leaves of scordium, which is an ingredient therein. [ 1 ]  The other ingredients are red roses,  bole armoniac ,  storax , cinnamon,  cassia lignea  (coarse bark of  Cinnamomum cassia ),  dittany ,  tormentil  roots,  bistort ,  gentian ,  galbanum , amber,  terra sigillata ,  opium , long pepper, ginger,  mel rosatum , and  malmsey . It was used against malignant fevers, the plague, worms,  colic , to promote sleep, and resist putrefaction. [ 2 ]  In 1746, diascordium was offered in two forms: with or without opium. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_663", "text": "In 1654,  Nicholas Culpeper  wrote in his  London Dispensatorie  about the mixture: \"It is a well composed Electuary, a something appropriate to the nature of women, for it Provokes the Terms, hastens their Labor, helps their usual sickness at the time of their Lying-in, I know nothing better.\" [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_664", "text": "Over the years, the composition of diascordium was modified, until it gradually changed into what became known as  pulvis catechu compositus  (\"compound powder of  catechu \"). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_665", "text": "Dibenzylpiperazine  ( DBZP ) is a  piperazine  derivative often found as an impurity in the recreational  stimulant  drug  benzylpiperazine  (BZP). [ 1 ]  Presence of DBZP is a marker for low quality or badly made BZP. It can be made as a reaction  byproduct  during BZP synthesis, either because the reaction has been run at too high a temperature, or because an excess of  benzyl chloride  has been used."}
{"_id": "WikiPedia_Pharmacology$$$corpus_666", "text": "It is not known to have any stimulant effects in its own right, although this has not been tested."}
{"_id": "WikiPedia_Pharmacology$$$corpus_667", "text": "The toxicity of DBZP is unknown."}
{"_id": "WikiPedia_Pharmacology$$$corpus_668", "text": "As of October 2015 DBZP is a controlled substance in China. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_669", "text": "DBZP is not scheduled as a  controlled substance  at the federal level in the  United States . [ 3 ]  It is possible that it could be considered an analog BZP, in which case, sales or possession intended for human consumption could be prosecuted under the  Federal Analog Act ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_670", "text": "DBZP is a  Schedule I controlled substance  in the state of  Florida  making it illegal to buy, sell, or possess in Florida. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_671", "text": "Diethyl lutidinate  is a chemical compound. It has been studied for its potential use in hair care. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_672", "text": "It can be synthesized by reacting  lutidinic acid  with  ethanol  at elevated temperature in presence of  sulfuric acid . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_673", "text": "5\u03b1-Dihydrolevonorgestrel  ( 5\u03b1-DHLNG ) is an  active metabolite  of the  progestin   levonorgestrel  which is formed by  5\u03b1-reductase . [ 1 ] [ 2 ]  It has about one-third of the  affinity  of levonorgestrel for the  progesterone receptor . [ 1 ]  In contrast to levonorgestrel, the compound has both  progestogenic  and  antiprogestogenic  activity, and hence has a  selective progesterone receptor modulator -like profile of activity. [ 3 ] [ 4 ]  This is analogous to the case of  norethisterone  and  5\u03b1-dihydronorethisterone . [ 3 ] [ 5 ]  In addition to the progesterone receptor, 5\u03b1-DHLNG interacts with the  androgen receptor . [ 6 ]  It has similar  affinity  for the androgen receptor relative to levonorgestrel (34.3% of that of  metribolone  for levonorgestrel and 38.0% of that of metribolone for 5\u03b1-DHLNG), and has  androgenic  effects similarly to levonorgestrel and  testosterone . [ 6 ]  5\u03b1-DHLNG is further  transformed  into 3\u03b1,5\u03b1- and 3\u03b2,5\u03b1- THLNG , which bind weakly to the  estrogen receptor  (0.4 to 2.4% of the  RBA  of  E2 Tooltip estradiol (medication) ) and have weak  estrogenic  activity. [ 7 ] [ 8 ] [ 4 ]  These  metabolites  are considered to be responsible for the weak estrogenic activity of high doses of levonorgestrel. [ 8 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_674", "text": "5\u03b1-Dihydronormethandrone  ( 5\u03b1-DHNMT ; developmental code name  RU-575 ), also known as  17\u03b1-methyl-4,5\u03b1-dihydro-19-nortestosterone  or as  17\u03b1-methyl-5\u03b1-estran-17\u03b2-ol-3-one , is an  androgen / anabolic steroid  and a likely  metabolite  of  normethandrone  formed by  5\u03b1-reductase . [ 1 ] [ 2 ]  Analogously to nandrolone and its 5\u03b1-reduced metabolite  5\u03b1-dihydronandrolone , 5\u03b1-DHNMT shows reduced  affinity  for the  androgen receptor  relative to normethandrone. [ 1 ]  Its affinity for the androgen receptor is specifically about 33 to 60% of that of normethandrone. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_675", "text": "Diodone  is a  radiocontrast agent  that was used in  urography . [ 1 ]  It was usually formulated as a  salt  with  diethanolamine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_676", "text": "Diphenidol  is a  muscarinic antagonist  employed as an  antiemetic  and as an anti vertigo  agent. It is not marketed in the United States or Canada."}
{"_id": "WikiPedia_Pharmacology$$$corpus_677", "text": "Although the mechanism of action of diphenidol on the  vestibular system  has not yet been elucidated, it exerts an  anticholinergic  effect due to interactions with  mACh receptors , particularly M 1 , M 2 , M 3  and M 4 . Hence, its actions may take place at the vestibular nuclei, where a significant excitatory input is mediated by ACh receptors, and also at the vestibular periphery where mACh receptors are expressed at efferent synapses. A series of selective mACh-receptor antagonists based on the diphenidol molecule has been synthesized, but they have not yet been the subject of clinical trials. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_678", "text": "Alkylation of  1-Bromo-3-chloropropane  [109-70-6] ( 1 ) with  piperidine  ( 2 ) gives 3-Piperidinopropyl chloride [1458-63-5] ( 3 ). The Grignard reaction of this intermediate with benzophenone [119-61-9] gives the benzhydrol and hence, Diphenidol ( 4 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_679", "text": "Ditt Apotek  is a chain of 80  pharmacies  owned and run by independent pharmacists on  franchise  from  Norsk Medisinaldepot , a subsidiary of  McKesson Europe . The chain is the fourth largest, and thus smallest, in Norway. The chain was established in 2001 after the deregulation of the pharmacy market in Norway. The sister company  Vitusapotek  operates 133 pharmacies owned by the mother company."}
{"_id": "WikiPedia_Pharmacology$$$corpus_680", "text": "Among the members are the four state owned  pharmaceutical trusts  that operate the pharmacies at the  hospitals :  Southern and Eastern Norway Pharmaceutical Trust ,  Western Norway Pharmaceutical Trust ,  Central Norway Pharmaceutical Trust , and  Northern Norway Pharmaceutical Trust ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_681", "text": "Docirbrutinib  is an  investigational new drug  that is being evaluated for the treatment of cancer.  It is a selective  Bruton's tyrosine kinase  (BTK) inhibitor that targets  chronic lymphocytic leukemia  (CLL) and other  B-cell malignancies . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_682", "text": "Domesticine  is an  \u03b1 1D -adrenergic receptor   antagonist . [ 1 ]  The compound belongs to the group of  aporphine alkaloids ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_683", "text": "This article about an  alkaloid  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_684", "text": "d -DOPA   ( D -3,4- d ihydr o xy p henyl a lanine;   dextrodopa ) is similar to  L -DOPA  (levodopa), but with opposite  chirality .  Levo - and  dextro - rotation refer to a molecule's ability to rotate planes of  polarized light  in one or the other direction. Whereas  L -DOPA  is moderately effective in the  treatment  of  Parkinson's disease  (PD) and  dopamine-responsive dystonia  (DRD) by stimulating the production of dopamine in the brain,  D -DOPA  is  biologically  inactive."}
{"_id": "WikiPedia_Pharmacology$$$corpus_685", "text": "Dordaviprone  is an  investigational new drug  that is being evaluated for the treatment of  diffuse intrinsic pontine glioma  (a type of brain tumor). [ 1 ]   It is  dopamine receptor D2  antagonist and an allosteric activator of the mitochondrial  caseinolytic protease P . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_686", "text": "In  pharmacology  and medicine,  dosage  refers to the  prescribed regimen  for administering a  medication  or substance, encompassing the amount, frequency, and duration of use. [ 1 ]  It is distinct from  dose , which denotes a single, specific quantity of a drug or substance given at one time. [ 2 ]  Dosage typically includes information on the number of doses, intervals between administrations, and the overall treatment period. [ 3 ]  For example, a dosage might be described as \"200 mg twice daily for two weeks,\" where 200\u00a0mg represents the individual dose, twice daily indicates the frequency, and two weeks specifies the duration of treatment. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_687", "text": "Dose dumping  is a phenomenon of  drug metabolism  in which environmental factors can cause the premature and exaggerated release of a  drug . This can greatly increase the  concentration  of a drug in the body and thereby produce  adverse effects  or even drug-induced  toxicity . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_688", "text": "Dose dumping is most commonly seen in drugs taken by mouth and digested in the  gastrointestinal tract . Around the same time patients take their medication, they can also ingest other substances like fatty meals or  alcohol  that increase  drug delivery . The substances may act on the drug's  capsule  to speed up drug release, or they may stimulate the body's absorptive surfaces to increase the rate of drug uptake."}
{"_id": "WikiPedia_Pharmacology$$$corpus_689", "text": "Dose dumping is a disadvantage found in extended release dosage form."}
{"_id": "WikiPedia_Pharmacology$$$corpus_690", "text": "In general,  drug companies  try to avoid drugs with significant dose dumping effects. Such drugs are prone to problems and are often pulled from the market. Such was the case with the  pain  medication  Palladone  Once Daily formulation due to its dose-dumping effects when taken with alcohol. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_691", "text": "It is by definition an unintended rapid release in large amounts of a  modified-release dosage  due to a co-ingestion with ethanol. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_692", "text": "Some interactions between alcohol, biological factors and the presentation of the drug can influence the apparition of AIDD by:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_693", "text": "Food intake produces dynamic changes in digestion and  pharmacokinetics  through a variety of mechanisms, which can produce an unintended release of modified-release dosages under certain circumstances. Usually, high fat diets are the most associated with this phenomenon, but there is evidence that standard-composition food can cause this even in  immediate release  formulations, such as the case of  methylphenidate . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_694", "text": "Some of the mechanisms involved in FIDD are: [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_695", "text": "Drofenine  is an  antimuscarinic   antispasmodic  drug used for relaxing smooth muscle, thereby treating conditions, such as: dysmenorrhea, and pain in the gastrointestinal tract, biliary passages, and urogenital tract. Drofenine is assumed to work by increasing the levels of the protein  TRPV3 . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_696", "text": "Dronabinol/acetazolamide  (investigational name IHL-42X) is a  combination therapy  under investigation for  sleep apnea . It is developed by Incannex Healthcare. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_697", "text": "The  Drug Effectiveness Review Project  (DERP) is a self-governed collaboration of state  Medicaid  and public pharmacy programs that commission high-quality evidence-based research products to assist policymakers and other decision-makers grappling with difficult drug coverage decisions. Housed at the Center for Evidence-based Policy at  Oregon Health & Science University  in Portland,  Oregon , DERP produces concise, comparative, evidence-based research products that evaluate the efficacy, effectiveness, and safety of  drugs  in many widely used drug classes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_698", "text": "Nationally recognized for its clinical objectivity and high-quality research, DERP focuses on specialty and other high-impact drugs \u2013 particularly those that have potential to change clinical practice. The program's goal is to ultimately help improve appropriate patient access, safety, and quality of care while helping government programs contain exploding costs for new pharmaceutical therapies. DERP uses a collaborative governing model to develop work plans that provide independent and objective research on drug effectiveness and safety to bring evidence to health policy decisions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_699", "text": "DERP reports include up-to-date clinical evidence on efficacy, adverse events, and safety information for the drugs reviewed. These reports and research products are not usage guidelines, nor should they be read as an endorsement of or recommendation for any particular drug, use or approach. Rather, DERP reports are used by policy makers to develop criteria for drug coverage, such as prior authorizations, clinical edits, drug utilization management policies, and provider or patient education materials. DERP research products include a comprehensive search of the global evidence, an objective appraisal of the quality of the studies found, and a thorough synthesis of high-quality evidence. Policymakers are able to use these reports and research products to make informed policy decisions that improve patient outcomes and contain costs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_700", "text": "Any product defined as a  drug  under the  Canadian   Food and Drugs Act  must have an associated  drug identification number  (or DIN). [ citation needed ]  A DIN also pertains to veterinary drugs permitted for sale in Canada. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_701", "text": "The drug identification number (DIN) is the 8 digit number located on the label of prescription and  over-the-counter drug  products that have been evaluated by the  Therapeutic Products Directorate  (TPD) and approved for sale in Canada. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_702", "text": "Once a drug has been approved, the Therapeutic Products Directorate issues a DIN, which permits the manufacturer to market the drug in Canada. For drugs, where there is minimal market history in Canada, there is a more stringent review and the drug is required to have a Notice of Compliance and a DIN in order to be marketed in Canada. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_703", "text": "A DIN lets the user know that the product has undergone and passed a review of its formulation, labeling, and instructions for use. A drug product sold in Canada without a DIN is not in compliance with Canadian law, with limited exceptions, such as foreign drug products imported under emergency authorization. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_704", "text": "The DIN is also a tool to help in the follow-up of products on the market, recall of products, inspections, and quality monitoring. \nA drug product can be looked up via its DIN with the Health Canada's Drug Product Database (DPD) to find specific information of drugs approved by the Ministry. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_705", "text": "The  drug policy  of  Germany  is considered to be one of the most lenient among  European Union  (EU) countries. Policies vary depending on the  state ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_706", "text": "In 1994, the  Federal Constitutional Court  ruled that drug addiction and the possession of small quantities of narcotics for personal use were not crimes. In 2000, the German law on narcotics ( Bet\u00e4ubungsmittelgesetz ) was changed to allow supervised injection rooms. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_707", "text": "In 2002, a pilot project was started in seven German cities to evaluate the effects of  heroin-assisted treatment  on addicts, compared to  methadone -assisted treatment. In 2009, the positive results of the study led to heroin-assisted treatment becoming included in mandatory health insurance. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_708", "text": "As of November 2010, the youth organisation of  Alliance 90/The Greens , namely the  Green Youth , support the decriminalisation of those who consume drugs and the regulated sale of drugs via specialist stores along with drug education. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_709", "text": "In February 2021, authorities in Germany and  Belgium  seized more than 23 tonnes (23 long tons; 25 short tons) of  cocaine , worth billions of  euros , from shipments that originated in  Paraguay  and  Panama . In an international operation that resulted in one arrest, a man from  Vlaardingen , Netherlands, German and Belgian authorities seized the largest amount of cocaine in Europe. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_710", "text": "In 2017, Germany re-allowed medical cannabis. After the  2021 German federal election , the  new government  announced in their  coalition agreement  that they intend to legalise cannabis for all purposes (including  recreational ), and legislation to this effect was passed on 23 February 2024. The  German cannabis control bill  law went into effect on 1 April."}
{"_id": "WikiPedia_Pharmacology$$$corpus_711", "text": "In March 2023, the health minister,  Karl Lauterbach , reported a positive reaction from European Commission on the plan, and intended to bring a bill forward soon. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_712", "text": "This  crime -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_713", "text": "This  Germany -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_714", "text": "This article about  German law  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_715", "text": "This article about  politics  in  Germany  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_716", "text": "This  psychoactive drug -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_717", "text": "Drug titration  is the process of adjusting the  dose  of a  medication  for the maximum benefit without  adverse effects . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_718", "text": "When a drug has a narrow  therapeutic index , titration is especially important, because the range between the dose at which a drug is effective and the dose at which side effects occur is small. [ 2 ]  Some examples of the types of drugs commonly requiring titration include  insulin ,  anticonvulsants ,  blood thinners ,  anti-depressants , and  sedatives . [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_719", "text": "Titrating off of a medication instead of stopping abruptly is recommended in some situations.  Glucocorticoids  should be tapered after extended use to avoid adrenal insufficiency. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_720", "text": "Drug titration is also used in  phase I  of  clinical trials . The  experimental drug  is given in increasing dosages until side effects become intolerable. [ 7 ]   A clinical trial in which a suitable dose is found is called a  dose-ranging study ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_721", "text": "In  pharmacology  and  medicine ,  vectorization of drugs  refers to ( intracellular )  targeting  with plastic,  noble metal  or  silicon   nanoparticles  or  liposomes  to which  pharmacologically active  substances are reversibly bound or attached by  adsorption . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_722", "text": "CNRS  researchers have devised a way to overcome the problem of  multidrug resistance  using polyalkyl  cyanoacrylate  (PACA) nanoparticles as \" vectors \". [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_723", "text": "As a developing concept,  drug nanocarriers  are expected to play a major role in delivering multiple drugs to  tumor  tissues by overcoming semi-permeable membranes and biological barriers such as the  blood\u2013brain barrier . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_724", "text": "Dual amylin and calcitonin receptor agonists  (DACRAs) are a class of drugs that act as agonists at the  amylin receptor  and  calcitonin receptor  that are under development as therapies for obesity and type 2 diabetes. Examples are  cagrilintide ,  Petrelintide ,  ACCG-2671  and the KBP family derived from  salmon calcitonin , [ 1 ]  including  KBP\u2010042 , [ 2 ]   KBP-066A , [ 3 ]   KBP-089 , [ 4 ]  and  KBP-336 . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_725", "text": "Durlobactam  is a  beta-lactamase inhibitor  used in combination with  sulbactam  to treat susceptible strains of bacteria in the genus  Acinetobacter [ 1 ]  It is an analog of  avibactam ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_726", "text": "The combination therapy  sulbactam/durlobactam  was approved for medical use in the United States in May 2023. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_727", "text": "Ear instillation  is the process of introducing  otic medication  or other liquids into the  ear canal . Proper care is needed in delivering such liquids."}
{"_id": "WikiPedia_Pharmacology$$$corpus_728", "text": "Edotreotide  ( USAN , also known as ( DOTA 0 - Phe 1 - Tyr 3 )  octreotide ,  DOTA-TOC ,  DOTATOC ) is a substance which, when bound to various  radionuclides , is used in the treatment and diagnosis of certain types of cancer. [ 3 ]  When used therapeutically it is an example of  peptide receptor radionuclide therapy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_729", "text": "A  phase I clinical trial  of  yttrium-90  labelled edotreotide concluded in 2011, [ 4 ]  aiming to investigated effects in young cancer patients (up to 25 years of age).  Specific cancers being included in the trial include  neuroblastoma , childhood  brain tumours  and  gastrointestinal cancer . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_730", "text": "A  phase II trial  for the use of  90 Y DOTA-TOC for patients with  metastatic   carcinoid , where  octreotide  treatment was no longer effective, also reported results in 2010. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_731", "text": "Lutetium-177  labelled edotreotide ( 177 Lu-DOTA-TOC), with the  trade name  Solucin, is the subject of a  phase 3 clinical trial  for treatment of  GEP-NETs . [ 7 ] [ 8 ]  It was granted  orphan drug designation  by the  European Medicines Agency  in 2014. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_732", "text": "Gan Ee Kiang  (born 23 June 1944) is a  Malaysian  pharmacologist. He is Professor of Pharmacology at the  University of Science, Malaysia , and currently holds the honorary office of  Chancellor  of the  International Medical University  in  Kuala Lumpur . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_733", "text": "He joined the University of Science in 1977 and was Dean of School of Pharmaceutical Sciences from 1979 to 1995. He has also served as an adviser to the  World Health Organization . From 1999 to 2013 he was Managing Director of the USAINS Group, the commercial arm of the University of Science. He is a member of the Board of Directors of several companies. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_734", "text": "He earned a PhD in Pharmacology at the  University of Western Australia  in 1972 under the supervision of Mary Fauriel Lockett, the first female professor in Australia. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_735", "text": "This biographical article related to medicine in Malaysia is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_736", "text": "EF-24  is a compound that is a synthetic analogue of  curcumin , a bioactive  phytochemical  from  turmeric . Curcumin has  antioxidant ,  antibiotic ,  anti-inflammatory  and anti- cancer  properties  in vitro  but has low potency and very poor bioavailability when taken orally, resulting in limited efficacy. EF-24 was developed to try to improve upon these properties, and has been found to be around 10 times more potent than curcumin and with much higher systemic bioavailability. It has never been developed for medical use, though research continues to investigate whether it may be useful as an  adjuvant treatment  for some  cancers  alongside conventional  chemotherapy  drugs. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_737", "text": "Efaroxan  is an  \u03b1 2 -adrenergic receptor   antagonist [ 1 ]  and  antagonist  of the  imidazoline receptor ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_738", "text": "The  Darzens reaction  between 2-fluorobenzaldehyde [57848-46-1] ( 1 ) and Ethyl 2-bromobutyrate [533-68-6] ( 2 ) gives ethyl 2-ethyl-3-(2-fluorophenyl)oxirane-2-carboxylate,  CID:100942311  ( 3 ). A catalytic hydrogenation over Pd/C would give ethyl 2-[(2-fluorophenyl)methyl]-2-hydroxybutanoate,  CID:77591056  ( 4 ).  Saponification  of the ester then gives 2-[(2-Fluorophenyl)methyl]-2-hydroxybutanoic acid,  CID:53869347  ( 5 ). Treatment with 2 molar equivalents of  sodium hydride  apparently gives 2-Ethyl-2,3-dihydrobenzofuran-2-carboxylic acid [111080-50-3] ( 6 ). Treatment of the carboxylic acid with  thionyl chloride  then gives the acid chloride and subsequent treatment of this with  ethylenediamine  in the presence of trimethylaluminium completed the synthesis of  Efaroxan  ( 8 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_739", "text": "Efgartigimod alfa/hyaluronidase , sold under the brand name  Vyvgart Hytrulo , is a  coformulation medication  used for the treatment of generalized  myasthenia gravis  and  chronic inflammatory demyelinating polyneuropathy . [ 1 ]  It contains  efgartigimod alfa , a  neonatal Fc receptor  blocker, and  hyaluronidase  (human recombinant), an  endoglycosidase . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_740", "text": "Efgartigimod alfa/hyaluronidase may increase the risk of infection, including urinary tract infection and respiratory tract infections. [ 2 ]  In clinical trials, hypersensitivity reactions, including rash, angioedema (swelling), dyspnea (shortness of breath), and urticaria (itchy welts) were observed in people treated with efgartigimod alfa. [ 2 ]  The most common adverse reactions (\u2265 10%) of people with myasthenia gravis treated with efgartigimod alfa were respiratory tract infections, headache, and urinary tract infection. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_741", "text": "It was approved for medical use in the United States in June 2023. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_742", "text": "Efgartigimod alfa/hyaluronidase is  indicated  for the treatment of generalized myasthenia gravis in adults who are anti-acetylcholine receptor antibody positive. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_743", "text": "In June 2024, the US  Food and Drug Administration  (FDA) expanded the indication for the combination to include the treatment of  chronic inflammatory demyelinating polyneuropathy  in adults. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_744", "text": "The effectiveness of the combination for the treatment of adults with chronic inflammatory demyelinating polyneuropathy was established in a two stage, multicenter study (Study 3; NCT04281472). [ 2 ]  Study 3 included an open-label period (stage A) to identify people who had evidence of improvement with the use of Vyvgart Hytrulo, who then entered a randomized, double-blind, placebo-controlled, withdrawal period (stage B). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_745", "text": "Efinopegdutide  (MK-6024) is a dual agonist of the  glucagon  and  GLP-1 receptors . It is being developed by  Merck  for  non-alcoholic fatty liver disease . It was also developed for type 2 diabetes and obesity but these indications were discontinued. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_746", "text": "Efocipegtrutide  (HM15211) is a triple agonist of the  glucagon ,  GIP , and  glucagon-like peptide 1 receptors . It is being studied for obesity and  nonalcoholic steatohepatitis . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_747", "text": "Efpeglenatide  is a  GLP-1 receptor agonist  under development for the treatment of type 2 diabetes and obesity and reducing the risk of cardiovascular incidents in people with these conditions. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]  Its developer is  Hanmi Pharmaceutical . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_748", "text": "EHNA  ( e rythro-9-(2- h ydroxy-3- n only) a denine) is a potent  adenosine deaminase  inhibitor, [ 1 ]  which also acts as a  phosphodiesterase inhibitor  that selectively inhibits  phosphodiesterase type 2  (PDE2). [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_749", "text": "Eladocagene exuparvovec , sold under the brand name  Upstaza  among others, is a  gene therapy  product for the treatment of  aromatic L\u2011amino acid decarboxylase (AADC) deficiency . [ 3 ]  It infuses the gene encoding for the human aromatic L-amino acid decarboxylase enzyme into the  putamen region of the brain . [ 3 ]  The subsequent expression of aromatic L-amino acid decarboxylase results in  dopamine  production and, as a result, development of motor function in people with aromatic L-amino acid decarboxylase deficiency. [ 3 ]  Eladocagene exuparvovec is an adeno-associated virus vector-based gene therapy. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_750", "text": "The most common side effects include initial insomnia, irritability and dyskinesia. [ 3 ]  The most common side effects of eladocagene exuparvovec (Kebilidi) include dyskinesia (involuntary muscle movements), fever, low blood pressure, anemia (low red blood cell count), increased saliva production, insomnia, low levels of potassium, phosphate, and/or magnesium, and procedural complications such as respiratory and cardiac arrest. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_751", "text": "Eladocagene exuparvovec was approved for medical use in the European Union in July 2022, [ 3 ]  and in the United States in November 2024. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_752", "text": "Eladocagene exuparvovec is  indicated  for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_753", "text": "Aromatic L-amino acid decarboxylase deficiency is a rare genetic disorder that affects the production of some neurotransmitters, which are chemical messengers that allow cells in the body's nervous system to communicate with each other. [ 4 ]  Affected individuals may experience symptoms such as delays in gross motor function (head control, sitting, standing, and walking), hypotonia (weak muscle tone), and developmental and cognitive delays. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_754", "text": "Eladocagene exuparvovec is contraindicated in people who have not achieved skull maturity assessed by neuroimaging. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_755", "text": "The safety and effectiveness of eladocagene exuparvovec were demonstrated in an open-label, single-arm clinical study in 13 children with confirmed diagnosis of aromatic L-amino acid decarboxylase deficiency. [ 4 ]  At the start of the study, all participants had no gross motor function (the most severe presentation of aromatic L-amino acid decarboxylase deficiency) and decreased aromatic L-amino acid decarboxylase activity in the plasma. [ 4 ]  Participants treated with eladocagene exuparvovec were compared to untreated participants (natural history). [ 4 ]  Motor milestone assessments were completed for 12 of the 13 participants at week 48 after receiving the treatment. [ 4 ]  The efficacy of eladocagene exuparvovec was demonstrated based on gross motor function improvement in 8 of 12 treated participants, which has not been reported in untreated participants with the severe presentation of aromatic L-amino acid decarboxylase deficiency. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_756", "text": "In May 2022, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Upstaza, intended for the treatment of aromatic L\u2011amino acid decarboxylase (AADC) deficiency. [ 6 ] [ 7 ]  As Upstaza is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies. [ 6 ]  The applicant for this medicinal product is PTC Therapeutics International Limited. [ 6 ]  Eladocagene exuparvovec was approved for medical use in the European Union in July 2022. [ 3 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_757", "text": "Eladocagene exuparvovec was approved for medical use in the United States in November 2024. [ 4 ] [ 9 ]  The US  Food and Drug Administration  (FDA) granted the application for eladocagene exuparvovec  priority review  and  orphan drug  designations, and a rare pediatric disease priority review voucher. [ 4 ]  It was approved under the  accelerated approval  pathway. [ 4 ]  The FDA granted approval of Kebilidi to PTC Therapeutics. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_758", "text": "Eladocagene exuparvovec is the  international nonproprietary name  (INN), [ 10 ]  and the  United States Adopted Name . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_759", "text": "Elezanumab  (development names AE12-1Y-QL and ABT-555) is a fully human  monoclonal antibody  developed by  AbbVie  against  repulsive guidance molecule A  (RGMa). It has been tested in people with  multiple sclerosis  and  acute ischemic stroke . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_760", "text": "The  elimination rate constant   K  or  K e  is a value used in  pharmacokinetics  to describe the rate at which a  drug  is removed from the human system. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_761", "text": "It is often abbreviated  K  or  K e . It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of  T \u22121 . This can be expressed mathematically with the  differential equation"}
{"_id": "WikiPedia_Pharmacology$$$corpus_762", "text": "where  \n \n \n \n \n C \n \n t \n \n \n \n \n {\\displaystyle C_{t}} \n \n  is the  blood plasma  concentration of drug in the system at a given point in time  \n \n \n \n t \n \n \n {\\displaystyle t} \n \n ,  \n \n \n \n d \n t \n \n \n {\\displaystyle dt} \n \n  is an infinitely small change in time, and  \n \n \n \n \n C \n \n t \n + \n d \n t \n \n \n \n \n {\\displaystyle C_{t+dt}} \n \n  is the concentration of drug in the system after the infinitely small change in time."}
{"_id": "WikiPedia_Pharmacology$$$corpus_763", "text": "The solution of this differential equation is useful in calculating the concentration after the administration of a single dose of drug via IV bolus injection:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_764", "text": "In first-order (linear) kinetics, the plasma concentration  \n \n \n \n \n C \n \n t \n \n \n \n \n {\\displaystyle C_{t}} \n \n  of a drug at a given time t after single dose administration via IV bolus injection is given by;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_765", "text": "C \n \n t \n \n \n = \n \n \n \n C \n \n 0 \n \n \n \n 2 \n \n \n t \n \n t \n \n 1 \n \n / \n \n 2 \n \n \n \n \n \n \n \n \n \n \n {\\displaystyle C_{t}={\\frac {C_{0}}{2^{\\frac {t}{t_{1/2}}}}}\\,}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_766", "text": "where:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_767", "text": "Therefore, the amount of drug present in the body at time t  \n \n \n \n \n A \n \n t \n \n \n \n \n {\\displaystyle A_{t}} \n \n  is;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_768", "text": "A \n \n t \n \n \n = \n \n V \n \n d \n \n \n \u22c5 \n \n C \n \n t \n \n \n = \n \n V \n \n d \n \n \n \u22c5 \n \n \n \n C \n \n 0 \n \n \n \n 2 \n \n \n t \n \n t \n \n 1 \n \n / \n \n 2 \n \n \n \n \n \n \n \n \n \n \n {\\displaystyle A_{t}=V_{d}\\cdot C_{t}=V_{d}\\cdot {\\frac {C_{0}}{2^{\\frac {t}{t_{1/2}}}}}\\,}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_769", "text": "where  V d  is the apparent volume of distribution"}
{"_id": "WikiPedia_Pharmacology$$$corpus_770", "text": "Then, the amount eliminated from the body after time t  \n \n \n \n \n E \n \n t \n \n \n \n \n {\\displaystyle E_{t}} \n \n  is;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_771", "text": "E \n \n t \n \n \n = \n \n V \n \n d \n \n \n \u22c5 \n \n \n C \n \n 0 \n \n \n \n \n \n ( \n \n \n 1 \n \u2212 \n \n \n 1 \n \n 2 \n \n \n t \n \n t \n \n 1 \n \n / \n \n 2 \n \n \n \n \n \n \n \n \n \n ) \n \n \n \n \n \n {\\displaystyle E_{t}=V_{d}\\cdot {C_{0}}{\\Biggl (}1-{\\frac {1}{2^{\\frac {t}{t_{1/2}}}}}{\\Biggr )}\\,}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_772", "text": "Then, the rate of elimination at time t is given by the derivative of this function with respect to t;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_773", "text": "d \n \n E \n \n t \n \n \n \n \n d \n t \n \n \n \n = \n \n \n \n \n ln \n \u2061 \n 2 \n \u22c5 \n \n \n V \n \n d \n \n \n \u22c5 \n \n \n C \n \n 0 \n \n \n \n \n \n \n \n 2 \n \n \n t \n \n t \n \n 1 \n \n / \n \n 2 \n \n \n \n \n \n \u22c5 \n \n \n t \n \n 1 \n \n / \n \n 2 \n \n \n \n \n \n \n \n \n \n \n {\\displaystyle {dE_{t} \\over dt}={{\\frac {\\ln 2\\cdot {V_{d}\\cdot {C_{0}}}}{2^{\\frac {t}{t_{1/2}}}\\cdot {t_{1/2}}}}\\,}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_774", "text": "And since  \n \n \n \n K \n \n \n {\\displaystyle K} \n \n  is fraction of the drug that is removed per unit time measured at any particular instant, then if we divide the rate of elimination by the amount of drug in the body at time t, we get;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_775", "text": "K \n = \n \n \n \n d \n \n E \n \n t \n \n \n \n \n d \n t \n \n \n \n \u00f7 \n \n A \n \n t \n \n \n = \n \n \n \n ln \n \u2061 \n 2 \n \n \n t \n \n 1 \n \n / \n \n 2 \n \n \n \n \n \u2248 \n \n \n 0.693 \n \n t \n \n 1 \n \n / \n \n 2 \n \n \n \n \n \n \n {\\displaystyle K={dE_{t} \\over dt}\\div A_{t}={\\frac {\\ln 2}{t_{1/2}}}\\approx {\\frac {0.693}{t_{1/2}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_776", "text": "Finley Ellingwood  was an American doctor of  eclectic medicine  who was the author of the influential  American Materia Medica , therapeutics, and pharmacognosy in 1919. Ellingwood was an active Chicago physician with many years experience, and an acknowledged expert in  obstetrical / gynecological  medicine. He was a vocal advocate of women physicians, and edited  Ellingwood's Therapeutist  for many years. His brand of Eclectic Medicine differed from the more subdued Cincinnati style as mentored by Scudder, Lloyd, Fyfe, and Felter. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_777", "text": "The American Materia Medica, Therapeutics and  Pharmacognosy  is a serious medical text from the early 20th century, intended for practicing physicians and surgeons, which refers to difficult medical situations found in that period. There is an emphasis on physical diagnosis.  The book is organized by organ system affected instead of by herbal name, so it will have headings such as \"agents acting on the  nervous system \" or \"agents acting on the  heart \". This type of listing is somewhat controversial as  herbal medicines  tend to work on more than one system.  The book had been substantially lost until it was scanned by herbalist  Michael Moore  in pdf format. [ 2 ]  The book is also available in  HTML  format at  Henriette Kress 's website. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_778", "text": "This article about a  herbalist  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_779", "text": "This biographical article related to a physician in the United States is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_780", "text": "Eltrekibart  (LY3041658) is a \"septa-specific  monoclonal antibody  that neutralizes all seven ELR+\u2009CXC chemokines ( CXCL1-3  and  CXCL5-8 ), thereby limiting signaling through  CXCR1  and  CXCR2 \". [ 1 ]  It was tested in clinical trials for  hidradenitis suppurativa . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_781", "text": "Emavusertib  ( CA-4948 ) is a drug which acts as a selective inhibitor of the enzyme  Interleukin-1 receptor-associated kinase 4  (IRAK-4) and was developed for the treatment of some forms of  cancer . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_782", "text": "Emraclidine  (developmental code names  CVL-231 ,  PF-06852231 ) is an investigational  antipsychotic  for the treatment of both  schizophrenia  and  Alzheimer's disease  psychosis developed by  Cerevel Therapeutics . [ 1 ] [ 2 ]  As of August 2024, it is in  phase 2   clinical trials . [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_783", "text": "Emraclidine is a  positive allosteric modulator  that selectively targets the  muscarinic acetylcholine receptor M4  subtype. The M4 receptor subtype is expressed in the  striatum  of the brain, which plays a key role in regulating  acetylcholine  and  dopamine  levels. An imbalance of these neurotransmitters has been linked to psychotic symptoms in schizophrenia. Unlike other  muscarinic receptors , M4 receptor subtypes are selectively expressed in the striatum and activation of these receptors has been shown to indirectly regulate dopamine levels without blocking  D2 / D3  receptors, which may lead to unwanted motor side effects seen in current antipsychotics. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_784", "text": "Enbezotinib  ( TPX-0046 ) is an experimental  anticancer medication  which acts as a  RET inhibitor , as well as an inhibitor of  SRC kinase . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_785", "text": "An  endocannabinoid enhancer  ( eCBE ) is a type of  cannabinoidergic [ 1 ]   drug  that enhances the activity of the  endocannabinoid system  by increasing  extracellular   concentrations  of  endocannabinoids . [ 2 ] [ 3 ] [ 4 ] [ 5 ]  Examples of different types of eCBEs include  fatty acid amide hydrolase  (FAAH)  inhibitors ,  monoacylglycerol lipase  (MAGL)  inhibitors , and  endocannabinoid transporter  (eCBT) inhibitors (or \" endocannabinoid reuptake inhibitors \" (\"eCBRIs\")). [ 2 ] [ 3 ] [ 4 ] [ 5 ]  An example of an actual eCBE is  AM404 , the  active metabolite  of the  analgesic   paracetamol  (acetaminophen; Tylenol) and a dual FAAH inhibitor and eCBRI. [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_786", "text": "An  endopeptidase inhibitor  is a drug that  inhibits  one or more  endopeptidase   enzymes . Endopeptidases are one of two types of  proteases  (enzymes that break down  proteins  and  peptides ), the other being  exopeptidases . Endopeptidases cleave  peptide bonds  of non-terminal  amino acids  (that is, they cut proteins/peptides into two chains), whereas exopeptidases break terminal bonds, resulting in the release of a single amino acid or  dipeptide  from the peptide chain."}
{"_id": "WikiPedia_Pharmacology$$$corpus_787", "text": "Some examples of endopeptidase inhibitors include the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_788", "text": "Enitociclib  is an  experimental drug  that is being investigated for the treatment of cancer. [ 1 ]  It is an inhibitor of the kinase  CDK9 . [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_789", "text": "Enlicitide chloride  (INN; [ 1 ]  previously known as  MK-0616 ) is a  macrocyclic  peptide  investigational drug  who is being evaluated for the treatment of  hypercholesterolaemia . It is a  PCSK9  inhibitor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_790", "text": "Merck has launched a Phase 3 clinical trial to evaluate the efficacy and safety of  MK-0616  in Adults With Hypercholesterolemia.  [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_791", "text": "Ensartinib , sold under the brand name  Ensacove , is an  anti-cancer medication  used for the treatment of  non-small cell lung cancer . [ 1 ]  Ensartinib is an  Anaplastic lymphoma kinase  (ALK) inhibitor used as the salt ensartinib hydrochloride. [ 1 ]  It is taken  by mouth . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_792", "text": "The most common adverse reactions include rash, musculoskeletal pain, constipation, cough, pruritis, nausea, edema, pyrexia, and fatigue. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_793", "text": "Ensartinib was approved for medical use in the United States in December 2024. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_794", "text": "Ensartinib is  indicated  for the treatment of adults with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer who have not previously received an ALK-inhibitor. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_795", "text": "Efficacy was evaluated in eXALT3 (NCT02767804), an open-label, randomized, active-controlled, multicenter trial in 290 participants with locally advanced or metastatic ALK-positive non-small cell lung cancer who had not previously received an ALK-targeted therapy. [ 2 ]  Participants were randomized 1:1 to receive ensartinib or crizotinib. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_796", "text": "Ensartinib was approved for medical use in the United States in December 2024. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_797", "text": "Ensartinib is the  international nonproprietary name . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_798", "text": "Ensartinib is sold under the brand name Ensacove. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_799", "text": "Envafolimab  is an anti- PD-L1   nanobody  used in  cancer immunotherapy . [ 1 ]   It has been approved in China for the treatment of  microsatellite instability -high (MSI-H) or  MisMatch Repair  deficient (dMMR) solid tumours. [ 2 ]  Envafolimab (KN035) has obtained the US FDA's orphan drug designation for advanced biliary tract cancer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_800", "text": "Envudeucitinib  is an  investigational new drug  that is being evaluated for the treatment of  psoriasis .  It is a selective  tyrosine kinase  2 (TYK2) inhibitor developed by \nFronthera U.S. Pharmaceuticals LLC for the treatment of  autoimmune diseases . Envudeucitinib targets the TYK2 signaling pathway, which plays a crucial role in regulating multiple pro-inflammatory cytokines such as  IL-12 ,  IL-23 , and  type I interferons . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_801", "text": "Enzomenib  is an  investigational new drug  that is being evaluated for the treatment of acute leukemia. [ 1 ]   It is a small molecule inhibitor that targets the interaction between  menin  and  mixed-lineage leukemia  (MLL) proteins. [ 2 ]  Enzomenib particularly in patients with KMT2A (MLL) rearrangements or NPM1 mutations. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_802", "text": "The U.S. Food and Drug Administration (FDA) has granted both  Fast Track  and  Orphan Drug  designations to Enzomenib. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_803", "text": "An  enzyme modulator  is a type of  drug  which modulates  enzymes . They include  enzyme inhibitors  and  enzyme inducers . In an homogeneous  assay , \"an enzyme modulator ... is  covalently  linked to the ligand which competes with free ligand from the test sample for the available antibodies.\" [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_804", "text": "Epaminurad  is an  investigational new drug   being developed by JW Pharmaceutical for the treatment of  gout  and  hyperuricemia . It is a urate-lowering agent that selectively inhibits the human  uric acid transporter 1  (hURAT1), promoting  urate  excretion. [ 1 ] [ 2 ]  As of 2024, epaminurad is undergoing Phase 3 clinical trials to evaluate its efficacy and safety compared to  febuxostat  in gout patients across multiple Asian countries. [ 3 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_805", "text": "Eplontersen , sold under the brand name  Wainua , is a  medication  used for the treatment of  transthyretin-mediated amyloidosis . [ 3 ]  It is a transthyretin-directed antisense oligonucleotide. [ 3 ]  It was developed to treat hereditary transthyretin amyloidosis by  Ionis Pharmaceuticals  and  AstraZeneca . [ 4 ] [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_806", "text": "Eplontersen was approved for medical use in the United States in December 2023 and in the UK in October 2024. [ 3 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_807", "text": "Eplontersen is  indicated  for the treatment of the  polyneuropathy  of hereditary transthyretin-mediated amyloidosis in adults. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_808", "text": "The most common adverse reactions include decreased vitamin A and vomiting. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_809", "text": "In October 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Wainzua, intended for the treatment of adults with hereditary transthyretin-mediated amyloidosis (ATTRv) and stage 1 or 2 polyneuropathy. [ 12 ]  The applicant for this medicinal product is AstraZeneca AB. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_810", "text": "Eplontersen is the  international nonproprietary name . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_811", "text": "Epoetin theta , sold under the brand name  Biopoin  among others, is a copy of the human hormone  erythropoietin . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_812", "text": "The most common side effects include shunt thrombosis (clots that can form in blood vessels of patients on dialysis, a blood clearance technique),  headache ,  hypertension  (high blood pressure),  hypertensive crisis  (sudden, dangerously high blood pressure),  skin reactions ,  arthralgia  (joint pain) and  influenza  (flu)-like illness. [ 1 ] Epoetin theta was approved for medical use in the European Union in October 2009. [ 1 ]  It is on the  World Health Organization's List of Essential Medicines . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_813", "text": "Epoetin theta is  indicated  for the treatment of symptomatic  anemia  in adults. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_814", "text": "attribution  contains material copied from Biopoin | European Medicines Agency  https://www.ema.europa.eu/en/medicines/human/EPAR/biopoin  2021"}
{"_id": "WikiPedia_Pharmacology$$$corpus_815", "text": "Epsametostat  is an  investigational new drug  that is being evaluated for the treatment of peripheral  T-cell lymphoma .  It is a  EZH1 / EZH2  inhibitor developed by Shanghai Haihe Pharmaceutical Research & Development Co., Ltd. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_816", "text": "Erastin  is a small molecule capable of initiating  ferroptotic cell death . [ 1 ]  Erastin binds and activates  voltage-dependent anion channels  (VDAC) by reversing tubulin's inhibition on   VDAC2  and  VDAC3 , [ 2 ]  and functionally inhibits the cystine-glutamate antiporter  system X c \u2212 . [ 3 ]  Cells treated with erastin are deprived of  cysteine  and are unable to synthesize the antioxidant  glutathione . Depletion of glutathione eventually leads to excessive  lipid peroxidation  and  cell death ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_817", "text": "Erastin was first described in 2003. Its name is short for \"eradicator of RAS and ST-expressing cells\". [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_818", "text": "Erfonrilimab  is a  investigational drug  being evaluated for use in  cancer immunotherapy . [ 1 ]  It is a bispecific antibody targeting  PD-L1  and  CTLA-4 . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_819", "text": "Erythromycin/sulfafurazole  ( trade name   Pediazole ) is a  combination drug  with the  antibiotics   erythromycin  and  sulfafurazole  (the latter is also known as sulfisoxazole). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_820", "text": "It is indicated in  acute otitis media  in children, particularly when  Hemophilus influenzae  is the suspected pathogen. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_821", "text": "4-Ethylphenyl sulfate  ( 4EPS ) is a metabolite produced by gut bacteria, which can be toxic when present in large amounts. Elevated levels of this metabolite have been associated with some medical conditions including  chronic kidney disease  and  autism . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_822", "text": "Evazarsen sodium  (IONIS-AGT-LRx) is an  antisense RNA  designed to inhibit  angiotensinogen  as an alternative to other mechanisms to target the  renin\u2013angiotensin\u2013aldosterone system . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_823", "text": "An  excitatory amino acid receptor antagonist , or  glutamate receptor antagonist , is a  chemical substance  which  antagonizes  one or more of the  glutamate receptors . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_824", "text": "Examples include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_825", "text": "Excitatory amino acid receptor ligands  are  ligands  of  excitatory amino acid receptors  (EAARs), also known as  glutamate receptors . They include  excitatory amino acid receptor agonists  and  excitatory amino acid receptor antagonists . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_826", "text": "This  biochemistry  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_827", "text": "An  excitatory amino acid reuptake inhibitor  ( EAARI ) is a type of  drug  which inhibits the  reuptake  of the  excitatory   neurotransmitters   glutamate  and  aspartate  by blocking one or more of the  excitatory amino acid transporters  (EAATs)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_828", "text": "Examples of EAARIs include  dihydrokainic acid  (DHK) and  WAY-213,613 , selective blockers of  EAAT2  (GLT-1), [ 1 ] [ 2 ]  and  L - trans -2,4-PDC , a non-selective blocker of all five EAATs. [ 3 ]   Amphetamine  is a selective noncompetitive reuptake inhibitor of presynaptic  EAAT3  (via transporter endocytosis) in dopamine neurons. [ 4 ] [ 5 ] [ 6 ]   L -Theanine  is reported to competitively inhibit reuptake at  EAAT1  (GLAST) and  EAAT2  (GLT-1). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_829", "text": "An  exopeptidase inhibitor  is a  drug  that  inhibits  one or more  exopeptidase   enzymes . Exopeptidases are one of two types of  proteases  (enzymes that break down  proteins  and  peptides ), the other being  endopeptidases . Exopeptidases cleave  peptide bonds  of terminal  amino acids , resulting in the release of a single amino acid or  dipeptide  from the peptide chain, whereas endoeptidases break non-terminal bonds (that is, they cut proteins/peptides into two chains)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_830", "text": "Some examples of exopeptidase inhibitors include  amastatin ,  bestatin  (ubenimex),  puromycin ,  1,10-phenanthroline ,  D -phenylalanine ,  ACE inhibitors ,  DPP-4 inhibitors , and  exogenous   MMP inhibitors  like  batimastat  and  marimastat . Various  enkephalinase inhibitors , such as  ketalorphan ,  spinorphin , and  tynorphin , are mainly exopeptidase inhibitors. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_831", "text": "The  Fabunan Antiviral Injection  ( FAI ) is a patented medicine administered to patients by US-based  Filipino  doctors Ruben and Willie Fabunan, who assured that it can treat  dengue fever ,  chikungunya , dog bite, snakebite, and  HIV /AIDS. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_832", "text": "Fabunan contains  procaine hydrochloride , a water-soluble ester  anesthetic , and  dexamethasone sodium phosphate , a  corticosteroid  with well-known  anti-inflammatory  and  immunosuppressant  properties. [ 2 ]  The solution is intended to be administered as an  intramuscular injection ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_833", "text": "The patent application cites six case studies for conditions such as  dengue ,  dengue hemorrhagic fever  and  AIDS , which were all conducted at the Fabunan Medical Clinic in  Burgos . To date, no registered  clinical trials  of the Fabunan Antiviral Injection have been performed to validate the Fabunans' claims."}
{"_id": "WikiPedia_Pharmacology$$$corpus_834", "text": "Recent claims promoted on social media that it can cure  COVID-19  are not supported by the  Philippine government , which has issued a  cease and desist order  to Fabunan Medical Clinic in  Zambales , prompting the clinic to stop its operations on April 2. [ 3 ] [ 4 ]  On April 15, 2020, the  fact-checking  website  Rappler  warned against false claims on  YouTube  and  Facebook  that the so-called treatment had been approved, and pointed out that on April 8, 2020, the FDA warned the public against the use of drugs or vaccines that are not yet certified to treat COVID-19, particularly the Fabunan Antiviral Injection. [ 5 ]  Similarly, claims popularly spread in YouTube videos in June 2020 that Fabunan has been approved in Indonesia have been demonstrated to be false. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_835", "text": "This article about the  COVID-19 pandemic  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_836", "text": "The  Farmacotherapeutisch Kompas  (FK) contains a wide spectrum of information on prescribing and  pharmacology , among others indications,  side effects  and costs of the prescription of all  pharmaceutical drugs  available in the  Netherlands . It was first published in 1982 and is now the most used drug reference by  doctors ,  pharmacists  and students in the Netherlands. It is published by the  College voor zorgverzekeringen  (CVZ)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_837", "text": "In English, the name means  ' pharmacotherapeutic compass ' ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_838", "text": "This  Netherlands -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_839", "text": "Favezelimab  (MK-4280) is an experimental anti-cancer  monoclonal antibody  developed by  Merck . It is being tested by itself [ 1 ]  and in a  fixed-dose combination  with  pembrolizumab . [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_840", "text": "Favezelimab/pembrolizumab  is a fixed-dose combination of two  monoclonal antibodies  developed by  Merck  to treat various cancers. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_841", "text": "FEM-1689  is a drug which acts as a potent and selective  sigma-2 receptor  ligand with a binding affinity of 11 nM, and was developed for the treatment of  neuropathic pain . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_842", "text": "Ferroquine  is a synthetic compound related to  chloroquine  which acts as an  antimalarial , and shows good activity against chloroquine-resistant strains. [ 1 ]  It contains an  organometallic   ferrocene  ring which is unusual in pharmaceuticals, [ 2 ] [ 3 ] [ 4 ]  and while it was first reported in 1997, [ 5 ]  it has progressed slowly through  clinical trials , with results from Phase II trials showing reasonable safety and efficacy, and further trials ongoing. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_843", "text": "Fexofenadine/pseudoephedrine , sold under the brand name  Allegra-D  among others, is a  fixed-dose combination  medication used for the treatment of nasal congestion and other symptoms of  allergies [ 4 ]  and the  common cold . [ 2 ]  It contains  fexofenadine , as the hydrochloride, an  antihistamine ; and  pseudoephedrine , as the hydrochloride, a  nasal decongestant . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_844", "text": "In 2021, it was the 279th most commonly prescribed medication in the United States, with more than 800,000 prescriptions. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_845", "text": "A  flacon  (from  Late Latin   flasco , meaning \"bottle\"; cf. \" flagon \") is a small, often decorative, bottle. It has an opening seal or stopper and is designed to hold valuable liquids which may deteriorate upon contact with the air. They are widespread in the food industry, the pharmaceutical industry, and the cosmetics industry. They are generally made of glass for perfumes, but can also be made out of plastics for other uses. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_846", "text": "The plastic bottles can be manufactured using different processes depending on the size and the proposed application (i.e. what the content will be, what the surrounding environment will be etc.). A common technique is  blow molding . Like any object made by  extrusion , it is possible to produce multilayer plastic bottles. This is called  coextrusion . The combination of different materials or colours can be used to produce flacons with different properties, such as: impermeability to light, oxygen, recycled inner layer. The glass bottles are manufactured by blow molding."}
{"_id": "WikiPedia_Pharmacology$$$corpus_847", "text": "Charles Baudelaire  wrote a poem about the flacon, entitled  Le Flacon  (The Perfume Flask). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_848", "text": "Other words derived from  flasco :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_849", "text": "This  food -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_850", "text": "Flazalone  is an  anti-inflammatory  drug that has not been approved as a medicine. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_851", "text": "According to  Shaomeng Wang  and co-workers, replacement of the para-fluoro halogen with a meta,para-dichloro substitution resulted in dopamine reuptake inhibitors useful in treating cocaine addiction. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_852", "text": "Flip\u2013flop kinetics , or  flip\u2013flop pharmacokinetics , describes an atypical situation in  pharmacokinetics  where a drug's rate of  absorption  or the rate at which it enters the  bloodstream  is slower than its  elimination  rate. [ 1 ] [ 2 ]  That is, when the  k a  ( absorption constant ) is slower than  k e  ( elimination constant )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_853", "text": "These circumstances can occur with  sustained-release  formulations,  depot injections , and some  subcutaneous  or  intradermal injections . [ 3 ] [ better\u00a0source\u00a0needed ]  In the resulting slope of log plasma concentration (log Cp) versus time, the apparent  k e  is determined by the  k a , and the apparent  k e  is smaller than when the drug is administered intravenously or by immediate-release formulation.  Depot injections such as  depot antipsychotics  and long-acting injectable  steroid hormone  medications like  estradiol valerate ,  testosterone enanthate , and  medroxyprogesterone acetate  are examples of drugs with flip\u2013flop kinetics. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_854", "text": "The term \"flip\u2013flop\" indicates that the downward slope more closely represents  k a  rather than  k e ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_855", "text": "Flip\u2013flop kinetics can create difficulties in the determination and interpretation of pharmacokinetic parameters if not recognized. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_856", "text": "Flotufolastat ( 18 F) , sold under the brand name  Posluma , is a  radioactive diagnostic agent  for use with  positron emission tomography  (PET)  imaging  for  prostate cancer . [ 1 ]  The active ingredient is flotufolastat ( 18 F). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_857", "text": "Flotufolastat ( 18 F) was approved for medical use in the United States in May 2023. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_858", "text": "Flotufolastat ( 18 F) is  indicated  for positron emission tomography of prostate-specific membrane antigen positive lesions in men with prostate cancer. [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_859", "text": "4'-Fluoro-4-methylaminorex  ( 4F-MAR ,  4-FPO ) is a recreational  designer drug  from the substituted  aminorex  family, with  stimulant  effects. It was first detected in Slovenia in 2018. [ 1 ] [ 2 ] [ 3 ]  It was made illegal in Italy in March 2020. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_860", "text": "18 F-Fluorocholine  is a fluorinated  choline  derivative and an  oncologic   PET  tracer. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_861", "text": "Fluorodeoxyglycosylamine  is a product of  fluorodeoxyglucose  and biological amines. [ 1 ]  The  Maillard reaction  of sugars and amines results in the formation of glycosylamines and  Amadori products  that are of biological significance, for drug delivery, role in central nervous system, and other potential applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_862", "text": "This approach has also been used to prepare  oximes  of fluorodeoxyglucose using peptides, [ 2 ]  folic acid [ 3 ]  and rhodamine. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_863", "text": "Fluorodeoxyglycosylamine in the form of fluorodeoxyglycosylamines ( 18 F ) may be reduced to provide fluorodeoxyglucamine ( 18 F) [ 5 ]  as a  positron emission tomography  (PET)  radiotracer ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_864", "text": "Fluoroethyl- l -tyrosine ( 18 F)  commonly known as [ 18 F]FET, is a radiopharmaceutical tracer used in positron emission tomography (PET) imaging. This synthetic amino acid, labeled with the radioactive isotope fluorine-18, is a valuable radiopharmaceutical tracer for use in neuro-oncology for diagnosing, planning treatment, and following up on brain tumors such as gliomas. The tracer's ability to provide detailed metabolic imaging of tumors makes it an essential tool in the clinical management of brain cancer patients. Continued advancements in PET imaging technology and the development of more efficient synthesis methods are expected to further enhance the clinical utility of [ 18 F]FET. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_865", "text": "There are two common pathways for the radiosynthesis of [ 18 F]FET. The first one utilizes a nucleophilic  18 F-fluorination of ethyleneglycol-1,2-ditosylate with a subsequent  18 F-fluoroethylation of a precursor di-potassium salt of L-tyrosine. This sequence requires two purification steps, two different precursors and a dual-reactor synthesis module which is not widely available in research or commercial centers.  [ 3 ] [ 4 ] [ 5 ]  Schematic for this pathway is presented in Figure 1. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_866", "text": "Second route of radiosynthesis is a direct nucleophilic  18 F-fluorination a TET (O-(2-tosyloxy-ethyl)-N-trityl-L-tyrosine tertbutylester) pretected precursor followed by acidic hydrolysis of protecting groups.  [ 3 ] [ 4 ] [ 7 ]  Schematic for this pathway is presented in Figure 2. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_867", "text": "The use of radiolabeled amino acids for brain tumor imaging utilizes the increased proiliferation of tumor cells and overexpression in the amino acid transport system observed in malignant brain tumors.  [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_868", "text": "As far as the [ 18 F]FET is concerned following intravenous injection it is transported into cells primarily through amino acid transporters, particularly system L transporters, which are upregulated in many tumor cells. Once inside the cells, [ 18 F]FET does not undergo significant further metabolism but accumulates in tumor tissues, allowing for their visualization and quantification using PET imaging.  [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_869", "text": "The differential uptake provides a high tumor-to-background contrast, facilitating the detection of primary and recurrent brain tumors. Unlike some other PET tracers, [ 18 F]FET does not significantly accumulate in inflammatory tissues, reducing false positives and improving diagnostic specificity.  [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_870", "text": "Animal studies in rodents have demonstrated high uptake of [ 18 F]FET in brain tumors, with a significant tumor-to-brain ratio, making it a useful tracer for brain tumor imaging. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_871", "text": "Heiss et al. conducted in vitro and in vivo investigation of transport mechanism and uptake of [ 18 F]FET.\u00a0 The experimented utilized human colon carcinoma cells (SW 707) and \u00a0xenotransplanted, tumor-bearing mice. [ 18 F]FET was shown to be transported mainly (>80%) by the l-type amino acid transporter system, which was inhibited by 2-amino-2-norbornanecarboxylic acid (BCH) and not incorporated into proteins in SW 707 cells. This study also help to establish the half-life of [ 18 F]FET in the plasma (94 min), brain-to-blood ratio (0.86) and shower statistically significant higher uptake of [ 18 F]FET in the xenotransplanted tumor than in any other organ beside the pancreas. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_872", "text": "In 1999 biodistribution studies in mice with colon carcinoma cells were conducted by Wester et al. The study showed a high uptake of radioactivity in the pancreas (18% injected dose (ID)/g) at 60 min after injection of [ 18 F]FET. [ 5 ]  The brain (2.17% ID/g) and the tumors (6.37% ID/g) showed moderate uptakes of the radiotracer. \u00a0Rapid distribution of [ 18 F]FET with completion time of less than 5 min was observed for liver, kidney and blood. The other organs showed little elevated uptake with time. [ 18 F]FET remained intact in the tissue tested samples (pancreas, brain, tumor and plasma) and no \u00a0incorporation of radiotracer into proteins was observed. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_873", "text": "Another biodistribution study was carried out by Wang et al. In this study the comparison between [ 18 F]FDG and [ 18 F]FET in rats with gliomas showed a moderate uptake and a long retention time of [ 18 F]FET in liver, kidneys, lung, heart and blood whereas a diminished uptake was observed in healthy brain. The maximum uptake of [ 18 F]FET and [ 18 F]FDG in the glioma was observed at 60 min post injection 1.49% and 2.77% ID/g, respectively. The tumor-to-brain ratios were 3.15 for [ 18 F]FET and 1.44 for [ 18 F]FDG. PET images of [ 18 F]FET showed higher uptake and better contrast for tumor vs health tissue. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_874", "text": "Biodistribution studies in mice and rats have shown that [ 18 F]FET is retained in tumor tissues and exhibits low uptake in inflammatory tissues, enhancing its specificity for tumor imaging. [ 14 ]  In vivo experiments have also indicated that [ 18 F]FET can effectively differentiate between high-grade and low-grade tumors based on the level of tracer uptake. [ 13 ]  Additionally, longitudinal studies in animal models have shown that [ 18 F]FET PET imaging can be used to monitor tumor progression and response to therapy, providing valuable insights into the efficacy of treatment regimens. [ 15 ]  These preclinical findings have laid the groundwork for the successful translation of [ 18 F]FET PET imaging into clinical practice."}
{"_id": "WikiPedia_Pharmacology$$$corpus_875", "text": "[ 18 F]FET radiotracer has several clinical applications, particularly in neuro-oncology: [ 9 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_876", "text": "Initial [ 18 F]FET dosimetry was estimated by Pauleit et al. based on human dynamic PET scans after injection of 400 MBq of radiotracer at 70 and 200 min. [ 17 ]  The highest dose was received by bladder (0.060 mGy/MBq) and subsequently by kidneys (0.020 mGy/MBq) and uterus (0.022 mGy/MBq). No increased uptake was observed in the liver, bone, intestine, lung, heart, or pancreas. The effective dose determined by human study was 0.0165 mSv/MBq \u00a0whereas the effective dose based on biodistribution data of mice was estimated to be 0.009 mSv/MBq. [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_877", "text": "Recommended activity dose for and adult (weight 70 kg) is in the range of 180 to 250 MBq."}
{"_id": "WikiPedia_Pharmacology$$$corpus_878", "text": "Based on the Radiation Dose to Patients from Radiopharmaceuticals (4th addendum) the absorbed doses in human organs are presented in the table below. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_879", "text": "[ 18 F]FET has a relatively short shelf life which is a result of radioactive isotope fluorine-18 half life (109.8 minutes). However, in comparison to radiotracers labelled with carbon-11 isotope, it still allows for radiotracer to be  distributed through land and air up to 6 hour delivery radius."}
{"_id": "WikiPedia_Pharmacology$$$corpus_880", "text": "Currently [ 18 F]FET is comercially available in Europe as IASOglio\u00a9 in France (MA number 34009 550 105 1 7/34009 550 105 2 4) and in Poland (MA number 27420). The Marketing Authorization Holder is radiopharmaceutical company called Curium\u2122. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_881", "text": "Flurpiridaz ( 18 F) , sold under the brand name  Flyrcado , is a  cyclotron -produced  radioactive diagnostic agent  for use with  positron emission tomography  (PET)  myocardial perfusion imaging  under rest or stress (pharmacologic or exercise). [ 3 ]  Flurpiridaz ( 18 F) It is given by  intravenous injection . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_882", "text": "The most common adverse reactions include  dyspnea  (shortness of breath),  headache ,  angina pectoris  (severe pain in the chest),  chest pain ,  fatigue ,  ST segment  changes,  flushing ,  nausea ,  abdominal pain ,  dizziness , and  arrhythmia  (irregular heartbeat). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_883", "text": "Flurpiridaz ( 18 F) was approved by the FDA for medical use evaluate for myocardial ischemia and infarction in the United States in September 2024. [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_884", "text": "Flurpiridaz ( 18 F) is  indicated  for positron emission tomography myocardial perfusion imaging under rest or stress (pharmacologic or exercise) in adults with known or suspected coronary artery disease to evaluate for  myocardial ischemia  and infarction. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_885", "text": "Flurpiridaz F-18 is a fluorine 18-labeled agent developed by Lantheus Medical Imaging for the diagnosis of coronary artery disease. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_886", "text": "The efficacy and safety of flurpiridaz ( 18 F) were evaluated in two prospective, multicenter, open-label clinical studies in adults with either suspected CAD (Study 1: NCT03354273) or known or suspected CAD (Study 2: NCT01347710). [ 3 ]  Study 1 evaluated the sensitivity (ability to designate an imaged patient with disease as positive) and specificity (ability to designate an imaged patient without disease as negative) of flurpiridaz ( 18 F) for the detection of significant CAD in subjects with suspected CAD who were scheduled for invasive coronary angiography (ICA). [ 3 ]  Across three flurpiridaz ( 18 F) imaging readers, estimates of sensitivity ranged from 74% to 89% and estimates of specificity ranged from 53% to 70% for CAD defined as at least 50% narrowing of an artery. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_887", "text": "Study 2 evaluated the sensitivity and specificity of flurpiridaz ( 18 F) for the detection of significant CAD in subjects with known or suspected CAD who had ICA without intervention within 60 days prior to imaging or were scheduled for ICA. [ 3 ]  Across three flurpiridaz ( 18 F) imaging readers, estimates of sensitivity ranged from 63% to 77% and estimates of specificity ranged from 66% to 86% for CAD defined as at least 50% narrowing of an artery. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_888", "text": "Flurpiridaz ( 18 F) was approved for medical use in the United States in September 2024. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_889", "text": "Flurpiridaz ( 18 F) is the  international nonproprietary name . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_890", "text": "Fluticasone  is a  manufactured   glucocorticoid  used to treat  nasal congestion . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  Both the  esters ,  fluticasone propionate  (sold as Flovent) and  fluticasone furoate , are also used as  topical   anti-inflammatories  and inhaled  corticosteroids , and are used much more commonly in comparison. [ 3 ] [ 2 ] [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_891", "text": "It is on the  World Health Organization's List of Essential Medicines . [ 7 ]  In 2022, it was the 25th most commonly prescribed medication in the United States, with more than 22 \u00a0 million prescriptions, [ 8 ] [ 9 ]  although it is also sold  over-the-counter  (OTC). [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_892", "text": "Foltx  is a vitamin supplement containing a combination of  vitamin B6  (pyridoxine),  vitamin B12  (cyanocobalamin), and  folic acid  (folacin).  It may be used to treat  hyperhomocysteinemia , a medical condition. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_893", "text": "Fosgonimeton  is an  investigational new drug  that is being evaluated to treat  neurodegenerative  diseases such as  Alzheimer's  and  Parkinson's disease . [ 1 ]  It is a  pro-drug  of the active metabolite  dihexa . Dihexa in turn binds to the  hepatocyte growth factor  (HGF) and potentiates its activity at its receptor,  c-Met . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_894", "text": "Fosigotifator  is an experimental small-molecule developed by  AbbVie , which is running clinical trials to determine if the drug can treat  amyotrophic lateral sclerosis  (ALS). [ 1 ] [ 2 ] [ 3 ]  A formulation of fosigotifator, as its monosodium  phosphate  salt mixed with  tromethamine , is known as ABBV-CLS-7262. Fosigotifator has been patented by AbbVie and  Calico Life Sciences  as a  prodrug  for modulation of the  integrated stress response  pathway. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_895", "text": "Fotagliptin  ( SAL067 ) is a  DPP-4 inhibitor  under development for the treatment of  type 2 diabetes . Like other DPP-4 inhibitors, it works by increasing endogenously produced  GLP-1  and  GIP . [ 1 ] [ 2 ] [ 3 ]  In a phase 3 trial it showed similar results as  alogliptin . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_896", "text": "Fotretamine  ( INN Tooltip International Nonproprietary Name ), also known as  fotrin , is an  alkylating   antineoplastic  and  immunosuppressant . [ 1 ] [ 2 ]  The drug entered  clinical trials  in the  Soviet Union . [ 3 ]  It was first described in the literature by 1972. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_897", "text": "Gloria Niemeyer Francke  (April 28, 1922 \u2013 August 3, 2008) [ 1 ]  was an American pharmacist. She became assistant director of the  American Pharmacists Association  (APhA) Division of Hospital Pharmacy (1946\u20131956); executive secretary of the American Society of Hospital Pharmacists (1949\u20131960); and research associate for the Audit of Pharmaceutical Service in Hospitals (1956\u20131964)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_898", "text": "A native of  Dillsboro, Indiana , Gloria Niemeyer earned her B.S. degree in Pharmacy from  Purdue University  in 1942 and her  Pharm.D  in 1971 from the  University of Cincinnati ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_899", "text": "She then served as a drug literature specialist at the  National Library of Medicine  (1965\u20131967); as a clinical pharmacy teaching coordinator for the Veterans Administration Hospital in Cincinnati (1967\u20131971); as secretary of the American Institute of the History of Pharmacy (1968\u20131978); and as Chief of the program evaluation branch in the Alcohol and Drug Dependence Service, Veterans Administration (1971\u20131975)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_900", "text": "She rejoined the APhA staff (1975\u20131985) and was elected Honorary President in 1986 and received the  Remington Honor Medal  in 1987. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_901", "text": "She served as a member of the APhA Foundation Advisory Committee. The society's Gloria Niemeyer Francke Leadership Mentor Award is named for her. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_902", "text": "Francke became the first executive secretary of the American Society of Health-System Pharmacists [ASHP] in 1949 and was Associate Editor of the American Journal of Hospital Pharmacy from 1944 to 1964. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_903", "text": "Francke's journalistic achievements include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_904", "text": "She was married to Donald Francke, who founded Drug Intelligence (now The Annals of Pharmacotherapy). Following his death in 1978, she became the owner of Drug Intelligence Publications.  [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_905", "text": "This  Indiana -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_906", "text": "Fruquintinib , sold under the brand name  Fruzaqla , is an  anti-cancer medication  used for the treatment of  colorectal cancer . [ 6 ]  Fruquintinib is a  kinase inhibitor . [ 6 ]  It is taken  by mouth . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_907", "text": "The most common adverse reactions include  hypertension ,  palmar-plantar erythrodysesthesia ,  proteinuria ,  dysphonia ,  abdominal pain ,  diarrhea , and  asthenia . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_908", "text": "Fruquintinib was approved for medical use in the United States in November 2023. [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_909", "text": "Fruquintinib is  indicated  for adults with metastatic colorectal cancer who received prior  fluoropyrimidine -,  oxaliplatin -, and  irinotecan -based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. [ 6 ] [ 9 ] [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_910", "text": "Efficacy was evaluated in FRESCO-2 (NCT04322539) and FRESCO (NCT02314819). [ 9 ]  FRESCO-2 (NCT04322539), an international, multicenter, randomized, double-blind, placebo-controlled trial, evaluated 691 participants with metastatic colorectal cancer who had disease progression during or after prior fluoropyrimidine-, oxaliplatin-, irinotecan-based chemotherapy, an anti-VEGF biological therapy an anti-EGFR biological therapy if RAS wild type, and at least one of trifluridine/tipiracil or regorafenib. [ 9 ]  FRESCO, a multicenter, placebo-controlled trial conducted in China, evaluated 416 participants with metastatic colorectal cancer who had disease progression during or after prior fluoropyrimidine-, oxaliplatin, and irinotecan-based chemotherapy. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_911", "text": "In April 2024, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Fruzaqla, intended for the treatment of people with previously treated metastatic colorectal cancer (mCRC). [ 7 ] [ 13 ]  The applicant for this medicinal product is Takeda Pharmaceuticals International AG Ireland Branch. [ 7 ]  Fruzaqla was approved for medical use in the United States in June 2024. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_912", "text": "Fudosteine  ( Cleanal ) is a  mucolytic agent . [ 1 ]   In Japan, it is approved for the treatment of  bronchial asthma ,  chronic bronchitis ,  pulmonary emphysema ,  bronchiectasis ,  pulmonary tuberculosis ,  pneumoconiosis , atypical  mycobacterial disease , and  diffuse panbronchiolitis . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_913", "text": "Fudosteine works by increasing  mucin  secretion by inhibiting expression of the protein  mucin 5AC . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_914", "text": "Fumarranol  is a drug which acts as an inhibitor of the type 2 methionine aminopeptidase  enzyme   METAP2 . It was derived by structural modification of the natural product  fumagillin . It was originally developed as an anti- angiogenesis  drug for the treatment of cancer, [ 1 ]  but it was subsequently found to bind with high affinity to the METAP2 enzyme in  malaria  parasites and has been investigated as a potential treatment for malaria. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_915", "text": "In chemistry and pharmacology,  functional analogs  are  chemical compounds  that have similar  physical ,  chemical ,  biochemical , or  pharmacological  properties. Functional analogs are not necessarily  structural analogs  with a similar  chemical structure . [ 1 ]   An example of pharmacological functional analogs are  morphine ,  heroin  and  fentanyl , which have the same mechanism of action, but fentanyl is structurally quite different from the other two with significant variance in dosage. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_916", "text": "Funobactam  is an  investigational new drug  that is being evaluated for the treatment of hospital-acquired  bacterial pneumonia . [ 1 ]  It is a  \u03b2-lactamase inhibitor . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_917", "text": "Futibatinib , sold under the brand name  Lytgobi , is an  anti-cancer medication  used for the treatment of  cholangiocarcinoma  (bile duct cancer). [ 1 ] [ 3 ]  It is a kinase inhibitor. [ 1 ] [ 6 ]  It is taken  by mouth . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_918", "text": "Futibatinib was approved for medical use in the United States in September 2022, [ 1 ] [ 3 ] [ 7 ] [ 2 ]  in Japan in June 2023 [ 8 ] [ 9 ]  and in the European Union in July 2023. [ 4 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_919", "text": "Futibatinib is  indicated  for the treatment of adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements. [ 1 ] [ 3 ] [ 2 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_920", "text": "On 26 April 2023, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Lytgobi, intended for the second-line treatment of locally advanced or metastatic cholangiocarcinoma characterized by fusion or rearrangements of fibroblast growth factor receptor (FGFR) 2. [ 12 ]  The applicant for this medicinal product is Taiho Pharma Netherlands B.V. [ 12 ]  Futibatinib was approved for medical use in the European Union in July 2023. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_921", "text": "Futibatinib is the  international nonproprietary name  (INN). [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_922", "text": "Gadobenic acid  ( INN , brand name  Multihance ) is a complex of  gadolinium  with the  ligand  BOPTA. In the form of the  methylglucamine  salt  meglumine gadobenate  ( INNm ) or  gadobenate dimeglumine  ( USAN ), it is used as a  gadolinium-based MRI contrast medium . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_923", "text": "BOPTA is a derivative of  DTPA  in which one terminal  carboxyl group , \u2013C(O)OH is replaced by -C\u2013O\u2013CH 2 C 6 H 5 . Thus gadobenic acid is closely related to  gadopentetic acid . BOPTA itself was first synthesized in 1995. [ 5 ]  In the \"gadobenate\" ion gadolinium ion is 9- coordinate  with BOPTA acting as an 8-coordinating ligand. The ninth position is occupied by a water molecule, which exchanges rapidly with water molecules in the immediate vicinity of the strongly  paramagnetic  complex, providing a mechanism for  MRI contrast enhancement .  139 La NMR studies on the diamagnetic La-BOPTA 2\u2212  complex suggest that the Gd complex maintains in solution the same kind of  coordination  as found, by  X-ray crystallography , in the  solid state  for Gd-BOPTA disodium salt. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_924", "text": "Gadofosveset  (trade names  Vasovist ,  Ablavar ) is a  gadolinium-based MRI contrast agent . It was used as the trisodium salt monohydrate form. [ 2 ] [ 3 ]  It acts as a  blood pool agent  by binding to  human serum albumin . The manufacturer ( Lantheus Medical ) discontinued production in 2017 due to poor sales. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_925", "text": "Gadofosveset consists of a  gadolinium  cation bound to the  chelating agent  fosveset.  It facilitates high-resolution  magnetic resonance angiography . [ 5 ]  Ferumoxytol (trade names Feraheme, Rienso), an intravenous iron-replacement therapy, has been shown to potentially be superior to gadofosveset as a blood pool agent for MR venography in pediatric patients. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_926", "text": "Gadopiclenol , sold under the brand name  Elucirem  among others, is a  contrast agent  used with  magnetic resonance imaging  (MRI) to detect and visualize lesions with abnormal vascularity in the central nervous system and in the body. [ 2 ] [ 7 ]  Gadopiclenol is a paramagnetic macrocyclic non-ionic complex of  gadolinium . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_927", "text": "Gadopiclenol was approved for medical use in the United States in September 2022, [ 2 ] [ 8 ] [ 9 ]  and in the European Union in December 2023. [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_928", "text": "Gadopiclenol has a higher  relaxivity  compared with standard gadolinium-based contrast agents (GBCAs). The higher relaxivity allows for a lower dose of gadopiclenol, reducing the total amount of gadolinium administered to the patient while preserving imaging quality. Gadopiclenol was approved by the FDA with a recommended dose of 0.05 mmol/kg for adults and pediatric patients aged 2 years and older. This is half the dose of standard macrocyclic GBCAs, which have a recommended dose of 0.1 mmol/kg. [ 2 ] [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_929", "text": "Gadopiclenol was approved for medical use in the United States in September 2022 by the  Food and Drug Administration . [ 2 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_930", "text": "In October 2023, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Elucirem, intended for contrast-enhanced magnetic resonance imaging (MRI) to improve detection and, visualization of pathologies when diagnostic information is essential and not available with unenhanced MRI. [ 3 ]  The applicant for this medicinal product is Guerbet. [ 3 ]  In October 2023, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vueway, intended for contrast-enhanced magnetic resonance imaging (MRI) to improve detection and, visualization of pathologies when diagnostic information is essential and not available with unenhanced MRI. [ 5 ]  The applicant for this medicinal product is Bracco Imaging S.p.A. [ 5 ]  Gadopiclenol was approved for medical use in the European Union in December 2023. [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_931", "text": "Gadopiclenol is the  international nonproprietary name . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_932", "text": "Gadopiclenol is sold under the brand names Elucirem and Vueway. [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_933", "text": "Gadoteridol  ( INN ) is a  gadolinium-based MRI contrast agent , used particularly in the imaging of the  central nervous system . It is sold under the brand name  ProHance . [ 3 ]  Gadoteridol was first approved for use in the United States in 1992. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_934", "text": "This article about  magnetic resonance imaging  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_935", "text": "Gadoversetamide  is a  gadolinium-based MRI contrast agent , particularly for imaging of the  brain ,  spine  and  liver . [ 1 ] [ 2 ]  It is marketed under the trade name  OptiMARK ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_936", "text": "Gadoxetic acid  is a  gadolinium-based MRI contrast agent . [ 4 ]  Its salt,  gadoxetate disodium , is marketed as  Primovist  in Europe and  Eovist  in the United States by  Bayer HealthCare Pharmaceuticals . [ 2 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_937", "text": "It is used to increase the T1 signal intensity while imaging the liver lesions such as benign cysts, hemangioma, and liver cancer. It is excreted into bile by active secretion. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_938", "text": "In those with end-stage renal failure, the clearance rate is only 17% with terminal half-life of 12 times longer than those with normal renal function. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_939", "text": "A  gallipot  is a small  jar , traditionally of glazed earthenware, used by  apothecaries  for holding  ointment  or  medicine . [ 1 ]  In the 21st century, gallipots are available in plastic as well."}
{"_id": "WikiPedia_Pharmacology$$$corpus_940", "text": "The term  gallipot , recorded from the 15th century, may derive from the idea of pots originally imported in  galleys , [ 2 ]  and has also been used for small pots used for other purposes \u2013 such as preparing an individual portion of custard [ 3 ]  or melting wax while making  fishing flies . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_941", "text": "The 16th-century Gallipot Inn in  Hartfield , Sussex, England, is said to take its name \"from the small glazed earthenware pots made to contain medicines and ointments that were once produced on-site\". [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_942", "text": "Gallipots in a variety of shapes are held in several museums."}
{"_id": "WikiPedia_Pharmacology$$$corpus_943", "text": "This tool article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_944", "text": "Gamithromycin , sold under the brand name  Zactran , is a  veterinary medication  used for the treatment of cattle, pigs, and sheep. [ 3 ] [ 4 ] [ 5 ]  It is a macrolide antibacterial. [ 3 ] [ 4 ]  It is a 7a- azalide . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_945", "text": "It was approved for veterinary use in the European Union in 2008. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_946", "text": "In the EU, gamithromycin is  indicated  for the treatment and prevention of  bovine respiratory disease  in cattle,  swine respiratory disease  in pigs, and infectious  pododermatitis  (foot rot) in sheep. [ 3 ] [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_947", "text": "In the US, gamithromycin is indicated for the treatment of bovine respiratory disease in cattle. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_948", "text": "Garadacimab  is an experimental  human monoclonal antibody  under investigation for the treatment of  hereditary angioedema . [ 1 ]  Garadacimab is a monoclonal antibody against the activated coagulation factor XIIa (FXIIa), with potential anti-inflammatory and anticoagulant activities. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_949", "text": "Garadacimab is a fully human, recombinant, IgG4 lambda monoclonal antibody that binds to the catalytic domain of activated factor XII (FXIIa). [ 1 ]  FXIIa is the first factor activated in the contact system, which leads to the production of bradykinin. [ 1 ]  The inhibition of FXIIa therefore prevents the activation of prekallikrein into kallikrein and the generation of bradykinin, which is associated with inflammation and swelling in attacks of hereditary angioedema. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_950", "text": "In December 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Andembry, intended for the prevention of recurrent attacks of hereditary angioedema. [ 1 ]  The applicant for this medicinal product is CSL Behring GmbH. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_951", "text": "Garadacimab was designated an orphan medicine by the EMA. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_952", "text": "Garadacimab is the  international nonproprietary name . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_953", "text": "Immune activation :  Dostarlimab \n Other:   Ibalizumab"}
{"_id": "WikiPedia_Pharmacology$$$corpus_954", "text": "The  Global Antibiotic Research and Development Partnership  ( GARDP ) is a Swiss nonprofit pharmaceutical research and development organization that aims to assist  antibiotic   drug development  to counter the threat of  antibiotic resistance . [ 1 ] [ 2 ]  It was founded in 2016 by the  World Health Organization  and the  Drugs for Neglected Diseases initiative . [ 3 ] [ 4 ] [ 5 ]  GARDP became a Swiss foundation in 2018. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_955", "text": "This organization-related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_956", "text": "This  medical  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_957", "text": "Gasping syndrome  is a life-threatening condition characterized by  multi-system failure ,  death  and other symptoms resulting from  benzyl alcohol  poisoning. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_958", "text": "The symptoms caused by benzyl alcohol exposure include  respiratory failure ,  hypotension ,  renal failure , severe  metabolic acidosis ,  hematologic  abnormalities,  convulsions ,  paralysis  gradual  neurologic deterioration ,  cardiovascular collapse , sudden onset of  gasping respiration ,  skin changes  and  vasodilation . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_959", "text": "Generally recognized as safe and effective  (abbreviated as  GRASE ,  GRAS/E , or  GRAS/GRAE ) is designation for certain old drugs that do not require prior approval from the  U.S. Food and Drug Administration  in order to enter the  United States  marketplace because they are generally recognized as safe and effective by medical professionals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_960", "text": "The  Federal Food, Drug, and Cosmetic Act  defines a \" new drug \", which requires prior approval, as any drug \"the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling.\" [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_961", "text": "\"Safe and effective\" is always conditional on following the directions. For example,  aspirin  can be lethal when taken in large amounts but is approved to be GRAS/E by FDA for  over-the-counter  use as directed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_962", "text": "FDA has acknowledged the possible existence of drugs that could be considered GRAS/E that they have not found to be GRAS/E yet. As FDA stated in its 2006 Guidance on Marketed Unapproved drugs: \"A product would not be considered a new drug if it is generally recognized as safe and effective (GRAS/GRAE) and has been used to a material extent and for a material time\u2026 As mentioned above, the Agency believes it is not likely that any currently marketed prescription drug product is grandfathered or is otherwise not a new drug. However, the Agency recognizes that it is at least theoretically possible.\" [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_963", "text": "The  Generic Product Identifier  ( GPI ) is a 14-character  hierarchical classification  system created by Wolters Kluwer's Medi-Span that identifies drugs from their primary therapeutic use down to the unique interchangeable product regardless of manufacturer or package size. The code consists of seven subsets, each providing increasingly more specific information about a drug available with a prescription in the United States. The GPI is created and maintained by UpToDate, Inc a Wolters Kluwer Company."}
{"_id": "WikiPedia_Pharmacology$$$corpus_964", "text": "The GPI defines Drug Group, Drug Class, Drug Subclass, Drug Base Name, Drug Name, Dose Form, and GPI Name in a codified manner. The first six characters of the GPI define the therapeutic class code, the next two pairs the drug name, and the last four define route, dosage or strength. For example GPI 58-20-00-60-10-01-05 is for the drug  nortriptyline  HCl cap 10\u00a0mg (an  antidepressant ) and can be further classified as follows: [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_965", "text": "Alternate drug classification systems include the AHFS Drug Information brand run by the  American Society of Health-System Pharmacists  and  First DataBank 's Generic Sequence Number (GSN) also known as the Clinical Formulation ID or formerly as Generic Code Number Sequence Number (GCN Seq No). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_966", "text": "Wolters Kluwer  provides a database under their Medi-Span brand called Medi-Span Electronic Drug File v2.5 that provides this therapeutic classification system which can be mapped to other prescription drug classification codes commonly used for payment and analysis in the United States Health Care System. This classification system is used in conjunction with other embedded drug information like adverse drug effects, drug interactions, drug dosing, and more. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_967", "text": "Gentamicin/betamethasone valerate/clotrimazole  is a fixed dose combination veterinary drug, sold under the trade name  Otomax . [ 1 ]  It is a suspension for  otic  use in dogs. The active ingredients are  gentamicin ,  betamethasone valerate  and  clotrimazole ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_968", "text": "This drug product is used for treatment of acute external  otitis . It is also used for the treatment of short term exacerbation of acute signs of chronic external otitis of bacterial and fungal origin due to bacteria susceptibility to gentamicin. This includes bacteria such as Staphylococcus intermedius  and fungi susceptible to clotrimazole, in particular  Malassezia pachydermatis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_969", "text": "The normal treatment is twice daily for a duration of seven days. The dosage amount varies and should be as prescribed by a veterinarian."}
{"_id": "WikiPedia_Pharmacology$$$corpus_970", "text": "Otomax is a  prescription medication  only licensed for use in dogs. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_971", "text": "This  veterinary medicine \u2013related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_972", "text": "Gildeuretinol  is an  investigational new drug  being developed by Alkeus Pharmaceuticals for the treatment of retinal diseases, particularly  Stargardt disease  and  geographic atrophy  secondary to  age-related macular degeneration  (AMD). Stargardt disease is caused by a defect in the  ABCA4  gene that clears toxic byproducts resulting from the dimerization of  vitamin A .  Gildeuretinol is a  deuterated  derivative of Vitamin A that is designed to reduce the dimerization of vitamin A without affecting the visual cycle. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_973", "text": "Gildeuretinol has received  breakthrough therapy  and  orphan drug  designations from the U.S. Food and Drug Administration. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_974", "text": "Giredestrant  is an investigational oral  selective estrogen receptor degrader  (SERD) being developed for the treatment of  estrogen receptor -positive (ER+)  breast cancer . [ 1 ] [ 2 ]  It is a potent, nonsteroidal compound that antagonizes estrogen effects by competitively binding to both wild-type and mutant estrogen receptors with nanomolar potency. [ 1 ] [ 3 ]  Giredestrant works by inducing an inactive conformation of the estrogen receptor ligand-binding domain and promoting  proteasome -mediated degradation of the receptor protein. [ 1 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_975", "text": "In clinical trials, giredestrant has been evaluated in patients with ER+ breast cancer, including those with ESR1 mutations, both as a single agent and in combination with other therapies. [ 2 ] [ 6 ]  Its orally  bioavailable . [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_976", "text": "Glass of antimony ,  vitrum antimonii , is a yellow to red, translucent  glass  created from a preparation of antimony, though historically used as an  emetic , the glass was a subject of much interest from alchemists due to its unusual properties. It was created using crude  antimony , ground and calcined by a vehement fire, in an earthen  crucible , until it no longer fumed, indicating that its  sulfur  was evaporated. The remaining substance ( antimony trioxide ) was then  vitrified  in a wind  furnace , and stirred with an iron rod, upon which it became translucent and displayed a ruddy and shining yellow-red color. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_977", "text": "It has been considered the strongest emetic of any preparation of antimony. Yet, if dissolved in  spirit of urine , it ceased to be either emetic or  cathartic . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_978", "text": "This  glass  material related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_979", "text": "In  molecular biology  and  biochemistry ,  glycoconjugates  are the classification family for  carbohydrates  \u2013 referred to as  glycans  \u2013 which are  covalently linked  with  chemical species  such as  proteins ,  peptides ,  lipids , and other compounds. [ 1 ]  Glycoconjugates are formed in processes termed  glycosylation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_980", "text": "Glycoconjugates are very important compounds in  biology  and consist of many different categories such as  glycoproteins ,  glycopeptides ,  peptidoglycans ,  glycolipids ,  glycosides , and  lipopolysaccharides .  They are involved in  cell \u2013cell interactions, including  cell\u2013cell recognition ; in cell\u2013 matrix  interactions; in detoxification processes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_981", "text": "Generally, the carbohydrate part(s) play an integral role in the function of a glycoconjugate; prominent examples of this are  neural cell adhesion molecule  (NCAM) and  blood proteins  where fine details in the carbohydrate structure determine cell binding (or not) or lifetime in circulation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_982", "text": "Although the important molecular species  DNA ,  RNA ,  ATP ,  cAMP ,  cGMP ,  NADH ,  NADPH , and  coenzyme A  all contain a carbohydrate part, generally they are not considered as glycoconjugates."}
{"_id": "WikiPedia_Pharmacology$$$corpus_983", "text": "Glycocojugates of carbohydrates covalently linked to antigens and protein scaffolds can achieve a long term immunological response in the body. [ 2 ]  Immunization with glycoconjugates successfully induced long term immune memory against carbohydrates antigens. Glycoconjugate vaccines was introduced since the 1990s have yielded effective results against  influenza  and  meningococcus . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_984", "text": "In 2021 glycoRNAs were observed for the first time. [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_985", "text": "Glycopyrronium tosylate , sold under the brand name  Qbrexza  among others, is a  medication  used for the treatment of primary  axillary hyperhidrosis . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_986", "text": "It was approved for medical use in the United States in June 2018, [ 4 ]  and in Japan in January 2022. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_987", "text": "The  Graduate of Pharmacy  ( Ph.G. ) is an obsolete academic  pharmacy  degree. It was superseded by the  Bachelor of Pharmacy  degree (B.Pharm.) in the early part of the 20th century. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_988", "text": "GRC-6211  is a drug developed by  Glenmark Pharmaceuticals  which acts as a potent and selective  antagonist  for the  TRPV1  receptor. It has  analgesic  and  antiinflammatory  effects and reached  Phase IIb  human trials, but was ultimately discontinued from development as a medicine, though it continues to have applications in scientific research. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_989", "text": "Gridegalutamide  is an investigational oral androgen receptor (AR) degrader being developed for the treatment of  metastatic castration-resistant prostate cancer  (mCRPC). It belongs to a class of drugs called  proteolysis targeting chimeras  (PROTACs), which are designed to selectively degrade specific proteins by hijacking the  ubiquitin-proteasome system . [ 1 ] [ 2 ]  CC-94676 employs a unique dual mechanism of action, combining AR degradation with  AR antagonism , potentially offering advantages over traditional AR inhibitors in overcoming resistance mechanisms. [ 3 ]  Initially developed by  Celgene  and now under  Bristol Myers Squibb , CC-94676 has demonstrated AR protein degradation and suppression of tumor growth in CRPC mouse models. [ 2 ]  As of 2024, CC-94676 is being evaluated in phase I clinical trials for patients with mCRPC who have progressed on androgen-deprivation therapy and at least one prior secondary hormonal therapy. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_990", "text": "GSK-4112  is an experimental drug that was developed by  GlaxoSmithKline  as an agonist of  Rev-ErbA\u03b1 . [ 1 ]  It is used for studying regulation of the  circadian rhythm  and its influence on diverse processes such as  adipogenesis , [ 2 ] [ 3 ]  regulation of  bone density , [ 4 ]  and  inflammation . [ 5 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_991", "text": "GSK-971086  is an  investigational new drug  that is a  selective androgen receptor modulator  (SARM) that was being developed by  GlaxoSmithKline  (GSK) for the potential treatment of  sarcopenia . [ 1 ] [ 2 ]  As a SARM, GSK-971086 was designed to target  androgen receptors  in specific tissues, potentially offering therapeutic benefits for muscle wasting conditions while minimizing unwanted  androgenic  side effects. The compound underwent early-stage clinical trials to evaluate its safety, tolerability, and  pharmacokinetic  profile in human subjects. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_992", "text": "GSK-2849466  is an  investigational new drug  that is a  selective androgen receptor modulator  (SARM) that was being developed by  GlaxoSmithKline  (GSK). This experimental compound reached  Phase I clinical trials  for the treatment of  cachexia  and  heart failure . [ 1 ] [ 2 ] [ 3 ]  However, as of February 2014, GSK discontinued the development of GSK-2849466 for both indications after completing Phase I studies. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_993", "text": "GSK1016790A  (aka  GSK101 ) is a drug developed by  GlaxoSmithKline  which acts as a potent and selective  agonist  for the  TRPV4  receptor. It has been used to study the role of TRPV4 receptors in the function of  smooth muscle  tissue, particularly that lining blood vessels,  lymphatic system , and the  bladder . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_994", "text": "GSK2881078  is a  drug  which acts as a  selective androgen receptor modulator  (SARM). It was developed for the prevention of  muscle wasting  and  sarcopenia  in  elderly  people. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_995", "text": "In a phase II trial the drug was shown to be well tolerated and increased muscle strength in men with  COPD . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_996", "text": "Guaifenesin/codeine  is a  fixed-dose combination   cold medicine  used for the treatment of cough. [ 1 ]  It contains  guaifenesin , an  expectorant ; and  codeine , as the phosphate, an  opioid   antitussive . [ 1 ]  It is taken  by mouth . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_997", "text": "It was approved for medical use in the United States in 2006. [ 1 ]  In 2022, it was the 272nd most commonly prescribed medication in the United States, with more than 800,000 prescriptions. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_998", "text": "Guaifenesin/codeine is available under multiple brand names including Allfen CD, Antituss AC, Bitex, Bron-Tuss, Brontex, Cheracol with Codeine, Cheratussin, Cheratussin AC, Codafen, Codar GF, Coditussin AC, Dex-Tuss, Diabetic Tussin C, Duraganidin NR, ExeClear-C, G Tussin AC, Gani-Tuss NR, Glydeine, Guaiatussin AC, Guaiatussin AC Sugar Free, Guaifen AC, Guaifenesin AC, Guiatuss AC, Guiatussin with Codeine, Halotussin AC, Iophen, Iophen-C NR, M-Clear, M-Clear WC, Mar-cof CG, Maxi-Tuss AC, Mytussin AC, Relcof C, Robafen AC, Robichem AC, Robitussin AC, Romilar AC, Tussi Organidin, Tussiden C, Tusso-C, Virtussin A/C, and Virtussin AC. [ 5 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_999", "text": "Gusacitinib  ( ASN002 ) is an investigational drug which acts as a pan- Janus kinase inhibitor , binding with similar affinity at  JAK1 ,  JAK2 ,  JAK3  and  TYK2 , and also inhibiting  spleen tyrosine kinase  (SYK). [ 1 ]  It is taken orally and was developed for the treatment of  eczema  and  dermatitis . [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1000", "text": "GW 788388  is a synthetic compound which acts as a potent and selective inhibitor for  TGF beta receptor 1 . [ 1 ]  It has applications in research into various disorders such as liver, kidney and heart disease (especially associated with  Chagas disease ), [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]  and potential  antiviral  properties. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1001", "text": "An  H5N8 vaccine  is an  influenza vaccine  intended to provide  acquired immunity  against H5 subtype influenza A viruses. [ 1 ]  It is given via  Intramuscular injection . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1002", "text": "Zoonotic influenza vaccine Seqirus  is authorized for use in the European Union. [ 1 ]  It contains a flu strain called A/Astrakhan/3212/2020 (H5N8)-like strain (CBER-RG8A) (clade 2.3.4.4b). [ 1 ]  Zoonotic influenza vaccine Seqirus was considered to be the best candidate to provide protection against circulating H5 influenza A strains. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1003", "text": "The most common side effects include reactions at the site of injection (swelling, pain, redness and hardening of the skin), myalgia (muscle pain), headache, tiredness, chills and feeling generally unwell. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1004", "text": "Zoonotic Influenza Vaccine Seqirus H5N8 is  indicated  for active immunization against H5 subtype influenza A viruses in adults 18 years of age and older. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1005", "text": "The European Commission arranged for a supply of zoonotic influenza vaccine. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1006", "text": "The  Hausner ratio  is a number that is correlated to the  flowability  of a  powder  or  granular material . It is named after the engineer Henry H. Hausner (1900\u20131995). [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1007", "text": "The Hausner ratio is calculated by the formula"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1008", "text": "where  \n \n \n \n \n \u03c1 \n \n B \n \n \n \n \n {\\displaystyle \\rho _{B}} \n \n  is the freely settled  bulk density  of the powder, and  \n \n \n \n \n \u03c1 \n \n T \n \n \n \n \n {\\displaystyle \\rho _{T}} \n \n  is the tapped bulk density of the powder. The Hausner ratio is not an absolute property of a material; its value can vary depending on the methodology used to determine it."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1009", "text": "The Hausner ratio is used in a wide variety of industries  [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]  as an indication of the flowability of a powder. [ 8 ]   A Hausner ratio greater than 1.25 - 1.4 [ 9 ]  is considered to be an indication of poor flowability.  The Hausner ratio (H) is related to the  Carr index  (C), another indication of flowability, by the formula  \n \n \n \n H \n = \n 100 \n \n / \n \n ( \n 100 \n \u2212 \n C \n ) \n \n \n {\\displaystyle H=100/(100-C)} \n \n . Both the Hausner ratio and the Carr index are sometimes criticized, despite their relationships to flowability being established empirically, as not having a strong theoretical basis. Use of these measures persists, however, because the equipment required to perform the analysis is relatively cheap and the technique is easy to learn."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1010", "text": "HC-030031  is a drug which acts as a potent and selective  antagonist  for the  TRPA1  receptor, and has  analgesic  and  antiinflammatory  effects. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1011", "text": "HC-067047  is a drug which acts as a potent and selective antagonist for the  TRPV4  receptor. It has been used to investigate the role of TRPV4 receptors in a number of areas, such as regulation of blood pressure, bladder function and some forms of pain, as well as neurological functions. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1012", "text": "Hebei Yuxing Bio-Engineering Co. Ltd  is a Chinese active pharmaceutical ingredient (API) company that exports to the United States of America. [ 1 ]  Recently, the  US FDA  issued a warning letter due to \"evidence that the company was keeping incomplete documentation and did not adequately investigate instances of microbial contamination.\" [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1013", "text": "Hesperadin  is an  aurora kinase inhibitor ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1014", "text": "The small molecule inhibits  chromosome  alignment and segregation by limiting the function of  mitotic  kinases  Aurora B  and  Aurora A . Hesperadin causes cells to enter  anaphase  much faster, sometimes before the chromosomes are properly bi-oriented. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1015", "text": "Hesperadin, like other miotic inhibitors, limits and sometimes can stop the process of mitosis in  cells . For this reason, some have considered hesperadin's potential as a  cancer -preventing drug. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1016", "text": "Hesperadin works as an  inhibitor , attaching to the active sites of Aurora A and Aurora B kinases. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1017", "text": "Hexaminolevulinate , sold under the brand name  Cysview  among others, is an imaging agent that lights up under  blue light  during a blue light  cystoscopy . It is used to help detect non-muscle invasive  bladder cancer  (NMIBC), in particular papillary tumors and  carcinoma in situ  (CIS)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1018", "text": "It made by  Photocure  ASA, a Norwegian pharmaceutical company."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1019", "text": "Hexaminolevulinate is a structural analogue to  5-aminolevulinic acid  (a precursor to the porphyrin ring of heme), and is internalized and processed into the photoactive  protoporphyrin IX  at a high rate by tumor cells. After exposure to 360-450 nm light, the porphyrin will fluoresce red. [1]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1020", "text": "2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a  ( HPPH ) is a photosensitiser chemical that is used in  photodynamic therapy . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1021", "text": "It is being developed under the brand name  Photochlor ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1022", "text": "A phase I/II clinical trial started in 1997 for  esophageal cancer . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1023", "text": "A phase II trial for  non-small cell lung cancer  is due to run from 2007 to 2011. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1024", "text": "Himbacine  is an alkaloid isolated from the bark of  Australian magnolias . Himbacine has been synthesized using a  Diels-Alder reaction  as a key step. [ 1 ]  Himbacine's activity as a  muscarinic   receptor antagonist , with specificity for the  muscarinic acetylcholine receptor M2 , made it a promising starting point in  Alzheimer's disease  research. [ 2 ] [ 3 ]   The development of a muscarinic antagonist based on himbacine failed but an analog,  vorapaxar , has been approved by the  FDA  as a  thrombin  receptor antagonist. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1025", "text": "A  histamine agonist  is a drug which causes increased activity at one or more of the four  histamine receptor  subtypes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1026", "text": "H 1  agonists promote wakefulness. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1027", "text": "H 2 :  Betazole  and  Impromidine  are examples of agonists used in diagnostics to increase histamine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1028", "text": "H 3 :  Betahistine  is a weak Histamine 1  agonist and a very strong antagonist of the Histamine 3   autoreceptor . Antagonizing H 3  increases histaminergic tone."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1029", "text": "Histamine glutarimide  is an  investigational new drug  that is being evaluated for the treatment of  cough  in  acute respiratory infection . [ 1 ] [ 2 ]  It is a  glutaminyl cyclase  inhibitor. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1030", "text": "Histamine trifluoromethyl toluidide  ( HTFMT ) is a mixed  H 1 / H 2   histamine agonist  which is significantly more potent than  histamine  itself. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1031", "text": "It also produces additional actions which appear to be independent of  histamine receptors . [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1032", "text": "HL156A  is a derivative of  metformin  and a potent  oxidative phosphorylation  inhibitor and  AMP-activated protein kinase  activating biguanide. [ 1 ] [ 2 ]  Certain types of cancer cells requires oxidative phosphorylation to survive. By targeting it, HL156A might help in improving anticancer therapy. [ 3 ]  It is more potent than  acadesine  or metformin at activating AMP-activated protein kinase. [ 2 ]  It is synthesized by Hanall Biopharma. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1033", "text": "It is in  phase 1 trial  in patients with advanced solid tumor and  lymphoma . [ 5 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1034", "text": "Apart from AMP-activated protein kinase activation, it also inhibits expression and activation of  insulin-like growth factor-1 ,  protein kinase B ,  mammalian target of rapamycin  (mTOR), and  extracellular signal-regulated kinases . [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1035", "text": "It is researched in multiple conditions like liver and renal  fibrosis , [ 2 ] [ 8 ]   cancer [ 6 ] [ 9 ]  and drug resistance in cancer. [ 7 ]  HL176OUT04, a drug with similar pharmacology, has been also developed. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1036", "text": "The Domiciliary Medication Management Review  (DMMR), also named as a  Home Medicines Review  (HMR), [ 1 ]  in an Australian scheme for the patients residing in community setting. [ 2 ]   There are many steps included in a Home Medicine Review Service (Figure 1). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1037", "text": "Introduced in 2001 into the Medicare Benefits Schedule (MBS) as item 900, [ 4 ]  it is aimed at preventative care."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1038", "text": "Following an assessment of the patient's needs, a medication management plan is made."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1039", "text": "Consultant Pharmacist"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1040", "text": "HOPO 14-1  is an investigational drug product for removing  radioactive contaminants  from the body. It is an oral capsule designed to act as a defence against radioactive threats such as  nuclear power plant accidents  or  dirty bomb  attacks. [ 1 ] [ 2 ]  The active ingredient is the  hydroxypyridinone  ligand 3,4,3-LI(1,2-HOPO), which is a powerful  chelating  agent. [ 1 ] [ 3 ]  HOPO 14-1 works by selectively binding to heavy metals in the body and forming a complex that the body can naturally excrete. [ 4 ]  The drug is also being studied as a treatment for other forms of  heavy metal toxicity , including  lead poisoning  and exposure to  gadolinium  from  MRI contrast agents . [ 5 ] [ 6 ] [ 7 ] [ 8 ]  HOPO 14-1 was developed at  Lawrence Berkeley National Laboratory  by actinide chemist  Rebecca Abergel . Abergel and former postdoc  Julian Avery Rees  co-founded  HOPO Therapeutics , a company commercializing HOPO 14-1 and other treatments for heavy metal poisoning."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1041", "text": "HPTE , also known as  hydroxychlor ,  p,p' -hydroxy-DDT , or  2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane , is a  metabolite  of  methoxychlor , a  synthetic   insecticide  related to  DDT . [ 1 ]  Like  bisphenol A  with similar  chemical structure , HPTE is an  endocrine disruptor  which has  estrogenic  activity, [ 2 ]  and also inhibits  Cholesterol side-chain cleavage enzyme  (P450scc, CYP11A1) [ 3 ]  and  3\u03b1-hydroxysteroid dehydrogenase  (3\u03b1-HSD). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1042", "text": "HU-320  ( 7-nor-7-carboxy-CBD-1,1-DMH ) is a drug related to  cannabidiol , which has strong  antiinflammatory  and  immunosuppressive  properties while demonstrating no  psychoactive  effects. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1043", "text": "Huprine X  is a synthetic cholinergic compound developed as a hybrid between the natural product  Huperzine A  and the synthetic drug  tacrine . It is one of the most potent reversible inhibitors of  acetylcholinesterase  known, with a  binding affinity  of 0.026nM, [ 1 ]  as well as showing direct agonist activity at both nicotinic and muscarinic  acetylcholine receptors . [ 2 ] [ 3 ]  In animal studies it has  nootropic  and  neuroprotective  effects, and is used in research into  Alzheimer's disease , [ 4 ] [ 5 ] [ 6 ] [ 7 ]  and although huprine X itself has not been researched for medical use in humans, a large family of related derivatives have been developed. [ 8 ] [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1044", "text": "HY-124798  ( Rheb inhibitor NR1 ) is the first compound to be developed that acts as a potent and selective inhibitor of  Rheb , a  GTP-binding protein  which acts as an endogenous activator of the  mechanistic target of rapamycin  (mTOR) subtype  mTORC1 . Since many of the side effects of  rapamycin  and its analogues are thought to result from binding to the other subtype  mTORC2 , it is hoped that selective inhibition of mTORC1 should have a more selective effects profile. As mTORC1 and mTORC2 have binding sites that are very similar in structure, it has been challenging to develop highly subtype selective inhibitors, making indirect inhibition via modulation of other messenger proteins such as Rheb an attractive approach. However, since HY-124798 has a relatively weak IC 50  of 2.1\u03bcM, and Rheb also has other targets in addition to mTORC1, it remains to be established whether it will deliver the hoped for improvements in pharmacological profile. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1045", "text": "Hydrocodone/guaifenesin , sold under the brand name  Obredon  among others, is a  fixed-dose combination  medication used for the treatment of  cough . [ 2 ]  It contains  hydrocodone , as the  bitartrate , an  opioid agonist ; and  guaifenesin , an  expectorant . [ 2 ]  It is taken  by mouth . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1046", "text": "Hydrocodone/guaifenesin was approved for medical use in the United States in 2014. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1047", "text": "In the US, the label for hydrocodone/guaifenesin contains a  black box warning  about addiction, abuse, and misuse. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1048", "text": "Hydrocodone/homatropine , sold under the brand name  Tussigon  among others, is a  fixed-dose combination  medication used for the treatment of  cough . [ 1 ] [ 2 ]  It contains  hydrocodone , as the bitartrate, an  opioid agonist ; and  homatropine , as the methylbromide, a  muscarinic antagonist . [ 1 ] [ 2 ]  It is taken  by mouth . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1049", "text": "Hydrocodone/homatropine was approved for medical use in the United States in 1943. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1050", "text": "In the US, the label for hydrocodone/homatropine contains a  black box warning  about addiction, abuse, and misuse. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1051", "text": "2-Hydroxybenzylamine  ( 2-HOBA , marketed as  Hobamine ) is a natural product found in Himalayan tartary buckwheat ( Fagopyrum tataricum ). It acts as an antioxidant and scavanger of  free radicals  and  isolevuglandins  and is sold as a dietary supplement. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1052", "text": "6-Hydroxydopa  ( 6-OH-DOPA ;  6-OHDOPA ) is a  catecholaminergic neurotoxin  that damages  noradrenergic  and  dopaminergic   neurons  and is used in  scientific research . [ 1 ] [ 2 ] [ 3 ]  It is a  precursor  and  prodrug  of  6-hydroxydopamine  (6-OHDA). [ 1 ] [ 2 ] [ 3 ]  The drug is a  derivative  of  levodopa  ( L -DOPA). [ 1 ] [ 2 ] [ 3 ]  It has certain advantages over 6-OHDA, such as the ability to cross the  blood\u2013brain barrier  into the  central nervous system  and hence the ability to be administered  systemically  rather than  directly into the brain . [ 1 ] [ 2 ] [ 3 ]  6-OH-DOPA was first described in the  scientific literature  by 1969. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1053", "text": "5\u03b1-Hydroxylaxogenin  is a chemical compound which is a semi-synthetic derivative of laxogenin. It is not found in the  Chinese medicinal plant   Smilax sieboldii , instead, identification of several synthetic impurities by Dr. Chittiboyina's group suggested that it is synthesized from  diosgenin . [ 1 ] [ 2 ]  It acts as a  partial agonist  at  androgen receptors  and has been sold as a bodybuilding supplement and  pre-workout  product. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1054", "text": "Hyzetimibe  is a pharmaceutical drug that  inhibits cholesterol absorption . [ 1 ] [ 2 ]  It targets the  NPC1-like intracellular cholesterol transporter 1 . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1055", "text": "It reduces plasma levels of low-density lipoprotein cholesterol (LDL-C) by blocking the Niemann-Pick C1-like 1 protein, a transporter mainly found in the intestine that allows dietary cholesterol to enter the body from the intestinal  lumen . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1056", "text": "In China, it is used as a lipid-lowering agent and it has efficacy similar to  ezetimibe . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1057", "text": "IAG933  is an  investigational new drug  that is being evaluated for the treatment of cancer. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1058", "text": "IAG933 is a small molecule inhibitor developed by  Novartis Pharmaceuticals  to directly disrupt the  YAP / TAZ - TEAD  protein-protein interaction, a critical mediator of oncogenic signaling in the  Hippo pathway . This  drug has demonstrated potent and selective inhibition of all four TEAD paralogs, resulting in YAP eviction from  chromatin  and reduced Hippo-mediated  transcription . [ 2 ]  As of 2024, IAG933 is undergoing Phase I clinical trials to evaluate its safety, tolerability, and preliminary anti-tumor activity in patients with advanced  mesothelioma  and other solid tumors harboring specific molecular alterations in the Hippo pathway. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1059", "text": "Ibcasertib  is an  investigational new drug  that is being evaluated to treat  small-cell lung cancer . [ 1 ]  Ibcasertib inhibits several  angiogenesis -related kinases, including  VEGFR1 ,  VEGFR2 ,  VEGFR3 ,  PDGFR\u03b1 , and  c-Kit , as well as the  mitosis -related kinase  Aurora B  and the  chronic inflammation -related kinase  CSF-1R . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1060", "text": "Iboxamycin  is a synthetic  lincosamide  or  oxepanoprolinamide   antibiotic . It binds to the bacterial  ribosome  in both  Gram-negative  and  Gram-positive bacteria  and it has been found to effective against  bacteria which are resistant  to other antibiotics that target the large ribosomal subunit. It was developed by combining an  oxepano proline  unit with the aminooctose residue of  clindamycin . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1061", "text": "Iboxamycin is effective against  ESKAPE  bacteria,  methicillin-resistant Staphylococcus aureus  (MRSA),  Enterococcus ,  Clostridioides difficile , [ 1 ]  and  Listeria monocytogenes , [ 2 ]  indicating an extended  spectrum  when compared to clindamycin. [ 1 ]   Isotopic labeling  of iboxamycin with  tritium  indicated that it binds 70 times more tightly to the ribosome than clindamycin. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1062", "text": "Iboxamycin can be administered orally and is safe when administered to mice. [ 1 ]  It is a  bacteriostatic  antibiotic. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1063", "text": "Iclepertin  (developmental code name  BI 425809 ) is an investigational  nootropic  to enhance the cognition and functional capacity in  schizophrenia  developed by  Boehringer Ingelheim . As of May 2020, it is in  phase III  of clinical trial under the code name CONNEX-3. [ 1 ]  BI 425809 is an inhibitor of  glycine transporter 1  (Gly-T1) that in phase II improved cognition after 12 weeks in patients with schizophrenia. Doses of 10\u00a0mg and 25\u00a0mg showed the largest separation from placebo. If these encouraging results are confirmed in phase 3 trials, BI 425809 could provide an effective treatment for cognitive impairment associated with schizophrenia. [ 2 ]  Schizophrenia is characterized by abnormalities in glutamatergic pathways related to  NMDA receptor  hypofunction. Inhibition of GlyT1 on the presynaptic membrane or astrocytes is hypothesized to increase  glycine  levels within the synapse. The NMDA receptor function may be enhanced by increasing levels of its co-agonist, glycine, within the synaptic cleft, which may lead to improvements in cognitive function. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1064", "text": "Icotrokinra  is an investigational targeted oral peptide used in the treatment of  plaque psoriasis . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1065", "text": "Icotrokinra is designed to selectively block the  IL-23 receptor , which plays a vital role in the pathogenic  T-cell  activation of  plaque psoriasis . [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1066", "text": "The phase 3 ICONIC-LEAD trial has been evaluating icotrokinra in adult and adolescent patients aged 12 years and older with moderate-to-severe cases of  plaque psoriasis . [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1067", "text": "The Phase 3 ICONIC-TOTAL study showed once daily icotrokinra met the primary endpoint of IGA of 0/1 at week 16 compared to placebo. [ 2 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1068", "text": "Phase 3 studies ICONIC-ADVANCE 1 and ICONIC-ADVANCE 2 will evaluate the safety and efficacy of icotrokinra compared with both placebo and  deucravacitinib  in moderate-to-severe  plaque psoriasis . [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1069", "text": "Icotrokinra was jointly discovered by  Johnson & Johnson  (J&J) and Protagonist Therapeutics. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1070", "text": "IDRX-42  (formerly  M4205 ) is a highly selective small molecule  KIT  inhibitor compound developed for the treatment of gastrointestinal stromal tumors. [ 1 ] [ 2 ] [ 3 ]  The compound was originally discovered by the German company  Merck   [ 4 ]  and later out-licensed to  IDRX . In November 2024, promising anti-tumor data from ongoing Phase 1/1B studies were reported. [ 5 ]  In January 2025, the compound played a key role in the $1 billion acquisition of IDRX by  GSK . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1071", "text": "IMCY-0098  is a peptide immunotherapy based on  proinsulin  and developed by Imcyse to reduce the progression of  type 1 diabetes . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1072", "text": "Imidazothiazoles  are a class of chemical compounds containing a  bicyclic   heterocycle  (a double ring system) consisting of an  imidazole  ring fused to a  thiazole  ring. [ 1 ]  The structure contains three non- carbon  or  heteroatoms : two  nitrogen  atoms and one  sulfur  atom. Imidazothiazole derivatives show a broad spectrum of  in vitro , i.e. \"in the  petri dish \", activity such as anticancer, [ 2 ] [ 3 ] [ 4 ]   antipsychotic , [ 5 ]   antimicrobial , [ 6 ]   antifungal , [ 7 ]  and  anthelmintic [ 8 ]  (against cancer,  psychosis ,  microorganisms , fungi and worms, respectively)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1073", "text": "Iminoaspartic acid  (also known as  iminosuccinate  or  iminoaspartate ) is a dicarboxylic acid in the biosynthesis of  nicotinic acid . It is synthesised by the oxidation of  aspartate  and is condensed by  quinolinate synthase  with  glycerone phosphate  to form  quinolinic acid . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1074", "text": "IMM-101  is an  immunomodulatory   drug  that is being studied to see if it is useful in  chemotherapy . [ 1 ]  It consists of heat-killed  Mycobacterium obuense  bacteria. It may have relatively few  side effects  compared to other drugs. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1075", "text": "Immethridine  is a  histamine agonist  selective for the  H 3  subtype. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1076", "text": "Immuron  is a  biotechnology  company based in  Melbourne ,  Australia . [ 1 ]  In 2008, the company changed its name to Immuron Limited, [ 2 ]  having previously operated as Anadis Limited. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1077", "text": "Immuron is focused on  antigen -primed and dairy-derived health products. Its proprietary technologies allow for rapid development of polyclonal antibody and other proteins-based solutions for a range of diseases. [ citation needed ] . The company specialises in  nutraceutical , pharmaceutical and therapeutic technology products for conditions such as oral and GI  mucositis ,  avian influenza ,  E. coli   travellers' diarrhoea  (TD) and  Anthrax  containment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1078", "text": "In 2005, Anadis signed an agreement with Quebec's Baralex Inc. and Valeo Pharma Inc. for the distribution of Travelan, a product made by Anadis for the Canadian market. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1079", "text": "This  biotechnology  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1080", "text": "Imocitrelvir  is an  investigational new drug  that is being evaluated for the treatment of viral infections. It is a  3C protease  inhibitor in  picornaviruses . Originally developed by Pfizer for treating human  rhinovirus  infections, [ 1 ]  this  small molecule  has shown promise against a broader range of viruses, including  polioviruses . [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1081", "text": "Impentamine  is a  histamine antagonist  selective for the  H 3  subtype . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1082", "text": "In vivo supersaturation  is the behavior of orally administered compounds that undergo  supersaturation  as they pass through the  gastrointestinal (GI) tract . Typically these compounds have a weakly basic nature ( p K a  in the range of 5 to 8) [ 1 ]  and a relatively low solubility in aqueous solutions. In vivo supersaturation is a recent phenomenon that was first observed by Yamashita et al. in 2003. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1083", "text": "Incyclinide  (proposed trade name  Metastat ) is a chemically modified  tetracycline antibiotic  that was investigated in clinical trials for the treatment of  rosacea , [ 1 ]  various tumours, allergic and inflammatory diseases and a number of other conditions. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1084", "text": "Data from animal studies suggest that centrally infused incyclinide attenuates  microglial  mediated neuroinflammation in the  paraventricular nucleus  of the  hypothalamus  and sympathetic activation in  angiotensin II -induced hypertension. This was also associated with unique changes in gut microbial communities and profound attenuation of gut pathology in animal models of hypertension. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1085", "text": "Like other tetracyclines, incyclinide inhibits  matrix metalloproteinases . In contrast to traditional tetracyclines, it lacks antibiotic properties. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1086", "text": "The  Indian Pharmacist Association  ( IPA ) is the professional body for  pharmacists  of  India . Members include  hospital  pharmacists, manufacturing pharmacists,  teachers  and  clinical pharmacists . Founded in 2011, the association is a member of the Global Health Workforce Alliance (WHO). The IPA is emerging as one of the largest organizations of pharmacists in India. The main objective of IPA is proper placement of pharmacists to play a role in the health care sector in India."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1087", "text": "Indian Pharmacist Association (IPA) recently organised a national conference on Indian pharmacists at Maulana Azad Institute of Dental Sciences in Delhi. The theme for the conference was \u2018Challenges Today and Tomorrow.\u2019 Different associations representing various states participated in the conference. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1088", "text": "The  initial volume of distribution  ( V i ) is a  pharmacological  term used to quantify the distribution of a  drug  throughout the body relatively soon after oral or intravenous  dosing  of a drug and prior to the drug reaching a  steady state equilibrium . Following distribution of the drug, measurement of blood levels indicate the  apparent volume of distribution . Calculation of the initial volume of distribution is the same calculation as that for the apparent  volume of distribution , given by the equation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1089", "text": "Therefore the dose required to give a certain plasma concentration can be determined if the V D  for that drug is known. The V D  is not a real volume; it is more a reflection of how a drug will distribute throughout the body depending on several  physicochemical  properties, e.g. solubility, charge, size, etc. The V D  may also be used to determine how readily a drug will displace into the body tissue compartments relative to the blood:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1090", "text": "Where:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1091", "text": "V P  = plasma volume"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1092", "text": "V T  = apparent tissue volume"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1093", "text": "fu = fraction unbound in plasma"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1094", "text": "fu T  = fraction unbound in tissue"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1095", "text": "The use of  insect cell lines  as production hosts is an emerging technology for the production of bio pharmaceuticals. There are currently more than 100 insect cell lines available for recombinant protein production with lines derived from  Bombyx mori ,  Mamestra brassicae ,  Spodoptera frugiperda ,  Trichoplusia ni , and  Drosophila melanogaster  being of particular interest. Insects cell lines are commonly used in place of  prokaryotic  ones because post-translational modifications of proteins are possible in insect cells whereas this mechanism is not present in prokaryotic systems. [ 1 ]  The  Sf9  cell line is one of the most commonly used lines in insect cell culture. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1096", "text": "The  Institute for Safe Medication Practices  (ISMP) is an American  501(c)(3) organization  focusing on the prevention of medication errors and promoting safe medication practices. [ 1 ]  It is affiliated with  ECRI . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1097", "text": "Among others, ISMP maintains and disseminates a list of \"do not crush\" medications, [ 3 ]  as well as clinical best practices. [ 4 ]  The ISMP's Medication Safety Self-Assessment tool has been used in surveys of medication safety in hospitals in the United States and elsewhere. [ 5 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1098", "text": "The ISMP frequently investigates and reports on medication errors that have occurred in practice. These investigations are often published in the peer-reviewed journal  Hospital Pharmacy . [ 9 ] [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1099", "text": "Insulin efsitora alfa  (LY3209590) is a novel insulin analog developed by  Eli Lilly  for the treatment of diabetes. Its  glycemic control  and safety were found similar to  insulin degludec  in a phase II trial. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1100", "text": "A systematic review and metanalysis of insulin efsitora alfa, published in 2024, found that it may be useful in the management of type \u00a0 1 and type \u00a0 2 diabetes. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1101", "text": "Insulin tregopil  is a fast-acting  insulin  analog, unlike other forms of insulin it is delivered by mouth. It is developed by Biocon for diabetes. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1102", "text": "The  International Psychopharmacology Algorithm Project  (IPAP) is a  non-profit   corporation  whose purpose is to \"enable, enhance, and propagate\" use of  algorithms  for the  treatment  of some  Axis I psychiatric disorders . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1103", "text": "Kenneth O Jobson founded the Project.  The Dean Foundation  provides funding."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1104", "text": "IPAP has organized and supported several international conferences on  psychopharmacology  algorithms. It has also supported the creation of several algorithms based on  expert opinion . It is now in the process of creating \"evidence-based algorithms,\" that is algorithms created by experts and annotated with the evidence that leads to these algorithms. A  schizophrenia  algorithm has been created and one on Post Traumatic Stress Disorder ( PTSD ) was released in July 2005. A  general anxiety disorder  (GAD) algorithm was released in 2006. Periodic updates of the algorithms are released as the basis of evidence changes. In addition, the algorithms are being translated into various non-English languages (Chinese, Japanese, Spanish, and Thai) as the availability of translators permits. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1105", "text": "This article about a scientific organization is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1106", "text": "This  psychiatry -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1107", "text": "The  International Society of Pharmacovigilance  (ISoP), previously the European Society of Pharmacovigilance (ESOP), is an international non-profit scientific organisation, which aims to foster  pharmacovigilance  both scientifically and educationally, and enhance all aspects of the safe and proper use of  medicines , in all countries. Its official journal is  Drug Safety . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1108", "text": "INZ-701  is a recombinant  ENPP1  enzyme developed to treat some genetic disorders that prevent normal production of ENPP1. It is developed by Inozyme Pharma. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1109", "text": "Iobenzamic acid  is a pharmaceutical drug used as an  X-ray contrast  agent. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1110", "text": "It is a water-soluble, hepatotropic contrast medium, meaning it is taken up by the liver and gallbladder. This makes it useful for imaging these organs. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1111", "text": "Iocarmic acid  (trade name  Dimer-X ) is a pharmaceutical drug used as an  iodinated contrast  medium for X-ray imaging in the 1970s and 80s. Uses included imaging of the  uterus  and  fallopian tubes . It was applied in form of its salt,  meglumine  iocarmate. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1112", "text": "It is not known to be marketed anywhere in the world in 2021."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1113", "text": "Iocetamic acid  (trade name  Cholebrin ) is a pharmaceutical drug taken by mouth and used as an  iodinated contrast  medium for X-ray imaging of the  gall bladder . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1114", "text": "It is not known to be marketed anywhere in the world in 2021. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1115", "text": "Iodamide  (trade name  Renovue ) is a pharmaceutical drug used as an  iodinated contrast  medium for X-ray imaging. Its uses include imaging of the  uterus  and  fallopian tubes . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1116", "text": "Iodobenzamide  ( IBZM  or  iolopride ) is a pharmaceutical drug used for diagnostic purposes. It is a  dopamine antagonist  and it can be used by  nuclear medicine physicians  as a  radioactive tracer  for  SPECT  where the radioactive  isotope  is  iodine-123  or  iodine-125 . [ 1 ] [ 2 ]  The main purpose of a brain study with IBZM is the differentiation of  Parkinson's disease  from other  neurodegenerative  diseases such as  Lewy Body dementia  and  multiple system atrophy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1117", "text": "Iodobenzamide can also be used to treat people that have  schizophrenia . The Iodobenzamide binds to the  Dopamine D2 receptors  in the person\u2019s brain and blocks excess neurons that cause an asymmetry in the brain, leaning heavily to the left side. People that receive doses of Iodobenzamide have their brain scanned to monitor their dopamine activity. A study found that patients that were drug-naive (did not have tolerance to the drug) had significant reactions in the left hemisphere of their brain to the drug. Patients with a first dose of Iodobenzamide were scanned and given  benperidol  (a drug used to treat hypersexuality) then scanned again. Male patients showed a left side heavy brain asymmetry of dopamine receptor binding in a drug-naive state.  Benperidol  leads to a reversal of the asymmetry. Drug-naive patient\u2019s brains have a harder time binding the  antipsychotic drugs  to the part of their brain that receives the  Dopamine D2 receptor . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1118", "text": "This  nuclear medicine  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1119", "text": "Iodocholesterol , or  19-iodocholesterol , also as  iodocholesterol ( 131 I)  ( INN ) and  NP-59 , is a  derivative  of  cholesterol  with an  iodine   atom  in the C19 position and a  radiopharmaceutical . [ 1 ] [ 2 ]  When the iodine atom is a  radioactive isotope  ( iodine-125  or  iodine-131 ), it is used as an  adrenal cortex   radiotracer  in the diagnosis of patients suspected of having  Cushing's syndrome ,  hyperaldosteronism , [ 3 ]   pheochromocytoma , and adrenal remnants following total  adrenalectomy . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1120", "text": "Iodophenpropit  is a  histamine antagonist  which binds selectively to the  H 3  subtype . Its  125 I  radiolabelled  form has been used for mapping the distribution of H 3  receptors in animal studies. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1121", "text": "5-Iodowillardiine  is a selective  agonist  for the  kainate receptor , with only limited effects at the  AMPA receptor . [ 1 ]  It is selective for kainate receptors composed of GluR5 subunits. [ 2 ] [ 3 ]  It is an  excitotoxic   neurotoxin   in vivo , [ 4 ] [ 5 ]  but has proved highly useful for characterising the subtypes and function of the various kainate receptors in the  brain  and  spinal cord . [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1122", "text": "Iodoxamic acid  (trade name  Endobil ) is an  organoiodine compound  used as a  radiocontrast agent . [ 1 ]  It features both a high iodine content as well as several  hydrophilic  groups."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1123", "text": "Iofendylate  is a molecule that was used as a  radiocontrast agent , typically for performing  myelography  studies. It was marketed under the trade names  Pantopaque  (in North America) and  Myodil  (rest of the world)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1124", "text": "Iofendylate is a highly  lipophilic  (oily) substance and as such it was recommended that the physician remove it from the patient at the end of the myelography study, which was a difficult and painful part of the procedure. Moreover, because complete removal could not always be achieved (or even attempted by some physicians), iofendylate's persistence in the body might sometimes lead to  arachnoiditis , a potentially painful and debilitating lifelong disorder of the spine. [ 1 ] [ 2 ]  As a result, the substance, which was used extensively for over three decades, became the subject of multiple lawsuits filed around the world. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1125", "text": "Iofendylate's use ceased when water-soluble agents suitable for spinal imaging (such as  metrizamide ) became available in the late 1970s. With those substances it was no longer necessary to manually remove the  contrast agent  as it would eventually be removed by the body. [ 4 ]  Also, with the advent of  MRI , myelography studies are nowadays much less-frequently performed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1126", "text": "Ioglicic acid  is a pharmaceutical drug that was used as an  iodinated contrast  medium for  X-ray imaging , in form of its salt  meglumine  ioglicate. Uses included imaging of the brain, [ 1 ]  the  aorta  and  femoral arteries , [ 2 ]  and the urinary system (an examination called  intravenous urography ). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1127", "text": "Ioglycamic acid  (trade name  Biligram ) is a pharmaceutical drug that was used as an  iodinated contrast  medium for  X-ray imaging  of the  gall bladder . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1128", "text": "Iomeprol , sold under the brand name  Imeron  among others, is a  medication  used as a  radiocontrast agent  in  X-ray imaging . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1129", "text": "It is classified as a  water-soluble , nephrotrophic, low  osmolar   X-ray  contrast medium. [ 2 ]  Low osmolar non- ionic  agents are better tolerated and less likely to cause  side effects  than the high osmolar ionic agents. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1130", "text": "The substance is not  metabolized  in the human body but excreted in unchanged form. It is decomposed slowly and can therefore accumulate in the environment. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1131", "text": "Iomeprol was approved for medical use in the United States in November 2024. [ 1 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1132", "text": "Iomeprol is sold under the brand name Iomervu. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1133", "text": "Iopamidol  ( INN ), sold under the brand name  Isovue  among others, is a nonionic, low-osmolar iodinated  contrast agent , developed by  Bracco Diagnostics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1134", "text": "It is available in various concentrations, from 200 to 370 mgI/mL. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1135", "text": "Iopamidol is indicated for  angiography  throughout the cardiovascular system, including cerebral and peripheral arteriography, coronary arteriography and ventriculography, pediatric angiocardiography, selective visceral arteriography and aortography, peripheral venography (phlebography), and adult and pediatric intravenous excretory urography and intravenous adult and pediatric contrast enhancement of computed tomographic (CECT) head and body imaging. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1136", "text": "It is also indicated for intrathecal administration in adult neuroradiology including  myelography  (lumbar, thoracic, cervical, total columnar), and for contrast enhancement of  computed tomographic (CECT) cisternography  and ventriculography. Isovue-M 200 (lopamidol Injection) is indicated for thoraco-lumbar  myelography  in children over the age of two years. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1137", "text": "As with other iodinated contrast agents there are concerns regarding safety, particularly relating to effects on renal function and allergic type reaction. Early generations of  intravenous  (IV) contrast carried considerable nephrotoxicity, necessitating continual assessment of renal function. IV and PO (per os, by mouth) fluids are encouraged post operation to facilitate excretion of contrast. Shellfish allergies have previously thought to have crossover with iodine allergies with caution being advised with regards to the use of iodinated contrast in patients with shellfish, however shellfish have been demonstrated to be due to proteins produced by the organisms, not due to iodine. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1138", "text": "Iopanoic acid  is an  iodine -containing  radiocontrast medium  used in  cholecystography . Both iopanoic acid and  ipodate sodium  are potent inhibitors of  thyroid hormone  release from  thyroid gland , as well as of peripheral conversion of  thyroxine  (T 4 ) to  triiodothyronine  (T 3 ). These compounds inhibit 5'deiodinase (5'DID-1 and 5'DID-2) enzymes, which catalyse T 4 -T 3  conversion in the thyroid cell, liver, kidney, skeletal muscle, heart, brain, pituitary. This accounts for the dramatic improvement in both subjective and objective symptoms of  hyperthyroidism , particularly when they are used as an adjunctive therapy with  thioamides  ( propylthiouracil ,  carbimazole ). They can be used in the treatment of patients with severe  thyrotoxicosis  (thyroid storm) and significant morbidity (e.g.,  myocardial infarction , or stroke) for rapid control of elevated plasma triiodothyronine concentrations.  The use of iopanoic acid for treatment of thyrotoxicosis has been discontinued in the United States."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1139", "text": "In addition to inhibiting deiodinase enzymes, iopanoic acid is also a substrate of type 1 deiodinase. Iopanoic acid underwent monodeiodination in the presence of type 1 deiodinase in a microsomal mouse liver preparation. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1140", "text": "Iopromide  is an  iodinated contrast  medium for  X-ray imaging . It is marketed under the name  Ultravist  which is produced by Bayer Healthcare. It is a low  osmolar ,  non-ionic   contrast agent  for  intravascular  use; i.e., it is injected into blood vessels. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1141", "text": "It is commonly used in radiographic studies such as  intravenous urograms , brain  computer tomography  (CT) [ 2 ]  and  CT pulmonary angiograms  (CTPAs)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1142", "text": "The radiocontrast agent is given intravenously in computed tomography (CT) scans, angiography and excretory urography. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1143", "text": "Iopromide use is contraindicated in  myelography ,  cerebral ventriculography  and  cisternography  procedures. It is also contraindicated in those with hyperthyroidism, or with known allergy to the drug. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1144", "text": "Iopromide is also contraindicated in children with prolonged fasting, fluid restriction, on  laxative , or dehydration as it can cause renal failure. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1145", "text": "Iopydol  is a pharmaceutical drug used as a  radiocontrast agent  in  X-ray imaging . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1146", "text": "Iotalamic acid , sold under the brand name  Conray , is an  iodine -containing  radiocontrast  agent. It is available in form of its salts,  sodium  iotalamate and  meglumine  iotalamate. It can be given  intravenously  or  intravesically  (into the  urinary bladder ). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1147", "text": "A radioactive formulation is also available as sodium iothalamate  I-125  injection (brand name  Glofil-125 ). It is  indicated  for evaluation of  glomerular filtration  in the diagnosis or monitoring of people with  kidney disease . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1148", "text": "Iotroxic acid  (trade name  Biliscopin ), used in the form of  meglumine  iotroxate , is a molecule used as a  contrast medium  during  X-rays . [ 1 ] [ 2 ]  It is specifically used during tests looking at the  gallbladder  and  biliary tract . [ 2 ]  It is given by  slow injection into a vein . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1149", "text": "Side effects are uncommon. [ 3 ]  They include vomiting,  skin flushing , headache, itchiness, and  low blood pressure . [ 2 ]  Rare side effects include  seizures  and  allergic reactions . [ 2 ]  It should not be used by those who have an  iodine allergy . [ 2 ]  Iotroxic acid is an  iodine containing contrast media  of the  diionic dimer  type. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1150", "text": "Iotroxic acid was first made in 1976. [ 5 ]  It is on the  World Health Organization's List of Essential Medicines . [ 6 ]  It is rarely used in the  developed world  due to the availability of  magnetic resonance cholangiopancreatography  (MRCP). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1151", "text": "Ioversol  ( INN ; trade name  Optiray ) is an  organoiodine compound  that is used as a  contrast medium .  It features both a high iodine content, as well as several  hydrophilic  groups. It is used in clinical diagnostics including  arthrography ,  angiocardiography  and  urography . [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1152", "text": "Ioxilan  is a diagnostic  contrast agent . [ 1 ]   It is injected  intravenously  before taking  X-ray images  to increase  arterial  contrast in the final image. It was marketed in the US under the trade name  Oxilan  by  Guerbet , L.L.C., but was discontinued in 2017. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1153", "text": "Ioxilan is an  iodinated contrast  agent. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1154", "text": "Ioxitalamic acid  (brand name  Telebrix ) is a pharmaceutical drug used as an  iodinated contrast  medium for  X-ray imaging . [ 1 ] [ 2 ]  It is used in form of its salts, ioxitalamate sodium and ioxitalamate  meglumine . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1155", "text": "An  irreversible agonist  is a type of  agonist  that binds permanently to a receptor in such a manner that the receptor is permanently activated.  It is distinct from a mere (reversible) agonist in that the association of an agonist to a receptor is reversible, whereas the binding of an irreversible agonist to a receptor is, at least in theory, irreversible. Oxymorphazone is an example of an irreversible agonist. [ 1 ]  In practice, the distinction may be more a matter of degree, in which the binding affinity of an irreversible agonist is some orders of magnitude greater than that of an agonist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1156", "text": "An  irreversible antagonist  is a type of  antagonist  that binds permanently to a  receptor , either by forming a  covalent bond  to the active site, or alternatively just by binding so tightly that the rate of dissociation is effectively zero at relevant time scales. [ 1 ]  This permanently deactivates the receptor and is usually followed by rapid  internalisation  and recycling of the non-functional receptor protein. Irreversible  enzyme inhibitors  that act similarly are clinically used and include drugs such as  aspirin ,  omeprazole  and  monoamine oxidase inhibitors . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1157", "text": "Irsogladine  is a  phosphodiesterase inhibitor . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1158", "text": "Antiulcer  drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1159", "text": "2,4-Dichloro-6-(2,5-dichlorophenyl)-1,3,5-triazine [61479-79-6] (1)\n(2)\n Dicyandiamide  [461-58-5] (3)\n 2,5-Dichlorobenzonitrile  [21663-61-6] (4)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1160", "text": "Isamide , also known as  N -chloroacetyl-5-methoxytryptamine , is a  serotonin receptor antagonist  and the  N - chloro acetyl   derivative  of  5-methoxytryptamine . [ 1 ] [ 2 ] [ 3 ]  It was first described in the  scientific literature  by 1969 and was first  pharmacologically  characterized by 1979. [ 4 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1161", "text": "Iscartrelvir  is an  investigational new drug  developed by the  Westlake University  for the treatment of  COVID-19 .  It targets the SARS-CoV-2  3CL protease , which is crucial for the replication of the virus responsible for COVID-19. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1162", "text": "Isopromethazine  is an  antihistamine  and  anticholinergic  of the  phenothiazine   chemical class . It is an  enantiomer  of  promethazine . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1163", "text": "Isopropylmalic acid  ( isopropylmalate ) is an intermediate in the  biosynthesis  of  leucine , [ 1 ]  synthesized from  oxoisovalerate  by  2-isopropylmalate synthase  and converted into  isopropyl-3-oxosuccinate  by  3-isopropylmalate dehydrogenase . Two isomers are important, the 2- and 3-isopropyl derivatives, and these are interconverted by  isopropylmalate dehydratase ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1164", "text": "Isosulfan blue , sold under the brand name  Lymphazurin  among others, is a  contrast agent  medication used to delineate the  lymphatic vessels [ 1 ]  during a  lymphography  procedure. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1165", "text": "Israpafant  ( Y-24180 )  is a drug which acts as a selective antagonist for the  platelet-activating factor receptor , [ 1 ]  and was originally developed for the treatment of  asthma . [ 2 ]  Its chemical structure is a  thienotriazolodiazepine , closely related to the sedative  benzodiazepine  derivative  etizolam . However israpafant binds far more tightly to the platelet-activating factor receptor, with an IC 50  of 0.84nM for inhibiting PAF-induced human platelet aggregation (compared to etizolam's IC 50  of 998nM at this target), while it binds only weakly to benzodiazepine receptors, with a Ki of 3680nM. [ 3 ]  Israpafant has been found to inhibit the activation of  eosinophil  cells, [ 4 ] [ 5 ] [ 6 ]  and consequently delays the development of immune responses. It has also been shown to have anti- nephrotoxic  properties, [ 7 ]  and to mobilize calcium transport. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1166", "text": "The  Italian Medicines Agency  ( Agenzia italiana del farmaco , AIFA) is the public institution responsible for the regulatory activity of pharmaceuticals  in  Italy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1167", "text": "This article about an organisation based in Italy is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1168", "text": "Itameline  ( INN Tooltip International Nonproprietary Name ; developmental code name  RU-47213 ) is a  non-selective   muscarinic acetylcholine receptor   agonist  which was under development for the treatment of  Alzheimer's disease  and  memory disorders  but was never marketed. [ 1 ] [ 2 ] [ 3 ]  It has been referred to as a \" nootropic \" (cognitive enhancer). [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1169", "text": "The drug is a  prodrug  of  RU-35963 , an  arecoline   derivative . [ 6 ] [ 7 ] [ 2 ]  It is an agonist of the muscarinic acetylcholine  M 1  receptor  as well as of other muscarinic acetylcholine receptors. [ 8 ] [ 6 ] [ 9 ] [ 7 ] [ 2 ]  Itameline is described as being superior to arecoline in terms of  potency ,  central   selectivity , and  duration of action . [ 6 ] [ 7 ]  The drug shows  antiamnesic  effects in animals, for instance reversing  scopolamine -induced  memory deficits . [ 10 ] [ 6 ] [ 2 ] [ 3 ]   Structurally , it is a  tetrahydropyridine  similarly to  xanomeline  and  milameline . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1170", "text": "Itameline was first described in the  scientific literature  by 1992. [ 3 ]  It was under development by  Hoechst Marion Roussel  and reached  phase 2   clinical trials  by 1998 prior to the discontinuation of its development. [ 12 ] [ 7 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1171", "text": "Izencitinib  ( TD-1473 ) is a drug which acts as a pan- Janus kinase inhibitor , binding with high affinity at all three subtypes  JAK1 ,  JAK2  and  JAK3 . It is taken orally and was developed to be gut selective with minimal absorption into the rest of the body, allowing targeting of  inflammatory bowel disease  but with reduced side effects compared to other similar drugs. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1172", "text": "Jaktinib  is a  janus kinase inhibitor  under development for  myelofibrosis . [ 1 ] [ 2 ]  It is a  deuterated-drug  analog of  momelotinib . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1173", "text": "A  Japanese Accepted Name  ( Japanese :  \u65e5\u672c\u533b\u85ac\u54c1\u4e00\u822c\u7684\u540d\u79f0 ,  Hepburn :  Nihon Iyakuhin Ippan-teki Meish\u014d )  ( JAN ) is the official non-proprietary or generic name given to a  pharmaceutical   substance  by the  Government of Japan . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1174", "text": "Jedi1  (IUPAC name: 2-methyl-5-phenylfuran-3-carboxylic acid) is a chemical compound which acts as an  agonist  for the  mechanosensitive ion channel   PIEZO1 , and is used in research into the function of touch perception. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1175", "text": "Jedi2  is a chemical compound which acts as an  agonist  for the  mechanosensitive ion channel   PIEZO1 , and is used in research into the function of touch perception. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1176", "text": "Jingui Yaol\u00fce  ( simplified Chinese :  \u91d1\u532e\u8981\u7565 ;  traditional Chinese :  \u91d1\u5331\u8981\u7565 ;  pinyin :  J\u012bngu\u00ec Y\u00e0ol\u00fc\u00e8 ),  Essential Prescriptions from the Golden Cabinet   is a classic clinical book of  traditional Chinese medicine  written by  Zhang Zhongjing  (150-219) at the end of the  Eastern Han  dynasty and was first published in the Northern  Song dynasty .  The oldest known extant copy, believed to be bibliographically closest to the original, dates to 1340 and was printed with  woodcuts  in the early  Ming dynasty . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1177", "text": "There is an annotated English translation by Luo Xiwen, with three hundred modern case histories titled:  Synopsis of Prescriptions of the Golden Chamber with 300 Cases.  First published in 1995 by New World Press."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1178", "text": "JJC8-089  is a  dopamine reuptake inhibitor  (DRI) that was  derived  from  modafinil  and is related to  JJC8-016 ,  JJC8-088 , and  JJC8-091 . [ 1 ] [ 2 ]  Its  affinity  (K i ) for the  dopamine transporter  (DAT) is 37.8 \u00a0 nM, for the  norepinephrine transporter  (NET) is 11,820 \u00a0 nM (313-fold lower than for the DAT), for the  serotonin transporter  (SERT) is 6,800 \u00a0 nM (180-fold lower than for the DAT), and for the  sigma   \u03c3 1  receptor  is 2.24 \u00a0 nM (17-fold higher than for the DAT). [ 2 ] [ 3 ]  It also has significant affinity for several  dopamine receptors . [ 3 ]  JJC8-089 has substantially higher affinity for the DAT than modafinil. [ 1 ] [ 2 ] [ 3 ]  The drug shows  pro-motivational  effects in animals. [ 4 ] [ 5 ]  It was first described in the  scientific literature  by 2016. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1179", "text": "JNJ-7777120  was a drug being developed by  Johnson & Johnson Pharmaceutical Research & Development  which acts as a potent and selective  antagonist  at the  histamine H 4  receptor . [ 1 ]  It has  anti-inflammatory  effects, [ 2 ]  and has been demonstrated to be superior to traditional (H1) antihistamines in the treatment of  pruritus  (itching). [ 3 ]  The drug was abandoned because of its short  in vivo   half-life  and  hypoadrenocorticism  toxicity in rats and dogs, that prevented advancing it into clinical studies. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1180", "text": "JNJ-28330835  is a drug which acts as a  selective androgen receptor modulator  (SARM). [ 1 ]  In studies on rats it was found to enhance muscle growth and sexual behavior but with minimal effects on  prostate gland  size. A number of related compounds are known, though JNJ-28330835 has progressed furthest through development. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1181", "text": "JNJ-37654032  is a  selective androgen receptor modulator  (SARM) which was developed by  Johnson & Johnson  for the potential treatment of  muscular atrophy  but was never marketed. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1182", "text": "The drug is a  nonsteroidal   androgen receptor  (AR)  modulator  with mixed  agonistic  ( androgenic ) and  antagonistic  ( antiandrogenic ) effects. [ 4 ]  In animals, it has shown  full agonist -like effects in  muscle ,  agonistic   suppressive effects  on  follicle-stimulating hormone  (FSH)  secretion , and antagonistic or  partially agonistic  effects in the  prostate . [ 5 ] [ 6 ] [ 3 ] [ 4 ]  It was the lead  compound  of a novel  benzimidazole  series of SARMs described as being reminiscent of but distinct from the  arylpropionamides  (e.g.,  enobosarm ). [ 5 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1183", "text": "JNJ-37654032 did not advance past the  preclinical research  and was never tested in humans. [ 1 ] [ 7 ]  It was first described in the  scientific literature  by 2008. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1184", "text": "The  K i  Database  (or  K i  DB ) is a  public domain   database  of published  binding affinities  ( K i ) of  drugs  and  chemical compounds  for  receptors ,  neurotransmitter transporters ,  ion channels , and  enzymes . The resource is maintained by the  University of North Carolina at Chapel Hill  and is funded by the  NIMH  Psychoactive Drug Screening Program and by a gift from the  Heffter Research Institute . As of April\u00a02010 [update] , the database had data for 7 449 compounds at 738 different receptors and, as of 27\u00a0April\u00a02018 [update] , 67 696  K i  values."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1185", "text": "The Ki database has data useful for both chemical biology and  chemogenetics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1186", "text": "Kissei Pharmaceutical  is a pharmaceutical company based in  Matsumoto, Nagano , Japan. Products discovered or developed by Kissei include: [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1187", "text": "In March 2020, Kissei and CG Oncology, Inc. announced an exclusive license, development, and commercialization agreement for CG's oncolytic immunotherapy drug CG0070. The agreement covered Japan, South Korea, Taiwan, and other Asian countries, but not China. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1188", "text": "This corporation or company article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1189", "text": "Kobret  is a low-grade form of  heroin , [ citation needed ]  notable for its use in  Campania ,  Italy  and its sale by criminal organizations in the area.  In  Scampia , a neighborhood of  Naples , the drug is sold by the criminal organization  Camorra . [ 1 ]  In the large open-air drug market within Scampia, Kobret is sold along with  cocaine ,  crack ,  hashish  and heroin. [ citation needed ]   The drug is common along with heroin and cocaine along the Viale della Resistenza. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1190", "text": "This  Italy -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1191", "text": "Krebs\u2013Henseleit solution , developed by  Hans Krebs  and  Kurt Henseleit , is a  solution  containing  sodium  (Na),  potassium  (K),  chloride  (Cl),  calcium  (Ca),  magnesium sulfate  (MgSO 4 ),  bicarbonate  (HCO 3 ),  phosphate  (PO 4 ),  glucose , [ 1 ]  and sometimes supplemented with  albumin , and  tromethamine  (THAM). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1192", "text": "It has been used experimentally, for instance to study arteries  ex vivo , [ 3 ]  in  Langendorff heart  preparations, [ 4 ]  and during  isolated muscle testing  of mammalian  skeletal muscles ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1193", "text": "L-163,491  is an experimental drug which acts as a  partial agonist  of  angiotensin II receptor type 1 , and with lower affinity as an agonist of  angiotensin II receptor type 2 , mimicking the action of  angiotensin II . [ 1 ]  Its practical applications to date have been limited to scientific research into the function of the angiotensin receptor system, [ 2 ]  but it has been suggested as a potential therapeutic agent for the treatment of  inflammation of the lungs  associated with certain viral diseases such as  COVID-19 . [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1194", "text": "L-165041  is a phenyloxyacetate  PPAR\u03b4   receptor agonist . It is less potent and PPAR\u03b4 selective than  GW 501516 . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1195", "text": "Latanoprost/timolol , sold under the brand name  Xalacom , is a  combination drug  used for the treatment of  glaucoma , consisting of  latanoprost  (increase uveoscleral outflow of  aqueous humor [ 3 ] ) and  timolol  (a  beta blocker  decreasing the production of aqueous fluid)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1196", "text": "In some countries, Xalacom is marketed by  Viatris  after Upjohn was spun off from Pfizer. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1197", "text": "Lazertinib , sold under the brand name  Lazcluze  among others, is an  anti-cancer medication  used for the treatment of  non-small cell lung cancer . [ 1 ] [ 2 ] [ 3 ]  It is a kinase inhibitor of epidermal growth factor receptor. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1198", "text": "The most common adverse reactions include rash, nail toxicity, infusion-related reactions (amivantamab), musculoskeletal pain, edema, stomatitis, venous thromboembolism, paresthesia, fatigue, diarrhea, constipation, COVID-19 infection, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1199", "text": "Lazertinib was approved for medical use in  South Korea  in January 2021, [ 4 ] [ 5 ]  and in the United States in August 2024 to treat non-small cell lung cancer. [ 2 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1200", "text": "Lazertinib is  indicated  in combination with  amivantamab  for the  first-line treatment  of adults with locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 L858R substitution mutations. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1201", "text": "Efficacy was evaluated in MARIPOSA (NCT04487080), a randomized, active-controlled, multicenter trial of 1074 participants with exon 19 deletion or exon 21 L858R substitution mutation-positive locally advanced or metastatic non-small cell lung cancer and no prior systemic therapy for advanced disease. [ 2 ]  Participants were randomized (2:2:1) to receive lazertinib in combination with amivantamab, osimertinib monotherapy, or lazertinib monotherapy (an unapproved regimen for non-small cell lung cancer) until disease progression or unacceptable toxicity. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1202", "text": "Lazertinib was approved for medical use in the United States in August 2024. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1203", "text": "In November 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Lazcluze, intended in combination with amivantamab, for the treatment of non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations. [ 8 ]  The applicant for this medicinal product is Janssen-Cilag International NV. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1204", "text": "Lazertinib is the  international nonproprietary name . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1205", "text": "Lecirelin , sold under the brand names  Dalmarelin ,  Ovucron , and  Reproreline , is a short-acting  gonadotropin-releasing hormone agonist  (GnRH agonist) medication which is used in  veterinary medicine  in  Europe  and  Israel . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It is a  GnRH analogue  and a  synthetic   peptide , specifically a  nonapeptide . [ 1 ] [ 2 ] [ 3 ]  The drug was introduced for veterinary use by 2000. [ 5 ]  It is used in form of the  acetate  salt. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1206", "text": "LEO Pharma A/S  is a multinational  Danish   pharmaceutical  company, founded in 1908, with a presence in about 100 countries. Its headquarters are in  Ballerup , near  Copenhagen [ 1 ]  The company is 100% integrated into a private foundation owned by the LEO Foundation. [ 2 ]  LEO Pharma develops and markets products for  dermatology ,  bone remodeling   thrombosis  and  coagulation . [ 3 ]  In 1945, it was the first producer of  penicillin  outside the  US  and  UK ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1207", "text": "In 1908, pharmacists August Kongsted and Anton Antons bought the LEO Pharmacy in Copenhagen, Denmark. With the purchase, they established 'K\u00f8benhavns L\u00f8veapoteks kemiske Fabrik', today known as LEO Pharma. LEO Pharma celebrated its centennial in 2008. [ 4 ]  Flags bearing the LEO logo were flying in every country where LEO products are available, more than a hundred flags in total. Today, LEO Pharma has an ever growing pipeline with over 4,800 specialists focusing on dermatology and thrombosis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1208", "text": "In 2015, the company announced it would acquire  Astellas Pharmas  dermatology business for $725 million. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1209", "text": "In 2018, the company acquired Bayer's dermatology unit for an undisclosed amount. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1210", "text": "In April 2022, the company appointed Christophe Bourdon as its new CEO. [ 8 ]  Prior to this, he served as the CEO of Orphazyme A/S."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1211", "text": "In January 2023, the company started extensive layoffs [ 9 ]  (of about 300 of its current employees, or ~5% of the workforce) as a part of major restructuring and reorganization in anticipation of a possibly planned  IPO . [ 10 ]  Because of slimming down of the company's R&D program, new early-stage drug candidates will have to be sourced externally. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1212", "text": "In August 2023, it was announced LEO Pharma had entered into a definitive agreement to acquire key assets of the  Basking Ridge -headquartered biopharma company, Timber Pharmaceuticals, for $36 million. [ 12 ]  This transaction included TMB-001, a topical  isotretinoin  ointment currently under development for the treatment of moderate to severe subtypes of  Congenital Ichthyosis  (CI), which has no treatment options. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1213", "text": "In September 2023, the company announced the implementation of a new capital structure with over 4 billion Danish kroner (approximately $587 million) allocated for business development and  mergers and acquisitions . [ 14 ]  The company is focused on acquiring assets aimed at treating rare dermatological diseases with unmet medical needs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1214", "text": "In February 2024, LEO Pharma announced a net loss of 3.6 billion Danish kroner (equivalent to $528 million) for 2023 due to non-recurring project impairments, tax asset adjustments, and rising interest expenses. [ 15 ]  It also reported that it had cut its operating costs by 14% and increased its revenues by 7% in 2023. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1215", "text": "LEO Pharma, along with 21 other Danish companies, was accused of bribery and corruption in connection with the  Oil-for-Food Programme  that came to light in 2005. The accusation was that LEO Pharma had acted outside the UN system during the first Gulf War by bribing employees in the relief program and thereby helping  Saddam Hussein . LEO Pharma quickly settled with the police and paid 8.5 million.  [ 17 ]  The new CEO quickly cracked down on corruption both abroad and internally. This can affect employee flexibility and cause delays in production. In Berlingske Business on June 6, 2015, Gitte Aabo speaks about her personal responsibility and that LEO is ready for a few years of lower earnings, which is a possible consequence of her intervention in employee relations. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1216", "text": "Lepidolide  is a  chemical compound  with formula  C 30 H 40 O 6  \u2014 specifically, a  terpenoid  with the  cucurbitane  skeleton \u2014 isolated from the fruiting bodies of the mushroom  Russula lepida  (23\u00a0mg/7\u00a0kg). It is a pale yellow oil, soluble in  chloroform . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1217", "text": "Lepodisiran  (LY3819469) is a  small interfering RNA  that was developed to reduce  lipoprotein(a)  in people at risk of  cardiovascular disease . It was developed by  Eli Lilly and Company . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1218", "text": "Leriglitazone  is a  PPAR-gamma  agonist and metabolite of the  glitazone   pioglitazone . It is developed for  adrenomyeloneuropathy , and other neurodegenerative diseases. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1219", "text": "In January 2024, the  European Medicines Agency  (EMA) recommended the refusal of the marketing authorization for leriglitazone (Nezglyal) requested by Minoryx Therapeutics S.L. [ 5 ]  In May 2024, the EMA confirmed its recommendation to refuse marketing authorization for leriglitazone. [ 5 ]  Leriglitazone was intended for the treatment of cerebral adrenoleukodystrophy. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1220", "text": "Leuprorelin/norethisterone acetate , also known as  leuprolide/norethindrone acetate  and sold under the brand name  Lupaneta Pack , is a co-packaged  medication  used to treat  endometriosis . [ 1 ]  It contains  leuprorelin  as the acetate, a  gonadotropin-releasing hormone agonist , and  norethisterone acetate , a  progestin . [ 1 ]  The leuprorelin is given by  intramuscular injection  and the norethisterone acetate is taken  by mouth . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1221", "text": "The co-packaged medication was approved for medical use in the United States in December 2012. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1222", "text": "Leuprorelin/norethisterone acetate is  indicated  for the initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1223", "text": "Levacetylleucine , sold under the brand name  Aqneursa , is a  medication  used for the treatment of neurological manifestations of  Niemann-Pick disease type C . [ 1 ] [ 2 ]  Levacetylleucine is a modified version of the amino acid  leucine  (N-Acetyl-L-Leucine). [ 1 ]  It is the L form of  acetylleucine . It is taken  by mouth . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1224", "text": "The most common side effects include  abdominal pain ,  difficulty swallowing ,  upper respiratory tract infections , and  vomiting . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1225", "text": "Levacetylleucine was approved for medical use in the United States in September 2024. [ 1 ] [ 2 ] [ 3 ]  Levacetylleucine is the second medication approved by the US  Food and Drug Administration  (FDA) for the treatment of Niemann-Pick disease type C. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1226", "text": "Levacetylleucine is  indicated  for the treatment of neurological manifestations of Niemann-Pick disease type C in people weighing at least 15 kilograms (33\u00a0lb). [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1227", "text": "The most common side effects include abdominal pain, difficulty swallowing, upper respiratory tract infections, and vomiting. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1228", "text": "Levacetylleucine may cause embryo-fetal harm if used during pregnancy. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1229", "text": "The safety and efficacy of levacetylleucine for the treatment of Niemann-Pick disease type C were evaluated in a randomized, double-blind, placebo-controlled, two-period, 24-week crossover study. [ 2 ]  The duration was twelve weeks for each treatment period. [ 2 ]  The study enrolled 60 participants. [ 2 ]  To be eligible for the study participants had to be four years of age or older with a confirmed diagnosis of Niemann-Pick disease type C and at least mild disease-related neurological symptoms. [ 2 ]  Participants could receive  miglustat , an  enzyme inhibitor , as background treatment in the study. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1230", "text": "The US  Food and Drug Administration  (FDA) granted the application for levacetylleucine  priority review ,  fast track ,  orphan drug , and rare pediatric disease designations. [ 2 ]  The FDA granted approval of Aqneursa to IntraBio Inc. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1231", "text": "Levacetylleucine was approved for medical use in the United States in September 2024. [ 1 ] [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1232", "text": "Levacetylleucine is the  international nonproprietary name . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1233", "text": "N-Acetyl-L-Leucine is being studied for the treatment of  GM2 gangliosidoses  ( Tay-Sachs  and  Sandhoff diseases ), [ 6 ]   ataxia-telangiectasia , [ 7 ]   Lewy body dementia , [ 8 ]   amyotrophic lateral sclerosis ,  restless legs syndrome ,  multiple sclerosis , and  migraine . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1234", "text": "Levilimab  is an  anti-IL-6   monoclonal antibody  initially developed to treat  rheumatoid arthritis . In 2020, it was approved as a treatment for  COVID-19  in Russia. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1235", "text": "Levodopa/benserazide , sold under the brand name  Prolopa  among others, is a  fixed-dose combination  medication used for the treatment of Parkinson's disease. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1236", "text": "Levodopa/benserazide is  indicated  for the treatment of Parkinson's disease with the exception of drug-induced parkinsonism. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1237", "text": "Lexipafant  ( BB-882 ,  Zacutex ) is a drug which acts as a potent and selective inhibitor of the  phospholipid  mediator  platelet-activating factor  (PAF). It was developed in the 1990s by  British Biotech  with several potential applications, including  HIV-associated neurocognitive disorder  and acute  pancreatitis . Initial results were encouraging and it progressed as far as Phase III clinical trials, but final analysis of trial results showed that it failed to improve survival rates in pancreatitis despite some symptomatic improvement, and it was ultimately discontinued from development as a medicine, though it continues to be used as a model PAF inhibitor for pharmacology research. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1238", "text": "LGD-2941  is a  drug  which acts as a  selective androgen receptor modulator  (SARM). [ 1 ]   It is no longer being developed. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1239", "text": "Liarozole  is a  retinoic acid  metabolism-blocking drug and  aromatase inhibitor . [ 1 ]  Liarozole is an  isomer  of  alprazolam , but the two compounds are completely unrelated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1240", "text": "Lifileucel , sold under the brand name  Amtagvi , is an  adoptive T cell therapy   used for the treatment of  melanoma . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1241", "text": "Specifically, lifileucel is a tumor-derived  T cell  immunotherapy composed of a recipient's own T cells. A portion of the recipient's  tumor tissue  is removed during a surgical procedure prior to treatment. [ 3 ]  The recipient's T cells (the  tumor-infiltrating lymphocytes ) are separated from the tumor tissue, multiplied and then infused into the patient in a single dose. [ 3 ]  T cells are a type of cell that helps the immune system fight cancer and infections. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1242", "text": "Lifileucel is the first tumor-derived T cell immunotherapy approved by the US  Food and Drug Administration  (FDA). [ 3 ]  It was approved for medical use in the United States in February 2024. [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1243", "text": "Lifileucel is  indicated  for the treatment of adults with unresectable (unable to be removed with surgery) or metastatic (spread to other parts of the body) melanoma previously treated with other therapies (a  PD-1  blocking  antibody , and if  BRAF  V600  mutation positive, a  BRAF  inhibitor with or without a MEK inhibitor). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1244", "text": "The most common adverse reactions include chills, fever, fatigue, tachycardia (abnormally fast heart rate), diarrhea, febrile neutropenia (fever associated with a low level of certain white blood cells), edema (swelling due to buildup of fluid in body tissues), rash, hypotension, hair loss, infection, hypoxia (abnormally low oxygen levels in the body) and feeling short of breath. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1245", "text": "The safety and effectiveness of lifileucel was evaluated in a global, multicenter, multicohort, clinical study including adult participants with unresectable or metastatic melanoma who had previously been treated with at least one systemic therapy, including a PD-1 blocking antibody, and if positive for the  BRAF  V600 mutation, a  BRAF  inhibitor or  BRAF  inhibitor with an MEK inhibitor. [ 3 ]  Effectiveness was measured via the  objective response rate  to treatment and duration of response (measured from the date of confirmed initial objective response to the date of progression, death from any cause, starting a new anti-cancer treatment or discontinuation from follow-up, whichever came first). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1246", "text": "The US  Food and Drug Administration  (FDA) approved Lifileucel through the accelerated approval pathway and granted the application  orphan drug ,  regenerative medicine advanced therapy ,  fast track , and  priority review  designations under the brand name Amtagvi to  Iovance Biotherapeutics . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1247", "text": "Lifileucel was approved for medical use in the United States in February 2024. [ 2 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1248", "text": "Lifileucel is the  international nonproprietary name . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1249", "text": "This article incorporates  public domain material  from  US Food and Drug Administration .  United States Department of Health and Human Services ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1250", "text": "Lipo-oxytocin-1  ( LOT-1 ) is a  synthetic   peptide  and  derivative  of  oxytocin  that acts as an  agonist  of the  oxytocin receptor . [ 1 ]  The  lipidation strategy  was applied to oxytocin to create a new peptide with improved  pharmacokinetics . [ 1 ]  LOT-1 consists of oxytocin conjugated with two  palmitoyl groups . [ 1 ]  After adjusting for  molecular weight  (LOT-1 is ~1.5x the weight of oxytocin), oxytocin and LOT-1 are equipotent. [ 1 ]  In addition, LOT-1 appears to have a significantly longer  duration  of effect relative to that of oxytocin. [ 1 ]  It has yet to be determined whether LOT-1 possesses improved  blood-brain-barrier  permeability relative to oxytocin. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1251", "text": "Lisaftoclax  is an  investigational new drug  being developed by Ascentage Pharma for the treatment of hematological malignancies, particularly  chronic lymphocytic leukemia  (CLL) and  small lymphocytic lymphoma  (SLL). It is a selective inhibitor of the  B-cell lymphoma 2  (BCL-2) protein, designed to restore the normal process of  programmed cell death  (apoptosis) in cancer cells. [ 1 ] [ 2 ] [ 3 ]  As of 2024, lisaftoclax is undergoing multiple Phase 3 clinical trials, including studies in combination with  BTK inhibitors  for relapsed/refractory CLL/SLL. [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1252", "text": "Litifilimab  is an  investigational drug  being evaluated for the treatment of  cutaneous lupus erythematosus  and  systemic lupus erythematosus .  It is an anti- BDCA2  monocolonal antibody. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1253", "text": "In  toxicodynamics  and  pharmacodynamics ,  Loewe additivity  (or  dose additivity ) is one of several common  reference models  used for measuring the effects of  drug  combinations. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1254", "text": "Let  \n \n \n \n \n d \n \n 1 \n \n \n \n \n {\\displaystyle d_{1}} \n \n   and  \n \n \n \n \n d \n \n 2 \n \n \n \n \n {\\displaystyle d_{2}} \n \n   be doses of compounds 1 and 2 producing in combination an effect  \n \n \n \n e \n \n \n {\\displaystyle e} \n \n . We denote by  \n \n \n \n \n D \n \n e \n 1 \n \n \n \n \n {\\displaystyle D_{e1}} \n \n  and  \n \n \n \n \n D \n \n e \n 2 \n \n \n \n \n {\\displaystyle D_{e2}} \n \n  the doses of compounds 1 and 2  required to produce  effect  \n \n \n \n e \n \n \n {\\displaystyle e} \n \n  alone (assuming this conditions uniquely define them, i.e. that the individual dose-response functions are bijective).\n \n \n \n \n \n D \n \n e \n 1 \n \n \n \n / \n \n \n D \n \n e \n 2 \n \n \n \n \n {\\displaystyle D_{e1}/D_{e2}} \n \n  quantifies the potency of compound 1  relatively to that of compound 2."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1255", "text": "d \n \n 2 \n \n \n \n D \n \n e \n 1 \n \n \n \n / \n \n \n D \n \n e \n 2 \n \n \n \n \n {\\displaystyle d_{2}D_{e1}/D_{e2}} \n \n  can be interpreted as the dose  \n \n \n \n \n d \n \n 2 \n \n \n \n \n {\\displaystyle d_{2}} \n \n  of compound 2 converted into the corresponding dose of compound 1 after accounting for difference in potency."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1256", "text": "Loewe additivity is defined as the situation where  \n \n \n \n \n d \n \n 1 \n \n \n + \n \n d \n \n 2 \n \n \n \n D \n \n e \n 1 \n \n \n \n / \n \n \n D \n \n e \n 2 \n \n \n = \n \n D \n \n e \n 1 \n \n \n \n \n {\\displaystyle d_{1}+d_{2}D_{e1}/D_{e2}=D_{e1}} \n \n  or \n \n \n \n \n \n d \n \n 1 \n \n \n \n / \n \n \n D \n \n e \n 1 \n \n \n + \n \n d \n \n 2 \n \n \n \n / \n \n \n D \n \n e \n 2 \n \n \n = \n 1 \n \n \n {\\displaystyle d_{1}/D_{e1}+d_{2}/D_{e2}=1} \n \n ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1257", "text": "Geometrically, Loewe additivity is the situation where isoboles are segments joining the points  \n \n \n \n ( \n \n D \n \n e \n 1 \n \n \n , \n 0 \n ) \n \n \n {\\displaystyle (D_{e1},0)} \n \n  and  \n \n \n \n ( \n 0 \n , \n \n D \n \n e \n 2 \n \n \n ) \n \n \n {\\displaystyle (0,D_{e2})} \n \n  in the domain  \n \n \n \n ( \n \n d \n \n 1 \n \n \n , \n \n d \n \n 2 \n \n \n ) \n \n \n {\\displaystyle (d_{1},d_{2})} \n \n ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1258", "text": "If we denote by  \n \n \n \n \n f \n \n 1 \n \n \n ( \n \n d \n \n 1 \n \n \n ) \n \n \n {\\displaystyle f_{1}(d_{1})} \n \n ,  \n \n \n \n \n f \n \n 2 \n \n \n ( \n \n d \n \n 2 \n \n \n ) \n \n \n {\\displaystyle f_{2}(d_{2})} \n \n  and  \n \n \n \n \n f \n \n 12 \n \n \n ( \n \n d \n \n 1 \n \n \n , \n \n d \n \n 2 \n \n \n ) \n \n \n {\\displaystyle f_{12}(d_{1},d_{2})} \n \n  the dose-response functions of compound 1, compound 2 and of the mixture respectively, then dose additivity holds when"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1259", "text": "The Loewe additivity equation provides a prediction of the dose combination eliciting a given effect. Departure from Loewe additivity can be assessed informally by comparing this prediction to observations. This approach is known in toxicology as the model deviation ratio (MDR). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1260", "text": "This approach can be rooted in a more formal statistical method with the derivation of approximate  p-values  with  Monte Carlo simulation , as implemented in the R package MDR. [ 5 ] [ clarification needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1261", "text": "Lomedeucitinib  is an  investigational new drug  that is being evaluated for the treatment of  psoriasis  and  psoriatic arthritis .  It is  tyrosine kinase 2  (TYK2) inhibitor. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1262", "text": "Loteprednol/tobramycin , sold under the brand name  Zylet , is a  fixed-dose combination  medication used for the treatment of inflammation of the eye. [ 1 ]  It is a combination of  loteprednol , as the etabonate, a  corticosteroid ; and  tobramycin , an  aminoglycoside antibiotic . [ 1 ]  It is used as  drops in the eye . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1263", "text": "Loteprednol/tobramycin was approved for medical use in the United States in December 2004. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1264", "text": "Lovotibeglogene autotemcel , sold under the brand name  Lyfgenia , is a  lentiviral   gene therapy  used for the treatment of  sickle cell disease . [ 1 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1265", "text": "The most common side effects include stomatitis (mouth sores of the lips, mouth, and throat), low levels of platelets, white blood cells, and red blood cells, and febrile neutropenia (fever and low white blood cell count), consistent with chemotherapy and underlying disease. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1266", "text": "The US  Food and Drug Administration  (FDA) approved lovotibeglogene autotemcel in December 2023. [ 3 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1267", "text": "Lovotibeglogene autotemcel is  indicated  for the treatment of people aged twelve years of age and older with sickle cell disease and a history of  vaso-occlusive events . [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1268", "text": "The recipient's blood stem cells are genetically modified to produce HbA (T87Q), a gene-therapy derived  hemoglobin A , which is similar to the normal adult  hemoglobin  produced in persons not affected by sickle cell disease. [ 3 ]  Red blood cells containing HbA (T87Q) have a lower risk of sickling and occluding blood flow. [ 3 ]  These modified stem cells are then delivered to the recipient. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1269", "text": "The gene therapy is made from the recipient's own blood stem cells, which are modified, and are given back as a one-time, single-dose infusion as part of a hematopoietic (blood) stem cell transplant. [ 3 ]  Prior to treatment, the recipient's own stem cells are collected, and then the recipient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the modified cells in lovotibeglogene autotemcel. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1270", "text": "The US FDA label contains a black box warning about hematologic malignancy (blood cancer). [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1271", "text": "The safety and effectiveness of lovotibeglogene autotemcel is based on the analysis of data from a single-arm, 24-month multicenter study in participants with sickle cell disease and history of Vaso-occlusive episodes (VOEs) between the ages of twelve and fifty years. [ 3 ]  Effectiveness was evaluated based on complete resolution of VOEs (VOE-CR) between six and eighteen months after infusion with lovotibeglogene autotemcel. [ 3 ]  Twenty-eight (88%) of 32 participants achieved VOE-CR during this time period. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1272", "text": "The FDA granted the application for lovotibeglogene autotemcel  priority review ,  orphan drug ,  fast track , and regenerative medicine advanced therapy designations. [ 3 ]  The FDA granted approval of Lyfgenia to Bluebird Bio Inc. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1273", "text": "The cost effectiveness threshold of the therapy is estimated to be between  US$1.35 million  to $2.05 million. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1274", "text": "Lovotibeglogene autotemcel is the  international nonproprietary name . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1275", "text": "Lovotibeglogene autotemcel is sold under the brand name Lyfgenia. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1276", "text": "Lu 29-252  is a  selective   sigma   \u03c3 2  receptor   ligand  which was under development for the treatment of  anxiety disorders  but was never marketed. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  It reached the  preclinical stage of development  prior to the discontinuation of its development. [ 1 ]  The drug was under development by  Lundbeck . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1277", "text": "Lu AA41063  is a  selective   adenosine   A 2A  receptor   antagonist . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]   Structurally , it is a non- xanthine . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1278", "text": "The  affinities  (K i ) of the drug for the human  adenosine receptors  are 5.9 \u00a0 nM for the adenosine A 2A  receptor, 410 \u00a0 nM for the adenosine  A 1  receptor  (69-fold lower than for the A 2A  receptor), 260 \u00a0 nM for the adenosine  A 2B  receptor  (44-fold lower than for the A 2A  receptor), and >10,000 \u00a0 nM for the adenosine  A 3  receptor  (>1,695-fold lower than for the A 2A  receptor). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1279", "text": "Lu AA41063 was first described in the  scientific literature  by 2014. [ 1 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1280", "text": "Lu AA47070 , a  water-soluble   phosphate   ester   prodrug  of Lu AA41063, is  orally active  and was under development for the treatment of  Parkinson's disease  but was discontinued. [ 6 ] [ 1 ] [ 2 ] [ 7 ] [ 8 ]  In addition to its  antiparkinsonian -like effects, Lu AA47070 reverses  motivational deficits  in animals and hence shows  pro-motivational  effects. [ 9 ] [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1281", "text": "Lu AA47070  is a  selective   adenosine   A 2A  receptor   antagonist  that was under development for the treatment of  Parkinson's disease  but was never marketed. [ 1 ] [ 2 ] [ 3 ]  It has been found to reverse some of the effects of  dopamine   D 2  receptor   antagonists  like  pimozide  and  haloperidol , for instance tremulous jaw movements,  catalepsy ,  locomotor suppression , and other  anti-motivational  effects, in animals. [ 2 ] [ 4 ] [ 5 ]  The drug is a  prodrug  of  Lu AA41063 . [ 6 ] [ 7 ] [ 3 ]  It was discontinued in  phase 1   clinical trials  because it lacked the intended  pharmacological  properties in humans. [ 7 ] [ 1 ]  Lu AA47070 was first described by 2008. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1282", "text": "Lunresertib  is an  investigational new drug  that is being evaluated for the treatment of cancer.  It is an oral small molecule inhibitor of  PKMYT1 , developed by Repare Therapeutics. [ 1 ]  This drug targets cell cycle regulation in tumors with specific genetic alterations, including  CCNE1  amplifications or  FBXW7  and  PPP2R1A  loss of function mutations. It is currently in phase 1/2 clinical trials, both as monotherapy or in combination with  camonsertib , an  ATR  inhibitor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1283", "text": "Luxdegalutamide , also known as  ARV-766 , is an investigational oral androgen receptor (AR) degrader being developed by Arvinas for the treatment of  metastatic castration-resistant prostate cancer  (mCRPC). [ 1 ] [ 2 ]  It belongs to a class of drugs called  proteolysis targeting chimeras  (PROTACs), which are designed to selectively degrade specific proteins by hijacking the  ubiquitin-proteasome system . [ 3 ]  Luxdegalutamide is a second-generation PROTAC AR degrader that has demonstrated a broader efficacy profile and better tolerability compared to its predecessor, ARV-110, in clinical settings. [ 3 ]  It has shown promise in overcoming resistance associated with certain AR mutations, including the L702H mutation, which is prevalent in up to 24% of treated mCRPC patients. [ 3 ]  As of 2024, luxdegalutamide is being evaluated in phase I/II clinical trials for prostate cancer. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1284", "text": "LY-266,097  is a research ligand which acts as a  potent  and  selective   antagonist  for the  5-HT 2B   receptor , with more than 100x selectivity over the related  5-HT 2A  and  5-HT 2C  receptor subtypes. [ 1 ]  However, other sources have stated that LY-266,097 is actually a  biased agonist  of the receptor, selective for  G q   signaling  but not  \u03b2-arrestin2 . [ 2 ]  The drug has been used to study the role of the 5-HT 2B  receptor in modulating  dopamine  release in the brain, [ 3 ] [ 4 ]  as well as its involvement in other processes such as  allodynia . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1285", "text": "LY-88329  is an  opioid  receptor ligand related to medicines such as  pethidine . It has high affinity to the  \u03bc-opioid receptor , but unlike structurally related drugs such as  3-methylfentanyl  and  OPPPP , LY-88329 is a potent  opioid antagonist . In animal studies it blocks the effects of  morphine  and has  anorectic  action. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1286", "text": "LY-2109761  is a synthetic compound which acts as a potent and selective inhibitor for the  growth factor   receptor   TGF beta receptor 1 . It is used for research into conditions such as  pulmonary fibrosis  and  cancer . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1287", "text": "LY-2365109  is a  glycine reuptake inhibitor . It is able to inhibit the  type 1 glycine transporter . [ 1 ]  This inhibition increases extracellular levels of glycine. LY-2365109 has been shown to increase the seizure threshold in mice, meaning that this drug has potential as an anticonvulsant. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1288", "text": "M62812  is a drug which acts as a potent and selective antagonist of  toll-like receptor 4  (TLR4). In animal studies it blocks TLR4-mediated  cytokine  release and has  antiinflammatory  effects, showing efficacy in animal models of  arthritis  and  septic shock . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1289", "text": "Macitentan/tadalafil , sold under the brand name  Opsynvi , is a  fixed dose combination  medication used for the treatment of  pulmonary arterial hypertension . [ 2 ]  It contains  macitentan , an  endothelin receptor antagonist  (ERA); and  tadalafil , a  phosphodiesterase 5 (PDE5) inhibitor . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1290", "text": "Macitentan/tadalafil was approved for medical use in Canada in October 2021, [ 3 ]  and in the United States in March 2024. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1291", "text": "Macitentan/tadalafil is  indicated  for the chronic treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adults of WHO functional class (FC) II-III. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1292", "text": "Macitentan/tadalafil may cause harm to the fetus. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1293", "text": "In July 2024, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Yuvanci, intended for the treatment of pulmonary arterial hypertension (PAH). [ 6 ]  The applicant for this medicinal product is Janssen-Cilag International NV. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1294", "text": "Magnetic marker monitoring  is a method to monitor the passage of an orally applied  drug  ( tablet ,  capsule , etc.) through the  intestinal tract . The dosage form is enriched with a small amount (0.1 \u2013 2\u00a0mg) of  magnetite  (Fe 3 O 4 ), which then is magnetized by a high-energy magnetic field. After application the path of the dosage form can be monitored with special detectors, which contain  Superconducting Quantum Interference Devices  (SQUIDs). Due to the very low magnetic field of the iron oxide a specially shielded room is necessary in order to eliminate environmental magnetic interference. The method should be able to yield information about why tablets dissolve unequally before or after meals, which may be important for the  bioavailability  of drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1295", "text": "A more developed method, Advanced Magnetic Marker Monitoring, uses the magnetic capsule, a segmented capsule held together by magnetic forces. The magnetic capsule delivers drugs to any targeted location in the  gastrointestinal tract ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1296", "text": "The way the capsule takes is monitored on a PC screen. As soon as the capsule has reached its destination, the magnetic field is destroyed by pressing a button and the drug is released for resorption within milliseconds."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1297", "text": "The method is used during development or optimization of drug products and contributes significantly to the reduction in development time and costs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1298", "text": "Areas of use include the determination of resorption windows, early  proof of concept  studies,  interaction  studies, and optimization of pharmaceutical formulations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1299", "text": "Harriet Florence Maling  (n\u00e9e Mylander, October 2, 1918 \u2013 March 1987) was an American pharmacologist. [ 1 ] :\u200a833\u2013834\u200a  She graduated  Phi Beta Kappa  from  Goucher College  in 1940. [ 2 ]  She went to Harvard Medical School to continue her studies, earning a PhD in 1944."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1300", "text": "Her focus of study involved the physiology of the heart, the effects of various drugs upon the heart and on the autonomic and sympathetic nervous systems, experimenting with artificially created myocardial infarction. [ 1 ] :\u200a833\u2013834"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1301", "text": "Her daughter  Joan Maling  is a linguist and past president of the  Linguistic Society of America ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1302", "text": "Mangafodipir  (sold under the brand name  Teslascan  as mangafodipir trisodium) is a  contrast agent  delivered  intravenously  to enhance contrast in  magnetic resonance imaging  (MRI) of the liver, and has potential to serve as an  adjunct  for various  chemotherapeutic  agents and during coronary intervention. It has two parts, a  paramagnetic  manganese(II) ion and the fodipir (dipyridoxyl diphosphate, DPDP)  chelating  agent. When freed from the organic  ligand , the manganese shortens the  longitudinal relaxation  time (T1) in an MRI scan. Normal liver tissue absorbs the manganese more than abnormal or cancerous tissue, which makes the normal tissue appear brighter in MRIs. This enhanced contrast allows lesions to be more easily identified."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1303", "text": "Mangafodipir was withdrawn from the US market in 2003 [ 1 ]  and the European market in 2012 for commercial reasons by the manufacturer. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1304", "text": "Reactive oxygen species  (ROS) and  reactive nitrogen species  (RNS) participate in pathological tissue damage.  Mitochondrial  manganese  superoxide dismutase  (MnSOD) normally keeps ROS and RNS in check. During development of mangafodipir as an MRI contrast agent, it was discovered that it possessed MnSOD mimetic activity. Mangafodipir has been tested as a chemotherapy adjunct in cancer patients and as an adjunct to percutaneous coronary intervention in patients with myocardial infarctions, with promising results. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1305", "text": "Mangafodipir has shown promising results in human brain imaging without detectable toxicity [ 4 ] [ 5 ]  and usefulness in detecting lesions in multiple sclerosis. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1306", "text": "Whereas MRI contrast depends on release of Mn 2+ , the MnSOD mimetic activity depends on Mn 2+  that remains bound to DPDP.   Calmangafodipir  [Ca 4 Mn(DPDP) 5 ] (brand name  PledOx )  is stabilized with respect to Mn 2+  and has improved therapeutic activity. [ 3 ]  Calmangafodipir is being explored as a chemotherapy adjunct in cancer patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1307", "text": "Maridebart cafraglutide  (also known as  MariTide ; [ 1 ]  developmental name  AMG 133 ) is an investigational drug developed by  Amgen  for the treatment of  obesity . It is an agonist of the  GLP-1 receptor  (GLP-1R) and an antagonist of the  glucose-dependent insulinotropic polypeptide receptor  (GIPR). Namely, MariTide consists of a monoclonal antibody against GIPR conjugated to two peptidic GLP-1R agonist molecules via amino acid linkers. [ 2 ]  In a preliminary trial, AMG 133 resulted in a 14.5 percent weight loss after 12 weeks at the highest dose tested. [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1308", "text": "Masupirdine  is an  investigational new drug  that is being evaluated for the treatment of agitation in  Alzheimer's dementia . [ 1 ]   It is a selective  5-HT 6  receptor  antagonist. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1309", "text": "Mazdutide  (also known as IBI362 or LY3305677) is a dual  agonist  of the  GLP-1 receptor  and  glucagon receptor . It is an analog of  oxyntomodulin  (OXM). [ 1 ] [ 2 ] [ 3 ]  The drug is developed by  Eli Lilly  and is currently in multiple Phase III studies. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1310", "text": "MB-3  is a drug which acts as a potent and selective inhibitor of the  histone acetyltransferase   enzyme   GCN5 , which usually functions as a negative modulator of  PGC-1\u03b1 , and so MB-3 acts to indirectly activate PGC-1\u03b1. It is used in research into the role of the GCN5/PGC-1\u03b1 pathway in the regulation of metabolism and cell differentiation. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1311", "text": "3',4'-Methylenedioxy-4-methylaminorex  ( MDMAR ) is a  recreational   designer drug  from the  substituted aminorex  family, with  monoamine-releasing effects . [ 1 ] [ 2 ] [ 3 ]  It is a  potent   serotonin\u2013norepinephrine\u2013dopamine releasing agent  (SNDRA). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1312", "text": "MEDI6570  is an antibody of the  lectin-like oxidized low-density lipoprotein receptor-1  (LOX-1) that is being tested in people with type 2 diabetes to see if it reduces their risk of  cardiovascular disease . The drug is developed by  AstraZeneca . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1313", "text": "MEDI7352  is an experimental non-opioid  analgesic  drug that works as a bispecific  monoclonal antibody  against  tumour necrosis factor  (TNF) and  nerve growth factor  (NGF); it is developed by  AstraZeneca  for  chronic pain . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1314", "text": "In  toxicology , the  median toxic dose  ( TD 50 ) of a drug or toxin is the dose at which  toxicity  occurs in 50% of cases. [ 1 ] :\u200a73\u200a  The  type  of toxicity should be specified for this value to have meaning for practical purposes. The  median toxic dose  encompasses the category of toxicity that is greater than  half maximum effective concentration  ( ED 50 ) but less than the median lethal dose (LD 50 ). However, for some highly potent toxins (ex.  lofentanil ,  botulinum toxin ) the difference between the ED 50  and TD 50  is so minute that the values assigned to them may be approximated to equal doses. Since toxicity need not be lethal, the TD 50  is generally lower than the  median lethal dose  (LD 50 ), and the latter can be considered an  upper bound  for the former. However, since the toxicity is above the effective limit, the TD 50  is generally greater than the ED 50 . If the result of a study is a toxic effect that does not result in death, it is classified as this form of toxicity. [ 2 ]  Toxic effects can be defined differently, sometimes considering the therapeutic effect of a substance to be toxic (such as with  chemotherapeutics ) which can lead to confusion and contention regarding a substance's TD 50 . Examples of these toxic endpoints include cancer, blindness, anemia, and birth defects. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1315", "text": "Medicines reconciliation  or  medication reconciliation  is the process of ensuring that a hospital patient's  medication  list is as up-to-date as possible. It is usually undertaken by a  pharmacist  and may include consulting several sources such as the patient, their relatives or caregivers, or their  primary care physician ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1316", "text": "In the  United Kingdom , guidelines on medicines reconciliation are provided by the  National Institute for Health and Care Excellence  (NICE) in collaboration with the  National Patient Safety Agency . [ 1 ]  In accordance with these, it should be carried out within 24 hours of admission to hospital.  From April 2020 it is to be an essential service in the community pharmacy contract in England. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1317", "text": "In the  United States , the  Joint Commission  prioritizes medication reconciliation at hospital admission and during  ambulatory care  as one of the  National Patient Safety Goals . [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1318", "text": "Research has shown that, on average, there is around a 20% discrepancy between medications prescribed on admission to hospital and the true medication list for a given patient. [ 5 ]  Chronic medications are stopped in about 11% of the patients after elective  surgeries [ 6 ]  and 33% of the patients after admission to  intensive care unit . [ 7 ]  The most common omissions are  inhalers  and  analgesia . There are also a small minority of errors in prescribing drugs such as  insulin  or  warfarin , which could have catastrophic consequences including death of the patient.  Pharmacist  involvement help reasons for drug discontinuation being documented [ 8 ]  and  adverse drug reactions  being reconciled in the prescription charts. [ 9 ]  The value of medicines reconciliation is in noticing and correcting these errors before they have a chance to adversely affect the patient concerned. Research shows that the main activity of medicines reconciliation by pharmacists is to identify or assess drug-related problems and discuss them with other professionals. However, the process and the tools used in medicines reconciliation vary greatly. There is a wide variation in how medicines reconciliation is conducted and which methods are utilized in different country and hospitals. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1319", "text": "Meglumine  is a  sugar alcohol  derived from  glucose  that contains an   amino group  modification.  It is often used as an  excipient  in pharmaceuticals [ 1 ]  and in conjunction with iodinated compounds in  contrast media  such as  diatrizoate meglumine ,   iothalamate meglumine , and  iodipamide meglumine . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1320", "text": "Memantine/donepezil , sold under the brand name  Namzaric  among others, is a  fixed dose combination  medication used for the treatment of  dementia  of the  Alzheimer's type . [ 1 ]  It contains  memantine , as the hydrochloride, a  NMDA receptor antagonist ; and  donepezil  as the hydrochloride, an  acetylcholinesterase inhibitor . [ 1 ]  It is taken  by mouth . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1321", "text": "Memantine/donepezil was approved for medical use in the United States in 2014. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1322", "text": "Merotocin  ( INN ) (developmental code name  FE-202767 ), also known as  carba-1-(4-FBzlGly 7 )dOT , is a  peptidic   agonist  of the  oxytocin receptor  that was derived from  oxytocin . [ 1 ] [ 2 ] [ 3 ]  It is under development by  Ferring Pharmaceuticals  for the treatment of  preterm  mothers with lactation failure requiring  lactation  support, and is in  phase II   clinical trials  for this indication. [ 3 ]  Merotocin is potent ( EC 50  < 0.1 nM) and highly selective (>1000-fold over the related  vasopressin receptors )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1323", "text": "A  metallopharmaceutical  is a  drug  that contains a  metal  as an active ingredient. [ 1 ] [ 2 ]  Most commonly metallopharmaceuticals are used as  anticancer  or  antimicrobial  agents. The efficiency of metallopharmaceuticals is crucially dependent on the respective  trace metal  binding forms. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1324", "text": "Examples of metallopharmaceuticals include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1325", "text": "Metaphit  ( 1-[1-(3-Isothiocyanato)phenyl]cyclohexylpiperidine ) is a research chemical that acts as an acylator of  NMDARAn ,  sigma  and  DAT  binding sites in the  CNS . It is the  m -isothiocyanate derivative of  phencyclidine  (PCP) and binds irreversibly (forming a  covalent bond ) to the PCP binding site on the NMDA receptor complex. [ 1 ]  However, later studies suggest the functionality of metaphit is mediated by sites not involved in PCP-induced passive avoidance deficit, and not related to the NMDA receptor complex. [ 2 ]  Metaphit was also shown to prevent d-amphetamine induced hyperactivity, while significantly depleting dopamine content in the nucleus accumbens. [ 3 ]  Metaphit was the first acylating ligand used to study the  cocaine  receptor. [ 4 ]  It is a structural isomer of the similar research compound  fourphit , as it and metaphit both are isothiocyanate substituted derivatives of an analogous scaffold shared with PCP. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1326", "text": "Methimepip  is a  histamine agonist  which is highly selective for the  H 3  subtype. It is the  N - methyl  derivative of  immepip . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1327", "text": "Methiodal  is a pharmaceutical drug that was used as an  iodinated contrast  medium for  X-ray imaging . [ 1 ]  Its uses included  myelography  (imaging of the  spinal cord ); for this use, cases of adhesive  arachnoiditis  have been reported, similar to those seen under the contrast medium  iofendylate . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1328", "text": "It is not known to be marketed anywhere in the world in 2021. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1329", "text": "Methoxyetomidate  is an investigational anesthetic agent being developed by Jinzhou Ahon Pharmaceutical Co., Ltd. It is a short-acting intravenous  anesthetic  that acts as a  positive allosteric modulator  of  GABAA receptors . [ 1 ] [ 2 ]  As of 2024, methoxyetomidate is undergoing Phase 3 clinical trials for use in anesthesia. [ 3 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1330", "text": "3,4-Methylenedioxyphenmetrazine , also known as  3-MDPM , is a recreational  designer drug  with  stimulant  effects. It is a  substituted phenylmorpholine  derivative, closely related to better known drugs such as  phenmetrazine  and  3-fluorophenmetrazine . It has been identified as a synthetic impurity formed in certain routes of  MDMA  manufacture. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1331", "text": "3,4-Methylenedioxyphenylpropan-2-one [ 1 ]  or  piperonyl methyl ketone  ( MDP2P  or  PMK ) is a  chemical compound  consisting of a  phenylacetone   moiety   substituted  with a  methylenedioxy   functional group . It is commonly  synthesized  from either  safrole  (which, for comparison, is 3-[3,4-(methylenedioxy)phenyl]-2-propene) or its  isomer   isosafrole  via  oxidation  using the  Wacker oxidation  or  peroxyacid  oxidation methods. MDP2P is unstable at room temperature and must be kept in the freezer in order to be preserved properly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1332", "text": "MDP2P is a  precursor  in the  chemical synthesis  of the  methylenedioxyphenethylamine  (MDxx)  class  of compounds, the classic example of which is  3,4-methylenedioxy- N -methylamphetamine  (MDMA), and is also an  intermediate  between the MDxx family and their slightly more distant precursor safrole or isosafrole. On account of its relation to the MDxx chemical class, MDP2P, as well as safrole and isosafrole, are in the  United States  (U.S.)  Drug Enforcement Administration  (DEA)  List I of Chemicals  of the  Controlled Substances Act  (CSA) via the  Chemical Diversion and Trafficking Act  (CDTA). It is also considered a category 1 precursor in the European Union."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1333", "text": "4-Methylphenmetrazine  ( mephenmetrazine ,  4-MPM ,  PAL-747 ) is a recreational  designer drug  with  stimulant  effects. It is a  substituted phenylmorpholine  derivative, closely related to better known drugs such as  phenmetrazine  and  3-fluorophenmetrazine . It was first identified in Slovenia in 2015, [ 1 ] [ 2 ]  and has been shown to act as a monoamine releaser with some preference for  serotonin  release. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1334", "text": "Metrizoic acid  is a  pharmaceutical drug  that was used as an  iodinated contrast  medium for  X-ray imaging . Its uses included  angiography [ 1 ]  (imaging of blood vessels and  heart chambers ) and  urography [ 2 ]  (imaging of the  urinary tract ), but it has been discontinued, at least in the US. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1335", "text": "It was used in form of its salts,  metrizoates . Due to its high  osmolality , metrizoic acid had a risk of inducing allergic reactions higher than that of lower osmolar contrast media. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1336", "text": "The iodine content of metrizoate ranged from 370\u00a0mg/ml to 440\u00a0mg/ml, with osmolarity has high as 2100 mOsm/kg. The viscosity is 3.4 cP at 37 degree Celsius (human body temperature). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1337", "text": "Side effects of metrizoate are: urticaria, headache, nausea, vomiting, dizziness, and hypotension. Other side effects include minor electrocardiographic changes such as tachycardia, bradycardia, and inversion of T waves. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1338", "text": "Microtrol  is an extended-release drug delivery system. [ 1 ]  It is used in certain medications like  Adderall  and incorporates two types of beads. The first dissolves immediately, releasing half of the medication, while the second type dissolves much more slowly releasing the remaining medication four hours later. Maximum plasma concentration is achieved in seven hours, compared to instant-release which reaches maximum concentration in three hours. [ citation needed ]  Microtrol is manufactured by Supernus Pharmaceuticals, Inc. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1339", "text": "Milademetan  is an  investigational new drug  that is being evaluated to treat  liposarcoma . [ 1 ]  It is a  MDM2  inhibitor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1340", "text": "Miotine  is an  anticholinesterase  drug. Miotine was the first synthetic  carbamate  that was used clinically. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1341", "text": "Unlike the miotine analog  neostigmine , it doesn't have a quaternary  ammonium group  to give it a permanent positive charge. It can exist as an uncharged  free base  which could allow it to cross the  blood\u2013brain barrier  and cause unwanted  central nervous system  (CNS) side effects. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1342", "text": "Mitiperstat  (AZD4831) is an irreversible inhibitor of  myeloperoxidase  and experimental drug in development for  heart failure with preserved ejection fraction . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]  It is being developed by  AstraZeneca . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1343", "text": "Mitoquinone mesylate  ( MitoQ ) is a synthetic analogue of  coenzyme Q10  which has  antioxidant  effects. It was first developed in New Zealand in the late 1990s. [ 1 ]  It has significantly improved bioavailability and improved  mitochondrial  penetration compared to coenzyme Q10, [ 2 ] [ 3 ]  and has shown potential in a number of medical indications, [ 4 ] [ 5 ] [ 6 ] [ 7 ]  being widely sold as a  dietary supplement . [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1344", "text": "A 2014 review found insufficient evidence for the use of mitoquinone mesylate in  Parkinson's disease  and other movement disorders. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1345", "text": "Mitotropes  are a novel class of drugs that aim to improve cardiac performance by influencing the  mitochondria . Their intended effect is similar to the calcium-based  inotropes , and intend to have fewer long-term side effects. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1346", "text": "MK-3984  is a  drug  which acts as a  selective androgen receptor modulator  (SARM).  It is no longer being developed. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1347", "text": "MK-4541  is a dual  selective androgen receptor modulator  (SARM) and  5\u03b1-reductase inhibitor  (5\u03b1-RI) which has been of interest for the potential treatment of  prostate cancer  but has not been marketed at this time. [ 2 ] [ 3 ] [ 1 ] [ 4 ] [ 5 ] [ 6 ]  It is intended for use  by mouth . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1348", "text": "The drug is a  steroidal   androgen receptor  (AR)  modulator  with mixed  agonistic  ( androgenic ) and  antagonistic  ( antiandrogenic ) effects. [ 7 ] [ 8 ] [ 4 ] [ 5 ] [ 6 ]  In  preclinical research  and  animal studies , MK-4541 has been found to have androgenic or  anabolic  effects in  muscle  and  bone , to strongly suppress  testosterone  levels (likely via androgenic  antigonadotropic  effects), and to have antiandrogenic effects in the  prostate  and in  prostate cancer   cells . [ 7 ] [ 8 ] [ 4 ] [ 5 ] [ 6 ]   Structurally , it is specifically a  4-azasteroid   derivative . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1349", "text": "MK-4541 was first described in the  scientific literature  by 2014. [ 5 ] [ 6 ]  It was identified by screening of 3,000 compounds that were manually designed and predicted to have SARM activity. [ 9 ] [ 5 ]  The drug was developed by  Merck . [ 3 ]  It might be being developed for potential medical use, but its developmental status has not been publicly disclosed. [ 3 ]  In any case, MK-4541 is not known to have advanced past preclinical studies as of 2020. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1350", "text": "ML2-SA1  ( EVP-22 ) is a chemical compound which acts as an \"agonist\" (i.e. channel opener) for the  TRPML2  calcium channel, with high selectivity for TRPML2 and no significant activity at the related  TRPML1  and  TRPML3  channels. It has been used to demonstrate the role of TRPM2 in  immune system  function, both triggering release of the  chemokine   CCL2  from  macrophages  and stimulating macrophage migration and endolysosomal trafficking. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1351", "text": "Mochida Pharmaceutical Co., Ltd  ( \u6301\u7530\u88fd\u85ac\u682a\u5f0f\u4f1a\u793e ,  mochida seiyaku kabushiki gaisha )  is a Japanese  pharmaceutical   company . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1352", "text": "One of its products is the antidepressant  setiptiline  (Tecipul). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1353", "text": "This article about a Japanese corporation- or company-related topic is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1354", "text": "In  pharmacology  and  biochemistry ,  mode of action  ( MoA ) describes a functional or anatomical change, resulting from the exposure of a living organism to a substance. [ 1 ]  In comparison, a  mechanism of action  (MOA) describes such changes at the molecular level. [ 2 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1355", "text": "A mode of action is important in classifying chemicals, as it represents an intermediate level of complexity in between molecular mechanisms and physiological outcomes, especially when the exact molecular target has not yet been elucidated or is subject to debate. A mechanism of action of a chemical could be \"binding to DNA\" while its broader mode of action would be \"transcriptional regulation\". [ 3 ]  However, there is no clear consensus and the term mode of action is also often used, especially in the study of  pesticides , to describe molecular mechanisms such as action on specific  nuclear receptors  or  enzymes . [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ]  Despite this, there are classification attempts, such as the HRAC's  classification  to manage  pesticide resistance . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1356", "text": "Model-Informed Precision Dosing  (MIPD for short) is the use of  pharmacometric  models with  computer software  to optimize drug dosage for an individual patient. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1357", "text": "Developed in the late 1960s under the impetus of clinical pharmacologists such as Lewis Sheiner and Roger Jelliffe, these approaches involve applying the equations and parameters describing a drug's  pharmacokinetics  and  pharmacodynamics  to define the best dosage regimen for a given individual, likely to produce circulating concentrations associated with maximum efficacy and minimum toxicity. Models typically take into account the patient's demographic characteristics (age, gender, ethnicity), clinical profile (body measurements, renal and hepatic function, comorbidities, co-medications, dietary habits, substances use) and possibly genetic factors (e.g. polymorphisms affecting  cytochromes  or  drug transporters ). When starting a treatment, these models can be used to select  a priori  the optimal dosage for a patient, based on simulations. During the treatment course, these same models can be used to integrate the results of  Therapeutic Drug Monitoring  (i.e. the measurement and medical interpretation of circulating drug concentrations) or the measurement of biomarkers of efficacy or toxicity, in an  a posteriori  approach to dose optimization, derived from  Bayesian inference  and  feedback loops . Practically, these approaches make extensive use of computer software dedicated to the clinical use of  pharmacokinetic/pharmacodynamic models , belonging to the  computerized clinical decision support tools . [ 2 ] [ 3 ]  They complement  Model-Informed Drug Development  (MIDD), which is mainly carried out by pharmaceutical industry researchers prior to marketing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1358", "text": "Prescribers are expected to make increasingly regular use of model-driven precision dosing tools for patient treatment and follow-up. Dosage individualization represents the quantitative aspect of  precision medicine , while the qualitative aspect lies in the personalized choice of the best drug to treat a given pathology. This optimization of dose selection is especially desirable for drugs with narrow  therapeutic index  (i.e. effective concentration close to toxic ones). It is also important when a treatment is to be applied to patients with peculiarities, such as children, frail elderly persons, polymorbid patients or those already heavily treated. Technical hurdles still limit the wide implementation of these approaches in clinical practice, but it is to be expected that  electronic patient records  will pursue their development, thus enabling the increasing integration of model-informed precision dosing into medical practice. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1359", "text": "Monastrol  is a cell-permeable small molecule inhibitor discovered by Thomas U. Mayer in the lab of  Tim Mitchison . Monastrol was shown to inhibit the  kinesin -5 (also known as  KIF11 , Kinesin Eg5), a  motor protein  important for spindle bipolarity. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1360", "text": "Monastrol binds to a long loop that is specific to the Eg5 (also known as  KIF11  or kinesin-5) kinesin family, and allosterically inhibits ATPase activity of the kinesin  [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1361", "text": "Moprolol  is a  beta-adrenergic antagonist ,  or  beta blocker . It is typically prescribed to treat hypertension, high blood pressure, angina pectoris, arrhythmias, anxiety, and glaucoma. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1362", "text": "Moprolol is currently off the market, most likely due to the manufacturer being in violation of US good manufacturing practices. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1363", "text": "MRTX1133  is an  investigational drug  that targets the G12D mutation in  KRAS  dependent cancers. [ 1 ] [ 2 ]   It is currently in a phase 1/2 clinical trial for the treatment of solid tumors. [ 3 ]  MRTX1133 is considered to be harmful from direct skin or eye exposure other than transient irritation. It may cause irritation of the respiratory system if inhaled. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1364", "text": "MSX-2  is a  selective   adenosine   A 2A  receptor   antagonist  used in  scientific research . [ 1 ]  It is a  xanthine  and a  derivative  of the  non-selective   adenosine receptor antagonist   caffeine . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1365", "text": "The  affinities  (K i ) of MSX-2 for the human  adenosine receptors  are 5.38 to 14.5 \u00a0 nM for the adenosine A 2A  receptor, 2,500 \u00a0 nM for the adenosine  A 1  receptor  (172- to 465-fold lower than for the A 2A  receptor), and >10,000 \u00a0 nM for the adenosine  A 2B  and  A 3  receptors  (>690-fold lower than for the A 2A  receptor). [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1366", "text": "MSX-2 has poor  water solubility , which has limited the use of MSX-2 itself. [ 1 ] [ 5 ]  Water-soluble  ester   prodrugs  of MSX-2, including  MSX-3  (a  phosphate  ester prodrug) and  MSX-4  (an  amino acid  ester prodrug), have been developed and used in place of MSX-2. [ 1 ] [ 5 ]  MSX-3 is best-suited for use by  intravenous administration , whereas MSX-4 can be administered by  oral administration . [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1367", "text": "MSX-3 and MSX-4 reverse  motivational deficits  in animals and hence have the capacity to produce  pro-motivational  effects. [ 7 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1368", "text": "MSX-2 and MSX-3 were first described in the  scientific literature  by 1998. [ 10 ] [ 11 ]  Subsequently, MSX-4 was developed and described by 2008. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1369", "text": "MSX-4  is a  selective   adenosine   A 2A  receptor   antagonist  used in  scientific research . [ 1 ]  It is a  water-soluble   amino acid   ester   prodrug  of  MSX-2 , the  active metabolite  of the drug. [ 2 ] [ 1 ]  MSX-4 reverses the  motivational deficits  induced by the  dopamine   D 2  receptor   antagonist   eticlopride  in animals and hence has the capacity to produce  pro-motivational  effects. [ 3 ] [ 4 ]  MSX-4 was first described in the  scientific literature  by 2008. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1370", "text": "Heinrich M\u00fcckter  (14 June 1914 \u2013 22 May 1987) was a German medical doctor, pharmacologist and chemist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1371", "text": "During the Nazi occupation of Poland, M\u00fcckter was deputy director of the Krak\u00f3w Institute for Typhus and Virus Research. M\u00fcckter and his colleagues repeatedly experimented on  concentration camp  prisoners in  Buchenwald . Many prisoners died as a result of the experiments."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1372", "text": "Accused by Polish war crimes prosecutors of conducting medical experiments on concentration camp prisoners and Nazi forced labourers, M\u00fcckter escaped arrest and fled back to Germany. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1373", "text": "In 1946 M\u00fcckter became Head of Research at the  Gr\u00fcnenthal  pharmaceutical company, where he further developed the infamous drug  thalidomide  which had been synthesized in 1952 by Chemical Industry Basel. Aggressively-marketed as an over-the-counter sleeping pill and remedy for morning sickness in pregnancy, thalidomide was first made available on 1 October 1957, and it became the second best-selling medication in Germany after Bayer Aspirin. Thalidomide was eventually found to cause  miscarriages, severe birth defects in babies whose mothers had taken the medication while pregnant, and severe nerve damage . [ 1 ] [ failed verification ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1374", "text": "In January 1968, M\u00fcckter was put on trial along with other Gr\u00fcnenthal employees. The trial ended abruptly in April 1970 with a settlement. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1375", "text": "M\u00fcckter was never charged in relation to his role in experiments on concentration camp prisoners, nor his role in the thalidomide scandal. He died on 22 May 1987. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1376", "text": "This article about a German chemist is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1377", "text": "This article related to  Nazi Germany  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1378", "text": "The  Multistate Pharmacy Jurisprudence Examination  ( MPJE ) is a  pharmacy  law examination created by the  National Association of Boards of Pharmacy  (NABP) in the United States to help individual state boards of pharmacy assess the competency and knowledge of  pharmacy  law. [ 1 ]  It is required as a prerequisite for a pharmacy license by 48 states and the  District of Columbia . Arkansas, California, and  Idaho  utilize state administered examinations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1379", "text": "Murodermin  ( INN ), also known as  recombinant murine epidermal growth factor  ( rmEGF ), is a  recombinant  form of  mouse   epidermal growth factor  (EGF) and an  EGF receptor   agonist  which was never marketed. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1380", "text": "N-0385  is an experimental  small molecule   TMPRSS2 -inhibitor being investigated for its potential use in the prevention and treatment of  COVID-19 . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1381", "text": "N-0385 is thought to have antiviral effects by targeting key proteins involved in the viral entry process, including TMPRSS2,  ACE2 , and  DPP4 . By interfering with the interactions between these proteins and the  SARS-CoV-2   spike protein , N-0385 effectively blocks the virus from gaining access to host cells. [ 3 ] [ 4 ] [ 5 ]  Additionally, N-0385 appears to modify the immune responses and inflammatory pathways associated with the infection by regulating  TLR7 ,  NLRP3 , and  IL-10 , potentially reducing the severity of COVID-19 symptoms and reducing tissue damage associated with the infection. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1382", "text": "N-Ethyl-2C-B  is a recreational  designer drug  with  psychedelic  effects. [ 1 ]  It was first synthesised in the 1990s, [ 2 ]  and was first identified as a new psychoactive substance in Finland in 2007. [ 3 ]  It is specifically listed as an illegal drug in Finland, [ 4 ]  and controlled under analogue provisions in a number of other jurisdictions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1383", "text": "Nacubactam  is an investigational  \u03b2-lactamase inhibitor  being developed for the treatment of  infections  caused by  carbapenem-resistant Enterobacteriaceae  (CRE). It belongs to the  diazabicyclooctane  (DBO) class of compounds and exhibits a dual mechanism of action. Nacubactam inhibits serine \u03b2-lactamases, including classes A and C and some class D enzymes, while also directly inhibiting  penicillin-binding protein 2  (PBP2) in  Enterobacteriaceae . [ 1 ] [ 2 ]  This unique profile allows nacubactam to both protect partner \u03b2-lactam antibiotics from degradation and exert direct antibacterial effects. As of 2024, nacubactam is undergoing clinical trials in combination with other \u03b2-lactam antibiotics such as  meropenem ,  cefepime , and  aztreonam  for the treatment of complicated  urinary tract infections  and other serious bacterial infections caused by multidrug-resistant pathogens. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1384", "text": "Nadofaragene firadenovec , sold under the brand name  Adstiladrin , is a  gene therapy  for the treatment of  bladder cancer . [ 1 ] [ 3 ] [ 4 ]  It is a non-replicating (cannot multiply in human cells)  adenoviral  vector-based gene therapy. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1385", "text": "The most common adverse events including laboratory abnormalities, include increased glucose, instillation site discharge, increased triglycerides, fatigue, bladder spasm, micturition urgency, increased creatinine, hematuria, decreased phosphate, chills, dysuria, and pyrexia. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1386", "text": "Nadofaragene firadenovec was approved for medical use in the United States in December 2022. [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1387", "text": "Nadofaragene firadenovec is  indicated  for the treatment of adults with high-risk  Bacillus Calmette-Gu\u00e9rin  (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1388", "text": "The safety and effectiveness of nadofaragene firadenovec was evaluated in a multicenter clinical study (Study CS-003 (NCT02773849)) that included 157 participants with high-risk Bacillus Calmette-Gu\u00e9rin (BCG)-unresponsive non-muscle-invasive bladder cancer, 98 of whom had BCG-unresponsive carcinoma in situ with or without papillary tumors and could be evaluated for response. [ 3 ] [ 4 ]  Participants received nadofaragene firadenovec once every three months for up to twelve months, or until unacceptable toxicity to therapy or recurrent high-grade non-muscle-invasive bladder cancer. [ 3 ] [ 4 ]  Overall, 51% of enrolled participants using nadofaragene firadenovec therapy achieved a complete response (the disappearance of all signs of cancer as seen on cystoscopy, biopsied tissue, and urine). [ 3 ]  The median duration of response was 9.7 months. [ 3 ]  Forty-six percent of responding participants remained in complete response for at least one year. [ 3 ]  The major efficacy outcome measures were complete response at any time and duration of response. [ 4 ]  Complete response was defined as negative cystoscopy with applicable transurethral resection of bladder tumor and biopsies and urine cytology. [ 4 ]  Random bladder biopsies of five sites were conducted in participants remaining in complete response at twelve months. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1389", "text": "The US  Food and Drug Administration  (FDA) granted the application for nadofaragene firadenovec  priority review ,  breakthrough therapy ,  fast track , and  orphan drug  designations. [ 3 ] [ 4 ]  The FDA granted approval of Adstiladrin to  Ferring Pharmaceuticals  A/S. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1390", "text": "Nadofaragene firadenovec is the  international nonproprietary name  (INN). [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1391", "text": "National Association of Boards of Pharmacy  ( NABP ) is a  501(c)(3)   nonprofit organization  that assists member boards of pharmacy for the purpose of protecting public health. [ 3 ]  It has 54 active members and 12 associate members. [ 6 ]  Active member boards include all 50 United States, the District of Columbia, Guam, Puerto Rico, and the Virgin Islands. Associate member boards are The Bahamas, and 10 Canadian provinces. [ 6 ]  Australia was formerly an associate member but was removed in 2020. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1392", "text": "NABP supports its member boards of pharmacy by offering: [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1393", "text": "Representatives of twenty [ a ]  state and territorial boards of pharmacy met at the  Coates House Hotel  in Kansas City, Missouri, on September 7, 1908. At the meeting, they formed the National Association of Boards of Pharmacy that would provide for interstate reciprocity in pharmaceutical licenses based on a uniform minimum standard of education and uniform legislation. [ 1 ] [ 9 ]  It was intended to act independently from the  American Pharmaceutical Association , as it would help resolve differences between state boards of pharmacy. [ 1 ]  NABP's  constitution  stated that the NABP would become operative when ten state or territorial boards of pharmacy had adopted the rules and regulations that had NABP adopted. [ 1 ]  George Reimann was elected its first  president , and J. M. A. Laue was elected its first  vice president . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1394", "text": "NABP was  incorporated  in Kentucky on November 5, 1913. [ 10 ]  Its original governing board consisted of J. W. Gayle, E. Berger, M. G. Beehe, John Culley, and J. J Campbell. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1395", "text": "In 1999, the NABP developed the Verified Internet Pharmacy Practice Sites (VIPPS) program to accredit online pharmacies. [ 11 ]  NABP says it looks at an online pharmacy's state licenses, its state inspection reports, and its procedures for dispensing of drugs when determining whether to accredit an online pharmacy, and it requires the online pharmacy to adhere to the VIPPS criteria and program requirements. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1396", "text": "In 2004, the NABP developed the  Verified-Accredited Wholesale Distributors  (VAWD) program to accredit Wholesale Distributors and to help protect the public from the threat of counterfeit drugs. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1397", "text": "In 2011, the NABP implemented a data exchange that allows authorized pharmacists, law enforcement agents, and regulatory boards to access patient-specific controlled substance prescription information. Known as  NABP PMP InterConnect\u00ae , the platform provides a single page summary of patient's drug seeking activities across state lines. As of 2018, authorized users in 42 states have accessed data using the system in order to prevent drug abuse and drug diversion. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1398", "text": "In 2014, the NABP launched the  generic top-level domain  (gTLD)  .pharmacy , \"to provide consumers around the world a means for identifying safe, legal, and ethical online pharmacies and related resources\". [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1399", "text": "The impartiality of the domain has been questioned, because  Eli Lilly and Company ,  Merck & Co. , and  Pfizer  are the main contributors to the NABP application.  Previously, that application was challenged by  Public Citizen ,  Knowledge Ecology International , and the  Canadian International Pharmacy Association . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1400", "text": "Navafenterol  is an  investigational drug  that had been evaluated for  chronic obstructive pulmonary disease . [ 1 ]  It is a  Beta2 agonist  and a  muscarinic antagonist . Further development has been discontinued for strategic reasons. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1401", "text": "Nebivolol/valsartan , sold under the brand name  Byvalson  among others, is a  medication  used to treat  hypertension . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1402", "text": "It is available as a  generic medication . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1403", "text": "Trans -NED-19  is a drug which acts as a potent and selective antagonist of the endogenous calcium channel opener  nicotinic acid adenine dinucleotide phosphate  (NAADP), thereby reducing the normal NAADP-mediated calcium flux without blocking calcium channels directly. It is used in research into the functions of NAADP signalling inside many different cell types. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1404", "text": "Nemtabrutinib  (MK-1026, formerly ARQ 531) is a small molecule drug that works as a reversible  Bruton's tyrosine kinase  (BTK) inhibitor; unlike other BTK inhibitors it also works against some mutated forms of BTK. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]   Merck  paid $2.7 billion to acquire the company ArQule and the drug, which is being investigated as a cancer treatment. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1405", "text": "Neo-Viagra-Y.R.  ( Korean :  \ub124\uc624\ube44\uc544\uadf8\ub77c-Y.R.(\uccad\ucd98\ubd80\ud65c))  is a pharmaceutical product produced by the  Korea Oriental Instant Medicinal Centre , a state-owned North Korean company. [ 1 ]  The product was developed in 2005, by north Korean doctor Ryu Il nam. [ 2 ] \nAlthough marketed as a  herbal   health supplement  based in  Koryo medicine  ( traditional Korean medicine  promoted by North Korea), analysis of the product shows that its  active ingredient  is 50\u00a0mg of  Sildenafil  (the lowest dose of  Pfizer 's genuine Viagra tablets), though used in a different formulation to genuine Viagra tablets. [ 3 ]   As the drug has not been independently clinically tested, it may cause serious side effects such as a  heart attack  or death. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1406", "text": "The product is marketed as medicine which can cure  sexual dysfunction  in both men and women, cure  hepatitis , [ 5 ]  ease  bone pain , cure  kidney dysfunction  and  arteriosclerosis , with testimonials describing it as \"the magic medication of the 21st century\". [ 1 ]  Promotional material for the product describes it as \"the best  sexual function  activator at the moment\" [ 6 ]  which is \"officially recognized in many countries for its excellent effect in immediately increasing stamina and it is believed to be better than American Sildenafil (Viagra)\". [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1407", "text": "It is believed to be primarily targeted for export, as a means for the  North Korean government  (which is  subject to economic sanctions ) to earn foreign currency. It is sold by websites based in China and Russia. [ 3 ]  In 2017, police in  Busan , South Korea, arrested three Russian nationals for illegally selling North Korean Sildenafil and Neo-Viagra-Y.R. tablets in South Korea. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1408", "text": "Neostigmine/glycopyrronium bromide , sold under the brand name  Prevduo  , is a fixed-dose  combination medication  used for the reversal of the effects of  non-depolarizing   neuromuscular blocking agents  after  surgery . [ 2 ]  It contains  neostigmine  as the methylsulfate, a  cholinesterase inhibitor , and  glycopyrronium bromide , an  antimuscarinic agent . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1409", "text": "Neostigmine/glycopyrronium bromide was approved for medical use in the United Kingdom in 2007, [ 1 ]  and in the United States in February 2023. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1410", "text": "Neostigmine/glycopyrronium bromide is  indicated  for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery, while decreasing the peripheral muscarinic effects (e.g., bradycardia and excessive secretions) associated with cholinesterase inhibition following non-depolarizing neuromuscular blocking agent reversal administration. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1411", "text": "Nexafed  is a formulation of  pseudoephedrine  developed by  Acura Pharmaceuticals  used to deter the use of the pseudoephedrine contained in the product for illicit  methamphetamine  synthesis. [ 1 ]  Nexafed uses a polymer matrix that forms a thick gel when hydrated, preventing the extraction of pseudoephedrine. [ 2 ]  Nexafed is the only meth-resistant formulation of pseudoephedrine that shows therapeutic equivalence to Sudafed. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1412", "text": "It is sold at various pharmacies in the US, including Fruth Pharmacy [ 4 ] [ 5 ]  and  Kroger , particularly in communities where illicit methamphetamine production is an issue. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1413", "text": "Nibrozetone  is an  investigational new drug  that is being evaluated by  EpicentRx  for the treatment of oral  mucositis  in  head and neck cancer  patients.  It is a small molecule that combines direct inhibition of the  NLRP3   inflammasome , induction of  NRF2 , and release of  nitric oxide  under  hypoxic  conditions. [ 1 ] [ 2 ]  It has received  Fast Track  designation from the FDA for severe oral mucositis in head and neck cancer patients. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1414", "text": "A  nicotine nasal spray  is a  nasal spray  that contains a small dose of  nicotine , which enters the  blood  by being absorbed through the lining of the nose. This helps stop nicotine  cravings  and relieves symptoms that occur when a person is trying to  quit smoking . A  prescription  is needed for nicotine nasal spray in many countries. In the  United Kingdom , it can be purchased in a pharmacy as an  over-the-counter drug ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1415", "text": "This article incorporates  public domain material  from  Dictionary of Cancer Terms .  U.S. National Cancer Institute ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1416", "text": "Nidufexor  ( LMB-763 ) is a drug which acts as a  partial agonist  of the  farnesoid X receptor  (FXR). It has reached Phase II  clinical trials  for the treatment of  diabetic nephropathy  and  nonalcoholic steatohepatitis . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1417", "text": "Nifene  is a high affinity, selective nicotinic \u03b14\u03b22* receptor partial agonist used in medical research for  nicotinic acetylcholine receptors , usually in the form of  nifene ( 18 F ) [ 1 ] [ 2 ]  as a  positron emission tomography  (PET)  radiotracer . [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1418", "text": "Nifene has been used to assess the efficacy of acetylcholinesterase inhibitors in animal models, because the neurotransmitter acetylcholine competes with the binding of nifene at the nicotinic receptor site. [ 5 ] [ 6 ]   Learning and behavior studies in animal models using nifene have suggested a potential role of the nicotinic receptors located in distinct white matter tracts. [ 7 ]   Nifene studies in animal models of lung cancer have suggested an upregulation of the nicotinic receptor in the lung tumors. [ 8 ] [ 9 ]   Novel PET and SPECT imaging agents as potential  receptor antagonists  have been developed based on the structure of nifene; niodene for SPECT, [ 10 ]  nifrolene for PET  [ 11 ]  and niofene for PET/SPECT. [ 12 ]  These new derivatives take advantage of the unique  in vivo  imaging properties of nifene. [ 13 ]  Human studies with ( 18 F )-nifene make it a promising nicotinic \u03b14\u03b22* receptor PET radiotracer for scientific research and has exhibited reliable test-retest reproducibility. [ 14 ]  Human white matter thalamic radiations (or tracts) were well demarcated and quantified using ( 18 F )-nifene. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1419", "text": "( R )-3-Nitrobiphenyline  is a drug which acts as an  \u03b1 2 -adrenergic   agonist , selective for the  \u03b1 2C  subtype, as well as being a weak  antagonist  at the  \u03b1 2A  and  \u03b1 2B  subtypes. It has been used in scientific research to characterize the binding and functional properties of the  \u03b1 2C  subtype. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1420", "text": "Nitrosoproline  is a  nitroso   derivative  of the  amino acid   proline ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1421", "text": "Nivolumab/hyaluronidase , sold under the brand name  Opdivo Qvantig , is a  fixed-dose combination   anti-cancer medication  used for the treatment of various forms of  cancer . [ 1 ] [ 2 ]  Nivolumab/hyaluronidase contains  nivolumab , a  programmed death receptor-1  (PD-1)-blocking  monoclonal antibody ; and  hyaluronidase , an  endoglycosidase . [ 1 ]  It is given by  subcutaneous injection . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1422", "text": "Nivolumab/hyaluronidase was approved for medical use in the United States in December 2024. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1423", "text": "In December 2024, the US  Food and Drug Administration  (FDA) approved the combination of nivolumab and  hyaluronidase  across approved adult, solid tumor nivolumab  indications  as monotherapy, monotherapy maintenance following completion of hyaluronidase plus  ipilimumab  combination therapy, or in combination with  chemotherapy  or  cabozantinib . [ 2 ]  The approval includes indications for renal cell carcinoma, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, esophageal carcinoma, gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1424", "text": "The subcutaneous injection of nivolumab and hyaluronidase was evaluated in CHECKMATE-67T (NCT04810078), a multicenter, randomized, open-label trial in participants with advanced or metastatic clear cell renal cell carcinoma who received no more than two prior systemic treatment regimens. [ 2 ]  A total of 495 participants were randomized to receive either subcutaneous nivolumab and hyaluronidase or intravenous nivolumab. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1425", "text": "Nivolumab/hyaluronidase was approved for medical use in the United States in December 2024. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1426", "text": "NJK14047  is a drug which acts as a selective inhibitor of the enzyme  p38 mitogen-activated protein kinase  (p38 MAPK). It has  antiviral  and  antiinflammatory  effects and was originally developed as a potential treatment for inflammatory lung conditions such as  influenza . Subsequent research has also shown promise for various other conditions in which inflammation plays a role, including  Alzheimer's disease ,  asthma ,  arthritis  and  psoriasis . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1427", "text": "NMDA receptor modulators  ( glutamate  modulators) are a new form of  antipsychotic  that are in Phase II FDA studies. The first compound studied was  glycine  which was hypothesized by Daniel Javitt after observation that people with  phencyclidine (PCP)-induced  psychosis  were lacking in  glutamate  transmission. [ 1 ]  (PCP is an  NMDA receptor antagonist  that blocks glutamate.) In giving glycine to people with PCP-induced psychosis a recovery rate was noted. From there, it was hypothesized that people with psychosis from  schizophrenia  would benefit from increased glutamate transmission and glycine was added with strong recovery rates noted especially in the area of negative and cognitive symptoms. Glycine, however, sporadic results aside (dose 60 g/day or 0.8 g/kg, [ 2 ] [ 3 ]  approximately the amount in 300 g of gelatin powder or two kilograms of sunflower seeds [ 4 ] ) remains an adjunct  antipsychotic  and an unworkable compound. However, the  Eli Lilly and Company  study drug  LY-2140023  is being studied as a primary  antipsychotic  and is showing strong recovery rates, especially in the area of negative and cognitive symptoms of  schizophrenia .  Tardive dyskinesia ,  diabetes  and other standard complications have not been noted:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1428", "text": "Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P = 0.001 at week 4). Notably, patients treated with LY-2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1429", "text": "Other NMDA receptor modulators are being studied and this modality of treatment may once approved as  antipsychotic  medications gradually replace the current (dopaminergic) antipsychotics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1430", "text": "NNC2215  is a  bioengineered  glucose-sensitive  insulin . The drug is designed by a team of  Novo Nordisk  researchers. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1431", "text": "NNC2215 can sense the glucose concentration presence in blood. The protein's sensitivity is reduced when low concentration of glucose, thus reducing the risk of  hypoglycemia . [ 2 ]  In addition, it can effectively cover the risk of fluctuations of blood sugar levels."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1432", "text": "The study was published on scientific journal  Nature  on October 16, 2024. [ 3 ]  This study demonstrated the ability of protein engineering in future medicine and a major advancement in treatment capabilities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1433", "text": "A glucose sensitive treatment method for  diabetes  have long been pursued by science since 1979. [ 4 ]  Such protein is expected to solve the problem of  fluctuations of blood sugar levels .  For diabetes patients, skipping meal alone could lead to  hypoglycemia , which is a common complication could cause  loss of consciousness  or  seizures . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1434", "text": "There are several attempts to create such a medicine with various levels of success. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1435", "text": "Nomeco , a wholly owned subsidiary of  Phoenix Group , is the largest wholesaler of pharmaceutical products in  Denmark . The company is headquartered in  Copenhagen  and is building a 20,000 square metre Nordic logistics centre in  K\u00f8ge  which is expected to open in 2017. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1436", "text": "Nomeco was founded in 1991, through the merger of Mecobenzon A/S (founded 1919),  and Nordisk Droge og Kemikalie A/S (founded 1903). In 1998, the company was merged with  Finnish  Tamro Oyj, the largest wholesaler of pharmaceutical products in the  Nordic  and  Baltic countries . In 2000,  Phoenix Pharmahandel  became the largest shareholder of the company with 33.7% of the shares and in 2005, the company acquired full ownership. In August 2015, it was announced that Nomeco will build a new Nordic logistics centre for pharmaceuticals in  K\u00f8ge  south of Copenhagen. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1437", "text": "Nomeco is headquartered in the  South Harbour  area of Copenhagen. The new logistics centre for pharmaceuticals in K\u00f8ge will cover 20,000 square metres and be located in Skandinavisk Transport Center. Will open in the summer of 2018. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1438", "text": "The company is Denmark's largest distributor of  pharmaceuticals  and other products that promote health and well-being. Nomeco's wide range of services include various information logistics, marketing, sales and registration expert services. Pharmaceutical distribution is Nomeco's core business. Nomeco's customers are pharmaceutical companies, pharmacies, hospitals and retailers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1439", "text": "This Danish corporation or company article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1440", "text": "NONMEM  is a  non-linear mixed-effects modeling software  package developed by Stuart L. Beal and Lewis B. Sheiner in the late 1970s at  University of California, San Francisco , and expanded by Robert Bauer at Icon PLC. Its name is an acronym for  nonlinear mixed effects modeling  but it is especially powerful in the context of  population pharmacokinetics ,  pharmacometrics , and  PK/PD models . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  \nNONMEM models are written in NMTRAN, a dedicated  model specification language  that is translated into  FORTRAN , compiled on the fly and executed by a command-line script. Results are presented as text output files including tables. [ 5 ]   There are multiple interfaces to assist modelers with housekeeping of files, tracking of model development, goodness-of-fit evaluations and graphical output, such as PsN and xpose [ 6 ]  and Wings for NONMEM. [ 7 ]  Current version for NONMEM is 7.5."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1441", "text": "NONMEM estimates its models according to principles of  maximum likelihood estimation .  nonlinear mixed-effects model  generally do not have close-formed solutions, and therefore specific estimation methods are applied, such as linearization methods as first-order (FO), first-order conditional (FOCE) or the laplacian (LAPL), approximation methods such as iterative-two stage (ITS), importance sampling (IMP), stochastic approximation estimation (SAEM) or direct sampling. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1442", "text": "A  nonsteroidal  compound is a drug that is not a  steroid  nor a steroid derivative. [ 1 ] [ 2 ]   Nonsteroidal anti-inflammatory drugs  (NSAIDs) are distinguished from  corticosteroids  as a class of  anti-inflammatory agents . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1443", "text": "Examples include the following: [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1444", "text": "19-Noretiocholanolone , also known as  5\u03b2-estran-3\u03b1-ol-17-one , is a  metabolite  of  nandrolone  (19-nortestosterone) and  bolandione  (19-norandrostenedione) that is formed by  5\u03b1-reductase . It is on the list of substances prohibited by the  World Anti-Doping Agency  since it is a detectable metabolite of nandrolone, an  anabolic-androgenic steroid  (AAS). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1445", "text": "Consumption of boar meat, liver, kidneys and heart have been found to increase urinary 19-noretiocholanolone output. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1446", "text": "Hospital Pharmacy of North Norway Trust  ( Norwegian :  Sykehusapotek Nord HF ,  Northern Sami :  Davvi Buohcceviessoapotehka ) is a  health trust  owned by  Northern Norway Regional Health Authority  that operates six  hospital pharmacies . The pharmacies are part of the  Ditt Apotek  chain and use  Norsk Medisinaldepot  as  wholesaler ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1447", "text": "The pharmacies are located at  Troms\u00f8 University Hospital ,  Bod\u00f8 Hospital ,  Harstad Hospital ,  Narvik Hospital ,  Lofoten Hospital  and  Stokmarknes Hospital ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1448", "text": "The  Norwegian Medical Products Agency  formerly the  Norwegian Medicines Agency  ( Direktoratet for Medisinske Produkter  tidl.  Statens legemiddelverk ,  Legemiddelverket ) is the national regulatory authority in  Norway  for new and existing  pharmaceuticals ,  medical devices  and for the  supply chain  security of these. The Agency is responsible for supervising the production,  trials  and  marketing  of medicines. It approves medicines and monitors their use, and ensures cost-efficient, effective and well-documented use of medicines. The Inspectorate also supervises the supply chain and regulates pharmacy prices and trade conditions. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1449", "text": "Norwegian Pharmacy Association  ( Norwegian :  Apotekforeningen ) is a  trade organization  representing the  pharmacies  and pharmacy owners in  Norway . In addition to the three large chains and hospital pharmacies, 20 independent pharmacists are members of the organization."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1450", "text": "The Norwegian Pharmacy Association is a trade association for Pharmacies located in Norway. It was established in 1881. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1451", "text": "Notable people include  Leif Brendel , secretary-general from 1940 to 1968."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1452", "text": "This article about an organisation based in Norway is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1453", "text": "Novolin  is the  brand name  of three distinct insulin-containing products [ 1 ]  manufactured by  Novo Nordisk : [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1454", "text": "NPS-2143  ( SB-262,470A ) is a  calcilytic  drug which acts as an  antagonist  at the  Calcium-sensing receptor  (CaSR), and consequently stimulates release of  parathyroid hormone . [ 1 ]  Calcilytic drugs have been researched as potential treatments for  osteoporosis , and as the first such compound developed, NPS-2143 is still widely used in research into the CaSR receptor as well as design of newer calcilytic agents. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1455", "text": "NRICM101  ( Chinese :  \u6e05\u51a0\u4e00\u865f ; Taiwan: Chingguan Yihau; Mainland: Q\u012bng-gu\u0101n Y\u012b-h\u00e0o), is a treatment for  COVID-19  developed in  Taiwan  using  Traditional Chinese Medicine  (TCM), created by the  National Research Institute of Chinese Medicine  (NRICM), a governmental body of Taiwan. [ 1 ]  The prescription has gained legal approval in several countries, the first TCM recipe to do so for COVID-19 treatment. [ 2 ]  In its native Taiwan, the treatment is used in conjunction with vaccinations. [ 3 ]  Amongst the formulations available are  RespireAid  from  Sun Ten (\u9806\u5929\u5802) \u00a0[ zh ] , and  COVRelief  from  Chuang Song Zong (\u838a\u677e\u69ae) \u00a0[ zh ] . [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1456", "text": "NRICM101 contains 10  herbal medicinal components , including  indigowoad root ,  fish mint ,  Chinese skullcap ,  houttuynia , and  licorice . [ 4 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1457", "text": "According to the NRICM, the herbal medicine is supposed to work by preventing the  SARS-CoV2  virus from binding with ACE2. [ 7 ]  This would reduce the chance of severe illness. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1458", "text": "On 2021 May 18, Taiwan licensed NRICM101 for distribution under emergency access policy. It became available as  dietary supplement  in the  U.S ., the  UK ,  Australia , the EU. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1459", "text": "This  Taiwan -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1460", "text": "This  China -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1461", "text": "NS-136  is a  selective   muscarinic acetylcholine   M 4  receptor   positive allosteric modulator  which is under development for the treatment of  schizophrenia  and  Alzheimer's disease . [ 1 ] [ 3 ] [ 2 ]  It has been found to possess  pro-cognitive  effects in rodents. [ 2 ]  The drug is under development by NeuShen Therapeutics. [ 1 ] [ 3 ]  As of May 2024, it is in  phase 1   clinical trials  for schizophrenia and is in the  preclinical stage of development  for Alzheimer's disease. [ 1 ] [ 3 ]  The drug is a  small molecule , but its  chemical structure  does not seem to have been disclosed. [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1462", "text": "Nufenoxole  ( SC-27166 ) is an  antidiarrhoeal  drug which acts as a peripherally selective  opioid  agonist, in a similar manner to  loperamide . while it is able to activate  \u03bc-opioid receptors , it fails to cross the  blood\u2013brain barrier  and so has a selective action against diarrhoea without producing  analgesic  effects. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1463", "text": "NV-5440  is a drug which acts as both a non-specific inhibitor of the  glucose transporters  and also a selective inhibitor of  mTORC1 , with no significant action at the related  mTORC2  subtype. Compounds of this type have potential application in the treatment of  cancer , and it is also used for research into the links between  calorie restriction  and  longevity . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1464", "text": "O-4310  ( 1-isopropyl-6-fluoro-psilocin ) is a  tryptamine   derivative  developed by  Organix Inc  which acts as a  serotonin receptor   agonist . It is claimed to have an EC 50  of 5 \u00a0 nM at the  5-HT 2A  receptor  with 89%  efficacy  relative to  serotonin , and 100-fold  selectivity  over the  5-HT 2C  receptor , while being apparently inactive at the  5-HT 2B   antitarget . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1465", "text": "Obecabtagene autoleucel , sold under the brand name  Aucatzyl , is an  anti-cancer medication  used for the treatment of  acute lymphoblastic leukemia . [ 1 ] [ 2 ]  It is a  CD19 -directed genetically modified autologous  T-cell  immunotherapy. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1466", "text": "The most common side effects include  cytokine release syndrome , infections-pathogen unspecified, musculoskeletal pain, viral infections, fever, nausea, bacterial infectious disorders, diarrhea, febrile neutropenia, immune effector cell-associated  neurotoxicity syndrome , hypotension, pain, fatigue, headache, encephalopathy, and hemorrhage. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1467", "text": "Obecabtagene autoleucel was approved for medical use in the United States in November 2024. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1468", "text": "Obecabtagene autoleucel is  indicated  for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1469", "text": "The US  Food and Drug Administration  (FDA) approved prescribing information for obecabtagene autoleucel has a  boxed warning  for  cytokine release syndrome , immune effector cell-associated  neurotoxicity syndrome , and  T-cell  malignancies. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1470", "text": "The most common side effects include cytokine release syndrome, infections-pathogen unspecified, musculoskeletal pain, viral infections, fever, nausea, bacterial infectious disorders, diarrhea, febrile neutropenia, immune effector cell-associated neurotoxicity syndrome, hypotension, pain, fatigue, headache, encephalopathy, and hemorrhage. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1471", "text": "Efficacy was evaluated in FELIX (NCT04404660), an open-label, multicenter, single-arm trial that enrolled adults with relapsed or refractory CD19-positive B-cell acute lymphoblastic leukemia. [ 2 ]  Enrolled participants were required to have relapsed following a remission lasting twelve months or less, relapsed or refractory acute lymphoblastic leukemia following two or more prior lines of systemic therapy, or disease that was relapsed or refractory three or more months after allogeneic stem cell transplantation. [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1472", "text": "The major efficacy outcome measures were rate and duration of complete remission achieved within three months after infusion. [ 2 ]  Additional outcome measures were rate and duration of overall complete remission which includes complete remission and complete remission with incomplete hematologic recovery, at any time. [ 2 ]  Of the 65 participants evaluable for efficacy, 27 participants (42%; 95% confidence interval [CI]: 29%, 54%) achieved complete remission within three months. [ 2 ]  The median duration of complete remission achieved within three months was 14.1 months (95% CI: 6.1, not reached). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1473", "text": "The US  Food and Drug Administration  (FDA) granted the application for obecabtagene autoleucel regenerative medicine advanced therapy (RMAT) and  orphan drug  designations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1474", "text": "Obecabtagene autoleucel was approved for medical use in the United States in November 2024. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1475", "text": "Obecabtagene autoleucel is the  international nonproprietary name . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1476", "text": "It is sold under the brand name Aucatzyl. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1477", "text": "Obefazimod  is an  investigational new drug  that is being evaluated for the treatment of  ulcerative colitis . [ 1 ]   It is  miR-124  micro RNA upregulator. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1478", "text": "Obexelimab  is an experimental drug developed to treat  IgG4-related disease  and  lupus . It works as a \"bifunctional, non-cytolytic, humanised  monoclonal antibody  that binds  CD19  and  Fc gamma receptor IIb  to inhibit  B cells ,  plasmablasts , and CD19-expressing  plasma cells .\" [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1479", "text": "Ocedurenone , formerly known as  KBP-5074 , [ 1 ]  is a nonsteroidal, selective  mineralocorticoid receptor antagonist  that is being developed to treat  hypertension  in patients with  chronic kidney disease  with less risk of  hyperkalemia  than existing treatments. [ 2 ] [ 3 ]  In 2023, KPB Biosciences entered into talks to sell the drug to  Novo Nordisk  for USD$1.3 billion. It is a  small molecule  drug administered orally and is in a Phase III trial that is scheduled to complete in 2024. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1480", "text": "Ocrelizumab/hyaluronidase , sold under the brand name  Ocrevus Zunovo , is a  fixed-dose combination  medication used for the treatment of  multiple sclerosis . [ 1 ]  It contains  ocrelizumab , a recombinant humanized  monoclonal antibody  directed at CD20; [ 1 ]  and  hyaluronidase  (human recombinant), an  endoglycosidase . [ 1 ]  It is taken by  subcutaneous injection . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1481", "text": "Ocrelizumab/hyaluronidase was approved for medical use in the United States in September 2024. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1482", "text": "Ocrelizumab/hyaluronidase is  indicated  for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease; [ 1 ]  and primary progressive multiple sclerosis. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1483", "text": "Odilorhabdins  are a class of natural  antibacterial agents  produced by the bacterium  Xenorhabdus nematophila . [ 1 ]  Odilorhabdins act against both  Gram-positive  and  Gram-negative  pathogens, and were shown to eliminate infections in mouse models. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1484", "text": "Odilorhabdins interfere with the pathogen's  protein synthesis  and are  ribosome -targeting. They bind to the small ribosomal subunit at a site not exploited by previous antibiotics and induce miscoding and premature  stop codon  bypass. [ 1 ]  Odilorhabdins were shown to act particularly against  carbapenem -resistant members of bacteria family  Enterobacteriaceae , having potential to kill pathogens with  antimicrobial resistance . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1485", "text": "The discovery of odilorhabdins was announced in 2013 [ 2 ]  and formally described in 2018 by the researchers of the  University of Illinois at Chicago  and Nosopharm. To identify the antibiotic, the Nosopharm researchers tested 80  cultured  bacterial  strains  for antimicrobial properties and then isolated the active compounds. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1486", "text": "Odronextamab , sold under the brand name  Ordspono , is a  CD20  x  CD3  bispecific  monoclonal antibody  that is used for the treatment of  follicular lymphoma  or  diffuse large B-cell lymphoma . [ 1 ] [ 2 ]  It was developed by  Regeneron Pharmaceuticals . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1487", "text": "The most common side effects include  cytokine release syndrome ,  infections ,  neutropenia ,  pyrexia  (fever),  anemia ,  thrombocytopenia , and  diarrhea . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1488", "text": "Odronextamab was approved for medical use in the European Union in August 2024. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1489", "text": "Odronextamab is  indicated  for the treatment of adults with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy; [ 1 ]  and for the treatment of adults with relapsed or refractory diffuse large B\u2011cell lymphoma after two or more lines of systemic therapy. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1490", "text": "The most common side effects include cytokine release syndrome, infections, neutropenia, pyrexia, anemia, thrombocytopenia, and diarrhea. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1491", "text": "In June 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Ordspono, intended for the treatment of follicular lymphoma and diffuse large B-cell lymphoma. [ 1 ] [ 3 ]  The applicant for this medicinal product is Regeneron Ireland Designated Activity Company. [ 1 ]  Odronextamab was approved for medical use in the European Union in August 2024. [ 1 ] [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1492", "text": "Odronextamab is the  international nonproprietary name . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1493", "text": "Oenethyl , also known as  2-methylaminoheptane  and sold under the brand names  Pacamine  and  Neosupranol , is a  sympathomimetic  and  vasopressor   medication  of the  alkylamine  which is no longer marketed. [ 1 ] [ 2 ] [ 3 ]  It was used as a  nasal decongestant  and to control  blood pressure  during  anesthesia . [ 3 ]  It is closely  structurally related  to other alkylamines, for instance  methylhexanamine  and  tuaminoheptane , among others. [ 3 ]  These compounds are known to act as structurally simple  monoamine releasing agents  and to produce  psychostimulant -like effects. [ 4 ] [ 5 ] [ 6 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1494", "text": "Olezarsen , sold under the brand name  Tryngolza , is a  medication  used in the treatment of  familial chylomicronemia syndrome . [ 1 ] [ 2 ]  Olezarsen is an  apolipoprotein C-III -directed  antisense oligonucleotide . [ 1 ]  It is given by  injection under the skin . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1495", "text": "Olezarsen was approved for medical use in the United States in December 2024. [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1496", "text": "Olezarsen is  indicated  as an adjunct to diet to reduce triglycerides in adults with  familial chylomicronemia syndrome . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1497", "text": "The US  Food and Drug Administration  (FDA) granted the application of olezarsen  orphan drug  designation in February 2024. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1498", "text": "Olezarsen was approved for medical use in the United States in December 2024. [ 3 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1499", "text": "Olezarsen is the  international nonproprietary name . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1500", "text": "Olezarsen is sold under the brand name Tryngolza. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1501", "text": "Olpasiran  (AMG890) is an experimental  antisense therapy  designed to lower the level of  lipoprotein(a) , which is believed to be a causal factor in the development of  cardiovascular disease . The drug is developed by  Amgen . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1502", "text": "Olutasidenib , sold under the brand name  Rezlidhia , is an  anticancer medication  used to treat relapsed or refractory  acute myeloid leukemia  with a susceptible IDH1 mutation. [ 2 ] [ 3 ]  Olutasidenib is an  isocitrate dehydrogenase-1  (IDH1) inhibitor. [ 2 ]  It is taken  by mouth . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1503", "text": "The most common adverse reactions include nausea, fatigue/malaise, arthralgia, constipation, leukocytosis, dyspnea, fever, rash, mucositis, diarrhea, and transaminitis. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1504", "text": "Olutasidenib was approved for medical use in the United States in December 2022, [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]  based on the phase 1 results of a phase 1/2 trial. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1505", "text": "Olutasidenib is indicated for the treatment of adults with relapsed or refractory acute myeloid leukemia with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1506", "text": "Olutasidenib is the international nonproprietary name. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1507", "text": "Omidubicel , sold under the brand name  Omisirge , is a blood-based  cell therapy  used for the treatment of  blood cancers . [ 3 ] [ 4 ] [ 5 ]  Omidubicel is a  nicotinamide -modified allogeneic hematopoietic progenitor cell therapy derived from  cord blood . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1508", "text": "The most common adverse reactions include infections,  graft-versus-host disease , and infusion reactions. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1509", "text": "Omidubicel is composed of human allogeneic stem cells from umbilical cord blood that are processed and cultured with nicotinamide (a form of vitamin B3). [ 3 ]  Each dose is patient-specific, containing healthy stem cells from an allogeneic pre-screened donor, meaning it comes from a different individual rather than using the patient's own cells. [ 3 ]  Omidubicel was approved for medical use in the United States in April 2023. [ 3 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1510", "text": "Omidubicel is  indicated  for use in people twelve years of age and older with blood cancers (hematologic malignancies) planned for umbilical cord blood  transplantation  following myeloablative conditioning to reduce the time to  neutrophil  recovery and the incidence of infection. [ 3 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1511", "text": "The US  Food and Drug Administration  (FDA) evaluated the safety and effectiveness of omidubicel based on a randomized, multicenter study comparing transplantation of omidubicel to transplantation of umbilical cord blood, in subjects between the ages of 12 and 65 years. [ 3 ]  The study enrolled a total of 125 participants. [ 3 ]  All participants in the study had confirmed blood cancers. [ 3 ]  The efficacy of omidubicel was based on the amount of time needed for recovery of the participant's neutrophils (a type of white blood cell that helps protect the body from infections) and the incidence of infections following transplantation. [ 3 ]  In total, 125 participants were randomized--62 participants to receive omidubicel-onlv and 63 to the unmanipulated cord blood group. [ 6 ]  Fifty-two participants were transplanted with omidubicel-onlv receiving a median CD34+ cell dose of 9.0 X 106 cells/kg (range 2.1 \u2013 47.6 X 106 cells/kg). [ 6 ]  Fifty-six participants were transplanted in the unmanipulated cord blood arm with one or two cord units (66% received two cord units). [ 6 ]  In the 42 participants with reported post-thaw cell dose, the median CD34+ cell dose was 0.2 X 106 cells/kg (range 0.0 \u2013 0.8 X 106 cells/kg). Multiple conditioning regimens were used, including total body irradiation-based or chemotherapy-based options. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1512", "text": "The FDA granted the application for omidubicel  priority review ,  breakthrough therapy , and  orphan drug  designations. [ 3 ] [ 6 ]  The FDA granted regular approval of Omisirge to Gamida Cell Ltd. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1513", "text": "Omzotirome  ( INN ), formerly codenamed  TRC-150094 , is a  thyromimetic  drug which acts as a metabolic modulator which restores  metabolic flexibility . It has been shown to improve  insulin resistance  and  hyperglycemia , and is in Phase III human  clinical trials  for the treatment of Cardiometabolic-Based Chronic Disease (CMBCD) by improving  dysglycemia , dyslipidemia and hypertension. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1514", "text": "Onchidal  is a naturally occurring  neurotoxin  produced as a defensive secretion by the  mollusc   Onchidella binneyi  and several other related species in  Onchidella ,  a genus of small, air-breathing sea slugs. It acts as an irreversible  acetylcholinesterase inhibitor , the same mechanism of action as that of the deadly  nerve agents , however onchidal is not an  organophosphorus  or  carbamate  compound and bears little resemblance to other compounds of this nature. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1515", "text": "The  Oncologic Drugs Advisory Committee  (ODAC) receives requests for technical and clinical evaluation of new drugs by the  U.S. Food and Drug Administration  (FDA).  The committee, consisting of members from academic and clinical oncology biostatistics, the general public, and the pharmaceutical industry, makes non-binding recommendations to both the  CDER  and  CBER  divisions of the FDA about the advisability of approving new medications to treat  cancer ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1516", "text": "This  oncology  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1517", "text": "Onfasprodil  ( MIJ821 ) is a drug delivered via  intravenous infusion  that is designed as a fast-acting treatment for  treatment-resistant depression . It works as a  negative allosteric modulator  of the  NMDA receptor   subunit 2B  (NR2B). The drug is developed by  Novartis . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1518", "text": "Onset of action  is the duration of time it takes for a  drug 's effects to come to prominence upon administration. With  oral administration , it typically ranges anywhere from 20 minutes to over an hour, depending on the drug in question. Other methods of ingestion such as  smoking  or  injection  can take as little as seconds to minutes to take effect. The determination of the onset of action, however, is not completely dependent upon  route of administration . There are several other factors that determine the onset of action for a specific drug, including  drug formulation ,  dosage , and the patient receiving the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1519", "text": "A drug's pharmacological effects can only occur once it has been fully solubilized and has entered the blood stream. For most drugs administered orally, the drug must be ingested, pass through the stomach, and into the small intestine, where the drug molecules enter the blood stream through the  villi  and  microvilli . [ 1 ]  A few drugs such as alcohol are absorbed by the lining of the stomach, and therefore tend to take effect much more quickly than the vast majority of oral medications which are absorbed in the small intestine. Gastric emptying time can vary from 0 to 3 hours, [ 2 ]  and therefore plays a major role in onset of action for orally administered drugs. For intravenous administration, the pathway is much shorter because the drug is administered (usually already in solution) directly to the bloodstream."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1520", "text": "OPC-64005  is a  serotonin\u2013norepinephrine\u2013dopamine reuptake inhibitor  (SNDRI), or \"triple reuptake inhibitor\" (TRI), which is under development for the treatment of  major depressive disorder . [ 1 ] [ 2 ] [ 3 ]  It was also under development for the treatment of  attention deficit hyperactivity disorder  (ADHD), but development for this indication was discontinued. [ 1 ] [ 4 ]  It is taken  by mouth . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1521", "text": "As of December 2022, OPC-64005 is in  phase 2   clinical trials  for major depressive disorder. [ 1 ] [ 2 ]  It reached phase 2 clinical trials for ADHD prior to the discontinuation of its development for this use. [ 1 ]  It completed a phase 2 clinical trial for ADHD comparing it with  placebo  and  atomoxetine , but the results of this trial were not disclosed. [ 5 ]  The drug is under development by  Otsuka Pharmaceutical . [ 1 ] [ 2 ]  It is a  small molecule , but its  chemical structure  does not appear to have been disclosed. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1522", "text": "Opevesostat  is an  investigational new drug  being developed for the treatment of  metastatic castration-resistant prostate cancer  (mCRPC). [ 1 ]  It is a non-steroidal, selective inhibitor of  CYP11A1  (cholesterol side-chain cleavage enzyme) [ 2 ]  discovered by  Orion Corporation  and currently undergoing clinical development by  Merck & Co., Inc.  Opevesostat's mechanism of action involves suppressing the production of steroid hormones and their precursors that may activate the  androgen receptor  signaling pathway, which is crucial in prostate cancer progression. As of 2024, opevesostat is being evaluated in two Phase 3 clinical trials, OMAHA1 and OMAHA2a, which are assessing its efficacy and safety in combination with hormone replacement therapy for patients with mCRPC who have failed prior treatments. [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1523", "text": "Opnurasib  (JDQ-443) is a  small-molecule  covalent  KRASG12C  inhibitor developed for  non-small-cell lung cancer . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1524", "text": "Opodeldoc  is a medical plaster or  liniment  invented, or at least named, by the  German Renaissance   physician   Paracelsus  in the 1500s.  In modern form opodeldoc is a mixture of  soap  in  alcohol , to which  camphor  and sometimes a number of  herbal  essences, most notably  wormwood , are added."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1525", "text": "In his  Bertheonea Sive Chirurgia Minor  published in 1603, Paracelsus mentioned \"oppodeltoch\" twice, but with uncertain ingredients. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1526", "text": "As to the origin of the name,  Kurt Peters  speculated that it was coined by Paracelsus from syllables from the words \" opo ponax, b del lium, and aristol och ia.\"  Opoponax  is a variety of  myrrh ;  bdellium  is  Commiphora wightii , which produces a similar resin; and  Aristolochia  is a widely distributed  genus  which includes  A. pfeiferi ,  A. rugosa  and  A.  trilobata  that are used in folk medicine to cure snakebites. The name suggests that these aromatic plants may have figured in Paracelsus's recipe. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1527", "text": "In his  Medicina Militaris  of 1620, German military physician Raymund Minderer (\"Mindererus\"; 1570-1621) praised the Paracelsus compound as a plaster, good for wounds. Minderer compared it to his own variant, which set more like sealing wax. [ 3 ]  Opodeldoc and Paracelsus were acknowledged in English no later than 1646, in  Sir Thomas Browne 's popular and influential  Pseudodoxia Epidemica . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1528", "text": "Paracelsus's recipe is completely unrelated to later preparations of the same name. [ 5 ]  By the second printing of the  Edinburgh Pharmacopoeia  in 1722 the name applied to a soap-based liniment. Such a liniment in patent form, sold by  John Newbery 's company in Great Britain \"ever since A.D. 1786\", was called \"Dr. Steer's Opodeldoc\". [ 6 ]  Produced for decades, the \"Dr. Steer\" preparation had been successfully imported into the U.S., and was common enough there to rank as one of the eight patent medicines to be analyzed (although not condemned) by the  Philadelphia College of Pharmacy  in 1824. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1529", "text": "The name  Old Opodeldoc  was formerly used as a standard name for a  stock character  who was a physician, especially when played as a  comic  figure.  Edgar Allan Poe  used \"Oppodeldoc\" as a  pseudonym  for a character in the  short story  \" The Literary Life of Thingum Bob, Esq. \" [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1530", "text": "The  Pharmacopoeia  of the  United States  (U.S.P.) gives a recipe for opodeldoc that contains:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1531", "text": "As late as the early 1990s 'Epideldoc' (sic) was compounded on request by several pharmacists in the Northwest of England."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1532", "text": "Ordesekimab  is an anti- interleukin 15   monoclonal antibody  developed by  Amgen  to treat refractory  celiac disease . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1533", "text": "Oritinib  is an  investigational new drug  currently under investigation for its potential use in cancer treatment. [ 1 ] [ 2 ]  As a  epidermal growth factor receptor  (EGFR)  tyrosine kinase inhibitor , oritinib targets specific enzymes involved in the signaling pathways that regulate cell division and survival, which are often dysregulated in cancer cells. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1534", "text": "Ortho-McNeil Pharmaceutical  (now operating under  Janssen Pharmaceuticals ) was a pharmaceutical company based in Raritan, New Jersey, that was formed from the merger of  Ortho Pharmaceutical  and  McNeil Pharmaceutical  in 1993. [ 1 ]  Both of these pharmaceutical companies were pioneers and leaders in areas such as  pain management ,  acid reflux disease , and  infectious diseases . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1535", "text": "Ortho-McNeil and  Janssen Pharmaceuticals  together composed the  Ortho-McNeil-Janssen  group within  Johnson & Johnson  prior to a decision to operate under the Janssen Pharmaceuticals name in 2011. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1536", "text": "Amongst its many  prescription drugs  are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1537", "text": "In 2010, Ortho-McNeil pled guilty in U.S. District Court to one count of misdemeanor violation of the  Food, Drug & Cosmetic Act  for illegally promoting its epilepsy drug  Topamax  for uses that were not approved by the FDA. The company was charged with using a program called \"Doctor for a Day\" to promote Topamax to psychiatrists for treatment of mental health conditions, despite never applying for FDA approval of Topimax for any psychiatric indication. The company was sentenced to pay a fine of $6.14 million. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1538", "text": "Ortho-McNeil's parent company, Johnson and Johnson, also paid $75.37 million to resolve civil allegations under the  False Claims Act  that it caused false claims to be submitted to government health care programs for a variety of psychiatric uses that were not FDA approved. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1539", "text": "Ortho-McNeil was found liable in two 2013 civil suits by women who gave birth to children with birth defects after taking Topamax while pregnant. The jury found that they negligently failed to warn the patients and their doctors of the risks associated with Topamax when used by patients during pregnancy. [ 5 ]  They awarded $11 million in damages to one family [ 6 ]  and $4 million to the other. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1540", "text": "As a result of these and other patient reports, the FDA ordered that a warning be added to the prescribing information for Topamax detailing the risk of birth defects such as cleft lip and cleft palate. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1541", "text": "Oryzalin  is a  herbicide  of the  dinitroaniline  class.  It acts through the disruption ( depolymerization ) of microtubules, thus blocking  anisotropic  growth of plant cells. [ 1 ]  It can also be used to induce  polyploidy  in plants as an alternative to  colchicine . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1542", "text": "Osoresnontrine  ( BI-409306 ) is a  phosphodiesterase 9 inhibitor  in development for  schizophrenia , [ 1 ]   attenuated psychosis syndrome , [ 2 ]  and  Alzheimer's disease . [ 3 ]  A preclinical study suggested that it increases memory in rodents. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1543", "text": "OUP-16  is a  histamine agonist  selective for the  H 4  subtype. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1544", "text": "Oxomemazine/guaifenesin  is a  sedative   antihistamine  plus  expectorant . [ 1 ] [ 2 ]   It is a combination of  oxomemazine  and  guaifenesin ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1545", "text": "It is sold under a variety of brand names including  Toplexil  by  Aventis . It is sold over the counter in  France ,  Morocco ,  Egypt , Algeria,  South Korea  and the  UAE [ citation needed ] . The  oxomemazine  ingredient (antihistamine) is not approved by the U.S.  Food and Drug Administration  (FDA), either for over the counter or prescription use. It is sold in France as cough syrup. French travelers also use it as a sleeping aid for long flights. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1546", "text": "Padeliporfin , sold under the brand name  Tookad , is a  medication  used to treat men with  prostate cancer . [ 1 ] [ 2 ]  It is used in the form padeliporfin di-potassium. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1547", "text": "The most common side effects include problems with urinating (pain, inability to pass urine, strong urge to pass urine, frequent urination, and incontinence), sexual problems (erectile dysfunction and ejaculation failure), blood in urine, urinary tract infection, and pain and bleeding around the genital area. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1548", "text": "Padeliporfin was approved for medical use in the European Union in November 2017. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1549", "text": "Padeliporfin is  indicated  as monotherapy for adults with previously untreated, unilateral, low risk,  adenocarcinoma  of the  prostate  with a life expectancy of at least ten years and clinical stage  T1c  or  T2a ;  Gleason score  \u2264 6, based on high-resolution biopsy strategies;  prostate-specific antigen  (PSA) \u2264 10 \u00a0 ng/mL; three positive cancer cores with a maximum cancer core length of 5 \u00a0 mm in any one core or 1-2 positive cancer cores with \u2265 50% cancer involvement in any one core or a PSA density \u2265 0.15 \u00a0 ng/mL/cm 3 . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1550", "text": "Padeliporfin was approved for use in the European Union in November 2017. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1551", "text": "In February 2020, the oncologic drugs advisory committee of the US  Food and Drug Administration  (FDA) voted against approving padeliporfin di-potassium powder for solution for injection, submitted by Steba Biotech, S.A. The proposed indication (use) for the product is for the treatment of men with localized prostate cancer, meeting the following criteria: Stage T1-T2a and prostate specific antigen less than or equal to 10\u00a0ng/mL and Gleason Grade Group 1 based on transrectal ultrasound guided biopsy or unilateral Gleason Grade Group 2 based on multiparametric magnetic resonance imaging-targeted biopsy with less than 50 percent of cores positive. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1552", "text": "Paediatric-use marketing authorisations  ( PUMA ) are granted by the  European Medicines Agency  (EMA) for medical products that are intended exclusively for  paediatric  use, that is, for use in patients younger than 18 years. Like ordinary EMA marketing authorisations, a PUMA approval is valid in all countries of the  European Economic Area  (the  European Union  as well as  Iceland ,  Liechtenstein , and Norway). The PUMA process was established to make it more profitable for pharmaceutical companies to market drugs for children. For this purpose, new data used for PUMA approved drugs are protected for 10 years, and the applications are partially exempt from fees. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1553", "text": "In September 2011, the first drug was approved under this process. It was Buccolam, a  buccal  application form of  midazolam  for the treatment of  seizures . [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1554", "text": "Palazestrant  is an  investigational new drug  which is being evaluated for the treatment of estrogen receptor-positive (ER+)  breast cancer , with a dual mechanism of action as both a complete  estrogen receptor antagonist  (CERAN) and a  selective estrogen receptor degrader  (SERD). This orally bioavailable small molecule has demonstrated potent activity against both wild-type and mutant forms of the estrogen receptor. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1555", "text": "Paltusotine  is a selective  somatostatin receptor  type 2 (SST2) agonist in development for the treatment of  acromegaly  and certain neuroendocrine tumors. It is a  small molecule  delivered orally. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1556", "text": "Pamapimod  is an  investigational drug  which is being evaluated for the treatment of  autoimmune diseases . It is a  p38 mitogen-activated protein kinase  inhibitor. [ 1 ]  It has been evaluated in a phase 2 clinical trial for the treatment of  rheumatoid arthritis , but was found not to be effective. [ 2 ] [ 3 ]  It has subsequently been investigated as a possible treatment for  osteoarthritis . [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1557", "text": "Pan-assay interference compounds  ( PAINS ) are  chemical compounds  that often give  false positive  results in  high-throughput screens . [ 1 ]  PAINS tend to  react  nonspecifically with numerous  biological targets  rather than specifically affecting one desired target. [ 2 ]  A number of disruptive  functional groups  are shared by many PAINS. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1558", "text": "While a number of filters have been proposed and are used in  virtual screening  and  computer-aided drug design , [ 5 ]  the accuracy of filters with regard to compounds they flag and don't flag has been criticized. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1559", "text": "Common PAINS include  toxoflavin ,  isothiazolones ,  hydroxyphenyl hydrazones ,  curcumin ,  phenol-sulfonamides ,  rhodanines ,  enones ,  quinones , and  catechols . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1560", "text": "Pantopon , also known as Opium Alkaloids Hydrochlorides, is a preparation of  opiates  made up of all of the  alkaloids  present in  opium  in their natural proportions as  hydrochlorides   salts . [ 1 ] [ 2 ] [ 3 ]  It can sometimes be tolerated by people who are allergic to  morphine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1561", "text": "Pantopon is prepared by treating standardized medicinal opium with  hydrochloric acid  or, more commonly, mixing 20 parts morphine HCl, 5 parts codeine, 6 parts thebaine, 8 parts noscapine, 2 parts narcotine, 6 parts miscellaneous alkaloids hydrochlorides. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1562", "text": "Pantopon is, in other words,  opium  with all of the tar and other insolubles removed in an injectable form which, by weight, is nearly as potent as  morphine . It was invented in 1909 by the  Hoffmann-La Roche  pharmaceutical company. Other drugs of the same type have included  in the opium alkaloid  hydrobromides ,  sulfates ,  phosphates , and  valerates .  \"Opium in a syringe \" and \"Injectable Whole Opium\" were common advertising slogans for the product from Roche. An example of similar product to Pantopon is Omnopon, which contains morphine, codeine, and papaverine. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1563", "text": "Pantopon gave its name to the poem \"Pantopon Rose\" by the American writer  William Burroughs [ 7 ]  and to a song with the same name by the  Northern Ireland   alternative metal  band  Therapy?  on their 1994 album  Troublegum . Pantopon also gave its name to the 1996  Mexican  documentary  Rosa Pantopon . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1564", "text": "Papaveretum  ( BAN ) is a preparation containing a mixture of  hydrochloride  salts of  opium   alkaloids . [ 1 ]  Since 1993, papaveretum has been defined in the  British Pharmacopoeia  (BP) as a mixture of 253 parts  morphine hydrochloride , 23 parts  papaverine hydrochloride , and 20 parts  codeine hydrochloride . [ 2 ]  It is commonly marketed to medical agencies under the  trade name   Omnopon ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1565", "text": "Although the use of papaveretum is now relatively uncommon following the wide availability of single-component  opiates  and synthetic  opioids  (e.g.  pethidine ), it is still used to relieve moderate to severe pain and for pre-operative sedation. In clinical settings, papaveretum is usually administered to patients via  subcutaneous ,  intramuscular , or  intravenous  routes. Additionally, the morphine  syrettes  found in combat medical kits issued to military personnel actually contain Omnopon."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1566", "text": "Prior to 1993, papaveretum also contained  noscapine , though this component was removed from the BP formulation due to the  genotoxic  potential of noscapine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1567", "text": "Parachuting  or  bombing  is a method of swallowing  drugs  by rolling or folding powdered or crushed drugs in a piece of edible paper to ingest while avoiding the unpleasant  taste  of the  chemical . [ 1 ]  It is sometimes called a \"snow bomb\", especially if using  cocaine .\nThis method is used among many pharmaceuticals that are commonly crushed for recreational use. The toilet paper method must use single ply toilet paper or one must separate the layers of double ply. Tissues are also a common go to for this method of drug ingestion. Another common paper used is  rolling paper  for smoking herbal substances or tobacco. Rice or starch papers known as  oblaat  in  Japan  is a method that is becoming more popular.  Opioids ,  amphetamines ,  benzodiazepines  and other narcotics are commonly parachuted. This method's purpose is recreational because the drugs become absorbed all at once when the paper unravels in one's stomach."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1568", "text": "Paraoxon  is a  parasympathomimetic drug  which acts as an  cholinesterase inhibitor . It is an  organophosphate   oxon , and the active  metabolite  of the insecticide  parathion .  It is also used as an  ophthalmological  drug against  glaucoma . Paraoxon is one of the most potent acetylcholinesterase-inhibiting  insecticides  available, around 70% as potent as the nerve agent  sarin , and so is now rarely used as an insecticide due to the risk of  poisoning  to humans and other animals. Paraoxon has been used by scientists to study acute and chronic effects of organophosphate intoxication. [ 1 ] [ 2 ]  It is easily absorbed through skin, and was allegedly used as an  assassination  weapon by the apartheid-era  South African   chemical weapons  program  Project Coast . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1569", "text": "A  parasympathomimetic drug , sometimes called a  cholinomimetic drug [ 1 ]  or  cholinergic receptor   stimulating agent , [ 2 ]  is a substance that stimulates the  parasympathetic nervous system  (PSNS). [ 3 ] [ 2 ]  These chemicals are also called  cholinergic  drugs  because  acetylcholine  (ACh) is the  neurotransmitter  used by the PSNS. [ 1 ] [ 4 ]  Chemicals in this family can act either directly by stimulating the  nicotinic  or  muscarinic  receptors (thus mimicking acetylcholine), or indirectly by inhibiting  cholinesterase , promoting acetylcholine release, or other mechanisms. [ 5 ]  Common uses of parasympathomimetics include  glaucoma ,  Sj\u00f6gren syndrome  and  underactive bladder . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1570", "text": "Some  chemical weapons  such as  sarin  or  VX , non-lethal  riot control agents  such as  tear gas , and insecticides such as  diazinon  fall into this category."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1571", "text": "For a cholinergic agent, the following criteria describe the structure activity relationship:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1572", "text": "These act by stimulating the  nicotinic  or  muscarinic  receptors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1573", "text": "Indirect acting parasympathomimetic substances may be either reversible cholinesterase inhibitors, irreversible cholinesterase inhibitors or substances that promote ACh release or  anti-adrenergics . The latter inhibits the antagonistic system, the  sympathetic nervous system ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1574", "text": "Parsaclisib  is an  investigational drug  that it being evaluated for the treatment of  B-cell malignancies .  It is a  PI3K\u03b4  ( phosphoinositide 3-kinase ) inhibitor. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1575", "text": "In  pharmacology ,  partial agonists  are drugs that bind to and activate a given  receptor , but have only partial  efficacy  at the receptor relative to a  full agonist . They may also be considered  ligands  which display both  agonistic  and  antagonistic  effects\u2014when both a full agonist and partial agonist are present, the partial agonist actually acts as a  competitive antagonist , [ citation needed ]   competing with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone. [ 1 ]  Clinically, partial agonists can be used to activate receptors to give a desired submaximal response when inadequate amounts of the endogenous ligand are present, or they can reduce the overstimulation of receptors when excess amounts of the endogenous ligand are present. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1576", "text": "Some currently common drugs that have been classed as partial agonists at particular receptors include  buspirone ,  aripiprazole ,  buprenorphine ,  nalmefene  and  norclozapine . Examples of ligands activating  peroxisome proliferator-activated receptor gamma  as partial agonists are  honokiol  and  falcarindiol . [ 3 ] [ 4 ]  Delta 9-tetrahydrocannabivarin ( THCV ) is a partial agonist at  CB2 receptors  and this activity might be implicated in \u22069-THCV-mediated  anti-inflammatory  effects. [ 5 ]  Additionally, Delta-9-Tetrahydrocannabinol ( THC ) is a partial agonist at both the  CB1  and CB2 receptors, with the former being responsible for its psychoactive effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1577", "text": "Peak-to-trough ratio  ( PTR ), also known as  peak-to-trough variation  or  peak-to-trough fluctuation , is a parameter in  pharmacokinetics  which is defined as the ratio of  C max  (peak) concentration and  C min  (trough) concentration over a dosing interval for a given drug. [ 1 ] [ 2 ]  A drug with an  elimination half-life  of 24\u00a0hours taken once per day will have a peak-to-trough ratio of approximately 2. [ 1 ]  Peak-to-trough ratio depends on half-life and dosing interval, with longer half-lives and shorter dosing intervals giving smaller ratios. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1578", "text": "Peforelin  ( INN Tooltip International Nonproprietary Name ), or  peforelin acetate , sold under the brand name  Maprelin , is a  gonadotropin-releasing hormone agonist  (GnRH agonist) medication which is used in  veterinary medicine  in  Europe  and  Canada . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It is a  GnRH analogue  and a  synthetic   peptide , specifically a  decapeptide . [ 1 ] [ 3 ] [ 4 ]  The drug was introduced for veterinary use by 2001. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1579", "text": "Polyethylene glycol\u2013polyvinyl alcohol  ( PEG-PVA ) brand name  Kollicoat  IR  ( BASF ) is a  multifunctional  excipient [ 1 ]  used as a pill binder as well as a wet binder. A typical formulation is composed of 25%  polyethylene glycol  (PEG) and 75%  polyvinyl alcohol  (PVA); where the vinyl alcohol moieties are grafted on a  polyethylene glycol   backbone . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1580", "text": "Pegol  is a term used in generic names for pharmaceutical drugs to indicate the presence of a  polyethylene glycol  attachment ( pegylation ). The term is used for  monoclonal antibodies  and  engineered proteins  as well as for  small molecules . The purpose of the pegylation is to extend the  half-life  of the drug. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1581", "text": "Pegozafermin  (BIO89-100) is a long-acting, glycopegylated  FGF21  analog developed for the treatment of  nonalcoholic steatohepatitis  and  hypertriglyceridemia . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1582", "text": "Pegzilarginase , sold under the brand name  Loargys , is a  medication  used for the treatment of  hyperargininemia . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1583", "text": "The most common side effects include allergic reactions. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1584", "text": "Pegzilarginase was approved for medical use in the European Union in December 2023. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1585", "text": "Pegzilarginase is  indicated  for the treatment of arginase 1 deficiency, also known as hyperargininemia. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1586", "text": "In October 2023, the  Committee for Medicinal Products for Human Use  adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Loargys, intended for the treatment of hyperargininemia. [ 1 ]  The applicant for this medicinal product is Immedica Pharma AB. [ 1 ]  Pegzilarginase was approved for medical use in the European Union in December 2023. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1587", "text": "Pegzilarginase is the  international nonproprietary name . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1588", "text": "Pegzilarginase is sold under the brand name Loargys. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1589", "text": "Pelacarsen  is an  antisense therapy  that is designed to reduce  Lipoprotein(a)  concentrations in people with high levels of the lipoprotein and who are at risk of  cardiovascular disease . [ 1 ] [ 2 ] [ 3 ]  It was developed by  Ionis Pharmaceuticals  and  Novartis . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1590", "text": "Pelanserin  ( TR2515 ) is a chemical compound that acts as an  antagonist  of the  5-HT 2  and  \u03b1 1 -adrenergic receptors . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1591", "text": "Pelanserin ( 3 ) can be  synthesized  by a reaction between  isatoic anhydride  ( 1 ) and 1-(3-aminopropyl)-4-phenylpiperazine ( 2 ) in the presence of  phosgene . [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1592", "text": "Pemivibart , sold under the brand name  Pemgarda , is a  monoclonal antibody  medication authorized for the  pre-exposure prophylaxis  (prevention) of  COVID\u201119 . [ 4 ]  Pemivibart was developed by  Invivyd . [ 3 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1593", "text": "The US  Food and Drug Administration  (FDA) issued an  emergency use authorization  for pemivibart in March 2024. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1594", "text": "In the US, pemivibart is authorized for the pre-exposure prophylaxis (prevention) of COVID\u201119 in people aged twelve years of age and older weighing at least 40 kilograms (88\u00a0lb). [ 4 ]  It is authorized for individuals who are not currently infected with  SARS\u2011CoV\u20112  and who have not had a known recent exposure to an individual infected with SARS\u2011CoV\u20112; and who have moderate-to-severe immune compromise due to a medical condition or due to taking immunosuppressive medications or treatments and are unlikely to mount an adequate immune response to COVID\u201119 vaccination. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1595", "text": "In August 2024, the US  Food and Drug Administration  (FDA) revised the emergency use authorization for pemivibart to limit its use to when the combined national frequency of variants with substantially reduced susceptibility to pemivibart is less than or equal to 90%. [ 2 ] [ 3 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1596", "text": "The US  Food and Drug Administration  (FDA) issued an  emergency use authorization  for pemivibart in March 2024. [ 4 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1597", "text": "Pemivibart is the  international nonproprietary name . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1598", "text": "This article incorporates  public domain material  from the  United States Department of Health and Human Services"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1599", "text": "Pemvidutide  (ALT-801) is an experimental dual GLP-1/ glucagon receptor agonist  developed by  Altimmune . [ 1 ] [ 2 ]  The drug reduced LDL-C in a clinical trial [ 3 ]  and does not require dose titration as with GLP-1 mono agonists. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1600", "text": "Pendetide  ( GYK-DTPA ) is a  chelating agent . It consists of  pentetic acid  (DTPA) linked to the  tripeptide   glycine  (G) \u2013  L - tyrosine  (Y) \u2013  L - lysine  (K). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1601", "text": "The following  monoclonal antibodies  are linked to pendetide to chelate a  radionuclide ,  indium-111 . The antibodies selectively bind to certain tumour cells, and the radioactivity is then used for imaging of the tumours."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1602", "text": "Pentyl nitrite  is a chemical compound with the molecular formula, classified as an  alkyl nitrite , used as an antihypertensive medicine. [ 2 ]  It is also used to treat cyanide poisoning. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1603", "text": "It is one of the active ingredients for a recreational drug known as  poppers ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1604", "text": "Perflubron  ( INN / USAN , or  perfluorooctyl bromide ; brand name  Imagent ) is a  contrast medium  for  magnetic resonance imaging ,  computer tomography  and  sonography . [ 1 ]  It was approved for this use in the United States by the  Food and Drug Administration  in 1993. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1605", "text": "Perflubron has also been tested experimentally for use in  liquid breathing  in premature infants with respiratory distress. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1606", "text": "Perfluoropentane  ( PFP ) or  dodecafluoropentane ; also known as  Perflenapent  ( INN / USAN ) is a  fluorocarbon , the fluorinated analogue of  pentane . It is a liquid that boils at slightly over room temperature."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1607", "text": "It has several biomedical applications including: propellant for pressurized metered dose inhalers; [ 3 ]  gas core in  microbubble   ultrasound contrast agents ; [ 4 ]  and  occlusion therapy  via the conversion of nanometer liquid  droplets  into micrometer sized gas microbubbles ( acoustic droplet vaporization ). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1608", "text": "Perimycin , also known as  aminomycin  and  fungimycin , is  polyene antibiotic  produced by  Streptomyces coelicolor  var. aminophilus. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The compound exhibits  antifungal  properties. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1609", "text": "Perimycin is produced naturally as a mixture of three types: A, B and C, with type A being the major component. All types consist of a  polyketide  core with a  perosamine  sugar moiety. The variations occur at the end of the core opposite the perosamine moiety. Perimycin A has an aromatic group in this position, whereas the identities of the analogous groups in the other perimycin types are currently undetermined. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1610", "text": "Polyene antibiotics in general are often toxic to humans and have poor  bioavailability . Thus, with the notable exception of  amphotericin B , they are often not used clinically. Perimycin has been shown to be an effective antifungal compound, but is not widely used in clinical settings. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1611", "text": "Pethidinic acid  ( meperidinic acid ,  pethidine intermediate C ) is a 4- phenyl piperidine  derivative that is both a  metabolite  of and a  precursor  to  pethidine  (meperidine). [ 2 ] [ 3 ]   It is scheduled by  UN   Single Convention on Narcotic Drugs .  It is a Schedule II Narcotic controlled substance in the United States and has an ACSCN of 9234.  The 2014 annual manufacturing quota was 6 grams.  [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1612", "text": "Pethidinic acid is a controlled drug because of its potential uses in manufacturing both pethidine itself and some of its substituted derivatives, but it has little  opioid  activity in its own right. Metabolism of pethidine to pethidinic acid is carried out mainly by the  carboxylesterase  enzyme hCE-1 in the liver, [ 5 ]  and since the activity of this enzyme can vary between individuals, the rate and extent of pethidinic acid production can vary. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1613", "text": "Frank W\u00e4tjen used pethidinic acid as a precursor chemical to a heterocyclic moiety. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1614", "text": "PF-03654746  is a potent and selective  histamine H 3  receptor   antagonist  developed by  Pfizer  and currently undergoing  clinical trials  for the treatment of  ADHD ,  Tourette syndrome [ 1 ]  as well as potential anti- allergy  applications. [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1615", "text": "PF-04479745  is a research ligand developed by  Pfizer . It is related to  lorcaserin , and acts as a  potent  and  selective   agonist  for the  5-HT 2C   receptor , with lower affinity and  antagonist  action at the related  5-HT 2A  and  5-HT 2B  receptor subtypes. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1616", "text": "PF-04745637  is a drug which acts as a potent and selective  antagonist  for the  TRPA1  receptor, with an IC 50  of 17nM, vs ~3\u03bcM at the related  TRPV1  and  TRPM  channels. It has  antiinflammatory  effects and was developed as a potential treatment for conditions such as  atopic dermatitis . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1617", "text": "PF-4800567  is a drug developed by  Pfizer  which acts as a selective inhibitor of the  enzyme   Casein kinase 1 epsilon  (CK1-\u03b5), and has mainly been used in the study of the casein kinase 1 enzymes in the regulation of  circadian rhythm , [ 1 ] [ 2 ]  as well as showing potential  neuroprotective  effects. [ 3 ]  While this research has shown that circadian rhythm is modulated primarily by the alternate isoform CK1-\u03b4 rather than CK1-\u03b5, [ 4 ]  both PF-4800567 and the related non-selective CK1-\u03b4/\u03b5 inhibitor PF-670462 were found in animal studies to enhance responses to certain drugs of abuse such as  methamphetamine  and  fentanyl , which suggests a role for CK1-\u03b5 in negative regulation of sensitivity to  stimulant  and  opioid  drugs. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1618", "text": "PF-05105679  is a drug which acts as a potent and selective blocker of the  TRPM8   ion channel , which is the main receptor responsible for the sensation of  cold . It was developed as a potential  analgesic , and blocks the sensation of cold in both animals and human trials. It also lowers  core body temperature  in small mammals, but does not produce this effect in humans in the normal dosage range. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1619", "text": "Poly-[1-6]--D-glucopyranosyl-[1-3]--D-glucopyranose glucan  ( PGG glucan , proprietary name  Betafectin ) [ 1 ]  is an anti-infective agent and a form or type of  beta-glucan ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1620", "text": "Betafectin is a PGG-glucan, a novel \u03b2-(1,6) branched \u03b2-(1,3) glucan, purified from the cell walls of  Saccharomyces cerevisiae . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1621", "text": "It is a  macrophage -specific  immunomodulator ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1622", "text": "PH-797804  is a drug which acts as a selective inhibitor of the enzyme  p38 mitogen-activated protein kinase  (p38 MAPK). It has  antiinflammatory  effects and has been researched for the treatment of inflammatory lung conditions such as  chronic obstructive pulmonary disease  and  COVID-19 . While it has not been adopted for clinical use, it remains widely used in research. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1623", "text": "Pharmaceutical codes  are used in  medical classification  to uniquely identify  medication . They may uniquely identify an  active ingredient , drug system (including  inactive ingredients  and time-release agents) in general, or a specific pharmaceutical product from a specific manufacturer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1624", "text": "Drug system identifiers (manufacturer-specific including inactive ingredients):"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1625", "text": "Hierarchical systems:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1626", "text": "Ingredients:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1627", "text": "Proprietary database identifiers include those assigned by  First Databank ,  Micromedex ,  MediSpan , Gold Standard Drug Database (published by  Elsevier ), and  Cerner Multum  MediSource Lexicon; these are cross-indexed by  RxNorm , which also assigns a unique identifier (RxCUI) to every combination of active ingredient and dose level. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1628", "text": "The  Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme  ( PIC/S ) are two international instruments between countries and pharmaceutical inspection authorities. The PIC/S is meant as an instrument to improve co-operation in the field of  Good Manufacturing Practices  between  regulatory authorities  and the  pharmaceutical industry ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1629", "text": "The PIC (Pharmaceutical Inspection Convention) was founded in October 1970 by the  European Free Trade Association  (EFTA), under the title of the  Convention for the Mutual Recognition of Inspections in Respect of the Manufacture of Pharmaceutical Products . [ 1 ] [ 2 ]  The initial members comprised the 10 member countries of EFTA at that time. In the early 1990s it was realized that because of an incompatibility between the Convention and  European law , it was not possible for new countries to be admitted as members of PIC. European law did not permit individual EU countries that were members of PIC to sign agreements with other countries seeking to join PIC. As a consequence the Pharmaceutical Inspection Co-operation Scheme was formed on 2 November 1995. The Pharmaceutical Inspection Co-operation Scheme is an informal agreement between health authorities instead of a formal treaty between countries. PIC and the PIC Scheme, which operate together in parallel, are jointly referred to as PIC/S. PIC/S became operational in November 1995. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1630", "text": "Since its conception until 2003, PIC/S did not have a distinct legal identity. Its Secretariat was provided by the European Free Trade Association. Based on PIC/S meeting in June 2003, its committee decided to constitute itself as a Swiss Association in accordance with article 60 of the  Swiss Civil Code  which refer to other internationally active organizations established in Switzerland such as the  International Committee of the Red Cross  (ICRC). On 1 January 2004, PIC/S established its own Secretariat in Geneva, Switzerland. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1631", "text": "PIC/S has a number of provisions intended to establish the following: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1632", "text": "The following are the state members of PIC/S as of October 2021: [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1633", "text": "Pharmaceutical Society of Nigeria (PSN)  is a professional body for practicing pharmacists in  Nigeria  and was established in  1927 to instill discipline and maintain professional ethics among members of the organization. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1634", "text": "The first president of the association was Late Mr T.K.E Phillips, who was inaugurated as the president in the year 1947. In 1956, the association was formally incorporated under its Articles of Association and was recognized as a professional society in Nigeria by the Federal government. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1635", "text": "Some past executives of the society include Olumide Akintayo, [ 3 ]   Adelusi Adeluyi , Lady Eme Ufot Ekaette, Ahmed Yakasai, Sam Ohuabunwa and the Current President Prof.  Cyril Usifoh  FPSN etc. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1636", "text": "This article about an organization in Nigeria is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1637", "text": "Pharmaceutics  is the discipline of  pharmacy  that deals with the process of turning a  new chemical entity  (NCE) or an existing drug into a medication to be used safely and effectively by patients. [ 1 ]  The patients could be either humans or animals. Pharmaceutics helps relate the formulation of drugs to their delivery and disposition in the body. [ 2 ]  Pharmaceutics deals with the formulation of a pure drug substance into a  dosage form ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1638", "text": "Pharmaceutics is also called the science of dosage form design. There are many chemicals with  pharmacological  properties, but need special measures to help them achieve therapeutically relevant amounts at their sites of action. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1639", "text": "Branches of pharmaceutics include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1640", "text": "Pharmaceutics deals with the formulation of a pure drug substance into a  dosage form . Pure drug substances are usually white  crystalline  or  amorphous  powders. Before the advent of medicine as a science, it was common for pharmacists to dispense drugs  as is . Most drugs today are administered as parts of a dosage form. The clinical performance of drugs depends on their form of presentation to the patient. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1641", "text": "Pharmaceutics is a specialization in the field of pharmacy. Typically, Pharm-D graduates can choose to continue studies in this field towards a PhD degree."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1642", "text": "Pharmacodiagnostic testing  is  pre-treatment testing  performed in order to determine whether or not a  patient  is likely to  respond  to a given  therapy . This type of test is  classified  as a  predictive test  and is a prerequisite for the implementation of  stratified  and  personalized medicine . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1643", "text": "This  medical  diagnostic article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1644", "text": "Pharmacological dissection  discriminates among varieties of superficially similar disorders or syndromes by their differential response to a drug. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1645", "text": "The term was introduced in 1957, [ 2 ]  and popularized in psychopharmacology by  Donald Klein . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1646", "text": "The  Pharmacopoeia of the People's Republic of China  (PPRC) or the  Chinese Pharmacopoeia  (ChP), compiled by the  Pharmacopoeia  Commission of the  Ministry of Health of the People's Republic of China , is an official compendium of drugs, covering  Traditional Chinese  and  western medicines , which includes information on the standards of purity, description, test, dosage, precaution, storage, and the strength for each drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1647", "text": "It is recognized by the  World Health Organization  as the official  pharmacopoeia  of China. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1648", "text": "The ChP, as of its tenth (2015) edition, comes in 4 volumes for both the Chinese and the English versions:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1649", "text": "The English version is collectively coded as  ISBN \u00a0 978-7-5067-8929-5 . The 2015 ChP requires  Good Manufacturing Practices  for all ChP-compliant medications and in general uses  INN  for English names. The Chinese version arranges medicines in ascending  stroke order , [ 2 ]  while the English translations do so in alphabetical order."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1650", "text": "The 1997  English  version consists of two volumes: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1651", "text": "The 1997  Chinese  version (in simplified Chinese) also consists of two volumes, but the English and Chinese versions are not direct translations of each other, as they are sorted differently as is in the current edition."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1652", "text": "A third volume was added in the 2005 version. The English edition ( ISBN \u00a0 7117069821 ) describes itself as a \"compendium of almost all traditional Chinese medicines and most western medicines and preparations. Information is given for each drug on standards of purity, description, test, dosage, precaution, storage and strength. Key features: A total of 2691 monographs: 992 for traditional Chinese medicines and 1699 for modern western drugs. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1653", "text": "\"Volume I contains  monographs  of Chinese material medica and pared slice,  vegetable oil / fat  and its extract, Chinese traditional patent medicines, single ingredient of Chinese crude drug preparations etc.;\nVolume II deals with monographs of chemical  drugs ,  antibiotics , biochemical preparations,  Radiopharmaceuticals  and excipients for pharmaceutical use;\nVolume III contains biological products.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_1654", "text": "The  Pharmacy Act 1852 [ 1 ]  ( 15 & 16 Vict.  c. 56) was the first legislation in the United Kingdom to regulate  pharmacists  and druggists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1655", "text": "It set up a register of pharmacists and limited the use of the title to people registered with the  Pharmaceutical Society , but proposals to give the society exclusive rights to sell drugs or poisons were rejected.  It did not provide a legal definition for the trade and practice of pharmacy. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1656", "text": "This article relating to  law in the United Kingdom , or its constituent jurisdictions, is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1657", "text": "The  Pharmacy College Admission Test (PCAT)  was a  computer-based   standardized test  administered to prospective  pharmacy school  students by  Pearson Education, Inc  as a service for the American Association of Colleges of Pharmacy (AACP); it is offered in January, July, and September. [ 1 ]  The test is divided into five sections to be taken in approximately three and a half hours.  The test includes  Writing ,  Biology ,  Chemistry ,  Critical reading , and  Quantitative Reasoning  sections. [ 2 ]  The composite score is based on the multiple-choice sections, and can range from 200 \u2013 600. There is no passing score; pharmacy schools set their own standards for acceptable scores. Calculators are not allowed during the testing period and no penalty is given for incorrect answers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1658", "text": "The test was retired effective January 10, 2024."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1659", "text": "This article relating to education in the United States is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1660", "text": "Pharmasave  is a Canadian  independent pharmacy  and  drugstore   retailer  with over 800 stores across  Canada . Pharmasave produces a line of over 700 private-label Pharmasave Brand products. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1661", "text": "Pharmasave was created in September 1981 through the merger of two  British Columbia -based pharmacy chains,  United Pharmacy  and  Western Drug Mart . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1662", "text": "Pharmasave's national office is located in  Langley, British Columbia . Its stores are located in nine provinces and territories across Canada and are organized into 2 regions with each region having their own regional offices: West ( British Columbia ,  Alberta ,  Saskatchewan ,  Manitoba , and  Yukon ), and East ( Ontario ,  Newfoundland and Labrador ,  New Brunswick ,  Nova Scotia , and  Prince Edward Island ). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1663", "text": "Each of Pharmasave's stores operates independently and they range in size from small dispensaries to large-format home healthcare pharmacies. Each region has a  Board of Directors  as well as representation on the  national  Board of Directors. Pharmasave's business model is one of  self-governance , where pharmacy owners are elected to serve on its regional Boards of Directors. This way, the needs of the owners are served by other owners, and not by a separate corporate entity. The success of this model has played an important part in the attracting of new members and its growing store count across the country."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1664", "text": "Phendioxan  is an  \u03b1 1 -adrenergic receptor   antagonist . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1665", "text": "Phenomorphan [ 2 ]  is an  opioid   analgesic . It is not currently used in medicine, but has similar side-effects to other opiates, which include  itching ,  nausea  and  respiratory depression ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1666", "text": "Phenomorphan is a highly potent drug due to the N-phenethyl group, which boosts affinity to the  \u03bc-opioid receptor , and so phenomorphan is around 10x more potent than  levorphanol , which is itself 6-8x the potency of  morphine . Other analogues where the N-(2-phenylethyl) group has been replaced by other aromatic rings [ 3 ]  are even more potent, with the  N-(2-(2-furyl)ethyl)  and the N-(2-(2- thienyl )ethyl) analogues being 60x and 45x stronger than levorphanol, respectively. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1667", "text": "Phenylacetylrinvanil  ( IDN-5890 ) is a synthetic analogue of  capsaicin  which acts as a potent and selective agonist for the  TRPV1  receptor, with slightly lower potency than  resiniferatoxin , though still around 300 times the potency of capsaicin. It is an  amide  of  vanillylamine  and  ricinoleic acid , with the hydroxyl group on ricinoleic acid  esterified  with  phenylacetic acid . It is used to study the function of the TRPV1 receptor and its downstream actions, and has also shown anti-cancer effects  in vitro . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1668", "text": "Phenylbiguanide  ( PBG ) is a  5-HT3 agonist  used to study the role of 5-HT3 receptors in the  central nervous system . [ 1 ]  It has been found to trigger  dopamine  release in the  nucleus accumbens  of rats. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1669", "text": "Phenylephrine/ketorolac , sold under the brand name  Omidria , is a  combination drug  used during  cataract surgery [ 3 ]  or  intraocular lens  replacement to prevent  intraoperative   miosis  and to reduce  postoperative pain . [ 1 ]  It contains  phenylephrine  and  ketorolac . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1670", "text": "Phenylephrine/ketorolac was approved for medical use in the United States in May 2014, [ 4 ]  and in the European Union in July 2015. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1671", "text": "Phenyltriazines  are a class of molecules containing a  phenyl  group and a  triazine  group. These molecules are pharmacologically important. As an example,  lamotrigine  is a phenyltriazine derivative used as an  anticonvulsant  drug and has been shown to be useful for alleviating  epilepsy [ 1 ]  and  bipolar disorder ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1672", "text": "Phosphodiesterase 9 inhibitors  or  PDE9 inhibitors  are a class of drugs that work by inhibiting the activity of  PDE9 . The first compound with this effect,  BAY 73-6691 , was reported in 2004. [ 1 ]  PDE9 inhibitors are under investigation for the treatment of obesity, [ 2 ]   hepatic fibrosis , [ 3 ]   Alzheimer's disease ,  schizophrenia , other psychotic disorders,  heart failure , and  sickle cell anemia . [ 1 ]  Drug candidates include  CRD-733 , [ 4 ]   osoresnontrine ,  tovinontrine , and  PF-04447943 . [ 1 ]   Cannabidiol  acts as a PDE9 inhibitor  in vitro . [ 5 ]  There are no PDE9 inhibitors that have been approved as of 2023. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1673", "text": "Phospholipidosis  is a  lysosomal  storage disorder characterized by the excess accumulation of  phospholipids  in tissues. [ 1 ] [ 2 ] [ 3 ]  Certain cases may be triggered by medications. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1674", "text": "The traditional method to evaluate drug-induced phospholipidosis (DIPL) is visual confirmation of myeloid bodies in tissues by  electron microscopy . Electron microscopy has limited utility to monitor DIPL in humans because of the invasive nature of acquiring patient tissue biopsy samples.  A qualified biomarker of DIPL in the blood or urine is needed to provide a more routine, non-invasive, and cost effective means to monitor DIPL in the clinic. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1675", "text": "Photosens  is a mixture of sulfonated aluminium  phthalocyanines  with various degrees of sulfonation. [ 1 ]  Developed in Russia."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1676", "text": "It is a photosensitiser (activated by 675\u00a0nm red light) sometimes used in  photodynamic therapy  trials. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1677", "text": "It has been tried on  Age-related macular degeneration [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1678", "text": "PHTPP  is a  synthetic ,  nonsteroidal , and highly selective  antagonist  of  ER\u03b2  that is used in  scientific research  to study the function of this  receptor . [ 1 ] [ 2 ]  It possesses 36-fold selectivity for ER\u03b2 over  ER\u03b1 , and is a  silent antagonist  of ER\u03b2. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1679", "text": "Phytoprogestogens , also known as  phytoprogestins , are  phytochemicals  (that is, naturally occurring, plant-derived chemicals) with  progestogenic  effects. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1680", "text": "Relative to their  phytoestrogen  counterparts, phytoprogestogens are rare. [ 1 ]  However, a number have been identified, including  kaempferol ,  diosgenin  (found in  yam ),  apigenin  (found in  chasteberry ), [ 1 ] [ 3 ]   naringenin , and  syringic acid , among others. [ 2 ]  In addition,  3,8-dihydrodiligustilide  from  Ligusticum chuanxiong  is a  potent  progestogen ( EC 50  = 90\u00a0nM), whereas  riligustilide  is a weak progestogen (EC 50  \u2248 81\u00a0\u03bcM). [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1681", "text": "Picloxydine  (trade name  Vitabact [ 1 ] ) is a  bisbiguanide   antiseptic  used in  eye drops . It is structurally similar to  chlorhexidine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1682", "text": "Pill dispensers  are items which release  medication  at specified times, to assist patients in adhering to their prescribed medication regime. They may also alert the patient that it is time to take the medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1683", "text": "Some devices can alert a monitoring station if the patient does not take the medication from the device promptly. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1684", "text": "Pipermethystine  is a toxic  alkaloid  present in the aerial (aboveground) portions of the  kava  plant. It is not a  kavalactone , containing no  lactone  structure. Correctly prepared kava root products will contain almost no pipermethystine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1685", "text": "Several studies suggest pipermethystine induces  hepatotoxicity  in humans, and was first believed to be the cause of liver failure in individuals consuming kava supplements, but not in proper root powder or fresh root, which is consumed in the traditional  kava cultures  of Polynesia. [ 1 ]  Later analyses of the implicated drug materials and products revealed that medical kava extracts contain less than 45\u00a0ppm of this alkaloid, while the leaves contain about 0.2% (2000\u00a0ppm). Based on this retrospective study, pipermethystine is an unlikely cause for the observed hepatotoxicity of commercial kava preparations. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1686", "text": "Pipethiaden  is a  benzothiepin -based drug candidate that was at one time studied as a potential preventive to reduce the frequency of recurrent  migraine  headaches. It also has some activity as an  antihistamine  acting mainly at the  5-HT 2A  and  5HT 2C   receptors . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1687", "text": "Pirenoxine  (abbreviated  PRX , trade name  Catalin ) is a  medication  used in the possible treatment and prevention of  cataracts ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1688", "text": "A report in the   Inorganic Chemistry  journal s howed that in liquid solutions, pirenoxine could cause decreased cloudiness of a  crystallin  solution produced to mimic the environment of the eye. Pirenoxine interacts with  selenite  or  calcium  ions that have been proven as factors leading to the formation of lens cataract. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1689", "text": "Pirenoxine reduces the cloudiness of the  lens  solution, containing calcium by 38% and reducing the cloudiness of the selenite solution by 11%. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1690", "text": "\u201c...there are not any proctored studies that prove the utility of these drops. In Canada and in the U.S. they are considered  homeopathic \u2014where they probably do no harm but doubtful that they will have any protective value.\" [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1691", "text": "PK/PD modeling  ( pharmacokinetic/pharmacodynamic modeling ) (alternatively abbreviated as PKPD [ 1 ]  or PK-PD [ 2 ]  modeling) is a technique that combines the two classical  pharmacologic  disciplines of  pharmacokinetics  and  pharmacodynamics . [ 3 ]  It integrates a pharmacokinetic and a pharmacodynamic model component into one set of  mathematical expressions  that allows the description of the time course of effect intensity in response to administration of a  drug  dose. PK/PD modeling is related to the field of  pharmacometrics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1692", "text": "Central to PK/PD models is the concentration-effect or exposure-response relationship. [ 4 ]  A variety of PK/PD modeling approaches exist to describe  exposure-response relationships . PK/PD relationships can be described by simple equations such as linear model, Emax model or  sigmoid Emax model . [ 5 ]  However, if a delay is observed between the drug administration and the drug effect, a temporal dissociation needs to be taken into account and more complex models exist: [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1693", "text": "PK/PD modeling has its importance at each step of the drug development [ 9 ] [ 10 ]  and it has shown its usefulness in many diseases. [ 11 ]  The  Food and Drug Administration  also provides guidances for Industry to recommend how exposure-response studies should be performed. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1694", "text": "Polymyxin B/trimethoprim , sold under the brand name  Polytrim  is an  antimicrobial  solution for topical  ophthalmic  use in the treatment of  acute   bacterial   conjunctivitis  and  blepharoconjunctivitis . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1695", "text": "In 2022, it was the 252nd most commonly prescribed medication in the United States, with more than 1 \u00a0 million prescriptions. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1696", "text": "Polymyxin B/trimethoprim is  indicated  in the treatment of surface ocular bacterial infections, [ 4 ]  including acute bacterial conjunctivitis, and blepharoconjunctivitis, caused by susceptible strains of the following microorganisms:  Staphylococcus aureus ,  Staphylococcus epidermidis ,  Streptococcus pneumoniae ,  Streptococcus viridans ,  Haemophilus influenzae , and  Pseudomonas aeruginosa . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1697", "text": "Ponsegromab   (PF-06946860) is a  monoclonal antibody  that works as a  GDF-15  inhibitor. It is developed by  Pfizer  for  cancer cachexia . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1698", "text": "In September 2024, Pfizer disclosed that ponsegromab led to significant body weight increases in patients with non-small cell lung cancer, pancreatic cancer, or colorectal cancer in a phase 2 clinical trial. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1699", "text": "Poseltinib  ( HM71224 ,  LY3337641 ) is an experimental  Bruton's tyrosine kinase  inhibitor for the treatment of  rheumatoid arthritis . It was developed by  Hanmi Pharmaceutical  and licensed to  Eli Lilly . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1700", "text": "Phase II  clinical trials  began in August 2016 in patients with rheumatoid arthritis. Additional phase II trials are planned for treatment of  lupus ,  lupus nephritis ,  Sj\u00f6gren's syndrome , and other immunological conditions. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1701", "text": "A  potassium channel opener  is a type of  drug  which facilitates  ion  transmission through  potassium channels ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1702", "text": "Some examples include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1703", "text": "6 T  & 1 P"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1704", "text": "2 T  & 1 P"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1705", "text": "4 T  & 2 P"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1706", "text": "Potassium citrate/potassium hydrogen carbonate , sold under the brand name  Sibnayal , is a  fixed-dose combination  medication intended for the treatment of  distal renal tubular acidosis . [ 1 ]  It contains  potassium citrate  and  potassium hydrogen carbonate . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1707", "text": "Potassium citrate/potassium hydrogen carbonate was approved for medical use in the European Union in April 2021. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1708", "text": "Potassium citrate/potassium hydrogen carbonate is indicated for the treatment of distal renal tubular acidosis (dRTA) in people aged one year and older. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1709", "text": "In December 2020, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Sibnayal. [ 1 ]  The applicant for this medicinal product is Advicenne S.A. [ 1 ]  Potassium citrate/potassium hydrogen carbonate was approved for medical use in the European Union in April 2021. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1710", "text": "Potassium citrate/potassium hydrogen carbonate is recommended for approval in the United Kingdom. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1711", "text": "Potassium citrate/potassium hydrogen carbonate is undergoing phase III trials in preparation for evaluation by the US  Food and Drug Administration  (FDA). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1712", "text": "Potrasertib  is an  investigational new drug  that is being evaluated by IMPACT Therapeutics for the treatment of advanced solid tumors. It is oral inhibitor of  WEE1  kinase, a key regulator of  cell cycle checkpoints . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1713", "text": "Povorcitinib  is an  investigational new drug  that is being evaluated for the treatment of the skin conditions  hidradenitis suppurativa [ 1 ] [ 2 ]  and  chronic prurigo . [ 3 ] [ 4 ]  It is a  JAK1  inhibitor. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1714", "text": "Pramlintide/insulin A21G  (development name ADO09) is a combination of the  amylin  analogue  pramlintide  and an  insulin analog . It is being developed by Adocia for diabetes. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1715", "text": "PRE-084  is a  sigma receptor   agonist , selective for the  \u03c3 1  subtype. It has  nootropic  and  antidepressant  actions in animal studies, as well as  antitussive  and reinforcing effects. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  PRE-084 increases the expression of  GDNF . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1716", "text": "The  drug  combination  prednisolone / promethazine  is an  antidote  for snake bites."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1717", "text": "Pregnancy-specific biological substances , which include the  placenta ,  umbilical cord ,  amniotic fluid , and  amniotic membrane  are being studied for a number of health uses. [ 1 ]  For example, Placental-derived stem cells are being studied so they can serve as a potential treatment method for  cell therapy . [ 2 ]  Hepatocyte-like cells (HLC) are generated from differentiated human amniotic epithelial cells (hAEC) that are abundant in the placenta. [ 2 ] [ 3 ]  HLC may replace  hepatocytes  for hepatocyte transplantation to treat acute or chronic liver damage. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1718", "text": "Recent research has shown that the placenta and placenta derivatives are being regenerative cell therapies and also includes immunological features. Placenta structures consist of unique physiognomies. Placenta's structure not only regulates its function but also gives the probability of efficient use in clinics and in biotechnology. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1719", "text": "According to a research study by Bhattacharya N.,  Anemia  caused by  Diabetes mellitus  in patients with  albuminuria  can be treated with  cord blood transfusion . [ 5 ]  The research showed increased in  albumin  per gram of  creatinine  that assessed for albuminuria for patients that received cord blood transfusions. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1720", "text": "A  pregnenedione  (singular  pregnanediol ) is an unsaturated diketone derivative of a  pregnane . [ 1 ]  Examples are  budesonide  and  progesterone  (pregn-4-ene-3,20-dione). [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1721", "text": "This article about a  steroid  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1722", "text": "Prescribed daily dose  ( PDD ) is the usual  dose  of  medication  calculated by looking at a group of  prescriptions  for the medication in question. [ 1 ]  At times the PDD needs to be related to the  condition  being  treated . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1723", "text": "Prescription analytics  is the practice of  analyzing   consumers '  prescription drug  histories in order to provide useful information for  health insurers ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1724", "text": "In the United States, two-thirds of health insurers use  prescription history reports  to help identify consumers who may prove expensive to insure, and to set prices or deny coverage. [ 1 ]   The reports, created and sold by medical data brokers such as MedPoint and IntelliScript, cost about $15 each and include information going back five years covering drug names,  dosage , fill dates, refills, pharmacy and physician information, and possible medical conditions. The reports also include a \u201crisk score\u201d, based on a  health risk assessment , predicting what an individual might cost an insurer in the future, as well as listing medical conditions the person may be being treated for. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1725", "text": "This article related to  health informatics  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1726", "text": "A  Product Licence Number  (or PL code for short) is a unique identifier on the packaging of medicines, used to uniquely identify the product. This code will normally remain the same despite the varying marketing and branding of the companies selling it. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1727", "text": "The code itself is issued by the  Medicines and Healthcare products Regulatory Agency [ 2 ]  in the  UK  and the  European Medicines Agency . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1728", "text": "In 1981, the  Professional Compounding Centers of America (PCCA)  was incorporated to provide  compounded   medications  to patients, when the medicine became unavailable commercially."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1729", "text": "PCCA services pharmacies who provide these compounded medications, giving them training, recipes, and materials. [ 1 ]  However, according to  Science-Based Medicine , \" the enthusiasm can outpace the evidence, and there may be a lack of evidence that compounded products really are safe and effective.\" [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1730", "text": "The organization supported pharmacies in 2011 who were helping provide alternatives to  hydroxyprogesterone  in an attempt to prevent early labor. [ 2 ]  In 2014 the company acquired two manufacturers and distributors of materials and compounded medications. [ 3 ]  They were sued in 2019 for providing the formulation of an injection that caused 68 people to go blind. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1731", "text": "Professional Further Education in Clinical Pharmacy and Public Health  ( Danish :  Faglig videreuddannelse i Klinisk farmaci og Folkesundhed ) is a  Danish   professional   postgraduate   higher   further   education  for Danish  pharmaconomists (experts in pharmaceuticals) ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1732", "text": "The education programme is developed by  Pharmakon\u2014Danish College of Pharmacy Practice , the  Danish Association of Pharmaconomists  and the  Danish Pharmaceutical Association . The further education takes place at Pharmakon\u2014Danish College of Pharmacy Practice in  Hiller\u00f8d , Denmark."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1733", "text": "The  admission   requirement  is a Danish  pharmaconomist   degree   diploma  granted by Pharmakon\u2014Danish College of Pharmacy Practice. The education corresponds to 30  ECTS credits  that are equivalent to \u00bd year of  full-time   study  for a  Clinical Pharmacy  and  Public Health   Student . The education programme can be taken as a  part-time  further education over two to four years. Nevertheless, the education must be completed within 6 years."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1734", "text": "The purpose of the  Professional Further Education in Clinical Pharmacy and Public Health  is to  qualify  each pharmaconomist (expert in pharmaceuticals) to practice clinical pharmacy at a higher and more  professional  level. The education consists of five modules:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1735", "text": "The total  fee  for the entire education programme amounts to 170,000  DKK  (31,000  USD  or 18,200  GBP )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1736", "text": "Propyliodone  ( INN , trade name  Dionosil ) is a molecule used as a  contrast medium  in  bronchography . [ 1 ]  It was developed by a team at  Imperial Chemical Industries [ 2 ]  in the late 1930s."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1737", "text": "Propylpyrazoletriol  ( PPT ) is a  synthetic ,  nonsteroidal   agonist  of  ER\u03b1  with 400-fold selectivity over  ER\u03b2 [ 1 ]  that is used widely in  scientific research  to study the function of  ER\u03b1 . [ 2 ] [ 3 ] [ 4 ]  Though originally thought to be highly selective for ER\u03b1, PPT has subsequently been found to also act as an  agonist  of the  GPER  (GPR30). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1738", "text": "Proroxan  ( INN ; also known as  pyrroxane  and  pirroksan ) is a pharmaceutical drug used as an  antihypertensive  and in the treatment of  M\u00e9ni\u00e8re's disease ,  motion sickness , and  allergic dermatitis . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1739", "text": "Proroxan is a non-selective  alpha-blocker  (\u03b1-adrenoreceptor antagonist). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1740", "text": "Proroxan was developed in the 1970s at the Institute of Toxicology of the USSR Ministry of Health [ 3 ]  and today is primarily used in Russia.  Though originally developed as an antihypertensive, its use can lead to a decrease in alcohol and drug consumption. Currently proroxan is used almost exclusively in psychiatry, narcology, and neurology. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1741", "text": "ProSavin  is an experimental drug believed to be of use in the treatment of  Parkinson's disease . It is administered to the  striatum  in the  brain , inducing production of  dopamine . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1742", "text": "It is manufactured by  Oxford BioMedica . Results from a Phase I/II clinical trial were published in the Lancet [ 2 ]  and showed safety, but little efficacy. [ 3 ]  ProSavin was superseded by AXO-Lenti-PD (OXB-102), an optimized version of the drug. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1743", "text": "Prosavin uses Oxford BioMedica's  Lentivector  delivery system to transfer three genes,  aromatic amino acid dopa decarboxylase ,  tyrosine hydroxylase  and  GTP-cyclohydrolase 1 , to the striatum in the brain, reprogramming transduced  cells  to  secrete  dopamine. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1744", "text": "Prospekta  is a  nootropic  drug reported to act on the  S100 proteins . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It was developed by the company Materia Medica and approved in Russia for the treatment of ADHD in 2022. [ 5 ]  It was also studied for  vascular dementia . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1745", "text": "Prospidium chloride  ( prospidine ) is a drug with cytostatic (alkylating) and anti-inflammatory properties.  It has been studied for the treatment of  rheumatoid arthritis . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1746", "text": "Chemically, it is a  spiro compound ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1747", "text": "This article about an  alcohol  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1748", "text": "The  protective index  ( PI ) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. Quantitatively, it is the ratio given by the toxic dose divided by the therapeutic dose. A protective index is the toxic dose of a drug for 50% of the population ( TD 50 ) divided by the minimum effective dose for 50% of the population ( ED 50 ). A high protective index is preferable to a low one: this corresponds to a situation in which one would have to take a much higher dose of a drug to reach the toxic threshold than the dose taken to elicit the therapeutic effect. A drug should ordinarily only be administered if the protective index is greater than one, indicating that the benefit outweighs the risk."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1749", "text": "Protective index \n \n = \n \n \n \n T \n \n D \n \n 50 \n \n \n \n \n E \n \n D \n \n 50 \n \n \n \n \n \n \n \n {\\displaystyle {\\text{Protective index}}={\\frac {TD_{50}}{ED_{50}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1750", "text": "The protective index is similar to the  therapeutic index , but concerns toxicity ( TD 50 ) rather than lethality ( LD 50 ); thus, the protective index is a smaller ratio. Toxicity can take many forms, as drugs typically have multiple side effects of varying severity, so a specific criterion of toxicity must be specified for the protective index to be meaningful. Ideally a choice is made such that the harm caused by the toxicity just outweighs the benefit of the drug's effect. Thus, the protective index is a more accurate measure of the benefit-to-risk ratio than the therapeutic index, but is less objectively defined.  Nevertheless, the therapeutic index can be viewed as an  upper bound  to the protective index for a given substance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1751", "text": "Protective index can also defined as the factor by which the dose of a toxicant must be multiplied to produce a defined level of toxicity in the presence of a nontoxic dose of another chemical. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1752", "text": "Protective index \n \n \n = \n \n \n \n \n \n L \n D \n \n \n 50 \n \n \n \n of A with B \n \n \n \n \n \n L \n D \n \n \n 50 \n \n \n \n of A alone \n \n \n \n \n \n \n {\\displaystyle {\\mbox{Protective index}}={\\frac {\\mathrm {LD} _{50}{\\text{of A with B}}}{\\mathrm {LD} _{50}{\\text{of A alone}}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1753", "text": "The higher the protective index, better is the antidotal value of a given substance. Sometimes the protective index is higher in the presence of two or more substances than in the presence of either of the substances alone. For example, the LD50 of potassium cyanide alone is 11\u00a0mg/kg, whereas it is 21\u00a0mg/kg in the presence of sodium nitrite, giving a protective index of 1.91. The LD50 of potassium cyanide in the presence of sodium thiosulfate is 35\u00a0mg/kg, giving a protective index of 3.2. The LD50 of potassium cyanide in the presence of both nitrite and thiosulfate is 52\u00a0mg/kg with a protective index of 4.73. Since the protective index is higher for the simultaneous use of nitrite and thiosulfate, the two chemicals constitute the antidote against cyanide intoxication. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1754", "text": "Protein therapeutics  are  proteins  used as experimental or approved therapies for disease states. They include \" monoclonal antibodies  (mAbs),  peptide hormones ,  growth factors ,  plasma proteins ,  enzymes , and  hemolytic factors \" [ 1 ]  While proteins can be more specific and flexible in their  mechanism of action  compared to  small-molecule drugs ,  duration of action  and  drug delivery  can be a challenge. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1755", "text": "Protollin  is a  drug  initially formulated as a  vaccine adjuvant . [ 1 ] [ 2 ]  It is composed of  lipopolysaccharides  derived from the  Shigella flexneri  or  Pleisiomonas shigelloides  bacterium combined with  hydrophobic  outer membrane proteins derived from  Neisseria meningitidis . [ 3 ]   [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1756", "text": "On November 16, 2021,  Brigham and Women's Hospital  announced that it was beginning a  Phase I clinical trial  of Protollin as a nasally-delivered vaccine to activate the body's immune response against amyloid proteins that form in the brain and are thought to contribute to the symptoms of Alzheimer's disease. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1757", "text": "A  provocation test , also called a  provocation trial  or  provocation study , is a form of medical  clinical trial  whereby participants are exposed to either a substance or \"thing\" that is claimed to provoke a response, or to a sham substance or device that should provoke no response,  or a severe exercise as in Erb's test for low serum calcium . [ 1 ]  An example of a provocation test, performed on an individual, is a  skin allergy test ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1758", "text": "40\u00b033\u203203\u2033N   74\u00b025\u203223\u2033W \ufeff / \ufeff 40.550722\u00b0N 74.423071\u00b0W \ufeff /  40.550722; -74.423071"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1759", "text": "PTC Therapeutics, Inc.  is a  US  pharmaceutical company focused on the development of orally administered small molecule drugs and gene therapy which regulate gene expression by targeting  post-transcriptional control  (PTC) mechanisms in  orphan diseases . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1760", "text": "In September 2009, PTC entered into an agreement with  Roche  for the development of orally bioavailable  small molecules  for  central nervous system  diseases. [ 3 ]  PTC acquired the Bio-e platform in 2019. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1761", "text": "In 2017, PTC acquired  Emflaza  (deflazacort) from  Marathon  Pharmaceuticals. [ 5 ]  PTC also owns Translarna, ( Ataluren ) marketed for  nonsense mutation   Duchenne muscular dystrophy . [ 6 ]   Together, the two products generated revenues of 174 million dollars and 260 million dollars in 2017 and 2018 respectively. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1762", "text": "PTC has the commercialization rights for WAYLIVRA (volanesorsen) in Latin America. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1763", "text": "In 2018, PTC acquired Agilis Biotherapeutics and a gene therapy candidate, GT-AADC, with its compelling clinical data in treating aromatic L-amino acid decarboxylase (AADC) deficiency. [ 9 ]  AADC deficiency is a rare CNS disorder arising from reductions in the enzyme AADC that result from mutations in the dopa decarboxylase (DDC) gene. As of 2024, the  AAV  based treatment for AADC deficiency has been approved by the FDA and commercialized in the United States as Kebilidi. It is the first FDA-approved gene therapy treatment for AADC deficiency. [ 10 ]  This same product was granted  EMA approval  for use in the European Union under the name Upstaza. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1764", "text": "In 2020, PTC acquired Censa Pharmaceuticals, Inc., a biopharmaceutical company focused on the development of CNSA-001 (sepiapterin), a clinical-stage investigational therapy for orphan metabolic diseases, including phenylketonuria (PKU) and other diseases associated with defects in the tetrahydrobiopterin (BH4) biochemical pathways diagnosed at birth. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1765", "text": "In 2020, PTC announced the FDA approval of Evrysdi (risdiplam) for the treatment of spinal muscular atrophy (SMA) in adults and children 2 months and older. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1766", "text": "In 2024, Novartis has committed $1 billion upfront in a licensing deal with PTC Therapeutics for an experimental treatment for Huntington\u2019s disease, with the potential for an additional $1.9 billion tied to achieving specific development, regulatory, and commercial milestones. [ 14 ]  PTC Therapeutics\u2019 therapy, known as PTC518, is an oral medication designed to reduce the production of the mutant protein linked to the genetic mutation responsible for the disease. [ 15 ]  This mutant protein is believed to contribute to neuronal death, driving disease progression. [ 16 ]  In June, interim data from a Phase 2 trial indicated that PTC518 successfully lowered levels of the mutant protein in both blood and cerebrospinal fluid. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1767", "text": "PXL065  ( d-R-pioglitazone ) is a drug candidate for the treatment of  nonalcoholic steatohepatitis  (NASH). [ a ]  It is the deuterium-stabilized ( R )- enantiomer  of  pioglitazone  which lacks  PPAR\u03b3  agonist activity and the associated side effects of weight gain and edema. [ 1 ]  PXL065 (formerly known as DRX-065) has demonstrated preclinical efficacy for both NASH [ 1 ]  and X-linked  adrenoleukodystrophy  (X-ALD). [ 2 ]  In 2022, it successfully completed a 9 month Phase 2 trial in biopsy-proven NASH patients where it met the primary endpoint for reduction in liver fat without weight gain or edema. [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1768", "text": "PXL065 was discovered and advanced to Phase 1 by DeuteRx, LLC using the strategy of deuterium-enabled chiral switching (DECS). [ 6 ]   In August 2018, PXL065 and a portfolio of deuterated thiazolidinediones (TZDs) was acquired by Poxel SA. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1769", "text": "Pyrometallide gels  are types of  gels  based on  pyromellitamide  molecules. [ 1 ] [ 2 ]  Such gels being developed which will enable the repair of severed  muscles  and  spinal cords  in patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1770", "text": "These types of  artificial muscles  are made possible by creating  synthetic materials  which are very similar to the ones which make up human tissues and cells. These artificial materials are so similar that the body does not reject the material and instead allows normal  cell growth  in the materials which eventually become absorbed into the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1771", "text": "The gel molecule is composed of a tetra-alkane benzene-1,2,4,5-tetracarboxamide. The gel structure is made up of millions of tiny fibres, which form a 3D mesh by trapping a  liquid  in the same way that a  sponge  absorbs water, to form a solid. The unique feature of self-assembled gels is that  chemical reactions  are not required to form the fibres; it is simply a case of heating them up in a liquid and waiting for them to set."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1772", "text": "There is huge range of potential applications for these gels. Aside from the artificial muscles, these gels could also be used for  drug delivery  in  cancer  patients, where they can injected into the patient, and the gel will slowly release a constant stream of anti-cancer drugs in the body. There are also applications for computer and television screens, where gels are used for  LCD  screens. These gels could lower the  manufacturing  costs and be used to construct  flexible display  screens."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1773", "text": "This  muscle  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1774", "text": "Pyrrolobenzodiazepines,  (PBD) are a class of compound that may have  antibiotic  or anti-tumor properties. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1775", "text": "Some dimeric pyrrolobenzodiazepines are used as the cytotoxic drug payloads in  antibody-drug conjugates , for example in  loncastuximab tesirine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1776", "text": "Anthramycin , the first PBD monomer, was first synthesized in the 1960s. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1777", "text": "This article about a  heterocyclic compound  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1778", "text": "Under  European Union (EU) law , the  qualified person  ( QP ) is responsible for certifying that each batch of a medicinal product meets all required provisions when released from a manufacturing facility within the EU, or imported into the EU. [ 1 ]  Such provisions include that the batch was manufactured under appropriate standards, and that it passed all required testing. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1779", "text": "The regulations specify that no batch of medicinal product can be released for sale or supply prior to certification by a QP that the batch is in accordance with the relevant requirements.( EudraLex , Volume 4, Chapter 1) The QP is typically a licensed  pharmacist ,  biologist  or  chemist  (or a person with another permitted academic qualification) who has several years' experience working in pharmaceutical manufacturing operations, and has passed examinations attesting to his or her knowledge. \nThe requirement for QP oversight has been extended to material for use in clinical trials since the introduction of EU Directive 2001/20/EC."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1780", "text": "In countries that are part of the  Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme  (PIC/S), the same role may be termed  responsible person  ( RP ) or  authorized person  ( AP )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1781", "text": "The Quantitative Biosciences Institute (QBI)  was established in 2016 as an organized research unit (ORU) within the  School of Pharmacy at the University of California-San Francisco . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The current director of QBI is  Nevan Krogan . [ 5 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1782", "text": "In 1993,  Irwin Kuntz , created an ORU within the School of Pharmacy, called the Molecular Design Institute (MDI). The Dean of the School of Pharmacy, B. Joseph Guglielmo with the support of the UCSF campus and the UC Office of the President transformed MDI into QBI. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1783", "text": "Previously, QBI was a part of QB3, also known as QB3-UCSF. [ 4 ]  In March 2016, UCSF established QBI as a Organized Research Unit (ORU) within the School of Pharmacy. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1784", "text": "The institute formed the QBI Coronavirus Research Group (QCRG), a collaborative group of labs, aimed at finding solutions for COVID-19. [ 1 ] [ 2 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1785", "text": "This  California -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1786", "text": "Quinazosin  is an  antihypertensive   \u03b1 1 -adrenergic receptor   antagonist . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1787", "text": "3-Quinuclidinyl thiochromane-4-carboxylate  is a research compound which is the most potent  muscarinic antagonist  known. Tests  in vitro  showed it to have a binding affinity over 1000 times more potent than 3-quinuclidinyl benzilate with a  K i  of 2.47 picomolars (pM). [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1788", "text": "QX39  ( Compound A ,  CA39 ) is a synthetic compound that activates  chaperone-mediated autophagy  (CMA) by increasing the expression of the lysosomal receptor for this pathway,   LAMP2A   lysosomes . It showed potent activity  in vitro  but has poor pharmacokinetic properties and was not suitable for animal research. Subsequent research led to the development of  CA77.1 , a CMA activator suitable for  in vivo  use. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1789", "text": "Raphamin  is a drug developed as an antiviral. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It is manufactured by the Russian company Materia Medica. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1790", "text": "In  pharmacokinetics , the  rate of infusion  (or  dosing rate ) refers not just to the rate at which a drug is administered, but the desired rate at which a drug  should  be administered to achieve a steady state of a fixed dose which has been demonstrated to be therapeutically effective."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1791", "text": "Abbreviations include K in , [ 1 ]  K 0 , [ 2 ]  or R 0 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1792", "text": "It can be calculated as the  steady-state concentration  in the plasma multiplied by the  clearance :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1793", "text": "K \n \n i \n n \n \n \n = \n \n C \n \n s \n s \n \n \n \u22c5 \n C \n L \n \n \n \n {\\displaystyle \\textstyle K_{in}=C_{ss}\\cdot CL}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1794", "text": "RB-64  is a semi-synthetic  derivative  of  salvinorin A . It is an   irreversible agonist , with a reactive  thiocyanate  group that forms a  bond  to the  \u03ba-opioid receptor  (KOR), resulting in very high potency. [ 1 ]  It is  functionally selective , activating  G proteins  more potently than  \u03b2-arrestin-2 . [ 2 ]  RB-64 has a  bias factor  of up to 96 and is  analgesic  with fewer of the side-effects associated with unbiased KOR agonists. [ 3 ]  The analgesia is long-lasting. Compared with unbiased agonists, RB-64 evokes considerably less  receptor internalization ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1795", "text": "Rebecsinib  ( 17S-FD-895 ) is an experimental  anticancer medication  derived by modification of the natural product  Pladienolide B , which acts as an inhibitor of splicing-mediated activation of the  enzyme   ADAR1 , and is in development as a potential treatment for  leukemia . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1796", "text": "A  receptor degrader  binds to a  receptor  and induces its breakdown, causing  down-regulation  of signaling of that receptor. It is distinct from the mechanism of action of  receptor antagonists  and  inverse agonists , which reduce receptor signaling but do not cause receptor breakdown. Examples include  selective estrogen receptor degraders  and  androgen receptor degraders , both developed for hormone-sensitive cancers. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1797", "text": "Reldesemtiv  is an  investigational new drug  that is being evaluated to treat  amyotrophic lateral sclerosis . [ 1 ]  It is a  troponin  activator. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1798", "text": "A  release modulator , or  neurotransmitter release modulator , is a type of  drug  that  modulates  the  release  of one or more  neurotransmitters . Examples of release modulators include  monoamine releasing agents  such as the  substituted amphetamines  (which induce the release of  norepinephrine ,  dopamine , and/or  serotonin ) [ 1 ]  and  release inhibitors  such as  botulinum toxin A  (which inhibits  acetylcholine  release by inactivating  SNAP-25 , thereby preventing  exocytosis  from occurring). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1799", "text": "Remestemcel , sold under the brand name  Ryoncil , is an  allogeneic  bone marrow-derived mesenchymal stromal  cell therapy  used for the treatment of  graft-versus-host disease . [ 1 ] [ 2 ]  Remestemcel contains mesenchymal stromal cells, which are a type of cell that can have various roles in the body and can differentiate into multiple other types of cells. [ 3 ]  These mesenchymal stromal cell are isolated from the bone marrow of healthy adult human donors. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1800", "text": "The most common adverse reactions include viral infectious disorders, bacterial infectious disorders, infection \u2013 pathogen unspecified, pyrexia, hemorrhage, edema, abdominal pain, and hypertension. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1801", "text": "Remestemcel was approved for medical use in the United States in December 2024. [ 2 ] [ 3 ] [ 4 ]  Remestemcel is the first mesenchymal stromal cell therapy approved by the US  Food and Drug Administration . [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1802", "text": "Remestemcel is  indicated  for the treatment of steroid-refractory acute  graft-versus-host disease . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1803", "text": "The safety and effectiveness of remestemcel were evaluated in a multicenter, single-arm study in 54 pediatric study participants with steroid-refractory acute graft-versus-host disease after undergoing allogeneic hematopoietic (blood) stem cell transplantation. [ 4 ]  Study participants received intravenous infusion of remestemcel twice weekly for four consecutive weeks, for a total of eight infusions. [ 4 ]  Each study participant's condition at baseline was analyzed using the international blood and marrow transplantation registry severity index criteria (IBMTR) to evaluate which organs have been affected and the overall severity of the disease. [ 4 ]  The effectiveness of remestemcel was based primarily on the rate and duration of response to treatment 28 days after initiating remestemcel. [ 4 ]  Study participants who had a partial or mixed response to treatment\u2014meaning that there was improved condition in one organ with either no change (partial) or worsening condition (mixed) in another organ\u2014received additional infusions once weekly for an additional four weeks. [ 4 ]  Sixteen study participants (30%) had a complete response to treatment 28 days after receiving remestemcel, while 22 study participants (41%) had a partial response. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1804", "text": "The US  Food and Drug Administration  (FDA) granted the application for remestemcel  fast track ,  orphan drug , and  priority review  designations. [ 3 ] [ 4 ]  The FDA granted approval of Ryoncil to Mesoblast, Inc. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1805", "text": "Remestemcel was approved for medical use in the United States in December 2024. [ 2 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1806", "text": "Remestemcel is the  international nonproprietary name . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1807", "text": "Remestemcel-L is the  United States Adopted Name . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1808", "text": "Remibrutinib  is a  small molecule  drug that acts as a  Bruton's tyrosine kinase  (BTK) inhibitor. It is in development for the treatment of  chronic spontaneous urticaria . [ 1 ] [ 2 ]  In November 2023, Novartis announced that the compound \"demonstrated clinically meaningful and statistically significant reduction in urticaria activity vs placebo\" in a Phase III trial. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1809", "text": "Joseph P. Remington  (March 26, 1847 \u2013 January 1, 1918) was a community  pharmacist , manufacturer, and educator. [ 1 ]  An active participant and a supporter of the International Pharmaceutical Congress, Remington served as president of the 7th Congress in  Chicago  in 1893. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1810", "text": "Remington was elected to the  American Philosophical Society  in 1899. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1811", "text": "The  Remington Medal  was established in 1918 and awarded by the  American Pharmacists Association . The award is considered the most prestigious award given in the profession of  pharmacy  in the  United States . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1812", "text": "Remternetug  is an experimental anti-amyloid  monoclonal antibody  that targets  pyroglutamate A\u03b2 . It is developed by  Eli Lilly and Company . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1813", "text": "Reparagen  is a joint health product that scientists at  Albany Medical College  ran clinical trials on to test the theory that the combination of  Uncaria guianensis  and  Lepidium meyenii  can turn on Insulin-like growth factor [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1814", "text": "Resigratinib  ( KIN-3248 ) is an experimental  anticancer medication  which acts as a  fibroblast growth factor receptor  inhibitor (FGFRi) and is in early stage human  clinical trials . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1815", "text": "Respimat , also known as  Respimat Soft Mist Inhaler , is a drug delivery device used for the treatment of  asthma ,  chronic obstructive pulmonary disease  (COPD), and other respiratory conditions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1816", "text": "Its developer,  Boehringer Ingelheim , is currently [ when? ]  conducting approved in the U.S. with a variety of their products, such as  tiotropium  and  ipratropium/salbutamol .  According to the manufacturer, the reusability of the inhaler reduces its  carbon footprint  by 71%. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1817", "text": "Retatrutide  ( LY-3437943 ) is an experimental drug for  obesity  developed by American pharmaceutical company  Eli Lilly and Company . It is a triple  glucagon  hormone receptor agonist ( GLP-1 ,   GIP , and  GCGR  receptors). [ 1 ]  It has been shown to achieve a more than 17.5% mean weight reduction in adults without diabetes but with obesity or preobesity (overweight) during a  phase 2 trial . [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1818", "text": "The drug is a peptide with amino acid sequence [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1819", "text": "where superscript numbers refer to unique chemical modifications:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1820", "text": "A  reuptake modulator , or  transporter modulator , is a type of  drug  which  modulates  the  reuptake  of one or more  neurotransmitters  via their respective  neurotransmitter transporters . Examples of reuptake modulators include  reuptake inhibitors  (transporter blockers) and  reuptake enhancers ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1821", "text": "In the field of  drug discovery ,  reverse pharmacology [ 1 ] [ 2 ] [ 3 ]  also known as  target-based drug discovery  (TDD), [ 4 ]  a hypothesis is first made that modulation of the activity of a specific  protein target  thought to be disease modifying will have beneficial therapeutic effects.   Screening  of  chemical libraries  of  small molecules  is then used to identify compounds that bind with high affinity to the target.  The hits from these screens are then used as starting points for drug discovery.  This method became popular after the  sequencing  of the  human genome  which allowed rapid cloning and synthesis of large quantities of purified proteins.  This method is the most widely used in drug discovery today. [ 5 ]  Differently than the classical ( forward ) pharmacology, with the reverse pharmacology approach  in vivo  efficacy of identified active ( lead ) compounds is usually performed in the final  drug discovery  stages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1822", "text": "Reverse tolerance  or  drug sensitization  is a  pharmacological  phenomenon describing subjects' increased reaction (positive or negative) to a drug following its repeated use. [ 4 ]  Not all drugs are subject to reverse tolerance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1823", "text": "This is the opposite of  drug tolerance , in which the effect or the subject's reaction decreases following its repeated use. The two notions are not incompatible, and tolerance may sometimes lead to reverse tolerance. For example, heavy drinkers initially develop tolerance to alcohol, requiring them to drink larger amounts to achieve a similar effect, but as excessive drinking can cause  liver damage , this can then put this group at risk of intoxication when drinking even very small amounts of alcohol. [ 5 ]   Sensitization, a form of reverse tolerance, develops rapidly to the positive, euphoric effects of alcohol, but not to the physical effects, such as sedation and respiratory depression, which diminish with prolonged use.  This sensitization does not occur, however, with administration of benzodiazepines or neuroactive steroids, which only exhibit weakening of effect with repeated use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1824", "text": "Reverse tolerance can also occur in users of stimulants such as cocaine or amphetamines. A previously recreational dose may become enough to cause psychosis in regular users, or users who previously had a psychotic episode may be more likely to have one in the future and at lower doses once drug usage continues. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1825", "text": "In some cases drug sensitization may also refer to medical interventions (e.g. a  drug holiday ) that aim to reduce the insensitivity caused by drug tolerance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1826", "text": "Reverse transport , or  transporter reversal , is a phenomenon in which the  substrates  of a  membrane transport protein  are moved in the opposite direction to that of their typical movement by the transporter. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  Transporter reversal typically occurs when a membrane transport protein is  phosphorylated  by a particular  protein kinase , which is an  enzyme  that adds a  phosphate  group to  proteins . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1827", "text": "The primary function of most  neurotransmitter transporters  is to facilitate  neurotransmitter reuptake  (i.e., the reabsorption of  neurotransmitters  by the cell which released them). [ 1 ] [ 2 ] [ 6 ]  During neurotransmitter reuptake, neurotransmitter transporters will move specific types of neurotransmitters from the  extracellular space  into the  cytosol  of a  neuron  or  glial cell . [ 1 ] [ 2 ] [ 6 ]   When these transporters operate in reverse, they produce  neurotransmitter efflux  (i.e., the movement of neurotransmitters from the cytosol to the extracellular space via transporter-mediated release, as opposed to  exocytotic  release). [ 1 ] [ 2 ]  In neurons, transporter reversal facilitates the release of neurotransmitters into the  synaptic cleft , resulting in a higher concentration of synaptic neurotransmitters and increased signaling through the corresponding  neurotransmitter receptors ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1828", "text": "For example,  monoamine releasing agents , such as  amphetamines , cause  monoamine neurotransmitter  efflux (i.e., the release of monoamine neurotransmitters from neurons into the synaptic cleft via  monoamine transporter -mediated release) by triggering reverse transport at  vesicular monoamine transporters  (specifically,  VMAT1  and  VMAT2 ) and other monoamine transporters that are located along the  plasma membrane  of neurons (specifically,  DAT ,  NET , and  SERT ). [ 1 ] [ 2 ] [ 7 ]  The exact mechanisms by which amphetamines and other monoamine releasing agents mediate induction of reverse transport are poorly understood. [ 8 ] [ 9 ] [ 10 ]  However, the process may involve  intracellular   calcium ion  (Ca 2+ ) elevation,  protein kinase C  (PKC) activation, and  Ca 2+ /calmodulin-dependent protein kinase II alpha  (CaMKII\u03b1) activation. [ 8 ] [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1829", "text": "RG-7351  is a  trace amine-associated receptor 1  (TAAR1)  partial agonist  that is or was under development for the treatment of  major depressive disorder . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It reached  phase 1   clinical trials  for this indication in 2010. [ 1 ] [ 2 ] [ 4 ]  However, as of November 2023, no further recent development has been reported since July 2016. [ 1 ]  The drug was developed by  Hoffmann-La Roche . [ 1 ] [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1830", "text": "Rifasutenizol  is an  investigational new drug  developed by TenNor Therapeutics, primarily aimed at treating  Helicobacter pylori  infections. [ 1 ]  It is a novel multi-targeting small molecule that functions as a bacterial DNA-directed  RNA polymerase  inhibitor. [ 2 ]  This drug has been granted  Qualified Infectious Disease Product  and  Fast Track designations  by the  U.S. FDA . [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1831", "text": "Rigerimod  (IPP-201101,  Lupuzor ) is a  polypeptide  corresponding to the sequence 131-151 of the  70k snRNP  protein with a serine phosphorylated in position 140. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1832", "text": "It gave encouraging results in a phase IIb trial for severe  lupus . [ 1 ] \nAnother phase IIb trial has started recruiting in the US. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1833", "text": "Rimoprogin  is an  antifungal  compound. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1834", "text": "Rindopepimut  (CDX-110) is an injectable  peptide   cancer vaccine [ 1 ]  which targets a mutant protein called  EGFRvIII  present in about 25% to 30% of  glioblastoma  cases. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1835", "text": "The vaccine consists of the EGFRv3-specific peptide (a 13- amino acid  mutant vIII  epitope [ 3 ] ) conjugated to the non-specific  immunomodulator   keyhole limpet hemocyanin  (KLH). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1836", "text": "The  US FDA  granted it  Breakthrough Therapy  designation for  glioblastoma  in Feb 2015 meaning that it might be able to get approval sooner if it is effective. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1837", "text": "The phase II ACT III study reported encouraging results in June 2015. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1838", "text": "The ReACT clinical trial for glioblastoma reported encouraging results in 2015. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1839", "text": "In March 2016 the phase III ACT IV trial  [ 6 ]  was terminated because it did not increase  overall survival . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1840", "text": "Rintodestrant  is an orally bioavailable  selective estrogen receptor degrader  (SERD) developed by  G1 Therapeutics  for the treatment of estrogen receptor-positive (ER+)  breast cancer . Structurally inspired by the 6-OH- benzothiophene  scaffold used in  arzoxifene  and  raloxifene , rintodestrant selectively binds to the  estrogen receptor  and inhibits ER signaling, demonstrating efficacy in endocrine-resistant tumors. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1841", "text": "A phase I clinical trial evaluated rintodestrant as monotherapy and in combination with the CDK4/6 inhibitor  palbociclib  in patients with ER+/HER2- advanced breast cancer. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1842", "text": "RKI-1447  is a drug which acts as a potent and selective inhibitor of the  enzyme   Rho kinase , with an IC 50  of 14.5 nM at  ROCK1  and 6.2\u2009nM at  ROCK2 . It has been investigated for applications in  cancer  treatment, [ 1 ] [ 2 ] [ 3 ]  as well as  glaucoma , [ 4 ]  and  nonalcoholic fatty liver disease . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1843", "text": "RMC-9805  is an  investigational drug  that selectively targets the  G12D mutation  in  KRAS  dependent cancers. [ 1 ] [ 2 ] [ 3 ]  RMC-9805 functions as  molecular glue  that forms a non-covalent ligand-mediated protein-protein interaction between  cyclophilin A  and GTP-bound RAS. Subsequent  covalent modification  of the mutant Asp12 residue affords selectivity over wild-type RAS. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1844", "text": "RMC-9805 is currently in a phase 1/1b clinical trial for the treatment of KRAS G12D-mutant solid tumors. [ 6 ]  Preliminary data indicated that KRAS G12D\u2013mutant PDAC patients dosed at 1200\u00a0mg daily or 600\u00a0mg twice daily achieved a 30% objective response rate (n = 12) and 80% disease control rate (n = 32). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1845", "text": "RN-9893  is a drug which acts as a potent and selective blocker of the  TRPV4   ion channel . It has been used to investigate the role of TRPV4 channels in the function of  heart valves . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1846", "text": "Ro 3-0412  is an  acetylcholinesterase inhibitor . It is the  organophosphate   analog  of  neostigmine . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1847", "text": "Ro07-5220  ( 6'-Chlorodiclazepam ) is a  benzodiazepine  derivative with  sedative ,  anxiolytic ,  anticonvulsant  and  muscle relaxant  effects, [ 1 ] [ 2 ] [ 3 ]  which has been sold as a  designer drug . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1848", "text": "Ro07-9749  is a  benzodiazepine  derivative with  sedative  and  anxiolytic  effects, [ 1 ]  which has been used as an internal standard in the analysis of other benzodiazepines, [ 2 ]  and also sold as a  designer drug . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1849", "text": "Ro20-8065  ( 8-Chloronorflurazepam ) is a  benzodiazepine  derivative with  anticonvulsant  and  muscle relaxant  effects, [ 1 ]  which has been sold as a  designer drug . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1850", "text": "Ropsacitinib  ( PF-06826647 ) is a drug which is an orally active, selective  tyrosine kinase 2  (TYK2)  inhibitor . It has been researched for various autoimmune inflammatory conditions, primarily  plaque psoriasis . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1851", "text": "Rovafovir etalafenamide  (development code  GS-9131 ) is an experimental drug for the treatment of  HIV-1 infection . [ 1 ]   Rovafovir etalafenamide is a  nucleotide reverse transcriptase inhibitor  and  prodrug  of GS-9148.  Rovafovir etalafenamide itself has no antiviral activity, but once consumed it is metabolized through the  hydrolysis  of the phosphonoamidate group to generate the antiviral compound GS-9148. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1852", "text": "The drug is being  developed  by  Gilead Sciences . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1853", "text": "Rovafovir etalafenamide shows antiviral activity against viruses containing major mutations associated with resistance to the  nucleoside analog reverse-transcriptase inhibitors  which are commonly used to treat  HIV/AIDS  infection. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1854", "text": "The methods by which the drug is synthesized has been published. [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1855", "text": "Rozanolixizumab , sold under the brand name  Rystiggo , is a  monoclonal antibody  used for the treatment of  myasthenia gravis . [ 1 ]  Rozanolixizumab is a humanized and chimeric monoclonal antibody; [ 4 ]  and is a neonatal Fc receptor blocker. [ 1 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1856", "text": "The most common adverse reactions include headache, infections, diarrhea, pyrexia, hypersensitivity reactions, and nausea. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1857", "text": "Rozanolixizumab was approved for medical use in the United States in June 2023, [ 6 ] [ 7 ] [ 8 ]  and in the European Union in January 2024. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1858", "text": "Rozanolixizumab is  indicated  for the treatment of generalized myasthenia gravis in adults who are anti-acetylcholine receptor or anti-muscle-specific tyrosine kinase antibody positive. [ 1 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1859", "text": "Rozanolixizumab is the  international nonproprietary name . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1860", "text": "In November 2023, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Rystiggo, intended for the treatment of myasthenia gravis. [ 10 ]  The applicant for this medicinal product is UCB Pharma. [ 10 ]  Rozanolixizumab was approved for medical use in the European Union in January 2024. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1861", "text": "RQ-00203078  is a drug which acts as a potent and selective blocker of the  TRPM8   ion channel , which is the main receptor responsible for the sensation of  cold . It was developed as a potential  analgesic , and blocks the development of  hyperalgesia  following exposure to cold temperatures or chronic  morphine  administration. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1862", "text": "Lithium chloride \n Potassium chloride \n Rubidium chloride \n Sodium chloride"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1863", "text": "Rubidium-82 chloride  is a form of  rubidium chloride  containing a radioactive isotope of  rubidium .  It is marketed under the brand name Cardiogen-82 by  Bracco Diagnostics  for use in  Myocardial perfusion imaging . [ 1 ]   It is rapidly taken up by  heart muscle  cells, and therefore can be used to identify regions of heart muscle that are receiving poor  blood flow  in a technique called  PET  perfusion imaging. [ 2 ]  The  half-life  of  rubidium-82  is only 1.27 minutes; it is normally produced at the place of use by rubidium generators. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1864", "text": "Ruzinurad  (SHR4640) is a selective  urate transporter 1  (URAT1) inhibitor in development for  hyperuricaemia  and  gout . It is developed by  Jiangsu Hengrui . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1865", "text": "RxList  is an online medical resource of US  prescription medications  providing full prescribing information and patient education. It was founded in 1995 by Neil Sandow, Pharm.D. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1866", "text": "RxList is an owned and operated site in the  WebMD  Consumer Network  [ 3 ]  and was acquired by WebMD in December 2004. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1867", "text": "RxList provides content written by  pharmacists  and physicians and data provided by credible sources including the  FDA , Cerner Multum, and  First Data Bank , Inc. [ 5 ]  RxList, as part of the WebMD Consumer Network, adheres to the same privacy policy as WebMD.com and is certified by  TRUSTe  . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1868", "text": "As of March\u00a02023 [update]  RxList was ranked #14 in the eBizMBA Top 15 Best Health Websites. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1869", "text": "RxNorm  is US-specific terminology in  medicine  that contains all  medications  available on the US market. [ 1 ]  It can also be used in  personal health records  applications. [ citation needed ]  RxNorm is part of  Unified Medical Language System  (UMLS) terminology and is maintained by the  United States National Library of Medicine  (NLM). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1870", "text": "As of May\u00a02017, [update]  NLM provides six  APIs  related to RxNorm. [ 3 ]  There is also a web application called RxMix that allows users to access the RxNorm APIs without writing their own programs. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1871", "text": "Sakigake  (\u3055\u304d\u304c\u3051, lit. \"pathfinder\", \"harbinger\") is a drug designation by the  Pharmaceuticals and Medical Devices Agency , the pharmaceuticals regulator of  Japan . It was designed to provide easier access to novel advanced treatments. [ 1 ]  It is analogous to the  Regenerative Medicine Advanced Therapy  designation in the  United States  and the  Advanced Therapy Medicinal Product  designation in the  European Union ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1872", "text": "The Sakigake designation was first announced as a pilot by the  Ministry of Health, Labour and Welfare  on 17 June 2014. The designation system is part of a wider strategy, also named Sakigake, to promote  R&D  and improve access to new pharmaceuticals. [ 2 ]  The Pharmaceutical & Medical Device Act Amendments of 2019, which entered into force on 1 September 2020, made the Sakigake designation system a permanent fixture. [ 3 ]  While application for the Sakigake designation was only open for a short period every year, the permanent Sakigake regime is open year-round."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1873", "text": "The Sakigake designation opens up the possibility for sponsors to seek pre-application consultations, which provide clients with a fixed-price multi-track review of their application. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1874", "text": "As of 31\u00a0December\u00a02020 [update] , 24 drugs received Sakigake designation, but only 8 of these (33.33%) were approved. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1875", "text": "Salbutamol/budesonide , sold under the brand name  Airsupra , is a  fixed-dose combination  medication for the treatment of  bronchoconstriction  and  asthma . [ 1 ] [ 2 ]  It is a combination of  salbutamol sulfate  (albuterol sulfate), a short-acting  beta2-adrenergic agonist , and  budesonide , an inhaled  corticosteroid . [ 1 ] [ 2 ]  It is inhaled using a pressurized  metered-dose inhaler . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1876", "text": "The most common side effects include headache,  oral candidiasis , cough, and difficulty speaking. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1877", "text": "Salbutamol/budesonide was approved for medical use in the United States in January 2023. [ 2 ] [ 3 ]  It is the first combination of an inhaled corticosteroid and a short-acting beta-agonist to be approved by the US  Food and Drug Administration  (FDA). [ 2 ]  It is the first product containing an inhaled corticosteroid to be approved by the FDA as a reliever treatment (rather than as a controller) for asthma. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1878", "text": "Salbutamol/budesonide is  indicated  for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of asthma attacks. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1879", "text": "The efficacy of salbutamol/budesonide to reduce the risk of severe asthma attacks was evaluated in participants with moderate to severe asthma in MANDALA (NCT03769090), a randomized, double-blind, multicenter study. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1880", "text": "Salicyluric acid  is the  glycine   conjugate  of  salicylic acid  and is the primary form in which salicylates are  excreted  from the body, [ 1 ]  via the  kidneys . The pathway is very similar to the pathway of  benzoic acid  excretion as  hippuric acid ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1881", "text": "Samarium ( 153 Sm) lexidronam  (chemical name  Samarium-153-ethylene diamine tetramethylene phosphonate , abbreviated   Samarium-153 EDTMP , trade name  Quadramet ) is a  chelated complex  of a  radioisotope  of the  element   samarium  with  EDTMP . It is used to treat pain when  cancer  has spread to the  bone . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1882", "text": "It is  injected into a vein  and distributed throughout the body, where it is preferentially absorbed in areas where cancer has invaded the bone. The radioisotope  153 Sm, with a  half-life  of 46.3\u00a0hours, decays by emitting  beta particles  ( electrons ), which kill the nearby cells. Pain begins to improve in the first week for most people and the effects can last several months. It is commonly used in  lung cancer ,  prostate cancer ,  breast cancer , and  osteosarcoma ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1883", "text": "Side effects [ 3 ]  include the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1884", "text": "Samarium lexidronam is supplied as a frozen solution for intravenous use with an activity of 50\u00b15\u00a0 mCi /mL [ 4 ]  and a maximum beta energy of 0.808  MeV . [ 5 ]  Due to the short half-life of the radioisotope, the drug expires 56 hours after the noted calibration time. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1885", "text": "Samelisant  ( INN Tooltip International Nonproprietary Name ; developmental code name  SUVN-G3031 ) is an  experimental   wakefulness-promoting agent  acting as a  selective   histamine   H 3  receptor   inverse agonist  which is under development for the treatment of  narcolepsy . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It was also under development for the treatment of  cognition disorders  and  Parkinson's disease , but no recent development has been reported for these indications. [ 1 ] [ 3 ]  As of June 2024, samelisant is in  phase 2   clinical trials  for the treatment of narcolepsy. [ 1 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1886", "text": "Saralasin  is a  competitive   angiotensin II receptor antagonist  with  partial agonistic  activity. The aminopeptide sequence for saralasin differs from  angiotensin II  at three sites:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1887", "text": "Saruparib  is a  investigational new drug  that is being evaluated for the treatment of cancer. [ 1 ]  It first-in-class selective inhibitor of  poly-ADP ribose polymerase 1  (PARP1), designed to treat cancers with  homologous recombination repair  (HRR) deficiencies as a result of mutations in  BRCA1 ,  BRCA2 ,  PALB2 ,  RAD51C , or  RAD51D  genes. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1888", "text": "SB-228357  is a  drug  which acts as a  selective   antagonist  of the  serotonin   5-HT 2B  and  5-HT 2C   receptors . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1889", "text": "It has  antidepressant  and  anxiolytic  effects in  animal models [ 1 ] [ 2 ]  and inhibits 5-HT 2B  mediated  proliferation  of  cardiac   fibroblasts . [ 3 ]  It has also been found to reverse  meta -chlorophenylpiperazine  (mCPP)-induced  hypolocomotion [ 2 ]  and to attenuate  haloperidol -induced  catalepsy . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1890", "text": "The drug was under development by  GlaxoSmithKline  for the treatment of  major depressive disorder  and  anxiety disorders . [ 4 ]  It reached the  preclinical research  phase of development. [ 4 ]  However, development of the drug was discontinued. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1891", "text": "SB-705498  is a drug which acts as a potent and selective blocker of the  TRPV1   ion channel . [ 1 ] [ 2 ]  It has been evaluated in  clinical trials  for the treatment of  rhinitis  and  chronic cough . [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1892", "text": "SCH 900271  is a  nicotinic acid  derivative designed to treat  dyslipidemia . It reduced plasma  free fatty acids  levels, but without significant  flushing , a side effect common with  niacin  that limits its usefulness. SCH 900271 is currently in human trials. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1893", "text": "SCH-202,596  is a  natural product  which is a metabolite derived from an  Aspergillus  fungus. It acts as a selective non-peptide  antagonist  for the receptor  GAL-1 , which is usually activated by the  neuropeptide   galanin . SCH-202,596 is used for scientific research into this still little characterised receptor subtype. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1894", "text": "SCH-79687  is a  histamine antagonist  selective for the  H 3  subtype . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1895", "text": "SCH-79797  is a drug which acts as a potent and selective antagonist of the  thrombin  receptor  proteinase activated receptor 1  (PAR1). [ 1 ]  It has  anticoagulant ,  anticonvulsant  and  antiinflammatory  effects and has been researched as a treatment for  heart attack  and  stroke , though never developed for medical use. [ 2 ] [ 3 ] [ 4 ] [ 5 ]  It also shows  antibiotic  actions which are not shared with other PAR1 antagonists such as  vorapaxar , so may be mediated through a different target than PAR1. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1896", "text": "SCHEMBL19952957  is an  oxadiazole  based  antibiotic , originally developed in 2014 as a potential treatment for infections with  methicillin-resistant  Staphylococcus aureus  (MRSA) and other antibiotic-resistant bacteria. Subsequently, it has been found to be useful against  Clostridioides difficile  as it not only kills active bacteria but also inhibits the germination of the dormant spores which can otherwise often lead to persistent infections that repeatedly recur upon cessation of antibiotic treatment. While it is still only being researched in animals at this stage, this dual action is a significant advance over existing antibiotics, and it is likely that drugs from this class may be developed as new medications for the treatment of antibiotic-resistant infections in humans. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1897", "text": "Heinz Otto Schild   FRS  (18 May 1906\u201315 June 1984), was a pharmacologist now known for the development of the  Schild plot . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1898", "text": "H.O. Schild was born into a Jewish family in what was  Fiume , Austria-Hungary, and is now  Rijeka , Croatia. During the rise of fascism he was schooled in Munich (from 1915) then Budapest (from 1917). [ 1 ]  He studied medicine in Munich and Berlin in the 1920s, with later studies focused on Pharmacology. In 1932s he moved to England to work in  Henry Dale 's laboratory, working also with  John Gaddum ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1899", "text": "In 1937 he married Mireille Madeline Haquin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1900", "text": "As an enemy alien (in his case, an Italian citizen) in the UK before the  Second World War , he was interned during 1939-1940 on the Isle of Man. [ 2 ]  However, his release from the camp was eventually secured by appeals from the scientific community; he stayed in Britain and gained British citizenship in 1948. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1901", "text": "He is particularly known for: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1902", "text": "Scriptaid  is a drug which acts as a  histone deacetylase inhibitor , and was one of the first compounds discovered via  high-throughput screening  that acts at this target. [ 1 ]  Scriptaid itself was never developed for medical applications, but led to the development of structurally related drugs such as  vorinostat , which have been accepted into clinical use. Most early research using these compounds focused on their  anti-cancer  activity, [ 2 ]  but more recent research has found scriptaid to be useful in other applications such as  cloning  and research into regulation of metabolism. [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1903", "text": "Sebetralstat  is an  investigational new drug  that is being evaluated for the treatment of  hereditary angioedema . [ 1 ]   It is a  plasma kallikrein  inhibitor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1904", "text": "Selatogrel  is a  P2Y 12  inhibitor [ 1 ] [ 2 ]  that has been proposed as a treatment for  acute myocardial infarction . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1905", "text": "A  selective PPAR modulator  ( SPPARM ) is a  selective receptor modulator  of the  peroxisome proliferator-activated receptor  (PPAR). [ 1 ] [ 2 ] [ 3 ]  Examples include SPPARMs of the  PPAR\u03b3 ,  BADGE ,  EPI-001 ,  INT-131 ,  MK-0533 , and  S26948 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1906", "text": "In the field of  pharmacology , a  selective receptor modulator  or  SRM  is a type of  drug  that has different effects in different tissues. [ 1 ]   A SRM may behave as an  agonist  in some tissues while as an  antagonist  in others.  Hence selective receptor modulators are sometimes referred to as  tissue selective drugs  or  mixed agonists / antagonists . This tissue selective behavior is in contrast to many other drugs that behave either as agonists or antagonists regardless of the tissue in question."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1907", "text": "Classes of selective receptor modulators include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1908", "text": "Selfotel  ( CGS-19755 ) is a drug which acts as a competitive  NMDA antagonist , directly competing with  glutamate  for binding to the receptor. [ 1 ]  Initial studies showed it to have  anticonvulsant ,  anxiolytic ,  analgesic  and  neuroprotective  effects, [ 2 ] [ 3 ]  and it was originally researched for the treatment of  stroke , [ 4 ]  but subsequent animal and human studies showed  phencyclidine -like effects, [ 5 ] [ 6 ] [ 7 ] [ 8 ]  as well as limited efficacy and evidence for possible  neurotoxicity  under some conditions, [ 9 ] [ 10 ] [ 11 ]  and so clinical development was ultimately discontinued. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1909", "text": "Senaparib  is an  investigational new drug  that is being evaluated to treat  ovarian cancer . [ 1 ]  It is a  PARP inhibitor . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1910", "text": "Sepetaprost  is an  investigational new drug  that is being evaluated for the treatment of  open angle glaucoma  and  ocular hypertension . [ 1 ]   It is an agonist of the prostaglandin  EP3  and  F receptors . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1911", "text": "A  serotonin\u2013norepinephrine\u2013dopamine releasing agent  ( SNDRA ), also known as a  triple releasing agent  ( TRA ), is a type of  drug  which induces the  release  of  serotonin ,  norepinephrine / epinephrine , and  dopamine  in the  brain  and body. SNDRAs produce  euphoriant ,  entactogen , and  psychostimulant  effects, and are almost exclusively encountered as  recreational drugs ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1912", "text": "A closely related type of drug is a  serotonin\u2013norepinephrine\u2013dopamine reuptake inhibitor  (SNDRI)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1913", "text": "Examples of SNDRAs include specific  amphetamines  such as  MDMA ,  MDA ,  4-methylamphetamine ,  methamphetamine  (in high doses), certain  substituted benzofurans  such as  5-APB  and  6-APB ,  naphthylisopropylamine ;  cathinones  such as  mephedrone  and  methylone ;  tryptamines  such as  \u03b1MT  and  \u03b1ET ; along with agents of other  chemical classes  such as  4,4'-DMAR , and  5-IAI . [ 1 ]  \u03b1ET and \u03b1MT are of special notability among SNDRAs in that those tryptamines were once used as  pharmaceutical drugs , specifically as  antidepressants , but were withdrawn shortly after introduction in the 1960s due to problems with  toxicity  and  recreational use . [ 2 ] [ 3 ] [ 4 ]  Such tryptamines were originally thought to act as  monoamine oxidase inhibitors  (MAOIs) before the signature monoamine-releasing actions were elucidated. [ 3 ] [ 4 ]  Many years after being withdrawn, \u03b1ET was also determined to produce  serotonergic  neurotoxicity, similarly to MDMA and various other SNDRAs; the same is very likely true for \u03b1MT as well, although it has not specifically been assessed. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1914", "text": "A  serotonin\u2013norepinephrine releasing agent  ( SNRA ) is a type of  drug  which induces the  release  of  serotonin  and  norepinephrine  (and  epinephrine ) in the body and/or brain."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1915", "text": "Only a few SNRAs are known, examples of which include  norfenfluramine ,  ( R )-MDMA ,  MBDB , and  MDAI .  Fenfluramine  produces norfenfluramine as a major active metabolite and hence is an SNRA similarly. It was formerly used as an  appetite suppressant  for the treatment of  obesity . ( R )-MDMA, MBDB, and MDAI are  entactogens ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1916", "text": "A closely related type of drug is a  serotonin\u2013norepinephrine reuptake inhibitor  (SNRI)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1917", "text": "Serovera  is a  nutritional supplement  marketed by TeamTrade, Inc. As of October 2022, Serovera products were formulated to support immune and digestive health. It is sold at retailers as well as through direct  Internet marketing ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1918", "text": "Currently sold in the  United States , Serovera contains the stabilized and isolated agent  aloe   mucilaginous   polysaccharide . Like many  nutraceuticals , its efficacy is questionable. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1919", "text": "Serovera promotes itself as being created by Dr. Ivan Danhof. Various other doctors, including Lawrence Plaskett, John C. Pittman, Jeffrey Bland, Julian J. Blitz, James W. Smith, and Bruce Eric Hedendal, have contributed to and written articles regarding the uses of aloe mucilaginous polysaccharides. These articles suggest that consumption of aloe polysaccharides may have a beneficial effect on the body. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1920", "text": "Serplulimab  is a  monoclonal antibody  used for the treatment of  cancers . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1921", "text": "It was approved for medical use in China in 2022, for the treatment of microsatellite instability-high  solid tumors [ 2 ]  and squamous  non-small cell lung cancer , [ 3 ]  and in 2023 for the treatment of extensive-stage  small cell lung cancer  (ES-SCLC) and  esophageal squamous cell carcinoma . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1922", "text": "In December 2023, the  Indonesian Food and Drug Authority  approved serplulimab for medical use in Indonesia.  [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1923", "text": "In September 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Hetronifly, intended for the treatment of extensive-stage small cell lung cancer (ES-SCLC). [ 1 ]  The applicant for this medicinal product is Henlius Europe GmbH. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1924", "text": "Serplulimab is the  International nonproprietary name . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1925", "text": "SET2  is a drug which acts as a selective  antagonist  for the  TRPV2  receptor. It is moderately potent with an IC 50  of 460nM, but is highly selective for TRPV2 over the other subtypes of  TRPV , and is the first such compound to be developed. A role has been suggested for TRPV2 in tumor  metastasis , making this a target of interest in the treatment of cancer. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1926", "text": "SGT-003  is an experimental  gene therapy  being tested for  Duchenne's muscular dystrophy . [ 1 ] [ 2 ] [ 3 ]  It is hoped to be an improvement on Solid Bioscience's earlier gene therapy  SGT-001 . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1927", "text": "SH-053-R-CH3-2\u2032F  is a drug used in scientific research which is a  benzodiazepine  derivative. It produces some of the same effects as other benzodiazepines, but is much more subtype-selective than most other drugs of this class, having high selectivity,  binding affinity  and  efficacy  at the  \u03b1 5  subtype  of the  GABA A  receptor. This gives much tighter control of the effects produced, and so while SH-053-R-CH3-2\u2032F retains  sedative  and  anxiolytic  effects, it does not cause  ataxia  at moderate doses. [ 1 ]  SH-053-R-CH3-2\u2032F also blocks the  nootropic  effects of the \u03b1 5 -selective  inverse agonist   PWZ-029 , so  amnesia  is also a likely side effect. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1928", "text": "Replacement of the ester function by an  amide , realized in analogs such as MP-III-022 and  GL-II-73 , improves selectivity, efficacy, and kinetic behavior. [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1929", "text": "SHEN26  is an  investigational new drug  which is being evaluated by Shenzhen Kexing Pharmaceuticals for the treatment of  COVID-19 . It is an  RNA replicase  inhibitor. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1930", "text": "SHR9352  is a drug which acts as a potent and selective biased agonist at the  \u03bc-opioid receptor , selective for activation of the  G-protein  signalling pathway over  \u03b2-arrestin 2  recruitment. It was structurally derived from  oliceridine  by replacing the benzylic side chain with a cyclised group, although only some compounds in the series retained the desired biased agonist profile, with some derivatives such as compound 12 being potent, unbiased \u03bc-opioid full agonists. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1931", "text": "SIB-1553A  is a  nicotinic acetylcholine receptor   agonist  that is selective for receptors with a  \u03b2 4  subunit . Administration of SIB-1553A improved memory and attention in a  Parkinson's disease  model. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1932", "text": "Siguazodan  is a  phosphodiesterase inhibitor . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1933", "text": "Sihuan Pharmaceutical  is a Chinese  pharmaceutical manufacturer  with headquarters in  Beijing  and branch office in  Haikou , Hainan Province. [ 1 ]  The main company in the group is the holding company  Sihuan Pharmaceutical Holdings Group Ltd , which is listed on the  Hong Kong stock market ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1934", "text": "Sihuan Pharmaceutical is collaborating with the  Academy of Military Medical Science  in the development of the drug  JK-05 , intended for the treatment of  Ebola virus disease . [ 1 ]  The company has been challenged by  Fujifilm Holdings Corporation , which has stated that JK-05 infringes its patent rights regarding  Avigan . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1935", "text": "Sincalide  ( INN ) is a  cholecystokinetic  drug administered by  injection  to aid in diagnosing disorders of the  gallbladder  and  pancreas . It is the 8-amino acid  C-terminal  fragment of  cholecystokinin , and also known as  CCK-8 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1936", "text": "Common adverse effects following administration include abdominal discomfort and nausea.  These effects are more pronounced following rapid infusion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1937", "text": "Sincalide may be used to stimulate  gallbladder  contraction, as may be assessed by  contrast agent   cholecystography  or  ultrasonography , or to obtain by duodenal aspiration a sample of concentrated bile for analysis of cholesterol,  bile salts , phospholipids, and crystals. [ 1 ]  It can also be used to stimulate pancreatic secretion (especially in conjunction with  secretin ) prior to obtaining a duodenal aspirate for analysis of enzyme activity, composition, and  cytology . In some instances it is used to accelerate the transit of a  barium meal  through the small bowel, thereby decreasing the time and-extent of radiation associated with  fluoroscopy  and x-ray examination of the intestinal tract. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1938", "text": "Sintilimab , sold under the brand  Tyvyt  among others, is a medication used to treat  Hodgkin's disease , [ 2 ]  and has been approved in  China . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1939", "text": "It is a fully  human   IgG4   monoclonal antibody [ 4 ]  that binds to  programmed cell death protein 1 . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1940", "text": "It was jointly developed by Innovent Biologics [ 6 ]  and Eli Lilly. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1941", "text": "Sintilimab is medication that is indicated for the treatment of relapsed or refractory classical  Hodgkin's lymphoma [ 8 ]  after failure of at least second-line systemic chemotherapy. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1942", "text": "Common side effects include  fever ,  thyroid dysfunction , elevation of liver enzymes, and  lung   inflammation . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1943", "text": "Currently, more than 20  clinical trials  are ongoing to evaluate the  anti-tumor  effect of sintilimab injection, either as  monotherapy  or in combination with other agents, on a variety of solid tumors. [ 10 ]  In January 2019, the result of the registration trial of sintilimab in people with refractory or relapsed classical Hodgkin's lymphoma was published. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1944", "text": "Sipavibart  is an  experimental medication  under investigation for the prevention of  COVID-19  in people who are immunocompromised. [ 1 ]  Sipavibart is a recombinant human IgG1  monoclonal antibody  that provides passive immunization against  SARS-CoV-2  by binding its spike protein receptor binding domain. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1945", "text": "In December 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kavigale, intended for the prevention of COVID-19 in immunocompromised people aged twelve years of age and older. [ 1 ]  Kavigale was reviewed under the EMA's accelerated assessment program. [ 1 ]  The applicant for this medicinal product is AstraZeneca AB. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1946", "text": "Sipavibart is the  international nonproprietary name . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1947", "text": "Siramesine  (or  Lu 28-179 ) is a  sigma receptor   agonist , selective for the \u03c32 subtype. [ 1 ]  In  animal studies , siramesine has been shown to produce  anxiolytic [ 2 ]  and  antidepressant [ 3 ]  effects. It was developed by the pharmaceutical company  H Lundbeck  for the treatment of  anxiety , [ 4 ]  although development was discontinued after clinical trials showed a lack of efficacy in  humans . Siramesine has been shown to produce an enhanced antidepressant effect when co-administered with  NMDA antagonists . [ 5 ]  It has also been used to study the \u03c32 activity of  cocaine , [ 6 ]  and has been shown to produce  anticancer  properties both  in vitro [ 7 ]  and  in vivo . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1948", "text": "Sisunatovir  is an  investigational new drug  that is being evaluated for the treatment of  respiratory syncytial virus  (RSV) infections. [ 1 ]  It functions as an orally administered RSV  fusion inhibitor , targeting the  RSV-F  protein on the viral surface to prevent viral replication. [ 2 ]  Sisunatovir has been granted  Fast Track  designation by the  U.S. Food and Drug Administration  (FDA) due to its potential to address serious RSV infections, which can lead to severe respiratory conditions such as  bronchiolitis  and  pneumonia . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1949", "text": "Site enhancement oil  are compounds injected into muscles to increase their size. Synthol [ 1 ]  is injected into muscles to create larger bulges, or injecting  PMMA  into muscles to shape them. Use of PMMA to shape muscles is prohibited in the United States. [ 2 ]  However, it is not illegal to use synthol. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1950", "text": "Site enhancement oil, often called  santol  or  synthol  (no relation to the  Synthol  mouthwash brand), refers to oils injected into muscles to increase the size or change the shape. Some bodybuilders, particularly at the professional level, inject their muscles with such mixtures to mimic the appearance of developed muscle where it may otherwise be disproportionate or lacking. [ 4 ]  This is known as \"fluffing\". [ 1 ] [ 5 ]  Synthol is 85% oil, 7.5%  lidocaine , and 7.5% alcohol. [ 1 ]  It is not restricted, and many brands are available on the Internet. [ 6 ]  The use of injected oil to enhance muscle appearance is common among bodybuilders, [ 7 ] [ 8 ]  despite the fact that synthol can cause  pulmonary embolisms , nerve damage, infections,  sclerosing lipogranuloma , [ 9 ]  stroke, [ 1 ]  and the formation of oil-filled  granulomas ,  cysts  or ulcers in the muscle. [ 8 ] [ 10 ] [ 11 ]  Rare cases might require surgical intervention to avoid further damage to the muscle and/or to prevent loss of life. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1951", "text": "Sesame oil  is often used in such mixtures, which can cause allergic reactions such as  vasculitis . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1952", "text": "As the injected muscle is not actually well-developed, it might droop under gravity. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1953", "text": "Skin popping  is a  route of administration  of  street drugs  where they are injected or deposited under the skin. [ 1 ]  It is usually a  depot injection , either  subcutaneous  or  intradermal , and not an  intramuscular injection . After deposition, the drug then diffuses slowly from the depot into the  capillary  networks, where it enters  circulation . Skin popping is distinct from  intravenous injection  in that the latter deposits the drug directly into the  bloodstream  via a  vein . Nonetheless, it is included with IV injection in the category of  injection drug use  because both involve injection, both are often done with the same drugs, and both carry many of the same risks (such as bloodborne disease risks, injection site infection risks, and risk of death from overdose). Higher-potency prescription opioids, such as  morphine ,  fentanyl , or  meperidine  can be injected subcutaneously, [ 2 ]  as can cocaine.  Skin  popping increases the duration of the high one gets from drugs such as  cocaine . The sites where skin popping with cocaine has been performed have an area of central pallor surrounded by bruising ( ecchymosis ). This pattern is due to the vasoconstrictive properties of cocaine acting locally at the injection site with hemorrhage occurring in the surrounding tissue.  Skin popping puts one at risk for developing secondary   amyloid associated  (AA)  amyloidosis .  Tetanus  has also been associated with skin-popping [ 3 ]  as has  botulism . [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1954", "text": "SN 35210  is an  arylcyclohexylamine   dissociative   anesthetic  drug. It was derived from  ketamine  with the intention of producing a shorter acting agent more suitable to be used as a stand-alone drug, whereas ketamine itself generally has to be used in combination with other drugs such as  midazolam  to minimise the occurrence of  emergence reactions  due to its  hallucinogenic  side effects. In common with other short-acting anaesthetic drugs such as  remifentanil  and  remimazolam , SN 35210 has had the  chemical structure  modified to incorporate a methyl  ester  group which is rapidly metabolised to a  carboxylic acid , producing an inactive compound and thus rapidly terminating the effects of the drug. It was selected for development from a series of structurally related alkyl esters due to having the shortest duration of action and the most similar pharmacological profile to ketamine itself. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1955", "text": "SN-2  is a chemical compound which acts as an \"agonist\" (i.e. channel opener) for the  TRPML3  calcium channel, with high selectivity for TRPML3 and no significant activity at the related  TRPML1  and  TRPML2  channels. [ 1 ]  It has demonstrated  antiviral  activity in an  in vitro  model. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1956", "text": "SN-22  is a chemical compound which acts as a moderately  selective   agonist  at the  5-HT 2  family of  serotonin   receptors , with a K i  of 19\u00a0nM at 5-HT 2  subtypes versus 514\u00a0nM at 5-HT 1A  receptors. [ 1 ]  Many related derivatives are known, most of which are ligands for 5-HT 1A , 5-HT 6  or dopamine D 2  receptors or show  SSRI  activity. [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1957", "text": "SNAP-7941  is a drug used in scientific research, which is a selective, non-peptide  antagonist  at the  melanin concentrating hormone   receptor   MCH 1 . In initial animal studies it had promising  anxiolytic ,  antidepressant  and  anorectic  effects, [ 1 ] [ 2 ]  but subsequent trial results were disappointing, [ 3 ]  and the main significance of SNAP-7941 is as the  lead compound  from which more potent and selective antagonists such as  SNAP-94847  were developed, [ 4 ] [ 5 ]  although it continues to be used for research into the function of the MCH 1  receptor. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1958", "text": "The  Society of Pharmacovigilance, India  (SoPI), is an Indian national non-profit scientific organisation, which aims at organizing training programmes and providing expertise in  pharmacovigilance  and enhance all aspects of the safe and proper use of  medicines [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1959", "text": "The  International Society of Pharmacovigilance  (ISoP) granted status of 'associated society' to Society of Pharmacovigilance India (SoPI). It is the second professional society in the world after ISoP."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1960", "text": "The founder of SoPI is  KC Singhal ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1961", "text": "Sodelglitazar , formerly known as  GW 677954 , is a thiazole  PPAR\u03b4   receptor agonist  developed by  GlaxoSmithKline . [ 2 ]  While it is primarily active at the PPAR\u03b4 receptor, it is considered a pan agonist with activity at  PPAR\u03b1  and  PPAR\u03b3  receptors. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1962", "text": "Phase 2 studies were terminated prior to completion due to safety findings in  rodent studies . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1963", "text": "Sodium cellulose phosphate  is a drug used to treat  hypercalcemia  and  hypercalciuria . It has been investigating for the prevention of  kidney stones , [ 1 ] [ 2 ]  but with limited efficacy. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1964", "text": "This compound is an ion-exchange resin that can not be absorbed by the body. However, it can be used to restore the normal intestinal calcium absorption. When it is taken orally, it binds strongly to calcium and inhibits its absorption into the blood. From there, inhibition is caused due to the lower intraluminal calcium levels, which is typically available for absorption. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1965", "text": "The mechanism of action of the drug compound can cause a couple of internal effects. Due to the binding activity of the compound with calcium, it will also bind with magnesium and cause a depletion in the body. Working off of this effect, sodium cellulose phosphate will bind with divalent intestinal cations. Because of this binding, more oxalate is available in the blood. This high level of oxalate within the intestine can also be a source of renal stones."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1966", "text": "Hypercalcemia  occurs when there is a raised level of  calcium  in the  blood , compared to the normal range of  2.2\u20132.6\u00a0mmol/L. Typical symptoms of this condition include renal stones, bone pain, abdominal discomfort, and nausea/vomiting. More severe symptoms are associated with psychiatric overtones which are consumed with anxiety, depression, and insomnia."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1967", "text": "Hypercalciuria  occurs when there is an elevated level of  calcium in the urine . This condition is due to severe  calcium reabsorption  within the intestines."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1968", "text": "The major US  dosage form  of sodium cellulose phosphate is  Calcibind , which was developed and brought to market by Mission Pharma. Calcibind is a powder dosage form, which comes in small, 2.5 gram doses, individually packaged. The  patent  for this product was approved on December 28, 1982. The product was eventually removed from the market for reasons that have not been found at this time."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1969", "text": "In the late 1970s and early 1980s, physiological action studies took place to show how intestinal calcium was absorbed and how it affects other functions within the body. By a study done at the University of Texas, it was found that sodium cellulose phosphate inhibited calcium absorption through three separate techniques:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1970", "text": "Through these studies, major conclusions were made regarding the drug compound. Sodium cellulose phosphate reduces the renal excretion of magnesium and calcium. Phosphate and oxalate were both increased in the urine, one due to intestinal hydrolysis and the other to a reduced oxalate complex. Overall, it was noted that the drug could be used to correct the increased calcium absorption that occurs in absorptive hypercalciuria. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1971", "text": "A  sodium channel opener  is a type of  drug  which facilitates  ion  transmission through  sodium channels ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1972", "text": "Examples include  toxins , such as  aconitine ,  veratridine ,  batrachotoxin ,  robustoxin ,  palytoxin  and  ciguatoxins  and  insecticides  ( DDT  and  pyrethroids ), which activate  voltage-gated sodium channels  (VGSCs), and  solnatide  (AP301), which activates the  epithelial sodium channel  (ENaC). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1973", "text": "Sodium nitrite/sodium thiosulfate , sold under the brand name  Nithiodote , is a  fixed-dose combination  medication used as an antidote for  cyanide poisoning . [ 1 ]  It contains  sodium thiosulfate  and  sodium nitrite . [ 1 ]  It is given by  intravenous infusion  into a vein. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1974", "text": "It was approved for medical use in the United States in January 2011. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1975", "text": "Sodium nitrite/sodium thiosulfate is  indicated  for the treatment of acute cyanide poisoning. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1976", "text": "Sodium polydihydroxyphenylene thiosulfonate  ( \u0433\u0438\u043f\u043e\u043a\u0441\u0435\u043d ,  Hypoxen ) is under laboratory studies in Russia as a potential regulator of  cell metabolism . [ 1 ]  It is purported to affect  mitochondrial  function, [ 2 ]  though this has not been proven in any high-quality,  peer-reviewed  publications. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1977", "text": "It is registered in Russia as an  antihypoxic agent , but has not been subjected to any  clinical trials  meeting internationally accepted standards, and has no  regulatory approval  as a  prescription drug  outside Russia and some former Soviet states. Although called an \"oxygen booster\" in  public media  to imply its potential to \"increase endurance and reduce fatigue\", [ 3 ] [ 4 ]  there is no scientific evidence it has this property, and it is not used in conventional  cardiology  as a therapy for treating  heart disease . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1978", "text": "Hypoxen is sold online without a prescription, mainly from Russian websites, and does not appear to be sold in  health stores  in the United States. [ 5 ]  Hypoxen is not listed on the  prohibited substance list  of the  World Anti-Doping Agency . [ 5 ]  In 2017, the  United States Anti-Doping Agency  applied to have hypoxen banned from athletic competitions, but the ban was not implemented. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1979", "text": "It has been identified in tests on athletes in competition, such as  Kamila Valieva , a Russian  figure-skater  competing at the  2022 Winter Olympics , but is not itself banned in international competitions, as of 2022. [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1980", "text": "It is claimed to be a polymeric mixture containing between 2 and 6 repeat units of 2,4-dihydroxyphenylene with a thiosulphonate group joined at the end. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1981", "text": "A  softgel  is an  oral   dosage form  for  medicine  in the form of a specialized  capsule . They consist of a shell, usually  gelatin  based, surrounding a liquid fill. Softgel shells are a combination of  gelatin ,  water ,  opacifier  and a  plasticiser  such as  glycerin  or  sorbitol ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1982", "text": "Softgels are produced in a process known as encapsulation using the Rotary Die Encapsulation process invented by Robert Pauli Scherer.  The encapsulation process has been described as a form/fill/seal process.  Two flat ribbons of shell material are manufactured on the machine and brought together on a twin set of rotating dies.  The dies contain recesses in the desired size and shape, which cut out the ribbons into a two-dimensional shape, and form a seal around the outside. At the same time a pump delivers a precise dose of fill material through a nozzle incorporated into a filling wedge whose tip sits between the two ribbons in between two die pockets at the point of cut out.  The wedge is heated to facilitate the sealing process.  The wedge injection causes the two flat ribbons to expand into the die pockets, giving rise to the three-dimensional finished product.  After encapsulation, the softgels are dried for two days to two weeks depending on the product."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1983", "text": "Since the 1990s, manufacturers have been able to replace gelatin in the shell with other polymers based on, for example,  starch  and  carrageenan ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1984", "text": "Catalent Pharma Solutions  is the current owner of the RPScherer technology. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1985", "text": "Solbinsiran,   is a  GalNAc  conjugated  small interfering RNA  (siRNA) therapy, that targets angiopoietin-like 3. It is developed by  Eli Lilly and Company  to reduce the level of  apolipoprotein B  and reduce the risk of  cardiovascular disease . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1986", "text": "Solbinsiran is a GalNAc-conjugated Dicer-substrate siRNA (DsiRNA) that targets ANGPTL3 expression in the liver. ANGPTL3 plays a role in regulating lipid metabolism, and by inhibiting its expression, Solbinsiran aims to lower lipid levels, particularly triglycerides and low-density lipoprotein cholesterol (LDL-C) ( Triglyceride Forum )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1987", "text": "In preclinical studies, Solbinsiran demonstrated significant reductions in human ANGPTL3 mRNA expression in hepatocytes and a substantial reduction in circulating ANGPTL3 protein levels in cynomolgus monkeys ( Triglyceride Forum ). In Phase 1 studies, it showed potential as a therapeutic option for reducing ANGPTL3 levels and triglycerides (TG) in patients with dyslipidemia ( Triglyceride Forum )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1988", "text": "The therapy is currently investigational and has undergone testing in clinical settings for  cardiovascular diseases ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1989", "text": "Soluble guanylate cyclase (sGC) stimulators  are a class of drugs developed to treat  heart failure ,  pulmonary hypertension , and other diseases. The  first-in-class medication  was   riociguat , approved in 2013 for pulmonary hypertension. [ 1 ] [ 2 ]  They have also been investigated for  hypertension ,  systemic sclerosis , and  sickle cell disease . [ 3 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1990", "text": "In 1998, the role of  nitric oxide  (NO) in cardiovascular disease received the  Nobel Prize in Physiology . Although NO is still used to treat angina, its side effects, potential for tolerance, short duration of action, and narrow  therapeutic index  limit its therapeutic use. [ 1 ] [ 4 ]   PDE5 inhibitors  increase NO and are approved for  erectile dysfunction ,  pulmonary arterial hypertension  (PAH), and  benign prostatic hyperplasia , but they are less effective in patients for whom NO production is suppressed, such as people with diabetes or obesity.  Soluble guanylate cyclase  is one of the downstream targets of NO, but the stimulators operate independently of it. [ 1 ]  sGC activators, another experimental class of drugs, may be more effective than stimulators when  oxidative stress  is high. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1991", "text": "The drugs are also considered to possibly have the potential to treat kidney disease,  lung fibrosis ,  scleroderma , and  sickle cell disease . [ 3 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1992", "text": "Somantadine  ( INN Tooltip International Nonproprietary Name ; developmental code name  PR 741-976 ), or  somantadine hydrochloride  ( USAN Tooltip United States Adopted Name ) in the case of the  hydrochloride   salt , is an  experimental   antiviral   drug  of the  adamantane  family related to  amantadine  and  rimantadine  that was never marketed. [ 1 ] [ 2 ] [ 3 ]  It was first described by 1978. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1993", "text": "Somatorelin  is a  diagnostic agent  for determining  growth hormone deficiency . [ 1 ]  It is a  recombinant  version of  growth hormone-releasing hormone  (GHRH)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1994", "text": "Somatorelin has been used to study hormone deficiency (particularly  growth hormone deficiency ), cognitive impairment, sleep disorders, and aging. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1995", "text": "http://www.hghninja.com/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1996", "text": "Sonrotoclax  is an  investigational new drug  that is being evaluated for the treatment of  hematologic malignancies , particularly  chronic lymphocytic leukemia  (CLL) and  small lymphocytic lymphoma  (SLL). [ 1 ]   It is a potent and selective  BCL2  inhibitor that can overcome resistance associated with BCL2 mutations, such as the G101V variant, which limits the effectiveness of first-generation inhibitors like  venetoclax . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_1997", "text": "Southern and Eastern Norway Pharmaceutical Trust  ( Norwegian :  Sykehusapotekene ANS ) is a  health trust  owned by  Southern and Eastern Norway Regional Health Authority  that operates nineteen hospital  pharmacies . The pharmacies are part of the  Ditt Apotek [ 1 ]  chain and use  Norsk Medisinaldepot  as  wholesaler ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1998", "text": "The pharmacies are located at  Ullev\u00e5l University Hospital ,  Rikshospitalet ,  Radiumhospitalet ,  Akershus University Hospital ,  Aker University Hospital ,  Asker og B\u00e6rum Hospital ,  Drammen Hospital ,  T\u00f8nsberg Hospital ,  Skien Hospital ,  Arendal Hospital ,  Arendal Hospital ,  Kristiansand Hospital ,  Fredrikstad Hospital ,  Sarpsborg Hospital ,  Moss Hospital ,  Kongsvinger Hospital ,  Elverum Hospital ,  Hamar Hospital ,  Gj\u00f8vik Hospital  and  Lillehammer Hospital ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_1999", "text": "Spesolimab , sold under the brand name  Spevigo , is a  monoclonal antibody  used for the treatment of  generalized pustular psoriasis  (GPP). [ 4 ]  It is an interleukin-36 receptor (IL-36R) antagonist. [ 4 ] [ 6 ]  It is given via injection into a vein. [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2000", "text": "The most common adverse reactions include fatigue, nausea and vomiting, headache,  pruritus  (itching) and  prurigo  (itchy bumps), bruising, and urinary tract infection. [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2001", "text": "It was approved for medical use in the United States in September 2022, [ 7 ] [ 8 ] [ 9 ] [ 10 ]  and in European Union in December 2022. [ 5 ]  The US  Food and Drug Administration  (FDA) considers it to be a  first-in-class medication . [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2002", "text": "Spesolimab is  indicated  for the treatment of generalized pustular psoriasis flares in adults. [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2003", "text": "The US  Food and Drug Administration  (FDA) approved spesolimab based on evidence from a clinical trial of 53 adults with generalized pustular psoriasis flare. [ 6 ]  The trial was conducted at three sites in the United States and 23 sites globally (Africa, Asia, and Europe). [ 6 ]  Spesolimab was evaluated in one clinical trial (Study Effisayil-1/NCT03782792) of 53 adults with generalized pustular psoriasis flare. [ 6 ]  In the trial, participants received a single treatment with either spesolimab or placebo. [ 6 ]  Participants were evaluated for clearance of pustules based on a Generalized Pustular Psoriasis Physician Global Assessment (GPPPGA) pustulation sub score of 0 (indicating no visible pustules) at Week 1. [ 6 ]  Neither the participant nor the healthcare providers knew which treatment was being given until after week 1. [ 6 ]  After week 1, all participants, whether they initially received spesolimab or placebo, who continued to experience flare symptoms, had the option to receive a single open-label treatment of spesolimab (second treatment and first treatment for participants in the spesolimab and placebo groups, respectively). [ 6 ]  After week 1 to week 12, participants in either original treatment group whose generalized pustular psoriasis flare reoccurred after achieving a clinical response were eligible to receive a single open-label rescue treatment of spesolimab, with a maximum of three total treatments of spesolimab throughout the trial. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2004", "text": "In October 2022, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Spevigo, intended for the treatment of flares in adult patients with generalised pustular psoriasis. [ 13 ]  The applicant for this medicinal product is Boehringer Ingelheim International GmbH. [ 13 ]  Spesolimab was approved for medical use in the European Union in December 2022. [ 5 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2005", "text": "The FDA granted the application  breakthrough therapy  designation. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2006", "text": "SR-14968  is a drug which acts as a biased agonist at the  \u03bc-opioid receptor , selective for activation of the  G-protein  signalling pathway over  \u03b2-arrestin 2  recruitment. It is closely related to other compounds such as  brorphine  and  SR-17018 . Similarly to brorphine, SR-14968 shows robust biased agonist activity  in vitro , but in animal studies  in vivo  behaves more like a typical opioid agonist at higher dose ranges, though still with a superior safety profile compared to unbiased agonists such as  fentanyl . Compounds of this class are under development as potential  analgesic  medications with lower risk of overdose and drug dependence compared to traditional opioid drugs. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2007", "text": "SR-16435  is a drug which acts as a potent  partial agonist  at both the  \u03bc-opioid receptor  and  nociceptin receptor . In animal studies it was found to be a potent analgesic, with results suggestive of reduced development of tolerance and increased activity against  neuropathic pain  compared to classic \u03bc-selective agonists. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2008", "text": "SR-17018  is a drug which acts as a biased agonist at the  \u03bc-opioid receptor , selective for activation of the  G-protein  signalling pathway over  \u03b2-arrestin 2  recruitment. [ 1 ]  In animal studies it produces  analgesic  effects but with less  respiratory depression  and development of  tolerance  than conventional opioids. [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2009", "text": "SR-8278  is an experimental drug that was developed as an antagonist of  Rev-ErbA\u03b1 . [ 1 ]  It has been used to demonstrate potential applications of Rev-ErbA\u03b1 antagonists in the treatment of conditions such as  Duchenne muscular dystrophy  and  Alzheimer's disease . [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2010", "text": "SR9009 , also known as  Stenabolic , is a research drug that was developed by professor Thomas Burris of the  Scripps Research Institute  as an  agonist  of   Rev-ErbA  (i.e., increases the constitutive  repression  of  genes regulated  by Rev-ErbA) [ 1 ]  with a half-maximum inhibitory concentration ( IC 50 ) = 670 nM for  Rev-ErbA\u03b1  and IC 50  = 800 nM for  Rev-ErbA\u03b2 . [ 2 ]  In an animal study, some of its effects were found to be independent of REV-ERB with an unknown  mechanism of action . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2011", "text": "Activation of Rev-ErbA-\u03b1 by SR9009 in mice increases exercise capacity by increasing  mitochondria  counts in  skeletal muscle . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2012", "text": "Abuse of SR9009 has been reported within the bodybuilding community, resulting in SR9009 being placed on the  World Anti-Doping Agency  list of  prohibited drugs . SR9009 and the related  SR9011  drug are described as \"Hormone and Metabolic Modulators\". [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2013", "text": "SR9011  is a research drug that was developed by Professor Thomas Burris of  Scripps  as an  agonist  of  Rev-ErbA\u03b1 \nwith a half-maximum inhibitory concentration ( IC 50 ) = 790 nM for Rev-Erb\u03b1 and IC 50  = 560 nM for  Rev-ErbA\u03b2 . [ 1 ]  It has been used in the study of the regulation of the  circadian rhythm  and its links to  immune system  function,  inflammation  and  cancer . [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2014", "text": "SRT-1460  is a drug in development by  Sirtris Pharmaceuticals  intended as a  small-molecule   activator  of the  sirtuin  subtype  SIRT1 . It has similar activity in animal studies to the known SIRT1 activator  resveratrol , but is closer in potency to  SRT-1720 . In animal studies it was found to improve  insulin sensitivity  and lower  plasma glucose  levels in fat, muscle and liver tissue, and increased  mitochondrial  and  metabolic function . [ 1 ] \nHowever, the claim that SRT1460 is a SIRT1 activator has been questioned [ 2 ]  and further defended. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2015", "text": "SRT-2104  is an experimental drug that was studied by  Sirtris Pharmaceuticals  as a  small-molecule   activator  of the  sirtuin  subtype  SIRT1 . The compound progressed to Phase II human trials for  Type II diabetes  before development was discontinued, however it continues to be widely used in animal research into the functions of SIRT1. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2016", "text": "SRT-3025  is an experimental drug that was studied by  Sirtris Pharmaceuticals  as a  small-molecule   activator  of the  sirtuin  subtype  SIRT1 . It has been investigated as a potential treatment for  osteoporosis , [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  and  anemia . [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2017", "text": "SSR180711  is a drug that acts as a potent and selective  partial agonist  for the  \u03b17  subtype of neural  nicotinic acetylcholine receptors . [ 1 ] [ 2 ]  In animal studies, it shows  nootropic  effects and may be useful in the treatment of  schizophrenia . [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2018", "text": "STAC-9  is an experimental drug that was developed by  GlaxoSmithKline  as a  small-molecule   activator  of the  sirtuin  subtype  SIRT1 , with potential applications in the treatment of  diabetes . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2019", "text": "STAT inhibitors  are drugs which target  signal transducer and activator of transcription  (STAT) proteins, a family of cytoplasmic induction factors. Inhibitors of STAT proteins are being developed for use in cancer therapy. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2020", "text": "Anabolic/androgenic steroids  are drugs that are obtained from the male hormone,  testosterone . Anabolic steroids are used for muscle-building and strength gain [ 1 ]  for cosmetic reasons as well as for performance-enhancement in athletics and bodybuilding. Anabolic steroids work in many ways by increasing  protein synthesis  in the muscles and by eliminating the catabolic process (the process of breaking down skeletal muscle for energy). It is common for teens and adults to use steroids as they stimulate and encourage muscle growth much more rapidly than natural body building."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2021", "text": "In Australia, many people are encouraged to use steroids due to the body image expectations created by society. In secondary schools, 3.2% of boys and 1.2% of girls are using steroids. [ 2 ]  Many Australian  bodybuilders  visit  Bangkok  and  Pattaya  in Thailand because the  pharmacies  there sell some steroid brands ten times cheaper than they available on the Australian black market. Australians were also purchasing their steroids in other countries to avoid a possible criminal record at home.  Australian Crime Commission [ 3 ]  statistics have shown that there was a 106% increase in the last [ which? ]  financial year of \"performance and image-enhancing-drugs\", showing 5,561 border detections."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2022", "text": "In the first 3 months of 2008, 300 AAS seizures were reported by the  Australian Customs and Border Protection Service . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2023", "text": "Stomatol  is a brand of  toothpaste  first sold in Sweden at the beginning of the 20th century.  It was particularly notable as having been one of the first Swedish brands to recognise and to use the power of  mass media . The brand was originally made by the soap manufacturer Grumme & Son, acquired 1985 by pharmaceutical company  Cederroth AB . The company made extensive use of press, film and signs, both enamel and neon."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2024", "text": "It is particularly known for the large advertisement sign which has been a prominent local landmark at  Slussen  in  Stockholm  since 1909. The  Stomatol Sign , made from lightbulbs, not neon tubes, was the first animated advertisement sign in Sweden (one can see the toothpaste being squeezed out of the tube). It was originally placed on the  Katarinahissen  elevator, but was moved in 1933 to the roof of the nearby building at Klevgr\u00e4nd 1 B. Technical problems forced the electricity to be shut down between 1963 and 1972 and from 1981 until 1986."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2025", "text": "Many Stomatol film commercials were animated. At least ten of the commercials produced in and around 1930 were drawn by Arvid Olson and Victor Bergdahl, creator of  Captain Grogg ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2026", "text": "Live action, near-feature quality ads were produced around that time by Kinocentralen and which starred popular Swedish comedic actor  Thor Mod\u00e9en .  Mod\u00e9en was well known for living a rather extravagant lifestyle, mostly paid for through his work for Stomatol."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2027", "text": "The brand's slogan was \"Stomatol - the only way to obtain healthy and strong teeth!\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_2028", "text": "Stomatol was also manufactured and sold in  Norway . Stomatol toothpaste was first manufactured by  Carl A. H\u00f8yers Stomatolfabrikk A/S  i  Oslo , which got the exclusive rights for the Norwegian market in 1896. They continued to make Stomatol until they were acquired by competitor Marwell Hauge in 1970, and the Stomatol brand name was discontinued in Norway some time after. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2029", "text": "From its beginnings, Stomatol devoted part of its budget to advertising, whether in newspapers or in the streets. At the turn of the twentieth century, a building located at the 92-94  Regeringsgatan  in Stockholm sported a large Stomatol painting."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2030", "text": "This Swedish corporation or company article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2031", "text": "This  product  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2032", "text": "The  Study of Tamoxifen and Raloxifene  ( STAR ) is a  clinical trial  from the early 2000s designed determine how the drug  raloxifene  compares with the drug  tamoxifen  in reducing the incidence of  breast cancer  in women who are at increased risk of the disease. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2033", "text": "One of the largest breast cancer prevention studies ever, [ 2 ]  it included 22,000 women in 400 medical centers in the United States and Canada. [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2034", "text": "The study concluded that raloxifene caused fewer side-effects and less endometrial cancer than tamoxifen. [ 6 ] [ 7 ]  Raloxifene was found to be more effective at preventing noninvasive breast cancer but less effective at preventing invasive breast cancer. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2035", "text": "This  women's health  related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2036", "text": "Sublabial administration , literally \"under the  lip \", from  Latin , refers to the pharmacological  route of administration  by which the active substance is placed between the lip and the  gingiva  (gum) to diffuse through the  oral mucosa . Sublabial administration should not be confused with  sublingual administration , which is under the  tongue . The  frenulum of the tongue  may be irritated when in contact with corrosive materials but can be avoided with this route. It is usually used for  medications  such as  glyceryl trinitrate , for example, in  angina pectoris . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2037", "text": "Some drugs are inactive in the  digestive tract , but this can be avoided if held between the  upper lip  and gum. This prevents the substances from getting swallowed with  salivation , as would normally occur between the  lower lip  and gum, permitting slow release of the drug to prolong the duration of action."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2038", "text": "Sulbactam/durlobactam , sold under the brand name  Xacduro  (by Innoviva Specialty Therapeutics), is a co-packaged medication used for the treatment of bacterial pneumonia caused by  Acinetobacter baumannii-calcoaceticus  complex. [ 1 ] [ 2 ]  It contains  sulbactam , a  beta-lactam antibacterial  and  beta-lactamase inhibitor ; and  durlobactam , a beta-lactamase inhibitor. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2039", "text": "Sulbactam/durlobactam was approved for medical use in the United States in May 2023. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2040", "text": "Sulbactam/durlobactam is  indicated  for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by susceptible isolates of  Acinetobacter baumannii-calcoaceticus  complex. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2041", "text": "The efficacy of sulbactam/durlobactam was established in a multicenter, active-controlled, open-label (investigator-unblinded, assessor-blinded), non-inferiority clinical trial in 177 hospitalized adults with pneumonia caused by carbapenem-resistant  A. baumannii . [ 2 ]  Participants received either sulbactam/durlobactam or  colistin  (a comparator antibiotic) for up to 14 days. [ 2 ]  Both treatment arms also received an additional antibiotic,  imipenem/cilastatin , as background therapy for potential hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia pathogens other than  Acinetobacter baumannii-calcoaceticus  complex. [ 2 ]  The primary measure of efficacy was mortality from all causes within 28 days of treatment in participants with a confirmed infection with carbapenem-resistant A. baumannii. [ 2 ]  Of those who received sulbactam/durlobactam, 19% (12 of 63 participants) died, compared to 32% (20 of 62 participants) who received colistin; this demonstrated that sulbactam/durlobactam was noninferior to colistin. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2042", "text": "Overall, 2.3% of  Acinetobacter baumannii  strains are resistant to sulbactam/durlobactam. This percentage increases to 3.4% and 3.7% in the subgroups of carbapenem-resistant and colistin-resistant  Acinetobacter , respectively. In  Acinetobacter  strains producing metallo-beta-lactamases, sulbactam/durlobactam resistance is 100%. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2043", "text": "Sulbactam/durlobactam was approved for medical use in the United States in May 2023. [ 1 ] [ 2 ]  The FDA granted the application for sulbactam/durlobactam  fast track  and  priority review  designations. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2044", "text": "Sulfadicramide  (marketed as  Irgamid ) is an anti-infective. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2045", "text": "This  antiinfective   drug  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2046", "text": "Sulfinalol  is a  beta adrenergic receptor antagonist . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2047", "text": "The methyl group on a sulfoxide is sufficiently acidic to substitute for phenolic hydroxyl."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2048", "text": "The preparation of this combined \u03b1- and \u03b2-blocker sulfinalol begins by protection of the phenolic hydroxyl as its benzoate ester. Bromination followed by condensation with 4-(4-methoxyphenyl)butan-2-amine (not  PMA ) gives the aminoketone  3 . Successive catalytic reduction and saponification affords aminoalcohol  4 . Oxidation of the  sulfide  to the  sulfoxide  with a reagent such as  metaperiodate  gives sulfinalol ( 5 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2049", "text": "Sulopenem/probenecid , sold under the brand name  Orlynvah , is a  fixed-dose combination  medication used for the treatment of  urinary tract infections . [ 1 ]  It contains  sulopenem , a  penem antibacterial , as the  prodrug  sulopenem etzadroxil; and  probenecid , a  renal tubular transport inhibitor . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2050", "text": "The most common side effects include diarrhea, nausea, vaginal yeast infection, headache, and vomiting. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2051", "text": "The combination was approved for medical use to treat uncomplicated urinary tract infections in the United States in October 2024. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2052", "text": "Sulopenem/probenecid is  indicated  for the treatment of uncomplicated urinary tract infections caused by the designated microorganisms  Escherichia coli ,  Klebsiella pneumoniae , or  Proteus mirabilis  in adult women who have limited or no alternative oral antibacterial treatment options. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2053", "text": "Sulopenem/probenecid is contraindicated in people with a history of  hypersensitivity reactions  to sulopenem etzadroxil or probenecid or other  beta-lactam antibacterial  drugs; people with known  blood dyscrasias ; people with known  uric acid kidney stones ; and people who are also taking  ketorolac tromethamine .  [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2054", "text": "The US  Food and Drug Administration  (FDA) prescribing information for sulopenem/probenecid includes warnings for hypersensitivity reactions,  Clostridioides difficile -associated diarrhea , and potential exacerbation of  gout  when given to people with a known history of gout. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2055", "text": "The effectiveness of sulopenem/probenecid was evaluated in two phase III controlled, randomized, double blind clinical trials (trial 1 and trial 2) which enrolled adult women with uncomplicated urinary tract infections. [ 2 ]  Trial 1 (NCT05584657) was a noninferiority trial in which 2214 adult women with uncomplicated urinary tract infections were randomized and treated. [ 2 ]  Sulopenem/probenecid demonstrated efficacy in participants with amoxicillin/clavulanate-susceptible pathogens with a composite response rate (combined microbiological response and clinical response) of 62% compared to a composite response rate of 55% in the amoxicillin/clavulanate group. [ 2 ]  Trial 2 (NCT03354598) was a noninferiority trial in which 1660 adult women with uncomplicated urinary tract infections were randomized and treated. [ 2 ]  Sulopenem/probenecid demonstrated efficacy in participants with ciprofloxacin-resistant pathogens with a composite response rate of 48% compared to a composite response rate of 33% in the ciprofloxacin group. [ 2 ]  Overall, in the two trials combined, 1932 participants were treated with sulopenem/probenecid. [ 2 ]  Clinical trials evaluating sulopenem/probenecid for the treatment of participants with complicated urinary tract infections and complicated intra-abdominal infections did not demonstrate effectiveness. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2056", "text": "In the field of  pharmacology , a  superagonist  is a type of  agonist  that is capable of producing a maximal response greater than the  endogenous agonist  for the target  receptor , and thus has an  efficacy  of more than 100%. [ 1 ] [ 2 ]  For example,  goserelin  is a superagonist of the  gonadotropin-releasing hormone receptor ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2057", "text": "Synaptic pharmacology  is the study of drugs that act on the  synapses . It deals with the composition, uses, and effects of drugs that may enhance ( receptor ) or diminish (blocker) activity at the synapse, which is the junction across which a nerve impulse passes from an  axon  terminal to a neuron, muscle cell, or gland cell."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2058", "text": "A partial list of pharmacological agents that act at synapses follows."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2059", "text": "Systemic administration  is a  route of administration  of medication, nutrition or other substance into the  circulatory system  so that the entire body is affected. [ 1 ]   Administration can take place via  enteral  administration (absorption of the drug through the gastrointestinal tract) [ 2 ]  or  parenteral  administration (generally injection, infusion, or implantation). [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2060", "text": "Contrast with  topical  administration where the effect is generally local. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2061", "text": "Systems pharmacology  is the application of  systems biology  principles to the field of  pharmacology . It seeks to understand how  drugs  affect the human body as a single complex  biological system . \nInstead of considering the effect of a drug to be the result of one specific  drug-protein interaction , systems pharmacology considers the effect of a drug to be the outcome of the  network  of interactions a drug may have. In 1992, an article on systems medicine and pharmacology was published in China. [ 1 ]   Networks of interaction  may include chemical-protein,  protein\u2013protein , genetic,  signalling  and physiological (at cellular, tissue, organ and whole body levels).  Systems pharmacology uses  bioinformatics  and statistics techniques to integrate and interpret these networks."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2062", "text": "Systems pharmacology can be applied to drug safety studies as a complement to  pharmacoepidemiology . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2063", "text": "Taksta  (previously  CEM-102 ) is a front-loaded [ clarification needed ]  oral dosing regimen of sodium  fusidate  under development in the U.S. as an  antibiotic  for  gram-positive  infections including drug-resistant strains such as  methicillin-resistant Staphylococcus aureus . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2064", "text": "Jan 2010: Taksta has completed enrollment in a phase 2 trial (due to run until March 2010) and is preparing for phase 3 studies in the U.S. for acute bacterial  skin structure infections  (being compared with  linezolid ). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2065", "text": "Sep 2010: Taksta demonstrated comparable clinical success rates compared to linezolid in a phase 2 trial in the U.S. for acute bacterial skin and skin structure infections. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2066", "text": "Jun 2011: Taksta may be effective in the treatment of chronic prosthetic joint infections and osteomyelitis. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2067", "text": "Dec 2015: Cempra doses first patient in a phase 3 clinical trial of Taksta in acute bacterial skin and skin structure infections. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2068", "text": "Nov 2016: Cempra completes a phase 3 clinical trial of Taksta in acute bacterial skin and skin structure infections. Results remain pending. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2069", "text": "Feb 2017: Cempra achieves the primary endpoint of a 10% non-inferiority margin. The microbiological success in each ME [ clarification needed ]  population with methicillin-resistant S. aureus infection is 100 percent (99/99) at both the EOT [ clarification needed ]  and PTE [ clarification needed ]  visits. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2070", "text": "Talnetant  ( SB-223,412 ) is a  neurokinin 3  receptor antagonist developed by  GlaxoSmithKline , which is being researched for several functions (primarily treatment of  irritable bowel syndrome , despite a 2007 study finding no statistically significant improvement in rectal hypersensitivity over placebo). Its use as a potential  antipsychotic  drug for the treatment of  schizophrenia  has also been discontinued. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2071", "text": "Taragarestrant  is an orally bioavailable  selective estrogen receptor degrader  (SERD) developed by Inventis Bio for the treatment of estrogen receptor-positive (ER+)  breast cancer . Structurally similar to AZD9496, taragarestrant has demonstrated potent efficacy across multiple breast cancer cell lines expressing ER and related xenograft models. In preclinical studies, taragarestrant exhibited anti-tumor activity, warranting further clinical investigation. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2072", "text": "A phase I study (NCT03471663) evaluated taragarestrant in females with ER+/HER2- advanced or metastatic breast cancer, both as monotherapy and in combination with the CDK4/6 inhibitor  palbociclib . [ 2 ]  A phase III clinical trial has been initiated in China in patients with ER+/HER2- advanced or metastatic breast cancer. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2073", "text": "Tarextumab  (formerly  OMP-59R5 ) is a fully human  monoclonal antibody  targeting the  Notch 2 / 3  receptors. It is being tested as a possible treatment for cancer. In January 2015, the  US FDA  granted  orphan drug  designation to tarextumab for the treatment of  pancreatic cancer  and  lung cancer . [ 1 ]  Two early stage clinical trials have reported encouraging results. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2074", "text": "Target-mediated drug disposition  ( TMDD ) is the process in which a  drug  binds with high affinity to its pharmacological target (for example, a  receptor ) to such an extent that this affects its  pharmacokinetic  characteristics. Various drug classes can exhibit TMDD, most often these are large compounds (biologics such as  antibodies ,  cytokines  or  growth factors [ 1 ] ) but also smaller compounds can exhibit TMDD (such as  warfarin ).\nA typical TMDD pattern of antibodies displays non-linear clearance and can be seen at concentration ranges that are usually defined as 'mid-to-low'. In this concentration range, the target is partly  saturated . [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2075", "text": "Taurolidine/heparin , sold under the brand name  Defencath , is a  fixed-dose combination   catheter lock solution  used for central venous catheter instillation. [ 1 ] [ 2 ]  It contains  taurolidine , a  thiadiazinane  antimicrobial; and  heparin , an  anti-coagulant . Its use is limited to people with  kidney failure  receiving chronic  hemodialysis  through a  central venous catheter . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2076", "text": "The most frequently reported adverse reactions include hemodialysis catheter malfunction, hemorrhage/bleeding, nausea, vomiting, dizziness, musculoskeletal chest pain, and thrombocytopenia. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2077", "text": "Taurolidine/heparin was approved for medical use in the United States in November 2023. [ 2 ] [ 3 ]  The US  Food and Drug Administration  (FDA) considers it to be a  first-in-class medication . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2078", "text": "Taurolidine/heparin is  indicated  to reduce catheter-related bloodstream infections in adults with kidney failure who are receiving chronic hemodialysis through a central venous catheter. [ 1 ] [ 2 ] [ 5 ]  It is indicated in this limited and specific patient population. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2079", "text": "Taurolidine/heparin was studied in a single, randomized, active-controlled phase III clinical trial. [ 2 ]  In this trial, taurolidine/heparin delayed the time it took to acquire a catheter related bloodstream infection. [ 2 ]  Taurolidine/heparin demonstrated a 71% risk reduction in catheter related bloodstream infections versus the heparin comparator arm (95% confidence interval for risk reduction: 38% to 86%; p value = 0.0006). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2080", "text": "Taxadiene  ( taxa-4,11-diene ) is a  diterpene .  Taxadiene is the first committed intermediate in the synthesis of  taxol . [ 1 ]  Six hydroxylation reactions, and a few others, are needed to convert taxadiene to  baccatin III ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2081", "text": "Enzymatically, taxadiene is produced from  geranylgeranyl pyrophosphate  by  taxadiene synthase . A biochemical gram-scale production of taxadiene has been reported in 2010 using genetically engineered  Escherichia coli . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2082", "text": "TC-S 7001  ( Azaindole-1 ) is a drug which acts as a potent and selective inhibitor of the  enzyme   Rho kinase , with an IC 50  of 0.6 nM at  ROCK1  and 1.1\u2009nM at  ROCK2 . [ 1 ]  It has  vasodilatory  effects and has been used in research for a variety of applications. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2083", "text": "TDBzcholine  is a  diazirine  analog of  acetylcholine  that can be used to label the  nicotinic acetylcholine receptor ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2084", "text": "TDBzcholine is able to bind to the nicotinic acetylcholine receptor. Once TDBzcholine is bound to the receptor, TDBzcholine can be activated by exposing the sample to  UV  light. This led to formation of a highly reactive  carbene  radical that can react with amino acid residues in the receptor and become covalently bound to the receptor. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2085", "text": "TDI-11861  is a chemical compound which acts as a potent  [ 1 ]  and selective inhibitor of  soluble adenylyl cyclase  (sAC). [ 2 ]  In animal studies it reversibly inhibits  sperm motility , producing temporary  infertility  without hormonal side effects. While TDI-11861 is at an early developmental stage and is unlikely to be developed for medical uses in humans itself, it represents an important proof of concept which may potentially lead to the development of future  male contraceptive  drugs. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2086", "text": "TDIQ  (also known as  6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline  or  MDTHIQ ) is a drug used in scientific research, which has  anxiolytic  and  anorectic  effects in animals. [ 1 ] [ 2 ]  It has an unusual effects profile in animals, with the effects generalising to  cocaine  and partially to  MDMA  and  ephedrine , [ 3 ]  but the effects did not generalise to  amphetamine  and TDIQ does not have any  stimulant  effects. [ 4 ]  It is thought these effects are mediated via a  partial agonist  action at  Alpha-2 adrenergic receptors , and TDIQ has been suggested as a possible drug for the treatment of cocaine dependence. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2087", "text": "Technetium ( 99m Tc) etarfolatide  is an investigational non-invasive,  folate receptor -targeting companion imaging agent that is being developed by  Endocyte . [ 1 ]   \nEtarfolatide consists of a  small molecule  targeting the  folate receptor  and an imaging agent, which is based on  technetium-99m . This companion imaging agent identifies cells expressing the  folate receptor , including cancer and inflammatory cells. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2088", "text": "Etarfolatide is currently being investigated together with the corresponding  small molecule drug conjugate  (SMDC)  vintafolide  in a Phase 3 study in  platinum-resistant ovarian cancer  and in a Phase 2b study in  non-small cell lung cancer . It identifies patients with  metastases  that are positive for the  folate receptor  and therefore more likely to respond to treatment with  vintafolide . [ 1 ] [ 2 ]  \nOther  folate receptor  targeting SMDCs for the treatment of  cancer , inflammatory diseases and kidney disease are in preclinical development and will also utilize etarfolatide as companion imaging agent. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2089", "text": "The  European Medicines Agency  (EMA) is reviewing the  Marketing Authorization Application  (MAA) filings for both  vintafolide  and etarfolatide, for the treatment of patients with  folate receptor -positive platinum-resistant  ovarian cancer  in combination with pegylated liposomal  doxorubicin  (PLD). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2090", "text": "Technetium ( 99m Tc) exametazime  is a  radiopharmaceutical  sold under the trade name  Ceretec , and is used by  nuclear medicine  physicians for the detection of altered regional cerebral perfusion in  stroke [ 1 ]  and other cerebrovascular diseases. It can also be used for the labelling of  leukocytes  to localise intra- abdominal  infections [ 2 ]  and  inflammatory bowel disease . [ 3 ]  Exametazime (the part without technetium) is sometimes referred to as  hexamethylpropylene amine oxime  or  HMPAO , although correct chemical names are: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2091", "text": "The drug consists of exametazime as a  chelating agent  for the  radioisotope   technetium-99m . Both  enantiomeric  forms of exametazime are used\u2014the drug is  racemic . [ 5 ]   The third  stereoisomer  of this structure, the  meso  form , is not included."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2092", "text": "Technetium ( 99m Tc) medronic acid   is a  pharmaceutical  product used in  nuclear medicine  to localize  bone metastases [ 1 ]  as well as other diseases that can alter the natural turn-over in the  bone  by  bone scintigraphy . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2093", "text": "The drug is a  complex  of  medronic acid  (MDP, methylene diphosphonate), the simplest  bisphosphonate , with  technetium-99m  ( 99m Tc), a  radionuclide  that emits  gamma rays . The exact structure of the complex is not known. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2094", "text": "99m Tc-MDP must be prepared in a  radiopharmacy . It is usually supplied as a \"cold kit\" to which radioactive  99m Tc from a  generator  is added. Kit composition may vary between suppliers, but contents typically includes medronic acid,  stannous chloride dihydrate  and sometimes  ascorbic acid . [ 4 ]   Pertechnetate ,  eluted  from the generator is added to the kit vial, which is swirled and left to stand. The labelling efficiency, an indication of how much  99m Tc remains in pertechnetate form rather than bound to the MDP, can be measured using  chromatography . [ 5 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2095", "text": "Technetium ( 99m Tc) tetrofosmin  is a drug used in  nuclear medicine   cardiac  imaging. It is sold under the brand name  Myoview  ( GE Healthcare ). The  radioisotope ,  technetium-99m , is chelated by two 1,2- bis [di-(2-ethoxyethyl)phosphino]ethane  ligands  which belong to the group of  diphosphines  and which are referred to as  tetrofosmin . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2096", "text": "Tc-99m tetrofosmin is rapidly taken up by myocardial tissue and reaches its maximum level in approximately 5 minutes. About 66% of the total injected dose is excreted within 48 hours after injection (40% urine, 26% feces).  \nTc-99m tetrofosmin is indicated for use in scintigraphic imaging of the myocardium under stress and rest conditions.  It is used to determine areas of reversible ischemia and infarcted tissue in the heart. It is also indicated to detect changes in perfusion induced by pharmacologic stress ( adenosine ,  lexiscan ,  dobutamine  or  persantine ) in patients with coronary artery disease.   Its third indication is to assess left ventricular function (ejection fraction) in patients thought to have heart disease.\nNo contraindications are known for use of Tc-99m tetrofosmin, but care should be taken to constantly monitor the cardiac function in patients with known or suspected coronary artery disease.\nPatients should be encouraged to void their bladders as soon as the images are gathered, and as often as possible after the tests to decrease their radiation doses, since the majority of elimination is renal.  \nThe recommended dose of Tc-99m tetrofosmin is between 5 and 33 millicuries (185-1221 megabecquerels).  For a two-dose stress/rest dosing, the typical dose is normally a 10 mCi dose, followed one to four hours later by a dose of 30 mCi.  Imaging normally begins 15 minutes following injection. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2097", "text": "Technetium ( 99m Tc) tilmanocept , sold under the brand name  Lymphoseek , is a  radiopharmaceutical  diagnostic imaging agent used to locate lymph nodes which may be draining from  tumors , and assist doctors in locating lymph nodes for removal during  surgery . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2098", "text": "The most common side effects include pain or irritation at the injection site. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2099", "text": "It was approved for medical use in the United States in March 2013, [ 4 ] [ 7 ]  and in the European Union in November 2014. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2100", "text": "In the US, technetium ( 99m Tc) tilmanocept is  indicated  with or without scintigraphic imaging for lymphatic mapping using a handheld gamma counter to locate lymph nodes draining a primary tumor site in people with solid tumors for which this procedure is a component of intraoperative management; and guiding sentinel lymph node biopsy using a handheld gamma counter in people with clinically node negative squamous cell carcinoma of the oral cavity, breast cancer or melanoma. [ 4 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2101", "text": "In the EU, technetium ( 99m Tc) tilmanocept is indicated for imaging and intraoperative detection of sentinel lymph nodes draining a primary tumor in adults with breast cancer, melanoma, or localized squamous cell carcinoma of the oral cavity. [ 5 ]  External imaging and intraoperative evaluation may be performed using a gamma detection device. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2102", "text": "The safety and effectiveness of technetium ( 99m Tc) tilmanocept were established in two clinical trials of 332 participants with melanoma or breast cancer. [ 7 ]  All participants were injected with technetium ( 99m Tc) tilmanocept and blue dye, another drug used to help locate lymph nodes. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2103", "text": "Technetium ( 99m Tc) mertiatide   is a  radiopharmaceutical  medication used in  nuclear medicine  to image the  kidneys . [ 1 ]  It is a  renal imaging  agent that is given by  intravenous injection . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2104", "text": "It was approved for medical use in the United States in June 1990. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2105", "text": "Technetium ( 99m Tc) mertiatide is  indicated  for use in the diagnosis of congenital and acquired abnormalities, renal failure, urinary tract obstruction, and calculi. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2106", "text": "The active ingredient,  betiatide , is reconstituted with  sodium pertechnetate   99m Tc injection to form technetium ( 99m Tc) mertiatide. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2107", "text": "Technetium ( 99m Tc) pentetic acid , sold under the brand name  Draximage DTPA  among others, is a  radiopharmaceutical  medication used in  nuclear medicine  to image the  brain ,  kidneys , or  lungs . [ 1 ]  It is given by  intravenous injection  or via aerosol spray. [ 1 ]  It consists of  technetium-99m  bound to the conjugate base of  pentetic acid , with  sodium  as an additional cation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2108", "text": "Technetium ( 99m Tc) pentetic acid is  indicated  for use in the diagnosis of the brain, kidneys, or lungs. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2109", "text": "Tegileridine  is a drug which acts as a  \u03bc-opioid receptor  agonist. It is closely related to compounds such as  oliceridine ,  TRV734 , and  SHR9352 , and shares a similar profile as a biased agonist selective for activation of the  G-protein  signalling pathway over  \u03b2-arrestin 2  recruitment. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2110", "text": "In January 2024, tegileridine was approved in China for the treatment of moderate to severe pain after abdominal surgery. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2111", "text": "Tegoprubart  (AT-1501) is an experimental humanized  monoclonal antibody  that inhibits  CD40L . It is developed for  ALS [ 1 ]  and  transplant rejection . [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2112", "text": "TERN-501  is a selective  thyromimetic  drug that is being developed for the treatment of  non-alcoholic fatty liver disease . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2113", "text": "In  medicine  and  food law , a  test article  is a  prototype   product  specifically manufactured to test the product. Since medical and food test products involve human safety, they are subject to legal regulation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2114", "text": "In the  United States , medical and food test products are regulated by the  Food and Drug Administration  (FDA).  [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2115", "text": "Title 21 \"Food and Drugs\" , Part 50 \"Protection of Human Subjects\" defines test article as \"drug (including a biological product for human use), medical device for human use, human  food additive , color additive, electronic product, or any other article subject to regulation under the act or under sections 351 and 354-360F of the Public Health Service Act (42 U.S.C. 262 and 263b-263n).\" [ 2 ]  Title 21 \"Food and Drugs\" , Part 58 \"Good Laboratory Practice for Nonclinical Laboratory Studies\"  defines test article similarly: as \"any food additive, color additive, drug, biological product, electronic product, medical device for human use, or any other article subject to regulation under the act or under sections 351 and 354-360F of the Public Health Service Act\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2116", "text": "Generally, prior to the usage of test articles in research involving human subjects, and approval from the  institutional review board  (IRB), however emergency life-threatening situations are exempt form this requirement. IRB must be notified about an emergency usage of test articles within 5 business days.  [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2117", "text": "( R , R )-Tetrahydrochrysene  ( ( R , R )-THC ) is a  drug  used to study the  estrogen receptors  (ERs) in  scientific research . It is an  ER\u03b2   antagonist  and an  ER\u03b1   agonist  with 10-fold higher  affinity  for ER\u03b2 relative to ER\u03b1. [ 1 ] [ 2 ]  ( R , R )-THC is a  silent antagonist  of ER\u03b2, [ 3 ]  and, uniquely relative to other known ER\u03b2 antagonists, a  passive antagonist  of the receptor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2118", "text": "( S , S )-Tetrahydrochrysene  (( S , S )-THC) also binds to the ERs, but in contrast to ( R , R )-THC, ( S , S )-THC is an agonist of both ER\u03b1 and ER\u03b2 and has 20-fold lower affinity for ER\u03b2 relative to ( R , R )-THC. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2119", "text": "( S , S )-Tetrahydrochrysene  ( ( S , S )-THC ) is a  steroid -like  nonsteroidal   estrogen  and  agonist  of both the  estrogen receptors ,  ER\u03b1  and  ER\u03b2 . [ 1 ]  It is an  enantiomer  of  ( R , R )-tetrahydrochrysene  (( R , R )-THC), which, in contrast, is an ER\u03b2  silent antagonist  and ER\u03b1 agonist with 10-fold  selectivity  (i.e.,  affinity ) for the ER\u03b2 over the ER\u03b1 and with 20-fold greater affinity for the ER\u03b2 relative to that of ( S , S )-THC. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2120", "text": "Theraplix  is a  European   pharmaceutical company . Founded in 1931 [ 1 ]  by the pharmacist  Fran\u00e7ois Albert-Buisson , [ 2 ] [ 3 ]  It is now a subsidiary of  Sanofi . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2121", "text": "One of their products is the  antipsychotic   cyamemazine  ( Tercian )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2122", "text": "Their products include: Amidezel, Diamex, Hexomedine Solution, Cathomycine, Kanamylone, Theraleneand Trecator. In the 1960s, they distributed gifts to physicians in the form of collage cards.  They were mostly of Asian subjects and were suitable for framing. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2123", "text": "Thermogenic  means tending to produce  heat , and the term is commonly applied to drugs which increase heat through metabolic stimulation, [ 1 ]  or to  microorganisms  which create heat within  organic waste . Approximately all  enzymatic reaction  in the  human body  is thermogenic, which gives rise to the  basal metabolic rate . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2124", "text": "In  bodybuilding , athletes wishing to reduce  body fat percentage  use thermogenics in order to attempt to increase their  basal metabolic rate , thereby increasing overall energy expenditure.  Caffeine  and  ephedrine  are commonly used for this purpose in the  ECA stack .  2,4-Dinitrophenol  (DNP) is a very strong thermogenic drug used for fat loss which produces a dose-dependent increase in body temperature, to the point where it can induce death by hyperthermia. It works as a  mitochondrial   oxidative phosphorylation  uncoupler, disrupting the  mitochondrial electron transport chain . This stops the mitochondria from producing  adenosine triphosphate , causing energy to be released as heat."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2125", "text": "Thiazovivin  is a drug which acts as a potent and selective inhibitor of the  enzyme   Rho kinase . It is used alongside a cocktail of other growth factors and modulators in  cell culture  techniques for the generation of  induced pluripotent stem cells , which can then be used for a wide variety of applications. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2126", "text": "Thiolutin  is a sulfur-containing antibiotic, which is a potent inhibitor of bacterial and yeast RNA polymerases. [ 1 ]  It was found to inhibit  in vitro  RNA synthesis directed by all three yeast RNA polymerases (I, II, and III). Thiolutin is also an inhibitor of  mannan  and  glucan  formation in  Saccharomyces cerevisiae  and used for the analysis of  mRNA stability . Studies have shown that thiolutin inhibits adhesion of human umbilical vein endothelial cells ( HUVECs ) to  vitronectin  and thus suppresses tumor cell-induced angiogenesis in vivo."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2127", "text": "Thiolutin is formed in submerged  fermentation  by several strains of  Streptomycetes luteosporeus . Some sources erroneously specify \"aureothricin\" as a synonym of thiolutin. Aureothricin is an antibiotic very similar to thiolutin, and is created as a by-product during the thiolutin fermentation. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2128", "text": "Thiotetrabarbital  ( INN ;  Thionarcex ) is a  drug  which is a short-acting  barbiturate  derivative that is used as an  anesthetic . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  It has been used in  veterinary medicine . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2129", "text": "Thrombopoietic agents  are drugs that induce the growth and maturation of  megakaryocytes . [ 1 ]  Some of them are currently in clinical use:  romiplostim , [ 2 ]   eltrombopag ,  oprelvekin  (a recombinant  interleukin 11 ) and  thrombopoietin . Several others are under clinical investigation such as  lusutrombopag  and  avatrombopag ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2130", "text": "Thymectacin  ( NB-1011 ,  NB-101 ) is an experimental anticancer  prodrug  of  brivudine  monophosphate. It is being  developed  by  New Biotics  and it entered in phase I clinical trials for colon cancer in 2006. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2131", "text": "Thymectacin is a small molecule phosphoramidate derivative of ( E )-5-(2-bromovinyl)-2'-deoxyuridine (BVdU) with potential antineoplastic activity. [ 2 ]   It is selectively active against tumor cells expressing high levels of  thymidylate synthase  (TS). Thymectacin is converted intracellularly by TS to bromovinyldeoxyuridine monophosphate (BVdUMP) which competes with the natural substrate,  deoxyuridine monophosphate , for binding to TS. Unlike TS inhibitors, this agent is a reversible substrate for TS catalysis. Thus, TS retains activity and converts BVdUMP into cytotoxic metabolites."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2132", "text": "Tidiacic  is a  hepatoprotective  drug.  It is a component of  tidiacic arginine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2133", "text": "Tidiacic arginine (trade name  Tiadilon ) is a 1:1 combination of the  amino acid   arginine  and tidiacic (thiazolidine-2,4-dicarboxylic acid), which acts as a sulfur donor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2134", "text": "In France, its indications and use have been described as \"identical to those of  silymarin \". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2135", "text": "This  drug  article relating to the  gastrointestinal system  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2136", "text": "Tigulixostat  is an  investigational new drug  that is being evaluated for the treatment of  gout . [ 1 ]   It is a  xanthine oxidase  inhibitor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2137", "text": "Tildipirosin , sold under the brand name  Zuprevo , is a  macrolide  antibiotic used in pigs and cattle. [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2138", "text": "In the United States, tildipirosin is  indicated  for the treatment or control of  bovine respiratory disease  associated with  Mannheimia haemolytica ,  Pasteurella multocida , and  Histophilus somni  in beef and non-lactating dairy cattle. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2139", "text": "In the European Union, tildipirosin is indicated for the treatment and metaphylaxis of swine respiratory disease associated with  Actinobacillus pleuropneumoniae ,  P. multocida ,  Bordetella bronchiseptica , and  Glaesserella parasuis  sensitive to tildipirosin; [ 3 ]  and for the treatment and prevention of bovine respiratory disease associated with  M. haemolytica ,  P. multocida]] , and  H. somni  sensitive to tildipirosin. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2140", "text": "Tinengotinib  is an  investigational new drug  that is being evaluated for the treatment of cancer. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2141", "text": "It is an multi- kinase inhibitor  designed to target a range of kinases involved in cancer  cell proliferation ,  angiogenesis , and  immune response  modulation. Specifically, it inhibits  fibroblast growth factor receptors  (FGFRs) 1\u20133,  janus kinase  (JAK) 1/2,  vascular endothelial growth factor receptors  (VEGFRs), and  aurora kinases  A/B. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2142", "text": "Tinlarebant  is a  investigational new drug  that is being evaluated to treat  dry macular degeneration  and  Stargardt disease . [ 1 ]    It is a  retinol binding protein 4  antagonist. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2143", "text": "Tinofedrine  ( INN Tooltip International Nonproprietary Name ; developmental code name  D-8955 , proposed brand name  Novocebrin ), also known as  N -(3,3-di-3-thienyl)-2-propenyl)norephedrine , is a  sympathomimetic  and  cerebral vasodilator  of the  amphetamine  family which was never marketed. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]  It is a  derivative  of  norephedrine  and an  analogue  of related agents like  oxyfedrine ,  buphenine  (nylidrin), and  isoxsuprine . [ 4 ]  The drug was first described in the literature by 1978. [ 1 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2144", "text": "Tiodazosin  is an  \u03b1 1 -adrenergic receptor   antagonist . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2145", "text": "Tissue selectivity  is a topic in  distribution (pharmacology)  and property of some  drugs . It refers to when a drug occurs in disproportionate concentrations and/or has disproportionate effects in specific  tissues  relative to other tissues. [ 1 ]  An example of such drugs are  selective estrogen receptor modulators  (SERM) like  tamoxifen , which show  estrogenic  effects in some tissues and  antiestrogenic  effects in other tissues. Another example is  peripherally-selective drugs , which do not cross the  blood-brain-barrier  into the  central nervous system  and hence are tissue-selective for the periphery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2146", "text": "Tixocortol pivalate  is a  corticosteroid .  It has  anti-inflammatory  properties similar to  hydrocortisone . [ 1 ]   It is marketed under the brand name  Pivalone . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2147", "text": "It is sometimes used in  patch testing  in  atopic dermatitis . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2148", "text": "TLR4-IN-C34  (or  C34 ) is a drug which acts as a potent and selective antagonist of  Toll-like receptor 4  (TLR4). In animal studies it blocks TLR4-mediated  cytokine  release and has  antiinflammatory  effects. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2149", "text": "TNB-486  (also known as  AZD0486 ) [ 1 ]  \"is a novel  CD19x CD3  bispecific  T-cell engager  (TCE) that incorporates a unique anti-CD3 moiety designed to reduce  cytokine release syndrome  by binding to  T-cells  with low affinity\". [ 2 ]  The drug is developed for cancer by  AstraZeneca  since its acquisition of TeneoTwo in 2022. [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2150", "text": "A  Toba  medicine container is an object that was used to hold herbs and medicines of the  Toba  people. They were generally carved from bone, as well as cherry wood, and fashioned into a variety of shapes representing figures such as animals and deities. Their stoppers resembled Bali Timur statues, with a serpent head atop a Batak warrior. \nThe outside of the container showed a calendar, marked to represent the days of use and non-use for the tube's contents."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2151", "text": "Tolebrutinib  is an  investigational new drug  that is being evaluated to treat  multiple sclerosis . [ 1 ]  It is a  Bruton's tyrosine kinase  (BTK) inhibitor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2152", "text": "Tolerability  refers to the degree to which overt  adverse effects  of a drug can be tolerated by a patient. [ 1 ]  Tolerability of a particular drug can be discussed in a general sense, or it can be a quantifiable measurement as part of a clinical study. Usually, it is measured by the rate of \"dropouts\", or patients that forfeit participation in a study due to extreme adverse effects. Tolerability, however, is often relative to the severity of the medical condition a drug is designed to treat. [ 1 ]  For instance, cancer patients may tolerate significant pain or discomfort during a chemotherapeutic study with the hope of prolonging survival or finding a cure, whereas patients experiencing a benign condition, such as a headache, are less likely to."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2153", "text": "As an example,  tricyclic antidepressants  (TCAs) are very poorly tolerated and often produce severe side effects including  sedation ,  orthostatic hypotension , and  anticholinergic  effects, whereas newer antidepressants have far fewer adverse effects and are well tolerated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2154", "text": "Drug tolerability should not be confused with  drug tolerance , which refers to subjects' reduced reaction to a drug following its repeated use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2155", "text": "Topical tac  is a  topical anesthetic  solution [ 1 ]  introduced by Pryor et al. in 1980. It is a mixture of 5 to 12%  tetracaine , 0.05%  adrenaline , and 4 or 10%  cocaine  hydrochloride (hence the \"TAC\" nomenclature). It has been used in ear, nose, and throat surgery and in the emergency department where numbing of the surface is needed rapidly. Use in the pediatric patient cohort has been documented, including when children have been injured in the eye, ear, or other sensitive locations. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2156", "text": "Due to drug diversion concerns surrounding the use of cocaine in medicine, along with concern regarding toxicity and expense, the cocaine was replaced with lidocaine and a new anesthetic was created -  lidocaine ,  epinephrine , and tetracaine (LET). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2157", "text": "This  surgery  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2158", "text": "Toreforant  ( JNJ-38518168 ) is an orally-dosed selective  antagonist  of the  histamine H 4  receptor  that has been studied for various health conditions. It is the successor of a number of H 4 -selective compounds developed by  Johnson & Johnson . [ 1 ]  Phase IIa clinical trials completed as recently as November 2018 continue to suggest that toreforant is safe. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2159", "text": "As of the end of 2020, there is no regulator-approved H 4  antagonist. In U.S. Phase II clinical trials, toreforant, by itself, did not show efficacy against  eosinophilic asthma . [ 2 ]  The drug did show at least partial efficacy against  rheumatoid arthritis  in patients who were nonresponsive to  methotrexate . [ 3 ]  As the H 4  receptor is widely implicated in the regulation of inflammatory states, the potential uses for an H 4  antagonist remain significant. [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2160", "text": "Torin_1  is a drug which was one of the first non- rapalog  derived  inhibitors  of the  mechanistic target of rapamycin  (mTOR) subtypes  mTORC1  and  mTORC2 . [ 1 ] [ 2 ] [ 3 ]  In animal studies it has  anti-inflammatory , [ 4 ] [ 5 ]  anti- cancer , [ 6 ] [ 7 ]  and anti- aging  properties, [ 8 ] [ 9 ] [ 10 ] [ 11 ]  and shows activity against  neuropathic pain . [ 12 ] [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2161", "text": "Tozorakimab  (formerly MEDI 3506) is a  monoclonal antibody  against  interleukin-33  (IL-33) that works via  RAGE  and  epidermal growth factor receptors . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2162", "text": "Tramadol/paracetamol , also known as  tramadol/acetaminophen  and sold under the brand name  Ultracet  among others, is a  fixed-dose combination  medication used for the treatment of moderate to severe pain. [ 3 ] [ 4 ]  It contains  tramadol , as the  hydrochloride , an  analgesic ; and  paracetamol  an analgesic. [ 3 ] [ 4 ]  It is taken  by mouth . [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2163", "text": "This  analgesic -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2164", "text": "Trastuzumab/hyaluronidase , sold under the brand name  Herceptin SC  among others, is a  fixed-dose combination  medication for the treatment of  HER2 -overexpressing  breast cancer  in adults. [ 1 ] [ 2 ]  It is a combination of  trastuzumab  and  hyaluronidase . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2165", "text": "The most common adverse reactions include fatigue, arthralgia, diarrhea,  injection site reaction , upper respiratory tract infection, rash, myalgia, nausea, headache, edema, flushing, pyrexia, cough, and pain in extremity. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2166", "text": "Trastuzumab/hyaluronidase was approved for medical use in the European Union in August 2013. [ 4 ]  Trastuzumab/hyaluronidase was approved for medical use in the United States in February 2019. [ 1 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2167", "text": "Trastuzumab/hyaluronidase is indicated for adjuvant treatment of adults with HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature; and it is indicated in combination with  paclitaxel  for first-line treatment of HER2-overexpressing metastatic breast cancer. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2168", "text": "Trastuzumab/hyaluronidase (Herceptin SC) was approved for medical use in the European Union in August 2013. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2169", "text": "Trastuzumab/hyaluronidase (Herceptin Hylecta) was approved for medical use in the United States in February 2019. [ 1 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2170", "text": "Approval of trastuzumab/hyaluronidase was based on two randomized trials, HannaH (NCT00950300) and SafeHER (NCT01566721). [ 1 ]  In HannaH, 596 participants with HER2-positive operable or locally advanced breast cancer, including inflammatory breast cancer, were randomized to receive 8 cycles of either trastuzumab/hyaluronidase or intravenous trastuzumab concurrently with chemotherapy, followed by surgery and continued therapy with either trastuzumab/hyaluronidase or intravenous trastuzumab, for an additional 10 cycles. [ 1 ]  HannaH demonstrated comparability between trastuzumab/hyaluronidase and intravenous trastuzumab based on co-primary endpoints of pathologic complete response and pharmacokinetics. [ 1 ]  Pathological complete response (pCR) was observed in 118 participants (45.4%) on the trastuzumab/hyaluronidase arm and in 107 participants (40.7%) receiving intravenous trastuzumab (95% CI for difference in pCR: -4.0; 13.4). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2171", "text": "SafeHER was a prospective, two-cohort, non-randomized, multinational, open-label trial assessing the overall safety and tolerability of trastuzumab/hyaluronidase with chemotherapy in 1,864 participants with HER2-positive breast cancer. [ 1 ]  Participants received a fixed dose of 600\u00a0mg trastuzumab/hyaluronidase every 3 weeks for 18 cycles. [ 1 ]  trastuzumab/hyaluronidase was initiated either sequentially with chemotherapy, concurrently with chemotherapy, or without adjuvant chemotherapy, or in combination with neoadjuvant chemotherapy followed by trastuzumab. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2172", "text": "Travoprost/timolol , sold under the brand name  Duotrav  among others, is a  fixed-dose combination  medication used for the treatment of  glaucoma . [ 4 ] [ 5 ] [ 6 ] [ 7 ]  It contains  travoprost  and  timolol maleate . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2173", "text": "It was approved for medical use in the European Union in April 2006. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2174", "text": "Tremorine  is a drug which is used in scientific research to produce  tremor  in animals. This is used for the development of drugs for the treatment of  Parkinson's disease , as tremor is a major symptom which is treated by anti-Parkinson's drugs. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]   Beta blockers  are also effective in counteracting the effects of tremorine. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2175", "text": "Tremorine was first reported by Everett et al. in 1956-57. [ 7 ] [ 8 ] [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2176", "text": "Trepipam  ( INN Tooltip International Nonproprietary Name ; developmental code name  SCH-12679 ) is a  dopamine receptor   agonist  of the  benzazepine  group that was never marketed. [ 1 ]  It acts specifically as an agonist of the  dopamine   D 1  receptor . [ 2 ]  It is closed related  structurally  to  fenoldopam , a  peripherally acting   selective  D 1  receptor partial agonist which is used as an  antihypertensive agent ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2177", "text": "Trichosanthin  is a  ribosome-inactivating protein . [ 1 ] [ 2 ]   It is derived from  Trichosanthes kirilowii . [ 3 ]   It is also an  abortifacient . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2178", "text": "Trimix  is a prescription  combination drug  containing  alprostadil ,  papaverine , and  phentolamine . It is used to treat  erectile dysfunction . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2179", "text": "Trimix is available in several different formulations, including a gel that can be used  topically , a gel that can be administered into the urethra, and an  injectable  form that is administered via  intracavernosal injection  (an injection at either side, not the base, of the  penis ). [ 2 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2180", "text": "Adverse effects from injecting Trimix may include pain,  fibrosis ,  hematoma , and  priapism  (a prolonged erection of the penis). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2181", "text": "Trimix is a combination of three drugs: alprostadil, papaverine, and phentolamine. These medications work in combination to increase blood flow to the penis, resulting in an erection. [ 1 ] [ 2 ] [ 3 ]  Alprostadil is a  prostaglandin  vasodilator that allows more blood to flow into the area by relaxing the smooth muscle in the blood vessels of the penis. [ 3 ] [ 7 ]  Papaverine is a smooth muscle relaxant that acts by increasing blood flow to the penis. [ 3 ] [ 8 ]  Phentolamine is an  alpha blocker  that relaxes blood vessel muscles, allowing more blood to flow to the penis. [ 3 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2182", "text": "While the active drugs in Trimix have all been individually approved by the  U.S. Food and Drug Administration  (FDA), Trimix as a combination drug has not been approved by the FDA and is only available from  compounding pharmacies . [ 1 ] [ 3 ] [ 10 ]  Trimix is typically prepared by the compounding pharmacy in a sterile environment and then frozen. [ 11 ]  The compound is stable for up to six months while stored frozen and for one month if stored refrigerated beginning at the time of manufacture. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2183", "text": "Triphenylethylene  ( TPE ) is a simple  aromatic hydrocarbon  that possesses weak  estrogenic  activity. [ 1 ] [ 2 ]  Its estrogenic effects were discovered in 1937. [ 3 ]  TPE was derived from structural modification of the more potent estrogen  diethylstilbestrol , which is a member of the  stilbestrol  group of  nonsteroidal  estrogens. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2184", "text": "TPE is the  parent compound  of a group of nonsteroidal  estrogen receptor   ligands . [ 1 ] [ 2 ] [ 5 ]  It includes the  estrogens   chlorotrianisene ,  desmethylchlorotrianisene ,  estrobin  (DBE),  M2613 ,  triphenylbromoethylene ,  triphenylchloroethylene ,  triphenyliodoethylene ,  triphenylmethylethylene ; the  selective estrogen receptor modulators  (SERMs)  afimoxifene ,  brilanestrant ,  broparestrol ,  clomifene ,  clomifenoxide ,  droloxifene ,  endoxifen ,  etacstil ,  fispemifene ,  idoxifene ,  miproxifene ,  miproxifene phosphate ,  nafoxidine ,  ospemifene ,  panomifene , and  toremifene . The  antiestrogen   ethamoxytriphetol  (MER-25) is also closely related, but is technically not a derivative of TPE and is instead a  triphenylethanol  derivative. The tamoxifen  metabolite  and  aromatase inhibitor   norendoxifen  is also a TPE derivative. In addition to their estrogenic activity, various TPE derivatives like tamoxifen and clomifene have been found to act as  protein kinase C inhibitors . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2185", "text": "The  affinity  of triphenylethylene for the rat  estrogen receptor  is about 0.002% relative to  estradiol . [ 7 ] [ 8 ]  For comparison, the relative binding affinities of derivatives of triphenylethylene were 1.6% for  tamoxifen , 175% for  afimoxifene  (4-hydroxytamoxifen), 15% for  droloxifene , 1.4% for  toremifene  (4-chlorotamoxifen), 0.72% for  clomifene , and 0.72% for  nafoxidine . [ 9 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2186", "text": "Trontinemab  (RG6102) is a monoclonal antibody developed by  Roche / Genentech  for the treatment of  Alzheimer's disease . It is based on  gantenerumab , an anti- amyloid  monoclonal antibody, and using a  Brainshuttle  domain for transfer through the blood-brain barrier. [ 1 ]  Compared to  gantenerumab, it has 50 times as much penetrance into the brain. [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2187", "text": "Tropicamide/hydroxyamfetamine  ( trade name   Paremyd ) is a  combination drug  used as an  ophthalmic solution  to induce  mydriasis .  It consists of: [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2188", "text": "Tropicamide/phenylephrine , sold under the brand name  Mydcombi  is a  fixed dose combination  of tropicamide and phenylephrine used to dilate the eyes ( mydriasis ). [ 1 ]  It contains, tropicamide, an  anticholinergic , and phenylephrine, as the hydrochloride, an  alpha-1 adrenergic receptor agonist . [ 1 ]  It is sprayed into the eyes. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2189", "text": "It was approved for medical use in the United States in May 2023. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2190", "text": "Tropicamide/phenylephrine is used for the short-term dilation of the pupils. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2191", "text": "In  medicine  and  pharmacology , a  trough level  or  trough concentration  ( C trough ) is the  concentration  reached by a  drug  immediately before the next dose is administered, [ 1 ] [ 2 ]  often used in  therapeutic drug monitoring . The name comes from the idea that on a graph of concentration versus time, the line forms a U-shaped trough at the lowest region, before a new  dose  sends it higher again. The usual criterion is concentration in the  blood serum , although in some instances local concentration within  tissues  is relevant. It is  pharmacokinetically  normal that over time, the drug  molecules  are being  metabolized  or  cleared  by the body, so the concentration of drug that remains available is dropping. In a medicine that is administered periodically, the trough level should be measured just before the administration of the next dose in order to avoid overdosing. [ 3 ]  A trough level is contrasted with a \"peak level\" ( C max ), which is the highest level of the medicine in the body, and the \"average level\", which is the mean level over time. It is widely used in clinical trials for newer medicines to investigate therapeutic effectiveness and safety."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2192", "text": "C trough  is slightly different from  C min , the minimum concentration during the time interval between administration of two doses. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2193", "text": "Troxacitabine  (brand name  Troxatyl ) is a  nucleoside analogue  with anticancer activity. Its use is being studied in patients with refractory  lymphoproliferative diseases . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2194", "text": "TRPM4-IN-5  is a drug which acts as a moderately potent but highly selective blocker of the  TRPM4   ion channel , with an IC 50  of 1.5 \u03bcM. [ 1 ]  It is protective against glutamate mediated neuronal excitotoxicity. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2195", "text": "TRPV3-74a  is a drug which acts as a selective  antagonist  for the  TRPV3   calcium channel . It has  analgesic  effects in animal studies against both  neuropathic pain  and normal  pain  responses. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2196", "text": "TRV734  is a drug developed by  Trevena Inc  which acts as a biased agonist at the  \u03bc-opioid receptor , selective for activation of the  G-protein  signalling pathway over  \u03b2-arrestin 2  recruitment. It is closely related to  oliceridine  and has a similar pharmacological profile, but unlike oliceridine which has to be injected, TRV734 is suitable to be administered orally. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2197", "text": "TTX-030  is an experimental anti- CD39   monoclonal antibody  developed by  AbbVie  to treat  pancreatic cancer . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2198", "text": "Turkesterone  is a  phytoecdysteroid   found in numerous plant species, including  Ajuga turkestanica , [ 1 ]  various  Vitex  species, [ 2 ] [ 3 ] [ 4 ]   Triticum aestivum , [ 5 ]  and  Rhaponticum acaule . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2199", "text": "Tylvalosin , sold under the brand name  Aivlosin , is a  macrolide antibiotic  used for the treatment of bacterial infections with  Mycoplasma hyopneumoniae  in swine, that causes enzootic pneumonia. [ 3 ] [ 6 ]  It is used as tylvalosin tartrate. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2200", "text": "Macrolides are generally considered to be bacteriostatic agents that exert their antibiotic effect by reversibly binding to the 23S rRNA of the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2201", "text": "Tylvalosin is  indicated  for the control of porcine proliferative enteropathy associated with  Lawsonia intracellularis  infection in groups of swine intended for slaughter and female swine intended for breeding in buildings experiencing an outbreak of PPE. [ 3 ]  Not for use in male swine intended for breeding; and for the control of swine respiratory disease associated with  Bordetella bronchiseptica ,  Glaesserella (Haemophilus) parasuis ,  Pasteurella multocida ,  Streptococcus suis , and  Mycoplasma hyopneumoniae  in groups of swine intended for slaughter and female swine intended for breeding in buildings experiencing an outbreak of swine respiratory disease. [ 3 ]  Not for use in male swine intended for breeding. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2202", "text": "Tyropanoic acid  and its salt  sodium tyropanoate  are  radiocontrast  agents used in  cholecystography  ( X-ray  diagnosis of  gallstones ).  Trade names include Bilopaque, Lumopaque, Tyropaque, and Bilopac. [ 1 ]   This molecule contains three heavy  iodine  atoms which obstruct X-rays in the same way as the calcium in bones to produce a visible image.  After injection it is rapidly excreted into the  bile . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2203", "text": "This article about an  organic halide  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2204", "text": "Ubenimex  ( INN ), also known more commonly as  bestatin , is a competitive, reversible  protease inhibitor . It is an  inhibitor  of  arginyl aminopeptidase  (aminopeptidase B), [ 3 ]   leukotriene A 4  hydrolase  (a  zinc metalloprotease  that displays both  epoxide hydrolase  and  aminopeptidase  activities), [ 4 ]   alanyl aminopeptidase  (aminopeptidase M/N), [ 5 ]   leucyl/cystinyl aminopeptidase  (oxytocinase/vasopressinase), [ 6 ] [ 7 ]  and  membrane dipeptidase  (leukotriene D 4  hydrolase). It is being studied for use in the treatment of  acute myelocytic leukemia [ 8 ]  and  lymphedema . [ 9 ] \nIt is derived from  Streptomyces olivoreticuli . [ 10 ]  Ubenimex has been found to inhibit the enzymatic degradation of  oxytocin ,  vasopressin ,  enkephalins , and various other  peptides  and compounds. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2205", "text": "Ucenprubart  (LY3454738) is a  monoclonal antibody  that acts as an agonist at  CD200R1  and is developed by  Eli Lilly and Company  for atopic dermatitis and other autoimmune diseases. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2206", "text": "Ulixacaltamide  is an  investigational new drug  developed by Praxis Precision Medicines, designed to treat  essential tremor , [ 1 ]  a common neurological disorder characterized by involuntary rhythmic shaking. It functions as a selective inhibitor of  T-type calcium channels , which are implicated in the abnormal neuronal activity associated with tremor. [ 2 ]  The drug is currently undergoing Phase 3 clinical trials. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2207", "text": "Unapproved Drugs Initiative  is a program by the U.S  Food and Drug Administration  announced in June 2006 to remove unapproved drugs from the market. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2208", "text": "As of October 2011 [update]  some 14 categories of drugs have been affected. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2209", "text": "It has been controversial due to the resulting increase in some drug prices."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2210", "text": "In April 2010, in an editorial in the  New England Journal of Medicine  (NEJM), A.S. Kesselheim and D.H. Solomon said that the rewards of this legislation are not calibrated to the quality or value of the information produced, that there is no evidence of meaningful improvement to public health, that it would be much less expensive for the FDA or  National Institutes of Health  to pay for trials themselves on widely available drugs such as colchicine, and that the cost burden falls primarily on patients or their insurers. [ 3 ]  URL Pharma posted a detailed rebuttal of the NEJM editorial. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2211", "text": "In  neuropsychopharmacology ,  uncoupling , also known as  decoupling , is the process of  receptor - or  ligand - binding sites  or domains becoming separated, moving alignments and/or becoming  internalised  as a result of  drug tolerance  resulting from prolonged exposure to  bioavailable   psychoactive substances  or  toxins . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2212", "text": "Unguentine  is an  over-the-counter   topical   antiseptic   ointment  produced by Lee Pharmaceuticals. It was introduced in 1893 as the first antiseptic surgical dressing ointment by  Norwich Pharmaceuticals , who later brought  Pepto Bismol  to market."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2213", "text": "It is used for treating the pain of minor burns, poison ivy, poison oak, itching, minor skin wounds and insect bites. [ 1 ]  Its active ingredients are  camphor  (3%),  phenol  (2.5%),  tannic acid  (2.2%) and  zinc oxide  (6.6%). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2214", "text": "Uniformity of Content  is a  pharmaceutical   analysis  parameter for the quality control of  capsules  or  tablets . Multiple capsules or tablets are selected at random and a suitable analytical method is applied to assay the individual content of the active ingredient in each capsule or tablet."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2215", "text": "The preparation complies if not more than one (all within limits) individual content is outside the limits of 85 to 115% of the average content and none is outside the limits of 75 to 125% of the average content. The preparation fails to comply with the test if more than 3 individual contents are outside the limits of 85 to 115% of the average content or if one or more individual contents are outside the limits of 75% to 125% of the average content. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2216", "text": "Unoprostone  ( INN ) is a  prostaglandin analogue . Its  isopropyl   ester ,  unoprostone isopropyl , was marketed under the trade name  Rescula  for the management of  open-angle glaucoma  and  ocular hypertension . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2217", "text": "It was approved by the  Food and Drug Administration  in 2000. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2218", "text": "In 2009,  Sucampo Pharmaceuticals  acquired the rights to the drug in the U.S. and Canada. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2219", "text": "In 2015, the drug was discontinued in the U.S. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2220", "text": "UrgentRx  is an American  pharmaceutical manufacturer . It is headquartered in  Denver, Colorado  and was founded in 2010 by serial  entrepreneur  and consumer product executive Jordan Eisenberg. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2221", "text": "UrgentRx makes a line of single-dose  OTC  medications that are flavored and powdered. The products can be taken without water and come in single-dose, credit card-sized packets. The company claims the powder acts faster than pills. [ 2 ]  UrgentRx was initially developed as a way for potential  heart attack  victims to carry aspirin with them. The company now makes medications for other ailments such as  headaches ,  aches and pains ,  allergy  attacks,  heartburn , and  upset stomach . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2222", "text": "In July 2013 UrgentRx was named one of \"The 25 Most Innovative Consumer And Retail Brands\" by Forbes, [ 4 ]  and in February 2014 UrgentRx made an appearance on \"The Doctors\" TV show. [ 5 ]  In July 2013 UrgentRx named Michael Valentino to the company's board. Valentino has over 30 years of experience working with both major pharmaceutical companies and venture-backed start-ups. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2223", "text": "In November 2015, UrgentRx was acquired by Synergy CHC Corporation. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2224", "text": "The  USP Controlled Room  Temperature  is a series of  United States Pharmacopeia  guidelines for the storage of pharmaceuticals; [ 1 ]  the relevant omnibus standard is USP 797. [ 2 ] [ 3 ]  Although 100% compliance remains challenging for any given facility, [ 4 ]  the larger protocol may be regarded as constituting a form of  clean room [ 5 ]  which is included in a suite of  best practices ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2225", "text": "Valiltramiprosate   is an  investigational new drug  that is being evaluated to treat early  Alzheimer's disease . [ 1 ]   It is an  amyloid precursor protein  antagonist. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2226", "text": "Valisure  is an American independent laboratory focused on the testing the purity and safety of pharmaceutical drugs and consumer products. [ 1 ]  Valisure was founded in 2015 in  New Haven . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2227", "text": "Valisure was founded in 2015 by Adam Clark-Joseph and David Light. [ 2 ]  After taking an anticonvulsant medication and experiencing negative side effects due to the poor quality of the drug, Clark-Joseph contacted Light about establishing a business testing pharmaceutical products. [ 2 ]  Valisure was originally established as a pharmacy, which, unlike typical pharmacies, tested drugs before distributing them. [ 1 ]  Valisure divested of the pharmacy business in 2021, opting instead to focus on testing. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2228", "text": "In 2019, Valisure reported that it had tested  Zantac  and generic equivalents and discovered that they contained  N -Nitrosodimethylamine , which is thought to be a carcinogen. [ 3 ]  In 2021, Johnson & Johnson recalled sun tan lotions after Valisure discovered they contained high levels of  benzene . [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2229", "text": "In February 2024, Valisure announced  Chip Phillips as their new CEO, succeeding David Light. They also announced funding from   the AlleyCorp  and Connecticut Innovations. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2230", "text": "Clients of Valisure include  Kaiser Permanente  and the  United States Armed Forces . [ 2 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2231", "text": "Vanzacaftor/tezacaftor/deutivacaftor , sold under the brand name  Alyftrek , is a  fixed-dose combination  medication used for the treatment of  cystic fibrosis . [ 1 ]  It is a combination of  deutivacaftor , a  CFTR  potentiator;  tezacaftor ; and  vanzacaftor , as the calcium salt, vanzacaftor calcium dihydrate. [ 1 ]  It is taken  by mouth . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2232", "text": "The combination was approved for medical use in the United States in December 2024. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2233", "text": "The combination is  indicated  for the treatment of  cystic fibrosis  in people aged six years of age and older who have at least one  F508del  mutation or another responsive mutation in the  cystic fibrosis transmembrane conductance regulator  (CFTR) gene. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2234", "text": "The US  Food and Drug Administration  (FDA) prescription label for the combination contains a  boxed warning  about drug-induced liver injury and liver failure. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2235", "text": "The FDA granted the application for vanzacaftor, tezacaftor, and deutivacaftor combination therapy  orphan drug  designation. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2236", "text": "The combination was approved for medical use in the United States in December 2024. [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2237", "text": "It is sold under the brand name Alyftrek. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2238", "text": "VAPCO  Manufacturing CO. Ltd. is a company based in  Amman ,  Jordan , that produces veterinary and agrochemical products.  It was established in 1975. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2239", "text": "This article related to a  manufacturing  company is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2240", "text": "Vaping cessation , usually called \"quitting  vaping \", is the process of stopping using  electronic cigarettes , usually those containing  nicotine . Professional assistance for quitting is similar to that given for stopping smoking, though stopping vaping may have unique challenges; as noted by  Harvard Medical School , \"'vapes' can deliver a much higher dose much faster than traditional cigarettes.\" This can make vapes harder to quit than cigarettes. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2241", "text": "While the strength of addiction may be stronger, the nature of withdrawal symptoms appears similar to that seen with smoking. These symptoms can include depression, irritability, anxiety, and strong, focus-consuming cravings. However, smoking cessation training sometimes emphasizes avoiding environments that can trigger the urge to smoke. Because smoking is successfully prohibited in many public areas, the relatively few areas where it is allowed can remind a former smoker of the tempting behavior. However, vapers report vaping in many of these same places where smoking is prohibited, so such physically identified trigger warnings and avoidance, can be ineffective for people who use these smoke free devices. \n [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2242", "text": "To address the fact that nicotine cravings can happen anywhere, designers of \"serious games\" have created  cessation apps for phones, available for download online.\n [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2243", "text": "In 2024, the CDC started promoting  online cessation programs specifically designed for people addicted to vaping nicotine. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2244", "text": "A  vasoactive  substance is an  endogenous  agent or  pharmaceutical drug  that has the effect of either increasing or decreasing  blood pressure  and/or  heart rate  through its  vasoactivity , that is, vascular activity (effect on  blood vessels ). By adjusting  vascular compliance  and  vascular resistance , typically through  vasodilation  and  vasoconstriction , it helps the body's  homeostatic  mechanisms (such as the  renin\u2013angiotensin system ) to keep  hemodynamics  under control. For example,  angiotensin ,  bradykinin ,  histamine ,  nitric oxide , and  vasoactive intestinal peptide  are important endogenous vasoactive substances. Vasoactive drug therapy is typically used when a patient has the blood pressure and heart rate  monitored  constantly. The  dosage  is typically titrated (adjusted up or down) to achieve a desired effect or  range of values  as determined by competent clinicians."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2245", "text": "Vasoactive drugs are typically administered using a volumetric infusion device (IV pump).  This category of  drugs  require close observation of the patient with near immediate intervention required by the  clinicians  in charge of the patient's care. Important vasoactive substances are  angiotensin -11,  endothelin -1, and alpha- adrenergic agonists ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2246", "text": "Various vasoactive agents, such as  prostanoids ,  phosphodiesterase inhibitors , and endothelin antagonists, are approved for the treatment of  pulmonary arterial hypertension . The use of vasoactive agents for patients with pulmonary hypertension may cause harm and unnecessary expense to persons with  left heart disease  or  hypoxemic  types of  lung diseases . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2247", "text": "The  Verified-Accredited Wholesale Distributors  ( VAWD ) program was established in 2004 to help protect the public from the\nthreat of  counterfeit drugs . [ 1 ]   The VAWD program was developed and is administered by the  National Association of Boards of Pharmacy  (NABP). [ 1 ]   The program offers an accreditation to  wholesale distribution facilities  by offering an objective, third-party audit system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2248", "text": "The criteria to earn VAWD accreditation program includes a compliance review, criteria including: licensure verification, on-site survey and examination, screening through NABP's Clearinghouse, and  criminal background checks  for responsible persons.  The facility must employ security and best practices for safe distribution.  Resurveys of accredited sites will be performed by trained NABP surveyors before accreditation may be renewed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2249", "text": "Verosudil  ( AR-12286 ) is a drug which acts as a potent and selective inhibitor of the  enzyme   Rho kinase , and has been investigated for the treatment of  glaucoma . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2250", "text": "Vesamicol  is an experimental drug, acting  presynaptically  by inhibiting  acetylcholine  (ACh) uptake into synaptic vesicles and reducing its release. [ 1 ]  Vesamicol may have applications for the treatment of  adenocarcinoma in situ of the lung . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2251", "text": "Vesamicol can be broadly categorized as a cholinergic  physiological antagonist , because it reduces the apparent activity of cholinergic  neurons , but does not act at the postsynaptic ACh receptor. Vesamicol causes a non-competitive and reversible block of the intracellular transporter  VAChT  responsible for carrying newly synthesized ACh into secretory vesicles in the presynaptic nerve terminal. This transport process is driven by a proton gradient between cell organelles and the cytoplasm.  Blocking of acetylcholine loading leads to empty vesicles fusing with neuron membranes, decreasing ACh release. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2252", "text": "Vesatolimod  ( GS-9620 ) is an  antiviral  drug developed by  Gilead Sciences , which acts as a potent and selective agonist of  Toll-like receptor 7  (TLR7), a receptor involved in the regulation of the  immune system . It is used to stimulate the immune system, which can increase its ability to combat chronic viral infections. Vesatolimod is in  clinical trials  to determine whether it is safe and effective in patients with  Hepatitis B  and  HIV/AIDS , [ 1 ] [ 2 ]  and has also shown activity against other viral diseases such as  norovirus  and  enterovirus 71 . [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2253", "text": "VGX-1027  ( GIT-27 ) is a drug which acts as an  immunomodulator . It acts by blocking downstream signalling of the  Toll-like receptors   TLR2 ,  TLR4  and  TLR6 , and thereby reducing production of various  cytokines , including  interleukins  and  TNF-\u03b1 . In animal studies it has  antiinflammatory  effects and has been investigated for conditions such as  arthritis  and lung inflammation. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2254", "text": "Vicenistatin  is a macrolactam antibiotic synthesized by  Streptomyces halstedii  HC34. It was originally isolated from this bacterium in 1993. [ 1 ]   It includes the unusual starter unit   methylaspartate . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2255", "text": "Vidofludimus  is an  investigational new drug  that is being evaluated to treat  Crohn's disease  and  ulcerative colitis . [ 1 ]  It is a  dihydroorotate dehydrogenase  inhibitor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2256", "text": "Vilobelimab , sold under the brand name  Gohibic , is an investigational  medication  that is used for the treatment of  COVID-19 . [ 1 ]  It is a human-mouse chimeric  IgG4   kappa  antibody that targets human  C5a  in plasma. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2257", "text": "The most common adverse reactions include pneumonia, sepsis, delirium, pulmonary embolism, hypertension, pneumothorax, deep vein thrombosis, herpes simplex, enterococcal infection, bronchopulmonary aspergillosis, hepatic enzyme increased, urinary tract infection, hypoxia, thrombocytopenia, pneumomediastinum, respiratory tract infection, supraventricular tachycardia, constipation, and rash. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2258", "text": "Vilobelimab is a recombinant chimeric monoclonal IgG4 antibody that specifically binds to the soluble human complement split product C5a after cleavage from C5 to block its interaction with the C5a receptor, both of which are components of the complement system thought to contribute to inflammation and worsening of COVID-19. [ 2 ]  Vilobelimab was granted an  emergency use authorization  (EUA) by the US  Food and Drug Administration  (FDA) in April 2023. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2259", "text": "In the US, vilobelimab is authorized for use in hospitalized adults when initiated within 48 hours of receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (artificial life support). [ 1 ]  Vilobelimab is not approved by the FDA for any indication, including for the treatment of COVID-19. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2260", "text": "The clinical trial supporting the authorization showed that participants treated with vilobelimab had a lower risk of death by day 28 and day 60 of treatment compared to placebo. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2261", "text": "In November 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Gohibic intended for the treatment of adults with SARS\u2011CoV2\u2011induced acute respiratory distress syndrome (ARDS) who are receiving systemic corticosteroids. [ 6 ]  The applicant for this medicinal product is InflaRx GmbH. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2262", "text": "Vilobelimab is the  international nonproprietary name . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2263", "text": "Vimseltinib  is an  investigational new drug  that is being evaluated to treat  tenosynovial giant cell tumor . [ 1 ]  It is a  macrophage colony-stimulating factor receptor  antagonist. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2264", "text": "Vishnevsky liniment  or  balsamic liniment  ( Russian :  \u043c\u0430\u0437\u044c \u0412\u0438\u0448\u043d\u0435\u0432\u0441\u043a\u043e\u0433\u043e ,  Latin :  Linimentum balsamicum Wishnevsky ) is a  topical medication  which has been used to treat  wounds ,  burns ,  skin ulcers  and  suppurations . Developed by  Russian   surgeon   Alexander Vishnevsky  in 1927, the  liniment  contains  birch tar ,  xeroformium  ( bismuth  tribromophenolate) and  castor oil  which have been broadly used as a topical medication in the former  Soviet Union . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2265", "text": "Vishnevsky liniment was broadly used in the  Soviet army  during   World War II . [ 1 ]  It was later shown that a prolonged application of Vishnevsky liniment for chronic skin ulcers, wounds or burns can be associated with higher risk of  skin cancer ,  hematologic  or other malignancy. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2266", "text": "Vitusapotek  is a chain of 300  pharmacies  in Norway owned and run by  Norsk Medisinaldepot , a subsidiary of   McKesson Europe . The pharmacy chain is based in  Oslo , and is the second largest in Norway, after  Apotek1 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2267", "text": "The chain was established in 2001 after the deregulation of the pharmacy market in Norway. The sister company  Ditt Apotek  is a  franchise  chain for independent pharmacies. Until 2007 the chain was a separate company, but is now merged into the parent company along with the wholesaler  NMD Grossisthandel . NMD is one of the largest suppliers of pharmaceuticals and health-related products via pharmacies. NMD currently has a distribution center in Oslo and a branch in  Harstad ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2268", "text": "Vixarelimab  (KPL-716) is a fully human  monoclonal antibody  that works by binding to the  oncostatin M receptor  \u03b2, thus inhibiting both  interleukin 31  and  oncostatin M . It is developed by Kiniksa Pharmaceuticals for  prurigo nodularis . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2269", "text": "Vofopitant  ( GR205171 ) is a drug which acts as an  NK 1  receptor   antagonist . It has  antiemetic  effects as with other NK 1  antagonists, [ 1 ]  and also shows  anxiolytic  actions in animals. [ 2 ]  It was studied for applications such as the treatment of  social phobia  and  post-traumatic stress disorder , but did not prove sufficiently effective to be marketed. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2270", "text": "Volagidemab  (development name REMD-477) is a  monoclonal antibody  that targets the  glucagon receptor . It is developed by REMD Biotherapeutics for type 1 and type 2 diabetes. A phase II trial did not meet its primary endpoint. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2271", "text": "A systematic review and meta-analysis of volagidemab, published in 2024, found it to be potentially beneficial in the treatment of type \u00a0 1 diabetes. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2272", "text": "Volenrelaxin  (LY3540378) is a long-acting, synthetic analogue of  relaxin  developed by  Eli Lilly and Company  to treat  heart failure . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2273", "text": "Voxtalisib  ( XL-765 ,  SAR245409 ) is a drug which acts as a dual  inhibitor  of the  kinase  enzymes  phosphatidylinositol 3-kinase  (PI3K) and  mechanistic target of rapamycin  (mTOR). It is in  clinical trials  for the treatment of various types of  cancer . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2274", "text": "VUF-5681  is a potent and selective  histamine antagonist  which binds selectively to the  H 3  subtype . [ 1 ]  However while VUF-5681 blocks the activity of more potent H 3  agonists, recent studies suggest that it may have some weak  partial agonist  activity when administered by itself. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2275", "text": "VUF-8430  is a  histamine agonist [ 1 ]  selective for the  H 4  subtype. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2276", "text": "Vutiglabridin  ( HSG4112 ) is an experimental anti-obesity drug that is a synthetic structural analog of  glabridin . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2277", "text": "VVD-118313  is a chemical compound which acts as a potent and selective negative  allosteric modulator  of  JAK1 , and was developed for research into the treatment of inflammatory diseases, especially chronic inflammation involved in the development of  cancer . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2278", "text": "WB-4101  is a compound which acts as an  antagonist  at the  \u03b1 1B -adrenergic receptor . It was one of the first selective antagonists developed for this receptor and was invented in 1969, but is still commonly used in research into adrenergic receptors, especially as a  lead compound  from which to develop more selective drugs. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2279", "text": "WEDINOS  (an acronym for  Welsh Emerging Drugs and Identification of Novel Substances ) is a  public health laboratory  in  Cardiff, Wales  devoted to  drug checking  and  epidemiological surveillance  of  recreational drugs  and  prescription drugs  obtained from unsanctioned sources. It is the only fixed-site facility in the  United Kingdom  devoted to this task. [ 1 ] [ 2 ]  It was established in 2013, and is funded by  Public Health Wales . [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2280", "text": "Although based and funded in Wales, WEDINOS analyzes samples sent from anywhere in the United Kingdom. [ 1 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2281", "text": "This  Wales -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2282", "text": "Western Norway Pharmaceutical Trust  ( Norwegian :  Apotekene Vest HF ) is a  health trust  owned by  Western Norway Regional Health Authority  that operates four hospital  pharmacies  at  Haukeland University Hospital  in  Bergen ,  Stavanger Hospital ,  Haugesund Hospital  and  F\u00f8rde Hospital . The pharmacies are part of the  Ditt Apotek  chain and use  Norsk Medisinaldepot  as  wholesaler ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2283", "text": "Harvey A.K. Whitney  (1894-1957) was an American  pharmacist . He was instrumental in the formation and was the first chairman and President of the  American Society of Health-System Pharmacists , [ 1 ]  where he served from 1942 to 1943. He also co-founded The Bulletin of the ASHP in 1943 which later became the  American Journal of Health-System Pharmacy . [ 2 ]  The  Harvey A.K. Whitney Lecture Award , considered to be the highest award in health-system pharmacy, is named after him. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2284", "text": "Whitney was born on November 7, 1894, in  Adrian, Michigan . During high school, he worked part-time at a local drugstore. Whitney graduated high school in 1912 and in the following year, he went to work for the Rupp & Bowman Drug Company after high school. [ 4 ]  During  World War I , he served in the  Army Medical Corps  before being  honorably discharged  and later attended the  College of Pharmacy at the University of Michigan . He graduated in 1923 with his Ph.C. degree. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2285", "text": "Harvey A.K. Whitney passed away in 1957."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2286", "text": "The award was established in 1950 by the Michigan Society of Hospital Pharmacists and is considered one of the highest awards in health-system pharmacy. [ 2 ]  The award is given out annually."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2287", "text": "Wholesale acquisition cost  is the price of a medication set by a pharmaceutical manufacturer in the United States when selling to a wholesaler. [ 1 ]  Generally 20% is added to create the  average wholesale price . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2288", "text": "The  Wushi'er Bingfang  ( Chinese :  \u4e94\u5341\u4e8c\u75c5\u65b9 ;  pinyin :  W\u01d4sh\u00ed\u2019\u00e8r B\u00ecngf\u0101ng ), or  Recipes for Fifty-Two Ailments , is an  ancient Chinese  medical text that was discovered in 1973 in  Mawangdui  in a tomb that was sealed in 168 BCE under the  Han dynasty . [ 4 ]  The text was copied in  seal script  on  sheets of silk  around 215 BCE, under the  Qin dynasty , but might have dated from even earlier. [ 5 ]  Modern editors chose its title because the text starts with a list of fifty-two ailments for which recipes are given. [ 6 ]  The  formulary  presents more than 250  exorcistic  and drug-based cures for ailments such as  warts ,  hemorrhoids ,  inguinal swellings , and  snake bites . [ 7 ]  Among other medical treatments, the text also recommends  lancing  and  cauterization , but mention neither  acupuncture  nor  moxibustion  (cauterization with moxa). [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2289", "text": "With roughly 9,950 characters,  Wushi'er bingfang  is the longest of the medical texts that have been found in ancient Chinese tombs. [ 9 ]  Along with other excavated manuscripts (from  Zhangjiashan  and  Wuwei , among others), it has shed light on the early development of  Chinese medicine . [ 10 ]  It illustrates, for instance, that magical  incantations  were a common therapeutic method among the  social elite of the time . [ 11 ]  And because it shows the development of  channel theory  in a primitive stage and does not mention the doctrine of  Yinyang  and the  Five Phases , it has pushed historians to date the more sophisticated  Huangdi Neijing  ( Yellow Emperor's Inner Canon ) to the first century BCE. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2290", "text": "The original manuscript of  Wushi'er bingfang  is kept at the  Hunan Provincial Museum  in  Changsha . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2291", "text": "WYE-687  is a drug which acts as an  inhibitor  of both subtypes of the  mechanistic target of rapamycin  (mTOR),  mTORC1  and  mTORC2 . It is being researched for potential applications in the treatment of various forms of  cancer . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2292", "text": "Xeligekimab  (GR1501) is a  monoclonal antibody  that neutralizes  interleukin-17A ; [ 1 ]  it is being developed for  plaque psoriasis , [ 2 ]   axial spondyloarthritis , [ 3 ]  and  lupus nephritis . [ 4 ]  It is in a Phase III trial in 2023. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2293", "text": "Xevinapant  is an  investigational new drug  that is being evaluated to treat  squamous cell cancer . [ 1 ]  By acting as a  SMAC mimetic , it functions as an inhibitor of several members of the  IAP  protein family (including  XIAP ,  c-IAP1 , and  c-IAP2 ). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2294", "text": "XF-73 (Exeporfinium chloride)  is an experimental drug candidate. It is an  anti-microbial  that works via weakening bacteria cell walls. [ 1 ]  It is a potential treatment for  methicillin-resistant  Staphylococcus aureus  (MRSA) and possibly  Clostridioides difficile . It is being  developed  by Destiny Pharma Ltd. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2295", "text": "Structurally, it is a dicationic  porphyrin . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2296", "text": "It has completed a phase I clinical trial for nasal decolonisation of MRSA\u2014being tested against 5 bacterial strains. It seems unlikely to cause MRSA to develop resistance to it. [ 1 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2297", "text": "In 2014, a phase 1 clinical trial for nasal administration was run. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2298", "text": "As of June\u00a02022 [update] , another phase 1 clinical trial (for nasal administration) completed recruiting in 2016 but no results have been posted. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2299", "text": "XL-388  is a drug which acts as a potent and selective  inhibitor  of both subtypes of the  mechanistic target of rapamycin  (mTOR),  mTORC1  and  mTORC2 . [ 1 ]  It is being researched for the treatment of various forms of  cancer , [ 2 ] [ 3 ] [ 4 ]  and has also been used to demonstrate a potential application for mTOR inhibitors in the treatment of  neuropathic pain . [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2300", "text": "XL-413  is a drug which acts as a selective inhibitor of the  enzyme   cell division cycle 7-related protein kinase  (CDC7). It is being researched for the treatment of some forms of  cancer , and also has applications in  genetic engineering . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2301", "text": "This  genetics  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2302", "text": "This article about  biological engineering  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2303", "text": "YM-254890  is a  macrolide antibiotic  derived from  Chromobacterium  species. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It is used as a pharmacological research compound which acts as a selective inhibitor of  G q  mediated signalling. [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]  However the claimed selectivity for G q  has been disputed. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2304", "text": "Yoda1  is a chemical compound which is the first  agonist  developed for the  mechanosensitive ion channel   PIEZO1 . This protein is involved in regulation of  blood pressure  and  red blood cell  volume, and Yoda1 is used in scientific research in these areas. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2305", "text": "Z583  ( GLXC-26150 ) is a chemical compound which acts as a potent and highly selective  inhibitor  of  JAK3 , and was developed for the treatment of  rheumatoid arthritis . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2306", "text": "Zandelisib  is an  investigational new drug  that is being evaluated to treat  follicular lymphoma . [ 1 ]  It is a  phosphatidylinositol 3 kinase delta  inhibitor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2307", "text": "Zanidatamab , sold under the brand name  Ziihera , is a  humanized monoclonal antibody  used for the treatment of HER2-positive  biliary tract cancer . [ 1 ] [ 2 ]  It is an IgG-like  bispecific HER2-directed antibody  directed against two non-overlapping domains of HER2. [ 1 ] [ 2 ] [ 3 ]  Zanidatamab is produced in  Chinese hamster ovary cells . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2308", "text": "The most common adverse reactions include  diarrhea ,  infusion-related reaction ,  abdominal pain , and  fatigue . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2309", "text": "Zanidatamab was approved for medical use in the United States in November 2024. [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2310", "text": "Zanidatamab is  indicated  for the treatment of adults with previously treated, unresectable or  metastatic  HER2-positive (IHC 3+)  biliary tract cancer , as detected by an FDA-approved test. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2311", "text": "The US  Food and Drug Administration  prescribing information contains a  boxed warning  for embryo-fetal toxicity. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2312", "text": "The most common adverse reactions include diarrhea, infusion-related reactions, abdominal pain, and fatigue. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2313", "text": "Efficacy was evaluated in HERIZON-BTC-01 (NCT04466891), an open-label multicenter, single-arm trial in 62 participants with unresectable or metastatic HER2-positive (IHC3+)  biliary tract cancer . [ 2 ]  Participants were required to have received at least one prior  gemcitabine -containing regimen in the advanced disease setting. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2314", "text": "The US  Food and Drug Administration  (FDA) granted the application for zanidatamab  priority review ,  breakthrough therapy , and  orphan drug  designations. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2315", "text": "Zanidatamab was approved for medical use in the United States in November 2024. [ 2 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2316", "text": "Zanidatamab is the  international nonproprietary name . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2317", "text": "Zanidatamab is sold under the brand name Ziihera. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2318", "text": "Zapomeran , sold under the brand name  Kostaive  is a self-amplifying  mRNA-based   COVID-19 vaccine . [ 1 ]  It contains a self-amplifying mRNA that encodes the  SARS-CoV-2  spike protein. [ 1 ]  Self-amplifying means that the mRNA also carries instructions to make a protein called  replicase . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2319", "text": "Kostaive was approved for medical use in Japan in November 2023, and it is the first self-amplifying mRNA-based COVID-19 vaccine to be approved. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2320", "text": "Zapomeran is used to provide protection against  COVID-19 , caused by infection with the  SARS-CoV-2  virus. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2321", "text": "Kostaive was approved for medical use in Japan in November 2023. [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2322", "text": "In December 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kostaive, a vaccine intended for the prevention of COVID-19 in adults. [ 1 ]  The applicant for this medicinal product is Arcturus Therapeutics Europe B.V. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2323", "text": "Zapomeran is the  international nonproprietary name . [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2324", "text": "Zaprinast  was an unsuccessful clinical drug candidate that was a precursor to the chemically related  PDE5 inhibitors , such as  sildenafil  (Viagra), which successfully reached the market. It is a  phosphodiesterase inhibitor , [ 1 ]  selective for the subtypes  PDE5 ,  PDE6 ,  PDE9  and  PDE11 .   IC 50  values are 0.76, 0.15, 29.0, and 12.0  \u03bc M, respectively. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2325", "text": "Zaprinast inhibits the growth of asexual blood-stage  malaria  parasites ( P. falciparum )  in vitro  with an  ED 50  value of 35  \u03bc M, and inhibits PfPDE1, a  P. falciparum  cGMP-specific phosphodiesterase, with an IC 50  value of 3.8  \u03bc M. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2326", "text": "Zaprinast has also been shown to activate the orphan  G-protein coupled receptor  known as  GPR35 , both in rats and humans, [ 5 ]  and to inhibit the mitochondrial  pyruvate  carrier.  [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2327", "text": "Zasocitinib  ( TAK-279 ,  NDI-034858 ) is a drug which is an orally active, highly selective  tyrosine kinase 2  (TYK2)  inhibitor . It has been researched for various inflammatory conditions including  psoriatic arthritis  and  Crohn's disease . [ 1 ] [ 2 ] [ 3 ]   It is significantly more selective than earlier compounds over side targets such as  JAK1 , which is hoped to give it an improved side effect profile. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2328", "text": "Zatolmilast  is a  investigational new drug  that is being evaluated to treat  fragile X syndrome . [ 1 ]  It is a  PDE4D  allosteric inhibitor. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2329", "text": "Zeteletinib  ( BOS-172738 ,  DS-5010 ) is an experimental  anticancer medication  which acts as a  RET inhibitor . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2330", "text": "Zicronapine  ( / z a\u026a \u02c8 k r \u0252 n \u0259 p i\u02d0 n /   zye- KRON -\u0259-peen , previously known as  Lu 31-130 ) is an  atypical antipsychotic  medication [ 1 ]  formerly under development by  H. Lundbeck A/S . In  phase II studies  zicronapine showed statistically significant separation from placebo and convincing efficacy and safety data when compared to  olanzapine . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2331", "text": "Zicronapine exhibits monoaminergic activity and has a multi-receptorial profile.  In vitro  and  in vivo  it has shown potent antagonistic effects at dopamine  D 1 ,  D 2  and serotonin  5HT 2A  receptors. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2332", "text": "In 2014 Lundbeck removed zicronapine from its development portfolio in favor of pursuing the more promising antipsychotic  Lu AF35700  (a  prodrug  of  Lu AF356152 ). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2333", "text": "Zimlovisertib  ( PF-06650833 ) is a drug which acts as a selective inhibitor of the enzyme  Interleukin-1 receptor-associated kinase 4  (IRAK-4). It has  antiinflammatory  effects and has been trialed for various indications including  hidradenitis suppurativa  and treatment of  COVID-19  infection, and while it has not been adopted into clinical use it continues to be used for research in this area. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2334", "text": "ZINC17988990  is a drug which acts as a potent and selective inhibitor for the  TRPV5  calcium channel, with an IC 50  of 177 nM and high selectivity for TRPV5 over  TRPV6  and the other subtypes of  TRPV . It is the first selective inhibitor to be developed for TRPV5, and may be useful for modulating calcium reabsorption in the kidneys. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2335", "text": "Zinterol  is a  beta-adrenergic agonist . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2336", "text": "Its structure is based on  soterenol  ( antiarrhythmic ) and phentermine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2337", "text": "Zipalertinib  is an  investigational new drug  that is being evaluated for the treatment of  non-small cell lung cancer  (NSCLC) with  EGFR  mutations, particularly  exon  20 insertion mutations. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2338", "text": "Ziritaxestat  is a small-molecule, selective  autotaxin  inhibitor that was investigated as a potential treatment for  idiopathic pulmonary fibrosis  (IPF). [ 1 ]  Initially showing promise in early-phase studies, ziritaxestat underwent evaluation in two large-scale phase 3 clinical trials, ISABELA 1 and ISABELA 2. [ 1 ] [ 2 ]  These trials aimed to assess the efficacy and safety of ziritaxestat in patients with IPF, including those receiving standard of care treatment with pirfenidone or nintedanib. [ 1 ]  However, both trials were prematurely terminated due to a lack of efficacy, as ziritaxestat failed to demonstrate significant improvement in lung function or other clinical outcomes compared to placebo. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2339", "text": "ZLY18  is an experimental drug that acts as an agonist of the  free fatty acid receptor 1  (FFA1) and all three types of  peroxisome proliferator-activated receptor  ( alpha ,  delta , and  gamma ). It is in development for the treatment of  non-alcoholic fatty liver disease . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2340", "text": "ZM447439  is an  aurora inhibitor . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2341", "text": "Zofenoprilat  is an  angiotensin-converting enzyme inhibitor , and is the free  sulfhydryl   active metabolite  of  zofenopril . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2342", "text": "Zolertine  is an  alpha-1 adrenoceptor antagonist . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2343", "text": "\u03b1-Eucaine  ( alpha -eucaine) is a drug that was previously used as a  local anesthetic . [ 1 ]  It was designed as an  analog  of  cocaine  and was one of the first synthetic chemical compounds to find general use as an anesthetic. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2344", "text": "The  Aldol condensation  between two equivalents of acetone gives  Mesityl oxide  [141-79-7] ( 1 ) ( isophorone  is a side-product of this reaction). Ammonolysis of mesityl oxide formed diacetonamine [625-04-7] ( 2 ). The reaction of this product with acetone then gives 2,2,6,6-tetramethyl-4-piperidone [826-36-8] ( 3 ).  N -methylation of the secondary amine gives 1,2,2,6,6-pentamethylpiperidin-4-one [5554-54-1] ( 4 ). Cyanohydrin formation gives  CID:434556  ( 5 ). Esterification of the tertiary alcohol with benzoyl chloride gives ( 6 ). Pinner reaction of the nitrile with EtOH/H+ affords alpha-eucaine ( 7 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2345", "text": "\u03b13IA , also known as  GTPL4094 , is an inverse agonist of the  GABA A  receptor . It is more selective for the  \u03b13  subunit, hence its name."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2346", "text": "Agonism of the \u03b13 subunit shows anxiolytic properties. However, by being an inverse agonist, \u03b13IA has the opposite action: it shows  anxiogenic  properties. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2347", "text": "This compound also has affinity for the other subunits of the  GABA A  receptor , but it is more selective for the \u03b13 subunit. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2348", "text": "\u0394-3-Tetrahydrocannabinol  (often abbreviated as  delta-3-THC  or  \u0394 3 -THC ) is a synthetic  isomer  of  tetrahydrocannabinol  (THC) developed during the original research in the 1940s to develop synthetic routes to the  natural products   \u0394 8 -THC  and \u0394 9 -THC found in the  cannabis . [ 1 ]  While the normal  trans  configuration of THC is in this case flattened by the double bond, it still has two  enantiomers  as the 9-methyl group can exist in an (R) or (S) conformation. The (S) enantiomer has similar effects to \u0394 9 -THC though with several times lower potency, while the (R) enantiomer is many times less active or inactive, depending on the assay used. [ 2 ] [ 3 ] [ 4 ]  It has been identified as a component of  vaping  liquid products. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2349", "text": "\u0394-7-Tetrahydrocannabinol  ( Delta-5-THC ,  \u0394 5 -THC ; alternatively numbered as  \u0394-5-Tetrahydrocannabinol ,  \u0394 7 -THC ) is a synthetic isomer of  tetrahydrocannabinol . The (6aR,9S,10aR)-\u0394 7 -THC epimer is only slightly less potent than \u0394 9 -THC itself, while the (9R) epimer is much less potent. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2350", "text": "Clinical pharmacology  is \"that discipline that teaches, does research, frames policy, gives information and advice about the actions and proper uses of medicines in humans and implements that knowledge in clinical practice\". [ 1 ] [ 2 ]  Clinical pharmacology is inherently a translational discipline underpinned by the basic science of  pharmacology , engaged in the experimental and observational study of the disposition and effects of drugs in humans, and committed to the translation of science into evidence-based therapeutics. [ 3 ]  It has a broad scope, from the discovery of new target  molecules  to the effects of drug usage in whole  populations . [ 4 ]  The main aim of clinical pharmacology is to generate data for optimum use of drugs and the practice of ' evidence-based medicine '."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2351", "text": "Clinical pharmacologists have  medical  and scientific training that enables them to evaluate  evidence  and produce new data through well-designed  studies .  Clinical pharmacologists must have access to enough patients for  clinical care , teaching and education, and research. Their responsibilities to patients include, but are not limited to, detecting and analysing adverse drug effects and reactions, therapeutics, and toxicology including reproductive toxicology, perioperative drug management, and  psychopharmacology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2352", "text": "Modern clinical pharmacologists are also trained in data analysis skills. Their approaches to analyse data can include modelling and simulation techniques (e.g. population analysis, non-linear mixed-effects modelling)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2353", "text": "Clinical pharmacology consists of multiple branches listed below:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2354", "text": "Medicinal uses of plant and animal resources have been common since prehistoric times. Many countries, such as China, Egypt, and India, have written documentation of many traditional remedies. A few of these remedies are still regarded as helpful today, but most have them have been discarded,  because they  were ineffective and potentially harmful."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2355", "text": "For many years, therapeutic practices were based on Hippocratic  humoral theory , popularized by the Greek physician  Galen  (129 \u2013 c. AD 216) and not on experimentation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2356", "text": "In around the 17th century physicians started to apply use methods to study traditional remedies, although they still lacked methods to test the hypotheses they had about how drugs worked. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2357", "text": "By the late 18th century and early 19th century, methods of experimental physiology and pharmacology began to be developed by scientists such as Fran\u00e7ois Magendie and his student Claude Bernard."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2358", "text": "From the late 18th century to the early 20th century, advances were made in chemistry and physiology that laid the foundations needed to understand how drugs act at the tissue and organ levels.  The advances that were made at this time gave manufacturers the ability to make and sell medicines that they claimed to be effective, but were in many cases worthless. There were no methods for evaluating such claims until rational therapeutic concepts were established in medicine, starting at about the end of the 19th century."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2359", "text": "The development of receptor theory at the start of the 20th century and later developments led to better understanding of how medicines act and the development of many new medicines that are both safe and effective. Expansion of the scientific principles of pharmacology and clinical pharmacology continues today. [ 9 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2360", "text": "\" Addiction Rare in Patients Treated with Narcotics \" is the title of a  letter to the editor  written by Jane Porter and  Hershel Jick  and published in the January 10, 1980, issue of  The New England Journal of Medicine . The letter analyzed data on patients who had been treated with  opioids  in a hospital setting, and concluded that addiction was uncommon among such patients. It has since been frequently misrepresented to claim that opioids are not addictive when prescribed for use at home. This misrepresentation has been blamed for contributing to the  opioid epidemic in the United States ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2361", "text": "The letter reported on an examination of medical files of patients who had been hospitalized and treated with small doses of  opioids . The authors concluded that of the 11,882 patients who received at least one narcotic drug, only four of them had developed a \"reasonably well documented\" addiction among patients who had no history of addiction. Its text read, in its entirety:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2362", "text": "Recently, we examined our current files to determine the incidence of narcotic addiction in 39,946 hospitalized medical patients who were monitored consecutively. Although there were 11,882 patients who received at least one narcotic preparation, there were only four cases of reasonably well documented addiction in patients who had no history of addiction. The addiction was considered major in only one instance. The drugs implicated were meperidine in two patients, Percodan in one, and hydromorphone in one. We conclude that despite widespread use of narcotic drugs in hospitals, the development of addiction is rare in medical patients with no history of addiction. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2363", "text": "The article has been cited extensively as evidence that addiction was very rare among patients who were prescribed narcotics (more specifically, opioids). [ 2 ] [ 3 ]  It became so well known that it is sometimes referred to simply as  Porter and Jick . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2364", "text": "Methodological limitations from which the letter suffered included that the patients it reported on were all given opioids in small doses in a hospital. [ 2 ] [ 3 ]  Additionally, in 2003, Jick told  The New York Times  that the study did not follow patients after they left the hospital. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2365", "text": "In 2017, the letter attracted renewed interest because the  New England Journal of Medicine  published a bibliographic analysis of the letter showing that it had been cited 608 times since it was published. In comparison, the other letters to the editor in the same issue of the  Journal  as Porter and Jick's letter had been cited a median of 11 times. [ 6 ]  Of these 608 citations, the analysis also showed that 72.2% of them cited it in support of the claim that patients treated with opioids rarely developed addiction, and 80.8% did not mention that the letter only included data on prescriptions given to hospitalized patients. [ 7 ]  It was also misrepresented in the popular media; a 1990  Scientific American  article described it as an \"extensive study,\" and a 2001  Time  story dubbed it a \"landmark study\" showing that concerns about opioid addiction were \"basically unwarranted.\" [ 8 ]  In addition,  Purdue Pharma , the manufacturer of  OxyContin , trained its sales representatives to say that the risk of addiction among patients using the drug was less than 1 percent, citing Porter and Jick's letter as one of their sources. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2366", "text": "Because the letter has been frequently misrepresented to argue that opioids were rarely addictive, these misrepresentations have been blamed for contributing to the opioid epidemic. [ 3 ] [ 10 ]  For example, a co-author of the 2017 bibliographic analysis,  David Juurlink , has stated that he thinks the letter's appearance in a prestigious journal helped convince doctors that opioids were safe, saying, \"I think it's fair to say that this letter went quite a long way.\" [ 11 ]  Jick, who wrote the letter, has since said that \"The letter wasn't of value to health and medicine in and of itself. So if I could take it back\u2014if I knew then what I know now, I would never have published it. It wasn't worth it.\" [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2367", "text": "In medicine,  patient compliance  (also  adherence ,  capacitance ) describes the degree to which a patient correctly follows medical advice. Most commonly, it refers to medication or drug compliance, but it can also apply to other situations such as medical device use,  self care , self-directed exercises, or therapy sessions. Both patient and health-care provider affect compliance, and a positive physician-patient relationship is the most important factor in improving compliance. [ 1 ]  Access to care plays a role in patient adherence, whereby greater wait times to access care contributing to greater absenteeism. [ 2 ]  The  cost of prescription medication  also plays a major role. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2368", "text": "Compliance can be confused with  concordance , which is the process by which a patient and clinician make decisions together about treatment. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2369", "text": "Worldwide, non-compliance is a major obstacle to the effective delivery of health care. 2003 estimates from the  World Health Organization  indicated that only about 50% of patients with chronic diseases living in  developed countries  follow treatment recommendations with particularly low rates of adherence to therapies for  asthma ,  diabetes , and  hypertension . [ 1 ]  Major barriers to compliance are thought to include the complexity of modern medication regimens, poor  health literacy  and not understanding treatment benefits, the occurrence of undiscussed side effects, poor treatment satisfaction, cost of prescription medicine, and poor communication or lack of trust between a patient and his or her health-care provider. [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]  Efforts to improve compliance have been aimed at simplifying medication packaging, providing effective medication reminders, improving patient education, and limiting the number of medications prescribed simultaneously. Studies show a great variation in terms of characteristics and effects of interventions to improve medicine adherence. [ 10 ]  It is still unclear how adherence can consistently be improved in order to promote clinically important effects. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2370", "text": "In medicine, compliance (synonymous with adherence, capacitance) describes the degree to which a patient correctly follows medical advice. Most commonly, it refers to medication or drug compliance, but it can also apply to medical device use,  self care , self-directed exercises, or therapy sessions. Both patient and health-care provider affect compliance, and a positive physician-patient relationship is the most important factor in improving compliance. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2371", "text": "As of 2003, US health care professionals more commonly used the term \"adherence\" to a regimen rather than \"compliance\", because it has been thought to reflect better the diverse reasons for patients not following treatment directions in part or in full. [ 6 ] [ 11 ]  Additionally, the term adherence includes the ability of the patient to take medications as prescribed by their physician with regards to the correct drug, dose, route, timing, and frequency. [ 12 ]  It has been noted that compliance may only refer to passively following orders. [ 13 ]  The term  adherence  is often used to imply a collaborative approach to decision-making and treatment between a patient and clinician. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2372", "text": "The term concordance has been used in the  United Kingdom  to involve a patient in the treatment process to improve compliance, and refers to a 2003  NHS  initiative. In this context, the patient is informed about their condition and treatment options, involved in the decision as to which course of action to take, and partially responsible for monitoring and reporting back to the team. [ 15 ]  Informed intentional non-adherence is when the patient, after understanding the risks and benefits, chooses not to take the treatment. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2373", "text": "As of 2005, the preferred terminology remained a matter of debate. [ 17 ]  As of 2007, concordance has been used to refer specifically to patient adherence to a treatment regimen which the physician sets up collaboratively with the patient, to differentiate it from adherence to a physician-only prescribed treatment regimen. [ 18 ] [ 19 ] [ 20 ]  Despite the ongoing debate, adherence has been the preferred term for the  World Health Organization , [ 1 ]  The  American Pharmacists Association , [ 5 ]  and the U.S.  National Institutes of Health  Adherence Research Network. [ 21 ]  The  Medical Subject Headings  of the  United States National Library of Medicine  defines various terms with the words  adherence  and  compliance .  Patient Compliance   and  Medication Adherence  are distinguished under the MeSH tree of  Treatment Adherence and Compliance ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2374", "text": "An estimated half of those for whom treatment regimens are prescribed do not follow them as directed. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2375", "text": "Negative side effects of a medicine can influence adherence. [ 22 ] :\u200a280"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2376", "text": "Cost and poor understanding of the directions for the treatment, referred to as ' health literacy ' have been known to be major barriers to treatment adherence. [ 23 ] [ 6 ] [ 24 ]   There is robust evidence that education and physical health are correlated. Poor educational attainment is a key factor in the cycle of health inequalities. [ 25 ] [ 26 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2377", "text": "Educational qualifications help to determine an individual's position in the labour market, their level of income and therefore their access to resources. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2378", "text": "In 1999 one fifth of UK adults, nearly seven million people, had problems with basic skills, especially  functional literacy  and functional numeracy, described as: \"The ability to read, write and speak in English, and to use mathematics at a level necessary to function at work and in society in general.\" This made it impossible for them to effectively take medication, read labels, follow drug regimes, and find out more. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2379", "text": "In 2003, 20% of adults in the UK had a long-standing illness or disability and a national study for the UK  Department of Health , found more than one-third of people with poor or very poor health had literary skills of Entry Level 3 or below. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2380", "text": "Low levels of literacy and numeracy were found to be associated with socio-economic deprivation. [ 29 ]  Adults in more deprived areas, such as the North East of England, performed at a lower level than those in less deprived areas such as the South East. Local authority tenants and those in poor health were particularly likely to lack basic skills. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2381", "text": "A 2002 analysis of over 100 UK  local education authority  areas found educational attainment at 15\u201316 years of age to be strongly associated with coronary heart disease and subsequent infant mortality. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2382", "text": "A study of the relationship of literacy to asthma knowledge revealed that 31% of asthma patients with a reading level of a ten-year-old knew they needed to see the doctors, even when they were not having an asthma attack, compared to 90% with a high school graduate reading level. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2383", "text": "In 2013 the US National Community Pharmacists Association sampled for one month 1,020 Americans above age 40 for with an ongoing prescription to take medication for a chronic condition and gave a grade C+ on adherence. [ 32 ] [ better\u00a0source\u00a0needed ]  In 2009, this contributed to an estimated cost of $290 billion annually. [ 33 ]  In 2012, increase in patient medication cost share was found to be associated with low adherence to medication. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2384", "text": "The United States is among the countries with the highest  prices of prescription drugs  mainly attributed to the government's lack of negotiating lower prices with monopolies in the pharmaceutical industry especially with brand name drugs. [ 35 ]  In order to manage medication costs, many US patients on long term therapies fail to fill their prescription, skip or reduce doses. According to a Kaiser Family Foundation survey in 2015, about three quarters (73%) of the public think drug prices are unreasonable and blame pharmaceutical companies for setting prices so high. [ 36 ]  In the same report, half of the public reported that they are taking prescription drugs and a \"quarter (25%) of those currently taking prescription medicine report they or a family member have not filled a prescription in the past 12 months due to cost, and 18 percent report cutting pills in half or skipping doses\". [ 36 ]  In a 2009 comparison to Canada, only 8% of adults reported to have skipped their doses or not filling their prescriptions due to the cost of their prescribed medications. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2385", "text": "The elderly often have multiple health conditions, and around half of all  NHS  medicines are prescribed for people over retirement age, despite representing only about 20% of the UK population. [ 38 ] [ 39 ]  The recent  National Service Framework  on the care of older people highlighted the importance of taking and effectively managing medicines in this population. However, elderly individuals may face challenges, including multiple medications with frequent dosing, and potentially decreased dexterity or cognitive functioning. Patient knowledge is a concern that has been observed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2386", "text": "In 1999 Cline et al. identified several gaps in knowledge about medication in elderly patients discharged from hospital. [ 40 ]  Despite receiving written and verbal information, 27% of older people discharged after heart failure were classed as non-adherent within 30 days. Half the patients surveyed could not recall the dose of the medication that they were prescribed and nearly two-thirds did not know what time of day to take them. A 2001 study by Barat et al. evaluated the medical knowledge and factors of adherence in a population of 75-year-olds living at home. They found that 40% of elderly patients do not know the purpose of their regimen and only 20% knew the consequences of non-adherence. [ 41 ]  Comprehension,  polypharmacy , living arrangement, multiple doctors, and use of compliance aids was correlated with adherence."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2387", "text": "In children with asthma, self-management compliance is critical and co-morbidities have been noted to affect outcomes; in 2013 it has been suggested that electronic monitoring may help adherence. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2388", "text": "People of different ethnic backgrounds have unique adherence issues through literacy, physiology, culture or poverty. [ citation needed ]  There are few published studies on adherence in medicine taking in ethnic minority communities. Ethnicity and culture influence some health-determining behaviour, such as participation in screening programmes and attendance at follow-up appointments. [ 43 ] [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2389", "text": "Prieto  et al  emphasised the influence of ethnic and cultural factors on adherence. They pointed out that groups differ in their attitudes, values and beliefs about health and illness. This view could affect adherence, particularly with preventive treatments and medication for asymptomatic conditions. Additionally, some cultures fatalistically attribute their good or poor health to their god(s), and attach less importance to self-care than others. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2390", "text": "Measures of adherence may need to be modified for different ethnic or cultural groups. In some cases, it may be advisable to assess patients from a cultural perspective before making decisions about their individual treatment. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2391", "text": "Recent studies have shown that black patients and those with non-private insurance are more likely to be labeled as non-adherent. [ 46 ]  The increased risk is observed even in patients with a controlled A1c, and after controlling for other socioeconomic factors. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2392", "text": "Not all patients will fill the prescription at a pharmacy. In a 2010 U.S. study, 20\u201330% of prescriptions were never filled at the pharmacy. [ 48 ] [ 49 ]  Reasons people do not fill prescriptions include the cost of the medication, [ 3 ] [ 5 ]  A US nationwide survey of 1,010 adults in 2001 found that 22% chose not to fill prescriptions because of the price, which is similar to the 20\u201330% overall rate of unfilled prescriptions. [ 3 ]  Other factors are doubting the need for medication, or preference for self-care measures other than medication. [ 50 ] [ 51 ]  Convenience, side effects and lack of demonstrated benefit are also factors. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2393", "text": "Prescription medical claims records can be used to estimate medication adherence based on fill rate. Patients can be routinely defined as being 'Adherent Patients' if the amount of medication furnished is at least 80% based on days' supply of medication divided by the number of days patient should be consuming the medication. This percentage is called the medication possession ratio (MPR). 2013 work has suggested that a medication possession ratio of 90% or above may be a better threshold for deeming consumption as 'Adherent'. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2394", "text": "Two forms of MPR can be calculated, fixed and variable. [ 53 ]  Calculating either is relatively straightforward, for Variable MPR (VMPR) it is calculated as the number of days' supply divided by the number of elapsed days including the last prescription."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2395", "text": "V \n M \n P \n R \n = \n \n \n \n All days' supply \n Elapsed days (inclusive of last prescription) \n \n \n \n \n \n {\\displaystyle VMPR={\\dfrac {\\text{All days' supply}}{\\text{Elapsed days (inclusive of last prescription)}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2396", "text": "For the Fixed MPR (FMPR) the calculation is similar but the denominator is the number of days in a year whilst the numerator is constrained to be the number of days' supply within the year that the patient has been prescribed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2397", "text": "F \n M \n P \n R \n = \n \n \n \n \n \n All days' supply \n \n \u2264 \n 365 \n \n 365 \n \n \n \n \n \n {\\displaystyle FMPR={\\dfrac {{\\text{All days' supply}}\\leq 365}{365}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2398", "text": "For medication in tablet form it is relatively straightforward to calculate the number of days' supply based on a prescription. Some medications are less straightforward though because a prescription of a given number of doses may have a variable number of days' supply because the number of doses to be taken per day varies, for example with preventative corticosteroid inhalers prescribed for asthma where the number of inhalations to be taken daily may vary between individuals based on the severity of the disease. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2399", "text": "Contextual factors along with intrapersonal circumstances such as mental states affect decisions. They can accurately predict decisions where most contextual information is identified. [ 54 ]  General compliance with recommendations to follow isolation is influenced beliefs such as taking health precaution to be protected against infection, perceived vulnerability, getting COVID-19 and trust in the government. [ 55 ]  Mobility reduction, compliance with quarantine regulations in European regions where level of trust in policymakers is high can influence whether one complies with isolation rules. [ 56 ]  In addition, perceived infectiousness of COVID-19 is a strong predictor of rule compliance such that the more contagious people think COVID-19 is, the less willing social distancing measures are taken, while the sense of duty and fear of the virus contribute to staying at home. [ 57 ] [ 58 ] [ 59 ]  People might not leave their homes due to trusting regulations to be effective or placing it in a higher power such that individuals who trust others demonstrate more compliance than those who do not. [ 60 ] [ 61 ]  Compliant individuals see protective measures as effective, while non-compliant people see them as problematic. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2400", "text": "Once started, patients seldom follow treatment regimens as directed, and seldom complete the course of treatment. [ 5 ] [ 6 ]  In respect of hypertension, 50% of patients completely drop out of care within a year of diagnosis. [ 63 ]  Persistence with first-line single antihypertensive drugs is extremely low during the first year of treatment. [ 64 ]  As far as lipid-lowering treatment is concerned, only one third of patients are compliant with at least 90% of their treatment. [ 65 ]  Intensification of patient care interventions (e.g. electronic reminders, pharmacist-led interventions, healthcare professional  education  of patients) improves patient adherence rates to lipid-lowering medicines, as well as total cholesterol and LDL-cholesterol levels. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2401", "text": "The World Health Organization (WHO) estimated in 2003 that only 50% of people complete long-term therapy for chronic illnesses as they were prescribed, which puts patient health at risk. [ 67 ]  For example, in 2002  statin  compliance dropped to between 25 and 40% after two years of treatment, with patients taking statins for what they perceive to be preventative reasons being unusually poor compliers. [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2402", "text": "A wide variety of packaging approaches have been proposed to help patients complete prescribed treatments. These approaches include formats that increase the ease of remembering the dosage regimen as well as different labels for increasing patient understanding of directions. [ 69 ] [ 70 ]  For example, medications are sometimes packed with reminder systems for the day and/or time of the week to take the medicine. [ 70 ]  Some evidence shows that reminder packaging may improve clinical outcomes such as blood pressure. [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2403", "text": "A not-for-profit organisation called the Healthcare Compliance Packaging Council of Europe] (HCPC-Europe) was set up [ when? ]  between the pharmaceutical industry, the packaging industry with representatives of European patients organisations. The mission of HCPC-Europe is to assist and to educate the healthcare sector in the improvement of patient compliance through the use of packaging solutions. A variety of packaging solutions have been developed by this collaboration. [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2404", "text": "The World Health Organization (WHO) groups barriers to medication adherence into five categories; health care team and system-related factors, social and economic factors, condition-related factors, therapy-related factors, and patient-related factors. Common barriers include: [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2405", "text": "Health care providers play a great role in improving adherence issues. Providers can improve patient interactions through  motivational interviewing  and active listening. [ 73 ]  Health care providers should work with patients to devise a plan that is meaningful for the patient's needs. A relationship that offers trust, cooperation, and mutual responsibility can greatly improve the connection between provider and patient for a positive impact. [ 13 ]  The wording that health care professionals take when sharing health advice may have an impact on adherence and health behaviours, however, further research is needed to understand if positive framing (e.g., the chance of surviving is improved if you go for screening) versus negative framing (e.g., the chance of dying is higher if you do not go for screening) is more effective for specific conditions. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2406", "text": "In 2012 it was predicted that as telemedicine technology improves, physicians will have better capabilities to remotely monitor patients in real-time and to communicate recommendations and medication adjustments using personal mobile devices, such as smartphones, rather than waiting until the next office visit. [ 75 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2407", "text": "Medication Event Monitoring Systems (MEMS), as in the form of smart medicine bottle tops, smart pharmacy vials or smart blister packages as used in clinical trials and other applications where exact compliance data are required, work without any patient input, and record the time and date the bottle or vial was accessed, or the medication removed from a blister package. The data can be read via proprietary readers, or NFC enabled devices, such as smartphones or tablets. A 2009 study stated that such devices can help improve adherence. [ 76 ]  More recently a 2016 scoping review suggested that in comparison to MEMS, median mediction adherence was grossly overestimated by 17% using self-report, by 8% using pill count and by 6% using rating as alternative methods for measuring medication adherence. [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2408", "text": "The effectiveness of two-way email communication between health care professionals and their patients has not been adequately assessed. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2409", "text": "As of 2019 [update] , 5.15 billion people, which equates to 67% of the global population, have a mobile device and this number is growing. [ 79 ]  Mobile phones have been used in healthcare and has fostered its own term,  mHealth . They have also played a role in improving adherence to medication. [ 80 ]  For example, text messaging has been used to remind patients to take medication in patients with chronic conditions such as  asthma  and  hypertension . [ 81 ]  Other examples include the use of smartphones for synchronous and asynchronous Video Observed Therapy (VOT) as a replacement for the currently resource intensive [ 82 ]  standard of  Directly Observed Therapy  (DOT) (recommended by the WHO [ 83 ] ) for Tuberculosis management. [ 84 ]  Other mHealth interventions for improving adherence to medication include smartphone applications, [ 85 ]  voice recognition in interactive phone calls [ 86 ]  and  Telepharmacy . [ 87 ]  Some results show that the use of mHealth improves adherence to medication and is cost-effective, [ 87 ]  though some reviews report mixed results. [ 88 ]  Studies show that using mHealth to improve adherence to medication is feasible and accepted by patients. [ 88 ] [ 87 ]  Specific mobile applications might also support adherence. [ 89 ] [ 90 ]  mHealth interventions have also been used alongside other  telehealth  interventions such as wearable wireless pill sensors, [ 91 ]  smart pillboxes [ 91 ]  and smart inhalers [ 92 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2410", "text": "Depot injections  need to be taken less regularly than other forms of medication and a medical professional is involved in the administration of drugs so can increase compliance. Depot's are used for  oral contraceptive pill [ 93 ]  and  antipsychotic  medication used to treat  schizophrenia [ 94 ]  and  bipolar disorder . [ 95 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2411", "text": "Sometimes drugs are given  involuntarily  to ensure compliance. This can occur if an individual has been  involuntarily committed [ 96 ]  or are subjected to an  outpatient commitment  order, where failure to take medication will result in detention and involuntary administration of treatment. [ 97 ] :\u200a16\u200a  This can also occur if a patient is not deemed to have  mental capacity  to consent to treatment in an  informed  way. [ 98 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2412", "text": "A  WHO  study estimates that only 50% of patients with chronic diseases in developed countries follow treatment recommendations. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2413", "text": "Asthma non-compliance (28\u201370% worldwide) increases the risk of severe asthma attacks requiring preventable ER visits and hospitalisations; compliance issues with asthma can be caused by a variety of reasons including: difficult inhaler use, side effects of medications, and cost of the treatment. [ 99 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2414", "text": "200,000 new cases of cancer are diagnosed each year in the UK. One in three adults in the UK will develop cancer that can be life-threatening, and 120,000 people will be killed by their cancer each year. This accounts for 25% of all deaths in the UK. However while 90% of cancer pain can be effectively treated, only 40% of patients adhere to their medicines due to poor understanding. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2415", "text": "Results of a recent (2016) systematic review found a large proportion of patients struggle to take their oral antineoplastic medications as prescribed. This presents opportunities and challenges for patient education, reviewing and documenting treatment plans, and patient monitoring, especially with the increase in patient cancer treatments at home. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2416", "text": "The reasons for non-adherence have been given by patients as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2417", "text": "Partridge  et al  (2002) identified evidence to show that adherence rates in cancer treatment are variable, and sometimes surprisingly poor. The following table is a summary of their findings: [ 100 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2418", "text": "In 1998, trials evaluating  Tamoxifen  as a preventative agent have shown dropout rates of around one-third:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2419", "text": "In March 1999, the \"Adherence in the International Breast Cancer Intervention Study\" evaluating the effect of a daily dose of Tamoxifen for five years in at-risk women aged 35\u201370 years was [ 103 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2420", "text": "Patients with diabetes are at high risk of developing coronary heart disease and usually have related conditions that make their treatment regimens even more complex, such as hypertension, obesity and depression [ 104 ]  which are also characterised by poor rates of adherence. [ 105 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2421", "text": "Other aspects that drive medicine adherence rates is the idea of perceived  self-efficacy  and risk assessment in managing diabetes symptoms and decision making surrounding rigorous medication regiments. Perceived control and self-efficacy not only significantly correlate with each other, but also with diabetes distress psychological symptoms and have been directly related to better medication adherence outcomes. [ 107 ]  Various external factors also impact diabetic patients' self-management behaviors including health-related knowledge/beliefs, problem-solving skills, and self-regulatory skills, which all impact perceived control over diabetic symptoms. [ 108 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2422", "text": "Additionally, it is crucial to understand the decision-making processes that drive diabetics in their choices surrounding risks of not adhering to their medication. While patient decision aids (PtDAs), sets of tools used to help individuals engage with their clinicians in making decisions about their healthcare options, have been useful in decreasing decisional conflict, improving transfer of diabetes treatment knowledge, and achieving greater risk perception for disease complications, their efficacy in medication adherence has been less substantial. [ 109 ]  Therefore, the risk perception and decision-making processes surrounding diabetes medication adherence are multi-faceted and complex with socioeconomic implications as well. For example, immigrant health disparities in diabetic outcomes have been associated with a lower risk perception amongst foreign-born adults in the United States compared to their native-born counterparts, which leads to fewer protective lifestyle and treatment changes crucial for combatting diabetes. [ 110 ]  Additionally, variations in patients' perceptions of time (i.e. taking rigorous, costly medication in the present for abstract beneficial future outcomes can conflict with patients' preferences for immediate versus delayed gratification) may also present severe consequences for adherence as diabetes medication often requires systematic, routine administration. [ 111 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2423", "text": "As a result of poor compliance, [ citation needed ]  75% of patients with a diagnosis of hypertension do not achieve optimum blood-pressure control. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2424", "text": "A 2003 review found that 41\u201359% of patients prescribed antipsychotics took the medication prescribed to them infrequently or not at all. [ 113 ]  Sometimes non-adherence is due to  lack of insight , [ 114 ]  but psychotic disorders can be episodic and antipsychotics are then use prophylactically to reduce the likelihood of relapse rather than treat symptoms and in some cases individuals will have no further episodes despite not using antipsychotics. [ 115 ]   A 2006 review investigated the effects of compliance therapy for schizophrenia: and found no clear evidence to suggest that compliance therapy was beneficial for people with schizophrenia and related syndromes. [ 116 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2425", "text": "A longitudinal study has shown that adherence with treatment about 60%. [ 117 ]  The predictors of adherence were found to be more of psychological, communication and logistic nature rather than sociodemographic or clinical factors. The following factors were identified as independent predictors of adherence:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2426", "text": "An  adverse drug reaction  ( ADR ) is a harmful, unintended result caused by taking  medication . [ 1 ] :\u200a1.1 Adverse Drug Reaction (ADR)\u200a [ 2 ]  ADRs may occur following a single dose or prolonged administration of a  drug  or may result from the combination of two or more drugs. The meaning of this term differs from the term \" side effect \" because side effects can be beneficial as well as detrimental. [ 3 ]  The study of ADRs is the concern of the field known as  pharmacovigilance . [ 3 ]  An  adverse event  (AE) refers to any unexpected and inappropriate occurrence at the time a drug is used, whether or not the event is associated with the administration of the drug. [ 1 ] :\u200a1.2 Adverse Event (AE)\u200a  An ADR is a special type of AE in which a causative relationship can be shown. [ 3 ]  ADRs are only one type of medication-related harm. Another type of medication-related harm type includes not taking prescribed medications, known as  non-adherence . [ 4 ]  Non-adherence to medications can lead to death and other negative outcomes. [ 4 ]  Adverse drug reactions require the use of a  medication . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2427", "text": "Types A and B were proposed in the 1970s, [ 8 ]  and the other types were proposed subsequently when the first two proved insufficient to classify ADRs. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2428", "text": "Other types of adverse drug reactions are Type C, Type D, Type E, and Type F. [ 10 ]  Type C was categorized for chronic adverse drug reactions, Type D  for delayed adverse drug reactions, Type E for withdrawal adverse drug reactions, and Type F for failure of therapy as an adverse drug reaction. Adverse drug reactions can also be categorized using time-relatedness, dose-relatedness, and susceptibility, which collectively are called the DoTS classification. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2429", "text": "The U.S  Food and Drug Administration  defines a serious  adverse event  as one when the patient outcome is one of the following: [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2430", "text": "Severity is a measure of the intensity of the adverse event in question. [ 12 ]  The terms \"severe\" and \"serious\", when applied to adverse events, are technically very different. [ 12 ]  They are easily confused but can not be used interchangeably, requiring care in usage. [ 12 ]  Seriousness usually indicates patient outcome (such as negative outcomes including disability, long-term effects, and death). [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2431", "text": "In adverse drug reactions, the seriousness of the reaction is important for reporting. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2432", "text": "Some  ocular antihypertensives  cause systemic effects, [ 13 ]  although they are administered locally as  eye drops , since a fraction escapes to the systemic circulation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2433", "text": "Various diseases, especially those that cause  renal  or  hepatic  insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2434", "text": "The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia [ 15 ]  ( MATCH-D ) criteria warns that people with  dementia  are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2435", "text": "Pharmacogenomics  includes how genes can predict potential adverse drug reactions. [ 17 ]  However, pharmacogenomics is not limited to adverse events (of any type), but also looks at how genes may impact other responses to medications, such as low/no effect or expected/normal responses (especially based on drug metabolism). [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2436", "text": "Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation. [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2437", "text": "Phase I reactions include metabolism by cytochrome P450. [ 20 ]  Patients have abnormal metabolism by  cytochrome P450  due to either inheriting abnormal  alleles  or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions. [ 21 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2438", "text": "Inheriting abnormal  butyrylcholinesterase  ( pseudocholinesterase ) may affect metabolism of drugs such as  succinylcholine . [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2439", "text": "Inheriting abnormal  N -acetyltransferase  which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as  isoniazid ,  hydralazine , and  procainamide . [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2440", "text": "Inheriting abnormal  thiopurine  S -methyltransferase  may affect the metabolism of the  thiopurine  drugs  mercaptopurine  and  azathioprine . [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2441", "text": "Protein binding interactions are usually transient and mild until a new steady state is achieved. [ 24 ] [ 25 ]  These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are: [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2442", "text": "Some drug interactions with  warfarin  are due to changes in protein binding. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2443", "text": "The risk of  drug interactions  is increased with  polypharmacy , especially in older adults. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2444", "text": "Two or more drugs that contribute to the same mechanism in the body can have additive  toxic  or adverse effects. One example of this is multiple medications administered concurrently that prolong the  QT interval , such as  antiarrhythmics  like  sotalol  and some  macrolide antibiotics , such as systemic  azithromycin . [ 28 ]  Another example of additive effects for adverse drug reactions is in  serotonin toxicity  ( serotonin syndrome ). [ 29 ]  If medications that cause increased  serotonin  levels are combined, they can cause  serotonin toxicity  (though therapeutic doses of one agent that increases  serotonin  levels can cause  serotonin toxicity  in certain cases and individuals). [ 29 ]  Some of the medications that can contribute to  serotonin toxicity  include  MAO inhibitors ,  SSRIs , and  tricyclic antidepressants . [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2445", "text": "Some medications can either  inhibit  or  induce  key  drug metabolizing   enzymes  or  drug transporters , which when combined with other medications that utilize the same proteins can lead to either toxic or sub-therapeutic adverse effects. One example of this is a patient taking a  cytochrome P450 3A4  (CYP3A4) inhibitor such as the  antibiotic   clarithromycin , as well as another medication metabolized by CYP3A4 such as the  anticoagulant   apixaban , which results in elevated blood concentrations of apixaban and greater risk of serious bleeds. [ 30 ]  Additionally, Clarithromycin is a  permeability glycoprotein  (P-gp) efflux pump inhibitor, which when given with apixaban (a substrate for P-gp) will lead to increased absorption of apixaban, resulting in the same adverse effects as with CYP3A4 inhibition. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2446", "text": "Causality  assessment is used to determine the likelihood that a drug caused a suspected ADR. [ 3 ]  There are a number of different methods used to judge causation, including the  Naranjo algorithm , the Venulet algorithm and the WHO causality term assessment criteria. Each have pros and cons associated with their use and most require some level of expert judgement to apply. [ 31 ] \nAn ADR should not be labeled as 'certain' unless the ADR abates with a  challenge-dechallenge-rechallenge  protocol (stopping and starting the agent in question). [ 3 ]  The  chronology  of the onset of the suspected ADR is important, as another substance or factor may be implicated as a cause; co-prescribed medications and underlying  psychiatric conditions  may be factors in the ADR. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2447", "text": "Assigning  causality  to a specific agent often proves difficult, unless the event is found during a clinical study or large databases are used. Both methods have difficulties and can be fraught with error. Even in clinical studies, some ADRs may be missed as large numbers of test individuals are required to find a specific adverse drug reaction, especially for rare ADRs. Psychiatric ADRs are often missed as they are grouped together in the questionnaires used to assess the population. [ 32 ] [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2448", "text": "Many countries have official bodies that monitor drug safety and reactions. On an international level, the  WHO  runs the  Uppsala Monitoring Centre . [ 34 ]  The  European Union  runs the  European Medicines Agency  (EMA). [ 35 ]  In the  United States , the  Food and Drug Administration  (FDA) is responsible for monitoring post-marketing studies. [ 36 ]  The FDA has a reporting system called the  FDA Adverse Event Reporting System , where individuals can report adverse drug events. [ 36 ]  Healthcare professionals, consumers, and the pharmaceutical industry can all submit information to this system. [ 36 ]  For health products marketed in  Canada , a branch of  Health Canada  called The Canada Vigilance Program is responsible for surveillance. [ 37 ]  Both healthcare professionals and consumers can report to this program. [ 37 ]  In  Australia , the  Therapeutic Goods Administration  (TGA) conducts postmarket monitoring of therapeutic products. [ 38 ]  In the UK, a monitoring system called the  Yellow Card Scheme  was established in 1964. [ 39 ]  The  Yellow Card Scheme  was set up to surveil medications and other health products. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2449", "text": "A study by the  Agency for Healthcare Research and Quality  (AHRQ) found that in 2011,  sedatives  and  hypnotics  were a leading source for adverse drug events seen in the  hospital  setting.  Approximately 2.8% of all ADEs present on admission and 4.4% of ADEs that originated during a hospital stay were caused by a sedative or hypnotic drug. [ 41 ]   A second study by AHRQ found that in 2011, the most common specifically identified causes of adverse drug events that originated during hospital stays in the U.S. were  steroids ,  antibiotics , opiates/narcotics, and  anticoagulants . Patients treated in urban teaching hospitals had higher rates of ADEs involving  antibiotics  and opiates/narcotics compared to those treated in urban nonteaching hospitals.  Those treated in private, nonprofit hospitals had higher rates of most ADE causes compared to patients treated in public or private, for-profit hospitals. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2450", "text": "Medication related harm (MRH) is common after hospital discharge in older adults, but methodological inconsistencies between studies and a paucity of data on risk factors limits clear understanding of the epidemiology. There was a wide range in incidence, from 0.4% to 51.2% of participants, and 35% to 59% of harm was preventable. Medication related harm incidence within 30 days after discharge ranged from 167 to 500 events per 1,000 individuals discharged (17\u201351% of individuals). [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2451", "text": "In the U.S., females had a higher rate of ADEs involving  opiates  and  narcotics  than males in 2011, while male patients had a higher rate of  anticoagulant  ADEs.  Nearly 8 in 1,000 adults aged 65 years or older experienced one of the four most common ADEs (steroids, antibiotics, opiates/narcotics, and anticoagulants) during hospitalization. [ 42 ]  A study showed that 48% of patients had an adverse drug reaction to at least one drug, and pharmacist involvement helps to pick up adverse drug reactions. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2452", "text": "In 2012,  McKinsey & Company  concluded that the cost of the 50-100 million preventable error-related adverse drug events would be between US$18\u2013115 billion. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2453", "text": "An article published in  The Journal of the American Medical Association  (JAMA) in 2016 reported adverse drug event statistics from  emergency departments  around the  United States  in 2013-2014. [ 46 ]  From this article, an estimated prevalence of adverse drug events that were presented to the emergency department (ED) was 4 events out of every 1000 people. [ 46 ]  This article reported that 57.1% of these adverse drug events presented to the ED were in females. [ 46 ]  As well, out of all of the adverse drug events presented to the emergency department documented in this article, 17.6% were from  anticoagulants , 16.1% were from  antibiotics , and 13.3% from  diabetic  agents. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2454", "text": "An  adverse effect  is an undesired harmful effect resulting from a  medication  or other  intervention , such as  surgery . [ 1 ]  An adverse effect may be termed a \" side effect \", when judged to be secondary to a main or  therapeutic effect . The term  complication  is similar to adverse effect, but the latter is typically used in pharmacological contexts, or when the negative effect is expected or common. If the negative effect results from an unsuitable or incorrect  dosage  or procedure, this is called a  medical error  and not an adverse effect. Adverse effects are sometimes referred to as \" iatrogenic \" because they are generated by a  physician /treatment. Some adverse effects occur only when starting, increasing or discontinuing a treatment. \nUsing a drug or other medical intervention which is  contraindicated  may increase the  risk  of adverse effects. Adverse effects may cause complications of a  disease  or procedure and negatively affect its  prognosis . They may also lead to  non-compliance  with a treatment regimen. Adverse effects of medical treatment resulted in 142,000 deaths in 2013 up from 94,000 deaths in 1990 globally. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2455", "text": "The harmful outcome is usually indicated by some result such as  morbidity ,  mortality , alteration in  body weight , levels of  enzymes , loss of function, or as a  pathological  change detected at the microscopic, macroscopic or physiological level. It may also be indicated by  symptoms  reported by a patient. Adverse effects may cause a reversible or irreversible change, including an increase or decrease in the susceptibility of the individual to other chemicals,  foods , or procedures, such as  drug interactions ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2456", "text": "In terms of drugs, adverse events may be defined as: \"Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.\" [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2457", "text": "In  clinical trials , a distinction\nis made between an  adverse event  and a  serious adverse event . Generally, any event which causes death, permanent damage,  birth defects , or requires  hospitalization  is considered a serious adverse event. [ 4 ]  The results of trials are often included in the labelling of the medication to provide information both for patients and the prescribing physicians."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2458", "text": "The term \"life-threatening\" in the context of a serious adverse event refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2459", "text": "In many countries, adverse effects are required by law to be reported, researched in  clinical trials  and included into the patient information accompanying  medical devices  and  drugs  for sale to the public. Investigators in human clinical trials are obligated to report these events in  clinical study reports . [ 5 ]  Research suggests that these events are often inadequately reported in publicly available reports. [ 6 ]  Because of the lack of these data and uncertainty about methods for synthesising them, individuals conducting  systematic reviews  and meta-analyses of therapeutic interventions often unknowingly overemphasise health benefit. [ 7 ]  To balance the overemphasis on benefit, scholars have called for more complete reporting of harm from clinical trials. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2460", "text": "The  Yellow Card Scheme  is a  United Kingdom  initiative run by the  Medicines and Healthcare products Regulatory Agency (MHRA)  and the  Commission on Human Medicines (CHM)  to gather information on adverse effects to  medicines . This includes all licensed medicines, from medicines issued on  prescription  to medicines bought  over the counter  from a supermarket. The scheme also includes all  herbal supplements  and unlicensed medicines found in cosmetic treatments. Adverse drug reactions (ADRs) can be reported by a number of health care professionals including  physicians ,  pharmacists  and  nurses , as well as  patients ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2461", "text": "In the  United States  several reporting systems have been built, such as the  Vaccine Adverse Event Reporting System  (VAERS), the Manufacturer and User Facility Device Experience Database (MAUDE) and the Special Nutritionals Adverse Event Monitoring System.  MedWatch  is the main reporting center, operated by the  Food and Drug Administration ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2462", "text": "In  Australia , adverse effect reporting is administered by the  Adverse Drug Reactions Advisory Committee  (ADRAC), a subcommittee of the  Australian Drug Evaluation Committee  (ADEC). Reporting is voluntary, and ADRAC requests healthcare professionals to report all adverse reactions to its current drugs of interest, and serious adverse reactions to any drug. ADRAC publishes the Australian Adverse Drug Reactions Bulletin every two months. The Government's  Quality Use of Medicines  program is tasked with acting on this reporting to reduce and minimize the number of preventable adverse effects each year."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2463", "text": "Adverse reaction reporting is an important component of New Zealand's  pharmacovigilance  activities. The  Centre for Adverse Reactions Monitoring (CARM)  in Dunedin is New Zealand's national monitoring centre for adverse reactions. It collects and evaluates spontaneous reports of adverse reactions to medicines, vaccines, herbal products and dietary supplements from health professionals in New Zealand. Currently the CARM database holds over 80,000 reports and provides New Zealand-specific information on adverse reactions to these products, and serves to support clinical decision making when unusual symptoms are thought to be therapy related"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2464", "text": "In Canada, adverse reaction reporting is an important component of the surveillance of marketed health products conducted by the Health Products and Food Branch (HPFB) of Health Canada. Within HPFB, the Marketed Health Products Directorate leads the coordination and implementation of consistent monitoring practices with regards to assessment of signals and safety trends, and risk communications concerning regulated marketed health products."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2465", "text": "MHPD also works closely with international organizations to facilitate the sharing of information.  Adverse reaction reporting is mandatory for the industry and voluntary for consumers and health professionals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2466", "text": "In principle, medical professionals are required to report all adverse effects related to a specific form of therapy. In practice, it is at the discretion of the professional to determine whether a medical event is at all related to the therapy. As a result, routine adverse effects reporting often may not include long-term and subtle effects that may ultimately be attributed to a therapy. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2467", "text": "Part of the difficulty is identifying the source of a complaint. A headache in a patient taking medication for  influenza  may be caused by the underlying disease or may be an adverse effect of the treatment. In patients with end-stage  cancer , death is a very likely outcome and whether the drug is the cause or a bystander is often difficult to discern. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2468", "text": "Surgery  may have a number of undesirable or harmful effects, such as  infection ,  hemorrhage ,  inflammation ,  scarring , loss of function, or changes in local  blood flow . They can be reversible or irreversible, and a compromise must be found by the physician and the patient between the beneficial or life-saving consequences of surgery versus its adverse effects. For example, a limb may be lost to  amputation  in case of untreatable  gangrene , but the patient's life is saved. Presently, one of the greatest advantages of  minimally invasive  surgery, such as  laparoscopic surgery , is the reduction of adverse effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2469", "text": "Other nonsurgical physical procedures, such as high-intensity  radiation therapy , may cause  burns  and alterations in the  skin . In general, these therapies try to avoid damage to healthy  tissues  while maximizing the therapeutic effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2470", "text": "Vaccination  may have adverse effects due to the nature of its biological preparation, sometimes using  attenuated   pathogens  and  toxins . Common adverse effects may be  fever ,  malaise  and local reactions in the vaccination site. Very rarely, there is a serious adverse effect, such as  eczema vaccinatum , a severe, sometimes fatal complication which may result in persons who have  eczema  or atopic  dermatitis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2471", "text": "Diagnostic  procedures may also have adverse effects, depending much on whether they are  invasive ,  minimally invasive  or  noninvasive . For example,  allergic  reactions to  radiocontrast  materials often occur, and a  colonoscopy  may cause the perforation of the  intestinal  wall."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2472", "text": "Adverse effects can occur as a collateral or side effect of many interventions, but they are particularly important in  pharmacology , due to its wider, and sometimes uncontrollable, use by way of  self-medication . Thus,  responsible drug use  becomes an important issue here. Adverse effects, like  therapeutic effects  of drugs, are a function of  dosage  or drug levels at the target  organs , so they may be avoided or decreased by means of careful and precise  pharmacokinetics , the change of drug levels in the organism in function of time after administration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2473", "text": "Adverse effects may also be caused by  drug interaction . This often occurs when patients fail to inform their physician and pharmacist of all the medications they are taking, including herbal and dietary supplements. The new medication may interact agonistically or antagonistically (potentiate or decrease the intended therapeutic effect), causing significant  morbidity  and mortality around the world. Drug-drug and food-drug interactions may occur, and so-called \"natural drugs\" used in  alternative medicine  can have dangerous adverse effects. For example, extracts of  St John's wort  ( Hypericum perforatum ), a  phytotherapic  used for treating mild  depression  are known to cause an increase in the  cytochrome P450   enzymes  responsible for the  metabolism  and elimination of many drugs, so patients taking it are likely to experience a reduction in  blood  levels of drugs they are taking for other purposes, such as  cancer   chemotherapeutic  drugs,  protease inhibitors  for  HIV  and  hormonal contraceptives ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2474", "text": "The scientific field of activity associated with drug safety is increasingly government-regulated, and is of major concern for the public, as well as to  drug manufacturers . The distinction between adverse and nonadverse effects is a major undertaking when a new drug is developed and tested before  marketing  it. This is done in  toxicity  studies to determine the nonadverse effect level (NOAEL). These studies are used to define the dosage to be used in human testing (phase I), as well as to calculate the maximum admissible daily intake. Imperfections in clinical trials, such as insufficient number of patients or short duration, sometimes lead to  public health  disasters, such as those of  fenfluramine  (the so-called  fen-phen  episode),  thalidomide  and, more recently, of  cerivastatin  (Baycol, Lipobay) and  rofecoxib  (Vioxx), where drastic adverse effects were observed, such as  teratogenesis ,  pulmonary hypertension ,  stroke ,  heart disease ,  neuropathy , and a significant number of deaths, causing the forced or voluntary  withdrawal  of the drug from the market."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2475", "text": "Most drugs have a large list of nonsevere or mild adverse effects which do not rule out continued usage. These effects, which have a widely variable incidence according to individual sensitivity, include  nausea ,  dizziness ,  diarrhea ,  malaise ,  vomiting ,  headache ,  dermatitis , dry mouth, etc. These can be considered a form of pseudo-allergic reaction, as not all users experience these effects; many users experience none at all."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2476", "text": "The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia [ 10 ]  ( MATCH-D ) warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2477", "text": "Sometimes, putative medical adverse effects are regarded as controversial and generate heated discussions in society and  lawsuits  against drug manufacturers. One example is the recent controversy as to whether  autism  was linked to the  MMR vaccine  (or to  thiomersal , a  mercury -based preservative used in some  vaccines ). No link has been found in several large studies, and despite removal of thimerosal from most early childhood vaccines beginning with those manufactured in 2003, the rate of autism has not decreased as would be expected if it had been the causative agent. [ 40 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2478", "text": "Another instance is the potential adverse effects of  silicone   breast implants , which led to class actions brought by tens of thousands of plaintiffs against manufacturers of gel-based implants, due to allegations of damage to the  immune system  which have not yet been conclusively proven. [ 42 ]  In 1998, Dow Corning settled its remaining suits for $3.2 Billion and went into bankruptcy. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2479", "text": "Due to the exceedingly high impact on public health of widely used medications, such as  hormonal contraception  and  hormone replacement therapy , which may affect millions of users, even marginal probabilities of adverse effects of a severe nature, such as  breast cancer , have led to public outcry and changes in medical therapy, although its benefits largely surpassed the statistical risks."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2480", "text": "The  antimicrobial spectrum  of an  antibiotic  means the range of  microorganisms  it can kill or inhibit. Antibiotics can be divided into  broad-spectrum antibiotics , extended-spectrum antibiotics and  narrow-spectrum antibiotics  based on their spectrum of activity. Detailedly, broad-spectrum antibiotics can kill or inhibit a wide range of microorganisms; extended-spectrum antibiotic can kill or inhibit  Gram positive bacteria  and some  Gram negative bacteria ; narrow-spectrum antibiotic can only kill or inhibit limited species of bacteria. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2481", "text": "Currently no antibiotic's spectrum can completely cover all types of microorganisms. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2482", "text": "The antimicrobial spectrum of an antibiotic can be determined by testing its antimicrobial activity against a wide range of microbes  in vitro   . Nonetheless, the range of microorganisms which an antibiotic can kill or inhibit  in vivo  may not always be the same as the antimicrobial spectrum based on data collected in vitro. [ 2 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2483", "text": "Narrow-spectrum antibiotics  have low propensity to induce  bacterial resistance  and are less likely to disrupt the  microbiome  (normal  microflora ). [ 3 ]   On the other hand, indiscriminate use of  broad-spectrum antibiotics  may not only induce the development of bacterial resistance and promote the emergency of  multidrug-resistant  organisms, but also cause off-target effects due to  dysbiosis . [ 3 ] [ 6 ]  They may also have side effects, such as diarrhea or rash. [ 7 ]  Generally, a broad antibiotic has more clinical indications, and therefore are more widely used. [ 2 ] [ 8 ]   The Healthcare Infection Control Practices Advisory Committee (HICPAC) recommends the use of narrow-spectrum antibiotics whenever possible. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2484", "text": "Augmentation , in the context of the pharmacological management of  psychiatry , refers to the combination of two or more  drugs  to achieve better treatment results. Examples include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2485", "text": "In  pharmacology , the term is occasionally used to describe treatments that increase (augment) the concentration of some substance in the body. This might be done when someone is deficient in a hormone, enzyme, or other endogenous substance. For example:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2486", "text": "The  Cancer Trials Support Unit   (CTSU)  is a service of the  National Cancer Institute  (NCI)  in the United States."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2487", "text": "The CTSU facilitates access to NCI-funded  clinical trials  for qualified clinical sites and supports the management and conduct of those clinical trials."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2488", "text": "The NCI launched the CTSU in 1999 to streamline and harmonize support services for Phase III Cooperative Group cancer clinical trials funded by the NCI."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2489", "text": "CTSU now supports multiple NCI-funded networks and clinical trials of all phases and types.  These include  cancer treatment , prevention and control,  advanced imaging  and correlative science studies.  The CTSU collaborates with the NCI and its funded organizations to develop and support operational processes and  informatics  solutions leading to cost-effective solutions that reduce administrative burden on clinical sites. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2490", "text": "The CTSU supports the following NCI cancer research networks: [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2491", "text": "Additional NCI and NIH services that work in conjunction with the CTSU include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2492", "text": "Clinical trials  are prospective biomedical or behavioral research studies on  human participants  designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel  vaccines ,  drugs ,  dietary choices ,  dietary supplements , and  medical devices ) and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. [ 1 ] [ 2 ]  They are conducted only after they have received  health authority/ethics committee  approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the  risk/benefit ratio  of the trial\u2014their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2493", "text": "Depending on product type and development stage, investigators initially enroll volunteers or patients into small  pilot studies , and subsequently conduct progressively larger scale comparative studies. Clinical trials can vary in size and cost, and they can involve a single research center or  multiple centers , in one country or in multiple countries.  Clinical study design  aims to ensure the  scientific validity  and  reproducibility  of the results."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2494", "text": "Costs for clinical trials can range into the billions of dollars per approved drug, [ 3 ]  and the complete trial process to approval may require 7\u201315 years. [ 4 ] [ 5 ]  The sponsor may be a governmental organization or a  pharmaceutical ,  biotechnology  or medical-device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a  contract research organization  or a central laboratory. Only 10 percent of all drugs started in human clinical trials become  approved drugs . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2495", "text": "Some clinical trials involve healthy subjects with no  pre-existing medical conditions . Other clinical trials pertain to people with specific health conditions who are willing to try an experimental treatment. Pilot experiments are conducted to gain insights for design of the clinical trial to follow. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2496", "text": "There are two goals to testing medical treatments: to learn whether they work well enough, called \"efficacy\", or \"effectiveness\"; and to learn whether they are safe enough, called \"safety\". [ 1 ]  Neither is an absolute criterion; both safety and efficacy are evaluated relative to how the treatment is intended to be used, what other treatments are available, and the severity of the disease or condition. The benefits must outweigh the risks. [ 7 ] [ 8 ] :\u200a8\u200a  For example, many drugs to treat cancer have severe side effects that would not be acceptable for an over-the-counter pain medication, yet the cancer drugs have been approved since they are used under a physician's care and are used for a life-threatening condition. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2497", "text": "In the US the elderly constitute 14% of the population, while they consume over one-third of drugs. [ 10 ]  People over 55 (or a similar cutoff age) are often excluded from trials because their greater health issues and drug use complicate data interpretation, and because they have different physiological capacity than younger people. Children and people with unrelated medical conditions are also frequently excluded. [ 11 ]  Pregnant women are often excluded due to potential risks to the  fetus ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2498", "text": "The sponsor designs the trial in coordination with a panel of expert clinical investigators, including what alternative or existing treatments to compare to the new drug and what type(s) of patients might benefit. If the sponsor cannot obtain enough test subjects at one location investigators at other locations are recruited to join the study. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2499", "text": "During the trial, investigators recruit subjects with the predetermined characteristics, administer the treatment(s) and collect data on the subjects' health for a defined time period. Data include measurements such as  vital signs , concentration of the study drug in the blood or tissues, changes to symptoms, and whether improvement or worsening of the condition targeted by the study drug occurs. The researchers send the data to the trial sponsor, who then analyzes the pooled data using  statistical tests . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2500", "text": "Examples of clinical trial goals include assessing the safety and relative effectiveness of a medication or device: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2501", "text": "While most clinical trials test one alternative to the novel intervention, some expand to three or four and may include a  placebo . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2502", "text": "Except for small, single-location trials, the design and objectives are specified in a document called a  clinical trial protocol . The protocol is the trial's \"operating manual\" and ensures all researchers perform the trial in the same way on similar subjects and that the data is comparable across all subjects. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2503", "text": "As a trial is designed to test  hypotheses  and rigorously monitor and assess outcomes, it can be seen as an application of the  scientific method , specifically the experimental step. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2504", "text": "The most common clinical trials evaluate new pharmaceutical products, medical devices,  biologics ,  diagnostic assays ,  psychological therapies , or other interventions. [ 12 ]  Clinical trials may be required before a national  regulatory authority [ 13 ]  approves marketing of the innovation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2505", "text": "Similarly to drugs, manufacturers of medical devices in the United States are required to conduct clinical trials for  premarket approval . [ 14 ]  Device trials may compare a new device to an established therapy, or may compare similar devices to each other. An example of the former in the field of  vascular surgery  is the Open versus Endovascular Repair (OVER trial) for the treatment of  abdominal aortic aneurysm , which compared the older  open aortic repair  technique to the newer  endovascular aneurysm repair  device. [ 15 ]  An example of the latter are clinical trials on mechanical devices used in the management of adult female  urinary incontinence . [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2506", "text": "Similarly to drugs, medical or surgical procedures may be subjected to clinical trials, [ 17 ]  such as comparing different surgical approaches in treatment of  fibroids  for  subfertility . [ 18 ]  However, when clinical trials are unethical or logistically impossible in the surgical setting,  case-controlled studies  will be replaced. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2507", "text": "Besides being participants in a clinical trial, members of the public can be actively collaborate with researchers in designing and conducting  clinical research . This is known as  patient and public involvement  (PPI). Public involvement involves a working partnership between patients, caregivers, people with lived experience, and researchers to shape and influence what is researcher and how. [ 20 ]  PPI can improve the quality of research and make it more relevant and accessible. People with current or past experience of illness can provide a different perspective than professionals and compliment their knowledge. Through their personal knowledge they can identify research topics that are relevant and important to those living with an illness or using a service. They can also help to make the research more grounded in the needs of the specific communities they are part of. Public contributors can also ensure that the research is presented in  plain language  that is clear to the wider society and the specific groups it is most relevant for. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2508", "text": "Although early medical experimentation was performed often, the use of a  control group  to provide an accurate comparison for the demonstration of the intervention's efficacy was generally lacking. For instance,  Lady Mary Wortley Montagu , who campaigned for the introduction of  inoculation  (then called variolation) to prevent  smallpox , arranged for seven prisoners who had been sentenced to death to undergo variolation in exchange for their life. Although they survived and did not contract smallpox, there was no control group to assess whether this result was due to the inoculation or some other factor. Similar experiments performed by  Edward Jenner  over his  smallpox vaccine  were equally conceptually flawed. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2509", "text": "The first proper clinical trial was conducted by the Scottish physician  James Lind . [ 23 ]  The disease  scurvy , now known to be caused by a  Vitamin C  deficiency, would often have terrible effects on the welfare of the crew of long-distance ocean voyages. In 1740, the catastrophic result of  Anson 's  circumnavigation  attracted much attention in Europe; out of 1900 men, 1400 had died, most of them allegedly from having contracted scurvy. [ 24 ]   John Woodall , an English military surgeon of the  British East India Company , had recommended the consumption of  citrus fruit  from the 17th century, but their use did not become widespread. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2510", "text": "Lind conducted the first systematic  clinical trial  in 1747. [ 26 ]  He included a dietary supplement of an acidic quality in the experiment after two months at sea, when the ship was already afflicted with scurvy. He divided twelve scorbutic sailors into six groups of two. They all received the same diet but, in addition, group one was given a quart of  cider  daily, group two twenty-five drops of elixir of  vitriol  ( sulfuric acid ), group three six spoonfuls of  vinegar , group four half a pint of seawater, group five received two  oranges  and one  lemon , and the last group a spicy paste plus a drink of  barley water . The treatment of group five stopped after six days when they ran out of fruit, but by then one sailor was fit for duty while the other had almost recovered. Apart from that, only group one also showed some effect of its treatment. [ 27 ]  Each year, May 20 is celebrated as Clinical Trials Day in honor of Lind's research. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2511", "text": "After 1750 the discipline began to take its modern shape. [ 29 ] [ 30 ]  The English doctor  John Haygarth  demonstrated the importance of a control group for the correct identification of the  placebo effect  in his celebrated study of the ineffective remedy called  Perkin's tractors . Further work in that direction was carried out by the eminent physician  Sir William Gull, 1st Baronet  in the 1860s. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2512", "text": "Frederick Akbar Mahomed  (d. 1884), who worked at  Guy's Hospital  in  London , made substantial contributions to the process of clinical trials, where \"he separated chronic  nephritis  with  secondary hypertension  from what we now term  essential hypertension . He also founded the Collective Investigation Record for the  British Medical Association ; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials.\" [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2513", "text": "Ideas of Sir  Ronald A. Fisher  still play a role in clinical trials. While working for the  Rothamsted experimental station  in the field of agriculture, Fisher developed his  Principles of experimental design  in the 1920s as an accurate methodology for the proper design of experiments. Among his major ideas include the importance of  randomization \u2014the random assignment of individuals to different groups for the experiment; [ 32 ]   replication \u2014to reduce  uncertainty , measurements should be repeated and experiments replicated to identify sources of variation; [ 33 ]   blocking \u2014to arrange experimental units into groups of units that are similar to each other, and thus reducing irrelevant sources of variation; use of  factorial experiments \u2014efficient at evaluating the effects and possible  interactions  of several independent factors. [ 22 ]  Of these, blocking and factorial design are seldom applied in clinical trials, because the experimental units are human subjects and there is typically only one independent intervention: the treatment. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2514", "text": "The  British Medical Research Council  officially recognized the importance of clinical trials from the 1930s. The council established the  Therapeutic Trials Committee  to advise and assist in the arrangement of properly controlled clinical trials on new products that seem likely on experimental grounds to have value in the treatment of disease. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2515", "text": "The first randomised curative trial was carried out at the MRC Tuberculosis Research Unit by Sir Geoffrey Marshall (1887\u20131982). The trial, carried out between 1946 and 1947, aimed to test the efficacy of the chemical  streptomycin  for curing  pulmonary tuberculosis . The trial was both  double-blind  and  placebo-controlled . [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2516", "text": "The methodology of clinical trials was further developed by Sir  Austin Bradford Hill , who had been involved in the streptomycin trials. From the 1920s, Hill applied  statistics  to medicine, attending the lectures of renowned mathematician  Karl Pearson , among others. He became famous for a landmark study carried out in collaboration with  Richard Doll  on the correlation between  smoking  and  lung cancer . They carried out a  case-control study  in 1950, which compared lung cancer patients with matched control and also began a sustained  long-term prospective study  into the broader issue of smoking and health, which involved  studying the smoking habits and health of more than 30,000 doctors  over a period of several years. His certificate for election to the  Royal Society  called him \"... \u00a0 the leader in the development in medicine of the precise experimental methods now used nationally and internationally in the evaluation of new therapeutic and  prophylactic agents .\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_2517", "text": "International clinical trials day is celebrated on 20 May. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2518", "text": "The acronyms used in the  titling of clinical trials  are often contrived, and have been the subject of derision. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2519", "text": "Clinical trials are classified by the research objective created by the investigators. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2520", "text": "Trials are classified by their purpose. After approval for human research is granted to the trial sponsor, the U.S.  Food and Drug Administration  (FDA) organizes and monitors the results of trials according to type: [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2521", "text": "Clinical trials are conducted typically in four phases, with each phase using different numbers of subjects and having a different purpose to construct focus on identifying a specific effect. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2522", "text": "Clinical trials involving new drugs are commonly classified into five phases. Each phase of the drug approval process is treated as a separate clinical trial. The  drug development  process will normally proceed through phases I\u2013IV over many years, frequently involving a  decade  or longer. If the drug successfully passes through phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. [ 12 ]  Phase IV trials are performed after the newly approved drug, diagnostic or device is marketed, providing assessment about risks, benefits, or best uses. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2523", "text": "A fundamental distinction in  evidence-based practice  is between  observational studies  and  randomized controlled trials . [ 45 ]  Types of observational studies in  epidemiology , such as the  cohort study  and the  case-control study , provide less compelling evidence than the randomized controlled trial. [ 45 ]  In observational studies, the investigators retrospectively assess associations between the treatments given to participants and their health status, with potential for considerable errors in design and interpretation. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2524", "text": "A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2525", "text": "Some Phase II and most Phase III drug trials are designed as randomized,  double-blind , and  placebo -controlled. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2526", "text": "Clinical studies having small numbers of subjects may be \"sponsored\" by single researchers or a small group of researchers, and are designed to test simple questions or feasibility to expand the research for a more comprehensive randomized controlled trial. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2527", "text": "Clinical studies can be \"sponsored\"  (financed and organized) by academic institutions, pharmaceutical companies, government entities and even private groups. Trials are conducted for new drugs, biotechnology, diagnostic assays or medical devices to determine their safety and efficacy  prior to being submitted for regulatory review that would determine market approval. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2528", "text": "In cases where giving a placebo to a person suffering from a disease may be unethical, \"active comparator\" (also known as \"active control\") trials may be conducted instead. [ 48 ]  In trials with an active control group, subjects are given either the experimental treatment or a previously approved treatment with known effectiveness. In other cases, sponsors may conduct an active comparator trial to establish an efficacy claim relative to the active comparator instead of the placebo in  labeling . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2529", "text": "A master protocol includes multiple substudies, which may have different objectives and involve coordinated efforts to evaluate one or more medical products in one or more diseases or conditions within the overall study structure. Trials that could develop a master protocol include the umbrella trial (multiple medical products for a single disease),  platform trial  (multiple products for a single disease entering and leaving the platform), and basket trial (one medical product for multiple diseases or disease subtypes). [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2530", "text": "Genetic testing  enables researchers to group patients according to their genetic profile, deliver drugs based on that profile to that group and compare the results. Multiple companies can participate, each bringing a different drug. The first such approach targets  squamous cell cancer , which includes varying genetic disruptions from patient to patient. Amgen, AstraZeneca and Pfizer are involved, the first time they have worked together in a late-stage trial. Patients whose genomic profiles do not match any of the trial drugs receive a drug designed to stimulate the immune system to attack cancer. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2531", "text": "A  clinical trial protocol  is a document used to define and manage the trial. It is prepared by a panel of experts. All study investigators are expected to strictly observe the protocol. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2532", "text": "The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations and organization of the planned trial. Details of the trial are provided in documents referenced in the protocol, such as an  investigator's brochure . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2533", "text": "The protocol contains a precise study plan to assure safety and health of the trial subjects and to provide an exact template for trial conduct by investigators. This allows data to be combined across all investigators/sites. The protocol also informs the study administrators (often a  contract research organization ). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2534", "text": "The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan have been standardized to follow Good Clinical Practice guidance [ 51 ]  issued by the  International Conference on Harmonisation  (ICH). [ 52 ]  Regulatory authorities in  Canada ,  China ,  South Korea , and  the UK  also follow ICH guidelines. Journals such as  Trials , encourage investigators to publish their protocols."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2535", "text": "Clinical trials recruit study subjects to sign a document representing their \" informed consent \". [ 53 ]  The document includes details such as its purpose, duration, required procedures, risks, potential benefits, key contacts and institutional requirements. [ 54 ]  The participant then decides whether to sign the document. The document is not a contract, as the participant can withdraw at any time without penalty. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2536", "text": "Informed consent is a legal process in which a recruit is instructed about key facts before deciding whether to participate. [ 53 ]  Researchers explain the details of the study in terms the subject can understand. The information is presented in the subject's native language. Generally, children cannot autonomously provide informed consent, but depending on their age and other factors, may be required to provide informed assent. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2537", "text": "In any clinical trial, the number of subjects, also called the sample size, has a large impact on the ability to reliably detect and measure the effects of the intervention. This ability is described as its \" power \", which must be calculated before initiating a study to figure out if the study is worth its costs. [ 55 ]  In general, a larger sample size increases the statistical power, also the cost."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2538", "text": "The statistical power estimates the ability of a trial to detect a difference of a particular size (or larger) between the treatment and control groups. For example, a trial of a  lipid -lowering drug versus placebo with 100 patients in each group might have a power of 0.90 to detect a difference between placebo and trial groups receiving dosage of 10\u00a0mg/dL or more, but only 0.70 to detect a difference of 6\u00a0mg/dL. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2539", "text": "Merely giving a treatment can have nonspecific effects. These are controlled for by the inclusion of patients who receive only a placebo. Subjects are assigned  randomly  without informing them to which group they belonged. Many trials are doubled-blinded so that researchers do not know to which group a subject is assigned."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2540", "text": "Assigning a subject to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment. The  Declaration of Helsinki  provides guidelines on this issue."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2541", "text": "Clinical trials are only a small part of the research that goes into developing a new treatment. Potential drugs, for example, first have to be discovered, purified, characterized, and tested in labs (in cell and animal studies) before ever undergoing clinical trials. In all, about 1,000 potential drugs are tested before just one reaches the point of being tested in a clinical trial. [ 56 ]  For example, a new cancer drug has, on average, six years of research behind it before it even makes it to clinical trials. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. On average, about eight years pass from the time a cancer drug enters clinical trials until it receives approval from regulatory agencies for sale to the public. [ 57 ]  Drugs for other diseases have similar timelines."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2542", "text": "Some reasons a clinical trial might last several years:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2543", "text": "A clinical trial might also include an extended post-study follow-up period from months to years for people who have participated in the trial, a so-called \"extension phase\", which aims to identify long-term impact of the treatment. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2544", "text": "The biggest barrier to completing studies is the shortage of people who take part. All drug and many device trials target a subset of the population, meaning not everyone can participate. Some drug trials require patients to have unusual combinations of disease characteristics. It is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit (because they are not paid, the study drug is not yet proven to work, or the patient may receive a placebo). In the case of cancer patients, fewer than 5% of adults with cancer will participate in drug trials. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), about 400 cancer medicines were being tested in clinical trials in 2005. Not all of these will prove to be useful, but those that are may be delayed in getting approved because the number of participants is so low. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2545", "text": "For clinical trials involving potential for seasonal influences (such as  airborne allergies ,  seasonal affective disorder ,  influenza , and  skin diseases ), the study may be done during a limited part of the year (such as spring for pollen allergies), when the drug can be tested. [ 60 ] [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2546", "text": "Clinical trials that do not involve a new drug usually have a much shorter duration. (Exceptions are epidemiological studies, such as the  Nurses' Health Study )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2547", "text": "Clinical trials designed by a local investigator, and (in the US) federally funded clinical trials, are almost always administered by the researcher who designed the study and applied for the grant. Small-scale device studies may be administered by the sponsoring company. Clinical trials of new drugs are usually administered by a  contract research organization  (CRO) hired by the sponsoring company. The sponsor provides the drug and medical oversight. A CRO is contracted to perform all the administrative work on a clinical trial. For Phases \u00a0 II\u2013IV the CRO recruits participating researchers, trains them, provides them with supplies, coordinates study administration and  data collection , sets up meetings, monitors the sites for compliance with the clinical protocol, and ensures the sponsor receives data from every site. Specialist  site management organizations  can also be hired to coordinate with the CRO to ensure rapid IRB/IEC approval and faster site initiation and patient recruitment. Phase \u00a0 I clinical trials of new medicines are often conducted in a specialist clinical trial clinic, with dedicated pharmacologists, where the subjects can be observed by full-time staff. These clinics are often run by a CRO which specialises in these studies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2548", "text": "At a participating site, one or more research assistants (often nurses) do most of the work in conducting the clinical trial. The research assistant's job can include some or all of the following: providing the local  institutional review board  (IRB) with the documentation necessary to obtain its permission to conduct the study, assisting with study start-up, identifying eligible patients, obtaining consent from them or their families, administering study treatment(s), collecting and statistically analyzing data, maintaining and updating data files during followup, and communicating with the IRB, as well as the sponsor and CRO."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2549", "text": "In the context of a clinical trial, quality typically refers to the absence of errors which can impact decision making, both during the conduct of the trial and in use of the trial results. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2550", "text": "An Interactional Justice Model may be used to test the effects of willingness to talk with a doctor about clinical trial enrollment. [ 63 ]  Results found that potential clinical trial candidates were less likely to enroll in clinical trials if the patient is more willing to talk with their doctor. The reasoning behind this discovery may be patients are happy with their current care. Another reason for the negative relationship between perceived fairness and clinical trial enrollment is the lack of independence from the care provider. Results found that there is a positive relationship between a lack of willingness to talk with their doctor and clinical trial enrollment. Lack of willingness to talk about clinical trials with current care providers may be due to patients' independence from the doctor. Patients who are less likely to talk about clinical trials are more willing to use other sources of information to gain a better insight of alternative treatments. Clinical trial enrollment should be motivated to utilize websites and television advertising to inform the public about clinical trial enrollment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2551", "text": "The last decade has seen a proliferation of  information technology  use in the planning and conduct of clinical trials.  Clinical trial management systems  are often used by research sponsors or CROs to help plan and manage the operational aspects of a clinical trial, particularly with respect to investigational sites. Advanced analytics for identifying researchers and research sites with expertise in a given area utilize public and private information about ongoing research. [ 64 ]  Web-based  electronic data capture  (EDC) and  clinical data management systems  are used in a majority of clinical trials [ 65 ]  to collect case report data from sites, manage its quality and prepare it for analysis.  Interactive voice response  systems are used by sites to register the enrollment of patients using a phone and to allocate patients to a particular treatment arm (although phones are being increasingly replaced with web-based (IWRS) tools which are sometimes part of the EDC system). While  patient-reported outcome  were often paper based in the past, measurements are increasingly being collected using web portals or hand-held  ePRO  (or eDiary) devices, sometimes wireless. [ 66 ]   Statistical software  is used to analyze the collected data and prepare them for regulatory submission. Access to many of these applications are increasingly aggregated in web-based  clinical trial portals . In 2011, the FDA approved a Phase \u00a0 I trial that used telemonitoring, also known as remote patient monitoring, to collect biometric data in patients' homes and transmit it electronically to the trial database. This technology provides many more data points and is far more convenient for patients, because they have fewer visits to trial sites. As noted below, decentralized clinical trials are those that do not require patients' physical presence at a site, and instead rely largely on digital health data collection, digital informed consent processes, and so on."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2552", "text": "A clinical trial produces data that could reveal quantitative differences between two or more interventions;  statistical analyses  are used to determine whether such differences are true, result from chance, or are the same as no treatment (placebo). [ 67 ] [ 68 ]  Data from a clinical trial accumulate gradually over the trial duration, extending from months to years. [ 53 ]  Accordingly, results for participants recruited early in the study become available for analysis while subjects are still being assigned to treatment groups in the trial. Early analysis may allow the emerging evidence to assist decisions about whether to stop the study, or to reassign participants to the more successful segment of the trial. [ 67 ]  Investigators may also want to stop a trial when data analysis shows no treatment effect. [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2553", "text": "Clinical trials are closely supervised by appropriate regulatory authorities. All studies involving a medical or therapeutic intervention on patients must be approved by a supervising ethics committee before permission is granted to run the trial. The local ethics committee has discretion on how it will supervise noninterventional studies (observational studies or those using already collected data). In the US, this body is called the  Institutional Review Board  (IRB); in the EU, they are called  Ethics committees . Most IRBs are located at the local investigator's hospital or institution, but some sponsors allow the use of a central (independent/for profit) IRB for investigators who work at smaller institutions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2554", "text": "To be ethical, researchers must obtain the full and  informed consent  of participating human subjects. (One of the IRB's main functions is to ensure potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In addition, the clinical trial participants must be made aware that they can withdraw from the clinical trial at any time without any adverse action taken against them. [ 69 ]  In  California , the state has prioritized the individuals who can serve as the legally authorized representative. [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2555", "text": "In some US locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy ( HIPAA ) law and good clinical practice. The International Conference of Harmonisation Guidelines for Good Clinical Practice is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure the \"rights, safety and well being of trial subjects are protected\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2556", "text": "The notion of informed consent of participating human subjects exists in many countries but its precise definition may still vary."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2557", "text": "Informed consent is clearly a 'necessary' condition for ethical conduct but does not 'ensure' ethical conduct. In  compassionate use  trials the latter becomes a particularly difficult problem. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. See also  Expanded access . However, it may be hard to turn this objective into a well-defined, quantified, objective function. In some cases this can be done, however, for instance, for questions of when to stop sequential treatments (see  Odds algorithm ), and then quantified methods may play an important role."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2558", "text": "Additional ethical concerns are present when conducting  clinical trials on children  ( pediatrics ), and in emergency or epidemic situations. [ 71 ] [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2559", "text": "Ethically balancing the rights of multiple stakeholders may be difficult. For example, when drug trials fail, the sponsors may have a duty to tell current and potential investors immediately, which means both the research staff and the enrolled participants may first hear about the end of a trial through public  business news . [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2560", "text": "In response to specific cases in which unfavorable data from pharmaceutical company-sponsored research were not published, the  Pharmaceutical Research and Manufacturers of America  published new guidelines urging companies to report all findings and limit the financial involvement in drug companies by researchers. [ 74 ]  The  US Congress  signed into law a bill which requires Phase \u00a0 II and Phase \u00a0 III clinical trials to be registered by the sponsor on the  clinicaltrials.gov  website compiled by the  National Institutes of Health . [ 75 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2561", "text": "Drug researchers not directly employed by pharmaceutical companies often seek grants from manufacturers, and manufacturers often look to academic researchers to conduct studies within networks of universities and their hospitals, e.g., for  translational  cancer research. Similarly, competition for tenured academic positions, government grants and prestige create conflicts of interest among academic scientists. [ 76 ]  According to one study, approximately 75% of articles retracted for misconduct-related reasons have no declared industry financial support. [ 77 ]   Seeding trials  are particularly controversial. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2562", "text": "In the United States, all clinical trials submitted to the FDA as part of a drug approval process are independently assessed by clinical experts within the Food and Drug Administration, [ 79 ]  including inspections of primary data collection at selected clinical trial sites. [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2563", "text": "In 2001, the editors of 12 major journals issued a joint editorial, published in each journal, on the control over clinical trials exerted by sponsors, particularly targeting the use of contracts which allow sponsors to review the studies prior to publication and withhold publication. They strengthened editorial restrictions to counter the effect. The editorial noted that  contract research organizations  had, by 2000, received 60% of the grants from  pharmaceutical companies  in the US. Researchers may be restricted from contributing to the trial design, accessing the raw data, and interpreting the results. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2564", "text": "Despite explicit recommendations\u00a0 by stakeholders of measures to improve the standards of industry-sponsored medical research, [ 82 ] \u00a0 \u00a0in 2013,  Tohen  warned of the persistence of a gap in the credibility of conclusions arising from industry-funded clinical trials, and called for ensuring strict adherence to ethical standards in industrial collaborations with academia, in order to avoid further erosion of the public's trust. [ 83 ]  Issues referred for attention in this respect include potential observation bias, duration of the observation time for maintenance studies, the selection of the patient populations, factors that affect placebo response, and funding sources. [ 84 ] [ 85 ] [ 86 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2565", "text": "Conducting clinical trials of vaccines during epidemics and pandemics is subject to ethical concerns. For diseases with high mortality rates like Ebola, assigning individuals to a placebo or control group can be viewed as a death sentence. In response to ethical concerns regarding clinical research during epidemics, the  National Academy of Medicine  authored a report identifying seven ethical and scientific considerations. These considerations are: [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2566", "text": "Pregnant women and children are typically excluded from clinical trials as vulnerable populations, though the data to support excluding them is not robust. By excluding them from clinical trials, information about the safety and effectiveness of therapies for these populations is often lacking. During the early history of the  HIV/AIDS  epidemic, a scientist noted that by excluding these groups from potentially life-saving treatment, they were being \"protected to death\". Projects such as  Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) have advocated for the ethical inclusion of pregnant women in vaccine trials. Inclusion of children in clinical trials has additional moral considerations, as children lack decision-making autonomy. Trials in the past had been criticized for using hospitalized children or orphans; these ethical concerns effectively stopped future research. In efforts to maintain effective pediatric care, several European countries and the US have policies to entice or compel pharmaceutical companies to conduct pediatric trials. International guidance recommends ethical pediatric trials by limiting harm, considering varied risks, and taking into account the complexities of pediatric care. [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2567", "text": "Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor, the local site investigators (if different from the sponsor), the various IRBs that supervise the study, and (in some cases, if the study involves a marketable drug or device), the regulatory agency for the country where the drug or device will be sold."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2568", "text": "A systematic concurrent safety review is frequently employed to assure research participant safety. The conduct and on-going review is designed to be proportional to the risk of the trial. Typically this role is filled by a  Data and Safety Committee , an externally appointed Medical Safety Monitor, [ 88 ]  an  Independent Safety Officer , or for small or low-risk studies the principal investigator. [ 89 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2569", "text": "For safety reasons, many clinical trials of drugs [ 90 ]  are designed to exclude women of childbearing age, pregnant women, or women who become pregnant during the study. In some cases, the male partners of these women are also excluded or required to take birth control measures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2570", "text": "Throughout the clinical trial, the sponsor is responsible for accurately informing the local site investigators of the true historical safety record of the drug, device or other medical treatments to be tested, and of any potential interactions of the study treatment(s) with already approved treatments. This allows the local investigators to make an informed judgment on whether to participate in the study or not. The sponsor is also responsible for  monitoring  the results of the study as they come in from the various sites as the trial proceeds. In larger clinical trials, a sponsor will use the services of a  data monitoring committee  (DMC, known in the US as a data safety monitoring board). This independent group of clinicians and statisticians meets periodically to review the  unblinded  data the sponsor has received so far. The DMC has the power to recommend termination of the study based on their review, for example if the study treatment is causing more deaths than the standard treatment, or seems to be causing unexpected and study-related serious  adverse events . The sponsor is responsible for collecting  adverse event  reports from all site investigators in the study, and for informing all the investigators of the sponsor's judgment as to whether these adverse events were related or not related to the study treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2571", "text": "The sponsor and the local site investigators are jointly responsible for writing a site-specific  informed consent  that accurately informs the potential subjects of the true risks and potential benefits of participating in the study, while at the same time presenting the material as briefly as possible and in ordinary language. FDA regulations state that participating in clinical trials is voluntary, with the subject having the right not to participate or to end participation at any time. [ 91 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2572", "text": "The ethical principle of  primum non-nocere  (\"first, do no harm\") guides the trial, and if an investigator believes the study treatment may be harming subjects in the study, the investigator can stop participating at any time. On the other hand, investigators often have a financial interest in recruiting subjects, and could act unethically to obtain and maintain their participation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2573", "text": "The local investigators are responsible for conducting the study according to the study protocol, and supervising the study staff throughout the duration of the study. The local investigator or his/her study staff are also responsible for ensuring the potential subjects in the study understand the risks and potential benefits of participating in the study. In other words, they (or their legally authorized representatives) must give truly informed consent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2574", "text": "Local investigators are responsible for reviewing all adverse event reports sent by the sponsor. These adverse event reports contain the opinions of both the investigator (at the site where the adverse event occurred) and the sponsor, regarding the relationship of the adverse event to the study treatments. Local investigators also are responsible for making an independent judgment of these reports, and promptly informing the local IRB of all serious and study treatment-related adverse events."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2575", "text": "When a local investigator is the sponsor, there may not be formal adverse event reports, but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected. The local investigator is responsible for being truthful to the local IRB in all communications relating to the study."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2576", "text": "Approval by an  Institutional Review Board  (IRB), or  Independent Ethics Committee  (IEC), is necessary before all but the most informal research can begin. In commercial clinical trials, the study protocol is not approved by an IRB before the sponsor recruits sites to conduct the trial. However, the study protocol and procedures have been tailored to fit generic IRB submission requirements. In this case, and where there is no independent sponsor, each local site investigator submits the study protocol, the consent(s), the data collection forms, and supporting documentation to the local IRB. Universities and most hospitals have in-house IRBs. Other researchers (such as in walk-in clinics) use independent IRBs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2577", "text": "The IRB scrutinizes the study both for medical safety and for protection of the patients involved in the study, before it allows the researcher to begin the study. It may require changes in study procedures or in the explanations given to the patient. A required yearly \"continuing review\" report from the investigator updates the IRB on the progress of the study and any new safety information related to the study."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2578", "text": "In the US, the  FDA  can  audit  the files of local site investigators after they have finished participating in a study, to see if they were correctly following study procedures. This audit may be random, or for cause (because the investigator is suspected of fraudulent data). Avoiding an audit is an incentive for investigators to follow study procedures. A 'covered clinical study' refers to a trial submitted to the FDA as part of a marketing application (for example, as part of an  NDA  or  510(k) ), about which the FDA may require disclosure of financial interest of the  clinical investigator  in the outcome of the study. For example, the applicant must disclose whether an investigator owns equity in the sponsor, or owns proprietary interest in the product under investigation. The FDA defines a covered study as \"... \u00a0 any study of a drug, biological product or device in humans submitted in a marketing application or reclassification petition that the applicant or FDA relies on to establish that the product is effective (including studies that show equivalence to an effective product) or any study in which a single investigator makes a significant contribution to the demonstration of safety.\" [ 92 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2579", "text": "Alternatively, many American pharmaceutical companies have moved some clinical trials overseas. Benefits of conducting trials abroad include lower costs (in some countries) and the ability to run larger trials in shorter timeframes, whereas a potential disadvantage exists in lower-quality trial management. [ 93 ]  Different countries have different regulatory requirements and enforcement abilities. An estimated 40% of all clinical trials now take place in Asia, Eastern Europe, and Central and South America. \"There is no compulsory registration system for clinical trials in these countries and many do not follow European directives in their operations\", says Jacob Sijtsma of the Netherlands-based WEMOS, an advocacy health organisation tracking clinical trials in developing countries. [ 94 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2580", "text": "Beginning in the 1980s, harmonization of clinical trial protocols was shown as feasible across countries of the European Union. At the same time, coordination between Europe, Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use  (ICH) [ 95 ] \nCurrently, most clinical trial programs follow ICH guidelines, aimed at \"ensuring that good quality, safe and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness.\" [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2581", "text": "Aggregating safety data across clinical trials during drug development is important because trials are generally designed to focus on determining how well the drug works. The safety data collected and aggregated across multiple trials as the drug is developed allows the sponsor, investigators and regulatory agencies to monitor the aggregate safety profile of experimental medicines as they are developed. The value of assessing aggregate safety data is: a) decisions based on aggregate safety assessment during development of the medicine can be made throughout the medicine's development and b) it sets up the sponsor and regulators well for assessing the medicine's safety after the drug is approved. [ 97 ] [ 98 ] [ 99 ] [ 100 ] [ 101 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2582", "text": "Clinical trial costs vary depending on trial phase, type of trial, and disease studied. A study of clinical trials conducted in the United States from 2004 to 2012 found the average cost of Phase \u00a0 I trials to be between $1.4 million and $6.6 million, depending on the type of disease. Phase II trials ranged from $7 million to $20 million, and Phase \u00a0 III trials from $11 million to $53 million. [ 102 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2583", "text": "The cost of a study depends on many factors, especially the number of sites conducting the study, the number of patients involved, and whether the study treatment is already approved for medical use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2584", "text": "The expenses incurred by a pharmaceutical company in administering a Phase III or \u00a0 IV clinical trial may include, among others:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2585", "text": "These expenses are incurred over several years."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2586", "text": "In the US, sponsors may receive a 50 percent  tax credit  for clinical trials conducted on drugs being developed for the treatment of  orphan diseases . [ 103 ]  National health agencies, such as the US  National Institutes of Health , offer grants to investigators who design clinical trials that attempt to answer research questions of interest to the agency. In these cases, the investigator who writes the grant and administers the study acts as the sponsor, and coordinates data collection from any other sites. These other sites may or may not be paid for participating in the study, depending on the amount of the grant and the amount of effort expected from them. Using internet resources can, in some cases, reduce the economic burden. [ 104 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2587", "text": "Investigators are often compensated for their work in clinical trials. These amounts can be small, just covering a partial salary for research assistants and the cost of any supplies (usually the case with national health agency studies), or be substantial and include \"overhead\" that allows the investigator to pay the research staff during times between clinical trials. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2588", "text": "Participants in Phase I drug trials do not gain any direct health benefit from taking part. They are generally paid a fee for their time, with payments regulated and not related to any risk involved. Motivations of healthy volunteers is not limited to financial reward and may include other motivations such as contributing to science and others. [ 105 ]  In later phase trials, subjects may not be paid to ensure their motivation for participating with potential for a health benefit or contributing to medical knowledge. Small payments may be made for study-related expenses such as travel or as compensation for their time in providing follow-up information about their health after the trial treatment ends."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2589", "text": "Phase 0 and Phase I drug trials seek healthy volunteers. Most other clinical trials seek patients who have a specific disease or medical condition. The diversity observed in society should be reflected in clinical trials through the appropriate inclusion of  ethnic minority  populations. [ 106 ]   Patient recruitment  or participant recruitment plays a significant role in the activities and responsibilities of sites conducting clinical trials. [ 107 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2590", "text": "All volunteers being considered for a trial are required to undertake a medical screening. Requirements differ according to the trial needs, but typically volunteers would be screened in a  medical laboratory  for: [ 108 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2591", "text": "It has been observed that participants in clinical trials are disproportionately white. [ 109 ] [ 110 ]  Often, minorities are not informed about clinical trials. [ 111 ]  One recent systematic review of the literature found that race/ethnicity as well as sex were not well-represented nor at times even tracked as participants in a large number of clinical trials of hearing loss management in adults. [ 112 ]  This may reduce the validity of findings in respect of non-white patients [ 113 ]  by not adequately representing the larger population s ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2592", "text": "Depending on the kind of participants required, sponsors of clinical trials, or contract research organizations working on their behalf, try to find sites with qualified personnel as well as access to patients who could participate in the trial. Working with those sites, they may use various recruitment strategies, including patient databases, newspaper and radio advertisements, flyers, posters in places the patients might go (such as doctor's offices), and personal recruitment of patients by investigators."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2593", "text": "Volunteers with specific conditions or diseases have additional online resources to help them locate clinical trials. For example, the Fox Trial Finder connects  Parkinson's disease  trials around the world to volunteers who have a specific set of criteria such as location, age, and symptoms. [ 114 ]  Other disease-specific services exist for volunteers to find trials related to their condition. [ 115 ]  Volunteers may search directly on  ClinicalTrials.gov  to locate trials using a registry run by the  U.S. National Institutes of Health  and  National Library of Medicine . There also is software that allows clinicians to find trial options for an individual patient based on data such as genomic data. [ 116 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2594", "text": "The risk information seeking and processing (RISP) model analyzes social implications that affect attitudes and decision making pertaining to clinical trials. [ 117 ]  People who hold a higher stake or interest in the treatment provided in a clinical trial showed a greater likelihood of seeking information about clinical trials. Cancer patients reported more optimistic attitudes towards clinical trials than the general population. Having a more optimistic outlook on clinical trials also leads to greater likelihood of enrolling. [ 117 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2595", "text": "Matching involves a systematic comparison of a patient's clinical and demographic information against the eligibility criteria of various trials. Methods include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2596", "text": "Although trials are commonly conducted at major medical centers, some participants are excluded due to the distance and expenses required for travel, leading to hardship, disadvantage, and inequity for participants, especially those in rural and underserved communities. Therefore, the concept of a \"decentralized clinical trial\" that minimizes or eliminates the need for patients to travel to sites, [ 122 ]  is now more widespread, a capability improved by  telehealth  and  wearable technologies . [ 123 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2597", "text": "Accidental  ( CDI ), or  multiple drug intake  ( MDI ), is a cause of death by  drug overdose  from  poly drug use , often implicated in  polysubstance dependence ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2598", "text": "People who engage in  polypharmacy  are at an elevated risk of death from CDI. Other dangers of combining drugs such as \"brain damage, heart problems, seizures, stomach bleeding, liver damage/ liver failure, heatstroke, coma, suppressed breathing, and respiratory failure\", along with many other complications. Disorders like depression and anxiety can also stem from polydrug use. [ 1 ]  Elderly people are at the highest risk of CDI, because of having many age-related and health problems requiring many medications combined with age-impaired judgment, leading to confusion in taking medications. [ 2 ] [ 3 ]  Elderly patients are often prescribed more than one drug within the same drug class, and doctors may treat the side effects of prescribed drugs with even more drugs, which can overwhelm the patient. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2599", "text": "In general, the simultaneous use of multiple drugs should be carefully monitored by a qualified individual such as  board certified  and  licensed   medical doctor , either an  MD  or  DO . Close association between prescribing physicians and pharmacies, along with the  computerization  of  prescriptions  and patients' medical histories, aim to avoid the occurrence of dangerous drug interactions. Lists of contraindications for a drug are usually provided with it, either in monographs, package inserts (accompanying prescribed medications), or in warning labels (for OTC drugs). CDI/MDI might also be avoided by physicians requiring their patients to return any unused prescriptions. Patients should ask their doctors and pharmacists if there are any interactions between the drugs they are taking."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2600", "text": "In 2004, there were 3,800 deaths in the US resulting from a fatal medication error involving  alcohol , while in 1983 there were fewer than 100 such deaths. [ 5 ]  It is more of a risk for older patients. [ 3 ] [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2601", "text": "Alcohol  can exacerbate the symptoms and may directly contribute to increased severity of symptoms. The reasons for  toxicity  vary depending on the mixture of drugs. Usually, most victims die after using two or more drugs in combination that suppress breathing, and the low blood  oxygen  level causes  brain death . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2602", "text": "The  Commission on Human Medicines  ( CHM ) is a committee of the UK's  Medicines and Healthcare products Regulatory Agency .  It was formed in October 2005, and assumed the responsibilities of the  Medicines Commission  and the  Committee on Safety of Medicines . Membership in this various and extensive body is listed on  a governmental website ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2603", "text": "The CHM's responsibilities include advising the UK government ministers on matters relating to regulation of human medicinal products, giving advice in relation to the safety, quality and efficacy of human medicinal products, and promoting the collection and investigation of information relating to adverse reactions for human  medicines ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2604", "text": "The Medicines and Healthcare products Regulatory Agency undertook a public consultation on proposals to amend the advisory body structure laid down in the  Medicines Act 1968  in February 2005. Ministers agreed to a new structure with the establishment of the Commission that amalgamated the responsibilities of the Medicines Commission and the Committee on Safety of Medicines. The commission was established under Section 2 of the Medicines Act 1968 (SI 2005 No. 1094)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2605", "text": "The work done by the CHM is parcelled out to  Expert Advisory Groups  (EAGs), which in effect constitute a subcommittee structure. The EAG chairs and members are also required to follow the  NHS Code of Practice . Three statutory EAGs [ citation needed ]  - namely Pharmacovigilance; Chemistry, Pharmacy and Standards; and Biologicals/Vaccines - are appointed by the  NHS Appointments Commission  because they are also standing members of the commission."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2606", "text": "A list of all EAGs, as they were on 16 May 2011:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2607", "text": "The duties of the Commission which came into being on 30 October 2005 are set out in Section 3 of the Medicines Act 1968, as amended by the Medicines (Advisory Bodies) Regulations 2005 and include the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2608", "text": "The first Chairman of the Committee on Safety of Medicines was Sir  Derrick Dunlop . [ 1 ]  Other Chairmen are listed at  Committee on Safety of Medicines ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2609", "text": "The chairs of the Commission on Human Medicines have been"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2610", "text": "The term \u201cdormant therapy\u201d refers to a new drug or a new biological product which was made the subject of a request for designation in compliance with the Dormant Therapies Act. [ 1 ]   According to the legislation, the assignment of dormant therapy is given to a drug or new biological product that has been determined to have insufficient  patent  protection and meets an unmet medical need, improves outcomes, or reduces risks compared to an existing treatment. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2611", "text": "Many drugs may be abandoned due to their failure to meet a  clinical endpoint . Over time, manufacturers wanting to re-investigate the abandoned drug will not because the  patent  for the drug has expired or will expire prior to the completion of research and the federal approval process. Weak or no patent protection is a disincentive for drug development as it hinders a manufacturer\u2019s ability to recoup the investment in expensive  clinical trials . This disincentive is even more pronounced for treatments for more complex conditions such as  Alzheimer\u2019s , which require more clinical data than conditions which currently have existing treatments."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2612", "text": "In  medicine , a  drug eruption  is an  adverse drug reaction  of the  skin . Most drug-induced cutaneous reactions are mild and disappear when the offending drug is withdrawn. [ 1 ]  These are called \"simple\" drug eruptions. However, more serious drug eruptions may be associated with organ injury such as liver or kidney damage and are categorized as \"complex\". [ 2 ]  Drugs can also cause  hair  and  nail  changes, affect the  mucous membranes , or cause  itching  without outward skin changes. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2613", "text": "The use of synthetic pharmaceuticals and  biopharmaceuticals  in medicine has revolutionized human health, allowing us to live longer lives. Consequently, the average human adult is exposed to many drugs over longer treatment periods throughout a lifetime. [ 4 ]  This unprecedented rise in pharmaceutical use has led to an increasing number of observed adverse drug reactions. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2614", "text": "There are two broad categories of adverse drug reactions.  Type A  reactions are known side effects of a drug that are largely predictable and are called,  pharmatoxicologic. [ 5 ]  Whereas  Type B  or  hypersensitivity  reactions, are often immune-mediated and reproducible with repeated exposure to normal dosages of a given drug. [ 5 ]  Unlike type A reactions, the mechanism of type B or hypersensitivity drug reactions is not fully elucidated. However, there is a complex interplay between a patient's inherited genetics, the pharmacotoxicology of the drug and the immune response that ultimately give rise to the manifestation of a drug eruption. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2615", "text": "Because the manifestation of a drug eruption is complex and highly individual, there are many subfields in medicine that are studying this phenomenon. For example, the field of  pharmacogenomics  aims to prevent the occurrence of severe adverse drug reactions by analyzing a person's inherited genetic risk. [ 6 ]  As such, there are clinical examples of inherited genetic  alleles  that are known to predict drug hypersensitivities and for which diagnostic testing is available. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2616", "text": "Some of the most severe and life-threatening examples of drug eruptions are  erythema multiforme ,  Stevens\u2013Johnson syndrome  (SJS),  toxic epidermal necrolysis  (TEN),  hypersensitivity vasculitis ,  drug induced hypersensitivity syndrome  (DIHS),  erythroderma  and  acute generalized exanthematous pustulosis  (AGEP). [ 4 ]  These severe cutaneous drug eruptions are categorized as hypersensitivity reactions and are immune-mediated. There are four types of hypersensitivity reactions and many drugs can induce one or more hypersensitivity reactions. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2617", "text": "basophil surface receptors"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2618", "text": "angioedema"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2619", "text": "complement-driven cell lysis"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2620", "text": "hemolytic anemia , Goodpasture's,  ANCA vasculitis"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2621", "text": "in tissues-triggers recruitment of  leukocytes"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2622", "text": "inflammation leading to tissue destruction"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2623", "text": "The most common type of eruption is a  morbilliform  (resembling  measles ) or  erythematous rash  (approximately 90% of cases). [ 7 ]  Less commonly, the appearance may also be  urticarial ,  papulosquamous ,  pustular ,  purpuric ,  bullous  (with blisters) or  lichenoid . [ 3 ]   Angioedema  can also be drug-induced (most notably, by  angiotensin converting enzyme inhibitors )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2624", "text": "The underlying mechanism can be immunological (such as in  drug allergies ) or non-immunological (for example, in  photodermatitis  or as a side effect of  anticoagulants ). A  fixed drug eruption  is the term for a drug eruption that occurs in the same skin area every time the person is exposed to the drug. Eruptions can occur frequently with a certain drug (for example, with  phenytoin [ 8 ] ), or be very rare (for example,  Sweet's syndrome  following the administration of  colony-stimulating factors [ 9 ] )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2625", "text": "The culprit can be both a  prescription drug  or an  over-the-counter medication ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2626", "text": "Examples of common drugs causing drug eruptions are  antibiotics  and other  antimicrobial  drugs,  sulfa drugs ,  nonsteroidal anti-inflammatory drugs  (NSAIDs),  biopharmaceuticals ,  chemotherapy  agents,  anticonvulsants  and  psychotropic drugs . Common examples include photodermatitis due to local NSAIDs (such as  piroxicam ) or due to antibiotics (such as  minocycline ), fixed drug eruption due to acetaminophen or NSAIDs (Ibuprofen), and the rash following  ampicillin  in cases of  mononucleosis . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2627", "text": "Certain drugs are less likely to cause drug eruptions (rates estimated to be \u22643 per 1000 patients exposed). These include: digoxin, aluminum hydroxide, multivitamins, acetaminophen, bisacodyl, aspirin, thiamine, prednisone, atropine, codeine, hydrochlorothiazide, morphine, insulin, warfarin and spironolactone. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2628", "text": "Drug eruptions are diagnosed mainly from the  medical history  and  clinical examination . However, they can mimic various other conditions, thus delaying diagnosis (for example, in  drug-induced lupus erythematosus , or the  acne -like rash caused by  erlotinib ). A  skin biopsy ,  blood tests  or  immunological  tests can also be useful."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2629", "text": "Drug reactions have characteristic timing. The typical amount of time it takes for a rash to appear after exposure to a drug can help categorize the type of reaction. For example,  Acute generalized exanthematous pustulosis  usually occurs within 4 days of starting the culprit drug.  Drug Reaction with Eosinophilia and Systemic Symptoms  usually occurs between 15 and 40 days after exposure.  Toxic epidermal necrolysis  and  Stevens\u2013Johnson syndrome  typically occur 7\u201321 days after exposure.  Anaphylaxis occurs within minutes. Simple exanthematous eruptions occur between 4 and 14 days after exposure. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2630", "text": "TEN and SJS are severe cutaneous drug reactions that involve the skin and  mucous membranes . To accurately diagnose this condition, a detailed drug history is crucial. [ 4 ]  Often, several drugs may be causative and allergy testing may be helpful. [ 4 ]  Sulfa drugs are well known to induce TEN or SJS in certain people. For example, HIV patients have an increased incidence of SJS or TEN compared to the general population and have been found to express low levels of the drug metabolizing enzyme responsible for detoxifying sulfa drugs. [ 5 ]  Genetics plays an important role in predisposing certain populations to TEN and SJS. As such, there are some  FDA  recommended genetic screening tests available for certain drugs and ethnic populations to prevent the occurrence of a drug eruption. [ 5 ]  The most well known example is carbamezepine (an anti-convulsant used to treat seizures) hypersensitivity associated with the presence of HLA-B*5801 genetic allele in Asian populations. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2631", "text": "US African"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2632", "text": "Australian"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2633", "text": "Thai, European"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2634", "text": "Malaysian, Korean"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2635", "text": "HLA-B*1502"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2636", "text": "Han"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2637", "text": "DIHS is a delayed onset drug eruption, often occurring a few weeks to 3 months after initiation of a drug. [ 2 ]  Worsening of systemic symptoms occurs 3\u20134 days after cessation of the offending drug. [ 5 ]  There are genetic risk alleles that are predictive of the development of DIHS for particular drugs and ethnic populations. [ 5 ]  The most important of which is abacavir (an anti-viral used in the treatment of HIV) hypersensitivity associated with the presence of the HLA-B*5701 allele in European and African population in the United States and Australians. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2638", "text": "AGEP is often caused by antimicrobial, anti-fungal or antimalarial drugs. [ 4 ]  Diagnosis is often carried out by  patch testing . This testing should be performed within one month after resolution of the rash and patch test results are interpreted at different time points: 48 hours, 72hours and even later at 96 hours and 120 hours in order to improve the sensitivity. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2639", "text": "[ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2640", "text": "A  drug holiday  (sometimes also called a  drug vacation ,  medication vacation ,  structured treatment interruption ,  tolerance break ,  treatment break  or  strategic treatment interruption ) is when a patient stops taking a medication(s) for a period of time; anywhere from a few days to many months or even years if the doctor or medical provider feels it is best for the patient. It is recommended not to discontinue any medication without the close supervision of the prescribing party."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2641", "text": "Planned drug holidays are used in numerous fields of medicine. They are perhaps best known in  HIV  therapy, after a study showed that stopping medication may stimulate the  immune system  to attack the virus. [ 1 ] \nAnother reason for drug holidays is to permit a drug to regain  effectiveness  after a period of continuous use, and to reduce the  tolerance effect  that may require increased dosages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2642", "text": "In addition to drug holidays that are intended for therapeutic effect, they are sometimes used to reduce  drug side effects  so that patients may enjoy a more normal life for a period of time such as a weekend or holiday, or engage in a particular activity. For example, it is common for patients using  SSRI   anti-depressant  therapies to take a drug holiday to reduce or avoid side effects associated with  sexual dysfunction . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2643", "text": "In the treatment of mental illness, a drug holiday may be part of a progression toward treatment cessation. The holiday is also a tool to assess a drug's benefits against unwanted side effects, assuming that both will dissipate after an extended vacation. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2644", "text": "One-day drug holidays in the lithium treatment of bipolar disorder, known as \"lithium-free days\", have been in use since the pioneering work of Noack and Trautner in 1951. This was found to reduce toxic buildup of the drug in some patients. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2645", "text": "Drug holidays from  L-dopa  found use in the early 1970s when Sweet et al. reported they were beneficial in terms of restoring the effectiveness of the treatment after adaptation by the brain had diminished its effectiveness. [ 4 ] [ 5 ] [ 6 ] \nHowever, later studies revealed that such drug holidays conferred only temporary benefits to L-dopa responsiveness. Furthermore, there was an increased risk of death from associated complications, namely aspiration pneumonia, depression, and thromboembolic disease. L-dopa drug holidays are thus no longer recommended. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2646", "text": "Drug holidays from antipsychotic medication such as  chlorpromazine  have been used since the early 1980s to alleviate adverse reactions associated with long-term treatment. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2647", "text": "According to Ann Mortimer, it is acknowledged that established guidelines require long-term treatment in established schizophrenia, because the vast majority of evidence from discontinuation, \"drug holiday\", and ultra-low-dose studies conducted over many years points to significantly higher relapse rates when compared to maintenance treatment. If  antipsychotics  cannot be avoided in the near term, there is no reason to question their long-term usefulness. The same might be said of insulin in diabetes. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2648", "text": "HIV selectively targets activated  helper T-cells . Thus, over time,  HIV  will tend to selectively destroy those helper  T-cells  most capable of fighting the HIV infection off, effectively desensitizing the immune system to the infection. The purpose of a structured treatment interruption is to create a short interval in which the virus becomes common enough to stimulate reproduction of T-cells capable of fighting the virus."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2649", "text": "A 2006 HIV literature review noted that \"two studies suggested that so-called drug holidays were of no benefit and might actually harm patients, while a third study suggested that the idea might still have value and should be revisited.\" [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2650", "text": "In  pharmaceutical sciences ,  drug interactions  occur when a drug's  mechanism of action  is affected by the  concomitant  administration of substances such as foods, beverages, or other drugs. A popular example of drug\u2013food interaction is the effect of  grapefruit on the metabolism of drugs ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2651", "text": "Interactions may occur by simultaneous targeting of  receptors , directly or indirectly. For example, both  Zolpidem  and alcohol affect  GABA A  receptors , and their simultaneous consumption results in the overstimulation of the receptor, which can lead to loss of consciousness.  When two drugs affect each other, it is a  drug\u2013drug interaction (DDI) . The risk of a DDI increases with the number of drugs used. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2652", "text": "A large share of  elderly  people regularly use five or more medications or supplements, with a significant risk of side-effects from drug\u2013drug interactions. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2653", "text": "Drug interactions can be of three kinds:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2654", "text": "It may be difficult to distinguish between synergistic or additive interactions, as individual effects of drugs may vary."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2655", "text": "Direct interactions between drugs are also possible and may occur when two drugs are mixed before  intravenous injection . For example, mixing  thiopentone  and  suxamethonium  can lead to the  precipitation  of thiopentone. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2656", "text": "Pharmacodynamic  interactions are the drug\u2013drug interactions that occur at a  biochemical  level and depend mainly on the biological processes of organisms. These interactions occur due to action on the same targets; for example, the same receptor or  signaling pathway ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2657", "text": "Pharmacodynamic interactions can occur on protein  receptors . [ 5 ]   Two drugs can be considered to be  homodynamic , if they act on the same receptor. Homodynamic effects include drugs that act as (1) pure  agonists , if they bind to the main  locus  of the  receptor , causing a similar effect to that of the main drug, (2) partial  agonists  if, on binding to a secondary site, they have the same effect as the main drug, but with a lower intensity and (3)  antagonists , if they bind directly to the receptor's main locus but their effect is opposite to that of the main drug. These may be c ompetitive antagonists , if they compete with the main drug to bind with the receptor. or u ncompetitive antagonists,  when the antagonist binds to the receptor irreversibly. The drugs can be considered  heterodynamic  competitors, if they act on distinct receptor with similar  downstream pathways ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2658", "text": "The interaction my also occur via signal transduction mechanisms. [ 6 ]  For example,  low blood glucose  leads to a release of  catecholamines , triggering  symptoms  that hint the organism to take action, like consuming sugary foods. If a patient is on  insulin , which reduces blood sugar, and also  beta-blockers , the body is less able to cope with an insulin overdose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2659", "text": "Pharmacokinetics  is the field of research studying the chemical and biochemical factors that directly affect  dosage  and the  half-life  of drugs in an organism, including absorption, transport, distribution, metabolism and excretion. Compounds may affect any of those process, ultimately interfering with the flux of drugs in the  human body , increasing or reducing drug availability."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2660", "text": "Drugs that change intestinal motility may impact the level of other drugs taken. For example,  prokinetic agents  increase the  intestinal motility , which may cause drugs to go through the digestive system too fast, reducing absorption.  [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2661", "text": "The pharmacological modification of  pH  can affect other compounds. Drugs can be present in ionized or  non-ionized  forms depending on  pKa , and neutral compounds are usually better absorbed by membranes. [ 7 ]  Medication like  antacids  can increase pH and inhibit the absorption of other drugs such as  zalcitabine ,  tipranavir  and  amprenavir . The opposite is more common, with, for example, the antacid  cimetidine   stimulating  the absorption of  didanosine . Some resources describe that a gap of two to four hours between taking the two drugs is needed to avoid the interaction. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2662", "text": "Factors such as food with  high-fat content  may also alter the solubility of drugs and impact its absorption. This is the case for oral  anticoagulants  and  avocado . [ citation needed ]  The formation of non-absorbable complexes may occur also via  chelation , when  cations  can make certain drugs harder to absorb, for example between  tetracycline  or the  fluoroquinolones  and dairy products, due to the presence of  calcium ions . [ citation needed ]  .  Other drugs bind to proteins. Some drugs such as  sucralfate  bind to proteins, especially if they have a high  bioavailability . For this reason its administration is  contraindicated  in  enteral feeding . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2663", "text": "Some drugs also alter absorption by acting on the  P-glycoprotein  of the  enterocytes . This appears to be one of the mechanisms by which  grapefruit  juice increases the  bioavailability  of various drugs beyond its inhibitory activity on  first pass metabolism . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2664", "text": "Drugs also may affect each other by competing for transport proteins in  plasma , such as  albumin . In these cases the drug that arrives first binds with the plasma protein, leaving the other drug dissolved in the plasma, modifying its expected concentration. The organism has mechanisms to counteract these situations (by, for example, increasing  plasma clearance ), and thus they are not usually clinically relevant. They may become relevant if other problems are present, such as issues with drug excretion. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2665", "text": "Many drug interactions are due to alterations in  drug metabolism . [ 12 ]  Further, human drug-metabolizing enzymes are typically activated through the engagement of  nuclear receptors . [ 12 ]  One notable system involved in metabolic drug interactions is the enzyme system comprising the  cytochrome P450 oxidases ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2666", "text": "Cytochrome P450  is a very large family of  haemoproteins  (hemoproteins) that are characterized by their  enzymatic  activity and their role in the metabolism of a large number of drugs. [ 13 ]  Of the various families that are present in humans, the most interesting in this respect are the 1, 2 and 3, and the most important enzymes are  CYP1A2 ,  CYP2C9 ,  CYP2C19 ,  CYP2D6 ,  CYP2E1  and  CYP3A4 . [ 14 ] \nThe majority of the enzymes are also involved in the metabolism of  endogenous  substances, such as  steroids  or  sex hormones , which is also important should there be interference with these substances. The function of the enzymes can either be stimulated ( enzyme induction ) or inhibited ( enzyme inhibition )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2667", "text": "If a drug is metabolized by a CYP450 enzyme and drug B blocks the activity of these enzymes, it can lead to pharmacokinetic alterations. A. This alteration results in drug A remaining in the bloodstream for an extended duration, and eventually increase in concentration. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2668", "text": "In some instances, the inhibition may reduce the therapeutic effect, if instead the metabolites of the drug is responsible for the effect. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2669", "text": "Compounds that increase the efficiency of the enzymes, on the other hand, may have the opposite effect and increase the rate of metabolism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2670", "text": "An example of this is shown in the following table for the  CYP1A2  enzyme, showing the substrates (drugs metabolized by this enzyme) and some inductors and inhibitors of its activity: [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2671", "text": "Some foods also act as inductors or inhibitors of enzymatic activity. The following table shows the most common:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2672", "text": "Drugs tightly bound to proteins (i.e. not in the  free fraction ) are not available for  renal excretion . [ 17 ] \nFiltration depends on a number of factors including the  pH  of the urine. Drug interactions may affect those points.  [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2673", "text": "Herb-drug interactions are drug interactions that occur between  herbal medicines  and conventional drugs. [ 18 ]  These types of interactions may be more common than drug-drug interactions because herbal medicines often contain multiple pharmacologically active ingredients, while conventional drugs typically contain only one. [ 18 ]  Some such interactions are  clinically significant , [ 19 ]  although most herbal remedies are not associated with drug interactions causing serious consequences. [ 20 ]  Most catalogued herb-drug interactions are moderate in severity. [ 21 ]  The most commonly implicated conventional drugs in herb-drug interactions are  warfarin ,  insulin ,  aspirin ,  digoxin , and  ticlopidine , due to their narrow  therapeutic indices . [ 21 ] [ 22 ]  The most commonly implicated herbs involved in such interactions are those containing  St. John\u2019s Wort , magnesium, calcium, iron, or  ginkgo . [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2674", "text": "Examples of herb-drug interactions include, but are not limited to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2675", "text": "The mechanisms underlying most herb-drug interactions are not fully understood. [ 25 ]  Interactions between herbal medicines and anticancer drugs typically involve enzymes that metabolize  cytochrome P450 . [ 23 ]  For example, St. John's Wort has been shown to induce  CYP3A4  and  P-glycoprotein  in vitro and in vivo. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2676", "text": "The factors or conditions that predispose the appearance of interactions include factors such as  old age . [ 26 ]  This is where human physiology changing with age may affect the interaction of drugs. For example, liver metabolism, kidney function, nerve transmission, or the functioning of bone marrow all decrease with age. In addition, in old age, there is a sensory decrease that increases the chances of errors being made in the administration of drugs. [ 27 ]  The elderly are also more vulnerable to  polypharmacy , and the more drugs a patient takes, the higher is the chance of an interaction. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2677", "text": "Genetic factors  may also affect the enzymes and receptors, thus altering the possibilities of interactions.  [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2678", "text": "Patients with  hepatic  or  renal  diseases already may have difficulties metabolizing and excreting drugs, which may exacerbate the effect of interactions. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2679", "text": "Some drugs present an intrinsic increased risk for a harmful interaction, including drugs with a narrow  therapeutic index ,  where the difference between the  effective dose  and the  toxic dose  is small. [ n. 1 ]  The drug  digoxin  is an example of this type of drug. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2680", "text": "Risks are also increased when the drug presents a steep  dose-response curve , and small changes in the dosage produce large changes in the drug's concentration in the blood plasma. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2681", "text": "As of 2008, among adults in the  United States of America  older than 56, 4% were taking medication and/ or supplements that put them at risk of a major drug interaction. [ 30 ]  Potential drug-drug interactions have increased over time [ 31 ]  and are more common in the less-educated  elderly  even after controlling for age, sex, place of residence, and  comorbidity . [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2682", "text": "A  drug of last resort  ( DoLR ), also known as a  heroic dose , [ 1 ]  is a  pharmaceutical drug  which is tried after all other drug options have failed to produce an adequate response in the patient.  Drug resistance , such as  antimicrobial resistance  or  antineoplastic resistance , may make the first-line drug ineffective, especially in case of  multidrug-resistant  pathogens and tumors. Such an alternative may be outside of extant regulatory requirements or medical best practices, in which case it may be viewed as  salvage therapy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2683", "text": "The use of a drug of last resort may be based on agreement among members of a patient's care network, including physicians and healthcare professionals across multiple specialties, or on a patient's desire to pursue a particular course of treatment and a practitioner's willingness to administer that course. Certain situations such as severe bacterial related  sepsis  or  septic shock  can more commonly lead to last resorts."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2684", "text": "Therapies considered to be drugs of last resort may at times be used earlier in the event that an agent would likely show the most immediate  dose-response  related efficacy in time-critical situations such as high mortality circumstances. Many of the drugs considered last resorts fall into one or more of the categories of  antibiotics ,  antivirals , and  chemotherapy  agents. These agents often exhibit what are considered to be among the most efficient dose-response related effects, or are drugs for which few or no resistant strains are known."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2685", "text": "With regard to antibiotics, antivirals, and other agents indicated for treatment of infectious pathological disease, drugs of last resort are commonly withheld from administration until after the trial and failure of more commonly used treatment options to prevent the development of drug resistance. One of the most commonly known examples of both antimicrobial resistance and the relationship to the classification of a drug of last resort is the emergence of  Staphylococcus aureus  (MRSA) (sometimes also referred to as multiple-drug resistant  S. aureus  due to resistance to non-penicillin antibiotics that some strains of  S. aureus  have shown to exhibit). In cases presenting with suspected  S. aureus , it is suggested by many public health institutions (including the  World Health Organization  (WHO) and the  Centers for Disease Control and Prevention  (CDC) in the United States) to treat first with empirical therapies for  S. aureus , with an emphasis on evaluating the response to initial treatment and laboratory diagnostic techniques to isolate cases of drug resistance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2686", "text": "Due to the possibility of potential severe or fatal consequences of resistant strains, initial treatment often includes concomitant administration of multiple antimicrobial agents that are not known to show cross-resistance, so as to reduce the possibility of a resistant strain remaining inadequately treated by a single agent during the evaluation of drug response. Once a specific resistance profile has been isolated via clinical laboratory findings, treatment is often modified as indicated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2687", "text": "Vancomycin  has long been considered a drug of last resort, due to its efficiency in treating multiple drug-resistant infectious agents and the requirement for  intravenous  administration. Recently, resistance to even vancomycin has been shown in some strains of  S. aureus  (sometimes referred to as  vancomycin resistant  S. aureus  (VRSA) or vancomycin intermediate-resistance  S. aureus  (VISA)) often coinciding with methicillin/penicillin resistance, prompting the inclusion of newer antibiotics (such as  linezolid ) that have shown efficacy in highly drug-resistant strains. There are also strains of enterococci that have developed resistance to vancomycin referred to as  vancomycin resistant enterococcus  (VRE)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2688", "text": "Agents classified as fourth-line (or greater) treatments or experimental therapies could be considered by default to be drugs of last resort due to their low placement in the treatment hierarchy. Such placement may result from a multitude of considerations, including greater efficacy of other agents, socioeconomic considerations, availability issues,  unpleasant side effects  or similar issues relating to patient tolerance. Some experimental therapies might also be called drugs of last resort when administered following the failure of all other currently accepted treatments."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2689", "text": "Although most of the notable drugs of last resort are antibiotics or antivirals, other drugs are sometimes considered drugs of last resort, such as  cisapride . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2690", "text": "Drug reaction testing  uses a  genetic test  to predict how a particular person will respond to various prescription and non-prescription  medications .  It checks for genes that code for specific  liver   enzymes  which activate, deactivate, or are influenced by various drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2691", "text": "There are currently four  genetic markers  commonly tested for:  2D6 ,  2C9 ,  2C19 , and  1A2 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2692", "text": "This testing has been done for some time by drug companies working on new drugs, but is relatively newly available to the general public.   Strattera  is the first drug to mention the test in the official documentation, although it doesn't specifically recommend that patients get the test before taking the medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2693", "text": "There are four possible categories for each marker:  poor metabolizer ,  intermediate metabolizer ,  extensive metabolizer , or  ultra-extensive metabolizer .  Different testing companies may call these by different names.  Extensive metabolizers (that is, people who are extensive metabolizers of a given type) are the most common, and are the type of people for which drugs are designed.  Up to 7% of Caucasians are poor metabolizers of drugs metabolized by the  CYP2D6  enzyme. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2694", "text": "People who cannot  metabolize  a drug will require a much lower dose than is recommended by the manufacturer, and those who metabolize it quickly may require a higher dose.  Some drugs, such as  codeine , will not be effective in people without the requisite enzymes to activate them."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2695", "text": "People who are poor metabolizers of a drug may overdose while taking less than the recommended dose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2696", "text": "Drug-induced amnesia  is  amnesia  caused by drugs.  Amnesia may be therapeutic for medical treatment or for medical procedures, or it may be a side-effect of a drug, such as  alcohol , or certain medications for psychiatric disorders, such as  benzodiazepines . [ 1 ]  It is seen also with slow acting parenteral general anaesthetics. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2697", "text": "Amnesia is desirable during surgery, so  general anaesthesia  procedures are designed to induce it for the duration of the operation. Sedatives such as benzodiazepines, which are commonly used for anxiety disorders, can reduce the encoding of new memories, particularly in high doses (for example, prior to surgery in order for a person not to recall the surgery). [ 2 ]  Amnestic drugs can be used to induce a  coma  for a child breathing using mechanical ventilation, or to help reduce intracranial pressure after  head trauma . [ 3 ] [ failed verification ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2698", "text": "Researchers are currently experimenting with drugs which induce amnesia in order to improve understanding of human memory, and develop better drugs to treat psychiatric disorders and memory-related disorders. People with  Alzheimer's disease  and other forms of  dementia  are likely to benefit. By understanding the ways in which amnesia-inducing drugs interact with the brain, researchers hope to better understand the ways in which  neurotransmitters  aid in the formation of memory. By stimulating rather than depressing these neurotransmitters, memory may improve. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2699", "text": "Holmes et al. (2010) [ 4 ]  commented that the media misrepresented two recent studies as research on \"erasing\" traumatic memories, but showed the fear response associated with stressful memory could be greatly reduced whilst the factual memory of the trauma remained intact. Similarly, Brunet et al. (2008) found that the people with chronic  posttraumatic stress disorder  who were treated with  propranolol  for a single day had a reduced response to existing trauma while retaining memory of the trauma. [ 5 ]  In the process of remembering, the memory needs to be restored in the brain. By introducing an amnesia-inducing drug during this process, the memory can be disrupted. While the memory remains intact, the emotional reaction is damped, making the memory less overwhelming. Researchers believe this drug will help patients with post-traumatic stress disorder be able to better process the trauma without reliving the trauma emotionally. [ citation needed ]  This has raised legal and ethical concerns should drugs be found to have altered the memory of traumatic events that occur in victims of crimes (e.g. murder attempt), and whether it is therapeutically desirable to do so. [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2700", "text": "Amnesia can result from a side-effect of prescription or non-prescription drugs. Both  substance use  and alcohol can cause both long-term and short-term memory loss, resulting in  blackouts ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2701", "text": "The most commonly used group of prescription drugs which can produce amnesia are benzodiazepines, especially if combined with alcohol, however, in limited quantities,  triazolam  (Halcion) is not associated with amnesia or memory impairment. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2702", "text": "Nepenthe , literally named anti-sorrow, is a substance mentioned in the  Odyssey  given to  Helen of Troy , said to originate from  Egypt . Consumption causes sorrowful memories to be forgotten. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2703", "text": "In  pharmacology , an  effective dose  ( ED ) or  effective concentration  ( EC ) is the  dose  or  concentration  of a  drug  that produces a biological response. [ 1 ] [ 2 ]  The term \"effective dose\" is used when measurements are taken  in vivo ,  while \"effective concentration\" is used when the measurements are taken  in vitro . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2704", "text": "It has been stated  that any substance can be toxic at a high enough dose. This concept was exemplified in 2007 when a California woman died of  water intoxication  in  a contest sanctioned by a radio station . [ 4 ]  The line between efficacy and toxicity is dependent upon the particular patient, although the dose administered by a physician should fall into the predetermined  therapeutic window  of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2705", "text": "The importance of determining the therapeutic range of a drug cannot be overstated. This is generally defined by the range between the  minimum effective dose  (MED) and the  maximum tolerated dose  (MTD). The MED is defined as the lowest dose level of a pharmaceutical product that provides a clinically significant response in average efficacy, which is also statistically significantly superior to the response provided by the placebo. [ 5 ]  Similarly, the MTD is the highest possible but still tolerable dose level with respect to a pre-specified clinical limiting toxicity. [ 5 ]  In general, these limits refer to the average patient population. For instances in which there is a large difference between the MED and MTD, it is stated that the drug has a large therapeutic window. Conversely, if the range is relatively small, or if the MTD is less than the MED, then the pharmaceutical product will have little to no practical value. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2706", "text": "The  median effective dose  is the dose that produces a quantal effect (all or nothing) in 50%  of the population that takes it (median referring to the 50% population base). [ 6 ]  It is also sometimes abbreviated as the ED 50 , meaning \"effective dose for 50% of the population\". The ED50 is commonly used as a measure of the reasonable expectancy of a drug effect, but does not necessarily represent the dose that a clinician might use. This depends on the need for the effect, and also the toxicity. The toxicity and even the lethality of a drug can be quantified by the TD 50  and LD 50  respectively. Ideally, the effective dose would be substantially less than either the toxic or lethal dose for a drug to be therapeutically relevant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2707", "text": "The  ED 95  is the dose required to achieve the desired effect in 95% of the population."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2708", "text": "In anaesthesia, the term ED 95  is also used when referring to the pharmacology of neuromuscular blocking drugs. In this context, it is the dose which will cause 95% depression of the height of a single muscle twitch, in half of the population. Put another way, it is the ED 50  for 95% reduction in twitch height. [ 7 ]  The single twitch response occurs when a nerve stimulator is used to stimulate the ulnar nerve, and the degree of twitch of the adductor pollicus muscle is measured. A more accurate nomenclature when used in this way would be \"ED 50 95\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2709", "text": "An  equianalgesic  chart is a  conversion chart  that lists equivalent doses of  analgesics  (drugs used to relieve pain). Equianalgesic charts are used for calculation of an equivalent dose (a dose which would offer an equal amount of  analgesia ) between different analgesics. [ 1 ]  Tables of this general type are also available for  NSAIDs ,  benzodiazepines ,  depressants ,  stimulants ,  anticholinergics  and others."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2710", "text": "Equianalgesic tables are available in different formats, such as pocket-sized cards for ease of reference. [ 1 ]  A frequently-seen format has the drug names in the left column, the route of administration in the center columns and any notes in the right column. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2711", "text": "There are several reasons for switching a patient to a different pain medication. These include practical considerations such as lower cost or unavailability of a drug at the patient's preferred pharmacy, or medical reasons such as lack of effectiveness of the current drug or to minimize adverse effects. Some patients request to be switched to a different narcotic due to stigma associated with a particular drug (e.g. a patient refusing  methadone  due to its association with  opioid   addiction treatment ). [ 4 ]  Equianalgesic charts are also used when calculating an equivalent dosage of the same drug, but with a different  route of administration . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2712", "text": "An equianalgesic chart can be a useful tool, but the user must take care to correct for all relevant variables such as route of administration,  cross tolerance ,  half-life  and the  bioavailability  of a drug. [ 5 ]  For example, the narcotic  levorphanol  is 4\u20138 times  stronger  than  morphine , but also has a much longer half-life. Simply switching the patient from 40\u00a0mg of morphine to 10\u00a0mg of levorphanol would be dangerous due to dose accumulation, and hence frequency of administration should also be taken into account."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2713", "text": "There are other concerns about equianalgesic charts. Many charts derive their data from studies conducted on opioid-naive patients. Patients with  chronic  (rather than acute) pain may respond to analgesia differently. Repeated administration of a medication is also different from single dosing, as many drugs have active metabolites that can build up in the body. [ 6 ]  Patient variables such as sex, age, and organ function may also influence the effect of the drug on the system. These variables are rarely included in equianalgesic charts. [ 7 ] [ 3 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2714", "text": "Opioids  are a class of compounds that elicit  analgesic  (pain killing) effects in humans and animals by binding to the  \u03bc-opioid receptor  within the  central nervous system . The following table lists opioid and non-opioid analgesic drugs and their relative  potencies . Values for the potencies represent opioids taken orally unless another  route of administration  is provided. As such, their  bioavailabilities  differ, and they may be more potent when taken  intravenously . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2715", "text": "This chart measures pain relief versus mass of medication. Not all medications have a fixed relationship on this scale.  Methadone  is different from most opioids because its potency can vary depending on how long it is taken. Acute use (1\u20133 days) yields a potency about 1.5\u00d7 stronger than that of  morphine  and chronic use (7 days+) yields a potency about 2.5 to 5\u00d7 that of morphine. Similarly, the effect of  tramadol  increases after consecutive dosing due to the accumulation of its active metabolite and an increase of the oral bioavailability in chronic use. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2716", "text": "300\u00a0mg ( PO )"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2717", "text": "Unknown (researches are still being made)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2718", "text": "( IV / IM ) or other parental administrations apart from spinal administration"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2719", "text": "IV / IM ) or other parental administrations apart from spinal administration [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2720", "text": "2\u20132.5  (insufflated) [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2721", "text": "(morphine  prodrug ) [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2722", "text": "( IV , IM )"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2723", "text": "62%"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2724", "text": "Buccal: 28% \nSublingual: 37.5%\nIntranasal: 43%\nIV, IM & IT: 100%"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2725", "text": "2\u20136 hours parenteral"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2726", "text": "Explanatory notes"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2727", "text": "Citations"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2728", "text": "Bibliography"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2729", "text": "Expanded access  or  compassionate use  is the use of an unapproved drug or medical device under special forms of  investigational new drug applications  (IND) or  IDE application  for devices, outside of a  clinical trial , by people with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2730", "text": "These programs go under various names, including  early access ,  special access , or  managed access program ,  compassionate use ,  compassionate access ,  named-patient access ,  temporary authorization for use ,  cohort access , and  pre-approval access . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2731", "text": "In general the person and their doctor must apply for access to the investigational product, the company has to choose to cooperate, and the medicine's regulatory agency needs to agree that the risks and possible benefits of the drug or device are understood well enough to determine if putting the person at risk has sufficient potential benefit.  In some countries the government will pay for the drug or device, but in many countries the person must pay for the drug or device, as well as medical services necessary to receive it."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2732", "text": "In the US, compassionate use started with the provision of investigational medicine to certain patients in the late 1970s, and a formal program was established in 1987 in response to HIV/AIDS patients requesting access to drugs in development. An important legal case was  Abigail Alliance v. von Eschenbach , in which the Abigail Alliance, a group that advocates for access to investigational drugs for people who are terminally ill, tried to establish such access as a legal right. The Supreme Court declined to hear the case, effectively upholding previous cases that have maintained that there is not a constitutional right to unapproved medical products."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2733", "text": "As of 2016, [update]  regulation of access to pharmaceuticals that were not approved for marketing was handled on a country by country basis, including in the European Union, where the  European Medicines Agency  issued guidelines for national regulatory agencies to follow. In the US, Europe, and the EU, no company could be compelled to provide a drug or device that it was  developing . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2734", "text": "Companies sometimes provide drugs under these programs to people who were in clinical trials and who responded to the drug, after the clinical trial ends. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2735", "text": "In the US as of 2018, people could try obtain unapproved drugs or medical devices that were in development under specific conditions. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2736", "text": "These conditions were: [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2737", "text": "Drugs can be made available to individuals, small groups, or large groups. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2738", "text": "In the US, actual provision of the drug depends on the manufacturer's willingness to provide it, as well as the person's ability to pay for it; it is the company's decision whether to require payment or to provide the drug or device for free. [ 1 ]   The manufacturer can only charge  direct costs  for individual INDs; it can add some but not all  indirect costs  for small group or larger expanded access programs. [ 6 ]  To the extent that a doctor or clinic is required for use of the drug or device, they too may require payment. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2739", "text": "In some cases, it may be in the manufacturer's commercial interest to provide access under an EA program; this is a way, for example, for a company to make money before the drug or device is approved.  Companies must provide data collected from people getting the drug or device under EA programs to the FDA annually; this data may be helpful with regard to getting the drug or device approved, or may be harmful, should unexpected adverse events occur.  The manufacturer remains legally liable as well. If the manufacturer chooses to charge for the investigational product, that price influences later discussions about the price if the product is approved for marketing. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2740", "text": "As of February\u00a02019 [update] , 41 states have passed  right-to-try laws  that permit manufacturers to provide experimental medicines to terminally ill people without US FDA authorization. [ 7 ]   Legal, medical, and bioethics scholars, including Jonathan Darrow and Arthur Caplan, have argued that these state laws have little practical significance because people can already obtain pre-approval access through the FDA's expanded access program, and because the FDA is generally not the limiting factor in obtaining pre-approval access. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2741", "text": "In Europe, the  European Medicines Agency  issued guidelines that members may follow. Each country has its own regulations, and they vary. In the UK, for example, the program is called \"early access to medicine scheme\" or EAMS and was established in 2014. If a company that wants to provide a drug under EAMS, it must submit its Phase I data to the  Medicines and Healthcare products Regulatory Agency  and apply for what is called a \"promising innovative medicine\" (PIM) designation. If that designation is approved, the data is reviewed, if that review is positive, the  National Health Service  is obligated to pay for people who fit the criteria to have access to the drug. As of 2016, governments also paid for early access to drugs in Austria, Germany, Greece, and Spain. [ 1 ]  Since 2021, France has a system of early and expanded access separated in two systems: AAC and AAP. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2742", "text": "Companies sometimes make use of expanded programs in Europe even after they receive EMA approval to market a drug, because drugs also must go through regulatory processes in each member state, and in some countries this process can take nearly a year; companies can start making sales earlier under these programs. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2743", "text": "In the Philippines, the usage of unregistered drugs may be allowed through a doctor, a specialist, or health institution or society obtaining a specific compassionate use permit (CSP) from the country's  Food and Drug Administration  for the treatment of their terminally or seriously ill patients. The issuance of CSP is stated under  Department of Health  Administrative Order No. 4 of 1992. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2744", "text": "Those seeking CSP are required to provide the following information; estimated amount of the unregistered drug the patient, the \"licensed drug/device establishment through which the unregistered drug may be procured\", and \"the names and address of the specialists qualified and authorized to use the product.\" A CSP may also be obtained for processed  medical cannabis  despite cannabis in general being illegal in the Philippines. [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2745", "text": "In the US, one of the earliest expanded access programs was a compassionate use IND that was established in 1978, which allowed a limited number of people to use  medical cannabis  grown at the  University of Mississippi , under the direction of Marijuana Research Project Director Dr.  Mahmoud ElSohly .  It is administered by the  National Institute on Drug Abuse . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2746", "text": "The program was started after  Robert C. Randall   brought a lawsuit ( Randall v. U.S ) [ 13 ]  against the FDA, the  Drug Enforcement Administration , the  National Institute on Drug Abuse , the  Department of Justice , and the  Department of Health, Education & Welfare .  Randall, who had  glaucoma , had successfully used the  Common Law doctrine of necessity  to argue against criminal charges of marijuana cultivation that had been brought against him, because his use of cannabis was deemed a  medical necessity  ( U.S. v. Randall ). [ 13 ]  On November 24, 1976, federal Judge James Washington ruled in his favor. [ 14 ] :\u200a142\u200a [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2747", "text": "The settlement in  Randall v. U.S.  became the legal basis for the FDA's compassionate IND program. [ 13 ]   People were only allowed to use cannabis under the program who had certain conditions, like glaucoma, known to be alleviated with cannabis.  The scope was later expanded to include people with  AIDS  in the mid-1980s. At its peak, fifteen people received the drug. 43 people were approved for the program, but 28 of the people whose doctors completed the necessary paperwork never received any cannabis. [ 16 ] [ 14 ]  The program stopped accepting new people in 1992 after public health authorities concluded there was no scientific value to it, and due to President  George H. W. Bush  administration's policies.  As of 2011, four people continued to receive cannabis from the government under the program. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2748", "text": "The closure of the program during the height of the AIDS epidemic led to the formation of the medical cannabis movement in the United States, a movement which initially sought to provide cannabis for treating anorexia and wasting syndrome in people with AIDS. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2749", "text": "In November 2001 the Abigail Alliance for Better Access to Developmental Drugs was established by Frank Burroughs in memory of his daughter, Abigail. [ 19 ]    The Alliance seeks broader availability of investigational drugs on behalf of people with terminal illnesses.  It is best known for a legal case, which it lost,  Abigail Alliance v. von Eschenbach , in which it was represented by the  Washington Legal Foundation . On August 7, 2007, in an 8\u20132 ruling, the  U.S. Court of Appeals for the District of Columbia Circuit  reversed an earlier ruling in favor of the Alliance. [ 20 ]   In 2008, the  Supreme Court of the United States  declined to hear their appeal. This decision left standing the appellate court decision that people who are terminal ill patients have no legal right to demand \"a potentially toxic drug with no proven therapeutic benefit\". [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2750", "text": "In March 2014, Josh Hardy, a 7-year-old boy from Virginia, made national headlines that sparked a conversation on pediatric access to investigational drugs when his family's request for  brincidofovir  was declined by the drug manufacturer, Chimerix. [ 22 ]  The company reversed its decision after pressure from cancer advocacy organizations, and Josh received the drug that saved his life. [ 23 ] [ 24 ]  Hardy later passed away in September 2016 due to complications related to his underlying cancer diagnosis. [ 25 ]  In 2016 Kids v Cancer, a pediatric cancer advocacy organization, launched the Compassionate Use Navigator to assist physicians and guide families about the application process. [ 26 ]  Since then, FDA simplified the application process, but stressed that it cannot require a manufacturer to provide a product. [ 27 ] [ 28 ]  FDA receives about 1,500 expanded access requests per year and authorizes 99% of it. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2751", "text": "The  first-dose phenomenon  is a sudden and severe fall in  blood pressure  that can occur when changing from a lying to a standing position the first time that an  alpha blocker  drug is used [ 1 ]  or when resuming the drug after many months off. [ 2 ]  This  postural hypotension  usually happens shortly after the first dose is absorbed into the blood and can result in  syncope  (fainting). Syncope occurs in approximately 1% of patients given an initial dose of 2\u00a0mg  prazosin  or greater. This adverse effect is self-limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2752", "text": "The alpha blocker  prazosin  (Minipress) is most notorious for producing a first dose phenomenon. Other drugs of the same family,  doxazosin  (Cardura) and  terazosin  (Hytrin), can also cause this phenomenon, though less frequently."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2753", "text": "The cause is not clear. It occurs more commonly in patients who are salt and fluid volume depleted (as happens due to the use of  diuretics ), or were using  beta blockers . [ 4 ]  Diuretics and beta blockers are frequently used to control  hypertension . For this reason, treatment with  prazosin  (Minipress) should always be initiated with a low dose and should be taken at bedtime to avoid standing position."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2754", "text": "This effect is also observed after the administration of the first dose of drugs in the ACEi class ( angiotensin-converting enzyme inhibitor ). [ 5 ]  This may occur with the class's better known side effect of dry cough (due to decreased breakdown of bradykinin), though there is no clear relationship between the two side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2755", "text": "The first dose phenomenon in ACEi is reduced and made safer by avoiding diuretics for 24 hours prior to first dose, taking first dose at night (so avoiding falls, etc) and starting on low doses and titrating upwards."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2756", "text": "Redirect to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2757", "text": "In  pharmacology ,  hazardous drugs  are drugs that are known to cause harm, which may or may not include  genotoxicity  (the ability to cause a change or mutation in genetic material). Genotoxicity might involve  carcinogenicity , the ability to cause  cancer  in animal models, humans or both;  teratogenicity , which is the ability to cause defects on  fetal  development or fetal malformation; and lastly hazardous drugs are known to have the potential to cause fertility impairment, which is a major concern for most clinicians. [ 1 ]  These drugs can be classified as  antineoplastics , cytotoxic agents, biologic agents, antiviral agents and immunosuppressive agents. This is why safe handling of hazardous drugs is crucial."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2758", "text": "Safe handling refers to the process in which health care workers adhere to practices set forth by national health and safety organizations, that have been designed to eliminate or significantly reduce occupational exposure. Some of these practices include but are not limited to, donning of personal protective equipment such as a disposable gown, gloves, masks and the utilization of a closed-system drug transfer device. The key safe handling is to protect the health care worker throughout the three phases of contact with the hazardous drugs. These phases are drug preparation, administration and disposal. Some studies have shown that while compounding hazardous drugs in a Class II BSC in conjunction with a closed-system drug transfer device, a  significant decrease in drug contaminants inside a Class II BSC has resulted. [ 2 ]  This led the Oncology Nursing Society (ONS) to make the statement in 2003 that a closed-system drug transfer device is viewed as one of safest measures to prevent hazardous drug exposure in a clinician\u2019s working environment. [ 3 ]  However, a  Cochrane  review published in 2018 that synthesized all available controlled studies found no evidence of a closed-system drug transfer device offering an additional decrease in contamination or exposure to safe handling practices alone. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2759", "text": "It has been determined that current  personal protective equipment  (PPE) does not provide adequate protection against workers handling hazardous drugs - NIOSH states that \u201c... measurable concentrations of some hazardous drugs have been documented in the urine of health care workers who prepared or administered them \u2212 even after safety precautions had been employed.\u201d [ 1 ]  Further, NIOSH recommends that institutions should \"consider using devices such as closed-system transfer devices. Closed systems limit the potential for generating aerosols and exposing workers\". [ 1 ]  Other guidelines outline that \"As other products become available, they should meet the definition of a  closed system drug transfer device  established by NIOSH and should be required to demonstrate their effectiveness in independent studies\". [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2760", "text": "Hormesis  is a two-phased  dose-response relationship  to an environmental agent whereby low-dose amounts have a beneficial effect and high-dose amounts are either inhibitory to function or toxic. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Within the  hormetic zone , the biological response to low-dose amounts of some  stressors  is generally favorable. An example is the breathing of  oxygen , which is required in low amounts (in air) via  respiration  in living animals, but can be toxic in high amounts, even in a managed clinical setting. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2761", "text": "In  toxicology , hormesis is a dose-response phenomenon to  xenobiotics  or other stressors. \nIn  physiology  and nutrition, hormesis has regions extending from low-dose deficiencies to  homeostasis, and potential toxicity at high levels. [ 6 ]  Physiological concentrations of an agent above or below homeostasis may adversely affect an organism, where the hormetic zone is a region of homeostasis of balanced nutrition. [ 7 ]  In  pharmacology , the hormetic zone is similar to the  therapeutic window ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2762", "text": "In the context of toxicology, the hormesis model of dose response is vigorously debated. [ 8 ]  The biochemical mechanisms by which hormesis works (particularly in applied cases pertaining to behavior and toxins) remain under early laboratory research and are not well understood. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2763", "text": "The term \"hormesis\" derives from  Greek   h\u00f3rm\u0113sis  for \"rapid motion, eagerness\", itself from ancient Greek  horm\u00e1ein  to excite. [ 4 ]  The same Greek root provides the word  hormone . The term \"hormetics\" is used for the study of hormesis. [ 6 ]  The word hormesis was first reported in English in 1943. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2764", "text": "A form of hormesis famous in antiquity was  Mithridatism , the practice whereby  Mithridates VI  of  Pontus  supposedly made himself immune to a variety of toxins by regular exposure to small doses.  Mithridate  and  theriac ,  polypharmaceutical   electuaries  claiming descent from his formula and initially including flesh from poisonous animals, were consumed for centuries by emperors, kings, and queens as protection against poison and ill health. In the  Renaissance , the  Swiss  doctor  Paracelsus  said, \" All things are poison, and nothing is without poison; the dosage alone makes it so a thing is not a poison. \""}
{"_id": "WikiPedia_Pharmacology$$$corpus_2765", "text": "German  pharmacologist   Hugo Schulz  first described such a phenomenon in 1888 following his own observations that the growth of yeast could be stimulated by small doses of poisons. This was coupled with the work of German physician  Rudolph Arndt , who studied animals given low doses of drugs, eventually giving rise to the  Arndt\u2013Schulz rule . [ 8 ]  Arndt's advocacy of  homeopathy  contributed to the rule's diminished credibility in the 1920s and 1930s. [ 8 ]  The term \"hormesis\" was coined and used for the first time in a scientific paper by  Chester M. Southam  and J. Ehrlich in 1943 in the journal  Phytopathology , volume 33, pp.\u00a0517\u2013541."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2766", "text": "In 2004,  Edward Calabrese  evaluated the concept of hormesis. [ 9 ] [ 10 ]  Over 600 substances show a U-shaped  dose\u2013response relationship ; Calabrese and Baldwin wrote: \"One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria [of a U-shaped response indicative of hormesis]\" [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2767", "text": "Carbon monoxide  is produced in small quantities across  phylogenetic  kingdoms, where it has essential roles as a  neurotransmitter  (subcategorized as a  gasotransmitter ). The majority of endogenous carbon monoxide is produced by  heme oxygenase ; the loss of heme oxygenase and subsequent loss of carbon monoxide signaling has catastrophic implications for an organism. [ 12 ]  In addition to physiological roles, small amounts of carbon monoxide can be inhaled or administered in the form of  carbon monoxide-releasing molecules  as a therapeutic agent. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2768", "text": "Regarding the hormetic curve graph:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2769", "text": "Many organisms maintain a hormesis relationship with oxygen, which follows a hormetic curve similar to carbon monoxide:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2770", "text": "Physical exercise intensity may exhibit a hormetic curve. Individuals with low levels of physical activity are at risk for some diseases; however, individuals engaged in moderate, regular exercise may experience less disease risk. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2771", "text": "The possible effect of small amounts of oxidative stress is under laboratory research. [ 16 ]   Mitochondria  are sometimes described as \"cellular power plants\" because they generate most of the cell's supply of adenosine triphosphate (ATP), a source of chemical energy.  Reactive oxygen species  (ROS) have been discarded as unwanted byproducts of  oxidative phosphorylation  in mitochondria by the proponents of the free-radical theory of aging promoted by  Denham Harman . The  free-radical theory  states that compounds inactivating ROS would lead to a reduction of oxidative stress and thereby produce an increase in lifespan, although this theory holds only in  basic research . [ 17 ]  However, in over 19  clinical trials , \"nutritional and genetic interventions to boost antioxidants have generally failed to increase life span.\" [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2772", "text": "Whether this concept applies to humans remains to be shown, although a 2007  epidemiological  study supports the possibility of mitohormesis, indicating that supplementation with  beta-carotene ,  vitamin A  or  vitamin E  may increase disease  prevalence  in humans. [ 19 ]  More recent studies have reported that  rapamycin  exhibits hormesis, where low doses can enhance cellular longevity by partially inhibiting mTOR, unlike higher doses that are toxic due to complete inhibition. This partial inhibition of  mTOR  (by the hormetic effect of low-dose rapamycin) modulates mTOR\u2013mitochondria  cross-talk , thereby demonstrating mitohormesis; and consequently reducing  oxidative damage , metabolic dysregulation, and  mitochondrial dysfunction , thus slowing cellular  aging . [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2773", "text": "Alcohol  is believed to be hormetic in preventing heart disease and stroke, [ 20 ]  although the benefits of light drinking may have been exaggerated. [ 21 ] [ 22 ]  The  gut microbiome  of a typical healthy individual naturally ferments small amounts of ethanol, and in rare cases dysbiosis leads to  auto-brewery syndrome , therefore whether benefits of alcohol are derived from the behavior of consuming alcoholic drinks or as a homeostasis factor in normal physiology via metabolites from commensal microbiota remains unclear. [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2774", "text": "In 2012, researchers at UCLA found that tiny amounts (1\u00a0mM, or 0.005%) of ethanol doubled the lifespan of  Caenorhabditis elegans , a roundworm frequently used in biological studies, that were starved of other nutrients. Higher doses of 0.4% provided no longevity benefit. [ 25 ]  However, worms exposed to 0.005% did not develop normally (their development was arrested). The authors argue that the worms were using ethanol as an alternative energy source in the absence of other nutrition, or had initiated a stress response. They did not test the effect of ethanol on worms fed a normal diet."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2775", "text": "In 2010, a paper in the journal  Environmental Toxicology & Chemistry  showed that low doses of  methylmercury , a potent neurotoxic pollutant, improved the hatching rate of  mallard  eggs. [ 26 ]  The author of the study, Gary Heinz, who led the study for the  U.S. Geological Survey  at the  Patuxent Wildlife Research Center  in  Beltsville , stated that other explanations are possible. For instance, the flock he studied might have harbored some low, subclinical infection and that mercury, well known to be antimicrobial, might have killed the infection that otherwise hurt reproduction in the untreated birds. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2776", "text": "Hormesis has been observed in a number of cases in humans and animals exposed to chronic low doses of ionizing radiation. A-bomb survivors who received high doses exhibited shortened lifespan and increased cancer mortality, but those who received low doses had lower cancer mortality than the Japanese average. [ 27 ] [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2777", "text": "In Taiwan, recycled  radiocontaminated  steel was inadvertently used in the construction of over 100 apartment buildings, causing the long-term exposure of 10,000 people. The average dose rate was 50\u00a0mSv/year and a subset of the population (1,000 people) received a total dose over 4,000\u00a0mSv over ten years. In the widely used  linear no-threshold model  used by regulatory bodies, the expected cancer deaths in this population would have been 302 with 70 caused by the extra ionizing radiation, with the remainder caused by natural background radiation. The observed cancer rate, though, was quite low at 7 cancer deaths when 232 would be predicted by the LNT model had they not been exposed to the radiation from the building materials. Ionizing radiation hormesis appears to be at work. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2778", "text": "No experiment can be performed in perfect isolation. Thick lead shielding around a chemical dose experiment to rule out the effects of ionizing radiation is built and rigorously controlled for in the laboratory, and certainly not the field. Likewise the same applies for ionizing radiation studies. Ionizing radiation is released when an unstable particle releases radiation, creating two new substances and energy in the form of an  electromagnetic wave . The resulting materials are then free to interact with any environmental elements, and the energy released can also be used as a catalyst in further ionizing radiation interactions. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2779", "text": "The resulting confusion in the low-dose exposure field (radiation and chemical) arise from lack of consideration of this concept as described by Mothersill and Seymory. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2780", "text": "Veterans of the  Gulf War  (1991) who suffered from the persistent symptoms of  Gulf War Illness  (GWI) were likely exposed to stresses from toxic chemicals and/or radiation. [ 32 ]   The DNA damaging ( genotoxic ) effects of such exposures can be, at least partially, overcome by the DNA  nucleotide excision repair  (NER) pathway.   Lymphocytes  from GWI veterans exhibited a significantly elevated level of NER repair. [ 32 ]   It was suggested that this increased NER capability in exposed veterans was likely a hormetic response, that is, an induced protective response resulting from battlefield exposure. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2781", "text": "One of the areas where the concept of hormesis has been explored extensively with respect to its applicability is aging. [ 33 ] [ 34 ]  Since the basic survival capacity of any biological system depends on its  homeostatic  ability,  biogerontologists  proposed that exposing cells and organisms to mild stress should result in the adaptive or hormetic response with various biological benefits. This idea has preliminary evidence showing that repetitive mild stress exposure may have anti-aging effects in laboratory models. [ 35 ] [ 36 ]  Some mild stresses used for such studies on the application of hormesis in aging research and interventions are  heat shock , irradiation,  prooxidants ,  hypergravity , and food restriction. [ 35 ] [ 36 ] [ 37 ]  Such compounds that may modulate stress responses in cells have been termed \"hormetins\". [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2782", "text": "Hormesis suggests dangerous substances have benefits. Concerns exist that the concept has been leveraged by  lobbyists  to weaken environmental regulations of some well-known toxic substances in the US. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2783", "text": "The hypothesis of hormesis has generated the most controversy when applied to  ionizing radiation . This hypothesis is called radiation hormesis. For policy-making purposes, the commonly accepted model of dose response in radiobiology is the  linear no-threshold model  (LNT), which assumes a strictly linear dependence between the risk of radiation-induced adverse health effects and radiation dose, implying that there is no safe dose of radiation for humans."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2784", "text": "Nonetheless, many countries including the  Czech Republic ,  Germany ,  Austria ,  Poland , and the  United States  have  radon therapy  centers whose whole primary operating principle is the assumption of radiation hormesis, or beneficial impact of small doses of radiation on human health. Countries such as Germany and Austria at the same time have imposed very strict antinuclear regulations, which have been described as  radiophobic  inconsistency."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2785", "text": "The  United States National Research Council  (part of the  National Academy of Sciences ), [ 39 ]  the  National Council on Radiation Protection and Measurements  (a body commissioned by the  United States Congress ) [ 40 ]  and the United Nations Scientific Committee on the Effects of Ionizing Radiation  all agree that radiation hormesis is not clearly shown, nor clearly the rule for radiation doses."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2786", "text": "A United States\u2013based  National Council on Radiation Protection and Measurements  stated in 2001 that  evidence for radiation hormesis is insufficient and radiation protection authorities should continue to apply the LNT model for purposes of risk estimation. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2787", "text": "A 2005 report commissioned by the French National Academy concluded that evidence for hormesis occurring at low doses is sufficient  and LNT should be reconsidered as the methodology used to estimate risks from low-level sources of radiation, such as  deep geological repositories  for  nuclear waste . [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2788", "text": "Hormesis remains largely unknown to the public, requiring a policy change for a possible toxin to consider exposure risk of small doses. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2789", "text": "Idiosyncratic drug reactions , also known as  type B reactions , are  drug reactions  that occur rarely and unpredictably amongst the population. This is not to be mistaken with  idiopathic , which implies that the cause is not known. They frequently occur with exposure to new drugs, as they have not been fully tested and the full range of possible side-effects have not been discovered; they may also be listed as an  adverse drug reaction  with a drug, but are extremely rare. Some patients have  multiple- drug intolerance . Patients who have multiple idiopathic effects that are nonspecific are more likely to have anxiety and depression. [ 1 ]  Idiosyncratic drug reactions appear to not be concentration dependent. A minimal amount of drug will cause an immune response, but it is suspected that at a low enough concentration, a drug will be less likely to initiate an  immune response ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2790", "text": "In adverse drug reactions involving overdoses, the toxic effect is simply an extension of the pharmacological effect (Type A adverse drug reactions). On the other hand, clinical symptoms of idiosyncratic drug reactions (Type B adverse drug reactions) are different from the pharmacological effect of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2791", "text": "The proposed mechanism of most idiosyncratic drug reactions is immune-mediated toxicity. To create an immune response, a foreign molecule must be present that antibodies can bind to (i.e. the antigen) and cellular damage must exist. Very often, drugs will not be immunogenic because they are too small to induce immune response. However, a drug can cause an immune response if the drug binds a larger molecule. Some unaltered drugs, such as  penicillin , will bind avidly to proteins. Others must be bioactivated into a toxic compound that will in turn bind to proteins. The second criterion of cellular damage can come either from a toxic drug/drug metabolite, or from an injury or infection.\nThese will sensitize the immune system to the drug and cause a response.\nIdiosyncratic reactions fall conventionally under toxicology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2792", "text": "Kindling  due to  substance withdrawal  is the neurological condition which results from repeated withdrawal episodes from  sedative\u2013hypnotic drugs  such as  alcohol  and  benzodiazepines ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2793", "text": "Each withdrawal leads to more severe withdrawal symptoms than in previous episodes. Individuals who have had more withdrawal episodes are at an increased risk of very severe withdrawal symptoms, up to and including seizures and death. Long-term activation of the  GABA receptor  by sedative\u2013hypnotic drugs causes chronic GABA  receptor downregulation  as well as  glutamate  overactivity, which can lead to drug and neurotransmitter  sensitization ,  central nervous system  hyperexcitability, and  excitotoxicity ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2794", "text": "Binge drinking  is believed to increase impulsivity due to altered functioning of prefrontal\u2013subcortical and orbitofrontal circuits. Binge drinking in alcoholics who have undergone repeated detoxification is associated with an inability to interpret  facial expressions  properly; this is believed to be due to kindling of the amygdala with resultant distortion of neurotransmission. Adolescents, females and young adults are most sensitive to the neuropsychological effects of binge drinking. Adolescence, particularly early adolescence, is a developmental stage which is particularly vulnerable to the neurotoxic and neurocognitive adverse effects of binge drinking due to it being a time of significant brain development. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2795", "text": "Approximately 3 percent of people who are alcohol dependent experience psychosis during acute intoxication or withdrawal. Alcohol-related psychosis may manifest itself through a kindling mechanism. The mechanism of alcohol-related  psychosis  is due to distortions to neuronal membranes,  gene expression , as well as  thiamine  deficiency. It is possible in some cases that alcohol abuse via a kindling mechanism can cause the development of a chronic substance-induced psychotic disorder (e.g., schizophrenia). The effects of an alcohol-related psychosis include an increased risk of depression and suicide as well as psychosocial impairments. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2796", "text": "Repeated acute intoxication followed by acute withdrawal is associated with profound behavioural changes and neurobiological alterations in several brain regions. Much of the documented evidence of kindling caused by repeated detoxification regards increased seizure frequency. Increased fear and anxiety and cognitive impairments are also  associated with alcohol withdrawal kindling due to binge drinking or alcoholics with repeated  alcohol withdrawal  experiences. The impairments induced by binge drinking or repeated detoxification of alcoholics cause a loss of behavioural inhibition of the prefrontal cortex; the  prefrontal cortex  is mediated by subcortical systems such as the amygdala. This loss of behavioral control due to brain impairment predisposes an individual to  alcoholism  and increases the risk of an abstaining alcoholic relapsing. This impairment may also result in long-term adverse effects on emotional behavior. Impaired associative learning may make behavioural therapies involving conditioning approaches for alcoholics less effective. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2797", "text": "Binge drinking regimes are associated with causing an imbalance between  inhibitory  and  excitatory   amino acids  and changes in  monoamine  release in the central nervous system, which increases neurotoxicity; this may result in cognitive impairments, psychological problems, and may cause irreversible brain damage in both adolescent and adult long-term binge drinkers. [ 3 ] [ 4 ]  Similar to binge drinkers, individuals suffering from  alcohol dependence  develop changes to neurotransmitter systems, which occur as a result of kindling and sensitization during withdrawal. This progressively lowers the threshold needed to cause  alcohol-related brain damage  and cognitive impairments, leading to altered neurological function. The changes in activity of excitatory and inhibitory neurotransmitter systems is similar to that which occurs in individuals suffering from limbic or  temporal lobe epilepsy . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2798", "text": "Adaptational changes at the GABA A  benzodiazepine receptor complex do not fully explain  tolerance ,  dependence , and  withdrawal  from benzodiazepines. Other receptor complexes may be involved; in particular, the excitatory  glutamate  system is implicated. The involvement of glutamate in  benzodiazepine dependence  explains long-term potentiation as well as neuro-kindling phenomena. There is some evidence that a prior history of CNS depressant dependence (e.g. alcohol) increases the risk of dependence on benzodiazepines. Tolerance to drugs is commonly believed to be due to receptor  down-regulation ; however, there is very limited evidence to support this, and this hypothesis comes from animal studies using very high doses. Instead, other mechanisms, such as  receptor uncoupling , may play a more important role in the development of benzodiazepine dependence; this may lead to prolonged conformational changes in the receptors or altered subunit composition of the receptors. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2799", "text": "Repeated benzodiazepine withdrawal episodes may result in similar neuronal kindling as that seen after repeated withdrawal episodes from alcohol, with resultant increased neuro-excitability. The glutamate system is believed to play an important role in this kindling phenomenon with AMPA receptors which are a subtype of glutamate receptors being altered by repeated withdrawals from benzodiazepines. The changes which occur after withdrawal in AMPA receptors in animals have been found in regions of the brain which govern anxiety and seizure threshold; thus kindling may result in increased severity of anxiety and a lowered seizure threshold during repeated withdrawal. Changes in the glutamate system and GABA system may play an important role at different time points during  benzodiazepine withdrawal syndrome . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2800", "text": "Binge drinking may induce brain damage due to the repeated cycle of acute intoxication followed by an acute abstinence withdrawal state. [ 7 ]  Based on animal studies, regular binge drinking in the long-term is thought to be more likely to result in brain damage than chronic (daily) alcoholism. This is due to the 4- to 5-fold increase in glutamate release in nucleus accumbens during the acute withdrawal state between binges but only in dose 3\u00a0g/kg, in 2\u00a0g/kg there is no increase in glutamate release. In contrast, during withdrawal from chronic alcoholism only a 2- to 3-fold increase in glutamate release occurs. The high levels of glutamate release causes a chain reaction in other neurotransmitter systems. The reason that chronic sustained alcoholism is thought by some researchers to be less brain damaging than binge drinking is because tolerance develops to the effects of alcohol and unlike binge drinking repeated periods of acute withdrawal does not occur, [ 3 ] [ 4 ]  but there are also many alcoholics who typically drink in binges followed by periods of no drinking. [ 8 ]   Excessive glutamate release is a known major cause of neuronal cell death. Glutamate causes  neurotoxicity  due to  excitotoxicity  and oxidative glutamate toxicity. Evidence from animal studies suggests that some people may be more genetically sensitive to the neurotoxic and brain damage associated with binge drinking regimes. Binge drinking activates microglial cells which leads to the release of inflammatory  cytokines  and mediators such as  tumour necrosis factor , and  nitric oxide  causing  neuroinflammation  leading to neuronal destruction. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2801", "text": "Repeated acute withdrawal from alcohol which occurs in heavy binge drinkers has been shown in several studies to be associated with cognitive deficits as a result of neural kindling; neural kindling due to repeated withdrawals is believed to be the mechanism of cognitive damage in both binge drinkers and alcoholics. Neural kindling may explain the advancing pathogenesis and progressively deteriorating course of alcoholism and explain continued alcohol abuse as due to avoidance of distressing acute withdrawal symptoms which get worse with each withdrawal. Multiple withdrawals from alcohol is associated with long-term nonverbal memory impairment in adolescents and to poor memory in adult alcoholics. Adult alcoholics who experienced two or more withdrawals showed more frontal lobe impairments than alcoholics who had a history of one or no prior alcohol withdrawals. The finding of kindling in alcoholism is consistent with the mechanism of brain damage due to binge drinking and subsequent withdrawal. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2802", "text": "Kindling refers to the phenomenon of increasingly severe withdrawal symptoms, including an increased risk of seizures, that occurs as a result of repeated withdrawal from alcohol or other sedative\u2013hypnotics with related modes of action.  Ethanol  (alcohol) has a very similar mechanism of tolerance and withdrawal to benzodiazepines, involving the  GABA A \n receptors ,  NMDA receptors  and  AMPA receptors , but the majority of research into kindling has primarily focused on alcohol. [ 6 ]  An intensification of anxiety and other psychological symptoms of alcohol withdrawal also occurs. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2803", "text": "Failure to manage the alcohol withdrawal syndrome appropriately can lead to permanent brain damage or death. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2804", "text": "Acamprosate , a drug used to promote abstinence from alcohol, an  NMDA antagonist  drug, reduces excessive glutamate activity in the central nervous system and thereby may reduce excitotoxicity and withdrawal related brain damage. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2805", "text": "Monitored Emergency Use of Unregistered and Investigational Interventions  ( MEURI ) is an  ethical protocol  developed by the  World Health Organization  to evaluate the potential use of experimental drugs in the event of  public health emergencies . [ 1 ] [ 2 ] \nThe protocol was created by the  WHO Ebola Ethics Working Group  in 2014 [ 3 ] [ 4 ]  in the context of the  2014 West Africa Ebola outbreak . The WHO recommends that the term be preferred to the term \" compassionate use \" or \" expanded access \" for the controlled use of unregistered treatments in public health emergency measures. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2806", "text": "Morning pseudoneutropenia  is a transient reduction in the measured neutrophil count from peripheral samples. This is noticed in some patients who are taking  antipsychotic  medication. Morning pseudoneutropenia is thought to be due to  diurnal variation  in the amount of circulating white blood cells and changes in the levels of hematopoietic  cytokines  and  granulocyte colony stimulating factor  (GCSF). [ 1 ]   Antipsychotics may amplify the natural variation in these hematopoietic factors. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2807", "text": "Neutropenia  is a hematological disorder characterized by an abnormally low number of  neutrophils  in the blood.  Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against infections.  There is some variability in the neutrophil counts depending upon when the sample is taken, where the blood sample is taken from, and the system used by the  medical lab  for measuring the blood cells, but any significant reduction in function or number below the appropriate  range may predispose individuals to infections. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2808", "text": "Case reports of such incidents are reported with  clozapine , [ 2 ] [ 3 ]   risperidone , [ 4 ]  and  aripiprazole . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2809", "text": "These case reports suggest that the observed cases of the morning pseudoneutropenia did not proceed to become  agranulocytosis  which is a significant and dangerous side effect of some of antipsychotics. Hence it was suggested [ 6 ]  that although the morning neutrophil count may appear low, if the antipsychotic medication were considered efficacious then white cell counts may be repeated in the afternoon prior to making a decision based only on the morning counts. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2810", "text": "The  National Institute for Health and Care Excellence  ( NICE ) is an executive  non-departmental public body  of the  Department of Health and Social Care . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2811", "text": "As the national  health technology assessment  body of England, it is responsible for judging the cost-effectiveness of medicines and making them available on the NHS through reimbursement, with its judgements informing decisions in Wales and Northern Ireland. [ 2 ] [ 3 ]  It also provides a range of clinical guidance to the NHS in England and Wales, which are considered by Northern Ireland. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2812", "text": "It was set up as the  National Institute for Clinical Excellence  in 1999, and on 1 April 2005 joined with the  Health Development Agency  to become the new  National Institute for Health and Clinical Excellence [ 5 ] [ 6 ]  (still abbreviated as NICE). Following the  Health and Social Care Act 2012 , NICE was renamed the National Institute for Health and Care Excellence on 1 April 2013 reflecting its new responsibilities for social care, and changed from a  special health authority  to an executive non-departmental public body (NDPB)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2813", "text": "NICE was established in an attempt to end the so-called  postcode lottery  of healthcare in England and Wales, where availability of  treatments depended on the NHS Health Authority area in which the patient happened to live, but it has since acquired a high reputation internationally as a role model for the development of clinical guidelines. One aspect of this is the explicit determination of cost\u2013benefit boundaries for certain technologies that it assesses. [ 7 ]  NICE also plays an important role in pioneering technology assessment in other healthcare systems through NICE International, established in May 2008 to help cultivate links with foreign governments. [ 8 ]  NICE International has received financial support from the  Bill & Melinda Gates Foundation  and  Rockefeller Foundation . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2814", "text": "The notion of an Institute to determine the clinical effectiveness of interventions first emerged at the end of  John Major 's Conservative Government as moves elsewhere were being made to set professionally agreed standards for clinical care. In 1997, the  UK National Screening Committee  (NSC) had been established by  Sir Kenneth Calman  and  Muir Gray  (now Sir Muir Gray) by the Policy Team led by Timothy Riley for the Department of Health. [ 10 ]  The NSC aimed to ensure that  evidence-based medicine  informed policy making on what national screening programmes were approved for funding and what quality assurance mechanisms should be in place. This was a timely action as screening quality in breast cancer screening services came under question at Exeter in 1997 [ 11 ]  and followed in the wake of the 1995  Calman-Hine Report . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2815", "text": "The idea of what was originally called the National Institute for Clinical Excellence took root when Labour came to power in 1997.  Frank Dobson  became Secretary of State and was supported by a team of Ministers keen on introducing clinical and health outcome measures to achieve improvements in the quality and delivery of care. The team included  Alan Milburn ,  Baroness Margaret Jay , and  Tessa Jowell . The name and mission was agreed in a meeting between the Ministerial team, Timothy Riley and Felicity Harvey shortly after the election and it was agreed that NICE should be described in the first policy  white paper , The New NHS: Modern, Dependable 1997. [ 13 ]  Timothy Riley led the team that developed the policy and for NICE and which managed the legislation through Parliament in addition to implementing the new institute as a  Special Health Authority . Timothy Riley joined  Sir Michael Rawlins  (the then recently appointed Chair of NICE) at the  Health Select Committee  in February 1999 where questions were raised as to whether NICE was just a means to \"ration\" healthcare. Sir Michael Rawlins and Timothy Riley presented a compelling case that positioned NICE as a standards setting body first and foremost. [ 14 ] \nHowever, the reality was that although NICE was principally aimed at aligning professional standards through clinical guidelines and audit, the acceptability of drugs, devices and technological interventions in defining those standards, could not be ignored and so the concept of a \"fourth hurdle\" for drugs accessing the NHS market was invoked. This controversial policy shift meant that NICE was critical for decisions on drug reimbursement. Indeed, the first drug appraisal by NICE was on the drug  Relenza  which was turned down amidst criticisms from  Glaxo-Wellcome  that the appraisal had been fast tracked. [ 15 ]  Later, this policy development whereby the criteria for decision making, the role of costs, and the degree to which decisions of NICE and the secretary of state would be binding on clinicians was analysed by  Andrew Dillon , Trevor Gibbs, Timothy Riley, and  Trevor A. Sheldon . [ 16 ]  As of 1 February 2022, its chief executive is Samantha Roberts, who succeeded  Gillian Leng . [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2816", "text": "NICE publishes guidelines in four areas:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2817", "text": "These appraisals are based primarily on  evidence-based  evaluations of efficacy, safety and cost-effectiveness in various circumstances."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2818", "text": "Since January 2005, the NHS in  England  has been legally obliged to provide funding for medicines and treatments recommended by NICE's technology appraisal board. [ 18 ]  This was at least in part as a result of well-publicised postcode lottery anomalies in which certain less-common treatments were funded in some parts of the UK but not in others due to local decision making in the NHS. [ 19 ] [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2819", "text": "Before an appraisal, the Advisory Committee on Topic Selection draws up a list of potential topics of clinical significance for appraisal. The  Secretary of State for Health and Social Care  must then refer any technology so that the appraisal process can be formally initiated. Once this has been done NICE works with the Department of Health to draw up the scope of the appraisal. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2820", "text": "NICE then invites consultee and commentator organisations to take part in the appraisal. A consultee organisation would include patient groups, organisations representing health care professionals and the manufacturers of the product undergoing appraisal. Consultees submit evidence during the appraisal and comment on the appraisal documents. Commentator organisations include the manufacturers of products to which the product undergoing appraisal is being compared. They comment on the documents that have been submitted and drawn up but do not actually submit information themselves. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2821", "text": "An independent academic centre then draws together and analyses all of the published information on the technology under appraisal and prepares an assessment report. This can be commented on by the Consultees and Commentators. Comments are then taken into account and changes made to the assessment report to produce an evaluation report. An independent Appraisal Committee then looks at the evaluation report, hears spoken testimony from clinical experts, patient groups and carers. They take their testimony into account and draw up a document known as the 'appraisal consultation document'. This is sent to all consultees and commentators who are then able to make further comments. Once these comments have been taken into account the final document is drawn up called the 'final appraisal determination'. This is submitted to NICE for approval. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2822", "text": "The process aims to be fully independent of government and lobbying power, basing decisions fully on clinical and cost-effectiveness. There have been concerns that  lobbying  by pharmaceutical companies to mobilise media attention and influence public opinion are attempts to influence the decision-making process. [ 23 ]  A fast-track assessment system has been introduced to reach decisions where there is most pressure for a conclusion. [ citation needed ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2823", "text": "NICE carries out assessments of the most appropriate treatment regimes for different diseases. This must take into account both desired medical outcomes (i.e. the best possible result for the patient) and also economic arguments regarding differing treatments. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2824", "text": "NICE has set up several National Collaborating Centres bringing together expertise from the royal medical colleges, professional bodies and patient/carer organisations which draw up the guidelines. The centres are the National Collaborating Centre for Cancer, the National Clinical Guideline Centre, the National Collaborating Centre for Women and Children\u00b4s Health, and the  National Collaborating Centre for Mental Health . [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2825", "text": "The National Collaborating Centre appoints a Guideline Development Group whose job it is to work on the development of the clinical guideline. This group consists of medical professionals, representatives of patient and carer groups and technical experts. They work together to assess the evidence for the guideline topic (e.g.  clinical trials  of competing products) before preparing a draft guideline. There are then two consultation periods in which stakeholder organisations are able to comment on the draft guideline. After the second consultation period, an independent Guideline Review Panel reviews the guideline and stakeholder comments and ensures that these comments have been taken into account. The Guideline Development Group then finalises the recommendations and the National Collaboration Centre produces the final guideline. This is submitted to NICE to formally approve the guideline and issue the guidance to the NHS. [ citation needed ]  To date NICE has produced more than 200 different guidelines. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2826", "text": "In October 2014  Andy Burnham  said that a Labour government could reduce variation in access to drugs and procedures by making it mandatory for commissioners to follow NICE clinical guidelines. \"We need to look at how you strengthen NICE. Where they have said something is effective and affordable, on what basis does a local commissioner withhold that from somebody? I\u2019m not comfortable with that. I don\u2019t support that.\" [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2827", "text": "NICE has a service called Clinical Knowledge Summaries (CKS) which provides primary care practitioners with a readily accessible summary of the current evidence base and practical guidance. [ 29 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2828", "text": "In 2022  PricewaterhouseCoopers  did a study for the  Association of the British Pharmaceutical Industry  of 13 medicines recommended for asthma, kidney disease, stroke prevention and type 2 diabetes.  They found that  1.2 million patients had not received the drugs which could have given them the equivalent of 429,000 extra years in \u201ccomplete good health\u201d which could have translated into \u00a317.9bn in \u201cproductivity gains\u201d for the British economy. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2829", "text": "Under the  Health and Social Care Act 2012 , NICE was given responsibility for developing guidance and quality standards for  social care , using an evidence-based model. This was delivered by the NICE Collaborating Centre for Social Care (NCCSC), hosted by the  Social Care Institute for Excellence  (SCIE) and four partner organisations - Research in Practice, Research in Practice for Adults, Personal Social Services Research Unit and the  EPPI-Centre . Over a five year period, the NCCSC developed social care guidelines and supported the implementation of both the guidelines and social care quality standards. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2830", "text": "NICE received referrals for social care guidance from the Department of Health and the  Department for Education , and commission the guidance from the NCCSC. NICE, along with the NCCSC, carried out a  scoping exercise  with a scoping group and with input from key stakeholders, at both a workshop and a public consultation, to ensure the guidance to be produced was focused and achievable. A  chairperson  and members of the Guidance Development Group were appointed, and posed review questions which enabled  systematic evidence reviews  to take place, thus delivering the guidance and subsequent recommendations. Service user and carer involvement took place throughout, as well as public consultation on the draft guidance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2831", "text": "The Guidance Development Group then finalised the recommendations and the NCCSC produced the final guideline. This was submitted to NICE for formal approval and publication. The entire process from pre-scoping to publication took approximately 24 months. The guidance was then available to NICE standing committees to develop a quality standard on the topic. The quality standard was developed using the guidance and other accredited sources, to produce high-level concise statements that can be used for quality improvement by social care providers and commissioners, as well as setting out what service users and carers can expect of high quality social care services."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2832", "text": "The NCCSC is unique within NICE, in that it is the only collaborating centre to have responsibility for the adoption and dissemination support for guidance and quality standards in the  social care arena . Drawing on the expertise of SCIE and their partners within the sector, each of the guidance products and quality standards had a needs assessment carried out to determine the requirements for tools to help embed the guidance and quality standards within the sector. These could include tailored versions of guidance for specific audiences, costing and commissioning tools and even training and learning packages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2833", "text": "As of August 2013, NICE and the NCCSC had scheduled guidance delivery for five topics:  domiciliary care , older adults with long-term conditions, transition between health and social care settings, transition from children's to adults' services and  child abuse and neglect ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2834", "text": "As with any system financing health care, the NHS has a limited budget and a vast number of potential spending options. Choices must be made as to how this limited budget is spent.  Economic evaluations  are carried out within a  health technology assessment  framework to compare the cost-effectiveness of alternative activities and to consider the  opportunity cost  associated with their decisions. [ 33 ]  By choosing to spend the finite NHS budget upon those treatment options that provide the most efficient results, society can ensure it does not lose out on possible health gains through spending on inefficient treatments and neglecting those that are more efficient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2835", "text": "NICE attempts to assess the cost\u2013effectiveness of potential expenditures within the NHS to assess whether or not they represent 'better value' for money than treatments that would be neglected if the expenditure took place. It assesses the cost\u2013effectiveness of new treatments by analysing the cost and benefit of the proposed treatment relative to the next best treatment that is currently in use. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2836", "text": "NICE guidance supports the use of  quality-adjusted life years  (QALY) as the primary outcome for quantifying the expected health benefits associated with a given treatment regime. By comparing the present value (see  discounting ) of expected QALY flows with and without treatment, or relative to another treatment, the net/relative health benefit derived from such a treatment can be derived. When combined with the relative cost of treatment, this information can be used to estimate an  incremental cost-effectiveness ratio  (ICER), which is considered in relation to NICE's threshold willingness-to-pay value. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2837", "text": "As a guideline rule, NICE accepts as cost-effective those interventions with an incremental cost-effectiveness ratio of less than \u00a320,000 per QALY and that there should be increasingly strong reasons for accepting as cost-effective interventions with an incremental cost-effectiveness ratio of over a threshold of \u00a330,000 per QALY. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2838", "text": "Over the years, there has been great controversy as to what value this threshold should be set at. Initially, there was no fixed number. But the appraisal teams created a consensus amount of about \u00a330,000. However, in November 2008  Alan Johnson , the then Secretary of State, announced that for end-of-life cancer drugs the threshold could be increased above \u00a330,000. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2839", "text": "The first drug to go through the new process was  lenalidomide , whose ICER was \u00a343,800. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2840", "text": "The following example from NICE explains the QALY principle and the application of the cost per QALY calculation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2841", "text": "A patient has a life-threatening condition and is expected to live on average for one year receiving the current best treatment which costs the NHS \u00a33,000. A new drug becomes available that will extend the life of the patient by three months and improve his or her quality of life, but the new treatment will cost the NHS more than three times as much at \u00a310,000. Patients score their perceived quality of life on a scale from 0 to 1 with 0 being worst possible health and 1 being best possible health. On the standard treatment, quality of life is rated with a score of 0.4 but it improves to 0.6 with the new treatment. Patients on the new treatment on average live an extra 3 months, so 1.25 years in total. The quality of life gained is the product of  life span  and  quality rating  with the new treatment less the same calculation for the old treatment, i.e. (1.25 x 0.6) less (1.0 x 0.4) = 0.35 QALY. The marginal cost of the new treatment to deliver this extra gain is \u00a37,000 so the cost per quality life year gained is \u00a37000/0.35 or \u00a320,000. This is within the \u00a320,000-\u00a330,000 that is suggested by NICE to be the limit for drugs to be cost-effective. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2842", "text": "If the patient was expected to live only one month extra and instead of three then NICE would issue a recommendation not to fund. The patient's  primary care trust [ needs update ]  could still decide to fund the new treatment, but if not, the patient would then have two choices. He or she could opt to take the free NHS standard treatment, or he or she may decide to pay out of pocket to obtain the benefit of the new treatment from a different health care provider. If the person has a private health insurance policy the person could check to see whether the private insurance provider will fund the new treatment. About 8% of the population has some private health insurance from an employer or trade association and 2% pay from their own resources."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2843", "text": "Theoretically, it might be possible to draw up a table of all possible treatments sorted by cost per QALY gained. Those treatments with lowest cost per QALY gained would appear at the top of the table and deliver the most benefit per value spent and would be easiest to justify funding for. Those where the delivered benefit is low and the cost is high would appear at the bottom of the list. Decision makers would, theoretically, work down the table, adopting services that are the most cost effective. The point at which the NHS budget is exhausted would reveal the  shadow price , the threshold lying between the CQG (cost per QALY gained) of the last service that is funded and that of the next most cost effective service that is not funded."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2844", "text": "In practice this exercise is not done, but an assumed shadow price has been used by NICE for many years in its assessments to determine which treatments the NHS should and should not fund. NICE states that for drugs the CQG should not normally exceed \u00a330,000 but that there is not a hard threshold, [ 39 ]  though research has shown that any threshold is \"somewhat higher\" than being in the range \u00a335,000 - \u00a340,000. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2845", "text": "The  House of Commons Health Select Committee , in its report on NICE, stated in 2008 that \"the ... cost-per-QALY it uses to decide whether a treatment is cost-effective is of serious concern. The threshold it employs is not based on empirical research and is not directly related to the NHS budget, nor is it at the same level as that used by  primary care trusts  (PCTs) in providing treatments not assessed by NICE, which tends to be lower. Some witnesses, including patient organisations and pharmaceutical companies, thought NICE should be more generous in the cost per QALY threshold it uses, and should approve more products. On the other hand, some PCTs struggle to implement NICE guidance at the current threshold and other witnesses argued that a lower level should be used. However, there are many uncertainties about the thresholds used by PCTs.\" It went on to recommend that \"an independent body should determine the threshold used when making judgements of the value of drugs to the NHS.\" [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2846", "text": "The work that NICE is involved in, attracts the attention of many groups, including doctors, the pharmaceutical industry, and patients. NICE is often associated with controversy, because the requirement to make decisions at a national level, can conflict with what is (or is believed to be) in the best interests of an individual patient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2847", "text": "Approved cancer drugs and treatments such as  radiotherapy  and  chemotherapy  are funded by the NHS without any financial contribution being taken from the patient. Where NICE has approved a treatment, the NHS must fund it. But not all treatments have been assessed by NICE and these treatments are usually dependent on local NHS decision making. In the case of cancer the  Cancer Drugs Fund  was set up in 2011 after complaints about NICE decisions on new and expensive cancer drugs with limited benefits. [ citation needed ]  Treatment for fertility problems are approved but not always funded by  clinical commissioning groups  and they may cap the number of rounds. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2848", "text": "NICE has been criticised for being too slow to reach decisions. On one occasion, the  Royal National Institute of Blind People  said it was outraged over its delayed decision for further guidance regarding two drugs for  macular degeneration  that are already approved for use in the NHS. However the Department of Health said that it had 'made it clear to PCTs that funding for treatments should not be withheld simply because guidance from NICE is unavailable'. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2849", "text": "Some of the more controversial NICE decisions have concerned  donepezil ,  galantamine ,  rivastigmine  (review) and  memantine  for the treatment of  Alzheimer's disease  and  bevacizumab ,  sorafenib ,  sunitinib  and  temsirolimus  for  renal cell carcinoma . All these are drugs with a high cost per treatment and NICE has either rejected or restricted their use in the NHS on the grounds that they are not cost-effective."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2850", "text": "A statement published by the Royal College of Physicians expressed concern that the 2021 NICE guidelines for ME/CFS did not properly evaluate or recommend graded exercise therapy and cognitive behavioral therapy for the treatment of ME/CFS. [ 44 ]  A study by 49 academics argued that the dissonance between the 2021 guidelines and the previous guideline was the result of deviating from usual scientific standards of the NICE process. [ 45 ]  NICE responded that they did follow the standard  GRADE approach , and evidence from  unblinded trials  with subjective outcomes was appropriately downgraded. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2851", "text": "A Conservative shadow minister once criticized NICE for spending more on communications than assessments. In its defence, NICE said the majority of its communications budget was spent informing doctors about which drugs had been approved and new guidelines for treatments and that the actual cost of assessing new drugs for the NHS includes money spent on NICE's behalf by the Department of Health. When these were added to NICE's own costs, the total cost of the technology appraisal programme far outstrips the cost of NICE communications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2852", "text": "A report from the  University of York  Centre for Health Economics written by  Karl Claxton  in February 2015 suggested that the maximum threshold, currently around \u00a330,000 a year, for judging a medicine cost-effective should be more than halved. They found that any intervention costing more than \u00a313,000 per  quality-adjusted life year  risked causing more harm than good by denying cost effective treatment to other patients. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2853", "text": "The institute's approach to the introduction of new oral therapy for  hepatitis C  has been criticised.  Sofosbuvir  was approved in 2015. It costs about \u00a330,000 for 12 weeks treatment.  NHS England  established 22 Operational Delivery Networks to roll out delivery and proposes to fund 10,000 courses of treatment in 2016-17. Each has been given a \u201crun rate\u201d of how many patients they are allowed to treat. This is the NHS\u2019 single biggest new treatment investment this year. [ 48 ]  In the North East London network patients with  cirrhosis  or  fibrosis  go to the front of the queue and three new patients at the Grahame Hayton Unit at the  Royal London Hospital  start treatment each month. Those without such complications may faced considerable delays before they start treatment. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2854", "text": "Opioid rotation \u00a0or\u00a0 opioid switching \u00a0is the process of changing one opioid to another to improve  pain  control or reduce unwanted  side effects . [ 1 ]  This technique was introduced in the 1990s to help manage severe chronic pain and improve the opioid response in  cancer  patients. [ 2 ]  In order to obtain adequate levels of pain relief, patients requiring chronic opioid therapy may require an increase in the original prescribed dose for a number of reasons, including increased pain or a worsening disease state. [ 3 ]  Over the course of long-term treatment, an increase in dosage cannot be continued indefinitely as unwanted side effects\u00a0of treatment often become intolerable once a certain dose is reached, even though the pain may still not be properly managed. One strategy used to address this is to switch the patient between different opioid drugs over time, usually every few months. [ 4 ]  Opioid rotation requires strict monitoring in patients with ongoing levels of high opioid doses for extended periods of time, since long term opioid use can lead to a patient developing\u00a0 tolerance \u00a0to the analgesic effects of the drug. [ 5 ]  Patients may also not respond to the first opioid prescribed to them at all, therefore needing to try another opioid to help manage their pain. [ 3 ]  A patient's specific response and sensitivity to opioids include many factors that include physiology, genetics and pharmacodynamic parameters, which together determine the amount of pain control and tolerance of a particular opioid. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2855", "text": "Opioid analgesic drugs tend to exhibit incomplete  cross-tolerance , so that even when a patient has developed a high level of tolerance to one drug from this class, they may find that a different opioid drug will still be effective. [ 6 ]  The reasons for this are still not completely understood, but are thought to result from variations in  opioid receptor   affinity  and occupancy levels at  equianalgesic  doses, as well as additional mechanisms of action possessed by some drugs such as the  NMDA antagonist  action of  methadone  or  levorphanol , or the  SNRI  activity of  tramadol  or  tapentadol . [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2856", "text": "There are no clinical guidelines outlining the use and implementation of opioid rotation.  However, this strategy is commonly used for these various situations: pain not controlled by current opioid, pain controlled but in the presence of intolerable adverse events, pain not controlled despite rapid increase in opioid dose, switching to utilize different alternative routes of administration, or switching due to high cost of current opioid (or other patient-specific cost considerations). [ 1 ] [ 5 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2857", "text": "While there is good evidence for the efficacy of opioid rotation as a treatment approach in general [ citation needed ] , there is less evidence for what particular opioid analgesics are most suitable, and in practice the choice of opioid drugs used depends on many factors such as patient characteristics, prescriber preferences and safety. One issue with opioid rotation is that an opioid therapy failure poorly predicts whether other opioids would be effective. In certain situations, multiple switches may be required before pain therapy is optimized. [ 10 ]  In addition, recent studies explore which opioid drugs are most effective in implementing in an opioid rotation, but have so far found no difference in efficacy between opioid drugs like methadone and fentanyl in cancer patients. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2858", "text": "Diversion of prescribed opioid drugs for illicit recreational use is also a particular concern in this field, as the drugs which are most effective for relieving  suffering  in  palliative care  also tend to be those most sought after by  drug abusers . The choice of what opioid drug to use in which patient thus tends to be a balance between many different factors that must be considered, and the need for opioid rotation in chronic pain patients makes it advantageous for a wide range of different opioid drugs to be available, even though they may be broadly equivalent in action when used in shorter term treatment. [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ]  Additionally, newer studies may explore which patient populations can benefit the most from opioid rotation and which populations can have their pain managed by other means. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2859", "text": "Ototoxicity  is defined as the toxic effect on the functioning of the inner ear, which may lead to temporary or permanent  hearing loss  (cochleotoxic) and balancing problems (vestibulotoxic). [ 1 ]  Drugs or pharmaceutical agents inducing ototoxicity are regarded as  ototoxic medications ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2860", "text": "There is a wide range of ototoxic medications, for example,  antibiotics ,  antimalarials ,  chemotherapeutic agents ,  non-steroidal anti-inflammatory drugs (NSAIDs)  and  loop diuretics . [ 2 ]  While these drugs target on different body systems, they also trigger ototoxicity through different mechanisms, for example, destruction to cellular tissues of inner ear parts and disturbance on auditory nervous system. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2861", "text": "Onset of ototoxicity ranges from taking a single dose to long-term usage of the drugs. [ 3 ]  Signs and symptoms of ototoxicity include  tinnitus ,  hearing loss , dizziness and  nausea  and/or vomiting. [ 3 ]  The diagnosis of medicine-induced ototoxicity is challenging as it usually shows only mild symptoms in early stages. Thus, prospective ototoxicity monitoring would be required when patients are using ototoxic medications. [ 1 ]  Fortunately, the majority of ototoxicity cases are reversible by stopping the medication concerned."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2862", "text": "Alcohol  is one of the leading substances known to have  ototoxic  effects. [ 4 ]  A 2023 systematic review and meta-analysis found that alcohol consumption is associated with an increased risk of  hearing loss . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2863", "text": "The most common classes of ototoxic medications include  antibiotics  (including  aminoglycosides  and  glycopeptides ) and  chemotherapeutic agents .  Aminoglycosides  and some chemotherapeutic agents are associated with both cochleotoxicity and vestibulotoxicity. They are thought to damage the hair cells of the  cochlea . Long-term exposure to these drugs may cause damage that progresses to the upper turn of the cochlea, impairing hearing or even causing deafness. [ 6 ]   Glycopeptides , on the other hand, are rarely associated with ototoxicity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2864", "text": "Aminoglycosides  are a class of antibiotics. The most frequently used aminoglycosides include  gentamicin ,  amikacin  and  streptomycin . These antibiotics are usually used in combination with other antimicrobial agents to treat drug-resistant organisms. For example, they are used with  \u03b2-lactam  for bacterial infections in  pneumonia . [ 7 ]  They are usually given either  intravenously  or  intramuscularly  due to their poor oral absorption."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2865", "text": "Aminoglycosides irreversibly inhibit  protein synthesis  of bacteria, which specifically helps kill the  gram-negative bacteria . The drug is first transported into the bacterial cell and it binds to the  30S ribosomal subunit . [ 8 ]  This action interferes with the reading of codons during  mRNA translation , causing misreading and premature termination of the process. This inhibits  protein synthesis  and ultimately leads to the death of bacterial cells. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2866", "text": "All  aminoglycosides  can cause either reversible or irreversible ototoxicity. Ototoxicity is more frequently observed in individuals who received the treatment for more than five days and those who have  renal insufficiency . [ 7 ]  The mechanism of aminoglycosides-induced ototoxicity is not well understood. It is thought that because cochlear cells are rich in mitochondria, these antibiotics may also target cochlear cells and cause their death. [ 10 ]  Another hypothesis suggests that these drugs lead to the production of  reactive oxygen species  which generate oxidative stress and damage the inner ear. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2867", "text": "Glycopeptides  are another class of antibiotics.  Vancomycin  is the class originator for the glycopeptides. Lipoglycopeptides are a subclass of glycopeptides and they are derived from the structure of  vancomycin . Examples are  telavancin  and  dalbavancin . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2868", "text": "Vancomycin  and the lipoglycopeptides have slight differences in their mechanism of actions. Vancomycin inhibits  cell wall  synthesis of bacteria by preventing the cell wall component of bacteria,  peptidoglycan , from elongating and cross-linking. With weakened  peptidoglycan , the bacterial cell becomes susceptible to lysis. [ 9 ]  Lipoglycopeptides, additionally, can increase the membrane permeability of the bacterial cell and disrupt the bacterial cell membrane potential. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2869", "text": "This class of antibiotics can be used to treat skin or joint infections, where  gram-positive bacteria  are the pathogens responsible. Vancomycin is also used as an initial empirical treatment agent of community-acquired  bacterial meningitis  in locations where penicillin-resistant  S. pneumoniae  is common. [ 12 ]  This drug has other clinical uses, including  endocarditis  and  respiratory tract infections  caused by  Methicillin-resistant Staphylococcus aureus (MRSA) ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2870", "text": "Case reports suggested that long-term use of vancomycin has been associated with ototoxicity. [ 13 ]  However, there is no well-established causal link between vancomycin and ototoxicity. For instance, preclinical studies showed that vancomycin had a low risk of inducing ototoxicity. [ 2 ]  Despite these findings, literature generally agreed that pre-existing hearing abnormalities, concomitant use of aminoglycosides and renal dysfunction are risk factors for vancomycin-induced ototoxicity. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2871", "text": "Chemotherapeutic agents are drugs that are used in  chemotherapy  for the treatment of  cancer . Many of these agents are known to have the potential to cause hearing loss. Such agents include  cisplatin  and  bleomycin ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2872", "text": "Cisplatin  is known as a platinum coordination complex.  Carboplatin  and  oxaliplatin  also belong to platinum coordination complexes, but they are less commonly associated with ototoxicity. These agents are used in the treatment of ovarian, head and neck, bladder, lung and colon cancers. Cisplatin and other platinum coordination complexes work by reacting with various sites on DNA in mainly cancer cells in order to form cross-links. The formed DNA-platinum complexes inhibit  replication  and  transcription , leading to miscoding and cell death. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2873", "text": "The mechanism of cisplatin in inducing ototoxicity is believed to involve the accumulation of  reactive oxygen species , which exert cytotoxic effect on cochlear cells. [ 16 ]  Some  pharmacogenetics  research have opened up new perspectives on the contributing factors of cisplatin-induced ototoxicity. They investigated several cancer-inducing  genes  and  genetic polymorphisms . Results showed that some  genes  are associated with protective effect on ototoxicity, while others may show no effect or even increased effect on ototoxicity. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2874", "text": "Bleomycin  is one of the antitumour antibiotics and is a fermentation product of  Streptomyces verticillus . It has a unique mechanism of action, making it an important agent in treating  Hodgkin disease  and testicular cancer. This unique chemotherapeutic agent causes oxidative damage to the  nucleotides  and leads to single- and double-stranded breaks in DNA. Excess breaks in DNA eventually causes cell death. [ 9 ]  Few case reports have identified the development of ototoxicity in some elderly patients who were administered with bleomycin. [ 17 ]  Since such cases are rare, the mechanisms behind have yet to be discovered."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2875", "text": "Non-steroidal anti-inflammatory drugs (NSAIDs)  are one of the most recurrently used classes of drug clinically, indicated for anti-inflammatory, analgesic and  antipyretic  effects. [ 18 ]  Examples include high-dose  aspirin ,  ibuprofen  and  naproxen . Its therapeutic effect is achieved by inhibiting the activity of  cyclooxygenase  (COX), an enzyme mediating the biosynthesis of  prostaglandins  (PGs) and  thromboxanes  (TXAs). As this enzyme is inhibited,  prostaglandin  and  thromboxane  production is reduced, hence inhibiting the inflammatory response of pain and swelling caused by prostaglandin. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2876", "text": "Studies have proven that high-dose usage of aspirin can be associated with ototoxicity, manifesting reversible  hearing loss  and  tinnitus . [ 20 ]  The underlying mechanism is associated with a change in isolated cochlear outer  hair cells  (OHCs). Due to the COX inhibition, there is an increasing amount of  leukotrienes  in the inner ear. This leukotriene elevation leads to an alteration in the shape of isolated OHCs, thus disrupting their functions. Cochlear blood flow is eventually reduced, causing hearing impairment. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2877", "text": "Phosphodiesterase-5 (PDE-5) inhibitors  are the first-line drugs indicated for  erectile dysfunction  (ED), implying the sustained impairment of erectile functioning, which may lead to unsatisfactory sexual performance. [ 22 ]  Specific PDE-5 inhibitors are also approved for the treatment of  benign prostatic hyperplasia ,  pulmonary hypertension  and lower urinary tract symptoms. [ 23 ]  Common drug examples include  sildenafil ,  vardenafil  and  tadalafil . The enzyme PDE-5, found in the  corpus cavernosum  smooth muscle, is responsible for degrading  cyclic guanosine monophosphate  (cGMP) to 5-GMP. Inhibitors of this enzyme compete with cGMP for binding sites, which in turn increases the level of cGMP in smooth muscles. Through this mechanism, penis erection in male is eventually prolonged, resulting in a correction of ED. These drugs are known to cause headache, flushing and abnormal vision as their adverse effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2878", "text": "PDE-5 inhibitors are also known for inducing sudden sensorineural hearing loss. It is mainly related to the obstruction and dysfunction of  eustachian tubes  which affects middle-ear pressure. Due to the high similarity in structure between the  penile corpus cavernosum  and nasal erectile tissue, PDE-5 inhibitors targeting on corpus cavernosum smooth muscle will also act on nasal erectile tissues, which are mainly located at the  inferior turbinate , the  middle turbinate  and  nasal septum . Hence, specific nasal areas may become congested. This mediates inflammatory responses in the  eustachian tube  which connects to the  middle ear , causing an impact on middle ear pressure. Such events will eventually lead to sudden hearing loss. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2879", "text": "Antimalarial drugs  can be classified into several classes based on different mechanisms of action and effects, including quinoline-type drugs,  naphthoquinone ,  antifolates , guanidine derived drugs,  sesquiterpene lactones , etc. In particular, quinoline-type drugs are known to be ototoxic. Examples include  chloroquine  and  hydroxychloroquine  which are quinine-like. Apart from antimalarial effects, these drugs are also used in the treatment of other diseases such as  dermatological , immunological,  rheumatological , and severe infectious diseases. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2880", "text": "Various ototoxic effects are manifested by using antimalarial drugs, with dizziness being one of the most common one. Other effects include vestibular symptoms,  hearing loss  and  tinnitus , which can appear to be both temporary or permanent. [ 25 ]  Nonetheless, the underlying mechanisms of antimalarial-induced ototoxicity are still poorly understood. Studies have suggested that high doses of quinine have an impact on the central auditory pathway and auditory periphery, which leads to elongation and subsequent contraction of isolated OHCs in the  cochlea . This structural alteration affects their functions and results in cochlear blood flow reduction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2881", "text": "Loop diuretics  is a major class of  diuretic drugs  indicated for  oedema  due to  heart failure ,  liver disease  and  kidney disease . It is also used for treating  hypertension . [ 26 ]  Common examples include  furosemide ,  bumetanide  and  ethacrynic acid . Loop diuretics act on the thick ascending limb of the  loop of Henle  in the kidney nephrons. The major mechanism of ion reabsorption in the thick ascending limb is the active transport of ions through  Na + -K + -2Cl \u2212  co-transporters (NKCCs) . By binding to and inhibiting NKCCs at the apical membrane of the  loop of Henle , the reabsorption of Na+, K+ and Cl- is impaired, contributing to a higher ion concentration in the lumen. [ 26 ]  Hence, the ultimate effect of loop diuretics is a reduction in salt reabsorption and an increase in water excretion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2882", "text": "Loop diuretics -induced ototoxicity is suggested to be associated with their action on  stria vascularis  located on the lateral wall of the cochlea. This area is responsible for maintaining the balance of ions of  endolymph . A high potassium concentration as well as a low sodium concentration should be maintained in the  endolymph  to allow cochlear  hair cells  to function normally. [ 27 ]  As the inhibitory actions of loop diuretics will also target on NKCCs existing on membrane surfaces of  stria vascularis  marginal cells, there will be a disturbance on the ionic composition of  endolymph . [ 28 ]  Once the  endocochlear potential  cannot be maintained, hearing is temporarily impaired. It is noticed that the risk of ototoxicity caused by  furosemide  is much higher than that of  bumetanide ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2883", "text": "Several approaches can be considered in managing patients who developed ototoxicity as an adverse reaction to the medications. One approach to managing ototoxicity is the use of otoprotective agents. An example is  sodium thiosulfate , which the  US FDA  approved in 2022 to minimise the risk of ototoxicity and hearing loss in newborn, child, and adolescent cancer patients receiving cisplatin. [ 29 ] [ 30 ] [ 31 ]  Other agents being investigated for their potential to reduce ototoxicity include  D-methionine  and  L-N-acetylcysteine . [ 3 ]  The use of D-methionine to protect against hearing loss induced by drugs like cisplatin and aminoglycosides is preliminarily supported by animal studies. [ 32 ]   NMDA antagonists  are also shown to limit aminoglycoside-induced ototoxicity. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2884", "text": "Restorative care, which aims to regenerate hair cells that are damaged by ototoxic drugs, can also be considered. For example, the infusion of neurotrophic factors ( neurotrophin-3 ) was shown to produce otoprotective effects. [ 34 ]  This protective agent was also found to be associated with the survival of cochlear  spiral ganglion neurones  after hearing loss or deafness. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2885", "text": "Audiological management can be implemented, for example, by providing  hearing aids . In more seriously affected patients,  cochlear implantation  may be considered and discussed with the patient. It is also important for the healthcare team to educate affected patients and their family members on  communication skills  in order to minimise the impact on patients\u2019 daily life. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2886", "text": "Paradoxical disinhibition  is a  paradoxical reaction , an uncommon but recognized phenomenon, characterized by acute  excitement  and an altered  mental state , caused by  benzodiazepines . The mechanism is poorly known, but the most accepted theory is that it occurs secondary\nto inhibition of the restraining influences of the  cortex  and  frontal lobe  due to the GABA-mimetic action of  benzodiazepines . [ 1 ]  Reversal of this action could be attained by an  NMDA-receptor   antagonist ,  ketamine . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2887", "text": "It is thought that blockage of presynasptic GABA receptors of GABAergic neurons induce stimulation as a net effect, because the action of the most powerful inhibitory  neurotransmitter ,  GABA , is blocked. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2888", "text": "A  paradoxical reaction  (or  paradoxical effect ) is an effect of a  chemical substance , such as a  medical drug , that is opposite to what would usually be expected. An example of a paradoxical reaction is  pain  caused by a  pain relief medication ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2889", "text": "Amphetamines  are a class of  psychoactive drugs  that are  stimulants . Paradoxical drowsiness can sometimes occur in adults. [ 1 ]  Research from the 1980s popularized the belief that ADHD stimulants such as amphetamine have a calming effect in individuals with ADHD, but opposite effects in the general population. [ 2 ]  Research in the early 2000s, however, disputes this claim, suggesting that ADHD stimulants have similar effects in adults with and without ADHD. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2890", "text": "The paradoxical effect or  Eagle effect  (named after  Harry Eagle , who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an  antimicrobial  agent. [ 5 ]  Initially when an  antibiotic  agent is added to a culture media, the number of  bacteria  that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2891", "text": "In a minority of cases,  antidepressants  can lead to violent  thoughts of suicide or self-harm , as observed in some patients during and after treatment, which is in marked contrast to their intended effect. [ 6 ]  A 1991 study found that children and adolescents were more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking  fluoxetine  (commonly known as Prozac). [ 7 ]  This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalized overinhibition of a patient's actions enters remission before that patient's dysphoria does and if the patient was already suicidal but too depressed to act on their inclinations, the patient may find themself in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2892", "text": "Chlorpromazine , an  antipsychotic  and  antiemetic  drug which is classed as a \"major\"  tranquilizer , may cause paradoxical effects such as agitation, hallucinations, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2893", "text": "These may be more common in elderly dementia patients. The apparent worsening of  dementia  may be due to the  anticholinergic  side effects of many antipsychotics. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2894", "text": "Phenobarbital  can cause hyperactivity in children. This may follow after a small dose of 20\u00a0mg, on condition of no phenobarbital administered in previous days. [ 10 ]  Prerequisite for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2895", "text": "Barbiturates  such as  pentobarbital  have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of  attention deficit hyperactivity disorder . Intravenous  caffeine  administration can return these patients' behavior to baseline levels. [ 11 ]  Some case reports postulate a high rate (10-20%) of paradoxical response to anesthesia in ADHD patients, though this has not been objectively corroborated in controlled studies. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2896", "text": "Benzodiazepines , a class of psychoactive drugs called the \"minor\"  tranquilizers , have varying  hypnotic ,  sedative ,  anxiolytic ,  anticonvulsant , and  muscle relaxing  properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in  anxiety ,  aggressiveness ,  agitation ,  confusion ,  disinhibition , loss of  impulse control ,  talkativeness ,  violent  behavior, and even  convulsions . Paradoxical adverse effects may even lead to  criminal behavior . [ 13 ]  Severe behavioral changes resulting from benzodiazepines have been reported including  mania ,  hypomania ,  psychosis , anger and impulsivity. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2897", "text": "Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates  automatic behaviors ,  anterograde amnesia  and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting  serotonergic  mechanism. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2898", "text": "Paradoxical effects of benzodiazepines appear to be dose-related, that is, likelier to occur with higher doses. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2899", "text": "In a letter to the  British Medical Journal , it was reported that a high proportion of parents referred for actual or threatened  child abuse  were taking medication at the time, often a combination of  benzodiazepines  and  tricyclic antidepressants . Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilizers may precipitate a child abuse event. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2900", "text": "Self-aggression  has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people's willingness to harm themselves. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2901", "text": "Benzodiazepines can sometimes cause a paradoxical worsening of  EEG  readings in patients with seizure disorders. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2902", "text": "Caffeine  is believed by many to cause paradoxical calmness or sedation in individuals with ADHD. [ 20 ]  There is insufficient evidence to determine if sedation caused by caffeine is due to a true paradoxical reaction, or rather from dehydration and sleep deprivation caused by the caffeine. [ 21 ]  Furthermore, there are no conclusive studies showing a differential effect of caffeine in individuals with ADHD compared to the general population."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2903", "text": "Naltrexone  blocks the opioid receptors, acting opposite to most opioid pain medications. [ 22 ]  It can be used to negate the effects of opioid painkillers. At doses around one-tenth of the typical dose, naltrexone has been used for pain relief.  Low-dose naltrexone  is believed to have an anti-inflammatory effect. This is an off-label use and not widely accepted by the medical and scientific community. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2904", "text": "Diphenhydramine  (often referred to by the trade name  Benadryl ) is an  anticholinergic   antihistamine  medicine commonly used to treat allergic reactions and symptoms of a  common cold , such as  coughing . Its central antihistaminergic properties also cause it to act as a  sedative , and for this reason it is also used to treat  insomnia . [ 24 ]  Diphenhydramine is also used off-label for its sedative properties, particularly by parents seeking to make their children sedated or sleep during  long-haul flights . This use of diphenhydramine has been criticized for a number of reasons, ranging from ethical to safety concerns, [ 25 ]  but also due to the risk of diphenhydramine's paradoxical reaction, which induces hyperactivity and  irritability . [ 26 ]  This phenomenon can also be observed in adults who use the medication as a sleep aid. The prevalence of this paradoxical reaction is unknown, but research into the phenomenon suggests that it may be as a result of the medicine's interactions with the  CYP2D6 enzyme , and that a  metabolite  of diphenhydramine may be to blame. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2905", "text": "The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of single  neurons  in  subcortical  areas of the human brain is usually not accessible. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2906", "text": "There are, however, multiple indications that paradoxical reactions upon \u2013 for example \u2013 benzodiazepines, barbiturates,  inhalational anesthetics ,  propofol ,  neurosteroids , and  alcohol  are associated with structural deviations of  GABA A  receptors . The combination of the five subunits of the receptor (see image) can be altered in such a way that for example, the receptor's response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2907", "text": "Pharmaceutical medicine  is a medical discipline concerned with the discovery, evaluation, registration, monitoring and clinical aspects of pharmaceutical development. [ 1 ] [ 2 ] [ 3 ]  All medical specialties overlap to some extent, and likewise the boundaries of pharmaceutical medicine are elastic.  But, at its centre is the clinical testing of medicines, translation of pharmaceutical drug research into new medicines, safety and well-being of patients and research participants in  clinical trials , and understanding the safety profile of medicines and their benefit-risk balance. Pharmaceutical physicians work in the  pharmaceutical industry , universities / medical schools, drug regulatory authorities and  contract research organisations , but have a close affinity with their medical colleagues elsewhere."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2908", "text": "As a postgraduate medical discipline, pharmaceutical medicine has a recognised international syllabus, training courses with examinations and qualifications, its own research methodologies, professional bodies and academic societies, journals [ 4 ]  and texts, and embraces new technologies and regulations in pursuit of proof of efficacy, safety and effectiveness of medicines."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2909", "text": "Pharmaceutical medicine is a listed medical specialty in the UK, [ 5 ]  Ireland, Switzerland, [ 6 ]  Mexico [ 7 ]  and Belgium. [ 8 ]  This official recognition is underlined by the availability of accredited education and training of specialist pharmaceutical physicians and the establishment and maintenance of standards of practice and professionalism in the competency, care and conduct applied to their work and of growing public recognition and accountability. In the UK, the  Faculty of Pharmaceutical Medicine  of the  Royal College of Physicians  provides accreditation for the specialty."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2910", "text": "The basics of pharmaceutical medicine are founded in clinical pharmacology. In addition to expertise in basic research,  drug development , and the structure and function of clinical trials, pharmaceutical physicians must possess a thorough understanding of  pharmacoeconomics , medical aspects of the marketing pharmaceuticals, and business administration, and public health [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2911", "text": "Entry-level jobs with this qualification are often clinical research-related. At the entry level, PMST specialists often place into clinical research associate, clinical research analyst, pharmacodynamic data observer, clinical research project manager, drugs and pharmaceutical control manager in clinical research project, etc."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2912", "text": "A  Pharmaceutical Physician  is a  healthcare professional , usually a medical physician, who works in  drug development . They work in biotechnology companies, Contract Research Organisations (CROs), Regulatory Authorities, [ 1 ]  and pharmaceutical companies. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2913", "text": "Pharmaceutical physicians are key players in the development and lifecycle management of medicines, acting as crucial intermediaries between science, medicine, and regulatory frameworks. Their primary responsibility lies in overseeing the safe and effective development of new drugs, as well as investigating new uses for existing medications or medical devices. They engage extensively with a wide array of stakeholders, including pharmaceutical and biotech companies, CROs, government agencies, regulatory bodies, scientific communities, and patient organizations. The overarching goal of these collaborations is to bring innovative and promising therapies from the research lab to the market or to extend the use of already-approved drugs to new medical indications.  [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2914", "text": "Pharmaceutical physicians contribute to the design, conduct, and monitoring of clinical trials. They work closely with sponsors\u2014often large pharmaceutical companies or biotech firms\u2014who fund these trials. In their regulatory role, they collaborate with agencies like the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other competent authorities in different jurisdictions. These physicians help navigate the complex regulatory processes necessary to obtain market approval for new therapies, ensuring that trials meet stringent scientific, ethical, and safety standards."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2915", "text": "In addition to regulatory guidance, pharmaceutical physicians often lead clinical development teams, shaping the medical strategy for drug development. They may occupy various senior roles within companies, such as Chief Medical Officer (CMO), Medical Director, Clinical Development Physician, or Clinical Research Physician. In these roles, they not only oversee clinical trial phases but also ensure compliance with legal and safety standards while balancing commercial considerations and ensuring a return on investment for sponsors. Their tasks range from working on early-stage drug discovery to post-market safety monitoring and the medical aspects of product marketing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2916", "text": "Pharmaceutical Medicine as a Specialty \nPharmaceutical medicine, a lesser-known yet vital medical specialty, deals with the discovery, development, evaluation, licensing, and marketing of medicinal products. It officially became a recognized specialty in the UK in 2002 under the Faculty of Pharmaceutical Medicine (FPM) of the Royal College of Physicians. The specialty has grown rapidly and is now global, with a significant number of professionals working outside the UK, reflecting the international nature of the pharmaceutical industry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2917", "text": "Training in pharmaceutical medicine usually involves a blend of on-the-job experience and formal education, such as obtaining the Diploma in Pharmaceutical Medicine. Over a four-year training period, pharmaceutical physicians acquire expertise in various areas, including regulatory affairs, pharmacology, drug safety, clinical development, and the healthcare marketplace."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2918", "text": "Bringing Drugs to Market \nOne of the primary roles of a pharmaceutical physician is to shepherd new drugs through the clinical trial process, from initial concept to market. This involves several phases of clinical testing to demonstrate a drug's safety and efficacy before it can be submitted for regulatory approval. Pharmaceutical physicians ensure that these trials meet ethical and scientific standards (in accordance with National and regional Good Clinical Practice and other applicable Clinical Trial Directives and Regulations) while navigating the logistical and regulatory hurdles involved in bringing new therapies to market. Additionally, they may conduct trials to explore new indications for existing medications through various regulatory procedures, expanding their use for different diseases or patient populations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2919", "text": "In summary, pharmaceutical physicians play a critical role in drug development by engaging a range of stakeholders\u2014from regulatory bodies and industry sponsors to CROs and patient groups\u2014to bring innovative therapies to market or explore new uses for existing treatments. Their diverse roles within companies, ranging from clinical research to medical strategy, highlight their vital position at the intersection of medicine, science, and industry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2920", "text": "Pharmaceutical physicians were first recruited after the second World War to fluctuate medical aspects of drug development. British Association of Pharmaceutical Physicians was the first industry composed of pharmaceutical physicians. It was created in 1957 in  Britain . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2921", "text": "Pharmacotherapy , also known as  pharmacological therapy  or drug therapy, is defined as medical treatment that utilizes one or more pharmaceutical drugs to improve ongoing symptoms (symptomatic relief), treat the underlying condition, or act as a prevention for other diseases ( prophylaxis ). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2922", "text": "It can be distinguished from therapy using  surgery  (surgical therapy), radiation ( radiation therapy ), movement ( physical therapy ), or other modes. Among  physicians , sometimes the term  medical therapy   refers specifically  to pharmacotherapy as opposed to surgical or other therapy; for example, in  oncology , medical oncology is thus distinguished from  surgical oncology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2923", "text": "Today's pharmacological therapy has evolved from a long history of medication use, and it has changed most rapidly in the last century due to advancements in  drug discovery . The therapy is administered and adjusted by healthcare professionals according to the  evidence-based guidelines  and the patient's health condition.  Personalized medicine  also plays a crucial role in pharmacological therapy.  Personalized medicine , or precision medicine, takes account of the patient's  genetic variation , liver function, kidney function, etc, to provide a tailor-made treatment for a patient. In pharmacological therapy, pharmacists will also consider  medication compliance .  Medication compliance , or medication adherence, is defined as the degree to which the patient follows the therapy that is recommended by the healthcare professionals. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2924", "text": "The use of medicinal substances can be traced back to 4000 BC in the  Sumer  civilization. [ 3 ]  Healers at the time (called  apothecaries ), for example, understood the application of  opium  for pain relief. [ 4 ]  The history of natural remedies can also be found in other cultures, including  traditional Chinese medicine  in China and  Ayurvedic medicine  in India, which are still in use nowadays. [ 5 ]   Dioscorides , a 1st -century Greek surgeon, described more than six hundred animals, plants, and their derivatives in his medical botany, which remained the most influential pharmacopeia for fourteen hundred years. [ 6 ]  Besides substances derived from living organisms, metals, including  copper ,  mercury , and  antimony , were also used as medical therapies. [ 6 ]  They were said to cure various diseases during the late  Renaissance . In 1657,  tartar emetic , which is an antimony compound, was credited with curing  Louis XIV  of  typhoid fever . [ 6 ]  The drug was also administered intravenously for the treatment of  schistosomiasis  in the 20th century. [ 7 ]  However, due to the concern over acute and chronic antimony poisoning, the role of tartar emetic as an antischistosomal agent was gradually replaced after the advent of  praziquantel . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2925", "text": "Other than using natural products, humans also learned to compound medicine by themselves. The first pharmaceutical text was found on clay tablets from the  Mesopotamians , who lived around 2100 BC. [ 5 ]  Later in the 2nd century AD, compounding was formally introduced by  Galen  as \u201ca process of mixing two or more medicines to meet the individual needs of a patient\u201d. [ 5 ]  Initially, compounding was only done by individual pharmacists, but in the post-World War II period, pharmaceutical manufacturers surged in number and took over the role of making medicine. [ 3 ]  Meanwhile, there was a marked increase in pharmaceutical research, which led to a growing number of new drugs. [ 3 ]  Most drug discovery milestones were made in the last hundred years, from  antibiotics  to  biologics , [ 5 ]  contributing to the foundation of current pharmacological therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2926", "text": "Most drugs were discovered by empirical means, including observation, accident, and trial and error. [ 6 ]  One famous example is the  discovery of penicillin , the first  antibiotic  in the world. The substance was discovered by  Alexander Fleming  in 1928 after a combination of unanticipated events occurred in his laboratory during his summer vacation. [ 8 ]  The  Penicillium  mold on the  petri dish  was believed to secrete a substance (later named \"penicillin\") that inhibited bacterial growth. [ 8 ]  Large pharmaceutical companies then started to establish their microbiological departments and search for new antibiotics. [ 9 ]  The screening program for antimicrobial compounds also led to the discovery of drugs with other pharmacological properties, such as  immunosuppressants  like  Cyclosporin A . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2927", "text": "The discovery of  penicillin  was a  serendipitous  (i.e. chance) discovery. Another, more advanced approach to drug discovery is  rational drug design . The method is underpinned by an understanding of the biological targets of the drugs, including  enzymes ,  receptors , and other proteins. In the late 19th century,  Paul Ehrlich  observed the selective affinity of dyes for different  tissues  and proposed the existence of  chemoreceptors  in our bodies. [ 9 ] [ 10 ]  Receptors were believed to be the specific binding sites for drugs. [ 9 ]  The drug-receptor recognition was described as a key-and-lock interplay by  Emil Fischer  in the early 1890s. [ 11 ]  It was later found that the receptors can either be stimulated or inhibited by chemotherapeutic agents to attain the desired physiological response. [ 9 ]  Once the  ligand  interacting with the target macromolecule is identified, drug candidates can be designed and optimized based on the  structure-activity relationship . [ 11 ]  Nowadays, artificial intelligence is employed in drug design to predict drug-protein interactions, drug activity, the 3D configuration of  proteins , etc. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2928", "text": "Evidence-based medicine  is defined as deploying the best current scientific evidence that is available to give the best treatment and make the best decision effectively and efficiently. [ 12 ]  Clinical guidelines are developed based on scientific evidence; for example, the  ACC / AHA  guidelines (for  cardiovascular diseases ), the GOLD guidelines (for  chronic obstructive pulmonary disease ), the GINA guidelines (for  asthma ), etc. They convert and classify the evidence using a systematic method, aiming to provide care with quality. [ 13 ]  The guidelines cannot substitute clinical judgment, as they cannot meet all the circumstances. [ 13 ]  Healthcare professionals can use the  clinical guidelines  as references or evidence to support their clinical judgement when prescribing therapy to patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2929", "text": "Example: Clinical Guideline for controlling blood pressure ( hypertension )"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2930", "text": "If there is an Asian male patient who is 40 years old and has recently been diagnosed with high blood pressure (with a blood pressure of 140/90) and without any other  chronic diseases  ( comorbidities ), such as  type-2 diabetes ,  gout ,  benign prostatic hyperplasia , etc. His estimated 10-year risk of cardiovascular disease is 15%."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2931", "text": "According to the  NICE  2019 Hypertension guideline, the healthcare professional can consider starting anti-hypertensive therapy after a discussion with the patient. [ 14 ]  The first-line therapy will be either an  Angiotensin Converting Enzyme Inhibitor (ACEi)  or an  Angiotensin receptor blocker (ARB)  (if the patient cannot tolerate ACEi). [ 14 ]  If the blood pressure of the patient is not well controlled, the healthcare professionals can consider adding a  calcium channel blocker (CCB) [ 15 ]  or a  Thiazide-like diuretic  to the previous therapy, i,e, ACEi or ARBs with a CCB or a thiazide-like diuretic. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2932", "text": "Every patient has their own body condition, for example, kidney function, liver function, genetic variations, medical history, etc. These are all the factors that should be considered by healthcare professionals before giving any pharmacological therapy. Most importantly, the advancing technology in  genetics  guides us to have more insight into the linkage between health and genes. [ 16 ]  In pharmacological therapy, two areas of study are evolving:  pharmacogenetics  and  pharmacogenomics .  Age will affect the  pharmacokinetics  and  pharmacodynamics  of drugs, and hence the efficacy of the therapy. The effect of age causes deterioration of organ function, [ 17 ]  like liver function and kidney function.  Pharmacokinetics  is the study of drugs' effects on absorption, distribution, metabolism, and elimination.  Pharmacodynamics  is the study of drugs' effects on our body and their mechanisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2933", "text": "Pharmacogenetics  is defined as the study of inherited genes causing different  drug metabolisms  that vary from each other, such as the rate of metabolism and metabolites. [ 18 ]   Pharmacogenomics  is defined as the study of associating the drug response with one's  gene . [ 19 ]  Both terms are similar in nature, so they are used interchangeably."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2934", "text": "Multiple  alleles  can contribute together to a change in response to a drug by expressing a different form of an  enzyme  that responds differently than the normal ones. [ 18 ]  The different forms of  enzymes  ( phenotypes ) include ultra-rapid metabolizers, moderate metabolizers, no-enzyme activity, etc. The  genetic variations  can also be used to match the particular  adverse drug reaction  in order to prevent the patient from suffering the unfavorable outcomes. [ 20 ]  The genetic make-up can affect the  pharmacokinetics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2935", "text": "Azathioprine  is an  immunomodulator  for  inflammatory bowel disease , for instance. Its  metabolite  relies on two different  enzymes  ( TPMT  and  NUDT15 ) to eliminate its effect on our body during its  metabolism . If the patient has the  phenotype  of the  enzymes  that metabolize it poorly, i.e., the poor metabolizer, more toxic metabolites are accumulated in the body. Thus, the patient has a greater risk of the related side-effect. [ 21 ]  The side effect causes the adjustment of dosage [ 21 ]  or switching to another drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2936", "text": "Omalizumab  is a  humanized monoclonal antibody  for the treatment of various  allergic diseases , including  asthma ,  urticaria , and  allergic rhinitis . [ 22 ]  It targets the  immunoglobulin E  (IgE) in human body, which plays an important role in  allergic reactions . [ 23 ]  The efficacy of  omalizumab  may vary among patients. To identify responders to  omalizumab , the level of several  biomarkers  can be measured, including serum  eosinophils , fractional exhaled nitric oxide, and serum IgE. [ 23 ] [ 24 ]  For instance, patients with higher baseline  eosinophil  counts are likely to respond better to  omalizumab  therapy. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2937", "text": "Medication compliance  is defined as the degree to which the patient follows the therapy that is recommended by healthcare professionals. [ 2 ]  There are  direct and indirect methods to evaluate compliance. Direct method refers to the measurement that the healthcare professionals observed  or measure the patient's drug-taking behavior. Indirect method refers to the healthcare professionals do not observe or measure the drug-taking behavior of the patient but use the other source of information to evaluate the compliance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2938", "text": "The direct method includes measurement of drug (or the corresponding  metabolite ) concentration, [ 2 ] [ 25 ]  while the indirect method includes pill counting [ 2 ] [ 25 ]  and the self-report from the patient. [ 2 ] [ 25 ]  The direct method is more time-consuming, more expensive, more invasive, but it is more accurate. [ 2 ]  The indirect method has a lower accuracy but is easier to administer to the patient. [ 2 ]  If the patient fails to comply with treatment, for example, by not taking the medication according to the instructions, it leads to risk and a poor treatment outcome."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2939", "text": "For  tuberculosis  patients, directly observed therapy is still part of the treatment. [ 26 ]  This is to increase  medication compliance . [ 27 ]  This is to prevent treatment failure, relapse, and transmission in the community. [ 28 ]  Apart from the traditional direct observed therapy (DOT), there is another method proposed to try increasing medication compliance.  Video-observed therapy (VOT)  is one of the methods. It has some advantages and disadvantages. It reduces the cost of healthcare and the travel costs for the patient. [ 27 ]  The downside of the intervention is the need for quality control training as it would be hard to confirm the patient's adherence. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2940", "text": "Pharmacists  are experts in pharmacotherapy and are responsible for ensuring the safe, appropriate, and economical use of pharmaceutical drugs. The skills required to function as a pharmacist require knowledge, training and experience in biomedical, pharmaceutical and  clinical sciences . [ 29 ]   Pharmacology  is the science that aims to continually improve pharmacotherapy. The  pharmaceutical industry  and  academia  use  basic science ,  applied science , and  translational science  to create new pharmaceutical drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2941", "text": "As pharmacotherapy specialists and pharmacists have responsibility for direct  patient care , often functioning as a member of a multidisciplinary team, and acting as the primary source of drug-related information for other  healthcare professionals . A pharmacotherapy specialist is an individual who is specialized in administering and prescribing medication, and requires extensive academic knowledge in pharmacotherapy. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2942", "text": "In the US, a pharmacist can gain Board Certification in the area of pharmacotherapy upon fulfilling eligibility requirements and passing a certification examination. [ 31 ] [ 32 ]  While pharmacists provide valuable information about medications for patients and healthcare professionals, they are not typically considered covered pharmacotherapy providers by insurance companies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2943", "text": "Photosensitivity  is the amount to which an object reacts upon receiving  photons , especially  visible light . In medicine, the term is principally used for abnormal reactions of the skin, and two types are distinguished,  photoallergy  and  phototoxicity . [ 1 ] [ 2 ]  The  photosensitive ganglion cells  in the mammalian eye are a separate class of light-detecting cells from the  photoreceptor cells  that function in vision."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2944", "text": "Sensitivity of the  skin  to a light source can take various forms. People with particular skin types are more sensitive to  sunburn . Particular medications make the skin more sensitive to sunlight; these include most of the  tetracycline antibiotics , heart drugs  amiodarone , and  sulfonamides .\nSome dietary supplements, such as  St. John's Wort , include photosensitivity as a possible side effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2945", "text": "Particular conditions lead to increased light sensitivity. Patients with  systemic lupus erythematosus  experience skin symptoms after sunlight exposure; some types of  porphyria  are aggravated by sunlight. A rare hereditary condition  xeroderma pigmentosum  (a defect in DNA repair) is thought to increase the risk of UV-light-exposure-related cancer by increasing photosensitivity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2946", "text": "Photosensitivity occurs in multiple species including  sheep ,  bovine , and  horses . They are classified as primary if an ingested plant contains a photosensitive substance, like  hypericin  in  St John's wort  poisoning and ingestion of biserrula ( Biserrula pelecinus ) [ 3 ]  in sheep, or  buckwheat plants  (green or dried) in horses. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2947", "text": "In  hepatogenous photosensitization , the photosensitzing substance is  phylloerythrin , a normal end-product of  chlorophyll  metabolism.\u00a0 [ 5 ]  It accumulates in the body because of liver damage, reacts with UV light on the skin, and leads to free radical formation. These free radicals damage the skin, leading to ulceration, necrosis, and sloughing. Non-pigmented skin is most commonly affected."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2948", "text": "A  pill organiser  (or  pill organizer ),  pill container ,  dosette box ,  pillcase  or  pillbox  is a multicompartment  compliance  aid for storing scheduled doses of  medications . Pill organisers usually have square-shaped compartments for each day of the week, although other more compact and discreet versions have come to market, including cylindrical and pen-shaped cases. [ 1 ] [ 2 ]  Some organisers have sections corresponding to times of the day. Pill organisers are viewed as a way to prevent or reduce medication errors on the part of the patient, though evidence of effectiveness is not strong and they have been linked to medication errors. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2949", "text": "The first pill organizer was invented by Phil Cherrin of Cherrin Brothers Corporation in Detroit, Michigan.  The brothers patent was filed July 21, 1966, US-3432951-A, and approved on March 18, 1969.  This patent for \"a compartmented container made of clear plastic for use in dispensing medicinal pills at periodic intervals such as daily on a mistake-proof basis\" has been cited as the first, seminal patent for all subsequent pill organizer patent filings. [ 4 ]  Cherrin Brothers Corporation, a distributor of candy, tobacco and personal care paper products was a pioneer in the design of plastics for packaging consumables that preserved freshness and bundled multi-packs including but not limited to seminal patents for the clear invoice/packing slip envelope used by Fedex/UPS/USPS etc today as well as the adhesive tape dispenser.  [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2950", "text": "Pill organisers are useful for all types of  patients , including the  elderly , those who have  memory deficiencies , and those taking multiple medications as an aid in remembering to take proper doses of their medications in  compliance  with their doctor's recommended dose. They allow a patient to know whether or not they have taken a particular dose of their medication; if a pill still remains in its compartment, it is apparent that it has not yet been taken, whereas if it is missing, it has already been taken. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2951", "text": "Pill organisers often have various features to make them easier for special-needs patients to use, such as  color-coding ,  Braille  for the  blind , or a locking mechanism to prevent double dosing. [ 8 ]  Some organisers used for  diabetes  patients have sections for  insulin  and  hypodermic syringes ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2952", "text": "Some pharmacists will pre-load pills into pill organisers for their patients, as a convenient service. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2953", "text": "Electronic pill organisers,  pill dispensers , and  pill reminders  have been developed that alert patients when their  prescription medication ,  OTC medication , or daily  food supplements  must be taken. [ 8 ]  These devices have been credited with saving lives and saving money in the health care system. [ 10 ]  Advanced models can be linked via the Internet to a medical facility, to aid in monitoring and reminding a patient to take his/her medications. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2954", "text": "A  pill reminder  is any device that reminds users to take medications.  Traditional pill reminders are  pill containers  with electric timers attached, which can be preset for certain times of the day to set off an alarm.  More sophisticated pill reminders can also detect when they have been opened, and therefore when the user is away during the time they were supposed to take their medication, they will be reminded of it when they return.  This reminder can be in the form of a light, which also helps for deaf or hearing-impaired users."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2955", "text": "A newer type of pill reminder is a  mobile app  that reminds the owner to take the medication. [ 1 ]  Some of these applications might effectively support  adherence  to taking medications. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2956", "text": "This article related to  medical equipment  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2957", "text": "Polysubstance dependence  refers to a type of  substance use disorder  in which an individual uses at least three different classes of substances indiscriminately and does not have a favorite substance that qualifies for dependence on its own. Although any combination of three substances can be used, studies have shown that  alcohol  is commonly used with another substance. [ 1 ]  One study on polysubstance use categorized participants who used multiple substances according to their substance of preference. The results of a  longitudinal study  on substance use led the researchers to observe that excessively using or relying on one substance increased the probability of excessively using or relying on another substance. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2958", "text": "The three substances were  cocaine , alcohol, and  heroin , which implies that those three are very popular. [ 3 ]  Other studies have found that opiates, cannabis, amphetamines, hallucinogens, inhalants, and benzodiazepines are often used in combination as well. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2959", "text": "Cognition refers to what happens in the mind, such as mental functions like \" perception , attention, memory, language, problem solving, reasoning, and decision making.\" [ 5 ]  Although many studies have looked at the cognitive impairments of individuals who are dependent on one substance, there are few researchers who have tried to determine the problems with cognitive functioning that are caused by dependence on multiple substances. [ 6 ]  Therefore, what is known about the effects of polysubstance dependence on mental abilities is based on the results of a few studies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2960", "text": "The effect of polysubstance dependence on learning ability is one area of interest to researchers. A study involving 63 polysubstance dependent women and 46 controls (participants who were not using substances) used the  Benton Visual Retention Test  (BVRT) and the  California Verbal Learning Test  (CVLT) to look at visual memory and verbal ability. [ 7 ]  This study showed that in polysubstance dependent women, verbal learning ability was significantly decreased, though visual memory was not affected. In addition, alcohol and cocaine use led to more severe issues with verbal learning, recall, and recognition. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2961", "text": "Sometimes studies about specific groups in the general population can be informative. One study decided to test the cognitive abilities of participants in  rave  parties who used multiple substances. To do this, they compared 25 rave party attenders with 27 control participants who were not using substances. The results of this study indicated that in general, the rave attender group did not perform as well on tasks that tested speed of information processing,  working memory , knowledge of similarities between words, ability to attend to a task with interference in the background, and decision making. [ 3 ]  Certain substances were associated with particular mental functions, but the researchers suggested that the impairments for working memory and reasoning were caused by the misuse of multiple substances. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2962", "text": "Another study that tried to find differences between the effects of particular substances focused on people with polysubstance use who were seeking treatment for addictions to  cannabis , cocaine, and heroin. They studied a group of people with polysubstance use and a group that was not dependent on any substances. Because alcohol was a common co-substance for nearly all of the people in the polysubstance use group, it was difficult to tell exactly which substances were affecting certain cognitive functions. The researchers found that the difference in the two groups' performance levels on  executive function , or higher-level cognitive processing tasks were consistently showing that the polysubstance group scored lower than the control group. [ 8 ]  In general, this meant that multiple substances negatively affected the polysubstance group's cognitive functioning. More specifically, the researchers found that the amount of cannabis and cocaine affected the verbal part of working memory, the reasoning task, and decision making, while cocaine and heroin had a similar negative effect on visual and spatial tasks, but cannabis particularly affected visual and spatial working memory. [ 8 ]  These results suggest that the combined use of cannabis, cocaine, and heroin impair more cognitive functions more severely than if used separately. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2963", "text": "Alcohol's negative effects on learning, spatial abilities and memory has been shown in many studies. [ 9 ]  This raises a question: does using alcohol in combination with other substances impair cognitive functioning even more? One study decided to try to determine if people with polysubstance use who also recreationally use alcohol would display poorer performance on a verbal learning and memory test in comparison to those who consumed excessive amounts of alcohol specifically. [ 10 ]  The California Verbal Learning Test (CVLT) was used due to its ability to \"quantify small changes in verbal learning and memory\" by evaluating errors made during the test and the strategies used to make those errors. [ 10 ]  The results of this study showed that the group of people with polysubstance and alcohol use performed poorly on the CVLT recall and recognition tests compared to the group of people who exclusively consumed excessive alcohol only, which implies that polysubstance use impaired the memory and learning in a different way than the effects of alcohol alone can explain. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2964", "text": "To examine whether abstinence for long periods of time helps people with polysubstance use recover their cognitive function, a group of researchers tested 207 polysubstance dependent men, of whom 73.4% were dependent on three or more substances. [ 6 ]  The researchers were interested in six areas of cognitive functioning, which included visual memory, verbal memory, knowledge of words, abstract reasoning, inhibition (interference), and attention. [ 6 ]  The study used the Benton Visual Retention Test (BVRT) for testing visual memory, the California Verbal Learning Test (CVLT) for verbal memory, the  Wechsler Adult Intelligence Scale  vocabulary portion for knowledge of words, the Booklet Category Test for abstract reasoning, the  Stroop  Neuropsychological Screening task for inhibition, and the  Trail Making Test  for attention. [ 6 ]  The results showed that neuropsychological ability did not improve with increases in the length of time abstinent. This suggests that polysubstance dependence leads to serious impairment which cannot be recovered much over the span of a year. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2965", "text": "There is data to support that some genes contribute to substance dependence. [ 11 ]  Some studies have focused on finding genes that predispose the person to be dependent on marijuana, cocaine, or heroin by studying genes that control a person's  dopamine  and  opioid  receptors, but no conclusive findings were reported. [ 12 ]  Other researchers found a connection between dopamine receptor genes and dependency on a substance. [ 12 ]  A potential problem with this study was that alcohol is commonly used with another substance, so the results of the study may not have been caused by dependency on a single substance. This means that multiple substances may have been contributing to the results, but the researchers suggested that further research should be done. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2966", "text": "However, there are studies that have found evidence of the influence of genes on vulnerability to substance dependence. [ 13 ]  These studies often use genotype, or the genetic information found on a person's chromosomes, and phenotype, which consists of the visible features of a person, to look at genetic patterns. [ 14 ]  One study examined the phenotype and genotype of 1,858 participants from 893 families to look at differences in three  nicotinic acetylcholine receptor  genes found within these individuals. [ 13 ]  The experimenters found significant connections between receptor genes for nicotine and polysubstance dependence, which indicated that differences in these genes can create the risk of being dependent on multiple substances. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2967", "text": "A 1985 study conducted by Khantzian and Treece found that 65% of their opioid-dependent sample met criteria for a  personality disorder  diagnosis. In the same study, 93% of the sample had a  comorbid  disorder, implying that the comorbid disorder plays some role in the addiction. [ 15 ] [ 16 ]  It has also been shown that depression and polysubstance dependence are often both present at the same time. If a person is genetically predisposed to be depressed then they are at a higher risk of having polysubstance dependence. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2968", "text": "Possibly the most widely accepted cause of addictions is the  self-medication  hypothesis, that views substance addiction as a form of coping with stress through  negative reinforcement , by temporarily alleviating awareness of or concerns over the stressor. [ 18 ]  People who use substances learn that the effects of each type of substance works to relieve or better painful states. They use substances as a form of self-medication to deal with difficulties of self-esteem, relationships, and self-care. Individuals with substance use disorders often are overwhelmed with emotions and painful situations and turn to substances as a coping method. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2969", "text": "The sociocultural causes are areas in a person's life that might have influenced their decision to start and continue using multiple substances. Sociocultural causes can be divided into social causes and cultural causes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2970", "text": "For most of these disorders, in relation to polysubstance dependence, there is a vicious cycle that those with a dependence go through. First, ingesting the substance creates a need for more, which creates a dopamine surge, which then creates pleasure. As the dopamine subsides, the pleasure adds to the emotional and physical pain and triggers stress transmitters, which in turn creates a craving, which must then be medicated, and thus the cycle begins again. However, the next time they use, more of the substance will need to be used to get to the same degree of intoxication . [ 21 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2971", "text": "Scientists have hypothesized that the use of a substance either causes a mood disorder such as depression or at least attributes to a pre-existing one. Additionally, the substances that people with depression use can be a misguided method of self-medication in order to manage their depression. [ 23 ]  This is the classic  chicken or egg  hypothesis, does the pre-existing condition cause dependence or does dependence cause the condition? The underlying mental illness needs to be identified and treated in conjunction with treating the polysubstance dependence in order to increase the success rate of treatment and decrease the probability of relapse. [ 17 ]  One specific study focused on alcohol and depression, because they are so commonly inter-related. Researchers have discovered that depression continues for several weeks after a patient had been rehabilitated and those who relapsed developed depression again. This means that the onset of depression happens after alcohol dependence occurs, which means that alcohol is a major contributor to depression. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2972", "text": "One study showed that patients who are recovering from an addiction, who have had an eating disorder in the past, often use food to try to replace the substance that they are no longer getting. Or they obsess over controlling their weight and appearance. Some rehabilitation centers have licensed nutritionists to help patients develop healthy eating habits to help them cope while recovering from their addictions. It is important that those who have a former eating disorder be taught how to eat healthfully, so they don't continuously switch from one addiction back to another. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2973", "text": "According to the DSM-IV, a diagnosis of polysubstance dependence must include a person who has used at least three different substances (not including caffeine or nicotine) indiscriminately, but does not have a preference to any specific one. In addition they must show a minimum of three of the following symptoms listed below, all within the past twelve months. [ 24 ]  There is a distinct difference between a person having three separate dependence issues and having Polysubstance dependence the main difference is polysubstance dependence means that they are not specifically addicted to one particular substance. This is often confused with multiple specific dependences present at the same time. To elaborate, if a person is addicted to three separate substance such as cocaine, methamphetamines and alcohol and is dependent on all three then they would be diagnosed with three separate dependence disorders existing together (cocaine dependence, methamphetamine dependence and  alcohol dependence ,) not polysubstance dependence. [ 24 ]  In addition to using three different substances without a preference to one, there has to be a certain level of dysfunction in a person's life to qualify for a diagnosis of polysubstance dependence. [ 25 ]  One of the bigger challenges that often occurs when trying to diagnose is the fact that people don't always report what they are taking because they are afraid of getting into legal trouble. [ 20 ]  When coding polysubstance Dependence in a DSM-IV it would be a  multiaxial diagnosis  304.80- Polysubstance Dependence\", next to the classification, it is accompanied by a list of other types of  Substance dependence  (e.g. \"305.00 Alcohol Abuse\" or \"305.60 Cocaine Abuse\"). [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2974", "text": "The DSM-IV requires at least three of the following symptoms present during a 12-month period for a diagnoses of polysubstance dependence. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2975", "text": "DSM-5  eliminated polysubstance disorder; there the substances must be specified, among other related changes. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2976", "text": "Treatment for polysubstance dependence has many critical aspects.  Substance rehabilitation  is a lengthy and difficult process. Treatment must be individualized and last a sufficient amount of time to ensure the patient has kicked the addictions and to ensure the prevention of relapse. The most common forms of treatment for polysubstance dependence include: inpatient and outpatient treatment centers, counseling and behavioral treatments, and medications. It is important that treatments be carried on throughout the patient's life in order to  prevent relapse . It is a good idea that recovering addicts continue to attend social support groups or meet with counselors to ensure they do not relapse. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2977", "text": "Inpatient treatment centers are treatment centers where addicts move to the facility while they are undergoing treatment. Inpatient treatment centers offer a safe environment where patients will not be exposed to potentially harmful situations during their treatments as they would on the outside. Inpatients usually undergo the process of  detoxification . Detox involves withdrawing the user (usually medically) from all substances of concern. During their stay in the treatment facility, patients often are learning to manage and identify their substance addictions and to find alternate ways to cope with whatever is the cause of their addiction. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2978", "text": "Outpatient treatments include many of the same activities offered in an inpatient treatment facility, [ 31 ]  but the patient is not protected by the secure and safe environment of an inpatient treatment center. For this reason, they are significantly less effective. The patient usually continues to hold a job and goes to treatment nightly. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2979", "text": "Both in-patient and out-patient treatments can offer introductions to  Twelve-step programs  such as  Alcoholics Anonymous  and  Narcotics Anonymous . They offer regular meetings where members can discuss their experiences in a non-judgmental and supportive place. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2980", "text": "Also offered to patients are one-on-one  counseling sessions  and  cognitive behavioral therapy (CBT) . [ 30 ]  When looked at through a cognitive-behavioral perspective, addictions are the result of learned behaviors developed through positive experiences. In other words, when an individual uses a substance and receives desired results (happiness, reduced stress, etc.) it may become the preferred way of attaining those results, leading to addictions. The goal of CBT is to identify the needs that the addictions are being used to meet and to develop skills and alternative ways of meeting those needs. The therapist will work with the patient to educate them on their addictions and give them the skills they need to change their cognitions and behaviors. Addicts will learn to identify and correct problematic behavior. They will be taught how to identify harmful thoughts and substance cravings. CBT is an effective treatment for addictions. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2981", "text": "Medications can be very helpful in the long-term treatment of polysubstance dependence. Medications are a useful aid in helping to prevent or reducing substance cravings. Another benefit of medications is helping to preventing relapse. Since substance use disorders affect brain functioning, medications assist in returning to normal brain functioning. People who use multiple substances require medications for each substance they use, as the current medications do not treat all substance use disorders simultaneously. Medications are a useful aid in treatments, but are not effective when they are the sole treatment method. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2982", "text": "There are not very many studies that have examined how often polysubstance dependence occurs or how many people are dependent on multiple substances. However, according to a study that analyzed the results from the National Epidemiological Survey on Alcohol and Related Conditions, approximately 215.5 out of a total of 43,093 individuals in the United States (0.5%) met the requirements for polysubstance use disorder. [ 36 ]  Another study suggested that the number of new cases of polysubstance dependence has been going up. [ 37 ]  This idea was supported by a study that took place in  Munich ,  Germany . A group of researchers chose to look at responses to a survey using the M-Composite International Diagnostic Interview (M-CIDI). The M-CIDI is a version of the  Composite International Diagnostic Interview  (CIDI). [ 38 ]  The researchers collected data from 3,021 participants, all between the ages of 14 and 24, to estimate the  prevalence , or total number of cases, of substance use and of polysubstance use/dependence. [ 39 ]  The results of this study indicated that of the 17.3% who said that they regularly used substances, 40% said that they used more than one substance, but 3.9% specifically reported using three or more substances, indicating that there is a lot of overlap in the use of different substances. [ 39 ]  The researchers compared their results to earlier German studies and found that substance dependence seems to be increasing, at least in Germany. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2983", "text": "Women and men differ in various ways when it comes to addictions. Research has shown that women are more likely to be polysubstance dependent. It has been noted that a larger percentage of women use licit (legal) substances such as tranquilizers, sedatives, and stimulants. On the other hand, men are more likely to use illicit (illegal) substances such as cocaine, methamphetamine, and other illicit substances. Research suggests that women addicts more frequently have a family history of substance use. When asked to describe their onset of addictions, women more frequently describe their addiction as sudden where as men describe them as gradual. Females have a higher percentage of fatty tissues and a lower percentage of body water than men. Therefore, women absorb substances more slowly. This means these substances are at a higher concentration in a woman's bloodstream. Female addicts are known to be at greater risk for fatty liver disease, hypertension, anemia, and other disorders. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2984", "text": "The  rebound effect , or  rebound phenomenon , is the emergence or re-emergence of  symptoms  that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re-emergence, the severity of the symptoms is often worse than pretreatment levels."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2985", "text": "The rebound effect, or  pharmaceutical  rebound phenomenon, is the emergence or re-emergence of  symptoms  that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re-emergence, the severity of the symptoms is often worse than pretreatment levels. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2986", "text": "Rebound insomnia is  insomnia  that occurs following discontinuation of  sedative  substances taken to relieve primary insomnia. Regular use of these substances can cause a person to become  dependent  on its effects in order to fall asleep. Therefore, when a person has stopped taking the medication and is 'rebounding' from its effects, they may experience insomnia as a symptom of  withdrawal . Occasionally, this insomnia may be worse than the insomnia the drug was intended to treat. [ 1 ]  Common medicines known to cause this problem are  eszopiclone ,  zolpidem , and  anxiolytics  such as  benzodiazepines  and which are prescribed to people having difficulties falling or staying asleep."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2987", "text": "Rebound depression may appear to arise in patients previously free of such an illness. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2988", "text": "Daytime rebound effects of anxiety, metallic taste, perceptual disturbances which are typical  benzodiazepine withdrawal symptoms  can occur the next day after a short-acting  benzodiazepine  hypnotic wears off. Rebound phenomena do not necessarily only occur on discontinuation of a prescribed dosage. Another example is early morning rebound insomnia which may occur when a rapidly eliminated hypnotic wears off which leads to rebounding awakeness forcing the person to become wide awake before he or she has had a full night's sleep. One drug which seems to be commonly associated with these problems is  triazolam , due to its high potency and ultra short half life, but these effects can occur with other short-acting  hypnotic drugs . [ 3 ] [ 4 ] [ 5 ]   Quazepam , due to its selectivity for type1 benzodiazepine receptors and long half-life, does not cause daytime anxiety rebound effects during treatment, showing that half-life is very important for determining whether a nighttime  hypnotic  will cause next-day rebound withdrawal effects or not. [ 6 ]  Daytime rebound effects are not necessarily mild but can sometimes produce quite marked psychiatric and psychological disturbances. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2989", "text": "Rebound effects from  stimulants  such as  methylphenidate  or  dextroamphetamine  include  stimulant psychosis ,  depression  and a return of ADHD symptoms but in a temporarily exaggerated form. [ 8 ] [ 9 ] [ 10 ]  Up to a third of ADHD children experience a rebound effect when methylphenidate is withdrawn. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2990", "text": "Many  antidepressants , including  SSRIs , can cause rebound  depression ,  panic attacks ,  anxiety , and  insomnia  when discontinued. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2991", "text": "Sudden and severe emergence [ 13 ]   or re-emergence [ 14 ]  of psychosis may appear when  antipsychotics  are  switched  or  discontinued  too rapidly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2992", "text": "Rebound hypertension, above pre-treatment level, was observed after  clonidine , [ 15 ]  and  guanfacine [ 16 ]  discontinuation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2993", "text": "Continuous usage of  topical decongestants  ( nasal sprays ) can lead to constant  nasal congestion , known as  rhinitis medicamentosa ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2994", "text": "Denosumab  inhibits osteoclast recycling, which results in the accumulation of pre-osteoclasts and osteomorphs. When denosumab therapy is discontinued, the induced cells quite quickly and abundantly differentiate into osteoclasts causing  bone resorption  (rebound effect) and increasing the risk of fractures. For improving mineral bone density and preventing fractures after denosumab discontinuation,  bisphosphonate  administration is recommended. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2995", "text": "Another example of  pharmaceutical  rebound is a  rebound headache  from painkillers when the dose is lowered, the medication wears off, or the drug is abruptly discontinued. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2996", "text": "In 2022, reports of viral RNA and symptom rebound in people with  COVID-19  treated with  Paxlovid  were published. In May, CDC even issued a health alert informing physicians about \"Paxlovid rebounds\", which received attention when US president  Joe Biden  experienced a rebound. The cause of the rebound is unclear however, since around a third of people with COVID-19 experience a symptom rebound regardless of treatment. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2997", "text": "Abrupt withdrawal of highly potent  corticosteroids , such as  clobetasol  for  psoriasis  can cause a much more severe case of the psoriasis to develop. Therefore, withdrawal should be gradual, until very little actual medication is being applied. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_2998", "text": "Research on Adverse Drug Events and Reports (RADAR)  is a  pharmacovigilance  team of 25 doctors who receive calls about possible  adverse drug reactions  (ADR) and investigate.  RADAR is based at  Northwestern 's  Feinberg School of Medicine . RADAR is led by Dennis West. Though it was without funding for its first four years, RADAR has raised about $12 million through grants from the  National Institutes of Health , the  American Cancer Society  and other such institutions. Its work has identified safety problems with 33 drugs.   Adverse drug events  are a serious health problem."}
{"_id": "WikiPedia_Pharmacology$$$corpus_2999", "text": "The aims of RADAR are to disseminate safety reports for serious adverse drug reactions (sADRs) and to identify barriers to identification and reporting of these clinical events. Investigators have developed a well-coordinated system to accurately compile case report information on sADRs and to identify milestones associated with identification and reporting of the relevant ADR information. This ADR identification system allows us to amass pertinent sADR information from a diverse set of data sources in order to identify and report sADRs in a timely and thorough manner. With increasingly shortened review periods,  postmarketing surveillance  for sADRs has become very important. In some instances, initial cases are identified at hospital case conferences and reported to the  U.S. Food and Drug Administration  (FDA) or to the  pharmaceutical manufacturer . The RADAR methodology relies on initial recognition of these \u201csentinel\u201d cases that then prompts hypothesis\u2013driven inquiries as to whether an unrecognized  adverse drug event  signal is present in the population of those exposed to that drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3000", "text": "Between 1998 and 2007, 33 serious adverse drug or device reactions have been reported by RADAR investigators. The  toxicities  involved multiple  biological system  and included  thrombotic thrombocytopenic purpura  (TTP) ( ticlopidine  and  clopidogrel ),  thromboembolism  ( thalidomide  and  lenalidomide ),  liver failure  ( gemtuzumab  and  nevirapine ),  hypersensitivity  ( drug eluting coronary arterial stents ),  pure red-cell aplasia  (PRCA) ( epoetin ), vision changes ( amiodarone ,  sildenafil , and  tadalafil ), late  thrombotic events  ( drug eluting cardiac stents ),  leukemia  ( G-CSF ), and  interstitial pneumonitis  ( gemcitabine ). For each individual ADR, the number of unique event reports collected by RADAR ranged from 0 to 96. Twenty-seven sADRs were associated with drugs and four were associated with a device."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3001", "text": "The success of the RADAR program has previously been largely based on the use of diverse data sources to identify, clarify, and verify ADRs.   Databases ,  registries ,  clinical trials , referral centers, and case reports have all been utilized as sites of detection. In particular, RADAR has made use of reports submitted to  MedWatch  as well as more focused databases such as the  Medicare -SEER database. Hypothesis-driven active surveillance of a few hundred safety reports serves as the underlying conceptual framework of RADAR  pharmacovigilance . Fewer than 20 individual ADR reports led to RADAR investigators identifying safety signals for the majority of the ADRs described to date. Despite a small number of reports for each ADR,  causality  assessments have been supported by  pathology  studies,  antibody  studies, and  autopsies . For example, the initial description of  thrombotic thrombocytopenic purpura  associated with  clopidogrel  included only 11 cases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3002", "text": "RADAR has also identified key barriers to timely and efficiently identifying ADRs and to comprehensively reporting these findings. In particular, we identified quality concerns with MedWatch reports (the FDA's primary source of adverse event reports) and poor quality of dissemination of adverse event findings from the FDA and the  pharmaceutical  sponsor. Our efforts have found that RADAR sADR identification and dissemination efforts can be as rapid as one to two years after FDA approval, in contrast to the seven years generally seen with safety efforts from the FDA and pharmaceutical sponsors. Thus, the RADAR project has developed into an important adjunct to the current pharmaceutical drug and device safety system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3003", "text": "RADAR has analyzed historical data on many drugs from their initial inception, through approval by the FDA, and to the\npresent.  These analyses synthesize the various sources of statistical information on the presence of adverse reactions to these drugs and assess whether the actual risk is in line with studies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3004", "text": "Serotonin syndrome  ( SS ) is a group of symptoms that may occur with the use of certain  serotonergic  medications or  drugs . [ 1 ]  The symptoms can range from mild to severe, and are potentially fatal. [ 4 ] [ 5 ] [ 2 ]  Symptoms in mild cases include  high blood pressure  and a  fast heart rate ; usually without a  fever . [ 2 ]  Symptoms in moderate cases include  high body temperature , agitation,  increased reflexes ,  tremor ,  sweating ,  dilated pupils , and  diarrhea . [ 1 ] [ 2 ]  In severe cases,  body temperature  can increase to greater than 41.1\u00a0\u00b0C (106.0\u00a0\u00b0F). [ 2 ]  Complications may include  seizures  and  extensive muscle breakdown . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3005", "text": "Serotonin syndrome is typically caused by the use of two or more serotonergic medications or drugs. [ 2 ]  This may include  selective serotonin reuptake inhibitor  (SSRI),  serotonin norepinephrine reuptake inhibitor  (SNRI),  monoamine oxidase inhibitor  (MAOI),  tricyclic antidepressants  (TCAs),  amphetamines ,  pethidine  (meperidine),  tramadol ,  dextromethorphan ,  buspirone ,  L-tryptophan ,  5-hydroxytryptophan ,  St.\u00a0John's wort ,  triptans ,  MDMA ,  ondansetron ,  metoclopramide , or  cocaine . [ 2 ]  It occurs in about 15% of SSRI overdoses. [ 3 ]  It is a predictable consequence of excess  serotonin  on the  central nervous system . [ 6 ]  Onset of symptoms is typically within a day of the extra serotonin. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3006", "text": "Diagnosis is based on a person's symptoms and history of medication use. [ 2 ]  Other conditions that can produce similar symptoms such as  neuroleptic malignant syndrome ,  malignant hyperthermia ,  anticholinergic toxicity ,  heat stroke , and  meningitis  should be ruled out. [ 2 ]  No laboratory tests can confirm the diagnosis. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3007", "text": "Initial treatment consists of discontinuing medications which may be contributing. [ 1 ]  In those who are agitated,  benzodiazepines  may be used. [ 1 ]  If this is not sufficient, a  serotonin antagonist  such as  cyproheptadine  may be used. [ 1 ]  In those with a high body temperature,  active cooling  measures may be needed. [ 1 ]  The number of cases of SS that occur each year is unclear. [ 3 ]  With appropriate medical intervention the risk of death is low, likely less than 1%. [ 7 ]  The high-profile  case of Libby Zion , who is generally accepted to have died from SS, resulted in changes to graduate medical school education in  New York State . [ 6 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3008", "text": "Symptom onset is usually relatively rapid, and SS encompasses a wide range of clinical findings. Mild symptoms may consist of  increased heart rate , shivering,  sweating ,  dilated pupils ,  myoclonus  (intermittent jerking or twitching), as well as  hyperreflexia  (overresponsive reflexes). [ 6 ]  Many of these symptoms may be side effects of the drug or drug interaction causing excessive levels of serotonin rather than an effect of elevated serotonin itself."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3009", "text": "Tremor  is a common side effect of  MDMA 's action on  dopamine , whereas hyperreflexia is symptomatic of exposure to  serotonin agonists . Moderate intoxication includes additional abnormalities such as hyperactive bowel sounds,  high blood pressure  and  hyperthermia ; a temperature as high as 40\u00a0\u00b0C (104\u00a0\u00b0F). The overactive reflexes and  clonus  in moderate cases may be greater in the lower limbs than in the  upper limbs . Mental changes include  hypervigilance  or  insomnia  and  agitation . [ 6 ]  Severe symptoms include severe increases in heart rate and blood pressure. Temperature may rise to above 41.1\u00a0\u00b0C (106.0\u00a0\u00b0F) in life-threatening cases. Other abnormalities include  metabolic acidosis ,  rhabdomyolysis ,  seizures ,  kidney failure , and  disseminated intravascular coagulation ; these effects usually arising as a consequence of hyperthermia. [ 6 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3010", "text": "The symptoms are often present as a clinical triad of abnormalities: [ 6 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3011", "text": "Numerous medications and street drugs can cause SS when taken alone at high doses or in combination with other serotonergic agents. The table below lists some of these."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3012", "text": "Many cases of serotonin toxicity occur in people who have ingested drug combinations that synergistically increase synaptic serotonin. [ 10 ]  It may also occur due to an overdose of a single serotonergic agent. [ 29 ]  The combination of  monoamine oxidase inhibitors  (MAOIs) with precursors such as  L-tryptophan  or  5-hydroxytryptophan  pose a particularly acute risk of life-threatening serotonin syndrome. [ 30 ]  The case of combination of MAOIs with tryptamine agonists (commonly known as  ayahuasca ) can present similar dangers as their combination with precursors, but this phenomenon has been described in general terms as the  cheese effect . Many MAOIs irreversibly inhibit  monoamine oxidase . It can take at least four weeks for this enzyme to be replaced by the body in the instance of irreversible inhibitors. [ 31 ]  With respect to tricyclic antidepressants, only clomipramine and imipramine have a risk of causing SS. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3013", "text": "Many medications may have been incorrectly thought to cause SS. For example, some case reports have implicated  atypical antipsychotics  in SS, but it appears based on their pharmacology that they are unlikely to cause the syndrome. [ 33 ]  It has also been suggested that  mirtazapine  has no significant serotonergic effects and is therefore not a dual action drug. [ 34 ]  Bupropion has also been suggested to cause SS, [ 35 ] [ 36 ]  although as there is no evidence that it has any significant serotonergic activity, it is thought unlikely to produce the syndrome. [ 37 ]  In 2006 the US  Food and Drug Administration  (FDA) issued an alert suggesting that the combined use of either SSRIs or SNRIs with triptan medications or sibutramine could potentially lead to severe cases of SS. [ 38 ]  This has been disputed by other researchers, as none of the cases reported by the FDA met the Hunter criteria for SS. [ 38 ] [ 39 ]  The condition has however occurred in surprising clinical situations, and because of phenotypic variations among individuals, it has been associated with unexpected drugs, including mirtazapine. [ 40 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3014", "text": "The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. SS has been reported in patients of all ages, including the elderly, children, and even newborn infants due to  in utero  exposure. [ 42 ] [ 43 ] [ 44 ] [ 45 ]  The serotonergic toxicity of SSRIs increases with dose, but even in overdose, it is insufficient to cause fatalities from SS in healthy adults. [ 46 ] [ 47 ]  Elevations of  central nervous system  (CNS) serotonin will typically only reach potentially fatal levels when drugs with different  mechanisms of action  are mixed together. [ 9 ]  Various drugs, other than SSRIs, also have clinically significant potency as serotonin reuptake inhibitors, (such as  tramadol ,  amphetamine , and MDMA) and are associated with severe cases of the syndrome. [ 6 ] [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3015", "text": "Although the most significant health risk associated with  opioid overdoses  is  respiratory depression , [ 49 ]  it is still possible for an individual to develop SS from certain opioids without the  loss of consciousness . However, most cases of opioid-related SS involve the concurrent use of a  serotergenic drug  such as  antidepressants . [ 50 ]  Nonetheless, it is not uncommon for individuals taking opioids to also be taking antidepressants due to the comorbidity of pain and depression. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3016", "text": "Cases where opioids alone are the cause of SS are typically seen with tramadol, because of its dual mechanism as a  serotonin-norepinephrine reuptake inhibitor . [ 52 ] [ 53 ]  SS caused by tramadol can be particularly problematic if an individual taking the drug is unaware of the risks associated with it and attempts to self-medicate symptoms such as headache, agitation, and tremors with more opioids, further exacerbating the condition."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3017", "text": "Serotonin is a  neurotransmitter  involved in multiple complex biological processes including aggression, pain, sleep, appetite, anxiety, depression, migraine, and vomiting. [ 10 ]  In humans the effects of excess serotonin were first noted in 1960 in patients receiving an MAOI and  tryptophan . [ 54 ]  The syndrome is caused by increased serotonin in the CNS. [ 6 ]  It was originally suspected that  agonism  of  5-HT 1A  receptors  in  central grey  nuclei and the  medulla oblongata  was responsible for the development of the syndrome. [ 55 ]  Further study has determined that overstimulation of primarily the  5-HT 2A  receptors  appears to contribute substantially to the condition. [ 55 ]  The 5-HT 1A  receptor may still contribute through a  pharmacodynamic  interaction in which increased synaptic concentrations of a serotonin agonist saturate all receptor subtypes. [ 6 ]  Additionally, noradrenergic CNS hyperactivity may play a role as CNS  norepinephrine  concentrations are increased in SS and levels appear to correlate with the clinical outcome. Other neurotransmitters may also play a role;  NMDA receptor  antagonists and  \u03b3-aminobutyric acid  have been suggested as affecting the development of the syndrome. [ 6 ]  Serotonin toxicity is more pronounced following supra-therapeutic doses and  overdoses , and they merge in a continuum with the toxic effects of overdose. [ 46 ] [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3018", "text": "A postulated \"spectrum concept\" of serotonin toxicity emphasises the role that progressively increasing serotonin levels play in mediating the clinical picture as side effects merge into toxicity. The  dose-response relationship  is the effect of progressive elevation of serotonin, either by raising the dose of one drug, or combining it with another serotonergic drug which may produce large elevations in serotonin levels. [ 57 ] [ 58 ]  Some experts prefer the terms serotonin toxicity or serotonin toxidrome, to more accurately reflect that it is a form of  poisoning . [ 9 ] [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3019", "text": "There is no specific test for SS. Diagnosis is by symptom observation and investigation of the person's history. [ 6 ]  Several criteria have been proposed. The first evaluated criteria were introduced in 1991 by Harvey Sternbach. [ 6 ] [ 31 ] [ 59 ]  Researchers later developed the Hunter Toxicity Criteria Decision Rules, which have better  sensitivity and specificity , 84% and 97%, respectively, when compared with the gold standard of diagnosis by a medical toxicologist. [ 6 ] [ 10 ]  As of 2007, Sternbach's criteria were still the most commonly used. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3020", "text": "The most important symptoms for diagnosing SS are tremor, extreme aggressiveness,  akathisia , or clonus (spontaneous, inducible and ocular). [ 10 ]   Physical examination  of the patient should include assessment of  deep tendon reflexes  and muscle rigidity, the dryness of the  mucosa of the mouth , the size and reactivity of the pupils, the intensity of bowel sounds, skin color, and the presence or absence of sweating. [ 6 ]  The patient's history also plays an important role in diagnosis, investigations should include inquiries about the use of prescription and  over-the-counter drugs , illicit substances, and  dietary supplements , as all these agents have been implicated in the development of SS. [ 6 ]  To fulfill the Hunter Criteria, a patient must have taken a  serotonergic agent  and meet one of the following conditions: [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3021", "text": "Serotonin toxicity has a characteristic picture which is generally hard to confuse with other  medical conditions , but in some situations it may go unrecognized because it may be mistaken for a  viral illness ,  anxiety disorders ,  neurological disorder ,  anticholinergic  poisoning,  sympathomimetic  toxicity, or worsening psychiatric condition. [ 6 ] [ 9 ] [ 60 ]  The condition most often confused with serotonin syndrome is  neuroleptic malignant syndrome  (NMS). [ 61 ] [ 62 ]  The clinical features of neuroleptic malignant syndrome and SS share some features which can make differentiating them difficult. [ 63 ]  In both conditions,  autonomic  dysfunction and altered  mental status  develop. [ 55 ]  However, they are actually very different conditions with different underlying dysfunction (serotonin excess vs dopamine blockade). Both the time course and the clinical features of NMS differ significantly from those of serotonin toxicity. [ 10 ]  Serotonin toxicity has a rapid onset after the administration of a serotonergic drug and responds to serotonin blockade such as drugs like  chlorpromazine  and  cyproheptadine .  Dopamine receptor  blockade (NMS) has a slow onset, typically evolves over several days after administration of a  neuroleptic  drug, and responds to dopamine agonists such as  bromocriptine . [ 6 ] [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3022", "text": "Differential diagnosis  may become difficult in patients recently exposed to both serotonergic and neuroleptic drugs.  Bradykinesia  and  extrapyramidal  \"lead pipe\" rigidity are classically present in NMS, whereas SS causes  hyperkinesia  and clonus; these distinct symptoms can aid in differentiation. [ 24 ] [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3023", "text": "Management is based primarily on stopping the usage of the precipitating drugs, the administration of  serotonin antagonists  such as  cyproheptadine  (with a regimen of 12\u00a0mg for the initial dose followed by 2\u00a0mg every 2\u2009hours until clinical, while some claim that a higher initial dose up to 32\u00a0mg has more benefit [ 65 ] ), [ 66 ]  and supportive care including the control of agitation, the control of autonomic instability, and the control of hyperthermia. [ 6 ] [ 67 ] [ 68 ]  Additionally, those who ingest large doses of serotonergic agents may benefit from gastrointestinal decontamination with  activated charcoal  if it can be administered within an hour of overdose. [ 9 ]  The intensity of therapy depends on the severity of symptoms. If the symptoms are mild, treatment may only consist of discontinuation of the offending medication or medications, offering supportive measures, giving  benzodiazepines  for myoclonus, and waiting for the symptoms to resolve. Moderate cases should have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotonin antagonists. The serotonin antagonist cyproheptadine is the recommended initial therapy, although there have been no  controlled trials  demonstrating its efficacy for SS. [ 9 ] [ 69 ] [ 70 ]  Despite the absence of controlled trials, there are a number of case reports detailing apparent improvement after people have been administered cyproheptadine. [ 9 ]  Animal experiments also suggest a benefit from serotonin antagonists. [ 71 ]  Cyproheptadine is only available as tablets and therefore can only be administered orally or via a  nasogastric tube ; it is unlikely to be effective in people administered activated charcoal and has limited use in severe cases. [ 9 ]  Cyproheptadine can be stopped when the person is no longer experiencing symptoms and the half life of serotonergic medications already passed. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3024", "text": "Additional pharmacological treatment for severe case includes administering atypical antipsychotic drugs with serotonin antagonist activity such as  olanzapine  or  asenapine . [ 6 ]  Critically ill people should receive the above therapies as well as sedation or neuromuscular paralysis. [ 6 ]  People who have autonomic instability such as low  blood pressure  require treatment with direct-acting sympathomimetics such as  epinephrine , norepinephrine, or  phenylephrine . [ 6 ]  Conversely, hypertension or tachycardia can be treated with short-acting  antihypertensive  drugs such as  nitroprusside  or  esmolol ; longer acting drugs such as  propranolol  should be avoided as they may lead to hypotension and shock. [ 6 ]  The cause of serotonin toxicity or accumulation is an important factor in determining the course of treatment. Serotonin is catabolized by  monoamine oxidase\u00a0A  in the presence of  oxygen , so if care is taken to prevent an unsafe spike in body temperature or metabolic acidosis, oxygenation will assist in dispatching the excess serotonin. The same principle applies to alcohol intoxication. In cases of SS caused by MAOIs, oxygenation will not help to dispatch serotonin. In such instances, hydration is the main concern until the enzyme is regenerated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3025", "text": "Specific treatment for some symptoms may be required. One of the most important treatments is the control of agitation due to the extreme possibility of injury to the person themselves or caregivers, benzodiazepines should be administered at first sign of this. [ 6 ]   Physical restraints  are not recommended for agitation or delirium as they may contribute to mortality by enforcing isometric  muscle contractions  that are associated with severe  lactic acidosis  and hyperthermia. If physical restraints are necessary for severe agitation they must be rapidly replaced with pharmacological  sedation . [ 6 ]  The agitation can cause a large amount of muscle breakdown. This breakdown can cause severe damage to the kidneys through a condition called  rhabdomyolysis . [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3026", "text": "Treatment for hyperthermia includes reducing muscle overactivity via sedation with a benzodiazepine. More severe cases may require muscular paralysis with  vecuronium ,  intubation , and artificial ventilation. [ 6 ] [ 9 ]   Suxamethonium  is not recommended for muscular paralysis as it may increase the risk of cardiac dysrhythmia from hyperkalemia associated with rhabdomyolysis. [ 6 ]   Antipyretic  agents are not recommended as the increase in  body temperature  is due to muscular activity, not a  hypothalamic  temperature set point abnormality. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3027", "text": "Upon the discontinuation of serotonergic drugs, most cases of SS resolve within 24 hours, [ 6 ] [ 9 ] [ 73 ] [ 74 ]  although in some cases  delirium  may persist for a number of days. [ 31 ]  Symptoms typically persist for a longer time frame in patients taking drugs which have a long elimination  half-life , active metabolites, or a protracted duration of action. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3028", "text": "Cases have reported persisting chronic symptoms, [ 75 ]  and  antidepressant discontinuation  may contribute to ongoing features. [ 76 ]  Following appropriate medical management, SS is generally associated with a favorable prognosis. [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3029", "text": "Epidemiological studies of SS are difficult as many physicians are unaware of the diagnosis or they may miss the syndrome due to its variable manifestations. [ 6 ] [ 78 ]  In 1998 a survey conducted in England found that 85% of the  general practitioners  that had prescribed the antidepressant  nefazodone  were unaware of SS. [ 43 ]  The incidence may be increasing as a larger number of pro-serotonergic drugs (drugs which increase serotonin levels) are now being used in clinical practice. [ 69 ]  One  postmarketing surveillance  study identified an incidence of 0.4 cases per 1000 patient-months for patients who were taking nefazodone. [ 43 ]  Additionally, around 14\u201316% of persons who overdose on SSRIs are thought to develop SS. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3030", "text": "The most widely recognized example of SS was the death of  Libby Zion  in 1984. [ 79 ]  Zion was a freshman at  Bennington College  at her death on March 5, 1984, at age 18. She died within 8 hours of her emergency admission to the  New York Hospital Cornell Medical Center . She had an ongoing history of depression, and came to the Manhattan hospital on the evening of March 4, 1984, with a fever, agitation and \"strange jerking motions\" of her body. She also seemed  disoriented  at times. The emergency room physicians were unable to diagnose her condition definitively but admitted her for  hydration  and observation. Her death was caused by a combination of  pethidine  and  phenelzine . [ 80 ]  A medical intern prescribed the pethidine. [ 81 ]  The case influenced graduate medical education and residency work hours. Limits were set on  working hours for medical postgraduates , commonly referred to as interns or residents, in hospital training programs, and they also now require closer senior physician supervision. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3031", "text": "Creutzfeldt\u2013Jakob disease"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3032", "text": "In  medicine , a  side effect  is an effect of the use of a medicinal  drug  or other treatment, usually  adverse  but sometimes beneficial,  that is unintended. Herbal and  traditional medicines  also have side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3033", "text": "A drug or procedure usually used for a specific effect may be used specifically because of a beneficial side-effect; this is termed \" off-label use \" until such use is approved. [ 1 ]  For instance,  X-rays  have long been used as  an imaging technique ; the discovery of their oncolytic capability led to their use in  radiotherapy  for ablation of  malignant   tumours ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3034", "text": "The  World Health Organization  and other health organisations characterise the probability of experiencing side effects as: [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3035", "text": "The  European Commission  recommends that the list should contain only effects where there is \"at least a reasonable possibility\" that they are caused by the drug and the frequency \"should represent crude incidence rates (and not differences or relative risks calculated against placebo or other comparator)\". [ 6 ]  The frequency describes how often symptoms appear  after  taking the drug, without assuming that they were necessarily  caused by  the drug. Both healthcare providers [ 7 ]  and lay people [ 8 ]  misinterpret the frequency of side effects as describing the increase in frequency caused by the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3036", "text": "Most drugs and procedures have a multitude of reported adverse side effects; the information leaflets provided with virtually all drugs list possible side effects. Beneficial side effects are less common; some examples, in many cases of side-effects that ultimately gained regulatory approval as intended effects, are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3037", "text": "Structured intermittent therapy  (SIT) was coined in early 2000 by  Mark Dybul ,  Anthony Fauci , and other research scientists from the  National Institute of Health , as a form of reduced treatment for patients with  HIV .  HIV+ patients took anti-HIV drugs for seven days, and then took no drugs for seven days. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3038", "text": "Generally, patients with HIV who were being treated aggressively with continuous  highly active antiretroviral therapy  (HAART) lived longer lives, but they were not able to eliminate the HIV  virus  altogether and experienced many undesirable side effects. The long-term toxicity and financial expense of HAART makes it undesirable as the standard, long-term treatment for HIV patients. Consequently, a short study on administering medications in a structured intermittent manner was designed.  The hope of this 2001 study was that alternating weeks of drug-taking with weeks of drug abstinence would both reduce toxicity and cost to the patients. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3039", "text": "This small, uncontrolled study found that a structured intermittent therapy (SIT) approach may help to maintain health while also reducing cost and toxicity of antiretroviral therapy. This approach might have had particular applicability in resource-poor settings where access to therapy is limited by the cost of antiretroviral agents. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3040", "text": "The Strategies for the Management of Antiretroviral Therapy (SMART) trial was intended to provide good information on whether this approach worked for HIV+ people.  The double-blind controlled study began in 2002 and enrolled 5,472 participants in 33 countries.  Unfortunately for proponents of SIT, the study had to be stopped in 2006 because of the excessive number of \"interrupted\" patients who died or got much sicker. [1]   People on the SIT protocol were more than twice as likely to die during the study than people who took HAART drugs continuously. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3041", "text": "In  medicine ,  tapering  is the practice of gradually reducing the dosage of a medication to reduce or discontinue it. Generally, tapering is done is to avoid or minimize withdrawal symptoms that arise from neurobiological adaptation to the drug. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3042", "text": "Prescribed psychotropic drugs that may require tapering due to this physical dependence include  opioids , [ 3 ] [ 4 ] [ 5 ]   selective serotonin reuptake inhibitors , [ 6 ]   antipsychotics , [ 7 ]   anticonvulsants , [ 8 ]  and  benzodiazepines . [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3043", "text": "Cross-tapering refers to the practice of reducing one drug, while introducing a new medication that is  titrated  to an effective dose. This can be used, for example, when changing  antipsychotic medications . [ 11 ] :\u200a156"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3044", "text": "Peer support groups , such as  survivingantidepressants.org , provide a medium where those tapering medication can discuss approaches and withdrawal symptoms. [ 12 ]   Surviving antidepressants  advocate for a slower rate of tapering than that used in standard medical practice. [ 13 ] :\u200a4\u200a  Many such groups exist on Facebook and other social media platforms. [ 14 ]  Along with sharing tapering tips, members of the groups discuss the risks of  prescription cascade , where withdrawal symptoms or the side effects of a  psychotropic medication  result in further medication, and the risk of neurobiological  \"kindling\"  effects where repeated unsuccessful withdrawal attempts yield progressively poor results upon drug reinstatement or, later, may increase the risk of withdrawal symptoms. [ 15 ] [ 16 ] [ 13 ] :\u200a5"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3045", "text": "A  therapeutic interfering particle  is an antiviral preparation that reduces the replication rate and pathogenesis of a particular viral infectious disease. A therapeutic interfering particle is typically a biological agent (i.e., nucleic acid) engineered from portions of the viral genome being targeted. Similar to  Defective Interfering Particles (DIPs) , the agent competes with the pathogen within an infected cell for critical viral replication resources, reducing the viral replication rate and resulting in reduced pathogenesis. [ 1 ] [ 2 ]  But, in contrast to DIPs, TIPs are engineered to have an in vivo  basic reproductive ratio  ( R 0 ) that is greater than 1 ( R 0 >1). [ 3 ]  The term \"TIP\" was first introduced in 2011 [ 4 ]  based on models of its mechanism-of-action from 2003. [ 3 ]  Given their unique  R 0 >1 mechanism of action, TIPs exhibit high barriers to the evolution of antiviral resistance [ 5 ]  and are predicted to be resistance proof. [ 4 ]  Intervention with therapeutic interfering particles can be prophylactic (to prevent or ameliorate the effects of a future infection), or a single-administration therapeutic (to fight a disease that has already occurred, such as HIV or COVID-19). [ 6 ] [ 4 ] [ 3 ] [ 7 ] [ 5 ]  Synthetic DIPs that rely on stimulating innate antiviral immune responses (i.e., interferon) were proposed for influenza in 2008 [ 8 ]  and shown to protect mice to differing extents  [ 9 ] [ 10 ] [ 11 ]  but are technically distinct from TIPs due to their alternate molecular mechanism of action which has not been predicted to have a similarly high barrier to resistance. [ 12 ]   Subsequent work tested the pre-clinical efficacy of TIPs against HIV, [ 6 ]  a synthetic DIP for SARS-CoV-2 (in vitro), [ 7 ]  and a TIP for SARS-CoV-2 (in vivo). [ 5 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3046", "text": "Therapeutic Interfering Particles, often referred to as TIPs, are typically synthetic, engineered versions of naturally occurring  defective interfering particles  (DIPs), in which critical portions of the virus genome are deleted rendering the TIP unable to replicate on its own. Often a TIP has the vast majority of the virus genome deleted. [ 5 ]  However, TIPs are engineered to retain specific elements of the genome that allow them to efficiently compete with the wild-type virus for critical replication resources inside an infected cell. TIPs thereby deprive wild-type virus of replication material through  competitive inhibition , [ 14 ]  and therapeutically reduce viral load. [ 6 ]  Competitive inhibition enables TIPs to conditionally replicate and efficiently mobilize between cells, essentially \"piggybacking\" on wild-type virus, to act as single-administration antivirals with a high genetic barrier to the evolution of resistance. [ 15 ]  TIPs have been engineered for HIV [ 6 ] [ 14 ]  and SARS-CoV-2, [ 7 ]  and do not induce innate immune responses such as  interferon [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3047", "text": "Three mechanistic criteria define a TIP:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3048", "text": "As a result of these mechanistic criteria, TIPs have been referred to as \"piggyback\" [ 17 ]  or alternatively as \"virus hijackers\". [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3049", "text": "TIPs do not stimulate or function through the induction of innate cellular immune responses (such as interferon). In fact, stimulation of innate cellular antiviral mechanisms has been shown to contravene criterion (#3) (i.e.,  R 0 >1), as innate immune mechanisms inhibit efficient mobilization of TIPs. [ 3 ]  As such, several VLP-based therapy proposals for influenza and other viruses [ 20 ]  that do not satisfy these criteria are DIPs, but not TIPs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3050", "text": "TIPs are built off the phenomenon of  defective interfering particles  (DIPs) discovered by  Preben Von Magnus  in the early 1950s, during his work on influenza viruses. [ 21 ] [ 22 ] [ 23 ] [ 2 ]  DIPs are spontaneously arising virus mutants, first described by von Magnus as \"incomplete\" viruses, in which a critical portion of the viral genome has been lost. Direct evidence for DIPs was only found in the 1960s by Hackett, who observed the presence of \"stumpy\" particles of vesicular stomatitis virus in electron micrographs, [ 24 ]  and the DIP terminology was formalized in 1970 by Huang and Baltimore. [ 25 ]  DIPs have been reported for many classes of DNA and RNA viruses in clinical and laboratory settings."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3051", "text": "Whereas DIPs had been proposed as potential therapeutics that would act via stimulation of the immune system [ 20 ]  \u2013 a concept [ 8 ]   [ 26 ]   tested in influenza with mixed results [ 9 ]   [ 10 ]  \u2013 the TIP R 0 >1 mechanism of action was first proposed in 2003 [ 3 ]  with the term \u201cTIP\u201d and the unique benefits of the R 0 >1 mechanism shown in 2011. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3052", "text": "In 2016 the US government launched a major funding initiative ( DARPA  INTERCEPT, [ 26 ] [ 27 ] [ 28 ]  ) to discover and engineer antiviral TIPs for diverse viruses, based on prior investments from the US  National Institutes of Health . [ 29 ]  This program led to renewed interest in the concept of interfering particles as therapies with the development of technologies to isolate DIPs for influenza [ 30 ] [ 31 ] [ 32 ]  and engineer TIPs for HIV and Zika virus. [ 14 ]  The first successful experimental demonstration of the TIP concept was reported in 2019 [ 6 ]  for HIV, and the discovery of a TIP for SARS-CoV-2 was reported in 2020 [ 7 ]  and results on the effect on hamsters in 2021. [ 33 ]  In 2020, the US government funded first-in-human clinical trials of TIPs. [ 34 ] [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3053", "text": "Threshold dose  is the minimum dose of drug that triggers minimal detectable biological effect in an animal. [ 1 ]  At extremely low doses, biological responses are absent for some of the drugs. The increase in dose above threshold dose induces an increase in the percentage of biological responses. [ 2 ]  Several benchmarks have been established to describe the effects of a particular dose of drug in a particular species, such as NOEL(no-observed-effect-level),  NOAEL (no-observed-adverse-effect-level) and  LOAEL (lowest-observed-adverse-effect-level). [ 3 ]  They are established by reviewing the available studies and  animal studies . [ 1 ]  The application of threshold dose in risk assessment safeguards the participants in human clinical trials and evaluates the risks of chronic exposure to certain substances. [ 4 ]  However, the nature of animal studies also limits the applicability of experimental results in the human population and its significance in evaluating potential risk of certain substances. [ 5 ]  In toxicology, there are some other safety factors including  LD50 ,  LC50  and  EC50 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3054", "text": "Threshold dose is a dose of drug barely adequate to produce a biological effect in an animal. In dose-response assessment, the term \u2018threshold dose\u2019 is refined into several terminologies, such as NOEL,  NOAEL , and  LOAEL . They define the limits of doses resulting in biological responses or toxic effects. [ 3 ]  Common responses are alterations in structures, growth, development and average lifespan of the treated group of organisms. [ 6 ]  The changes are found by comparing the observations between the  treated and control groups . Both groups are of the same species and have the same environment of exposure in the trial. The only difference is that the treated group receives the experimental substance while the control group does not. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3055", "text": "For the drugs administered by  oral  and  dermal route , the units of threshold dose are mg/kg body-weight/day (dose of the drug in mg per body weight in kg per day) or  ppm  (parts per million), while the threshold dose of drugs by inhalation delivery has the unit of mg/L 6h/day (amount of drug in mg in 1L of air, for 6 hours per day). [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3056", "text": "NOEL is no-observed-effect-level. It is the maximum dose of a substance that has no observable effect on the treated group in human clinical trials or animal experimental trials. [ 3 ]  In some literature, NOEL is the only dose level referred by the terminology \u2018threshold dose\u2019. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3057", "text": "NOAEL  is no-observed-adverse-effect-level. It is the maximum dose of a substance that has no observable adverse effect on the treated group in human clinical trials or animal experimental trials. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3058", "text": "LOAEL  is lowest-observed-adverse-effect-level. It is the minimum dose of a substance that produces an observable adverse effect on the treated group in human clinical trials or animal experimental trials. [ 3 ]  There is a biologically or  statistically significant  increase in the prevalence of adverse effect in the treated group above this level. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3059", "text": "The  dose-response relationship  is dependent on various factors. They include the physicochemical properties of the drug,  route of administration  or exposure, duration of exposure, population size, and the characteristics of the studied organism such as their species, sex, ages, etc. [ 3 ]  The type of biological responses is also a significant factor for the variations of a dose-response relationship. Each response corresponds to one unique relationship. [ 16 ]  As it is not practical to establish the  dose-response relationships  for all possible responses, the studies usually narrow down the scopes to a few responses. All available studies examining the correlation between the target drug and its biological responses will be reviewed. The selection criteria for the critical responses for assessment is that the dose required to produce that particular response is the lowest. [ 1 ]  The precursor of a biological effect can also be the response for assessment. [ 1 ]  For instance, the risk factors of a disease may eventually precipitate the disease. In the study of the relationship between a drug and the development of a particular  cardiovascular disease , the risk factors of the disease can be considered as the responses for measurement as well."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3060", "text": "A two-step process is adopted to evaluate the specific dose levels,  NOAEL  and  LOAEL . The first step is to carry out reviews of available studies or  animal studies  to obtain data on the effect of different doses of the target drug. [ 1 ]  They allow the establishment of  dose-response relationships  over the range of doses reported in the data collected. Often the data collected is inadequate to produce a range wide enough to observe the dose in which biological responses are not induced in humans. [ 17 ]  The dose which is sufficiently low to prevent the occurrence of the response in humans cannot be evaluated and therefore paves the way to the second step, extrapolation of the  dose-response relationship . [ 17 ] \u00a0The results beyond the range covered by the available data are estimated. It attempts to make inferences of the region that the critical dose levels such as  NOAEL  and  LOAEL  fell within. [ 18 ]  Thus the doses starting to trigger adverse effects in humans can be evaluated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3061", "text": "For step one, the two common approaches for evaluating threshold doses are qualitative examination of available studies and animal studies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3062", "text": "The effects of the target drug at different doses are obtained from available studies. The  dose-response relationship  will be identified and extrapolation is often required to make inferences about the dose levels below the range of data collected. [ 4 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3063", "text": "Animal studies  are conducted when the data collected from qualitative examination of available studies is scarce. It is for expanding the range of doses. [ 19 ]  Also, animal studies allow the manipulation of the study design, such as the age and gender of treated animals. Animal study is therefore less susceptible to the influences of  confounders  than  observational studies  and therefore contributes to a more rigorous dose-response assessment. [ 1 ]  As the assessed animals exhibit variation in characteristics with humans such as body size,  extrapolation  should be carried out to estimate the dose-response relationship in humans. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3064", "text": "A common animal study is repeated dose toxicity testing. The participating species are divided into 4 groups, receiving  placebo , low dose, mid-dose and high dose of the drugs respectively. [ 21 ]  Within the same group, the same dose is given on a daily basis for a specified period, such as 28 days or 90 days. [ 22 ]  Subsequent to the specified period,  necropsy  or tissue samples collection allows identification of the dose levels bring about certain effects and therefore establishment of  NOAEL  and  LOAEL . [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3065", "text": "The threshold doses such as NOAEL, LOAEL and NOEL are essential values in risk assessment. The maximum safe starting doses of different drugs can be obtained from them prior to human clinical trials. [ 23 ]   Another application is to assess the safe dose for chronic exposure. They are utilized to estimate the daily exposure which does not induce detrimental effects in humans in their lifetime, which is also known as the  Reference Dose  (RfD). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3066", "text": "The variations between different species and the extrapolation of dose-response relationship generated from animal studies to that for humans introduce uncertainties into the analysis of dose-response. Humans also manifest intra-variation of sensitivity towards a particular substance among the population. [ 20 ]  As a result, 10-fold uncertainty factors (UF) are applied to convert NOAEL to the reference dose. The UFinter and UFintra account for the inter- and intra-species variation respectively. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3067", "text": "R \n f \n D \n = \n N \n O \n A \n E \n L \n \u00f7 \n ( \n U \n F \n i \n n \n t \n e \n r \n \u00d7 \n ( \n U \n F \n i \n n \n t \n r \n a \n ) \n ) \n \n \n {\\displaystyle RfD=NOAEL\\div (UFinter\\times (UFintra))} \n \n [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3068", "text": "For carcinogenic substances, theoretically NOAEL and LOAEL do not exist as there is no safe dose for the  carcinogens . A  linear no-threshold model  is commonly used for illustrating the probability of  cancer  development from  radiation . There is no threshold value at which stochastic health effects start emerging. [ 25 ]  Only for non-cancer health outcomes, there is an assumption of the presence of a safety margin below which no negative biological effect is expected. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3069", "text": "Most dose-response models are obtained from animal experiments out of ethical concerns. Therefore, the results might not be consistent with that of the human population. [ 5 ]  Individual differences also arise among people in terms of age, weight, gender, health status, etc. [ 20 ]  Thus, in most circumstances, the threshold dose serves as a reference to evaluate the probable outcome of a certain dosage of a substance for the general population, while great deviations might exist in special populations such as  immunocompromised  patients, pregnant women and young children. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3070", "text": "The threshold dose is only a measure of  acute toxicity  since the drug or toxic substance investigated is administered at once. The consequence of long-term administration remains unknown. [ 27 ]  As the threshold dose is the measured minimal response, its accuracy heavily depends on the machinery used. It is possible that further refinement is needed. [ 28 ]  Furthermore, the threshold dose only reflects the dose required for a minimum detectable response but it should not be misunderstood that health effects are absolutely absent in the doses below the threshold dose. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3071", "text": "The median lethal dose ( LD50 ) of a substance is defined as the dose that leads to death in 50% of the tested population. It is a significant parameter in toxicology study and indicates the  acute toxicity  of a particular substance. LD50 is usually expressed in the weight of the chemical administered in milligram per unit of body weight (mg/kg). [ 29 ]  In the discussion of  environmental toxins , as there is no direct administration of toxic materials, a similar parameter  LC50  will be mentioned instead. LC50 is the concentration of substance in air that kills half of the tested population during the experimental period. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3072", "text": "The median effective concentration ( EC50 ) is the concentration of a drug required to reach 50% of the maximal biological effect the drug can exert. It is a reflection of the potency of a drug and is expressed in  molar units  such as mol/L. [ 31 ]  The value of EC50 greatly depends on the  affinity  of the drug for its  receptor , as well as the  efficacy  of the drug, which conveys receptor occupancy and the ability of the drug to trigger a biological response. [ 32 ]  EC50 is incorporated in the  Hill's Equation , a function that demonstrates the relationship between  agonist  concentration and  ligand  binding. EC50 is mathematically given as the  inflection point  of the equation. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3073", "text": "Zoopharmacognosy  is a behaviour in which non-human  animals   self-medicate  by selecting and  ingesting  or  topically applying   plants ,  soils  and  insects  with medicinal properties, to prevent or reduce the harmful effects of pathogens, toxins, and even other animals. [ 1 ] [ 2 ]   The term derives from Greek roots  zoo  (\"animal\"),  pharmacon  (\"drug, medicine\"), and  gnosy  (\"knowing\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3074", "text": "An example of zoopharmacognosy occurs when dogs eat grass to induce vomiting. However, the behaviour is more diverse than this.  Animals ingest or apply non-foods such as  clay ,  charcoal  and even  toxic  plants and invertebrates, apparently to prevent  parasitic  infestation or  poisoning . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3075", "text": "Whether animals truly self-medicate remains a somewhat controversial subject because early evidence is mostly circumstantial or anecdotal. [ 4 ]  However, more recent examinations have adopted an experimental, hypothesis-driven approach."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3076", "text": "The methods by which animals self-medicate vary, but can be classified according to function as prophylactic (preventative, before infection or poisoning) or therapeutic (after infection, to combat the pathogen or poisoning). [ 4 ]  The behaviour is believed to have widespread adaptive significance. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3077", "text": "In 1978, Janzen suggested that vertebrate  herbivores  might benefit medicinally from the  secondary metabolites  in their plant food. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3078", "text": "In 1993, the term \"zoopharmacognosy\" was coined, derived from the Greek roots  zoo  (\"animal\"),  pharma  (\"drug\"), and  gnosy  (\"knowing\"). [ 7 ]  The term gained popularity from academic works [ 4 ]  and in a book by Cindy Engel entitled  Wild Health: How Animals Keep Themselves Well and What We Can Learn from Them . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3079", "text": "The  anti-parasitic  effect of zoopharmacognosy could occur by at least two mechanisms, namely demonstrated through the modes of  deglutition  or  ingestion .  First, ingested material may have pharmacological antiparasitic properties, such as  phytochemicals  decreasing the ability of worms to attach to the mucosal lining of the intestines or  chemotaxis  attracting worms into the folds of leaves. Additionally, many plants have  trichomes , often presented as hooked and spiky hairs, that can attach to parasites and dislodge them from the intestines. Another possible mode of action is that the ingested material may initiate a purging response of the gastrointestinal tract by rapidly inducing diarrhoea. This substantially decreases gut transit time, causing worm expulsion and interruption in the life cycle of parasites. This, or a similar, mechanism could explain undigested materials in the faeces of various animals such as birds, carnivores and primates. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3080", "text": "The  topical application  of materials is often used by animals to treat wounds or repel insects. [ 10 ]  When plant leaves are chewed and then directly rubbed onto fur, compounds from said leaves are released for use. These compounds can often be analgesic or antiparasitic in nature. In regards to an insect repellant, the  secondary metabolites  traditionally used by plants to deter herbivores and insects from eating them [ 11 ]  can be used by animals as a protective measure. By interfering with neuroreceptors, these secondary metabolites can specifically act as olfactory cues for insects to avoid a certain source. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3081", "text": "The three reported methods of self-medication are deglutition, ingestion, and topical application. When using one of these methods while appearing well, an animal may be using self-medication as a  prophylactic  measure. When it is unwell, the animal could be using self-medication as a  curative  measure."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3082", "text": "Some examples of zoopharmacognosy are demonstrated when animals, namely apes, swallow materials whole instead of chewing and ingesting them."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3083", "text": "Wild chimpanzees sometimes seek leaves of the  Aspilia  plant.  These contain thiarubrine-A, a chemical active against intestinal  nematode  parasites. Because this compound is quickly broken down by the stomach, chimpanzees will pick up the  Aspilia  leaves and, rather than chewing them, they roll them around in their mouths, sometimes for as long as 25 seconds. They then swallow the capsule-like leaves whole. Afterwards, the trichomes of the leaves can attach to any intestinal parasites, namely the nodular worm ( Oesophagostomum stephanostomum ) and tapeworm ( Bertiella studeri ), and allow the chimpanzee to physically expel the parasites. [ 13 ]  As many as 15 to 35  Aspilia  leaves may be used in each bout of this behaviour, particularly in the rainy season when there is an abundance of many parasitic larvae that can cause an increased risk of infection. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3084", "text": "Chimpanzees sometimes eat the leaves of the herbaceous  Desmodium gangeticum .  Undigested, non-chewed leaves were recovered in 4% of faecal samples of wild chimpanzees and clumps of sharp-edged grass leaves in 2%. The leaves have a rough surface or sharp-edges and the fact they were not chewed and excreted whole indicates they were not ingested for nutritional purposes. Furthermore, this leaf-swallowing was restricted to the rainy season when parasite re-infections are more common, and parasitic worms ( Oesophagostomum stephanostomum ) were found together with the leaves. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3085", "text": "Bonobos sometimes swallow non-chewed stem-strips of  Manniophyton fulvum .  Despite the plant being abundantly available all year,  M. fulvum  is ingested only at specific times, in small amounts, and by a small proportion of bonobos in each group, demonstrating that it is indeed only utilized when the bonobos are unwell. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3086", "text": "Tamarins  were observed swallowing the large seeds of the fruit they regularly ingest. Although they are consumed along with the rest of the fruit, these seeds have no nutritional value for the monkeys. Since tamarins are routinely infected by trematodes, cestodes, nematodes, and acanthocephalans, there is speculation that the deliberate swallowing of these large seeds can help dislodge the parasites from the monkey's body. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3087", "text": "Similar to the wild chimpanzees,  Alaskan brown bears  will swallow whole  Carex  leaves in the springtime to ensure the complete expulsion of parasites during their hibernation. [ 17 ]  Specifically, as tapeworms thrive off previously digested nutrients in the gut, the rough  Carex  leaves will lacerate their scolices, facilitating the defecation process. The proactive swallowing of these leaves will ensure low levels of active parasites within a hibernating bear."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3088", "text": "Many examples of zoopharmacognosy involve an animal ingesting a substance with (potential) medicinal properties."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3089", "text": "Many  parrot  species in the Americas, Africa, and Papua New Guinea consume  kaolin  or  clay , which both releases minerals and absorbs toxic compounds from the  gut . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3090", "text": "Great bustards  eat  blister beetles  of the genus  Meloe  maybe to decrease parasite load in the digestive system; [ 19 ]   cantharidin , the toxic compound in blister beetles, can kill a great bustard if too many beetles are ingested. [ 20 ]  Great bustards may eat toxic  blister beetles  of the genus  Meloe  to increase the sexual arousal of males. [ 21 ]  Some plants selected in the mating season showed in-vitro activity against laboratory models of parasites and pathogens. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3091", "text": "Woolly bear  caterpillars ( Grammia incorrupta ) are sometimes lethally  endoparasitised  by  tachinid  flies.  The caterpillars ingest plant toxins called  pyrrolizidine alkaloids , which improve survival by conferring resistance against the flies.  Crucially, parasitised caterpillars are more likely than non-parasitised caterpillars to specifically ingest large amounts of pyrrolizidine alkaloids, and excessive ingestion of these toxins reduces the survival of non-parasitised caterpillars.  These three findings are all consistent with the adaptive plasticity theory. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3092", "text": "The  tobacco hornworm  ingests  nicotine  which reduces colony growth and toxicity of  Bacillus thuringiensis , leading to increased survival of the hornworm. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3093", "text": "Ants infected with  Beauveria bassiana , a fungus, selectively consume harmful substances (reactive oxygen species, ROS) upon exposure to a fungal pathogen, yet avoid these in the absence of infection. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3094", "text": "Great apes often consume plants that have no nutritional values but which have beneficial effects on gut acidity or combat intestinal parasitic infection. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3095", "text": "Chimpanzees  sometimes select bitter leaves for chewing. Parasite infection drops noticeably after chimpanzees chew leaves of pith ( Vernonia amygdalina ), which contain  sesquiterpene lactones  and steroid glucosides that are particularly effective against  schistosoma ,  plasmodium  and  Leishmania . [ 25 ]  Specifically, these compounds can induce paralysis within the parasites and impair its ability to absorb nutrients, move, and reproduce. [ 26 ]  Chimpanzees do not consume bitter on a regular basis, but when they do, it is often in small amounts by individuals that appear ill. [ 27 ]   Jane Goodall  witnessed  chimpanzees  eating particular bushes, apparently to make themselves vomit. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3096", "text": "Chimpanzees ,  bonobos , and  gorillas  eat the fruits of  Aframomum   angustifolium . Laboratory assays of homogenized fruit and seed extracts show significant  anti-microbial  activity. [ 28 ]  \nIllustrating the medicinal knowledge of some species, apes have been observed selecting a particular part of a medicinal plant by taking off leaves and breaking the stem to suck out the juice. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3097", "text": "Anubis baboons  ( Papio anubis ) and  hamadryas baboons  ( Papio hamadryas ) in Ethiopia use fruits and leaves of  Balanites aegyptiaca  to control  schistosomiasis . [ 30 ]  Its fruits contain  diosgenin , a hormone precursor that presumably hinders the development of schistosomes. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3098", "text": "African elephants  ( Loxodonta africana ) apparently self-medicate to induce labour by chewing on the leaves of a particular tree from the family  Boraginaceae ;  Kenyan  women brew a tea from this tree for the same purpose. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3099", "text": "White-nosed  coatis  ( Nasua narica ) in Panama take the menthol-scented resin from freshly scraped bark of  Trattinnickia aspera  ( Burseraceae ) and vigorously rub it into their own fur or that of other coatis, possibly to kill  ectoparasites  such as fleas, ticks, and lice, as well as biting insects such as mosquitoes; [ 32 ]  the resin contains  triterpenes  \u03b1- and \u03b2-amyrin, the eudesmane derivative \u03b2-selinene, and the  sesquiterpene  lactone 8\u03b2-hydroxyasterolide. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3100", "text": "Domestic cats and dogs often select and ingest plant material either to induce vomiting [ 33 ]  or for anti-parasitic purposes. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3101", "text": "Indian wild boars selectively dig up and eat the roots of  pigweed  which humans use as an  anthelmintic .  Mexican folklore indicates that pigs eat  pomegranate  roots because they contain an alkaloid that is toxic to tapeworms. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3102", "text": "A study on  domestic sheep  ( Ovis aries ) has provided clear experimental proof of self-medication via individual learning. [ 6 ]  Lambs in a treatment group were allowed to consume foods and toxins (grain, tannins, oxalic acid) that lead to  malaise  (negative internal states) and then allowed to eat a substance known to alleviate each malaise ( sodium bentonite ,  polyethylene glycol  and  dicalcium phosphate , respectively). Control lambs ate the same foods and medicines, but this was disassociated temporally so they did not recuperate from the illness. After the conditioning, lambs were fed grain or food with tannins or oxalates and then allowed to choose the three medicines. The treatment animals preferred to eat the specific compound known to rectify the state of malaise induced by the food previously ingested. However, control animals did not change their pattern of use of the medicines, irrespective of the food consumed before the choice. [ 36 ]  Other  ruminants  learn to self-medicate against gastrointestinal parasites by increasing consumption of plant secondary compounds with antiparasitic actions. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3103", "text": "Standard laboratory cages prevent mice from performing several natural behaviours for which they are highly motivated. As a consequence,  laboratory mice  sometimes develop abnormal behaviours indicative of emotional disorders such as depression and anxiety. To improve welfare, these cages are sometimes enriched with items such as nesting material, shelters and running wheels. Sherwin and Olsson [ 37 ]  tested whether such enrichment influenced the consumption of  Midazolam , a drug widely used to treat anxiety in humans.  Mice in standard cages, standard cages but with unpredictable husbandry, or enriched cages, were given a choice of drinking either non-drugged water or a solution of the Midazolam.  Mice in the standard and unpredictable cages drank a greater proportion of the anxiolytic solution than mice from enriched cages, presumably because they had been experiencing greater anxiety.  Early studies indicated that  autoimmune  (MRL/lpr) mice readily consume solutions with  cyclophosphamide , an immunosuppressive drug that prevents inflammatory damage to internal organs. However, further studies provided contradictory evidence. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3104", "text": "During the cold and rainy seasons, the crested porcupines ( Hystrix cristata ) in Central Italy tend to become infected by seven different species of ectoparasites and seven different species of  endoparasites . [ 38 ]  During this time, it is observed that these porcupine populations actively sought out a rather large variety of medicinal plants, mostly with antiparasitic properties, to consume. When ingested, these plants appeared to be relieving the symptoms of the infections, such as inflammation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3105", "text": "Many animals eat soil or clay, a behaviour known as  geophagy .  Clay is the primary ingredient of  kaolin . [ 39 ]   It has been proposed that for primates, there are four hypotheses relating to geophagy in alleviating gastrointestinal disorders or upsets: [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3106", "text": "Furthermore, two hypotheses pertain to geophagy in supplementing minerals and elements:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3107", "text": "Tapirs ,  forest elephants ,  colobus monkeys ,  mountain gorillas  and chimpanzees seek out and eat clay, which absorbs intestinal bacteria and their toxins and alleviates stomach upset and  diarrhoea . [ 41 ]   Cattle eat clay-rich termite mound soil, which deactivates ingested pathogens or fruit toxins. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3108", "text": "Some animals apply substances with medicinal properties to their skin.  Again, this can be prophylactic or curative. In some cases, this is known as  self-anointing ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3109", "text": "A female  capuchin monkey  in captivity was observed using tools covered in a sugar-based syrup to groom her wounds and those of her infant. [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3110", "text": "North American  brown bears  ( Ursos arctos ) make a paste of Osha roots ( Ligusticum porteri ) and saliva and rub it through their fur to repel insects or soothe bites. This plant, locally known as \"bear root\", contains 105 active compounds, such as  coumarins  that may repel insects when topically applied.  Navajo Indians  are said to have learned to use this root medicinally from the bear for treating stomach aches and infections. [ 28 ] [ 44 ] [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3111", "text": "A range of primates rub  millipedes  onto their fur and skin; millipedes contain  benzoquinones , compounds known to be potently repellent to insects. [ 46 ] [ 47 ] [ 48 ]  As the millipede secretions are also  psychoactive , the behavior may also be a form of  recreational drug use in animals . [ 49 ] [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3112", "text": "Tufted capuchins  ( Cebus apella ) rub various parts of their body with  carpenter ants  ( Camponotus rufipes ) or allow the ants to crawl over them, in a behaviour called  anting .  The capuchins often combine anting with urinating into their hands and mixing the ants with the urine. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3113", "text": "Callicebus oenanthes  have been observed rubbing leaves of  Piper aduncum  on their furs and abdominal areas. Since these leaves contain insecticides like  dillapiole  and  phenylpropanoids , it is speculated that this fur-rubbing is an indication of a preventative measure to ward off insects. [ 52 ]  Additionally, another species of titi monkeys,  Plecturocebus   cupreus , were seen rubbing their furs with the leaves of  Psychotria , whose compounds have antiviral, antifungal, and analgesic properties. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3114", "text": "A male Sumatran orangutan known to researchers as Rakus \"appeared to have used the plant intentionally\" when he chewed up leaves of the \"antibacterial, anti-inflammatory, anti-fungal, antioxidant, pain-killing and anticarcinogenic\" vine  Fibraurea tinctoria  and applied the masticated plant material to an open wound on his face. According to primatologists who had been observing Rakus at a nature preserve, \"Five days later the facial wound was closed, while within a few weeks it had healed, leaving only a small scar\". [ 53 ] [ 54 ] [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3115", "text": "More than 200 species of song birds rub insects, usually ants, on their feathers and skin, a behaviour known as  anting . [ 14 ]  Birds either grasp ants in their bill and wipe them vigorously along the spine of each  feather  down to the base, or sometimes roll in ant hills twisting and turning so the ants crawl through their feathers. Birds most commonly use ants that spray formic acid. In laboratory tests, this acid is harmful to feather lice.  Its vapour alone can kill them."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3116", "text": "Some birds select nesting material rich in anti-microbial agents that may protect themselves and their young from harmful infestations or infections.  European starlings  ( Sturnus vulgaris ) preferentially select and line their nests with wild carrot ( Daucus carota ); chicks from nests lined with this have greater levels of  haemoglobin  compared to those from nests which are not, although there is no difference in the weight or feather development of the chicks.  Laboratory studies show that wild carrot substantially reduces the emergence of the  instars  of mites. [ 56 ]   House sparrows  ( Passer domesticus ) have been observed to line their nests with materials from the  neem  tree ( Azadirachta indica ) but change to  quinine -rich leaves of the Krishnachua tree ( Caesalpinia pulcherrima ) during an outbreak of  malaria ; quinine controls the symptoms of malaria. [ 28 ] [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3117", "text": "Zoopharmacognosy is not always exhibited in a way that benefits the individual.  Sometimes the target of the medication is the group or the colony."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3118", "text": "Wood ants ( Formica paralugubris ) often incorporate large quantities of solidified  conifer  resin into their nests. Laboratory studies have shown this resin inhibits the growth of bacteria and fungi in a context mimicking natural conditions. [ 58 ]   The ants show a strong preference for resin over twigs and stones, which are building materials commonly available in their environment. There is seasonal variation in the foraging of ants: the preference for resin over twigs is more pronounced in spring than in summer, whereas in autumn the ants collect twigs and resin at equal rates. The relative collection rate of resin versus stones does not depend on infection with the entomopathogenic fungus  Metarhizium anisopliae  in laboratory conditions, indicating the resin collection is prophylactic rather than therapeutic. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3119", "text": "Honey bees also incorporate plant-produced resins into their nest architecture, which can reduce chronic elevation of an individual bee's immune response. When colonies of honey bees are challenged with the fungal parasite ( Ascophaera apis ), the bees increase their resin foraging. Additionally, colonies experimentally enriched with resin have decreased infection intensities of the fungus. [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3120", "text": "Zoopharmacognosy can be classified depending on the target of the medication.  Some animals lay their eggs in such a way that their offspring are the target of the medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3121", "text": "Adult  monarch butterflies  preferentially lay their eggs on toxic plants such as milkweed which reduce parasite growth and disease in their offspring caterpillars. [ 61 ]   This has been termed  transgenerational therapeutic medication . [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3122", "text": "When detecting  endoparasitoid  wasps, fruit flies ( Drosophila melanogaster ) lay their eggs in leaves with high  ethanol  content as a means of protection for their offspring. [ 63 ]  These wasps, especially those of the  Leptopilina  genus, will inject their eggs in approximately 80% of fruit fly larvae. [ 64 ]  As these wasp eggs develop, they will consume extensively through the larvae. To combat this, the fruit fly larvae will consume a large amount of ethanol from the food source to medicate themselves after wasp infection. Specifically, as the wasps are consuming more of the larvae, they will unknowingly consume more ethanol, which promptly leads to their deaths. This has been termed  transgenerational prophylaxis . [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3123", "text": "In an interview with  Neil Campbell , Eloy Rodriguez describes the importance of  biodiversity to medicine :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3124", "text": "Some of the compounds we've identified by zoopharmacognosy kill parasitic worms, and some of these chemicals may be useful against  tumors . There is no question that the templates for most drugs are in the natural world. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3125", "text": "Bacillus  isolates  have a variety of  biotechnological  applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3126", "text": "Natt\u014d -derived  Bacillus  isolates include nootropics  pyrazine  and  tetramethylpyrazine , as well as the anticoagulant enzyme  nattokinase ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3127", "text": "Bacillus  is utilized in the production of the chemotherapy medicine  L-asparaginase .  Bacillus subtilis  is utilized in the production of  hyaluronic acid  and  \u03b1-amylase .  Bacillus thuringiensis  isolates are utilized as  biopesticides ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3128", "text": "Bacillus megaterium  has been an important industrial organism for decades. It produces  penicillin amidase  used to make synthetic penicillin, various  amylases  used in the baking industry and  glucose dehydrogenase  used in glucose blood tests.  B. megaterium  is also used for the production of  pyruvate ,  vitamin B12 , drugs with  fungicidal  and  antiviral  properties, etc. [ 2 ]  It produces enzymes for modifying  corticosteroids , as well as several amino acid  dehydrogenases ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3129", "text": "Bacillus subtilis  can biosynthesize  silver nanoparticles .  Bacillus badius  can be used to cleaves penicillin G to 6-amino penicillanic acid (6-APA) and phenyl acetic acid (PAA). Certain  Bacillus  have  mycorrhiza -like activity and potential  bioremediation  applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3130", "text": "Bacillus isolates are used industrially as nutritional  probiotics . [ 3 ]  Additional  Bacillus  isolates include  gamma-D-Glutamyl-meso-diaminopimelate peptidase , sonorensin, [ 4 ]  gamma-cyclodextrin,   2,5-Diketopiperazines ,  laccases ,  bacteriocin , paenicidin A, tridecaptin A\u2081, and paenicidin B."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3131", "text": "Bark isolates  are chemicals which have been extracted from  bark . Prominent medical examples are  salicylic acid  (active metabolite of  aspirin ) and  paclitaxel  ( Taxol ). The  pharmacology  of bark isolates is an ongoing topic of medical research."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3132", "text": "Fungal isolates  have been researched for decades. Because  fungi  often exist in thin  mycelial   monolayers , with no protective shell,  immune system , and limited mobility, they have developed the ability to synthesize a variety of unusual compounds for survival. Researchers have discovered fungal isolates with  anticancer ,  antimicrobial ,  immunomodulatory , and other  bio-active  properties. The first  statins ,  \u03b2-Lactam antibiotics , as well as a few important antifungals, were discovered in fungi."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3133", "text": "BMS  manufactures  paclitaxel  using  Penicillium  and plant cell fermentation. Fungi can synthesize  podophyllotoxin  and  camptothecin , precursors to  etoposide ,  teniposide ,  topotecan , and  irinotecan ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3134", "text": "Lentinan ,  PSK , and  PSP , are registered anticancer immunologic adjuvants.  Irofulven  and  acylfulvene  are anticancer derivatives of  illudin S .  Clavaric acid  is a reversible farnesyltransferase inhibitor.  Inonotus obliquus  creates  betulinic acid  precursor  betulin .  Flammulina velutipes  creates  asparaginase .  Plinabulin  is a fungal isolate derivative currently being researched for anticancer applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3135", "text": "The statins  lovastatin ,  mevastatin , and  simvastatin  precursor monacolin J, are fungal isolates. Additional fungal isolates that inhibit cholesterol are  zaragozic acids ,  eritadenine , and  nicotinamide riboside ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3136", "text": "Ciclosporin ,  mycophenolic acid ,  mizoribine ,  FR901483 , and  gliotoxin , are immunosuppressant fungal isolates."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3137", "text": "Penicillin ,  cephalosporins ,  fusafungine ,  usnic acid ,  fusidic acid ,  fumagillin ,  brefeldin A ,  verrucarin A ,  alamethicin , are antibiotic fungal isolates. Antibiotics  retapamulin ,  tiamulin , and  valnemulin  are derivatives of the fungal isolate  pleuromutilin .  Griseofulvin ,  echinocandins ,  strobilurin ,  azoxystrobin ,  caspofungin ,  micafungin , are fungal isolates with antifungal activity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3138", "text": "The headache medications  cafergot ,  dihydroergotamine ,  methysergide ,  methylergometrine , the dementia medications  hydergine ,  nicergoline , the Parkinson's disease medications  lisuride ,  bromocriptine ,  cabergoline , and  pergolide  were all derived from  Claviceps  isolates.  Polyozellus multiplex  synthesizes prolyl endopeptidase inhibitors  polyozellin ,  thelephoric acid , and  kynapcins .  Boletus badius  synthesizes  L-theanine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3139", "text": "Researchers have discovered other interesting fungal isolates like the antihyperglycemic compounds  ternatin ,  aspergillusol A ,  sclerotiorin , and antimalarial compounds  codinaeopsin ,  efrapeptins , and  antiamoebin . The fungal isolate  ergothioneine  is actively absorbed and concentrated by the human body via  SLC22A4 . Other notable fungal isolates include vitamin D 1 , vitamin D 2 , and vitamin D 4 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3140", "text": "Lacking an  immune system , protective shell, or mobility,  sponges  have developed an ability to synthesize a variety of unusual compounds for survival.  C- nucleosides  isolated from Caribbean  Cryptotethya crypta , were the basis for the synthesis of  zidovudine  ( AZT ),  aciclovir  ( Cyclovir ),  cytarabine  ( Depocyt ), and cytarabine derivative  gemcitabine  ( Gemzar )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3141", "text": "Semisynthetic analogs of the sponge isolate jasplakinolide, were submitted to  National Cancer Institute \u2019s Biological Evaluation Committee in 2011."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3142", "text": "Trabectedin ,  aplidine ,  didemnin , were isolated from  sea squirts .  Monomethyl auristatin E  is a derivative of a dolastatin 10, a compound made by  Dolabella auricularia .  Bryostatins  were first isolated from  Bryozoa ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3143", "text": "Salinosporamides  are derived from  Salinispora tropica .  Ziconotide  is derived from the sea snail  Conus magus ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3144", "text": "Streptomyces  isolates  have yielded the majority of human, animal, and agricultural antibiotics, as well as a number of fundamental chemotherapy medicines.  Streptomyces  is the largest  antibiotic -producing genus of  Actinomycetota , producing chemotherapy, antibacterial,  antifungal , antiparasitic drugs, and  immunosuppressants . [ 1 ]   Streptomyces  isolates are typically initiated with the aerial  hyphal  formation from the  mycelium . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3145", "text": "Streptomyces , yielded the medicines  doxorubicin  ( Doxil ),  daunorubicin  ( DaunoXome ), and  streptozotocin  ( Zanosar ). Doxorubicin is the precursor to  valrubicin  ( Valstar ),  myocet , and  pirarubicin . Daunorubicin is the precursor to  idarubicin  ( Idamycin ),  epirubicin  ( Ellence ), and  zorubicin . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3146", "text": "Streptomyces  is the original source of  dactinomycin  ( Cosmegen ),  bleomycin  ( Blenoxane ),  pingyangmycin  ( Bleomycin A 5 ),  mitomycin C  ( Mutamycin ),  rebeccamycin ,  staurosporine  (precursor to  stauprimide  and  midostaurin ),  neothramycin ,  aclarubicin , tomaymycin,  sibiromycin , and mazethramycin. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3147", "text": "Derivatives of  Streptomycetes  isolate  migrastatin , including  isomigrastatin , dorrigocin A & B, and the synthetic derivative  macroketone , are being researched for anticancer activity. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3148", "text": "Most clinical antibiotics were found during the \"golden age of antibiotics\" (1940s\u20131960s).  Actinomycin  was the first antibiotic isolated from  Streptomyces  in 1940, followed by  streptomycin  three years later. Antibiotics from  Streptomyces  isolates (including various  aminoglycosides ) would go on to comprise over two-thirds of all marketed antibiotics. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3149", "text": "Streptomyces -derived antibiotics include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3150", "text": "Clavulanic acid  ( Streptomyces clavuligerus ) is used in combination with some antibiotics (such as  amoxicillin ) to weaken bacterial-resistance. Novel anti-infectives being developed include the  guadinomines  (from  Streptomyces  sp. K01-0509), [ 14 ]  inhibitors of the  type III secretion system ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3151", "text": "Non- Streptomyces   actinomycetes , filamentous  fungi , and non-filamentous  bacteria , have also yielded important antibiotics. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3152", "text": "Nystatin  ( Streptomyces noursei ),  amphotericin B  ( Streptomyces nodosus ),  ossamycin  ( Streptomyces hygroscopicus ), and  natamycin  ( Streptomyces natalensis ) are antifungals isolated from  Streptomyces . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3153", "text": "Sirolimus  ( Rapamycin ),  ascomycin , and  tacrolimus  were isolated from  Streptomyces .   Pimecrolimus  is a derivative of ascomycin.  Ubenimex  is derived from  S. olivoreticuli . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3154", "text": "Streptomyces avermitilis  synthesizes the antiparasitic  ivermectin  ( Stromectol ). Other antiparasitics made by  Streptomyces  include,  milbemycin oxime ,  moxidectin , and  milbemycin . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3155", "text": "Traditionally,  Escherichia coli  is the choice bacterium to express  eukaryotic  and  recombinant  genes.  E. coli  is well understood and has a successful track record producing  insulin , the  artemisinin  precursor artemisinic acid, and  filgrastim  ( Neupogen ). [ 16 ] [ 17 ]  However, use of  E. coli  has limitations including misfolding of eukaryotic proteins, insolubility issues, deposition in inclusion bodies, [ 18 ]  low secretion efficiency, secretion to periplasmic space."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3156", "text": "Streptomyces  offers potential advantages including superior secretion mechanisms, higher yields, a simpler end-product purification process, making  Streptomyces  an attractive alternative to  E. coli  and  Bacillus subtilis . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3157", "text": "Streptomyces coelicolor ,  Streptomyces avermitilis ,  Streptomyces griseus , and  Saccharopolyspora erythraea , are capable of secondary metabolite production.  Streptomyces coelicolor  has shown useful for the  heterologous expression  of proteins. Methods like \"ribosome engineering\" have been used to achieve 180-fold higher yields with  S. coelicolor . [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3158", "text": "StreptomeDB, a directory of  Streptomyces  isolates, contains over 2400 compounds isolated from more than 1900 strains. [ 20 ] [ 21 ]   Streptomyces hygroscopicus  and  Streptomyces viridochromeogenes  produce the herbicide  bialaphos .  Expansion of  Streptomyces  screenings have included  endophytes ,  extremophiles , and  marine  varieties. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3159", "text": "A recent screening of  TCM  extracts revealed a  Streptomyces  that produces a number of antitubercular  pluramycins . [ 22 ]  Wailupemycins are bio-active  pyrones  isolated from marine  Streptomyces . [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3160", "text": "Mayamycin  has been shown to have  cytotoxic  properties. [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3161", "text": "Germicidin  are a group of four compounds that act as autoregulatory inhibitors of  spore germination . [ 26 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3162", "text": "An  anticarcinogen  (also known as a  carcinopreventive  agent) is a substance that counteracts the effects of a  carcinogen  or inhibits the development of  cancer . [ 1 ]   Anticarcinogens are different from  anticarcinoma agents  (also known as anticancer or anti-neoplastic agents) in that anticarcinoma agents are used to selectively destroy or inhibit cancer cells  after  cancer has developed.  Interest in anticarcinogens is motivated primarily by the principle that it is preferable to prevent disease ( preventive medicine ) than to have to treat it ( rescue medicine ). [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3163", "text": "In theory, anticarcinogens may act via different mechanisms including enhancement of natural defences against cancer, deactivation of  carcinogens , and blocking the mechanisms by which carcinogens act (such as  free radical  damage to  DNA ).  Confirmation that a substance possesses anticarcinogenic activity requires extensive  in vitro ,  in vivo , and  clinical  investigation.  Health claims for anticarcinogens are regulated by various national and international organizations like the  US Food and Drug Administration (FDA)  and  European Food Safety Authority (EFSA) . [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3164", "text": "This  antineoplastic  or  immunomodulatory   drug  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3165", "text": "Barbigerone  is one of a few  pyranoisoflavones  among several groups of  isoflavones . It was first isolated from the seed of a  leguminous plant   Tephrosia barbigera ; hence the name \"barbigerone\". [ 1 ]  Members of the  genus   Millettia  are now known to be rich in barbigerone, including  M. dielsiena , [ 2 ]   M. ferruginea , [ 3 ]   M. usaramensis , [ 4 ]  and  M. pachycarpa . [ 5 ]  It has also been isolated from the medicinal plant  Sarcolobus globosus . [ 6 ]  Barbigerone from  S. globosus  is validated to have significant  antioxidant  property. [ 7 ]  Barbigerone exhibits profound antiplasmodial activity against the  malarial parasite   Plasmodium falciparum . [ 8 ]  It is also demonstrated that it has  anti-cancer  potential as it causes  apoptosis  of  murine   lung-cancer cells . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3166", "text": "Fluasterone , also known as  3\u03b2-dehydroxy-16\u03b1-fluoro- DHEA  or  16\u03b1-fluoroandrost-5-en-17-one , is a  fluorinated   synthetic   analogue  of  dehydroepiandrosterone  (DHEA) which was under investigation by Aeson Therapeutics for a variety of therapeutic indications including  cancer ,  cardiovascular diseases ,  diabetes ,  obesity , and  traumatic brain injury  among others but was ultimately never marketed. [ 1 ] [ 2 ]  It is a  modification  of DHEA in which the C3\u03b2  hydroxyl  has been removed and a  hydrogen  atom has been  substituted  with a  fluorine  atom at the C16\u03b1 position. Fluasterone reached  phase II   clinical trials  prior to the discontinuation of its development. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3167", "text": "The  mechanism of action  of DHEA and fluasterone is unknown. [ 4 ] [ 5 ] [ 6 ]  However, similarly to DHEA but more strongly, fluasterone is a  potent   uncompetitive inhibitor  of  G6PDH Tooltip glucose-6-phosphate dehydrogenase  (K i  = 0.5\u00a0\u03bcM versus 17\u00a0\u03bcM for DHEA). [ 4 ]  The drug retains the  antiinflammatory ,  antihyperplastic ,  chemopreventative ,  antihyperlipidemic ,  antidiabetic , and  antiobesic , as well as certain  immunomodulating  activities of DHEA, much but not all of which it is thought may possibly be mediated via G6PDH inhibition (with some experimental evidence to support this notion available). [ 4 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3168", "text": "Conversely, unlike DHEA, fluasterone has minimal or no  androgenic  or  estrogenic  activity, and due to the presence of the fluorine atom at the C16\u03b1 position, its  metabolism  at the C17\u03b1 position is  sterically hindered  and thus it cannot be metabolized into  androgens  like  testosterone  or  estrogens  like  estradiol . [ 6 ] [ 9 ] [ 4 ]  Also in contrast to DHEA, fluasterone does not produce  sedation  or  seizures  in animals and hence is not thought to interact with the  GABA A  receptor . [ 10 ]  In addition, unlike DHEA, fluasterone has reduced or no effects as a  peroxisome proliferator  (i.e., lacks activity at the  PPAR\u03b1 Tooltip peroxisome proliferator-activated receptor alpha ), and hence does not pose a risk of  liver toxicities  such as  hepatomegaly  or  hepatocellular carcinoma . [ 4 ]  It is for these reasons that fluasterone was developed and was considered to be advantageous to DHEA. [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3169", "text": "Due to extensive  first-pass   hepatic  and/or  gastrointestinal  metabolism, very high doses of DHEA and fluasterone are necessary for effectiveness. [ 4 ]  In animals, the  efficacy  of fluasterone is increased 40-fold when administered  parenterally , and for this reason, a non- oral  formulation of fluasterone was selected for clinical development. [ 4 ]  However, the development of fluasterone was nonetheless stopped reportedly due to its low potency and low oral  bioavailability , which are said to have rendered it unsuitable for clinical use. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3170", "text": "In  biochemistry ,  medicine , and related sciences,  inositol  generally refers to  myo -inositol  (formerly  meso -inositol ), the most important  stereoisomer  of the  chemical compound   cyclohexane-1,2,3,4,5,6-hexol . Its  formula  is  C 6 H 12 O 6 ; the molecule has a ring of six  carbon  atoms, each with an  hydrogen  atom and a  hydroxyl  group (\u2013OH). In  myo -inositol, two of the hydroxyls, neither adjacent not opposite, lie above the respective hydrogens relative to the mean plane of the ring."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3171", "text": "The compound is a  carbohydrate , specifically a  sugar alcohol  (as distinct from  aldoses  like  glucose ) with half the  sweetness  of  sucrose  (table sugar). It is one of the most ancient components of living beings with multiple functions in eukaryotes, including structural lipids and  secondary messengers . [ 3 ]  A human kidney makes about two grams per day from  glucose , but other tissues synthesize it too. The highest concentration is in the brain, where it plays an important role in making other  neurotransmitters  and some  steroid hormones  bind to their receptors. [ 4 ]  In other tissues, it mediates cell signal transduction in response to a variety of  hormones ,  neurotransmitters , and growth factors and participates in  osmoregulation . [ 5 ]  In most mammalian cells the concentrations of  myo -inositol are 5 to 500\u00a0times greater inside cells than outside them. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3172", "text": "A 2023 meta-analysis found that inositol is a safe and effective treatment in the management of  polycystic ovary syndrome  (PCOS). [ 7 ]  However, there is only evidence of very low quality for its efficacy in increasing fertility for IVF in women with PCOS. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3173", "text": "The other naturally occurring stereoisomers of cyclohexane-1,2,3,4,5,6-hexol are  scyllo -,  muco -,  D - chiro -,  L - chiro -, and  neo -inositol , although they occur in minimal quantities compared to  myo -inositol. The other possible isomers are  allo -,  epi -, and  cis -inositol ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3174", "text": "myo -Inositol was first isolated from muscle extracts by Johanes Joseph Scherer (1814\u20131869) in 1850. [ 3 ]  It was formerly called  meso -inositol to distinguish it from the  chiro - isomers. However, since all other isomers are meso (non- chiral ) compounds, the name  myo -inositol is now preferred ( myo - being a  medical prefix  for \"muscle\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3175", "text": "Inositol was once considered a member of the  vitamin B  complex, namely  vitamin B 8  before the discovery that it is made naturally in the human body, and therefore cannot be a  vitamin  or  essential nutrient . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3176", "text": "myo -Inositol is a  meso compound , meaning it is  optically inactive  because it has a  plane of symmetry . [ 10 ]  It is a white crystalline powder, relatively stable in the air. It is highly soluble in water, slightly soluble in  glacial acetic acid ,  ethanol ,  glycol , and  glycerin , but insoluble in  chloroform  and  ether . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3177", "text": "In its most stable  conformation , the  myo -inositol isomer assumes the  chair conformation , which moves the maximum number of hydroxyls to the equatorial position, where they are farthest apart from each other. In this conformation, the natural  myo  isomer has a structure in which five of the six  hydroxyls  (the first, third, fourth, fifth, and sixth) are  equatorial , whereas the second hydroxyl group is  axial . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3178", "text": "myo -Inositol plays an important role as the structural basis for a number of  secondary messengers  in  eukaryotic   cells , the various  inositol phosphates . In addition, inositol serves as an important component of the structural lipids  phosphatidylinositol  (PI) and its various phosphates, the  phosphatidylinositol phosphate  (PIP) lipids."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3179", "text": "In humans,  myo -Inositol is  synthesized  de novo  but  D - chiro -inositol is not. [ 6 ]   myo -Inositol is synthesized from  glucose 6-phosphate  (G6P) in two steps. First, G6P is  isomerised  by an  inositol-3-phosphate synthase  enzyme (for example,  ISYNA1 ) to  myo -inositol 1-phosphate, which is then dephosphorylated by an  inositol monophosphatase  enzyme (for example,  IMPA1 ) to give free  myo -inositol. In humans, most inositol is synthesized in the kidneys, followed by testicles, typically in amounts of a few grams per day. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3180", "text": "At the peripheral level,  myo -inositol is converted to  D - chiro -inositol by a specific epimerase. Only a minor fraction of  myo -inositol is converted into  D - chiro -inositol. [ 6 ]  The activity of this epimerase is insulin dependent, causing a reduction of  D - chiro -inositol in muscle, fat, and liver when there is  insulin resistance . [ 12 ] [ 6 ]   D - chiro -inositol reduces the conversion of testosterone to estrogen, thereby increases the levels of testosterone and worsening PCOS. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3181", "text": "Inositol hexaphosphate, also called  phytic acid  or IP6, is a  phytochemical  and the principal storage form of  phosphorus  in many  plant   tissues , especially  bran  and  seed . [ 13 ]  Phosphorus and inositol in phytate form are not generally  bioavailable  to non- ruminant  animals because these animals lack the digestive  enzyme   phytase  required to remove the phosphate groups. Ruminants readily digest phytate because of the phytase produced by microorganisms in the  rumen . [ 14 ]  Moreover, phytic acid also  chelates  important minerals such as  calcium ,  magnesium ,  iron , and  zinc , making them unabsorbable, and contributing to mineral deficiencies in people whose diets rely highly on bran and seeds for their mineral intake, such as occurs in  developing countries . [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3182", "text": "Inositol penta- (IP5), tetra- (IP4), and triphosphate (IP3) are also called \"phytates\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3183", "text": "Inositol or its phosphates and associated lipids are found in many foods, in particular fruit, especially  cantaloupe  and  oranges . [ 17 ]  In plants, the hexaphosphate of inositol,  phytic acid  or its salts, the phytates, serve as phosphate stores in seed, for example in nuts and beans. [ 18 ]  Phytic acid also occurs in  cereals  with high  bran  content. Phytate is, however, not directly  bioavailable  to humans in the diet, since it is not digestible. Some food preparation techniques partly break down phytates to change this. However, inositol in the form of  phospholipids , as found in certain plant-derived substances such as  lecithins , is well absorbed and relatively bioavailable."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3184", "text": "Inositol, phosphatidylinositol, and some of their mono- and polyphosphates function as  secondary messengers  in a number of intracellular  signal transduction  pathways. They are involved in a number of biological processes, including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3185", "text": "In one important family of pathways,  phosphatidylinositol 4,5-bisphosphate  (PIP 2 ) is stored in cellular membranes until it is released by any of a number of signalling proteins and transformed into various secondary messengers, for example  diacylglycerol  and  inositol trisphosphate . [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3186", "text": "' myo -Inositol has very low toxicity, with a reported  LD 50  10,000 mg/kg body weight (oral) in rats. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3187", "text": "At the 1936 meeting of the  American Chemical Society , professor  Edward Bartow  of the  University of Iowa  presented a commercially viable means of extracting large amounts of inositol from the phytic acid naturally present in waste corn. As a possible use for the chemical, he suggested 'inositol nitrate' as a more stable alternative to  nitroglycerin . [ 26 ]  Today, inositol nitrate is used to gelatinize  nitrocellulose  in many modern explosives and solid rocket propellants. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3188", "text": "When plants are exposed to increasing concentrations of  road salt , the plant cells become dysfunctional and undergo  apoptosis , leading to inhibited growth. Inositol pretreatment could reduce these effects. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3189", "text": "High doses of inositol may be used to treat  trichotillomania  (compulsive hair-pulling) and related disorders. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3190", "text": "D- chiro -inositol is an important messenger molecule in insulin signaling. [ 30 ]  Inositol supplementation has been shown to significantly decrease  triglycerides  and  LDL cholesterol  in patients with  metabolic diseases . [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3191", "text": "myo -Inositol is important for  thyroid hormone  synthesis. [ 31 ]  Depletion of  myo -inositol may predispose to development of  hypothyroidism . [ 31 ]  Patients with hypothyroidism have a higher demand for  myo -inositol than healthy subjects. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3192", "text": "Inositol should not be routinely implemented for the management of preterm babies who have or are at a risk of  infant respiratory distress syndrome  (RDS). [ 32 ]   Myo -inositol helps prevent  neural tube defects  with particular efficacy in combination with  folic acid . [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3193", "text": "Inositol is considered a safe and effective treatment for  polycystic ovary syndrome  (PCOS). [ 7 ]  It works by increasing insulin sensitivity, which helps to improve ovarian function and reduce  hyperandrogenism . [ 34 ]  It is also shown to reduce the risk of  metabolic disease  in women with PCOS. [ 35 ]  In addition, thanks to its role as FSH second messenger,  myo -inositol is effective in restoring FSH/LH ratio and menstrual cycle regularization. [ 36 ]   myo -Inositol's role as FSH second messenger leads to a correct ovarian follicle maturation and consequently to a higher oocyte quality. Improving the oocyte quality in both women with or without PCOS,  myo -inositol can be considered as a possible approach for increasing the chance of success in assisted reproductive technologies. [ 37 ] [ 38 ]  In contrast,  D - chiro -inositol can impair oocyte quality in a dose-dependent manner. [ 39 ]  The high level of DCI seems to be related to elevated insulin levels retrieved in about 70% of PCOS women. [ 40 ]  In this regard, insulin stimulates the irreversible conversion of  myo -inositol to  D - chiro -inositol causing a drastic reduction of  myo -inositol.  myo -Inositol depletion is particularly damaging to ovarian follicles because it is involved in FSH signaling, which is impaired due to  myo -inositol depletion. [ 12 ]  Recent evidence reports a faster improvement of the metabolic and hormonal parameters when these two isomers are administered in their physiological ratio. The plasmatic ratio of  myo -inositol and  D - chiro -inositol in healthy subjects is 40:1 of  myo - and  D - chiro -inositol respectively. [ 41 ]  The use of the 40:1 ratio shows the same efficacy of  myo -inositol alone but in a shorter time. In addition, the physiological ratio does not impair oocyte quality. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3194", "text": "The use of inositols in PCOS is gaining more importance, and an efficacy higher than 70% with a strong safety profile is reported. On the other hand, about 30% of patients could show as inositol-resistant. [ 43 ]  New evidence regarding PCOS aetiopathogenesis describes an alteration in the species and the quantity of each strain characterizing the normal gastrointestinal flora. This alteration could lead to chronic, low-level inflammation and malabsorption. [ 44 ]  A possible solution could be represented by the combination of  myo -inositol and  \u03b1-lactalbumin . This combination shows a synergic effect in increasing myo-inositol absorption. [ 45 ]  A recent study reported that the  myo -inositol and \u03b1-lactalbumin combination increases  myo -inositol plasmatic content in inositol-resistant patients with a relative improvement of hormonal and metabolic parameters. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3195", "text": "Inositol has been used as an adulterant or  cutting agent  for many illegal drugs, such as  cocaine ,  methamphetamine , and sometimes  heroin , [ 47 ]  probably because of its solubility, powdery texture, or reduced  sweetness  (50%) compared to more common sugars."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3196", "text": "Inositol is also used as a stand-in  film prop  for  cocaine  in  filmmaking . [ 48 ] [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3197", "text": "myo -Inositol is naturally present in a variety of foods, although tables of food composition do not always distinguish between  lecithin , the relatively bioavailable lipid form and the biounavailable phytate/phosphate form. [ 17 ]  Foods containing the highest concentrations of  myo -inositol and its compounds include fruits, beans, grains, and nuts. [ 17 ]  Fruits in particular, especially oranges and cantaloupe, contain the highest amounts of  myo -inositol. [ 50 ]  It is also present in beans, nuts, and grains, however, these contain large amounts of  myo -inositol in the phytate form, which is not bioavailable without transformation by  phytase  enzymes.  Bacillus subtilis , the microorganism which produces the fermented food  natto , produces phytase enzymes that may convert  phytic acid  to a more bioavailable form of inositol polyphosphate in the gut. [ 51 ]  Additionally,  Bacteroides  species in the gut secrete vesicles containing an active enzyme which converts the phytate molecule into bioavailable phosphorus and inositol polyphosphate, which is an important signaling molecule in the human body. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3198", "text": "myo -Inositol can also be found as an ingredient in  energy drinks , [ 53 ]  either in conjunction with or as a substitute for glucose. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3199", "text": "In humans, myo-inositol is naturally made from glucose-6-phosphate through enzymatic dephosphorylation. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3200", "text": "As of 2021, the main industrial process for the production of  myo -inositol (mostly in China and Japan) started with phytate (IP6) extracted from the soaking water resulting from corn and rice bran processing. After purification, the phytate is hydrolized, and  myo -inositol is separated by crystallization. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3201", "text": "Another route is microbial fermentation of carbohydrates by various organisms, such as the fungus  Neurospora crassa  (Beadle and Tatum, 1945),  Candida boidini  (Shirai et al., 1997),  Saccharomyces cerevisiae  (Culbertson et al., 1976),  Escherichia coli  (Hansen, 1999). [ 3 ]  Alternatively, enzyme extracts from microbial cultures can be used in vitro to obtain  myo -inositol from various substrates, including glucose,  sucrose ,  starch ,  xylose , and  amylose . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3202", "text": "Miraculin  is a  taste modifier , a  glycoprotein  extracted from the fruit of  Synsepalum dulcificum . [ 2 ]  The berry, also known as the miracle fruit, was documented by explorer  Chevalier des Marchais , who searched for many different fruits during a 1725 excursion to its native West Africa."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3203", "text": "Miraculin itself does not taste  sweet . When  taste buds  are exposed to miraculin, the protein binds to the sweetness receptors. This causes normally sour-tasting acidic foods, such as  citrus , to be perceived as sweet. [ 2 ] [ 3 ]  The effect can last for one or two hours. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3204", "text": "The sweetening properties of  Synsepalum dulcificum  berries were first noted by des Marchais during expeditions to West Africa in the 18th century. [ 6 ]  The term  miraculin  derived from experiments to isolate and purify the active  glycoprotein  that gave the berries their sweetening effects, results that were published simultaneously by Japanese and Dutch scientists working independently in the 1960s (the Dutch team called the glycoprotein  mieraculin ). [ 7 ] [ 8 ]  The word  miraculin  was in common use by the mid-1970s. [ 9 ] [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3205", "text": "Miraculin was first sequenced in 1989 and was found to be a 24.6\u00a0 kilodalton [ 2 ]  glycoprotein consisting of 191  amino acids [ 12 ]  and 13.9% by weight of various sugars. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3206", "text": "The sugars consist of a total of 3.4\u00a0kDa, composed of a molar ratio of  glucosamine  (31%),  mannose  (30%),  fucose  (22%),  xylose  (10%), and  galactose  (7%). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3207", "text": "The  native state  of miraculin is a  tetramer  consisting of two  dimers , each held together by a  disulfide  bridge. [ 14 ]  Both tetramer miraculin and native dimer miraculin in its crude state have the taste-modifying activity of turning sour tastes into sweet tastes. [ 15 ]  Miraculin belongs to the  Kunitz STI protease inhibitor  family."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3208", "text": "Miraculin, unlike  curculin  (another taste-modifying agent), [ 16 ]  is not sweet by itself, but it can change the perception of sourness to sweetness, even for a long period after consumption. [ 4 ]  The duration and intensity of the sweetness-modifying effect depends on various factors, such as miraculin concentration, duration of contact of the miraculin with the tongue, and acid concentration. [ 3 ] [ 4 ]  Miraculin reaches its maximum sweetness with a solution containing at least 4*10 \u22127 \u00a0 mol/L  miraculin, which is held in the mouth for about 3\u00a0minutes. Maximum is equivalent in sweetness to a 0.4\u00a0mol/L solution of  sucrose . [ 17 ]  Miraculin degrades permanently via  denaturation  at high temperatures and at  pH  below 3 or above 12. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3209", "text": "Although the detailed mechanism of the taste-inducing behavior is unknown, it appears the sweet receptors are activated by acids which are related to sourness, an effect remaining until the  taste buds  perceive a neutral pH. [ 3 ] [ 4 ]  Sweeteners are perceived by the human sweet taste receptor, hT1R2-hT1R3, which belongs to  G protein-coupled receptors , [ 4 ]  modified by the two  histidine  residues (i.e. His30 and His60) which participate in the taste-modifying behavior. [ 19 ]  One site maintains the attachment of the protein to the membranes while the other (with attached  xylose  or  arabinose ) activates the sweet receptor membrane in acid solutions. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3210", "text": "As miraculin is a readily soluble protein and relatively heat stable, it is a potential  sweetener  in acidic food, such as  soft drinks . While attempts to express it in  yeast  and  tobacco plants  have failed, researchers have succeeded in preparing  genetically modified   E. coli  bacteria that express miraculin. [ 20 ]   Lettuce  and  tomato  have also been used for mass production of miraculin. [ 21 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3211", "text": "The use of miraculin as a food additive was denied in 1974 by the United States  Food and Drug Administration . [ 23 ]  However, it can still be sold in the form of whole berries or tablets (as \"dietary supplements\"). [ 24 ] [ 25 ]  In 2011 the FDA banned a certain brand of miraculin tablets imported from Taiwan as it was thought to be \"hard candy\" with non-approved sweeteners. [ 26 ]  Miraculin has a  novel food  status in the  European Union . [ 27 ]  It is approved in  Japan  as a safe  food additive , according to the List of Existing Food Additives published by the Ministry of Health and Welfare (published by the  Japan External Trade Organization )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3212", "text": "A  polyphenol antioxidant  is a  hypothesized type  of  antioxidant  studied  in vitro . Numbering over 4,000 distinct  chemical structures  mostly from  plants , such polyphenols have not been demonstrated to be antioxidants  in vivo . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3213", "text": "In vitro at high experimental doses, polyphenols may affect cell-to-cell signaling,  receptor  sensitivity, inflammatory  enzyme  activity or  gene regulation . [ 3 ] [ 4 ]  None of these hypothetical effects has been confirmed in humans by high-quality  clinical research , as of 2020 [update] . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3214", "text": "The main source of polyphenols is dietary, since they are found in a wide array of  phytochemical -bearing foods.  For example,  honey ; most  legumes ; fruits such as  apples ,  blackberries ,  blueberries ,   cantaloupe ,  pomegranate ,  cherries ,  cranberries ,  grapes ,  pears ,  plums ,  raspberries ,  aronia berries , and  strawberries  (berries in general have high polyphenol content [ 5 ] ) and  vegetables  such as  broccoli ,  cabbage ,  celery ,  onion  and  parsley  are rich in polyphenols.  Red wine ,  chocolate , black tea,  white tea ,  green tea ,  olive oil  and many  grains  are sources. [ 1 ]  Ingestion of polyphenols occurs by consuming a wide array of plant foods. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3215", "text": "The regulation theory considers a polyphenolic ability to scavenge  free radicals   and up-regulate certain metal  chelation  reactions. [ 1 ]   Various  reactive oxygen species , such as  singlet oxygen ,  peroxynitrite  and   hydrogen peroxide , must be continually removed from cells to maintain healthy metabolic function. Diminishing the concentrations of reactive oxygen species can have several benefits possibly associated with  ion transport  systems and so may affect  redox signaling . [ 1 ]  There is no substantial evidence, however, that dietary polyphenols have an antioxidant effect in vivo. [ 1 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3216", "text": "The \u201cdeactivation\u201d of oxidant species by polyphenolic antioxidants (POH) is based, with regard to food systems that are deteriorated by peroxyl radicals (R\u2022), on the donation of hydrogen, which interrupts chain reactions:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3217", "text": "Phenoxyl radicals (PO\u2022) generated according to this reaction may be stabilized through  resonance  and/or intramolecular hydrogen bonding, as proposed for  quercetin , or combine to yield  dimerisation  products, thus terminating the chain reaction:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3218", "text": "Consuming dietary polyphenols have been evaluated for biological activity in vitro, but there is no evidence from high-quality  clinical research  as of 2015 [update]  that they have effects in vivo. [ 1 ]  Preliminary research has been conducted and regulatory status was reviewed in 2009 by the U.S.  Food and Drug Administration  (FDA), with no recommended intake values established, indicating absence of proof for nutritional value. [ 6 ]  Other possible effects may result from consumption of foods rich in polyphenols, but are not yet proved scientifically in humans; accordingly, health claims on food labels are not allowed by the FDA. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3219", "text": "It is difficult to evaluate the physiological effects of specific natural phenolic antioxidants, since such a large number of individual compounds may occur even in a single food and their fate in vivo cannot be measured. [ 1 ] [ 6 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3220", "text": "Other more detailed chemical research has elucidated the difficulty of isolating individual phenolics. Because significant variation in phenolic content occurs among various brands of tea, there are possible [ 9 ]  inconsistencies among epidemiological studies implying beneficial health effects of phenolic antioxidants of  green tea  blends. The  Oxygen Radical Absorbance Capacity  (ORAC) test is a laboratory indicator of antioxidant potential in foods and  dietary supplements . However, ORAC results cannot be confirmed to be physiologically applicable and have been designated as unreliable. [ 3 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3221", "text": "There is  debate regarding the total body absorption of dietary intake of polyphenolic compounds.  While some indicate potential health effects of certain specific polyphenols, most studies demonstrate low  bioavailability  and rapid excretion of polyphenols, indicating their potential roles only in small concentrations in vivo. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  More research is needed to understand the interactions between a variety of these chemicals acting in concert within the human body. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3222", "text": "There is no substantial evidence that reactive oxygen species play a role in the process of skin  aging . [ 11 ]  The skin is exposed to various  exogenous  sources of  oxidative stress , including  ultraviolet  radiation whose spectral components may be responsible for the  extrinsic  type of skin aging, sometimes termed  photoaging . Controlled long-term studies on the efficacy of low molecular weight antioxidants in the prevention or treatment of  skin  aging in humans are absent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3223", "text": "Experiments on  linoleic acid  subjected to  2,2\u2032-azobis (2-amidinopropane) dihydrochloride -induced oxidation with different combinations of phenolics show that binary mixtures can lead to either a  synergetic  effect or to an  antagonistic  effect. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3224", "text": "Antioxidant levels of purified anthocyanin extracts were much higher than expected from anthocyanin content indicating  synergistic  effect of anthocyanin mixtures. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3225", "text": "Tamoxifen , sold under the brand name  Nolvadex  among others, is a  selective estrogen receptor modulator  used to prevent  breast cancer  in women and men. [ 13 ]  It is also being studied for other types of  cancer . [ 13 ]  It has been used for  Albright syndrome . [ 14 ]  Tamoxifen is typically taken daily  by mouth  for five years for breast cancer. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3226", "text": "Serious side effects include a small increased risk of  uterine cancer ,  stroke , vision problems, and  pulmonary embolism . [ 14 ]  Common side effects include  irregular periods , weight loss, and  hot flashes . [ 14 ]  It may cause harm to the baby if taken during  pregnancy  or  breastfeeding . [ 14 ]  It is a  selective estrogen-receptor modulator  (SERM) and works by decreasing the growth of breast cancer cells. [ 14 ] [ 15 ]  It is a member of the  triphenylethylene  group of  compounds . [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3227", "text": "Tamoxifen was initially made in 1962, by chemist  Dora Richardson . [ 17 ] [ 18 ]  It is on the  World Health Organization's List of Essential Medicines . [ 19 ]  Tamoxifen is available as a  generic medication . [ 14 ]   In 2020, it was the 317th most commonly prescribed medication in the United States, with more than 900 \u00a0 thousand prescriptions. [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3228", "text": "Dysmenorrhea  is the term for menstrual pain, usually centered in the lower abdomen but often spreading to the back and inner thighs. It is a common gynecological condition that can seriously affect daily activities and well-being. Tamoxifen has been identified and used to effectively improve blood flow, reduce uterine contractility and pain in dysmenorrhea patients. [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3229", "text": "Tamoxifen is used for the treatment of both early and advanced  estrogen receptor -positive (ER-positive or ER+) breast cancer in  pre-  and  postmenopausal  women. [ 24 ]  Tamoxifen increases the risk of  postmenopausal bleeding ,  endometrial polyps ,  hyperplasia , and  endometrial cancer ; using tamoxifen with an  intrauterine system  releasing  levonorgestrel  might increase vaginal bleeding after 1 to 2 years, but reduces somewhat endometrial polyps and hyperplasia, but not necessarily endometrial cancer. [ 25 ]  Additionally, it is the most common hormone treatment for male breast cancer. [ 26 ]  It is also approved by the  FDA  for the prevention of breast cancer in women at high risk of developing the disease. [ 27 ]  The effectiveness of tamoxifen is primarily influenced by estrogen receptor (ER) status, which was the key predictor of the proportional benefits observed. It has been further approved for the reduction of  contralateral  (in the opposite breast) cancer. Five years of adjuvant tamoxifen treatment significantly lowers the 15-year risk of breast cancer recurrence and mortality. The overall use of tamoxifen is recommended for 10 years. [ 28 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3230", "text": "In 2006, the large STAR clinical study concluded that  raloxifene  is also effective in reducing the incidence of breast cancer. Updated results after an average of 6.75 years of follow up found that raloxifene retains 76% of tamoxifen's effectiveness in preventing invasive breast cancer, with 45% fewer  uterine cancers  and 25% fewer blood clots in women taking raloxifene than in women taking tamoxifen. [ 30 ] [ 31 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3231", "text": "Tamoxifen is used for  ovulation induction  to treat infertility in women with  anovulatory  disorders. It is given at days three to seven of a woman's cycle. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3232", "text": "Tamoxifen improves fertility in males with infertility by disinhibiting the  hypothalamic\u2013pituitary\u2013gonadal axis  (HPG axis) via ER antagonism and thereby increasing the secretion of  luteinizing hormone  (LH) and  follicle-stimulating hormone  (FSH) and increasing testicular  testosterone  production. [ 34 ]  Some animal studies have suggested tamoxifen could have negative effects on sperm quality and prostatic and gonadal health. [ 35 ] [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3233", "text": "Benign enlargement of the male breast, whether  asymptomatic  or painful, is a common condition thought to result from an increased estrogen/testosterone ratio or from heightened  estrogenic  or reduced  androgenic  activity via receptor interactions.Tamoxifen is used to prevent and treat  gynecomastia . [ 37 ] [ 38 ]  It is taken as a preventative measure in small doses, or used at the onset of any symptoms such as nipple soreness or sensitivity. Current treatments typically involve pain relief through medication or surgery. However, targeting the underlying estrogenic stimulation may offer a more specific therapeutic approach. In a double-blind crossover study, patients were given either a placebo or tamoxifen (10 mg orally twice daily) for one month, in random order. Seven out of ten patients saw a reduction in gynecomastia size with tamoxifen (P < 0.005), and the overall reduction for the group was statistically significant (P < 0.01). [ 39 ]  No benefits were observed with the placebo (P > 0.1). Additionally, all four patients with painful gynecomastia experienced relief of their symptoms, and no toxicity was noted. Although the breast size reduction was partial, this suggests that longer treatment may be necessary. Follow-up examinations conducted 9 to 12 months after treatment revealed no significant changes, except in two cases: one tamoxifen responder had a recurrence of breast tenderness after six months, and one non-responder developed increased breast size and new tenderness after ten months. Other medications are taken for similar purposes such as  clomifene  and  aromatase inhibitor  drugs; which are used in order to try to avoid the hormone-related adverse effects. Overall, tamoxifen appears to be a safe and effective treatment option for selected cases of gynecomastia."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3234", "text": "Tamoxifen is useful in the treatment of  peripheral precocious puberty , for instance due to  McCune\u2013Albright syndrome , in both girls and boys. [ 42 ] [ 43 ] [ 44 ]  It has been found to decrease  growth velocity  and the rate of  bone maturation  in girls with precocious puberty, and hence to improve final  height  in these individuals. [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3235", "text": "Tamoxifen is available as a tablet or oral solution. [ 45 ] [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3236", "text": "Tamoxifen has a number of  contraindications , including known  hypersensitivity  to tamoxifen or other ingredients, individuals taking concomitant  coumarin -type  anticoagulant  therapy, and women with a history of  venous thromboembolism  ( deep vein thrombosis  or  pulmonary embolism ). [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3237", "text": "A report in September 2009 from Health and Human Services' Agency for Healthcare Research and Quality suggests that tamoxifen, raloxifene, and tibolone used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3238", "text": "Tamoxifen is a  selective estrogen receptor modulator  (SERM). [ 48 ]  Even though it is an  antagonist  in breast tissue it acts as  partial agonist  on the  endometrium  and has been linked to  endometrial cancer  in some women. Therefore, endometrial changes, including cancer, are among tamoxifen's side effects. [ 49 ]  With time, risk of endometrial cancer may be doubled to quadrupled, which is a reason tamoxifen is typically only used for five years. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3239", "text": "The  American Cancer Society  lists tamoxifen as a known  carcinogen , stating that it increases the risk of some types of uterine cancer while lowering the risk of breast cancer recurrence. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3240", "text": "Tamoxifen treatment of postmenopausal women is associated with beneficial effects on serum lipid profiles. However, long-term data from clinical trials have failed to demonstrate a cardioprotective effect. [ 52 ]  For some women, tamoxifen can cause a rapid increase in  triglyceride  concentration in the blood. In addition, there is an increased risk of  thromboembolism  especially during and immediately after major surgery or periods of immobility. [ 53 ]  Use of tamoxifen has been shown to slightly increase risk of  deep vein thrombosis ,  pulmonary embolism , and  stroke . [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3241", "text": "Tamoxifen has been associated with a number of cases of  hepatotoxicity . [ 55 ]  Several different varieties of hepatotoxicity have been reported. [ 55 ]  Tamoxifen can also precipitate  non-alcoholic fatty liver disease  in obese and overweight women (not in normal weight women) at an average rate of 40% after a year use with 20\u00a0mg/day. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3242", "text": "Acute  overdose  of tamoxifen has not been reported in humans. [ 12 ]  In  dose-ranging studies , tamoxifen was administered at very high doses in women (e.g., 300\u00a0mg/m 2 ) and was found to produce acute  neurotoxicity  including  tremor ,  hyperreflexia ,  unsteady gait , and  dizziness . [ 12 ]  These symptoms occurred within three to five days of therapy and disappeared within two to five days of discontinuation of therapy. [ 12 ]  No indications of permanent neurotoxicity were observed. [ 12 ]   QT prolongation  was also observed with very high doses of tamoxifen. [ 12 ]  There is no specific  antidote  for overdose of tamoxifen. [ 12 ]  Instead, treatment should be based on  symptoms . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3243", "text": "Patients with variant forms of the gene  CYP2D6  may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolites. [ 57 ] [ 58 ]  On 18 October 2006, the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert. [ 59 ]  Certain CYP2D6 variations in breast cancer patients lead to a worse clinical outcome for tamoxifen treatment. [ 60 ]   Genotyping  therefore has the potential for identification of women who have these CYP2D6 phenotypes and for whom the use of tamoxifen is associated with poor outcomes. Recent research has shown that 7\u201310% of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their genetic make-up. DNA Drug Safety Testing can examine DNA variations in the CYP2D6 and other important drug processing pathways. More than 20% of all clinically used medications are metabolized by CYP2D6 and knowing the CYP2D6 status of a person can help the doctor with the future selection of medications. [ 61 ]  Other molecular biomarkers may also be used to select appropriate patients likely to benefit from tamoxifen. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3244", "text": "Recent studies suggest that taking the  selective serotonin reuptake inhibitors  (SSRIs) antidepressants  paroxetine  (Paxil),  fluoxetine  (Prozac), and  sertraline  (Zoloft) can decrease the effectiveness of tamoxifen, as these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into its active forms. [ 63 ]  A U.S. study presented at the American Society of Clinical Oncology's annual meeting in 2009 found that after two years, 7.5% of women who took only tamoxifen had a recurrence, compared with 16% who took either paroxetine, fluoxetine or sertraline, drugs considered to be the most potent CYP2D6 inhibitors. That difference translates to a 120% increase in the risk of breast cancer recurrence. Patients taking the SSRIs Celexa ( citalopram ), Lexapro ( escitalopram ), and Luvox ( fluvoxamine ) did not have an increased risk of recurrence, due to their lack of competitive metabolism for the CYP2D6 enzyme. [ 64 ]  A newer study demonstrated a clearer and stronger effect from paroxetine in causing the worst outcomes. Patients treated with both paroxetine and tamoxifen have a 67% increased risk of death from breast cancer, from 24% to 91%, depending on the duration of coadministration. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3245", "text": "Tamoxifen interacts with certain other  antiestrogens . [ 5 ]  The  aromatase inhibitor   aminoglutethimide  induces the metabolism of tamoxifen. [ 5 ]  Conversely, the aromatase inhibitor  letrozole  does not affect the metabolism of tamoxifen. [ 5 ]  However, tamoxifen induces the metabolism of letrozole and significantly reduces its concentrations. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3246", "text": "Tamoxifen acts as a  selective estrogen receptor modulator  (SERM), or as a  partial agonist  of the  estrogen receptors  (ERs). It has mixed  estrogenic  and  antiestrogenic  activity, with its profile of effects differing by  tissue . For instance, tamoxifen has predominantly antiestrogenic effects in the  breasts  but predominantly estrogenic effects in the  uterus  and  liver . In breast tissue, tamoxifen acts as an ER  antagonist  so that  transcription  of estrogen-responsive genes is inhibited. [ 67 ]  A beneficial side effect of tamoxifen is that it prevents bone loss by acting as an ER  agonist  (i.e., mimicking the effects of estrogen) in this cell type. Therefore, by inhibiting  osteoclasts , it prevents  osteoporosis . [ 68 ] [ 69 ]  When tamoxifen was launched as a drug, it was thought that tamoxifen would act as an ER antagonist in all tissues, including bone, and therefore it was feared that it would contribute to osteoporosis. It was therefore very surprising that the opposite effect was observed clinically. Hence tamoxifen's tissue selective action directly led to the formulation of the concept of SERMs. [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3247", "text": "Tamoxifen is a long-acting SERM, with a  nuclear retention  of the ER\u2013tamoxifen (or metabolite) complex of greater than 48\u00a0hours. [ 71 ] [ 72 ]  It has relatively little  affinity  for the ERs itself and instead acts as a  prodrug  of  active metabolites  such as  endoxifen  (4-hydroxy- N -desmethyltamoxifen) and  afimoxifene  (4-hydroxytamoxifen; 4-OHT). [ 9 ]  These metabolites have approximately 30 to 100 times greater affinity for the ERs than tamoxifen itself. [ 8 ] [ 73 ]  Per one study, tamoxifen had 7% and 6% of the affinity of  estradiol  for the  ER\u03b1  and  ER\u03b2 , respectively, whereas afimoxifene had 178% and 338% of the affinity of estradiol for the ER\u03b1 and ER\u03b2, respectively. [ 74 ]  Hence, afimoxifene showed 25-fold higher affinity for the ER\u03b1 and 56-fold higher affinity for the ER\u03b2 than tamoxifen. [ 75 ]  The antiestrogenic potencies of endoxifen and afimoxifene are very similar. [ 9 ]  However, endoxifen occurs in much higher concentrations than afimoxifene and is now thought to be the major active form of tamoxifen in the body. [ 8 ] [ 9 ] [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3248", "text": "Tamoxifen binds to ER competitively (with respect to the endogenous agonist estrogen) in tumor cells and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for  binding sites  in breast and other tissues. Tamoxifen causes cells to remain in the G 0  and G 1  phases of the  cell cycle . Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal. Tamoxifen binds to ER, the ER/tamoxifen complex recruits other proteins known as  co-repressors , and the complex then binds to DNA to modulate gene expression. Some of these proteins include  NCoR  and  SMRT . [ 77 ]  Tamoxifen function can be regulated by a number of different variables including growth factors. [ 78 ]  Tamoxifen needs to block growth factor proteins such as  ErbB2/HER2 [ 79 ]  because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers. [ 80 ]  Tamoxifen seems to require a protein  PAX2  for its full anticancer effect. [ 79 ] [ 81 ]  In the presence of high PAX2 expression, the tamoxifen/ER complex is able to suppress the expression of the pro-proliferative  ERBB2  protein. In contrast, when  AIB-1  expression is higher than PAX2, tamoxifen/ER complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth. [ 79 ] [ 82 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3249", "text": "Tamoxifen is  antigonadotropic  in  postmenopausal  women and partially suppresses levels of the  gonadotropins ,  luteinizing hormone  (LH) and  follicle-stimulating hormone  (FSH) in such women. [ 83 ]  However, it has  progonadotropic  effects in  premenopausal  women and increases estrogen levels by 6-fold in them. [ 83 ]  Due to the nature of tamoxifen as a competitive ER ligand, this increase in estrogen levels is liable to interfere with the antiestrogenic efficacy of tamoxifen. [ 83 ]  The effects of tamoxifen on  breast cancer   Ki-67   expression ,  sex hormone-binding globulin  (SHBG) levels, and IGF-1 levels are  dose-dependent  across a dosage range of 1 to 20\u00a0mg/day in women with breast cancer. [ 84 ]  Tamoxifen has been found to decrease  insulin-like growth factor 1  (IGF-1) levels by 17 to 38% in women and men. [ 85 ]  Suppression of IGF-1 production in the liver is a well-known action of estrogens and SERMs. [ 85 ]  A 10\u00a0mg/day dosage of tamoxifen is nearly as effective as a 20\u00a0mg/day dosage in suppressing IGF-1 levels. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3250", "text": "Afimoxifene is an  agonist  of the  G protein-coupled estrogen receptor  (GPER) with relatively low  affinity . [ 86 ]  Its affinity for the receptor is in the range of 100 to 1,000\u00a0nM, relative to 3 to 6\u00a0nM for estradiol. [ 86 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3251", "text": "In addition to its activity as a SERM, afimoxifene binds to both the  estrogen-related receptor \u03b2  and  estrogen-related receptor \u03b3  and is an antagonist of the  estrogen-related receptor \u03b3  (ERR\u03b3). [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3252", "text": "Norendoxifen  (4-hydroxy- N , N -didesmethyltamoxifen), another  active metabolite  of tamoxifen, has been found to act as a  potent   competitive   aromatase inhibitor  ( IC 50  = 90\u00a0nM), and may also be involved in the antiestrogenic activity of tamoxifen. [ 88 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3253", "text": "In addition to its activity as a SERM, tamoxifen is a  potent  and  selective   protein kinase C   inhibitor , and is active in this regard at therapeutic concentrations. [ 89 ]  This action is thought to underlie the efficacy of tamoxifen in the treatment of  bipolar disorder . [ 89 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3254", "text": "Tamoxifen is an inhibitor of  P-glycoprotein . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3255", "text": "In 2018, it was discovered that tamoxifen directly interacts with the  dopamine transporter  (DAT) and acts as an atypical  dopamine reuptake inhibitor  (DRI). [ 90 ] [ 91 ]  It has weak  potency  (54% inhibition of dopamine uptake at 10 \u00a0 \u03bcM) and lacks any  stimulant  or  depressant  effects when administered by itself. [ 90 ] [ 91 ]  However, tamoxifen  dose-dependently  blocks  amphetamine -mediated  dopamine release  and psychostimulant-like effects in animals. [ 90 ] [ 91 ]  This unusual profile of DRI activity has made tamoxifen of potential interest as a starting point for  structural modification  to develop novel pharmaceutical drugs for treatment of  stimulant use disorder . [ 90 ] [ 91 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3256", "text": "Tamoxifen is rapidly and extensively  absorbed  from the  intestines  with  oral administration . [ 5 ] [ 6 ]  The  oral   bioavailability  of tamoxifen is approximately 100%, which is suggestive of minimal  first-pass metabolism  in the intestines and  liver . [ 5 ]  Following intake,  peak levels  of tamoxifen occur after three to seven hours. [ 92 ] [ 5 ]   Steady state levels  of tamoxifen are reached typically after 3 to 4\u00a0weeks but possibly up to 16\u00a0weeks of daily administration. [ 5 ] [ 11 ]  Steady state levels of afimoxifene are achieved after 8\u00a0weeks of daily tamoxifen administration. [ 11 ] [ 7 ]  Peak levels of tamoxifen after a single 40\u00a0mg oral dose were 65\u00a0ng/mL and steady state levels at 20\u00a0mg/day were 310\u00a0ng/mL. [ 5 ]  Levels of tamoxifen show clear  dose dependency  across a dosage range of 1 to 20\u00a0mg/day. [ 5 ] [ 93 ]  Endoxifen levels are approximately 5 to 10 times higher than afimoxifene levels, with large  interindividual variability . [ 8 ] [ 9 ]  Endoxifen levels have been reported as 10.8 to 15.9\u00a0ng/mL at steady state in  CYP2D6  normal metabolizers during therapy with 20\u00a0mg/day tamoxifen. [ 8 ]  The most abundant  metabolites  of tamoxifen in terms of circulating concentrations are  N -desmethyltamoxifen ,  N , N -didesmethyltamoxifen ,  ( Z )-endoxifen , and tamoxifen  N -oxide. [ 10 ] [ 94 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3257", "text": "The  volume of distribution  of tamoxifen is 50 to 60\u00a0L/kg and its  clearance  has been estimated as 1.2 to 5.1\u00a0L/hour. [ 5 ] [ 92 ]  High concentrations of tamoxifen have been found in  breast ,  uterus , liver,  kidney ,  lung ,  pancreas , and  ovary  tissue in animals and humans. [ 5 ]  Levels of tamoxifen in the uterus have been found to be 2- to 3-fold higher than in the circulation [ 5 ]  and in the breasts 10-fold higher than in the circulation. [ 93 ]  The  plasma protein binding  of tamoxifen and afimoxifene is greater than 99%. [ 7 ]  A majority of tamoxifen is bound to  albumin . [ 5 ]  Albumin alone binds 98.8% of tamoxifen while other  plasma proteins  are not greatly involved. [ 95 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3258", "text": "Tamoxifen is a  prodrug  and is  metabolized  in the  liver  by the  cytochrome P450   isoforms   CYP3A4 ,  CYP2C9 , and  CYP2D6  into  active metabolites  such as  endoxifen  (4-hydroxy- N -desmethyltamoxifen) and  afimoxifene  (4-hydroxytamoxifen). [ 5 ] [ 12 ] [ 8 ]  Conversion of tamoxifen by  N -demethylation into  N -desmethyltamoxifen , which is catalyzed primarily by CYP3A4 and  CYP3A5 , is responsible for approximately 92% of tamoxifen metabolism. [ 9 ]  Conversely, 4-hydroxylation of tamoxifen into afimoxifene is responsible for only about 7% of tamoxifen metabolism. [ 9 ]  Following its formation,  N -desmethyltamoxifen is  oxidized  into several other metabolites, the most notable of which is endoxifen. [ 9 ]  Another active metabolite,  norendoxifen  (4-hydroxy- N , N -didesmethyltamoxifen), is formed via  N -demethylation of endoxifen or 4-hydroxylation of  N , N -didesmethyltamoxifen . [ 8 ]  Tamoxifen and its metabolites undergo  conjugation , including  glucuronidation  and  sulfation . [ 11 ]  Tamoxifen may inhibit its own metabolism. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3259", "text": "Tamoxifen has a long  elimination half-life  of typically 5 to 7\u00a0days, with a range of 4 to 11\u00a0days. [ 5 ] [ 8 ] [ 92 ]  Similarly, the half-life of afimoxifene is 14\u00a0days. [ 7 ]  Conversely, the half-life of  endoxifen  is 50 to 70\u00a0hours (2\u20133\u00a0days). [ 8 ]  The long half-lives of tamoxifen and afimoxifene are attributed to their high plasma protein binding as well as to  enterohepatic recirculation . [ 7 ]  Upon discontinuation of treatment, levels of tamoxifen and its metabolites persist in the circulation for at least 6\u00a0weeks. [ 7 ]  Tamoxifen is  excreted  in  bile  and is  eliminated  in  feces , while small amounts are eliminated in  urine . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3260", "text": "Tamoxifen is a  nonsteroidal  SERM of the  triphenylethylene  family and was structurally derived from  diethylstilbestrol -like estrogens and  antiestrogens  such as  chlorotrianisene  and  ethamoxytriphetol . [ 97 ] [ 98 ] [ 99 ] [ 100 ]  Initially,  clomifene  was synthesized, and tamoxifen was developed subsequently. [ 97 ] [ 99 ] [ 100 ]  Tamoxifen is closely related structurally to other triphenylethylenes, such as clomifene,  nafoxidine ,  ospemifene ,  toremifene , and numerous others. [ 101 ] [ 102 ]  Other SERMs, like  raloxifene , are structurally distinct from tamoxifen and other triphenylethylenes. [ 102 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3261", "text": "In the late 1950s, pharmaceutical companies were actively researching a newly discovered class of anti-estrogen compounds in the hope of developing a morning-after contraceptive pill. Arthur L Walpole was a reproductive  endocrinologist  who led such a team at the  Alderley Park  research laboratories of  ICI  Pharmaceuticals. [ 18 ]  It was there in 1962 that chemist Dora Richardson first synthesized tamoxifen, back then known as ICI-46,474, when she was looking to create triphenylethylene derivatives for the contraceptive pill project that her team was researching. [ 103 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3262", "text": "This compound was originally created to work as an estrogen inhibitor, but instead was found to stimulate ovulation in participants of the drug testing trial. [ 17 ]  Walpole and his colleagues filed a UK patent covering this compound in 1962, but patent protection on this compound was repeatedly denied in the US until the 1980s. [ 104 ]  Tamoxifen did eventually receive marketing approval as a fertility treatment, but the class of compounds never proved useful in human contraception. A link between estrogen and breast cancer had been known for many years, but cancer treatments were not a corporate priority at the time, and Walpole's personal interests were important in keeping support for the compound alive in the face of this and the lack of patent protection. [ 18 ]  It was only when Walpole threatened to leave his position that corporate decided to allow trials and testing for tamoxifen as a drug that could be used to treat breast cancer. Without Walpole's effort towards defending the work that his team had done in discovering a possibly revolutionary source for breast cancer treatment, tamoxifen could have become a discarded or under-researched idea. Walpole's team consisted of Dora Richardson and G. A. Snow, who worked on the chemistry portion of the project, along with G. E. Paget and J. K. Walley, who focused primarily on the biological side. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3263", "text": "Tamoxifen is one of three drugs in an  anti-angiogenetic  protocol developed by  Dr. Judah Folkman , a researcher at Children's Hospital at Harvard Medical School in Boston. Folkman discovered in the 1970s that  angiogenesis  \u2013 the growth of new blood vessels \u2013 plays a significant role in the development of cancer. Since his discovery, an entirely new field of cancer research has developed. Clinical trials on  angiogenesis inhibitors  have been underway since 1992 using many different drugs. The Harvard researchers developed a specific protocol for a golden retriever named Navy who was cancer-free after receiving the prescribed cocktail of  celecoxib ,  doxycycline , and tamoxifen \u2013 the treatment subsequently became known as the Navy Protocol. [ 105 ]  Furthermore, tamoxifen treatment alone has been shown to have anti-angiogenetic effects in animal models of cancer which appear to be, at least in part, independent of tamoxifen's ER antagonist properties. [ 106 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3264", "text": "Other antiestrogens, such as  ethamoxytriphetol  (MER-25) and  clomifene  (MRL-41), were assessed for treatment of breast cancer and found to be effective before tamoxifen, but were plagued with  toxicity  issues. [ 107 ] [ 108 ]  The first clinical study of tamoxifen took place at the  Christie Hospital  in 1971, and showed a convincing effect in advanced breast cancer, but nevertheless ICI's development programme came close to termination when it was reviewed in 1972. [ 109 ]  In an unpublished article from the early days of the trial, Dora Richardson documented her team's excitement about tamoxifen's effects in counteracting infertility problems and the early positive effects found in breast cancer patients. Unfortunately, this work was not well received by everyone, as the team was supposed to be looking for a contraceptive pill. [ 17 ]  Tamoxifen's further development may have been bolstered by a second clinical study by Harold W.C. Ward  [ 110 ]  at the  Queen Elizabeth Hospital, Birmingham . Ward's study showed a more definitive response to the drug at a higher dosage. Walpole also may have helped to convince the company to market tamoxifen for late stage breast cancer in 1973. [ 104 ]  He was also instrumental in funding  V. Craig Jordan  to work on tamoxifen. In 1972, ICI Pharmaceuticals Division abandoned development of tamoxifen for financial reasons. The drug was subsequently reinvented from a failed contraceptive, to become tamoxifen, the gold standard for the adjuvant treatment of breast cancer and the pioneering medicine for chemprevention for high-risk women. [ 111 ] [ 112 ]  Two books,  Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health  (Imperial College Press 2013) and  Tamoxifen: Pioneering Medicine in Breast Cancer  (Springer 2013) tell this story."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3265", "text": "1980 saw the publication of the first trial to show that tamoxifen given in addition to chemotherapy improved survival for patients with early breast cancer. [ 114 ]  In advanced disease, tamoxifen is now only recognized as effective in ER+ patients, but the early trials did not select ER+ patients, and by the mid-1980s the clinical trial picture was not showing a major advantage for tamoxifen. [ 115 ]  Nevertheless, tamoxifen had a relatively mild side-effect profile, and a number of large trials continued."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3266", "text": "The pharmacology of SERMs was discovered, defined, and deciphered during the 1980s. [ 116 ]  A clinical strategy was described [ 117 ]  that led to the creation of SERMs as a group of multifunctional medicines aimed at the treatment or prevention of many conditions in postmenopausal women, e.g. osteoporosis and breast cancer. [ 118 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3267", "text": "The early sales of tamoxifen in both the UK and in the U.S. far exceeded ICI's original estimate, but despite this, at the annual portfolio review ICI's board members still asserted that \"there was no market for cancer\", leaving the drug's marketing success to rely on its clinical results and clinicians' and scientists' interests in it. Shortly after, Dora Richardson published a history of tamoxifen that, unusually for that type of paper, included personal accounts and letters from patients who attributed their healing to the drug. This testimony from cancer patients using tamoxifen helped to shape and push forward research, by justifying it both morally and scientifically to corporations. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3268", "text": "It was not until 1998 that the meta-analysis of the Oxford-based Early Breast Cancer Trialists' Collaborative Group showed definitively that tamoxifen was effective for early breast cancer. [ 119 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3269", "text": "Tamoxifen is marketed under the brand names Nolvadex and Soltamox, and a variety of other brand names throughout the world. [ 1 ] [ 120 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3270", "text": "Global sales of tamoxifen in 2001 were approximately $1.02 billion. [ 121 ]  Since the expiration of the patent in 2002, it is widely available as a  generic drug  around the world. As of 2004 [update] , tamoxifen was the world's largest selling hormonal drug for the treatment of breast cancer. [ 122 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3271", "text": "In  McCune-Albright syndrome  (MAS) tamoxifen has been used to treat  premature puberty  and the consequences of premature puberty. Tamoxifen has been seen to decrease rapid  bone maturation  which is the result of  excessive estrogen  and alter predicted adult height (PAH). [ 123 ] [ 124 ]  The same effects have also been seen in short pubertal boys. [ 125 ]  However, one  in vitro  study in 2007 and later an  in vivo  study in 2008 have shown that tamoxifen induces apoptosis in growth plate chondrocytes, reduces serum  insulin-like growth factor 1  (IGF-1) levels and causes persistent retardation of longitudinal and cortical radial bone growth in young male rats, leading the researchers to express concern giving tamoxifen to growing individuals. [ 126 ] [ 127 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3272", "text": "Tamoxifen has been studied in the treatment of the rare conditions of  retroperitoneal fibrosis [ 128 ]  and  idiopathic sclerosing mesenteritis . [ 129 ]  It has also been proposed as part of a treatment plan for  Riedel's thyroiditis . [ 130 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3273", "text": "Tamoxifen is used as a research tool to trigger tissue-specific gene expression in many conditional expression constructs in  genetically modified animals  including a version of the  Cre-Lox recombination  technique. [ 131 ]  While widely used in transgenic research, the strong anabolic effect of tamoxifen on bone might confound this approach, especially as it relates to bone-targeted constructs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3274", "text": "Tamoxifen may be effective in the treatment of  mania  in people with  bipolar disorder . [ 132 ]  This is thought to be due to blockade of  protein kinase C  (PKC), an  enzyme  that regulates  neuron  activity in the  brain . [ 132 ] [ 133 ]  Researchers believe PKC is overactive during the mania in bipolar patients. [ 132 ] [ 133 ]  As of September 2019 [update] ,  endoxifen , a major active metabolite of tamoxifen with a 4-fold more potent PKC inhibition, was in  phase III  clinical trials for bipolar disorder. [ 134 ] [ 135 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3275", "text": "The  FDA   animal efficacy rule  (also known as  animal rule ) applies to  development  and testing of  drugs  and  biologicals  to reduce or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic agents ( chemical ,  biological ,  radiological , or nuclear substances), where human efficacy  trials  are not feasible or  ethical . [ 1 ]  The animal efficacy rule was finalized by the FDA and authorized by the  United States Congress  in 2002, following the  September 11 attacks  and concerns regarding  bioterrorism . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3276", "text": "The FDA can rely on evidence from  animal studies  to provide substantial evidence of product effectiveness if:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3277", "text": "FDA published a  Guidance for Industry  on the Animal Rule in October 2015. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3278", "text": "A  biopharmaceutical , also known as a  biological medical product , [ 1 ]  or  biologic , is any  pharmaceutical drug  product manufactured in, extracted from, or  semisynthesized  from  biological  sources. Different from  totally synthesized  pharmaceuticals, they include  vaccines ,  whole blood , blood components,  allergenics ,  somatic cells ,  gene therapies ,  tissues ,  recombinant therapeutic protein , and  living medicines  used in  cell therapy . Biologics can be composed of  sugars ,  proteins ,  nucleic acids , or complex combinations of these substances, or may be living cells or tissues. They (or their  precursors  or components) are isolated from  living  sources\u2014human, animal, plant, fungal, or microbial. They can be used in both human and animal medicine. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3279", "text": "Terminology surrounding biopharmaceuticals varies between groups and entities, with different terms referring to different subsets of therapeutics within the general biopharmaceutical category. Some  regulatory agencies  use the terms  biological medicinal products  or  therapeutic biological product  to refer specifically to engineered  macromolecular  products like protein- and  nucleic acid -based  drugs , distinguishing them from products like blood, blood components, or vaccines, which are usually extracted directly from a biological source. [ 4 ] [ 5 ] [ 6 ]   Biopharmaceutics  is  pharmaceutics  that works with biopharmaceuticals.  Biopharmacology  is the branch of  pharmacology  that studies biopharmaceuticals.  Specialty drugs , a recent classification of pharmaceuticals, are high-cost drugs that are often biologics. [ 7 ] [ 8 ] [ 9 ]  The  European Medicines Agency  uses the term  advanced therapy medicinal products  (ATMPs) for medicines for human use that are \"based on genes, cells, or tissue engineering\", [ 10 ]  including gene therapy medicines, somatic-cell therapy medicines, tissue-engineered medicines, and combinations thereof. [ 11 ]  Within EMA contexts, the term  advanced therapies  refers specifically to ATMPs, although that term is rather nonspecific outside those contexts."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3280", "text": "Gene-based and cellular biologics, for example, often are at the forefront of  biomedicine  and  biomedical research , and may be used to treat a variety of medical conditions for which no other treatments are available. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3281", "text": "Building on the market approvals and sales of recombinant virus-based biopharmaceuticals for veterinary and human medicine, the use of engineered plant viruses has been proposed to enhance crop performance and promote sustainable production. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3282", "text": "In some jurisdictions, biologics are regulated via different pathways from other small molecule drugs and  medical devices . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3283", "text": "Some of the oldest forms of biologics are extracted from the bodies of animals, and other humans especially. Important biologics include: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3284", "text": "Some biologics that were previously extracted from animals, such as insulin, are now more commonly produced by  recombinant DNA ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3285", "text": "Biologics  can refer to a wide range of biological products in medicine. However, in most cases, the term is used more restrictively for a class of therapeutics (either approved or in development) that are produced using biological processes involving  recombinant DNA  technology. These medications are usually one of three types:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3286", "text": "Biologics as a class of medications in this narrower sense have had a profound impact on many medical fields, primarily  rheumatology  and  oncology , but also  cardiology ,  dermatology ,  gastroenterology ,  neurology , and others. In most of these disciplines, biologics have added major therapeutic options for treating many diseases, including some for which no effective therapies were available, and others where previously existing therapies were inadequate. However, the advent of biologic therapeutics has also raised complex regulatory issues (see below), and significant pharmacoeconomic concerns because the cost for biologic therapies has been dramatically higher than for conventional (pharmacological) medications. This factor has been particularly relevant since many biological medications are used to treat  chronic diseases , such as rheumatoid arthritis or inflammatory bowel disease, or for the treatment of otherwise untreatable cancer during the remainder of life. The cost of treatment with a typical monoclonal antibody therapy for relatively common indications is generally in the range of \u20ac7,000\u201314,000 per patient per year."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3287", "text": "Older patients who receive biologic therapy for diseases such as  rheumatoid arthritis ,  psoriatic arthritis , or  ankylosing spondylitis  are at increased risk for life-threatening infection, adverse cardiovascular events, and  malignancy . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3288", "text": "The first such substance approved for therapeutic use was biosynthetic \"human\"  insulin  made via  recombinant DNA . Sometimes referred to as rHI, under the  trade name   Humulin , was developed by  Genentech , but licensed to  Eli Lilly and Company , who manufactured and marketed it starting in 1982."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3289", "text": "Major kinds of biopharmaceuticals include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3290", "text": "Research and development investment in new medicines by the biopharmaceutical industry stood at $65.2 billion in 2008. [ 16 ]  A few examples of biologics made with  recombinant DNA  technology include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3291", "text": "Many vaccines are grown in tissue cultures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3292", "text": "Viral gene therapy  involves artificially manipulating a  virus  to include a desirable piece of genetic material."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3293", "text": "Viral gene therapies using engineered plant viruses have been proposed to enhance crop performance and promote sustainable production. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3294", "text": "With the expiration of many  patents  for  blockbuster biologics  between 2012 and 2019, the interest in biosimilar production, i.e., follow-on biologics, has increased. [ 17 ]  Compared to  small molecules  that consist of chemically identical  active ingredients , biologics are vastly more complex and consist of a multitude of subspecies. Due to their heterogeneity and the high process sensitivity, originators and follow-on biosimilars will exhibit variability in specific variants over time. The safety and clinical performance of both originator and biosimilar biopharmaceuticals must remain equivalent throughout their lifecycle. [ 18 ] [ 19 ]  Process variations are monitored by modern analytical tools (e.g.,  liquid chromatography ,  immunoassays ,  mass spectrometry , etc.) and describe a unique design space for each biologic. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3295", "text": "Biosimilars require a different regulatory framework compared to small-molecule generics. Legislation in the 21st century has addressed this by recognizing an intermediate ground of testing for biosimilars. The filing pathway requires more testing than for small-molecule generics, but less testing than for registering completely new therapeutics. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3296", "text": "In 2003, the  European Medicines Agency  introduced an adapted pathway for biosimilars, termed  similar biological medicinal products . This pathway is based on a thorough demonstration of comparability of the product to an existing approved product. [ 21 ]  Within the United States, the  Patient Protection and Affordable Care Act  of 2010 created an abbreviated approval pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed reference biological product. [ 20 ] [ 22 ]  Researchers are optimistic that the introduction of biosimilars will reduce medical expenses to patients and the healthcare system. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3297", "text": "When a new biopharmaceutical is developed, the company will typically apply for a  patent , which is a grant to exclusive manufacturing rights. This is the primary means by which the drug developer can recover the investment cost for development of the biopharmaceutical. The  patent laws  in the  United States  and  Europe  differ somewhat on the requirements for a patent, with the European requirements perceived as more difficult to satisfy. The total number of patents granted for biopharmaceuticals has risen significantly since the 1970s. In 1978 the total patents granted was 30. This had climbed to 15,600 in 1995, and by 2001 there were 34,527 patent applications. [ 23 ]  In 2012 the US had the highest IP (Intellectual Property) generation within the biopharmaceutical industry, generating 37 percent of the total number of granted patents worldwide; however, there is still a large margin for growth and innovation within the industry. Revisions to the current IP system to ensure greater reliability for R&D (research and development) investments is a prominent topic of debate in the US as well. [ 24 ]  Blood products and other human-derived biologics such as breast milk have highly regulated or very hard-to-access markets; therefore, customers generally face a supply shortage for these products. Institutions housing these biologics, designated as 'banks', often cannot distribute their product to customers effectively. [ 25 ]  Conversely, banks for reproductive cells are much more widespread and available due to the ease with which  spermatozoa  and  egg cells  can be used for fertility treatment. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3298", "text": "Biopharmaceuticals may be produced from microbial cells (e.g., recombinant  E. coli  or yeast cultures), mammalian cell lines (see  Cell culture ) and plant cell cultures (see  Plant tissue culture ) and  moss  plants in  bioreactors  of various configurations, including  photo-bioreactors . [ 27 ]  Important issues of concern are cost of production (low-volume, high-purity products are desirable) and microbial contamination (by  bacteria ,  viruses ,  mycoplasma ). Alternative platforms of production which are being tested include whole plants ( plant-made pharmaceuticals )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3299", "text": "A potentially controversial method of producing biopharmaceuticals involves  transgenic  organisms, particularly plants and animals that have been  genetically modified  to produce drugs. This production is a significant risk for its investor due to production failure or scrutiny from regulatory bodies based on perceived risks and ethical issues. Biopharmaceutical crops also represent a risk of cross-contamination with non-engineered crops, or crops engineered for non-medical purposes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3300", "text": "One potential approach to this technology is the creation of a transgenic mammal that can produce the biopharmaceutical in its milk, blood, or urine. Once an animal is produced, typically using the  pronuclear microinjection  method, it becomes efficacious to use cloning technology to create additional offspring that carry the favorable modified genome. [ 28 ]  The first such drug manufactured from the milk of a genetically modified  goat  was  ATryn , but marketing permission was blocked by the  European Medicines Agency  in February 2006. [ 29 ]  This decision was reversed in June 2006 and approval was given August 2006. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3301", "text": "In the  European Union , a biological medicinal product [ 31 ]  is one of the active substance(s) produced from or extracted from a biological (living) system, and requires, in addition to physicochemical testing, biological testing for full characterisation. The characterisation of a biological medicinal product is a combination of testing the active substance and the final medicinal product together with the production process and its control. For example:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3302", "text": "In the  United States , biologics are licensed through the biologics license application (BLA), then submitted to and regulated by the FDA's  Center for Biologics Evaluation and Research  (CBER) whereas drugs are regulated by the  Center for Drug Evaluation and Research . Approval may require several years of  clinical trials , including trials with human volunteers. Even after the drug is released, it will still be monitored for performance and safety risks. The manufacture process must satisfy the FDA's \"Good Manufacturing Practices\", which are typically manufactured in a  cleanroom  environment with strict limits on the amount of airborne particles and other microbial contaminants that may alter the efficacy of the drug. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3303", "text": "In  Canada , biologics (and radiopharmaceuticals) are reviewed through the Biologics and Genetic Therapies Directorate within  Health Canada . [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3304", "text": "Stromagen  is a product that is made of  stem cells  taken from a patient's  bone marrow  and grown in the laboratory. After a patient's bone marrow is destroyed by treatment with whole body  irradiation  or  chemotherapy , these cells are injected back into the patient to help rebuild bone marrow. Stromagen has been studied in the prevention of  graft-versus-host disease  during stem cell transplant in patients receiving  treatment  for  cancer . Stromagen is used in cellular therapy. Also called  autologous  expanded  mesenchymal stem cells  OTI-010. [ 1 ] [ 2 ]  Peripheral stem cell transplantation may allow doctors to give higher doses of chemotherapy and kill more tumor cells. It is not yet known whether Stromagen improves the success of stem cell transplantation in women with breast cancer. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3305", "text": "Bacterial therapy  is the  therapeutic  use of  bacteria  to treat  diseases . Bacterial therapeutics are  living medicines , and may be  wild type  bacteria (often in the form of  probiotics ) or bacteria that have been  genetically engineered  to possess  therapeutic  properties that is injected into a patient. [ 2 ] [ 3 ] \nOther examples of living medicines include  cellular therapeutics  (including  immunotherapeutics ), activators of anti-tumor immunity, or synergizing with existing tools and approaches. and  phage therapeutics , or as delivery vehicles for treatment, diagnosis, or imaging, complementing or synergizing with existing tools and approaches."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3306", "text": "Development of bacterial therapeutics is an extremely active research area in the fields of  synthetic biology  and  microbiology . [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 1 ] [ 10 ] [ 11 ]  Currently, there is a large focus on: 1) identifying bacteria that naturally produce therapeutic effects (for example, probiotic bacteria), and 2)  genetically programming  bacteria to produce therapeutic effects. [ 12 ] [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3307", "text": "Optimal strain design often requires a balance between strain suitability for function in the target microenvironment and concerns for feasibility of manufacturing and clinical development. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3308", "text": "The development workflow should incorporate technologies for optimizing strain potency, as well as predictive in vitro and in vivo assays, as well quantitative pharmacology models, to maximize translational potential for patient populations. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3309", "text": "There is tremendous interest in using bacteria as a therapy to treat tumors. In particular,  tumor-homing bacteria  that thrive in  hypoxic  environments are particularly attractive for this purpose, as they will tend to migrate to, invade (through the  leaky vasculature  in the  tumor microenvironment ) and  colonize  tumors. This property tends to increase their residence time in the tumor, giving them longer to exert their therapeutic effects, in contrast to other bacteria that would be quickly cleared by the immune system. [ 15 ] [ 16 ] [ 17 ]  In addition, colonized bacteria can lyze the tumor, activate anti-tumor immune response, can be engineered as a delivery vehicle for anti-cancer therapeutics and may have the potential as  contrast agents  for cancer imaging. Microbial-based cancer therapy may offer an opportunity to address the issue of global cancer therapy disparity and introduce more suitable cancer immunotherapy approach to low- and middle-income countries. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3310", "text": "After systemic administration, bacteria localize to the tumor microenvironment. The interactions between bacteria, cancer cells, and the surrounding microenvironment cause various alterations in  tumor-infiltrating immune cells , cytokines, and chemokines, which further facilitate tumor regression. \u2460 Bacterial toxins from S. Typhimurium, Listeria, and Clostridium can kill tumor cells directly by inducing apoptosis or autophagy. Toxins delivered via Salmonella can upregulate Connexin 43 (Cx43), leading to bacteria-induced gap junctions between the tumor and dendritic cells (DCs), which allow cross-presentation of tumor antigens to the DCs. \u2461 Upon exposure to tumor antigens and interaction with bacterial components, DCs secrete robust amounts of the proinflammatory cytokine IL-1\u03b2, which subsequently activates CD8+ T cells. \u2462 The antitumor response of the activated CD8+ T cells is further enhanced by bacterial flagellin (a protein subunit of the bacterial flagellum) via TLR5 activation. The perforin and granzyme proteins secreted by activated CD8+ T cells efficiently kill tumor cells in primary and metastatic tumors. \u2463 Flagellin and TLR5 signaling also decreases the abundance of CD4+ CD25+ regulatory T (Treg) cells, which subsequently improves the antitumor response of the activated CD8+ T cells. \u2464 S. Typhimurium flagellin stimulates NK cells to produce interferon-\u03b3 (IFN-\u03b3), an important cytokine for both innate and adaptive immunity. \u2465 Listeria-infected MDSCs shift into an immune-stimulating phenotype characterized by increased IL-12 production, which further enhances the CD8+ T and NK cell responses. \u2466 Both S. Typhimurium and Clostridium infection can stimulate significant neutrophil accumulation. Elevated secretion of TNF-\u03b1 and TNF-related apoptosis-inducing ligand (TRAIL) by neutrophils enhances the immune response and kills tumor cells by inducing apoptosis. \u2467 The macrophage inflammasome is activated through contact with bacterial components (LPS and flagellin) and Salmonella-damaged cancer cells, leading to elevated secretion of IL-1\u03b2 and TNF-\u03b1 into the tumor microenvironment. NK cell: natural killer cell. Treg cell: regulatory T cell. MDSCs: myeloid-derived suppressor cells. P2X7 receptor: purinoceptor 7-extracellular ATP receptor. LPS: lipopolysaccharide [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3311", "text": "Alterations in the gut microbiome are thought to be associated with  C. difficile infection  and recurrence. [ 19 ]  Therapies include probiotics and  fecal microbiota transplantation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3312", "text": "There is considerable interest in using bacterial therapeutics to alter  human gastrointestinal microbiota  to help diseases like  small intestinal bacterial overgrowth , gut dysbiosis associated with the pathogenesis of food allergy, [ 20 ]  and other forms of  dysbiosis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3313", "text": "Biomanufacturing  (or  bioproduction ) is a type of  manufacturing  or  biotechnology  that utilizes biological systems to produce commercially important  biomaterials  and  biomolecules  for use in  medicines , food and beverage processing, and industrial applications.  Biomanufacturing products are recovered from natural sources, such as blood, or from cultures of  microbes ,  animal cells , or  plant cells  grown in specialized equipment.  The cells used during the production may have been naturally occurring or derived using  genetic engineering  techniques. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3314", "text": "There are thousands of biomanufacturing products on the market today.  Some examples of general classes are listed below:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3315", "text": "A partial listing of unit operations utilized during biomanufacturing includes the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3316", "text": "Equipment and facility requirements are dictated by the product(s) being manufactured. Process equipment is typically constructed of stainless steel or plastic.  Stainless steel equipment can be cleaned and reused.  Some plastic equipment is disposed of after a single use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3317", "text": "Products manufactured for medical or food use must be produced in facilities designed and operated according to   Good Manufacturing Practice (GMP)  regulations.   Cleanrooms  are often required to control the levels of particulates and microorganisms.   Sterilization  and  aseptic  processing equipment are required for production of  injectable  products."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3318", "text": "Skilled professionals are required for positions throughout the life cycle of a biomanufacturing product, which includes:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3319", "text": "Details for some of these positions are listed in \u201cThe Model Employee,\u201d published by the  North Carolina Biotechnology Center . [ 1 ]  In addition, the North Carolina Association for Biomedical Research (NCABR) maintains the website  About Bioscience  that offers free online videos on various careers. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3320", "text": "Several academic institutions have developed curricula and built facilities to provide education and training in biomanufacturing to students from community colleges, universities, and/or industry.    NCBioImpact , established in 2004, is an example of a comprehensive state-wide training network.  Member institutions  Golden LEAF Biomanufacturing Training and Education Center (BTEC)  at  North Carolina State University , (BRITE) at  North Carolina Central University , and  North Carolina Community College System\u2019s  BioNetwork operate multidisciplinary centers dedicated to workforce development for the biomanufacturing industry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3321", "text": "MiraCosta College  and  Solano College  in California developed the first bachelor of science degree in biomanufacturing.  The degree is largely lab-based and is built on a contextualized science and statistics backbone.  The upper division classes recognize the unique environment of biological production where the process sciences and technology thrive in partnership with quality and regulatory compliance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3322", "text": "A  biosimilar  (also known as  follow-on biologic  or  subsequent entry biologic ) is a  biologic medical product  that is almost an identical copy of an original product that is manufactured by a different company. [ 1 ]  Biosimilars are officially approved versions of original \"innovator\" products and can be manufactured when the original product's  patent  expires. [ 2 ]  Reference to the innovator product is an integral component of the approval. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3323", "text": "Unlike with  generic drugs  of the more common  small-molecule  type, biosimilar drugs generally exhibit high molecular complexity and may be quite sensitive to changes in manufacturing processes. Despite this heterogeneity, all  biopharmaceuticals , including biosimilars, must maintain consistent quality and clinical performance throughout their lifecycle. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3324", "text": "Drug-related authorities such as the  European Medicines Agency  (EMA) of the European Union, the United States  Food and Drug Administration  (FDA), and the  Health Products and Food Branch  of  Health Canada  hold their own guidance on requirements for demonstration of the similar nature of two biological products in terms of safety and efficacy. According to them, analytical studies demonstrate that the biological product is highly similar to the reference product, despite minor differences in clinically inactive components, animal studies (including the assessment of toxicity), and a clinical study or studies (including the assessment of  immunogenicity  and  pharmacokinetics  or  pharmacodynamics ). They are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and is intended to be used and for which licensure is sought for the biological product. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3325", "text": "The  World Health Organization  (WHO) published its \"Guidelines for the evaluation of similar biotherapeutic products (SBPs)\" in 2009. The purpose of this guideline is to provide an international norm for evaluating biosimilars. [ 5 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3326", "text": "The EMA has granted marketing authorizations for more than 50 biosimilars since 2006. The first biosimilar of a  monoclonal antibody  to be approved worldwide was a biosimilar of  infliximab  in the EU in 2013. [ 9 ]  On March 6, 2015, the FDA approved the United States' first biosimilar product, the biosimilar of  filgrastim  called filgrastim-sndz (trade name Zarxio) by  Sandoz ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3327", "text": "In the United States, the  Food and Drug Administration  (FDA) held that new legislation was required to enable them to approve biosimilars to those biologics originally approved through the PHS Act pathway. [ 10 ]  Additional Congressional hearings have been held. [ 11 ]  On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House. [ 2 ]  Since 2004 the FDA has held a series of public meetings on biosimilars. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3328", "text": "The FDA gained the authority to approve biosimilars (including interchangeables that are substitutable with their reference product) as part of the  Patient Protection and Affordable Care Act  signed into law by President Obama on March 23, 2010. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3329", "text": "The FDA has previously approved biologic products using comparability, for example,  Omnitrope  in May 2006, but this like  Enoxaparin  was also to a reference product,  Genotropin , originally approved as a  biologic  under the FD&C Act. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3330", "text": "On March 6, 2015,  Zarxio  obtained the first approval of FDA. [ 15 ]  Sandoz's Zarxio is biosimilar to Amgen's Neupogen (filgrastim), which was originally licensed in 1991. This is the first product to be passed under the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), which was passed as part of the Affordable Healthcare Act. But Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. And under the BPCI Act, only a biologic that has been approved as an \"interchangeable\" may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The FDA said its approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates  Zarxio  is biosimilar to Neupogen. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3331", "text": "In March 2020, most protein products that were approved as drug products (including every insulin currently on the market as of December 2019 [update] ) are scheduled to open up to biosimilar and interchangeable competition in the United States. [ 16 ]  However, \"chemically synthesized polypeptides\" are excluded from this transition, which means that a product that falls within this category won't be able to come to market as a biosimilar or interchangeable product, but will have to come to the market under a different pathway. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3332", "text": "Cloning of human genetic material and development of in vitro biological production systems has allowed the production of virtually any  recombinant DNA  based biological substance for eventual development of a drug.  Monoclonal antibody  technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines.  Gene-  and  cell-based  therapies are emerging as new approaches."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3333", "text": "Recombinant therapeutic  proteins  are of a complex nature (composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells (bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are produced: choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3334", "text": "After the expiry of the patent of approved recombinant drugs (e.g.,  insulin , human  growth hormone ,  interferons ,  erythropoietin , monoclonal antibodies and more) any other biotech company can develop and market these  biologics  (thus called biosimilars)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3335", "text": "The typical reference product has undergone numerous changes in its manufacturing processes, and such changes in the manufacturing process (ranging from a change in the supplier of cell culture media to new purification methods or new manufacturing sites) was substantiated with appropriate data and was approved by the EMA."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3336", "text": "The current concept of development of biosimilar  monoclonal antibodies  follows the principle that an extensive state of the art physicochemical, analytical and functional comparison of the molecules is complemented by comparative non-clinical and clinical data that establish equivalent efficacy and safety in a clinical \"model\" indication that is most sensitive to detect any minor differences (if these exist) between the biosimilar and its reference monoclonal antibody also at the clinical level."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3337", "text": "The EMA has recognized this fact, which has resulted in the establishment of the term \"biosimilar\" in recognition that, whilst biosimilar products are similar to the original product, they are not exactly the same. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3338", "text": "Originally the complexity of biological molecules led to requests for substantial efficacy and safety data for a biosimilar approval. This has been progressively replaced with a greater dependence on assays, from quality through to clinical, that show assay sensitivity sufficient to detect any significant difference in dose. [ 18 ]  However, the safe application of biologics depends on an informed and appropriate use by healthcare professionals and patients. Introduction of biosimilars also requires a specifically designed  pharmacovigilance  plan. It is difficult and costly to recreate biologics because the complex proteins are derived from living organisms that are genetically modified. In contrast, small molecule drugs made up of a chemically based compound can be easily replicated and are considerably less expensive to reproduce. In order to be released to the public, biosimilars must be shown to be as close to identical to the parent innovator biologic product based on data compiled through clinical, animal, analytical studies and conformational status. [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3339", "text": "Generally, once a drug is released in the market by the FDA, it has to be re-evaluated for its safety and efficacy once every six months for the first and second years. Afterward, re-evaluations are conducted yearly, and the result of the assessment should be reported to authorities such as FDA. Biosimilars are required to undergo pharmacovigilance (PVG) regulations as its reference product. Thus biosimilars approved by the EMA are required to submit a risk management plan (RMP) along with the marketing application and have to provide regular safety update reports after the product is in the market. The RMP includes the safety profile of the drug and proposes the prospective pharmacovigilance studies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3340", "text": "Several PK studies, such as studies conducted by Committee for Medicinal Products for Human Use (CHMP), have been conducted under various ranges of conditions; Antibodies from an originator's product versus antibodies from a biosimilar; combination therapy and monotherapy; various diseases, etc. on the purpose to verify comparability in pharmacokinetics of the biosimilar with the reference medicinal product in a sufficiently sensitive and homogeneous population."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3341", "text": "In the European Union, no unique identifier of a biosimilar medicine product is required, as the same rules are followed as for all biologics. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3342", "text": "The US decided on a different approach, requiring the assignment of a four-letter suffix to the nonproprietary name of the original product to distinguish between innovator drugs and their biosimilars. [ 21 ]  Japan has similar requirements. [ 22 ]  The suffix approach has been criticized on the grounds of compromising the INN system and delaying the marketing of biosimilars. [ 22 ]  Australia decided not to use a 4-letter suffix. [ 23 ] [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3343", "text": "A version of the four-letter suffix has been proposed to the WHO as the biological qualifier (BQ). It is not part of the  international nonproprietary name  (INN), but is proposed to be managed under the same registry. [ 26 ]  The report 1 of the May 2017 WHO Expert Consultation on Improving Access to and Use of Similar Biotherapeutic Products, published in October 2017, revealed on page 4, that following the outcome arising from the meeting: \"No consensus was reached on whether WHO should continue with the BQ... WHO will not be proceeding with this at present.\" [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3344", "text": "Biosimilars available in Australia include adalimumab, bevacizumab, enoxaparin, epoetin lambda, etanercept, filgrastim, follitropin alfa, infliximab, insulin aspart, insulin glargine, pegfilgrastim, rituximab, teriparatide, and trastuzumab. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3345", "text": "A research article about \"Maximizing the benefits of using biosimilars in Egypt\" proposed a regulatory framework for biosimilars in Egypt. The article summarized the recommendations of a number of stakeholders. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3346", "text": "Biosimilar medicines approved in the European Union (EU) are interchangeable with their reference medicine or with an equivalent biosimilar. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3347", "text": "As of October 2024, the US FDA has approved 60 biosimilars. [ 132 ] [ 133 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3348", "text": "The  Biologics Price Competition and Innovation Act  of 2009 (BPCI Act) was originally sponsored and introduced on June 26, 2007, by Senator  Edward Kennedy  (D-MA). It was formally passed under the  Patient Protection and Affordable Care Act  (PPAC Act), signed into law by President Barack Obama on March 23, 2010. The BPCI Act was an amendment to the Public Health Service Act (PHS Act) to create an abbreviated approval pathway for biological products that are demonstrated to be highly similar (biosimilar) to a  Food and Drug Administration  (FDA) approved biological product. [ 134 ]  The BPCI Act is similar, conceptually, to the Drug Price Competition and Patent Term Restoration Act of 1984 (also referred to as the \"Hatch-Waxman Act\") which created biological drug approval through the Federal Food, Drug, and Cosmetic Act (FFD&C Act). The BPCI Act aligns with the FDA's longstanding policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing. The FDA has released a total of four draft guidelines related to biosimilar or follow-on biologics development. Upon the release of the first three guidance documents the FDA held a public hearing on May 11, 2012. [ 135 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3349", "text": "In 2018, the FDA released a Biosimilars Action Plan to implement regulations from the BPCI, including limiting the abuse of the Risk Evaluation and Mitigation Strategy (REMS) system for  evergreening  and transitioning insulin and human growth hormone to regulation as biologics rather than drugs. [ 136 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3350", "text": "Bovhyaluronidase azoximer , sold under the brand name Longidaze, is a  conjugate  of  proteolytic   enzyme   hyaluronidase  with high- molecular weight  copolymer  that forms a component of combination therapy regimens for treatment and prevention of diseases associated with  connective tissue   hyperplasia . [ 1 ] \nThe most frequently observed adverse reactions seen with bovhyaluronidase azoximer include pain at site of injection and  injection site reactions  such as skin redness, itching and  oedema . Local reactions typically resolve themselves in 48\u201372 hours. [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3351", "text": "Type: Hyaluronidases"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3352", "text": "Other names: hyaluronidase conjugate with co-polymer of N-oxide 1,4-ethylenepiperazine and (N-carboxymethyl)-1,4- ethylenepiperazine bromide"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3353", "text": "Pharmaceutical form: suppositories"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3354", "text": "Pharmacotheapeutic group: enzymes"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3355", "text": "ATC Code: V03AX"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3356", "text": "Bovhyaluronidase azoximer is a porous white or white with a yellowish or brownish tint mass and prepared in ampules 1500 IU or 3000 IE with mannitol excipient (up to 15\u00a0mg [for 1500 IE dos] or up to 20\u00a0mg (for 3000 IE dose)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3357", "text": "The active ingredient belongs to the  hyaluronidases  family of  enzymes  that  catalyse  the degradation of  hyaluronic acid . By catalyzing the  hydrolysis  of  hyaluronan , a constituent of the body's  extracellular matrix  (ECM), hyaluronidase lowers the  viscosity  of hyaluronan, thereby increasing tissue  permeability ... [ 2 ]  It is, therefore, often used in medicine in conjunction with other drugs to speed their dispersion and delivery. It also increases the absorption rate of parenteral fluids given by  hypodermoclysis , and is an adjunct in subcutaneous urography for improving resorption of radiopaque agents. Hyaluronidases are also used for  extravasation  of hyperosmolar solutions. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3358", "text": "Approved applications include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3359", "text": "Gynaecology: treatment and prevention of adhesive process in lesser pelvis during inflammatory diseases of internal genital organs, including tubo-peritoneal  infertility ,  intrauterine synechiae , chronic  endometritis . [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3360", "text": "Urology: treatment of chronic  prostatitis ,  interstitial cystitis . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3361", "text": "Pulmonology and  phthisiology : treatment of pneumosclerosis, \n fibrosing alveolitis , and  tuberculosis  (fibro-cavity, infiltrative, tuberculoma). [ 8 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3362", "text": "Orthopaedics: treatment of joint contracture,  arthrosis , Marie-Striinipell disease,  haematomas . [ 1 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3363", "text": "Medicines incorporating hyaluronidase have been used in medical applications for over 60 years. [ 10 ]  The  US Food and Drug Administration  has approved hyaluronidase for the following indications: (1) subcutaneous fluid infusion ( hypodermoclysis ), (2) as an adjuvant to accelerate the absorption and dispersion of drugs in subcutaneous tissue or to manage extravasation, and (3) as an adjunct to promote the absorption of contrast media in urinary tract  angiography  (subcutaneous urography). [ 2 ]  They have also been approved and used for the purpose of increasing hematoma absorption in Europe. [ 2 ]  Hyaluronidase has a variety of uses in addition to its approved indications. Its current off-label uses include dissolving hyaluronic acid fillers, treating granulomatous foreign body reactions, and treating skin  necrosis  associated with filler injections. [ 2 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3364", "text": "Recognised limitations for hyaluronidase-based medicines include allergenic properties, presence of ballast impurities, loss of enzymatic activity due to temperature and inhibitors of blood serum. [ 12 ]  Since administration is via a  parenteral  route of administration, the enzyme is inactivated by blood serum inhibitors, which shortens its half-life. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3365", "text": "Conjugation ( covalent binding ) of hyaluronidase with polymeric carriers prevents the unfolding of enzyme globule  Hyal , increasing resistance to denaturation and the action of inhibitors while preserving the enzymes native structure and activity, thus prolonging its activity. [ 13 ]  The water-soluble copolymer 1,4-ethylene-piperazine N-oxide and (N-carboxymethyl)-1,4-ethylene-piperazinium bromide, itself an  immunomodulator  with anti-inflammatory properties, [ 14 ]  was found to confer increased stability. A comparative study of the stability of commercial hyaluronidase (Lydase\u00ae) and bovhyaluronidase azoximer showed a 20-fold increase in length of activity at 37\u00a0\u00b0C (24 hours vs. 20 days, respectively). [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3366", "text": "Frequently observed adverse events include (\u2265 1/100 to < 1/10) \u2013 pain at injection site. Less frequent adverse events (\u2265 1/1,000 to < 1/100) include injection site reaction such as skin redness, itching and oedema. All local reactions resolve themselves in 48 \u2013 72 hours. Very rare (< 1/10000) \u2013 allergic reactions.\nUse of bovhyaluronidase azoximer is contraindicated in known cases of hypersensitivity to hyaluronidase, acute infectious diseases, pulmonary haemorrhage and haemoptysis, recent vitreous haemorrhage, malignant neoplasms, acute renal failure, age under 18 years (no clinical study data available). It should also be used with caution in cases of chronic liver failure (administer not more than once per week) and is contraindicated for use in pregnant and breast-feeding women. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3367", "text": "Bovhyaluronidase azoximer can be prescribed with other medications such as antifungal drugs, bronchial spasmolytics, antibiotics and antivirals. When administered in combination with other medicinal product (antibiotics, local anesthetics, diuretics) bovhyaluronidase azoximer increases their bioavailability and enhances their effect. In case of co-administration with high doses of salicylates, cortisone, adrenocorticotrophic hormone (ACTH), estrogens or antihistaminic drugs bovhyaluronidase azoximer enzymatic activity can decrease. It is advised that bovhyaluronidase azoximer is not administered with medicinal products containing furosemide, benzodiazepines, phenytoin. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3368", "text": "Catridecacog , sold under the brand name  Tretten  in the US and  NovoThirteen  in the EU [ 1 ] ) is a class of  recombinant   factor XIII  A-subunit based  biopharmaceutical  medicine, indicated in patients with a rare clotting disorder, congenital factor XIII A-subunit deficiency, which is a kind of  Factor XIII deficiency . The medication prevents bleeding in patients with this condition, and has been approved by the U.S.  Food and Drug Administration  (FDA) for this use in the US in 2014. [ 2 ]   It was brought to market by  Novo Nordisk . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3369", "text": "This  drug  article relating to the  blood  and  blood forming organs  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3370", "text": "Condoliase  ( Hernicore ) is a  biopharmaceutical  for the treatment of  lumbar disc herniation . Clinical trials have shown its benefit in alleviation of lumbar disc herniation associated low back pain and disability, although some concerns have been suggested with regard to promotion of disc degeneration. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3371", "text": "Condoliase is derived from the enzyme  mucopolysaccharidase  from the  Gram-negative bacteria   Proteus vulgaris . [ 3 ] [ 4 ]   It functions as an enzymatic  chemonucleolysis  product, specifically designed to reduce the size of the protruded herniation. [ 5 ]  It is an enzyme that specifically degrades  glycosaminoglycans . [ 6 ] [ 7 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3372", "text": "It was approved for use in Japan in 2018 as a treatment for lumbar disc herniation. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3373", "text": "The  Golden LEAF Biomanufacturing Training and Education Center (BTEC)  is a multidisciplinary instructional center at  North Carolina State University  that provides education and training to develop skilled professionals for the  biomanufacturing  industry. Biomanufacturing refers to the use of living organisms or other biological material to produce commercially viable products. Examples include therapeutic proteins,  monoclonal antibodies , and  vaccines  for medical use; amino acids and enzymes for food manufacturing; and biofuels and biochemicals for industrial applications. BTEC provides hands-on education and training in bioprocessing concepts and biomanufacturing methods that comply with  cGMP  (current Good Manufacturing Practice), a set regulations published by the United States  Food and Drug Administration (FDA) ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3374", "text": "BTEC reports administratively through the university's  College of Engineering  and is guided by an advisory board made up of representatives from the biomanufacturing industry and other organizations interested in biotechnology and biomanufacturing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3375", "text": "In 2003, North Carolina's  Golden LEAF Foundation  provided almost $39 million to build BTEC, as part of a larger grant to establish a statewide public-private partnership now called  NCBioImpact . [ 1 ] [ 2 ]  The state of North Carolina provided funds for process equipment and supports the operation of the facility.  The NCBioImpact partnership now includes BTEC, BRITE (Biomanufacturing Research Institute and Technology Enterprise) at  North Carolina Central University , North Carolina BioNetwork of the  North Carolina Community College System , NCBIO (North Carolina Biosciences Organization), the  North Carolina Biotechnology Center , and the Golden LEAF Foundation.  It was created to provide workforce training and development for the biotechnology industry, thereby fostering the growth of this economic sector in the state. According to the North Carolina Biotechnology Center, North Carolina is home to 528 biotechnology companies that provide 57,000 jobs and $1.92 billion in taxes for state and local government. [ 3 ]   Employment in the industry has grown 4.1% from 2008 to 2010, when other industries shed thousands of jobs. [ 4 ]  In recent years some of the world's largest pharmaceutical companies, e.g.  Novartis  and  Merck & Co , have located and/or expanded manufacturing operations in North Carolina. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3376", "text": "BTEC opened in fall 2007 and was the first facility dedicated to biomanufacturing training. [ 7 ]  BTEC is 82,500 gross square feet and contains 63,000-gross square feet of laboratories, which range from small or bench scale to large-scale suites that simulate a biomanufacturing pilot plant capable of producing  biopharmaceutical  products.  Upstream processes utilize bacteria, yeast, animal  cells , and insect cells.  Equipment in these spaces includes the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3377", "text": "The main BTEC facility is home to the North Carolina Community College System's BioNetwork Capstone Center, which operates an aseptic processing/filling suite and several bench-scale labs. [ 8 ]  In 2012, BTEC completed construction of additional laboratories in a nearby facility for cell culture, purification, and processing of active virus."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3378", "text": "BTEC delivers undergraduate and graduate courses to North Carolina State University students. Academic programs include the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3379", "text": "Curriculum was created with extensive input from industry professionals, and most courses include substantial hands-on laboratory work. Most BTEC courses are offered in a half-semester (eight-week) format, which enables students to complete a series of courses in one academic year."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3380", "text": "BTEC collaborates with industry partners to design, develop and deliver courses that provide professionals working for biomanufacturing companies, equipment vendors, or regulatory agencies with continuing education opportunities.  Open-enrollment courses are offered throughout the year and are available to all interested parties.  BTEC also regularly delivers courses customized to meet a client's specific needs for training."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3381", "text": "BTEC provides biomanufacturing training specified in contracts of grants to provide training for government agencies.  In 2007, the  FDA  awarded BTEC a 5-year contract to develop and deliver biomanufacturing training for FDA inspectors. [ 9 ]   In 2010, BTEC received a grant for almost $900,000 from  Biomedical Advanced Research and Development Authority  (BARDA), part of the  United States Department of Health and Human Services . [ 10 ]  With funding from this grant, a team of instructors from BTEC,  Duke University , and industry provide a three-week course on influenza vaccine manufacturing. Trainees were selected by institutions participating in a U.S. government-sponsored program to build vaccine production capacity among countries with developing economies. Countries represented included Egypt, India, Indonesia, Mexico, Romania, Serbia, Russia, South Korea, Thailand, and Vietnam."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3382", "text": "When laboratories are not being used for training, BTEC uses them to perform a variety of services for scientists from industry, government, and academia.  Projects involve technology development, process improvement/scale-up, analytical testing, and preparation of material for preclinical studies.  These services allow scientists to advance their research projects toward commercialization.  In turn, these advancements stimulate the North Carolina economy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3383", "text": "BTEC is located on the  Centennial Campus  of  North Carolina State University  in  Raleigh, North Carolina , United States. The campus is approximately 15 miles east of  Research Triangle Park  and  Raleigh-Durham International Airport ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3384", "text": "A  living medicine  is a type of  biologic  that consists of a living organism that is used to treat a disease. This usually takes the form of a cell (animal, bacterial, or fungal) or a virus that has been  genetically engineered  to possess  therapeutic  properties that is injected into a patient. [ 2 ] [ 3 ]  Perhaps the oldest use of a living medicine is the use of  leeches  for  bloodletting , though living medicines have advanced tremendously since that time."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3385", "text": "Examples of living medicines include  cellular therapeutics  (including  immunotherapeutics ),  phage therapeutics , and  bacterial therapeutics , a subset of the latter being  probiotics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3386", "text": "Development of living medicines is an extremely active research area in the fields of  synthetic biology  and  microbiology . [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ]  Currently, there is a large focus on: 1) identifying microbes that naturally produce therapeutic effects (for example, probiotic bacteria), and 2)  genetically programming  organisms to produce therapeutic effects. [ 15 ] [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3387", "text": "There is tremendous interest in using bacteria as a therapy to treat tumors. In particular,  tumor-homing bacteria  that thrive in  hypoxic  environments are particularly attractive for this purpose, as they will tend to migrate to, invade (through the  leaky vasculature  in the  tumor microenvironment ) and  colonize  tumors. This property tends to increase their residence time in the tumor, giving them longer to exert their therapeutic effects, in contrast to other bacteria that would be quickly cleared by the immune system. [ 19 ] [ 20 ] [ 21 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3388", "text": "Metazym  is an experimental recombinant  enzyme  that was studied in patients with late infantile  metachromatic leukodystrophy , [ 1 ]  but found to be ineffective under the conditions of that trial. A subsequent clinical trial is ongoing. [ 2 ]  The drug became a source of controversy when a family attempted to purchase the drug for their child before it was approved. [ 3 ]  Jonckheere, Kingma, Eyskens, Bordon, & Jansen (2023) highlight the shift towards the need for newborn screening for metachromatic leukodystrophy as it allows for improved early detection and timely treatment as well. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3389", "text": "This  enzyme -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3390", "text": "Patisiran , sold under the brand name  Onpattro , is a  medication  used for the treatment of  polyneuropathy  in people with  hereditary transthyretin-mediated amyloidosis , [ 7 ]  a fatal  rare disease  that is estimated to affect 50,000 people worldwide. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3391", "text": "It is the first  small interfering RNA -based drug approved by the U.S.  Food and Drug Administration  (FDA) and the first drug approved by the FDA to treat this condition. [ 8 ]  It is a  gene silencing  drug that interferes with the production of an abnormal form of  transthyretin . [ 10 ]  Patisiran utilizes a novel approach to target and reduce production of the  TTR  protein in the liver via the RNAi pathway. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3392", "text": "Patisiran was developed and is marketed by  Alnylam . [ 12 ]  The FDA considers it to be a  first-in-class medication . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3393", "text": "Patisiran was granted  orphan drug status ,  fast track designation ,  priority review  and  breakthrough therapy designation  due to its novel mechanism and the rarity of the condition it treats. [ 14 ] [ 15 ]  It was approved for medical use in the United States and in the European Union in August 2018. [ 16 ] [ 17 ]  The per-patient cost is between  US$451,430  and  US$677,145  per year, depending on the number of vials needed. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3394", "text": "[ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3395", "text": "The  siRNA  active component of Patisiran is formulated into  lipid nanoparticles , which protect the  RNA  and facilitate its delivery to target tissues. The lipid  nanoparticle  formulation includes buffer components, as well as the  lipid  components DLin-MC3-DMA,  Distearoylphosphatidylcholine ,  cholesterol , and the PEGylated lipid  DMG-PEG 2000 . [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3396", "text": "As of 2020, there were 1050 people globally receiving patisiran, generating $65.5M in net-revenues for  Alnylam Pharmaceuticals . [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3397", "text": "Plasminogen , sold under the brand name  Ryplazim , is a  biologic medication  for the treatment of  hypoplasminogenemia  (plasminogen deficiency type 1). [ 1 ] [ 2 ] [ 4 ]  It is purified from human plasma [ 1 ] [ 2 ]  and is administered  intravenously . [ 1 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3398", "text": "The most common side effects include abdominal pain, bloating, nausea, bleeding, limb pain, fatigue, constipation, dry mouth, headache, dizziness, joint pain, and back pain. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3399", "text": "Individuals with hypoplasminogenemia lack a protein called plasminogen, which is responsible for the ability of the body to break down fibrin clots. [ 2 ]  Plasminogen deficiency leads to an accumulation of fibrin, causing the development of growths (lesions) that can impair normal tissue and organ function and may lead to blindness when these lesions affect the eyes. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3400", "text": "Plasminogen, human-tvmh was approved for medical use in the United States in June 2021. [ 2 ]  It is the first therapy for hypoplasminogenemia approved by the U.S.  Food and Drug Administration  (FDA). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3401", "text": "Plasminogen, human-tvmh is  indicated  for the treatment of people with plasminogen deficiency type 1, also referred to as hypoplasminogenemia, a disorder that can impair normal tissue and organ function and may lead to blindness. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3402", "text": "The effectiveness and safety of plasminogen is primarily based on one single-arm, open-label (unblinded) clinical trial enrolling 15 adult and pediatric participants with plasminogen deficiency type 1. [ 2 ]  All participants received plasminogen administered every two to four days for 48 weeks. [ 2 ]  The effectiveness of plasminogen was demonstrated by at least 50% improvement of their lesions in all 11 participants who had lesions at baseline, and absence of recurrent or new lesions in any of the 15 participants through the 48 weeks of treatment. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3403", "text": "The U.S.  Food and Drug Administration  (FDA) granted the application for plasminogen   orphan drug  designation, [ 6 ]   fast track  designation,  priority review , and a rare pediatric disease priority review voucher. [ 2 ]  The FDA granted approval of Ryplazim to ProMetic Biotherapeutics Inc. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3404", "text": "Recombinant DNA  ( rDNA ) molecules are  DNA  molecules formed by laboratory methods of  genetic recombination  (such as  molecular cloning ) that bring together genetic material from multiple sources, creating  sequences  that would not otherwise be found in the  genome ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3405", "text": "Recombinant DNA is the general name for a piece of DNA that has been created by combining two or more fragments from different sources. Recombinant DNA is possible because DNA molecules from all organisms share the same chemical structure, differing only in the  nucleotide  sequence. Recombinant DNA molecules are sometimes called  chimeric DNA  because they can be made of material from two different species like the mythical  chimera . rDNA technology uses  palindromic sequences  and leads to the production of  sticky and blunt ends ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3406", "text": "The DNA sequences used in the construction of recombinant DNA molecules can originate from any  species . For example, plant DNA can be joined to bacterial DNA, or human DNA can be joined with fungal DNA. In addition, DNA sequences that do not occur anywhere in nature can be created by the  chemical synthesis of DNA  and incorporated into recombinant DNA molecules. Using recombinant DNA technology and synthetic DNA, any DNA sequence can be created and introduced into living organisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3407", "text": "Proteins that can result from the expression of recombinant DNA within living cells are termed  recombinant proteins . When recombinant DNA encoding a protein is introduced into a host organism, the recombinant protein is not necessarily produced. [ 1 ]  Expression of foreign proteins requires the use of specialized expression vectors and often necessitates significant restructuring by\nforeign coding sequences. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3408", "text": "Recombinant DNA differs from genetic recombination in that the former results from artificial methods while the latter is a normal biological process that results in the remixing of existing DNA sequences in essentially all organisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3409", "text": "Molecular cloning is the laboratory process used to produce recombinant DNA. [ 3 ] [ 4 ] [ 5 ] [ 6 ]  It is one of two most widely used methods, along with  polymerase chain reaction  (PCR), used to direct the replication of any specific DNA sequence chosen by the experimentalist. There are two fundamental differences between the methods. One is that molecular cloning involves replication of the DNA within a living cell, while PCR replicates DNA in the test tube, free of living cells. The other difference is that cloning involves cutting and pasting DNA sequences, while PCR amplifies by copying an existing sequence."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3410", "text": "Formation of recombinant DNA requires a  cloning vector , a DNA molecule that replicates within a living cell. Vectors are generally derived from  plasmids  or  viruses , and represent relatively small segments of DNA that contain necessary genetic signals for replication, as well as additional elements for convenience in inserting foreign DNA, identifying cells that contain recombinant DNA, and, where appropriate, expressing the foreign DNA. The choice of vector for molecular cloning depends on the choice of host organism, the size of the DNA to be cloned, and whether and how the foreign DNA is to be expressed. [ 7 ]  The DNA segments can be combined by using a variety of methods, such as restriction enzyme/ligase cloning or  Gibson assembly . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3411", "text": "In standard cloning protocols, the cloning of any DNA fragment essentially involves seven steps: (1) Choice of host organism and cloning vector, (2) Preparation of vector DNA, (3) Preparation of DNA to be cloned, (4) Creation of recombinant DNA, (5) Introduction of recombinant DNA into the host organism, (6) Selection of organisms containing recombinant DNA, and (7) Screening for clones with desired DNA inserts and biological properties. [ 6 ] \n These steps are described in some detail in a related article ( molecular cloning )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3412", "text": "DNA expression requires the transfection of suitable host cells. Typically, either bacterial, yeast, insect, or mammalian cells (such as  Human Embryonic Kidney cells  or  CHO cells ) are used as host cells. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3413", "text": "Following transplantation into the host organism, the foreign DNA contained within the recombinant DNA construct may or may not be  expressed . That is, the DNA may simply be replicated without expression, or it may be  transcribed  and  translated  and a recombinant protein is produced. Generally speaking, expression of a foreign gene requires restructuring the gene to include sequences that are required for producing an  mRNA  molecule that can be used by the host's  translational apparatus  (e.g.  promoter ,  translational initiation signal , and  transcriptional terminator ). [ 9 ]  Specific changes to the host organism may be made to improve expression of the ectopic gene. In addition, changes may be needed to the coding sequences as well, to optimize translation, make the protein soluble, direct the recombinant protein to the proper cellular or extracellular location, and stabilize the protein from degradation. [ 10 ] [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3414", "text": "In most cases, organisms containing recombinant DNA have apparently normal  phenotypes . That is, their appearance, behavior and metabolism are usually unchanged, and the only way to demonstrate the presence of recombinant sequences is to examine the DNA itself, typically using a polymerase chain reaction (PCR) test. [ 13 ]  Significant exceptions exist, and are discussed below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3415", "text": "If the rDNA sequences encode a gene that is expressed, then the presence of RNA and/or protein products of the recombinant gene can be detected, typically using  RT-PCR  or  western hybridization  methods. [ 13 ]  Gross phenotypic changes are not the norm, unless the recombinant gene has been chosen and modified so as to generate biological activity in the host organism. [ 14 ]  Additional phenotypes that are encountered include toxicity to the host organism induced by the recombinant gene product, especially if it is  over-expressed  or expressed within inappropriate cells or tissues. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3416", "text": "In some cases, recombinant DNA can have deleterious effects even if it is not expressed. One mechanism by which this happens is  insertional inactivation , in which the rDNA becomes inserted into a host cell's gene. In some cases, researchers use this phenomenon to \" knock out \" genes to determine their biological function and importance. [ 15 ]  Another mechanism by which rDNA insertion into chromosomal DNA can affect gene expression is by inappropriate activation of previously unexpressed host cell genes. This can happen, for example, when a recombinant DNA fragment containing an active promoter becomes located next to a previously silent host cell gene, or when a host cell gene that functions to restrain gene expression undergoes insertional inactivation by recombinant DNA. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3417", "text": "Recombinant DNA is widely used in  biotechnology , medicine and research. Today, recombinant proteins and other products that result from the use of DNA technology are found in essentially every pharmacy, physician or veterinarian office, medical testing laboratory, and biological research laboratory. In addition, organisms that have been manipulated using recombinant DNA technology, as well as products derived from those organisms, have found their way into many farms,  supermarkets ,  home medicine cabinets , and even pet shops, such as those that sell  GloFish  and other  genetically modified animals ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3418", "text": "The most common application of recombinant DNA is in basic research, in which the technology is important to most current work in the biological and biomedical sciences. [ 13 ]  Recombinant DNA is used to identify, map and sequence genes, and to determine their function. rDNA probes are employed in analyzing gene expression within individual cells, and throughout the tissues of whole organisms. Recombinant proteins are widely used as reagents in laboratory experiments and to generate antibody probes for examining protein synthesis within cells and organisms. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3419", "text": "Many additional practical applications of recombinant DNA are found in industry, food production, human and veterinary medicine, agriculture, and bioengineering. [ 4 ]  Some specific examples are identified below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3420", "text": "Found in  rennet ,  chymosin  is the enzyme responsible for hydrolysis of  \u03ba - casein  to produce para- \u03ba -casein and  glycomacropeptide , which is the first step in formation of  cheese , and subsequently  curd , and  whey . [ 16 ]  It was the first genetically engineered food additive used commercially. Traditionally, processors obtained chymosin from rennet, a preparation derived from the fourth stomach of milk-fed calves. Scientists engineered a non-pathogenic strain (K-12) of  E. coli  bacteria for large-scale laboratory production of the enzyme. This microbiologically produced recombinant enzyme, identical structurally to the calf derived enzyme, costs less and is produced in abundant quantities. Today about 60% of U.S. hard cheese is made with genetically engineered chymosin. In 1990, FDA granted chymosin \" generally recognized as safe \" (GRAS) status based on data showing that the enzyme was safe. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3421", "text": "Recombinant human  insulin  has almost completely replaced insulin obtained from animal sources (e.g. pigs and cattle) for the treatment of  type 1 diabetes . A variety of different recombinant insulin preparations are in widespread use. [ 18 ]  Recombinant insulin is synthesized by inserting the human insulin gene into  E. coli , or yeast (Saccharomyces cerevisiae) [ 19 ]  which then produces insulin for human use. [ 20 ]  Insulin produced by E. coli requires further  post translational modifications  (e.g. glycosylation) whereas yeasts are able to perform these modifications themselves by virtue of being more complex host organisms. The advantage of recombinant human insulin is after chronic use patients don't develop an immune defence against it the way animal sourced insulin stimulates the human immune system. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3422", "text": "Administered to patients whose pituitary glands generate insufficient quantities to support normal growth and development. Before recombinant HGH became available, HGH for therapeutic use was obtained from pituitary glands of cadavers. This unsafe practice led to some patients developing  Creutzfeldt\u2013Jakob disease . Recombinant HGH eliminated this problem, and is now used therapeutically. [ 22 ]  It has also been misused as a performance-enhancing drug by athletes and others. [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3423", "text": "It is the recombinant form of  factor VIII , a blood-clotting protein that is administered to patients with the bleeding disorder  hemophilia , who are unable to produce factor VIII in quantities sufficient to support normal blood coagulation. [ 25 ]  Before the development of recombinant factor VIII, the protein was obtained by processing large quantities of human blood from multiple donors, which carried a very high risk of transmission of  blood borne infectious diseases , for example HIV and hepatitis B."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3424", "text": "Hepatitis B  infection can be successfully controlled through the use of a recombinant  subunit   hepatitis B vaccine , which contains a form of the hepatitis B virus surface antigen that is produced in yeast cells. The development of the recombinant subunit vaccine was an important and necessary development because hepatitis B virus, unlike other common viruses such as  polio virus , cannot be grown  in vitro . [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3425", "text": "Recombinant antibodies  (rAbs) are produced in vitro by the means of expression systems based on mammalian cells. Their monospecific binding to a specific epitope makes rAbs eligible not only for research purposes, but also as therapy options against certain cancer types, infections and autoimmune diseases. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3426", "text": "Each of the three widely used methods for  diagnosing HIV infection  has been developed using recombinant DNA. The antibody test ( ELISA  or  western blot ) uses a recombinant HIV protein to test for the presence of  antibodies  that the body has produced in response to an HIV infection. The DNA test looks for the presence of HIV genetic material using  reverse transcription polymerase chain reaction  (RT-PCR). Development of the RT-PCR test was made possible by the molecular cloning and sequence analysis of HIV genomes.  HIV testing page from US Centers for Disease Control (CDC)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3427", "text": "Golden rice  is a recombinant variety of rice that has been engineered to express the enzymes responsible for  \u03b2-carotene  biosynthesis. [ 14 ]  This variety of rice holds substantial promise for reducing the incidence of  vitamin A deficiency  in the world's population. [ 28 ]  Golden rice is not currently in use, pending the resolution of regulatory and intellectual property issues. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3428", "text": "Commercial varieties of important agricultural crops (including soy, maize/corn, sorghum, canola, alfalfa and cotton) have been developed that incorporate a recombinant gene that results in resistance to the herbicide  glyphosate  (trade name  Roundup ), and simplifies weed control by glyphosate application. [ 30 ]  These crops are in common commercial use in several countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3429", "text": "Bacillus thuringiensis  is a bacterium that naturally produces a protein ( Bt toxin ) with insecticidal properties. [ 28 ]  The bacterium has been applied to crops as an insect-control strategy for many years, and this practice has been widely adopted in agriculture and gardening. Recently, plants have been developed that express a recombinant form of the bacterial protein, which may effectively control some insect predators. Environmental issues associated with the use of these  transgenic  crops have not been fully resolved. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3430", "text": "The idea of recombinant DNA was first proposed by Peter Lobban, a graduate student of Prof.  Dale Kaiser  in the Biochemistry Department at Stanford University Medical School. [ 32 ]  The first publications describing the successful production and intracellular replication of recombinant DNA appeared in 1972 and 1973, from  Stanford  and  UCSF . [ 33 ] [ 34 ] [ 35 ] [ 36 ]  In 1980  Paul Berg , a professor in the Biochemistry Department at Stanford and an author on one of the first papers [ 33 ]  was awarded the Nobel Prize in Chemistry for his work on nucleic acids \"with particular regard to recombinant DNA\".  Werner Arber ,  Hamilton Smith , and  Daniel Nathans  shared the 1978  Nobel Prize in Physiology or Medicine  for the discovery of  restriction endonucleases  which enhanced the techniques of rDNA technology. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3431", "text": "Stanford University  applied for a U.S. patent on recombinant DNA on November 4, 1974, listing the inventors as  Herbert W. Boyer  (professor at the  University of California, San Francisco ) and  Stanley N. Cohen  (professor at  Stanford University ); this patent, U.S. 4,237,224A, was awarded on December 2, 1980. [ 37 ] [ 38 ]  The first licensed drug generated using recombinant DNA technology was human insulin, developed by  Genentech  and licensed by  Eli Lilly and Company . [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3432", "text": "Scientists associated with the initial development of recombinant DNA methods recognized that the potential existed for organisms containing recombinant DNA to have undesirable or dangerous properties. At the 1975  Asilomar Conference on Recombinant DNA , these concerns were discussed and a voluntary moratorium on recombinant DNA research was initiated for experiments that were considered particularly risky. This moratorium was widely observed until the US  National Institutes of Health  developed and issued formal guidelines for rDNA work. Today, recombinant DNA molecules and recombinant proteins are usually not regarded as dangerous. However, concerns remain about some organisms that express recombinant DNA, particularly when they leave the laboratory and are introduced into the environment or food chain. These concerns are discussed in the articles on  genetically modified organisms  and  genetically modified food controversies . Furthermore, there are concerns about the by-products in biopharmaceutical production, where recombinant DNA result in specific protein products. The major by-product, termed  host cell protein , comes from the host expression system and poses a threat to the patient's health and the overall environment. [ 40 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3433", "text": "Sebelipase alfa , sold under the brand name  Kanuma ,  is a  recombinant form  of  the  enzyme   lysosomal acid lipase  (LAL) that is used as a  medication  for the treatment of  lysosomal acid lipase deficiency  (LAL-D). [ 6 ] [ 7 ]  It is administered via intraveneous infusion. [ 5 ]  It was approved for medical use in the European Union and in the United States in 2015. [ 8 ] [ 6 ] [ 5 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3434", "text": "Sebelipase alfa is indicated for long-term enzyme replacement therapy (ERT) in people of all ages with lysosomal acid lipase (LAL) deficiency. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3435", "text": "Sebelipase was developed by  Synageva  that became part of  Alexion Pharmaceuticals  in 2015. For its production,  chickens  are  genetically modified  to  produce the recombinant form of LAL (rhLAL) in their  egg white . After extraction and purification it becomes available as the medication. [ 9 ]   On 8 December 2015 the  FDA  announced that its approval came from two centers: The  Center for Drug Evaluation and Research  (CDER) approved the human therapeutic application of the medication, while the  Center for Veterinary Medicine  (CVM) approved the application for a recombinant DNA construct in genetically engineered chicken to produce rhLAL in their egg whites. [ 10 ]  At the time it gained FDA approval Kanuma was the first only drug manufactured in chicken eggs and intended for use in humans. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3436", "text": "Sebelipase alfa is an  orphan drug ; its effectiveness was published after a  phase 3 trial  in 2015. [ 11 ]  The disease of LAL affects < 0.2 in 10,000 people in the EU. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3437", "text": "Specialty drugs  or  specialty pharmaceuticals  are a recent designation of pharmaceuticals [ 1 ] [ 2 ]  classified as high-cost, [ 3 ] [ 4 ] [ 5 ]  high complexity and/or  high touch . [ 4 ]  Specialty drugs are often  biologics [ 3 ] [ 6 ] \u2014\"drugs derived from living cells\" [ 7 ]  that are injectable or infused (although some are oral medications). [ 4 ]  They are used to treat complex or rare chronic conditions such as  cancer ,  rheumatoid arthritis ,  hemophilia ,  H.I.V. [ 5 ]   psoriasis , [ 3 ]   inflammatory bowel disease [ 3 ]  and  hepatitis C . [ 4 ] [ 8 ]  In 1990 there were 10 specialty drugs on the market, [ 9 ]  around five years later nearly 30, [ 10 ]  by 2008 200, [ 10 ]  and by 2015 300. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3438", "text": "Drugs can be defined as specialty because of their high price. [ 3 ] [ 4 ] [ 5 ]   Medicare  defines any drug with a negotiated price of $670 per month or more as a specialty drug. These drugs are placed in a specialty tier requiring a higher patient cost sharing. [ 11 ] [ 12 ]  Drugs are also identified as specialty when there is a special handling requirement [ 3 ]  or the drug is only available via a limited distributions network. [ 3 ]  By 2015 \"specialty medications accounted for one-third of all spending on drugs in the United States, up from 19 percent in 2004 and heading toward 50 percent in the next 10 years\", [ 5 ]  according to  IMS Health ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3439", "text": "According to a 2010 article in  Forbes , specialty drugs for rare diseases became more expensive \"than anyone imagined\" and their success came \"at a time when the traditional drug business of selling medicines to the masses\" was \"in decline\". [ 13 ]  In 2015 analysis by  The Wall Street Journal  suggested the large premium was due to the perceived value of rare disease treatments which usually are very expensive when compared to treatments for more common diseases. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3440", "text": "Medications must be either identified as high cost, high complexity or high touch to be classified as a specialty medication by Magellan Rx Management. [ 4 ]  Specialty pharmaceuticals are defined as \"high-cost oral or injectable medications used to treat complex chronic conditions\". [ 4 ]  According to a 2013 article in the  Journal of Managed Care & Specialty Pharmacy , on the increasingly important role of specialty drugs in the treatment of chronic conditions and their cost, drugs are most typically defined as specialty because they are expensive. [ 3 ]  Other criteria used to define a drug as specialty include \"biologic drugs, the need to inject or infuse the drug, the requirement for special handling, or drug availability only via a limited distribution network\". [ 3 ]  The price of specialty drugs compared to non-specialty drugs is very high, \"more than $1,000 per 30-day supply\". [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3441", "text": "Specialty drugs cover over forty therapeutic categories and special disease states with over 500 drugs. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3442", "text": "Vogenberg claims that there is no standard definition of a specialty drug which is one of the reasons they are difficult to manage. [ 6 ]  \"[T]hose pharmaceuticals that usually require special handling, administration, unique inventory management, and a high level of patient monitoring and support to consumers with specific chronic conditions, acute events, or complex therapies, and provides comprehensive patient education services and coordination with the patient and prescriber.\" [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3443", "text": "Drugs are most typically defined as specialty because they are expensive. [ 3 ]  They are high cost \"both in total and on a per-patient basis\". [ 16 ]  High-cost medications are typically priced at more than $1,000 per 30-day supply. [ 4 ] [ 5 ]  The Medicare Part D program \"defines a specialty drug as one that costs more than $600 per month\". [ 16 ] [ 17 ]  Most of the prescriptions filled by Pennsylvania-licensed  Philidor Rx Services , a specialty online mail-order pharmacy, which mainly sold [ 18 ] [ 19 ] [ 20 ]   Valeant Pharmaceuticals International Inc  expensive drugs directly to patients and handled insurance claims on the customers' behalf, [ 21 ] [ 22 ]  such as  Solodyn ,  Jublia , [ 14 ] [ 23 ] [ 24 ]  and  Tretinoin , would be considered specialty drugs. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3444", "text": "Specialty drugs are more complex to manufacture. [ 16 ]  They are \"highly complex medications, typically biology-based, that structurally mimic compounds found within the body\". [ 4 ]  Specialty drugs are often biologics [ 3 ] [ 6 ] \u2014\"drugs derived from living cells\"\u2014but biologics are \"not always deemed to be specialty drugs\". [ 7 ]  Biologics \"may be produced by biotechnology methods and other cutting-edge technologies. Gene-based and cellular biologics, for example, often are at the forefront of biomedical research, and may be used to treat a variety of medical conditions for which no other treatments are available.\" [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3445", "text": "\"In contrast to most drugs that are chemically synthesized and their structure is known, most biologics are complex mixtures that are not easily identified or characterized. Biological products, including those manufactured by biotechnology, tend to be heat sensitive and susceptible to microbial contamination. Therefore, it is necessary to use aseptic principles from initial manufacturing steps, which is also in contrast to most conventional drugs. Biological products often represent the cutting-edge of biomedical research and, in time, may offer the most effective means to treat a variety of medical illnesses and conditions that presently have no other treatments available.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_3446", "text": "According to the  U.S. Food and Drug Administration  (FDA) biologics, or [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3447", "text": "\"Biological products include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources\u2014human, animal, or microorganism...\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_3448", "text": "Some specialty drugs can be oral medications or self-administered injectables. Others may be professionally administered or injectables/infusions. [ 4 ]  High-touch patient care management is usually required to control side effects and ensure compliance. Specialized handling and distribution are also necessary to ensure appropriate medication administration. [ 4 ]  Specialty drugs patient care management is meant to be both high technology and high touch care, or  patient-centered care  with \"more face-to-face time, more personal connections\". Patient-centered care is defined by the  Institute of Medicine  as \"care that is respectful of and responsive to individual patient preferences, needs and values\". [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3449", "text": "Specialty drugs may be \"difficult for patients to take without ongoing clinical support\". [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3450", "text": "Specialty drugs might have special requirements for handling procedures and administration including the necessity of having controlled environments such as highly specific temperature controls to ensure product integrity. [ 16 ]  They are often only available via a limited distributions network such as a special pharmacy. [ 3 ]  Specialty drugs may be \"challenging for providers to manage\". [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3451", "text": "Specialty drugs may be taken \"by relatively small patient populations presenting with complex medical conditions\". [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3452", "text": "\"Specialty pharmacies have their roots in the 1970s, when they began delivering temperature-controlled drugs to treat cancer, HIV, infertility and hemophilia.\" [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3453", "text": "\"The business grew as more drugs became available for patients to inject themselves and as insurers sought to manage expenses for patients with chronic conditions, according to areport from IMS Health. Manufacturers have increasingly relied on these pharmacies when it comes to fragile medicines that need special handling or have potentially dangerous side effects that require them to be taken under a management program.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_3454", "text": "According to  The American Journal of Managed Care , in 1990 there were 10 specialty drugs on the market. [ 9 ]  According to the  National Center for Biotechnology Information , by the mid-1990s, there were fewer than 30 specialty drugs on the market, but by 2008 that number had increased to 200. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3455", "text": "Specialty drugs may also be designated as orphan drugs or ultra-orphan drugs under the U. S.  Orphan Drug Act of 1983 . This was enacted to facilitate development of orphan drugs\u2014drugs for rare diseases such as  Huntington's disease ,  myoclonus ,  amyotrophic lateral sclerosis ,  Tourette syndrome  and  muscular dystrophy  which affect small numbers of individuals residing in the United States. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3456", "text": "Not all specialty drugs are orphan drugs. According to  Thomson Reuters  in their 2012 publication \"The Economic Power of Orphan Drugs\", there has been increased investing in  orphan drug  research and development partly since the U.S. Congress enacted the Orphan Drug Act, giving an extra monopoly for drugs for \"orphan diseases\" that affected fewer than 200,000 people in the country. [ 13 ]  Similar acts came into existence in other regions of the world, many driven by \"high-profile philanthropic funding\". [ 30 ] [ 31 ]  According to a 2010 article in  Forbes , prior to 1983 drug companies largely ignored rare diseases and focused on drugs that affected millions of patients. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3457", "text": "The term  specialty drugs  was used as early as 1988 in a  New York Times  article about  Eastman Kodak Company 's acquisition of the New York-based  Sterling Drug Inc. , maker of specialty drugs along with many and diverse other products. [ 2 ]  When  Shire Pharmaceuticals  acquired BioChem Pharma in 2000 they created a specialty pharmaceuticals company. [ 32 ]  By 2001 Shire was one of the fastest growing specialty pharmaceutical companies in the world. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3458", "text": "By 2001  CVS 's specialty pharmacy ProCare was the \"largest integrated retail/mail provider of specialty pharmacy services\" in the United States. [ 34 ] :\u200a10\u200a  It was consolidated with their pharmacy benefit management company PharmaCare in 2002. In their 2001 annual report, CVS anticipated that the \"$16 billion specialty pharmacy market\" would grow at \"an even faster rate than traditional pharmacy due in large part to the robust pipeline of biotechnology drugs\". [ 34 ]  By 2014 CVS Caremark,  Express Scripts  and  Walgreens  represented more than 50% of the specialty drug market in the United States. [ 35 ] :\u200a4"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3459", "text": "When an increasing number of oral oncology agents first entered the market between 2000 and 2010, most cancer care was provided in a community oncology practices. By 2008 many other drugs had been developed to treat cancer, and drug development had grown into a multibillion-dollar industry. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3460", "text": "In 2003 the  Medicare Prescription Drug, Improvement, and Modernization Act [ 37 ]  was enacted [ 38 ] \u2014the largest overhaul of  Medicare  in the public health program's 38-year history\u2014included  Medicare Part D  an  entitlement  benefit for  prescription drugs , through tax breaks and subsidies. In 2004 the U. S.  Centers for Medicare and Medicaid Services  (CMS) prepared a report on final guidance regarding access to drug coverage enacted under in which they included the specialty drugs tier in the prescription drug formulary. [ 1 ]  At that time CMS guidelines included four tiers: tier 1 includes preferred generics, tier 2 includes preferred brands, tier 3 includes non-preferred brands and generics and tier 4 included specialty drugs. [ 1 ]  By January 1, 2006, the controversial [ according to whom? ]   Medicare Part D  was put in effect. It was a massive [ clarification needed ]  expansion of the federal government's provision of prescription drug coverage to previously uninsured Americans, particularly seniors. [ 39 ] :\u200a69\u200a  In 2006 in the United States there was no standard nomenclature, so sellers could call the plan anything they wanted and cover whatever drugs they wanted. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3461", "text": "By 2008 most prescription medication plans in the United States used specialty drug tiers, and some had a separate benefit tier for injectable drugs. Beneficiary cost sharing was higher for drugs in these tiers. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3462", "text": "By 2011 in the United States a growing number of Medicare Part D health insurance plans\u2014which normally include generic, preferred, and non-preferred tiers with an accompanying rate of cost-sharing or co-payment\u2014had added an \"additional tier for high-cost drugs which is referred to as a specialty tier\". [ 42 ] :\u200a1"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3463", "text": "By 2014 in the United States, in the new  Health Insurance Marketplace \u2014following the implementation of the U.S.  Affordable Care Act , also known as Obamacare [ 43 ] \u2014most health plans had a four- or five-tier prescription drug formulary with specialty drugs in the highest of the tiers. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3464", "text": "According to an  AARP  2015 report, \"All but 4 of the 46 therapeutic categories of specialty drug products had average annual retail price increases that exceeded the rate of general inflation in 2013. Price increases by therapeutic category ranged from 1.7 percent to 77.2 percent.\" [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3465", "text": "On September 27, 2007 President  George W. Bush  amended the  Food and Drug Administration Amendments Act of 2007  (FDAAA) to authorize the FDA to require  Risk Evaluation and Mitigation Strategies  (REMS) on medications if necessary to minimize the risks associated with some drugs\". These medications were designated as specialty drugs and required specialty pharmacies. When the FDA approves a new drug they may require a REMS program which \"may contain any combination of 5 criteria: Medication Guide, Communication Plan, Elements to Assure Safe Use, Implementation System, and Timetable for Submission of Assessments\". [ 46 ]  \"In 2010, 48% of all new molecular entities, and 60% of all new specialty drug approvals, required a REMS program.\" Risk-reduction mechanisms can include the \"use of specialized distribution partners\", special pharmacy. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3466", "text": "In 2013 the FDA introduced the  breakthrough therapy  designation program which cut the development process of new therapies by several years. This meant that the FDA could \"introduce important medicines to the market based on very promising phase 2 rather than phase 3 clinical trial results\". Shortly after the law was enacted,  Ivacaftor , in January 2013, became the first drug to receive the breakthrough therapy designation. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3467", "text": "On February 3, 2015 New York-based  Pfizer 's drug  Ibrance  was approved through the FDA's  Breakthrough Therapy  designation program as a treatment for advanced breast cancer. [ 49 ]  It can only be ordered through specialty pharmacies and sells for \"$9,850 for a month or $118,200 per year\". [ 50 ]  According to a statement by the New York-based  Pfizer  the price \"is not the cost that most patients or payors pay\" since most prescriptions are dispensed through health plans, which negotiate discounts for medicines or get government-mandated price concessions. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3468", "text": "According to Express Scripts, [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3469", "text": "\"[T]he pharmacy landscape [in the United States] underwent a seismic change, and the budgetary impact to healthcare payers was significant. U.S. prescription drug spend increased 13.1% in 2014 \u2013 the largest annual increase since 2003 \u2013 and this was largely driven by an unprecedented 30.9% increase in spending on specialty medications. Utilization of traditional medications stayed flat (-0.1%), while the use of specialty drugs increased 5.8%. The largest factors contributing to the increased spending, however, were the price increases for these medication categories \u2013 6.5% for traditional and 25.2% for specialty. While specialty medications represent only 1% of all U.S. prescriptions, these medications represented 31.8% of all 2014 drug spend \u2013 an increase from 27.7% in 2013.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_3470", "text": "By 2015 \"specialty medications account for one-third of all spending on drugs in the United States, up from 19 percent in 2004 and heading toward 50 percent in the next 10 years, according to IMS Health, which tracks prescriptions\". [ 5 ]  The specialty pharmacy business had $20 billion in sales in 2005. By 2014 it had grown to \"$78 billion in sales\". [ 5 ]  In Canada by 2013 \"specialty drugs made up less than 1.3 percent of all Canadian prescriptions, but accounted for 24 percent of Canada's total spending on prescription drugs\". [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3471", "text": "When Randy Vogenberg of the  Institute for Integrated Healthcare  in Massachusetts and a co-leader of the Midwest Business Group initiative, began investigating specialty drugs in 2003, it \"wasn't showing up on the radar\". By 2009 specialty drugs had started doubling in cost and payers such as employers began to question. [ 6 ]  Vogenberg observed that by 2014 health care reform had changed the landscape for specialty drugs. There is a shift away from a marketplace based on a predominately clinical perspective, to one that puts economics first and clinical second. [ 53 ] :\u200a15"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3472", "text": "Many factors contribute to the continuing increase in price of specialty drugs.  Development of specialty drugs not only costs more, but they also take longer to develop than other large market pharmaceuticals [ 54 ]  (See  Drug development ).  In addition, there are often fewer drug choices for rare or hard-to-treat diseases. [ 55 ]   This results in less competition in the marketplace for these drugs due to patent protection, which allows these firms to act as monopolists (See  Drug Price Competition and Patent Term Restoration Act ).  Due to this lack of competition, policies that serve to limit prices in other markets can be ineffective or even counter-productive when applied to specialty drugs. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3473", "text": "High prices for specialty drugs are a problem for both patients and payers.  Patients frequently have difficulty paying for these medications, which can lead to lack of access to treatment. [ 57 ]   Specialty drugs are now so expensive that they are leading to increases in insurance premiums. [ 58 ]   Control of specialty drug prices will require research to identify effective policy options, which may include: decreasing regulation, limiting patent protection, allowing negotiation of drug prices by Medicare, or pricing drugs based on their effectiveness. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3474", "text": "In the United States, private insurance payers will favour a lower-cost agent preferring generics and biosimilars to the more expensive specialty drugs if there is no peer-reviewed or evidence-based justification for them. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3475", "text": "According to a 2012 report by  Sun Life Financial  the average cost of specialty drug claims was $10,753 versus $185 for non-specialty drugs and the cost of specialty drugs continues to rise. With such steep prices by 2012 specialty drugs represented 15-20% of prescription drug reimbursement claims. [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3476", "text": "Patient advocacy groups that lobby for payment for specialty drugs include the  Alliance for Patient Access  (AfPA), formed in 2006 and which according to a 2014 article in the  Wall Street Journal  \"represents physicians and is largely funded by the pharmaceutical industry. The contributors mostly include brand-name drug makers and biotechs, but some\u2014such as Pfizer and Amgen\u2014are also developing biosimilars.\" [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3477", "text": "In 2013 AfPA director  David Charles  published an article on specialty drugs in which he agreed with the findings of the  Congressional Budget Office  that spending on prescription medications \"saves costs in other areas of healthcare spending\". [ 62 ]  He observed that specialty drugs are so high priced that many patients do not fill prescriptions resulting in more serious health problems increasing. His article referred to specialty drugs such as \"new cancer drugs specially formulated for patients with specific genetic markers\". [ 62 ]  He explained the high cost of these \"individualized medications based on diagnostic testing; and \"biologics\", or medicines created through biologic processes, rather than chemically synthesized like most pharmaceuticals\". [ 62 ]  He argued that there should be a slight increase in co-pays for the more commonly using lower-tier medications to allow a lower co-pay for those who \"require high-cost specialty tier medications\". [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3478", "text": "According to the 2014 Express Scripts Drug Trend Report, [ 51 ]  the most significant increase in prescription drugs in the United States in 2014 was due to \"increased inflation and utilization of hepatitis C and compounded medications\". [ 51 ]  \"Excluding those two therapy classes, overall drug spend would have increased only 6.4%. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3479", "text": "The cost of \"the top three specialty therapy classes\u2014inflammatory conditions, multiple sclerosis and oncology\u2014contributed 55.9% of the spend for all specialty medications billed through the pharmacy benefit in 2014. The U.S. spent 742.6% more on hepatitis C medications in 2014 than it did in 2013; this therapy class was not among the top 10 specialty classes in 2013. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3480", "text": "As the market demanded specialization in drug distribution and clinical management of complex therapies, specialized pharma (SP) evolved.\u0084 [ 63 ]  By 2001  CVS ' specialty pharmacy ProCare was the \"largest integrated retail/mail provider of specialty pharmacy services\" in the United States. [ 34 ] :\u200a10\u200a  It was consolidated with their pharmacy benefit management company, PharmaCare in 2002 to In their 2001 annual report CVS anticipated that the \"$16 billion specialty pharmacy market\" would grow at \"an even faster rate than traditional pharmacy due in large part to the robust pipeline of biotechnology drugs\". [ 34 ]  By 2014 CVS Caremark,  Express Scripts  and  Walgreens  represented more than 50% of the specialty drug market in the United States. [ 35 ] :\u200a4"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3481", "text": "The  specialty pharmacy  business had $20 billion in sales in 2005. By 2014 it had grown to \"$78 billion in sales\". [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3482", "text": "Specialty pharmacies came into existence to as a result of unmet needs. According to the  National Comprehensive Cancer Network  the \"primary goals of specialty pharmacies are to ensure the appropriate use of medications, maximize drug adherence, enhance patient satisfaction through direct interaction with healthcare professionals, minimize cost impact, and optimize pharmaceutical care outcomes and delivery of information\". [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3483", "text": "McKesson Specialty Care Solutions, a division of McKesson Corporation, is \"one of the largest distributors of specialty drugs, biologics and rheumatology drugs to community-based specialty practices\". It is \"a leader in the development, implementation and management of FDA-mandated Risk Evaluation and Mitigation Strategies (REMS) for manufacturers\". [ 65 ]  For example, in order ProStrakan Group plc, an international pharmaceutical company based in the UK works with McKesson Specialty Care Solutions to administer its FDA-approved Risk Evaluation and Mitigation Strategy (REMS) program for  Abstral . [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3484", "text": "URAC's Specialty Pharmacy Accreditation \"provides an external validation of excellence in Specialty Pharmacy Management and provides Continuous Quality Improvement (CQI) oriented processes that improve operations and enhance compliance\". [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3485", "text": "Specialty pharmaceuticals or biologics are a significant part of the treatment market, yet there is still additional work that should be done to manage costs.\u00a0 Defining biologics has been described as a matter of perspective, with variation between chemists, physicians, payers, microbiologists and regulators. [ 66 ] \u00a0A payer may define a biologic by cost, while a biochemist may look at composition and structure and a provider at means of delivery or action on the body. [ 66 ]  \u00a0The FDA generally defines biologics as, \"a wide range of products [that] ...can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources\u2014human, animal, or microorganism\u2014and may be produced by biotechnology methods and other cutting-edge technologies\". [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3486", "text": "Due to the complexity, risk of adverse events and allergic reactions associated with biologics, management is very important for the safety of patients. [ 68 ] \u00a0 Management includes areas from patient education and adherence to the delivery of the medication.\u00a0 These medications often require very specific storage conditions and monitoring of temperature, the level of agitation and proper reconstitution of the drug . [ 68 ] \u00a0 Because of the high risk of error and adverse events, provider management of delivery is required, especially for injection or infusion of some biologic medications. Such biologics are often coded in a way that ties reimbursement to delivery by a provider\u2014either a specialty pharmacist or medical care provider with those skills. [ 69 ]  \u00a0 As more biologics are being designed to be self-administered pharmacists are supporting the management of these drugs.\u00a0 They make calls to remind patients of the need for refills, provide education to patients, monitor patients for adverse events and work with primary care provider offices to monitor the outcomes of the medication. [ 69 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3487", "text": "The high cost of specialty pharmaceuticals is one of their defining characteristics; as such, cost-containment is high on the list of all the players in the arena.\u00a0 For physician-administered biologics, cost-containment is often handled by volume purchasing of biologic drugs for discounted pricing, formularies, step therapy to attempt other treatment before beginning biologics and administrative fees by insurers to keep physicians from artificially inflating requested reimbursement from insurance companies. [ 70 ] [ 69 ] [ 68 ] \u00a0 Cost-containment for self-administered biologics tends to occur via requiring authorization to be prescribed those drugs and benefit design, such as coinsurance for cost-sharing. [ 70 ] [ 69 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3488", "text": "The 21st Century Cures Act which addressed fast-tracking approval of specialty pharmaceuticals was particularly beneficial for dealing with the development of 2nd run biologics (which might be more easily understood as \"generic biologics\", though they do not exist). [ 71 ]  \u00a0Debate around the act raised some important questions about the efficacy of biologics and their continued high costs.\u00a0Some call for insurers to pay only the cost of production to manufacturers until the benefit of these biologics can be proven long-term, stating that insurers should not bear the full cost of products that may be unreliable or have only limited efficacy. [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3489", "text": "Achieving this would require conducting studies that assess value, such as comparative effectiveness studies and using those studies to determine pricing. Comparative effectiveness would examine all aspects of the use of biologics, from outcomes such as clinical benefits and potential harms, to efficiency of administration, public health benefits and patient productivity after treatment. [ 72 ]   This is a new direction in managing the high costs of specialty pharmaceuticals and not without challenges.\u00a0 One of the barriers is strict regulation by the Food and Drug Administration of what pharmaceutical manufacturers may communicate to the public, limiting that communication to formulary committees for managed care, for example. [ 73 ]  \u00a0 Additionally, studies tend to be constructed using observational design, instead of as randomized controlled trials, limiting their usefulness for real-world application. [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3490", "text": "Difficulties experienced with patient adherence to specialty pharmaceuticals also limit the availability of real-world outcomes data for biologics. [ 71 ] [ 69 ]   In 2016, real world data evaluating the efficacy of biologics was only publicly available for multiple myeloma through ICER (where biologics were found to be overpriced for their outcomes) [ 72 ]  and for hepatitis C treatment (which achieved high cure rates\u201490%\u2014for patients co-infected with HIV and Hep C) through Curant Health. [ 71 ]  \u00a0 These studies show how useful value-based pricing may become for cost-containment in the field.\u00a0 The good news is that there are effectiveness studies on biologics currently underway aiming to provide more of this data. [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3491", "text": "Biologics or biological products for human use are regulated by the  Center for Biologics Evaluation and Research  (CBER), overseen by the  Office of Medical Products and Tobacco , within the U.S. Food and Drug Administration which includes the  Public Health Service Act  and the  Federal Food, Drug and Cosmetic Act . [ 74 ]  \"CBER protects and advances the public health by ensuring that biological products are safe and effective and available to those who need them. CBER also provides the public with information to promote the safe and appropriate use of biological products.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_3492", "text": "There are multiple players in specialty drugs including the employer, the health plan, the  pharmacy benefits manager  and it is unclear who should be in charge of controlling costs and monitoring care. [ 6 ]  Pharmacies generally buy a product from a wholesaler and sell (Buy & Bill) it to the patient and provide basic drug use information and counseling. According to Maria Hardin, vice president of patient services for the  National Organization for Rare Disorders , an alliance of voluntary health and patient advocacy groups working with rare diseases, \"As the cost of drugs increases, management of the financial side has gotten more complex... The issues range from Medicare Part D to tiered benefits, prior authorizations, and no benefits. These patients need a pharmacy with the expertise and the clout to go to bat for them. If the patient doesn't get treated, the specialty pharmacy doesn't get paid.\" [ 75 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3493", "text": "Alexion Pharmaceuticals was one of the pioneers in the use of a business model of developing drugs to combat rare diseases. \"Knowing the value of specialty drugs as well as its own stock is Alexion's business.\" [ 76 ]  Since other big pharmaceutical companies had tended to ignore these markets, Alexion had minimal competition at first. Insurance companies have generally been willing to pay high prices for such drugs; since few of their customers need the drugs, a high price does not significantly impact the insurance companies outlays. [ 76 ]  Alexion is thus seeking a stronger position in the lucrative rare disease market, and is willing to pay a premium to obtain that position. [ 14 ] [ 76 ]   The rare disease market is seen as desirable because insurers have minimal motive to deny claims (due to small population sizes of patients) and are unable to negotiate better drug prices due to lack of competition. of May 2015, Alexion is currently seeking approval of its second drug, Strensiq.  It will be used to treat hypophosphatasia, a rare metabolic disorder. In 2015 Alexion estimated that Synageva, its specialty drug for  lysosomal acid lipase deficiency , a fatal genetic disorder, could eventually have annual sales of more than $1 billion. [ 14 ] [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3494", "text": "Companies like Magellan RX Management provide a \"single source for high-touch patient care management to control side effects, patient support and education to ensure compliance or continued treatment, and specialized handling and distribution of medications directly to the patient or care provider. Specialty medications may be covered under either the medical or pharmacy benefit.\" [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3495", "text": "According to an article published in 2014 in the journal  Pharmacoeconomics , [ 78 ]  \"[s]pecialty pharmacies combine medication dispensing with clinical disease management. Their services have been used to improve patient outcomes and contain costs of specialty pharmaceuticals. These may be part of independent pharmacy businesses, retail pharmacy chains, wholesalers, pharmacy benefit managers, or health insurance companies. Over the last several years, payers have been transitioning to obligate beneficiaries to receive self-administered agents from contracted specialty pharmacies, limiting the choice of acceptable specialty pharmacy providers (SPPs) for patient services.\" [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3496", "text": "Managed care organizations  contract with Specialty Pharmacy vendors. \"Managed care organizations (MCOs) are using varied strategies to manage utilization and costs. For example, 58% of 109 MCOs surveyed implement prior authorizations for MS specialty therapies.\" [ 78 ]  The  Academy of Managed Care Pharmacy  (AMCP) designates a product as a specialty drug if \"[i]t requires a difficult or unusual process of delivery to the patient (preparation, handling, storage, inventory, distribution, Risk Evaluation and Mitigation Strategy (REMS) programs, data collection, or administration) or, Patient management prior to or following administration (monitoring, disease or therapeutic support systems)\". [ 79 ]  Health plans consider \"high cost\" (on average a minimum monthly costs of $US1,200) to be is a determining factor in identifying a specialty drug. [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3497", "text": "Tom Westrich, of St. Louis, Missouri-based Centric Health Resources, a specialty pharmacy, described how their specialty drugs treat  ultra-orphan diseases  with a total patient population of 20,000 nationwide. [ 75 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3498", "text": "The top ten specialty pharmacies in 2014 were CVS Specialty parent company  CVS Health  with $20.5B in sales,  Express Scripts 's  Accredo  at $15B,  Walgreens Boots Alliance 's Walgreens Specialty at $8.5B,  UnitedHealth Group 's  OptumRx  at $2.4B, Diplomat Pharmacy at $2.1B, \n Catamaran 's BriovaRx at $2.0B, Specialty Prime Therapeutics's  Prime Therapeutics  at $1.8B,  Omnicare 's Advanced Care Scripts at $1.3B,  Humana 's RightsourceRx at $1.2B, Avella at $0.8B. All the other specialty pharmacies accounted for $22.4B of sales in 2014 with a total of $78B. [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3499", "text": "In 2010 the United States enacted a new health law which had unintended consequences. Because of the 2010 law, drug companies like  Genentech  informed children's hospitals that they would no longer get discounts for certain cancer medicines such as the orphan drugs  Avastin ,  Herceptin ,  Rituxan ,  Tarceva , or  Activase . This cost hospitals millions of dollars. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3500", "text": "There is a debate about whether specialty drugs should be managed as a medical benefit or a pharmaceutical benefit. Infused or injected medications are usually covered under the medical benefit and oral medications are covered under the pharmacy benefit. Self-injected medications may be either. [ 82 ]  \"Many biologics, such as chemotherapy drugs, are administered in a doctor's office and require extensive monitoring, further driving up costs.\" [ 6 ]  Chemotherapy is usually  delivered   intravenously , although a number of agents can be administered orally (e.g. specialty drugs,  melphalan  (trade name Alkeran),  busulfan ,  capecitabine ).  Delcath Systems, Inc.  (NASDAQ: DCTH) a specialty pharmaceutical and medical device company manufactures melphalan. [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3501", "text": "By 2011 the oral medications for cancer patients represented approximately 35% of cancer medications. Prior to the increase in cancer oral drugs community cancer centers were used to managing office-administered  chemotherapy  treatments. At that time \"the majority of community oncology practices were unfamiliar with the process of prescribing and obtaining drugs that are covered under the pharmacy benefit\" and \"conventional retail pharmacy chains were ill-prepared to stock oral oncology agents, and were not set up to deliver the counseling that often accompanies these medications\". [ 84 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3502", "text": "According to  IMS Health  \"Specialty pharmaceutical spending is on the rise and is expected to increase from approximately $55 billion in 2005 to $1.7 trillion in 2030, according to the Pharmaceutical Care Management Association. That reflects an increase from 24% of total drug spend in 2005 to an estimated 44% of a health plan's total drug expenditure in 2030.\" [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3503", "text": "While CVS, Accredo, and Walgreens led the Specialty Pharmacies (SP) market in revenue in 2014, there are constant changes through mergers and acquisitions in terms of SPs and specialty distributors (SDs). [ 85 ]  The SP/SD network faces common strengths such as \"in-depth clinical management, coordinated/comprehensive care, and early limited distribution network success\" and common weaknesses, \"lack of ability to customize services, poor integration experience and outcomes, and strained pharma relations\". [ 85 ]   BioScrip  was acquired by Walgreens in 2012. [ 86 ]  Specialty companies like Genzyme and MedImmune were acquired and are transitioning to a new business model. [ 53 ] :\u200a12"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3504", "text": "According to Nicolas Basta, by 2013 there was \"a spate of new entities\" called hub services, \"mechanisms by which manufacturers can keep a grip on the marketplace\" in specialty pharma. The \"biggest and oldest of these organizations\" are \"offshoots of insurance companies or [Pharmacy benefit managers] PBMs, such as Express Scripts' combination of  Accredo  and CuraScript (both specialty pharmacies) and HealthBridge (physician and patient support). UnitedHealth, an insurance company, operates OptumRx, a PBM, which has a specialty unit within it. Cigna has Tel-Drug, a mail-order pharmacy and support system.\" [ 87 ]  Basta described how Hubs have been around since about 2002 \"starting out as \"reimbursement hubs\"\", usually provided as a service by manufacturers to help patients and providers navigate the process of obtaining permission to use, and reimbursement for, expensive specialty therapies\". Industry observers look to pioneering efforts by  Genentech  and  Genzyme  under the tenure of  Henri Termeer , \"when some of their earliest biotech products entered the marketplace\". [ 87 ]  Specialty hubs provide reimbursement support to physicians and patients as well as patient education including medical hotlines. There is a voluntary program enrollment and registry intake with Patient Assistance Program management."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3505", "text": "According to a 2007 study by employees of  Express Scripts  or its wholly owned subsidiary  CuraScript  on specialty pharmacy costs, if payers manage cost control through copayments with patients, there is an increased risk that patients will forego essential but expensive specialty drugs. [ 88 ] :\u200a6\u200a  and health outcomes were compromised. [ 39 ] :\u200a69\u200a  In 2007 these researchers suggested in the adoption of formularies and other traditional drug-management tools. They also recommended specialty drug utilization management programs that guide treatment plans and improve outpatient compliance. [ 88 ] :\u200a88"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3506", "text": "By 2010  Alexion Pharmaceuticals 's  Soliris , was considered to be the most expensive drug in the world. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3507", "text": "In a 2012 article in the  New York Times,  journalist Andrew Pollack described how  Don M. Bailey , a mechanical engineer by training who became interim president of Questcor Pharmaceuticals, Inc. (Questcor) in May 2007, initiated a new pricing model for  Acthar  in August 2007 [ 89 ]  when it was classified by FDA as an  orphan drug  and a specialty drug to treat infantile spasms. [ 90 ]  Questcor, a biopharmaceutical company, focuses on the treatment of patients with \"serious, difficult-to-treat autoimmune and inflammatory disorders\". Its primary product is FDA-approved Acthar, an injectable drug that is used for the treatment of 19 indications. [ 91 ]  At the same time Questcor created \"an expanded safety net for patients using Acthar\", provided a \"group of  Medical Science Liaisons  to work with health care providers who are administering Acthar\" and limited distribution to its sole specialty distributor,  Curascript . The 2007 pricing model brought \"Acthar in line with the cost of treatments for other very rare diseases\". [ 89 ]  The cost for a course of treatment in 2007 was estimated at about \"$80,000\u2013$100,000\". [ 89 ]  Acthar is now manufactured through a contractor on  Prince Edward Island , Canada. [ 91 ]  The price increased from $40 a vial to $700 and continued to increase. [ 90 ]  By 2012 the price of a vial of Acthar was $28,400. [ 90 ]  and was considered to be one of the world's most expensive drugs in 2013."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3508", "text": "By 2014 the price of  Gilead 's specialty drug for hepatitis C,  Sovaldi  or  sofosbuvir , was $84,000 to $168,000 for a course of treatment in the U.S., \u00a335,000 in the UK for 12 weeks. [ 92 ]  Sovaldi is on the  World Health Organization's most important medications needed  in a basic health system and the steep price is highly controversial. [ 93 ] [ 94 ] [ 95 ]  In 2014 the U.S. spent 742.6% more on hepatitis C medications than it did in 2013. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3509", "text": "In September 2015,  Martin Shkreli  was criticized by several health organizations [ 96 ]  for obtaining manufacturing licenses on old,  out-of-patent , [ 97 ]  life-saving medicines including pyrimethamine (brand name  Daraprim ), which is used to treat patients with  toxoplasmosis ,  malaria , some cancers, and  AIDS , [ 98 ]  and then increasing the price of the drug in the US from $13.50 to $750 per pill, a 5,455% increase. [ 99 ] [ 100 ]  In an interview with  Bloomberg News , Shkreli claimed that despite the price increase, patient co-pays would be lower, that many patients would get the drug at no cost, that the company has expanded its free drug program, and that it sells half of the drugs for one dollar. [ 101 ] [ 102 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3510", "text": "In 2015  Bloomberg News  used the term 'captive pharmacies' to describe the alleged exclusive agreements such as that between the specialty mail-order pharmacy  Philodor  and  Valeant , mail-order pharmacy  Linden Care  and  Horizon Pharma Plc . In November 2015  Express Scripts  Holding Co.\u2014the largest U.S. manager of prescription drug benefits\u2014\"removed the mail-order pharmacy Linden Care LLC from its network after concluding it dispensed a large portion of its medications from Horizon Pharma Plc and didn't fulfill its contractual agreements\". Express Scripts was \"evaluating other 'captive pharmacies' that it said are mostly distributing Horizon drugs\". In 2015 specialty pharmacies like \"Philidor drew attention for the lengths they went to fill prescriptions with brand-name drugs and then secure insurance reimbursement. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3511", "text": "According to Pfenex, a clinical-stage biotechnology company, the proposed terms in the Trans-Pacific Partnership, a trade agreement between twelve  Pacific Rim  countries, meant that all participating countries had to adopt the United States' lengthy drug patent exclusivity protection period of 12 years for biologics and specialty drugs. [ 103 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3512", "text": "In 1981 an episode of the television series  Quincy, M.E.  starring star,  Jack Klugman  as Quincy, entitled \"Seldom Silent, Never Heard\" brought the plight of children with orphan diseases to public attention. In the episode, Jeffrey, a young boy with  Tourette syndrome , died after falling from a building. Dr. Arthur Ciotti ( Michael Constantine ), a medical doctor who had been researching Tourette syndrome for years wanted to study Jeffrey's brain to discover the cause and cure for the rare disease. He explained to Quincy that drug companies, like the one where he worked, were not interested in doing the research because so few people were afflicted with them that it was not financially viable. [ 104 ]  In 1982 another episode \"Give Me Your Weak\" Klugman as Quincy testified before Congress in an effort to get the Orphan Drug Act passed. He was moved by the dilemma of a young mother with  myoclonus . [ 13 ] [ 105 ] [ 106 ] [ 107 ] [ 108 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3513", "text": "Stem-cell therapy  uses  stem cells  to treat or prevent a disease or condition. [ 1 ]  As of 2024 [update] , the only FDA-approved therapy using stem cells is  hematopoietic stem cell transplantation . [ 2 ] [ 3 ]  This usually takes the form of a  bone marrow  or  peripheral blood stem cell  transplantation, but the cells can also be derived from  umbilical cord blood . Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for  neurodegenerative diseases [ 4 ]  and conditions such as  diabetes  and  heart disease ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3514", "text": "Stem-cell therapy has become controversial following developments such as the ability of scientists to isolate and culture  embryonic stem cells , to create stem cells using  somatic cell nuclear transfer , and their use of techniques to create  induced pluripotent stem cells . This controversy is often related to  abortion politics  and   human cloning . Additionally, efforts to market treatments based on transplant of stored umbilical  cord blood  have been controversial."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3515", "text": "For over 90 years,  hematopoietic stem cell transplantation  (HSCT) has been used to treat people with conditions such as  leukemia  and  lymphoma ; this is the only widely practiced form of stem-cell therapy. [ 5 ] [ 6 ] [ 7 ]  During  chemotherapy , most growing cells are killed by the  cytotoxic  agents. These agents, however, cannot discriminate between the leukaemia or neoplastic cells, and the  hematopoietic stem cells  within the bone marrow. This is the side effect of conventional chemotherapy strategies that the stem-cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to  graft vs host disease , the most serious side effect of this treatment. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3516", "text": "Another stem-cell therapy, called  Prococvhymal , was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids. [ 9 ]  It is an  allogenic stem therapy  based on  mesenchymal stem cells  (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3517", "text": "The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3518", "text": "In 2014, the  European Medicines Agency  recommended approval of  limbal stem cells  for people with severe limbal stem cell deficiency due to burns in the eye. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3519", "text": "Stem cells are being studied for several reasons. The molecules and  exosomes  released from stem cells are also being studied in an effort to make medications. [ 13 ]  In addition to the functions of the cells themselves,  paracrine soluble factors  produced by stem cells, known as the  stem cell secretome , have been found to be another mechanism by which stem cell-based therapies mediate their effects in  degenerative ,  autoimmune , and  inflammatory  diseases. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3520", "text": "Most stem cells intended for regenerative therapy are generally isolated either from the patient's  bone marrow  or from  adipose tissue . [ 15 ] [ 16 ]   Mesenchymal stem cells  can differentiate into the cells that make up bone, cartilage, tendons, and ligaments, as well as muscle, neural and other progenitor tissues. They have been the main type of stem cells studied in the treatment of diseases affecting these tissues. [ 17 ] [ 18 ]  The number of stem cells transplanted into damaged tissue may alter the efficacy of treatment. Accordingly, stem cells derived from bone marrow aspirates, for instance, are cultured in specialized laboratories for expansion to millions of cells. [ 15 ] [ 16 ]  Although adipose-derived tissue also requires processing prior to use, the culturing methodology for adipose-derived stem cells is not as extensive as that for bone marrow-derived cells. [ 19 ]  While it is thought that bone-marrow-derived stem cells are preferred for bone, cartilage, ligament, and tendon repair, others believe that the less challenging collection techniques and the multi-cellular microenvironment already present in adipose-derived stem cell fractions make the latter the preferred source for autologous transplantation. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3521", "text": "New sources of  mesenchymal stem cells  are being researched, including stem cells present in the skin and dermis which are of interest because of the ease at which they can be harvested with minimal risk to the animal. [ 21 ]  Hematopoietic stem cells have also been discovered to be travelling in the blood stream and possess equal differentiating ability as other  mesenchymal stem cells , again with a very non-invasive harvesting technique. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3522", "text": "There has been more recent interest in the use of extra embryonic  mesenchymal stem cells . Research is underway to examine the differentiating capabilities of stem cells found in the umbilical cord, yolk sac and placenta of different animals. These stem cells are thought to have more differentiating ability than their adult counterparts, including the ability to more readily form tissues of endodermal and ectodermal origin. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3523", "text": "As of 2010, there was widespread controversy over the use of human  embryonic stem cells . This controversy primarily targets the techniques used to derive new embryonic  stem cell lines , which often requires the destruction of the  blastocyst . Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral, or religious objections. [ 24 ]  There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells, and induced pluripotent stem cells."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3524", "text": "In January 2009, the US  Food and Drug Administration  gave clearance to  Geron Corporation  for the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed to evaluate the drug GRNOPC1,  embryonic stem cell -derived  oligodendrocyte  progenitor cells, on people with acute  spinal cord injury . The trial was discontinued in November 2011 so that the company could focus on therapies in the \"current environment of capital scarcity and uncertain economic conditions\". [ 25 ]  In 2013 biotechnology and  regenerative medicine  company  BioTime  ( AMEX :\u00a0 BTX ) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3525", "text": "Scientists reported 2012 that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth (fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in  in vitro  culture before administration. Re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various MSC clinical trials which used cryopreserved product immediately post thaw have failed as compared to those clinical trials which used fresh MSCs. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3526", "text": "The ability to grow up functional adult tissues indefinitely in culture through  Directed differentiation  creates new opportunities for drug research. Researchers are able to grow up differentiated cell lines and then test new drugs on each cell type to examine possible interactions  in vitro  before performing  in vivo  studies. This is critical in the development of drugs for use in veterinary research because of the possibilities of species-specific interactions. The hope is that having these cell lines available for research use will reduce the need for research animals used because effects on human tissue  in vitro  will provide insight not normally known before the animal testing phase. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3527", "text": "To be used for research or treatment applications, large numbers of high-quality stem cells are needed. Thus, it is necessary to develop culture systems which produce pure populations of tissue-specific stem cells  in vitro  without the loss of stem-cell potential. Two main approaches are taken for this purpose: two-dimensional and three-dimensional cell culture. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3528", "text": "Cell culture in two dimensions has been routinely performed in thousands of laboratories worldwide for the past four decades. In two-dimensional platforms, cells are typically exposed to a solid, rigid flat surface on the basal side and to liquid at the apical\nsurface. Inhabiting such a two-dimensional rigid substrate requires a dramatic adaption for the surviving cells because they lack the extracellular matrix that is unique to each cell type which may alter cell metabolism and reduce its functionality. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3529", "text": "Three-dimensional cell culture systems may create a biomimicking microenvironment for stem cells, resembling their native three-dimensional extracellular matrix (ECM). Advanced biomaterials have significantly contributed to three-dimensional cell culture systems in recent decades, and more unique and complex biomaterials have been proposed for improving stem-cell proliferation and controlled differentiation. Among them, nanostructured biomaterials are of particular interest because they have the advantage of a high surface-to-volume ratio, and they mimic the physical and biological features of natural ECM at the nanoscale. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3530", "text": "Stem cells are thought to mediate repair via five primary mechanisms: 1) providing an anti-inflammatory effect, 2) homing to damaged tissues and recruiting other cells, such as  endothelial progenitor cells , that are necessary for tissue growth, 3) supporting tissue remodeling over scar formation, 4) inhibiting  apoptosis , and 5) differentiating into bone, cartilage, tendon, and ligament tissue. [ 30 ] [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3531", "text": "To further enrich blood supply to the damaged areas, and consequently promote tissue regeneration, platelet-rich plasma could be used in conjunction with stem cell transplantation. [ 20 ] [ 15 ]  The efficacy of some stem cell populations may also be affected by the method of delivery; for instance, to regenerate bone, stem cells are often introduced in a scaffold where they produce the minerals necessary for generation of functional bone. [ 20 ] [ 15 ] [ 32 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3532", "text": "Stem cells have been shown to have low immunogenicity due to the relatively low number of MHC molecules found on their surface. In addition, they have been found to secrete chemokines that alter the immune response and promote tolerance of the new tissue. This allows for  allogeneic  treatments to be performed without a high rejection risk. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3533", "text": "Research has been conducted on the effects of stem cells on animal models of  brain degeneration , such as in  Parkinson's disease ,  Amyotrophic lateral sclerosis , and  Alzheimer's disease . [ 33 ] [ 34 ] [ 35 ]  Preliminary studies related to  multiple sclerosis  have been conducted, [ 36 ] [ 37 ] [ 38 ]  and a 2020 phase 2 trial found significantly improved outcomes for  mesenchymal stem cell  treated patients compared to those receiving a sham treatment. [ 39 ]  In January 2021 the FDA approved the first clinical trial for an investigational stem cell therapy to restore lost brain cells in people with advanced Parkinson's disease. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3534", "text": "Healthy adult brains contain  neural stem cells , which divide to maintain general stem-cell numbers, or become  progenitor cells . In healthy adult laboratory animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for  olfaction  (the sense of smell). Pharmacological activation of  endogenous  neural stem cells has been reported to induce  neuroprotection  and behavioral recovery in adult rat models of neurological disorders. [ 41 ] [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3535", "text": "Stroke and  traumatic brain injury  lead to  cell death , characterized by a loss of neurons and  oligodendrocytes  within the brain. Clinical and animal studies have been conducted into the experimental use of stem cells in cases of  spinal cord injury . [ 44 ] [ 45 ] [ 46 ] [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3536", "text": "In 2017, a small-scale study on individuals 60 years or older with aging frailty showed, after intravenous treatment with  Mesenchymal stem cells (MSC)  from healthy young donors, significant improvements in physical performance measures. MSC helps with the blockade of inflammation by decreasing it, causing the effects of frailty to reverse. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3537", "text": "In 2012, stem cells were studied in people with severe  heart disease . [ 48 ]  The work by  Bodo-Eckehard Strauer [ 49 ]  was discredited by identifying hundreds of factual contradictions. [ 50 ]  Among several clinical trials reporting that adult stem cell therapy is safe and effective, actual evidence of benefit has been reported from only a few studies. [ 51 ]  Some preliminary clinical trials achieved only modest improvements in heart function following the use of  bone marrow  stem cell therapy. [ 52 ] [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3538", "text": "Stem-cell therapy for the treatment of myocardial infarction usually makes use of autologous bone marrow stem cells, but other types of adult stem cells may be used, such as adipose-derived stem cells. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3539", "text": "Possible mechanisms of recovery include: [ 33 ] Generation of heart muscle cells, Stimulating growth of new blood vessels to repopulate damaged heart tissue and secretion of  growth factors ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3540", "text": "The specificity of the human immune-cell repertoire is what allows the human body to defend itself from rapidly adapting antigens. However, the immune system is vulnerable to degradation upon the pathogenesis of disease, and because of the critical role that it plays in overall defense, its degradation is often fatal to the organism as a whole. Diseases of hematopoietic cells are diagnosed and classified via a subspecialty of pathology known as  hematopathology . The specificity of the immune cells is what allows recognition of foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient are no longer required for successful transplantation.  Rather, haploidentical matches have facilitated numerous transplants, given improvements in post-transplant immunosuppressive regimens. [ 55 ]  Research using both hematopoietic adult stem cells and embryonic stem cells has provided insight into the possible mechanisms and methods of treatment for many of these ailments. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3541", "text": "Fully mature human  red blood cells  may be generated  ex vivo  by  hematopoietic stem cells  (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with  stromal cells , creating an environment that mimics the conditions of bone marrow, the natural site of red-blood-cell growth.  Erythropoietin , a  growth factor , is added, coaxing the stem cells to complete terminal differentiation into red blood cells. [ 57 ]  Further research into this technique should have potential benefits for gene therapy, blood transfusion, and topical medicine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3542", "text": "In 2004, scientists at  King's College London  discovered a way to cultivate a complete tooth in mice [ 58 ]  and were able to grow bioengineered teeth stand-alone in the laboratory. Researchers are confident that   tooth regeneration  technology can be used to grow live teeth in people."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3543", "text": "In theory, stem cells taken from the patient could be coaxed in the lab turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to be grown in a time over three weeks. [ 59 ]  It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth. Many challenges remain, however, before stem cells can be a choice for the replacement of missing teeth in the future. [ 60 ] [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3544", "text": "Heller has reported success in re-growing cochlea hair cells with the use of  embryonic stem cells . [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3545", "text": "In a 2019 review that looked at hearing regeneration and regenerative medicine, stem cell-derived otic progenitors have the potential to greatly improve hearing. [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3546", "text": "Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. \"Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable.\" When these sheets are transplanted over the damaged  cornea , the stem cells stimulate renewed repair, eventually restoring vision. [ 64 ]  The latest such development was in June 2005, when researchers at the  Queen Victoria Hospital  of  Sussex , England were able to restore the sight of forty people using the same technique. The group, led by  Sheraz Daya , was able to successfully use adult stem cells obtained from the patient, a relative, or even a  cadaver . Further rounds of trials are ongoing. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3547", "text": "People with  Type 1 diabetes  lose the function of insulin-producing  beta cells  within the pancreas. In a 2007 publication of experiments, scientists have been able to coax embryonic stem cells to turn into beta cells in the lab. In theory, if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient. [ 66 ]  There are adverse effects of high glucose concentrations on stem cell therapy, however. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3548", "text": "As of 2017, use of  mesenchymal stem cells (MSCs)  derived from adult stem cells was under preliminary research for potential  orthopedic  applications in bone and muscle trauma,  cartilage  repair,  osteoarthritis ,  intervertebral disc  surgery,  rotator cuff  surgery, and  musculoskeletal disorders , among others. [ 68 ]  Other areas of orthopedic research for uses of MSCs include  tissue engineering  and  regenerative medicine . [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3549", "text": "Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by  scar tissue , which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells. [ 69 ]  A possible method for tissue regeneration in adults is to place adult stem cell \"seeds\" inside a tissue bed \"soil\" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation. [ 69 ]  As of 2018, researchers were still investigating different aspects of the \"soil\" tissue that are conducive to regeneration. [ 69 ]  Because of the general healing capabilities of stem cells, they have gained interest for the treatment of cutaneous wounds, such as in  skin cancer . [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3550", "text": "In 2013, scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC). [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3551", "text": "In 2013, studies of autologous bone marrow stem cells on ventricular function were found to contain \"hundreds\" of discrepancies. [ 50 ]  Critics report that of 48 reports, just five underlying trials seemed to be used, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578-patient randomized trial and as a 391-subject observational study. Other reports required (impossible) negative standard deviations in subsets of people or contained fractional subjects, negative NYHA classes. Overall, many more people were reported as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013. [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3552", "text": "In 2014, a  meta-analysis  on stem cell therapy using bone-marrow stem cells for heart disease revealed discrepancies in published clinical trial reports, whereby studies with a higher number of discrepancies showed an increase in effect sizes. [ 73 ]  Another meta-analysis based on the intra-subject data of 12 randomized trials was unable to find any significant benefits of stem cell therapy on primary endpoints, such as major  adverse events  or increase in heart function measures, concluding there was no benefit. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3553", "text": "2018 results of the TIME trial, which used a randomized, double-blind, placebo-controlled trial design, concluded that \"bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years\" in people who had a myocardial infarction. [ 75 ]  Accordingly, the BOOST-2 trial conducted in 10 medical centers in Germany and Norway reported that the trial result \"does not support the use of nucleated BMCs in patients with STEMI and moderately reduced LVEF\". [ 76 ]  Furthermore, the trial also did not meet any other secondary MRI endpoints, [ 77 ]  leading to a conclusion that intracoronary bone marrow stem cell therapy does not offer a functional or clinical benefit. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3554", "text": "In 2021, stem cell injections in the US have caused grave infections in at least 20 patients who received umbilical cord blood-derived products marketed as \"stem cell treatment\". [ 79 ]  In 2023, the case of a woman who was infected with  Mycobacterium abscessus  and sustained meningitis after stem cell treatment for multiple sclerosis at a commercial clinic in Baja California, Mexico was published. [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3555", "text": "Research conducted on horses, dogs, and cats has led to the development of stem cell treatments in veterinary medicine which can target a wide range of injuries and diseases, such as  myocardial infarction , stroke,  tendon  and  ligament  damage,  osteoarthritis ,  osteochondrosis  and  muscular dystrophy , both in large animals as well as in humans. [ 81 ] [ 82 ] [ 83 ] [ 84 ]  While investigation of cell-based therapeutics generally reflects human medical needs, the high degree of frequency and severity of certain injuries in  racehorses  has put veterinary medicine at the forefront of this novel regenerative approach. [ 85 ]  Companion animals can serve as clinically relevant models that closely mimic human disease. [ 86 ] [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3556", "text": "Veterinary applications of stem cell therapy as a means of tissue regeneration have been largely shaped by research that began with the use of adult-derived  mesenchymal stem cells  to treat animals with injuries or defects affecting bone, cartilage, ligaments and/or tendons. [ 88 ] [ 17 ] [ 89 ]  There are two main categories of stem cells used for treatments: allogeneic stem cells derived from a genetically different donor within the same species, [ 16 ] [ 90 ]  and  autologous   mesenchymal stem cells , derived from the patient before use in various treatments. [ 20 ]  A third category,  xenogenic  stem cells, or stem cells derived from different species, are used primarily for research purposes, especially for human treatments. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3557", "text": "Bone has a unique and well-documented natural healing process that normally is sufficient to repair fractures and other common injuries. Misaligned breaks due to severe trauma, as well as treatments like tumor resections of bone cancer, are prone to improper healing if left to the natural process alone. Scaffolds composed of natural and artificial components are seeded with  mesenchymal stem cells  and placed in the defect. Within four weeks of placing the scaffold, newly formed bone begins to integrate with the old bone and within 32 weeks, full union is achieved. [ 91 ]  Further studies are necessary to fully characterize the use of cell-based therapeutics for treatment of bone fractures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3558", "text": "Stem cells have been used to treat degenerative bone diseases in dogs. The normally recommended treatment for dogs that have Legg\u2013Calve\u2013Perthes disease is to remove the head of the femur after the degeneration has progressed. Recently,  mesenchymal stem cells  have been injected directly in to the head of the femur, with success not only in bone regeneration, but also in pain reduction. [ 91 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3559", "text": "Autologous stem cell-based treatments for  ligament  injury,  tendon  injury,  osteoarthritis ,  osteochondrosis , and sub-chondral bone cysts have been commercially available to practicing veterinarians to treat horses since 2003 in the United States and since 2006 in the United Kingdom. Autologous stem cell based treatments for tendon injury, ligament injury, and  osteoarthritis  in dogs have been available to veterinarians in the United States since 2005. Over 3000 privately owned horses and dogs have been treated with autologous adipose-derived stem cells. The efficacy of these treatments has been shown in double-blind clinical trials for dogs with osteoarthritis of the hip and elbow and horses with tendon damage. [ 92 ] [ 93 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3560", "text": "Race horses are especially prone to injuries of the tendon and ligaments. Conventional therapies are very unsuccessful in returning the horse to full functioning potential. Natural healing, guided by the conventional treatments, leads to the formation of fibrous scar tissue that reduces flexibility and full joint movement. Traditional treatments prevented a large number of horses from returning to full activity and also have a high incidence of re-injury due to the stiff nature of the scarred tendon. Introduction of both bone marrow and adipose derived stem cells, along with natural mechanical stimulus promoted the regeneration of tendon tissue. The natural movement promoted the alignment of the new fibers and tendocytes with the natural alignment found in uninjured tendons. Stem cell treatment not only allowed more horses to return to full duty and also greatly reduced the re-injury rate over a three-year period. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3561", "text": "The use of embryonic stem cells has also been applied to tendon repair. The embryonic stem cells were shown to have a better survival rate in the tendon as well as better migrating capabilities to reach all areas of damaged tendon. The overall repair quality was also higher, with better tendon architecture and collagen formed. There was also no tumor formation seen during the three-month experimental period. Long-term studies need to be carried out to examine the long-term efficacy and risks associated with the use of embryonic stem cells. [ 23 ]  Similar results have been found in small animals. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3562", "text": "Osteoarthritis is the main cause of joint pain both in animals and humans. Horses and dogs are most frequently affected by arthritis. Natural cartilage regeneration is very limited. Different types of  mesenchymal stem cells  and other additives are still being researched to find the best type of cell and method for long-term treatment. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3563", "text": "Adipose-derived  mesenchymal cells  are currently the most often used for stem cell treatment of osteoarthritis because of the non-invasive harvesting. This is a recently developed, non-invasive technique developed for easier clinical use. Dogs receiving this treatment showed greater flexibility in their joints and less pain. [ 94 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3564", "text": "Stem cells have successfully been used to ameliorate healing in the heart after myocardial infarction in dogs. Adipose and bone marrow derived stem cells were removed and induced to a cardiac cell fate before being injected into the heart. The heart was found to have improved contractility and a reduction in the damaged area four weeks after the stem cells were applied. [ 95 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3565", "text": "In 2007, a trial was underway for a patch made of a porous substance onto which the stem cells are \"seeded\" in order to induce tissue regeneration in heart defects. Tissue was regenerated and the patch was well incorporated into the heart tissue. This is thought to be due, in part, to improved angiogenesis and reduction of inflammation. Although cardiomyocytes were produced from the  mesenchymal stem cells , they did not appear to be contractile. Other treatments that induced a cardiac fate in the cells before transplanting had greater success at creating contractile heart tissue. [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3566", "text": "2018 research, such as the European  nTRACK  research project, aims to demonstrate that multimodal nanoparticles can structurally and functionally track stem cell in muscle regeneration therapy. The idea is to label stem cells with gold nano-particles that are fully characterised for uptake, functionality, and safety. The labelled stem cells will be injected into an injured muscle and tracked using imaging systems. [ 97 ]  However, the system still needs to be demonstrated at lab scale."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3567", "text": "Spinal cord injuries are one of the most common traumas brought into veterinary hospitals. [ 91 ]  Spinal injuries occur in two ways after the trauma: the primary mechanical damage, and in secondary processes, like inflammation and scar formation, in the days following the trauma. These cells involved in the secondary damage response secrete factors that promote scar formation and inhibit cellular regeneration.  Mesenchymal stem cells  that are induced to a neural cell fate are loaded onto a porous scaffold and are then implanted at the site of injury. The cells and scaffold secrete factors that counteract those secreted by scar forming cells and promote neural regeneration. Eight weeks later, dogs treated with stem cells showed immense improvement over those treated with conventional therapies. Dogs treated with stem cells were able to occasionally support their own weight, which has not been seen in dogs undergoing conventional therapies. [ 98 ] [ 99 ] [ 100 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3568", "text": "In a study to evaluate the treatment of experimentally induced MS in dogs using laser activated non-expanded adipose derived stem cells. The results showed amelioration of the clinical signs over time confirmed by the resolution of the previous lesions on MRI. Positive migration of the injected cells to the site of lesion, increased remyelination detected by Myelin Basic Proteins, positive differentiation into Olig2 positive oligodendrocytes, prevented the glial scar formation and restored axonal architecture. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3569", "text": "Treatments are also in clinical trials to repair and regenerate peripheral nerves. Peripheral nerves are more likely to be damaged, but the effects of the damage are not as widespread as seen in injuries to the spinal cord. Treatments are currently in clinical trials to repair severed nerves, with early success. Stem cells induced to a neural fate injected in to a severed nerve. Within four weeks, regeneration of previously damaged stem cells and completely formed nerve bundles were observed. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3570", "text": "Stem cells are also in clinical phases for treatment in ophthalmology. Hematopoietic stem cells have been used to treat corneal ulcers of different origin of several horses. These ulcers were resistant to conventional treatments available, but quickly responded positively to the stem cell treatment. Stem cells were also able to restore sight in one eye of a horse with retinal detachment, allowing the horse to return to daily activities. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3571", "text": "Stem cells are being explored for use in conservation efforts. Spermatogonial stem cells have been harvested from a rat and placed into a mouse host and fully mature sperm were produced with the ability to produce viable offspring. Currently research is underway to find suitable hosts for the introduction of donor spermatogonial stem cells. If this becomes a viable option for conservationists, sperm can be produced from high genetic quality individuals who die before reaching sexual maturity, preserving a line that would otherwise be lost. [ 101 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3572", "text": "In the late 1990s and early 2000s, there was an initial wave of companies and clinics offering stem cell therapy, while not substantiating  health claims  or having regulatory approval. [ 102 ]  By 2012, a second wave of companies and clinics had emerged, usually located in developing countries where medicine is less regulated and offering stem cell therapies on a  medical tourism  model. [ 103 ] [ 104 ]  Like the first wave companies and clinics, they made similar strong, but unsubstantiated, claims, mainly by clinics in the United States, Mexico, Thailand, India, and  South Africa . [ 103 ] [ 104 ]  By 2016, research indicated that there were more than 550 stem cell clinics in the US alone selling generally unproven therapies for a wide array of medical conditions in almost every state in the country, [ 105 ]  altering the dynamic of  stem cell tourism . In 2018, the FDA sent a warning letter to StemGenex Biologic Laboratories in San Diego, which marketed a service in which it took body fat from people, processed it into mixtures it said contained various forms of stem cells, and administered it back to the person by inhalation, intravenously, or infusion into their spinal cords; the company said the treatment was useful for many chronic and life-threatening conditions. [ 106 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3573", "text": "One common marketing tactic is registering on  ClinicalTrials.gov , the US government database for clinical trials. Registration of a study notifies the agency but does not prove that review has taken place. Registration with the FDA similarly does not prove that approval has been granted. [ 107 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3574", "text": "Costs of stem cell therapies range widely by clinic, condition, and cell type, but most commonly range between $10,000-$20,000. [ 108 ]  Insurance does not cover stem cell injections at clinics so patients often use on-line fundraising. [ 109 ]  In 2018, the US  Federal Trade Commission  found health centers and an individual physician making unsubstantiated claims for stem cell therapies, and  forced refunds  of some $500,000. [ 110 ]  The FDA filed suit against two stem cell clinic firms around the same time, seeking permanent injunctions against their marketing and use of unapproved adipose stem cell products. [ 111 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3575", "text": "Although according to the NIH no stem cell treatments have been approved for  COVID-19 , and the agency recommends against the use of MSCs for the disease, [ 112 ]  some stem cell clinics began marketing both unproven and non-FDA-approved stem cells and exosomes for COVID-19 in 2020. [ 113 ]  The FDA took prompt action by sending letters to the firms in question. [ 114 ] [ 115 ]  The FTC also warned a stem cell firm for misleading COVID-19-related marketing. [ 116 ] [ 117 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3576", "text": "[ 118 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3577", "text": "Tumor-homing bacteria  are  facultative  or  obligate anaerobic bacteria  (capable of producing ATP when oxygen is absent or is destroyed in normal oxygen levels) that are able to target  cancerous cells  in the body, suppress tumor growth and survive in the body for a long time even after the infection. When this type of bacteria is administered into the body, it migrates to the cancerous tissues and starts to grow, and then deploys distinct mechanisms to destroy solid tumors. Each bacteria species uses a different process to eliminate the tumor. Some common tumor homing bacteria include  Salmonella ,  Clostridium ,  Bifidobacterium ,  Listeria , and  Streptococcus . [ 1 ]  The earliest research of this type of bacteria was highlighted in 1813 when scientists began observing that patients that had  gas gangrene , an infection caused by the bacteria  Clostridium , were able to have tumor regressions. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3578", "text": "Different strains of tumor homing bacteria in distinct environments use unique or similar processes to inhibit or destroy tumor growth."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3579", "text": "Bacterial cancer therapy is an emerging field for cancer treatment. Although many clinical trials are taking place, as of right now only a few confirmed treatments are being administered to patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3580", "text": "Tumor homing bacteria can be genetically engineered to enhance their anti-tumor activities and be used to transport therapeutic materials based on medical needs. [ 7 ]  They are usually transformed into a  plasmid  that contains the specific gene expression of these therapeutic proteins of the bacteria. After the plasmid reaches the target site, the protein's genetic sequence is expressed and the bacteria can have its full biological effect. Currently, there is no approved treatment with genetically engineered bacteria. However, research is being conducted on  Listeria  and  Clostridium  as vectors to transport  RNAi  (suppresses genes) for  colon cancer . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3581", "text": "Some active tumor-homing bacteria can be harmful to the human body, since they produce toxins that disturb the  cell cycle  which results in altered cell growth and chronic infections. However, many ways to enhance the safety of tumor homing bacteria in the body has been found. For example, when the virulent genes of the bacteria are removed by  gene targeting , a process where genes are deleted or modified, it can be reduced in  pathogenicity [ citation needed ]  (property of causing disease)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3582", "text": "The most researched bacteria for cancer therapy are  Salmonella ,  Listeria,  and  Clostridium.  A genetically engineered strain of  Salmonella  (TAPET-CD) has completed phase 1 clinical trials for patients with stage 4 metastatic cancer. [ 11 ]   Listeria- based cancer vaccines are currently being produced and are undergoing many clinical trials. [ 12 ]  Phase I trials of the  Clostridium  strain called  Clostridium novyi  ( C. novyi -NT) for patients with treatment-refractory tumors or tumors that are unresponsive to treatment is currently underway. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3583", "text": "Sex and drugs  refers to the influence of substances on sexual function and experience. Sex and drugs date back to ancient humans and have been interlocked throughout human history. Sexual performance is known as the execution of the act of sex and the quality of  sexual activity . This includes elements such as  libido  (a person's sexual drive),  sexual function  (including  erection  in males and  vaginal lubrication  in females), sensation (the ability to achieve  orgasm ).  Drugs  are termed as any chemical substance that produces a physiological and or psychological change in an organism. Drugs categorized as  psychoactive drugs ,  antihypertensive drugs ,  antihistamines ,  cancer treatment , and hormone medication have a significant impact on sexual performance. Various drugs result in different effects, both positive and negative. Negative effects may include low libido, erection issues (in males), vaginal dryness (in females) and  anorgasmia . Positive effects usually address these issues, overall enhancing sexual performance and contributing to a more enjoyable sexual experience. It is crucial to know that the impact of drugs on sexual performance varies among individuals, especially among different genders."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3584", "text": "Understanding sexual performance involves recognizing various factors that are responsible for a person's combined sexual experience and function. This includes libido, a person's overall sexual desire, and drive; sexual function, which encompasses the male's erectile function and a female's vaginal lubrication; and sensations, which in this context refers to a person's ability to have orgasms and/or ejaculations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3585", "text": "Libido is primarily regulated by the  hypothalamus , where  sex hormones  ( testosterone  and  estrogen ), and  neurotransmitters  ( dopamine ,  oxytocin  and  serotonin ), are the main components that influence sex drive. [ 1 ] [ 2 ]  A decreased libido is predominantly caused by low testosterone in males [ 2 ]  For females, serotonin acts as a inhibitor for sexual desire as it reduces the ability of stimulatory systems for sexual cues. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3586", "text": "Penile erection for men is a vascular event caused by the innervation of both  autonomic  (sympathetic and parasympathetic) and  somatic nervous systems  (sensory and motor). [ 4 ]   Sensory information  is received from the  genitals  towards these nervous systems, in which neurotransmitters such as  serotonin ,  dopamine ,  noradrenaline , and  adrenaline  would be released to control erectile function. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3587", "text": "Vaginal dryness refers to the situation when the vagina lacks lubrication which leads to serious pain during sexual intercourse. [ 6 ]  The production of lubricants in the vagina are highly sensitive to changes in hormones such as estrogen and testosterone, that are also responsible for blood flow. [ 7 ]  Low estrogen and testosterone circulating in the body contributes to vaginal dryness. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3588", "text": "Orgasms are sensory phenomena that take place in the cerebral cortex with an association with the  spinal reflex . [ 8 ]  Men can achieve orgasm through the penis, and can be categorised to two parts: emission and ejaculation. Neurotransmitters such as  serotonin ,  norepinephrine  and  dopamine  affect ejaculation in males the most. [ 9 ]  For women, orgasms are induced by stimulation of erotic sites, currently there are no definitive explanations on the chemical triggers for female orgasm. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3589", "text": "Drugs are frequently associated with reduced sexual inhibition, both when used voluntarily in social circumstances, and involuntarily, as in the case of some  date rape drugs . Because the use of drugs, including  alcohol , is commonly presented as an excuse for risky or socially unacceptable behavior, it is necessary to treat the idea of a direct causal relation between drug use and  unsafe sex  with caution. Drugs may provide a socially acceptable excuse for engaging in sexual behaviors in which people may want to engage but perhaps feel that they should not. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3590", "text": "Some forms of sexual dysfunction such as  erectile dysfunction  can be treated with drugs. Because of their effects, erectile dysfunction drugs are sometimes used for recreational purposes. Many drugs, both legal and illegal, some sold online, have side effects that affect the user's sexual function. Many drugs can cause  loss of libido  as a side effect. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3591", "text": "Since a partial cause of the  refractory period  is the inhibition of  dopamine  by an orgasm-induced  secretion  of  prolactin , [ 13 ]  such potent  dopamine receptor   agonists  as  cabergoline  may help achieve multiple  orgasms  as well as the retention of sexual arousal for longer periods of time. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3592", "text": "According to some studies, up to 22.1% of teenagers abused substances during their most recent sexual experience. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3593", "text": "Likewise, studies have shown adolescents who regularly abuse substances are more likely to initiate sexual activity at an earlier age, [ 15 ]  have a more significant number of sexual partners, [ 16 ]  and engage in unprotected sex more often. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3594", "text": "Additionally, substance abuse has been linked to an increased risk of  sexually transmitted infection  (STI). [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3595", "text": "Drugs on the market provide both benefits and detrimental effects to the person, especially regarding sexual performance, depending on the use and dosage. [ 19 ]  Drugs are classified into different categories in respect to their functions, including psychoactive drugs, antihypertensive drugs, antihistamines, cancer treatment drugs and hormone medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3596", "text": "Psychoactive drugs  refer to chemical substances that affect an individual's mental processes, such as emotions, cognition, perception, and consciousness. [ 20 ]  These substances directly impact the  central nervous system (CNS) , which also has an impact on the neurophysiologic phases of sexual response. [ 21 ]   Antidepressants  are a group of drugs that treat individuals with clinical depression, as well as other mental disorders. [ 22 ]  This group of drugs have shown to affect sexual functions in both male and females. [ 23 ]   Alcohol  is a group of psychoactive substances where signals of pleasure, rewards are sent to the human brain. It also causes a series of adverse effects on the body, including the brain and the liver, leading to health problems and sexual dysfunction. [ 24 ] [ 25 ]   Antipsychotics  are drugs that treat mental disorders such as schizophrenia, and other psychoses. [ 26 ]  These drugs block certain pathways in humans that contribute to sexual dysfunction, including reduced arousal and sexual desire. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3597", "text": "Alcohol inhibits neuronal excitability through acting on  gamma-aminobutyric acid (GABA)  receptors. [ 28 ]  Alcohol is often accessible in a number of social situations across many cultures and is frequently connected with uninhibited social activities. Alcohol has been shown in human research to have surprising effects on the human libido."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3598", "text": "While some studies indicates that alcohol improves sexual behavior and desire, other research indicates that alcohol impairs sexual function."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3599", "text": "The conditions under which the drinking occurs, laboratory research vs self-report studies from users, as well as the amounts of alcohol consumed, may all contribute to these controversial outcomes. [ 29 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3600", "text": "Laboratory studies have demonstrated that while low blood alcohol levels have no effect on or slightly enhance sexual arousal and responsiveness in men, elevated blood alcohol levels result in decreased erectile responsiveness, decreased arousal, and impaired ability to ejaculate. [ 29 ] [ 30 ]  Other laboratory research, on the other hand, found no significant influence of either low or high blood alcohol levels on measures of arousal. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3601", "text": "Even with mild alcohol use, women have decreased vaginal flow responses. In apparent contrast, women self-report heightened  sexual desire  and pleasure when they consume more alcohol and are more likely to engage in sexual activities with someone when intoxicated. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3602", "text": "Heavy alcohol intake impairs sexual and reproductive function, erectile, and ejaculatory dysfunction in males, and sexual arousal, interest, and orgasm in women. [ 29 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3603", "text": "Alcohol and sex  although alcohol may have varying impacts on sexual performance depending on the amount drank, it generally impairs sexual functioning and contributes to increased sexual risk taking. [ 33 ] [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3604", "text": "Psychiatrists and doctors commonly prescribe different types of antidepressants to patients.  SSRIs ,  SNRIs , and  NDRIs  are the most common types of antidepressants. [ 35 ]  Each has slightly different effects on sexual functioning, but generally, it has been found that antidepressants can delay/decrease orgasms and cause females to have  breast enlargement . [ 36 ]   Dapoxetine  in particular takes advantage of the side effect of delayed orgasm and is approved specifically as a medication for the treatment of  premature ejaculation  rather than as an antidepressant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3605", "text": "The side effects on sexual functioning can impact mental health and quality of life. [ 36 ]  However, the decrease in depressive symptoms from antidepressants make it worth the sexual side effects for many people. They can be managed by changing the dose, switching drugs, or taking \"antidotes\". [ 37 ]   Maca , a plant that grows in central Peru, aids with sexual dysfunction caused by antidepressant drugs for women. There are specific Maca products that can also increase sexual desire in men. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3606", "text": "2C-B  was first sold commercially in 5\u00a0mg pills as a purported aphrodisiac under the trade name \"Erox\", which was manufactured by the German pharmaceutical company Drittewelle. [ 38 ]  While being primarily a  psychedelic  it is also a mild  entactogen .  5-MeO-MiPT  is another psychedelic that some users find to be euphoric and tactile in low to moderate doses of 4-8 milligrams. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3607", "text": "Antihypertensive drugs are a group of drugs that prevent, control and treat hypertension. Hypertension imposes negative sexual effects on both men and women, where antihypertensive drugs help alleviate  erectile dysfunction  in men. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3608", "text": "Antihistamines are used for relieving symptoms of allergies and hay fever. [ 41 ]  Antihistamines may cause a drying effect of the mouth, nose and throat but can also cause a drying effect on other parts of the body, such as the vagina, decreasing moisture and lubrication. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3609", "text": "There are a variety of treatment types for  cancer , depending on the cancer type. [ 43 ]  The therapies for treating cancer vary, including hormone therapy, medications that treat pain, depression, nerves and blood vessels. These therapies will affect one's sexual desire and pose possible consequences on sexual response. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3610", "text": "Hormone therapy  directs its treatment towards hormones in the body, including reproductive hormones. One type is hormonal replacement therapy (HRT), which is used to supply menopausal women that lack estrogen and progesterone, increasing vaginal lubrication. [ 45 ]  Another type is testosterone replacement therapy, which treats men with hypogonadism and it helps increase libido. [ 46 ]  On the contractionary, selective oestrogen receptor modulators (SERMs) lead to a drop in oestrogen levels that would cause vaginal dryness. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3611", "text": "Amphetamines  may lead to an increase in  sexual drive  and delay in orgasm. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3612", "text": "Cocaine  is a potent  psycho-stimulant  that boosts dopamine levels by inhibiting dopamine transporters. It has been often linked to enhanced libido and risk-taking behavior in humans. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3613", "text": "Cocaine has been observed to increase sexual arousal or to trigger spontaneous erections and orgasms. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3614", "text": "In contrast, other data has shown that persistent cocaine use impairs sexual desire and the capacity of both men and females to achieve orgasm. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3615", "text": "Cannabis is the most commonly used illicit substance. [ 51 ] [ 52 ]  Studies on  cannabis and sex  have shown that THC has been linked to improved sexual desire and function. Specifically, in one study, 70 percent of users said marijuana was an  aphrodisiac , and 81 percent said it improved their sexual pleasure and satisfaction. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3616", "text": "Other research has found that long-term marijuana use lowers testosterone levels and other reproductive hormones, causing erectile dysfunction in males. [ 54 ] [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3617", "text": "MDMA  or \"ecstasy\" originally gained popularity in the 1980s among college students. According to a survey conducted, 10% of college students at a big US institution reported using  MDMA , with alcohol and marijuana being the most often used substances. [ 55 ]   MDMA  users report increased enjoyment in physical contact and proximity rather than a  sexual experience . [ 56 ] [ 57 ]   MDMA  has been shown to impair sexual performance, including erectile dysfunction and  delayed orgasm , [ 58 ] [ 59 ]  as well as to suppress  sex desire . [ 60 ] [ 61 ] [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3618", "text": "Opioids  (also known as  narcotics ) such as  morphine  and  heroin  attach to  opioid receptors  in the brain. These substances have long been known to inhibit sexual behavior. [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3619", "text": "Similar to the effects of  psycho-stimulants , both men and women who use  heroin  report engaging in high-risk sexual practices."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3620", "text": "Subjects typically report having several sexual partners, using  condoms  seldom or not at all, and having a high frequency of  STI  diagnosis. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3621", "text": "While small doses of heroin may enhance sexual desire and performance, [ 65 ]  chronic opiate use, including  methadone  and  buprenorphine , synthetic and semi-synthetic opiates prescribed for  opiate addiction   treatment , results in decreased sexual desire, response, and orgasms for both men and women, as well as  erectile ,  ejaculatory dysfunction , and  vaginismus . [ 50 ] [ 65 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3622", "text": "Libido  refers to a person's overall sexual desire and drive. Since low testosterone levels are associated with low sexual desire, testosterone replacement therapy can be prescribed for increasing testosterone in the body, increasing libido and restoring hormonal balance. [ 66 ]  While Phosphodiesterase-5 (PDE5) inhibitors such as sildenafil, tadalafil, vardenafil, and avanafil are primarily known for treating erectile dysfunction, it also has a positive effect on libido. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3623", "text": "Flibanserin is a drug that is both a  serotonin antagonist  and agonist that treats  hypoactive sexual desire disorder  (HSDD) for  premenopausal  women. The drug acts as  antagonist  and  agonist  on two different receptors. The binding of flibanserin causes downstream release of dopamine and  noradrenaline  and reduces the production of serotonin, increasing sex drive. [ 68 ]  However, currently there is still no evidence that this drug would enhance sexual performance, therefore this drug still needs to be further investigated. [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3624", "text": "For males, several drugs increases the blood flow to the penis which allows for the achievement and maintenance of an erection. [ 69 ]   Phosphodiesterase-5  (PDE5) inhibitors are widely known and commonly prescribed for erectile dysfunction. [ 70 ]  PDE5 enzymes are blocked by PDE5 inhibitors to prevent their function, this allows for the relaxation of penile blood vessels and muscles, facilitating increased blood circulation to the penis. [ 71 ]   Alprostadil  injections as a  vasodilator  are also used for the treatment of erectile dysfunction, expanding blood vessels that result in increasing blood flow to the penis. [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3625", "text": "For females, vaginal lubricant production can be increased by hormone replacement therapy (HRT) medicine such as  vaginal estrogen . [ 73 ]  Vaginal dryness results from a declined level in circulating estrogen within the body, most likely during  menopause . [ 74 ]  Treatment for vaginal dryness typically involves the use of localised estrogen, such as HRT medicine. This drug works by increasing estrogen in the body circulation, thereby enhancing lubrication production in the vaginal area. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3626", "text": "Delayed ejaculation , a type of male sexual disorder that is characterised by the delay of ejaculation or inability to achieve ejaculation. [ 75 ]  There are no approved drugs for the treatment of delayed ejaculation as of now, The majority of medications used for treating delayed ejaculation are primarily intended for treating different medical conditions. [ 76 ]   Amantadine , a Parkinson's medication,\u00a0is known to enhance  dopamine agonist  release and activate  dopamine receptors , which helps with ejaculation. [ 77 ]  However, there is not sufficient evidence to support the effectiveness of these medications on delayed ejaculation. [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3627", "text": "Several common medications can contribute to low libido. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) antidepressants, increase serotonin levels that decrease testosterone, leading to a decrease in libido. [ 78 ]  Antipsychotic drugs create blockages of  dopamine D2 receptors  that are  responsible  for dopamine production can lead to a low libido. [ 27 ]  Additionally, these drugs can increase production of  prolactin  in males which contribute to lower levels of testosterone. [ 27 ] [ 79 ]   Chemotherapy drugs  also lead to a decrease in testosterone but it is only temporary during the course of therapy. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3628", "text": "Drinking large amounts of alcohol regularly can lead to low libido due to a process called  aromatisation . [ 80 ]  This process refers to the conversion of testosterone or its precursors into  estrogen , leading to a decrease in testosterone levels in circulation. [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3629", "text": "Impotence  refers to the inability of a male's penis to become erect for sexual intercourse, in which the male is not able to get or maintain an erection. [ 81 ]  The medical term for this phenomenon is erectile dysfunction. Drugs such as antihypertensives including  thiazide diuretics ,  loop diuretics , and  beta-blockers  used for lowering blood pressure limiting blood flow to the penis area, making it difficult to get or maintain an erection. [ 82 ]  Direct effects caused by antihypertensives on the penile  vascular smooth muscle  lead to  vasoconstriction  which leads to impaired  perfusion . [ 83 ]  Antipsychotic drugs are also responsible for several mechanisms that lead to erectile dysfunction. Mechanisms such as  acetylcholine receptor   antagonism  and  alpha-adrenergic receptor  antagonism reduces periphery vasodilation, inducing erectile dysfunction. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3630", "text": "Overindulgence in alcohol may also cause temporary inability to achieve an erection. Alcohol, being a  diuretic , can cause a person to urinate more frequently, resulting in  dehydration . [ 84 ]  Dehydration reduces the volume of blood in the body, consequently decreasing blood flow towards the penis [ 84 ]  Additionally, dehydration also increases  angiotensin  levels in the body, which is a hormone associated with erectile dysfunction. [ 84 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3631", "text": "Birth control pills affect hormone levels in the body such as a decrease in estrogen, leading to vaginal dryness by thinning and shrinking of the vaginal tissue. [ 7 ]  Moreover, SERMs such as Evista and Tamoxifen which are used to treat breast cancer, results in vaginal dryness. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3632", "text": "Antihistamines narrow blood vessels, leading to lowering of moisture levels as well as mucous production, which includes lubricant production in the vagina. [ 47 ]  Anti-hypertensive drugs help reduce blood pressure by decreasing blood flow to organs in the body, resulting in decreased vaginal lubrication as well. [ 85 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3633", "text": "Antidepressants, particularly SSRIs, cause delayed ejaculation and orgasm due to its function of retaining serotonin, which inhibits ejaculation. [ 86 ]  Similarly, antipsychotics also contribute to delayed ejaculation by affecting  dopamine transporters , where dopamine plays a role in ejaculation via  D2 receptors . [ 87 ] [ 88 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3634", "text": "SSRI prevents reuptake of serotonin, thereby increasing serotonin in the body and decreasing their ability to produce lubricant in the vagina. It has been reported that around 42% of women that intake this type of medication have problems with orgasm production. [ 89 ]  Other medications such as antipsychotic drugs also reported signs of impaired orgasm. [ 90 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3635", "text": "Intake of too much alcohol can potentially cause depressant effects on the  central nervous system  (CNS). [ 91 ]  These effects contribute to sensory dullness, which leads to a delay effect on orgasm and ejaculation. [ 91 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3636", "text": "A  date rape drug  is any drug that is an  incapacitating agent  which\u2014when administered to another person\u2014incapacitates the person and renders them vulnerable to a  drug-facilitated sexual assault  (DFSA), including  rape . One of the most common types of DFSA are those in which a victim consumes a recreational drug such as  alcohol  that was administered surreptitiously. [ 92 ]  The other most common form of DFSA involves the non-surreptitiously administered consumption of alcohol. [ 93 ]  Here, the victims in these cases are drinking voluntarily which then makes them unable to make informed decisions or  give consent ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3637", "text": "Party and play , or chemsex, is the consumption of drugs to facilitate  sexual activity . Sociologically, both terms refer to a  subculture  of  recreational drug  users who engage in high-risk  sexual activities  under the influence of drugs within groups. [ 94 ]  The term PnP is commonly used by  gay men [ 94 ] [ failed verification ]  and other  men who have sex with men  (MSM) in North America, while chemsex is more associated with the gay scene in Europe. [ 95 ]  The drug of choice is typically  methamphetamine , known as tina or T, [ 96 ]  but other drugs are also used, such as  mephedrone ,  GHB ,  GBL [ 97 ]  and  alkyl nitrites  (known as  poppers ). [ 98 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3638", "text": "Drug-based contraception has been available since the development of the  contraceptive pill . As well as their contraceptive effects, contraceptive drugs can also have adverse sexual and reproductive side-effects. Prior to the availability of effective contraceptives, some substances were also used as  abortifacients  to terminate pregnancy;  medical abortion  exists as a modern medical practice."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3639", "text": "Alcohol and sex  deals with the effects of the consumption of  alcohol  on  sexual behavior . [ 2 ]  The effects of alcohol are balanced between its suppressive effects on sexual physiology, which will decrease sexual activity, and its suppression of  sexual inhibitions . [ 3 ]  A large portion of  sexual assaults  involve alcohol consumption by the perpetrator, victim, or both. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3640", "text": "Alcohol is a depressant. After consumption, alcohol causes the body's systems to slow down. Often, feelings of  drunkenness  are associated with elation and happiness but other feelings of anger or depression can arise. Balance, judgment, and coordination are also negatively affected. One of the most significant short term side effects of alcohol is reduced inhibition. Reduced inhibitions can lead to an increase in sexual behavior. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3641", "text": "Low to moderate alcohol consumption is shown to have protective effect for men's erectile function. Several reviews and  meta-analyses  of existing literature show that low to moderate alcohol consumption significantly decreases  erectile dysfunction  risk. [ 5 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3642", "text": "Men's sexual behaviors can be affected dramatically by high alcohol consumption. Both chronic and acute alcohol consumption have been shown in most studies\n [ 9 ] [ 10 ] [ 11 ]  (but not all [ 12 ] ) to inhibit  testosterone  production in the testes. This is believed to be caused by the metabolism of alcohol reducing the  NAD + / NADH  ratio both in the liver and the testes; since the synthesis of testosterone requires NAD + , this tends to reduce testosterone production. [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3643", "text": "As testosterone is critical for libido and physical arousal, alcohol tends to have deleterious effects on male sexual performance. Studies have been conducted that indicate increasing levels of alcohol intoxication produce a significant degradation in male masturbatory effectiveness (MME). This degradation was measured by measuring  blood alcohol concentration  (BAC) and ejaculation latency. [ 15 ]  Alcohol intoxication can decrease sexual arousal, decrease pleasureability and intensity of  orgasm , and increase difficulty in attaining orgasm. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3644", "text": "In women, the effects of alcohol on libido in the literature are mixed. Some women report that alcohol increases sexual arousal and desire, however, some studies show alcohol lowers the physiological signs of arousal. [ 16 ]  A 2016 study found that alcohol negatively affected how positive the sexual experience was in both men and women. [ 17 ]  Studies have shown that acute alcohol consumption tends to cause increased levels of testosterone and  estradiol . [ 18 ] [ 19 ]  Since testosterone controls in part the strength of libido in women, this could be a physiological cause for an increased interest in sex. Also, because women have a higher percentage of body fat and less water in their bodies, alcohol can have a quicker, more severe impact. Women's bodies take longer to process alcohol; more precisely, a woman's body often takes one-third longer to eliminate the substance. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3645", "text": "Sexual behavior in women under the influence of alcohol is also different from men. Studies have shown that increased BAC is associated with longer orgasmic latencies and decreased intensity of orgasm. [ 16 ]  Some women report a greater  sexual arousal  with increased alcohol consumption as well as increased sensations of pleasure during orgasm. Because ejaculatory response is visual and can more easily be measured in males, orgasmic response must be measured more intimately. In studies of the female orgasm under the influence of alcohol, orgasmic latencies were measured using a  vaginal photoplethysmograph , which essentially measures vaginal blood volume. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3646", "text": "Psychologically, alcohol has also played a role in sexual behavior. It has been reported that women who were intoxicated believed they were more sexually aroused than before consumption of alcohol. [ 16 ]  This psychological effect contrasts with the physiological effects measured, but refers back to the loss of inhibitions because of alcohol. Often, alcohol can influence the capacity for a woman to feel more relaxed and in turn, be more sexual. Alcohol may be considered by some women to be a sexual disinhibitor. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3647", "text": "Some studies have made a connection between  hookup culture  and substance use. [ 21 ]  Most students said that their hookups occurred after drinking alcohol. [ 21 ] [ 22 ] [ 23 ]  Frietas stated that in her study, the relationships between drinking and the party scene and between alcohol and hookup culture were \"impossible to miss\". [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3648", "text": "Studies suggest that the degree of  alcoholic intoxication  in young people directly correlates with the level of risky behavior, [ 25 ]  such as engaging in  multiple sex partners . [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3649", "text": "In 2018, the first study of its kind, found that  alcohol and caffeinated   energy drinks  is linked with casual, risky sex among college-age adults. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3650", "text": "Alcohol intoxication is associated with an increased risk that people will become involved in  risky sexual behaviors , such as unprotected sex. [ 15 ]  Both men, [ 28 ]  and women, [ 29 ]  reported higher intentions to  avoid using a condom  when they were intoxicated by alcohol."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3651", "text": "Coitus interruptus , also known as withdrawal, pulling out or the pull-out method, is a method of  birth control  during penetrative  sexual intercourse , whereby the  penis  is withdrawn from a  vagina  or  anus  prior to  ejaculation  so that the ejaculate ( semen ) may be directed away in an effort to avoid  insemination . [ 30 ] [ 31 ]  Coitus interruptus carries a risk of  STIs  and  unintended pregnancy . This risk is especially high during  alcohol intoxication  because lowered  sexual inhibition  can make it difficult to withdraw in time."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3652", "text": "Women with  unintended pregnancies  are more likely to  smoke tobacco , [ 32 ]  drink alcohol during pregnancy, [ 33 ] [ 34 ]  and binge drink during pregnancy, [ 32 ]  which results in poorer health outcomes. [ 33 ]  (See also:  fetal alcohol spectrum disorder )"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3653", "text": "Rape is any sexual activity that occurs without the freely given  consent  of one of the parties involved. This includes  alcohol-facilitated sexual assault  which is considered rape in most if not all jurisdictions, [ 35 ]  or  non-consensual condom removal  which is criminalized in some countries (see the map below)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3654", "text": "A 2008 study found that rapists typically consumed relatively high amounts of alcohol and infrequently used condoms during assaults, which was linked to a significant increase in STI transmission. [ 36 ]  This also increases the risk of  pregnancy from rape  for female victims. Some people turn to drugs or alcohol to cope with emotional trauma after a rape; use of these during pregnancy can harm the fetus. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3655", "text": "One of the most common  date rape drugs  is alcohol, [ 39 ] [ 40 ] [ 41 ]  administered either surreptitiously [ 42 ]  or consumed voluntarily, [ 39 ]  rendering the victim unable to make informed decisions or give consent. The perpetrator then facilitates  sexual assault  or  rape , a crime known as alcohol- or  drug-facilitated sexual assault  (DFSA). [ 43 ] [ 35 ] [ 44 ]  Many perpetrators use alcohol because their victims often drink it willingly, and can be encouraged to drink enough to lose inhibitions or consciousness. [ 45 ]  However, sex with an unconscious victim is considered rape in most if not all jurisdictions, and some assailants have committed \"rapes of convenience\" whereby they have assaulted a victim after he or she had become unconscious from drinking too much. [ 46 ]  The risk of individuals either experiencing or perpetrating  sexual violence  and  risky sexual behavior  increases with  alcohol abuse , [ 47 ]  and by the consumption of  caffeinated alcoholic drinks . [ 48 ] [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3656", "text": "Non-consensual condom removal , or \"stealthing\", [ 50 ]  is the practice of a person removing a  condom  during  sexual intercourse  without consent, when their sex partner has only  consented  to condom-protected sex. [ 51 ] [ 52 ]  Purposefully damaging a condom before or during intercourse may also be referred to as stealthing, [ 53 ]  regardless of who damaged the condom."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3657", "text": "Consuming alcohol can be risky in sexual situations. It can impair judgment and make it difficult for both people to give or receive informed  sexual consent . However, a history of sexual aggression and  alcohol intoxication  are factors associated with an increased risk of men employing non-consensual condom removal and engaging in sexually aggressive behavior with female partners. [ 54 ] [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3658", "text": "The use of alcohol is a documented factor in  wartime sexual violence ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3659", "text": "For example,  rape during the liberation of Serbia  was committed by Soviet  Red Army  soldiers against women during their advance to Berlin in late 1944 and early 1945 during  World War II . Serbian journalist Vuk Peri\u0161i\u0107 said about the rapes: \"The rapes were extremely brutal, under the influence of alcohol and usually by a group of soldiers. The Soviet soldiers did not pay attention to the fact that Serbia was their ally, and there is no doubt that the Soviet high command tacitly approved the rape.\" [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3660", "text": "While there wasn't a codified international law specifically prohibiting rape during World War II,  customary international law  principles already existed that condemned violence against civilians. These principles formed the basis for the development of more explicit laws after the war, [ 57 ]  including the  Nuremberg Principles  established in 1950."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3661", "text": "A study published in 2003 supported the beer goggles hypothesis; however, it also found that another explanation is that regular drinkers tend to have personality traits that mean they find people more attractive, whether or not they are under the influence of alcohol at the time. [ 58 ]  A 2009 study showed that while men found adult women (who were wearing  makeup ) more attractive after consuming alcohol, the alcohol did not interfere with their ability to determine a woman's age. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3662", "text": "A 2021 study found that bar patrons rated themselves as more attractive towards the end of the night, regardless of their level of intoxication, and that this effect had more to do with motivations to attract a mate. The \"closing time effect\" was tested in Danish bars, with researchers separating responses based on whether bar patrons had filled out their survey in the afternoon, evening, or night, and finding that people attending the bar at night rated themselves as more attractive than earlier visitors. [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3663", "text": "An  anaphrodisiac  (also  antaphrodisiac  or  antiaphrodisiac ) is a substance that quells or blunts the  libido . It is the opposite of an  aphrodisiac , something that enhances sexual appetite. The word  anaphrodisiac  comes from the  Greek   privative   prefix   \u1f00\u03bd- , denoting negation, and  aphrodisiac , from the Greek goddess of love,  Aphrodite . Some people use anaphrodisiacs in order to curb a very high libido or due to  hypersexuality . [ 1 ]  However anaphrodisiacs are also used by those with an average libido, at times due to having incessant schedules. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3664", "text": "Some common anaphrodisiacs are  ethanol  (alcohol) and  tobacco , but this is typically an unintended consequence and not often the main reason for use. While alcohol is used socially because it initially reduces mental inhibitions, studies have shown that over time alcohol physically decreases arousal and makes achieving climax more difficult. [ 3 ]  For this reason, alcohol is considered an anaphrodisiac."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3665", "text": "Opioids , a class of pain-reducing substances which include  morphine ,  heroin , and  hydrocodone , are anaphrodisiacs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3666", "text": "Side effects  of certain  antidepressant   medications  commonly include those taking anaphrodisiac form (there is even a term for the phenomenon among one particularly notorious group \u2013  SSRI -induced  sexual dysfunction ); however, psychotropic drugs are not currently prescribed for reliable anaphroditic effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3667", "text": "Antiandrogens  such as  cyproterone acetate  and  medroxyprogesterone acetate , or the LHRH agonist  leuprolide , are sometimes prescribed to convicted male sex offenders who are released on parole in an effort to stop them reoffending, in a treatment sometimes referred to as  chemical castration , however the high doses required often cause a range of side effects which may limit  compliance . Other antiandrogens such as  finasteride  and  spironolactone  may also lower sex drive, as can certain  antipsychotics  such as  benperidol .  Estrogens  can act as anaphrodisiacs in men by suppressing  testosterone  production by the  testicles ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3668", "text": "Herbal anaphrodisiacs have been employed by various religious sects and orders throughout history. Barrister Sir  Edward Marshall Hall  theorised that murderer  Hawley Harvey Crippen  was using  hyoscine  on his wife as an anaphrodisiac but accidentally gave her an  overdose  and then panicked when she died. [ 4 ] [ 5 ]  Various forms of anaphrodisiacs have been tried to cure  hypersexuality  in both  humans [ 6 ]  and non-human animals. [ 7 ]  In both medieval history and modern times, anaphrodisiacs have been used as a tool intended to reduce the sex drive of  sex offenders . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3669", "text": "Studies have evaluated the effect of herbal anaphrodisiacs on men and women. These include studies on the effect of substances on both hormone levels and behaviour."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3670", "text": "The mechanism of the active component of some plant-based anaphrodisiacs may be the inhibition of enzymes that catalyze the conversion of sex-hormone precursors into  androstenedione , which promotes the reduction of sexual urges. Studies have demonstrated that some of these products inhibit 17\u03b2-hydroxysteroid dehydrogenase and 17,20-lyase, which catalyzes the conversion of 17\u03b1-hydroxyprogesterone to androstenedione to testosterone. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3671", "text": "In one study a group of men were given an anaphrodisiac and the effect on the metabolism of mineralocorticoids in these men was recorded.  During the period of administration, the testosterone concentrations decreased and the serum 17\u03b1-hydroxyprogesterone concentrations increased.  Testosterone levels fell by about 40% after administration and returned to normal after usage was discontinued. [ 10 ]  However, the actual effect of these medicines on sexual desire was not measured in the study."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3672", "text": "The amino acid 5-HTP, or  5-hydroxytryptophan , has been anecdotally reported to be a mild anaphrodisiac, as has the serotonergic empathogen  MDMA , popularly known as \"ecstasy\". However, systematic study of these chemicals is lacking, due to the off-patent nature of 5-HTP, and the legal control of MDMA. In addition, other serotonergic euphoriant drugs, like the psychedelic  LSD , have been reportedly used to drastically increase sexual pleasure. MDMA in combination with a  PDE5 inhibitor  (trade names  Viagra ,  Levitra , and  Cialis ) is termed \"sextasy\". This combination increases libido and performance simultaneously.  A PDE5 inhibitor taken alone has no effect on sex drive, suggesting that serotonergic euphoriants like MDMA may actually increase libido while decreasing performance, similar to  alcohol ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3673", "text": "A 2003 study has found that  glycyrrhizin , the compound in  liquorice  root, can lower levels of testosterone. The findings back up a previous study about the hormonal effects of liquorice (whose results could not be replicated in other studies in the past). The scientists came to the conclusion that the regular consumption of liquorice can lower libido in men. However, the study also showed that the level of testosterone normalizes after abstinence of liquorice within a few days and the effects completely disappear. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3674", "text": "An  aphrodisiac  is a substance alleged to increase  libido ,  sexual desire ,  sexual attraction ,  sexual pleasure , or sexual behavior. [ 1 ] [ 2 ] [ 3 ]  These substances range from a variety of plants, spices, and foods to synthetic chemicals. [ 1 ] [ 4 ]  Natural aphrodisiacs, such as  cannabis  or  cocaine , are classified into plant-based and non-plant-based substances. [ 4 ] [ 5 ]  Synthetic aphrodisiacs include  MDMA  and  methamphetamine . Aphrodisiacs can be classified by their type of effects (psychological or physiological). [ 1 ]  Aphrodisiacs that contain  hallucinogenic  properties, such as  bufotenin , have psychological effects that can increase sexual desire and sexual pleasure. [ 1 ] [ 3 ]  Aphrodisiacs that have smooth muscle relaxing properties, such as  yohimbine , have physiological effects that can affect hormone concentrations and increase blood flow. [ 1 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3675", "text": "Aphrodisiac effects may be due to the  placebo effect . [ 2 ]  Substances that inhibit effects that aphrodisiacs aim to enhance are called  anaphrodisiacs , [ 2 ]  which have the opposite effects on libido."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3676", "text": "Both males and females can potentially benefit from the use of aphrodisiacs, but they are more focused on males, as their properties tend to increase testosterone concentrations rather than estrogen concentrations. [ 3 ]  This is in part due to the historical context of aphrodisiacs, which focused solely on males. Only recently has attention  been paid to understanding how aphrodisiacs can aid female sexual function. [ 5 ]  In addition, cultural influences on appropriate sexual behavior of males and females also play a part in the research gap. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3677", "text": "The word comes from the  Greek  \u1f00\u03c6\u03c1\u03bf\u03b4\u03b9\u03c3\u03b9\u03b1\u03ba\u03cc\u03bd,  aphrodisiakon , i.e. \"sexual, aphrodisiac\", from  aphrodisios , i.e. \"pertaining to  Aphrodite \", [ 6 ] [ 7 ]  the  Greek   goddess  of love. Throughout human history, food, drinks, and behaviors have had a reputation for making sex more attainable and/or pleasurable. However, from a historical and scientific standpoint, the alleged results may have been mainly due to mere belief on the part of their users that they would be effective (a  placebo effect ). Likewise, many medicines are reported to  affect  libido in inconsistent or idiopathic ways: [ 8 ]  enhancing or diminishing overall sexual desire, depending on the circumstances. For example, bupropion ( Wellbutrin ) is known as an  antidepressant  that can counteract other co-prescribed antidepressants with libido-diminishing effects. However, because bupropion increases libido only when it is already impaired by related medications, it is not generally classed as an aphrodisiac."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3678", "text": "Ancient civilizations like Chinese, Indian, Egyptian, Roman, and Greek cultures believed that certain substances could provide the key to improving sexual desire, sexual pleasure, and/or sexual behavior. [ 1 ] [ 4 ] [ 9 ]  This was important, because some men suffered from  erectile dysfunction  and could not reproduce. [ 1 ] [ 4 ]  Men who could not impregnate their wives and father large families were seen as failures, whereas those who could were respected. Hence, a stimulant was needed. [ 1 ] [ 5 ]  Others who did not suffer from this also desired performance enhancers. [ 4 ]  Regardless of their usage, these substances gained popularity and began to be documented, information being passed down generations. [ 3 ]  There are Hindu poems dated back to around 2000 to 1000 BCE that spoke of performance enhancers, ingredients, and usage tips. [ 3 ]  Chinese texts date back to 2697 to 2595 BC. [ 5 ]  Roman and Chinese cultures documented their belief in aphrodisiac qualities in animal genitalia, while Egyptians wrote tips for treating erectile dysfunction. [ 5 ]  In  Post-classical  West Africa, a volume titled  Advising Men on Sexual Engagement with Their Women  from the  Timbuktu Manuscripts  acted as a guide on aphrodisiacs and infertility remedies. It offered advice to men on \"winning back\" their wives. According to Hammer, \"At a time when women\u2019s sexuality was barely acknowledged in the West, the manuscript, a kind of  Baedeker  to orgasm, offered tips for maximizing sexual pleasure on both sides.\" [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3679", "text": "Ambergris ,  Bufo toad ,  yohimbine ,  horny goat weed ,  ginseng ,  alcohol , and certain foods are recorded throughout these texts as possessing aphrodisiac qualities. [ 1 ]  While many plants,  extracts , or manufactured hormones have been proposed as aphrodisiacs, there is little high-quality  clinical evidence  of their efficacy or long-term safety. [ 8 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3680", "text": "There has been increasing attention in recent years surrounding the use of aphrodisiac drugs. [ 12 ]  In 2020,  Brian Earp  and  Julian Savulescu  published a philosophy book entitled  Love Drugs: The Chemical Future of Relationships  (UK title  Love Is the Drug: The Chemical Future of Our Relationships) . They argued that certain forms of medications can be ethically consumed as a \"helpful complement\" in relationships. Both to fall in love and to fall out of it. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3681", "text": "Ambergris  is found in the gut of sperm whales. It is commonly used in Arab cultures as relief medication for headaches or as a performance enhancer.  The derived chemical  Ambrein  increases testosterone concentrations, triggering sexual desire and sexual behavior, but in animal studies only.  Further research is needed to know the effects in humans. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3682", "text": "Bufotenin  is found in the skin and glands of Bufo toads. It is commonly used in Caribbean and China. In the Caribbean, it is used as an aphrodisiac called 'Love Stone'.  In China, it is used as a heart medication called  Chan su . [ 3 ]  Research shows that the toad skin secretion containing this compound can reduce a toad\u2019s heart rate, but its effect on humans is unknown. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3683", "text": "Yohimbine  is a substance found in the bark of yohim trees in West Africa. [ 4 ]  It was traditionally used in West African cultures, in which the bark would be boiled and the resulting water drunk until it increased sexual desire. [ 1 ]  It  has been approved by the Food and Drug Administration and can be prescribed for sexual dysfunction in the USA and Canada. [ 1 ] [ 5 ]  It is also found in over-the-counter health products. [ 1 ]  Yohimbine is an indole alkaloid and is an adrenoceptor antagonist. It affects the central nervous system, autonomic nervous system, and the penile tissue and vascular smooth muscle cells that are involved in penile erection and it is also used to treat physiologically impaired and psychogenic erectile dysfunction, [ 1 ] [ 4 ]  preferably in combination with other treatments. [ 14 ]  Known adverse effects include nausea, anxiety, irregular heartbeats, and restlessness. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3684", "text": "Horny goat weed  ( Epimedii herba ) is used in Chinese folk medicine. [ 1 ]  It was thought to be useful for treating medical conditions and improving sexual desire, sexual pleasure, and/or sexual behavior. [ 1 ]  Horny goat weed contains  icariin , a flavanol glycoside. Its exotic name comes from the tendency of goats in the region to seek out this weed. Once farmers saw its effects on the goat population they began to use it to increase the number of workers on their farms. [ 1 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3685", "text": "Alcohol  has been associated as an aphrodisiac, owing to its effect as a central nervous system depressant. [ 5 ]  Depressants can increase sexual desire and sexual behavior through disinhibition. [ 2 ] [ 5 ]  Alcohol affects people both physiologically and psychologically, and it is therefore difficult to determine exactly how people experience its aphrodisiac effects (aphrodisiac qualities or the expectancy effect). [ 2 ]  Alcohol taken in moderate quantities can elicit a positive increase in sexual desire, whereas larger quantities are associated with difficulties in reaching sexual pleasure. [ 2 ] [ 15 ]  As the porter in Shakespeare's  Macbeth  observes, \"it provokes the desire, but it takes away the performance\". Chronic alcohol consumption is related to sexual dysfunction. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3686", "text": "Marijuana  reports are mixed. Half of users claim an increase in sexual desire and sexual pleasure while the other half report no effect. [ 2 ]  Consumption, individual sensitivity, and possibly marijuana strain, are factors that affect outcomes. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3687", "text": "Many cultures have turned to foods as sources of increasing sexual desire; however, significant research is lacking in the study of the aphrodisiac qualities of foods. Most claims can be linked to the placebo effect. [ 2 ]  Misconceptions revolve around the visual appearance of these foods in relation to male and female genitalia ( carrots ,  bananas ,  oysters , and the like). [ 2 ] [ 5 ]  Other beliefs arise from the thought of consuming animal genitalia and absorbing their properties (e.g. cow cod soup in  Jamaica  and balut in the  Philippines ). [ 1 ]   Korean bug  is a popular aphrodisiac in China, Korea, and Southeast Asia, either eaten alive or in gelatin form. [ 16 ]  The caterpillar fungus ( Ophiocordyceps sinensis ) is used as an aphrodisiac in China. [ 17 ]  The story of Aphrodite, who was born from the sea, is another reason why individuals believe seafood is another source of aphrodisiacs. [ 5 ]  Foods that contain volatile oils have gained little recognition in their ability to improve sexual desire, sexual pleasure, and/or sexual behavior, because they are irritants when released through the urinary tract. [ 3 ]   Chocolate  has been reported to increase sexual desire in women who consume it over those who do not. [ citation needed ]  Cloves and sage have been reported to demonstrate aphrodisiac qualities, but their effects have not been specified. [ 1 ]  Tropical fruits, such as  Boroj\u00f3  and  Chontaduro , are considered to be energizers in general and sexual energizers in particular. [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3688", "text": "Ginseng  is the root of any member of the genus  Panax . [ 1 ] [ 4 ]  Ginseng's active ingredients are ginsenosides and saponin glycosides. [ 20 ]  There are three different ways of processing ginseng. Fresh ginseng is cut at four years of growth, white ginseng is cut at four to six years of growth, and red ginseng is cut, dried, and steamed at six years of growth.  Red ginseng has been reported to be the most effective aphrodisiac of the three. [ 4 ]  Known adverse effects include mild gastrointestinal upsets. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3689", "text": "Maca  is a Peruvian plant sometimes called \"Peruvian ginseng\", although it is not related to  Panax . It has been used as a tonic to improve sexual performance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3690", "text": "Popular party substances have been reported by users to consist of aphrodisiac properties because of their enhancing effects with sexual pleasure.  Ecstasy  users have reported an increase in sexual desire and sexual pleasure; however, there have been reports of delayed orgasm in both sexes and erectile difficulties in men.  Poppers , containing drugs for inhalation, have been linked to increased sexual pleasure. Known adverse effects are headaches, nausea, and temporary erectile difficulties. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3691", "text": "Amphetamine ,  methylphenidate , and  methamphetamine  are  phenethylamine derivatives , which increase libido and cause frequent or prolonged erections as potential adverse effects, particularly in  supratherapeutic  doses, when sexual hyperexcitability and hypersexuality can occur; [ 21 ] [ 22 ] [ 23 ] [ 24 ]  however, in some individuals who use these drugs, libido is reduced. [ 22 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3692", "text": "2C-B  was sold commercially in 5\u00a0mg pills as a purported aphrodisiac under the trade name \"Erox\", which was manufactured by the German pharmaceutical company Drittewelle. [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3693", "text": "Libido  in males is linked to concentrations of sex hormones, particularly  testosterone . [ 11 ] [ 27 ] [ 28 ]  When there is reduced sex drive in individuals with relatively low concentrations of testosterone, particularly in  postmenopausal  women or men over the age of 60, [ 29 ]   dietary supplements  that are purported to increase  serum  testosterone concentrations have been used, with the intention of increasing libido, although with limited benefits. [ 11 ] [ 29 ]  Long-term therapy with synthetic oral testosterone is associated with increased risks of  cardiovascular diseases . [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3694", "text": "Solid evidence is hard to obtain, as these substances come from many different environments cross-culturally and therefore give variable results, because of variations in growth and extraction. [ 4 ]  The same is also true for unnatural substances, because variations in consumption and individual sensitivity can affect outcomes. [ 2 ]  Folk medicine and self-prescribed methods can be potentially harmful, as their adverse effects are not fully known and are therefore not made aware to the people searching this topic on the internet. [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3695", "text": "The invention of an aphrodisiac is the basis of a number of films including  Perfume: The Story of a Murderer ,  Spanish Fly ,  She'll Follow You Anywhere ,  Love Potion No. 9 ,  and  A Serbian Film . \nThe first segment of  Woody Allen 's movie  Everything You Always Wanted to Know About Sex* (*But Were Afraid to Ask)  is called \"Do Aphrodisiacs Work?\", and casts Allen as a  court jester  trying to seduce the  queen . \nThe \"Despair Arc\" of  Danganronpa 3: The End of Hope's Peak High School  features a class being dosed with aphrodisiacs. \nIn episode 2 of the anime  The Apothecary Diaries , Maomao makes aphrodisiacs and three of the  Ladies-in-waiting  eat them unaware that they are aphrodisiacs. In the film  Sexually Bewitched , a witch creates consumables that bring out and enhance the lust of whomever eats them; resulting in hijinks as the magic liberates the libido repressed by those who eat her magic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3696", "text": "Hormonal contraception  refers to  birth control  methods that act on the  endocrine system . Almost all methods are composed of  steroid hormones , although in  India  one  selective estrogen receptor modulator  is marketed as a contraceptive. The original hormonal method\u2014the  combined oral contraceptive pill \u2014was first marketed as a contraceptive in 1960. [ 1 ]  In the ensuing decades, many other delivery methods have been developed, although the oral and injectable methods are by far the most popular. Hormonal contraception is highly effective: when taken on the prescribed schedule, users of steroid hormone methods experience pregnancy rates of less than 1% per year. Perfect-use pregnancy rates for most hormonal contraceptives are usually around the 0.3% rate or less. [ 2 ]  Currently available methods can only be used by women; the development of a  male hormonal contraceptive  is an active research area."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3697", "text": "There are two main types of hormonal contraceptive formulations:  combined methods  which contain both an  estrogen  and a  progestin , and  progestogen-only methods  which contain only  progesterone  or one of its synthetic analogues (progestins). Combined methods work by suppressing  ovulation  and thickening  cervical mucus ; while progestogen-only methods reduce the frequency of ovulation, most of them rely more heavily on changes in cervical mucus. The incidence of certain side effects is different for the different formulations: for example,  breakthrough bleeding  is much more common with progestogen-only methods. Certain serious complications occasionally caused by estrogen-containing contraceptives are not believed to be caused by progestogen-only formulations:  deep vein thrombosis  is one example of this."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3698", "text": "Hormonal contraception is primarily used for the prevention of  pregnancy , but is also prescribed for the treatment of  polycystic ovary syndrome , menstrual disorders such as  dysmenorrhea  and  menorrhagia , and  hirsutism . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3699", "text": "Hormonal treatments, such as hormonal contraceptives, are frequently successful at alleviating symptoms associated with  polycystic ovary syndrome .  Birth control pills  are often prescribed to reverse the effects of excessive  androgen  levels, and decrease ovarian hormone production. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3700", "text": "Hormonal birth control methods such as  birth control pills , the  contraceptive patch ,  vaginal ring ,  contraceptive implant , and  hormonal IUD  are used to treat cramping and pain associated with primary  dysmenorrhea . [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3701", "text": "Oral contraceptives  are prescribed in the treatment of  menorrhagia  to help regulate menstrual cycles and prevent prolonged menstrual bleeding. The  hormonal IUD  ( Mirena ) releases  levonorgestrel  which thins the uterine lining, preventing excessive bleeding and loss of iron. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3702", "text": "Birth control pills are the most commonly prescribed hormonal treatment for  hirsutism , as they prevent  ovulation  and decrease  androgen  production by the  ovaries . Additionally,  estrogen  in the pills stimulates the liver to produce more of a protein that binds to androgens and reduces their activity. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3703", "text": "Modern contraceptives using steroid hormones have  perfect-use  or  method  failure rates of less than 1% per year. The lowest failure rates are seen with the implants Jadelle and Implanon, at 0.05% per year. [ 9 ] [ 10 ]  According to  Contraceptive Technology , none of these methods has a failure rate greater than 0.3% per year. [ 10 ]  The SERM ormeloxifene is less effective than the steroid hormone methods; studies have found a perfect-use failure rate near 2% per year. [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3704", "text": "Long-acting methods  such as the implant and the IUS are user-independent methods. [ 13 ]  For user-independent methods, the  typical  or  actual-use  failure rates are the same as the method failure rates. [ 10 ]  Methods that require regular action by the user\u2014such as taking a pill every day\u2014have typical failure rates higher than perfect-use failure rates.  Contraceptive Technology  reports a typical failure rate of 3% per year for the injection Depo-Provera, and 8% per year for most other user-dependent hormonal methods. [ 10 ]  While no large studies have been done, it is hoped that newer methods which require less frequent action (such as the patch) will result in higher user compliance and therefore lower typical failure rates. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3705", "text": "Currently there is little evidence that there is an association between being overweight and the effectiveness of hormonal contraceptives. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3706", "text": "While unpredictable  breakthrough bleeding  is a possible side effect for all hormonal contraceptives, it is more common with progestogen-only formulations. [ 16 ]  Most regimens of COCPs, NuvaRing, and the contraceptive patch incorporate a placebo or break week that causes regular withdrawal bleeding. While women using combined injectable contraceptives may experience  amenorrhea  (lack of periods), they typically have predictable bleeding comparable to that of women using COCPs. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3707", "text": "Although high-quality studies are lacking, [ 18 ]  it is believed that estrogen-containing contraceptives significantly decrease the quantity of milk in breastfeeding women. [ 19 ]  Progestogen-only contraceptives are not believed to have this effect. [ 19 ]  In addition, while in general the progestogen-only pill is less effective than other hormonal contraceptives, the added  contraceptive effect of breastfeeding  makes it highly effective in breastfeeding women. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3708", "text": "While combined contraceptives increase the risk for  deep vein thrombosis  (DVT \u2013 blood clots), progestogen-only contraceptives are not believed to affect DVT formation. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3709", "text": "Combined oral contraceptives can increase the risk of certain types of cardiovascular disease in women with a pre-existing condition or already-heightened risk of cardiovascular disease. Smoking (for women over 35), metabolic conditions like diabetes, obesity and family history of heart disease are all risk factors which may be exacerbated by the use of certain hormonal contraceptives. [ 2 ]  Oral contraceptives have also been linked to an inflated risk of myocardial infarction, arterial thrombosis, and ischemic stroke. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3710", "text": "Hormonal contraception methods are consistently linked with the risk of developing blood clots. However, the risk does vary depending on the hormone type or birth control method being used. [ 28 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3711", "text": "There are two main classes of hormonal contraceptives:  combined contraceptives  contain both an estrogen and a  progestin , [ 30 ]  and  progestogen-only contraceptives  that contain only  progesterone  or a synthetic analogue (progestin). There is also a non-hormonal contraceptive called  ormeloxifene  which acts on the hormonal system to prevent pregnancy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3712", "text": "The most popular form of hormonal contraception, is the  combined oral contraceptive pill  (COCP) known colloquially as  the pill . It is taken once a day, most commonly for 21 days followed by a seven-day break, although other regimens are also used. For women not using ongoing hormonal contraception, COCPs may be taken after intercourse as  emergency contraception : this is known as the  Yuzpe regimen . COCPs are available in  a variety of formulations . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3713", "text": "The  contraceptive patch  is applied to the skin and worn continuously. A series of three patches are worn for one week each, and then the user takes a one-week break.  NuvaRing  is worn inside the vagina. A ring is worn for three weeks. After removal, the user takes a one-week break before inserting a new ring. As with COCPs, other regimens may be used with the contraceptive patch or NuvaRing to provide  extended cycle combined hormonal contraception ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3714", "text": "Some  combined injectable contraceptives  can be administered as one injection per month."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3715", "text": "The  progestogen-only pill  (POP) is taken once per day within the same three-hour window.  Several different formulations  of POP are marketed. A low-dose formulation is known as  the minipill . Unlike COCPs, progestogen-only pills are taken every day with no breaks or placebos. For women not using ongoing hormonal contraception, progestogen-only pills may be taken after intercourse as  emergency contraception . There are a number of  dedicated products  sold for this purpose. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3716", "text": "Hormonal intrauterine contraceptives are known as  intrauterine systems  (IUS) or Intrauterine Devices (IUD). An IUS/IUD must be inserted by a health professional. The copper IUD does not contain hormones. While a copper-containing IUD may be used as emergency contraception, the IUS has not been studied for this purpose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3717", "text": "Depo-Provera  is an injection that provides three months of contraceptive protection. Noristerat is another injection; it is given every two months. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3718", "text": "Contraceptive implants  are inserted under the skin of the upper arm, and contain progesterone only.  Jadelle  (Norplant 2) consists of two rods that release a low dose of hormones. It is effective for five years. Nexplanon has replaced the former  Implanon  and is also a single rod that releases etonogestrel (similar to the body's natural progesterone). The only difference between Implanon and Nexplanon is Nexplanon is radio opaque and can be detected by x-ray. This is needed for cases of implant migration. It is effective for three years and is usually done in office. It is over 99% effective. It works in 3 ways:\n1. Prevents ovulation- usually an egg does not mature\n2. thickens cervical mucus so to prevent sperm from reaching the egg\n3. If those 2 fail, the last is the progesterone causes the lining of the uterus to be too thin for implantation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3719", "text": "Ormeloxifene  is a  selective estrogen receptor modulator  (SERM). Marketed as Centchroman, Centron, or Saheli, it is pill that is taken once per week. Ormeloxifene is legally available only in  India . [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3720", "text": "The effect of hormonal agents on the reproductive system is complex. It is believed that combined hormonal contraceptives work primarily by preventing ovulation and thickening cervical mucus. Progestogen-only contraceptives can also prevent ovulation, but rely more significantly on the thickening of cervical mucus. Ormeloxifene does not affect ovulation, and its mechanism of action is not well understood. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3721", "text": "Combined hormonal contraceptives were developed to prevent  ovulation  by suppressing the release of  gonadotropins . They inhibit  follicular development  and prevent ovulation as a primary mechanism of action. [ 33 ] [ 34 ] [ 35 ] [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3722", "text": "Progestogen  negative feedback  decreases the pulse frequency of  gonadotropin-releasing hormone  (GnRH) release by the  hypothalamus , which decreases the release of  follicle-stimulating hormone  (FSH) and greatly decreases the release of  luteinizing hormone  (LH) by the  anterior pituitary . Decreased levels of FSH inhibit follicular development, preventing an increase in  estradiol  levels. Progestogen negative feedback and the lack of estrogen  positive feedback  on LH release prevent a  mid-cycle  LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation. [ 33 ] [ 34 ] [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3723", "text": "Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding), but was also found to inhibit follicular development and help prevent ovulation. Estrogen negative feedback on the anterior pituitary greatly decreases the release of FSH, which inhibits follicular development and helps prevent ovulation. [ 33 ] [ 34 ] [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3724", "text": "Another primary mechanism of action of all progestogen-containing contraceptives is inhibition of  sperm  penetration through the  cervix  into the upper  genital tract  ( uterus  and  fallopian tubes ) by decreasing the amount of and increasing the  viscosity  of the  cervical mucus . [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3725", "text": "The estrogen and progestogen in combined hormonal contraceptives have other effects on the reproductive system, but these have not been shown to contribute to their contraceptive efficacy: [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3726", "text": "Insufficient evidence exists on whether changes in the endometrium could actually prevent implantation. The primary mechanisms of action are so effective that the possibility of fertilization during combined hormonal contraceptive use is very small. Since pregnancy occurs despite endometrial changes when the primary mechanisms of action fail, endometrial changes are unlikely to play a significant role, if any, in the observed effectiveness of combined hormonal contraceptives. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3727", "text": "The mechanism of action of progestogen-only contraceptives depends on the  progestogen  activity and dose. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3728", "text": "Low dose progestogen-only contraceptives include traditional progestogen-only pills, the subdermal implant  Jadelle  and the  intrauterine system  Mirena. These contraceptives inconsistently inhibit ovulation in ~50% of cycles and rely mainly on their progestogenic effect of thickening the  cervical mucus  and thereby reducing sperm viability and penetration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3729", "text": "Intermediate dose progestogen-only contraceptives, such as the progestogen-only pill Cerazette (or the subdermal implant  Implanon ), allow some follicular development but much more consistently inhibit ovulation in 97\u201399% of cycles. The same cervical mucus changes occur as with low dose progestogens."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3730", "text": "High dose progestogen-only contraceptives, such as the injectables  Depo-Provera  and Noristerat, completely inhibit follicular development and ovulation. The same cervical mucus changes occur as with very low dose and intermediate dose progestogens."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3731", "text": "In  anovulatory cycles  using progestogen-only contraceptives, the endometrium is thin and atrophic. If the endometrium was also thin and atrophic during an ovulatory cycle, this could theoretically interfere with implantation of a blastocyst (embryo). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3732", "text": "Ormeloxifene does not affect ovulation. It has been shown to increase the rate of  blastocyst  development and to increase the speed at which the blastocyst is moved from the  fallopian tubes  into the uterus. Ormeloxifene also suppresses proliferation and  decidualization  of the  endometrium  (the transformation of the endometrium in preparation for possible implantation of an embryo). [ 32 ]  While they are believed to prevent  implantation  rather than  fertilization , exactly how these effects operate to prevent pregnancy is not understood"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3733", "text": "The use of emergency contraceptives (ECs) allows for the prevention of a pregnancy after unprotected sex or contraception failure. [ 37 ]  In the United States, there are currently four different methods available, including ulipristal acetate (UPA), an oral progesterone receptor agonist-antagonist; levonorgestrel (LNG), an oral progestin; off-label use of combined oral contraceptives (Yuzpe regimen); and the copper intrauterine device (Cu-IUD). [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3734", "text": "UPA, a progesterone agonist-antagonist, was approved by the FDA in 2010 for use as an EC. [ 38 ]  UPA acts as a partial agonist and antagonist of the progesterone receptor and works by preventing both ovulation and fertilization. [ 39 ]  Users of UPA are likely to experience delayed menses after the expected date. [ 40 ]  In the United States, UPA is sold under the brand name Ella, which is a 30\u00a0mg single pill to be taken up to 120 hours after unprotected sex. [ 41 ]  /> UPA has emerged as the most effective EC pill, however, the access to UPA is very limited in US cities. [ 42 ] [ 43 ]  UPA is a prescription emergency contraceptive pill and a recent study has found that less than 10% of pharmacies indicated that a UPA prescription could be filled immediately. [ 44 ]  72% of pharmacies reported the ability to order UPA and the prescription to be filled in a median wait time of 24 hours. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3735", "text": "Plan B one step was the first levonorgestrel progestin-only EC approved by the FDA in 1999. [ 41 ]  Currently, there are many different brands of levonorgestrel EC pills, including Take Action, Next Choice One Dose, and My Way and regimens include a single 1.5\u00a0mg pill of levonorgestrel. [ 41 ]  Levonorgestrel EC pills should be taken up to 72 hours after unprotected sex due to the drug becoming less effective over time. [ 41 ]  Levonorgestrel acts as an agonist of the progesterone receptor, preventing ovulation. [ 39 ]  Users of levonorgestrel often experience menses before the expected date. [ 40 ]  A prescription for levonorgestrel is not needed and can be found over the counter at local pharmacies. [ 45 ]  Because levonorgestrel does not have any life-threatening side effects, it has been approved by the FDA for use by all age groups. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3736", "text": "The Yuzpe regimen used combination oral contraceptives for EC and has been used since 1974. [ 41 ]  This regimen is no longer commonly used due to side effects such as nausea and vomiting, as well as the discovery of more effective methods. [ 41 ]  The regimen consists of two pills, each containing a minimum 100 \u03bcg of ethinyl estradiol and a minimum of 500 \u03bcg of levonorgestrel. [ 41 ]  The first pill is taken 72 hours after unprotected sex and the second pill is taken 12 hours after the first. [ 41 ]  The Yuzpe regimen is often used in areas where dedicated EC methods are unavailable or where EC is not accepted. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3737", "text": "The most effective form of EC is the insertion of a Cu-IUD within 5 days of unprotected sex. [ 41 ]  Because the Cu-IUD is inserted into the uterus, it has the advantage of providing continued contraception for up to 10 years. [ 46 ] [ 47 ]  Cu-IUDs have been the only IUDs that have been approved as ECs due to the mechanism in hormonal and copper IUDs differing. [ 41 ]  Hormonal IUDs are used for the treatment of unplanned pregnancies by being placed in the uterus after an oral EC has been taken. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3738", "text": "Pills\u2014combined and progestogen-only\u2014are the most common form of hormonal contraception. Worldwide, they account for 12% of contraceptive use. 21% of users of reversible contraceptives choose COCPs or POPs. Pills are especially popular in more developed countries, where they account for 25% of contraceptive use. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3739", "text": "Injectable hormonal contraceptives are also used by a significant portion\u2014about 6%\u2014of the world's contraceptive users. [ 48 ] [ 49 ]  Other hormonal contraceptives are less common, accounting for less than 1% of contraceptive use. [ 48 ] [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3740", "text": "In 1921,  Ludwig Haberlandt  demonstrated a temporary hormonal contraception in a female rabbit by transplanting ovaries from a second, pregnant, animal. [ 50 ]  By the 1930s, scientists had isolated and determined the structure of the  steroid hormones  and found that high doses of  androgens ,  estrogens , or  progesterone  inhibited  ovulation . [ 51 ] [ 52 ]  A number of economic, technological, and social obstacles had to be overcome before the development of the first hormonal contraceptive, the  combined oral contraceptive pill  (COCP). In 1957  Enovid , the first COCP, was approved in the  United States  for the treatment of menstrual disorders. In 1960, the U.S.  Food and Drug Administration  approved an application that allowed Enovid to be marketed as a contraceptive. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3741", "text": "The first progestogen-only contraceptive was introduced in 1969:  Depo-Provera , a high-dose progestin injection. [ 54 ]  Over the next decade and a half, other types of progestogen-only contraceptive were developed: a low-dose  progestogen only pill  (1973); [ 55 ]  Progestasert, the first  hormonal intrauterine device  (1976); [ 56 ]  and  Norplant , the first contraceptive implant (1983). [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3742", "text": "Combined contraceptives have also been made available in a variety of forms. In the 1960s a few  combined injectable contraceptives  were introduced, notably Injectable Number 1 in  China  and Deladroxate in  Latin America . [ 58 ]  A third combined injection, Cyclo-Provera, was reformulated in the 1980s by lowering the dose and renamed Cyclofem (also called Lunelle). Cyclofem and Mesigyna, another formulation developed in the 1980s, were approved by the  World Health Organization  in 1993. [ 59 ]   NuvaRing , a contraceptive vaginal ring, was first marketed in 2002. [ 60 ]  2002 also saw the launch of Ortho Evra, the first  contraceptive patch . [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3743", "text": "In 1991,  ormeloxifene  was introduced as a contraceptive in  India . [ 62 ]  While it acts on the estrogen hormonal system, it is atypical in that it is a  selective estrogen receptor modulator  rather than an estrogen, and has the capacity for both estrogenic and  antiestrogenic  effects. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3744", "text": "Mechanism of action COCs prevent fertilization and, therefore, qualify as contraceptives. There is no significant evidence that they work after fertilization. The progestins in all COCs provide most of the contraceptive effect by suppressing ovulation and thickening cervical mucus, although the estrogens also make a small contribution to ovulation suppression. Cycle control is enhanced by the estrogen. Because COCs so effectively suppress ovulation and block ascent of sperm into the upper genital tract, the potential impact on endometrial receptivity to implantation is almost academic. When the two primary mechanisms fail, the fact that pregnancy occurs despite the endometrial changes demonstrates that those endometrial changes do not significantly contribute to the pill's mechanism of action."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3745", "text": "Party and play  ( PnP ), also known as  chemsex  or  wired play , refers to the practice of consuming drugs to enhance  sexual activity . [ 1 ] [ 2 ]  This  sexual subculture  involves  recreational drug  users engaging in high-risk sexual behaviors under the influence of drugs, often within specific sub-groups. [ 3 ]  Activities may include  unprotected sex  with multiple partners during sessions over extended periods, sometimes lasting days. The drug of choice is typically  methamphetamine , commonly referred to as  crystal meth ,  tina , or  T . [ 4 ]  Other substances like  mephedrone ,  GHB ,  GBL , [ 5 ] [ 6 ]   ketamine , and  alkyl nitrites  (known as  poppers ) are also used. [ 6 ] [ 7 ]  The term  slamsex  is used for  injection drug users . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3746", "text": "Studies indicate that individuals participating in such activities have a higher likelihood of acquiring  sexually transmitted infections , including  HIV/AIDS , due to unprotected sex with numerous partners. Consequently, addressing this issue is considered a significant  public health  priority. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3747", "text": "The practice is commonly referred to as \"party 'n' play\" (PNP or PnP) by some participants, while others use the term \"high 'n' horny\" (HnH). An academic study has labeled it \"sexualized drug use\" (SDU). [ 9 ]  The term PnP is widely used among  gay men [ 3 ] [ failed verification ]  and other  men who have sex with men  (MSM) in North America and Australia. Conversely, the term chemsex is more common in Europe. [ 10 ]  In certain Southeast Asian countries, it is commonly known as \"chem fun\" (CF or Cf)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3748", "text": "Methamphetamine is often used recreationally for its effects as a potent  aphrodisiac ,  euphoriant , and  stimulant . [ 11 ]  It has been further described that \"an entire subculture known as party and play is based around methamphetamine use.\" [ 11 ]   Gay men belonging to this subculture will typically meet up through internet dating sites to have sex. [ 11 ]   On such sites, men often include notations such as \"chems\" or \"PnP\". [ 11 ]   Since stimulant drugs such as methamphetamine drastically delay the need for  sleep , increase  sexual arousal , and tend to inhibit  ejaculation , PNP sexual encounters can continue for many hours or even days. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3749", "text": "Methamphetamine taken in excess of amounts prescribed or recommended will prolong symptoms of intoxication for up to eight hours. [ 12 ]  In some cases, these sexual encounters will sometimes occur continuously for several days along with repeated methamphetamine use. [ 11 ]  Methamphetamine is used to create euphoria, \"heighten sexual appetite\", and increase sexual stamina. [ 6 ]  The crash following the use of methamphetamine in this manner is very often severe, with marked  hypersomnia . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3750", "text": "Ketamine is very different from the main chemsex drugs, as it is a  dissociative hallucinogen  that distorts  perception  and causes  dissociation . Ketamine is used in chemsex encounters to \"improve the experience of receptive  anal intercourse  or  fisting \". [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3751", "text": "A study of sauna participants in Barcelona, Spain, in 2016, found that the most commonly used drugs in chemsex are \"GHB/GBL, cocaine, ecstasy, silver bars ( MDMA ), poppers and Viagra\". [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3752", "text": "A 2014 study on chemsex in London, UK, indicated that the drugs associated with chemsex include mephedrone, GHB/GBL, crystal meth, ketamine, and cocaine. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3753", "text": "Internet posts by men seeking PnP experiences often resort to slang to identify what drug they are partying with. [ 14 ] [ 15 ]  These drugs tend to inhibit  penile erection , [ 11 ] [ 12 ]  a phenomenon known by the slang term  crystal penis  or  tweaker dick . Consequently, many men who engage in PnP use  erectile dysfunction  drugs such as  sildenafil ,  vardenafil , and  tadalafil . [ 16 ]   Imodium  is often taken by participants in passive  anal sex  in order to be clean for longer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3754", "text": "For some PnP participants, substance use may facilitate a process of \"cognitive disengagement\u201d or  moral disengagement  from the fears and stipulations associated with sex in the time of  HIV/AIDS . Popular discourses of \" disinhibition \" provide a commonly accepted alibi for activities engaged in when under the influence of stimulants. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3755", "text": "The use of drugs like mephedrone, GHB/GBL, and crystal meth before or during sex, can have physical effects. These can include dehydration, a higher risk of HIV and other sexually transmitted infections (STIs), and drug-related injuries. Dehydration is a widespread problem with chemsex. This can lead to serious health problems, including seizures and even death. GHB/GBL and crystal meth can also increase the risk of injuries due to accidents or sexual encounters that go wrong. These injuries can be as minor as cuts and bruises, but they can also be dangerous in severe cases, such as haemorrhages, anal fissures, ripped anuses, anal prolapse, suffocation, and more. Furthermore, the use of these drugs can affect erection and ejaculation. Gay/Bisexual men often will use Viagra or other ED drugs to overcome this issue. Unfortunately, this means that their body has to cope with drug interactions that very often go wrong leading, in many cases, to overdose, seizures, drug induced heart attacks, stroke, paralysis, neurological damage and even death. These physical risks are particularly higher in older men and those with pre-existing medical conditions. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3756", "text": "The same drug-induced loss of inhibitions makes PNP enthusiasts more vulnerable to more immediate threats, such as  robbery ,  date rape ,  assault , or  murder , by someone whom they meet for sex. [ 17 ]  Men in the chemsex scene have stated that  sexual consent  is not clearly defined and there can be a perception that anyone at a \"party and play\" get-together is assumed to consent. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3757", "text": "The abuse of drugs such as methamphetamine may cause neurological damage. [ 19 ]  Impaired judgement due to intoxication may lead to  bareback sex , which increases the chances of contracting HIV. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3758", "text": "The use of crystal methamphetamine or mephedrone for chemsex is associated with \"high-risk sexual behaviour\u2026 with little regard to consequences, poor [ antiretroviral drug ] adherence for HIV, poor use of condoms, extended episodes of (often traumatic) sexual pursuits (e.g. fisting) typically lasting two to three days, [and] multiple sexual partners. Men who have sex with men in the chemsex scene who inject drugs tend to use 'clumsy injecting practices and knowledge', which increases the risks of injection problems. As well, since most chemsex takes place in private home parties, it is hard for public health staff to reach these participants to inform them of safer practices, as compared to reaching gay men in nightclubs, who can be approached by outreach workers\". [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3759", "text": "Methamphetamine suppresses autonomic response and can cause sores and abrasions in the mouth. Open wounds or damaged mucous membranes can turn typically low-HIV-risk sex acts such as oral sex into much-higher-risk sexual activity [ 21 ]  unless all HIV-positive participants are undetectable on HAART, and all HIV-negative participants are taking  pre-exposure prophylaxis  in strict accordance with prescription instructions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3760", "text": "Men who PNP with methamphetamine,  cocaine ,  MDMA , and  ketamine  are twice as likely to have unprotected sex (meaning sex without using a condom or taking PrEP), according to British research from 2006. The study also found that up to 20% of gay men from central London gyms had tried methamphetamine, the drug most associated with PNPing. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3761", "text": "Subcultures of psychoactive drug use have long existed within urban gay communities, since the 1970s  disco  era and before.  These substances have been used for dancing, socializing, communal celebration and other purposes. [ 23 ]  The rise of online websites and hookup apps in the 1990s gave men new ways of  cruising  and meeting sexual partners, including the ability to arrange private sexual gatherings in their homes. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3762", "text": "From the early 2000s, historic venues of gay socialization such as bars, clubs, and dance events reduced in number in response to a range of factors, including  gentrification ,  zoning  laws, licensing restrictions, and the increased number of  closeted  or sexually labile men who are under the influence of drugs and the increasing popularity of digital technologies for sexual and social purposes. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3763", "text": "In this context, PNP emerged as an alternative form of sexualized partying that enabled participants to avoid the public scrutiny and potentially judgmental and anxiety-provoking nature of the \"public space\".  Newly popular drugs such as methamphetamine and GHB/GBL replaced  dance drugs  such as Ecstasy within this context. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3764", "text": "While PNP sessions tend to be organized around sex, there is some evidence that they can serve a range of social purposes for their participants, including the opportunity to meet other gay men, become friends, and engage in erotic play and experimentation. In some instances, PNP sessions play a part in the formation of loose social networks that are valued and relied upon by participants. [ 24 ]  For other men, increasing reliance on  hookup apps  and websites to arrange sex may result in a sense of isolation that may exacerbate the risk of drug dependence, especially in the context of a lack of other venues for gay socializing and sexual community-formation. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3765", "text": "A 2014 study found that one of the key reasons for taking drugs before and during sex was to boost sexual confidence and reduce feelings of self-doubt, regarding feelings of \"internalised  homophobia \" from society, concerns about an HIV diagnosis, or \"guilt related to having or desiring gay sex\". A key self-confidence issue for study participants was \" body image \", a concern that was heightened by the focus on social networking apps on appearance, because on these apps, there is a focus on idealized male bodies that are \"toned and muscular\". Men were also anxious about their sexual performance, and as such, taking drugs can reduce these anxieties and enable them to enjoy sex more. [ 6 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3766", "text": "It has been observed that reliable data and relevant research are generally lacking and this situation is generating a climate of  moral panic . In an opinion piece published by  The Guardian , it has been argued that an exaggerated reporting might give the public a distorted impression of the magnitude of this phenomenon and that may increase the level of collective anxiety. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3767", "text": "Poppers  (or  popper ) is a slang term referring to recreational drugs belonging to the  alkyl nitrite  family of  chemical compounds . When fumes from these substances are  inhaled , they act as potent  vasodilators , producing mild euphoria, warmth, and dizziness. Most effects have a rapid onset and are short-acting. [ 2 ]  Its  recreational use  is believed to be potentially dangerous for people with  heart problems ,  anaemia , or  glaucoma . Reported adverse effects include  fainting , retinal toxicity, and vision loss. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3768", "text": "As poppers include a broad range of  chemical types , their legality differs across different jurisdictions. They are often packaged under the guise of room deodorizer, leather polish, nail polish remover, or  videotape head cleaner  to evade  anti-drug laws . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3769", "text": "The term  poppers  stems from the \"popping\" sound of  glass vials  containing the substance when crushed to release vapour for inhalation.  Amyl nitrite  was originally prescribed in the late 1800s for the medical management of  angina . [ 2 ]  Many analogues exist, such as  isoamyl nitrite, isopentyl nitrite ,  isopropyl nitrite , and  isobutyl nitrite . These substances are subject to different regulations; for example, isobutyl nitrite is banned in the  European Union ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3770", "text": "Poppers act as  muscle relaxants , causing the relaxation of  involuntary smooth muscles  such as the  throat  and  anus . [ 5 ] [ 6 ]  Such physiological effects, along with others (such as mild euphoria), have resulted in poppers being used as  recreational drugs , sometimes during  sexual intercourse , as the effects can heighten arousal and help facilitate acts such as  anal intercourse . [ 7 ]  It has been reported that poppers were a part of the club culture which began during the mid-1970s  disco  scene, and surged in popularity during the  rave  scene of the 1980s and 1990s. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3771", "text": "Poppers come in liquid form, but this liquid is not directly consumed. When the bottle is opened, the vapors are inhaled, rather than the liquid. This is typically done through the nasal cavities, commonly directly from the bottle (avoiding touching the bottle to the skin) or with the help of small inhalers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3772", "text": "Inhaling nitrites produces a fast-acting, short-lived and non-specific relaxation of  smooth muscles  (along with the  sphincter  muscles of the  anus  and the  vagina ). [ 10 ]  Blood vessels are surrounded by smooth musculature, which directly influences blood pressure by increasing or decreasing its inward pressure on the blood vessels."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3773", "text": "With relaxation of the smooth muscles, the 'inward' pressure on the blood vessels decreases and they  dilate , resulting in  a drop in blood pressure  and an immediate (compensatory) increase in  heart rate  (reflex tachycardia). Vasodilation may cause giddiness, dizziness, headache, nausea, vomiting and flushing, and may produce a sensation of heat and excitement. Maximum vasodilatory effect is usually reached within 30 seconds, with (secondary) physiological effects lasting for 5 to 10 minutes. [ 11 ] [ 12 ] [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3774", "text": "Inhaling nitrites produces several psychological effects such as euphoria, increased sensual awareness, lowered inhibitions or increased confidence, and potential for impaired judgement and disorientation. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3775", "text": "Alkyl nitrites  interact  with other  vasodilators , such as  sildenafil  (Viagra),  vardenafil  (Levitra), and  tadalafil  (Cialis), to cause a serious  decrease in blood pressure , which can cause strokes, and low blood pressure leading to people fainting. [ 16 ]  Side effects of popper abuse include  tachycardia ,  headaches ,  migraines ,  dizziness  and  fainting . [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3776", "text": "The  Merck Manual of Diagnosis and Therapy  reports insignificant hazard associated with inhalation of alkyl nitrites, [ 18 ]  and British governmental guidance on the relative harmfulness of alkyl nitrites places them among the less harmful of recreational drugs. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3777", "text": "If in contact with the skin, Butyl Nitrite poppers can cause  chemical burns  and contact  dermatitis  of the skin around the mouth and nose. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3778", "text": "Swallowing poppers (rather than inhaling the vapour) may cause  cyanosis ,  methemoglobinemia , unconsciousness, coma, and complications leading to death. [ 10 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ]  Accidental aspiration of amyl or butyl nitrites may cause  lipoid pneumonia . [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3779", "text": "Isopropyl nitrite poppers may be a cause of  maculopathy  (eye damage), as reported in France and the United Kingdom. [ 26 ]  Some studies have concluded that there may be increased risk for at least temporary retinal damage with habitual popper use in certain users; in a letter to the  New England Journal of Medicine , [ 27 ]  an ophthalmologist described four cases in which recreational users of isopropyl nitrite poppers suffered temporary changes in vision. [ 28 ]  In November 2014, it was observed  maculopathy  is a rare complication of isopropyl nitrite abuse. A full recovery of visual acuity in longterm abuse could be demonstrated after drug abstinence. [ 29 ]  Studies have shown that poppers users who have HIV and/or use Sildenafil in combination with poppers are at an increased risk of developing poppers\u2010associated maculopathy. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3780", "text": "Foveal (center-of-gaze) damage has also been described, in six habitual users of isopropyl nitrite poppers. [ 31 ]  Furthermore, in June 2014,  optometrists  and  ophthalmologists  reported having noticed an increase in vision loss in chronic popper users in the United Kingdom associated with isopropyl nitrite (substitute for isobutyl nitrite which was banned in 2007). [ 32 ] [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3781", "text": "A working group in 2019 from the  International Agency for Research on Cancer  determined there to be \"sufficient evidence\" to suggest  carcinogenic  properties of isobutyl nitrite on experimental animals, and because they could not find any sufficient studies regarding its carcinogenic effects on humans, they determined that isobutyl nitrite is \"possibly carcinogenic to humans\". The group primarily looked at 2 studies on animals, one on rats and one on mice. Both of these involved the administration of doses of isobutyl nitrite at seemingly low doses (0, 37.5, 75, or 150 ppm) 6 hours a day, 5 days a week, for a total of 103 weeks. [ 34 ]  This is different from the relatively brief exposure to isobutyl nitrite that inhaling poppers recreationally usually provides. Nonetheless, in the studies there was shown to be no increase in death rates for the animals exposed to isobutyl nitrite, but there was shown to be an increase in tumors in the lungs of the males and females of both species in the groups exposed, as well as in the thyroids of the male mice exposed. [ 34 ]  Isobutyl Nitrite is no longer sold as 'Poppers' having been banned in the EU since 2007 and banned in the USA since 1990.  [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3782", "text": "Early in the  AIDS  crisis, widespread use of poppers among AIDS patients led to the later disproved hypothesis that poppers contributed to the development of  Kaposi's sarcoma , a rare form of cancer that occurs in AIDS patients. [ 36 ] [ 37 ]  Modest, short-term reductions in immune function were observed in animal studies, but not replicated in human studies. [ 38 ] [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3783", "text": "Amyl nitrites were part of some kits used to treat  cyanide poisoning , containing amyl nitrite,  sodium nitrite , and  sodium thiosulfate . The nitrites were administered to produce  methemoglobin  and induce  vasodilation . [ 40 ] [ 41 ]  Amyl nitrites were discontinued in 2012 in standard cyanide kits. [ 42 ]  Cyanide kits now use  hydroxocobalamin . [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3784", "text": "Poppers contain a class of chemicals called alkyl nitrites. To the extent that poppers products contain alkyl nitrites, the following applies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3785", "text": "The following table summarizes alkyl nitrite chemical and physical properties, including chemical structure: [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3786", "text": "The French chemist  Antoine J\u00e9r\u00f4me Balard  synthesized  amyl nitrite  in 1844. [ 46 ]   Sir Thomas Lauder Brunton , a Scottish physician born in the year of amyl nitrite's first synthesis, documented its clinical use to treat  angina pectoris  in 1867 when patients experiencing chest pains would experience complete relief after inhalation. [ 47 ]   Brunton was inspired by earlier work with the same agent, performed by  Arthur Gamgee  and  Benjamin Ward Richardson . [ 47 ]  Brunton reasoned that the angina sufferer's pain and discomfort could be reduced by administering amyl nitrite\u2014to dilate the coronary arteries of patients, thus improving blood flow to the heart muscle. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3787", "text": "Amyl nitrites were originally enclosed in a glass mesh called \"pearls\". The usual administration of these pearls was done by crushing them between the fingers, followed by a popping sound. This administration process seems to be the origin of the  slang term  \"poppers\". It was then administered via direct inhalation of the vapors or inhalation through silk that covered the capsule."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3788", "text": "Brunton found that amyl nitrites had effects of dilating blood vessels and flushing of the face. Isobutyl nitrites were also documented around the late 1890s by Brunton and despite being found to have generally the same effects as amyl nitrites, they were never used as a clinical alternative to amyl nitrates. Brunton also found that propyl nitrites had the same effects as well. [ 48 ] [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3789", "text": "Although amyl nitrite is known for its practical therapeutic applications, the first documented case of recreational use was in 1964. [ 50 ] [ 51 ]  The poppers \"craze\" began in the early 1970s in the  gay male  community in  bars ,  discoth\u00e8ques  and  bathhouses . [ 52 ] [ 53 ]  It was packaged and sold pharmaceutically in fragile glass ampoules wrapped in cloth sleeves which, when crushed or \"popped\" in the fingers, released the amyl nitrite for inhalation, hence the colloquialism  poppers . [ 52 ]  The term extended to the drug in any form as well as to other drugs with similar effects, e.g.  butyl nitrite  which is packaged under a variety of trade names in small bottles. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3790", "text": "In the late 1970s,  Time  magazine [ 54 ]  and  The Wall Street Journal [ 55 ]  reported that popper use among  gay men  began as a way to enhance sexual pleasure, but \"quickly spread to  avant-garde   heterosexuals \". A series of interviews conducted in the late 1970s revealed a wide spectrum of users. [ 54 ] [ failed verification ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3791", "text": "Poppers were well established in the gay community, with more than a third of gay men having used poppers at least once. [ 56 ]  Poppers were partial inspiration for songs such as  Troye Sivan 's  Rush . [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3792", "text": "Poppers are legal in Australia, and from 2020, poppers can also be purchased as a schedule 3 substance from pharmacies, or a schedule 4 substance with a prescription. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3793", "text": "In June 2018, the  Therapeutic Goods Administration  (TGA) motioned to reschedule alkyl nitrites to be in the same category as heroin and cocaine ( Schedule 9 ). [ 59 ]  This was met by criticism from the LGBTQI community for being discriminatory and further evidence was demanded and further consultation sought. [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3794", "text": "In October 2018, the  Australian Federation of AIDS Organisations  (AFAO) pointed out the lack of quality evidence provided by the TGA to justify the rescheduling [ 61 ]  and that use of amyl nitrites has been stable over the past decade with very little evidence of harm and has been in use by a high proportion of gay men over a long period."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3795", "text": "A final decision was pushed back from 29 November 2018 to late January or early February 2019 for further consultation with the public. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3796", "text": "As of March 2019, two public meetings have taken place in Sydney and Melbourne with  The Kirby Institute  and the  Australian Research Centre in Sex, Health and Society  (ARCSHS). Along with 70 written public proposals, there was significant opposition to alkyl nitrites rescheduling. [ 63 ]  Banning alkyl nitrites was not considered acceptable as their use was said to help reduce harms such as anal injury and blood-borne disease transmission during anal sex. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3797", "text": "In June 2019, Australia decided not to ban poppers. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3798", "text": "Since 2013,  Health Canada  has banned all distribution and sales of poppers. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3799", "text": "Since 2007, reformulated poppers containing  isopropyl nitrite  are sold in the EU;  isobutyl nitrite  is prohibited. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3800", "text": "In  France , the sale of products containing  butyl nitrite  has been prohibited since 1990 on grounds of danger to consumers. [ 68 ]  In 2007, the government extended this prohibition to all  alkyl nitrites  that were not authorized for sale as  drugs . [ 69 ]  After litigation by  sex shop  owners, this extension was quashed by the  Council of State  on the grounds that the government had failed to justify such a blanket prohibition: according to the court, the risks cited, concerning rare accidents often following abnormal usage, rather justified compulsory warnings on the packaging. [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3801", "text": "The possession in  Germany ,  Austria  and  Switzerland  is not subject to any regulations regarding  anesthetic  drugs and is therefore legal; however, the purchase, sale or trade of  amyl nitrite  without permission violates the drug laws of the corresponding countries. Occasionally, poppers were seized from sex shops, when sold there illegally. [ 71 ] [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3802", "text": "Poppers are sold in  nightclubs ,  bars , sex shops,  drug paraphernalia   head shops , over the  Internet  and in markets. It is illegal under  Medicines Act 1968  to sell them advertised for human consumption. The  Advisory Council on the Misuse of Drugs  noted in 2011 that poppers, rather than being a psychoactive substance or a  legal high , \"appear to fall within the scope of  The Intoxicating Substances (Supply) Act 1985 \". [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3803", "text": "The  Psychoactive Substances Act 2016 , scheduled to be enacted 1 April 2016, was initially claimed to impose a blanket ban on the production, import and distribution of all poppers. [ 74 ]  On 20 January 2016 a motion to exempt poppers (alkyl nitrites) from this legislation was defeated. [ 75 ]  This was opposed by Conservative MP  Ben Howlett . Howlett's fellow Conservative MP  Crispin Blunt  declared that he has used and currently uses poppers. Manufacturers expressed concern over loss of business and potential unemployment. [ 76 ] [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3804", "text": "In March 2016, the Advisory Council on the Misuse of Drugs stated that, because alkyl nitrites do not directly stimulate or depress the  central nervous system , poppers do not fall within the scope of the Psychoactive Substances Act 2016. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3805", "text": "Amyl nitrite  was originally marketed as a  prescription drug  in 1937. It remained so until 1960, when the  Food and Drug Administration  removed the prescription requirement due to its safety record. This requirement was reinstated in 1969, after observing an increase in  recreational use . There was a huge increase in the number of brands for  butyl nitrites  after the FDA put in the prescription requirement again in 1969. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3806", "text": "Butyl nitrites were outlawed in 1988 by the  Anti-Drug Abuse Act of 1988 . [ 79 ]  This prompted distributors to sell other  alkyl nitrites  not yet banned, like  isopropyl nitrite . In 1990, isopropyl nitrites and other nitrites not yet banned were outlawed by the  Crime Control Act of 1990 . [ 80 ]  Both of these laws include an exception for  commercial purpose , defined as any use other than for the production of consumer products containing volatile alkyl nitrites meant for inhaling or otherwise introducing volatile alkyl nitrites into the human body for euphoric or physical effects. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3807", "text": "\" Wine, women, and song \" is a  hendiatris  that endorses  hedonistic  lifestyles or behaviors. A more modern form of the idea is often expressed as \" sex  and  drugs  and  rock 'n' roll \", a phrase popularized by British singer  Ian Dury  in  his song of the same title ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3808", "text": "Similar  tripartite mottoes  have existed for a long time in many languages, for example:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3809", "text": "Not all hendiatris including women are positive: in  Greek :  \u03a0\u03cd\u03c1, \u03b3\u03c5\u03bd\u03ae \u03ba\u03b1\u03b9 \u03b8\u03ac\u03bb\u03b1\u03c4\u03c4\u03b1 ,  lit. \u2009 'fire, women and the sea' instead suggest three dangers rather than pleasures, and  Turkish :  At, Avrat, Silah ,  lit. \u2009 'horse, woman, weapon' offers the three essentials of quite another culture."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3810", "text": "Roman inscriptions mention  Balnea vina Venus , ' Baths ,  wines ,  sex ', such as the ambivalent:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3811", "text": "balnea vina Venus  \ncorrumpunt corpora \nnostra se<t> vitam faciunt \nbalnea vina Venus \n \n\"Baths, wine, and sex corrupt our bodies, but baths, wine, and sex make life worth living.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_3812", "text": "The following poem mentions similar ideas, using four concepts rather than three:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3813", "text": "Omar Khayyam addressed the trio in 1120 in his  Rubaiyat, verse XII . For him singing was replaced by a book, but he acknowledged its importance for others."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3814", "text": "Among rural Arabs in the days before Muhammed, free women \"joined in the music of the family or tribal festivities with their instruments\". [ 2 ]  It was a time of the \" badaw\u012b  Arab\". A secular people then, for them \"love, wine, gambling, hunting, the pleasure of song and romance ... wit and wisdom\" were all important. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3815", "text": "The Irish poet Edward Lysaght (1763\u20131810) used the phrase 'poetry and pistols, wine and women'. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3816", "text": "In 1816 the English poet John Keats composed a poem, 'Give Me Women, Wine, and Snuff'. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3817", "text": "The English  couplet  \"Who loves not woman, wine, and song / Remains a fool his whole life long\" appears in print as early as 1837, translated from German verse attributed to Martin Luther. [ 5 ]   John Addington Symonds  used the phrase \"Wine, Women and Song\" as the title for his 1884 book of translations of medieval Latin students' songs. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3818", "text": "The phrase in  German  is apparently older than in English. Symonds and the anonymous 1837 writer both provide the German text, attributing it to Luther. The attribution to Luther has been questioned, however, [ 7 ] [ 8 ]  and the earliest known reference in German is to a folksong first printed in 1602. [ 9 ]   Bartlett's Familiar Quotations  cites  Johann Heinrich Voss  (1751\u20131826) as a likely source, [ 7 ]  but any use by him would have to be a later use of the phrase."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3819", "text": "The  waltz  \"Wine, Women and Song\" ( Wein, Weib und Gesang ) is Op. 333 (1869) of  Johann Strauss\u00a0II ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3820", "text": "The lines  Deutsche Frauen, deutsche Treue, / Deutscher Wein, und deutscher Sang  (German women, German loyalty, / German wine, and German song) are found in the second verse of  Das Lied der Deutschen ,  the third verse of which is the  German national anthem ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3821", "text": "Alpha blockers , also known as  \u03b1-blockers  or  \u03b1-adrenoreceptor antagonists , are a class of   pharmacological agents  that act as  antagonists  on  \u03b1-adrenergic receptors  ( \u03b1-adrenoceptors ). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3822", "text": "Historically, alpha-blockers were used as a tool for pharmacologic research to develop a greater understanding of the autonomic nervous system. Using alpha blockers, scientists began characterizing arterial blood pressure and central vasomotor control in the autonomic nervous system. [ 3 ]  Today, they can be used as clinical treatments for a limited number of diseases. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3823", "text": "Alpha blockers can treat a small range of diseases such as  hypertension ,  Raynaud's disease ,  benign prostatic hyperplasia  (BPH) and  erectile dysfunction . [ 2 ]  Generally speaking, these treatments function by binding an \u03b1-blocker to \u03b1 receptors in the arteries and smooth muscle. Ultimately, depending on the type of alpha receptor, this relaxes the smooth muscle or blood vessels, which increases fluid flow in these entities. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3824", "text": "When the term \"alpha blocker\" is used without further qualification, it can refer to an  \u03b1 1  blocker, an  \u03b1 2  blocker, a nonselective blocker (both  \u03b1 1  and  \u03b1 2  activity), or an  \u03b1  blocker with some \u03b2 activity. [ 2 ]  However, the most common type of alpha blocker is usually an  \u03b1 1  blocker."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3825", "text": "Non-selective \u03b1-adrenergic receptor antagonists include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3826", "text": "Selective \u03b1 1 -adrenergic receptor antagonists include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3827", "text": "Selective \u03b1 2 -adrenergic receptor antagonists include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3828", "text": "Finally, the agents  carvedilol  and  labetalol  are both \u03b1 and  \u03b2-blockers ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3829", "text": "Below are some of the most common drugs used in the clinic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3830", "text": "Irreversibly binds. [ 2 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3831", "text": "Blocks alpha induced vasconstriction. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3832", "text": "4 hours of action after initial administration. [ 2 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3833", "text": "Lowers blood pressure by decreasing peripheral resistance. [ 2 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3834", "text": "Cardura XL"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3835", "text": "Coreg CR"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3836", "text": "While there are limited clinical \u03b1-blocker uses, in which most \u03b1-blockers are used for  hypertension  or  benign prostatic hyperplasia , \u03b1-blockers can be used to treat a few other diseases, such as  Raynaud's disease ,  congestive heart failure  (CHF),  pheochromocytoma , and  erectile dysfunction . [ 15 ] [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3837", "text": "Furthermore, \u03b1-blockers can occasionally be used to treat anxiety and panic disorders, such as  posttraumatic stress disorder  (PTSD) induced  nightmares . [ 6 ]  Studies have also had great medical interest in testing alpha blockers, specifically \u03b1 2  blockers, to treat  type II diabetes  and  psychiatric depression . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3838", "text": "Hypertension  is due to an increase in vascular resistance and vasoconstriction. Using \u03b1 1  selective antagonists, such as  prazosin , has been efficacious in treating mild to moderate hypertension. This is because they can decrease vascular resistance and decrease pressure. [ 2 ] [ 18 ]  However, while these drugs are generally well tolerated, they have the potential to produce side effects such as orthostatic hypotension and dizziness. [ 2 ]  However, unlike other treatments for hypertension such as  ACE inhibitors ,  ARBs ,  calcium channel blockers ,  thiazide diuretics  or  beta blockers , alpha blockers have not demonstrated the same mortality and morbidity benefits, and are therefore not generally used as first or even second line agents."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3839", "text": "Another treatment for hypertension is using drugs that have both \u03b1 1  blocking activity, as well as nonselective \u03b2 activity, such as  Labetalol  or  carvedilol . [ 19 ]  In low doses, labetalol and carvedilol can decrease the peripheral resistance and block the effects of isoprenaline to reduce hypertensive symptoms. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3840", "text": "Pheochromocytoma  is a disease in which a catecholamine secreting tumor develops. [ 2 ] [ 20 ]  Specifically, norepinephrine and epinephrine are secreted by these tumors, either continuously or intermittently. [ 21 ]  The excess release of these catecholamines increases central nervous system stimulation, thus causing blood vessels to increase in vascular resistance, and ultimately giving rise to hypertension. [ 20 ]  In addition, patients with these rare tumors are often subject to headaches, heart palpitations, and increased sweating. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3841", "text": "Phenoxybenzamine , a nonselective \u03b1 1  and \u03b1 2  blocker, has been used to treat pheochromocytoma. [ 21 ]  This drug blocks the activity of epinephrine and norepinephrine by antagonizing the alpha receptors, thus decreasing vascular resistance, increasing vasodilation, and decreasing blood pressure overall. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3842", "text": "Blockers that have both the ability to block both \u03b1 and \u03b2 receptors, such as  carvedilol ,  bucindolol , and  labetalol , have the ability to mitigate the symptoms in  congestive heart failure . [ 22 ]  By binding to both the \u03b1 and \u03b2 receptors, these drugs can decrease the cardiac output and stimulate the dilation of blood vessels to promote a reduction in blood pressure. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3843", "text": "Yohimbine , an \u03b1 2  blocker derived from the bark of the  Pausinystalia johimbe  tree, has been tested to increase libido and treat erectile dysfunction. The proposed mechanism for yohimbine is blockade of the adrenergic receptors that are associated with  neurotransmitters  inhibition, including  dopamine  and  nitric oxide , and thus aiding with penile erection and libido. [ 23 ]  By doing so, they can alter the blood flow in the penis to aid in achieving an erection. However, some side effects can occur, such as  palpitation ,  tremor ,  elevated blood pressure , and  anxiety . [ 23 ] \n Yohimbe bark  contains both \u03b1 1  and \u03b1 2   adrenergic receptors  blocking  alkaloids ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3844", "text": "Phentolamine , a non-selective alpha blocker, has also been tested to treat erectile dysfunction. By reducing vasoconstriction in the penis, there appears to be increased blood flow that aids in penile erection. Side effects associated with phentolamine include headache, flushing, and nasal congestion. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3845", "text": "Phenoxybenzamine , a non-competitive \u03b1 1  and \u03b1 2  blocker was used by Dr.  Giles Brindley  in the first intracavernosal pharmacotherapy for erectile dysfunction. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3846", "text": "In  benign prostatic hyperplasia  (BPH), men experience urinary obstruction and are unable to urinate, thus leading to urinary retention. [ 2 ]  \u03b1 1  specific blockers have been used to relax the smooth muscle in the bladder and enlarged prostate. [ 25 ]   Prazosin ,  doxazosin , and  terazosin  have been particularly useful for patients with BPH, especially in patients with hypertension. [ 2 ]  In such patients, these drugs can treat both conditions at the same time. [ 2 ]  In patients without hypertension,  tamsulosin  can be used, as it has the ability to relax the bladder and prostate smooth muscle without causing major changes in blood pressure. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3847", "text": "Both \u03b1 1  blockers and \u03b1 2  blockers have been examined to treat  Raynaud's disease . Although \u03b1 1  blockers, such as  prazosin , have appeared to give slight improvement for the sclerotic symptoms of Raynaud's disease, there are many side effects that occur while taking this drug. Conversely, \u03b1 2  blockers, such as yohimbine, appear to provide significant improvement of the sclerotic symptoms in Raynaud's Disease without excessive side effects. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3848", "text": "Patients with  posttraumatic stress disorder  (PTSD) have often continued to be symptomatic despite being treated with PTSD-specific drugs. [ 27 ]  In addition, PTSD patients often have debilitating nightmares that continue, despite their treatments. [ 27 ]  High doses of the \u03b1 1  blocker,  prazosin , have been efficacious in treating patients with PTSD induced nightmares due to its ability to block the effects of norepinephrine. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3849", "text": "Adverse effects of prazosin to treat PTSD nightmares include  dizziness ,  first dose effect  (a sudden loss of consciousness),  weakness ,  nausea , and  fatigue . [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3850", "text": "Although alpha blockers have the ability to reduce some disease pathology, there are some side effects that come with these alpha blockers. [ 28 ]  However, because there are several structural compositions that make each alpha blocker different, the side effects are different for each drug. Side effects that arise when taking alpha blockers can include the  first dose effect ,  cardiovascular side effects, genitourinary side effects, as well as other side effects. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3851", "text": "One of the most common side effects with alpha blockers is the  first dose effect . [ 29 ]  This is a phenomenon in which patients with hypertension take an alpha blocker for the first time, and suddenly experience an intense decrease in blood pressure. Ultimately, this gives rise to  orthostatic hypotension ,  dizziness , and a sudden loss of consciousness due to the drastic drop in blood pressure. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3852", "text": "Alpha blockers that possess these side effects include  prazosin ,  doxazosin , and  terazosin . [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3853", "text": "There are some alpha blockers that can give rise to changes in the cardiovascular system, such as the induction of reflex tachycardia, orthostatic hypotension, or heart palpitations via alterations of the QT interval. [ 28 ] [ 31 ]  Alpha blockers that may have these side effects include  yohimbine ,  phenoxybenzamine , and  phentolamine . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3854", "text": "When alpha blockers are used to treat BPH, it causes vasodilation of blood vessels on the bladder and the prostate, thus increasing urination in general. [ 32 ]  However, these alpha blockers can produce the exact opposite side effect, in which  edema , or abnormal fluid retention, occurs. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3855", "text": "In addition, due to the relaxation of the prostate smooth muscle, another side effect that arises in men being treated for BPH is impotence, as well as the inability to ejaculate. [ 32 ] [ 34 ]  However, if any ejaculation activity does occur, oftentimes, it results in a phenomenon called  retrograde ejaculation , in which semen flows into the urinary bladder instead of exiting through the urethra. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3856", "text": "Drugs that may produce such side effects include  prazosin ,  terazosin ,  tamsulosin , and  doxazosin . [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3857", "text": "Finally, there are other general side effects that can be caused by most alpha blockers (however, more frequently in alpha-1 blockers). Such side effects include  dizziness ,  drowsiness ,  weakness ,  fatigue , psychiatric  depression , and  dry mouth . [ 28 ] [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3858", "text": "Priapism, an unwanted, painful long term erection not brought on by sexual arousal and lasting several hours has been associated with alpha blocker use. While this is extremely rare, particularly with tamsulosin, it can cause permanent impotence if not treated in a hospital setting. Male patients should be made aware of this as it can result from a single dose or develop over time."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3859", "text": "There is only one compelling indication for alpha blockers, which is for  benign prostatic hyperplasia . [ 33 ]  Patients who need alpha blockers for BPH, but have a history of  hypotension  or  postural heart failure , should use these drugs with caution, as it may result in an even greater decrease in blood pressure or make heart failure even worse. [ 35 ] [ 36 ]  The most compelling  contraindication  is  urinary incontinence  and overall fluid retention. [ 35 ] [ 36 ]  To combat such fluid retention, patients can take a diuretic in combination with the alpha-blocker. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3860", "text": "In the absence of compelling indications or contraindications, patients should take alpha blockers as a  step 4 therapy  to reduce blood pressure, but only if the use of ACE inhibitors, angiotensin-II receptor blockers, calcium channel blockers, or thazide diuretics (in full dose or in combinations) have not been efficacious. [ 33 ] [ 35 ] [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3861", "text": "As with any drug, there are drug interactions that can occur with alpha blockers. For instance, alpha blockers that are used for the reduction of blood pressure, such as  phenoxybenzamine  or  phentolamine  can have synergy with other drugs that affect smooth muscle, blood vessels, or drugs used for  erectile dysfunction  (i.e.  sildenafil ,  tamsulosin , etc.). This stimulates exaggerated  hypotension . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3862", "text": "Alternative alpha blockers, such as  prazosin ,  tamsulosin ,  doxazosin , or  terazosin  can have adverse interactions with  beta blockers ,  erectile dysfunction  drugs,  anxiolytics , and  antihistamines . [ 2 ]  Again, these interactions can cause dangerous  hypotension . Furthermore, in rare cases, drug interactions can cause irregular, rapid heartbeats or an increase blood pressure. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3863", "text": "Yohimbine  can interact with  stimulants ,  hypertension  drugs,  naloxone , and  clonidine . Interactions with such drugs can cause either an unintended increase in blood pressure or potentiate an increase in blood pressure. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3864", "text": "Finally, in drugs with both alpha and beta blocking properties, such as  carvedilol  and  labetalol , interactions with other alpha or beta blockers can exaggerate a decrease in blood pressure. [ 2 ]  Conversely, there are also drug interactions with carvedilol or labetalol in which blood pressure is increased unintentionally (such as with cough and cold medications). [ 2 ]  Finally, there may also be some alpha/beta blocker drug interactions that can worsen previous heart failure. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3865", "text": "Alpha blockers work by blocking the effect of nerves in the sympathetic nervous system. This is done by binding to the alpha receptors in smooth muscle or blood vessels. [ 37 ]  \u03b1-blockers can bind both reversibly and irreversibly. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3866", "text": "There are several \u03b1 receptors throughout the body where these drugs can bind. Specifically, \u03b1 1  receptors can be found in most vascular smooth muscle, the pupillary dilator muscle, the heart, the prostate, and pilomotor smooth muscle. [ 2 ]  On the other hand, \u03b1 2  receptors can be found in platelets, cholinergic nerve terminals, some vascular smooth muscle, postsynaptic CNS neurons, and fat cells. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3867", "text": "The structure of \u03b1 receptors is a classic  G protein\u2013coupled receptors  (GPCRs) consisting of 7 transmembrane domains, which form three intracellular loops and three extracellular loops. [ 2 ]  These receptors couple to heterotrimeric G proteins composed of \u03b1, \u03b2, and \u03b3 subunits. [ 2 ]  Although both of the \u03b1 receptors are GPCRs, there are large differences in their mechanism of action. Specifically,  \u03b1 1  receptors  are characterized as G q  GPCRs, signaling through  Phospholipase C  to increase  IP 3  and  DAG , thus increasing the release of calcium. Meanwhile,  \u03b1 2  receptors  are labeled as G i  GPCRs, which signal through  adenylyl cyclase  to decrease  cAMP . [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3868", "text": "Because the \u03b1 1  and \u03b1 2  receptors have different mechanisms of action, their antagonists also have different effects. [ 39 ]  \u03b1 1  blockers can inhibit the release of  IP 3  and  DAG  to decrease calcium release, thus, decreasing overall signaling. On the other hand, \u03b1 2  blockers prevent the reduction of cAMP, thus leading to an increase in overall signaling."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3869", "text": "Apomorphine , sold under the brand name  Apokyn  among others, is a type of  aporphine  having activity as a non- selective   dopamine agonist  which activates both  D 2 -like  and, to a much lesser extent,  D 1 -like receptors . [ 2 ]  It also acts as an  antagonist  of  5-HT 2  and  \u03b1-adrenergic receptors  with high  affinity . The compound is an alkaloid belonging to nymphaea caerulea, or blue lotus, but is also historically known as a  morphine  decomposition product made by boiling morphine with concentrated acid, hence the  -morphine  suffix. Contrary to its name, apomorphine does not actually contain morphine or its skeleton, nor does it bind to  opioid receptors . The  apo-  prefix relates to it being a  morphine  derivative (\"[comes] from morphine\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3870", "text": "Historically, apomorphine has been tried for a variety of uses, including as a way to relieve anxiety and craving in alcoholics, an emetic (to induce vomiting), for treating stereotypies (repeated behaviour) in farmyard animals, and more recently in treating  erectile dysfunction . Currently, apomorphine is used in the treatment of  Parkinson's disease . It is a potent  emetic  and should not be administered without an  antiemetic  such as  domperidone . The emetic properties of apomorphine are exploited in veterinary medicine to induce therapeutic  emesis  in canines that have recently ingested toxic or foreign substances."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3871", "text": "Apomorphine was also used as a private treatment of  heroin addiction , a purpose for which it was championed by the author  William S. Burroughs . Burroughs and others claimed that it was a \"metabolic regulator\" with a restorative dimension to a damaged or dysfunctional dopaminergic system. Despite anecdotal evidence that this offers a plausible route to an abstinence-based mode, no clinical trials have ever tested this hypothesis. A recent study indicates that apomorphine might be a suitable marker for assessing central  dopamine  system alterations associated with chronic heroin consumption. [ 3 ]  There is, however, no clinical evidence that apomorphine is an effective and safe treatment regimen for  opiate addiction . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3872", "text": "Apomorphine is used in advanced  Parkinson's disease  intermittent hypomobility (\"off\" episodes), where a decreased response to an anti-Parkinson drug such as  L -DOPA  causes  muscle stiffness  and loss of muscle control. [ 5 ] [ 6 ]  While apomorphine can be used in combination with  L -DOPA , the intention is usually to reduce the  L -DOPA dosing, as by this stage the patient often has many of  dyskinesias  caused by  L -DOPA and hypermobility periods. [ 7 ] [ 8 ]  When an episode sets in, the apomorphine is injected  subcutaneously  or applied sublingually, [ 9 ]  and signs subside. It is used an average of three times a day. [ 7 ]  Some people use portable mini-pumps that continuously infuse them with apomorphine, allowing them to stay in the \"on\" state and using apomorphine as an effective  monotherapy . [ 8 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3873", "text": "The main and  absolute contraindication  to using apomorphine is the concurrent use of  adrenergic receptor  antagonists; combined, they cause a severe  drop in blood pressure  and  fainting . [ 7 ] [ 6 ]   Alcohol  causes an increased frequency of  orthostatic hypotension  (a sudden drop in blood pressure when getting up), and can also increase the chances of  pneumonia  and  heart attacks . [ 7 ]   Dopamine antagonists , by their nature of competing for sites at dopamine receptors, reduce the effectiveness of the agonistic apomorphine. [ 7 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3874", "text": "IV administration  of apomorphine is highly discouraged, as it can crystallize in the veins and create a blood clot ( thrombus ) and block a pulmonary artery ( pulmonary embolism ). [ 7 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3875", "text": "Nausea and vomiting are common side effects when first beginning therapy with apomorphine; [ 11 ]  antiemetics such as trimethobenzamide or domperidone, dopamine antagonists, [ 12 ]  are often used while first starting apomorphine. Around 50% of people grow tolerant enough to apomorphine's emetic effects that they can discontinue the antiemetic. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3876", "text": "Other side effects include orthostatic hypotension and resultant fainting,  sleepiness ,  dizziness ,  runny nose ,  sweating ,  paleness , and  flushing . More serious side effects include dyskinesias (especially when taking  L -DOPA), fluid accumulation in the limbs ( edema ), suddenly falling asleep,  confusion  and  hallucinations ,  increased heart rate  and  heart palpitations , and persistent  erections  ( priapism ). [ 6 ] [ 7 ] [ 13 ]  The priapism is caused by apomorphine increasing arterial blood supply to the  penis . This side effect has been exploited in studies attempting to treat  erectile dysfunction . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3877", "text": "Apomorphine's  R-enantiomer  is an  agonist  of both  D 1  and  D 2  dopamine receptors , with higher activity at D 2 . [ 7 ] [ 12 ]  The members of the D 2  subfamily, consisting of D 2 ,  D 3 , and  D 4  receptors, are inhibitory  G protein\u2013coupled receptors . The D 4  receptor in particular is an important target in the signaling pathway, and is connected to several neurological disorders. [ 15 ]  Shortage or excess of dopamine can prevent proper function and signaling of these receptors leading to disease states. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3878", "text": "Apomorphine improves motor function by activating dopamine receptors in the  nigrostriatal pathway , the  limbic system , the  hypothalamus , and the  pituitary gland . [ 17 ]  It also increases blood flow to the  supplementary motor area  and to the  dorsolateral prefrontal cortex  (stimulation of which has been found to reduce the  tardive dyskinesia  effects of  L -DOPA ). [ 18 ] [ 19 ]  Parkinson's has also been found to have excess  iron  at the sites of neurodegeneration; both the ( R )- and ( S )-enantiomers of apomorphine are potent iron  chelators  and  radical scavengers . [ 12 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3879", "text": "Apomorphine also decreases the breakdown of dopamine in the brain (though it inhibits its synthesis as well). [ 21 ] [ 22 ]  It is an upregulator of certain neural growth factors, [ 23 ]  in particular  NGF  but not  BDNF ,  epigenetic  downregulation of which has been associated with addictive behaviour in rats. [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3880", "text": "Apomorphine causes vomiting by acting on dopamine receptors in the  chemoreceptor trigger zone  of the  medulla ; this activates the nearby  vomiting center . [ 17 ] [ 22 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3881", "text": "While apomorphine has lower  bioavailability  when taken orally, due to not being absorbed well in the GI tract and undergoing heavy  first-pass metabolism , [ 20 ] [ 10 ]  it has a bioavailability of 100% when given subcutaneously. [ 7 ] [ 17 ]  It reaches peak plasma concentration in 10\u201360 minutes. Ten to twenty minutes after that, it reaches its peak concentration in the  cerebrospinal fluid . Its lipophilic structure allows it to cross the  blood\u2013brain barrier . [ 7 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3882", "text": "Apomorphine possesses  affinity  for the following  receptors  (note that a  higher   K i  indicates a  lower  affinity): [ 27 ] [ 28 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3883", "text": "It has a  K i  of over 10,000 nM (and thus negligible affinity) for  \u03b2-adrenergic ,  H 1 , and  mACh . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3884", "text": "Apomorphine has a high  clearance rate  (3\u20135 L/kg/hr) and is mainly metabolized and excreted by the  liver . [ 17 ]  It is likely that while the  cytochrome P450 system  plays a minor role, most of apomorphine's metabolism happens via auto- oxidation ,  O -glucuronidation ,  O -methylation ,  N -demethylation , and  sulfation . [ 7 ] [ 17 ] [ 22 ]  Only 3\u20134% of the apomorphine is excreted unchanged and into the urine. The  half-life  is 30\u201360 minutes, and the effects of the injection last for up to 90 minutes. [ 7 ] [ 8 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3885", "text": "Toxicity depends on the route of administration; the  LD 50 s  in mice were 300\u00a0mg/kg for the oral route, 160\u00a0mg/kg for  intraperitoneal , and 56\u00a0mg/kg intravenous. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3886", "text": "Apomorphine has a  catechol  structure similar to that of dopamine. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3887", "text": "Several techniques exist for the creation of apomorphine from morphine. In the past,  morphine  had been combined with  hydrochloric acid  at high temperatures (around 150\u00a0\u00b0C) to achieve a low yield of apomorphine, ranging anywhere from 0.6% to 46%. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3888", "text": "More recent techniques create the apomorphine in a similar fashion, by heating it in the presence of any acid that will promote the essential dehydration rearrangement of morphine-type  alkaloids , such as  phosphoric acid . The method then deviates by including a water scavenger, which is essential to remove the water produced by the reaction that can react with the product and lead to decreased yield. The scavenger can be any reagent that will irreversibly react with water such as  phthalic anhydride  or  titanium chloride . The temperature required for the reaction varies based upon choice of acid and water scavenger. The yield of this reaction is much higher: at least 55%. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3889", "text": "The pharmacological effects of the naturally-occurring analog  aporphine  in the  blue lotus  ( Nymphaea caerulea ) [ 34 ]  were known to the ancient Egyptians and Mayans, [ 35 ]  with the plant featuring in tomb frescoes and associated with entheogenic rites. It is also observed in Egyptian erotic cartoons, suggesting that they were aware of its erectogenic properties."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3890", "text": "The modern medical history of apomorphine begins with its synthesis by  Arppe  in 1845 [ 36 ]  from morphine and  sulfuric acid , although it was named  sulphomorphide  at first. Matthiesen and Wright (1869) used hydrochloric acid instead of sulfuric acid in the process, naming the resulting compound  apomorphine . Initial interest in the compound was as an emetic, tested and confirmed safe by London doctor  Samuel Gee , [ 37 ]  and for the treatment of stereotypies in farmyard animals. [ 38 ]  Key to the use of apomorphine as a behavioural modifier was the research of Erich Harnack, whose experiments in rabbits (which do not vomit) demonstrated that apomorphine had powerful effects on the activity of rabbits, inducing licking, gnawing and in very high doses convulsions and death."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3891", "text": "Apomorphine was one of the earliest used pharmacotherapies for  alcoholism . The  Keeley Cure  (1870s to 1900) contained apomorphine, among other ingredients, but the first medical reports of its use for more than pure emesis come from James Tompkins [ 39 ]  and Charles Douglas. [ 40 ] [ 41 ]  Tompkins reported, after injection of 6.5\u00a0mg (\"one tenth of a grain\"):"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3892", "text": "In four minutes free emesis followed, rigidity gave way to relaxation, excitement to somnolence, and without further medication the patient, who before had been wild and delirious, went off into a quiet sleep."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3893", "text": "Douglas saw two purposes for apomorphine:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3894", "text": "[it can be used to treat] a paroxysm of dipsomania [an episode of intense alcoholic craving]...  in minute doses  it is much more rapidly efficient in stilling the dipsomaniac craving than strychnine or atropine\u2026 Four or even 3m [minim \u2013 roughly 60 microlitres] of the solution usually checks for some hours the incessant demands of the patient\u2026 when he awakes from the apomorphine sleep he may still be demanding alcohol, though he is never then so insistent as before. Accordingly it may be necessary to repeat the dose, and even to continue to give it twice or three times a day. Such repeated doses, however, do not require to be so large: 4 or even 3m is usually sufficient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3895", "text": "This use of small, continuous doses (1/30th of a grain, or 2.16\u00a0mg by Douglas) of apomorphine to reduce alcoholic craving comes some time before  Pavlov 's discovery and publication of the idea of the \"conditioned reflex\" in 1903. This method was not limited to Douglas; the Irish doctor Francis Hare, who worked in a sanatorium outside London from 1905 onward, also used low-dose apomorphine as a treatment, describing it as \"the most useful single drug in the therapeutics of inebriety\". [ 42 ]  He wrote:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3896", "text": "In (the) sanatorium it is used in three different sets of circumstances: (1) in maniacal or hysterical drunkenness: (2) during the paroxysm of dipsomania,  in order to still the craving for alcohol;  and (3) in essential insomnia of a special variety... [after giving apomorphine] the patient's mental condition is entirely altered. He may be sober: he is free from the time being from any craving from alcohol. The craving may return, however, and then it is necessary to repeat the injection, it may be several times at intervals of a few hours. These succeeding injections should be quite small, 3 to 6 min. being sufficient.  Doses of this size are rarely emetic.  There is little facial pallor, a sensation as of the commencement of sea-sickness, perhaps a slight malaise with a sudden subsidence of the craving for alcohol, followed by a light and short doze."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3897", "text": "He also noted there appeared to be a significant prejudice against the use of apomorphine, both from the associations of its name and doctors being reluctant to give hypodermic injections to alcoholics. In the US, the  Harrison Narcotics Tax Act  made working with any morphine derivatives extremely hard, despite apomorphine itself not being an opiate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3898", "text": "In the 1950s the neurotransmitter  dopamine  was discovered in the brain by  Katharine Montagu , and characterised as a neurotransmitter a year later by  Arvid Carlsson , for which he would be awarded the Nobel Prize. [ 43 ]  A. N. Ernst then discovered in 1965 that apomorphine was a powerful stimulant of dopamine receptors. [ 44 ]  This, along with the use of sublingual apomorphine tablets, led to a renewed interest in the use of apomorphine as a treatment for alcoholism. A series of studies of non-emetic apomorphine in the treatment of alcoholism were published, with mostly positive results. [ 45 ] [ 46 ] [ 47 ] [ 48 ] [ 49 ]  However, there was little clinical consequence."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3899", "text": "The use of apomorphine to treat \"the shakes\" was first suggested by Weil in France in 1884, [ 50 ]  although seemingly not pursued until 1951. [ 51 ]  Its clinical use was first reported in 1970 by  Cotzias  et al., [ 52 ]  although its emetic properties and short half-life made oral use impractical. A later study found that combining the drug with the  antiemetic   domperidone  improved results significantly. [ 53 ]  The commercialization of apomorphine for Parkinson's disease followed its successful use in patients with refractory motor fluctuations using intermittent rescue injections and continuous infusions. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3900", "text": "Aversion therapy  in alcoholism had its roots in Russia in the early 1930s, [ 55 ]  with early papers by Pavlov, Galant and Sluchevsky and Friken, [ 56 ]  and would remain a strain in the Soviet treatment of alcoholism well into the 1980s. In the US a particularly notable devotee was Dr Voegtlin, [ 57 ]  who attempted aversion therapy using apomorphine in the mid to late 1930s. However, he found apomorphine less able to induce negative feelings in his subjects than the stronger and more unpleasant emetic  emetine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3901", "text": "In the UK, however, the publication of J. Y. Dent's (who later went on to treat Burroughs) 1934 paper \"Apomorphine in the treatment of Anxiety States\" [ 58 ]  laid out the main method by which apomorphine would be used to treat alcoholism in Britain. His method in that paper is clearly influenced by the then-novel idea of aversion:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3902", "text": "He is given his favourite drink, and his favourite brand of that drink ... He takes it stronger than is usual to him ... The small dose of apomorphine, one-twentieth of a grain [3.24 mg], is now given subcutaneously into his thigh, and he is told that he will be sick in a quarter of an hour. A glass of whisky and water and a bottle of whisky are left by his bedside. At six o'clock (four hours later) he is again visited and the same treatment is again administered ... The nurse is told in confidence that if he does not drink, one-fortieth [1.62\u00a0mg] of a grain of apomorphine should be injected during the night at nine o'clock, one o'clock, and five o'clock, but that if he drinks the injection should be given soon after the drink and may be increased to two hourly intervals. In the morning at about ten he is again given one or two glasses of whisky and water ... and again one-twentieth of a grain [3.24\u00a0mg] of apomorphine is injected ... The next day he is allowed to eat what he likes, he may drink as much tea as he likes ... He will be strong enough to get up and two days later he leaves the home."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3903", "text": "However, even in 1934 he was suspicious of the idea that the treatment was pure conditioned reflex \u2013 \"though vomiting is one of the ways that apomorphine relives the patient, I do not believe it to be its main therapeutic effect.\" \u2013 and by 1948 he wrote: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3904", "text": "It is now twenty-five years since I began treating cases of anxiety and alcoholism with apomorphine, and I read my first paper before this Society fourteen years ago. Up till then I had thought, and, unfortunately, I said in my paper, that the virtue of the treatment lay in the conditioned reflex of aversion produced in the patient. This statement is not even a half truth\u2026 I have been forced to the conclusion that apomorphine has some further action than the production of a vomit."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3905", "text": "This led to his development of lower-dose and non-aversive methods, which would inspire a positive trial of his method in Switzerland by Dr Harry Feldmann [ 59 ]  and later scientific testing in the 1970s, some time after his death. However, the use of apomorphine in aversion therapy had escaped alcoholism, with its use to treat homosexuality leading to the death of a British Army Captain Billy Clegg Hill in 1962, [ 60 ]  helping to cement its reputation as a dangerous drug used primarily in archaic behavioural therapies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3906", "text": "In his  Deposition: Testimony Concerning a Sickness  in the introduction to later editions of  Naked Lunch  (first published in 1959),  William S. Burroughs  wrote that apomorphine treatment was the only effective cure to  opioid addiction  he has encountered:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3907", "text": "The apomorphine cure is qualitatively different from other methods of cure.  I have tried them all.  Short reduction, slow reduction,  cortisone ,  antihistamines ,  tranquilizers , sleeping cures, tolserol,  reserpine .  None of these cures lasted beyond the first opportunity to relapse.  I can say that I was never metabolically cured until I took the apomorphine cure... The doctor, John Yerbury Dent, explained to me that apomorphine acts on the back brain to regulate the metabolism and normalize the blood stream in such a way that the enzyme stream of addiction is destroyed over a period of four to five days.  Once the back brain is regulated apomorphine can be discontinued and only used in case of relapse."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3908", "text": "He goes on to lament the fact that as of his writing, little to no research has been done on apomorphine or variations of the drug to study its effects on curing addiction, and perhaps the possibility of retaining the positive effects while removing the side effect of vomiting."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3909", "text": "Despite his claims throughout his life, Burroughs never really cured his addiction and was back to using opiates within years of his apomorphine \"cure\". [ 61 ]  However, he insisted on apomorphine's effectiveness in several works and interviews. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3910", "text": "There is renewed interest in the use of apomorphine to treat addiction, in both  smoking cessation [ 62 ]  and alcoholism. [ 63 ]  As the drug is known to be reasonably safe for use in humans, it is a viable target for repurposing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3911", "text": "Apomorphine has been researched as a possible treatment for erectile dysfunction and female hypoactive sexual desire disorder, though its efficacy has been limited. [ 14 ] [ 64 ]  Nonetheless, it  was under  development  as a treatment for  erectile dysfunction  by  TAP Pharmaceuticals  under the brand name Uprima. In 2000, TAP withdrew its  new drug application  after an FDA review panel raised questions about the drug's safety, due to many clinical trial subjects fainting after taking the drug. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3912", "text": "Apomorphine is reported to be an inhibitor of  amyloid beta  protein fiber formation, whose presence is a hallmark of  Alzheimer's disease , and a potential therapeutic under the  amyloid hypothesis . [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3913", "text": "Two routes of administration are currently clinically utilized: subcutaneous (either as intermittent injections or continuous infusion) and sublingual. Other non-invasive administration routes were investigated as a substitute for parenteral administration, reaching different preclinical and clinical stages. These include: peroral, [ 67 ]  nasal, [ 68 ] [ 69 ] [ 70 ] [ 71 ]  pulmonary, [ 72 ]  transdermal, [ 73 ]  rectal, [ 74 ] [ 75 ]  and buccal, [ 76 ] [ 77 ]  as well as iontophoresis methods. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3914", "text": "Apomorphine is used to inducing vomiting in  dogs  after ingestion of various toxins or foreign bodies. It can be given subcutaneously, intramuscularly, intravenously, or, when a tablet is crushed, in the  conjunctiva  of the eye. [ 79 ] [ 80 ]  The oral route is ineffective, as apomorphine cannot cross the blood\u2013brain barrier fast enough, and blood levels don't reach a high enough concentration to stimulate the chemoreceptor trigger zone. [ 79 ]  It can remove around 40\u201360% of the contents in the stomach. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3915", "text": "One of the reasons apomorphine is a preferred drug is its reversibility: [ 82 ]  in cases of prolonged vomiting, the apomorphine can be reversed with dopamine antagonists like the  phenothiazines  (for example,  acepromazine ). Giving apomorphine after giving acepromazine, however, will no longer stimulate vomiting, because apomorphine's target receptors are already occupied. [ 79 ]  An animal who undergoes severe  respiratory depression  due to apomorphine can be treated with  naloxone . [ 79 ] [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3916", "text": "Apomorphine does not work in  cats , who have too few dopamine receptors. [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3917", "text": "Mdo-npa, the  methylenedioxy   analog  of apomorphine, has greater  bioavailability  and a longer duration of action. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3918", "text": "Benzoctamine  is a  drug  that possesses  sedative  and  anxiolytic  properties. Marketed as  Tacitin  by  Ciba-Geigy , it is different from most sedative drugs because in most  clinical trials  it does not produce  respiratory depression , but actually stimulates the  respiratory system . As a result, when compared to other  sedative  and  anxiolytic  drugs such as  benzodiazepines  like  diazepam , it is a safer form of  tranquilizing . However, when co-administered with other drugs that cause respiratory depression, like  morphine , it can cause increased respiratory depression."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3919", "text": "Medically, benzoctamine is used as a treatment for anxious outpatients to control  aggression , [ 2 ]   enuresis , [ 3 ]  fear, and minor social maladjustment in children. [ 2 ]  re Its anxiolytic effects are most similar to  diazepam , another anxiolytic, but unlike  diazepam , benzoctamine has  antagonistic  effects on  epinephrine  and  norepinephrine , and appears to increase  serotonin  levels. While little is understood about how it carries out its effects, studies point to reduced serotonin, epinephrine, and  norepinephrine  as partial causes of its  pharmacologic  and behavioral effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3920", "text": "Animal studies have shown sedative hypnotic drugs tend to show dependency in animals, but benzoctamine has been shown to not be addictive. Other animal studies also point to the drug as a possible mechanism by which to reduce blood pressure through the  adrenergic  system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3921", "text": "Chemically, benzoctamine belongs to the class of compounds called dibenzobicyclo-octadienes. It is a  tetracyclic compound , consisting of four rings in a three dimensional configuration, and is very closely related structurally to the  tetracyclic antidepressant  (TeCA)  maprotiline , differing only in the length of their  side chain ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3922", "text": "Benzoctamine's main clinical use is for the treatment of  anxiety , and evidence points to it being as effective as other clinical anxiety drugs, in particular  diazepam . [ 4 ]  In the treatment of symptoms of mild anxiety due to  psychoneurosis , a daily dosage of 30 to 80 mg of benzoctamine was shown to be just as effective as 6\u201320 mg of diazepam. [ 4 ]  In another study one group of patients were given 10 mg of benzoctamine three times a day, while another group was given 5 mg of diazepam, and the treatments were equivalent. [ 4 ]  While these studies point to higher doses of benzoctamine being needed to exert the same pharmacological effects, the drug is still popular because of its ability to act as an anxiolytic without producing the common respiratory depression associated with other sedative drugs. Some studies have even shown that it stimulates the respiratory system. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3923", "text": "In a study used to compare benzoctamine to  sodium amylobarbitone  as a sleep promoter, it was found that during administration of both drugs, patients reported that their sleep was less restless, and drowsiness was diminished. [ 6 ]  The study further showed that while sodium amylobarbitone caused withdrawal rebound symptoms, benzoctamine did not. [ 6 ]  It was also found that benzoctamine reduced plasma corticosteroid hormone levels. [ 6 ]  There is a relationship between anxiety and adreno-corticosteroid activity, with raised levels commonly being reported as an indication of stress. [ 6 ]  The study showed that benzoctamine, a drug reported to reduce anxiety, was also able to reduce the hormones that potentially cause it. [ 6 ]  This points to a phenomenon often seen within pharmacology where drugs intended for other uses often have far-reaching and rarely considered effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3924", "text": "Benzoctamine has been found to have the same efficacy as chlordiazepoxide when treating anxiety neurosis. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3925", "text": "While benzoctamine was made to be an alternative to the  benzodiazepine  line of anxiolytic drugs, other uses for the drug have been discovered. Due to benzoctamine's ability to  tranquilize  without causing respiratory depression, scientists are moving forward with studies that test its sedative effects in patients with respiratory failure. In one study that used benzoctamine in a clinical setting, researchers showed that the use of benzoctamine for sedation did not result in changes in  forced expiratory volume in one second  or  carbon dioxide partial pressure  ( p CO 2 ). [ 8 ]  This confirmed previous statements that claimed the drug did not cause respiratory failure. The main goal of this clinical study was to confirm the findings of another study that showed benzoctamine did not reduce CO 2  responsiveness, but instead increased the ventilatory response to CO 2 . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3926", "text": "There are usually many risks associated with using sedatives on patients who are suffering from respiratory failure, which has made it difficult to administer tranquillizing medications in situations when they are desirable. It is not known why this drug is safe and its benzodiazepine cousins are not, but a possible explanation for this phenomenon might come from its similarity in structure to  tricyclic antidepressants , which have also been shown to not cause respiratory failure. [ 8 ]  While further experimentation is necessary, this study points to benzoctamine's possible consideration for sedation in respiratory failure patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3927", "text": "A possible treatment for  hypertension  is blocking peripheral vascular seretonergic neurons or alpha- adrenergic  neurons on  postsynaptic cell  sites. [ 10 ]  One study showed that benzoctamine, a serotonin and alpha-adrenergic  antagonist , does not reduce blood pressure through a seretonin mechanism but does reduce  blood pressure  by antagonizing alpha- adrenergic receptors  in rats. [ 10 ]  Rats were given 10 mg of benzoctamine and drops in their blood pressure were approximately 30mm Hg. [ 10 ]  The researchers further confirmed that  serotonin antagonism  was not sufficient to reduce blood pressure by using the highly selective serotonin antagonist  1-(1-naphthyl)piperazine , which was not able to decrease the blood pressure of the rats. [ 10 ]  These studies have yet to be repeated in humans."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3928", "text": "Common side effects include drowsiness (incidence of 9%), gastro-intestinal upset, dry mouth, headache, and dizziness (incidence of 1-2% each). [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3929", "text": "Studies have shown that benzoctamine increases level of serotonin. [ 12 ]  Scientists confirmed these results and proposed that the method of action was inhibition of serotonin uptake since the drug also blocked the serotonin depleting action of extra-neuronal monoamine transporters (EMT). [ 13 ]  This would lead to increased stimulation of serotonin receptors through a  negative feed back  mechanism, eventually decreasing serotonin out put. However, the study points out that other studies have shown that drugs combined with EMT cause a lowering of body temperature that in fact results in a decrease in  serotonin  turnover. [ 13 ]  This means that body temperature effects cannot be ruled out."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3930", "text": "Not much is understood about how benzoctamine produces its anti-anxiety effects, but rat studies have shown that the possible mechanism of action is by way of increased turnover of  catecholamines . [ 14 ]  In addition to serotonin it has also been shown to decrease epinephrine,  dopamine , and norepinephrine turnover by antagonizing their receptors. [ 13 ]  When given intravenously in doses of 20\u201340 mg there are no significant differences in efficacy. [ 15 ]  Oral doses exceeding 10 mg three times daily do not increase the effects of the drug. [ 4 ]  Assuming serotonin postsynaptic antagonism is the main mechanism by which benzoctamine carries out its effects, studies have shown it to have an  IC 50  value of 115 mM at the serotonin receptor. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3931", "text": "Benzoctamine can be injected directly into the blood or given as tablets. When given as tablets, it is given in doses of 10\u00a0mg three times daily. [ 4 ]  And when given intravenously, patients are given the drug at a rate of 5\u00a0mg/minute until 20\u201340\u00a0mg of drug has been injected. [ 15 ]  Benzoctamine can be analyzed as the  3 H acetyl derivative and  N -methyl  metabolite  it gets broken down into using radioactive analysis. [ 17 ]  Benzoctamine has a half-life of 2\u20133\u00a0hours, [ 5 ]  with a  bioavailability  of  around >90% when given orally. [ 18 ]  The average time to achieve peak plasma concentrations is 1\u00a0hour [ 5 ]  and the  volume of distribution  for a 70\u00a0kg person is 1\u20132\u00a0L/kg. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3932", "text": "Bunazosin  ( INN ) is an  \u03b1 1 -adrenergic receptor   antagonist . [ 1 ]  Bunazosin was initially developed to treat benign prostatic hyperplasia (BPH). It has been approved in Japan in a topical form to treat  glaucoma . The mechanism of action is a reduction of aqueous outflow through the uveoscleral pathway resulting in lowering the intraocular pressure. It also may act to improve blood flow to the ocular nerve. Systemic Alpha-1 adrenergic receptor antagonists have been implicated in Intraoperative Floppy Iris Syndrome (IFIS). Bunazosin potentially could have the same effect but there has been no research to substantiate this as a risk for cataract surgery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3933", "text": "This  antihypertensive -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3934", "text": "Idazoxan  ( INN ) is a  drug  which is used in  scientific research . It acts as both a selective  \u03b1 2   adrenergic receptor   antagonist , and an antagonist for the  imidazoline receptor . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Idazoxan has been under investigation as an  antidepressant , but it did not reach the market as such. More recently, it is under investigation as an adjunctive treatment in  schizophrenia . Due to its \u03b1 2  receptor antagonism it is capable of enhancing therapeutic effects of  antipsychotics , possibly by enhancing  dopamine   neurotransmission  in the  prefrontal cortex  of the brain, a brain area thought to be involved in the  pathogenesis  of schizophrenia."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3935", "text": "Mice treated with idazoxan, which blocks the  \u03b1 2A  receptor  which regulates  norepinephrine , behaved similarly to control animals despite still having amyloid-beta plaques in the brain, as a proof-of-concept experiment that dramatically reduced  Alzheimer's  pathology and symptoms in two mouse models, potentially offering an immediate treatment for this devastating disease. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3936", "text": "Note that the literature method claims that the old original patented procedure gives a different reaction product formed through a rearrangement."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3937", "text": "The reaction of catechol ( 1 ) with 2-Chloroacrylonitrile [920-37-6] ( 2 ) gives 2-cyano-1,4-benzodioxan [1008-92-0] ( 3 ).  Pinner reaction  with alcoholic hydrogen chloride leads to the iminoether, [ 11 ]  ( 4 ). Treatment with  ethylenediamine  [107-15-3] ( 5 ) gives the imidazoline ring affording  Idazoxin  ( 6 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3938", "text": "Ifenprodil , sold under the brand names  Cerocral ,  Dilvax , and  Vadilex , is a  cerebral vasodilator  that has been marketed in some countries, including in  Japan ,  Hong Kong , and  France . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It is currently under development for treatment of a variety of additional indications. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3939", "text": "Ifenprodil has multiple known  pharmacological actions . [ 5 ]  It is an  inhibitor  of the  NMDA receptor , [ 6 ]  specifically of NMDA receptors containing  GluN1  and  GluN2B   subunits , the \"ifenprodil binding site\". [ 7 ]  Additionally, ifenprodil inhibits  GIRK channels [ 8 ]  and interacts with  \u03b1 1 -adrenergic , [ 5 ]   serotonin , [ 9 ]  and  sigma   receptors . [ 10 ] [ 11 ] [ 12 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3940", "text": "Chemically, ifenprodil is a  substituted phenethylamine  and  \u03b2-hydroxyamphetamine   derivative . [ 2 ] [ 3 ]  It is used  pharmaceutically  as the  tartrate   salt . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3941", "text": "Ifenprodil has been studied as a possible medication to prevent  tinnitus  after  acoustic trauma . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3942", "text": "It is currently in  phase II  trials for  cough  and  idiopathic pulmonary fibrosis , among other investigational uses. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3943", "text": "Imiloxan  is a drug which is used in  scientific research . It acts as a selective  antagonist  for the  \u03b1 2B   adrenergic receptor , [ 1 ]  and has been useful for distinguishing the actions of the different \u03b1 2  adrenergic subtypes. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3944", "text": "The  imidazole  portion of imiloxan is prepared by the reaction of an  imidate  with the diethyl acetal of  aminoacetaldehyde .  N -Alkylation of the imidazole with  ethyl iodide  gives imiloxan."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3945", "text": "Isoxaprolol  is an  adrenergic antagonist  with  antiarrhythmic  and  antihypertensive  properties. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3946", "text": "This  drug  article relating to the  cardiovascular system  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3947", "text": "Neldazosin  is an  \u03b1-adrenoreceptor antagonist . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3948", "text": "Nordoxepin , also known as  N -desmethyldoxepin , is an  organic compound .  A colorless solid, it attracted attention as the major  active metabolite  of the  tricyclic antidepressant  (TCA)  doxepin  (Sinequan). [ 2 ]  It has been found to play a significant role in the  antidepressant  effects of doxepin. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3949", "text": "Nordoxepin is a  mixture  of  ( E ) and ( Z )   stereoisomers . [ 2 ]  Whereas  pharmaceutical  doxepin is supplied in an approximate 85:15 ratio mixture of ( E )- and ( Z )-stereoisomers and plasma concentrations of doxepin remain roughly the same as this ratio with treatment, plasma levels of the ( E )- and ( Z )-stereoisomers of nordoxepin, due to  stereoselective   metabolism  of doxepin by  cytochrome P450   enzymes , are approximately 1:1. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3950", "text": "Nordoxepin is  pharmacologically active  similarly to doxepin, [ 4 ]  but relative to doxepin, is much more  potent  and  selective  as a  norepinephrine reuptake inhibitor . [ 2 ] [ 5 ] [ 6 ]  In general, the demethylated variants of  tertiary amine  TCAs like doxepin are much more potent  inhibitors  of  norepinephrine   reuptake , less potent inhibitors of  serotonin  reuptake, and less potent in their  antiadrenergic ,  antihistamine , and  anticholinergic  activities. [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3951", "text": "Nordoxepin is formed from doxepin mainly by  CYP2C19  (>50% contribution), while  CYP1A2  and  CYP2C9  are involved to a lesser extent, and  CYP2D6  and  CYP3A4  are not involved. [ 8 ]   Hydroxylation  of doxepin and nordoxepin is mediated mainly by CYP2D6. [ 3 ]  Total exposures to both doxepin and nordoxepin differ by almost 10-fold in CYP2D6  ultra-rapid  versus  poor metabolizers . [ 3 ]  Both doxepin and nordoxepin are also  transformed  into  glucuronide   conjugates . [ 3 ]  The  elimination half-life  of nordoxepin is approximately 31\u00a0hours, which is almost twice that of doxepin (mean 17\u00a0hours). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3952", "text": "Ocaperidone  ( R 79598 ) is a  benzisoxazole   antipsychotic . [ 1 ]  It was initially developed by  Janssen , later licensed to French laboratory Neuro3D and then acquired in 2007 by German company  Evotec . It was found to be more potent than  risperidone  in animal studies, [ 2 ]  but its testing was abandoned in 2010 after unfavorable results in human Phase II trials, [ 3 ]  as while it was effective at controlling symptoms of  schizophrenia , ocaperidone produced an unacceptable amount of  extrapyramidal  side effects. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3953", "text": "The last step requires attachment of the sidechain between 3-(2-bromoethyl)-2,9-dimethyl 4 H -pyrido[1,2-a]pyrimidin-4-one ( 1 ) and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole ( 2 ) completing the  convergent synthesis  of ocaperidone ( 3 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3954", "text": "Oxetorone  ( INN Tooltip International Nonproprietary Name ), as  oxetorone fumarate  ( USAN Tooltip United States Adopted Name ) (brand names  Nocertone ,  Oxedix ), is a  serotonin antagonist ,  antihistamine , and  alpha blocker  used as an  antimigraine drug . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Association with  hyperprolactinemia  has been described [ 5 ]  and  antidopaminergic  actions are also suspected. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3955", "text": "Piperoxan , also known as  benodaine , was the first  antihistamine  to be discovered. [ 1 ] [ 2 ]  This compound, derived from  benzodioxan , was prepared in the early 1930s by  Daniel Bovet  and  Ernest Fourneau  at the  Pasteur Institute  in  France . [ 1 ] [ 2 ]  Formerly investigated by Fourneau as an  \u03b1-adrenergic - blocking  agent, they demonstrated that it also  antagonized   histamine -induced  bronchospasm  in  guinea pigs , and published their findings in 1933. [ 1 ] [ 2 ] [ 3 ]  Bovet went on to win the 1957  Nobel Prize in Physiology or Medicine  for his contribution. [ 4 ]  One of Bovet and Fourneau's students,  Anne-Marie Staub , published the first  structure\u2013activity relationship  (SAR) study of antihistamines in 1939. [ 1 ]  Piperoxan and  analogues  themselves were not clinically useful due to the production of  toxic  effects in humans and were followed by  phenbenzamine  (Antergan) in the early 1940s, which was the first antihistamine to be marketed for medical use. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3956", "text": "Condensation of  catechol  [120-80-9] ( 1 ) with  epichlorohydrin  in the presence of an aqueous base can be visualized as proceeding initially with the epoxide ( 2 ) Opening of the oxirane ring by the phenoxide anion then leads to 2-hydroxymethyl-1,4-benzodioxane [3663-82-9] ( 3 ). Halogenation with  thionyl chloride  gives 2-chloromethyl-1,4-benzodioxane [2164-33-2] ( 4 ). Displacement of the leaving group by piperidine completed the synthesis of piperoxan ( 5 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3957", "text": "In  pharmacology  and  toxicology , a  route of administration  is the way by which a  drug , fluid, poison, or other substance is taken into the body. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3958", "text": "Routes of administration are generally classified by the  location at which the substance is applied.  Common examples include  oral  and  intravenous  administration. Routes can also be classified based on where the target of action is.  Action may be  topical  (local),  enteral  (system-wide effect, but delivered through the  gastrointestinal tract ), or  parenteral  (systemic action, but is delivered by routes other than the GI tract). Route of administration and  dosage form  are aspects of  drug delivery ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3959", "text": "Routes of administration are usually classified by application location (or exposition)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3960", "text": "The route or course the active substance takes from application location to the location where it has its target effect is usually rather a matter of  pharmacokinetics  (concerning the processes of uptake, distribution, and elimination of drugs). Exceptions include the  transdermal  or transmucosal routes, which are still commonly referred to as  routes of administration ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3961", "text": "The location of the target effect of active substances is usually rather a matter of  pharmacodynamics  (concerning, for example, the physiological effects of drugs [ 2 ] ). An exception is  topical administration , which generally means that both the application location and the effect thereof is local. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3962", "text": "Topical administration  is sometimes defined as both a local application location and local  pharmacodynamic  effect, [ 3 ]  and sometimes merely as a local application location regardless of location of the effects. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3963", "text": "Through the  gastrointestinal tract  is sometimes termed  enteral or enteric administration  (literally meaning 'through the  intestines ').  Enteral/enteric administration  usually includes  oral [ 6 ]  (through the  mouth ) and  rectal  (into the  rectum ) [ 6 ]  administration, in the sense that these are taken up by the intestines. However, uptake of drugs administered orally may also occur already in the  stomach , and as such  gastrointestinal  (along the  gastrointestinal tract ) may be a more fitting term for this route of administration. Furthermore, some application locations often classified as  enteral , such as  sublingual [ 6 ]  (under the tongue) and  sublabial  or  buccal  (between the cheek and gums/ gingiva ), are taken up in the proximal part of the  gastrointestinal tract  without reaching the intestines. Strictly  enteral administration  (directly into the intestines) can be used for systemic administration, as well as local (sometimes termed  topical ), such as in a contrast  enema , whereby contrast media are infused into the intestines for imaging. However, for the purposes of classification based on location of effects, the term enteral is reserved for substances with systemic effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3964", "text": "Many drugs as  tablets ,  capsules , or drops are taken orally. Administration methods directly into the stomach include those by  gastric feeding tube  or  gastrostomy . Substances may also be placed into the  small intestines , as with a  duodenal  feeding tube and  enteral nutrition . Enteric coated tablets are designed to dissolve in the intestine, not the stomach, because the drug present in the tablet causes irritation in the stomach."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3965", "text": "The  rectal  route is an effective route of administration for many medications, especially those used at the  end of life . [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ]  The walls of the rectum absorb many medications quickly and effectively. [ 14 ]  Medications delivered to the distal one-third of the rectum at least partially avoid the \" first pass effect \" through the liver, which allows for greater  bio-availability  of many medications than that of the oral route. Rectal  mucosa  is highly  vascularized  tissue that allows for rapid and effective absorption of medications. [ 15 ]  A  suppository  is a solid  dosage form  that fits for  rectal administration . In  hospice care , a specialized rectal  catheter , designed to provide comfortable and discreet administration of ongoing medications provides a practical way to deliver and retain liquid formulations in the  distal  rectum, giving health practitioners a way to leverage the established benefits of rectal administration. The  Murphy drip  is an example of rectal infusion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3966", "text": "The parenteral route is any route that is not  enteral  ( par-  +  enteral )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3967", "text": "Parenteral administration can be performed by  injection , that is, using a needle (usually a  hypodermic needle ) and a  syringe , [ 16 ]  or by the insertion of an  indwelling catheter ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3968", "text": "Locations of application of parenteral administration include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3969", "text": "The definition of the topical route of administration sometimes states that both the application location and the  pharmacodynamic  effect thereof is local. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3970", "text": "In other cases,  topical  is defined as applied to a localized area of the body or to the surface of a body part regardless of the location of the effect. [ 4 ] [ 5 ]  By this definition,  topical administration  also includes  transdermal  application, where the substance is administered onto the skin but is  absorbed  into the body to attain  systemic  distribution."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3971", "text": "If defined strictly as having local effect, the topical route of administration can also include  enteral administration  of medications that are poorly absorbable by the  gastrointestinal tract . One such medication is the antibiotic  vancomycin , which cannot be absorbed in the gastrointestinal tract and is used orally only as a treatment for  Clostridioides difficile  colitis . [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3972", "text": "The reason for choice of routes of drug administration are governing by various factors:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3973", "text": "In acute situations, in  emergency medicine  and  intensive care medicine , drugs are most often given intravenously. This is the most reliable route, as in acutely ill patients the absorption of substances from the tissues and from the digestive tract can often be unpredictable due to altered blood flow or bowel motility."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3974", "text": "Enteral routes are generally the most convenient for the patient, as no punctures or  sterile  procedures are necessary. Enteral medications are therefore often preferred in the treatment of chronic disease. However, some drugs can not be used enterally because their absorption in the digestive tract is low or unpredictable. Transdermal administration is a comfortable alternative; there are, however, only a few drug preparations that are suitable for transdermal administration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3975", "text": "Identical drugs can produce different results depending on the route of administration. For example, some drugs are not significantly absorbed into the bloodstream from the gastrointestinal tract and their action after enteral administration is therefore different from that after parenteral administration. This can be illustrated by the action of  naloxone  (Narcan), an antagonist of  opiates  such as  morphine . Naloxone counteracts opiate action in the  central nervous system  when given intravenously and is therefore used in the treatment of opiate overdose. The same drug, when swallowed, acts exclusively on the bowels; it is here used to treat constipation under opiate pain therapy and does not affect the pain-reducing effect of the opiate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3976", "text": "The oral route is generally the most convenient and costs the least. [ 25 ]  However, some drugs can cause  gastrointestinal tract  irritation. [ 26 ]  For drugs that come in  delayed release  or  time-release  formulations, breaking the tablets or capsules can lead to more rapid delivery of the drug than intended. [ 25 ]  The oral route is limited to  formulations  containing  small molecules  only while biopharmaceuticals (usually proteins) would be  digested in the stomach and thereby become ineffective. Biopharmaceuticals have to be given by injection or infusion. However, recent research found various ways to improve oral bioavailability of these drugs. In particular permeation enhancers, [ 27 ]   ionic liquids , [ 28 ]  lipid-based nanocarriers, [ 29 ]  enzyme inhibitors and microneedles [ 30 ]  have shown potential."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3977", "text": "Oral administration  is often denoted \"PO\" from \"per os\", the Latin for \"by mouth\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3978", "text": "The bioavailability of oral administration is affected by the amount of drug that is absorbed across the  intestinal epithelium  and  first-pass metabolism . [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3979", "text": "The  oral mucosa  is the mucous membrane lining the inside of the  mouth ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3980", "text": "Buccally administered  medication is achieved by placing the drug between  gums  and the inner lining of the  cheek . [ 32 ] [ 33 ]  In comparison with sublingual tissue, buccal tissue is less permeable resulting in slower  absorption . [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3981", "text": "Sublingual administration  is fulfilled by placing the drug between the tongue and the lower surface of the mouth. [ 33 ]  The  sublingual mucosa  is highly permeable and thereby provides access to the underlying expansive network composed of capillaries, leading to rapid drug absorption. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3982", "text": "Drug administration via the nasal cavity yields rapid drug absorption and therapeutic effects. [ 33 ]  This is because drug absorption through the nasal passages does not go through the gut before entering  capillaries  situated at  tissue cells  and then systemic circulation and such absorption route allows transport of drugs into the  central nervous system  via the pathways of  olfactory  and  trigeminal nerve . [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3983", "text": "Intranasal absorption features low lipophilicity, enzymatic degradation within the nasal cavity, large molecular size, and rapid mucociliary clearance from the nasal passages, which explains the low  risk of systemic exposure of the administered drug absorbed  via intranasal. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3984", "text": "By delivering drugs almost directly to the site of action, the risk of systemic  side effects  is reduced. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3985", "text": "Skin absorption (dermal absorption), for example, is to directly deliver drug to the skin and, hopefully, to the systemic circulation. [ 34 ]  However, skin irritation may result, and for some forms such as creams or lotions, the dosage is difficult to control. [ 26 ]  Upon contact with the skin, the drug penetrates into the dead  stratum corneum  and can afterwards reach the viable  epidermis , the  dermis , and the  blood vessels . [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3986", "text": "The term parenteral is from para-1 'beside' + Greek enteron 'intestine' + -al. This name is due to the fact that it encompasses a route of administration that is not intestinal. However, in common English the term has mostly been used to describe the four most well-known routes of injection."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3987", "text": "The term injection encompasses  intravenous  (IV),  intramuscular  (IM),  subcutaneous  (SC) and  intradermal  (ID) administration. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3988", "text": "Parenteral administration generally acts more rapidly than topical or enteral administration, with onset of action often occurring in 15\u201330 seconds for IV, 10\u201320 minutes for IM and 15\u201330 minutes for SC. [ 36 ]  They also have essentially 100%  bioavailability  and can be used for drugs that are poorly absorbed or ineffective when they are given orally. [ 25 ]  Some medications, such as certain  antipsychotics , can be administered as  long-acting intramuscular injections . [ 37 ]  Ongoing  IV infusions  can be used to deliver continuous medication or  fluids . [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3989", "text": "Disadvantages of injections include potential pain or discomfort for the patient and the requirement of trained staff using  aseptic techniques  for administration. [ 25 ]  However, in some cases, patients are taught to self-inject, such as SC injection of insulin in patients with  insulin-dependent diabetes mellitus . As the drug is delivered to the site of action extremely rapidly with IV injection, there is a risk of  overdose  if the dose has been calculated incorrectly, and there is an increased risk of side effects if the drug is administered too rapidly. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3990", "text": "Inhaled medications can be absorbed quickly and act both locally and systemically. [ 26 ]  Proper technique with  inhaler  devices is necessary to achieve the correct dose. Some medications can have an unpleasant taste or irritate the mouth. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3991", "text": "In general, only 20\u201350% of the pulmonary-delivered dose rendered in powdery particles will be deposited in the lung upon mouth inhalation. [ 47 ]  The remainder of 50-70% undeposited aerosolized particles are cleared out of lung as soon as  exhalation . [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3992", "text": "An inhaled powdery particle that is >8 \u03bcm is structurally predisposed to depositing in the central and conducting airways ( conducting zone ) by inertial impaction. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3993", "text": "An inhaled powdery particle that is between 3 and 8 \u03bcm in diameter tend to largely deposit in the  transitional zones  of the lung by sedimentation. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3994", "text": "An inhaled powdery particle that is <3 \u03bcm in diameter is structurally predisposed to depositing primarily in the  respiratory regions  of the peripheral lung via diffusion. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3995", "text": "Particles that deposit in the upper and central airways are generally absorbed systemically to great extent because they are only partially removed by  mucociliary  clearance, which results in orally mediated absorption when the transported mucus is swallowed, and first pass metabolism or incomplete absorption through loss at the fecal route can sometimes reduce the bioavailability. [ 48 ]  This should in no way suggest to clinicians or researchers that inhaled particles are not a greater threat than swallowed particles, it merely signifies that a combination of both methods may occur with some particles, no matter the size of or lipo/hydrophilicity of the different particle surfaces. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3996", "text": "Inhalation by nose of a substance is almost identical to oral inhalation, except that some of the drug is absorbed intranasally instead of in the oral cavity before entering the airways. Both methods can result in varying levels of the substance to be deposited in their respective initial cavities, and the level of mucus in either of these cavities will reflect the amount of substance swallowed. The rate of inhalation will usually determine the amount of the substance which enters the lungs. Faster inhalation results in more rapid absorption because more substance finds the lungs. Substances in a form that resists absorption in the lung will likely resist absorption in the nasal passage, and the oral cavity, and are often even more resistant to absorption after they fail absorption in the former cavities and are swallowed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3997", "text": "Neural drug delivery is the next step beyond the basic addition of  growth factors  to  nerve guidance conduits .  Drug delivery systems  allow the rate of growth factor release to be regulated over time, which is critical for creating an environment more closely representative of in vivo development environments. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_3998", "text": "In medicine, a  bolus  (from  Latin   bolus , ball) is the administration of a discrete amount of  medication ,  drug , or other compound within a specific time, generally 1\u201330 minutes, [ 1 ]  to raise its concentration in  blood  to an  effective level . The administration can be given by  injection :  intravenously ,  intramuscularly ,  intrathecally ,  subcutaneously , or by  inhalation . [ clarification needed ]  The article on  routes of administration  provides more information, as the preceding list of ROAs is not exhaustive."}
{"_id": "WikiPedia_Pharmacology$$$corpus_3999", "text": "The placement of the bolus dose depends on the systemic levels of the contents desired throughout the body. An intramuscular injection of  vaccines  allows for a slow release of the antigen to stimulate the body's  immune system  and to allow time for developing  antibodies . Subcutaneous injections are used by  heroin  addicts (called 'skin popping', referring to the bump formed by the bolus of heroin), to sustain a slow release that staves off  withdrawal  symptoms without producing  euphoria . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4000", "text": "A bolus delivered directly to the veins through an  intravenous drip  allows a much faster delivery which quickly raises the concentration of the substance in the blood to an effective level. This is typically done at the beginning of a treatment or after a removal of medicine from blood (e.g. through  dialysis )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4001", "text": "Diabetics  and health care professionals use bolus to refer to a dosage of fast-acting  insulin  with a meal (as opposed to  basal rate , which is a dose of slow-acting insulin or the continuous pumping of a small quantity of fast-acting insulin to cover the  glucose  output of the  liver ). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4002", "text": "In  veterinary medicine  a  bolus  is a large time-release tablet that stays in the  rumen  of  cattle ,  goats , and  sheep . It can also refer to a dose of liquid injected  subcutaneously  with a  hypodermic needle , such as  saline solution  administered either to counteract  dehydration  or especially to mitigate  kidney failure , a common ailment in  domestic cats . Before it is fully absorbed, which can take several minutes or longer, the liquid remains in the form of a  bolus , a ball or lump under the animal's  skin ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4003", "text": "In  radiation therapy , bolus is a waxy tissue equivalent material placed on the skin surface to homogenize or modulate the range of the dose from external beams of radiation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4004", "text": "Buccal administration  is a  topical   route of administration  by which  drugs  held or applied in the  buccal  ( / \u02c8 b \u028c k \u0259l / ) area (in the  cheek ) diffuse through the  oral mucosa  ( tissues  which line the  mouth ) and enter directly into the  bloodstream .  Buccal administration may provide better  bioavailability  of some drugs and a more rapid  onset of action  compared to oral administration because the medication does not pass through the  digestive system  and thereby avoids  first pass metabolism . [ 1 ]  Drug forms for buccal administration include tablets and  thin films ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4005", "text": "As of May 2014, the psychiatric drug  asenapine ; the opioid drugs  buprenorphine ,  naloxone , and  fentanyl ; the cardiovascular drug  nitroglycerin ; the nausea medication  prochlorperazine ; the hormone replacement therapy  testosterone ; and  nicotine  as a smoking cessation aid were commercially available in buccal forms, [ 1 ]  as was  midazolam , an  anticonvulsant , used to treat acute  epileptic seizures . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4006", "text": "Buccal administration of  vaccines  has been studied, but there are challenges to this approach due to  immune tolerance  mechanisms that prevent the body from overreacting to  immunogens  encountered in the course of daily life. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4007", "text": "Buccal tablets  are a type of solid  dosage form  administered orally in between the gums and the inner linings of the cheek. [ 4 ]  These  tablets , held within the buccal pouch, either act on the  oral mucosa  or are rapidly absorbed through the buccal mucosal membrane. [ 5 ]  Since drugs \"absorbed through the buccal mucosa bypass gastrointestinal  enzymatic  degradation and hepatic  first-pass effect \", [ 6 ]  prescribing buccal tablets is increasingly common among healthcare professionals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4008", "text": "Buccal tablets serve as an alternative drug delivery in patients where compliance is a known issue, including those who are  unconscious ,  nauseated , or having difficulty in swallowing (i.e.  dysphagia ). [ 7 ]  A wide variety of these drugs are available on the market to be prescribed in hospitals and other healthcare settings, including common examples like Corlan, Fentora, and Buccastem."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4009", "text": "The most common route for drug transport through the buccal mucosa is the  paracellular  pathway. Most  hydrophilic  drugs permeate the cheek linings via the paracellular pathway through the mechanism of  passive diffusion , and  hydrophobic  drugs are transported through the  transcellular  pathway. [ 7 ]  This route of administration is beneficial for  mucosal  administration and  transmucosal  administration. [ 8 ]  Buccal tablets are typically formulated through the direct compression of drug, powder mixture, swollen polymer, and other agents that assist in processing. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4010", "text": "Buccal tablets offer many advantages in terms of accessibility, ease of administration and withdrawal, and hence may improve  patient compliance . [ 9 ]  Notable drawbacks of buccal tablets include the hazard of choking by involuntarily swallowing the tablet and irritation of the gums. [ 7 ]  Caution should be exercised along with counselling from medical practitioners before use of these tablets."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4011", "text": "With recent advances on buccal tablets and in conditions where the conventional oral route (i.e. swallowing of tablet) cannot be delivered effectively, some commonly prescribed buccal tablets available in healthcare settings are listed below as examples."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4012", "text": "Hydrocortisone  is a  corticosteroid  that is clinically used to relieve the pain and discomfort of  mouth ulcers  and functions to speed the healing of mouth ulcers. [ citation needed ]  Common side effects include:  oral thrush , visual disturbances (e.g.  blurry vision ), worsening of  diabetes , worsening of mouth  infections , and  allergic reactions  (e.g. skin rash). Hydrocortisone is contraindicated in patients  hypersensitive  to hydrocortisone and those with mouth ulcers caused by  dentures  or infection as it can worsen the severity of mouth ulcers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4013", "text": "Some cautions and remarks include needing to gargle and spit water once tablet is fully dissolved to minimise risk of oral thrush, prolonged use may lead to withdrawal symptoms, chewing and swallowing of the tablet may limit its efficacy and give rise to additional side effects, and caution with  CYP3A4   inhibitors ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4014", "text": "Fentanyl  is an  opioid analgesic  used for the treatment of  breakthrough pain  in  cancer  patients who are already receiving and/or are tolerant to maintenance opioid therapy for chronic cancer pain [ 10 ] [ 11 ] [ 12 ]  Common side effects include:  nausea ,  vomiting ,  headache ,  constipation  and  drowsiness . Fentanyl is contraindicated in patients hypersensitive to fentanyl, opioid non-tolerant patients, management of acute or  postoperative  pain, and those with severe  hypotension  or severe obstructive airway diseases (e.g.  COPD )"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4015", "text": "Some cautions include needing to keep tablets out of the sight and reach of children, and must not be sucked, chewed or swallowed. Other remarks include caution when administered in patients with  hepatic or renal impairment , having drug interactions with CYP3A4 inducers and inhibitors and co-administration with CNS  sedative  agents (e.g.  antihistamines ) will increase CNS side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4016", "text": "Prochlorperazine maleate  is under the class of  antiemetics  and  antipsychotics . These buccal tablets are administered for the treatment of severe nausea and vomiting associated with  migraine , [ 13 ] [ 14 ]  as well as managed in symptoms of  schizophrenia . Side effects typically seen in patients using prochlorperazine maleate tablets include drowsiness, blurred vision,  dry mouth , and headache. In rare cases, these tablets may cause serious allergic reactions (i.e.  anaphylaxis ). Prochlorperazine maleate is contraindicated in certain patient groups, including hypersensitivity to prochlorperazine maleate, certain diseases like  glaucoma ,  epilepsy  and  Parkinson's disease . They are also avoided in those with hepatic and  prostate gland  problems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4017", "text": "Special caution is taken in patients with high risk of  blood clot  and  stroke , along with associated risk factors (e.g.  high blood pressure  and  high cholesterol  levels). Those taking prochlorperazine maleate should avoid exposure to direct sunlight due to  photosensitivity  and taken certain drugs that are either sedative and give dry mouth (e.g.  anticholinergics ) or target the heart (e.g.  antihypertensives  and  anticoagulants ). Other remarks include being most effective when taken after food and possible withdrawal symptoms if they are abruptly stopped."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4018", "text": "The buccal mucosa, along with the gingival and sublingual mucosa, is part of the  oral mucosa . [ 15 ]  It is composed of non-keratinised tissue. Unlike intestinal and nasal mucosae, it lacks tight junctions and is instead equipped with loose intercellular links of  desmosomes ,  gap junctions  and  hemidesmosomes . [ 7 ]  While it has a less  permeable  effect than  sublingual administration , buccal administration is still capable of creating local or  systemic effects  following drug administration. [ 7 ]  In the oral cavity, buccal tablets potentiate their effect by entering the bloodstream direction through the  internal jugular vein  into the  superior vena cava , [ 8 ]  avoiding acidic  hydrolysis  to take place in the  gastrointestinal tract . [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4019", "text": "There are two major routes for drug transportation through the buccal mucosa: transcellular and paracellular pathways. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4020", "text": "Small hydrophobic molecules and other lipophilic compounds mostly move across the buccal mucosa via the transcellular pathway. Drugs are transferred via the transcellular pathway through either  facilitated diffusion  for polar or  ionic compounds ,  diffusion  for low molecular weight molecules, or  transcytosis  and  endocytosis  for macromolecules. [ 8 ]  The physicochemical properties of the drug, for example, its oil/water  partition coefficient ,  molecular weight , structural conformation, determines whether the molecules are transported through the transcellular pathway. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4021", "text": "As the  cell membrane  is  lipophilic , it is more difficult for drugs that are hydrophilic to  permeate  the membrane. Hence, the  excipients  of the formulation and the phospholipid bilayer assist in enhancing the diffusion of hydrophilic compounds (i.e. peptides, proteins, macromolecules). [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4022", "text": "Generally, small low-molecular-weight hydrophilic compounds diffuse across the buccal epithelium through the paracellular pathway via passive diffusion. The extracellular  amphiphilic  lipid matrix proves to be a major barrier for  macromolecular  hydrophilic compounds. [ 8 ]  After the administration of the buccal tablet, it must transport either through the epithelial layers to achieve its effect on the systemic circulation (systemic effect) or remain at a target site to elicit a local effect. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4023", "text": "Buccal tablets offer many advantages over other solid dosage forms also intended for oral administration (e.g.  enteric-coated  tablets,  chewable  tablets, and capsules)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4024", "text": "Buccal tablets can be considered in patients who experience difficulty in swallowing, since these tablets are absorbed into the blood stream between the gum and cheek. [ 17 ] [ 4 ]  Difficulty in swallowing can occur in all age groups, especially in young infants and the elderly community. [ 18 ]  Buccal tablets are also used in unconscious patients. [ citation needed ]  Additionally, in the case of accidental swallowing of a buccal tablet, adverse effects are minimal as most buccal drugs cannot survive hepatic first-pass metabolism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4025", "text": "Compared to orally ingested capsules and tablets, buccal tablets provide a more rapid  onset of action  because the oral mucosa is highly vascularised. [ 17 ] [ 9 ]  Buccal tablets are also used in emergency situations because they can exert their effects quickly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4026", "text": "Buccal tablets directly enter the systemic circulation, bypassing the gastrointestinal tract and first-pass metabolism in the liver. [ 6 ]  As such, patients can take a reduced overall dose to minimise symptoms. In addition, buccal tablets can be removed if adverse reactions appear."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4027", "text": "In general, many drugs are not suitable to be delivered via the buccal mucosa due to the small dose criteria. Buccal tablets are rarely used in healthcare settings due to unwanted properties that may limit patient compliance, for example, unpleasant taste and irritation of the oral mucosa. [ 19 ]  These undesired characteristics may lead to accidental swallowing or involuntary expulsion of the buccal tablet. Buccal tablets are also not preferred for drugs that require  extended-release . [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4028", "text": "Absorption of drugs via the buccal membrane may not be suitable for all patients. Due to possible undesirable side effects and loss of drug effectiveness, buccal tablets must not be crushed, chewed, or swallowed under any circumstances. As such, buccal tablets are not always appropriate for patients (e.g. individuals on  enteral tube feeding ). It is also noted that eating, drinking or smoking should be avoided until the buccal tablet is fully dissolved to prevent drug efficacy changes and concerns of choking. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4029", "text": "Buccal tablets are dry formulations that attain bioadhesion through dehydrating local mucosal surfaces. [ 7 ]  Many bioadhesive buccal tablet formulations are created through the direct compression method with a release retardant and swollen  polymer , [ 8 ]  and are designed to either release the drug in a unidirectional or multidirectional manner into the saliva. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4030", "text": "Conventional dosage forms are unable to ensure therapeutic drug levels in the circulation and the mucosa for mucosal and transmucosal administration because of the washing effect of saliva, and the mechanical stress of the oral cavity. [ 7 ]  These two mechanisms act as a physiological removal system that removes the formulation from the mucosa, resulting in a decreased exposure time and unpredictable pharmacological profile of the drug's distribution. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4031", "text": "This effect can be countered by prolonging the contact between the  active substance  from the buccal tablet and the mucosa, the tablet should contain: mucoadhesive agents, penetration enhancers,  enzyme inhibitors  and solubility modifiers. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4032", "text": "The mucoadhesive agents assist in the maintenance of prolonged contact between the\u00a0drug with the absorption site. [ 7 ]  Penetration enhancers improve the ability of the drug to permeate the mucosa for transmucosal delivery or penetrate into the layers of the epithelium for mucosal delivery. Enzyme inhibitors partake in the protection of the drug from mucosal enzyme degradation, and solubility modifiers increase the  solubility  of drugs that are poorly absorbed. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4033", "text": "Cerate , historically  simple cerate , (from  Latin   cera  \"wax\") is an unctuous preparation for external application, of a consistency intermediate between that of an  ointment  and a  plaster .  It can be spread upon cloth without the use of heat, but does not melt when applied to the skin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4034", "text": "Cerate consists essentially of  wax  (for which  resin ,  lead acetate  or  spermaceti  is sometimes substituted) mixed with oil, lard, and various medicinal ingredients. The cerate of the United States Pharmacopoeia is a mixture of three parts of  paraffin  and seven parts of  lard ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4035", "text": "A  depot injection , also known as a  long-acting injectable  ( LAI ), is a term for an  injection  formulation of a medication which  releases slowly over time  to permit less frequent administration of a medication. They are designed to increase  medication adherence  and  consistency , especially in patients who commonly forget to take their medicine. Depot injections can be created by modifying the drug molecule itself, as in the case of  prodrugs , or by modifying the way it is administered, as in the case of oil/lipid suspensions. Depot injections can have a duration of action of one month or greater and are available for many types of drugs, including  antipsychotics  and  hormones ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4036", "text": "Depot injections provide longer duration drug action through slow absorption into the bloodstream. They are usually administered  in the muscle ,  into the skin , or  under the skin . The injected medication slowly releases the medication into the bloodstream. It may be used in patients who forget to take their medication; some doctors and patients consider the use of a depot injection to be coercion, and are opposed to their use for that reason. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4037", "text": "Drugs may be modified to be slowly activated by the body, or be absorbed slowly by the body. Many are dissolved in an organic oil, as the compound is  lipophilic  due to the addition of functional groups to provide slow action. An example of this is adding a functional group such as  decanoate . [ 2 ]  The combination of an oil base and modification to decrease metabolic activation prevent medications from being fully released. [ 2 ] [ 3 ]  This can result in length of activity of 2\u20134 weeks or more. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4038", "text": "The alteration of the  pharmacokinetics  of the drug (the absorption and activation) does not change the side effect profile of the medication; thus,  atypical antipsychotics  are still preferred over  typical antipsychotics . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4039", "text": "The first long-acting (depot) injections were antipsychotics  fluphenazine  and  haloperidol . [ 2 ]  The concept of a depot injection arose before 1950, and originally was used to describe antibiotic injections that lasted longer to allow for less frequent administration. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4040", "text": "Most commonly, depot injections are designed to have a duration of 2\u20134 weeks of action, [ 5 ]  however the pharmacokinetics of a specific formulation vary. Absorption and metabolism can both be affected by modifying the drug itself (for example, by attaching a  functional group ) or by the formulation of the product (examples are oil or  microsphere  preparations). [ 5 ]  Repeated administration of depot injections can lead to a half life over one month (as in some preparations of  fluphenazine ), but this can be variable in different patients. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4041", "text": "Hormonal depot injections of  estradiol  can last anywhere from one week to over one month. [ 7 ]   Medroxyprogesterone acetate  is available as a depot injection which is injected once every three months to provide continuous hormonal contraception and releases for up to nine months after injection. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4042", "text": "Many medications are available as depot injections, including many typical and atypical antipsychotics, [ 9 ]  as well as some  hormonal medications  and medication for  opioid use disorder . [ 10 ] [ 11 ] [ 1 ]  Depot injections of antipsychotics are used to improve historically low adherence in patients with diseases such as  schizophrenia . [ 9 ]  Different products may be administered or implanted either by a doctor or nurse, while some are designed to be administered by the patient themselves. [ 12 ]  Self-administered depot injections are used to increase healthcare access and decrease the need to visit the doctor as frequently, especially in  low and middle income countries . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4043", "text": "Insulin  may also be considered a depot injection depending on formulation.  Insulin glargine , for example, is designed to precipitate after injection so it can be slowly absorbed by the body over a longer period than  regular insulin  would be. [ 13 ]  Depot injections of insulins have been studied to better replicate the body's natural  basal  rate of insulin production, and which can be activated by light to control the release of insulin from the injected depot. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4044", "text": "The  dermis  or  corium  is a layer of  skin  between the  epidermis  (with which it makes up the  cutis ) and  subcutaneous tissues , that primarily consists of  dense irregular connective tissue  and cushions the body from stress and strain. It is divided into two layers, the superficial area adjacent to the epidermis called the papillary region and a deep thicker area known as the reticular dermis. [ 1 ]   The dermis is tightly connected to the epidermis through a  basement membrane . Structural components of the dermis are  collagen ,  elastic fibers , and  extrafibrillar matrix . [ 2 ]  It also contains  mechanoreceptors  that provide the sense of  touch  and  thermoreceptors  that provide the sense of  heat . In addition,  hair follicles ,  sweat glands ,  sebaceous glands (oil glands) ,  apocrine glands ,  lymphatic vessels , nerves and  blood vessels  are present in the dermis. Those blood vessels provide nourishment and waste removal for both dermal and epidermal cells."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4045", "text": "The dermis is composed of three major types of  cells : [ 3 ]   fibroblasts ,  macrophages , and  mast cells ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4046", "text": "Apart from these cells, the dermis is also composed of  matrix  components such as  collagen  (which provides  strength ),  elastin  (which provides  elasticity ), and  extrafibrillar matrix , an extracellular gel-like substance primarily composed of  glycosaminoglycans  (most notably  hyaluronan ),  proteoglycans , and  glycoproteins . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4047", "text": "The  papillary dermis  is the uppermost layer of the dermis. It intertwines with the  rete ridges  of the epidermis and is composed of fine and loosely arranged collagen fibers. [ 2 ] \nThe papillary region is composed of loose  areolar connective tissue . It is named for its fingerlike projections called  papillae  or  dermal papillae  specifically, that extend toward the epidermis and contain either terminal networks of  blood   capillaries  or tactile  Meissner's corpuscles . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4048", "text": "The dermal papillae (DP) (singular  papilla , diminutive of Latin  papula , 'pimple') are small, nipple-like extensions (or interdigitations) of the dermis into the  epidermis . At the surface of the skin in hands and feet,  they appear as epidermal, papillary or friction ridges (colloquially known as  fingerprints )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4049", "text": "Blood vessels in the dermal papillae nourish all  hair follicles  and bring nutrients and oxygen to the lower layers of epidermal cells. The pattern of ridges produced in hands and feet are partly genetically determined features that are developed before birth. They remain substantially unaltered (except in size) throughout life, and therefore determine the patterns of fingerprints, making them useful in certain functions of personal identification. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4050", "text": "The dermal papillae are part of the uppermost layer of the dermis, the papillary dermis, and the ridges they form greatly increase the surface area between the dermis and epidermis. Because the main function of the dermis is to support the epidermis, this greatly increases the exchange of oxygen, nutrients, and waste products between these two layers. Additionally, the increase in the surface area prevents the dermal and epidermal layers from separating by strengthening the junction between them. With age, the papillae tend to flatten and sometimes increase in number. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4051", "text": "The skin of the hands and fingers and the feet and toes is known by forensic scientists as friction ridge skin. It is known by anatomists as thick skin, volar skin or hairless skin. It has raised ridges, a thicker and more complex epidermis, increased sensory abilities, and the absence of hair and sebaceous glands. The ridges increase friction for improved grasping. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4052", "text": "Dermal papillae also play a pivotal role in hair formation, growth and cycling. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4053", "text": "In  mucous membranes , the equivalent structures to dermal papillae are generally termed \"connective tissue papillae\", which interdigitate with the  rete pegs  of the superficial epithelium.\nDermal papillae are less pronounced in thin skin areas."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4054", "text": "The  reticular dermis  is the lower layer of the dermis, found under the papillary dermis, composed of  dense irregular connective tissue  featuring densely-packed collagen fibers. It is the primary location of dermal elastic fibers. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4055", "text": "The reticular region is usually much thicker than the overlying papillary dermis. It receives its name from the dense concentration of  collagenous ,  elastic , and  reticular fibers  that weave throughout it. These  protein  fibers give the dermis its properties of  strength ,  extensibility , and elasticity. Within the reticular region are the  roots of the hair ,  sebaceous glands ,  sweat glands ,  receptors ,  nails , and blood vessels. The orientation of collagen fibers within the reticular dermis creates lines of tension called  Langer's lines , which are of some relevance in surgery and wound healing. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4056", "text": "Drug delivery to the brain  is the process of passing  therapeutically active molecules  across the  blood\u2013brain barrier  into the  brain . This is a complex process that must take into account the complex anatomy of the brain as well as the restrictions imposed by the special junctions of the blood\u2013brain barrier."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4057", "text": "The blood\u2013brain barrier is formed by special  tight junctions  between  endothelial cells  lining brain blood vessels. Blood vessels of all tissues contain this monolayer of  endothelial cells , however only brain  endothelial cells  have tight junctions preventing passive diffusion of most substances into the  brain tissue . [ 1 ]  The structure of these tight junctions was first determined in the 1960s by Tom Reese, Morris Kranovsky, and Milton Brightman. Furthermore,  astrocytic  \"end feet\", the terminal regions of the astrocytic processes, surround  the outside of brain  capillary   endothelial cells \". [ 1 ]    The  astrocytes  are  glial cells  restricted to the  brain  and  spinal cord  and help maintain blood-brain barrier properties in brain  endothelial cells . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4058", "text": "The primary function of the blood-brain barrier is to protect the brain and keep it isolated from harmful toxins that are potentially in the  blood stream . It accomplishes this because of its structure, as is usual in the body that structure defines its function. The  tight junctions  between the  endothelial cells  prevent large molecules and many  ions  from passing between the junction spaces. This forces molecules to go through the endothelial cells to enter the  brain tissue , meaning that they must pass through the  cell membranes  of the  endothelial cells . [ 2 ] \nBecause of this, the only molecules that can easily transverse the blood\u2013brain barrier are very  lipid - soluble  ones. These are not the only molecules that can transverse the blood\u2013brain barrier;  glucose ,  oxygen  and  carbon dioxide  are not  lipid-soluble  but are  actively transported  across the barrier, to support the normal cellular function of the  brain . [ 3 ]  The fact that molecules have to fully transverse the  endothelial cells  makes them a perfect barricade to unspecified particles from entering the brain, working to protect the brain at all costs. Also, because most molecules are transported across the barrier,  it does a very effective job of maintaining  homeostasis  for the most vital organ of the human body. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4059", "text": "Because of the difficulty for  drugs  to pass through the blood\u2013brain barrier, a study was conducted to determine the factors that influence a compound\u2019s ability to transverse the blood\u2013brain barrier. In this study, they examined several different factors to investigate  diffusion  across the blood\u2013brain barrier. They used  lipophilicity ,  Gibbs Adsorption Isotherm , a Co CMC Plot, and the surface area of the drug to water and air. They began by looking at compounds whose blood\u2013brain  permeability  was known and labeled them either CNS+ or CNS- for compounds that easily transverse the barrier and those that did not. [ 4 ]  They then set out to analyze the above factors to determine what is necessary to transverse the blood\u2013brain barrier. What they found was a little surprising;  lipophilicity  is not the leading characteristic for a drug to pass through the barrier. This is surprising because one would think that the most effective way to make a drug move through a  lipophilic  barrier is to increase its  lipophilicity , it turns out that it is a complex function of all of these characteristics that makes a drug able to pass through the blood\u2013brain barrier. The study found that barrier  permittivity  is \"based on the measurement of the surface activity and as such takes into account the molecular properties of both  hydrophobic  and charged residues of the molecule of interest.\" [ 4 ]  They found that there is not a simple answer to what compounds transverse the blood\u2013brain barrier and what does not. Rather, it is based on the complex analysis of the surface activity of the molecule as well as  relative size ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4060", "text": "Other problems persist besides just simply getting through the blood\u2013brain barrier. The first of these is that a lot of times, even if a compound transverses the barrier, it does not do it in a way that the  drug  is in a therapeutically relevant concentration. [ 5 ]  This can have many causes, the most simple being that the way the drug was produced only allows a small amount to pass through the barrier. Another cause of this would be the binding to other  proteins  in the body rendering the drug ineffective to either be therapeutically active or able to pass through the barrier with the adhered  protein . [ 6 ]  Another problem that must be accounted for is the presence of  enzymes  in the  brain tissue  that could render the drug inactive. The drug may be able to pass through the membrane fine, but will be deconstructed once it is inside the brain tissue rendering it useless. All of these are problems that must be addressed and accounted for in trying to deliver effective drug solutions to the brain tissue. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4061", "text": "A group from the  University of Oxford  led by Prof. Matthew Wood claims that exosomes can cross the blood\u2013brain barrier and deliver  siRNAs , antisense oligonucleotides, chemotherapeutic agents and proteins specifically to neurons after inject them systemically (in blood). Because these exosomes are able to cross the blood\u2013brain barrier, this protocol could solve the issue of poor delivery of medications to the central nervous system and cure Alzheimer's, Parkinson's Disease and brain cancer, among other diseases. The laboratory has been recently awarded a major new \u20ac30 million project leading experts from 14 academic institutions, two biotechnology companies and seven pharmaceutical companies to translate the concept to the clinic. [ 7 ] [ 8 ] [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4062", "text": "This is the process of disguising medically active molecules with  lipophilic  molecules that allow it to better sneak through the blood\u2013brain barrier.  Drugs can be disguised using more  lipophilic  elements or structures. This form of the drug will be inactive because of the  lipophilic  molecules but then would be activated, by either  enzyme  degradation or some other mechanism for removal of the  lipophilic  disguise to release the drug into its active form. There are still some major drawbacks to these pro-drugs. The first of which is that the pro-drug may be able to pass through the barrier and then also re-pass through the barrier without ever releasing the drug in its active form. The second is the sheer size of these types of molecules makes it still difficult to pass through the blood\u2013brain barrier. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4063", "text": "Similar to the idea of pro-drugs, another way of masking the drugs  chemical composition  is by masking a  peptide\u2019s  characteristics by combining with other molecular groups that are more likely to pass through the blood\u2013brain barrier. An example of this is using a  cholesteryl  molecule instead of  cholesterol  that serves to conceal the  water soluble  characteristics of the drug.  This type of masking as well as aiding in traversing the blood\u2013brain barrier.  It also can work to mask the drug peptide from peptide-degrading enzymes in the brain [ 7 ]  Also a \"targetor\" molecule could be attached to the drug that helps it pass through the barrier and then once inside the brain, is degraded  in such a way that the drug cannot pass back through the brain. Once the drug cannot pass back through the barrier the drug can be concentrated and made effective for therapeutic use. [ 7 ]  However drawbacks to this exist as well. Once the drug is in the brain there is a point where it needs to be degraded to prevent  overdose  to the  brain tissue . Also if the drug cannot pass back through the blood\u2013brain barrier, it compounds the issues of dosage and intense monitoring would be required. For this to be effective there must be a mechanism for the removal of the active form of the drug from the brain tissue. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4064", "text": "These are drug compounds that increase the permeability of the blood\u2013brain barrier. [ 12 ]  By decreasing the restrictiveness of the barrier, it is much easier to get a molecule to pass through it. These drugs increase the  permeability  of the blood\u2013brain barrier temporarily by increasing the  osmotic pressure  in the  blood  which loosens the  tight junctions  between the  endothelial cells . By loosening the  tight junctions  normal injection of drugs through an [IV] can take place and be effective to enter the brain. [ 8 ]  This must be done in a very controlled environment because of the risk associated with these drugs. Firstly, the brain can be flooded with molecules that are floating through the  blood stream  that are usually blocked by the barrier. Secondly, when the  tight junctions  loosen, the  homeostasis  of the brain can also be thrown off which can result in  seizures  and the compromised function of the brain. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4065", "text": "The most promising drug delivery system is using  nanoparticle  delivery systems, these are systems where the drug is bound to a nanoparticle capable of traversing the blood\u2013brain barrier. The most promising compound for the nanoparticles is  Human Serum Albumin  (HSA). The main benefits of this is that particles made of HSA are well tolerated without serious side effects  as well as the  albumin  functional groups can be utilized for surface modification that allows for specific cell uptake. [ 5 ]  These  nanoparticles  have been shown to transverse the blood\u2013brain barrier carrying host drugs.  To enhance the effectiveness of nanoparticles, scientists are attempting to coat the  nanoparticles  to make them more effective to cross the blood\u2013brain barrier. Studies have shown that \"the overcoating of the [nanoparticles] with polysorbate 80 yielded doxorubicin concentrations in the brain of up to 6 \u03bcg/g after i.v. injection of 5 mg/kg\" as compared to no detectable increase in an injection of the drug alone or the uncoated nanoparticle. [ 13 ]   This is very new science and technology so the real effectiveness of this process has not been fully understood. However young the research is, the results are promising pointing to  nanotechnology  as the way forward in treating a variety of  brain diseases ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4066", "text": "Microbubbles  are small \"bubbles\" of  mono-lipids  that are able to pass through the blood\u2013brain barrier. They form a  lipophilic  bubble that can easily move through the barrier. [ 14 ]  One barrier to this however is that these  microbubbles  are rather large, which prevents their diffusion into the brain. This is counteracted by a focused  ultrasound . The  ultrasound  increases the  permeability  of the blood\u2013brain barrier by causing interference in the  tight junctions  in localized areas. This combined with the  microbubbles  allows for a very specific area of  diffusion  for the  microbubbles , because they can only diffuse where the  ultrasound  is disrupting the barrier. [ 10 ]  The  hypothesis  and usefulness of these is the possibility of loading a  microbubble  with an active drug to diffuse through the barrier and target a specific area. [ 10 ]   There are several important factors in making this a viable solution for  drug delivery .  The first is that the loaded  microbubble  must not be substantially greater than the unloaded bubble. This ensures that the  diffusion  will be similar and the  ultrasound  disruption will be enough to induce  diffusion . A second factor that must be determined is the stability of the loaded micro-bubble. This means is the drug fully retained in the bubble or is there leakage. Lastly, it must be determined how the drug is to be released from the  microbubble  once it passes through the blood\u2013brain barrier. Studies have shown the effectiveness of this method for getting drugs to specific sites in the brain in animal models. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4067", "text": "An  enema , also known as a  clyster , is an injection of fluid into the rectum or into  lower bowel  by way of the  rectum . [ 1 ]  The word  enema  can also refer to the liquid injected, [ 2 ] [ 3 ]  as well as to a device for administering such an injection. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4068", "text": "In standard medicine, the most frequent uses of enemas are to relieve constipation and for bowel cleansing before a medical examination or procedure; [ 5 ]  also, they are employed as a  lower gastrointestinal series  (also called a barium enema), [ 6 ]  to treat  traveler's diarrhea , [ 7 ]  as a vehicle for the administration of food, water or medicine, as a stimulant to the general system, as a local application and, more rarely, as a means of reducing body temperature, [ 1 ]  as treatment for  encopresis , and as a form of  rehydration therapy  (proctoclysis) in patients for whom  intravenous therapy  is not applicable. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4069", "text": "The principal medical usages of enemas are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4070", "text": "As  bowel  stimulants, enemas are employed for the same purposes as orally administered  laxatives : to relieve  constipation ; to treat  fecal impaction ; to empty the colon prior to a medical procedure such as a  colonoscopy . When oral laxatives are not indicated or are not sufficiently effective, enemas may be a sensible and necessary measure. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4071", "text": "A large volume enema [ 10 ]  can be given to cleanse as much of the colon as possible of feces. [ 11 ] [ 12 ]  However, a low enema is generally useful only for stool in the rectum, not in the intestinal tract. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4072", "text": "Such enemas' mechanism consists of the volume of the liquid causing a rapid expansion of the intestinal tract in conjunction with, in the case of certain solutions, irritation of the intestinal  mucosa  which stimulates peristalsis and lubricates the stool to encourage a bowel movement. [ 14 ]  An enema's efficacy depends on several factors including the volume injected and the temperature and the contents of the infusion. [ 9 ]  In order for the enema to be effective the patient should retain the solution for five to ten minutes, as tolerated. [ 5 ] [ 14 ]  or, as some nursing textbooks recommend, for five to fifteen minutes or as long as possible. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4073", "text": "For emptying the entire colon as much as feasible [ 12 ]  deeper and higher enemas are utilized to reach large sections of the colon. [ 9 ]  The colon dilates and expands when a large volume of liquid is injected into it, and the colon reacts to that sudden expansion with general contractions,  peristalsis , propelling its contents toward the rectum. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4074", "text": "Soapsuds enema  is a frequently used synonym for a large volume enema (although soap is not necessary for effectivity). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4075", "text": "For relieving occasional constipation, a large volume enema may be used in a home setting, although for recurring or severe cases of constipation medical care may be required. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4076", "text": "Plain water can be used, simply functioning mechanically to expand the colon, thus prompting evacuation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4077", "text": "Normal saline  is least irritating to the colon. Like plain water, it simply functions mechanically to expand the colon, but having a neutral concentration gradient, it neither draws  electrolytes  from the body, as happens with plain water, nor draws water into the colon, as occurs with phosphates. Thus, a salt water solution can be used when a longer period of retention is desired, such as to soften an impaction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4078", "text": "Castile soap  is commonly added because its irritation of the colon's lining increases the urgency to defecate. [ 15 ]  However, liquid handsoaps and detergents should not be used. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4079", "text": "Glycerol  is a specific bowel mucosa irritant serving to induce peristalsis via a  hyperosmotic effect . [ 16 ]  It is used in a dilute solution, e.g., 5%. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4080", "text": "Equal parts of milk and molasses heated together to slightly above normal body temperature have been used. [ 18 ]  Neither the milk sugars and proteins nor the molasses are absorbed in the lower intestine, thus keeping the water from the enema in the intestine. [ 19 ]  Studies have shown that milk and molasses enemas have a low complication rate when used in the  emergency department [ 20 ]  and are safe and effective with minimal side effects. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4081", "text": "Mineral oil  functions as a lubricant and stool softener, but may have side effects including rectal skin irritation and leakage of oil. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4082", "text": "ATC code A06   Drugs for constipation  is a therapeutic subgroup of the  Anatomical Therapeutic Chemical Classification System , a system of alphanumeric codes developed by the  World Health Organization  (WHO) for the classification of  drugs  and other medical products. [ 23 ] [ 24 ] [ 25 ]  Subgroup A06 is part of the anatomical group  A  Alimentary tract and metabolism . [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4083", "text": "Codes for  veterinary  use ( ATCvet codes ) can be created by placing the letter Q in front of the human ATC code: for example,  QA06 . [ 27 ]   National issues of the ATC classification may include additional codes not present in this list, which follows the WHO version."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4084", "text": "In alphabetical order"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4085", "text": "In alphabetical order of the original brand names"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4086", "text": "Klyx contains  docusate sodium  1\u00a0mg/mL and sorbitol solution (70%)(crystallising) 357\u00a0mg/mL and is used for faecal impaction or constipation or for colon evacuation prior medical procedures, [ 44 ]  developed by  Ferring B.V."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4087", "text": "Micralax (not to be confused with MICROLAX\u00ae) [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4088", "text": "MICROLAX\u00ae  (not to be confused with Micralax) combines the action of  sodium citrate , a peptidising agent which can displace bound water present in the faeces, with sodium alkyl sulphoacetate, a wetting agent, and with glycerol, an anal mucosa irritant and hyperosmotic. However, also sold under the name \"Micralax\", is a preparation containing  sorbitol  rather than glycerol; [ 46 ]  which was initially tested in preparation for  sigmoidoscopy . [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4089", "text": "Micolette Micro-enema\u00ae contains 45\u00a0mg sodium lauryl sulphoacetate, 450\u00a0mg per 5 ml sodium citrate BP, and 625\u00a0mg glycerol BP [ 48 ]  and is a small volume stimulant enema suitable where large-volume enemas are contra-indicated. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4090", "text": "TAI , also termed  retrograde irrigation , is designed to assist evacuation using a water enema [ 49 ]  as a treatment for persons with bowel dysfunction, including  fecal incontinence  or constipation, especially  obstructed defecation . By regularly emptying the bowel using transanal irrigation, [ 50 ]  controlled bowel function is often re-established to a high degree, thus enabling development of a consistent bowel routine. [ 50 ]   Its effectiveness varies considerably, some individuals experiencing complete control of incontinence but others reporting little or no benefit. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4091", "text": "An international consensus on when and how to use transanal irrigation for people with bowel problems was published in 2013, offering practitioners a clear, comprehensive and simple guide to practice for the emerging therapeutic area of transanal irrigation. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4092", "text": "The term  retrograde irrigation  distinguishes this procedure from the  Malone antegrade continence enema , where irrigation fluid is introduced into the colon proximal to the anus via a surgically created irrigation port. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4093", "text": "Patients who have a bowel disability, a medical condition which impairs control of  defecation , e.g., fecal incontinence or constipation, [ 52 ]  can use bowel management techniques to choose a predictable time and place to evacuate. [ 52 ]  Without bowel management, such persons might either suffer from the feeling of not getting relief, or they might soil themselves. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4094", "text": "While simple techniques might include a controlled  diet  and establishing a toilet routine, [ 52 ]  a daily enema can be taken to empty the colon, thus preventing unwanted and uncontrolled bowel movements that day. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4095", "text": "In a  lower gastrointestinal series  an enema that may contain  barium sulfate  powder or a water-soluble  contrast agent  is used in the  radiological  imaging of the bowel. Called a  barium enema , such enemas are sometimes the only practical way to  view  the colon in a relatively safe manner. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4096", "text": "Failure to expel all of the barium may cause constipation or possible impaction [ 54 ]  and a patient who has no bowel movement for more than two days or is unable to pass gas rectally should promptly inform a physician and may require an enema or laxative. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4097", "text": "The administration of substances into the bloodstream. This may be done in situations where it is undesirable or impossible to deliver a medication by mouth, such as  antiemetics  given to reduce  nausea  (though not many antiemetics are delivered by enema). Additionally, several anti-angiogenic agents, which work better without digestion, can be safely administered via a gentle enema."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4098", "text": "The topical administration of medications into the rectum, such as  corticosteroids  and  mesalazine  used in the treatment of  inflammatory bowel disease . Administration by enema avoids having the medication pass through the entire  gastrointestinal tract , therefore simplifying the delivery of the medication to the affected area and limiting the amount that is absorbed into the bloodstream."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4099", "text": "Rectal corticosteroid enemas are sometimes used to treat mild or moderate ulcerative colitis. They also may be used along with systemic (oral or injection) corticosteroids or other medicines to treat severe disease or mild to moderate disease that has spread too far to be treated effectively by medicine inserted into the rectum alone."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4100", "text": "Improper administration of an enema can cause electrolyte imbalance (with repeated enemas) or ruptures to the bowel or rectal tissues which can be unnoticed as the rectum is insensitive to pain, [ 66 ]  resulting in internal  bleeding . However, these occurrences are rare in healthy,  sober  adults. Internal bleeding or rupture may leave the individual exposed to infections from intestinal bacteria. Blood resulting from tears in the colon may not always be visible, but can be distinguished if the feces are unusually dark or have a red hue. If intestinal rupture is suspected, medical assistance should be obtained immediately. [ 14 ]  Frequent use of enemas can cause laxative dependency. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4101", "text": "The enema tube and solution may stimulate the  vagus nerve , which may trigger an  arrhythmia  such as  bradycardia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4102", "text": "Enemas should not be used if there is an undiagnosed  abdominal pain  since the peristalsis of the bowel can cause an inflamed  appendix  to  rupture ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4103", "text": "There are arguments both for and against colonic irrigation in people with  diverticulitis ,  ulcerative colitis ,  Crohn's disease , severe or internal  hemorrhoids  or  tumors  in the rectum or  colon , and its usage is not recommended soon after bowel  surgery  (unless directed by one's  health care provider ). Regular treatments should be avoided by people with  heart disease  or  kidney failure . Colonics are inappropriate for people with bowel, rectal or anal  pathologies  where the pathology contributes to the risk of  bowel perforation . [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4104", "text": "Recent research has shown that ozone water, which is sometimes used in enemas, can immediately cause  microscopic colitis . [ 69 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4105", "text": "A recent case series [ 70 ]  of 11 patients with five deaths illustrated the danger of phosphate enemas in high-risk patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4106", "text": "Enema  entered the English language c. 1675 from Latin in which, in the 15th century, [ 3 ]  it was first used in the sense of a rectal injection, [ 2 ]  from Greek \u1f14\u03bd\u03b5\u03bc\u03b1 (\u00e9nema), \"injection\", itself from \u1f10\u03bd\u03b9\u03ad\u03bd\u03b1\u03b9 (enienai) \"to send in, inject\", from \u1f10\u03bd (en), \"in\" + \u1f31\u03ad\u03bd\u03b1\u03b9 (hienai), \"to send, throw\". [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4107", "text": "Clyster  entered the English language in the late 14th century from Old French or Latin, from Greek \u03ba\u03bb\u03c5\u03c3\u03c4\u03ae\u03c1 (klyster), \"syringe\", itself from \u03ba\u03bb\u03cd\u03b6\u03b5\u03b9\u03bd (klyzein), \"to wash out\", [ 72 ]  also spelled  glister  in the 18th century, [ 73 ]  is a generally archaic word used more particularly for enemas administered using a  clyster syringe ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4108", "text": "The first mention of the enema in medical literature is in the Ancient Egyptian  Ebers Papyrus  ( c. \u20091550  BCE). One of the many types of medical specialists was a Nery-Pehuyt, the Shepherd of the Anus. Many medications were administered by enemas. [ 74 ]  There was a Keeper of the Royal Rectum [ 75 ]  who may have primarily been the pharaoh's enema maker. The god  Thoth , according to Egyptian mythology, invented the enema. [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4109", "text": "In parts of Africa the  calabash  gourd is used traditionally to administer enemas. On the Ivory Coast the narrow neck of the gourd filled with water is inserted the patient's rectum and the contents are then injected by means of an attendant's forcible oral inflation, or, alternatively, a patient may self-administer the enema by using suction to create a negative pressure in the gourd, placing a finger at the opening, and then upon anal insertion, removing the finger to allow atmospheric pressure to effect the flow. In South Africa,  Bhaca  people used an ox horn to administer enemas. [ 77 ]  Along the upper Congo River an enema apparatus is made by making a hole in one end of the gourd for filling it, and using a resin to attach a hollow cane to the gourd's neck. The cane is inserted into the anus of the patient who is in a posture that allows gravity to effect infusion of the fluid. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4110", "text": "The  Olmec  from their middle preclassic period (10th through 7th centuries BCE) through the Spanish Conquest used trance-inducing substances ceremonially, and these were ingested via, among other routes, enemas administered using jars."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4111", "text": "As further described below in  religious rituals , the  Maya  in their late classic age (7th through 10th centuries CE) used enemas for, at least, ritual purposes, Mayan sculpture and ceramics from that period depicting scenes in which, injected by syringes made of gourd and clay, ritual hallucinogenic enemas were taken. [ 79 ]  In the Xibalban court of the God D, whose worship included ritual cult paraphernal, the Maya illustrated the use of a characteristic enema bulb syringe by female attendants administering clysters ritually. [ 80 ] [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4112", "text": "For combating illness and discomfort of the digestive tract, the Mayan also employed enemas, as documented during the colonial period, e.g., in the  Florentine Codex . [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4113", "text": "The  indigenous peoples of North America  employed  tobacco smoke enemas  to stimulate respiration, injecting the smoke using a rectal tube. [ 82 ] [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4114", "text": "A rubber bag connected with a conical nozzle, at an early period, was in use among the  indigenous peoples of South America   as an enema syringe, [ 84 ]  and the rubber enema bag with a connecting tube and ivory tip remained in use by them while in Europe a syringe was still the usual means for conducting an enema. [ 85 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4115", "text": "In Babylonia, by 600 BCE, enemas were in use, although it appears that initially they were in use because of a belief that the demon of disease would, by means of an enema, be driven out of the body. [ 86 ]  Babylonian and Assyrian tablets c. 600 BCE bear cuneiform inscriptions referring to enemas. [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4116", "text": "In China, c. 200 CE,  Zhang Zhongjing  was the first to employ enemas. \"Secure a large pig's bile and mix with a small quantity of vinegar. Insert a bamboo tube three or four inches long into the rectum and inject the mixture\" are his directions, according to  Wu Lien-teh . [ 88 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4117", "text": "In India, in the fifth century BCE,  Sushruta  enumerates the enema syringe among 121 surgical instruments described. Early Indian physicians' enema apparatus consisted of a tube of bamboo, ivory, or horn attached to the scrotum of a deer, goat, or ox. [ 86 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4118", "text": "In Persia,  Avicenna  (980\u20131037 A. D.) is credited with the introduction of the \"clyster-purse\" or collapsible portion of an enema outfit made from ox skin or silk cloth and emptied by squeezing with the hands. [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4119", "text": "Hippocrates  (460\u2013370 BCE) frequently mentions enemas, e.g., \"if the previous food which the patient has recently eaten should not have gone down, give an enema if the patient be strong and in the prime of life, but if he be weak, a suppository should be administered, should the bowels be not well moved on their own accord.\" [ 89 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4120", "text": "In the first century BCE the  Greek physician   Asclepiades of Bithynia  wrote \"Treatment consists merely of three elements: drink, food, and the enema\". [ 90 ]  Also, he contended that indigestion is caused by particles of food that are too big and his prescribed treatment was proper amounts of food and wine followed by an enema which would remove the improper food doing the damage. [ 91 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4121", "text": "In the second century CE the Greek physician  Soranus  prescribed, among other  techniques , enemas as a safe  abortion  method, [ 92 ]  and the Greek philosopher  Celsus  recommended an enema of pearl barley in milk or rose oil with butter as a nutrient for those with dysentery and unable to eat, [ 93 ]  and also Galen mentions enemas in several contexts. [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4122", "text": "In medieval times appear the first illustrations of enema equipment in the  Western world , a clyster syringe consisting of a tube attached to a pump action bulb made of a pig bladder. [ citation needed ] \nA simple piston  syringe  clyster was in use from the 15th through 19th centuries. This device had its rectal nozzle connected to a syringe with a plunger rather than to a bulb. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4123", "text": "Beginning in the 17th century enema apparatus was chiefly designed for self-administration at home and many were French as enemas enjoyed wide usage in France. [ 93 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4124", "text": "In 1694  Fran\u00e7ois Mauriceau  in his early-modern treatise,  The Diseases of Women with Child,  records that both midwives and man-midwives commonly administered clysters to labouring mothers just prior to their delivery. [ 94 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4125", "text": "Clysters were administered for symptoms of constipation and, with more questionable effectiveness, stomach aches and other illnesses. [ when? ] [ citation needed ] [ 95 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4126", "text": "In 1753 an enema bag prepared from a pig's or beef's bladder attached to a tube was described by Johann Jacob Woyts as an alternative to a syringe. [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4127", "text": "In the 18th century Europeans began emulating the  indigenous peoples of North America's  use of tobacco smoke enemas to resuscitate drowned people. [ 97 ]  Tobacco resuscitation kits consisting of a pair of bellows and a tube were provided by the Royal Humane Society of London and placed at various points along the Thames. [ 93 ]  Furthermore, these enemas came to be employed for headaches, respiratory failure, colds, hernias, abdominal cramps, typhoid fever, and cholera outbreaks. [ 97 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4128", "text": "Clysters were a favourite medical treatment in the  bourgeoisie  and  nobility  of the Western world up to the 19th century. As medical knowledge was fairly limited at the time, purgative clysters were used for a wide variety of  ailments , the foremost of which were  stomach aches  and constipation. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4129", "text": "According to  the duc de Saint-Simon , clysters were so popular at the court of King  Louis XIV of France  that  the duchess of Burgundy  had her servant give her a clyster in front of the King (her modesty being preserved by an adequate posture) before going to the  comedy . However, he also mentions the astonishment of the King and Mme de Maintenon that she should take it before them. [ 98 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4130", "text": "In the 19th century many new types of enema administration equipment were devised. Devices allowing gravity to infuse the solution, like those mentioned above used by South American indigenous people and like the enema bag described by Johann Jacob Woyts, came into common use. These consist of a nozzle at the end of a hose which connects a reservoir, either a bucket or a rubber bag, which is filled with liquid and held or hung above the recipient. [ 93 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4131", "text": "In the early 20th century the disposable  microenema , a squeeze bottle, was invented by  Charles Browne Fleet . [ 99 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4132", "text": "The term \"colonic irrigation\" is commonly used in  gastroenterology  to refer to the practice of introducing water through a colostomy or a surgically constructed conduit as a treatment for constipation. [ 100 ]  The  Food and Drug Administration  has ruled that colonic irrigation equipment is not approved for sale for the purpose of general well-being [ 101 ]  and has taken action against many distributors of this equipment, including a  Warning Letter . [ 102 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4133", "text": "The same term is also used in  alternative medicine  where it may involve the use of substances mixed with water in order to  detoxify  the body. Practitioners believe the accumulation of fecal matter in the large intestine leads to ill health. [ 103 ]   This resurrects the old medical concept of  autointoxication  which was orthodox doctrine up to the end of the 19th century but which has now been discredited. [ 104 ] [ 105 ] [ 106 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4134", "text": "In the late 19th century Dr.  John Harvey Kellogg  made sure that the bowel of each and every patient was plied with water, from above and below. His favorite device was an enema machine (\"just like one I saw in Germany\") that could run fifteen gallons of water through a person's bowel in a matter of seconds. Every water enema was followed by a pint of yogurt\u2014half was eaten, the other half was administered by enema \"thus planting the protective germs where they are most needed and may render most effective service.\" The yogurt served to replace \"the intestinal flora\" of the bowel, creating what Kellogg claimed was a completely clean intestine. [ 107 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4135", "text": "Chlorine dioxide  enemas have been fraudulently marketed as a medical treatment, primarily for  autism . This has resulted, for example, in a six-year-old boy needing to have his colon removed and a colostomy bag fitted, [ 108 ] [ 109 ]  complaints to the FDA reporting life-threatening reactions, [ 110 ]  and even death. [ 111 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4136", "text": "Proponents falsely claim that administering autistic children these enemas results in the expulsion of parasitic worms (\" rope worms \"), which actually are fragments of damaged intestinal  epithelium  that are misinterpreted as being human pathogens. [ 112 ] [ 113 ]  Oral and rectal use of the solution has also been promoted as a cure for  HIV ,  malaria ,  viral hepatitis ,  influenza ,  common colds ,  acne ,  cancer ,  Parkinson's , and much more."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4137", "text": "Chlorine dioxide is a potent and toxic bleach [ 114 ]  that is relabeled for \"medicinal purposes\" to a variety of brand names including, but not limited, to MMS,  Miracle Mineral Supplement , and CD protocol. [ 115 ]  For oral use, the doses recommended on the labeling can cause nausea, vomiting, diarrhea, and potentially life-threatening dehydration. [ 116 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4138", "text": "No clinical trials have been performed to test the health claims made for chlorine dioxide, which originate from former  Scientologist  Jim Humble [ 117 ]  in his 2006  self-published  book,  The Miracle Mineral Solution of the 21st Century [ 118 ]  and from anecdotal reports. The name MMS was coined by Humble. Sellers sometimes describe MMS as a  water purifier  so as to circumvent medical regulations. [ 119 ]  The  International Federation of Red Cross and Red Crescent Societies  rejected \"in the strongest terms\" reports by promoters of MMS that they had used the product to fight malaria. [ 120 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4139", "text": "Well documented as having no proven benefits and considered by medical authorities as rash and potentially dangerous is an enema of  coffee . [ 104 ] [ 121 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4140", "text": "A coffee enema can cause numerous maladies including  infections ,  sepsis  (including  campylobacter  sepsis), severe  electrolyte imbalance ,  colitis , polymicrobial enteric sepsis,  proctocolitis ,  salmonella ,  brain abscess , and heart failure, [ 122 ] [ 123 ] [ 124 ] [ 125 ] [ 126 ] [ 127 ] [ 128 ] [ 129 ] [ 130 ] [ excessive citations ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4141", "text": "and deaths related to coffee enemas have been documented. [ 131 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4142", "text": "Gerson therapy  includes administering enemas of coffee, [ 132 ]  as well as of  castor oil  and sometimes of  hydrogen peroxide  or of  ozone . [ 133 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4143", "text": "Some proponents of alternative medicine have claimed that coffee enemas have an anti- cancer  effect by \"detoxifying\" metabolic products of tumors [ 122 ]  but there is no medical scientific evidence to support this. [ 121 ] [ 123 ] [ 134 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4144", "text": "Enjoyment of enemas is known as  klismaphilia , which medically is classified as a  paraphilia . [ 135 ] [ 136 ]  A person with klismaphilia is a  klismaphile ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4145", "text": "Both women and men may enjoy sexual enema play, heterosexually and homosexually, experiencing  sexual arousal  from enemas which they find gratifying or sensual [ 137 ] [ 138 ]  and which can be an auxiliary to, or even a substitute for, genital  sexual activity . [ 137 ] [ 138 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4146", "text": "Klismaphiles may perceive pleasure from a large, water-distended belly, or the feeling of internal pressure. An enema fetish may include sexual attraction to the involved equipment, processes, environments, situations, or scenarios, [ 139 ]  Klismaphiles can gain satisfaction of enemas through fantasies, by actually receiving or giving one, or through the process of eliminating steps to being administered one (e.g., under the pretence of being constipated). [ 138 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4147", "text": "That some women use enemas while masturbating was documented by  Alfred Kinsey  in  Sexual Behavior in the Human Female : \"There were still other masturbatory techniques which were regularly or occasionally employed by some 11 percent of the females in the sample... Douches, streams of running water, vibrators, urethral insertions, enemas, other anal insertions, sado-masochistic activity, and still other methods were occasionally employed, but none of them in any appreciable number of cases.\" [ 140 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4148", "text": "Besides klismaphilia, the intrinsic enjoyment of enemas, there are other uses of enemas in sexual play. [ 141 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4149", "text": "Enemas are sometimes used in  sadomasochistic  activities [ 142 ] [ 143 ]  for  erotic humiliation [ 144 ]  or for physical discomfort. [ 145 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4150", "text": "Another sexual use for enemas is to empty the rectum as a prelude to other anal sexual activities such as  anal sex , [ 146 ]  possibly reducing risk of infection."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4151", "text": "This is different from klismaphilia, in which the enema is enjoyed for itself and as a part of sexual arousal and gratification. [ 146 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4152", "text": "Rectal douching is a common practice among people who take a receptive role in anal sex [ 147 ]  although rectal douching before anal sex may increase the risk of transferring  HIV , [ 148 ]   hepatitis B , [ 149 ]  and other diseases. [ 150 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4153", "text": "Noting that deaths have been reported from  alcohol poisoning  via enemas, [ 151 ]  an  alcohol enema  can be used to very quickly instill alcohol into the bloodstream, absorbed through the membranes of the colon. However, great care must be taken as to the amount of alcohol used. Only a small amount is needed as the intestine absorbs the alcohol far more quickly than the stomach."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4154", "text": "Preceding an enema for administration of drugs or alcohol, a cleansing enema may first be used for cleaning the colon to help increase the rate of absorption. [ 152 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4155", "text": "All across  Mesoamerica  ritual enemas were employed to consume psychoactive substances, e.g.,  balch\u00e9 ,  alcohol ,  tobacco ,  peyote , and other  hallucinogenic drugs  and  entheogens , most notably by the  Maya , thus attaining more intense trance states more quickly, and Mayan classic-period sculpture and ceramics depict hallucinogenic enemas used in rituals. [ 79 ]  Some tribes continue the practice in the present day. [ 153 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4156", "text": "With historical roots in the  Indian subcontinent , enemas in  Ayurveda , called  Basti  or Vasti, form part of  Panchakarma  procedure in which  herbal medicines  are introduced rectally. [ 154 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4157", "text": "Enemas have also been forcibly applied as a means of punishment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4158", "text": "Political dissenters in post-independence Argentina were given enemas of  chili pepper  and  turpentine . [ 155 ]  Turpentine enemas are very harsh purgatives. [ 156 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4159", "text": "In the  Guantanamo Bay Detention Camp , the  Senate Intelligence Committee report on CIA torture  documented instances of enemas being used by the  Central Intelligence Agency  in order to ensure \"total control\" over detainees. [ 157 ]  Enemas, officials said, are uncomfortable and degrading, [ 158 ]  The CIA forced nutrient enema on detainees who attempted hunger strikes, documenting \"With head lower than torso \u2026 sloshing up the large intestines \u2026 [what] I infer is that you get a tube up as you can \u2026 We used the largest Ewal  [ sic ] tube we had\" wrote an officer, [ 159 ]  and \"violent enemas\" is how a detainee described what he received. [ 160 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4160", "text": "In the  Dionysus '  satyr play   Limos ,  Silenus  attempts to give an enema to  Heracles . [ 161 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4161", "text": "In  Cervantes '  Don Quixote , a narrative to Sancho includes \u201cThe Knight of the Sun ... bound hand and foot ... was administered a clyster of snow water and sand that almost disracted him\" [ 162 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4162", "text": "In the 17th century, satirists made physicians a favorite target, resembling  Moli\u00e8re 's caricature whose prescription for anything was \"clyster, bleed, purge,\" or \"purge, bleed, clyster\". [ 163 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4163", "text": "In Moli\u00e8re's play  The Imaginary Invalid , Argan, a severe  hypochondriac , is addicted to enemas as indicated by such lines as when B\u0115ralde asks, \"Can't you be one moment without a purge?\" [ 164 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4164", "text": "In  Grace Metalious 's novel  Peyton Place , the town doctor tells of \"a young boy with the worst case of dehydration I ever saw. It came from getting too many enemas that he didn't need. Sex, with a capital S-E-X.\". [ 165 ]  As a teenager, the boy enjoys receiving enemas from his mother. [ 166 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4165", "text": "In  Flora Rheta Schreiber 's book  Sybil , Sybil's psychiatrist asks her \"What's Mama been doing to you, dear?...I know she gave you the enemas.\" [ 167 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4166", "text": "In  The Right Stuff , during flight training astronaut  Alan Shepard  retains a barium enema, [ 168 ]  given two floors away from a toilet, embarrassedly riding a public elevator wearing a  hospital gown  and holding the enema bag with its tip still inserted in him. [ 169 ] [ 170 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4167", "text": "Water Power  is a film loosely based on the real-life exploits of  Michael H. Kenyon , an American criminal who pleaded guilty to a decade-long series of armed robberies of female victims, some of which involved sexual assaults in which he would give them enemas. [ 171 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4168", "text": "The lyrics of  Frank Zappa 's song  The Illinois Enema Bandit  are concerned with  Michael H. Kenyon 's  sexual assaults  which included administering involuntary enemas. [ 172 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4169", "text": "A 365-kilogram (805-pound) brass statue of a syringe enema bulb held aloft by three cherubs stands in front of the \"Mashuk\" spa in the settlement of  Zheleznovodsk  in Russia. Inspired by the 15th century Renaissance painter Botticelli, it was created by a local artist who commented that \"An enema is an unpleasant procedure as many of us may know. But when cherubs do it, it's all right.\" When unveiled on 19 June 2008, posted on one of the spa's wall was a banner declaring \"Let's beat constipation and sloppiness with enemas.\"  The spa lying in the Caucasus Mountains region, known for dozens of spas that routinely treat digestive and other complaints with enemas of mineral spring water, the director commented \"An enema is almost a symbol of our region.\" [ 173 ] [ 174 ]  It is the only known monument to the enema. [ 175 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4170", "text": "Sources"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4171", "text": "\"A professional nursing instructional video demonstrating administering a cleansing enema\" .  Taber's Medical Dictionary . K. A. Davis Company . Retrieved  17 July  2014 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4172", "text": "Enteral  administration is food or  drug administration  via the  human gastrointestinal tract . This contrasts with  parenteral  nutrition or drug administration (Greek  para , \"besides\" +  enteros ), which occurs from routes outside the GI tract, such as  intravenous  routes. Enteral administration involves the esophagus, stomach, and small and large intestines (i.e., the gastrointestinal tract). Methods of administration include oral, sublingual (dissolving the drug under the tongue), and rectal. Parenteral administration is via a peripheral or central vein. [ 1 ]  In  pharmacology , the route of drug administration is important because it affects  drug metabolism ,  drug clearance , and thus  dosage . The term is from  Greek   enteros  'intestine'."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4173", "text": "Enteral administration may be divided into three different categories, depending on the entrance point into the GI tract: oral (by  mouth ), gastric (through the  stomach ), and rectal (from the  rectum ). (Gastric introduction involves the use of a tube through the nasal passage ( NG tube ) or a tube in the belly leading directly to the stomach ( PEG tube ). Rectal administration usually involves rectal  suppositories .)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4174", "text": "The mechanism for drug absorption from the intestine is for most drugs passive transfer, a few exceptions include  levodopa  and  fluorouracil , which are both absorbed through  carrier-mediated transport . For  passive transfer  to occur, the drug has to diffuse through the lipid  cell membrane  of the  epithelial cells  lining the inside of the intestines. The rate at which this happens is largely determined by two factors:  Ionization  and  lipid solubility . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4175", "text": "Factors influencing gastrointestinal absorption:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4176", "text": "Drugs given by enteral administration may be subjected to significant  first pass metabolism , and therefore, the amount of drug entering the systemic circulation following administration may vary significantly for different individuals and drugs. Rectal administration is not subject to extensive first pass metabolism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4177", "text": "Focused ultrasound for intracrainial drug delivery  is a  non-invasive technique  that uses  high-frequency  sound waves ( focused ultrasound , or FUS) to disrupt tight junctions in the  blood\u2013brain barrier  (BBB), allowing for increased passage of  therapeutics  into the brain. The BBB normally blocks nearly 98% of drugs from accessing the central  nervous system , so FUS has the potential to address a major challenge in intracranial drug delivery by providing targeted and reversible BBB disruption. Using FUS to enhance  drug delivery to the brain  could significantly improve patient outcomes for a variety of diseases including  Alzheimer's disease ,  Parkinson's disease , and  brain cancer ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4178", "text": "Ultrasound  is commonly used in the medical field for imaging and diagnostic purposes. With FUS, a curved  transducer ,  lens , or phased array is used to guide the ultrasound waves to a particular location, similar to the way a magnifying glass can focus sunlight to a single point. [ 1 ]  This strategy concentrates the acoustic energy in a small target area while having a minimal effect on the surrounding tissue. [ 2 ]  Depending on the acoustic parameters, FUS can be used to exert mechanical and/or thermal effects on target tissues, making it a versatile and promising tool for many therapeutic applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4179", "text": "The BBB is a highly specialized structure composed of  endothelial cells ,  pericytes , and  astrocytic  processes and is situated between the  cerebral  capillaries and brain  parenchyma . The  endothelial  cells form tight junctions, creating a semi- permeable membrane  that separates\ncirculating blood from the  central nervous system . Various mechanisms are used to transport molecules across the BBB. Small polar molecules such as  glucose ,  amino acids , and  nucleosides  enter the brain through carrier-mediated transport. Small  lipophilic molecules  and\ngaseous molecules such as oxygen and carbon dioxide can passively diffuse through the BBB. Large molecules such as  proteins  and  peptides  use receptor-mediated or absorption-mediated  endocytic transport  to access the brain. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4180", "text": "The BBB is crucial for structural and functional brain connectivity and plays a major role in protecting the brain from circulating  pathogens . [ 4 ]  However, the BBB is also a key impediment\nfor intracranial drug delivery and significantly limits entry of therapeutic molecules into the brain. Generally, only  lipid -soluble molecules with a low  molecular weight  (around ~400 Da) and a positive charge can cross the BBB. [ 5 ]  Many therapeutic molecules do not have these properties and thus have difficulty entering the brain. For example,  doxorubicin , a common\n chemotherapeutic , is ~540 Da in size and  trastuzumab , a  monoclonal antibody , is 148 kDa in size. [ 6 ]  The molecular weight of these molecules significantly hinders their ability to pass through the tight junctions present in the BBB."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4181", "text": "Since the BBB limits the  bioavailability  of therapeutics in treating neurological diseases, many strategies have been developed to circumvent the BBB.  Osmotic  agents disrupt the BBB by causing osmotic shrinkage of the  endothelial  cells and creating an osmotic pressure gradient. [ 7 ]  However, this strategy results in global rather than localized BBB opening which can lead to neurological deficits and  seizures . [ 8 ]  Intracranial injections can be used to directly deliver drugs to a specific part of the brain. [ 9 ]  While these injections limit systemic toxicities and remove the\nloss of drug from first pass clearance, these procedures are invasive and can pose additional risk to the patient.  Convection  enhanced delivery uses an intracranial  catheter  to deliver drug through the interstitial spaces of the central nervous system. This strategy is also quite invasive as it requires insertion of the catheter into the brain and the diffusion of drug from the catheter tip is limited. [ 10 ]   Radiation therapy  is known to increase BBB permeability, but the temporal characteristics of radiation-induced opening are unpredictable and radiation can damage the surrounding brain tissue by causing  necrosis ,  demyelination , and  gliosis . [ 11 ]  Focused ultrasound has the potential to address the limitations posed by these strategies by offering a\nmethod for non-invasive, temporally-controlled, and localized BBB disruption."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4182", "text": "Early studies that investigated the use of FUS for BBB disruption used ultrasound to increase the  permeability of the blood vessels  either by increasing the temperature (usually to 40-45\u00b0C) or forming gas bubbles (inertial  cavitation ). While these studies concluded that this method could be used to open the BBB, damage to healthy  tissue  was always reported. [ 12 ]   In 2004, it was discovered that the threshold for thermal BBB disruption is greater than the threshold for thermal damage, meaning thermal BBB disruption cannot be performed without causing some damage to the brain tissue. Nevertheless, ultrasound  hyperthermia  may still be useful for intracranial drug delivery. In vitro studies showed that moderate ultrasound hyperthermia (temperature elevations \u2264 6\u00b0C) increases endothelial cell permeability to  hydrophobic  molecules. [ 13 ]  FUS hyperthermia has also been used with radiation therapy to treat patients with brain  tumors  since FUS sensitizes tumor cells to radiation by inhibiting  DNA damage repair  and disrupting the  protein kinase B   signaling pathway . [ 14 ] [ 15 ]  Studies have also shown that FUS can be used to both thermally  ablate  brain tumors and improve delivery of  chemotherapy  through reversible BBB opening to kill any remaining  malignant  cells. [ 16 ]  However, since thermal BBB disruption cannot be induced without damaging tissue, it may not be useful for non-cancer applications in which preserving healthy tissue may be essential."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4183", "text": "Cavitation  occurs when gas bubbles grow, oscillate, and collapse in a fluid during exposure to ultrasound waves. There are two general types of cavitation: stable and inertial. Stable cavitation occurs when the gas bubbles oscillate, and these oscillations are sustained for many cycles of acoustic pressure. [ 17 ]  These oscillations move the surrounding fluid, generating flow around the bubble. This flow is known as microstreaming and can increase the amount of drug that passes through the openings in the tight junctions. Inertial cavitation is typically transient and results in the collapse or fragmentation of bubbles. Low acoustic pressures are used to induce stable cavitation while higher ultrasound intensities lead to inertial cavitation. Both stable and inertial cavitation apply mechanical stress to the blood vessel walls, temporarily disrupting the tight junctions between the endothelial cells. [ 18 ]  This is typically done through a push-pull action in which the bubble expansion separates the endothelial lining while the bubble contraction causes  invagination  of the  vascular  lining. Transiently disrupting the BBB allows for  paracellular transport  of molecules, and there is evidence that the physical stress induced on the vessel walls by the gas bubbles causes cellular changes that further enhance paracellular and  transcellular  transport of therapeutics across the BBB. [ 19 ]  However, this mechanical stress can damage the blood vessels, and inertial cavitation is generally avoided for BBB opening since it poses the greatest risk for injury. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4184", "text": "Due to the safety and efficacy issues related to thermal and cavitation-assisted FUS-induced BBB opening, research has focused on using preformed  microbubbles  to further enhance the effects of FUS. Microbubbles are small bubbles with diameters typically between .5 and 10  microns . The core is typically filled with gas, but microbubbles can also be loaded with active drug for therapeutic purposes. The microbubble shell is typically composed of  polymers , lipids,  proteins , or a combination of these components. Since these microbubbles are  lipophilic , they\ncan diffuse through the BBB. In 2001, Hynynen et al. used microbubbles in conjunction with FUS to induce BBB opening without causing tissue damage. [ 21 ]  By injecting microbubbles into the blood before sonication, they found the intensities required to disrupt the BBB were two times lower than the intensity required with FUS alone. Furthermore, they discovered that the BBB was restored 24 hours after the FUS treatment. Following this study, several groups have\nreported effective intracranial drug delivery using microbubbles with different FUS parameters. Many researchers have concluded that ultrasound pressure is the most important parameter to optimize to avoid injuring blood vessels and surrounding brain tissue. [ 22 ]  It has been seen that greater ultrasound pressure is required to allow a 2000 kDa drug to cross the BBB compared to a 70 kDa drug. [ 23 ]  In rodent models, it has been shown that BBB disruption with microbubbles\nis effective over a wide range of ultrasound frequencies from 28\u00a0kHz to 8\u00a0MHz. [ 24 ]  While the repetition frequency of the ultrasound bursts do not significantly affect BBB opening, if the burst frequency is too high, the microbubbles cannot effectively reperfuse the target area. [ 25 ]  The properties of the microbubbles themselves can affect treatment efficacy. As microbubble size and dose increase, BBB opening increases and there is a greater risk for damage. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4185", "text": "Microbubbles can also serve as effective drug carriers. Drugs can be adhered to the surface of microbubbles, encapsulated inside the microbubble, or embedded in the microbubble membrane. [ 27 ]   Ligands  can also be conjugated to the surface of microbubbles to target specific sites. [ 28 ]  FUS-induced cavitation can be used to burst the microbubbles and release drug near the diseased region. This method achieves local drug release while limiting off-target toxicities. [ 29 ]  Drug-loaded microbubbles with FUS has been shown to be an attractive combination  therapy  for brain tumors. One study found that the ultrasound-triggered release of  doxorubicin  from loaded microbubbles resulted in a two-fold decrease in human  glioblastoma  cell survival rate compared to free doxorubicin or loaded microbubbles without FUS. [ 30 ]  Another study found encapsulating  carmustine  in microbubbles led to a five-fold increase in the circulating half-life and a five-fold decrease in drug accumulation in the liver. [ 31 ]  This study also found combining these carmustine-loaded microbubbles with FUS increased the median survival time by 12% in a rat  glioma  model. Due to the promising results seen with drug-loaded microbubbles and FUS for brain tumor treatment, this method may also have potential for treating other neurological disorders such as Alzheimer's and  Parkinson's  disease. [ 32 ] [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4186", "text": "FUS for intracranial drug delivery has many potential benefits for both cancer and non-cancer applications. Examples of studies that used FUS to deliver therapeutics into the brain are summarized below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4187", "text": "While FUS has many potential advantages for intracranial drug delivery, there are several limitations. Heterogeneity in the acoustic properties of the  skull  leads to distortion and attenuation of the ultrasound. Intracranial structures such as gray and  white matter  and dense  vasculature  also vary between patients, so each individual may have a unique threshold for BBB opening. Patient-specific ultrasound arrays may need to be used to address this concern. After the procedure,  MRI contrast agents  are given to patients to measure BBB opening, so currently there is no method for intraoperative monitoring of BBB disruption. For strategies that use  magnetic resonance guidance , the need for pre-procedural removal of hair, substantial operating time, and use of  stereotactic frame  may limit the widespread use of FUS for intracranial drug delivery. Treatment protocols and dosing schedules for many therapeutic  molecules  still need to be better understood to ensure off-target toxicities are limited. Finally, many studies investigating FUS for intracranial drug delivery use animals with healthy BBBs, but several neurological  diseases  break down the BBB, so current animal  models  may not be very representative."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4188", "text": "Despite the limitations, FUS is a promising tool for improving the treatment of many disorders. FUS is currently being studied to facilitate intracranial  gene  delivery for the treatment of Alzheimer's disease. [ 49 ]  A similar approach is also being studied for Parkinson's disease. [ 50 ]  The ability to disrupt the BBB could also allow for delivery of therapeutics to the  motor cortex  to treat  amyotrophic lateral sclerosis . [ 51 ]  There may also be applications of FUS for both  neuromodulation  and targeted drug delivery in  epilepsy ,  Alzheimer's disease ,  Parkinson's disease , depression, and  traumatic brain injury . In the future, research efforts will focus on addressing the challenges and limitations of FUS to develop safe and effective therapies for the most challenging brain conditions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4189", "text": "The  gastrointestinal tract  ( GI tract ,  digestive tract ,  alimentary canal ) is the tract or passageway of the  digestive system  that leads from the  mouth  to the  anus . The GI tract contains all the major  organs  of the digestive system, in humans and other animals, including the  esophagus ,  stomach , and  intestines . Food taken in through the mouth is  digested  to extract  nutrients  and absorb  energy , and the waste expelled at the anus as  feces .  Gastrointestinal  is an adjective meaning of or pertaining to the stomach and intestines."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4190", "text": "Most animals  have a \"through-gut\" or complete digestive tract. Exceptions are more primitive ones:  sponges  have small pores ( ostia ) throughout their body for digestion and a larger dorsal pore ( osculum ) for excretion,  comb jellies  have both a ventral mouth and dorsal anal pores, while  cnidarians  and  acoels  have a single pore for both digestion and excretion. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4191", "text": "The human gastrointestinal tract consists of the  esophagus ,  stomach, and intestines, and is divided into the upper and lower gastrointestinal tracts. [ 3 ]  The GI tract includes all structures between the  mouth  and the  anus , [ 4 ]  forming a continuous passageway that includes the main organs of digestion, namely, the  stomach ,  small intestine , and  large intestine . The complete  human digestive system  is made up of the gastrointestinal tract plus the accessory organs of digestion (the  tongue ,  salivary glands ,  pancreas ,  liver  and  gallbladder ). [ 5 ]  The tract may also be divided into  foregut ,  midgut , and  hindgut , reflecting the  embryological  origin of each segment. The whole human GI tract is about nine meters (30 feet) long at  autopsy . It is considerably shorter in the living body because the intestines, which are tubes of  smooth muscle tissue , maintain constant  muscle tone  in a halfway-tense state but can relax in spots to allow for local distention and  peristalsis . [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4192", "text": "The gastrointestinal tract contains the  gut microbiota , with some 1,000 different  strains  of  bacteria  having diverse roles in the maintenance of  immune health  and  metabolism , and many other  microorganisms . [ 8 ] [ 9 ] [ 10 ]  Cells of the GI tract release  hormones  to help regulate the digestive process. These  digestive hormones , including  gastrin ,  secretin ,  cholecystokinin , and  ghrelin , are mediated through either  intracrine  or  autocrine  mechanisms, indicating that the cells releasing these hormones are conserved structures throughout  evolution . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4193", "text": "The structure and function can be described both as  gross anatomy  and as  microscopic anatomy  or  histology . The tract itself is divided into upper and lower tracts, and the intestines  small  and  large  parts. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4194", "text": "The upper gastrointestinal tract consists of the  mouth ,  pharynx ,  esophagus ,  stomach , and  duodenum . [ 13 ] \nThe exact demarcation between the upper and lower tracts is the  suspensory muscle of the duodenum . This differentiates the embryonic borders between the foregut and midgut, and is also the division commonly used by clinicians to describe  gastrointestinal bleeding  as being of either \"upper\" or \"lower\" origin. Upon  dissection , the duodenum may appear to be a unified organ, but it is divided into four segments based on function, location, and internal anatomy. The four segments of the duodenum are as follows (starting at the stomach, and moving toward the jejunum):  bulb , descending, horizontal, and ascending. The suspensory muscle attaches the superior border of the ascending duodenum to the  jejunum ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4195", "text": "The suspensory muscle is an important anatomical landmark that shows the formal division between the duodenum and the jejunum, the first and second parts of the small intestine, respectively. [ 14 ]  This is a thin muscle which is derived from the  embryonic   mesoderm ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4196", "text": "The lower gastrointestinal tract includes most of the  small intestine  and all of the  large intestine . [ 15 ]  In  human anatomy , the  intestine  ( bowel  or  gut ; Greek:  \u00e9ntera ) is the segment of the gastrointestinal tract extending from the pyloric sphincter of the  stomach  to the  anus  and as in other mammals, consists of two segments: the  small intestine  and the  large intestine . In humans, the small intestine is further subdivided into the  duodenum ,  jejunum , and  ileum  while the large intestine is subdivided into the  cecum , ascending, transverse, descending, and sigmoid  colon ,  rectum , and  anal canal . [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4197", "text": "The  small intestine  begins at the  duodenum  and is a tubular structure, usually between 6 and 7 m long. [ 18 ]  Its  mucosal  area in an adult human is about 30\u00a0m 2  (320\u00a0sq\u00a0ft). [ 19 ]  The combination of the  circular folds , the villi, and the microvilli increases the absorptive area of the mucosa about 600-fold, making a total area of about 250\u00a0m 2  (2,700\u00a0sq\u00a0ft) for the entire small intestine. [ 20 ]  Its main function is to absorb the products of digestion (including carbohydrates, proteins, lipids, and vitamins) into the bloodstream. There are three major divisions:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4198", "text": "The  large intestine , also called the colon, forms an arch starting at the  cecum  and ending at the  rectum  and  anal canal . It also includes the  appendix , which is attached to the  cecum . Its length is about 1.5 m, and the area of the mucosa in an adult human is about 2\u00a0m 2  (22\u00a0sq\u00a0ft). [ 19 ]  Its main function is to absorb water and salts. The colon is further divided into:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4199", "text": "The gut is an  endoderm -derived structure. At approximately the sixteenth day of human development, the  embryo  begins to fold  ventrally  (with the embryo's ventral surface becoming  concave ) in two directions: the sides of the embryo fold in on each other and the head and tail fold toward one another. The result is that a piece of the  yolk sac , an  endoderm -lined structure in contact with the  ventral  aspect of the embryo, begins to be pinched off to become the primitive gut. The yolk sac remains connected to the gut tube via the  vitelline duct . Usually, this structure regresses during development; in cases where it does not, it is known as  Meckel's diverticulum ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4200", "text": "During  fetal  life, the primitive gut is gradually patterned into three segments:  foregut ,  midgut , and  hindgut . Although these terms are often used in reference to segments of the primitive gut, they are also used regularly to describe regions of the definitive gut as well."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4201", "text": "Each segment of the gut is further specified and gives rise to specific gut and gut-related structures in later development. Components derived from the gut proper, including the  stomach  and  colon , develop as swellings or dilatations in the cells of the primitive gut. In contrast, gut-related derivatives \u2014 that is, those structures that derive from the primitive gut but are not part of the gut proper, in general, develop as out-pouchings of the primitive gut. The blood vessels supplying these structures remain constant throughout development. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4202", "text": "The gastrointestinal tract has a form of general histology with some differences that reflect the specialization in functional anatomy. [ 22 ]  The GI tract can be divided into four concentric layers in the following order:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4203", "text": "The mucosa is the innermost layer of the gastrointestinal tract. The mucosa surrounds the  lumen , or open space within the tube. This layer comes in direct contact with digested food ( chyme ). The mucosa is made up of:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4204", "text": "The mucosae are highly specialized in each organ of the gastrointestinal tract to deal with the different conditions. The most variation is seen in the epithelium."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4205", "text": "The submucosa consists of a dense irregular layer of connective tissue with large blood vessels, lymphatics, and nerves branching into the mucosa and  muscularis externa . It contains the  submucosal plexus , an  enteric nervous plexus , situated on the inner surface of the  muscularis externa ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4206", "text": "The  muscular layer  consists of an inner circular layer and a  longitudinal  outer layer. The circular layer prevents food from traveling backward and the longitudinal layer shortens the tract. The layers are not truly longitudinal or circular, rather the layers of muscle are helical with different pitches. The inner circular is helical with a steep pitch and the outer longitudinal is helical with a much shallower pitch. [ 23 ]  Whilst the muscularis externa is similar throughout the entire gastrointestinal tract, an exception is the stomach which has an additional inner oblique muscular layer to aid with grinding and mixing of food. The muscularis externa of the stomach is composed of the inner oblique layer, middle circular layer, and the outer longitudinal layer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4207", "text": "Between the circular and longitudinal muscle layers is the  myenteric plexus . This controls peristalsis. Activity is initiated by the pacemaker cells, (myenteric  interstitial cells of Cajal ). The gut has intrinsic peristaltic activity ( basal electrical rhythm ) due to its self-contained enteric nervous system. The rate can be modulated by the rest of the  autonomic nervous system . [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4208", "text": "The coordinated contractions of these layers is called  peristalsis  and propels the food through the tract. Food in the GI tract is called a bolus (ball of food) from the mouth down to the stomach. After the stomach, the food is partially digested and semi-liquid, and is referred to as  chyme . In the large intestine, the remaining semi-solid substance is referred to as  faeces . [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4209", "text": "The outermost layer of the gastrointestinal tract consists of several layers of  connective tissue ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4210", "text": "Intraperitoneal  parts of the GI tract are covered with  serosa . These include most of the  stomach , first part of the  duodenum , all of the  small intestine ,  caecum  and  appendix ,  transverse colon ,  sigmoid colon  and  rectum . In these sections of the gut, there is a clear boundary between the gut and the surrounding tissue. These parts of the tract have a  mesentery ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4211", "text": "Retroperitoneal  parts are covered with  adventitia . They blend into the surrounding tissue and are fixed in position. For example, the retroperitoneal section of the duodenum usually passes through the  transpyloric plane . These include the  esophagus ,  pylorus  of the stomach, distal  duodenum ,  ascending colon ,  descending colon  and  anal canal . In addition, the  oral cavity  has adventitia."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4212", "text": "Approximately 20,000 protein coding genes are expressed in human cells and 75% of these genes are expressed in at least one of the different parts of the digestive organ system. [ 24 ] [ 25 ]  Over 600 of these genes are more specifically expressed in one or more parts of the GI tract and the corresponding proteins have functions related to digestion of food and uptake of nutrients. Examples of specific proteins with such functions are  pepsinogen PGC  and the  lipase LIPF , expressed in  chief cells , and gastric  ATPase ATP4A  and  gastric intrinsic factor GIF , expressed in  parietal cells  of the stomach mucosa. Specific proteins expressed in the stomach and duodenum involved in defence include  mucin  proteins, such as  mucin 6  and  intelectin-1 . [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4213", "text": "The time taken for food to transit through the gastrointestinal tract varies on multiple factors, including age, ethnicity, and gender. [ 27 ] [ 28 ]  Several techniques have been used to measure transit time, including radiography following a  barium -labeled meal, breath  hydrogen  analysis,  scintigraphic  analysis following a  radiolabeled  meal, [ 29 ]  and simple ingestion and spotting of  corn kernels . [ 30 ]  It takes 2.5 to 3 hours for 50% of the contents to leave the stomach. [ medical citation needed ]  The rate of digestion is also dependent of the material being digested, as food composition from the same meal may leave the stomach at different rates. [ 31 ]  Total emptying of the stomach takes around 4\u20135 hours, and transit through the colon takes 30 to 50 hours. [ 29 ] [ 32 ] [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4214", "text": "The gastrointestinal tract forms an important part of the  immune system . [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4215", "text": "The surface area of the digestive tract is estimated to be about 32 square meters, or about half a badminton court. [ 19 ]  With such a large exposure (more than three times larger than the  exposed surface of the skin ), these immune components function to prevent pathogens from entering the blood and lymph circulatory systems. [ 35 ]  Fundamental components of this protection are provided by the  intestinal mucosal barrier , which is composed of physical, biochemical, and immune elements elaborated by the intestinal mucosa. [ 36 ]  Microorganisms also are kept at bay by an extensive immune system comprising the  gut-associated lymphoid tissue  (GALT)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4216", "text": "There are additional factors contributing to protection from pathogen invasion. For example, low  pH  (ranging from 1 to 4) of the stomach is fatal for many  microorganisms  that enter it. [ 37 ]  Similarly,  mucus  (containing  IgA   antibodies ) neutralizes many pathogenic microorganisms. [ 38 ]  Other factors in the GI tract contribution to immune function include  enzymes  secreted in the  saliva  and  bile ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4217", "text": "Beneficial bacteria also can contribute to the homeostasis of the gastrointestinal immune system. For example,  Clostridia , one of the most predominant bacterial groups in the GI tract, play an important role in influencing the dynamics of the gut's immune system. [ 39 ]  It has been demonstrated that the intake of a high fiber diet could be responsible for the induction of  T-regulatory cells  (Tregs). This is due to the production of  short-chain fatty acids  during the fermentation of plant-derived nutrients  such as  butyrate  and  propionate .  Basically, the butyrate induces the differentiation of Treg cells by enhancing  histone H3   acetylation  in the promoter and conserved non-coding sequence regions of the  FOXP3  locus, thus regulating the  T cells , resulting in the reduction of the inflammatory response and allergies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4218", "text": "The large intestine contains multiple types of  bacteria  that can break down molecules the human body cannot process alone, [ 40 ]  demonstrating a  symbiotic  relationship. These bacteria are responsible for gas production at  host\u2013pathogen interface , which is released as  flatulence . Intestinal bacteria can also participate in biosynthesis reactions. For example, certain strains in the large intestine produce vitamin B 12 ; [ 41 ]  an essential compound in humans for things like DNA synthesis and red blood cell production. [ 42 ]  However, the primary function of the large intestine is water absorption from digested material (regulated by the  hypothalamus ) and the reabsorption of  sodium  and nutrients. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4219", "text": "Beneficial  intestinal bacteria  compete with potentially harmful  bacteria  for space and \"food\", as the intestinal tract has limited resources. A ratio of 80\u201385% beneficial to 15\u201320% potentially harmful bacteria is proposed for maintaining  homeostasis . [ citation needed ]  An imbalanced ratio results in  dysbiosis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4220", "text": "Enzymes  such as  CYP3A4 , along with the  antiporter  activities, are also instrumental in the intestine's role of  drug metabolism  in the detoxification of  antigens  and  xenobiotics . [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4221", "text": "In most  vertebrates , including  amphibians ,  birds ,  reptiles ,  egg-laying mammals , and some  fish , the gastrointestinal tract ends in a  cloaca  and not an  anus . In the cloaca, the  urinary system  is fused with the genito-anal pore.  Therians  (all mammals that do not lay eggs, including humans) possess separate anal and uro-genital openings. The females of the subgroup  Placentalia  have even separate urinary and genital openings."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4222", "text": "During  early development , the asymmetric position of the bowels and inner organs is initiated (see also  axial twist theory )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4223", "text": "Ruminants  show many specializations for digesting and  fermenting  tough plant material, consisting of  additional stomach compartments ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4224", "text": "Many birds and other animals have a specialised stomach in the digestive tract called a  gizzard  used for grinding up food."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4225", "text": "Another feature found in a range of animals is the  crop . In birds this is found as a pouch alongside the esophagus."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4226", "text": "In 2020, the oldest known fossil digestive tract, of an extinct wormlike organism in the  Cloudinidae  was discovered; it lived during the late  Ediacaran   period  about 550 million years ago. [ 45 ] [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4227", "text": "A through-gut (one with both mouth and anus) is thought to have evolved within the  nephrozoan  clade of  Bilateria , after their ancestral ventral orifice (single, as in  cnidarians  and  acoels ; re-evolved in nephrozoans like  flatworms ) stretched antero-posteriorly, before the middle part of the stretch would get narrower and closed fully, leaving an anterior orifice (mouth) and a posterior orifice (anus plus  genital opening ). A stretched gut without the middle part closed is present in another branch of bilaterians, the extinct  proarticulates . This and the  amphistomic  development (when both mouth and anus develop from the gut stretch in the embryo) present in some nephrozoans (e.g.  roundworms ) are considered to support this hypothesis. [ 47 ] [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4228", "text": "There are many diseases and conditions that can affect the gastrointestinal system, including  infections ,  inflammation  and  cancer ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4229", "text": "Various  pathogens , such as  bacteria  that cause  foodborne illnesses , can induce  gastroenteritis  which results from  inflammation  of the stomach and small intestine.  Antibiotics  to treat such bacterial infections can decrease the  microbiome  diversity of the gastrointestinal tract, and further enable inflammatory mediators. [ 49 ]  Gastroenteritis is the most common disease of the GI tract."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4230", "text": "Diverticular disease  is a condition that is very common in older people in industrialized countries.  It usually affects the large intestine but has been known to affect the small intestine as well.   Diverticulosis  occurs when pouches form on the intestinal wall.  Once the pouches become inflamed it is known as  diverticulitis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4231", "text": "Inflammatory bowel disease  is an inflammatory condition affecting the bowel walls, and includes the subtypes  Crohn's disease  and  ulcerative colitis . While Crohn's can affect the entire gastrointestinal tract, ulcerative colitis is limited to the large intestine. Crohn's disease is widely regarded as an  autoimmune disease . Although ulcerative colitis is often treated as though it were an autoimmune disease, there is no consensus that it actually is such."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4232", "text": "Functional gastrointestinal disorders  the most common of which is  irritable bowel syndrome . Functional constipation and  chronic functional abdominal pain  are other functional disorders of the intestine that have physiological causes but do not have identifiable structural, chemical, or infectious pathologies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4233", "text": "Several symptoms can indicate problems with the gastrointestinal tract, including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4234", "text": "Gastrointestinal surgery  can often be performed in the outpatient setting.  In the United States in 2012, operations on the digestive system accounted for 3 of the 25 most common ambulatory surgery procedures and constituted 9.1 percent of all outpatient ambulatory surgeries. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4235", "text": "Various methods of imaging the gastrointestinal tract include the  upper  and  lower gastrointestinal series :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4236", "text": "Intestines from animals other than humans are used in a number of ways.  From each species of  livestock  that is a source of  milk , a corresponding  rennet  is obtained from the intestines of milk-fed  calves .   Pig  and  calf  intestines are eaten, and pig intestines are used as  sausage  casings. Calf intestines supply  calf-intestinal alkaline phosphatase  (CIP), and are used to make  goldbeater's skin .\nOther uses are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4237", "text": "In medicine,  infusion therapy  deals with all aspects of fluid and medication infusion, via  intravenous  or  subcutaneous  application. A special  infusion pump  can be used for this purpose. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4238", "text": "A  fenestrated  catheter is frequently inserted into the localized area to be treated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4239", "text": "There are a range of delivery methods for infusion of drugs via  catheter :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4240", "text": "Infusion therapy has a range of medical applications including sedation, anesthesia, post-operative analgesic pain management, chemotherapy, and treatment of infectious diseases"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4241", "text": "Advantages of infusion therapy over other non-site-specific delivery methodologies are primarily efficacy through precision of medication delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4242", "text": "New standards for infusible pharmaceuticals have been achieved in recent years with the advent of pre-filled, ready-to-use, dose-specific products. Advanced aseptic presentation, with hermetically sealed containers, allows predictable sterility, ease of use, improved control, and lower total costs. Essentially, systematizing the delivery mechanism and standardizing the delivery container. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4243", "text": "Infusion therapy involves the administration of medication through a needle or catheter. Typically, \"infusion therapy\" means that a drug is administered intravenously or subcutaneously. The term may pertain where drugs are provided through other non-oral  routes of administration , such as  intramuscular injection  and  epidural administration  (into the membranes surrounding the spinal cord)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4244", "text": "Until the 1980s, patients receiving infusion therapy often had to remain in an  inpatient setting  for the duration of their therapy. New technologies and heightened emphasis on  cost containment  in  health care , as well as developments in the clinical administration of the therapy, led to strategies to administer infusion therapy in alternate settings (at clinics and at home) [ 3 ]  in an effort to reduce hospital readmissions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4245", "text": "Insufflation  ( Latin :  insufflare ,  lit. \u2009 'to blow into') is the act of blowing something (such as a gas, powder, or vapor) into a body cavity. [ 1 ]  Insufflation has many medical uses, most notably as a route of administration for various drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4246", "text": "Gases are often insufflated into a body cavity to inflate the cavity for more workroom, e.g. during  laparoscopic surgery . The most common gas used in this manner is  carbon dioxide , because it is non-flammable, colorless, and dissolves readily in blood."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4247", "text": "Gases can be insufflated into parts of the body to enhance  radiological imaging [ 2 ]  or to gain access to areas for visual inspection (e.g. during  colonoscopy ). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4248", "text": "Oxygen can be insufflated into the nose by  nasal cannulae  to assist in respiration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4249", "text": "Mechanical insufflation-exsufflation  simulates a cough and assists  airway mucus clearance . It is used with patients with neuromuscular disease and muscle weakness due to central nervous system injury. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4250", "text": "Glossopharyngeal insufflation  is a breathing technique that consists of gulping boluses of air into the lungs. It is also used by  breath-hold divers  to increase their lung volumes. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4251", "text": "Positive airway pressure  is a mode of  mechanical  or  artificial ventilation  based on insufflation. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4252", "text": "Pump inhalers  for  asthmatics  deliver aerosolized drugs into the lungs via the mouth. However, the insufflation by the pump is not adequate for delivery to the lungs, necessitating an active inhalation by the patient. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4253", "text": "Insufflated gases and vapors are used to ventilate and oxygenate patients ( oxygen ,  air ,  helium ), and to induce, assist in or maintain  general anaesthesia  ( nitrous oxide ,  xenon ,  volatile anesthetic agents )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4254", "text": "Positive airway pressure  is a mode of  mechanical  or  artificial ventilation  based on insufflation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4255", "text": "Nasal insufflation is the most common method of  nasal administration . Other methods are nasal inhalation and nasal instillation. Drugs administered in this way can have a local effect or a systemic effect. The time of onset for systemic drugs delivered via nasal administration is generally only marginally slower than if given intravenously."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4256", "text": "Nasal administration can also be used for treatment of  children  or patients who are otherwise alarmed or frightened by needles, or where  intravenous  (IV) access is unavailable."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4257", "text": "In the 18th century, the  tobacco smoke enema , an insufflation of tobacco smoke into the rectum, was a common method of reviving drowning victims. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4258", "text": "An  intracavernous  (or  intracavernosal )  injection  is an  injection  into the base of the  penis .  This injection site is often used to administer medications to check for or treat  erectile dysfunction  in adult men (in, for example, a  combined intracavernous injection and stimulation test ). [ 1 ]  The more common medications administered in this manner include Caverject,  Trimix  ( prostaglandin ,  papaverine , and  phentolamine ), Bimix (papaverine and phentolamine), and Quadmix (prostaglandin, papaverine, phentolamine, and either  atropine  or  forskolin ). These medications are all types of  vasodilators  and cause  tumescence  within 15 minutes.\nCommon side effects include  priapism , bruising, fibrosis,  Peyronie's disease , and pain. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4259", "text": "Priapism is also often treated with intracavernous injections, usually with  sympathomimetic  vasoconstricting drugs like  adrenaline  or  phenylephrine . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4260", "text": "Intracerebroventricular injection  (often abbreviated as ICV injection) is a route of administration for drugs via injection into the  cerebral ventricles  so that it reaches the  cerebrospinal fluid  (CSF). This route of administration is often used to bypass the  blood-brain barrier  because it can prevent important medications from reaching the central nervous system. This injection method is widely used in diseased mice models to study the effect of drugs, plasmid DNA, and viral vectors on the central nervous system. In humans, ICV injection can be used for the administration of drugs for various reasons. Examples include the treatment of  Spinal Muscular Atrophy  (SMA), the administration of chemotherapy in  gliomas , and the administration of drugs for long-term  pain management . ICV injection is also used in the creation of diseased animal models specifically to model neurological disorders."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4261", "text": "Intracerebroventricular injection has been used to inject drugs that induce a diseased state to create animal models for a variety of diseases. Of these,  Alzheimer's disease  (AD) animal models are heavily represented in the literature."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4262", "text": "ICV injection of  Streptozotocin  has been used to create a metabolic model of Alzheimer's disease. This protocol works by damaging the control level of cerebral glucose metabolism to mimic Alzheimer's disease symptoms. An early sign of AD is glucose hypometabolism and impaired insulin signaling has been seen in AD patients. Streptozotocin has also largely been used to create diabetes animal models, by injecting either intravenously or intraperitoneally. [ 1 ]  These ICV injections result in models for the sporadic Alzheimer's disease (sAD) form, rather than familial. A characteristic of sAD is an insulin-resistant brain state (IRBS). Streptozotocin is a beta-cytotoxic drug and by injecting it directly into the cerebral ventricles, the treated mice develop symptoms that align with sAD symptoms in humans. Some of these symptoms include IRBS-associated memory impairment, glucose hypometabolism, oxidative stress, and neurodegeneration. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4263", "text": "More recently, a model for AD that represents both familial and sporadic AD has emerged. In the clinic, as well as independent experiments, an increase in amyloid beta (A\u03b2) levels in the brain has been seen to cause Alzheimer-like symptoms. To create an animal model of AD, A\u03b2 can be injected using ICV injection. A benefit of this pathogen-induced model is that it shows Alzheimer's-like symptoms, while also exhibiting A\u03b2 pathology. This is present in both familial and sporadic AD, making it a more inclusive model. Additionally, the level of A\u03b2 can be controlled, making it an ideal candidate for AD investigation. However, damage to the brain tissue during ICV injection must be minimized to prevent neuronal injury. This requires a highly trained individual or surgeon. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4264", "text": "Intracerebroventricular injection has also been used to test therapeutics and other drugs in animals. Examples of these studies include injection of  bromodeoxyuridine  for proliferation tracing, Apelin-13 for  cerebral ischemia , and \u03b1-interferon for its antiviral and antibiotic properties."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4265", "text": "ICV injection of bromodeoxyuridine (BrdU) has been used to determine the effectiveness of this injection method compared to intraperitoneal administration. BrdU is a widely used marker to detect proliferative cells in the brain. It is assumed that the number of labeled nuclei after BrdU administration is an indicator of the intensity of  cell proliferation . In the study, there was an increase in BrdU-positive nuclei in the parenchyma for ICV injection compared to the levels for  intraperitoneal administration . This indicates a greater level of the tracer is introduced when injected directly into the ventricular cerebrospinal fluid. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4266", "text": "Cerebral ischemia/reperfusion (I/R) injury is the main pathophysiological process present in  ischemic stroke . Apelin regulates many physiological functions including cardiovascular function, endocrine function, nervous system function, and feeding behavior. This regulation occurs through combination with the  APJ receptor , and this system is present in many brain regions. [ 5 ]  In previous studies, lateral ICV injection of Apelin-13 was done to observe apoptosis during cerebral I/R injury. This route of administration allows for the necessary level of Apelin-13 to reach the brain regions that are impacted by ischemia and hypoxia."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4267", "text": "ICV injection of \u03b1-Interferon has been used for the treatment of intracranial malignancies in the clinic. \u03b1-Interferon has antiviral, antibacterial, and immunostimulatory properties. However, severe central nervous system symptoms occur after injection for ICV, intravenous, and intramuscular routes of administration. Additionally, only .09-.18% of the total Interferon dose was seen to pass through the blood-brain barrier when injected intramuscularly. In one study, intraperitoneal injection of \u03b1-Interferon was done on mice and there was no impact on monoamine levels. Another study conducted a similar experiment using the ICV injection method. This study showed reduced monoamine levels in the frontal cortex, in a dose-dependent manner. [ 6 ]  This indicates that ICV injection increases the percentage of the dose that reaches the mouse brain."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4268", "text": "In recent years, gene and  cell therapy  therapeutic options have become increasingly present in the clinic. For some of these therapeutics, the administration of the drug directly into the central nervous system is optimal for the treatment of neurological disorders, while avoiding a severe immune response. Additionally, most of the dose is introduced directly into the target area with ICV injection. [ 7 ]  In addition to these therapies, ICV injection has been used for the delivery of  chemotherapies , treatment of carcinomatous meningitis, and other  neurological disorders ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4269", "text": "In the design of  gene therapies , the proper  adeno-associated virus  (AAV)  serotype  must be selected. AAV is effective at transporting genetic material in vivo, and there are more than 100 serotypes for AAV that have been identified. Each serotype has a different binding capacity to cell surface receptors. Three serotypes have been identified for their promising specificity to the central nervous system. In a 2017 study, AAV2/1, AAVDJ8, and AAV9 were administered to neonatal mice via ICV injection. The brains of these mice were analyzed for GFP expression following this procedure. The results of this showed that AAV2/1 had higher expression in the cortical layers while penetrating less to the midbrain compared to the AAVDJ8 and AAV9 serotypes. The results indicate that ICV injection of AAV vectors is successful for having a lasting expression of the transgene. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4270", "text": "Primary malignant brain tumors (PMBT) and brain metastases have a high impact on patients with both high morbidity and mortality rates. For patients impacted by this, treatment consists primarily of palliative care. However, multimodal therapy using intra-CSF chemotherapy has shown promise in overt leukemic or lymphomatous meningeosis and primary CNS lymphomas. This form of chemotherapy is less toxic while maintaining similar efficacy to cranial irradiation, by preventing the infiltration and proliferation of leukemic and tumor cells into the leptomeninges. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4271", "text": "In a 2019 study, autologous non-genetically modified adipose-derived stromal vascular fraction (ADSVF) was injected into 24 patients using an ICV injection procedure. Seven other patients were injected through ventriculoperitoneal shunts. These seven patients were being treated for varying neurodegenerative disorders including Alzheimer's disease (AD),  amyotrophic lateral sclerosis  (ALS),  progressive multiple sclerosis  (MS-P),  Parkinson's ,  spinal cord injury ,  traumatic brain injury , and stroke. A total of 113 injections were performed on the 31 patients, with one patient having up to 15 injections over three years. Follow-up was conducted for each participant, with varying follow-up times. One patient developed an infection from their implant, and four patients required hospitalization after their injections. Overall, the results indicate that ICV injections, both single and repeat, are safe. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4272", "text": "Intracerebroventricular injection has also been historically used for pain management. These procedures are primarily focused on refractory head and facial pain, peripheral nerve injury, and other persistent pain conditions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4273", "text": "Six patients with either refractory trigeminal neuralgia or cluster headaches were treated with an ICV opiate infusion pump. Visual analog scores (VAS) were obtained before and after injection to measure effectiveness. When compared, VAS scores improved from an average of 7.8 to 2.8 after the procedure. Most complications that occurred from this procedure consisted of nausea and drowsiness. These symptoms went away after the pump was adjusted. ICV pumps are typically kept in and replaced every four to five years, making the procedure ideal for patients with chronic pain. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4274", "text": "The CTK 01512-2 peptide toxin can act as a  voltage-gated calcium channel  (VGCC) blocker. In previous studies, it was shown to have a prolonged effect on preventing and reducing the processing of harmful stimuli by the central nervous system and peripheral nervous system. To strengthen this finding, the CTK 01512-2 toxin was tested on two models of persistent pain. These models include chronic post-ischemia pain (CPIP) and paclitaxel-induced peripheral neuropathy. Additionally, the peptide was injected using three routes of administration: intravenous, intrathecal, and intracerebroventricular. This approach is beneficial for patients who do not respond to traditional pain management approaches. This also addresses the side effects that occur when using opioid agents. The results of this study showed that pain-reducing effects were observed with all three methods of administration. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4275", "text": "The drugs  gabapentin  and  pregabalin  have long since been used for the treatment of neuropathic pain conditions. The mechanism behind the effectiveness of these drugs is not fully known. However, gabapentin and pregabalin were demonstrated to have supraspinal-mediated analgesic effects after peripheral nerve injury. This is due to the noradrenergic pain inhibitory system that is employed by these drugs, coupled with spinal receptors that produce analgesic effects. The results of this study indicate that ICV injection of these drugs decreases thermal and mechanical hypersensitivity in a murine chronic pain model that has partial ligation of the sciatic nerve. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4276", "text": "Many factors must be considered with intracerebroventricular injection to maintain safety. Some of these factors include osmolarity, pH, volume, and the presence of preservatives in the drug solution. Also, intracranial pressure, cerebrospinal fluid bulk flow rate, and buffering capacity have an impact on the distribution and safety of the injected drug. A major concern of ICV injection is neurovascular injury and intracranial hemorrhage. The risk of these conditions increases with each additional injection or \"tap\". For this reason, if repeated taps are needed, a catheter-based device can be implanted. These devices are connected to a subcutaneous reservoir, the most common being the  Ommaya reservoir . This can be accessed multiple times, with a sterile puncture through the scalp into the reservoir. There is also an associated risk of infection with this method, but it is less likely than other methods of accessing the intraventricular space. Other rare complications with this method include leukoencephalopathy, white matter necrosis, and intracerebral hemorrhage. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4277", "text": "Other complications can occur with this procedure, and they can be divided into infectious and noninfectious categories. Of the noninfectious complications, the most frequently reported were CSF leaks, hemorrhage, catheter malposition, catheter obstruction, and device malfunction. In one study, the most likely cause for device removals was due to infectious complications (73.75 percent). Of the infections, the most common cause was skin flora. The aseptic technique during insertion and handling has been shown to decrease the occurrence of these complications. Also, in some cases of infection, antibiotics could be given through the ICV system, avoiding the need for removal. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4278", "text": "The blood-brain barrier protects the brain by restricting the ability of large molecules to cross the barrier between the blood, CSF, and interstitial fluid of the brain. ICV injection circumvents this barrier, to be able to deliver drugs to the CSF. An ICV device is implanted under the scalp, into the subgaleal space where it is then connected to the ventricles with an outlet catheter. This allows for repeated doses of the drug without having to re-puncture the scalp. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4279", "text": "Production of CSF is at a rate of about .3 mL/minute and occurs at the  ependymal  and  parenchymal  regions and the  choroid plexus . Up to 80 percent of CSF production comes from the choroid plexus, which is present within the lateral, third, and fourth ventricles. The choroid is lined with  epithelium  with tight junctions at the ventricular side of the cells. This comprises the blood-CSF barrier. Whereas the blood-brain barrier is made up of vascular endothelium in capillary beds throughout the CNS parenchyma. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4280", "text": "For insertion in mice, a permanent ICV guide cannula must be inserted 1\u00a0mm above the lateral ventricle. A trained surgeon is ideal for insertion, and a stereotaxic frame and bone cement are needed. The cannula is implanted through the hindlimb area of the cerebral cortex. The surgeon must be careful to minimize damage to the surrounding brain tissue during this process. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4281", "text": "A catheter connected to a subcutaneous reservoir is implanted for permanent access in humans. The reservoir used is most commonly the Ommaya reservoir. A 25-gauge needle is used to puncture the scalp into the reservoir. A few milliliters of CSF are withdrawn before injecting the drug. This technique is typically used for long-term drug administration. Rarely will repeated taps be conducted to administer drugs due to the risk of damaging brain tissue. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4282", "text": "Intramuscular injection , often abbreviated  IM , is the  injection  of a substance into a  muscle . In  medicine , it is one of several methods for  parenteral administration  of medications. Intramuscular injection may be preferred because muscles have larger and more numerous  blood vessels  than subcutaneous tissue, leading to faster absorption than  subcutaneous  or  intradermal injections . Medication administered via intramuscular injection is not subject to the  first-pass metabolism  effect which affects oral medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4283", "text": "Common sites for intramuscular injections include the  deltoid muscle  of the upper arm and the  gluteal muscle  of the buttock. In infants, the  vastus lateralis muscle  of the thigh is commonly used. The injection site must be cleaned before administering the injection, and the injection is then administered in a fast, darting motion to decrease the discomfort to the individual. The volume to be injected in the muscle is usually limited to 2\u20135  milliliters , depending on injection site. A site with signs of infection or muscle atrophy should not be chosen. Intramuscular injections should not be used in people with  myopathies  or those with trouble clotting."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4284", "text": "Intramuscular injections commonly result in pain, redness, and swelling or  inflammation  around the injection site. These side effects are generally mild and last no more than a few days at most. Rarely,  nerves  or blood vessels around the injection site can be damaged, resulting in severe pain or  paralysis . If proper technique is not followed, intramuscular injections can result in localized infections such as  abscesses  and  gangrene . While historically aspiration, or pulling back on the syringe before injection, was recommended to prevent inadvertent administration into a vein, it is no longer recommended for most injection sites by some countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4285", "text": "Intramuscular injection is commonly used for medication administration. Medication administered in the muscle is generally quickly absorbed in the bloodstream, and avoids the  first pass metabolism  which occurs with oral administration. [ 1 ]  The medication may not be considered 100%  bioavailable  as it must still be absorbed from the muscle, which occurs over time. [ 2 ] :\u200a102\u2013103\u200a  An intramuscular injection is less invasive than an intravenous injection and also generally takes less time, as the site of injection (a muscle versus a vein) is much larger. Medications administered in the muscle may also be administered as  depot injections , which provide slow, continuous release of medicine over a longer period of time. [ 3 ]  Certain substances, including  ketamine , may be injected intramuscularly for  recreational  purposes. [ 4 ]  Disadvantages of intramuscular administration include skill and technique required, pain from injection, anxiety or fear (especially in children), and difficulty in self-administration which limits its use in  outpatient medicine . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4286", "text": "Vaccines , especially  inactivated vaccines , are commonly administered via intramuscular injection. [ 6 ]  However, it has been estimated that for every vaccine injected intramuscularly, 20 injections are given to administer drugs or other therapy. [ 6 ]  This can include medications such as  antibiotics ,  immunoglobulin , and  hormones  such as testosterone and  medroxyprogesterone . [ 5 ]  In a case of severe allergic reaction, or  anaphylaxis , a person may use an  epinephrine   autoinjector  to self-administer epinephrine into the muscle. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4287", "text": "Because an intramuscular injection can be used to administer many types of medications, specific  contraindications  depend in large part on the medication being administered. [ 8 ]  Injections of medications are necessarily more invasive than other forms of administration such as by mouth or topical and require training to perform appropriately, without which complications can arise regardless of the medication being administered. For this reason, unless there are desired differences in rate of absorption, time to onset, or other pharmacokinetic parameters in the specific situation, a less invasive form of drug administration (usually by mouth) is preferred. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4288", "text": "Intramuscular injections are generally avoided in people with  low platelet count  or clotting problems, to prevent harm due to potential damage to blood vessels during the injection. They are also not recommended in people who are in  hypovolemic shock , or have myopathy or  muscle atrophy , as these conditions may alter the absorption of the medication. [ 5 ]  The damage to the muscle caused by an intramuscular injections may interfere with the accuracy of certain cardiac tests for people with suspected  myocardial infarction  and for this reason other methods of administration are preferred in such instances. [ 5 ]  In people with an active myocardial infarction, the decrease in circulation may result in slower absorption from an IM injection. [ 9 ] :\u200a368\u2013369\u200a  Specific sites of administration may also be contraindicated if the desired injection site has an infection, swelling, or inflammation. [ 9 ] :\u200a368\u2013369\u200a  Within a specific site of administration, the injection should not be given directly over irritation or redness, birthmarks or moles, or areas with scar tissue. [ 9 ] :\u200a368\u2013369"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4289", "text": "As an injection necessitates piercing the skin, there is a risk of infection from  bacteria  or other organisms present in the environment or on the skin before the injection. This risk is minimized by using proper  aseptic technique  in preparing the injection and sanitizing the injection site before administration. [ 9 ] :\u200a369\u200a  Intramuscular injections may also cause an abscess or gangrene at the injection site, depending on the specific medication and amount administered. There is also a risk of nerve or vascular injury if a nerve or blood vessel is inadvertently hit during injection. If single-use or sterilized equipment is not used, there is the risk of transmission of infectious disease between users, or to a practitioner who inadvertently injures themselves with a used needle, termed a  needlestick injury . [ 5 ] [ 9 ] :\u200a372"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4290", "text": "Injections into the deltoid site in the arm can result in unintentional damage to the  radial  and  axillary nerves . In rare cases when not performed properly, the injection may result in shoulder dysfunction. [ 10 ]  The most frequent complications of a deltoid injection include pain, redness, and inflammation around the injection site, which are almost always mild and last only a few days at most. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4291", "text": "The dorsogluteal site of injection is associated with a higher risk of skin and tissue trauma, muscle  fibrosis  or  contracture ,  hematoma , nerve  palsy ,  paralysis , and infections such as  abscesses  and  gangrene . [ 12 ]  Furthermore, injection in the gluteal muscle poses a risk for damage to the  sciatic nerve , which may cause shooting pain or a sensation of burning. Sciatic nerve damage can also affect a person's ability to move their foot on the affected side, and other parts of the body controlled by the nerve. Damage to the sciatic nerve can be prevented by using the ventrogluteal site instead, and by selecting an appropriate size and length of needle for the injection. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4292", "text": "An intramuscular injection can be administered in multiple different muscles of the body. Common sites for intramuscular injection include:  deltoid ,  dorsogluteal ,  rectus femoris ,  vastus lateralis  and  ventrogluteal  muscles. [ 12 ] [ 14 ]  Sites that are bruised, tender, red, swollen, inflamed or scarred are generally avoided. [ 15 ]  The specific medication and amount being administered will influence the decision of the specific muscle chosen for injection."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4293", "text": "The injection site is first cleaned using an antimicrobial and allowed to dry. The injection is performed in a quick, darting motion perpendicular to the skin, at an angle between 72 and 90 degrees. The practitioner will stabilize the needle with one hand while using their other hand to depress the plunger to slowly inject the medication \u2013 a rapid injection causes more discomfort. The needle is withdrawn at the same angle inserted. Gentle pressure may be applied with gauze if bleeding occurs. [ 16 ]  Pressure or gentle massage of the muscle following injection may reduce the risk of pain. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4294", "text": "Aspirating for blood to rule out injecting into a blood vessel is not recommended by the US  CDC ,  Public Health Agency of Canada , or  Norway Institute of Public Health , as the injection sites do not contain large blood vessels and aspiration results in greater pain. [ 18 ] [ 19 ] [ 20 ]  There is no evidence that aspiration is useful to increase safety of intramuscular injections when injecting in a site other than the dorsogluteal site. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4295", "text": "Aspiration was recommended by the  Danish Health Authority  for  COVID-19 vaccines  for a time to investigate the potential rare risk of blood clotting and bleeding, but it is no longer a recommendation. [ 21 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4296", "text": "The Z-track method is a method of administering an IM injection that prevents the medication being tracked through the subcutaneous tissue, sealing the medication in the muscle, and minimizing irritation from the medication. Using the Z-track technique, the skin is pulled laterally, away from the injection site, before the injection; then the medication is injected, the needle is withdrawn, and the skin is released. This method can be used if the overlying tissue can be displaced. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4297", "text": "The deltoid muscle in the outer portion of the upper arm is used for injections of small volume, usually equal to or less than 1\u00a0mL. This includes most intramuscular vaccinations. [ 12 ]  It is not recommended to use the deltoid for repeated injections due to its small area, which makes it difficult to space out injections from each other. [ 12 ]  The deltoid site is located by locating the lower edge of the  acromion process , and injecting in the area which forms an upside down triangle with its base at the acromion process and its midpoint in line with the  armpit . [ 15 ]  An injection into the deltoid muscle is commonly administered using a 1-inch long needle, but may use a  5 \u2044 8 -inch long needle for younger people or very frail elderly people. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4298", "text": "The ventrogluteal site on the hip is used for injections which require a larger volume to be administered, greater than 1\u00a0mL, and for medications which are known to be irritating, viscous, or oily. It is also used to administer  narcotic  medications,  antibiotics ,  sedatives  and  anti-emetics . [ 12 ]  The ventrogluteal site is located in a triangle formed by the  anterior superior iliac spine  and the  iliac crest , and may be located using a hand as a guide. [ 15 ]  The ventrogluteal site is less painful for injection than other sites such as the deltoid site. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4299", "text": "The  vastus lateralis  site is used for infants less than 7 months old and people who are unable to walk or who have loss of muscular tone. [ 12 ]  The site is located by dividing the front  thigh  into thirds vertically and horizontally to form nine squares; the injection is administered in the outer middle square. [ 15 ]  This site is also the usual site of administration for  epinephrine autoinjectors , which are used in the outer thigh, corresponding to the location of the vastus lateralis muscle. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4300", "text": "The dorsogluteal site of the buttock site is not routinely used due to its location near major  blood vessels  and  nerves , as well as having inconsistent depth of  adipose tissue . [ 25 ]  Many injections in this site do not penetrate deep enough under the skin to be correctly administered in the muscle. [ 12 ] [ 26 ]  While current  evidence-based practice  recommends against using this site, many healthcare providers still use this site, often due to a lack of knowledge about alternative sites for injection. [ 27 ]  \nThis site is located by dividing the buttock into four using a cross shape, and administering the injection in the upper outer quadrant. This is the only intramuscular injection site for which aspiration is recommended of the syringe before injection, due to higher likelihood of accidental  intravenous administration  in this area. [ 12 ]  However, aspiration is not recommended by the  Centers for Disease Control and Prevention , which considers it outdated for any intramuscular injection. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4301", "text": "Some populations require a different injection site, needle length, or technique. In very young or weak elderly patients, a normal-length needle may be too long to inject properly. In these patients, a shorter needle is indicated to avoid injecting too deeply. [ 28 ]  It is also recommended to consider using the anterolateral thigh as an injection site in infants under one year old. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4302", "text": "To help infants and children cooperate with injection administration, the  Advisory Committee on Immunization Practices  in the United States recommends using distractions, giving something sweet, and rocking the baby side to side. In people who are overweight, a 1.5-inch needle may be used to ensure the injection is given below the  subcutaneous  layer of skin, while a  5 \u2044 8 -inch needle may be used for people who weigh under 60 kilograms (130\u00a0lb). In any case, the skin does not need to be pinched up before injecting when the appropriate length needle is used. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4303", "text": "Injections into muscular tissue may have taken place as early as the year 500 AD. Beginning in the late 1800s, the procedure began to be described in more detail and techniques began to be developed by physicians. In the early days of intramuscular injections, the procedure was performed almost exclusively by physicians. [ 8 ]  After the introduction of  antibiotics  in the middle of the 20th century, nurses began preparing equipment for intramuscular injections as part of their delegated duties from physicians, and by 1961 they had \"essentially taken over the procedure\". [ 8 ]  Until this delegation became virtually universal, there were no uniform procedures or education for nurses in proper administration of intramuscular injections, and complications from improper injection were common. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4304", "text": "Intramuscular injections began to be used for administration of vaccines for  diphtheria  in 1923,  whooping cough  in 1926, and  tetanus  in 1927. [ 30 ]  By the 1970s, researchers and instructors began forming guidance on injection site and technique to reduce the risk of injection complications and side effects such as pain. [ 8 ]  Also in the early 1970s,  botulinum toxin  began to be injected into muscles to intentionally paralyze them for therapeutic reasons, and later for cosmetic reasons. [ 31 ]  Until the 2000s, aspiration after inserting the needle was recommended as a safety measure, to ensure the injection was being administered in a muscle and not inadvertently in a vein. However, this is no longer recommended as evidence shows no safety benefit and it lengthens the time taken for injection, which causes more pain. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4305", "text": "In animals common sites for intramuscular injection include the  quadriceps , the lumbodorsal muscles, and the triceps muscle. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4306", "text": "Intraosseous infusion  ( IO ) is the process of  injecting   medication , fluids, or blood products directly into the  bone marrow ; [ 1 ]  this provides a non-collapsible entry point into the  systemic venous system . [ 2 ]  The intraosseous infusion technique is used to provide fluids and medication when  intravenous access  is not available or not feasible. Intraosseous infusions allow for the administered medications and fluids to go directly into the vascular system. [ 3 ]  The IO route of fluid and medication administration is an alternative to the preferred  intravascular  route when the latter cannot be established promptly in emergent situations. Intraosseous infusions are used when people have compromised intravenous access and need immediate delivery of life-saving fluids and medications. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4307", "text": "The use of the IV route to administer fluids has been around since the 1830s, and, in 1922,  Cecil K. Drinker  et al. saw that bone, specifically the sternum, could also be used as a route of administration for emergency purposes. [ 4 ]  To continue the expansion of knowledge regarding IO administration, a successful blood transfusion took place in 1940 using the sternum, and afterward, in 1941, Tocantins and O'Neill demonstrated successful vascular access using the bone marrow cavity of a  long bone  in rabbits. [ 4 ]  Because of Tocantins and O'Neill's success in their experiments with rabbits, human clinical trials were established using mainly the  body of the sternum  or the  manubrium  for access. [ 5 ]   Emanuel Papper  and others then continued to advocate, research, and make advances on behalf of the IO administration. [ 6 ]  Once Papper showed that the bone marrow space could be used with comparable success to administer IV fluids and drugs, intraosseous infusion was popularized during World War II to prevent soldiers' deaths via hemorrhagic shock. [ 7 ]  While popular in the field during WWII, the use of IO was not seen as a standard for emergencies until the 1980s, and only so for children. [ 7 ]  With the rise of technology allowing the ease of technique of IO, and a lower risk of complications like bloodstream infections than when using peripheral access, the alternative of IO access has increased throughout the years for adults, as well. [ 7 ]  IO is now recommended in Advanced Cardiac and Pediatric Advanced Life Support treatment protocols, in cases where access via IV cannot be established on time. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4308", "text": "Intraosseous access is indicated in emergency situations, such as when a person experiences some type of major trauma like  shock ,  cardiac arrest , severe  dehydration , [ 8 ]  or severe  gastrointestinal hemorrhage . [ 9 ]   IO access can provide the quickest way to rapidly infuse needed medications and fluids in an emergency situation. [ 8 ]  In people who experience critical trauma and who do not have adequate blood pressure, the IO route doubles the success rate of the peripheral IV route. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4309", "text": "In addition to the emergency clinical scenario that can call for an IO route to be used, IO access is only indicated when access to peripheral veins is either not possible or delayed. When IV access is either not possible or delayed, other indications for utilizing the IO route include administering  contrast  if needed for radiology scans and drawing blood for laboratory testing and analysis. [ 10 ]  Situations that can result in decreased or delayed  access to peripheral veins, and thus necessitate the use of an IO route to infuse medications and fluids include circumstances such as burns, fluid accumulation ( edema ), past IV drug use, obesity, and very low blood pressure. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4310", "text": "An IO infusion can be used on adult or pediatric populations when traditional methods of vascular access are difficult or otherwise cause unwanted delayed management of the administration of medications. The IO site can be used for 24 hours and should be removed as soon as intravenous access has been gained. Prolonged use of an IO site, lasting longer than 24 hours, is associated with  osteomyelitis  (an infection in the bone). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4311", "text": "The needle is inserted through the bone's hard  cortex  and into the soft marrow interior, which allows immediate access to the vascular system. The IO needle is positioned at a 90-degree angle to the injection site, and is advanced through manual traction, impact driven force, or power driven. Each IO device has different designated insertion locations. The most common site of insertion is the antero-medial aspect of the upper, proximal  tibia  as this site lies just under the skin and is easily located. Other insertion sites include the anterior aspect of the  femur , the superior iliac crest, proximal  humerus , proximal tibia, distal tibia and the sternum (manubrium). [ 1 ] \nAlthough intravascular access is still the preferred method for medication delivery in the prehospital area, IO access for adults has become more common. As of 2010, the  American Heart Association  no longer recommends using the  endotracheal tube  (ET) for  resuscitation  drugs, except as a last resort when IV or IO access cannot be gained. [ 1 ]  ET absorption of medications is poor, and optimal ET drug dosings are unknown. IO  administration is becoming more common in civilian and military pre-hospital  emergency medical services  (EMS) systems globally. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4312", "text": "Intraosseous access has roughly the same absorption rate as IV access, and allows for fluid resuscitation. For example,  sodium bicarbonate  can be administered IO during a cardiac arrest when IV access is unavailable. [ 1 ]  High flow rates are attainable with an IO infusion, up to 125 milliliters per minute. This high rate of flow is achieved using a pressure bag to administer the infusion directly into the bone. Large volume IO infusions are known to be painful. 1% lidocaine is used to ease the pain associated with large volume IO infusions in conscious people. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4313", "text": "Like any medical procedure, intraosseous infusion has some potential complications. In a review by Tyler et al., an analysis across the included studies found the overall complication rate associated with IO infusions to be less than 1% (0.9%). [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4314", "text": "Complications include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4315", "text": "Many of these potential complications can be prevented with simple measures like using good technique and keeping the period of IO infusion short by switching to IV as soon as it becomes feasible. [ 14 ]   Bone fracture complications can be decreased by using modern techniques and requiring more regular training in the methods of intraosseous marrow access for infusion. Extravasation can lead to the more serious complication of compartment syndrome. The risk of developing compartment syndrome can be reduced by medical personnel checking the infusion site regularly for any signs of swelling. Swelling could indicate misplacement of the catheter. Avoiding puncturing the same bone in 48 hours can also lessen the risk of developing this complication. The risk of osteomyelitis, while very low ( <1%), can be further lessened by using sterile, hygienic practices and modern devices to make the puncture. Damage to the epiphyseal plate can be avoided by training medical personnel about proper landmarks to be used for determining puncture sites. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4316", "text": "Intraosseous devices allow quick and safe access to the vascular system for fluid and drug administration. After proper education and training, medical professionals can obtain vascular access via the IO route of administration by using one of the multiple devices that have been approved by the FDA for 24-hour use. [ 7 ]  There are several FDA approved IO devices, categorized by their mechanism of action:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4317", "text": "Each device is capable of achieving rapid vascular access, despite the mechanism of action, with insertion times comparable to the IV administration route. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4318", "text": "A comparison of  intravenous \u00a0(IV),  intramuscular \u00a0(IM), and intraosseous\u00a0(IO)  routes of administration  concluded that the intraosseous (IO) route is the preferred method versus intramuscular (IM) and comparable to intravenous (IV) administration in delivering pediatric anaesthetic drugs. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4319", "text": "Intraosseous infusion (IO) is used in pediatric populations during anesthesia when other intravenous access,  central venous catherization  or  venous cutdown , are difficult to use or cannot be used. When individuals are severely ill and need \"rapid, efficient, and safe delivery of drugs\", IO is used. [ citation needed ]  When inserting the intraosseous needle into a conscious individual, this can be very painful. For children, anesthesia is not recommended before this procedure for non-emergency situations. Instead, distracting and holding the child is preferred. Intraosseous infusion is used in instances such as, \"immediate indication/life-threatening emergency, cardiac/respiratory arrest, acute shock, hypothermia, obesity, edema, thermal injury, etc.\" [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4320", "text": "For children, the preferred sites of IO are the distal tibia, proximal tibia, and distal femur. The distal end of the tibia is the preferred site because it is easy to access and the most reliable. Depending on the procedure, a variety of needles are used for IO. For example, \"standard steel hypodermic, butterfly, spinal, trephine, sternal, and standard bone marrow needles are used.\" Needles that have a short shaft are preferred and safe. For infants up to 6 to 8 months old, 18-gauge needles are used and for children more than 8 months old, 15- or 16- gauge needles are used. [ 18 ] \nA study by Glaeser et al., concluded that individuals who received IO vs. peripheral and central intravenous access were able to obtain much faster and more successful IO access. Another study, by Fiorito et al., observed the safety of IO use during the transportation of critically ill pediatric individuals. Based on the results, they concluded that the use of IO was safe, based on 78% successful placement of  the IO needle and complications that occurred in only 12% of the cases. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4321", "text": "Similarly to adults, contraindications for IO infusion use in pediatrics include bone diseases such as osteogenesis imperfecta and osteopetrosis, and fractures. Others include cellulitis, burns, and infections at the access site. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4322", "text": "Intraperitoneal injection  or  IP injection  is the injection of a substance into the  peritoneum  (body cavity). It is more often applied to non-human animals than to humans. In general, it is preferred when large amounts of blood replacement fluids are needed or when low blood pressure or other problems prevent the use of a suitable blood vessel for  intravenous injection . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4323", "text": "In humans, the method is widely used to administer  chemotherapy  drugs to treat some  cancers , particularly  ovarian cancer . Although controversial, intraperitoneal use in ovarian cancer has been recommended as a  standard of care . [ 1 ]  Fluids are injected intraperitoneally in infants, also used for  peritoneal dialysis . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4324", "text": "Intraperitoneal injections are a way to administer therapeutics and drugs through a peritoneal route (body cavity). They are one of the few ways drugs can be administered through injection, and have uses in research involving animals, drug administration to treat ovarian cancers, and much more. Understanding when intraperitoneal injections can be utilized and in what applications is beneficial to advance current drug delivery methods and provide avenues for further research. The benefit of administering drugs intraperitoneally is the ability for the peritoneal cavity to absorb large amounts of a drug quickly. A disadvantage of using intraperitoneal injections is that they can have a large variability in effectiveness and misinjection. [ 2 ]  Intraperitoneal injections can be similar to oral administration in that hepatic metabolism could occur in both."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4325", "text": "There are few accounts of the use of intraperitoneal injections prior to 1970. One of the earliest recorded uses of IP injections involved the insemination of a guinea-pig in 1957. [ 3 ]  The study however did not find an increase in conception rate when compared to mating. In that same year, a study injected egg whites intraperitoneally into rats to study changes in \"droplet\" fractions in kidney cells. The study showed that the number of small droplets decreased after administration of the egg whites, indicating that they have been changed to large droplets. [ 4 ]  In 1964, a study delivered chemical agents such as acetic acid, bradykinin, and kaolin to mice intraperitoneally in order to study a \"squirming\" response. [ 5 ]  In 1967, the production of amnesia was studied through an injection of physostigmine. [ 6 ]  In 1968, melatonin was delivered to rats intraperitoneally in order to study how brain  serotonin  would be affected in the midbrain. [ 7 ]  In 1969, errors depending on a variety of techniques of administering IP injections were analyzed, and a 12% error in placement was found when using a one-man procedure versus a 1.2% error when using a two-man procedure. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4326", "text": "A good example of how intraperitoneal injections work is depicted through \"The distribution of salicylate in mouse tissues after intraperitoneal injection\" because it includes information on how a drug can travel to the blood, liver, brain, kidney, heart, spleen, diaphragm, and skeletal muscle once it has been injected intraperitoneally. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4327", "text": "These early uses of Intraperitoneal injections provide good examples of how the delivery method can be used, and provides a base for future studies on how to properly inject mice for research."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4328", "text": "Currently, there are a handful of drugs that are delivered through intraperitoneal injection for chemotherapy. They are mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluorouracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed, and melphalan. [ 10 ]  There needs to be more research done to determine appropriate dosing and combinations of these drugs to advance intraperitoneal drug delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4329", "text": "There are few examples of the use of intraperitoneal injections in humans cited in literature because it is mainly used to study the effects of drugs in mice. The few examples that do exist pertain to the treatment of pancreatic/ovarian cancers and injections of other drugs in clinical trials. One study utilized IP injections to study pain in the abdomen after a hysterectomy when administering anesthetic continuously vs patient-controlled. [ 11 ]  The results depicted that ketobemidone consumption was significantly lower when patients controlled anesthetic through IP. This led to the patients being able to be discharged earlier than when anesthesia was administered continuously. These findings could be advanced by studying how the route of injection affects the organs in the peritoneal cavity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4330", "text": "In another Phase I clinical trial, patients with ovarian cancer were injected intraperitoneally with dl1520 in order to study the effects of a replication-competent/-selective virus. [ 12 ]  The effects of this study were the onset of flu-like symptoms, emesis, and abdominal pain. The study overall defines appropriate doses and toxicity levels of dl1520 when injected intraperitoneally."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4331", "text": "One study attempted to diagnose  hepatic hydrothorax  with the use of injecting Sonazoid intraperitoneally. Sonazoid was utilized to aid with contrast-enhanced ultrasonography by enhancing the peritoneal and pleural cavities. [ 13 ]  This study demonstrates how intraperitoneal injections can be used to help diagnose diseases by providing direct access to the peritoneal cavity and affecting the organs in the cavity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4332", "text": "In a case of a ruptured hepatocellular carcinoma, it was reported that the patient was treated successfully through the use of an intraperitoneal injection of OK-432, which is an immunomodulatory agent. [ 14 ]  The patient was a 51-year-old male who was hospitalized. The delivery of OK-432 occurred a total of four times in a span of one week. The results of this IP injection were the disappearance of the ascites associated with the rupture. This case is a good example of how IP injections can be used to deliver a drug that can help to treat or cure a medical diagnosis over the use of other routes of delivery. The results set a precedent of how other drugs may be delivered in this way to treat other similar medical issues after further research."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4333", "text": "In 2018, a patient with stage IV ovarian cancer and peritoneal metastases was injected intraperitoneally with 12g of mixed cannabinoid before later being hospitalized. [ 15 ]  The symptoms of this included impairment of cognitive and psychomotor abilities. Because of the injection of cannabis, the patient was predicted to have some level of THC in the blood from absorption. This case presents the question of how THC is absorbed in the peritoneal cavity. It also shows how easily substances are absorbed through the peritoneal cavity after an IP injection."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4334", "text": "Overall, this section provides a few examples of the effects and uses of intraperitoneal injections in human patients. There are a variety of uses and possibilities for many more in the future with further research and approval."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4335", "text": "Intraperitoneal injections are the preferred method of administration in many experimental studies due to the quick onset of effects post injection. This allows researchers to observe the effects of a drug in a shorter period of time, and allows them to study the effects of drugs on multiple organs that are in the peritoneal cavity at once. In order to effectively administer drugs through IP injections, the stomach of the animal is exposed, and the injection is given in the lower abdomen. The most efficient method to inject small animals is a two-person method where one holds the rodent and the other person injects the rodent at about 10 to 20 degrees in mice and 20 to 45 degrees in rats. The holder retains the arms of the animal and tilts the head lower than the abdomen to create optimal space in the peritoneal cavity. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4336", "text": "There has been some debate on whether intraperitoneal injections are the best route of administration for experimental animal studies. It was concluded in a review article that utilizing IP injections to administer drugs to laboratory rodents in experimental studies is acceptable when being applied to proof-of-concept studies. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4337", "text": "A study was conducted to determine the best route of administration to transplant mesenchymal stem cells for colitis. This study compared intraperitoneal injections, intravenous injections, and anal injections. It was concluded that the intraperitoneal injection had the highest survival rate of 87.5%. [ 17 ]  This study shows how intraperitoneal injections can be more effective and beneficial than other traditional routes of administration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4338", "text": "One article reviews the injection of sodium pentobarbital to euthanize rodents intraperitoneally. [ 2 ]  Killing the rodent through an intraperitoneal route was originally recommended over other routes such as inhalants because it was thought to be more efficient and ethical. The article overviews whether IP is the best option for euthanization based on evidence associated with welfare implications. It was concluded that there is evidence that IP may not be the best method of euthenasia due to possibilities of missinjection."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4339", "text": "Another example of how intraperitoneal injections are used in studies involving rodents is the use of IP for micro-CT contrast enhanced detection of liver tumors. [ 18 ]   Contrast agents  were administered intraperitoneally instead of intravenously to avoid errors and challenges. It was determined that IP injections are a good option for Fenestra to quantify liver tumors in mice."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4340", "text": "An example of how intraperitoneal injections can be optimized is depicted in a study where IP injections are used to deliver anesthesia to mice. This study goes over the dosages, adverse effects, and more of using intraperitoneal injections of anesthesia. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4341", "text": "An example of when intraperitoneal injections are not ideal is given in a study where the best route of administration was determined for cancer biotherapy. [ 20 ]  It was concluded that IP administration should not be used over intravenous therapy due to high radiation absorption in the intestines. This shows an important limitation to the use of IP therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4342", "text": "The provided examples show a variety of uses for intraperitoneal injections in animals for in vitro studies. Some of the examples depict situations where IP injections are not ideal, while others prove the advantageous uses if this delivery method. Overall, many studies utilize IP injections to deliver therapeutics to lab animals due to the efficiency of the administration route."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4343", "text": "Intrathecal administration  is a  route of administration  for drugs via an  injection  into the  spinal canal , or into the  subarachnoid space  so that it reaches the  cerebrospinal fluid  (CSF). It is useful in several applications, such as for  spinal anesthesia ,  chemotherapy , or  pain management . This route is also used to introduce drugs that fight certain infections, particularly post-neurosurgical. Typically, the drug is given this way to avoid being stopped by the  blood\u2013brain barrier , as it may not be able to pass into the brain when given orally. Drugs given by the intrathecal route often have to be compounded specially by a pharmacist or technician because they cannot contain any preservative or other potentially harmful inactive ingredients that are sometimes found in standard injectable drug preparations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4344", "text": "Intrathecal pseudodelivery is a technique where the drug is encapsulated in a porous capsule that is placed in communication with the cerebrospinal CSF. In this method, the drug is not released into the CSF. Instead, the CSF is in communication with the capsule through its porous walls, allowing the drug to interact with its target within the capsule itself. This allows for localized treatment while avoiding systemic distribution of the drug, potentially reducing side effects and enhancing the therapeutic efficacy for conditions affecting the central nervous system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4345", "text": "The route of administration is sometimes simply referred to as \"intrathecal\"; however, the term is also an adjective that refers to something occurring in or introduced into the  anatomic space  or  potential space  inside a sheath, most commonly the  arachnoid membrane  of the  brain  or  spinal cord [ 1 ]  (under which is the  subarachnoid space ). For example, intrathecal immunoglobulin production is production of antibodies in the spinal cord. [ 2 ]  The abbreviation \"IT\" is best not used; instead, \"intrathecal\" is spelled out to avoid medical mistakes. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4346", "text": "Intrathecal administration is often used for a single 24-hour dose of analgesia ( opioid  with  local anesthetic ). Caution should be exercised with intrathecal opioids due to the risk of late onset  hypoventilation . The use of intrathecal  morphine  may be limited by severe  pruritus  and  urinary retention . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4347", "text": "Pethidine  has the unusual property of being both a local anaesthetic and opioid  analgesic , which occasionally permits its use as the sole intrathecal anaesthetic agent. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4348", "text": "An intrathecal pump system can be used to deliver a local anaesthetic, and/or an opioid and/or an atypical analgesic agent as  ziconotide ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4349", "text": "Amphotericin B  is administered intrathecally to treat fungal infections involving the central nervous system infections. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4350", "text": "Currently, only four agents are licensed for intrathecal cancer chemotherapy:  methotrexate ,  cytarabine ,  hydrocortisone , and  thiotepa . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4351", "text": "Administration of any  vinca alkaloids , especially  vincristine , via the intrathecal route is nearly always fatal. [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4352", "text": "Often reserved for  spastic cerebral palsy ,  baclofen  can be administered through an  intrathecal pump  implanted just below the skin of the abdomen or behind the chest wall, with a catheter connected directly to the base of the spine. Intrathecal baclofen pumps sometimes carry serious clinical risks, such as infection or a possibly fatal sudden malfunction. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4353", "text": "Treatment of chronic spinal injuries via the administration of  mesenchymal stem cells , [ 8 ]  either from adipose tissue or bone marrow, is experimental, with better results from the former method. Introduction of mesenchymal stem cells promote the microenvironment needed for axonal regrowth and reduction of inflammation caused by astrocytes proliferation and glial scar tissue. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4354", "text": "Animal models have showed improved motor control under the site of injury. A clinical trial also showed statistically significant improved sensitivity under the site of injury in patients. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4355", "text": "Intravaginal administration  is a  route of administration  where the substance is applied inside the  vagina .  Pharmacologically , it has the potential advantage to result in effects primarily in the vagina or nearby structures (such as the  vaginal portion of cervix ) with limited systemic  adverse effects  compared to other routes of administration. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4356", "text": "Formulation methods include vaginal  tablets , vaginal  cream , vaginal gel, [ 4 ] [ medical citation needed ]  vaginal  suppository  and  vaginal ring ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4357", "text": "It is used as an administration method for issues related to women's health, such as contraception. [ 5 ]  Medicines primarily delivered by intravaginal administration include  vaginally administered estrogens  and  progestogens  (a group of hormones including  progesterone ), and  antibacterials  and  antifungals  to treat  bacterial vaginosis  and  yeast infections  respectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4358", "text": "Medicines may also be administered intravaginally as an alternative to  oral route  in the case of  nausea  or other digestive problems. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4359", "text": "It is a potential means of  artificial insemination  (referred to as intravaginal insemination or IVI), sometimes used at home without the presence of a professional. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4360", "text": "This  drug  article relating to the  genito-urinary system  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4361", "text": "Intubation  (sometimes  entubation ) is a medical procedure involving the insertion of a tube into the body. Patients are generally  anesthetized  beforehand. Examples include  tracheal intubation , and the  balloon tamponade  with a  Sengstaken\u2013Blakemore tube  (a tube into the  gastrointestinal tract ). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4362", "text": "An  invasome  is a type of artificial  vesicle   nanocarrier  that transport substances through the skin, the most superficial  biological barrier . Vesicles are small particles surrounded by a  lipid  layer that can carry substances into and out of the cell. Artificial vesicles can be engineered to deliver drugs within the cell, with specific applications within transdermal drug delivery. However, the skin proves to be a barrier to effective penetration and delivery of drug therapies. Thus, invasomes are a new generation of vesicle with added structural components to assist with skin penetration. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4363", "text": "Transdermal  drug delivery (TDD) systems aim to deliver drug therapies topically for local and systemic delivery. They have been gaining increasing attention within the field of drug delivery because of their potential to improve  bioavailability , reduce side effects, and avoid  first pass metabolism , compared to oral medications. However, TDD systems face the challenge of overcoming the barrier of the topmost skin layer, the  stratum corneum . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4364", "text": "Transdermal drug delivery systems are methods to transport drug therapies across the skin barrier. The skin is the largest organ of the body and its primary aim is to protect the body against chemical, thermal, radiation, and microbial threats. However, it is not completely waterproof, allowing some exchange of gas, heat, and fluids from its external environment. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4365", "text": "To effectively shield against external injuries, the skin is composed of several layers: the three distinguishing layers are the  epidermis , the  dermis , and the  subcutaneous layer , or hypodermis. The bottommost layer is the hypodermis. It is primarily composed of  adipose tissue . Next is the dermis, a 3-5 mm thick layer made up of fibrous proteins, an interfibrillar gel, salts, and water. The epidermis is the topmost layer of skin and where vascularization ends. Due to the lack of vascularization, the transfer of fluids, nutrients, and waste across the epidermis occurs through the epidermal-dermal junction. [ 4 ] [ 5 ]  The epidermis is further divided into five layers. From innermost to outermost is the germinative stratum, the spinous stratum, the granular stratum, the lucid stratum, and the stratum corneum. The majority of the epidermis is composed of  corneocytes , which develop from the proliferation, differentiation, and keratinization of  keratinocytes . These fundamental skin cells continually renew as they move upwards toward the surface of the skin. [ 3 ] [ 5 ]  The stratum corneum is a 10-15 \u03bcm thick layer of dead keratin-rich corneocytes tightly packed within a lipid-rich matrix, often described and depicted as a brick-and-mortar structure. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4366", "text": "Penetration of the stratum corneum is recognized as the largest challenge of TDD. Due to its tight cell structure, it is the rate limiting barrier for drug absorption. Thus, several methods of penetrating the stratum corneum have been explored. A couple of common methods include delivery through the intercellular route and the transcellular route. The roundabout, intercellular route seeks to bypass the corneocytes by transporting molecules through the lipid-rich intercellular space between the cells. The transcellular route seeks to transport molecules directly through the cells of the stratum corneum. In this method, molecules must travel through both corneocytes and the intercellular lipid space. The method of choice is dependent on physical and chemical properties of the transporting compounds; however, the intercellular route is the most common. Thus, the intercellular lipid barrier has been a subject of investigation to allow for greater understanding of how to develop transportation mechanisms of molecules through the stratum corneum. [ 3 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4367", "text": "In recent decades, due to the increasing use of therapeutic medications through transdermal pathways, techniques for improving permeation through the stratum corneum have been explored. The primary two routes of exploration have been chemical and physical penetration-enhancing mechanisms. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4368", "text": "A brief overview of physical penetration methods are summarized in the table below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4369", "text": "Chemical characteristics to enhance drug delivery include incorporating salt formations, drug-ion pairs, eutectic mixtures, chemical penetration enhancers, and utilizing  liposomal vesicles . [ 13 ]  Vesicles have shown the ability to be paired with current physical penetration techniques to synergistically improve drug penetration. [ 2 ] [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4370", "text": "Other vesicular systems, such as  liposomes  and  ethosomes , have already been extensively researched and utilized as drug transporters, but the penetration barrier has resulted in studies to modify current vesicles to add characteristics for improved penetration of the stratum corneum. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4371", "text": "Invasome vesicular systems are artificial vesicles composed of  phospholipids ,  terpene , and  ethanol . [ 1 ]  A phospholipid  bilayer  creates the external structure of the spherical particle. Within the bilayer are terpenes. Terpenes are naturally-occurring hydrocarbon chains that are commonly used in aromatics and scent products, but also have been used for the development of pharmaceuticals. Within the center of the terpene-and-phospholipid bilayer is a core that contains an aqueous hydroethanolic solution, along with the relevant drug. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4372", "text": "Compared with other vesicular systems, the terpenes and ethanol function synergistically to increase the flexibility of invasomes, which allows for a softer, fluidic structure that increases penetration efficacy of the skin barrier. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4373", "text": "Terpenes are known to be effective  penetration enhancers . They function in invasomes by breaking apart the tight phospholipid structure of the stratum corneum, increasing the permeability of the intercellular space. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4374", "text": "Like terpenes, ethanol has also been shown to disrupt the lipid structure of the stratum corneum, as well as loosening the invasome phospholipid bilayer. Ethanol also softens the lipids which increases the deformability of invasomes, allowing them to flatten to travel through the tight intercellular spaces of the skin. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4375", "text": "The terpenes and ethanol have been shown to loosen the invasome's phospholipid structure, allowing some of the terpenes and ethanolic solution to leak out of the invasome. There, they also separate the lipids of the stratum corneum. The smaller, flexible invasome is then able to travel intercellularly, passing through the stratum corneum to the viable cell layer where the drug is released and reaches systemic circulation. Thus, the terpenes and ethanol work in conjunction to both break up the phospholipids of the invasome they inhabit so they can pass through, as well as loosen the tight cellular matrix of the stratum corneum, giving the already-flexible invasomes an increased penetration ability. [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4376", "text": "Several preparation techniques of invasomes exist, but the most commonly used techniques are mechanical dispersion and thin-film hydration. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4377", "text": "During lipid dispersion, the lipid and organic solvent are added with a drug of choice; then the solution is vortexed and sonicated for five minutes. PBS is added to the solution with additional vortexing, and then an aqueous buffer is used to hydrate the mixture. The spontaneous swelling of the lipids then creates the invasome vesicles, which are finally sonicated,  lyophilized , and experience high-pressure extrusion. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4378", "text": "During thin-film hydration, also known as the conventional film method, [ 16 ]  lipids and drugs are added to ethanol and sonicated. A rotary flash evaporator is used to dry the mixture; nitrogen gas is used to remove harmful residual solvent. The resulting thin lipid films are hydrated using a  PBS , and after cooling the terpene mixture is added to form the invasomes. Finally, the invasome solution is vortexed and ultrasonicated. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4379", "text": "Invasomes have been considered in a range of applications. Apart from cosmetics, they are increasingly becoming a part of pharmaceuticals and drug delivery research. Areas for use include delivery of  immunosuppressive , anticancer, antiacne, contraceptive, erectile dysfunction,  antihypertensive ,  alopecia , and  antipsychotic  drug therapies. [ 18 ] [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4380", "text": "Invasomes can be paired with transdermal delivery methods to target the skin barrier. Examples of these techniques include  transdermal patches ,  microneedles , and creams."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4381", "text": "Transdermal patches are medicated adhesives that can be applied to the skin. Compared to conventional hypodermic needles and oral delivery methods, patches allow for controlled release of drugs through the skin using built-in release mechanisms that allow drug reservoirs to discharge. Additionally, patches can be paired with microneedles to increase drug absorption. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4382", "text": "Microneedles are minimally invasive arrays of needles that bypass the stratum corneum. They can range in length from a few micrometers up to 2000 \u03bcm, with the needles existing in several forms: solid, coated, dissolving, hollow, and hydrogel-forming. [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4383", "text": "Medical creams have been used for centuries due to their relative simplicity, ease of preparation, and ease of use. They are medically-treated, semi-solid formulations for topical drug delivery. Benefits of creams include increased  patient compliance  and avoidance of first pass metabolism. [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4384", "text": "Isotropic formulations  are  thermodynamically  stable  microemulsions  possessing  lyotropic liquid crystal  properties. [ 1 ]  They inhabit a state of matter and physical behaviour somewhere between conventional  liquids  and that of solid  crystals . [ 2 ]  Isotropic formulations are  amphiphillic , exhibiting selective synchronicity with both the water and  lipid  phases of the substrate to which they are applied. [ 3 ]  Most recently, isotropic formulations have been used extensively in  dermatology  for drug delivery. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4385", "text": "While it is well established that the skin provides an ideal site for the administration of local and systemic  drugs , it presents a formidable barrier to the permeation of most substances. [ 5 ]  Isotropic formulations have been used to deliver drugs locally and systemically via the skin appendages, intercellular and transcellular routes. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4386", "text": "Limb perfusion  is a medical technique that is used to deliver drugs locally directly to a site of interest. It is commonly used in human medicine for administration of  anticancer drugs  directly to an  arm  or  leg . It is also used in  veterinary medicine  to deliver drugs to a site of infection or injury, as well as for the treatment of cancer in dogs. In both cases, a  tourniquet  is used to reduce blood flow out of the area that is being treated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4387", "text": "Isolated limb perfusion was first introduced into the clinic by American surgeons from New Orleans in the mid-1950s. The main purpose of the isolated limb perfusion technique is to deliver a very high dose of chemotherapy, at elevated temperature, to tumour sites without causing overwhelming systemic damage. (Unfortunately, while these approaches can be useful against solitary or limited metastases, they are - by definition - not systemic and therefore do not treat distributed metastases or  micrometastases ). The flow of  blood  to and from the  limb  is temporarily stopped with a  tourniquet , and anticancer drugs are put directly into the blood of the limb. This allows the person to receive a high dose of drugs in the area where the  cancer  occurred. The temperature is also increased to 42C causing an increased uptake of the drug by the tumor.  The combination of high drug dose and high temperature is toxic systemically, thus the isolation of the limb.  Blood flow through the limb is typically achieved using an extracorporeal circuit consisting of cannulae, tubing, peristaltic roller pump, heat exchanger, and pressure monitoring/safety devices.  Care must be used in handling the drugs and waste material as they are extremely toxic.  Among other types of cancer, isolated limb perfusion has been used to treat in transit metastatic melanoma. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4388", "text": "In the early 1990s an alternative technique was developed at the Royal Prince Alfred Hospital in Sydney, Australia: isolated limb infusion. This technique is less complex and uses a minimal invasive percutaneous approach to circulatorily isolate a limb."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4389", "text": "Limb perfusion is also used in veterinary medicine, where is it usually referred to as  regional limb perfusion  (RLP). It is most commonly used in large animals, such as horses, cows, small ruminants, and camelids. These species often require large, cost-prohibitive doses of medications to treat  systemically . Regional limb perfusion allows drug dose to be reduced while maintaining therapeutic concentrations at the site of interest, thereby reducing the cost of treatment, localizing application, decreasing systemic side effects, and improving efficacy. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4390", "text": "Horses are sedated and the procedure is performed standing. [ 3 ]  Horses must be sedated, because movement can force blood past the tourniquet and reduce the concentration of drug below the site of the tourniquet. The area of needle insertion is clipped and scrubbed. A wide tourniquet is placed above the site of interest, and a needle inserted into a superficial vein of the limb below the tourniquet. The medication is delivered and the tourniquet is removed after 20\u201330 minutes. Because of the size of the limbs, RLP is not possible above the elbow or stifle of a horse because of inadequate compression of the underlying blood vessels."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4391", "text": "Limb perfusion is commonly used for antibiotic administration in cases of localized infection, such as lacerations,  cellulitis , infection of a synovial structure (joint, tendon sheath, bursa), or  osteomyelitis . [ 4 ] [ 5 ]  RLP has been shown to produce antibiotic concentrations 25-50 times the  minimum inhibitory concentration  in septic joints. [ 6 ]  Antibiotic selection is important. Antibiotics must be approved for intravenous use, and are ideally chosen based on  culture and susceptibility  results.  Concentration-dependent antibiotics , such as gentamicin and amikacin, are best suited for RLP because they have higher efficacy at higher concentrations, while time-dependent antibiotics such as penicillin and ceftiofur may be used, but have a shorter duration. [ 7 ]  However, expense is usually less of a limiting factor because a smaller amount may be used relative to systemic administration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4392", "text": "Limb perfusion of carbapenem antibiotics such as imipenem and meropenem have been studied in horses. [ 8 ] [ 9 ]  However, a retrospective study comparing horses that received meropenem via RLP for orthopedics sepsis to a group of horses that received gentamicin via RLP for the same condition had no differences in outcome. [ 10 ]  This suggests that initial RLP treatments should utilize less critically important antimicrobials for initial RLP treatment such a gentamicin, instead of critically important antimicrobials, such as meropenem. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4393", "text": "In the case of  lameness  in horses, local use of regenerative therapies, such as  stem cells , [ 12 ]  or bisphosphonates such as  tiludronic acid [ 13 ]  are also given by RLP."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4394", "text": "In dogs, RLP is also used to deliver chemotherapeutic agents. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4395", "text": "Side effects of RLP are relatively rare when performed correctly. Partial thrombosis of a vein can occur, especially with repeated use of a vein, but complete thrombosis is rare. There may also be localized tissue irritation. Topical application of an anti-inflammatory, such as  DMSO  or  Diclofenac sodium  may be used."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4396", "text": "The  Macy Catheter  is a specialized  catheter  designed to provide comfortable and discreet administration of ongoing medications via the  rectal  route. The catheter was developed to make rectal access more practical and provide a way to deliver and retain liquid formulations in the  distal  rectum so that health practitioners can leverage the established benefits of rectal  administration . Patients often need medication when the  oral route  is compromised, and the Macy Catheter provides an alternative for those medications that can be prescribed per rectum. The Macy Catheter is of particular relevance during the  end of life , when it can help patients to remain comfortable in their home. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4397", "text": "The Macy Catheter is a disposable device approved by the U.S.  Food and Drug Administration  (FDA), consisting of a dual-porl-lumen ballooned tube that is inserted by a  clinician  into the  rectum  just past the rectal  sphincter . Once inserted into the rectum, a soft balloon is inflated with water via a balloon inflation valve to hold the device in place. This small, flexible \"semi-retention\" balloon exerts very little pressure on the rectal wall, and is designed for safety and comfort, while also allowing the catheter to be easily expelled when the patient needs to  defecate . The catheter utilizes a small flexible  silicone  shaft, allowing the device to be placed safely and remain comfortably in the rectum for repeated administration of medications or liquids."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4398", "text": "Once in place, the medication delivery port of the Macy Catheter rests on the patient's leg or abdomen, where it is easily accessible for repeated administration of liquid medications in  solution  or  suspension  form. The device stays in place until the patient has a  bowel movement  and expels the retention balloon, or until manually removed after first deflating the balloon."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4399", "text": "The Macy Catheter medication port has a specialized  valve  to prevent leakage and is designed to be non-clogging and compatible only with the connectors on oral/ enteral   syringes  (not luer syringes) for safety. The device is FDA-approved to remain in the rectum for up to 28 days. The catheter has a small  lumen , allowing for small flush volumes to get medication to the rectum. Small volumes of medications (under 15ml) improve comfort by not stimulating the  defecation  response of the rectum, and can increase the overall  absorption  of a given  dose  by decreasing pooling of medication and migration of medication into more  proximal  areas of the rectum where absorption can be less effective. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4400", "text": "The Macy Catheter is intended to provide rectal access to administer liquids and medications. The Macy Catheter can be used in the following clinical situations:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4401", "text": "The Macy Catheter provides an immediate way to administer medication or liquids for patients in the home setting when the oral route of medication administration is compromised. Unlike  intravenous  lines, which usually need to be placed in an  inpatient  environment and require special formulation of  sterile  medications, [ 7 ]  the Macy Catheter can be placed by a clinician, such as a  hospice  nurse or home health nurse in the home. Many oral forms of medications can be crushed and suspended in water to be given via the Macy Catheter. The Macy Catheter is useful for patients who cannot swallow, including those near the end of life (an estimated 1.65 million people are in  hospice  care in the US each year [ 8 ] ). Because the Macy Catheter enables a rapid, safe, and lower cost alternative to administration of medications, [ 9 ]  it may also be applicable to care of patients in  long-term care  or  palliative care , or as an alternative to  intravenous  or  subcutaneous  medication delivery in some instances."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4402", "text": "The Macy Catheter is clinically indicated for the following scenarios:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4403", "text": "1.  Symptom  management at the  end of life , [ 10 ]  including but not limited to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4404", "text": "2.  Bowel obstruction"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4405", "text": "3. Discharge from  acute care  to the home setting"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4406", "text": "The Macy Catheter was invented by Brad Macy, RN, BSN, a 22-year veteran  hospice  nurse. Inspired by a patient who was terminally agitated and not responding to a solid form of a rectally delivered medication, Macy administered the same medication in a liquid suspension with a small tube inserted into the patient's  rectum . The patient's agitation rapidly diminished, and the patient was sleeping within 30 minutes. [ 11 ]  After practicing repeated successful interventions involving the application of medication in highly concentrated form to the  distal  one-third of the  rectum , Macy realized the potential implications for  hospice  and  palliative  patients worldwide. With this motivation, he proceeded to develop the Macy Catheter, a device designed and developed for commercial use. [ 12 ]  The commercial product is protected by two issued U.S. patents and received 510(k) clearance from the  Food and Drug Administration  in early 2014. [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4407", "text": "Rectal  drug delivery is an effective route of medication delivery for many medications used at the  end of life . [ 15 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ] [ 20 ] [ 21 ]  The walls of the rectum absorb many medications quickly and effectively. [ 22 ]  Medications delivered to the distal one-third of the rectum at least partially avoid the \"first pass effect\" through the liver, which allows for greater bio-availability of many medications than that of the oral route."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4408", "text": "The rectal route of administration is highly effective as the rectal  mucosa  is highly  vascularized  tissue that allows for rapid and effective absorption of medications. [ 23 ]  Although  intravenous  administration is the most commonly used alternate route in  acute care  settings, [ 24 ]  it is rarely used in  hospice care , given the associated cost and need for a high level of care and training for providers. [ 25 ]  It can also lead to complications such as  infection  and pain. [ 26 ]  Although subcutaneous medication delivery is more common in hospice, it is also expensive and can cause infection, pain and  swelling . [ 27 ]  The rectal route of administration is highly effective as the rectal mucosa is highly vascularized tissue that allows for rapid and effective absorption of medications. [ 28 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ] [ 33 ] [ 34 ]  The Macy Catheter provides a solution to overcome the challenges and leverage the benefits of  rectal administration ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4409", "text": "Magnetic-targeted carriers , also known as MTCs or magnetic vehicles, are micro- or nanoparticles that carry an  anticancer drug  to the target site by using an external magnetic field and field gradient to direct the desired drug. Usually, the complex involves microscopic beads of activated carbon, which bind the anticancer drug. A  magnet  applied from outside the body then can direct the drug to the  tumor  site. This can keep a larger dose of the drug at the tumor site for a longer period of time, and help protect healthy tissue from the  side effects of chemotherapy .  [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4410", "text": "The use of MTCs as therapeutic agents for oncology treatment has been increasing exponentially over the past decade. Currently the magnetic vehicle composition relies on the properties of the magnetic component, which is usually ferromagnetic, ferrimagnetic or superparamagnetic, owing to their ability of expressing strong magnetization in the same direction of the external magnetic field while also retaining their magnetization once the external magnetic field is removed.  [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4411", "text": "Magnetic vehicles have been focusing on the particle size, aiming to have the MTCs in the nanoscale, which is mainly due to the fact that ferromagnetic and ferrimagnetic materials show remnant magnetization with and without the external magnetic field, which in turn causes particle aggregation complications. Very small nanoparticles exhibit superparamagnetic properties, which are able to obtain a high degree of magnetization while being able to avoid the particle aggregation issue caused by remnant magnetization. Iron oxide is a common metal used for this purpose, which is usually used as magnetite, maghemite or a combination of the two, due to their high magnetization values between the different iron oxides. Iron oxide gives the impression of lacking remnant magnetization even though magnetite and maghemite are ferromagnetic due to thermal fluctuations, which mostly accounts for the internal interactions of the particles affecting energy densities. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4412", "text": "MTCs carry the drug molecules to the tumor site by either having them bound to the surface or by being enclosed within the magnetic vehicle, which can be referred to as the MTC-drug complex. Magnetic-targeted carriers possess unique intrinsic properties, developing magnetic polarization and magnetophoretic mobility once the external magnetic field and field gradient are applied. Selective application of the magnetic field gradient is applied to the target area, which in turn guides the MTC-drug complex to the desired location with a relatively high degree of accuracy, minimum surgical intervention and maximum dose. In order to be able to successfully deliver the drug at the desired tumor location, the magnetic vehicles are responsive to a specific tumor signal, which is commonly a temp- or pH-sensitive release due to the higher temperature and lower pH observed in tumor microenvironments, relative to the rest of the body. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4413", "text": "Different requirements exist for magnetic nanoparticles involved in site-specific targeting, which are dependent on either physical or biological reasons. The nine different main requirements the magnetic-targeted carrier should possess are the following: 1) Sufficient magnetic moment to overcome drag and yield forces. 2) Superparamagnetism to prevent agglomeration and embolism. 3) Biocompatibility to prevent toxicity, enhance cell survival and reduce inflammatory responses. 4)  Biodegradability  to improve clearance from the body. 5) Capability to act as a carrier and exhibit controlled sustained release. 6) Structural stability to allow delivery of therapeutic agents after reaching target site. 7) Stealth and functional surface characteristics to prolong the circulation half-life, improve colloidal stability, prevent agglomerations and reduce toxicity. 8) Reproducible sizes and shapes for clinical applications 9) Reproducible and scalable methods to allow mass production. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4414", "text": "The most common current clinical application involving a MTC-drug complex is the doxorubicin-magnetic targeted carrier complex, which is composed of a formulation of the anthracycline antibiotic doxorubicin and is bound to microscopic beads of activated carbon. Iron is used as the magnetic-targeted carrier.  [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4415", "text": "Magnetic vehicles started being used for drug delivery purposes of chemotherapeutic agents around 1960\u20131970. MTCs composition has varied over the years and differed between in-vitro and in-vivo studies. Dr. Widder synthesized albumin microspheres in the 1970s encasing Adriamycin, a chemotherapeutic drug, and used magnetite as the susceptible magnetic component to the external magnetic field. One of the first in vivo experiments using magnetic vehicles performed in humans was done by John F. Alksne and his associates in the 1960s, using carbon-coated iron and applied an external magnetic field in order to occlude intracranial aneurysms, which was considered a successful therapeutic once the X-ray results were analyzed. Currently, magnetic nanoparticles, such as iron oxide, take advantage of their multimodality since they can integrate various functionalities, such as imaging agents, targeted-delivery and induce hyperthermia. In addition, iron oxide nanoparticles are being tested in emerging medical fields, such as multimodal imaging, theranostics and image-guided therapies.  [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4416", "text": "Microdispensing  is the technique of producing liquid media dosages in volumes of less than one microlitre. The continuing miniaturization in almost all technical areas creates constant challenges for industry, development and research facilities. Microdispensing is one of those challenges. Ever smaller amounts of adhesive, liquid, oil, grease and a multitude of other media must be dispensed reliably and accurately in dosage and placement with short cycle times.  The precise positioning and quantity of fluids such as glue, reagents or any other substance has a great influence on the overall quality of a medical device. A few examples are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4417", "text": "Microdispensing is also used in non-medical applications, like on-demand soda flavoring (the  Coca-Cola Freestyle  and  Pepsi Spire ),  inkjet printing , and  3-D printing ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4418", "text": "There are two basic types of dispensing techniques: classic contact dispensing and non-contact dispensing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4419", "text": "In contact dispensing, the drop forms at the exit of a nozzle, and is deposited by contact, while the drop is still on the nozzle. The technique is as old as the wish to divide a medium, stored in a big container, into smaller amounts. A good example for this is applying adhesive with a tube: To apply the adhesive requires contact between the tip of the tube and the part for the bead of adhesive to be transferred. This method has disadvantages:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4420", "text": "Despite all of these disadvantages, contact dispensing is still used in the majority of automated processes today, because  of:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4421", "text": "Gear pump"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4422", "text": "Pressure-time systems"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4423", "text": "In non-contact dispensing, the drop also forms at the end of a nozzle, but far enough away from the target area that the drop separates from the nozzle before it hits. This, too, is a very old technique, as old as squirting liquid from a tube."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4424", "text": "Because of increasing requirements in regards to cycle time and accuracy in almost all areas of production, non-contact dispensing is constantly gaining importance. A good example for this is the attachment of very small electronic parts (SMD parts) onto printed circuit boards and substrates. For this, the part carrier only needs to be positioned in one plane - after that the adhesive can be transferred without contact. The following examples show the advantages of non-contact dispensing:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4425", "text": "Non-contact dispensing can be divided in two different methods:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4426", "text": "Jet-forming dispensing exists when the flow velocity of a medium at the nozzle exit is high enough that the effects of gravitation and surface tension on the separation of the fluid from the nozzle are of secondary importance. This state is characterized by the  Weber number :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4427", "text": "where"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4428", "text": "The physical border line between drop- and jet-forming is around a Weber-number of 8. At this point the dynamic pressure of the flowing medium exceeds the pressure from the surface tension of the drop, which therefore sticks to the nozzle. This transitional stage can be demonstrated at a water tap by gradually increasing the flow, going from the dropping status until a continuous water jet has formed. The Weber-number in this case is, however, clearly above 8, because of the jet exit conditions of the nozzle."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4429", "text": "By using the Weber-number, the theoretical lower limit of the mass flow can be found for the jet-forming conditions. In actual applications, to assure a safe dispensing process, the real Weber-numbers chosen should be between 20 and 50."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4430", "text": "For a calculated estimation of the fluid flow velocity in the nozzle, for fluids with Newtonian flow behavior, the formula for capillary fluid flow according to the  Hagen\u2013Poiseuille law  has been proven."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4431", "text": "To avoid atomizing of the fluid at the nozzle exit, the fluid flow in the nozzle must be laminar, which is the case as long as the  Reynolds number  (Re) of the nozzle is smaller than the  critical Reynolds-number  of the nozzle:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4432", "text": "Reynolds-number of the nozzle:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4433", "text": "Critical Reynolds-number of the nozzle:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4434", "text": "Thus, the theoretical range of the jet-forming dispension is enclosed at its lower limit by the Weber-number and at its upper limit by the critical Reynolds-number. For practical applications, a high kinetic energy in the fluid jet is not desirable, because the jet probably would burst and spatter tiny droplets around the target point. Jet-forming dispensing systems are therefore usually operated in the area of lower Weber-numbers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4435", "text": "In practice, the calculation of the Weber-number becomes more complicated when fluids with additives are used, which demonstrate a non-Newtonian (i.e. thixotropic) flow behavior and therefore the viscosity during the flow through the nozzle is different."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4436", "text": "Dynamic drop dispensing is characterised by separation of a drop from the nozzle exit through a dynamic process, because the static pressure of the liquid medium is insufficient for forming a fluid jet."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4437", "text": "A well-known example is  inkjet printing . In this application, the volume of a small dispensing chamber with adjoining nozzle becomes reduced through a short impulse, whereby the ink is ejected through the nozzle. Nozzle chamber, nozzle and ink reservoir are hereby fluidically connected without any valve in between. During the dispensing process, some of the medium is also flowing in the reverse direction (back into the reservoir). The surface tension of the fluid at the nozzle exit prevents air being sucked in and fluid from exiting the nozzle when the dispensing chamber is filled up again. The principle of this process is only useful for low-viscosity fluids and this principle is not applicable with higher fluid pressures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4438", "text": "Ink-jet systems have the following inherent properties:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4439", "text": "\u2022\tVery small single-drop volumes are achievable (8 picolitres) \n\u2022\tHigh dispensing frequencies can be realised (some kHz) \n\u2022\tLow costs for mass production \n\u2022\tOnly certain low-viscosity media are dispensable (i.e. no volatile media) \n\u2022\tPrincipally not leak-proof"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4440", "text": "For industrial production, the dispensing amounts and the range of viscosity spectra of ink-jet systems for most applications are too small. In these fields of production, specially-designed valves with tappet drives of high dynamic pressure are used instead. These microdispensing systems are characterised by the following properties:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4441", "text": "\u2022\tSingle drop volumes from 10 to 200 nanolitres \n\u2022\tDispensing frequencies up to 100\u00a0Hz \n\u2022\tDispensing accuracy < 1% \n\u2022\tMedia viscosities up to 200 Pa\u00b7s (thixotropic)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4442", "text": "Mucoadhesion  describes the attractive forces between a biological material and  mucus  or  mucous membrane . [ 1 ]  Mucous membranes adhere to epithelial surfaces such as the gastrointestinal tract (GI-tract), the vagina, the lung, the eye, etc. They are generally  hydrophilic  as they contain many hydrogen macromolecules due to the large amount of water (approximately 95%) within its composition. However, mucin also contains  glycoproteins  that enable the formation of a gel-like substance. [ 1 ]  Understanding the hydrophilic bonding and adhesion mechanisms of mucus to biological material is of utmost importance in order to produce the most efficient applications. For example, in  drug delivery  systems, the mucus layer must be penetrated in order to effectively transport micro- or nanosized drug particles into the body. [ 2 ]   Bioadhesion  is the mechanism by which two biological materials are held together by interfacial forces. The mucoadhesive properties of  polymers  can be evaluated via rheological synergism studies with freshly isolated  mucus , tensile studies and mucosal residence time studies. Results obtained with these in vitro methods show a high correlation with results obtained in humans. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4443", "text": "Mucoadhesion involves several types of  bonding  mechanisms, and it is the interaction between each process that allows for the adhesive process. The major categories are wetting theory, adsorption theory, diffusion theory, electrostatic theory, and fracture theory. [ 5 ]  Specific processes include mechanical interlocking, electrostatic, diffusion interpenetration, adsorption and fracture processes. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4444", "text": "Wetting theory :  Wetting  is the oldest and most prevalent theory of adhesion. The adhesive components in a liquid solution anchor themselves in irregularities on the substrate and eventually harden, providing sites on which to adhere. [ 6 ]  Surface tension effects restrict the movement of the adhesive along the surface of the substrate, and is related to the thermodynamic work of adhesion by  Dupre's Equation . [ 6 ]  Measuring the affinity of the adhesive for the substrate is performed by determining the contact angle. Contact angles closer to zero indicate a more wettable interaction, and those interactions have a greater spreadability. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4445", "text": "Adsorption theory :  Adsorption  is another widely accepted theory, where adhesion between the substrate and adhesive is due to primary and secondary bonding. [ 5 ]  The primary bonds are due to chemisorption, and result in comparatively long lasting covalent and non-covalent bonds. Among covalent bonds disulfide bonds are likely most important. Thiolated polymers \u2013 designated  thiomers  \u2013 are mucoadhesive polymers that can form disulfide bonds with cysteine-rich subdomains of mucus glycoproteins. [ 7 ]  Recently several new classes of polymers have been developed that are capable of forming covalent bonds with mucosal surfaces similarly to thiomers. These polymers have acryloyl, methacryloyl, maleimide, boronate and N\u2010hydroxy (sulfo) succinimide ester groups in their structure. [ 8 ]  Among non-covalent bonds likely ionic interactions such as interactions of mucoadhesive chitosans with the anionically charged mucus  [ 9 ]  and  Hydrogen bonding  are most important. [ 10 ]  The secondary bonds include weak  Van Der Waals  forces, and interactions between  hydrophobic  substructure. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4446", "text": "Diffusion theory : The mechanism for  diffusion  involves polymer and mucin chains from the adhesive penetrating the matrix of the substrate and forming a semipermanent bond. [ 6 ]  As the similarities between the adhesive and the substrate increase, so does the degree of mucoadhesion. [ 5 ]  The bond strength increases with the degree of penetration, increasing the adhesion strength. [ 11 ]  The penetration rate is determined by the  diffusion coefficient , the degree of flexibility of the adsorbate chains,  mobility  and contact time. [ 10 ]  The diffusion mechanism itself is affected by the length of the molecular chains being implanted and cross-linking density, and is driven by a  concentration gradient . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4447", "text": "Electrostatic theory : is an  electrostatic  process involving the transfer of electrons across the interface between the substrate and adhesive. [ 6 ]  The net result is the formation of a double layer of charges that are attracted to each other due to balancing of the Fermi layers, and therefore cause adhesion. [ 10 ]  This theory only works given the assumption that the substrate and adhesive have different electrostatic surface characteristics. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4448", "text": "Fracture theory :  Fracture  theory is the major mechanism by which to determine the  mechanical strength  of a particular mucoadhesive, and describes the force necessary to separate the two materials after mucoadhesion has occurred. [ 10 ]   Ultimate tensile strength  is determined by the separating force and the total surface area of the adhesion, and  failure  generally occurs in one of the surfaces rather than at the interface. [ 5 ]  Since the fracture theory only deals with the separation force, the diffusion and penetration of polymers is not accounted for in this mechanism. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4449", "text": "The mucoadhesive process will differ greatly depending on the surface and properties of the adhesive. However, two general steps of the process have been identified: the contact stage and the consolidation stage. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4450", "text": "The contact stage is the initial  wetting  that occurs between the adhesive and membrane. This can occur mechanically by bringing together the two surfaces, or through the bodily systems, like when particles are deposited in the nasal cavity by inhalation. The principles of initial  adsorption  of small molecule adsorbates can be described by  DLVO theory . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4451", "text": "According to  DLVO theory , particles are held in suspension by a balance of attractive and repulsive forces. This theory can be applied to the adsorption of small molecules like mucoadhesive polymers, on surfaces, like mucus layers. Particles in general experience attractive  van der Waals forces  that promote  coagulation ; in the context of  adsorption , the particle and mucus layers are naturally attracted. The attractive forces between particles increases with decreasing particle size due to increasing surface-area-to-volume ratio. This increases the strength of van der Waals interactions, so smaller particles should be easier to adsorb onto mucous membranes. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4452", "text": "DLVO theory  also explains some of the challenges in establishing contact between particles and mucus layers in mucoadhesion due to their repulsive forces. Surfaces will develop an  electrical double layer  if they are in a solution containing ions, as is the case with many bodily systems, creating electrostatic repulsive forces between the adhesive and surface.  Steric effects  can also hinder particle adsorption to surfaces.  Entropy  or disorder of a system will decrease as polymeric mucoadhesives adsorb to surfaces, which makes establishing contact between the adhesive and membrane more difficult. Adhesives with large surface groups will also experience a decrease in entropy as they approach the surface, creating repulsion. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4453", "text": "The initial adsorption of the molecule adhesive will also depend on the  wetting  between the adhesive and membrane. This can be described using Young's equation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4454", "text": "cos \n \u2061 \n ( \n \u03b8 \n ) \n \n = \n \n \n \n \n \n \u03b3 \n \n m \n g \n \n \n \n \u2212 \n \n \u03b3 \n \n b \n m \n \n \n \n \n \n \u03b3 \n \n b \n g \n \n \n \n \n \n \n \n {\\displaystyle {\\cos(\\theta )\\;=\\;{\\frac {\\gamma _{mg}\\;-\\gamma _{bm}\\;}{\\gamma _{bg}}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4455", "text": "where  \n \n \n \n \n \u03b3 \n \n m \n g \n \n \n \n \n {\\displaystyle \\gamma _{mg}} \n \n  is the interfacial tension between the membrane and gas or bodily environment,  \n \n \n \n \n \u03b3 \n \n b \n m \n \n \n \n \n {\\displaystyle \\gamma _{bm}} \n \n  is the interfacial tension between the bioadhesive and membrane,  \n \n \n \n \n \u03b3 \n \n b \n g \n \n \n \n \n {\\displaystyle \\gamma _{bg}} \n \n  is the interfacial tension between the bioadhesive and bodily environment, and  \n \n \n \n \u03b8 \n \n \n {\\displaystyle \\theta } \n \n  is the contact angle of the bioadhesive on the membrane. The ideal contact angle is 0\u00b0 meaning the bioadhesive perfectly wets the membrane and good contact is achieved. The interfacial tensions can be measured using common experimental techniques such as a  Wilhelmy plate  or the  Du No\u00fcy ring method  to predict if the adhesive will make good contact with the membrane. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4456", "text": "The consolidation stage of mucoadhesion involves the establishment of adhesive interactions to reinforce strong or prolonged adhesion. When moisture is present, mucoadhesive materials become activated and the system becomes plasticized. [ 10 ]  This stimulus allows the mucoadhesive molecules to separate and break free while proceeding to link up by weak  van der Waals  and  hydrogen bonds . [ 10 ]  Consolidation factors are essential for the surface when exposed to significant dislodging stresses. [ 1 ]  Multiple mucoadhesion theories exist that explain the consolidation stage, the main two which focus on macromolecular interpenetration and dehydration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4457", "text": "The Macromolecular Interpenetration theory, also known as the diffusion theory, states that the mucoadhesive molecules and mucus glycoproteins mutually interact by means of interpenetration of their chains and the forming of secondary semi-permanent adhesive bonds. [ 10 ]  It is necessary that the mucoadhesive device has features or properties that favor both chemical and mechanical interactions for the macromolecular interpenetration theory to take place. [ 10 ]  Molecules that can present mucoadhesive properties are molecules with hydrogen bond building groups, high molecular weight, flexible chains, and surface active properties. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4458", "text": "It is perceived that increase in adhesion force is associated with the degree of penetration of polymer chains. [ 10 ]  Literature states that the degree of penetration required for efficient bioadhesive bonds lies in the range of 0.2-0.5\u03bcm. [ 10 ]  The following equation can be used to estimate the degree of penetration of polymer and mucus chains:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4459", "text": "l \n = \n \n ( \n t \n \u00d7 \n \n D \n \n b \n \n \n \n \n ) \n \n 1 \n \n / \n \n 2 \n \n \n \n \n \n {\\displaystyle {l={(t\\times D_{b}})^{1/2}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4460", "text": "with  \n \n \n \n t \n \n \n {\\displaystyle t} \n \n  as contact time and  \n \n \n \n \n D \n \n b \n \n \n \n \n {\\displaystyle D_{b}} \n \n  as the  diffusion coefficient  of the mucoadhesive material in the mucus. [ 10 ]  Maximum adhesion strength is reached when penetration depth is approximately equal to polymer chain size. [ 10 ]  Properties of mutual  solubility  and structural similarity will improve the mucoadhesive bond. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4461", "text": "The dehydration theory explains why mucoadhesion can arise rapidly. When two gels capable of rapid gelation in an aqueous environment are brought into contact, movement occurs between the two gels until a state of equilibrium is reached. [ 1 ]  Gels associated with a strong affinity for water will have high osmotic pressures and large swelling forces. [ 1 ]  The difference in osmotic pressure when these gels contact mucus gels will draw water into the formulation and quickly dehydrate the mucus gel, forcing intermixing and consolidation until equilibrium results. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4462", "text": "This mixture of formulation and mucus can increase contact time with the mucous membrane, leading to the consolidation of the adhesive bond. [ 12 ]  However, the dehydration theory does not apply to solid formulations or highly hydrated forms. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4463", "text": "Depending on the dosage form and  route of administration , mucoadhesives may be used for either local or systemic  drug delivery . An overview on the mucoadhesive properties of mucoadhesives is provided by Vjera Grabovac and  Andreas Bernkop-Schn\u00fcrch . [ 13 ]  The  bioavailability  of such drugs is affected by many factors unique to each route of application. In general, mucoadhesives work to increase the contact time at these sites, prolonging the  residence time  and maintaining an effective release rate. These polymeric coatings may be applied to a wide variety of liquid and solid dosages, each specially suited for the route of administration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4464", "text": "Tablets  are small, solid dosages suitable for the use of mucoadhesive coatings. The coating may be formulated to adhere to a specific mucosa, enabling both systemic and targeted local administration. Tablets are generally taken enterally, as the size and stiffness of the form results in poor patient compliance when administered through other routes. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4465", "text": "In general,  patches  consist of three separate layers that contribute and control the release of medicine. The outer impermeable backing layer controls the direction of release and reduces drug loss away from the site of contact. It also protects the other layers and acts as a mechanical support. The middle reservoir layer holds the drug and is tailored to provide the specified dosage. The final inner layer consists of the mucoadhesive, allowing the patch to adhere to the specified mucosa. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4466", "text": "As a liquid or semisolid dosage,  gels  are typically used where a solid form would affect the patient\u2019s comfort. As a trade-off, conventional gels have poor retention rates. This results in unpredictable losses of the drug, as the non-solid dosage is unable to maintain its position at the site of administration. Mucoadhesives increase retention by dynamically increasing the viscosity of the gel after application. This allows the gel to effectively administer the drug at the local site while maintaining the comfort of the patient. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4467", "text": "These dosage forms are commonly used to deliver drugs to the eye and nasal cavity. They often include mucoadhesive polymers to improve retention on dynamic mucosal surfaces. Some advanced eye drop formulations may also turn from a liquid to a gel (so called in situ gelling systems) upon drug administration. For example, gel-forming solutions containing Pluronics could be used to improve the efficiency of eye drops and provide better retention on ocular surfaces. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4468", "text": "With a 0.1-0.7\u00a0mm thick mucus layer, the oral cavity serves as an important route of administration for mucoadhesive dosages. Permeation sites can be separated into two groups:  sublingual  and  buccal , in which the former is much more permeable than the latter. However, the sublingual mucosa also produces more  saliva , resulting in relatively low retention rates. Thus, sublingual mucosa is preferable for rapid onset and short duration treatments, while the buccal mucosa is more appropriate for longer dosage and onset times. Because of this dichotomy, the oral cavity is suitable for both local and systemic administration. Some common dosage forms for the oral cavity include gels, ointments, patches, and tablets. Depending on the dosage form, some drug loss can occur due to swallowing of saliva. This can be minimized by layering the side of the dosage facing the oral cavity with an impermeable coating(,) commonly seen in patches. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4469", "text": "With an active surface area of 160\u00a0cm 2 , the  nasal cavity  is another noteworthy route of mucoadhesive administration. Due to the sweeping motion of the  cilia  that lines the mucosa, nasal mucus has a quick turnover of 10 to 15 minutes. Because of this, the nasal cavity is most suitable for rapid, local medicinal dosages. Additionally, its close proximity to the  blood\u2013brain barrier  makes it a convenient route for administering specialized drugs to the central nervous system. Gels, solutions, and aerosols are common dosage forms in the nasal cavity. However, recent research into particles and microspheres have shown increased bioavailability over non-solid forms of medicine largely due to the use of mucoadhesives. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4470", "text": "Within the  eye , it is difficult to achieve therapeutic concentrations through systemic administration. Often, other parts of the body will reach toxic levels of the medication before the eye reaches the treatment concentration. Consequently, direct administration through the fibrous tunic is common. This is made difficult due to the numerous defense mechanisms in place, such as  blinking ,  tear production , and the tightness of the  corneal epithelium . Estimates put tear turnover rates at 5 minutes, meaning most conventional drugs are not retained for long periods of time. Mucoadhesives increase retention rates, either by enhancing the viscosity or bonding directly to one of the mucosae surrounding the eye. [ 15 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4471", "text": "Intravesical drug administration is the delivery of pharmaceuticals to the urinary bladder through a catheter. [ 18 ]  This route of administration is used for the therapy of bladder cancer and interstitial cystitis. The retention of dosage forms in the bladder is relatively poor, which is related to the need for a periodical urine voiding. Some mucoadhesive materials are able to stick to mucosal lining in the bladder, resist urine wash out effects and provide a sustained drug delivery. [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4472", "text": "Nasal administration , popularly known as  snorting , is a  route of administration  in which  drugs  are  insufflated  through the  nose . It can be a form of either  topical administration  or  systemic administration , as the drugs thus locally delivered can go on to have either purely local or systemic effects. Nasal sprays are locally acting drugs such as  decongestants  for cold and allergy treatment, whose systemic effects are usually minimal. Examples of systemically active drugs available as nasal sprays are  migraine drugs , rescue medications for overdose and seizure emergencies,  hormone treatments ,  nicotine nasal spray , and  nasal vaccines  such as  live attenuated influenza vaccine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4473", "text": "A  nasal septum perforation  is a medical condition in which the  nasal septum , the  bony/cartilaginous  wall dividing the  nasal cavities , develops a hole or fissure. [ 1 ]  Nasal administration may cause nasal septum perforation by gradually injuring and ulcerating the epithelium, causing cartilage exposure and  necrosis . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4474", "text": "Sharing snorting equipment (nasal spray bottles, straws, banknotes, bullets, etc) has been linked to the transmission of  hepatitis C . In one study, the University of Tennessee Medical Center researchers warned that other blood-borne diseases such as  HIV  could be transmitted as well. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4475", "text": "The nasal cavity is covered by a thin mucosa which is well vascularised. [ 5 ]  Therefore, a drug molecule can be transferred quickly across the single epithelial cell layer directly to the systemic blood circulation without first-pass hepatic and intestinal metabolism. The effect is often reached within 5 minutes for  smaller drug molecules . [ 6 ]  Nasal administration can therefore be used as an alternative to oral administration, by crushing or grinding tablets or capsules and snorting or sniffing the resulting powder, providing a rapid onset of effects if a fast effect is desired or if the drug is extensively degraded in the gut or liver. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4476", "text": "Large-molecule drugs can also be delivered directly to the brain by the intranasal route, the only practical means of doing so, following the olfactory and trigeminal nerves  (see section below) , for widespread central distribution throughout the  central nervous system  with little exposure to the blood. [ 8 ] [ 9 ] [ 10 ] [ 11 ]  This delivery method to the brain was functionally demonstrated in humans in 2006, using  insulin , a large  peptide  hormone that acts as a nerve growth factor in the brain. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4477", "text": "Nasal administration is primarily suitable for potent drugs since only a limited volume can be sprayed into the nasal cavity. Drugs for continuous and frequent administration may be less suitable because of the risk of harmful long-term effects on the nasal epithelium. [ 7 ]  Nasal administration has also been associated with a high variability in the amount of drug absorbed. Upper airway infections may increase the variability as may the extent of sensory irritation of the nasal mucosa, differences in the amount of liquid spray that is swallowed and not kept in the nasal cavity and differences in the spray actuation process. [ 13 ]  However, the variability in the amount absorbed after nasal administration should be comparable to that after oral administration. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4478", "text": "The area of intranasal medication delivery provides a huge opportunity for research \u2013 both for specifically developed pharmaceutical drugs designed for intranasal treatment, as well as for investigating off-label uses of commonly available generic medications. Steroids, and a large number of inhalational anaesthetic agents are being used commonly. The recent developments in intranasal drug delivery systems are prodigious.  Peptide drugs  (hormone treatments) are also available as nasal sprays, in this case to avoid drug degradation after oral administration. The peptide analogue  desmopressin  is, for example, available for both nasal and oral administration, for the treatment of  diabetes insipidus . The  bioavailability  of the commercial tablet is 0.1% while that of the nasal spray is 3-5% according to the SPC ( Summary of Product Characteristics ). [ 16 ]  Intranasal  calcitonin , calcitonin-salmon, is used to treat  hypercalcaemia  arising out of malignancy,  Paget's disease of bone , post menopausal and steroid induced  osteoporosis ,  phantom limb pain  and other metabolic bone abnormalities, available as Rockbone, Fortical and Miacalcin Nasal Spray.  GnRH analogues  like nafarelin and busurelin are used for the treatment of anovulatory infertility,  hypogonadotropic hypogonadism ,  delayed puberty  and  cryptorchidism . Other potential drug candidates for nasal administration include anaesthetics, antihistamines (Azelastine),  antiemetics  (particularly metoclopramide and ondansetron) and  sedatives  that all benefit from a fast onset of effect. [ 17 ]  Intranasal  midazolam  is found to be highly effective in acute episodes of seizures in children. Recently, the upper part of the nasal cavity, as high as the  cribriform plate , has been proposed for drug delivery to the brain. This \"transcribrial route\", published first in 2014, was suggested by the author for drugs to be given for Primary  Meningoencephalitis .  [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4479", "text": "Oxytocin  (brand name Syntocinon) nasal spray is used to increase duration and strength of contractions during labour. Intranasal oxytocin is also being actively investigated for many psychiatric conditions including  alcohol withdrawal ,  anorexia nervosa ,  PTSD ,  autism ,  anxiety disorders , pain sensation and  schizophrenia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4480", "text": "List of substances that have higher bioavailability when administered intranasally compared to oral administration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4481", "text": "Insufflation of  cocaine  leads to the longest duration of its effects (60\u201390 minutes). [ 19 ]  When insufflating cocaine, absorption through the nasal membranes is approximately 30\u201360%. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4482", "text": "Among the less invasive routes for  ketamine , the intranasal route has the highest bioavailability (45\u201350%). [ 21 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4483", "text": "Snuff  is a type of  smokeless tobacco   product  made from finely ground or pulverized  tobacco  leaves. [ 23 ]  It is  snorted  or \"sniffed\" (alternatively sometimes written as \"snuffed\") into the nasal cavity, delivering  nicotine  and a flavored scent to the user (especially if flavoring has been blended with the tobacco). [ 23 ]  Traditionally, it is sniffed or inhaled lightly after a pinch of snuff is either placed onto the back surface of the  hand , held pinched between thumb and index finger, or held by a specially made \"snuffing\" device."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4484", "text": "Snuff trays  and tubes similar to those commonly used for  yopo  were found in the central Peruvian coast dating back to 1200 BC, suggesting that insufflation of  Anadenanthera  beans is a more recent method of use. [ 24 ]  Archaeological evidence of insufflation use within the period 500-1000 AD, in northern Chile, has been reported. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4485", "text": "There is about 20 mL capacity in the adult human  nasal cavity . [ 26 ]  The major part of the approximately 150\u00a0cm 2  surface in the human nasal cavity is covered by  respiratory epithelium , across which systemic drug absorption can be achieved. The  olfactory epithelium  is situated in the upper posterior part and covers approximately 10\u00a0cm 2  of the human nasal cavity. The nerve cells of the olfactory epithelium project into the  olfactory bulb  of the brain, which provides a direct connection between the brain and the external environment. The transfer of drugs to the brain from the blood circulation is normally hindered by the  blood\u2013brain barrier  (BBB), which is virtually impermeable to  passive diffusion  of all but small, lipophilic substances. However, if drug substances can be transferred along the olfactory nerve cells, they can bypass the BBB and enter the brain directly. [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4486", "text": "The  olfactory transfer  of drugs into the brain is thought to occur by either slow transport inside the olfactory nerve cells to the olfactory bulb or by faster transfer along the perineural space surrounding the olfactory nerve cells into the  cerebrospinal fluid  surrounding the olfactory bulbs and the brain. [ 27 ] [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4487", "text": "Olfactory transfer could theoretically be used to deliver drugs that have a required effect in the central nervous system such as those for  Parkinson's  or  Alzheimer's  diseases. Studies have been presented showing that direct transfer of drugs is achievable. [ 28 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4488", "text": "Ophthalmic drug administration  is the administration of a drug to the eyes, most typically as an  eye drop  formulation. Topical formulations are used to combat a multitude of diseased states of the eye. These states may include  bacterial infections , eye injury,  glaucoma , and  dry eye . [ 1 ]  However, there are many challenges associated with topical delivery of drugs to the  cornea  of the eye."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4489", "text": "Two of the largest challenges faced when using topicals to treat pathological states of the eye include  patient compliance  and ineffective absorbance of drugs into the cornea due to short contact times, solution drainage, tears turnover, and dilution or lacrimation. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]  In fact, researchers in this field of drug delivery agree that less than 7% of drugs delivered to the eye reach and penetrate the corneal barrier, therefore, increasing the frequency of dosing used for topicals. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]  This is one of the fundamental problem associated with using topicals to deliver drugs to the cornea and therefore leads to the increased demand for patient compliance. Together, these two factors drive a need in the field of scientific research and engineering for a way to better deliver drugs to the cornea of the eye while decreasing dosing frequency and demand for patient compliance. Strategies to achieve a prolonged residence time of drug delivery systems on ocular surface include mucoadhesive and in situ gelling polymers and thiolated cyclodextrins (see  thiomers ). [ 8 ]  Besides the logistical problems associated with using topicals, there are also systemic side effects which result from the administration of some drugs used to combat the pathological states of the eye. [ 3 ]  With the increased concentration of drugs in topicals and the frequent application to the eye, a majority of the drug is drained from the eye via nasolacrimal drainage. [ 3 ]  This drainage is thought to be the reason that systemic side effects exist from such administration. [ 2 ] [ 3 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4490", "text": "The U.S.  Centers for Disease Control and Prevention  (CDC) claims that there were \"about 41 million  contact lens  wearers greater than 18 years old in the United States\" in 2018. [ 9 ]  Of all of these wearers, nearly 90% of them wear contact lenses known as 'soft contact lenses' (SCLs). [ 9 ]  Contact lenses are regulated by the United States  Food and Drug Administration  (FDA). [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4491", "text": "The main approaches that researchers in this field are using today are: molecular imprinting, supercritical soaking, solvent impregnation, and  nanoparticle  loading. [ 2 ] [ 4 ] [ 5 ] [ 7 ]  Each of these techniques assists by hoping to deliver drugs at a lower, more sustained, rate that does not require a demand for increased patient compliance nor the systemic side effects from  topical drug delivery  systems. However, each of these different types of loading techniques results in contact lenses that all have separate physical and chemical challenges when it comes to the sustained release and penetration of specific drugs at the molecular level in regards to the cornea of the eye."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4492", "text": "Molecular imprinting is a process by which polymerization of a polymer around template result in the polymer matrix with embedded templates. [ 2 ] [ 5 ]  After the template is removed, a cavity results with the functionalized monomers within the polymer cavity. This cavity is the idealized position for drug loading since this process can be designed specifically to recruit and hold onto drugs due to chemical specificity. [ 2 ] [ 5 ]  This technique can be better visualized by referring to Figure 3.0. This type of drug loading can be used as a way to create a pH responsive system, which releases drug(s) as the pH of the biological system changes. [ 2 ] [ 5 ]  Some drugs that have been successfully loaded via this method are:  timolol ,  norfloxacin ,  ketotifen ,  polyvinlypyrrolidone , and  hyaluronic acid . [ 5 ] [ 11 ] [ 12 ]  The molecular structures of each of these drugs are shown below in the index of important scientific terminology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4493", "text": "The supercritical soaking method is commonly used in hydrogel-based contact lenses and is the most common of all types of molecular drug loading techniques. Since this technique requires no special equipment or advanced knowledge of polymer-based hydrogels it is the least complex of all loading types. [ 4 ]  In order to load the hydrogel matrix with a certain drug, contact lenses are simply placed in a solution of the drug and the drug diffuses into the matrix. [ 4 ] [ 5 ] [ 7 ]  Since this loading technique is driven solely by the gradient of the drug concentration surrounding the lens relative to the hydrogel matrix, the diffusion rate and amount of drug that is loaded can be controlled solely by the concentration of the drug solution. [ 4 ] [ 7 ]  Since this process allows for specific amounts of a certain drug to be loaded to the hydrogel matrix, this method of loading has become important for patient-specific (personalized) medicine and treatments."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4494", "text": "The nanoparticle loading technique includes two major parts. The first part of this process is the creation and conjugation of a specific drug into or onto a nanoparticle or other colloidal particle. [ 5 ]  Next, the nanoparticle is loaded into the hydrogel matrix of the contact lens. [ 5 ]  In this case, before the drug can diffuse out of the hydrogel matrix to reach the cornea, it must also diffuse or be released out of the nanoparticle. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4495", "text": "It is important to recognize the positives and negatives associated with each type of drug loading for using contact lenses as drug delivery devices. In order to seriously address the possibility of clinical translation of these devices, it is important to recognize the physical and chemical barriers. By understanding this better, the mechanism of drug loading and the controlled and sustained release of drugs to a patient's eye can be optimized."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4496", "text": "Since contact lenses are used on a part of the body that is important for normal daily functioning (sight) it is critical that scientists take into account the transparency of the lens. [ 5 ]  As larger and more drugs/objects are loaded to a contact lens it begins to physically crowd the space available, making it more difficult for light to penetrate and reach the eye."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4497", "text": "Researchers have noted that by using the nanoparticle loading technique, the transparency decreases by nearly 10%. [ 5 ]  Conversely, researchers have confirmed that by using the molecular imprinting and supercritical soaking methods of drug loading, the lens transparency of the contact lenses has stayed at or above the lens transparency of the contact lenses currently approved by the FDA. [ 5 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4498", "text": "Oxygen permeability is another important feature of all contact lenses and much be optimized to the largest degree possible when creating drug delivery devices for the eye. The contact lens adheres to the external cornea of the eye which is made up of a layer of cells. [ 13 ]  Cells, being the basic component of living organisms, require sustained and constant access to oxygen in order to survive. The cornea of the eye is not supplied with blood as are most other cells in the body, making this a challenging part of the body to which to deliver drugs. [ 13 ]  Decreasing oxygenation to the eye can result in undesirable side effects. [ 5 ]  Researchers in this field have noted that different types of contact lenses have varying degrees of oxygen permeability. For example, it has been shown that SCLs have limited oxygen permeability while silicon-based contact lenses have much better oxygen permeability. [ 1 ] [ 5 ] [ 12 ] [ 14 ]  Silicon-base contact lenses have also been shown to have some other very important physical parameters. [ 1 ] [ 5 ] [ 12 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4499", "text": "Researchers have attempted to make the thickness of the contact lenses in order to increase the drug loading capacity of the contact lens. [ 12 ]  However, for silicon-based lenses this parameter is inversely proportion to oxygen permeability (i.e. as thickness of the contact lens increases the oxygen permeability decreases). [ 12 ]  Moreover, it has been shown that as water content increases in silicon-based lenses, the oxygen permeability decreases, another relationship that is inversely proportional. [ 12 ]  Surprisingly, as SCLs increase with water content the oxygen permeability also increases (a directly proportional relationship). [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4500", "text": "In regards to whether silicon-based lenses or SCLs are a better candidate as an ophthalmic drug delivery device is a question that remains unanswered and is not uniformly agreed upon in the scientific community. For example, Ciolino et al. claim that silicon-based contact lenses are better candidates for patients that are long-term contact lens wearer. [ 2 ] [ 3 ]  Conversely, Kim et al. suggest that SCLs are better candidates because they show the possibility to be able to overcome the difficult of oxygen permeability as well as mechanical integrity of the lens. [ 7 ]  Kim et al. have shown that the mechanical strength can be increased for SCLs by incorporating a nanodiamond (ND) infrastructure into contact lens matrix. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4501", "text": "Additionally, many researchers have investigated the implications of loading vitamin E into the contact lens matrix of SCLs. [ 6 ]  Although vitamin E incorporation into the matrix has been shown to slow the release of drugs into the eye and onto cornea (a desirable trait of an ophthalmic delivery system), it has also been shown to decrease oxygen permeability. [ 6 ]  Oxygen permeability continues to be an extremely important factor in the development of these devices and is one of the main reason that much research is beginning to focus on this area of drug delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4502", "text": "The amount of water content that a particular contact lens can retain is another extremely important factor that must be taken into account when these devices are designed. Research in this specific area of design suggests that contact lens wearers find it more comfortable to wear lenses that retain water more than those that deter water. [ 5 ] [ 12 ]  For SCLs, as the water content of a lens increases so does the oxygen permeability. [ 12 ]  Conversely, as the water content increases in silicon-based contact lenses, the oxygen permeability decreases. [ 2 ] [ 3 ] [ 12 ]  In reference to SCLs, higher water content in contact lenses allows for easier loading using the supercritical soaking method. [ 3 ] [ 5 ] [ 12 ] [ 15 ]  This could be due to the water acting as a lubricant to some drugs and allowing the drug to be more easily facilitated into the matrix. This would essentially allow for more drug to be loaded into contact lenses of this type. [ 5 ] [ 12 ]  This increase in drug loading capacity is an important advancement and would allow for patients wince it may allow for a longer period of drug release time and would hopefully be more sustained. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4503", "text": "Furthermore, Guzman-Aranguez et al. has shown that when using the molecular imprinting method for loading drugs such as ketotifen and norfloxacin into the contact lens, the water content is not largely impacted. [ 5 ]  Additionally, it has been predicted by Peng et al. by using Fickian release kinetic models that although water content changes once contact lenses are inserted onto the cornea of the eye, this will not pose significant challenges when it comes to the release of rugs from SCLs. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4504", "text": "The most important factor that must be taken into account when designing any type of drug delivery device, and specifically ocular devices, is the release rate of a drug. As discussed previously, the deliver rate and kinetics associated with drugs to the eye can reach levels that are toxic to the eye or could even cause undesirable side effects. The rate of release of a drug is also important because too slow of a release could have no beneficial outcome for the patient and a release that is too quick could result in negative side effects. [ 10 ] [ 14 ] [ 16 ] [ 17 ]  Thus, it is important to balance the factors that govern the release of drugs from contact lenses as potential drug delivery devices. Researchers such as C. Alvarez-Lorenzo have tested (with animal models) and have data which supports that molecularly imprinted contact lenses release drugs in a sustained and long period of time. [ 12 ]  It has also been supported by researchers that the rate of drug release can be controlled by incorporating vitamin E within the hydrogen matrix. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4505", "text": "Over time, it has been reported that many of the same drugs and eye drops used to treat particular eye diseases do, in fact, result in systemic side effects that could possibly be minimized or limited due to a slower, more sustained release of the drug. The systemic side effects of glaucoma medications such as latanoprost increased heart rate resulting in cardiac arrhythmias, bronchoconstriction, and hypotension. [ 16 ] [ 17 ] [ 18 ] \u00a0 These complications could be life-threatening. Some other drugs that help to reduce the effects of glaucoma in the eye result in vomiting, diarrhea, tachycardia and bronchospasm. [ 15 ] [ 16 ] [ 17 ] [ 18 ]  It has been found that some drugs delivered in the form of eye drops are highly toxic to children since their total body volume and tissue volumes are much lower than that of an adult for which the drugs are intended for use. [ 17 ]  In this case, some parents are not aware of these implications and could use the same drug they would use to help treat their children's bacterial infections in the eye. Moreover, some drugs administered to the eye have been shown to result in cardiac depression and propagation of some disorders such as asthma. [ 16 ] [ 17 ] [ 18 ]  With continued research in this area, it has become known that skin irritation, itching or rash are commonly associated with drugs used to treat ocular bacterial infections. [ 15 ] [ 16 ] [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4506", "text": "There are currently four main ocular disorders that have been heavily investigated and have shown success with using contact lenses as possible devices for molecular drug delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4507", "text": "The drug release rate is extremely important in treating many diseased states of the eye, bacterial infections being one of them. Ciprofloxacin and norfloxacin are drugs that are normally used to treat bacterial infections of the eye. It is of utmost importance that these drugs stay in the therapeutic window for an extended period of time in order to be fully effective and kill bacteria. [ 5 ] [ 12 ]  To keep the specific drug in the therapeutic window using eye drops the topical must be applied approximately every 30 minutes in order to be fully effective. [ 5 ] [ 12 ]  Having to apply eye drops every 30 minutes would be nearly impossible for anyone and is not the ideal mechanism by which to deliver such drugs to the eye. Researchers have gathered data to support the idea that silicon-based contact lenses with ciprofloxacin could release the drug in the therapeutic window for approximately one month. [ 5 ]  Ana Guzman-Aranguez et al. also confirmed that the contact lens used also retained important properties such as transparency, oxygen permeability, mechanical strength, and zero-order release pharmacokinetics. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4508", "text": "Many factors can result in corneal injury and cause the deterioration or death of cells that make up the cornea of the eye. [ 5 ] [ 12 ]  The epithelial cells that make up the cornea are important in order for normal vision. These cells play a role in creating a physical environment that can correctly bend light rays to help project images to the retina of the eye. [ 5 ] [ 12 ]  There have been successful human clinical trials with using SCLs infused with epidermal growth factor (EGF) that showed increased rate of healing of the epithelial cell layer of the cornea. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4509", "text": "Glaucoma  is the leading cause of blindness in the world and is a progressive and irreversible disease of the eye. [ 18 ]  A poly(lactic-co-glycolic acid)-based contact lens was shown to release  latanoprost  at a sustained release rate of up to a month in animal models by Ciolino et al. at Harvard Medical School and Massachusetts Institute of Technology. [ 18 ]  Latanoprost is one of the drug interventions used to treat patients with glaucoma, generally in the form of topicals such as  eye drops . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4510", "text": "More than 50% of all contact lens wearers report that they experience  dry eye . [ 5 ]  In order to help combat this issue and be assured that this does not occur in people that will one day be using drug eluting contact lenses, it is important to make sure that this complication is highly investigated. However, these investigations will not only be beneficial for contact lenses as drug delivery devices, but it will also have positive implications on contact lens wearers who use lenses for vision correction and appearance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4511", "text": "Oral administration  is a  route of administration  whereby a substance is taken through the  mouth , swallowed, and then processed via the  digestive system . This is a common route of administration for many medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4512", "text": "Oral administration can be easier and less painful than other routes of administration, such as injection. However, the onset of action is relatively low, and the effectiveness is reduced if it is not absorbed properly in the  digestive system , or if it is broken down by digestive enzymes before it can reach the bloodstream. Some medications may cause gastrointestinal side effects, such as nausea or vomiting, when taken orally. Oral administration can also only be applied to conscious patients, and patients able to swallow. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4513", "text": "Per os  ( / \u02cc p \u025c\u02d0r \u02c8 o\u028a s / ;  P.O. ) is an adverbial phrase meaning literally from Latin \"through the mouth\" or \"by mouth\". The expression is used in medicine to describe a treatment that is taken orally (but not used  in  the mouth  such as, for example,  caries  prophylaxis). [ 2 ]  The abbreviation  P.O.  is often used on  medical prescriptions . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4514", "text": "Enteral administration includes: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4515", "text": "Enteral medications come in various forms, including [ 3 ]  oral solid dosage (OSD) forms: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4516", "text": "and oral liquid dosage forms: [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4517", "text": "Concomitant ingestion of  water  facilitates in swallowing tablets and capsules. [ 6 ]  If the substance has disagreeable  taste , addition of a  flavor  may facilitate  ingestion . [ 6 ]  Substances that are harmful to the  teeth  are preferably given through a  straw . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4518", "text": "A powder is an assembly of dry particles dispersed in air. If two different powders are mixed perfectly, theoretically, three types of  powder mixtures  can be obtained: the random mixture, the ordered mixture or the interactive mixture."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4519", "text": "A  powder  is called  free-flowing  if the particles do not stick together. If particles are  cohesive , they cling to one another to form  aggregates . The significance of cohesion increases with decreasing size of the powder particles; particles smaller than 100  \u03bcm  are generally cohesive. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4520", "text": "A  random mixture  can be obtained if two different free-flowing powders of approximately the same particle size,  density  and  shape  are mixed (see figure A). [ 3 ]  Only primary particles are present in this type of mixture, i.e., the particles are not cohesive and do not cling to one another. The mixing time will determine the quality of the random mixture. However, if powders with particles of different size, density or shape are mixed,  segregation  can occur. [ 4 ]  Segregation will cause separation of the powders as, for example, lighter particles will be prone to travel to the top of the mixture whereas heavier particles are kept at the bottom."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4521", "text": "The term  ordered mixture  was first introduced to describe a completely  homogeneous  mixture where the two components adhere to each other to form ordered units. [ 5 ]  However, a completely homogeneous mixture is only achievable in theory and other denotations were introduced later such as adhesive mixture or interactive mixture."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4522", "text": "If a free-flowing powder is mixed with a cohesive powder an  interactive mixture  can be obtained. The cohesive particles adhere to the free-flowing particles (now called carrier particles) to form interactive units as shown in figure B. [ 3 ]  An interactive mixture may not contain free aggregates of the cohesive powder, which means that all small particles must be adhered to the larger ones. The difference from an ordered mixture is instead that all carrier particles do not need to be of the same size and a different number of small particles attached to each one. A narrow size range of the carrier particles is preferred to avoid segregation of the interactive units. [ 6 ]  In practice a combination of a random mixture and an interactive mixture may be obtained which consists of carrier particles, aggregates of the small particles and interactive units. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4523", "text": "The formation of interactive mixtures cannot automatically be assumed, especially if smaller carrier particles  [ 8 ]  or a greater proportion of fine particles  [ 9 ] [ 10 ]  are used. If an interactive mixture is to be formed, it is necessary that enough force is exerted by the carrier particles during dry mixing to break up the aggregates formed by the fine particles. Adhesion can then be achieved if the adhesive forces exceed the gravitational forces that otherwise lead to separation of the constituents. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4524", "text": "Interactive mixtures for example can be used in the manufacturing of tablets [ 11 ]  enhancing the dissolution of poorly  soluble   drugs   [ 12 ]  or for  nasal administration . [ 3 ]  One common application is for inhalation therapy, where the concept has been used in the development of alternatives to pressurised metered dose inhalers. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4525", "text": "The  quality by design  initiative (QbD) of the  U.S. Food and Drug Administration  requires a process to be controllable and predictable. Theories and methods to characterize powder mixture have facilitated the implementation of QbD approaches to predict flow properties of powder mixture. For example, QbD approach is shown to be useful for predicting flow performance and finding design space during formulation development. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4526", "text": "Pulmonary drug delivery  is a  route of administration  in which patients use an inhaler to inhale their medications and drugs are absorbed into the bloodstream via the lung mucous membrane. This technique is most commonly used in the treatment of lung diseases, for example,  asthma  and  chronic obstructive pulmonary disease (COPD) . Different types of inhalers include  metered-dose inhalers (MDI) ,  dry powder inhalers (DPI) , soft mist inhalers (SMI) and  nebulizers . The rate and efficacy of pulmonary drug delivery are affected by drug particle properties, breathing patterns and respiratory tract geometry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4527", "text": "Pulmonary drug delivery minimizes systemic side effects and increases bioavailability owing to the localised absorption through the lung. The disadvantages include possible drug irritation to the lung, limited drug  dissolution , relatively high drug  clearance , and the drug effectiveness depends on the inhaler techniques and patients'  compliance . Drug formulation can be challenging since the drug has to bypass the  defence mechanisms in the respiratory tract .  Pharmacokinetics  and  pharmacodynamics  of the drug in elderly patients can also be particularly difficult to predict due to age-related changes in body composition."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4528", "text": "Ongoing developments in inhaler device engineering, technology and drug formulations may improve the efficacy and overcome the challenges of pulmonary drug delivery. Recent advancements involve the utilization of the pulmonary route as an entry to  systemic circulation  for treating different diseases, as well as the development of pulmonary drug formulation and  particle engineering technology  to increase the efficacy of pulmonary delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4529", "text": "Pulmonary drug delivery is mainly utilized for topical applications in the lungs, such as the use of inhaled  beta-agonists ,  corticosteroids  and  anticholinergic  agents for the treatment of asthma and COPD, the use of inhaled  mucolytics  and  antibiotics  for the treatment of  cystic fibrosis (CT)  and respiratory viral infections, [ 1 ]  and the use of inhaled  prostacyclin   analogs  for the treatment of  pulmonary arterial hypertension (PAH) . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4530", "text": "In addition, this technique is employed for systemic application, for example the use of inhaled  insulin  for  diabetes  management, [ 3 ]  the use of inhaled  loxapine  for treatment of psychiatric disorders.  Vaccines , such as the  measles-rubella vaccines , can also be delivered via inhalation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4531", "text": "Metered-dose inhalers include pressurized metered-dose inhalers (pMDIs) and breath-actuated metered-dose inhalers (BAMDIs). pMDIs are the most commonly used inhalers for treating lung diseases. It requires coordination of patients\u2019 inhalation and inhaler actuation. BAMDIs are triggered by patients\u2019 inspiratory flow instead of hand actuation, solving the coordination issue. [ 4 ]  MDIs with  spacers  have similar effectiveness in drug delivery compared to nebulizers, with additional benefits in convenience and cost-effectiveness. [ 5 ]  The use of MDIs together with spacers, valved holding chambers (VHCs) or masks improve the efficacy of drug delivery into the lungs. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4532", "text": "The solid drug powders in DPIs are released by the force of the patient's inspiratory flow. Turbulent airflow generated inside the inhaler by the inhalation force is associated with the movement of airflow and the resistance inside the inhaler. [ 8 ]  Patients should inhale with adequate inspiratory flow to overcome the resistance of DPIs, leading to drug particle deaggregation for successful pulmonary delivery. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4533", "text": "Soft-mist inhaler aerosolized a fixed dose of liquid drug formulation into inhalable tiny particles through an extremely fine  nozzle  system using the energy generated by the lever-compressed spring, without the use of  propellants . [ 11 ]  The slow and prolonged duration of aerosolization facilitates the patient's coordination between inhaler actuation and inhalation. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4534", "text": "Nebulizer is mainly used in emergencies, or by patients with poor compliance to other handy inhalers. Nebulizer delivers medication into the lungs by converting water-based liquid drug formulations into inhalable droplets mechanically, such as the use of an ultrasonic system, or thermally. [ 14 ]  Major types of nebulizers include vibrating mesh nebulizers (VMN), jet nebulizers (JN) and ultrasonic nebulizers. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4535", "text": "To achieve successful pulmonary drug delivery, a fraction of the inhaled particles should not deposit on the upper respiratory tract since they will be swallowed or expectorated without reaching the lungs, leading to the loss of pharmacological effect or provoking unwanted systemic side effects. Factors affecting the deposition of drug particles in lungs include drug particle properties, breathing patterns and respiratory tract geometry. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4536", "text": "Particle diameter and particle density significantly affect the drug deposition pattern in the respiratory tract, and are the most common considerations for formulation of pulmonary drugs. Drug particles with diameter larger than 5 \u03bcm, predominantly deposit on the upper respiratory tract, limiting the amount of drug particles reaching the lung. Moderate-size drug particles with diameter between 2 \u03bcm to 5 \u03bcm, primarily deposit on the central and small airways. Small drug particles with diameter smaller than 2 \u03bcm, predominantly deposit on the alveolar sacs. [ 18 ]  Other factors affecting deposition of drugs include particle electrostatic charge, particle shape and particle volatility. Electrostatic charge of the drug particles enhances deposition due to the formation of electrostatic force on the wall of the respiratory tract. Non-spherical particle shape has a different entry pathway compared to that of the spherical particles, causing a change in deposition pattern. Particle volatility affects particle diameter due to the change of particle diameter during condensation and evaporation. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4537", "text": "Drug particle deposition is associated with mean  residence time  and  tidal volume . An increase in mean residence time or tidal volume enhances drug deposition in lungs, while an increase in air flow decreases the mean residence time, resulting in the decrease of total deposition of drug particles. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4538", "text": "The  bifurcation of trachea  into bronchi with smaller diameter increases turbulent flow, leading to an increase in deposition in the large respiratory tract by impaction. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4539", "text": "Several advantages are associated with the pulmonary route of administration. For respiratory diseases, drug can be delivered directly to the disease site to perform topical relief, thus rapid  onset of action  can be achieved and there is less systemic side effects. [ 21 ]  Less dosage of drug can also achieve similar therapeutic effect compared to other routes of administration. For drugs designed to exert systemic effect through the lung as a drug target, the drug can reach the circulation bypassing poor gastrointestinal absorption and  hepatic first pass metabolism  which improve drug bioavailability. [ 21 ]  The large absorptive surface area, highly permeable membrane with rich blood supply also enable rapid onset of action and increase  bioavailability  of the drug. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4540", "text": "Despite a number of advantages in the pulmonary route compared to other routes of administration, numerous disadvantages are associated with the pulmonary route. As the drug needs to be delivered through the respiratory tract to the lungs, drug formulation can be challenging due to the defense mechanisms which intend to remove or inactivate the exogenous chemicals.  Airway constriction  and  mucus  secretion with  ciliary  movement prevent drugs from reaching the lungs, while  enzymes ,  macrophages  and  surfactant  in the lungs may also inactivate the drugs leading to less drug being absorbed. [ 2 ]  Studies show that only around 20% of drug reaches the lung for each inhalation and drug loss is mainly due to the accumulation in the oropharynx in terms of pMDIs and DPIs and drug retention in the device for nebulisers. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4541", "text": "Some irritating drug particles may also cause local side effects at the respiratory tract, for example inhaled corticosteroid accumulating in the oropharynx can result in  dysphonia  and  oral thrush . Besides, drug dosing may be inaccurate due to the variations of breathing patterns between individuals and the presence of numerous factors affecting the deposition and absorption of drug particles in the lungs. [ 20 ]  In particular, elder patients may not have enough strength to generate sufficient inspiratory flow, resulting in less drug inhalation and hence low drug bioavailability. Finally, inhalers, especially nebulizers, require regular maintenance and cleaning. The inhaler devices are relatively expensive compared to oral tablets, [ 22 ]  which may not be affordable to low income patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4542", "text": "The effectiveness of drug delivery highly depends on the patient's compliance and proper inhaler technique with no significant error in using the inhalers. Poor compliance may lead to uncontrolled or poorly controlled disease status. [ 23 ]  For instance, a patient may feel recovered and discontinue the treatment, or a patient may forget to take the medication, resulting in suboptimal disease management. Reducing the amount of puffs by combination inhalers delivering two or more drugs in one breath or the use of electronic data loggers can improve compliance. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4543", "text": "Incorrect inhaler techniques, such as poor coordination, no exhalation before inhaling the drug aerosol or not holding breath for a few seconds after inhalation may lead to medication depositing inside the respiratory tract instead of the lungs, resulting in inefficient and inadequate treatment. [ 23 ] [ 24 ]  Practical demonstration instead of verbal instruction, education and rechecking on the inhaler technique after a period of time can reduce error and enhance true compliance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4544", "text": "The use of the pulmonary route as an entry into the systemic circulation is constantly developing due to the additional benefits of bypassing the hepatic first pass metabolism, rapid systemic absorption, higher patients compliance and its non-invasive nature. Potent drugs with the ability to penetrate the lung mucosa into the blood circulation may be available for treating diseases requiring systemic drug delivery. [ 25 ]  The ongoing researches include the use of inhaled  nicotine  for smoking cessation, [ 26 ]  the use of inhaled  levodopa  for the treatment of  Parkinson's disease , [ 27 ]  and the pulmonary delivery of various  biologics . [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4545", "text": "In addition to the development of new pulmonary drugs, the drug formulation and particle engineering technology is advancing, such as the use of Ultrasound Mediated Amorphous to Crystalline transition (UMAX) process to micronize drug into inhalable drug particles with better performance, [ 29 ]  the use of drug  nanoparticles  to minimize unwanted drug adverse effects and increase drug bioavailability at the target site, [ 30 ]  and the use of porous drug particles to improve pulmonary delivery efficacy. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4546", "text": "Rectal administration  (colloquially known as  boofing  or  plugging ) uses the  rectum  as a  route of administration  for  medication  and other fluids, which are  absorbed  by the rectum's  blood vessels , [ Note 1 ]  and flow into the body's  circulatory system , which distributes the drug to the body's  organs  and  bodily systems . [ Note 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4547", "text": "A drug that is administered rectally will in general (depending on the drug) have a faster onset, higher  bioavailability , shorter peak, and shorter duration than  oral  administration. [ 1 ] [ 2 ]  Another advantage of administering a drug rectally, is that it tends to produce less  nausea  compared to the oral route and prevents any amount of the drug from being lost due to  emesis  (vomiting). In addition, the rectal route bypasses around two-thirds of the  first-pass metabolism  as the rectum's venous drainage is two-thirds  systemic  ( middle  and  inferior rectal vein ) and one-third  hepatic portal system  ( superior rectal vein ). This means the drug will reach the circulatory system with significantly less alteration and in greater concentrations. [ Note 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4548", "text": "In addition to pharmacological effects, rectal administration has some properties which can be advantageous for the use in medicine. Rectal administration can allow patients to remain in the home setting when the oral route is compromised. Unlike  intravenous  lines, which usually need to be placed in an  inpatient  environment and require special formulation of  sterile  medications, [ 3 ]  a specialized rectal  catheter  can be placed by a clinician, such as a  hospice  nurse or home health nurse, in the home. Many oral forms of medications can be crushed and suspended in water to be given via a rectal  catheter ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4549", "text": "The rectal route of administration is useful for patients with any digestive tract motility problem, such as  dysphagia ,  ileus , or  bowel obstruction , that would interfere with the progression of the medication through the tract. This often includes patients  near the end of life  (an estimated 1.65 million people are in  hospice  care in the US each year). [ 4 ]  Because using the rectal route enables a rapid, safe, and lower cost alternative to administration of medications, [ 5 ]  it may also facilitate the care of patients in  long-term care  or  palliative care , or as an alternative to  intravenous  or  subcutaneous  medication delivery in other instances."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4550", "text": "Besides its application in medicine, rectal administration is also employed by users of  psychoactive substances . Like in the medical procedure, the psychoactive drug is inserted into the anus, where it gets absorbed by the rectum's  blood vessels ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4551", "text": "A study shows that awareness of rectal administration as a possible route of administration varies greatly among users of different drugs. The knowledge of rectal administration is highest among groups of users of  alcohol ,  stimulants  and  opioids , where over 30% of users are aware of it. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4552", "text": "The reasons for rectal administration are largely the same as with medicinal drugs: Bypassing the first-pass effect, fast onset, and a relatively high bioavailability with some drugs. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4553", "text": "Rectal administration is sometimes thought of as a safer alternative to  intravenous injection  of psychoactive substances, [ 8 ]  which carries a significant risk of infections and illnesses like  pulmonary granulomatosis . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4554", "text": "However, rectal administration of psychoactive drugs has risks associated with it also. [ 6 ]  The combination of a brief acting time (compared to oral administration) and an unpredictable absorption-rate can, particularly for new users, result in a risk of  overdoses . Use of shared or  non-sterile  equipment can increase the risk of acquiring  sexually transmitted infections . [ 10 ]  Some psychoactive substances like  substituted amphetamines  can induce a strong  vasoconstriction  in the rectal vasculature and lead to  intestinal ischemia . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4555", "text": "As with illicit psychoactive drugs in general, risks connected to rectal administration stem from the often unknown purity and composition of the drugs. This leads to the user not knowing if and what substances,  by-products  or  cutting agents  are present in their drugs [ 11 ]  before administering them rectally. Possible impurities or falsely marketed substances greatly increase the risk of administering illicit drugs rectally."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4556", "text": "Rectal administration of medication may be performed with any of the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4557", "text": "The  respiratory tract  is the subdivision of the  respiratory system  involved with the process of conducting air to the  alveoli  for the purposes of  gas exchange  in  mammals . [ 1 ]  The respiratory tract is lined with  respiratory epithelium  as respiratory mucosa. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4558", "text": "Air is breathed in through the  nose  to the  nasal cavity , where a layer of  nasal mucosa  acts as a filter and traps pollutants and other harmful substances found in the air. Next, air moves into the  pharynx , a passage that contains the intersection between the  oesophagus  and the  larynx . The opening of the larynx has a special flap of cartilage, the  epiglottis , that opens to allow air to pass through but closes to prevent food from moving into the airway."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4559", "text": "From the  larynx , air moves into the  trachea  and down to the intersection known as the  carina  that branches to form the right and left primary (main)  bronchi . Each of these bronchi branches into a  secondary (lobar) bronchus  that branches into  tertiary (segmental) bronchi , that branch into smaller airways called  bronchioles  that eventually connect with tiny specialized structures called  alveoli  that function in  gas exchange ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4560", "text": "The  lungs  which are located in the  thoracic cavity , are protected from physical damage by the  rib cage . At the base of the lungs is a sheet of skeletal muscle called the  diaphragm . The diaphragm separates the lungs from the  stomach  and  intestines . The diaphragm is also the main  muscle of respiration  involved in  breathing , and is controlled by the  sympathetic nervous system ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4561", "text": "The lungs are encased in a  serous membrane  that folds in on itself to form the  pleurae  \u2013 a two-layered protective barrier. The inner  visceral pleura  covers the surface of the lungs, and the outer  parietal pleura  is attached to the inner surface of the thoracic cavity. The pleurae enclose a cavity called the  pleural cavity  that contains  pleural fluid . This fluid is used to decrease the amount of friction that lungs experience during breathing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4562", "text": "The respiratory tract is divided into the  upper airways  and  lower airways . The upper airways or upper respiratory tract includes the  nose  and nasal passages,  paranasal sinuses , the  pharynx , and the portion of the  larynx  above the  vocal folds  (cords). The lower airways or lower respiratory tract includes the portion of the larynx below the vocal folds,  trachea ,  bronchi  and  bronchioles . The lungs can be included in the lower respiratory tract or as separate entity and include the respiratory bronchioles,  alveolar ducts ,  alveolar sacs , and  alveoli . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4563", "text": "The respiratory tract can also be divided into a  conducting zone  and a  respiratory zone , based on the distinction of transporting gases or  exchanging  them."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4564", "text": "The conducting zone includes structures outside of the lungs \u2013 the  nose ,  pharynx ,  larynx , and  trachea , and structures inside the lungs \u2013 the bronchi, bronchioles, and terminal bronchioles. The conduction zone conducts air breathed in that is filtered, warmed, and moistened, into the lungs. It represents the 1st through the 16th division of the respiratory tract. The conducting zone is most of the respiratory tract that conducts gases into and out of the lungs but excludes the respiratory zone that exchanges gases. The conducting zone also functions to offer a low resistance pathway for airflow. It provides a major  defense role  in its filtering abilities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4565", "text": "The respiratory zone includes the respiratory bronchioles, alveolar ducts, and alveoli, and is the site of oxygen and carbon dioxide  exchange  with the blood. The respiratory bronchioles and the alveolar ducts are responsible for 10% of the gas exchange. The alveoli are responsible for the other 90%. The respiratory zone represents the 16th through the 23rd division of the respiratory tract."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4566", "text": "From the bronchi, the dividing tubes become progressively smaller with an estimated 20 to 23 divisions before ending at an alveolus. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4567", "text": "The  upper respiratory tract  can refer to the parts of the  respiratory system  lying above the  vocal folds , or above the  cricoid cartilage . [ 4 ] [ 5 ]  The  larynx  is sometimes included in both the upper and lower airways. [ 6 ]  The larynx is also called the voice box and has the associated cartilage that produces sound. The tract consists of the  nasal cavity  and  paranasal sinuses , the  pharynx  ( nasopharynx ,  oropharynx  and  laryngopharynx ) and sometimes includes the larynx."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4568", "text": "The  lower respiratory tract  or  lower airway  is derived from the developing  foregut  and consists of the  trachea ,  bronchi  (primary, secondary and tertiary),  bronchioles  (including terminal and respiratory), and  lungs  (including  alveoli ). [ 7 ]  It also sometimes includes the larynx."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4569", "text": "The lower respiratory tract is also called the  respiratory tree  or  tracheobronchial tree , to describe the branching structure of airways supplying air to the lungs, and includes the trachea, bronchi and bronchioles. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4570", "text": "At each division point or  generation , one airway branches into two smaller airways. The human respiratory tree may consist on average of 23 generations, while the respiratory tree of the  mouse  has up to 13 generations.  Proximal divisions (those closest to the top of the tree, such as the bronchi) mainly function to transmit air to the lower airways. Later divisions including the respiratory bronchiole, alveolar ducts, and alveoli, are specialized for  gas exchange ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4571", "text": "The  trachea  is the largest tube in the respiratory tract and consists of  tracheal rings  of  hyaline cartilage . It branches off into two bronchial tubes, a left and a right main  bronchus . The bronchi branch off into smaller sections inside the lungs, called  bronchioles . These bronchioles give rise to the air sacs in the lungs called the  alveoli . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4572", "text": "The  lungs  are the largest organs in the lower respiratory tract. The lungs are suspended within the  pleural cavity  of the thorax. The  pleurae  are two thin membranes, one cell layer thick, which surround the lungs. The inner ( visceral pleura ) covers the lungs and the outer ( parietal pleura ) lines the inner surface of the chest wall. This membrane secretes a small amount of fluid, allowing the lungs to move freely within the pleural cavity while expanding and contracting during breathing. The lungs are divided into different lobes. The right lung is larger in size than the left, because of the heart's being situated to the left of the midline. The right lung has three lobes \u2013 upper, middle, and lower (or superior, middle, and inferior), and the left lung has two \u2013 upper and lower (or superior and inferior), plus a small tongue-shaped portion of the upper lobe known as the lingula. Each lobe is further divided up into segments called  bronchopulmonary segments . Each lung has a costal surface, which is adjacent to the ribcage; a diaphragmatic surface, which faces downward toward the diaphragm; and a mediastinal surface, which faces toward the center of the chest, and lies against the heart, great vessels, and the carina where the two mainstem bronchi branch off from the base of the trachea."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4573", "text": "The  alveoli  are tiny air sacs in the lungs where gas exchange takes place. The mean number of alveoli in a human lung is 480 million. [ 11 ]  When the diaphragm contracts, a negative pressure is generated in the thorax and air rushes in to fill the cavity. When that happens, these sacs fill with air, making the lung expand. The alveoli are rich with capillaries, called alveolar capillaries. Here the red blood cells absorb oxygen from the air and then carry it back in the form of oxyhaemaglobin, to nourish the cells. The red blood cells also carry carbon dioxide (CO 2 ) away from the cells in the form of  carbaminohemoglobin  and release it into the alveoli through the alveolar capillaries. When the diaphragm relaxes, a positive pressure is generated in the thorax and air rushes out of the alveoli expelling the carbon dioxide."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4574", "text": "The respiratory tract is covered in  epithelium , which varies down the tract. There are  glands  and  mucus  produced by  goblet cells  in parts, as well as  smooth muscle ,  elastin  or  cartilage . The epithelium from the nose to the bronchioles is covered in ciliated  pseudostratified columnar epithelium , commonly called  respiratory epithelium . [ 12 ]  The cilia beat in one direction, moving mucus towards the throat where it is swallowed. Moving down the bronchioles, the cells get more cuboidal in shape but are still ciliated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4575", "text": "Glands are abundant in the upper respiratory tract, but there are fewer lower down and they are absent starting at the bronchioles. The same goes for goblet cells, although there are scattered ones in the first bronchioles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4576", "text": "Cartilage is present until the bronchioles. In the trachea, they are C-shaped rings of  hyaline cartilage , whereas in the bronchi the cartilage takes the form of interspersed plates. Smooth muscle starts in the trachea, where it joins the C-shaped rings of cartilage. It continues down the  bronchi  and  bronchioles , which it completely encircles. Instead of hard cartilage, the bronchi and bronchioles are composed of elastic tissue."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4577", "text": "The lungs are made up of thirteen different kinds of cells, eleven types of  epithelial  cell and two types of  mesenchymal  cell. [ 13 ]  The epithelial cells form the lining of the tracheal, and bronchial tubes, while the mesenchymal cells line the lungs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4578", "text": "Most of the respiratory tract exists merely as a piping system for air to travel in the lungs, and  alveoli  are the only part of the lung that  exchanges   oxygen  and  carbon dioxide  with the  blood ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4579", "text": "Respiration is the  rhythmical process  of  breathing , in which air is drawn into the alveoli of the lungs via  inhalation  and subsequently expelled via  exhalation . When a human being inhales, air travels down the trachea, through the bronchial tubes, and into the lungs.  The entire tract is protected by the rib cage,  spine , and  sternum . In the lungs, oxygen from the inhaled air is transferred into the blood and circulated throughout the body. Carbon dioxide (CO 2 ) is transferred from returning blood back into gaseous form in the lungs and exhaled through the lower respiratory tract and then the upper, to complete the process of  breathing ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4580", "text": "Unlike the  trachea  and  bronchi , the upper airway is a collapsible, compliant tube. As such, it has to be able to withstand suction pressures generated by the rhythmic expansion of the  thoracic cavity  that sucks air into the lungs. This is accomplished by the contraction of upper airway muscles during inhalation, such as the  genioglossus  (tongue) and the  hyoid  muscles. In addition to rhythmic innervation from the  respiratory center  in the  medulla oblongata , the  motor neurons  controlling the muscles also receive tonic innervation that sets a baseline level of stiffness and size."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4581", "text": "The  diaphragm  is the primary muscle that allows for lung expansion and contraction. Smaller muscles between the ribs, the  external intercostals , assist with this process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4582", "text": "The epithelial lining of the upper respiratory tract is interspersed with  goblet cells  that secrete a protective  mucus . This helps to filter waste, which is eventually either swallowed into the highly acidic stomach environment or expelled via spitting. The epithelium lining the respiratory tract is covered in small hairs called  cilia . These beat rhythmically out from the lungs, moving secreted mucus foreign particles toward the  laryngopharynx  upwards and outwards, in a process called  mucociliary clearance , they prevent mucus accumulation in the lungs.  Macrophages  in the alveoli are part of the immune system which  engulf  and digest any inhaled harmful agents."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4583", "text": "Hair in the nostrils plays a protective role, trapping particulate matter such as dust. [ 14 ]  These hairs, called vibrissae, are thicker than body hair and effectively block larger particles from entering the respiratory tract.  They also increase the surface area for particle deposition, improving the nose's ability to filter pathogens.  [ 15 ]  The  cough reflex  expels all irritants within the mucous membrane to the outside. The airways of the lungs contain rings of muscle. When the passageways are irritated by some allergen, these muscles can constrict."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4584", "text": "The respiratory tract is a common site for infections."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4585", "text": "Upper respiratory tract infections  are probably the most common infections in the world."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4586", "text": "The respiratory system is very prone to developing infections in the lungs. Infants and older adults are more likely to develop infections in their lungs because their lungs are not as strong in fighting off these infections. Most of these infections used to be fatal, but with new research and medicine, they are now treatable. With bacterial infections, antibiotics are prescribed, while viral infections are harder to treat but still curable."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4587", "text": "The  common cold , and  flu  are the most common causes of an upper respiratory tract infection, which can cause more serious illness that can develop in the lower respiratory \ntract."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4588", "text": "Pneumonia  is the most common, and frequent  lower respiratory tract infection . This can be either viral, bacterial, or fungal. This infection is very common because pneumonia can be airborne, and when you inhale this infection in the air, the particles enter the lungs and move into the air sacs. This infection quickly develops in the lower part of the lung and fills the lung with fluid, and excess mucus. This causes difficulty in breathing and coughing as the lower respiratory tract tries to get rid of the fluid in the lungs. You can be more prone to developing this infection if you have asthma, flu, heart disease, or cancer [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4589", "text": "Bronchitis  is another common infection that takes place in the lower respiratory tract. It is an inflammation of the bronchial tubes. There are two forms of this infection: acute bronchitis, which is treatable and can go away without treatment, or chronic bronchitis, which comes and goes, but will always affect one's lungs. Bronchitis increases the amount of mucus that is natural in your respiratory tract.  Chronic bronchitis is common in smokers, because the tar from smoking accumulates over time, causing the lungs to work harder to repair themselves. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4590", "text": "Tuberculosis  is one of many other infections that occurs in the lower respiratory tract. You can contract this infection from airborne droplets, and if inhaled you are at risk of this disease. This is a bacterial infection that deteriorates the lung tissue resulting in coughing up blood. [ 18 ]  This infection is deadly if not treated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4591", "text": "Some of these  cancers  have environmental causes such as smoking. When a tobacco product is inhaled, the smoke paralyzes the cilia, causing mucus to enter the lungs. Frequent smoking, over time, causes the cilia hairs to die and can no longer filter mucus. Tar from the smoke inhaled enters the lungs, turning the pink-coloured lungs black. The accumulation of this tar could eventually lead to  lung cancer , or  chronic obstructive pulmonary disease . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4592", "text": "Chronic obstructive pulmonary disease  (COPD) is a common lower respiratory disease that can be caused by exposure to harmful chemicals, or prolonged use of tobacco. This disease is chronic and progressive, the damage to the lungs is irreversible and eventually fatal. COPD destroys the alveoli, and lung tissue which makes breathing very difficult, causing  shortness of breath ,  hyperventilation , and raised chest. The decreased number of alveoli causes loss of oxygen supply to the lungs and an increased accumulation of carbon dioxide. There are two types of COPD: primary and secondary. [ citation needed ]  Primary COPD can be found in younger adults. This type of COPD deteriorates the air sacs, and lung mass. Secondary COPD can be found in older adults who smoke or have smoked and have a history of bronchitis.  [ citation needed ]  COPD includes symptoms of  emphysema  and  chronic bronchitis . [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4593", "text": "The bronchi are the main passages to the right and left lungs. These airways carry oxygen to the bronchioles inside the lungs.  Inflammation  of the bronchii and bronchioles can cause them to swell up,  which could lead to an  asthma  attack. This results in  wheezing , tightness of the chest, and severe difficulty in breathing. There are different types of asthma that affect the functions of the bronchial tubes. Allergies can also set off an allergic reaction, causing swelling of the bronchial tubes; as a result, the air passage will swell up, or close up completely. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4594", "text": "In general, air is inhaled  through the nose . It can be inhaled through the mouth if it is not possible to breathe through the nose. However, chronic  mouth breathing  can cause a dry mouth and lead to infections. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4595", "text": "Subcutaneous administration  is the insertion of medications beneath the skin either by injection or infusion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4596", "text": "A  subcutaneous injection  is administered as a  bolus  into the  subcutis , the layer of skin directly below the  dermis  and  epidermis , collectively referred to as the  cutis . The instruments are usually a  hypodermic needle  and a  syringe . Subcutaneous injections are highly effective in administering medications such as  insulin ,  morphine ,  diacetylmorphine  and  goserelin . Subcutaneous administration may be  abbreviated  as  SC ,  SQ ,  subcu ,  sub-Q ,  SubQ ,  or  subcut .  Subcut  is the preferred abbreviation to reduce the risk of misunderstanding and potential errors. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4597", "text": "Subcutaneous tissue has few blood vessels and so drugs injected into it are intended for slow, sustained rates of absorption, often with some amount of  depot  effect. Compared with other  routes of administration , it is slower than  intramuscular injections  but still faster than  intradermal injections .  Subcutaneous infusion  (as opposed to subcutaneous injection) is similar but involves a continuous drip from a bag and line, as opposed to injection with a syringe."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4598", "text": "A subcutaneous injection is administered into the fatty tissue of the  subcutaneous tissue , located below the  dermis  and  epidermis . [ 2 ]  They are commonly used to administer medications, especially those which cannot be administered by mouth as they would not be absorbed from the  gastrointestinal tract . A subcutaneous injection is absorbed slower than a substance injected  intravenously  or  into a muscle , but faster than a medication administered by mouth. [ 3 ] :\u200a721"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4599", "text": "Medications commonly administered via subcutaneous injection or infusion include  insulin ,  live vaccines ,  monoclonal antibodies , and  heparin . These medications cannot be administered orally as the molecules are too large to be absorbed in the intestines. [ 4 ]  Subcutaneous injections can also be used when the increased bioavailability and more rapid effects over oral administration are preferred. They are also the easiest form of  parenteral administration  of medication to perform by lay people, and are associated with less adverse effects such as pain or infection than other forms of injection. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4600", "text": "Perhaps the most common medication administered subcutaneously is insulin. While attempts have been made since the 1920s to administer insulin orally, the large size of the molecule has made it difficult to create a formulation with absorption and predictability that comes close to subcutaneous injections of insulin. [ 5 ]  People with  type 1 diabetes  almost all require insulin as part of their treatment regimens, and a smaller proportion of people with  type 2 diabetes  do as well \u2014 with tens of millions of prescriptions per year in the United States alone. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4601", "text": "Insulin historically was injected from a vial using a syringe and needle, but may also be administered subcutaneously using devices such as  injector pens  or  insulin pumps . An insulin pump consists of a catheter which is inserted into the subcutaneous tissue, and then secured in place to allow insulin to be administered multiple times through the same injection site. [ 3 ] :\u200a722"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4602", "text": "Subcutaneous injection may also be used by people to (self-) administer  recreational drugs . This can be referred to as  skin popping . [ 7 ]  In some cases, the administration of illicit drugs in this way is associated with unsafe practices leading to infections and other adverse effects. In rare cases, this results in serious side effects such as  AA amyloidosis . [ 7 ]  Recreational drugs reported to be administered subcutaneously have included  cocaine , [ 8 ]   mephedrone , [ 9 ]  and  amphetamine  derivatives such as  PMMA . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4603", "text": "Contraindications to subcutaneous injections primarily depend on the specific medication being administered. Doses which would require more than 2 mL to be injected at once are not administered subcutaneously. [ 11 ]  Medications which may cause necrosis or otherwise be damaging or irritating to tissues should also not be administered subcutaneously. [ 12 ]  An injection should not be given at a specific site if there is inflammation or skin damage in the area. [ 13 ] :\u200a144"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4604", "text": "With normal doses of medicine (less than 2 mL in volume), complications or adverse effects are very rare. The most common adverse reactions after subcutaneous injections are administered are termed \" injection site reactions \". This term encompasses any combination of redness, swelling, itching, bruising, or other irritation that does not spread beyond the immediate vicinity of the injection. [ 14 ]  Injection site reactions may be minimized if repeated injections are necessary by moving the injection site at least one inch from previous injections, or using a different injection location altogether. [ 14 ]  There may also be specific complications associated with the specific medication being administered."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4605", "text": "Due to the frequency of injections required for the administration of insulin products via subcutaneous injection, insulin is associated with the development of  lipohypertrophy  and  lipoatrophy . This can lead to slower or incomplete absorption from the injection site. Rotating the injection site is the primary method of preventing changes in tissue structure from insulin administration. [ 15 ]  Heparin-based anticoagulants injected subcutaneously may cause  hematoma  and bruising around the injection site due to their anticoagulant effect. This includes  heparin  and  low molecular weight heparin  products such as enoxaparin. There is some low certainty evidence that administering the injection more slowly may decrease the pain from heparin injections, but not the risk of or extent of bruising. [ 16 ]  Subcutaneous heparin-based anticoagulation may also lead to necrosis of the surrounding skin or lesions, most commonly when injected in the abdomen. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4606", "text": "Many medications have the potential to cause local lesions or swelling due to the irritating effect the medications have on the skin and subcutaneous tissues. This includes medications such as  apomorphine [ 18 ]  and  hyaluronic acid  injected as a filler, which may cause the area to appear bruised. Hyaluronic acid \"bruising\" may be treated using injections of  hyaluronidase  enzyme around the location. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4607", "text": "Other common medication-specific side effects include pain, burning or stinging, warmth, rash, flushing, or multiple of these reactions at the injection site, collectively termed \"injection site reactions\". This is seen with the subcutaneous injection of  triptans  for migraine headache, [ 20 ]   medroxyprogesterone acetate  for contraception, [ 21 ]  as well as many monoclonal antibodies. In most cases, injection site reactions are self-limiting and resolve on their own after a short time without treatment, and do not require the medication to be discontinued. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4608", "text": "The administration of vaccines subcutaneously is also associated with injection site reactions. This includes the  BCG vaccine  which is associated with a specific scar appearance which can be used as evidence of prior vaccination. [ 22 ]  Other subcutaneous vaccines, many of which are live vaccines including the  MMR vaccine  and the  varicella vaccine , which may cause  fever  and rash, as well as a feeling of general  malaise  for a day or two following the vaccination. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4609", "text": "Subcutaneous injections are performed by cleaning the area to be injected followed by an injection, usually at a 45-degree angle to the skin when using a syringe and needle, or at a 90-degree angle (perpendicular) if using an injector pen. The appropriate injection angle is based on the length of needle used, and the depth of the subcutaneous fat in the skin of the specific person. A 90-degree angle is always used for medications such as  heparin . If administered at an angle, the skin and underlying tissue may be pinched upwards prior to injection. The injection is administered slowly, lasting about 10 seconds per milliliter of fluid injected, and the needle may be left in place for 10 seconds following injection to ensure the medicine is fully injected. [ 3 ] :\u200a724"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4610", "text": "The  gauge  of the needle used can range from 25 gauge to 27 gauge, while the length can vary between  1 \u2044 2 -inch to  5 \u2044 8 -inch for injections using a syringe and needle. [ 3 ] :\u200a722\u200a  For subcutaneous injections delivered using devices such as  injector pens , the needle used may be as thin as 34 gauge (commonly 30\u201332 gauge), and as short as 3.5\u00a0mm (commonly 3.5\u00a0mm to 5\u00a0mm). [ 24 ]  Subcutaneous injections can also be delivered via a pump system which uses a cannula inserted under the skin. The specific needle size/length, as well as appropriateness of a device such as a pen or pump, is based on the characteristics of a person's skin layers. [ 3 ] :\u200a722\u2013724"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4611", "text": "Commonly used injection sites include: [ 3 ] :\u200a723"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4612", "text": "The choice of specific injection site is based on the medication being administered, with  heparin  almost always being administered in the abdomen, as well as preference. Injections administered frequently or repeatedly should be administered in a different location each time, either within the same general site or a different site, but at least one inch away from recent injections. [ 3 ] :\u200a724"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4613", "text": "As opposed to intramuscular or intravenous injections, subcutaneous injections can be easily performed by people with minor skill and training required. The injection sites for self-injection of medication are the same as for injection by a healthcare professional, and the skill can be taught to patients using pictures, videos, or models of the subcutaneous tissue for practice. People who are to self-inject medicine subcutaneously should be trained how to evaluate and rotate the injection site if complications or contraindications arise. Self-administration by subcutaneous injection generally does not require disinfection of the skin outside of a hospital setting as the risk of infection is extremely low, but instead it is recommended to ensure that the site and person's hands are simply clean prior to administration. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4614", "text": "Subcutaneous infusion , also known as  interstitial infusion  or  hypodermoclysis , is a form of subcutaneous (under the skin) administration of fluids to the body, often  saline  or glucose solutions. [ 26 ]  It is the infusion counterpart of  subcutaneous injection  with a syringe."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4615", "text": "Subcutaneous infusion can be used where a slow rate of fluid uptake is required compared to  intravenous infusion .  Typically, it is limited to 1 mL per minute, although it is possible to increase this by using two sites simultaneously.  The chief advantages of subcutaneous infusion over intravenous infusion is that it is cheap and can be administered by non-medical personnel with minimal supervision.  It is therefore particularly suitable for home care.  The enzyme  hyaluronidase  can be added to the fluid to improve absorption during the infusion. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4616", "text": "Subcutaneous infusion can be speeded up by applying it to multiple sites simultaneously.  The technique was pioneered by  Evan O'Neill Kane  in 1900.  Kane was looking for a technique that was as fast as intravenous infusion but not so risky to use on trauma patients in unhygienic conditions in the field. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4617", "text": "Sublingual  ( abbreviated   SL ), from the  Latin  for \"under the  tongue \", refers to the  pharmacological   route of administration  by which substances diffuse into the  blood  through  tissues  under the tongue. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4618", "text": "Many drugs are absorbed through sublingual administration, including  cardiovascular  drugs,  steroids ,  barbiturates ,  benzodiazepines , [ 2 ]   opioid   analgesics ,  THC ,  CBD , some  proteins  and increasingly,  vitamins  and  minerals ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4619", "text": "When a  chemical  comes in contact with the  mucous membrane  beneath the tongue, it is absorbed.  Because the  connective tissue  beneath the epithelium contains a profusion of capillaries, the substance then diffuses into them and enters the venous circulation. [ 1 ]   In contrast, substances absorbed in the intestines are subject to  first-pass metabolism  in the liver before entering the general circulation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4620", "text": "Sublingual administration has certain advantages over oral administration.  Being more direct, it is often faster  onset of action , and it ensures that the substance will risk degradation only by salivary enzymes before entering the bloodstream, whereas orally administered drugs must survive passage through the hostile environment of the  gastrointestinal tract , which risks degrading them, by either stomach acid or bile, or by  enzymes  such as  monoamine oxidase  (MAO).  Furthermore, after absorption from the gastrointestinal tract, such drugs must pass to the  liver , where they may be extensively altered; this is known as the  first pass effect  of drug metabolism.  Due to the digestive activity of the stomach and intestines, the oral route is unsuitable for certain substances, such as  salvinorin A ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4621", "text": "Pharmaceutical preparations for sublingual administration are manufactured in the form of:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4622", "text": "Almost any form of substance may be amenable to sublingual administration if it dissolves easily in saliva.  Powders and aerosols may all take advantage of this method.  However, a number of factors, such as  pH ,  molecular weight , and  lipid solubility , may determine whether the route is practical.  Based on these properties, a suitably soluble drug may diffuse too slowly through the mucosa to be effective.  However, many drugs are much more potent taken sublingually, and it is generally a safer alternative than administration via the nasal mucosa. [ citation needed ]   This method is also extensively used by people administering certain psychoactive drugs.  One drawback, however, is  tooth discoloration  and decay caused by long-term use of this method with acidic or otherwise caustic drugs and fillers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4623", "text": "In addition to  salvinorin A , other psychoactives may also be applied sublingually.   LSD ,  MDMA ,  morphine ,  alprazolam ,  clonazepam ,  diazepam , and many other substances including the psychedelic  tryptamines  and  phenethylamines , and even recreational  cannabis edibles  ( THC ) are all viable candidates for administration via this route. [ citation needed ]   Most often, the drug in question is powdered and placed in the mouth (often directly under the tongue).  If held there long enough, the drug will diffuse into the blood stream, bypassing the GI tract.  This may be a preferred method to simple oral administration, because MAO is known to oxidize many drugs (especially the tryptamines such as  DMT ) and because this route translates the chemical directly to the brain, where most psychoactives act.  The method is limited by excessive salivation washing the chemical down the throat.  Also, many alkaloids have an unpleasant taste which makes them difficult to hold in the mouth.  Tablets of psychoactive pharmaceuticals usually include bitter chemicals such as  denatonium  in order to discourage abuse and also to discourage children from eating them. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4624", "text": "Allergens  may also be applied under the tongue as a part of  allergen immunotherapy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4625", "text": "A relatively new way of administration of therapeutic  peptides  and proteins (such as  cytokines , domain  antibodies ,  Fab fragments  or single chain antibodies)  is sublingual administration.  Peptides and proteins are not stable in the  gastro-intestinal tract , mainly due to degradation by enzymes and pH differences.  As a consequence, most peptides (such as  insulin ,  exenatide ,  vasopressin , etc.) or proteins (such as  interferon ,  EPO  and  interleukins ) have to be administered by injection. Recently, new technologies have allowed sublingual administration of such molecules.  Increased efforts are underway to deliver macromolecules (peptides, proteins and immunotherapies)  by sublingual route, by companies such as  Novo Nordisk ,  Sanofi  and BioLingus. [ 3 ] \nSublingual delivery may be particularly effective for immuno-active medicines, due to the presence of immune-receptor cells close to the sublingual area."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4626", "text": "The sublingual route may also be used for  vaccines  against various infectious diseases. Thus, preclinical studies have found that sublingual vaccines can be highly immunogenic and may protect against influenza virus [ 4 ] [ 5 ] \nand  Helicobacter pylori , [ 6 ]  but sublingual administration may also be used for vaccines against other infectious diseases. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4627", "text": "A  suppository  is a  dosage form  used to deliver  medications  by insertion into a  body orifice  (any opening in the body), where it dissolves or melts to exert local or systemic effects. There are three types of suppositories, each to insert into a different sections: rectal suppositories into the  rectum , vaginal suppositories into the  vagina , and urethral suppositories into the  urethra of a male ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4628", "text": "Suppositories are ideal for infants, elderly individuals and post-operative patients, who are unable to swallow oral medications, and for individuals experiencing severe nausea and/or vomiting. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4629", "text": "Several different ingredients can be used to form the base of a suppository:  cocoa butter  or a similar substitute,  polyethylene glycol ,  hydrogels , and glycerinated  gelatin . The type of material used depends on the type of suppository, the type of drug, and the conditions in which the suppository will be stored. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4630", "text": "In 1991, a study on suppository insertion in  The Lancet  found that the \"torpedo\" shape helps the device to travel internally, increasing its efficacy. [ 5 ]  The findings of this single study have been challenged as there is insufficient evidence on which to base clinical practice. [ 6 ]  Rectal suppositories are intended for localized or systemic action to relieve pain, constipation, irritation, inflammation, nausea and vomiting, fever, migraines, allergies, and sedation. [ 7 ] [ 8 ]  If they cause inflammation, chronic use of suppositories may cause  rectal stricture , [ 9 ]  but overall this is a safe method of drug delivery. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4631", "text": "Alprostadil  pellets are urethral suppositories used for the treatment of severe  erectile dysfunction (impotence) . They are marketed under the name  Muse  in the United States. [ 11 ]  Its use has diminished since the development of oral impotence medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4632", "text": "Modified-release dosage  is a mechanism that (in contrast to immediate-release  dosage ) delivers a  drug  with a delay after its  administration  (delayed-release dosage) or for a prolonged period of time (extended-release [ER, XR, XL] dosage) or to a specific target in the body (targeted-release dosage). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4633", "text": "Sustained-release dosage forms  are  dosage forms  designed to  release (liberate) a drug  at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum  side effects . This can be achieved through a variety of formulations, including  liposomes  and drug-polymer conjugates (an example being  hydrogels ). Sustained release's definition is more akin to a \"controlled release\" rather than \"sustained\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4634", "text": "Extended-release dosage consists of either sustained-release (SR) or controlled-release (CR) dosage. SR maintains drug release over a sustained period but not at a constant rate. CR maintains drug release over a sustained period at a nearly constant rate. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4635", "text": "Sometimes these and  other terms  are treated as synonyms, but the United States  Food and Drug Administration  has in fact defined most of these as different concepts. [ 1 ]  Sometimes the term \"depot tablet\" is used, by analogy to the term for an  injection formulation of a drug which releases slowly over time , but this term is not medically or pharmaceutically standard for oral medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4636", "text": "Modified-release dosage and its variants are mechanisms used in  tablets  (pills) and  capsules  to  dissolve  a  drug  over time in order to be released more slowly and steadily into the bloodstream, while having the advantage of being taken at less frequent intervals than immediate-release (IR) formulations of the same drug. For example, orally administered  extended-release morphine  can enable certain chronic pain patients to take only  1\u20132  tablets per day, rather than needing to redose every  4\u20136 \u00a0 hours  as is typical with standard-release morphine tablets."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4637", "text": "Most commonly it refers to time-dependent release in oral dose formulations. Timed release has several distinct variants such as sustained release where prolonged release is intended, pulse release, delayed release (e.g. to target different regions of the GI tract) etc. A distinction of controlled release is that it not only prolongs action, but it attempts to maintain drug levels within the  therapeutic window  to avoid potentially hazardous peaks in drug concentration following ingestion or injection and to maximize therapeutic efficiency."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4638", "text": "In addition to pills, the mechanism can also apply to capsules and injectable  drug carriers  (that often have an additional release function), forms of controlled release medicines include gels, implants and devices (e.g. the  vaginal ring  and  contraceptive implant ) and  transdermal patches ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4639", "text": "Examples for cosmetic, personal care, and food science applications often centre on odour or flavour release."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4640", "text": "The release technology scientific and industrial community is represented by the Controlled Release Society (CRS). The CRS is the worldwide society for delivery science and technologies. CRS serves more than 1,600 members from more than 50 countries. Two-thirds of CRS membership is represented by industry and one-third represents academia and government. CRS is affiliated with the  Journal of Controlled Release  and  Drug Delivery and Translational Research  scientific journals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4641", "text": "There is no industry standard for these abbreviations, and confusion and misreading have sometimes caused prescribing errors. [ 2 ]  Clear handwriting is necessary. For some drugs with multiple formulations, putting the meaning in parentheses is advisable."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4642", "text": "A few other abbreviations are similar to these (in that they may serve as suffixes) but refer to dose rather than release rate. They include  ES  and  XS  (Extra Strength)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4643", "text": "Today, most time-release drugs are formulated so that the  active ingredient  is embedded in a matrix of insoluble substance(s) (various: some  acrylics , even  chitin ; these substances are often  patented ) such that the dissolving drug must find its way out through the holes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4644", "text": "In some SR formulations, the drug dissolves into the matrix, and the matrix physically swells to form a gel, allowing the drug to exit through the gel's outer surface."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4645", "text": "Micro-encapsulation  is also regarded as a more complete technology to produce complex dissolution profiles. Through coating an active pharmaceutical ingredient around an inert core and layering it with insoluble substances to form a microsphere, one can obtain more consistent and replicable dissolution rates in a convenient format that can be mixed and matched with other instant release pharmaceutical ingredients into any two piece gelatin  capsule ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4646", "text": "There are certain considerations for the formation of sustained-release formulation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4647", "text": "The  biological half-life  of the drug refers to the drug's elimination from the bloodstream which can be caused by metabolism, urine, and other forms of excretion. If the active compound has a long half-life (over 6 hours), it is sustained on its own. If the active compound has a short half-life, it would require a large amount to maintain a prolonged effective dose. In this case, a broad therapeutic window is necessary to avoid toxicity; otherwise, the risk is unwarranted and another mode of administration would be recommended. [ 3 ]  Appropriate half-lives used to apply sustained methods are typically 3\u20134 hours and a drug dose greater than 0.5 grams is too high. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4648", "text": "The  therapeutic index  also factors whether a drug can be used as a time release drug. A drug with a thin therapeutic range, or small therapeutic index, will be determined unfit for a sustained release mechanism in partial fear of  dose dumping  which can prove fatal at the conditions mentioned. [ 6 ]  For a drug that is made to be released over time, the objective is to stay within the therapeutic range as long as needed. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4649", "text": "There are many different methods used to obtain a sustained release."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4650", "text": "Diffusion systems' rate release is dependent on the rate at which the drug dissolves through a barrier which is usually a type of polymer. Diffusion systems can be broken into two subcategories, reservoir devices and matrix devices. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4651", "text": "Dissolution systems must have the system dissolved slowly in order for the drug to have sustained release properties which can be achieved by using appropriate salts and/or derivatives as well as coating the drug with a dissolving material. [ 3 ]  It is used for drug compounds with high solubility in water. [ 6 ]  When the drug is covered with some slow dissolving coat, it will eventually release the drug. Instead of diffusion, the drug release depends on the solubility and thickness of the coating. Because of this mechanism, the dissolution will be the rate limiting factor for drug release. [ 3 ]  Dissolution systems can be broken down to subcategories called reservoir devices and matrix devices. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4652", "text": "Osmotic controlled-release oral delivery systems (OROS) have the form of a rigid  tablet  with a semi-permeable outer membrane and one or more small  laser drilled  holes in it. As the tablet  passes through the body , water is absorbed through the  semipermeable membrane  via  osmosis , and the resulting  osmotic pressure  is used to push the active  drug  through the opening(s) in the tablet. OROS is a trademarked name owned by  ALZA Corporation , which pioneered the use of osmotic pumps for oral drug delivery. [ 10 ] [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4653", "text": "Osmotic release systems have a number of major advantages over other controlled-release mechanisms. They are significantly less affected by factors such as  pH , food intake,  GI motility , and differing intestinal environments. Using an osmotic pump to deliver drugs has additional inherent advantages regarding control over drug delivery rates. This allows for much more precise drug delivery over an extended period of time, which results in much more predictable  pharmacokinetics . However, osmotic release systems are relatively complicated, somewhat difficult to manufacture, and may cause irritation or even blockage of the GI tract due to prolonged release of irritating drugs from the non-deformable tablet. [ 10 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4654", "text": "In the ion-exchange method, the resins are cross-linked water-insoluble polymers that contain ionisable functional groups that form a repeating pattern of polymers, creating a polymer chain. [ 3 ] [ 6 ]  The drug is attached to the resin and is released when an appropriate interaction of ions and ion exchange groups occur. The area and length of the drug release and number of cross-link polymers dictate the rate at which the drug is released, determining the SR effect. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4655", "text": "A floating system is a system where it floats on gastric fluids due to low density. The density of the gastric fluids is about 1 g/mL; thus, the drug/tablet administered must have a smaller density. The  buoyancy  will allow the system to float to the top of the stomach and release at a slower rate without worry of excreting it. This system requires that there are enough gastric fluids present as well as food. [ 3 ]  Many types of forms of drugs use this method such as powders, capsules, and tablets. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4656", "text": "Bio-adhesive  systems generally are meant to stick to mucus and can be favorable for mouth based interactions due to high mucus levels in the general area but not as simple for other areas. Magnetic materials can be added to the drug so another magnet can hold it from outside the body to assist in holding the system in place. However, there is low patient compliance with this system. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4657", "text": "The matrix system is the mixture of materials with the drug, which will cause the drug to slow down. However, this system has several subcategories: hydrophobic matrices, lipid matrices, hydrophilic matrices, biodegradable matrices, and mineral matrices. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4658", "text": "Examples of stimuli that may be used to bring about release include pH, enzymes, light, magnetic fields, temperature, ultrasonics, osmosis, cellular traction forces, [ 21 ]  and electronic control of  MEMS [ 22 ]  and  NEMS . [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4659", "text": "Spherical hydrogels, in micro-size (50-600\u00a0\u03bcm diameter) with 3-dimensional cross-linked polymer, can be used as drug carrier to control the release of the drug. These hydrogels are called microgels. They may possess a negative charge as example DC-beads. By ion-exchange mechanism, a large amount of oppositely charged amphiphilic drugs can be loaded inside these microgels. Then, the release of these drugs can be controlled by a specific triggering factor like pH, ionic strength or temperature. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4660", "text": "Some time release formulations do not work properly if split, such as controlled-release tablet coatings, while other formulations such as micro-encapsulation still work if the microcapsules inside are swallowed whole. [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4661", "text": "Among the  health information technology  (HIT) that pharmacists use are medication safety tools to help manage this problem. For example, the ISMP \"do not crush\" list [ 27 ]  can be entered into the system so that warning stickers can be printed at the point of dispensing, to be stuck on the pill bottle."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4662", "text": "Pharmaceutical companies that do not supply a range of half-dose and quarter-dose versions of time-release tablets can make it difficult for patients to be slowly tapered off their drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4663", "text": "The earliest SR drugs are associated with a patent in 1938 by Israel Lipowski, who coated pellets which led to coating particles. [ 7 ]  The science of controlled release developed further with more oral sustained-release products in the late 1940s and early 1950s, the development of controlled release of marine anti-foulants in the 1950s, and  controlled release fertilizer  in the 1970s where sustained and controlled delivery of nutrients was achieved following a single application to the soil. Delivery is usually effected by dissolution, degradation, or disintegration of an  excipient  in which the active compound is formulated.  Enteric coating  and other encapsulation technologies can further modify release profiles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4664", "text": "Topical drug delivery  (TDD) is a  route of drug administration  that allows the topical formulation to be delivered across the skin upon application, hence producing a localized effect to treat skin disorders like  eczema . [ 1 ] [ 2 ]  The formulation of topical drugs can be classified into  corticosteroids ,  antibiotics ,  antiseptics , and  anti-fungal . The mechanism of topical delivery includes the  diffusion  and  metabolism  of drugs in the skin. [ 1 ]  Historically, topical route was the first route of medication used to deliver drugs in humans in ancient Egyptian and Babylonian in 3000 BCE. In these ancient cities, topical medications like  ointments  and  potions  were used on the skin. [ 3 ] [ 4 ]  The delivery of topical drugs needs to pass through multiple skin layers and undergo  pharmacokinetics , hence factor like dermal diseases minimize the  bioavailability  of the topical drugs. [ 5 ]  The wide use of topical drugs leads to the advancement in topical drug delivery. These advancements are used to enhance the delivery of topical medications to the skin by using chemical and physical agents. For chemical agents, carriers like  liposomes  and  nanotechnologies  are used to enhance the absorption of topical drugs. [ 4 ] [ 6 ]  On the other hand, physical agents, like  micro-needles  is other approach for enhancement ofabsorption. [ 4 ]  Besides using carriers, other factors such as  pH ,  lipophilicity , and drug molecule size govern the effectiveness of topical formulation. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4665", "text": "In ancient times, human skin was used as a layer for self-expression by painting cosmetic products on it. They used those products as a protection for their skin from the sun and dry environment. [ 3 ]  Later on in 2000 BCE, the Chinese used topical  remedies  that wrap in bandages to treat skin diseases. [ 4 ] [ 3 ]  The contact between these topical remedies and skin deliver its  therapeutic effect  on the skin. The newer development of topical drugs occurred between 130 and 200 AD. This development was made by  Claudius Galenus , a Greek physician. He first loaded the herb medication to Western medicine and formulated it as cream. [ 3 ]  More recently in the 1920s, some observations were made when applying topical skin, such as to determine its  systemic effects . [ 4 ]  In 1938,  Zondek  successfully managed  urogenital  infections after applying  chloroxylenol  on the skin by the use of  disinfectant  in ointment form. After some years, observations were made from various experiments. These experiments led to the development of skin toxicology in the mid-1970s, including symptoms like irritation, skin inflammation, and skin photo-toxicity upon application of topical drugs. After the development of  toxicology , a mathematical model was also created for skin diffusion coefficient formulated by Michaels. This formulation suggests how they related to the aqueous solubility and  partition coefficient  in skin. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4666", "text": "The human body's largest organ is the skin layers, which protects against foreign particles. [ 7 ] [ 8 ]  Human skin contains several layers, including the  subcutaneous layer , the  dermis , the  epidermis , the  stratum corneum , and the  appendages . Each of these layers have an effect on the absorption of topical drug. [ 1 ]  When the topical drug is applied to the skin, it must pass via the  stratum corneum , which is the outermost skin layer. [ 8 ]   Stratum corneum 's function includes prevention of water loss in skin and inhibit the penetration of foreign molecules into the dermal layers. [ 8 ]  Hence, it also prevents the  hydrophilic  molecules to get absorbed into the skin since it is made out of bilayered lipids. [ 9 ]  With this barrier,  stratum corneum  affects the permeability of topical drugs. Another part of the skin is called the  appendages , and it is known as the \u201cshortcut\u201d for topical drug delivery. The shortcut pathway allows the drug molecules to first pass the  stratum corneum  barrier via  hair follicles . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4667", "text": "When drugs are applied to skin topically, the drug molecules will undergo passive  diffusion . This process occurs down the  concentration gradient  when drug molecules move to one area to another region.  Diffusion  is described by a mathematical equation. [ 1 ] [ 4 ]  The drug molecule (J), known as  flux  and it represents the entry of topical drug molecules across the skin  membrane . The skin membrane is the area (A) for the topical drug molecules to travel across. The skin membrane thickness is known as (h) in the expression, and it determines the  diffusion  path length. [ 4 ]  The (C) is the concentration of the diffusing substance across the skin layers and the (D) is the  diffusion coefficient . The expression illustrates the transportation of topical drug molecules across the  stratum corneum  membrane through  diffusion . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4668", "text": "Diffusion expression:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4669", "text": "J \n = \n A \n D \n C \n \n / \n \n h \n \n \n {\\displaystyle J=ADC/h}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4670", "text": "Upon application of the topical drug on the skin, it will  diffuse  to the outer layer of the skin, known as  stratum corneum . There are three routes possible for the drugs to cross the skin. The first route is through the  appendages . It is known as the \"first cut\" where the drug molecules will be  partitioned  into the  sweat gland  to bypass the  stratum corneum  barrier. [ 1 ]  If the drug molecules is not transported via the \"first cut\", it is usually remains in the  stratum corneum's  bilayered lipids, where the drug molecules transport through either the  transcellular  route or  paracellular  route into the deeper area of the skin like subcutaneous layer. For the  paracellular  route, it means that the solutes transport via the junction between the cell. [ 10 ]  When the topical drug molecules transport via the paracellular route, it needs to travel across the  stratum corneum , which is a highly fat region, but between the cells. [ 9 ] [ 1 ]  On the other hand, the topical drug molecules may travel through the  transcellular  route. This route allows molecules to be transported via the cell.  Transcellular  route transports the drug molecule into the bilayered lipid cells found in  stratum corneum . Inside of the bilayered lipids in the  stratum corneum  is a water-soluble environment, and the drug molecules will  diffuse  through these bilayered lipids into deeper area of the skin. [ 1 ] [ 11 ]  During the transportation of the topical drug molecules, it can bind to the  keratin  that exists as one of the skin components in the  stratum corneum . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4671", "text": "The activities of skin  metabolism  are commonly occurring on the skin surface,  appendages , the  stratum corneum , and the  viable epidermis . [ 1 ] [ 5 ]  This process comprises phase one  hydrolysis ,  reduction , and  oxidation , also known as functionalization phase. If phase one is insufficient to metabolize the drugs, phase two  conjugation reaction  occurs. This phase includes  glucuronidation ,  sulfation , and  acetylation .  It is found that phase two activities are lower than phase two in the skin. [ 12 ]  One common example is thearylamine-type hair dye, after it is applied topically, it will undergo  metabolism  in the skin through  enzyme   N-acetyltransferase , thus resulting in a N-acetylated  metabolite . [ 5 ] [ 3 ]  These metabolic  enzymes  cause the loss of topical drug activities, thus reducing its  bioavailability . They may eventually form atoxic compound that reaches to the  systemic circulation  and causes damage to the skin layers. [ 13 ]  The longer the topical drug remains in the skin, the greater amount of it will be metabolized by the underlying enzymes. To reduce such an effect, the topical drug needs to remain on the skin for a shorter period of time. Also, certain amount of topical molecules needs to be applied to the skin and cause metabolic  enzymes  saturation. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4672", "text": "The amount of topical drug molecules being delivered to the skin is affected solely by the  physicochemical  properties of the topical drug. [ 1 ]  The first factor is the weight of the drug molecule. The smaller of the drug  molecular weight  or particle size, the higher rate of its  diffusion  and absorption into the skin. [ 1 ] [ 14 ]  The second factor is the  lipophilicity  of the drug molecules, since the three pathways for absorption are quite  lipophilic . The higher  lipophilicity  of it, the easier of the drug molecules to be absorbed when compared to the  hydrophilic  drug molecules. [ 14 ]  The third parameter is the  pH  level of the skin. The pH of the skin layers are basic, hence basic topical drugs will be absorbed better than acidic topical drugs. [ 14 ]  These factors are vital to determine the permeability of topical drug delivery. [ 3 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4673", "text": "Colloidal system  is one of the techniques used for topical drug delivery into the skin and functions as skin permeability enhancers. They are known as carriers and can be classified into  nanoparticles ,  liposomes , and nanoemugel. [ 15 ] [ 6 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4674", "text": "Liposomes  contain a bilayer of  phospholipids  in a sphere shape that may exist as one or more than one bilayer of  phospholipids.  With this structure, its function is to trap  hydrophilic  or  lipophilic  drug molecules within the spherical bilayers. [ 4 ]  The  hydrophilic  drug molecule sticks to the  hydrophilic  head since it is  polar  and favours water. On the other hand, the  lipophilic  drug molecules will be entrapped in the  phospholipid  tails of the bilayer due to its  lipophilic  nature. [ 6 ] [ 4 ]  With these mechanisms,  liposomes  will behave like carriers and carry the  lipophilic  or  hydrophilic  drug molecules into the  stratum corneum  and release them into deeper layers of the skin by interacting with the bilayers lipids found in  stratum corneum . [ 15 ]  The Use of  liposome  as carrier enhances the overall permeability of topical drug into the skin to reach the target site. [ 15 ] [ 17 ]  For example, a drug like  amphotericin B , is used to treat fungal infections. [ 18 ]  The drug is loaded into  liposome  and this carrier enhances the penetration of  amphotericin B  into the skin, regardless of its  molecular weight . [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4675", "text": "Nanoemulgel is another type of enhancer for delivery of topical drugs into the skin. The formulation process for nanoemulgel is produced by incorporating the nanoemulsion into a  gel  matrix. The  gels  are made out of aqueous bases and it allows for a more rapid release of drugs through dissolution. The use of nanoemulgel enhances patient compliance because the use of gel is less greasy than traditional  cream  or  ointment , hence there is less incident in skin irritation. [ 16 ]  Nanoemulgel increases the topical drug  bioavailability  by inserting the  lipophilic  drug molecules into the oil droplet of the nanoemulgel and it will travel through the skin layers. With its high dissolution rate, the nanoemulgel produces a high  concentration gradient  toward the skin, thus allowing for a rapid uptake of oil droplet into the  stratum corneum . Also, the  surfactant  being incorporated into the nanoemulgel has the ability to penetrate through the bilayer lipid by interrupting the  hydrogen bond  between the lipid in the skin to further enhance its permeability. [ 16 ]  In terms of treatment, the use of nanoemulgel is against cancer cells and useful in skin cancer. [ 16 ]   Also, the formulation of nanoemulgel with  methoxsalen  is used to treat  psoriasis . The carrier enhances both the penetration and accumulation of  methoxsalen  in the skin layers. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4676", "text": "Micro-needle  belongs to the physical enhancer to improve absorption of topical drug molecules into the skin. It is known as \u2018poke and patch\u2019 because it uses tiny needles and stick into the skin across the  stratum corneum . [ 6 ] [ 4 ]  These tiny needles ensure that they will not contact the nerve endings or  cutaneous  blood vessels under the skin, hence they can be removed easily from the skin. [ 21 ]  There are several types of micro-needle, the first one is solid micro-needles. The solid micro-needles are used to project into the skin. Once the needles are removed after insertion, the topical drugs are applied to skin. This enhances the ability of drugs to diffuse across the  viable epidermis . The second type is the dissolvable micro-needle. These types of needles are composed of materials that allow them to dissolve after poking into the skin, hence no need to remove the needles after injection. The third type of micro-needle is the swell-able micro-needles, which consist of  hydrogel . [ 22 ]  After poking its needle into the skin, it allows the skin  interstitial fluid  diffuse into the micro-needles, thus it will swell to  diffuse  the drug molecules across the skin. [ 4 ] [ 23 ]  It is found that micro-needles are safe and effective in enhancing skin permeability. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4677", "text": "A  topical medication  is a  medication  that is applied to a particular place on or in the body. Most often topical medication means application to  body surfaces  such as the  skin  or  mucous membranes  to treat ailments via a large range of classes including  creams ,  foams ,  gels ,  lotions , and ointments. [ 1 ]   Many topical medications are epicutaneous, meaning that they are applied directly to the skin. Topical medications may also be  inhalational , such as  asthma medications , or applied to the surface of tissues other than the skin, such as  eye drops  applied to the  conjunctiva , or  ear drops  placed in the ear, or medications applied to the surface of a  tooth . The word  topical  derives from  Greek   \u03c4\u03bf\u03c0\u03b9\u03ba\u03cc\u03c2   topikos , \"of a place\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4678", "text": "Topical drug delivery is a route of administering  drugs  via the  skin  to provide topical therapeutic effects. As skin is one of the largest and most superficial  organs  in the  human  body,  pharmacists  utilise it to deliver various drugs. This system usually provides a local effect on certain positions of the body. In ancient times, people used  herbs  to put on wounds for relieving the inflammatory effect or as pain relievers. The use of  topical drug  delivery system is much broader now, from  smoking cessation  to beauty purposes. Nowadays, there are numerous  dosage forms  that can be used topically, including  cream ,  ointment ,  lotion ,  patches , dusting powder and much more. [ 2 ]  There are many advantages for this  drug delivery system  \u2013 avoiding  first pass metabolism  which can increase its  bioavailability , being convenient and easy to apply to a large area, being easy to terminate the medication and avoiding gastro-intestinal irritations. All these can increase patient compliance. However, there are several disadvantages to this system \u2013 causing  skin irritations  and symptoms like  rashes  and  itchiness  may occur. Also, only small  particles  can pass through the skin, which limits the choice of  drugs . Since skin is the main medium of the topical drug delivery system, its conditions determine the rate of skin penetration leading to affecting the  pharmacokinetics  of the  drug . The  temperature ,  pH value , and dryness of the skin need to be considered. There are some novel topical drugs in the market which can utilise the system as much as possible."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4679", "text": "This localized system provides topical therapeutic effects via skin,  eyes ,  nose  and  vagina [ 3 ]  to treat  diseases . The most common usage is for local  skin infection  problems. Dermatological products have various  formulations  and range in consistency though the most popular dermal products are semisolid dosage forms [ 4 ]  to provide topical treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4680", "text": "Topical drug absorption depends on two major factors \u2013 biological and physicochemical properties."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4681", "text": "The first factor concerns body structure effects on the  drugs . The degradation of drugs can be affected by the site of applications. Some studies discovered different  Percutaneous  absorption patterns. Apart from the place, age also affects the absorption as the skin structure changes with age. The lowered  collagen  and broadened  blood capillary  networks happen with aging. These features alter the effectiveness of absorption of both hydrophilic and  lipophilic substances  into  stratum  corneum underneath the surface of the skin. [ 5 ]  The skin surface integrity can also affect the permeability of drugs such as the density of  hair follicles ,  sweat glands  or disintegrated by  inflammation  or  dehydration ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4682", "text": "The other factor concerns metabolism of medications on skin. When the percutaneous drug is applied on skin, it will be gradually absorbed down the skin. Normally, when the drugs are absorbed, they will be metabolised by various  enzymes  in our body and the amount will be lower. The exact amount delivered to the target action site determines the potency and bioavailability of the drugs. If the  concentration  is too low, the therapeutic effect is impeded; if the concentration is too high, drug toxicity may happen to cause side effects or even do harm to our body. For the  topical drug  delivery way, degradation of drugs in skin is very low compared to  liver . The metabolism of drugs is mainly by metabolic enzyme  cytochrome P450 , and this enzyme is not active in skin. The  CYP450  actively metabolized drugs can then maintain high concentration when being applied on skin. Despite  CYP450  enzyme action, the  partition coefficient  (K) determines the activity of topical drugs. The ability of drug particles to go through the skin layer also affects the absorption of drugs. For transdermal activity, medicines with higher K value are harder to get rid of the  lipid layer of skin cells . The trapped molecules then cannot penetrate into the skin. This reduces the efficacy of the transdermal drugs. The drugs target cells underneath the skin or need to diffuse into  blood capillary  to exert their effect. Meanwhile, the size of particles affects this transdermal process. The smaller the drug molecules, the faster the rate of penetration.  Polarity  of the drugs can affect this diffusion rate too. If the drug shows lower degree of ionization, it is less polar. Therefore, it can have a faster absorption rate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4683", "text": "The definition of the topical  route of administration  sometimes states that both the application location and the  pharmacodynamic  effect thereof is local. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4684", "text": "In other cases,  topical  is defined as applied to a localized area of the body or to the surface of a body part regardless of the location of the effect. [ 7 ] [ 8 ]  By this definition, topical administration also includes  transdermal  application, where the substance is administered onto the skin but is  absorbed  into the body to attain  systemic  distribution. Such medications are generally  hydrophobic  chemicals, such as  steroid hormones . Specific types include  transdermal patches  which have become a popular means of administering some drugs for  birth control ,  hormone replacement therapy , and prevention of  motion sickness . One example of an  antibiotic  that may be applied topically is  chloramphenicol ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4685", "text": "If defined strictly as having a local effect, the topical  route of administration  can also include  enteral administration  of medications that are poorly absorbable by the  gastrointestinal tract . One poorly absorbable antibiotic is  vancomycin , which is recommended by mouth as a treatment for severe  Clostridioides difficile  colitis . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4686", "text": "A medication's potency often is changed with its base. For example, some  topical steroids  will be classified one or two strengths higher when moving from cream to ointment. As a rule of thumb, an ointment base is more occlusive and will drive the medication into the skin more rapidly than a solution or cream base. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4687", "text": "The manufacturer of each topical product has total control over the content of the base of a medication. Although containing the same active ingredients, one manufacturer's cream might be more acidic than the next, which could cause skin irritation or change its absorption rate. For example, a vaginal formulation of  miconazole  antifungal cream might irritate the skin less than an athlete's foot formulation of miconazole cream. These variations can, on occasion, result in different  clinical outcomes , even though the active ingredient is the same. No comparative potency labeling exists to ensure equal efficacy between brands of topical steroids (percentage of oil vs water dramatically affect the potency of topical steroid). Studies have confirmed that the potency of some topical steroid products may differ according to manufacturer or brand. An example of this is the case of brand name  Valisone  cream and  Kenalog  cream in clinical studies have demonstrated significantly better vasoconstrictions than some forms of this drug produced by  generic drug  manufacturers. [ 10 ]  However, in a simple base like an ointment, much less variation between manufacturers is common."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4688", "text": "In  dermatology , the base of a topical medication is often as important as the medication itself. It is extremely important to receive a medication in the correct base, before applying to the skin. A pharmacist should not substitute an ointment for a cream, or vice versa, as the potency of the medication can change. Some physicians use a thick ointment to replace the waterproof barrier of the inflamed skin in the treatment of eczema, and a cream might not accomplish the same clinical intention."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4689", "text": "There are many general classes, with no clear dividing line among similar formulations. As a result, what the manufacturer's marketing department chooses to list on the label of a topical medication might be completely different from what the form would normally be called."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4690", "text": "A  cream  is an emulsion of oil and water in approximately equal proportions. It penetrates the  stratum corneum  outer layer of skin wall. Cream is thicker than lotion, and maintains its shape when removed from its container. It tends to be moderate in moisturizing tendency. For topical steroid products, oil-in-water emulsions are common. Creams have a significant risk of causing  immunological sensitization  due to  preservatives  and have a high rate of acceptance by patients. There is a great variation in ingredients, composition, pH, and tolerance among generic brands. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4691", "text": "Topical corticosteroid foams are suitable for treating a range of skin conditions that respond to corticosteroids. These foams are typically simple to apply, which can lead to better patient compliance and, in turn, improve treatment results for those who favor a more convenient and cleaner topical option.  Foam  can be typically seen with topical steroids marketed for the scalp. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4692", "text": "Gels  are thicker than liquids. Gels are often a semisolid  emulsion  and sometimes use alcohol as a solvent for the active ingredient; some gels liquefy at body temperature. Gel tends to be cellulose cut with alcohol or acetone. Gels tend to be self-drying, tend to have greatly variable ingredients between brands, and carry a significant risk of inducing hypersensitivity due to fragrances and preservatives. Gel is useful for hairy areas and body folds. In applying gel one should avoid fissures in the skin, due to the stinging effect of the alcohol base. Gel enjoys a high rate of acceptance due to its cosmetic elegance. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4693", "text": "Lotions  are similar to solution but are thicker and tend to be more  emollient  in nature than the solution. They are usually oil mixed with water, and more often than not have less alcohol than solution. Lotions can be drying if they contain a high amount of alcohol."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4694", "text": "An  ointment  is a homogeneous, viscous, semi-solid preparation; most commonly a greasy, thick water-in-oil emulsion (80% oil, 20% water) having a high viscosity, that is intended for external application to the skin or mucous membranes. Ointments have a water number that defines the maximum amount of water that they can contain. They are used as  emollients  or for the application of active ingredients to the skin for protective, therapeutic, or prophylactic purposes and where a degree of occlusion is desired."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4695", "text": "Ointments are used topically on a variety of body surfaces. These include the  skin  and the  mucous membranes  of the  eye  (an  eye ointment ),  chest ,  vulva ,  anus , and  nose . An ointment may or may not be medicated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4696", "text": "Ointments are usually very moisturizing, and good for dry skin. They have a low risk of sensitization due to having few ingredients beyond the base oil or fat, and low irritation risk. There is typically little variability between brands of drugs. They are often disliked by patients due to greasiness. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4697", "text": "The vehicle of an ointment is known as the  ointment base . The choice of a base depends upon the clinical indication for the ointment. The different types of ointment bases are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4698", "text": "The medicaments are dispersed in the base and are divided after penetrating the living cells of the skin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4699", "text": "The water number of an ointment is the maximum quantity of water that 100g of a base can contain at 20\u00a0\u00b0C."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4700", "text": "Ointments are formulated using hydrophobic, hydrophilic, or water-emulsifying bases to provide preparations that are immiscible, miscible, or emulsifiable with  skin secretions . They can also be derived from hydrocarbon (fatty), absorption, water-removable, or water-soluble bases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4701", "text": "Evaluation of ointments: [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4702", "text": "Properties which affect choice of an ointment base are: [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4703", "text": "Methods of preparation of ointments:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4704", "text": "Paste  combines three agents \u2013 oil, water, and powder. It is an ointment in which a powder is suspended."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4705", "text": "Powder [ 14 ]  is either the pure drug by itself (talcum powder), or is made of the drug mixed in a carrier such as  corn starch  or corn cob powder (Zeosorb AF \u2013 miconazole powder). Can be used as an inhaled topical ( cocaine  powder used in nasal surgery)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4706", "text": "A shake lotion is a mixture that separates into two or three parts over time. Frequently, an oil mixed with a water-based solution needs to be shaken into suspension before use and includes the instructions: \"Shake well before use\". [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4707", "text": "Medication may be placed in a solid form. Examples are deodorants, antiperspirants, astringents, and hemostatic agents. Some solids melt when they reach body temperature (e.g. rectal suppositories)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4708", "text": "Certain contraceptive methods rely on  sponge  as a carrier of liquid medicine.  Lemon juice  embedded in a sponge has been used as a primitive contraception in some cultures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4709", "text": "Cordran tape is an example of a topical steroid applied under  occlusion  by tape. This greatly increases the potency and absorption of the topical steroid and is used to treat inflammatory skin diseases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4710", "text": "A  tincture  is a skin preparation that has a high percentage of alcohol. It would normally be used as a drug vehicle if drying of the area is desired."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4711", "text": "Topical solutions can be marketed as drops, rinses, or sprays, are generally of low viscosity, and often use alcohol or water in the base. [ 15 ] [ 16 ] [ 17 ]  These are usually a powder dissolved in alcohol, water, and sometimes oil; although a solution that uses alcohol as a base ingredient, as in topical steroids, can cause drying of the skin. [ 18 ] [ page\u00a0needed ]  There is significant variability among brands, and some solutions may cause irritation, depending on the preservative(s) and fragrances used in the base."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4712", "text": "Some examples of topical solutions are given below:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4713", "text": "Transdermal patches  can be a very precise time released method of delivering a drug. Cutting a patch in half might affect the dose delivered. The release of the active component from a transdermal delivery system (patch) may be controlled by diffusion through the adhesive which covers the whole patch, by diffusion through a membrane which may only have adhesive on the patch rim or drug release may be controlled by release from a polymer matrix. Cutting a patch might cause rapid dehydration of the base of the medicine and affect the rate of diffusion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4714", "text": "Some medications are applied as an ointment or gel, and reach the mucous membrane via vaporization. Examples are nasal  topical decongestants  and smelling salt."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4715", "text": "Topical drug classification system (TCS) is proposed by the  FDA . It is designed from the  Biopharmaceutics Classification System  (BCS) for oral immediate release solid drug products which is very successful for decades. There are 3 aspects to assess and 4 classes in total. The 3 aspects include qualitative (Q1), quantitative (Q2) and similarity of  in vitro  release (IVR) rate (Q3). [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4716", "text": "In the early 1970s, the  Alza Corporation , through their founder  Alejandro Zaffaroni , filed the first US patents describing transdermal delivery systems for  scopolamine ,  nitroglycerin  and  nicotine . [ 22 ]  People found that applying medicines on the body surfaces is beneficial in many aspects. Skin medicines can give faster onset and local effect on our body as the surface cream can bypass first pass metabolism such as hepatic and intestinal metabolism. Apart from the absorption, dermal drugs effectively prevent oral delivery limitations such as  nausea  and  vomiting  and poor appliances due to unpalatable tastes of the drugs . Topical application is an  easy way for patients to tackle skin infections in a painless and non-invasive way. From a patient perspective, applying drugs on skin also provides stable dosage in blood so as to give the optimal  bioavailability  and  therapeutic effects . In case of  overdose  or unwanted side effects, patients can take off or wash out the medicines quickly to eliminate  toxicity  by simply removing the patch to stop the delivery of drugs. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4717", "text": "The site of putting the patches for topical drugs may get irritated and have  rashes  and feel itchy. Hence, some topical drugs including  nicotine patches  for  smoking cessation  are advised to change places for each application to avoid continuous irritation of the skin. Also, since the drug needs to penetrate the skin, some drugs may not be able to pass through the skin. Some drugs are then \u201cwasted\u201d and the bioavailability of the drug will decrease."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4718", "text": "Skin penetration is the main challenge for any topical dosage form. The drug needs to penetrate the skin in order to get into the body to apply its function. The drug follows Fick's first law of diffusion. [ 24 ]  One of the most common versions of  Fick's first law of diffusion  is:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4719", "text": "For  D  is described by the  Stokes\u2013Einstein equation . The equation is:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4720", "text": "Assuming  concentration gradient  is constant for all newly applied topical drugs and the temperature is constant (normal body temperature: 37\u00a0\u00b0C), the viscosity and radius of the drug determine the flux of diffusion. The higher the  viscosity  or the larger the radius of the drug is, the lower the  diffusion flux  of the drug is. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4721", "text": "There are many factors for drug developers to consider in developing new topical formulations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4722", "text": "The first one is the effect of the drug vehicle. The medium to carry the topical drugs can affect the penetration of the drug  active ingredient  and  efficacy . For example, this carrier can have a cooling, drying, emollient or protective action to suit the required conditions of the application site such as applying  gel  or  lotion  for hairy areas. Meanwhile, scientists need to match the type of preparation with the type of lesions. For example, they need to avoid oily  ointments  for acute weepy  dermatitis . Chemists also need to consider the  irritation  or any  sensitization  potential to ensure that the topical application can be stable during storage and transport to maintain its efficacy. [ 22 ]  Another potential material is nanofiber-based dispersion to improve the adhesion of active ingredients on the skin. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4723", "text": "In order to enhance drug penetration into the skin, scientists have several ways to achieve their purposes by using chemical, biochemical, physical, and  super saturation  enhancement. Advanced Emulgel technology is a breakthrough in painkilling topical drugs. [ citation needed ]  It helps the gel to enter deeply down the skin layer to strengthen the delivery of diclofenac to the point of pain so as to achieve better  therapeutic effects  by modifying the above properties. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4724", "text": "Transdermal drug delivery  techniques include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4725", "text": "A  transdermal patch  is a  medicated   adhesive  patch that is placed on the  skin  to deliver a specific  dose  of medication through the skin and into the  bloodstream . An advantage of a transdermal drug delivery route over other types of medication delivery (such as oral, topical, intravenous, or intramuscular) is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal delivery systems stems from the fact that the skin is a very effective barrier; as a result, only medications whose molecules are small enough to penetrate the skin can be delivered by this method. The first commercially available prescription patch was approved by the U.S.  Food and Drug Administration  in December 1979. These patches administered  scopolamine  for  motion sickness . [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4726", "text": "In order to overcome restriction from the skin, researchers have developed  microneedle transdermal patches  (MNPs), which consist of an array of  microneedles , which allows a more versatile range of compounds or molecules to be passed through the skin without having to  micronize  the medication beforehand. MNPs offer the advantage of controlled release of medication and simple application without medical professional assistance required. [ 6 ]  With advanced MNPs technology, drug delivery can be specified for local usage, for example skin whitener [ 7 ]  MNPs that are applied to the face. Many types of MNPs have been developed to penetrate tissues other than skin, such as internal tissues of the mouth and digestive tract. These promote faster and more direct delivery of the molecule to the targeted area."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4727", "text": "The main components to a transdermal patch are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4728", "text": "Other components include stabilizers (antioxidants), preservatives, etc."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4729", "text": "There are five main types of transdermal patches."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4730", "text": "The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing. It is characterized by the inclusion of the drug directly within the skin-contacting adhesive placed onto the epidermis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4731", "text": "The multi-layer drug-in-adhesive patch is similar to the single-layer system; the multi-layer system is different, however, in that it adds another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases). One of the layers is for immediate release of the drug, and the other layer is for controlled release of the drug from the reservoir. This patch also has a temporary liner-layer and a permanent backing. The drug release from this depends on membrane permeability and diffusion of drug molecules."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4732", "text": "Unlike the single-layer and multi-layer drug-in-adhesive systems, the reservoir transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer. The drug reservoir is totally encapsulated in a shallow compartment molded from a drug-impermeable metallic plastic laminate, with a rate-controlling membrane made of a polymer like  vinyl acetate  on one surface. [ 24 ]  This patch is also backed by the backing layer. In this type of system the rate of release is zero order. Reservoir patches should not be cut (with the exception of hyoscine hyrdobromide 1.5mg patch according to the  British National Formulary for Children ). [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4733", "text": "The matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer, partially overlaying it. The release rate is determined by the physical properties of the matrix. [ 24 ]  Also known as a monolithic device. Limited research indicates that it may be possible to cut some matrix patches to provide lower doses, provided the cut part not immediately used is stored at cool temperatures. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4734", "text": "In a vapour patch, the adhesive layer not only serves to adhere the various layers together but also to release vapour. Vapour patches release essential oils for up to 6 hours and are mainly used for decongestion. Other vapour patches on the market improve quality of sleep or aid in  smoking cessation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4735", "text": "The microneedle patch (MNPs) is a type of transdermal patch which retains the advantages, but reduces the disadvantages of basic transdermal patches. Embedding as many as 102-104 needles per square centimetre of patch, encapsulated or coated with intended drug, MNPs can easily pass skin tissue known as the  stratum corneum  which is roughly 20 \u03bcm in thickness, allowing up to the size of  macromolecule  to pass. [ 6 ]  MNPs were developed mainly because transdermal patch can deliver smaller size or  micronized  molecules such as  nicotine  and  birth control  which easily diffuse and penetrate the skin, but lack in delivering macro or large size molecules. The 100-1000 \u03bcm needles spread across the patch, making sure people will not feel any discomfort from the patch. There are two types of needles used in MNPs, the first one is non-water-soluble needles made out of metal, ceramic, or  polymer , and the second one is water-soluble needles made out of  saccharides  or soluble polymers. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4736", "text": "MNPs can also be engineered to deliver molecules into other tissues. Some that as of 2018 have been under development include internal surfaces such as the mouth, vagina, gastrointestinal tract, and vascular wall; and external surfaces such as the skin, eyes, fingernails, anus, and scalp. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4737", "text": "As mentioned earlier, MNPs deliver more efficient delivery compared to topical or oral intake. In drug delivery study, researchers want to gain faster  peak concentrations  (C max ) in MNPs compared to other methods. Study shows that MNPs reach peak concentration as fast as 20 minutes (t max ), while oral intake reaches peak concentration in one hour. Furthermore, the C max  from MNPs is higher up to six times, compared to oral intake. [ 6 ]  Making the delivery fast and the body gets the most concentration of intended drugs. This value is only matched with direct injection, but with skin trauma and people with needle phobia, MNPs might be an alternative to reach roughly the same time and concentration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4738", "text": "In order to get more direct local delivery, MNPs can be used in different tissues other than the skin. [ 27 ]  In  Table 1 , there are at least five internal surfaces that MNPs have been studied for its delivery and four other external surfaces other than the skin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4739", "text": "There are many types of microneedle that are distinguished by the shape and other characteristics. The types include: Dissolvable MNPs, solid non-soluble MNPs, and hollow MNPs. Different MNPs may be chosen depending on the situation and the drug properties."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4740", "text": "One of the types of MNPs are water-soluble needles made out of soluble polymers or saccharide. However, dissolvable needles cannot efficiently deliver drugs to the dermal layer. Drug maximum concentration cannot be carried out to the skin, as the needles will dissolve beforehand. Fortunately, researchers have developed a water-insoluble backing layer, making the needle last longer in the human body environment. This design enables efficient delivery of more than 90% of the drug within 5 minutes of application of MNPs to the skin. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4741", "text": "Other than dissolvable MNPs, needles can also be made out of metal or ceramic that will not dissolve in the body environment. These coated drug needles can deliver consistent concentration of drugs without the needles dissolving in the body. This kind of MNPs has better performance, but compared to the soluble MNPs, metal or ceramic MNPs are the older version of MNPs. Even if the patches are small, the metal or ceramic MNPs may cause several waste issues. Recycling the metal and ceramic are very hard, as the quantity is very small to overcome the cost to recycle. That is why researchers try to develop the dissolvable MNPs with similar characteristic and performance of drug delivery in non-soluble MNPs. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4742", "text": "Among all of the MNPs, hollow needles allow a bigger amount of delivery up to 200\u03bcL. The mechanism mimics the operation of a hypodermic, but the fabrication is hard and complex. The hollow needles introduce a potential failure if the insertion is improper. That is why, among the others, hollow MNPs are the least popular because of the complex manufacturing and applying process. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4743", "text": "MNPs vaccination might be an alternative from direct injection. Able to deliver bigger molecules than transdermal patch, MNPs can also deliver bioactive molecules with different physical sizes. Meaning that inactive virus or pathogen can be introduced in the body without discomfort or skin irritation from conventional injection. Possibly it can also reduce the cost of storage that usually needs to be transported in a particular temperature and condition. Stated in cdc.gov website,  Mark Prausnitz , co-developer of the microneedle, says \"A major advantage of the microneedle patch would be the ease of delivery.\" The MNPs are small and thin compared to bottles of vial, making it possible to transport in massive quantities in a single trip. [ 33 ]  Medical waste such as syringes and dirty needles are also eliminated, reducing the possibility of pathogen transmission of blood-borne disease in rural areas. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4744", "text": "In a study, measles coated MNPs might be resistant to higher temperature compared to vial transport. Higher temperature resistance is a safe bet in low income countries, where there is no such luxury for refrigeration. Furthermore, the delivery of the vaccine is controlled by the MNPs. Less requiring highly trained medical workers in developing countries to apply the vaccine. However, the study in MNPs measles vaccine is still under development, but opening possibilities in the future for other types of vaccines [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4745", "text": "Skin treatment including face whitening agent and dark eye circles serum can also incorporated in MNPs. [ 34 ]  Its localized property enhance skin whitening delivery to the face area. Even a very specific spot like dark eye circles. By measuring the melanin (dark or black pigment found on the skin) index, subjects that are treated with whitening agents coated in MNPs show lower melanin index, compared to the whitening essence (topical) group. The treatment lasts for eight weeks, and the result shows MNPs might be a promising cosmetic vector because MNPs does not introduce skin irritation and can be engineered to localize or specific parts of the body. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4746", "text": "MNPs may cause skin irritation on people with sensitive skin. Majority of studies show that MNPs do not irritate the skin.\nEspecially for hollow MNPs, the not so stiff needles may cause unnecessary puncture of the skin outer layer, and may cause trauma to the skin and restricting the performance and flow of the drugs to the body. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4747", "text": "Because most of MNPs applications are still under development, it is important to note the long effect of the efficiency of the drug deliveries. Furthermore, more research is needed to get information of what molecule can be delivered using MNPs. Disposal is also an important topic, as the small plastic backing may contribute to water pollution remembering the compact size can be easily carried away by wind and water without proper disposal."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4748", "text": "A transdermal patch is classified by the U.S. Food and Drug Administration as a  combination product , consisting of a  medical device  combined with a drug or biological product that the device is designed to deliver. Prior to sale in the United States, any transdermal patch product must apply for and receive approval from the Food and Drug Administration, demonstrating safety and efficacy for its intended use. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4749", "text": "Transdermal  is a  route of administration  wherein active ingredients are delivered across the skin for systemic distribution. Examples include  transdermal patches  used for medicine delivery.\nThe drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4750", "text": "Although the skin is a large and logical target for drug delivery, its basic functions limit its utility for this purpose.  The skin functions mainly to protect the body from external penetration (by e.g. harmful substances and microorganisms) and to contain all body fluids."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4751", "text": "There are two important layers to the human skin: (1) the  epidermis  and (2) the  dermis .  For transdermal delivery, drugs must pass through the two sublayers of the epidermis to reach the microcirculation of the dermis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4752", "text": "The  stratum corneum  is the top layer of the skin and varies in thickness from approximately ten to several hundred micrometres, depending on the region of the body. [ 1 ]  It is composed of layers of dead, flattened keratinocytes surrounded by a lipid matrix, which together act as a brick-and-mortar system that is difficult to penetrate. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4753", "text": "The stratum corneum provides the most significant barrier to diffusion. In fact, the stratum corneum is the barrier to approximately 90% of transdermal drug applications. However, nearly all molecules penetrate it to some minimal degree. [ 3 ]  Below the stratum corneum lies the viable epidermis. This layer is about ten times as thick as the stratum corneum; however, diffusion is much faster here due to the greater degree of hydration in the living cells of the viable epidermis. Below the epidermis lies the dermis, which is approximately one millimeter thick, 100 times the thickness of the stratum corneum. The dermis contains small vessels that distribute drugs into the systemic circulation and to regulate temperature, a system known as the skin's microcirculation. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4754", "text": "There are two main pathways by which drugs can cross the skin and reach the systemic circulation. The more direct route is known as the transcellular pathway."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4755", "text": "By this route, drugs cross the skin by directly passing through both the phospholipids membranes and the cytoplasm of the dead keratinocytes that constitute the stratum corneum."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4756", "text": "Although this is the path of shortest distance, the drugs encounter significant resistance to permeation. This resistance is caused because the drugs must cross the lipophilic membrane of each cell, then the hydrophilic cellular contents containing keratin, and then the phospholipid bilayer of the cell one more time. This series of steps is repeated numerous times to traverse the full thickness of the stratum corneum. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4757", "text": "The other more common pathway through the skin is via the intercellular route. Drugs crossing the skin by this route must pass through the small spaces between the cells of the skin, making the route more tortuous. Although the thickness of the stratum corneum is only about 20\u00a0\u03bcm, the actual diffusional path of most molecules crossing the skin is on the order of 400\u00a0\u03bcm. [ 4 ]  The 20-fold increase in the actual path of permeating molecules greatly reduces the rate of drug penetration. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4758", "text": "Recent research has established that the intercellular route can be dramatically enhanced by attending to the physical chemistry of the system solubilizing the active pharmaceutical ingredient, rendering a dramatically more efficient delivery of payload and enabling the delivery of most compounds via this route. [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4759", "text": "A third pathway to breach the Stratum Corneum layer is via tiny microchannels created by a medical  micro-needling  device of which there are many brands and variants. [ 8 ]  Investigations at the University of Marburg, Germany, using a standard Franz diffusion cell showed that this approach is efficient in enhancing skin penetration ability for lipophilic as well as hydrophilic compounds. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4760", "text": "The micro-needling approach is also seen as 'the  vaccine  of the future'. [ 10 ]  The microneedles can be hollow, solid, coated, dissolving, or hydrogel-forming. [ 11 ]  Some have regulatory approval. [ 11 ]  Microneedle devices/patches can be used to deliver  nanoparticle medicines . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4761", "text": "Devices and formulations for transdermally administered substances include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4762", "text": "An  unguent  is a soothing preparation spread on  wounds ,  burns ,  rashes ,  abrasions  or other topical injuries (i.e. damage to the skin). It is similar to an  ointment , though typically an unguent is oilier and less  viscous . It is usually delivered as a semi-solid paste spread on the skin, and it is often oily in order to suspend the medication or other  active ingredients ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4763", "text": "During the  Victorian era , the use of the unguent  macassar oil  on the hair became so popular that  antimacassars  were invented to prevent damage to furniture. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4764", "text": "Various preparations of  mercurochrome  unguent are occasionally used as  adjunct therapy  in the treatment of  furunculosis , and palliative relief of  Kaposi sarcomas , although mercurials should only be used in extreme cases due to high toxicity and severe hypersensitivity or idiosyncratic reactions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4765", "text": "It was also used by the Egyptians to help soothe their skin from the dry heat."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4766", "text": "In  intravenous therapy  a  Y-Set ,  T-Set  and  V-Sets  are Y-, T- and V-shaped three-way connector sets made of connecting plastic tubes used for delivering intravenous drugs into the body from multiple fluid sources. As  Y-Sets [ 1 ]  are the most common shaped sets, Y-Set is a name that is sometimes used to represent the family of connector sets (sometimes called Y-tubes). The majority of these infusion sets have a left and right hand line that deliver fluid and drugs (often via a valve) to a short common limb attached to the female fitting on the  intravenous cannulae ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4767", "text": "3-way connectors allow for \" piggybacking \", that is, putting a second infusion set onto the same line, such as adding a dose of antibiotics to a continuous  volume expander  drip, with the etymology being to refer to the second infusion as \"riding on the back\" of the first one."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4768", "text": "Most 3+ way connectors can be opened to allow an infusion limb and a vertical limb to deliver fluid via a common limb to the female fitting of an IV  cannulae . V-shaped fittings allow multiple limbs to flow directly to the patient with no common space. As different tubes for these infusion sets usually have different flow rates and fluid delivered from different tubes, there is a risk that the common space (dead volume) of Y-Sets and T-Sets fills with high concentration drugs and accidentally gets flushed out at a high flow rate. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4769", "text": "A  drug  is any  chemical substance   other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. [ 1 ]  Consumption of drugs can be via  inhalation ,  injection ,  smoking ,  ingestion ,  absorption  via a  patch  on the skin,  suppository , or  dissolution under the tongue ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4770", "text": "In  pharmacology , a drug is a chemical substance, typically of known structure, which, when administered to a living organism, produces a biological effect. [ 2 ]  A  pharmaceutical drug , also called a medication or medicine, is a chemical substance used to  treat , cure,  prevent , or  diagnose  a  disease  or to promote  well-being . [ 3 ]  Traditionally drugs were obtained through extraction from  medicinal plants , but more recently also by  organic synthesis . [ 4 ]  Pharmaceutical drugs may be used for a limited duration, or on a regular basis for  chronic disorders . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4771", "text": "Pharmaceutical drugs are often classified into  drug classes \u2014groups of related drugs that have similar  chemical structures , the same  mechanism of action  (binding to the same  biological target ), a related  mode of action , and that are used to treat the same disease. [ 5 ] [ 6 ]  The  Anatomical Therapeutic Chemical Classification System  (ATC), the most widely used drug classification system, assigns drugs a unique ATC code, which is an alphanumeric code that assigns it to specific drug classes within the ATC system. Another major classification system is the  Biopharmaceutics Classification System . This classifies drugs according to their solubility and permeability or  absorption  properties. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4772", "text": "Psychoactive drugs  are substances that affect the function of the  central nervous system , altering  perception ,  mood  or  consciousness . [ 8 ]  These drugs are divided into different groups such as:  stimulants ,  depressants ,  antidepressants ,  anxiolytics ,  antipsychotics , and  hallucinogens . These psychoactive drugs have been proven useful in treating a wide range of  medical conditions  including  mental disorders  around the world. The most widely used drugs in the world include  caffeine ,  nicotine  and  alcohol , [ 9 ]  which are also considered  recreational drugs , since they are used for pleasure rather than medicinal purposes. [ 10 ]  All drugs can have potential  side effects . [ 11 ]  Abuse of several psychoactive drugs can cause  addiction  or  physical dependence . [ 12 ]  Excessive use of stimulants can promote  stimulant psychosis . Many recreational drugs are  illicit ; international treaties such as the  Single Convention on Narcotic Drugs  exist for the purpose of their  prohibition ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4773", "text": "In English, the noun \"drug\" is thought to originate from Old French \" drogue \", possibly deriving from \" droge  ( vate )\" from Middle Dutch meaning \"dry (barrels)\", referring to medicinal plants preserved as dry matter in barrels. [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4774", "text": "In the 1990s however, Spanish  lexicographer   Federico Corriente C\u00f3rdoba  documented the possible origin of the word in {\u1e25\u1e6dr} [ 15 ]  an early romanized form of the  Al-Andalus  language from the northwestern part of the  Iberian peninsula . [ 16 ]  The term could approximately be transcribed as \u062d\u0637\u0631\u0648\u0643\u0629 or  hatruka . [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4775", "text": "The term \"drug\" has become a  skunked term  with negative connotation, being used as a synonym for  illegal substances  like cocaine or heroin or for drugs used  recreationally . In other contexts the terms \"drug\" and \"medicine\" are used interchangeably. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4776", "text": "Drug action is highly specific and their effects may only be detected in certain individuals. For instance, the 10 highest-grossing drugs in the US may help only 4-25% of people. [ 19 ]  Often, the activity of a drug depends on the  genotype  of a patient. For example, Erbitux ( cetuximab ) increases the survival rate of  colorectal cancer  patients if they carry a particular mutation in the  EGFR  gene. [ 19 ]  Some drugs are specifically approved for certain genotypes.  Vemurafenib  is such a case which is used for  melanoma  patients who carry a mutation in the  BRAF  gene. [ 19 ]  The number of people who benefit from a drug determines if drug trials are worth carrying out, given that phase III trials may cost between $100 million and $700 million per drug. This is the motivation behind  personalized medicine , that is, to develop drugs that are adapted to individual patients. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4777", "text": "A  medication  or  medicine  is a  drug  taken to cure or ameliorate any symptoms of an  illness  or medical condition. The use may also be as  preventive medicine  that has future benefits but does not treat any existing or pre-existing diseases or symptoms. Dispensing of medication is often regulated by  governments  into three categories\u2014 over-the-counter  medications, which are available in  pharmacies  and supermarkets without special restrictions;  behind-the-counter  medicines, which are dispensed by a  pharmacist  without needing a doctor's prescription, and  prescription only medicines , which must be prescribed by a licensed  medical professional , usually a  physician . [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4778", "text": "In the United Kingdom, behind-the-counter medicines are called  pharmacy medicines  which can only be sold in registered pharmacies, by or under the supervision of a pharmacist. These medications are designated by the letter P on the label. [ 21 ]  The range of medicines available without a prescription varies from country to country. Medications are typically produced by  pharmaceutical companies  and are often  patented  to give the developer exclusive rights to produce them. Those that are not patented (or with expired patents) are called  generic drugs  since they can be produced by other companies without restrictions or licenses from the patent holder. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4779", "text": "Pharmaceutical drugs are usually categorised into  drug classes . A group of drugs will share a similar  chemical structure , have the same  mechanism of action  or the same related  mode of action , or target the same illness or related illnesses. [ 5 ] [ 6 ]  The  Anatomical Therapeutic Chemical Classification System  (ATC), the most widely used drug classification system, assigns drugs a unique  ATC code , which is an alphanumeric code that assigns it to specific drug classes within the ATC system. Another major classification system is the  Biopharmaceutics Classification System . This groups drugs according to their solubility and permeability or  absorption  properties. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4780", "text": "Some religions, particularly  ethnic religions , are based completely on the use of certain drugs, known as  entheogens , which are mostly  hallucinogens ,\u2014 psychedelics ,  dissociatives , or  deliriants . Some entheogens include  kava  which can act as a  stimulant , a  sedative , a  euphoriant  and an  anesthetic . The roots of the kava plant are used to produce a drink consumed throughout the cultures of the Pacific Ocean."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4781", "text": "Some  shamans  from different cultures use entheogens, defined as \"generating the divine within,\" [ 23 ]  to achieve  religious ecstasy . Amazonian shamans use  ayahuasca  (yag\u00e9), a hallucinogenic brew, for this purpose.  Mazatec shamans  have a long and continuous tradition of religious use of  Salvia divinorum , a  psychoactive  plant. Its use is to facilitate  visionary states of consciousness  during spiritual healing sessions. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4782", "text": "Silene undulata  is regarded by the  Xhosa people  as a sacred plant and used as an entheogen. Its roots are traditionally used to induce vivid (and according to the Xhosa, prophetic)  lucid dreams  during the initiation process of  shamans , classifying it a naturally occurring  oneirogen  similar to the more well-known dream herb  Calea ternifolia . [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4783", "text": "Peyote , a small spineless  cactus , has been a major source of psychedelic  mescaline  and has probably been used by  Native Americans  for at least five thousand years. [ 26 ] [ 27 ]  Most mescaline is now obtained from a few species of columnar cacti in particular from  San Pedro  and not from the vulnerable peyote. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4784", "text": "The  entheogenic use of cannabis  has also been widely practised [ 29 ]  for centuries. [ 30 ]   Rastafari  use  marijuana  (ganja) as a  sacrament  in their  religious ceremonies ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4785", "text": "Psychedelic mushrooms ( psilocybin mushrooms ), commonly called  magic mushrooms  or  shrooms  have also long been used as entheogens."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4786", "text": "Nootropics , also commonly referred to as \"smart drugs\", are drugs that are claimed to improve human  cognitive abilities . Nootropics are used to improve memory, concentration, thought, mood, and learning. An increasingly used nootropic among students, also known as a  study drug , is  methylphenidate  branded commonly as  Ritalin  and used for the treatment of  attention deficit hyperactivity disorder  (ADHD) and  narcolepsy . [ 31 ]  At high doses methylphenidate  can become highly addictive . [ 32 ]  Serious addiction can lead to  psychosis ,  anxiety  and heart problems, and the use of this drug is related to a rise in suicides, and overdoses. Evidence for use outside of student settings is limited but suggests that it is commonplace. [ 31 ] [ 32 ]  Intravenous use of methylphenidate can lead to  emphysematous  damage to the lungs, known as  Ritalin lung . [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4787", "text": "Other drugs known as  designer drugs  are produced. An early example of what today would be labelled a 'designer drug' was  LSD , which was synthesised from  ergot . [ 34 ]  Other examples include analogs of  performance-enhancing drugs  such as designer  steroids  taken to improve physical capabilities; these are sometimes used (legally or not) for this purpose, often by professional athletes. [ 35 ]  Other designer drugs mimic the effects of psychoactive drugs. Since the late 1990s there has been the identification of many of these synthesised drugs. In Japan and the United Kingdom this has spurred the addition of many designer drugs into a newer class of controlled substances known as a  temporary class drug ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4788", "text": "Synthetic cannabinoids  have been produced for a longer period of time and are used in the designer drug  synthetic cannabis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4789", "text": "Recreational drug use  is the use of a drug (legal, controlled, or illegal) with the primary intention of  altering the state of consciousness  through alteration of the central nervous system in order to create positive emotions and feelings. The hallucinogen  LSD  is a psychoactive drug commonly used as a recreational drug. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4790", "text": "Ketamine  is a drug used for  anesthesia , and is also used as a recreational drug, both in powder and liquid form, for its hallucinogenic and  dissociative effects . [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4791", "text": "Some national laws  prohibit the use of different recreational drugs; medicinal drugs that have the potential for recreational use are often heavily regulated. However, there are many recreational drugs that are  legal in many jurisdictions  and widely culturally accepted.\n Cannabis  is the most commonly consumed controlled recreational drug in the world (as of 2012). [ 39 ]  Its use in many countries is illegal but is  legally used  in several countries usually with the proviso that it can only be used for personal use. It can be used in the  leaf  form of  marijuana   (grass) , or in the resin form of  hashish . Marijuana is a more mild form of cannabis than hashish."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4792", "text": "There may be an age restriction on the consumption and purchase of legal recreational drugs. Some recreational drugs that are legal and accepted in many places include  alcohol ,  tobacco ,  betel nut , and  caffeine  products, and in some areas of the world the legal use of drugs such as  khat  is common. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4793", "text": "There are a number of legal intoxicants commonly called  legal highs  that are used recreationally. The most widely used of these is alcohol."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4794", "text": "All drugs have a  route  of  administration , and many can be administered by more than one."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4795", "text": "A  bolus  is the administration of a medication, drug or other compound that is given to raise its concentration in blood rapdily to an effective level, regardless of the route of administration"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4796", "text": "Numerous governmental offices in many countries deal with the control and supervision of drug manufacture and use, and the implementation of various drug laws. The  Single Convention on Narcotic Drugs  is an international  treaty  brought about in 1961 to prohibit the use of narcotics save for those used in  medical research  and treatment. In 1971, a second treaty the  Convention on Psychotropic Substances  had to be introduced to deal with newer recreational psychoactive and psychedelic drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4797", "text": "The  legal status of  Salvia divinorum  varies in many countries and even in  states within the United States . Where it is legislated against, the degree of prohibition also varies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4798", "text": "The  Food and Drug Administration  (FDA) in the United States is a  federal agency  responsible for protecting and promoting  public health  through the  regulation  and supervision of  food safety ,  tobacco products ,  dietary supplements ,  prescription  and  over-the-counter   medications ,  vaccines ,  biopharmaceuticals ,  blood transfusions ,  medical devices ,  electromagnetic radiation  emitting devices,  cosmetics ,  animal foods [ 42 ]  and  veterinary drugs ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4799", "text": "In India, the  Narcotics Control Bureau  (NCB), an  Indian federal law enforcement  and  intelligence  agency under the  Ministry of Home Affairs , is tasked with combating  drug trafficking  and assisting international use of illegal substances under the provisions of  Narcotic Drugs and Psychotropic Substances Act . [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4800", "text": "A  medication  (also called  medicament ,  medicine ,  pharmaceutical drug ,  medicinal product ,  medicinal drug  or simply  drug ) is a  drug  used to  diagnose ,  cure , treat, or  prevent  disease. [ 1 ] [ 2 ]  Drug therapy ( pharmacotherapy ) is an important part of the  medical field  and relies on the science of  pharmacology  for continual advancement and on  pharmacy  for appropriate management."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4801", "text": "Drugs are  classified  in many ways. One of the key divisions is by level of  control , which distinguishes  prescription drugs  (those that a pharmacist dispenses only on the  medical prescription ) from  over-the-counter drugs  (those that consumers can order for themselves). Medicines may be classified by mode of action,  route of administration ,  biological system  affected, or  therapeutic effects . The  World Health Organization  keeps a list of  essential medicines ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4802", "text": "Drug discovery  and  drug development  are complex and expensive endeavors undertaken by  pharmaceutical companies , academic scientists, and governments. As a result of this complex path from discovery to commercialization, partnering has become a standard practice for advancing drug candidates through development pipelines. Governments generally regulate what drugs can be marketed,  how drugs are marketed , and in some jurisdictions,  drug pricing . Controversies have arisen over drug pricing and disposal of used medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4803", "text": "Medication is a medicine or a  chemical compound  used to  treat  or  cure  illness. According to  Encyclop\u00e6dia Britannica , medication is \"a substance used in treating a disease or relieving  pain \". [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4804", "text": "As defined by the  National Cancer Institute ,  dosage forms  of medication can include  tablets ,  capsules , liquids,  creams , and patches. Medications can be administered in different ways, such as  by mouth , by  infusion into a vein , or by  drops put into the ear  or  eye . A medication that does not contain an  active ingredient  and is used in research studies is called a  placebo . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4805", "text": "In Europe, the term is \"medicinal product\", and it is defined by EU law as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4806", "text": "In the US, a \"drug\" is:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4807", "text": "Drug use among elderly Americans has been studied; in a group of 2,377 people with an average age of 71 surveyed between 2005 and 2006, 84% took at least one prescription drug, 44% took at least one  over-the-counter  (OTC) drug, and 52% took at least one  dietary supplement ; in a group of 2245 elderly Americans (average age of 71) surveyed over the period 2010 \u2013 2011, those percentages were 88%, 38%, and 64%. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4808", "text": "One of the key classifications is between traditional  small molecule  drugs; usually derived from chemical synthesis and  biological medical products ; which include  recombinant proteins ,  vaccines ,  blood products  used therapeutically (such as  IVIG ),  gene therapy , and  cell therapy  (for instance,  stem cell  therapies). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4809", "text": "Pharmaceuticals or drugs or medicines are classified into various other groups besides their origin on the basis of pharmacological properties like mode of action and their pharmacological action or activity, [ 8 ]  such as by  chemical properties , mode or  route of administration ,  biological system  affected, or  therapeutic effects . An elaborate and widely used  classification system  is the  Anatomical Therapeutic Chemical Classification System  (ATC system). The  World Health Organization  keeps a list of  essential medicines ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4810", "text": "A sampling of classes of medicine includes:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4811", "text": "Pharmaceuticals may also be described as \"specialty\", independent of other classifications, which is an ill-defined class of drugs that might be difficult to administer, require special handling during administration, require patient monitoring during and immediately after administration, have particular regulatory requirements restricting their use, and are generally expensive relative to other drugs. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4812", "text": "Drugs affecting the  central nervous system  include  psychedelics ,  hypnotics ,  anaesthetics ,  antipsychotics ,  eugeroics ,  antidepressants  (including  tricyclic antidepressants ,  monoamine oxidase inhibitors ,  lithium salts , and  selective serotonin reuptake inhibitors  (SSRIs)),  antiemetics ,  anticonvulsants /antiepileptics,  anxiolytics ,  barbiturates , movement disorder (e.g.,  Parkinson's disease ) drugs,  nootropics ,  stimulants  (including  amphetamines ),  benzodiazepines ,  cyclopyrrolones ,  dopamine antagonists ,  antihistamines ,  cholinergics ,  anticholinergics ,  emetics ,  cannabinoids , and  5-HT (serotonin) antagonists ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4813", "text": "The main classes of painkillers are  NSAIDs ,  opioids , and local  anesthetics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4814", "text": "For consciousness (anesthetic drugs)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4815", "text": "Some anesthetics include  benzodiazepines  and  barbiturates ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4816", "text": "The main categories of drugs for  musculoskeletal disorders  are:  NSAIDs  (including  COX-2 selective inhibitors ),  muscle relaxants ,  neuromuscular drugs , and  anticholinesterases ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4817", "text": "Antibiotics ,  sympathomimetics ,  antihistamines ,  anticholinergics ,  NSAIDs ,  corticosteroids ,  antiseptics ,  local anesthetics ,  antifungals , and cerumenolytics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4818", "text": "Bronchodilators ,  antitussives ,  mucolytics ,  decongestants , inhaled and systemic  corticosteroids ,  beta2-adrenergic agonists ,  anticholinergics ,  mast cell stabilizers ,  leukotriene antagonists ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4819", "text": "Androgens ,  antiandrogens ,  estrogens ,  gonadotropin ,  corticosteroids ,  human growth hormone ,  insulin ,  antidiabetics  ( sulfonylureas ,  biguanides / metformin ,  thiazolidinediones ,  insulin ),  thyroid hormones , antithyroid drugs,  calcitonin ,  diphosphonate ,  vasopressin analogues ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4820", "text": "Antifungal ,  alkalinizing agents ,  quinolones ,  antibiotics ,  cholinergics ,  anticholinergics ,  antispasmodics ,  5-alpha reductase inhibitor ,  selective alpha-1 blockers ,  sildenafils ,  fertility medications ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4821", "text": "NSAIDs ,  anticholinergics ,  haemostatic drugs ,  antifibrinolytics ,  Hormone Replacement Therapy  (HRT), bone regulators,  beta-receptor agonists ,  follicle stimulating hormone ,  luteinising hormone ,  LHRH ,  gamolenic acid ,  gonadotropin release inhibitor ,  progestogen ,  dopamine agonists ,  oestrogen ,  prostaglandins ,  gonadorelin ,  clomiphene ,  tamoxifen ,  diethylstilbestrol ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4822", "text": "Emollients ,  anti-pruritics ,  antifungals ,  antiseptics ,  scabicides ,  pediculicides ,  tar  products,  vitamin A derivatives ,  vitamin D analogues ,  keratolytics ,  abrasives ,  systemic antibiotics ,  topical   antibiotics ,  hormones , desloughing agents, exudate absorbents,  fibrinolytics ,  proteolytics ,  sunscreens ,  antiperspirants ,  corticosteroids , immune modulators."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4823", "text": "Antibiotics ,  antifungals ,  antileprotics ,  antituberculous drugs ,  antimalarials ,  anthelmintics ,  amoebicides ,  antivirals ,  antiprotozoals , probiotics, prebiotics,  antitoxins , and antivenoms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4824", "text": "Vaccines ,  immunoglobulins ,  immunosuppressants ,  interferons , and  monoclonal antibodies ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4825", "text": "Anti-allergics ,  antihistamines ,  NSAIDs , [ medical citation needed ]   corticosteroids ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4826", "text": "Tonics,  electrolytes  and mineral preparations (including iron preparations and  magnesium preparations ),  parenteral nutrition ,  vitamins ,  anti-obesity drugs ,  anabolic drugs , haematopoietic drugs, food product drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4827", "text": "Cytotoxic drugs ,  therapeutic antibodies ,  sex hormones ,  aromatase inhibitors , somatostatin inhibitors, recombinant  interleukins ,  G-CSF ,  erythropoietin ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4828", "text": "Contrast media ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4829", "text": "A euthanaticum is used for  euthanasia  and  physician-assisted suicide . Euthanasia is not permitted by law in many countries, and consequently, medicines will not be licensed for this use in those countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4830", "text": "A single drug may contain single or multiple  active ingredients ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4831", "text": "The administration is the process by which a patient takes medicine. There are three major categories of drug administration:  enteral  (via the  human gastrointestinal tract ),  injection  into the body, and by other routes ( dermal ,  nasal ,  ophthalmic ,  otologic , and  urogenital ). [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4832", "text": "Oral administration , the most common form of enteral administration, can be performed using various  dosage forms  including  tablets  or  capsules  and liquid such as syrup or suspension. Other ways to take the medication include  buccally  (placed inside the cheek),  sublingually  (placed underneath the tongue), eye and  ear drops  (dropped into the eye or ear), and transdermally (applied to the skin). [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4833", "text": "They can be administered in one dose, as a  bolus . Administration frequencies [ 12 ]  are often abbreviated from Latin, such as  every 8 hours  reading Q8H from  Quaque VIII Hora . The drug frequencies are often expressed as the number of times a drug is used per day (e.g., four times a day). It [ specify ]  may include event-related information (e.g., 1 hour before meals, in the morning, at bedtime), or complimentary to an interval, although equivalent expressions may have different implications (e.g., every 8 hours versus 3 times a day). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4834", "text": "In the fields of medicine,  biotechnology , and  pharmacology ,  drug discovery  is the process by which new drugs are discovered. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4835", "text": "Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by  serendipitous  discovery. Later  chemical libraries  of synthetic  small molecules ,  natural products , or  extracts  were screened in intact cells or whole organisms to identify substances that have a desirable therapeutic effect in a process known as  classical pharmacology .  Since  sequencing  of the  human genome  which allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use  high throughput screening  of large compound libraries against isolated  biological targets  which are hypothesized to be  disease-modifying  in a process known as  reverse pharmacology . Hits from these screens are then tested in cells and then in animals for  efficacy . Even more recently, scientists have been able to understand the shape of biological molecules at the atomic level and to use that knowledge to design (see  drug design ) drug candidates. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4836", "text": "Modern drug discovery involves the identification of screening hits,  medicinal chemistry , and optimization of those hits to increase the  affinity ,  selectivity  (to reduce the potential of side effects), efficacy/ potency ,  metabolic  stability (to increase the  half-life ), and oral  bioavailability . Once a compound that fulfills all of these requirements has been identified, it will begin the process of  drug development  prior to  clinical trials . One or more of these steps may, but not necessarily, involve  computer-aided drug design ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4837", "text": "Despite advances in technology and understanding of biological systems, drug discovery is still a lengthy, \"expensive, difficult, and inefficient process\" with a low rate of new therapeutic discovery. [ 13 ]  In 2010, the research and development cost of each  new molecular entity  (NME) was approximately US$1.8 billion. [ 14 ]  Drug discovery is done by pharmaceutical companies, sometimes with research assistance from universities. The \"final product\" of drug discovery is a patent on the potential drug. The drug requires very expensive Phase I, II, and III clinical trials, and most of them fail. Small companies have a critical role, often then selling the rights to larger companies that have the resources to run the clinical trials."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4838", "text": "Drug discovery is different from Drug Development. Drug Discovery is often considered the process of identifying new medicine. At the same time, Drug development is delivering a new drug molecule into clinical practice. In its broad definition, this encompasses all steps from the basic research process of finding a suitable molecular target to supporting the drug's commercial launch."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4839", "text": "Drug development  is the process of bringing a new drug to the market once a  lead compound  has been identified through the process of  drug discovery . It includes pre-clinical research (microorganisms/animals) and  clinical trials  (on humans) and may include the step of obtaining regulatory approval to market the drug. [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4840", "text": "Drug Development Process"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4841", "text": "Discovery:  The Drug Development process starts with Discovery, a process of identifying a new medicine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4842", "text": "Development:  Chemicals extracted from natural products are used to make pills, capsules, or syrups for oral use. Injections for direct infusion into the blood drops for eyes or ears."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4843", "text": "Preclinical research : Drugs go under laboratory or animal testing, to ensure that they can be used on Humans."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4844", "text": "Clinical  testing:  The drug is used on people to confirm that it is safe to use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4845", "text": "FDA   Review:  drug is sent to FDA before launching the drug into the market."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4846", "text": "FDA post-Market Review:  The drug is reviewed and monitored by FDA for the safety once it is available to the public."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4847", "text": "The regulation of drugs varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions, they are regulated at the state level, or at both state and national levels by various bodies, as is the case in Australia.  The role of therapeutic goods regulation is designed mainly to protect the health and safety of the population. Regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed. There is usually some degree of restriction on the availability of certain therapeutic goods depending on their risk to consumers. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4848", "text": "Depending upon the  jurisdiction , drugs may be divided into  over-the-counter drugs  (OTC) which may be available without special restrictions, and  prescription drugs , which must be  prescribed  by a licensed medical practitioner in accordance with  medical guidelines  due to the risk of adverse effects and  contraindications . The precise distinction between OTC and prescription depends on the legal jurisdiction. A third category, \"behind-the-counter\" drugs, is implemented in some jurisdictions. These do not require a prescription, but must be kept in the  dispensary , not visible to the public, and be sold only by a pharmacist or  pharmacy technician . Doctors may also prescribe prescription drugs for  off-label use  \u2013 purposes which the drugs were not originally approved for by the regulatory agency. The  Classification of Pharmaco-Therapeutic Referrals  helps guide the referral process between pharmacists and doctors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4849", "text": "The  International Narcotics Control Board  of the United Nations imposes a world law of  prohibition  of certain drugs. They publish a lengthy list of chemicals and plants whose trade and consumption (where applicable) are forbidden. OTC drugs are sold without restriction as they are considered safe enough that most people will not hurt themselves accidentally by taking it as instructed. [ 17 ]  Many countries, such as the United Kingdom have a third category of \"pharmacy medicines\", which can be sold only in registered  pharmacies  by or under the supervision of a pharmacist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4850", "text": "Medical errors  include over-prescription and  polypharmacy , mis-prescription, contraindication and lack of detail in dosage and administration instructions. In 2000 the definition of a prescription error was studied using a  Delphi method  conference; the conference was motivated by ambiguity in what a prescription error is and a need to use a uniform definition in studies. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4851", "text": "In many jurisdictions,  drug prices  are regulated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4852", "text": "In the UK, the Pharmaceutical Price Regulation Scheme is intended to ensure that the  National Health Service  is able to purchase drugs at reasonable prices. The prices are negotiated between the Department of Health, acting with the authority of Northern Ireland and the UK Government, and the representatives of the Pharmaceutical industry brands, the  Association of the British Pharmaceutical Industry  (ABPI). For 2017 this payment percentage set by the PPRS will be 4,75%. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4853", "text": "In Canada, the Patented Medicine Prices Review Board examines drug pricing and determines if a price is excessive or not. In these circumstances, drug manufacturers must submit a proposed price to the appropriate regulatory agency. Furthermore, \"the International Therapeutic Class Comparison Test is responsible for comparing the National Average Transaction Price of the patented drug product under review\" [ 20 ]  different countries that the prices are being compared to are the following: France, Germany, Italy, Sweden, Switzerland, the United Kingdom, and the United States [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4854", "text": "In Brazil, the prices are regulated through legislation under the name of  Medicamento Gen\u00e9rico  ( generic drugs ) since 1999. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4855", "text": "In India, drug prices are regulated by the  National Pharmaceutical Pricing Authority ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4856", "text": "In the United States, drug costs are partially unregulated, but instead are the result of negotiations between drug companies and insurance companies. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4857", "text": "High prices have been attributed to monopolies given to manufacturers by the government. [ 23 ]  New drug development costs continue to rise as well. Despite the enormous advances in science and technology, the number of new blockbuster drugs approved by the government per billion dollars spent has halved every 9 years since 1950. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4858", "text": "A blockbuster drug is a drug that generates more than $1 billion in revenue for a pharmaceutical company in a single year. [ 25 ]   Cimetidine  was the first drug ever to reach more than $1 billion a year in sales, thus making it the first blockbuster drug. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4859", "text": "In the pharmaceutical industry, a blockbuster drug is one that achieves acceptance by prescribing physicians as a therapeutic standard for, most commonly, a highly prevalent chronic (rather than acute) condition. Patients often take the medicines for long periods. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4860", "text": "Antibiotics  first arrived on the medical scene in 1932 thanks to  Gerhard Domagk ; [ 28 ]  and were coined the \"wonder drugs\". The introduction of the  sulfa drugs  led to the mortality rate from  pneumonia  in the U.S. to drop from 0.2% each year to 0.05% ( i.e. ,  1 \u2044 4  as much) by 1939. [ 29 ]  Antibiotics inhibit the growth or the metabolic activities of bacteria and other microorganisms by a chemical substance of microbial origin.  Penicillin , introduced a few years later, provided a broader spectrum of activity compared to sulfa drugs and reduced side effects.  Streptomycin , found in 1942, proved to be the first drug effective against the cause of  tuberculosis  and also came to be the best known of a long series of important antibiotics. A second generation of antibiotics was introduced in the 1940s:  aureomycin  and  chloramphenicol . Aureomycin was the best known of the second generation. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4861", "text": "Lithium  was discovered in the 19th century for nervous disorders and its possible mood-stabilizing or prophylactic effect; it was cheap and easily produced. As lithium fell out of favor in France,  valpromide  came into play. This antibiotic was the origin of the drug that eventually created the mood stabilizer category. Valpromide had distinct psychotrophic effects that were of benefit in both the treatment of acute manic states and in the maintenance treatment of manic depression illness.  Psychotropics  can either be  sedative  or  stimulant ; sedatives aim at damping down the extremes of behavior. Stimulants aim at restoring normality by increasing tone. Soon arose the notion of a tranquilizer which was quite different from any sedative or stimulant. The term tranquilizer took over the notions of sedatives and became the dominant term in the West through the 1980s. In Japan, during this time, the term tranquilizer produced the notion of a psyche-stabilizer and the term mood stabilizer vanished. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4862", "text": "Premarin  (conjugated estrogens, introduced in 1942) and  Prempro  (a combination estrogen-progestin pill, introduced in 1995) dominated the  hormone replacement therapy  (HRT) during the 1990s. HRT is not a life-saving drug, nor does it cure any disease. HRT has been prescribed to improve one's quality of life. Doctors prescribe estrogen for their older female patients both to treat short-term menopausal symptoms and to prevent long-term diseases. In the 1960s and early 1970s, more and more physicians began to prescribe estrogen for their female patients. Between 1991 and 1999, Premarin was listed as the most popular prescription and best-selling drug in America. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4863", "text": "The first oral contraceptive,  Enovid , was approved by FDA in 1960. Oral contraceptives inhibit ovulation and so prevent conception. Enovid was known to be much more effective than alternatives including the condom and the diaphragm. As early as 1960, oral contraceptives were available in several different strengths by every manufacturer. In the 1980s and 1990s, an increasing number of options arose including, most recently, a new  delivery system  for the oral contraceptive via a  transdermal patch . In 1982, a new version of  \"the pill\"  was introduced, known as the  biphasic pill . By 1985, a new  triphasic pill  was approved. Physicians began to think of \"the pill\" as an excellent means of birth control for young women. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4864", "text": "Stimulants such as  Ritalin  (methylphenidate) came to be pervasive tools for behavior management and modification in young children. Ritalin was first marketed in 1955 for  narcolepsy ; its potential users were middle-aged and the elderly. It was not until some time in the 1980s along with hyperactivity in children that Ritalin came onto the market. Medical use of methylphenidate is predominantly for symptoms of  attention deficit hyperactivity disorder  (ADHD). Consumption of methylphenidate in the U.S. out-paced all other countries between 1991 and 1999. Significant growth in consumption was also evident in Canada, New Zealand, Australia, and Norway. Currently, 85% of the world's methylphenidate is consumed in America. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4865", "text": "The first minor tranquilizer was  meprobamate . Only fourteen months after it was made available, meprobamate had become the country's largest-selling prescription drug. By 1957, meprobamate had become the fastest-growing drug in history. The popularity of meprobamate paved the way for  Librium  and  Valium , two minor tranquilizers that belonged to a new chemical class of drugs called the  benzodiazepines . These were drugs that worked chiefly as  anti-anxiety agents  and  muscle relaxants . The first benzodiazepine was Librium. Three months after it was approved, Librium had become the most prescribed tranquilizer in the nation. Three years later, Valium hit the shelves and was ten times more effective as a muscle relaxant and anti-convulsant. Valium was the most versatile of the minor tranquilizers. Later came the widespread adoption of major tranquilizers such as  chlorpromazine  and the drug  reserpine . In 1970, sales began to decline for Valium and Librium, but sales of new and improved tranquilizers, such as  Xanax , introduced in 1981 for the newly created diagnosis of panic disorder, soared. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4866", "text": "Mevacor  (lovastatin) is the first and most influential  statin  in the American market. The 1991 launch of  Pravachol  (pravastatin), the second available in the United States, and the release of  Zocor  (simvastatin) made Mevacor no longer the only statin on the market.\nIn 1998,  Viagra  was released as a treatment for erectile dysfunction. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4867", "text": "Using plants and plant substances to treat all kinds of diseases and medical conditions is believed to date back to  prehistoric medicine . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4868", "text": "The  Kahun Gynaecological Papyrus , the oldest known medical text of any kind, dates to about 1800 BC and represents the first documented use of any kind of drug. [ 31 ] [ 32 ]  It and other  medical papyri  describe  Ancient Egyptian medical practices , such as using  honey  to treat infections and the legs of bee-eaters to treat neck pains."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4869", "text": "Ancient  Babylonian medicine  demonstrated the use of medication in the first half of the  2nd millennium BC .  Medicinal creams  and  pills  were employed as treatments. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4870", "text": "On the Indian subcontinent, the  Atharvaveda , a sacred text of  Hinduism  whose core dates from the second millennium BC, although the hymns recorded in it are believed to be older, is the first Indic text dealing with medicine. It describes plant-based drugs to counter diseases. [ 34 ]  The earliest foundations of  ayurveda  were built on a synthesis of selected ancient herbal practices, together with a massive addition of theoretical conceptualizations, new  nosologies  and new therapies dating from about 400 BC onwards. [ 35 ]  The student of \u0100yurveda was expected to know ten arts that were indispensable in the preparation and application of his medicines: distillation, operative skills, cooking, horticulture, metallurgy, sugar manufacture, pharmacy, analysis and separation of minerals, compounding of metals, and preparation of  alkalis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4871", "text": "The  Hippocratic Oath  for physicians, attributed to fifth century BC Greece, refers to the existence of \"deadly drugs\", and  ancient Greek physicians  imported drugs from Egypt and elsewhere. [ 36 ]  The  pharmacopoeia   De materia medica , written between 50 and 70 CE by the Greek physician  Pedanius Dioscorides , was widely read for more than 1,500 years. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4872", "text": "Al-Kindi 's ninth century AD book,  De Gradibus  and  Ibn Sina  (Avicenna)'s  The Canon of Medicine , covers a range of drugs known to the practice of  medicine in the medieval Islamic world ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4873", "text": "Medieval medicine of Western Europe  saw advances in surgery compared to previously, but few truly effective drugs existed, beyond  opium  (found in such extremely popular drugs as the \"Great Rest\" of the  Antidotarium Nicolai  at the time) [ 38 ]  and  quinine . Folklore cures and potentially poisonous metal-based compounds were popular treatments.  Theodoric Borgognoni , (1205\u20131296), one of the most significant surgeons of the medieval period, responsible for introducing and promoting important surgical advances including basic  antiseptic  practice and the use of  anaesthetics .  Garcia de Orta  described some herbal treatments that were used. [ vague ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4874", "text": "For most of the 19th century, drugs were not highly effective, leading  Oliver Wendell Holmes Sr.  to famously comment in 1842 that \"if all medicines in the world were thrown into the sea, it would be all the better for mankind and all the worse for the fishes\". [ 27 ] :\u200a21"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4875", "text": "During the  First World War ,  Alexis Carrel  and  Henry Dakin  developed the Carrel-Dakin method of treating wounds with an irrigation, Dakin's solution, a germicide which helped prevent  gangrene ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4876", "text": "In the inter-war period, the first anti-bacterial agents such as the  sulpha  antibiotics were developed. The Second World War saw the introduction of widespread and effective antimicrobial therapy with the development and mass production of  penicillin  antibiotics, made possible by the pressures of the war and the collaboration of British scientists with the American  pharmaceutical industry ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4877", "text": "Medicines commonly used by the late 1920s included  aspirin ,  codeine , and  morphine  for pain;  digitalis ,  nitroglycerin , and  quinine  for heart disorders, and  insulin  for diabetes. Other drugs included  antitoxins , a few biological vaccines, and a few synthetic drugs. In the 1930s, antibiotics emerged: first  sulfa drugs , then  penicillin  and other antibiotics. Drugs increasingly became \"the center of medical practice\". [ 27 ] :\u200a22\u200a  In the 1950s, other drugs emerged including  corticosteroids  for  inflammation ,  rauvolfia alkaloids  as tranquilizers and antihypertensives,  antihistamines  for nasal allergies,  xanthines  for asthma, and typical  antipsychotics  for psychosis. [ 27 ] :\u200a23\u201324\u200a  As of 2007, thousands of approved drugs have been  developed . Increasingly,  biotechnology  is used to discover  biopharmaceuticals . [ 27 ]  Recently, multi-disciplinary approaches have yielded a wealth of new data on the development of novel antibiotics and antibacterials and on the use of biological agents for antibacterial therapy. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4878", "text": "In the 1950s, new psychiatric drugs, notably the antipsychotic  chlorpromazine , were designed in laboratories and slowly came into preferred use. Although often accepted as an advance in some ways, there was some opposition, due to serious adverse effects such as  tardive dyskinesia . Patients often opposed psychiatry and refused or stopped taking the drugs when not subject to psychiatric control."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4879", "text": "Governments have been heavily involved in the regulation of drug development and drug sales. In the U.S., the  Elixir Sulfanilamide disaster  led to the establishment of the  Food and Drug Administration , and the 1938 Federal Food, Drug, and Cosmetic Act required manufacturers to file new drugs with the FDA. The 1951 Humphrey-Durham Amendment required certain drugs to be sold by prescription. In 1962, a subsequent amendment required new drugs to be tested for efficacy and safety in  clinical trials . [ 27 ] :\u200a24\u201326"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4880", "text": "Until the 1970s, drug prices were not a major concern for doctors and patients. As more drugs became prescribed for chronic illnesses, however, costs became burdensome, and by the 1970s nearly every U.S. state required or encouraged the substitution of  generic drugs  for higher-priced brand names. This also led to the 2006 U.S. law,  Medicare Part D , which offers Medicare coverage for drugs. [ 27 ] :\u200a28\u201329"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4881", "text": "As of 2008, the United States is the leader in  medical research , including pharmaceutical development. U.S. drug prices are among the highest in the world, and drug innovation is correspondingly high. In 2000, U.S.-based firms developed 29 of the 75 top-selling drugs; firms from the second-largest market, Japan, developed eight, and the United Kingdom contributed 10. France, which imposes price controls, developed three. Throughout the 1990s, outcomes were similar. [ 27 ] :\u200a30\u201331"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4882", "text": "Controversies concerning pharmaceutical drugs include patient access to drugs under development and not yet approved, pricing, and environmental issues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4883", "text": "Governments worldwide have created provisions for granting access to drugs prior to approval for patients who have exhausted all alternative treatment options and do not match clinical trial entry criteria. Often grouped under the labels of compassionate use,  expanded access , or named patient supply, these programs are governed by rules which vary by country defining access criteria, data collection, promotion, and control of drug distribution. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4884", "text": "Within the United States, pre-approval demand is generally met through  treatment IND  (investigational new drug) applications (INDs), or single-patient INDs. These mechanisms, which fall under the label of expanded access programs, provide access to drugs for groups of patients or individuals residing in the US. Outside the US, Named Patient Programs provide controlled, pre-approval access to drugs in response to requests by physicians on behalf of specific, or \"named\", patients before those medicines are licensed in the patient's home country.  Through these programs, patients are able to access drugs in late-stage clinical trials or approved in other countries for a genuine, unmet medical need, before those drugs have been licensed in the patient's home country. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4885", "text": "Patients who have not been able to get access to drugs in development have organized and advocated for greater access.  In the United States,  ACT UP  formed in the 1980s, and eventually formed its  Treatment Action Group  in part to pressure the US government to put more resources into discovering treatments for AIDS and then to speed release of drugs that were under development. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4886", "text": "The  Abigail Alliance  was established in November 2001 by Frank Burroughs in memory of his daughter, Abigail. [ 42 ]  The Alliance seeks broader availability of investigational drugs on behalf of terminally ill patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4887", "text": "In 2013,  BioMarin Pharmaceutical  was at the center of a high-profile debate regarding expanded access of cancer patients to experimental drugs. [ 43 ] [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4888", "text": "Essential medicines, as defined by the  World Health Organization  (WHO), are \"those drugs that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in appropriate dosage forms, at a price the community can afford.\" [ 45 ]   Recent studies have found that most of the medicines on the WHO essential medicines list, outside of the field of HIV drugs, are not patented in the developing world, and that lack of widespread  access to these medicines  arise from issues fundamental to economic development \u2013 lack of infrastructure and poverty. [ 46 ]   M\u00e9decins Sans Fronti\u00e8res  also runs a  Campaign for Access to Essential Medicines  campaign, which includes advocacy for greater resources to be devoted to currently untreatable diseases that primarily occur in the developing world. The  Access to Medicine Index  tracks how well pharmaceutical companies make their products available in the developing world. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4889", "text": "World Trade Organization  negotiations in the 1990s, including the  TRIPS Agreement  and the  Doha Declaration , have centered on issues at the intersection of international trade in pharmaceuticals and  intellectual property rights , with developed world nations seeking strong intellectual property rights to protect investments made to develop new drugs, and developing world nations seeking to promote their generic pharmaceuticals industries and their ability to make medicine available to their people via  compulsory licenses ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4890", "text": "Some have raised ethical objections specifically with respect to pharmaceutical patents and the high prices for drugs that they enable their proprietors to charge, which poor people around the world, cannot afford. [ 47 ] [ 48 ]  Critics also question the rationale that exclusive patent rights and the resulting high prices are required for pharmaceutical companies to recoup the large investments needed for research and development. [ 47 ]  One study concluded that marketing expenditures for new drugs often doubled the amount that was allocated for research and development. [ 49 ]  Other critics claim that patent settlements would be costly for consumers, the health care system, and state and federal governments because it would result in delaying access to lower cost generic medicines. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4891", "text": "Novartis  fought a protracted battle with the government of India over the patenting of its drug,  Gleevec , in India, which ended up in a Supreme Court in a case known as  Novartis v. Union of India & Others .  The Supreme Court ruled narrowly against Novartis, but opponents of patenting drugs claimed it as a major victory. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4892", "text": "Pharmaceutical medications are commonly described as \"ubiquitous\" in nearly every type of environmental medium (i.e.  lakes ,  rivers ,  streams ,  estuaries ,  seawater , and  soil ) worldwide. [ 52 ] [ 53 ] [ 54 ] [ 55 ]  Their chemical components are typically present at relatively low  concentrations  in the ng/L to \u03bcg/L ranges. [ 56 ] [ 54 ]  The primary avenue for medications reaching the environment are through the  effluent  of wastewater  treatment plants , both from  industrial plants  during production, and from  municipal plants  after consumption. [ 57 ]   Agricultural pollution  is another significant source derived from the prevalence of  antibiotic use in livestock . [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4893", "text": "Scientists generally divide environmental impacts of a chemical into three primary categories: persistence,  bioaccumulation , and  toxicity . [ 53 ]  Since medications are inherently bio-active, most are naturally degradable in the environment, however they are classified as \"pseudopersistent\" because they are constantly being replenished from their sources. [ 52 ]  These  Environmentally Persistent Pharmaceutical Pollutants  (EPPPs) rarely reach toxic concentrations in the environment, however they have been known to bioaccumulate in some species. [ 58 ]  Their effects have been observed to compound gradually across  food webs , rather than becoming acute, leading to their classification by the  US Geological Survey  as \"Ecological Disrupting Compounds.\" [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4894", "text": "In an  adaptive design  of a  clinical trial , the parameters and conduct of the trial for a candidate  drug  or  vaccine  may be changed based on an  interim analysis . [ 2 ] [ 1 ] [ 3 ]  Adaptive design typically involves advanced statistics to interpret a clinical trial  endpoint . [ 1 ]  This is in contrast to traditional single-arm (i.e. non-randomized) clinical trials or  randomized clinical trials  (RCTs) that are static in their protocol and do not modify any parameters until the trial is completed. The adaptation process takes place at certain points in the trial, prescribed in the trial protocol. Importantly, this trial protocol is set before the trial begins with the adaptation schedule and processes specified. Adaptions may include modifications to: dosage, sample size, drug undergoing trial, patient selection criteria and/or \"cocktail\" mix. [ 4 ] [ 5 ]  The PANDA (A Practical Adaptive & Novel Designs and Analysis toolkit) provides not only a summary of different adaptive designs, but also comprehensive information on adaptive design planning, conduct, analysis and reporting. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4895", "text": "The aim of an adaptive trial is to more quickly identify drugs or devices that have a therapeutic effect, and to zero in on patient populations for whom the drug is appropriate. [ 7 ]  When conducted efficiently, adaptive trials have the potential to find new treatments while minimizing the number of patients exposed to the risks of clinical trials. Specifically, adaptive trials can efficiently discover new treatments by reducing the number of patients enrolled in treatment groups that show minimal efficacy or higher adverse-event rates. Adaptive  trials  can adjust almost any part of its design, based on pre-set rules and statistical design, such as sample size, adding new groups, dropping less effective groups and changing the probability of being randomized to a particular group, for example."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4896", "text": "In 2004, a Strategic Path Initiative was introduced by the United States  Food and Drug Administration  (FDA) to modify the way drugs travel from lab to market. This initiative aimed at dealing with the high attrition levels observed in the clinical phase. It also attempted to offer flexibility to investigators to find the optimal clinical benefit without affecting the study's validity. Adaptive clinical trials initially came under this regime. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4897", "text": "The FDA issued draft guidance on adaptive trial design in 2010. [ 7 ]  In 2012, the  President's Council of Advisors on Science and Technology  (PCAST) recommended that the FDA \"run pilot projects to explore adaptive approval mechanisms to generate evidence across the lifecycle of a drug from the pre-market through the post-market phase.\" While not specifically related to clinical trials, the council also recommended that they \"make full use of accelerated approval for all drugs meeting the statutory standard of addressing an unmet need for a serious or life-threatening disease, and demonstrating an impact on a clinical endpoint other than survival or irreversible morbidity, or on a surrogate endpoint, likely to predict clinical benefit.\" [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4898", "text": "By 2019, the FDA updated their 2010 recommendations and issued \"Adaptive Design Clinical Trials for Drugs and Biologics Guidance\". [ 10 ]   In October of 2021, the FDA Center for Veterinary Medicine issued the Guidance Document \"Adaptive and Other Innovative Designs for Effectiveness Studies of New Animal Drugs\". [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4899", "text": "Traditionally, clinical trials are conducted in three steps: [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4900", "text": "Any trial design that can change its design, during active enrollment, could be considered an adaptive clinical trial. There are a number of different types, and real life trials may combine elements from these different trial types: [ 1 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ]  In some cases, trials have become an ongoing process that regularly adds and drops therapies and patient groups as more information is gained. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4901", "text": "Phase I  of clinical research focuses on selecting a particular dose of a drug to carry forward into future trials. Historically, such trials have had a \"rules-based\" (or \"algorithm-based\") design, such as the 3+3 design. [ 17 ]  However, these \"A+B\" rules-based designs are not appropriate for phase I studies and are inferior to adaptive, model-based designs. [ 18 ]  An example of a superior design is the continual reassessment method (CRM). [ 19 ] [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4902", "text": "Group sequential design is the application of  sequential analysis  to clinical trials. At each interim analysis, investigators will use the current data to decide whether the trial should either stop or should continue to recruit more participants. The trial might stop either because the evidence that the treatment is working is strong (\"stopping for benefit\") or weak (\"stopping for futility\"). Whether a trial may stop for futility only, benefit only, or either, is stated in advance. A design has \"binding stopping rules\" when the trial must stop when a particular threshold of (either strong or weak) evidence is crossed at a particular interim analysis. Otherwise it has \"non-binding stopping rules\", in which case other information can be taken into account, for example safety data. The number of interim analyses is specified in advance, and can be anything from a single interim analysis (a \"two-stage\" design\") to an interim analysis after every participant (\"continuous monitoring\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4903", "text": "For trials with a binary (response/no response) outcome and a single treatment arm, a popular and simple group sequential design with two stages is the Simon design. In this design, there is a single interim analysis partway through the trial, at which point the trial either stops for futility or continues to the second stage. [ 22 ]  Mander and Thomson also proposed a design with a single interim analysis, at which point the trial could stop for either futility or benefit. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4904", "text": "For single-arm, single-stage binary outcome trials, a trial's success or failure is determined by the number of responses observed by the end of the trial. This means that it may be possible to know the conclusion of the trial (success or failure) with certainty before all the data are available. Planning to stop a trial once the conclusion is known with certainty is called  non-stochastic curtailment . This reduces the sample size on average. Planning to stop a trial when the probability of success, based on the results so far, is either above or below a certain threshold is called  stochastic curtailment . This reduces the average sample size even more than non-stochastic curtailment. Stochastic and non-stochastic curtailment can also be used in two-arm binary outcome trials, where a trial's success or failure is determined by the number of responses observed on each arm by the end of the trial."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4905", "text": "The adaptive design method developed mainly in the early 21st century. [ 1 ]  In November 2019, the US  Food and Drug Administration  provided guidelines for using adaptive designs in clinical trials. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4906", "text": "In April 2020, the  World Health Organization  published an \"R&D Blueprint (for the)  novel Coronavirus \" (Blueprint). The Blueprint documented a \"large, international, multi-site, individually randomized controlled clinical trial\" to allow \"the concurrent evaluation of the benefits and risks of each promising candidate vaccine within 3\u20136 months of it being made available for the trial.\" The Blueprint listed a  Global Target Product Profile  (TPP) for COVID\u201119, identifying favorable attributes of safe and effective vaccines under two broad categories: \"vaccines for the long-term protection of people at higher risk of COVID-19, such as healthcare workers\", and other vaccines to provide rapid-response immunity for new outbreaks. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4907", "text": "The international TPP team was formed to 1) assess the development of the most promising candidate vaccines; 2) map candidate vaccines and their clinical trial worldwide, publishing a frequently-updated \"landscape\" of vaccines in development; [ 25 ]  3) rapidly evaluate and screen for the most promising candidate vaccines simultaneously before they are tested in humans; and 4) design and coordinate a multiple-site, international  randomized controlled trial \u00a0\u2013 the \"Solidarity trial\" for vaccines [ 24 ] [ 26 ] \u00a0\u2013 to enable simultaneous evaluation of the benefits and risks of different vaccine candidates under clinical trials in countries where there are high rates of COVID\u201119 disease, ensuring fast interpretation and sharing of results around the world. [ 24 ]  The WHO vaccine coalition prioritized which vaccines would go into Phase \u00a0 II and III clinical trials, and determined harmonized Phase \u00a0 III protocols for all vaccines achieving the  pivotal trial  stage. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4908", "text": "The global  \"Solidarity\"  and European \"Discovery\" trials of hospitalized people with severe COVID\u201119 infection applied adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge. [ 27 ] [ 28 ] [ 29 ] [ 30 ]  The US  National Institute of Allergy and Infectious Diseases  (NIAID) initiated an adaptive design, international Phase III trial (called \"ACTT\") to involve up to 800 hospitalized COVID\u201119 people at 100 sites in multiple countries. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4909", "text": "An adaptive trial design enabled two experimental  breast cancer  drugs to deliver promising results after just six months of testing, far shorter than usual. Researchers assessed the results while the trial was in process and found that cancer had been eradicated in more than half of one group of patients. The trial, known as  I-Spy 2 , tested 12 experimental drugs. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4910", "text": "For its predecessor I-SPY 1, 10 cancer centers and the National Cancer Institute (NCI SPORE program and the NCI Cooperative groups) collaborated to identify response indicators that would best predict survival for women with high-risk breast cancer. During 2002\u20132006, the study monitored 237 patients undergoing  neoadjuvant therapy  before surgery. Iterative  MRI  and tissue samples monitored the biology of patients to chemotherapy given in a neoadjuvant setting, or presurgical setting. Evaluating chemotherapy's direct impact on tumor tissue took much less time than monitoring outcomes in thousands of patients over long time periods. The approach helped to standardize the imaging and tumor sampling processes, and led to miniaturized assays. Key findings included that tumor response was a good predictor of patient survival, and that tumor shrinkage during treatment was a good predictor of long-term outcome. Importantly, the vast majority of tumors identified as high risk by molecular signature. However, heterogeneity within this group of women and measuring response within tumor subtypes was more informative than viewing the group as a whole. Within genetic signatures, level of response to treatment appears to be a reasonable predictor of outcome. Additionally, its shared database has furthered the understanding of drug response and generated new targets and agents for subsequent testing. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4911", "text": "I-SPY 2 is an adaptive clinical trial of multiple Phase 2 treatment regimens combined with standard chemotherapy. I-SPY 2 linked 19 academic cancer centers, two community centers, the FDA, the NCI, pharmaceutical and biotech companies, patient advocates and philanthropic partners. The trial is sponsored by the Biomarker Consortium of the Foundation for the NIH (FNIH), and is co-managed by the FNIH and QuantumLeap Healthcare Collaborative. I-SPY 2 was designed to explore the hypothesis that different combinations of cancer therapies have varying degrees of success for different patients. Conventional clinical trials that evaluate post-surgical tumor response require a separate trial with long intervals and large populations to test each combination. Instead, I-SPY 2 is organized as a continuous process. It efficiently evaluates multiple therapy regimes by relying on the predictors developed in I-SPY 1 that help quickly determine whether patients with a particular genetic signature will respond to a given treatment regime. The trial is adaptive in that the investigators learn as they go, and do not continue treatments that appear to be ineffective. All patients are categorized based on tissue and imaging markers collected early and iteratively (a patient's markers may change over time) throughout the trial, so that early insights can guide treatments for later patients. Treatments that show positive effects for a patient group can be ushered to confirmatory clinical trials, while those that do not can be rapidly sidelined. Importantly, confirmatory trials can serve as a pathway for FDA  Accelerated Approval . I-SPY 2 can simultaneously evaluate candidates developed by multiple companies, escalating or eliminating drugs based on immediate results. Using a single standard arm for comparison for all candidates in the trial saves significant costs over individual Phase 3 trials. All data are shared across the industry. [ 32 ]  As of January\u00a02016 [update]  I-SPY 2 is comparing 11 new treatments against 'standard therapy', and is estimated to complete in Sept 2017. [ 33 ]  By mid 2016 several treatments had been selected for later stage trials. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4912", "text": "Researchers under the EPAD project by the  Innovative Medicines Initiative  are utilizing an adaptive trial design to help speed development of  Alzheimer's disease  treatments, with a budget of 53 million euros. The first trial under the initiative was expected to begin in 2015 and to involve about a dozen companies. [ 7 ] [ 35 ]  As of 2020, 2,000 people over the age of 50 have been recruited across Europe for a long term study on the earliest stages of Alzheimer's. [ 36 ]  The EPAD project plans to use the results from this study and other data to inform 1,500 person selected adaptive clinical trials of drugs to prevent Alzheimer's. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4913", "text": "The adjustable nature of adaptive trials inherently suggests the use of  Bayesian statistical analysis . Bayesian statistics inherently address updating information such as that seen in adaptive trials that change from updated information derived from interim analysis. [ 38 ]  The problem of adaptive clinical trial design is more or less exactly the  bandit problem  as studied in the field of  reinforcement learning ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4914", "text": "According to FDA guidelines, an adaptive Bayesian clinical trial can involve: [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4915", "text": "The Bayesian framework  Continuous Individualized Risk Index  which is based on dynamic measurements from cancer patients can be effectively used for adaptive trial designs.  Platform trials  rely heavily on Bayesian designs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4916", "text": "For regulatory submission of Bayesian clinical trial design, there exist two Bayesian decision rules that are frequently used by trial sponsors. [ 40 ]  First, posterior probability approach is mainly used in decision-making to quantify the evidence to address the question, \"Does the current data provide convincing evidence in favor of the alternative hypothesis?\" The key quantity of the posterior probability approach is the posterior probability of the alternative hypothesis being true based on the data observed up to the point of analysis. Second, predictive probability approach is mainly used in decision-making is to answer the question at an interim analysis: \"Is the trial likely to present compelling evidence in favor of the alternative hypothesis if we gather additional data, potentially up to the maximum sample size (or current sample size)?\" [ 38 ]  The key quantity of the predictive probability approach is the posterior predictive probability of the trial success given the interim data."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4917", "text": "In most regulatory submissions, Bayesian trial designs are calibrated to possess good frequentist properties. In this spirit, and in adherence to regulatory practice, regulatory agencies typically recommend that sponsors provide the frequentist type I and II error rates for the sponsor's proposed Bayesian analysis plan. In other words, the Bayesian designs for the regulatory submission need to satisfy the type I and II error requirement in most cases in the frequentist sense. Some exception may happen in the context of external data borrowing where the type I error rate requirement can be relaxed to some degree depending on the confidence of the historical information. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4918", "text": "The problem of adaptive clinical trial design is more or less exactly the  bandit problem  as studied in the field of  reinforcement learning ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4919", "text": "The logistics of managing traditional, non-adaptive design clinical trials may be complex. In adaptive design clinical trials, adapting the design as results arrive adds to the complexity of design, monitoring, drug supply, data capture and randomization. [ 8 ]  Furthermore, it should be stated in the trial's  protocol  exactly what kind of adaptation will be permitted. [ 1 ]  Publishing the trial protocol in advance increases the validity of the final results, as it makes clear that any adaptation that took place during the trial was planned, rather than ad hoc. According to PCAST \"One approach is to focus studies on specific subsets of patients most likely to benefit, identified based on validated biomarkers. In some cases, using appropriate biomarkers can make it possible to dramatically decrease the sample size required to achieve statistical significance\u2014for example, from 1500 to 50 patients.\" [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4920", "text": "Adaptive designs have added statistical complexity compared to traditional clinical trial designs. For example, any multiple testing, either from looking at multiple treatment arms or from looking at a single treatment arm multiple times, must be accounted for. Another example is  statistical bias , which can be more likely when using adaptive designs, and again must be accounted for."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4921", "text": "While an adaptive design may be an improvement over a non-adaptive design in some respects (for example, expected sample size), it is not always the case that an adaptive design is a better choice overall: in some cases, the added complexity of the adaptive design may not justify its benefits. An example of this is when the trial is based on a measurement that takes a long time to observe, as this would mean having an interim analysis when many participants have started treatment but cannot yet contribute to the interim results. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4922", "text": "Shorter trials may not reveal longer term risks, such as a cancer's return. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4923", "text": "The  Anatomical Therapeutic Chemical  ( ATC )  Classification System  is a  drug classification  system that classifies the  active ingredients  of  drugs  according to the  organ  or  system  on which they act and their  therapeutic ,  pharmacological  and  chemical  properties. Its purpose is an aid to  monitor drug use  and for  research  to improve quality medication use. It does not imply  drug recommendation  or  efficacy . [ 1 ]  It is controlled by the  World Health Organization  Collaborating Centre for Drug Statistics Methodology (WHOCC), and was first published in 1976. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4924", "text": "This  pharmaceutical coding system  divides drugs into different groups according to the organ or system on which they act, their  therapeutic  intent or nature, and the drug's  chemical characteristics . Different brands share the same code if they have the same active substance and indications. Each bottom-level ATC code stands for a pharmaceutically used substance, or a combination of substances, in a single indication (or use). This means that one drug can have more than one code, for example  acetylsalicylic acid  (aspirin) has  A01AD05  ( WHO ) as a drug for local  oral  treatment,  B01AC06  ( WHO ) as a  platelet inhibitor , and  N02BA01  ( WHO ) as an  analgesic  and  antipyretic ; as well as one code can represent more than one active ingredient, for example  C09BB04  ( WHO ) is the combination of perindopril with amlodipine, two active ingredients that have their own codes ( C09AA04  ( WHO ) and  C08CA01  ( WHO ) respectively) when prescribed alone."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4925", "text": "The ATC classification system is a strict hierarchy, [ 5 ]  meaning that each code necessarily has one and only one parent code, except for the 14 codes at the topmost level which have no parents. The codes are semantic identifiers, [ 5 ]  meaning they depict information by themselves beyond serving as identifiers (namely, the codes depict themselves the complete lineage of parenthood). As of 7 May 2020, there are 6,331 codes in ATC; the table below gives the count per level. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4926", "text": "The ATC system is based on the earlier Anatomical Classification System, which is intended as a tool for the pharmaceutical industry to classify pharmaceutical products (as opposed to their active ingredients). [ 7 ]  This system, confusingly also called ATC, was initiated in 1971 by the  European Pharmaceutical Market Research Association  (EphMRA) and is being maintained by the EphMRA and Intellus. Its codes are organised into four levels. [ 8 ]  The WHO's system, having five levels, is an extension and modification of the EphMRA's. It was first published in 1976. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4927", "text": "In this system, drugs are classified into groups at five different levels: [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4928", "text": "The first level of the code indicates the anatomical main group and consists of one letter. There are 14 main groups: [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4929", "text": "Example :  C   Cardiovascular system"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4930", "text": "The second level of the code indicates the therapeutic subgroup and consists of two digits. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4931", "text": "Example :  C 03   Diuretics"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4932", "text": "The third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4933", "text": "Example : C03 C  High-ceiling diuretics"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4934", "text": "The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4935", "text": "Example : C03C A   Sulfonamides"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4936", "text": "The fifth level of the code indicates the chemical substance and consists of two digits."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4937", "text": "Example : C03CA 01   furosemide"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4938", "text": "The  Anatomical Therapeutic Chemical Classification System for veterinary medicinal products  (ATCvet) is used to classify  veterinary  drugs. ATCvet codes can be created by placing the letter Q in front of the ATC code of most human medications. For example, furosemide for veterinary use has the code  Q C03CA01."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4939", "text": "Some codes are used exclusively for veterinary drugs, such as  QI  Immunologicals ,  QJ51  Antibacterials for intramammary use  or  QN05AX90  amperozide . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4940", "text": "The Herbal ATC system (HATC) is an ATC classification of  herbal substances ;  it differs from the regular ATC system by using 4 digits instead of 2 at the 5th level group. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4941", "text": "The herbal classification is not adopted by WHO. The  Uppsala Monitoring Centre  is responsible for the Herbal ATC classification, and it is part of the  WHODrug Global  portfolio available by  subscription . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4942", "text": "The ATC system also includes defined daily doses (DDDs) for many drugs. This is a measurement of drug consumption based on the usual daily dose for a given drug. According to the definition, \"[t]he DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults.\" [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4943", "text": "National issues of the ATC classification, such as the  German   Anatomisch-therapeutisch-chemische Klassifikation mit Tagesdosen , may include additional codes and DDDs not present in the WHO version. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4944", "text": "ATC follows guidelines [ 17 ]  in creating new codes for newly approved drugs. An application is submitted to WHO for ATC classification and DDD assignment. A preliminary or temporary code is assigned and published on the website and in the  WHO Drug Information  for comment or objection.  New ATC/DDD codes are discussed at the semi-annual Working Group meeting. If accepted it becomes a final decision and published semi-annually on the website and  WHO Drug Information  and implemented in the annual print/on-line ACT/DDD Index on January 1. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4945", "text": "Changes to existing ATC/DDD follow a similar process to become temporary codes and if accepted become a final decision as ATC/DDD alterations.  ATC and DDD alterations are only valid and implemented in the coming annual updates; the original codes must continue until the end of the year. [ 19 ] [ 20 ]  An updated version of the complete on-line/print ATC index with DDDs is published annually on January 1. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4946", "text": "An  astringent  (sometimes called  adstringent ) is a chemical that shrinks or constricts  body tissues . The word derives from the  Latin   adstringere , which means \"to bind fast\".  Astringency , the dry, puckering or numbing  mouthfeel  caused by the  tannins [ 1 ] [ 2 ]  in unripe fruits, lets the fruit mature by deterring eating. Tannins, being a kind of  polyphenol , bind salivary  proteins  and make them precipitate and  aggregate , [ 3 ] [ 4 ] [ 5 ]  producing a rough, \"sandpapery\", or dry sensation in the mouth."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4947", "text": "Smoking tobacco  is also reported to have an astringent effect. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4948", "text": "In a scientific study, astringency was still detectable by subjects who had  local anesthesia  applied to their taste nerves, but not when both these and the  trigeminal nerves  were disabled. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4949", "text": "In medicine, astringents cause constriction or contraction of  mucous membranes  and exposed tissues and are often used internally to reduce discharge of  blood serum  and mucous secretions. [ 8 ]  This can happen with a  sore throat ,  hemorrhages ,  diarrhea , and  peptic ulcers . Externally applied astringents, which cause mild coagulation of skin  proteins , dry, harden, and protect the  skin . [ 9 ]  People with  acne  are often advised to use astringents if they have oily skin. [ 10 ]  Mild astringents relieve such minor skin irritations as those resulting from superficial cuts;  allergies ;  insect bites ; [ 9 ]   anal hemorrhoids ; [ 11 ]  and  fungal infections  such as  athlete's foot . [ 12 ]  Redness-reducing eye drops contain an astringent. Use of  Goulard's Extract  has been discontinued due to  lead poisoning . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4950", "text": "Some common astringents are  alum ,  acacia ,  sage , [ 13 ]   yarrow , [ 14 ]   witch hazel ,  bayberry ,  distilled vinegar , very cold  water , and  rubbing alcohol . Astringent preparations include  silver nitrate ,  potassium permanganate ,  zinc oxide ,  zinc sulfate ,  Burow's solution ,  tincture of benzoin , and such vegetable substances as  tannic  and  gallic acids .  Balaustines  are the red  rose -like  flowers  of the  pomegranate , which are very bitter to the taste. In medicine, their dried form has been used as an astringent. [ 15 ]   Some metal  salts  and acids have also been used as astringents. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4951", "text": "Calamine lotion ,  witch hazel , and  yerba mansa , are astringents, [ 17 ]  as are the powdered leaves of the  myrtle . [ 18 ]  Ripe fruits and fruit parts including  blackthorn  (sloe berries),  Aronia  chokeberry,  chokecherry ,  bird cherry ,  rhubarb ,  quince ,  jabuticaba  and  persimmon  fruits (especially when unripe),  banana  skins (or unripe bananas),  cashew  fruits and acorns are astringent. [ 19 ]  Citrus fruits, like lemons, are somewhat astringent. The tannins in some  teas ,  coffee , and red grape  wines  like  Cabernet Sauvignon  and  Merlot  produce mild astringency. [ citation needed ]   Astringency  is used in classifications of  white wine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4952", "text": "Biodiversity  plays a vital role in maintaining human and animal health because numerous plants, animals, and fungi are used in medicine to produce vital  vitamins ,  painkillers ,  antibiotics , and other medications. [ 1 ] [ 2 ] [ 3 ]  Natural products have been recognized and used as medicines by ancient cultures all around the world. [ 4 ]  Some animals are also known to  self-medicate  using plants and other materials available to them. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4953", "text": "Many plant species have been studied thoroughly for their value as a source of medicine. [ 6 ] [ 7 ]  They have a wide range of benefits such as anti-fever and anti-inflammatory properties, can treat diseases such as  malaria  and  diabetes , and are used as vitamins and  antibiotic  and  antifungal  medications. [ 7 ] [ 8 ] [ 9 ] [ 10 ]  More than 60% of the world's population relies almost entirely on plant medicine for primary health care, [ 11 ]  and about 119 pure chemicals such as  caffeine ,  methyl salicylate , and  quinine  are extracted from less than 90 species of higher plants and used as medicines throughout the world. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4954", "text": "In China, Japan, India, and Germany, there is a great deal of interest in and support for the search for new drugs from higher plants. [ 4 ]  For example, the Herbalome Project was launched in China in 2008 and aims to use  high throughput sequencing  and  toxicity testing  to identify active components in traditional herbal remedies. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4955", "text": "Sweet Wormwood ( Artemisia annua ) grows in all continents besides Antarctica. [ 13 ]  It is the only known source of  artemisinin , a drug that has been used to treat  fevers  due to  malaria , exhaustion, or many other causes, since ancient times. [ 14 ]  Upon further study, scientists have found that Sweet Wormwood inhibits activity of various bacteria, viruses, and parasites and exhibits anti-cancer and anti-inflammatory properties. [ 14 ] [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4956", "text": "Animal-derived drugs are a major source of modern medications used around the world. [ 2 ] [ 17 ]  The use of these drugs can cause certain animals to become  endangered  or  threatened ; however, it is difficult to identify the animal species used in medicine since animal-derived drugs are often processed, which degrades their  DNA . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4957", "text": "Cells from animal horns and shells are included in a group of medications call Medicinal Animal Horns and Shells (MAHS). [ 2 ] [ 18 ]  These drugs are often used in  dermatology  and have been reported to have anti-fever and anti-inflammatory properties and treat some diseases. [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4958", "text": "Certain animals have obtained many adaptations of toxic substances due to a  coevolutionary arms race  between them and their predators. [ 20 ]  Some components of these toxins such as  enzymes  and inorganic salts are used in modern medicine. [ 21 ]  For example, drugs such as  Captopril  and  Lisinopril  are derived from snake venom and inhibit the  angiotensin-converting enzyme . [ 22 ] [ 21 ]  Another example is  Ziconotide , a drug from the cone snail,  Conus magus , that is used to reduce pain. [ 21 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4959", "text": "Edible fungi can contain important nutrients and  biomolecules  that can be used for medical applications. [ 3 ]  For example, medicinal fungi have  polysaccharides  that can be used to prevent the spread of cancer by activating different types of immune cells (namely  T lymphocytes ,  macrophages , and  NK cells ), which inhibit cancer cell reproduction and  metastasis  (the process by which cancer can spread to different parts of the body). [ 3 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4960", "text": "Fungi have been used to make many antibiotics since Sir Alexander Flemming discovered Penicillin from the mold,  Penicillium notatum . [ 25 ] [ 26 ]  Recently, there has been a renewed interest in using fungi to create antibiotics since many bacteria have obtained  antibiotic resistance  due to the heavy selection pressures that antibiotics cause. [ 25 ]  The diversity of  marine fungi  makes them a potential new source of antibiotic compunds; however, most are difficult to cultivate in a laboratory setting. [ 25 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4961", "text": "Countries in Asia such as Egypt and China have been using fungi for medical uses for centuries. [ 3 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4962", "text": "Toxoplasmosis  is a disease caused by an infection by the parasite:  Toxoplasma gondii  (T. gondii). [ 28 ] [ 29 ]  Current drugs used to treat this disease have many side effects and do not inhibit all forms of T. gondii. [ 30 ]  An  in vitro  study by Sharma et al. suggests that Turkey Tail mushroom extract could be used to treat Toxoplasmosis since it inhibited T. gondii growth. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4963", "text": "Pestalone is an antibiotic created from the marine fungus:  Pestalotia sp . [ 25 ] [ 31 ]  M. Cueto et al. (2001\u201311) found that it has antibiotic activity against two bacteria species that have gained resistance to antibiotics: vancomycin-resistant  Enterococcus faecium  and methicillin-resistant  Staphylococcus aureus . [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4964", "text": "Zoopharmacognosy  is the study of how animals select certain plants as self-medication to treat or prevent disease. [ 5 ]  Usually, this behavior is a result of  coevolution  between the animal and the plant that it uses for self-medication. [ 5 ]  For example, apes have been observed selecting a particular part of a medicinal plant by taking off leaves and breaking the stem to suck out the juice. [ 33 ]  In an interview with the late  Neil Campbell ,  Eloy Rodriguez  describes the importance of biodiversity:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4965", "text": "\"Some of the compounds we've identified by zoopharmacognosy kill parasitic worms, and some of these chemicals may be useful against tumors. There is no question that the templates for most drugs are in the natural world.\" [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4966", "text": "A  botanical drug  is defined in the United States  Federal Food, Drug, and Cosmetic Act  as a botanical product that is marketed as diagnosing, mitigating, treating, or curing a  disease ; a botanical product in turn, is a finished, labeled product that contains ingredients from  plants . Chemicals that are purified from plants, like  paclitaxel , and highly purified products of  industrial fermentation , like  biopharmaceuticals , are not considered to be botanical products."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4967", "text": "In 2006 the  Food and Drug Administration  approved the first botanical drug in the United States:  sinecatechins , a  green tea extract  for  genital warts . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4968", "text": "A botanical drug product is defined in the United States  Federal Food, Drug, and Cosmetic Act  (FD&C) as a botanical drug that is marketed as diagnosing, mitigating, treating, or curing a  disease ; a botanical product in turn, is a finished, labeled product that contains vegetable matter as ingredients. [ 2 ] :\u200a2\u20133\u200a  Chemicals that are purified from plants, like  paclitaxel  or  artemisinin , and highly purified products of  industrial fermentation , like  biopharmaceuticals , are not considered to be botanical products. [ 2 ] :\u200a3"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4969", "text": "The FD&C act separately regulates uses of botanical products as food (including  dietary supplements ),  medical devices  (e.g.,  gutta-percha ), and  cosmetics . [ 2 ] :\u200a2"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4970", "text": "Like other drugs, botanical drugs may be sold  over the counter  (OTC) or by prescription only. For OTC drugs, a  monograph  must be created by the company that wants to market the drug and then approved by the FDA, after which it is published in the  Federal Register . For prescription drugs, a  New Drug Application  (NDA) must be filed with and approved by the FDA; clinical data included in the NDA is gathered under an  Investigational New Drug  Application which the FDA also must approve before clinical testing begins. [ 2 ] :\u200a3\u20134"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4971", "text": "Assessment of the safety and toxicity of botanical drugs in clinical trials, and in ensuring their quality once the drug is on the market, is complicated by the nature of the raw ingredients; problems arise in identifying the correct plants to harvest, in the quality of plants harvested, in their processing, and in the stability of the active components, which are often poorly understood. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4972", "text": "The FDA relies on a combination of tests and controls to ensure the identity and quality of botanical drugs. The tests include \"fingerprinting\" using  spectroscopy  or  chromatography , chemical or biological assays, and  process controls  on raw material collection and processing. [ 2 ] :\u200a5\u200a  The standards are higher for botanical drugs than for extracts or plant matter used in  dietary supplements . [ 2 ] :\u200a5"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4973", "text": "If the substance being developed as a botanical drug has been used in  traditional medicine , it may be possible to begin initial, small clinical trials without conducting extensive  toxicology testing . [ 2 ] :\u200a13\u200a [ 4 ] [ 5 ]  However, toxicity testing is required before beginning larger clinical trials and trials that will be used to get approval to sell a botanical drug. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4974", "text": "The endogenous  Chinese pharmaceutical industry  is made up mostly of companies that make herbal  traditional chinese medicines  and sell them over the counter; the US regulatory pathway is similar to that established by the  China Food and Drug Administration . [ 6 ] :\u200a15,\u200a20"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4975", "text": "The European regulatory pathway is also similar. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4976", "text": "As of 2012, the  pharmaceutical industry  had expressed strong interest in developing botanical drugs, with more than 500 applications pending at the FDA. [ 15 ]  Part of the interest stems from a desire to address the Chinese market, where herbal medicines remain widely used and had $13 billion in sales in 2011. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4977", "text": "Commonly prescribed drugs  are drugs that are frequently provided by doctors in a prescription to treat a certain disease. These drugs are often first-line treatment for the target diseases and are effective in tackling the symptoms. An example of the target disease is ischemic heart disease. Some examples of commonly prescribed drugs for this disease are  beta-blockers ,  calcium-channel blockers  and  nitrates."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4978", "text": "In accordance with the pharmacological effects, commonly prescribed drugs can be divided into different groups. Drugs in the same group exert nearly identical effects, and can be utilized for treating the prevailing disease and sometimes, preventing complications of the existing diseases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4979", "text": "The use of commonly prescribed drugs can be reflected from the number of prescriptions of the drugs. Countries have their own dataset in recording the trend of commonly prescribed drugs. For example, the United States uses the Medical Expenditure Panel Survey (MEPS) [ 1 ]  and England uses the English Prescribing Dataset [ 2 ]  to record the prescription data for showing which drugs are commonly prescribed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4980", "text": "Understanding commonly prescribed drugs allows healthcare professionals to react to symptoms quickly and new treatment strategies can be developed. However, the data for commonly prescribed drugs may be outdated due to the time lag between data collection and publication as well as errors in data collection process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4981", "text": "Commonly prescribed drugs are prescribed according to guidelines around the world. For instance, for ischemic heart disease, the American College of Cardiology/American Heart Association (ACC/AHA) guideline is used in the United States and the European Society of Cardiology (ESC) guideline is used in Europe. Western guidelines are more commonly used for reference during the development of local practice guidelines due to the large number of western guidelines stored in guideline databases. [ 3 ]  The data of prescriptions are collected through the government, such as Medical Expenditure Panel Survey (MEPS) in America and the Pharmaceutical Benefit Scheme (PBS) in Australia, providing information on the actual prescription volume of drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4982", "text": "The  Medical Expenditure Panel Survey (MEPS)  conducted by the Agency for Healthcare Research and Quality (AHRQ) via the United States government is used to collect prescription data and data for other healthcare services, including home healthcare, children's health and preventive care in America.\u00a0The survey started in 1996 and was the predecessor of the National Medical Expenditure Survey (NMES) and the National Medical Care Utilization and Expenditure Survey (NMCUES), [ 4 ]  which were conducted in 1977 (NMES-1), 1980 (NMCUES), and 1987 (NMES-2). The survey is updated every year with the renewed data from the country. The prescription data is published in the Prescribed Medicines File of the MEPS. [ 5 ]  The collection of data involves two components: Household component and the Medical Provider component. The household component collects self-reported data of the prescribed medicines and the demographic information of the respondents. The Medical Provider component acts as a piece of follow-back information provided by the pharmacy including a computerized printout for all prescription filled for the patient. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4983", "text": "The English Prescribing Dataset (EPD) from the  NHS Business Services Authority  (NHSBSA) provides prescription data in the United Kingdom. [ 2 ]  The dataset was created in 2014. EPD is a combination of the Detailed Prescribing Information (DPI) and the Practice Level Prescribing in England (PLP). Both DPI and PLP are previous datasets from NHSBSA and NHS Digital respectively and EPD aims to replace them both in the future, but no specific date of replacement is given. EPD collects data from England, Wales, Scotland, Guernsey, Alderney, Jersey and the Isle of Man. EPD provides the item, quantity, net ingredient cost, actual cost, average daily quantity (ADQ), practice name and address details of the prescription. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4984", "text": "The  Pharmaceutical Benefits Scheme  (PBS) from the Australian Government Department of Health provides the prescription data of prescriptions under PBS. PBS started in 1948 and the under co-payment prescriptions were added into the dataset from 1 April 2012. It publishes the PBS expenditure and prescriptions report every year recording prescription data in the past 12 months. The examples of data it provides are the top 50 drugs by total prescription volume and the top 50 drugs by government cost. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4985", "text": "Understanding commonly prescribed drugs for different diseases can allow healthcare professionals to be more confident and decisive when choosing the most suitable treatment for the patient. This can also help develop new treatment strategies by researchers for more effective treatments. [ 9 ]  By enriching the knowledge of commonly prescribed drugs, pharmacy students will be more familiar with their mechanism of action, first-line therapy indications and side effects. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4986", "text": "Limitations include time lag for the conducted survey. The Medical Expenditure Panel Survey (MEPS) shows data recorded two years before the publishing of the survey. The time lag may lead to a difference in representing the current prescribing practice with the recorded data in the survey. Questionnaires which are self-reported tend to create  recall bias . Respondents are likely to underreport the number of prescription drugs they have as those drugs are usually for short-term use and intermittent use, such as analgesics and topical agents. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4987", "text": "Two diseases from the top 10 causes of death introduced by the World Health Organization (WHO) in 2019 are used as examples, namely ischemic heart disease (ranked 1st) from cardiovascular diseases and Chronic Obstructive Pulmonary Disease from respiratory diseases (ranked 3rd). [ 12 ]  Although stroke is ranked 2nd by WHO, drugs used are similar to ischemic heart disease. Moreover, surgical interventions are commonly required, so it will be out of the scope of this article and it will not be introduced. [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4988", "text": "Ischemic Heart Disease (IHD) or coronary heart disease is the lack of supply of blood to an area in the heart, often due to plaque formation (atherosclerosis), causing inadequacy of oxygen to heart muscle and eventually leading to myocardial infarction. This disease can be classified into acute and chronic coronary heart disease. This disease caused 8.9 million deaths in 2019 and was ranked 1st in the top 10 causes of death globally by the World Health Organization (WHO). [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4989", "text": "The treatment of Ischemic Heart Disease can be divided into two directions: risk factor control and symptomatic relief."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4990", "text": "Commonly prescribed drugs for Ischemic Heart Disease"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4991", "text": "anti-inflammatory drugs (NSAID)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4992", "text": "Chronic Obstructive Pulmonary Disease (COPD)  is a disease that causes chronic respiratory problems by gradually blocking the respiratory tracts. The continuous exposure to toxic fumes produced by cigarettes, vehicle engines and other human activities leads to inflammation of the respiratory tract, causing the development of\u00a0COPD. The problem will deteriorate over time if it is not well managed. It will eventually cause respiratory failure and death in the late stage. [ 28 ]  It is the third deadliest disease reported by WHO in 2019 and it accounted for 6% of total deaths. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4993", "text": "There are two types of management plan in COPD, namely  regular treatment  and  acute exacerbation . In acute exacerbation, new medications will be added to the existing prescription and they will be stopped once the exacerbation is managed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4994", "text": "Clavulanic acid [ 45 ] [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4995", "text": "Macrolides [ 45 ] [ 46 ] [ 47 ] [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4996", "text": "Tetracycline [ 45 ] [ 46 ] [ 47 ] [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_4997", "text": "In patients with COPD, multiple inhalers need to be used at a time. There are two major types of inhaler, namely dry-powder inhaler(DPI) and metered-dose inhaler(MDI), and many more subtypes with different techniques for using them. [ 51 ]   Adherence  is also an issue with the use of multiple inhalers. Generally with different types of inhalers, the adherence will be lowered. [ 52 ] [ 53 ]  Proper inhaler technique and adherence are two of the factors that affect the management of COPD. Other factors include  smoking cessation  and participation in physical activities, to name but a few. [ 54 ]  With inappropriately applied inhaler technique and low adherence, there will be ineffective management of COPD, thus increasing in the burden on the healthcare sector. [ 31 ] [ 55 ]  As a result, inhalers combining multiple medications are invented to tackle the problem."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4998", "text": "A  drug coupon  is a  coupon  intended to help consumers save money on  pharmaceutical drugs . They are offered by  drug companies  or distributed to consumers via  doctors  and  pharmacists , and most can be obtained online. There are drug coupons for drugs from many categories such as  cholesterol ,  acne ,  migraine ,  allergies , etc."}
{"_id": "WikiPedia_Pharmacology$$$corpus_4999", "text": "Direct-to-consumer or \"DTC\" marketing of prescription drugs is common in the  United States . Patients frequently inquire about or request medications they have seen advertised in print or on television."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5000", "text": "Pharmaceutical companies use drug coupons as a marketing tool to stimulate demand for their products."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5001", "text": "Drug coupons are commonly offered for new products to stimulate demand or ameliorate high co-pays for non-formulary (non-preferred products) as a way to level the playing field and remove the disincentive for using a drug that is not covered by insurance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5002", "text": "In an effort to avoid unregulated resale of drugs, the  Prescription Drug Marketing Act  of 1988 banned the traffic or  counterfeiting  of redeemable drug coupons. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5003", "text": "Most drug coupons are printed by consumers using their personal computers and printers. Drug coupons reduce out-of-pocket costs for consumers in a variety of ways such as instant savings offers, free trial offers (also known as try-before-you-buy offers),  copay  reduction or rebates."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5004", "text": "Generic drug  companies rarely offer coupons, though insurance companies occasionally offer discounts on generic drugs. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5005", "text": "In addition  PBMs  (Pharmacy Benefit Managers) offer discount cards that act similarly to coupons.  These cards work for both generic and brand medications and can save cash paying customers up to 75% on their prescription medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5006", "text": "Critics of prescription drug coupon programs have argued that these programs lead to higher healthcare costs for consumers. Typically, American patients with health insurance pay a percentage of the cost of a prescription drug out of pocket, with insurance companies responsible for the rest of the medication's cost. Insurance companies charge higher  copayments  for brand-name drugs than for generics in order to encourage patients to choose less expensive alternative medications when they are available. However, by reducing a patient's copayment, prescription drug coupons also reduce a patient's incentive to choose a less expensive generic medication. As an example,  NPR  reported in 2009 that the generic  acne  medication  Minocin  cost $109 a month while a newer alternative called  Solodyn  cost $514 a month. Solodyn can be taken only once daily, while Minocin must be taken twice daily. Since Solodyn's manufacturer offers a coupon to reduce copays, patients may believe that both drugs cost the same amount. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5007", "text": "Drug coupon advocates argue that coupon programs enhance medication adherence by reducing or eliminating drug copays. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5008", "text": "As of 2008, the  U.S. Food and Drug Administration  (FDA) was planning a study to see if coupons make patients overlook drug risks and side effects in their effort to save money. [ 2 ]  All medicines come with a certain level of risk. This is why all prescription drugs include information reviewed and approved by the U.S. Food and Drug Administration (FDA) about how the medication works in the body, its uses and when it should not be used, possible side effects, the recommended dosage, and other facts about the appropriate use of the drug. Most Americans have never heard of \u201cRisk Evaluation and Mitigation Strategies\u201d (REMS); yet, these drug safety protections give millions of Americans with serious diseases, such as cancer and multiple sclerosis, access to medicines that would otherwise be too dangerous to be allowed on the market. [ 4 ]  REMS programs exist because certain medicines can cause serious side effects, life-threatening infections, allergic reactions, liver damage or birth defects.\u00a0Before patients take one of these drugs, they and their prescriber should be aware of the risks, and may need to take certain steps that lessen these risks, in order to ensure they benefit from the treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5009", "text": "Unions have filed several lawsuits seeking to ban drug coupons, characterizing them as illegal kickbacks.  As of June, 2013 Three of these lawsuits have been dismissed.  Six more are pending.  This ruling is seen as vindication for the Pharmaceutical industry that drug coupons are an acceptable business practice. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5010", "text": "COVID-19 drug development  is the research process to develop preventative therapeutic  prescription drugs  that would alleviate the severity of  coronavirus disease 2019  (COVID-19). From early 2020 through 2021, several hundred  drug companies ,  biotechnology  firms, university research groups, and health organizations were developing therapeutic candidates for COVID-19 disease in various stages of  preclinical  or  clinical research  (506 total candidates in April 2021), with 419 potential COVID-19 drugs in  clinical trials , as of April 2021. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5011", "text": "As early as March 2020, the  World Health Organization  (WHO), [ 2 ]   European Medicines Agency  (EMA), [ 3 ]  US  Food and Drug Administration  (FDA), [ 4 ]  and the Chinese government and drug manufacturers [ 5 ] [ 6 ]  were coordinating with academic and industry researchers to speed development of vaccines,  antiviral drugs , and post-infection therapies. [ 7 ] [ 8 ] [ 9 ] [ 10 ]  The  International Clinical Trials Registry Platform  of the WHO recorded 536 clinical studies to develop post-infection therapies for COVID-19 infections, [ 11 ] [ 12 ]  with numerous established antiviral compounds for treating other infections  under clinical research to be repurposed . [ 7 ] [ 13 ] [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5012", "text": "In March 2020, the WHO initiated the \" SOLIDARITY Trial \" in 10 countries, enrolling thousands of people infected with COVID-19 to assess treatment effects of four existing antiviral compounds with the most promise of efficacy. [ 2 ] [ 16 ]  A dynamic, systematic review was established in April 2020 to track the progress of registered clinical trials for COVID-19 vaccine and therapeutic drug candidates. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5013", "text": "Drug development is a multistep process, typically requiring more than five years to assure safety and efficacy of the new compound. [ 17 ]   Several national regulatory agencies, such as the EMA and the FDA, approved procedures to expedite clinical testing. [ 4 ] [ 18 ]  By June 2021, dozens of potential post-infection therapies were in the final stage of human testing \u2013  phase III\u2013IV clinical trials . [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5014", "text": "Drug development  is the process of bringing a new infectious disease vaccine or  therapeutic drug  to the market once a  lead compound  has been identified through the process of  drug discovery . [ 17 ]  It includes  laboratory research  on microorganisms and animals, filing for regulatory status, such as via the FDA, for an  investigational new drug  to initiate  clinical trials  on humans, and may include the step of obtaining  regulatory approval  with a  new drug application  to market the drug. [ 20 ] [ 21 ]  The entire process \u2013 from concept through preclinical testing in the laboratory to clinical trial development, including Phase I\u2013III trials \u2013 to approved vaccine or drug normally takes more than a decade. [ 17 ] [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5015", "text": "The term \"preclinical research\" is defined by laboratory studies  in vitro  and  in vivo , indicating a beginning stage for development of a preventative vaccine, antiviral or other post-infection therapies, [ 7 ]  such as experiments to determine  effective doses  and  toxicity  in animals, before a candidate compound is advanced for safety and efficacy evaluation in humans. [ 22 ]  To complete the preclinical stage of drug development \u2013 then be tested for safety and efficacy in an adequate number of people infected with COVID-19 (hundreds to thousands in different countries) \u2013 is a process likely to require 1\u20132 years for COVID-19 therapies, according to several reports in early 2020. [ 9 ] [ 23 ] [ 24 ] [ 25 ]  Despite these efforts, the success rate for drug candidates to reach eventual regulatory approval through the entire drug development process for treating  infectious diseases  is only 19%. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5016", "text": "Phase I trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while Phase II trials \u2013 following success in Phase I \u2013 evaluate therapeutic efficacy against the COVID-19 disease at ascending dose levels (efficacy based on  biomarkers ), while closely evaluating possible  adverse effects  of the candidate therapy (or combined therapies), typically in hundreds of people. A common trial design for Phase II studies of possible COVID-19 drugs is  randomized ,  placebo -controlled,  blinded , and conducted at multiple sites, while determining more precise, effective doses and monitoring for adverse effects. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5017", "text": "The success rate for Phase II trials to advance to Phase III (for all diseases) is about 31%, and for infectious diseases specifically, about 43%. [ 26 ]  Depending on its duration (longer more expensive) \u2013 typically a period of several months to two years [ 27 ]  \u2013 an average-length Phase II trial costs  US$57  million (2013 dollars, including preclinical and Phase I costs). [ 28 ]  Successful completion of a Phase II trial does not reliably forecast that a candidate drug will be successful in Phase III research. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5018", "text": "Phase III trials for COVID-19 involve hundreds-to-thousands of hospitalized participants, and test effectiveness of the treatment to reduce effects of the disease, while monitoring for adverse effects at the optimal dose, such as in the multinational Solidarity and Discovery trials. [ 2 ] [ 17 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5019", "text": "According to one source (as of August 2020), diverse categories of preclinical or early-stage clinical research for developing COVID-19 therapeutic candidates included: [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5020", "text": "Pivotal Phase III trials  assess whether a candidate drug has efficacy specifically against a disease, and \u2013 in the case of people hospitalized with severe COVID-19 infections \u2013 test for an effective dose level of the repurposed or new drug candidate to improve the illness (primarily pneumonia) from COVID-19 infection. [ 2 ] [ 11 ] [ 32 ]  For an already-approved drug (such as  hydroxychloroquine  for malaria),  Phase III\u2013IV trials  determine in hundreds to thousands of COVID-19-infected people the possible extended use of an already-approved drug for treating COVID-19 infection. [ 32 ]  As of August 2020, over 500 candidate therapeutics were in preclinical or a stage of Phase I\u2013IV development, with new Phase II\u2013III trials announced for hundreds of therapeutic candidates during 2020. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5021", "text": "Numerous candidate drugs under study as \"supportive\" treatments to relieve discomfort during illness, such as  NSAIDs  or  bronchodilators , are not included in the table below. Others in early-stage Phase II trials or numerous treatment candidates in Phase I trials, [ 19 ]  are also excluded. Drug candidates in Phase I\u2013II trials have a low rate of success (under 12%) to pass through all trial phases to gain eventual approval. [ 20 ] [ 29 ]  Once having reached Phase III trials, therapeutic candidates for diseases related to COVID-19 infection \u2013  infectious  and  respiratory diseases  \u2013 have a success rate of about 72%. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5022", "text": "Drug repositioning  (also called drug repurposing) \u2013 the investigation of existing drugs for new therapeutic purposes \u2013 is one line of scientific research followed to develop safe and effective COVID-19 treatments. [ 15 ] [ 59 ]  Several existing antiviral medications, previously developed or used as treatments for  Severe acute respiratory syndrome  (SARS),  Middle East respiratory syndrome  (MERS),  HIV/AIDS , and  malaria , are being researched as COVID-19 treatments, with some moving into clinical trials. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5023", "text": "During the COVID-19 pandemic, drug repurposing is the  clinical research  process of rapidly screening and defining the safety and efficacy of existing drugs already approved for other diseases to be used for people with COVID-19 infection. [ 13 ] [ 15 ] [ 60 ]  In the usual drug development process, [ 17 ]  confirmation of repurposing for new disease treatment would take many years of clinical research \u2013 including  pivotal Phase III clinical trials  \u2013 on the candidate drug to assure its safety and efficacy specifically for treating COVID-19 infection. [ 13 ] [ 60 ]  In the emergency of a growing COVID-19 pandemic, the drug repurposing process was being accelerated during March 2020 to treat people hospitalized with COVID-19. [ 2 ] [ 13 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5024", "text": "Clinical trials using repurposed, generally safe, existing drugs for hospitalized COVID-19 people may take less time and have lower overall costs to obtain endpoints proving safety (absence of serious  side effects ) and post-infection efficacy, and can rapidly access existing drug  supply chains  for manufacturing and worldwide distribution. [ 2 ] [ 13 ] [ 61 ]  In an international effort to capture these advantages, the WHO began in mid-March 2020 expedited international  Phase II\u2013III trials  on four promising treatment options \u2013 the SOLIDARITY trial [ 2 ] [ 62 ] [ 63 ]  \u2013 with numerous other drugs having potential for repurposing in different disease treatment strategies, such as anti-inflammatory,  corticosteroid , antibody,  immune , and  growth factor  therapies, among others, being advanced into Phase II or III trials during 2020. [ 19 ] [ 13 ] [ 60 ] [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5025", "text": "In March 2020, the United States  Centers for Disease Control and Prevention  (CDC) issued a physician advisory concerning remdesivir for people hospitalized with  pneumonia  caused by COVID-19: \"While clinical trials are critical to establish the safety and efficacy of this drug, clinicians without access to a clinical trial may request remdesivir for  compassionate use  through the manufacturer for patients with clinical pneumonia.\" [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5026", "text": "Passive immunization  with  convalescent plasma  or  hyperimmune serum  has been proposed as a potential treatment for COVID-19. As of May 2021, there is strong evidence that convalescent plasma treatment is not associated with clinical improvements for people with moderate or severe disease and does not decrease the risk of dying. [ 65 ]  The potential for adverse effects associated with convalescent plasma treatment is unknown. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5027", "text": "In the United States, the FDA has granted temporary authorization to convalescent plasma (plasma from the blood of people who have recovered from COVID-19, which thus contains antibodies against SARS-CoV-2) as an experimental treatment in cases where the person's life is seriously or immediately threatened. [ 66 ]  As of May 2021, at least 12 randomized controlled trials on the effectiveness of convalescent plasma treatment were published in peer-reviewed medical journals. [ 65 ]  In addition, as of May 2021, 100 additional trials were 'ongoing' and 33 studies were reported as 'competed' but not yet published. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5028", "text": "Argentina, Brazil, Costa Rica, and Mexico have pursued development of  antisera . [ 67 ]  Brazil began development of an equine hyperimmune serum, obtained by inoculating  horses  with recombinant SARS-CoV-2  spike protein , in mid-2020. A consortium of Instituto Vital Brazil,  UFRJ , the  Oswaldo Cruz Foundation  and the D'Or Institute for Research and Education in Rio de Janeiro began preclinical trials in May 2020, [ 68 ]  while  Instituto Butantan  in S\u00e3o Paulo completed animal testing in September. [ 67 ]  In December 2020, Argentina granted emergency authorization to CoviFab, a locally developed formulation of equine hyperimmune serum, for use in cases of moderate to severe COVID-19, based on the initial results of a single phase 2/3 trial which suggested reductions in mortality, ICU admission, and mechanical ventilation requirements in patients who received the serum. [ 69 ] [ 70 ]  This was harshly criticized by the Argentine Intensive Care Society, which stated that the trial failed to achieve its primary or secondary endpoints and did not demonstrate any  statistically significant  differences between the serum and placebo groups. [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5029", "text": "Bamlanivimab/etesevimab  is a combination of two  monoclonal antibodies ,  bamlanivimab  and  etesevimab , administered together via intravenous infusion as a treatment for  COVID-19 . [ 71 ] [ 72 ] [ 73 ] [ 74 ]  Both types of antibody target the  surface spike protein  of  SARS\u2011CoV\u20112 . [ 75 ] [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5030", "text": "Bamlanivimab and etesevimab, administered together, are authorized in the United States for the treatment of mild-to-moderate COVID-19 in people aged twelve years of age and older weighing at least 40 kilograms (88\u00a0lb) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. [ 77 ] [ 78 ]  They are also authorized, when administered together, for use after exposure to the SARS-CoV-2 virus for  post-exposure prophylaxis  (PEP) for COVID-19 and are not authorized for pre-exposure prophylaxis to prevent COVID-19 before being exposed to the SARS-CoV-2 virus. [ 77 ] [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5031", "text": "Bebtelovimab  is a  monoclonal antibody  developed by  AbCellera  and  Eli Lilly  as a treatment for  COVID-19 . [ 80 ] [ 81 ] [ 82 ] [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5032", "text": "Possible side effects include itching, rash, infusion-related reactions, nausea and vomiting. [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5033", "text": "Bebtelovimab works by binding to the spike protein of the virus that causes COVID-19, similar to other monoclonal antibodies that have been authorized for the treatment of high-risk people with mild to moderate COVID-19 and shown a benefit in reducing the risk of hospitalization or death. [ 80 ]  Bebtelovimab is a neutralizing human immunoglobulin G1 (IgG1) monoclonal antibody, isolated from a patient who has recovered from the Coronavirus disease 2019 (COVID-19), directed against the spike (S) protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), that can potentially be used for immunization against COVID-19. [ 84 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5034", "text": "Casirivimab/imdevimab , sold under the brand name REGEN\u2011COV among others, [ 86 ] [ 87 ]  is a combination  medicine  used for the treatment and prevention of  COVID\u201119 . [ 87 ]  It consists of two  human monoclonal antibodies , casirivimab and imdevimab that must be mixed together and administered as an infusion or subcutaneous injection. [ 88 ] [ 86 ] [ 87 ]  The combination of two antibodies is intended to prevent  mutational escape . [ 89 ]  It is also available as a  co-formulated  product. [ 88 ]  It was developed by the American biotechnology company  Regeneron Pharmaceuticals . [ 90 ] [ 91 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5035", "text": "The most common side effects include allergic reactions, which include infusion related reactions, injection site reactions, [ 87 ]  brief pain, weakness and others. [ 92 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5036", "text": "The combination is approved under the brand name Ronapreve for medical use in Japan, the United Kingdom, the European Union, and Australia. [ 93 ] [ 94 ] [ 87 ] [ 95 ] [ 96 ] [ 97 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5037", "text": "Pemivibart , sold under the brand name Pemgarda, is a  monoclonal antibody  medication authorized for the  pre-exposure prophylaxis  (prevention) of  COVID\u201119 . [ 99 ]  Pemivibart was developed by  Invivyd . [ 100 ] [ 101 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5038", "text": "Regdanvimab , sold under the brand name Regkirona, is a  human monoclonal antibody  used for the treatment of  COVID-19 . [ 102 ]  The antibody is directed against the  spike protein  of  SARS-CoV-2 . It is developed by  Celltrion . [ 103 ] [ 104 ]  The medicine is given by infusion (drip) into a vein. [ 102 ] [ 105 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5039", "text": "The most common side effects include infusion-related reactions, including allergic reactions and anaphylaxis. [ 102 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5040", "text": "Sotrovimab , sold under the brand name Xevudy, is a human neutralizing  monoclonal antibody  with activity against severe acute respiratory syndrome coronavirus 2, known as  SARS-CoV-2 . [ 107 ] [ 108 ] [ 109 ]  It was developed by  GlaxoSmithKline  and Vir Biotechnology, Inc. [ 108 ] [ 110 ]  Sotrovimab is designed to attach to the  spike protein  of SARS-CoV-2. [ 108 ] [ 109 ] [ 111 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5041", "text": "The most common side effects include hypersensitivity (allergic) reactions and infusion-related reactions. [ 107 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5042", "text": "Vilobelimab , sold under the brand name Gohibic, is an investigational  medication  that is used for the treatment of  COVID-19 . [ 119 ]  It is a human-mouse chimeric  IgG4   kappa  antibody that targets human  C5a  in plasma. [ 120 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5043", "text": "The most common adverse reactions include pneumonia, sepsis, delirium, pulmonary embolism, hypertension, pneumothorax, deep vein thrombosis, herpes simplex, enterococcal infection, bronchopulmonary aspergillosis, hepatic enzyme increased, urinary tract infection, hypoxia, thrombocytopenia, pneumomediastinum, respiratory tract infection, supraventricular tachycardia, constipation, and rash. [ 119 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5044", "text": "Molnupiravir , sold under the brand name Lagevrio, is an  antiviral medication  that inhibits the replication of certain  RNA viruses . [ 124 ]  It is used to treat  COVID\u201119  in those infected by  SARS-CoV-2 . [ 124 ]  It is taken  by mouth . [ 124 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5045", "text": "Molnupiravir is a  prodrug  of the synthetic  nucleoside  derivative  N 4 -hydroxy cytidine  and exerts its antiviral action by introducing copying errors during viral RNA replication. [ 125 ] [ 126 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5046", "text": "Molnupiravir was originally developed to treat  influenza  at  Emory University  by the university's drug innovation company, Drug Innovation Ventures at Emory (DRIVE), but was reportedly abandoned for  mutagenicity  concerns. [ 127 ] [ 128 ]  It was then acquired by the Miami-based company  Ridgeback Biotherapeutics , which later partnered with  Merck & Co.  to develop the drug further. [ 129 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5047", "text": "Ensitrelvir , sold under the brand name Xocova is an  antiviral medication  used as a treatment for  COVID-19 . [ 140 ] [ 141 ] [ 142 ] [ 143 ]  It was developed by  Shionogi  in partnership with  Hokkaido University  and acts as an orally active  3C-like   protease inhibitor . [ 144 ] [ 145 ]  It is taken by mouth. [ 146 ] [ 147 ] [ 148 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5048", "text": "Nirmatrelvir/ritonavir , sold under the brand name Paxlovid, is a co-packaged  medication  used as a  treatment  for  COVID\u201119 . [ 149 ] [ 150 ] [ 151 ] [ 152 ]  It contains the  antiviral medications   nirmatrelvir  and  ritonavir  and was developed by  Pfizer . [ 149 ] [ 151 ]  Nirmatrelvir inhibits  SARS-CoV-2 main protease , while ritonavir is a strong  CYP3A inhibitor , slowing down nirmatrelvir  metabolism  and therefore boosting its effect. [ 151 ] [ 153 ]  It is taken  by mouth . [ 151 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5049", "text": "In unvaccinated high-risk people with COVID\u201119, nirmatrelvir/ritonavir can reduce the risk of hospitalization or death by 88% if taken within five days of symptom onset. [ 154 ]  People who take nirmatrelvir/ritonavir also test negative for COVID\u201119 about two and a half days earlier than people who do not. [ 155 ]   Side effects  of nirmatrelvir/ritonavir include changes in sense of taste ( dysgeusia ),  diarrhea , high blood pressure ( hypertension ), and muscle pain ( myalgia ). [ 151 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5050", "text": "Sabizabulin  is an  investigational new drug  that is being evaluated for the treatment of  castration-resistant prostate cancer [ 166 ]  and in  SARS-CoV-2  ( COVID-19 ) infections. [ 167 ]  It is a  tubulin  polymerization inhibitor. [ 168 ] [ 169 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5051", "text": "Over 2018\u201320, new initiatives to stimulate vaccine and antiviral drug development included partnerships between governmental organizations and industry, such as the European  Innovative Medicines Initiative , [ 171 ]  the US  Critical Path Initiative  to enhance innovation of drug development, [ 172 ]  and the  Breakthrough Therapy  designation to expedite development and regulatory review of promising candidate drugs. [ 173 ]  To accelerate refinement of  diagnostics  for detecting COVID-19 infection, a global diagnostic pipeline tracker was formed. [ 174 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5052", "text": "According to a tracker of clinical trial progress on potential therapeutic drugs for COVID-19 infections, 29 Phase II\u2013IV efficacy trials were concluded in March 2020 or scheduled to provide results in April from hospitals in China \u2013 which experienced the first outbreak of COVID-19 in late 2019. [ 19 ]  Seven trials were evaluating repurposed drugs already approved to treat  malaria , including four studies on hydroxychloroquine or chloroquine phosphate. [ 19 ]  Repurposed antiviral drugs make up most of the Chinese research, with 9 Phase III trials on remdesivir across several countries due to report by the end of April. [ 19 ]  Other potential therapeutic candidates under pivotal clinical trials concluding in March\u2013April are  vasodilators ,  corticosteroids ,  immune therapies ,  lipoic acid ,  bevacizumab , and  recombinant   angiotensin-converting enzyme 2 , among others."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5053", "text": "The COVID-19 Clinical Research Coalition has goals to 1) facilitate  rapid reviews  of clinical trial proposals by  ethics committees  and national regulatory agencies, 2) fast-track approvals for the candidate therapeutic compounds, 3) ensure standardised and rapid analysis of emerging efficacy and safety data, and 4) facilitate sharing of clinical trial outcomes before publication. [ 11 ]  A dynamic review of clinical development for COVID-19 vaccine and drug candidates was in place, as of April. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5054", "text": "By March 2020, the international  Coalition for Epidemic Preparedness Innovations  (CEPI) committed to research investments of US$100 million across several countries, [ 175 ]  and issued an urgent call to raise and rapidly invest $2 billion for vaccine development. [ 176 ]  Led by the  Bill and Melinda Gates Foundation  with partners investing  US$125  million and coordinating with the World Health Organization, the COVID-19 Therapeutics Accelerator began in March, facilitating drug development researchers to rapidly identify, assess, develop, and  scale up  potential treatments. [ 177 ]  The COVID-19 Clinical Research Coalition formed to coordinate and expedite results from international clinical trials on the most promising post-infection treatments. [ 11 ]  In early 2020, numerous established antiviral compounds for treating other infections were being repurposed or developed in new clinical research efforts to alleviate the illness of COVID-19. [ 7 ] [ 13 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5055", "text": "During March 2020, the  Coalition for Epidemic Preparedness Innovations  (CEPI) initiated an international COVID-19 vaccine development fund, with the goal to raise  US$2 billion  for vaccine research and development, [ 178 ]  and committed to investments of  US$100 million  in vaccine development across several countries. [ 175 ]  The  Canadian government  announced  CA$275 million  in funding for 96 research projects on medical countermeasures against COVID-19, including numerous vaccine candidates at Canadian universities, [ 179 ] [ 180 ]  with plans to establish a \"vaccine bank\" of new vaccines for implementation if another COVID-19 outbreak occurs. [ 180 ] [ 181 ]  The  Bill & Melinda Gates Foundation  invested  US$ 150 million in April for development of COVID-19 vaccines, diagnostics, and therapeutics. [ 182 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5056", "text": "In March 2020, the  United States Department of Energy ,  National Science Foundation ,  NASA , industry, and nine universities pooled resources to access supercomputers from  IBM , combined with cloud computing resources from  Hewlett Packard Enterprise ,  Amazon ,  Microsoft , and  Google , for drug discovery. [ 183 ] [ 184 ]  The COVID-19 High Performance Computing Consortium also aims to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy. [ 183 ] [ 184 ]  The Consortium used up 437 peta FLOPS  of computing power by May 2020. [ 185 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5057", "text": "The C3.ai Digital Transformation Institute, an additional consortium of Microsoft, six universities (including the  Massachusetts Institute of Technology , a member of the first consortium), and the  National Center for Supercomputer Applications  in Illinois, working under the auspices of C3.ai, an artificial intelligence software company, are pooling supercomputer resources toward drug discovery, medical protocol development and public health strategy improvement, as well as awarding large grants to researchers who proposed by May to use AI to carry out similar tasks. [ 186 ] [ 187 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5058", "text": "In March 2020, the  distributed computing  project  Folding@home  launched a program to assist drug developers, initially simulating protein targets from SARS-CoV-2 and the related SARS-CoV virus, which has been studied previously. [ 188 ] [ 189 ] [ 190 ] [ 191 ] [ 192 ] [ 193 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5059", "text": "Distributed computing project  Rosetta@home  also joined the effort in March. The project uses computers of volunteers to model SARS-CoV-2 virus proteins to discover possible drug targets or create new proteins to neutralize the virus. Researchers revealed that with the help of Rosetta@home, they had been able to \"accurately predict the atomic-scale structure of an important coronavirus protein weeks before it could be measured in the lab.\" [ 194 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5060", "text": "In May 2020, the OpenPandemics \u2013 COVID-19 partnership between  Scripps Research  and IBM's  World Community Grid  was launched. The partnership is a distributed computing project that \"will automatically run a simulated experiment in the background [of connected home PCs] which will help predict the effectiveness of a particular chemical compound as a possible treatment for COVID-19\". [ 195 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5061", "text": "In March, the World Health Organization (WHO) launched the coordinated \"Solidarity Trial\" in 10 countries on five  continents  to rapidly assess in thousands of COVID-19 infected people the potential efficacy of existing antiviral and  anti-inflammatory  agents not yet evaluated specifically for COVID-19 illness. [ 2 ] [ 16 ]  By late April, hospitals in over 100 countries were involved in the trial. [ 196 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5062", "text": "The individual or combined drugs undergoing initial studied are 1)  lopinavir \u2013 ritonavir  combined, 2) lopinavir\u2013ritonavir combined with  interferon-beta , 3)  remdesivir  or 4) (hydroxy) chloroquine  in separate trials and hospital sites internationally. [ 2 ] [ 16 ]  Following a study published by  The Lancet  on safety concerns with hydroxychloroquine, the WHO suspended use of it from the Solidarity trial in May 2020, [ 197 ] [ 198 ]  reinstated it after the research was retracted, [ 199 ]  then abandoned further use of the drug for COVID-19 treatment when analysis showed in June that it provided no benefit. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5063", "text": "With about 15% of people infected by COVID-19 having severe illness, and hospitals being overwhelmed during the pandemic, WHO recognized a rapid clinical need to test and repurpose these drugs as agents already approved for other diseases and recognized as safe. [ 2 ]  The Solidarity project is designed to give rapid insights to key clinical questions: [ 2 ] [ 200 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5064", "text": "Enrolling people with COVID-19 infection is simplified by using data entries, including  informed consent , on a WHO website. After the trial staff determines the drugs available at the hospital, the WHO website  randomizes  the hospitalized subject to one of the trial drugs or to the hospital standard of care for treating COVID-19. The trial physician records and submits follow-up information about the subject status and treatment, completing data input via the WHO Solidarity website. The design of the Solidarity trial is not  double-blind  \u2013 which is normally the standard in a high-quality clinical trial \u2013 but the WHO needed speed with quality for the trial across many hospitals and countries. [ 2 ]  A global  safety monitoring board of WHO physicians  examine  interim results  to assist decisions on safety and effectiveness of the trial drugs, and alter the trial design or recommend an effective therapy. [ 2 ] [ 200 ]  A similar web-based study to Solidarity, called \"Discovery\", was initiated in March across seven countries by  INSERM  ( Paris, France ). [ 2 ] [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5065", "text": "The Solidarity trial seeks to implement coordination across hundreds of hospital sites in different countries \u2013 including those with poorly-developed infrastructure for clinical trials \u2013 yet needs to be conducted rapidly. According to  John-Arne R\u00f8ttingen , chief executive of the  Research Council of Norway  and chairman of the Solidarity trial international  steering committee , the trial would be considered effective if therapies are determined to \"reduce the proportion of patients that need ventilators by, say, 20%, that could have a huge impact on our national health-care systems.\" [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5066", "text": "During March, funding for the Solidarity trial reached  US$108  million from 203,000 individuals, organizations and governments, with 45 countries involved in financing or trial management. [ 197 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5067", "text": "A clinical trial design in progress may be modified as an \"adaptive design\" if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment. [ 201 ] [ 202 ]  The global Solidarity and European Discovery trials of hospitalized people with severe COVID-19 infection apply adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge. [ 11 ] [ 34 ] [ 203 ]  Adaptive designs within ongoing Phase II\u2013III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations. [ 29 ] [ 202 ] [ 204 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5068", "text": "The US  National Institute of Allergy and Infectious Diseases  (NIAID) initiated an adaptive design, international Phase III trial (called \"ACTT\") to involve up to 800 hospitalized COVID-19 people at 100 sites in multiple countries. Beginning with use of remdesivir as the primary treatment over 29 days, the trial definition of its adaptive protocol states that \"there will be interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s).\" [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5069", "text": "Operation Warp Speed  (OWS) was a  public\u2013private partnership  initiated by the United States government to facilitate and accelerate the development, manufacturing, and distribution of  COVID-19 vaccines , therapeutics, and diagnostics. [ 205 ] [ 206 ]  The first news report of Operation Warp Speed was on April 29, 2020, [ 207 ] [ 208 ] [ 209 ]  and the program was officially announced on May 15, 2020. [ 205 ]  It was headed by  Moncef Slaoui  from May 2020 to January 2021 and by  David A. Kessler  from January to February 2021. [ 210 ]  At the end of February 2021, Operation Warp Speed was transferred into the responsibilities of the  White House COVID-19 Response Team . [ 211 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5070", "text": "The program promoted mass production of multiple vaccines, and different types of vaccine technologies, based on preliminary evidence. Then there were clinical trials. The plan anticipated that some of these vaccines would not prove safe or effective, making the program more costly than typical vaccine development, but potentially leading to the availability of a viable vaccine several months earlier than typical timelines. [ 212 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5071", "text": "A large-scale,  randomized controlled trial  named the  RECOVERY Trial  was set up in March 2020, in the UK to test possible treatments for COVID-19. It is run by the Nuffield Departments of Public Health and of Medicine at the  University of Oxford  and is testing five repurposed drugs and also  convalescent plasma . The trial enrolled more than 11,500 COVID-19 positive participants in the U.K by June 2020. [ 44 ] [ 213 ] [ 214 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5072", "text": "During April, the British RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial was launched initially in 132 hospitals across the UK, [ 215 ]  expanding to become one of the world's largest COVID-19 clinical studies, involving 5400 infected people under treatment at 165 UK hospitals, as of mid-April. [ 216 ]  The trial is examining different potential therapies for severe COVID-19 infection: lopinavir/ritonavir, low-dose  dexamethasone  (an anti-inflammatory  steroid ), hydroxychloroquine, and  azithromycin  (a common  antibiotic ). [ 213 ]  In June, the trial arm using hydroxychloroquine was discontinued when analyses showed it provided no benefit. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5073", "text": "On 16 June the trial group released a statement that dexamethasone had been shown to reduce mortality in patients receiving respiratory support. [ 217 ]  In a  controlled trial  around 2,000 hospital patients were given dexamethasone and were compared with more than 4,000 who did not receive the drug. For patients on ventilators, it cut the risk of death from 40% to 28% (1 in 8). For patients needing oxygen, it cut the risk of death from 25% to 20% (1 in 5). [ 218 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5074", "text": "By the end of June 2020, the trial had published findings regarding  hydroxychloroquine  and  dexamethasone . [ 44 ] [ 219 ]  It had also announced results for  lopinavir/ritonavir  which were published in October 2020. The lopinavir-ritonavir and hydroxychloroquine arms were closed to new entrants after being shown to be ineffective. [ 44 ] [ 220 ] [ 221 ]  Dexamethasone was closed to new adult entries after positive results and by November 2020, was open to child entries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5075", "text": "Launched in December 2021, the  PANORAMIC  trial will test the effectiveness of  molnupiravir  and  nirmatrelvir/ritonavir  in preventing hospitalisation and helping faster recovery for people aged over 50 and those at higher risk due to underlying health conditions. [ 222 ] [ 223 ]  PANORAMIC is sponsored by the  University of Oxford  and funded by the  National Institute for Health Research  (NIHR). [ 222 ]  As of March 2022 has over 16,000 people enrolled as participants making it the largest study into COVID-19 antivirals. [ 224 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5076", "text": "Drug cultures  are examples of  countercultures  that are primarily defined by  spiritual ,  medical , and  recreational drug use . They may be focused on a single drug, or endorse  polydrug  use. They sometimes eagerly or reluctantly initiate newcomers, but their main functions are to share drug experiences, to  reduce harm  by providing knowledge of how to use drugs as safely as possible, and to exchange information on suppliers and avoidance of  law enforcement ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5077", "text": "Drug subcultures are groups of people united by a common understanding of the meaning, value, and risks of the incorporation into one's life of the drug(s) in question. Such unity can take many forms, from friends who take the drug together, possibly obeying certain rules of  etiquette , groups banding together to help each other obtain drugs and avoid arrest, [ 1 ]  to full-scale  political movements  for the reform of  drug laws . [ 2 ]  The sum of these parts can be considered an individual drug's \"culture\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5078", "text": "Many artists, writers, and musicians have used various drugs to facilitate or enhance their  creativity . Writers have explored their influence on human life in general and particularly on the creative process. There are many writings that portray drug culture.  Hunter S. Thompson 's 1971 novel  Fear and Loathing in Las Vegas  employs multiple drug use as a major theme and provides an example of the  drug culture of the 1960s ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5079", "text": "After various drug cultures came to prominence during the 1960s, 1980s and early 2000s, the  internet  provided a new location and medium where drug cultures could be born and propagate. Technologies like  Tor  were able to offer anonymous  website hosting  and  browsing , which were used for the creation of the  darknet market   SilkRoad , the first of many to be used in the sale of psychoactive substances and other  illegal goods . There are  YouTube  channels devoted to recreational drug use and harm reduction, with the most popular being PsychedSubstance. Except for forums (like  Blue Light ) where individuals can post and discuss the properties and experiences of  psychoactive substances , there are websites and organizations specifically created to serve as  encyclopedias  of psychoactive drugs and drug culture, such as  Erowid  and PsychonautWiki."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5080", "text": "Cannabis  has been used in the ancient past in places such as  ancient India , Romania, Egypt, and Mesopotamia. [ 3 ]  It was often used as medicine or for hemp. Its main route of consumption was smoking. Over time the culture became more international and a general \"cannabis culture\" formed.  Cannabis  culture has been responsible for the genre of films known as  stoner films  which has come to be accepted as a mainstream cinema movement. [ 4 ] [ 5 ]  In the  United States  the culture has also spawned its own celebrities (such as  Tommy Chong  and  Terence McKenna ), magazines ( Cannabis Culture  and  High Times ), and, in North America, its own distinct holiday:  April 20  (420), which is marked as a day for calling for the  legalization of cannabis  and celebration of cannabis. [ 6 ] [ 7 ]  The consumption of cannabis influenced many artistic movements such as  jazz ,  electronic music  and  hip hop . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5081", "text": "Alcohol  (also known as ethanol) is a  psychoactive drug [ 8 ] [ 9 ]  found in  alcoholic beverages . Alcohol is one of the most commonly abused drugs in the world [ 10 ]  and is often used for  self-medication , [ 11 ]  and recreational use. [ 12 ] \""}
{"_id": "WikiPedia_Pharmacology$$$corpus_5082", "text": "The  hip hop ,  hardcore rap , and  trap  scenes, alongside their  derivative subgenres  and  subcultures , are most notorious for having continuously celebrated and promoted  drug trafficking ,  gangster lifestyle , and the consumption of alcohol and other drugs since their inception in the United States during the late 1980s\u2013early 1990s. [ 13 ] [ 14 ] [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5083", "text": "The drugs used in witchcraft are different depending on the culture. Most of the research done on drug use in witchcraft was done in the 60s during the hippie movement. Since then, the claim that ergot was taken in Salem has been disproven. However, because the research was done during the hippie and drug movement in the 70s, the theory is still a part of drug culture. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5084", "text": "Ancient Greek love magic used many rituals that show drug use in poisoning to deepen the emotion of love. Love magic would be used by ancient Greek women to gain or keep a man's love. Researchers of this period often look at the agency of the women. Greek love magic relates to drug culture as it deals with poisoning people. There can be similarities found in today's date rape drug. However, in ancient Greek time the women would slowly poison the men. Women would put the poisons on their robes to expose it to the men. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5085", "text": "Shamanism used hallucinogens to further their spirituality. These hallucinogens were used for different ceremonies of the Indians in the Northwest Amazon. These ceremonies include funerals and initiation of the young. Shamans had a wider range of use for these drugs. Shamans used these drugs to identify illnesses and find possible cures or to find an enemy. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5086", "text": "There is a theory, seemingly disproven due to timeline of events and number of those who experience the symptoms, that the Salem witch trials were caused by  ergot  poisoning. Ergot poisoning gives a similar effect to LSD, but like  ergine  the physical effects and dangers (including death due to higher toxicity of the  ergolines  in ergot) are much more substantial than the use of LSD for psychedelic research and ritual contexts. [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5087", "text": "A  cure  is a substance or procedure that ends a medical condition, such as a  medication , a  surgical operation , a change in lifestyle or even a philosophical mindset that helps end a person's sufferings; or the state of being healed, or cured. The medical condition could be a  disease ,  mental illness ,  genetic disorder , or simply a condition a person considers socially undesirable, such as  baldness  or lack of breast tissue."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5088", "text": "An incurable disease may or may not be a  terminal illness ; conversely, a curable illness can still result in the patient's death."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5089", "text": "The proportion of people with a disease that are cured by a given treatment, called the  cure fraction  or  cure rate , is determined by comparing  disease-free survival  of treated people against a matched control group that never had the disease. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5090", "text": "Another way of determining the cure fraction and/or \"cure time\" is by measuring when the hazard rate in a diseased group of individuals returns to the hazard rate measured in the general population. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5091", "text": "Inherent in the idea of a cure is the permanent end to the specific instance of the disease. [ 4 ] [ 5 ]  When a person has the  common cold , and then recovers from it, the person is said to be  cured , even though the person might someday catch another cold. Conversely, a person that has successfully managed a disease, such as  diabetes mellitus , so that it produces no undesirable symptoms for the moment, but without actually permanently ending it, is not cured."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5092", "text": "Related concepts, whose meaning can differ, include  response ,  remission  and  recovery ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5093", "text": "In complex diseases, such as cancer, researchers rely on statistical comparisons of  disease-free survival  (DFS) of patients against matched, healthy control groups. This logically rigorous approach essentially equates  indefinite remission  with cure. [ 6 ]  The comparison is usually made through the  Kaplan-Meier estimator  approach. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5094", "text": "The simplest  cure rate model  was published by  Joseph Berkson  and  Robert P. Gage  in 1952. [ 7 ]  In this model, the survival at any given time is equal to those that are cured plus those that are not cured, but who have not yet died or, in the case of diseases that feature asymptomatic remissions, have not yet re-developed signs and symptoms of the disease. When all of the non-cured people have died or re-developed the disease, only the permanently cured members of the population will remain, and the DFS curve will be perfectly flat. The earliest point in time that the curve goes flat is the point at which all remaining disease-free survivors are declared to be permanently cured. If the curve never goes flat, then the disease is formally considered  incurable  (with the existing treatments)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5095", "text": "The  Berkson and Gage equation  is\n \n \n \n \n S \n ( \n t \n ) \n = \n p \n + \n [ \n ( \n 1 \n \u2212 \n p \n ) \n \u00d7 \n \n S \n \n \u2217 \n \n \n ( \n t \n ) \n ] \n \n \n {\\displaystyle S(t)=p+[(1-p)\\times S^{*}(t)]}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5096", "text": "where  \n \n \n \n S \n ( \n t \n ) \n \n \n {\\displaystyle S(t)} \n \n  is the proportion of people surviving at any given point in time,  \n \n \n \n p \n \n \n {\\displaystyle p} \n \n  is the proportion that are permanently cured, and  \n \n \n \n \n S \n \n \u2217 \n \n \n ( \n t \n ) \n \n \n {\\displaystyle S^{*}(t)} \n \n  is an exponential curve that represents the survival of the non-cured people."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5097", "text": "Cure rate curves can be determined through an analysis of the data. [ 7 ]  The analysis allows the statistician to determine the proportion of people that are permanently cured by a given treatment, and also how long after treatment it is necessary to wait before declaring an asymptomatic individual to be cured. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5098", "text": "Several cure rate models exist, such as the  expectation-maximization algorithm  and  Markov chain Monte Carlo  model. [ 7 ]  It is possible to use cure rate models to compare the efficacy of different treatments. [ 7 ]  Generally, the  survival curves  are adjusted for the effects of normal aging on mortality, especially when diseases of older people are being studied. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5099", "text": "From the perspective of the patient, particularly one that has received a new treatment, the statistical model may be frustrating. [ 6 ]  It may take many years to accumulate sufficient information to determine the point at which the DFS curve flattens (and therefore no more relapses are expected). Some diseases may be discovered to be technically incurable, but also to require treatment so infrequently as to be not materially different from a cure. Other diseases may prove to have multiple plateaus, so that what was once hailed as a \"cure\" results unexpectedly in very late relapses. Consequently, patients, parents and psychologists developed the notion of  psychological cure , or the moment at which the patient decides that the treatment was sufficiently likely to be a cure as to be called a cure. [ 6 ]  For example, a patient may declare himself to be \"cured\", and to determine to live his life as if the cure were definitely confirmed, immediately after treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5100", "text": "Cures can take the form of natural  antibiotics  (for  bacterial infections ),  synthetic   antibiotics  such as the  sulphonamides , or  fluoroquinolones ,  antivirals  (for a very few  viral infections ),  antifungals ,  antitoxins ,  vitamins ,  gene therapy , surgery, chemotherapy, radiotherapy, and so on. Despite a number of cures being developed, the list of incurable diseases remains long."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5101", "text": "Scurvy  became curable (as well as preventable) with doses of vitamin C (for example, in limes) when  James Lind  published  A Treatise on the Scurvy  (1753). [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5102", "text": "Antitoxins to  diphtheria  and  tetanus toxins  were produced by  Emil Adolf von Behring  and his colleagues from 1890 onwards. The use of  diphtheria antitoxin  for the treatment of diphtheria was regarded by  The Lancet  as the \"most important advance of the [19th] Century in the medical treatment of acute infectious disease\". [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5103", "text": "Sulphonamides  become the first widely available cure for bacterial infections. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5104", "text": "Antimalarials  were first synthesized, [ 13 ] [ 14 ] [ 15 ]  making  malaria  curable. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5105", "text": "Bacterial infections became curable with the development of antibiotics. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5106", "text": "Hepatitis C , a viral infection, became curable through treatment with antiviral medications. [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5107", "text": "Signs and symptoms Syndrome Disease"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5108", "text": "Medical diagnosis Differential diagnosis Prognosis"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5109", "text": "Acute Chronic Cure"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5110", "text": "Eponymous disease Acronym or abbreviation Remission"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5111", "text": "Deprescribing  is a process of tapering or stopping  medications  to achieve improved health outcomes by reducing exposure to  medications  that are potentially either harmful or no longer required. [ 1 ]  Deprescribing is important to consider with changing health and care goals over time, as well as  polypharmacy  and  adverse effects . [ 2 ]  Deprescribing can improve adherence, cost, and health outcomes but may have adverse drug withdrawal effects. More specifically, deprescribing is the planned and supervised process of intentionally stopping a  medication  or reducing its dose to improve the person's health or reduce the risk of adverse  side effects .  Deprescribing is usually done because the drug may be causing harm, may no longer be helping the patient, or may be inappropriate for the individual patient's current situation. [ 3 ] [ 4 ]  Deprescribing can help correct  polypharmacy  and  prescription cascade ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5112", "text": "Deprescribing is often done with people who have  multiple long-term conditions  (multimorbidity), older people, and people who have a limited life expectancy. [ 5 ]  In all of these situations, certain medications may contribute to an increased risk of adverse events, and people may benefit from a reduction in the amount of  medication  taken.  Deprescribing aims to reduce medication burden and harm while maintaining or improving quality of life.  \"Simply because a patient has tolerated a therapy for a long duration does not mean that it remains an appropriate treatment. Thoughtful review of a patient's medication regimen in the context of any changes in medical status and potential future benefits should occur regularly, and those agents that may no longer be necessary should be considered for a trial of medication discontinuation.\" [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5113", "text": "The process of deprescribing is usually planned and supervised by healthcare professionals. [ 7 ]  To some, the definition of deprescribing includes only completely stopping a  medication , while to others, deprescribing also includes dose reduction, which can improve quality of life (minimize side effects) while maintaining benefits. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5114", "text": "The world\u2019s first published use of the term \u201cdeprescribing\u201d was described in 2003 by Michael Woodward in his article titled \u2018Deprescribing: Achieving Better Health Outcomes for Older People through Reducing Medications.' It was published in the Society of Hospital Pharmacists of Australia's flagship  Journal of Pharmacy Practice and Research  (JPPR).\u2019 [ 9 ] [ additional citation(s) needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5115", "text": "Older people are the heaviest users of medications and frequently take five or more medications (polypharmacy).   Polypharmacy  is associated with increased risks of adverse events, drug interactions,  falls , hospitalization, cognitive deficits, [ better\u00a0source\u00a0needed ]  and mortality. [ 10 ]  These effects are particularly seen in high-risk prescribing. [ 11 ]  Thus, optimizing medication through targeted deprescribing is a vital part of managing chronic conditions, avoiding adverse effects and improving outcomes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5116", "text": "Deprescribing is considered a potential intervention with reported safety and feasibility. [ 12 ] [ 13 ]  For a wide range of medications, including diuretics, blood pressure medication, sedatives, antidepressants, benzodiazepines and nitrates, adverse effects of deprescribing are rare. [ 14 ] [ 15 ]  While deprescribing has been shown to result in fewer medications, it is less certain if deprescribing is associated with significant changes in health outcomes. [ 12 ] [ 16 ]  Although it might be possible and safe to reduce the number of medicines that people use, reversing the potential harms associated with polypharmacy may not always be achievable. [ 17 ]  Early evidence suggested that deprescribing may reduce premature death, leading to calls to undertake a double-blind study.  A placebo-controlled, double-blind, randomized controlled trial was published in 2023.  This study undertook deprescribing in people over 65 years living in residential aged care. [ 18 ]   It found no change in mortality [ 19 ]  and that, if implemented in all residential aged care facilities across Australia, it could save up to $16 million annually. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5117", "text": "Deprescribing medications may improve patient function, generate a higher quality of life, and reduce bothersome signs and symptoms. Deprescribing has been shown to reduce the number of falls people experience but not to change the risk of having the first fall. [ 12 ]  Most health outcomes remain unchanged as an effect of deprescribing. The absence of a change has been viewed as a positive outcome, as the medications can often be safely withdrawn without altering health outcomes. This absence of an effect means that older people may not miss out on potentially beneficial effects of using medications due to deprescribing. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5118", "text": "Targeted deprescribing can improve adherence to other drugs. [ 5 ]  Deprescribing can reduce the complexity of medication schedules.  Complicated schedules are difficult for people to follow correctly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5119", "text": "The product information provided by drug companies provides much information on how to start medications and what to expect when using them. However, it provides little information on when and how to stop medications. [ 21 ]  Research into deprescribing is accumulating, with two papers showing a rapid acceleration in using the word since 2015. [ 8 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5120", "text": "In people with multiple long-term conditions and polypharmacy, deprescribing represents a complex challenge as clinical guidelines are usually developed for single conditions. In these cases, tools and guidelines like the  Beers Criteria  and STOPP/START could be used safely by clinicians, but not all patients might benefit from stopping their medication. There is a need for clarity about how much clinicians can do beyond the guidelines and the responsibility they need to take could help them prescribing and deprescribing for complex cases. Further factors that can help clinicians tailor their decisions to the individual are: access to detailed data on the people in their care (including their backgrounds and personal medical goals), discussing plans to stop a medicine already when it is first prescribed, and a good relationship that involves mutual trust and regular discussions on progress. Furthermore, longer appointments for prescribing and deprescribing would allow time to explain the process, explore related concerns, and support making the right decisions. [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5121", "text": "A review analysed way to improve deprescribing in  primary care . It concluded that clearly defined roles and responsibilities, with good communication between multidisciplinary team members, and pharmacists integrated within teams could aid deprescribing. Routine discussions about deprescribing when prescribing, with medication reviews tailored to patients\u2019 needs and preferences could also help. Patients and informal carers should be involved in decisions, and trusted relationships should be built up with professionals allowing continuity of care. Clinicians would also benefit from training and education on deprescribing. [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5122", "text": "It is possible for the patient to develop adverse  drug withdrawal  events (ADWE). [ 26 ]  These symptoms may be related to the original reason why the medication was prescribed, to withdrawal symptoms or to underlying diseases that medications have masked. [ 27 ]   For some medications, ADWEs can generally be minimized or avoided by tapering the dose slowly and carefully monitoring for symptoms. Prescribers should be aware of which medications usually require tapering (such as  corticosteroids  and  benzodiazepines ) and which can be safely stopped suddenly (such as  antibiotics  and  nonsteroidal anti-inflammatory drugs )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5123", "text": "Deprescribing requires detailed follow-up and monitoring, not unlike the attention required when starting a new medication. It is recommended that prescribers frequently monitor \"relevant signs, symptom, laboratory or diagnostic tests that were the original indications for starting the medication,\" as well as for potential withdrawal effects. [ 15 ]  The recommended schedule for monitoring during deprescribing is at two-week intervals. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5124", "text": "Several tools have been published to inform prescribers of inappropriate medications for various patient groups. The most common deprescribing algorithm is validated [ 29 ]  and has been tested in two RCTs. [ 16 ]   It is available for clinicians to identify medications that can be deprescribed. [ 29 ]  It prompts clinicians to consider if it is (1) an inappropriate prescription, (2) adverse effects or interactions that outweigh symptomatic effects or potential future benefits, (3) drugs taken for symptom relief but the symptoms are stable, and (4) drug intended to prevent future severe events but the potential benefit is unlikely to be realized due to limited life expectancy.  If the answer to any of the four prompts is yes, then the medication should be considered for deprescribing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5125", "text": "The CEASE algorithm prompts clinicians to consider if the treated condition remains a current concern for their patient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5126", "text": "The ERASE algorithm prompts clinicians to consider whether the treated condition still requires treatment. [ 30 ]  The ERASE mnemonic stands for \" e valuate diagnostic parameters,\"  \" r esolved conditions,\" \" a geing normally,\" \" s elect targets,\" and \" e liminate.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_5127", "text": "The  Beers Criteria  and the STOPP/START criteria present medications that may be inappropriate for use in older adults, [ 31 ]  including drugs associated with high risk of adverse reactions for this population or lacking evidence for their benefits when safer and more effective alternatives exist. [ 32 ]  Some countries, such as, Australia have their lists of Potentially Inappropriate Medicines. [ 33 ]  For people with dementia, the  Medication Appropriateness Tool for Comorbid Health Conditions in Dementia  (MATCH-D) [ 34 ]  can help clinicians identify when and what to consider deprescribing. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5128", "text": "RxFiles, an academic detailing group based in Saskatchewan, Canada, has developed a tool to help  long-term care  providers identify potentially inappropriate medications in their residents. [ 36 ]  Tasmanian Medicare Local has created resources to help clinicians deprescribe. [ 37 ]  Theoretical Underpinnings of a Model to Reduce Polypharmacy and Its Negative Health Effects: Introducing the Team Approach to Polypharmacy Evaluation and Reduction (TAPER) is a framework to support practitioners in deprescribing. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5129", "text": "An expert working group concluded that integrated healthcare provided by multidisciplinary patient-centred teams was the most appropriate approach to promote deprescribing and improve appropriate medication use. [ 39 ]  Deprescribing rounds in tertiary care hospitals have also been evaluated and shown to improve health-related outcomes. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5130", "text": "Although many trials have successfully resulted in a reduction in medication use, there are some barriers to deprescribing:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5131", "text": "The prescriber and patients were shown to have the most significant influence on each other rather than external influences.  9 out of 10 older people said they would be willing to stop one or more medications if their doctor said it was okay."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5132", "text": "Drug antagonism  refers to a medicine stopping the action or effect of another substance, preventing a biological response. [ 1 ] [ 2 ]  The stopping actions are carried out by four major mechanisms, namely chemical,  pharmacokinetic ,  receptor  and physiological  antagonism . [ 2 ]  The four mechanisms are widely used in reducing overstimulated physiological actions. Drug antagonists can be used in a variety of medications, including  anticholinergics ,  antihistamines , etc. The antagonistic effect can be quantified by  pharmacodynamics . Some can even serve as antidotes for toxicities and overdose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5133", "text": "Receptors  bind with endogenous  ligands  to produce a physiological effect and regulate the body and cellular homeostasis. In a ligand-receptor interaction, the ligand binds with the receptors to form a drug-receptor complex, producing a biological response. [ 3 ] [ 4 ]  The biological nature of receptors can be  enzymes ,  nucleic acids  or cellular proteins. Common types of receptors include  G-protein coupled receptors ,  nuclear receptors  and  ion channels . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5134", "text": "Functional antagonists would not produce a biological response after binding with a receptor. It blocks the binding of endogenous ligands to the receptors and thus inhibits the subsequent physiological effect. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5135", "text": "Both agonist and antagonist bond the same active site. Adding agonist dose can reverse the effect of reversible competitive antagonism. Irreversible competitive antagonism occurs when the antagonist binds to the same spot on the receptor as the agonist but dissociates from the receptors very slowly or not. As a result, when the agonist is delivered, there is no change in the antagonist occupancy. Since a receptor can only hold one molecule at a time, competitive antagonists can reduce the agonist occupancy (percentage of receptors to which the agonist is bound). Raising the agonist concentration can bring back the agonist occupancy and the subsequent tissue response due to their competition. Thus, the opposition is surmountable. The amount to which the competitive antagonist causes the agonist log concentration\u2013effect curve to shift to the right while maintaining its maximum slope is a measure of the dosage ratio. The antagonist concentration causes the dosage ratio to rise linearly. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5136", "text": "Different active sites are bonded by agonist and antagonist, which means in which the antagonist obstructs the chain of events that triggers the agonist to produce a response at a point downstream from the agonist binding site on the receptor. It irreversibly binds to the active site. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5137", "text": "One examples is when Ketamine enters the NMDA receptor's ion channel pore and blocks it, stopping ions from passing through the channels. Also, medication like nifedipine and verapamil stops Ca2+ from entering the cell membrane and so non-selectively prevent medications that act at any receptor that binds to these calcium channels from causing smooth muscle contraction. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5138", "text": "In the presence of a full agonist exerting its maximal effect,  a partial agonist  can behave like a competitive antagonist to lower the effect of receptor binding, generating merely a submaximal reaction. These variations can be evaluated regarding effectiveness, indicating the agonist-receptor complex's \"strength\" in causing a tissue response. It relies on  receptor occupancy  and  response . A particular medication of intermediate efficacy may appear as a partial agonist in one tissue (lower level of receptor expression) and a full agonist in another (high level of receptor expression) across distinct cell types expressing the same receptor but at varying densities. [ 5 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5139", "text": "Competitive antagonists are usually structurally similar to the active compound since they are structural analogues that have to bind to the same pocket. [ 10 ]  Examples of reversible competitive antagonists like  antihistamines  (Figure 1) compete with histamine (Figure 2) to bind to  histamine  receptors, blocking the allergic response by histamine. They are used in treating histamine-mediated allergies and  allergic rhinitis . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5140", "text": "Irreversible competitive antagonists like  phenoxybenzamine  do not dissociate from alpha-adrenergic receptors. It is used to block the activity of alpha receptors in sympathetic pathway and is used in the treatment of  paroxysmal hypertension  and sweating resulting from pheochromocytoma and  benign prostate hyperplasia . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5141", "text": "Chemical antagonism occurs when a chemical antagonist combines with a ligand to form an inactive product compound,  inhibiting the response. [ 8 ]  In chemical antagonism, the receptors are not involved in the process, and the antagonist directly binds with or removes the ligand. It prevents the ligand from binding to the receptor. As the ligand cannot stimulate the receptor, no physiological effect is generated by the receptors and thus provides an inhibitory effect. [ 13 ]  The common types of chemical antagonism include chelating agents, neutralising antibodies and salt aggregation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5142", "text": "Chelating agents  are organic compounds which are capable of linking to metal ions. [ 14 ]  They are usually useful for removing toxic heavy metal ions from body.  Dimercaprol  is a common chelating agent to treat toxic exposure to arsenic, mercury, gold, and lead. It is in the chelating class of drugs. [ 15 ]  From Figure 3, the SH-ligands of dimercaprol can compete with -SH groups in natural enzymes for heavy metal, forming a stable metal complex to be excreted through urine. [ 15 ]  The action antagonises the toxic metal ions and helps remove them from body circulation. However, dimercaprol has a narrow TI and is later replaced by its derivative, 2,3-dimercaptosuccinic acid ( DMSA ). [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5143", "text": "Neutralising antibodies  block pathogen entry into cells to prevent further infection and replication. [ 17 ]   Infliximab  is a monoclonal antibody binding with tumour necrosis factor-alpha (TNF-alpha), inhibiting its pro-inflammatory action. [ 18 ]  Its efficacious anti-inflammatory action is clinically used in  Crohn's Disease , active rheumatoid arthritis,  psoriatic arthritis , and active ankylosing spondylitis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5144", "text": "Salt aggregation refers to reactions between a drug and an active compound forming a salt. Strongly anionic  unfractionated heparin  reacts with the positive cationic protamine arginine peptide to generate a salt aggregation. [ 19 ]  The resulting salt aggregate is not anticoagulant and is inactive.  Protamine  acts quickly, taking only five minutes to neutralize unfractionated heparin, and its half-life is only ten minutes. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5145", "text": "A drug which can affect the  pharmacokinetics  ( absorption, digestion, metabolism, excretion)  profile of another chemical (or drugs), thereby reducing the action of the target chemical. There could be a rise in the active drug's rate of metabolic breakdown. As an alternative, there may be a decrease in the rate at which the active medication is absorbed from the digestive system or a rise in the rate at which the drug is excreted by the kidneys. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5146", "text": "Most drugs are taken orally and are absorbed through the  gastrointestinal tract . [ 20 ]   Antacids  would increase the pH environment in the stomach and cause premature release of  enteric coated drugs , which are designed to be protected from an acidic environment in stomach. [ 21 ]  For example,  proton-pump inhibitors (PPIs)  are enteric coated to protect them from decomposition under an acidic environment. [ 22 ]  Co-administration of antacids with PPIs would lead to premature release into acidic gastric environments and inactivate PPIs before absorption. These types of pharmacokinetics antagonism should be carefully avoided to prevent loss of drug efficacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5147", "text": "Since most drugs are either weakly acidic or weakly basic, modified pH would also affect the location at which the drug is deionised, thus affecting the required time for absorption and onset. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5148", "text": "Many drugs are metabolised by a set of liver enzymes called  CYP450s . [ 24 ]  The activity of these enzymes would determine the rate of pro-drug activation and the rate of inactivation of active drugs. For example,  warfarin , a commonly-used anticoagulant drug in atrial fibrillation, is metabolised by an enzyme called CYP2C9. Phenytoin, a CYP2C9 inducer, would increase its activity and the rate of warfarin breakdown, thereby reducing its efficacy. [ 25 ]  Patients should avoid the co-administration of warfarin and phenytoin. In cases where both drugs must be used together, warfarin dosing may be titrated up to cope with the reduced efficacy. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5149", "text": "The kidney excretes most drugs through urine. Since urine is weakly alkaline in nature, weakly acid drugs would ionise in urine, making it difficult for them to be reabsorbed. Therefore, in cases of aspirin (weak acid) toxicity, injecting intravenous sodium bicarbonate could increase urine pH, thereby increasing the excretion of aspirin through urine. [ 27 ]  A similar approach can be used in other weakly acidic drug toxicity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5150", "text": "Physiologic antagonism refers to the behaviour in which an antagonist behaves the opposite of the agonist but does not bind to the same active site as the agonist does. [ 8 ]  A physiologic antagonist binds to a different receptor but not the original agonist receptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5151", "text": "Both  insulin  and  glucagon  are synthesised naturally in the human body to regulate blood glucose levels at homeostasis. [ 28 ]  Insulin binds to insulin receptors to decrease blood glucose levels, whilst glucagon binds to glucagon receptors to increase blood glucose levels. In cases of insulin-induced  hypoglycaemia , glucagon injection could help increase blood glucose levels. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5152", "text": "Another example is epinephrine (a bronchodilator) and histamine (a bronchoconstrictor). Epinephrine binds to adrenergic receptors to promote bronchodilation whilst histamine binds to histamine receptors which leads to bronchoconstriction. [ 29 ] [ 30 ]  Since they have opposite effects in different pathways, they are considered physiological antagonists, and they are not advised to be taken together."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5153", "text": "Pharmacodynamics  (PD) is the core principle of quantifying the effects of antagonists by measuring the drug\u2019s efficacy and safety. PD emphasises the relationship between the dose and response of a certain drug, which can be illustrated using a  dose-response curve . [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5154", "text": "Efficacy is the maximal effect (Emax) that an agonist can produce. As a receptor antagonist does not affect receptors after binding, it is said to have zero efficacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5155", "text": "A competitive antagonist does not affect the Emax of the agonist. This is because the effect of an agonist can be maximized by adding the dose of the agonist as the action of the antagonist is reversible. The maximum effect of the agonist can be achieved by adding the concentration of the agonist. [ 6 ] [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5156", "text": "A non-competitive antagonist(or Allosteric antagonist) lowers the Emax of an agonist. The Emax of an agonist is inversely proportional to the concentration of the antagonist, which means a higher concentration of antagonist results in a lower Emax. The maximal efficacy of agonists is reduced as the inhibition cannot be reversed by adding the agonist concentration. [ 6 ] [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5157", "text": "Potency is the amount of drug needed to give a certain therapeutic effect. It is affected by the drug\u2019s affinity to the receptors and the number of receptors available. [ 32 ]  For antagonists,  half maximal inhibitory concentration (IC50)  is used to measure the potency of antagonists. IC50 means the concentration of antagonist needed to give a 50% inhibition. [ 33 ]  It can be directly compared with EC50, which is commonly used to measure the potency of an agonist.  EC50  means the concentration of agonist needed to give a 50% response."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5158", "text": "IC50 is significant in determining the optimal dose of antagonist. A high concentration of an antagonist in the body may result in toxicity in the cell and damage the cell membrane. A lower IC50 means the inhibitory effect can be met with a lower concentration of antagonist and, therefore a lower risk of toxicity. For example, the IC50 of antagonists on cancer cell growth is essential for determining the optimal dose which inhibits cancer cells while inducing less harmful systemic effects in the body. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5159", "text": "The  therapeutic index  (TI) is used to quantify the risks and benefits of a certain drug. It describes the relationship between toxic dose and minimum effective dose, thus providing an important insight into the safety of a drug. [ 35 ]  The Therapeutic Index is calculated using the following equation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5160", "text": "TI = TD50 / ED50, where  TD50  is the dose at which toxicity presents in 50% of the population, and  ED50  is the dose needed to produce 50% of maximal response. [ 35 ]  From the equation, a high TI indicates that the drug needs a high dose to induce toxicity in 50% of the population or a low dose to achieve the minimum effective dose, and vice versa."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5161", "text": "In the case of physiological antagonists, for example, insulin has a narrow TI. A narrow TI indicates that either excess or lack of insulin can cause significant risks. [ 31 ]  On one hand, lack of insulin may result in high blood glucose levels and kidney or cardiovascular damage. On the other hand, excess insulin may result in insulin-induced  hypoglycemia  as aforementioned. Another example is dimercaprol, a chemical antagonist in treating metal toxicity. Dimercaprol has a narrow TI so it is replaced by its derivative, 2,3-dimercaptosuccinic acid ( DMSA ). [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5162", "text": "Upregulation of receptors  is the increase in receptor number or sensitivity of receptors. The receptors involved in functional antagonism are regulated in sensitivity, number and location. [ 36 ]  Therefore, changes in receptors are common. Using a long-term antagonist drug or continuous exposure to an antagonist may cause the upregulation and hypersensitivity of receptors, which means an increase in the number and sensitivity of receptors. [ 35 ]  The increase in the number of receptors is due to the increased expression of receptors after prolonged inhibition. The upregulation of receptors is important in the clinical aspect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5163", "text": "One example of upregulation of receptors is the upregulation of \u03b2-receptors caused by  \u03b2 receptor antagonists  (also called \u03b2-blocker). The prolonged use of \u03b2-blockers results in the blockade of \u03b2-receptors, causing cells (mainly myocardial cells) to increase their expression of \u03b2-receptor. After removing the blockage, more receptors available for stimulation, resulting in higher sensitivity of \u03b2-receptors called the hypersensitivity of \u03b2-receptors. [ 37 ]  Abrupt discontinuation of \u03b2-blocker may potentially aggravate coronary artery disease, tachycardia, or even sudden cardiac death. [ 38 ]  Therefore, to prevent the adverse effects, doses of \u03b2-blocker must be reduced gradually over 10\u201314 days. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5164", "text": "Antidotes  are agents that can neutralise the effects of a poison or toxin. Antidotes counteract the effects of toxins in many ways, such as by blocking the absorption of the toxin, binding and neutralising the poison, opposing the toxin's end-organ function, or blocking the toxin's conversion to more hazardous metabolites. In addition to lowering the amount of free or active poison present, antidote delivery may also lessen the toxin's effects on organs through competitive inhibition, receptor blockage, or direct antagonistic interaction. [ 39 ] [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5165", "text": "The therapeutic index or ratio (TD50/ED50), which is the ratio of the toxic dosage (TD) or fatal dose (LD) to the effective dose (ED), determines the level of safety associated with a substance. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5166", "text": "Agents that \"bind\" to the toxin can reduce free or active toxin present. It is possible for this binding to be nonspecific or specific."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5167", "text": "Activated charcoal is the non-specific binding agent most frequently utilised as it has strong adsorption capacity and could prevent the toxin's enterohepatic recirculation. Chelation agents, immunotherapy, and bioscavenger therapy are examples of specific binders. Urinary alkalization or hemadsorption may improve elimination in some circumstances. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5168", "text": "It might occur either at the enzyme or receptor level. There are two possible outcomes at the enzyme level: competitive inhibition or enzyme activity reactivation.  Ethyl alcohol  or  fomepizole  used in methyl alcohol or ethylene glycol poisoning is a typical example of competitive enzyme inhibition. By posing competition for  alcohol dehydrogenase (ADH)  with methyl alcohol and ethylene glycol, these drugs reduce the production of harmful metabolites. [ 41 ]  For receptor level, the traditional antidotes include naloxone and flumazenil.  Flumazenil  functions as a competitive antagonist at the GABA-A receptor complex's benzodiazepine site. By doing this, the CNS and respiratory depression would reverse and the inward chloride current would reduce. Flumazenil is useful in treating and preventing benzodiazepine-induced coma from recurring. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5169", "text": "Antidotes can be employed to either mop up hazardous metabolites or change them into less toxic forms once they have developed. [ 39 ]   Hepatic glutathione  stores are replenished by N-acetyl cysteine, and this process is what leads to the conjugation of the poisonous metabolite  N-acetyl P-benzoquinone imine  (NAPQI). [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5170", "text": "Drug detoxification  (informally,  detox )  is variously construed or interpreted as a type of \"medical\" intervention or technique in regards to a  physical dependence  mediated by a  drug ; as well as the process and experience of a  withdrawal syndrome  or any of the treatments for acute  drug overdose  (toxidrome). The first definition however, in relation to substance dependence and its treatment is arguably a  misnomer  and even directly contradictory since  withdrawal  is neither contingent upon nor alleviated through biological excretion or  clearance  of the drug. In fact, excretion of a given drug from the body is one of the very processes that leads to withdrawal since the syndrome arises largely due to the  cessation  itself and the drug being absent from the body; especially the  blood plasma , not from \u2018leftover toxins\u2019 or traces of the drug still being in the system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5171", "text": "Some  addiction medicine  practitioners use the term  withdrawal management  instead of  detoxification . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5172", "text": "A detoxification program for physical dependence does not necessarily address the precedents of  addiction , social factors, psychological addiction, or the often-complex behavioral issues that intermingle with addiction. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5173", "text": "The  United States Department of Health and Human Services  acknowledges three steps in a drug detoxification process: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5174", "text": "Richard B. Resnick MD was the first scientist to investigate the idea of accelerated detox under anesthesia. In 1977, [ 6 ]  he published a paper detailing the first procedures using Naloxone and clonidine. Shortly afterward, physicians began discussing anesthesia to reduce pain during rapid detox. Norbert Loimer, MD, Ph.D. published a paper in the '80s outlining the success of opiate detoxification under general anesthesia. Resnick and Loimer's early research served as the foundation for all forms of detoxification under sedation procedures used today. While physicians' protocols significantly differ, they still adhere to the principles described in the early publications. [ 7 ]  The combined use of clonidine and naltrexone was found to be a rapid, safe, and effective treatment for abrupt withdrawal from methadone, as detailed in a paper published in The American Journal of Psychiatry in 1986. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5175", "text": "Since then, numerous clinics around the world have implemented detoxification under sedation procedures to assist patients in overcoming opioid use disorder. These procedures involve the administration of anesthesia and other medications to facilitate rapid detoxification of the body, effectively reducing the painful and uncomfortable symptoms of withdrawal. While the effectiveness of rapid detox has been a subject of debate, it remains a popular treatment option for certain individuals grappling with opioid addiction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5176", "text": "The concept of \"detoxification\" comes from the discredited autotoxin [ 9 ]  theory of  George E. Pettey  and others.   David F. Musto  says that \"according to Pettey, opiates stimulated the production of toxins in the intestines, which had the physiological effect associated with withdrawal phenomena. [...] Therefore treatment would consist of purging the body of toxins and any lurking morphine that might remain to stimulate toxin production in the future.\" [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5177", "text": "Naltrexone therapy, which critics claim lacks long-term efficacy and can actually be detrimental to a patient's long-term recovery, has led to controversy. Additionally, there have been many questions raised about the ethics as well as safety of rapid detox following a number of deaths resulting from the procedure. [ 12 ] [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5178", "text": "Some researchers say that relapses to injection use of illicit opioids during or following repeated detoxification episodes carry the substantial potential for injury associated with uncontrolled drug use and include  drug overdose ,  infections , and death. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5179", "text": "A  drug reference standard  or  pharmaceutical reference standard  is a highly characterized material suitable to test the identity, strength, quality and purity of substances for pharmaceutical use and medicinal products. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5180", "text": "Pharmacopoeial reference standards are a subset of pharmaceutical reference standards. They are established for the intended use described in  pharmacopeial  texts (monographs and general chapters).  Pharmacopeial reference standards are available from various pharmacopoeias such as  United States Pharmacopeia  and the  European Pharmacopoeia .\nWhere pharmacopoeial tests or assays call for the use of a pharmacopoeial reference standard, only those results obtained using the specified pharmacopoeial reference standard are conclusive. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5181", "text": "This  standards - or  measurement -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5182", "text": "Drugs and sexual desire  is about sexual desire being manipulated through drugs from various approaches.  Sexual desire  is generated under the effects from  sex hormones  and microcircuits from brain regions. [ 1 ]   Neurotransmitters  play essential roles in stimulating and inhibiting the processes that lead to  libido  production in both men and women. For instance, a positive stimulation is modulated by  dopamine  from the medial  preoptic area  in the  hypothalamus [ 2 ]  and  norepinephrine . At the same time, inhibition occurs when  prolactin  and  serotonin  are released for action. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5183", "text": "Drugs acting on the above neurotransmitters can be used to upregulate or downregulate sexual desire due to diseased conditions. During  drug development  specialized for women, the Female Sexual Function Index-Desire Domain (FSFI-D) provides a reference measurement for researchers to evaluate recipients' responses and results. [ 3 ]  FSFI values allow researchers to monitor the change of sexual desire with a more solid definition, and at the same time, establish records for the  U.S. Food and Drug Administration (FDA)  to process applications for drug approval. Similarly, the Male Desire Scale (MDS) is used for men. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5184", "text": "After evaluating symptom severity using the scales, patients are then prescribed different types of drugs. Flibanserin [ 1 ]  and Bremelanotide [ 3 ]  were developed for raising sexual desire in women, whereas similar conditions in men are treated using medications for sexual dysfunction. [ 4 ]  On the other hand, down-regulation on libido comes in two approaches: a direct or an indirect mechanism. Multiple drugs from each category have been proven effective. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5185", "text": "Marketized drugs have encountered market demands, also boosted personalized medication developments aiming at a broader range of recipients. [ 6 ] [ 7 ] [ 8 ] [ 9 ]  Still, disease establishment dilemmas and FDA drug approvals give rise to ethical concerns, posing obstacles in the field's development. [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5186", "text": "These drugs are expected to restore a normal libido in patients. Targeting acquired and generalized  hypoactive sexual desire disorder (HSDD) , improvement in sexual desire, and alleviation of psychological stress are to relieve the correlated symptoms. [ 12 ]  However, the treatments cannot cope with medically or psychiatrically related conditions, nor the effects from other medications. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5187", "text": "Flibanserin  is the first pharmaceutical product from Sprout Pharmaceuticals [ 14 ]   for premenopausal women with HSDD. The drug was approved by the FDA in 2015. It compiles a  serotonin 1A receptor   agonist  and a  serotonin 2A receptor   antagonist . [ 15 ]  and is an  antidepressant [ 16 ]  that was originally developed for  depression . [ 12 ]  This weak partial agonist that acts on dopamine D4 receptors, [ 17 ]  is also postsynaptic and functions by modulating various neurotransmitters, including dopamine, norepinephrine, and serotonin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5188", "text": "Flibanserin contains centrally active  piperazine / benzimidazole -derived molecules, that aim to limit  forskolin -stimulated  cAMP  production. Thus, eliminating the  phosphatidyl-inositol  turnover, which  5-HT    stimulates typically in the brain cortex. [ 14 ]  However, the precise mechanism is oblique. It is estimated that the drug targets brain regions, especially in the medial  prefrontal cortex , hypothalamus,  limbic regions , and  brainstem . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5189", "text": "After its launch in 2015 and marketed as Addyi, the drug experienced controversies and rejection from being acknowledged after three reviews on the clinical trials. [ 10 ]  Regarding the eligible prescription criteria concluded from the trials, [ 18 ]  the patient should have a diagnosed psychological pathology, medical comorbidities, and the presence of personal relationship issues. [ 13 ]  Despite being the first drug, its efficacy was not significant for treatment less than at least four weeks. [ 19 ]  Treatment withdrawal is also practiced if recipients do not experience improvements in symptoms after eight weeks. [ 16 ]  Nevertheless, around 18% of the gain was observed after 24 weeks of treatment. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5190", "text": "Due to a wide range of observed side-effects, flibanserin's safety has been called into question. Clinical trials reported adverse reactions including  dizziness ,  nausea ,  fatigue , and  insomnia . [ 16 ]   Hypotension  and  central nervous system depression (somnolence)  leading to  sedation and sleepiness symptoms were also observed. [ 16 ]  In order to lower the chances of occurrence, the drug is usually prescribed to be taken only once per day before bed. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5191", "text": "On the other hand, the third stage of the trial suggests that risks are derived from any moderate or strong  cytochrome P-450 3A4 (CYP3A4)  inhibitors that are often present in  antihypertensive drugs ,  antiretroviral drugs ,  antibiotics , or  fluconazole . [ 18 ]  An alcohol-interaction study was also carried out. [ 20 ]  Instead of premenopausal women, the study was on male participants, with the conclusion that alcohol may pose a risk of  systolic  and  diastolic  blood pressure reduction to recipients. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5192", "text": "Flibanserin is delivered through oral administrations on a half-life of 11 hours. [ 21 ]  A steady state can be achieved after three days of treatment. [ 22 ]  The metabolites of the drug are predominantly eliminated through urination and defecation. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5193", "text": "Bremelanotide  was first developed by Palatin Technologies, then out-licensed to AMAG Pharmaceuticals Inc. after its approval by the FDA on 21 June 2019. [ 23 ]  Marked as VyleesiTM, it was primarily designed for both men and women in the form of an intranasal formulation, particularly for treating  male erectile dysfunction . [ 23 ]  However, the research was discontinued and focused on targeting female HSDD [ 23 ]  in a subcutaneous injection to increase  bioavailability . [ 3 ]  Bremelanotide is usually injected a minimum of 45 minutes before sexual activity. Despite having identical prescription criteria as that of flibanserin, bremelanotide is not recommended for pregnant patients. No trial was tested on pregnant patients. [ 24 ]  Therefore, patients at childbearing ages are recommended to use contraception continuously during treatment and should discontinue once they become pregnant. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5194", "text": "The  melanocortin receptor  agonist proposes to activate multiple receptor subtypes nonselectively, with the highest affinity with  MC1R , then  MC4R ,  MC3R ,  MC5R , and  MC2R  receptors. [ 23 ]  As MC4R receptors are present on neurons in the central nervous system, a function in modulating brain pathways is suggested, albeit a precise mechanism remains unknown. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5195", "text": "Sustained and significant improvement in FSFI scores throughout a 52-week extension was attained, indicating a high efficacy of the drug treating HSDD, most notably when anticipating the challenge in psychological distress. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5196", "text": "Mild or moderate adverse events are common, expressing symptoms like nausea, facial flushing, headache, and sunburn. [ 3 ] [ 23 ]  Unlike flibanserin, bremelanotide induces fewer side effects and is not affected nor develops severe complications with alcohol. [ 20 ]  However, the drug slows down gastric emptying, which can cause an impact on oral drug uptake and the subsequent drug effectiveness. [ 24 ]  As activation of MC1R gives rise to hyperpigmentation, [ 3 ]  treatment dosage is at a maximum of eight doses per month. [ 24 ]  Besides, to minimize the chances of cardiovascular complications, the prescribed daily dosage is at one dose. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5197", "text": "Bremelanotide is exposed through a single subcutaneous administration. [ 26 ]  With a half-life of an hour, the drug is excreted through urine and faeces. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5198", "text": "There are already 26 drugs available for men's  sexual dysfunction . [ 19 ]  Since HSDD in men is not acknowledged and was categorized to be a distinct sexual dysfunction, [ 4 ]  there are currently no drugs specialized for men in similar conditions as stated above."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5199", "text": "Drugs down-regulating libido are generally either intended for libido suppression via direct down-regulating mechanisms or eliciting such side-effects by their unintended indirect mechanisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5200", "text": "Two types of drugs are mainly prescribed to people suffering from overwhelming sexual desire:  gonadotropin-releasing hormone agonists (GnRH agonists)  and  steroidal anti-androgens ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5201", "text": "GnRH  agonists are a group of drugs intended to activate  GnRH receptors  in the anterior pituitary gland. They are synthesized by replacing the sixth and tenth  amino acids  of the original gonadotropin-releasing  peptide  hormone. [ 28 ]  After the modification, they can bind to the GnRH receptors more strongly and are less degradable by enzymes when compared to the natural GnRH, making them more biologically active. [ 28 ] [ 29 ]  GnRH agonists commonly used are  leuprorelin ,  goserelin , and  triptorelin , which are marked as Lupron, Zoladex, and Decapetyl, respectively. [ 30 ]   Nafarelin , marked as Synarel, is also occasionally prescribed in the form of nasal spray. [ 31 ]  These drugs are all approved by the US FDA, and their working principles target both sexes equally."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5202", "text": "This class of drugs initially stimulates the anterior pituitary gland to secrete more GnRH, leading to a temporary surge in GnRH level in the circulation. [ 32 ]  Yet, because of the  desensitization  effect on the receptors upon continuous stimulation, in the long term, its secretion will be inhibited if continual medication is prescribed. [ 28 ] [ 32 ] [ 33 ]  Particularly, GnRH is essential for the release of  gonadotropic hormones , such as LH and  follicle-stimulating hormone (FSH) , from the anterior pituitary-body. These hormones are responsible for the synthesis of steroid sex hormones (testosterone in men;  progesterone  and  estrogen  in women). Therefore, GnRH inhibition by these drugs, in turn, reduces the secretion of steroid sex hormones from the sex organs, eventually leading to libido suppression. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5203", "text": "Many studies have shown that leuprorelin, goserelin and triptorelin are effective in suppressing sexual desires and increasing control against sex. [ 5 ]  Patients who were prescribed with these drugs have sexual thoughts less frequently and strongly. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5204", "text": "Common adverse effects elicited by these drugs include hot flushes, bone loss, headache, unpredictable mood changes, depression, vaginal dryness, or even  atrophy  for females and penile atrophy for males. [ 34 ]  These adverse effects can be counteracted and treated by add-back therapy, also known as  hormone replacement therapy . People treated with GnRH agonists are suggested to undergo this therapy simultaneously by taking adequate  progestin ,  vitamin D , and calcium supplement pills daily. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5205", "text": "Gonadotropin-releasing hormone agonists are largely parenterally administered to the body, that is, via  subcutaneous  or  intramuscular injection . [ 30 ] [ 32 ] [ 35 ] [ 36 ] [ 37 ]  At the same time, nafarelin is an exception in which its prescription is a nasal spray, and some may be implanted into fats. [ 31 ]  In general, their half-lives are approximately two to four hours. [ 31 ] [ 35 ] [ 36 ] [ 37 ]  Some agonists are mainly excreted via urine while other agonists are mainly excreted via faeces. [ 31 ] [ 35 ] [ 36 ] [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5206", "text": "Steroidal anti-androgens are a class of steroid drugs that inhibit the actions of  androgens .  Cyproterone acetate , a  17-hydroxyprogesterone acetate  derivative, is a very potent one and is widely used. [ 29 ]  Though it is not approved by the US FDA owing to its toxicity, it has been approved by Canada and a plethora of countries in Europe with the brand name Androcur in the market. [ 29 ] [ 38 ] [ 39 ]  This drug mainly targets men due to its mechanism of action."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5207", "text": "Cyproterone acetate suppresses libido by directly reducing the level of active androgen,  testosterone , in males. The suppression of testosterone level results from its inhibition of the release of  luteinizing hormone (LH)  from the  anterior section of the pituitary gland , interfering with testosterone production from the testes as LH stimulates testosterone production. [ 32 ] [ 39 ] [ 40 ]  It also blocks the conversion of testosterone to  dihydrotestosterone  for action. [ 38 ] [ 41 ]  In addition to this mechanism, it also competes for the  androgen receptors  against testosterone and dihydrotestosterone, causing interference with the androgen-receptor interaction on the reproductive organ, thereby lowering sexual desire. [ 29 ] [ 38 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5208", "text": "Cyproterone acetate has been proven effective in restraining sexual drive and fantasies in patients with high libido. [ 5 ]  Its usage in treating hypersexuality has been advocated by the World Federation of Societies of Biological Psychiatry (WFSBP). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5209", "text": "Common adverse effects of cyproterone acetate include depression,  hepatotoxicity ,  dyspnea , change in body weight,  hot flushes , sweating, fatigue, and  gynaecomastia. [ 29 ] [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5210", "text": "Cyproterone acetate is mainly orally administered to the body, and it has a  half-life  of 1.8 days. [ 29 ] [ 39 ] [ 42 ]  After  metabolism , its metabolites are predominantly excreted via faeces. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5211", "text": "There are many types of drugs that unintentionally lower sexual desire through indirect mechanisms. It is one of their side-effects as the outcome of libido suppression is not intended. However,  selective serotonin reuptake inhibitors (SSRIs) , being one of them, are indeed often prescribed to people who have immense sexual desire. SSRIs reduce the re-uptake of serotonin back to the neurons, leading to an increase in serotonin level in the body. Due to the fact that serotonin can interfere with other neurotransmitters and hormones, for instance, sex hormones, SSRIs can therefore lower sexual desire. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5212", "text": "Apart from SSRIs, other types of drugs that could lower sexual desire are not intended to suppress libido originally. Thus, sexually active people are suggested to avoid the usage of the following drugs: [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5213", "text": "Postmenopausal women may also suffer from HSDD due to a decline in androgen production from menopause. [ 6 ]  A research proposed two combinations of drugs, each designed against the different causes of HSDD. One combination is to utilise  sublingual   testosterone  with a 5-HT1A receptor agonist to raise motivation for sex, by lifting the inhibition mechanisms in the brain's prefrontal regions. [ 6 ] [ 7 ] [ 8 ]  Testosterone is also proposed to be coupled with the PDE5 inhibitor, targeting an insensitive system for the production of sexual desire. [ 6 ] [ 7 ] [ 8 ]  As both clinical trials showed desirable results, this indicates the prosperity of further developing a single drug targeting HSDD for all women of different status, even though the FDA has not approved the two combinations. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5214", "text": "In fact, HSDD was defined shortly before the release of flibanserin to the market and its approval by the US FDA. This has brought up a controversy about whether it is appropriate and ethical to create a medical condition for the benefit of the sales of pharmaceutical products. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5215", "text": "Apart from this ethical issue, there is a dilemma of whether a medical doctor should prescribe drugs to sexual offenders whose libido is subpar. On the one hand, it is considered unethical for doctors not to treat them as they are expected to treat patients indiscriminately. On the other hand, treating sexual offenders may impose a risk to society. Physicians have been struggling with this dilemma, and it is still difficult for them to make a choice at this moment in time. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5216", "text": "Drugs.com  is an online pharmaceutical encyclopedia that provides drug information for consumers and healthcare professionals, primarily in the United States. It self-describes its information as \"accurate and independent\" yet limited to being \"for educational purposes only and is not intended for medical advice, diagnosis or treatment.\" [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5217", "text": "The Drugs.com website is owned and operated by the Drugsite Trust, a privately held Trust administered by two  New Zealand  pharmacists, Karen Ann and Phillip James Thornton. [ 2 ]  Operated on the  IBM Cloud , Drugs.com provides information on some 24,000 drugs, was visited by 50 million users per month in 2021, and has a  download  time of one second. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5218", "text": "The site contains a library of reference information which includes content from  Cerner Multum ,  Micromedex ,  Truven Health Analytics , U.S.  Food and Drug Administration  (FDA),  AHFS ,  Harvard Health Publications ,  Mayo Clinic , and Animalytics (a  veterinary  products database). [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5219", "text": "Drugs.com is certified by the  TRUSTe  online privacy certification program [ 5 ]  and the HONcode of  Health on the Net Foundation . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5220", "text": "The Drugs.com encyclopedia contains drug information for consumers, a portal for drugs based on diseases, a health professionals database of drug monographs, a  natural products  database, and a poison control center. [ 2 ]  Drugs.com is not affiliated with any  pharmaceutical companies . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5221", "text": "The domain Drugs.com was originally registered by Bonnie Neubeck in 1994. [ 7 ]  In 1999 at the height of the dotcom boom, Eric MacIver purchased an option to buy the domain from Neubeck. [ 8 ]  In August 1999, MacIver sold the domain at auction for US$823,666 to Venture Frogs, a startup incubator run by  Tony Hsieh  and  Alfred Lin , best known for their involvement in  LinkExchange  and later  Zappos.com . [ 9 ]  Venture Frogs sold the Drugs.com domain name to a private investor in June 2001, allowing Hsieh and Lin to focus on Zappos.com. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5222", "text": "The Drugs.com website was officially launched in September 2001. [ 3 ]  In March 2008, Drugs.com announced the release of Mednotes [ 11 ]  \u2014 an online personal medication record application which connected to  Google Health  (On June 24, 2011, Google announced it was retiring Google Health on January 1, 2012). [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5223", "text": "In May 2010, U.S. FDA announced a collaboration with Drugs.com to distribute consumer health updates on the Drugs.com website and mobile platform. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5224", "text": "In February 2016,  comScore  stated that Drugs.com was the sixth most popular health network receiving approximately 23 million visitors for the month, while Searchmetrics listed Drugs.com in the top 100 US websites for search visibility. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5225", "text": "In April 2017,  The Harris Poll  listed Drugs.com as the Health Information Website Brand of the Year. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5226", "text": "Enisamium iodide  is a derivative of  isonicotinic acid . Based on its  systematic chemical name  of  N -benzyl-1-methylpyridin-1-ium-4-carboxamide iodide, the shortened name  carbabenzpiride  is sometimes used. Enisamium iodide is a registered antiviral drug sold in Ukraine,  Kazakhstan ,  Mongolia ,  Belarus , and other  Eastern European  countries under the trade names Amizon, Amizon Max, Amizonchik. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5227", "text": "In 2019, the  World Health Organization  assigned enisamium iodide  ATC code  \u2013 J05AX17 (Antivirals for systemic use of direct action) and included it in the ATC / DDD index. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5228", "text": "The compound enisamium iodide was first synthesized by scientists of the Institute of Pharmacology and Toxicology of the  National Academy of Medical Sciences of Ukraine . [ 3 ]  In 1997, enisamium iodide was registered as a non-narcotic analgesic and antipyretic. However, it is no longer used for these indications. Amizon is marketed as an antiviral drug for the treatment and prevention of influenza and SARS. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5229", "text": "In 2005, Doctor of Medical Sciences, Professor, and a corresponding member of the  National Academy of Sciences  and the National Academy of Medical Sciences of Ukraine, Frolov was the first to demonstrate the antiviral activity of enisamium iodide in in vitro experiments. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5230", "text": "Recent studies have shown that the antiviral effect of enisamium is due to inhibition of viral  RNA  polymerase of influenza virus. [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5231", "text": "Since 2008, the non-clinical program, which included a set of pharmacological, pharmacokinetic and toxicological studies, has been performed in several research institutes and laboratories in  Germany , the  United Kingdom , the  Czech Republic , the  Netherlands ,  Switzerland  and the  United States . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5232", "text": "The antiviral activity of enisamium iodide is associated with inhibition of influenza virus RNA polymerase. Enisamium iodide effectively inhibited SARS-CoV-2 virus replication in vitro in Caco-2 cells."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5233", "text": "Enisamium has antiviral activity against various strains of influenza A (H1N1, H3N2, H5N1, H7N9), influenza B virus, respiratory syncytial virus, as well as strains of alpha-coronavirus NL-63 and beta-coronavirus SARS-CoV-2, etc. In vitro studies using influenza virus-infected normal human bronchial epithelial cells conducted at the Illinois Institute of Technology Research Institute (IITRI), Chicago, USA, showed a decrease in viral titers due to incubation with enisamium iodide (24 FAV00A). year on 3 log (1000 times). In addition, the polymerase chain reaction with reverse transcription revealed suppression of the expression of the M-gene of influenza virus by almost 2 orders of magnitude. [ 8 ] [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5234", "text": "Amizon tablets are indicated for the treatment and prevention of influenza and acute respiratory viral infections. Amizon Max and Amizonchik syrup according to the instructions for medicines are intended for the treatment of influenza and SARS. Amizon Max is also used to treat COVID-19 of moderate severity in combination with basic therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5235", "text": "In 2010, the third phase of clinical trials on the basis of FBDU \"Research Institute of Influenza\" of the Ministry of Health of the Russian Federation (St. Petersburg, Russia) was completed with 100 patients (60 patients with influenza and SARS received enisamium iodide, 40 \u2013 placebo). [ 7 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5236", "text": "In the enisamium iodide group, the mean duration of fever was shown to be 2.7 days, and in the placebo group, 3.8 days. Thus, as a result of taking enisamium iodide, the duration of fever was reduced by an average of 1.1 days. When assessing well-being, a significant improvement on the 3rd day of treatment was noted by 43.3% of patients in the main group and 15% in the control group (p <0.001). On day 7 of treatment, almost all patients (59 out of 60) who received enisamium iodide returned to their usual way of life, while 37.5% of those who took placebo continued to feel unwell and had not yet returned to normal. work and leisure."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5237", "text": "Enisamium was more effective when treatment was started earlier. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5238", "text": "From May 2020 to March 2021, a batotocent clinical placebo-controlled, double-blind, randomized trial of enisamium iodide (Amizon Max) in patients with moderate to severe COVID-19 was conducted at 14 health care facilities in Ukraine. receiving inpatient treatment. [ 12 ] < [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5239", "text": "The results of the clinical trial allowed to include in the instructions for medical use of the drug Amizon Max new indications for use, in particular - the treatment of COVID-19 moderate severity in combination with basic therapy. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5240", "text": "An  exercise mimetic  is a drug that mimics some of the biological effects of physical exercise. Exercise is known to have an effect in preventing, treating, or ameliorating the effects of a variety of serious illnesses, including  cancer ,  type 2 diabetes ,  cardiovascular disease , and psychiatric and neurological diseases such as  Alzheimer's disease . As of 2021, no drug is known to have the same benefits. [ 2 ] [ 3 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5241", "text": "Known biological targets affected by exercise have also been targets of  drug discovery , with limited results. These known targets include: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5242", "text": "The majority of the effect of exercise in reducing cardiovascular and all-cause mortality cannot be explained via improvements in quantifiable risk factors, such as blood cholesterol. This further increases the challenge of developing an effective exercise mimetic. [ 1 ]  Moreover, even if a broad spectrum exercise mimetic were invented, it is not necessarily the case that its public health effects would be superior to interventions to increase exercise in the population. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5243", "text": "Ketamine  has had a wide variety of medicinal and recreational uses since its discovery in 1962."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5244", "text": "Ketamine  is the English  generic name  of the drug and its  INN Tooltip International Nonproprietary Name  and  BAN Tooltip British Approved Name , while  ketamine hydrochloride  is its  USAN Tooltip United States Adopted Name ,  USP Tooltip United States Pharmacopeia ,  BANM Tooltip British Approved Name , and  JAN Tooltip Japanese Accepted Name . [ 1 ] [ 2 ] [ 3 ]  Its generic name in Spanish and  Italian  and its  DCIT Tooltip Denominazione Comune Italiana  are  ketamina , in  French  and its  DCF Tooltip D\u00e9nomination Commune Fran\u00e7aise  are  k\u00e9tamine , in  German  is  Ketamin , and in  Latin  is  ketaminum . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5245", "text": "The  S (+)  stereoisomer  of ketamine is known as  esketamine , and this is its  BAN Tooltip British Approved Name  while  esketamine hydrochloride  is its  BANM Tooltip British Approved Name . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5246", "text": "Ketamine is sold throughout the world primarily under the brand name Ketalar. [ 2 ] [ 3 ]  It is also marketed under a variety of other brand names, including Calypsol, Ketamin, Ketamina, Ketamine, Ketaminol, Ketanest, Ketaset, Tekam, and Vetalar among others. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5247", "text": "Esketamine is sold mainly under the brand names Ketanest, Ketanest-S, and Spravato. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5248", "text": "After the publication of the  NIH -run antidepressant clinical trial, clinics began opening in which the intravenous ketamine is given for depression. [ 5 ] [ 6 ]  This practice is an  off label  use of IV ketamine in the United States, though the intranasal version of esketamine has been approved by the FDA for treatment of depression [ 5 ] [ 7 ]  In 2015 there were about 60 such clinics in the US; the procedure was not covered by insurance, and people paid between $400 and $1700  out of pocket  for a treatment. [ 8 ]  It was estimated in 2018 that there were approximately 300 of these clinics. [ 9 ]  The number of clinics has been increasing rapidly. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5249", "text": "A chain of such clinics in Australia, run by Aura Medical Corporation, was closed down by regulatory authorities in 2015. They found that the clinics' marketing was not supported by scientific research and the chain sent patients home with ketamine and needles to administer infusions to themselves. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5250", "text": "While ketamine is legally marketed in many countries worldwide, [ 2 ]  it is also a  controlled substance  in many countries. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5251", "text": "In Australia, ketamine is listed as a schedule 8-controlled drug under the  Poisons Standard  (October 2015). [ 12 ]  Schedule 8 drugs are outlined in the Poisons Act 1964 as \"Substances which should be available for use but require restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence.\" [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5252", "text": "In Canada, ketamine has been classified since 2005 as a Schedule I narcotic. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5253", "text": "In Hong Kong, since 2000, ketamine has been regulated under Schedule 1 of Hong Kong Chapter 134  Dangerous Drugs Ordinance . It can be used legally only by health professionals, for university research purposes, or with a physician's prescription. [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5254", "text": "By 2002, ketamine was classified as class III in  Taiwan ; given the recent rise of its prevalence in East Asia, however, rescheduling into class I or II is being considered. [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5255", "text": "In December 2013, the  government of India , in response to rising recreational use and the use of ketamine as a date rape drug, has added it to  Schedule X  of the  Drug and Cosmetics Act , requiring a special license for sale and maintenance for two years of records of all sales. [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5256", "text": "In the United Kingdom, it became labeled a  Class C drug  on 1 January 2006. [ 17 ] [ 21 ]  On 10 December 2013, the UK  Advisory Council on the Misuse of Drugs  (ACMD) recommended that the government reclassify ketamine to become a Class B drug. [ 22 ]  On 12 February 2014 the  Home Office  announced it would follow this advice \"in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage\". [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5257", "text": "The UK Minister of State for Crime Prevention,  Norman Baker , responding to the ACMD's advice, said the issue of ketamine's rescheduling for medical and veterinary use would be addressed \"separately to allow for a period of consultation\". [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5258", "text": "Because of the increase in recreational use, ketamine was placed in Schedule III of the United States  Controlled Substance Act  in August 1999. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5259", "text": "Recreational use of ketamine was documented in the early 1970s in underground literature (e.g.,  The Fabulous Furry Freak Brothers ). [ 26 ]  It was used in  psychiatric  and other academic research through the 1970s, culminating in 1978 with the publishing of  psychonaut   John Lilly 's  The Scientist , and  Marcia Moore  and Howard Alltounian's  Journeys into the Bright World , which documented the unusual phenomenology of ketamine intoxication. [ 27 ]  The incidence of non-medical ketamine use increased through the end of the century, especially in the context of  raves  and other parties. [ 28 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ]  Its emergence as a  club drug  differs from other club drugs (e.g.,  MDMA ), however, due to its  anesthetic  properties (e.g., slurred speech, immobilization) at higher doses; [ 32 ]  in addition, reports are common of ketamine being sold as \"ecstasy\". [ 33 ]  In the 1993 book  E for Ecstasy [ 34 ]  (about the uses of the street drug  Ecstasy  in the UK), the writer, activist, and ecstasy advocate  Nicholas Saunders  highlighted test results showing that certain consignments of the drug also contained ketamine. Consignments of ecstasy known as \"strawberry\" contained what Saunders described as a \"potentially dangerous combination of ketamine,  ephedrine , and  selegiline \", as did a consignment of \"Sitting Duck\" ecstasy tablets. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5260", "text": "The use of ketamine as part of a \"post-clubbing experience\" has also been documented. [ 36 ]  Ketamine's rise in the dance culture was most rapid in Hong Kong by the end of the 1990s. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5261", "text": "Ketamine use as a recreational drug has been implicated in deaths globally, with more than 90 deaths in England and Wales in the years of 2005\u20132013. [ 37 ]  They include accidental poisonings, drownings, traffic accidents, and suicides. [ 37 ]  The majority of deaths were among young people. [ 38 ]  This has led to increased regulation (e.g., upgrading ketamine from a Class C to a Class B banned substance in the U.K.). [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5262", "text": "Unlike the other well-known dissociatives  phencyclidine  (PCP) and  dextromethorphan  (DXM), ketamine is very short-acting. It takes effect within about 10 minutes, [ 40 ]  while its  hallucinogenic  effects last 60 minutes when  insufflated  or injected, and up to two hours when ingested orally. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5263", "text": "At subanesthetic doses\u2014under-dosaged from a medical point of view\u2014ketamine produces a  dissociative state , characterised by a sense of detachment from one's physical body and the external world which is known as  depersonalization  and  derealization . [ 42 ]  At sufficiently high doses, users may experience what is called the \"K-hole\", a state of dissociation with visual and auditory hallucinations. [ 43 ]   John C. Lilly ,  Marcia Moore ,  D. M. Turner  and  David Woodard  (amongst others) have written extensively about their own  entheogenic  use of, and  psychonautic  experiences with, ketamine. [ 44 ]  Turner died prematurely due to drowning during presumed unsupervised ketamine use. [ 45 ]  In 2006 the Russian edition of  Adam Parfrey 's  Apocalypse Culture II  was banned and destroyed by authorities owing to its inclusion of an essay by Woodard about the entheogenic use of, and psychonautic experiences with, ketamine. [ 46 ] :\u200a288\u2013295"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5264", "text": "Because of its ability to cause confusion and  amnesia , ketamine has been used for  date rape . [ 40 ] [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5265", "text": "Production for recreational use has been traced to 1967, when it was referred to as \"mean green\" and \"rockmesc\". [ 48 ]  Recreational names for ketamine include \"Special K\", [ 49 ]  \"K\", [ 50 ] [ 49 ]  \"Kitty\", \"Ket\", [ 51 ]  \"K2\", [ 50 ]  \"Vitamin K\", [ 49 ] [ 51 ]  \"Super K\", [ 49 ]  \"Jet\", [ 49 ] [ 52 ]  \"Super acid\", [ 49 ]  \"Mauve\", [ 49 ]  \"Special LA coke\", [ 49 ]  \"Purple\", [ 49 ]  \"Cat Valium\", [ 52 ] [ 53 ]  \"Keller\", [ 53 ]  \"Kelly's Day\", [ 53 ]  \"New ecstasy\", [ 54 ]  \"Psychedelic heroin\", [ 54 ]  \"bump\", [ 55 ]  \"Majestic\". [ 56 ]  A mixture of ketamine with  cocaine  is called \"Calvin Klein\" or \"CK1\". [ 57 ]  In Hong Kong, where illicit use of the drug is popular, ketamine is colloquially referred to as \"kai-jai\". [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5266", "text": "According to the ongoing  Monitoring the Future  study conducted by  University of Michigan , prevalence rates of recreational ketamine use among American secondary school students (grades 8, 10, and 12) have varied between 0.8 and 2.5% since 1999, with recent rates at the lower end of this range. [ 58 ]  The  2006  National Survey on Drug Use and Health  (NSDUH) reports a rate of 0.1% for persons ages 12 or older with the highest rate (0.2%) in those ages 18\u201325. [ 59 ]  Further, 203,000 people are estimated to have used ketamine in 2006, and an estimated 2.3 million people used ketamine at least once in their life. [ 59 ]  A total of 529 emergency department visits in 2009 were ketamine-related. [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5267", "text": "In 2003, the U.S.  Drug Enforcement Administration  conducted  Operation TKO , a probe into the quality of ketamine being imported from Mexico. [ 61 ]  As a result of operation TKO, U.S. and Mexican authorities shut down the Mexico City company Laboratorios Ttokkyo, which was the biggest producer of ketamine in Mexico. According to the DEA, over 80% of ketamine seized in the United States is of Mexican origin. As of 2011, it was mostly shipped from places like India, as cheap in cost as $5/gram. [ 61 ]  The  World Health Organization  Expert Committee on Drug Dependence, in its thirty-third report (2003), [ 62 ]  recommended research into ketamine's recreational use due to growing concerns about its rising popularity in Europe, Asia, and North America."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5268", "text": "Cases of ketamine use in club venues have been observed in the Czech Republic, France, Italy, Hungary, The Netherlands, and the United Kingdom. [ 63 ]  Additional reports of use and dependence have been reported in Poland and Portugal. [ 64 ] [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5269", "text": "Australia's  2019 National Drug Strategy Household Survey report  shows a prevalence of recent ketamine use of 0.3% in 2004, 0.2% in 2007 and 2010, 0.4% in 2016 and 0.9% in 2019 in persons aged 14 or older. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5270", "text": "In China, the small village of  Boshe  in eastern Guangdong was confirmed as a main production centre in 2013 when it was raided. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5271", "text": "Established by the Hong Kong Narcotics Division of the  Security Bureau , the Central Registry of Drug Abuse (CRDA) maintains a database of all the illicit drug users who have come into contact with law enforcement, treatment, health care, and social organizations. The compiled data are confidential under  The Dangerous Drugs Ordinance  of Hong Kong, and statistics are made freely available online on a quarterly basis. [ 68 ] [ 69 ]  Statistics from the CRDA show that the number of ketamine users (all ages) in Hong Kong has increased from 1605 (9.8% of total drug users) in 2000 to 5212 (37.6%) in 2009. [ 70 ]  Increasing trends of ketamine use among illicit drug users under the age of 21 were also reported, rising from 36.9% of young drug users in 2000 to 84.3% in 2009. [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5272", "text": "A survey conducted among school-attending Taiwanese adolescents reported prevalence rates of 0.15% in 2004, 0.18% in 2005, and 0.15% in 2006 in middle-school (grades 7 and 9) students; in Taiwanese high-school (grades 10 and 12) students, prevalence was 1.13% in 2004, 0.66% in 2005, and 0.44% in 2006. [ 71 ]  From the same survey, a large portion (42.8%) of those who reported ecstasy use also reported ketamine use. [ 71 ]  Ketamine was the second-most used  illicit drug  (behind ecstasy) in absconding Taiwanese adolescents as reported by a multi-city street outreach survey. [ 72 ]  In a study comparing the reporting rates between web questionnaires and paper-and-pencil questionnaires, ketamine use was reported a higher rate in the web version. [ 73 ]  Urine samples taken at a club in Taipei, Taiwan, showed high rates of ketamine use at 47.0%; this prevalence was compared with that of detainees suspected of recreational drug use in the general public, of which 2.0% of the samples tested positive for ketamine use. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5273", "text": "In the late 2010s and early 2020s, law enforcement agencies in some U.S. states began directing paramedics to use ketamine to sedate people under arrest, sometimes under the auspices of treatment for the controversial diagnosis \" excited delirium \". [ 75 ] [ 76 ] [ 77 ] [ 78 ] [ 79 ] [ 80 ]  The  American Society of Anesthesiologists  and  American College of Emergency Physicians  oppose the use of ketamine or any similar agent to incapacitate someone solely for a law enforcement purpose. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5274", "text": "The  Korea Oriental Instant Medicinal Centre ( Korean :  \uc870\uc120\ub3d9\ubc29\uc989\ud6a8\uc131\uc57d\ubb3c\uc13c\ud130 or \uc870\uc120\ub3d9\ubc29\uc989\ud6a8\uc57d\ubb3c\uac1c\ubc1c\uc0ac )  is a state-owned  North Korean   pharmaceutical company  founded in 1968. [ 1 ]  It is best known for selling  Neo-Viagra-Y.R. , an alleged  traditional Korean (Koryo)  medical supplement, [ 2 ] [ 3 ]  whose  active ingredient  is 50 mg of  Sildenafil  (Viagra), combined with Korean herbal medicines. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5275", "text": "This article about a North Korean company is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5276", "text": "This article about a  medical ,  pharmaceutical  or  biotechnological  corporation or company is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5277", "text": "Kumdang-2  is a cure for  AIDS ,  Ebola ,  MERS , and  tuberculosis  created in  North Korea . [ 1 ]  According to the website Minjok Tongshin, a version of the drug was originally produced in 1996. [ 2 ]  The name means \"golden shower\" in Korean. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5278", "text": "It is manufactured by the  Pugang Pharmaceutical Company . [ 4 ]  According to the  Korean Central News Agency , the drug's ingredients include  ginseng , small amounts of rare earth metals, [ 5 ]  and trace amounts of  gold  and  platinum . [ 6 ]  According to the KCNA, it can also cure cancer, morning sickness, and \"harm from the use of computers\". [ 7 ]  The drug was mentioned during the deadly  bird flu  outbreaks in 2006 and 2013. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5279", "text": "According to the chemical analysis by the South Korean  National Forensic Service , Kumdang-2 turned out to be mostly made of the anesthetic  Procaine . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5280", "text": "1EMR ,  1PVH ,  2Q7N"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5281", "text": "3976"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5282", "text": "16878"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5283", "text": "ENSG00000128342"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5284", "text": "ENSMUSG00000034394"}
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{"_id": "WikiPedia_Pharmacology$$$corpus_5286", "text": "P09056"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5287", "text": "NM_001257135 NM_002309"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5288", "text": "NM_001039537 NM_008501"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5289", "text": "NP_001244064 NP_002300"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5290", "text": "NP_001034626 NP_032527"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5291", "text": "Leukemia inhibitory factor , or  LIF , is an  interleukin 6  class  cytokine  that affects  cell  growth by inhibiting differentiation. When LIF levels drop, the cells differentiate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5292", "text": "LIF derives its name from its ability to induce the terminal  differentiation  of  myeloid leukemic  cells, thus preventing their continued growth. Other properties attributed to the cytokine include: the growth promotion and cell differentiation of different types of target cells, influence on  bone   metabolism ,  cachexia ,  neural development ,  embryogenesis  and  inflammation .  p53  regulated LIF has been shown to facilitate  implantation  in the mouse model and possibly in humans. [ 5 ]  It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5293", "text": "LIF binds to the specific LIF  receptor  ( LIFR -\u03b1) which forms a  heterodimer  with a specific subunit common to all members of that family of receptors, the  GP130  signal transducing subunit. This leads to activation of the  JAK / STAT  (Janus kinase/ signal transducer  and activator of  transcription ) and  MAPK  ( mitogen  activated  protein   kinase )  cascades . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5294", "text": "LIF is normally expressed in the  trophectoderm  of the developing embryo, with its receptor LIFR expressed throughout the  inner cell mass . As embryonic stem cells are derived from the inner cell mass at the blastocyst stage, removing them from the inner cell mass also removes their source of LIF. Recombinant LIF has been produced in plants by InVitria."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5295", "text": "LIF is often added to stem cell culture media as an alternative to feeder cell culture, due to the limitation that feeder cells present by only producing LIF on their cell surfaces. Feeder cells lacking the LIF  gene  do not effectively support stem cells. [ 7 ]  LIF promotes self-renewal by recruiting signal transducer and activator of transcription 3 ( Stat3 ). Stat3 is recruited to the activated LIF receptor and phosphorylated by  Janus kinase . It bears noting that LIF and Stat3 are not sufficient to inhibit stem cell differentiation, as cells will differentiate upon removal of serum. During the reversibility phase of differentiation from naive pluripotency, it is possible to revert cells back to naive pluripotency through the addition of LIF. [ 8 ] \nRemoval of LIF pushes stem cells toward  differentiation , however genetic manipulation of embryonic stem cells allows for LIF independent growth, notably overexpression of the gene  Nanog ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5296", "text": "LIF is typically added to stem cell culture medium to reduce spontaneous differentiation. [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5297", "text": "Lifestyle drug  is an imprecise term commonly applied to  medications  which treat non\u2013life-threatening and non-painful conditions such as  baldness ,  wrinkles ,  erectile dysfunction , or  acne , which the speaker perceives as either not medical problems at all or as minor medical conditions relative to others. It is sometimes intended as a pejorative, bearing the implication that the scarce medical research resources allocated to develop such drugs were spent frivolously when they could have been better spent researching cures for more serious medical conditions. Proponents, however, point out that improving the patient's subjective quality of life has always been a primary concern of  medicine , and argue that these drugs are doing just that. It finds broad use in both media and scholarly journals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5298", "text": "There is direct impact of lifestyle drugs on society, particularly in the developing world. Implications associated with labeling of indications and products sales of these lifestyle drugs may be varied. Drugs can, over time, switch from 'lifestyle' to 'mainstream' use. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5299", "text": "Though no precise widely accepted definition or criteria are associated with the term, there is much debate within the fields of  pharmacology  and  bioethics  around the propriety of developing such drugs, particularly after the commercial debut of  Viagra ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5300", "text": "The German government's health insurance scheme has denied insurance coverage for some  Lifestyle-Medikament  (\"lifestyle drugs\") which they deem spurious. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5301", "text": "Critics of pharmaceutical firms claim that pharmaceutical firms actively  medicalize ; that is, they invent novel  disorders  and  diseases  which were not recognized as such before their \"cures\" could be profitably marketed, in effect pathologizing what were widely regarded as normal conditions of human existence. The consequences are said to include generally greater worries about health, misallocation of limited medical research resources to comparatively minor conditions while many serious diseases remain uncured, and needless health care expenditure. This  medicalization  of some element of human condition has significance, in principle, as a matter for  political discourse  or  dialogue  in  civil society  concerning  values or morals . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5302", "text": "Social critics also question the propriety of devoting huge research budgets towards creating these drugs when far more dangerous diseases like  cancer  and  AIDS  remain uncured. It is sometimes claimed that lifestyle drugs amount to little more than medically sanctioned  recreational drug use . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5303", "text": "The term \" me-too drug \" or \" follow-on drug \" refers to a medication that is  similar  to a  pre-existing drug , usually by making minor modifications to the prototype, reflected in slight changes in the profiles of  side effects  or  activity , and used to treat conditions for which drugs already exist. [ 1 ] [ 2 ]  While pharmaceutical companies have justified the development of me-toos as offering incremental improvements in efficacy, side-effects, compliance and cost, critics have questioned the increasing  marketing  of me-toos, their absorption of  research and development  resources and their impact on the innovation of new treatments. [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5304", "text": "In 1956,  Louis S. Goodman , co\u2010editor of  Goodman and Gilman , referred to \u201cthe problem of the introduction of \u2018me too\u2019 drugs, that is, drugs without signal advantage of any sort\u201d. [ 1 ]  However, me-too drugs can be novel compounds themselves. [ 3 ] [ 6 ]  They are commonly used and include several  beta blockers ,  antidepressants  and  stomach acid reducing  and  cholesterol lowering  drugs. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5305", "text": "The term \"me\u2010too drugs\" was coined in the 1950s. In 1956,  Louis S. Goodman , co\u2010editor of  Goodman and Gilman , referred to \u201cthe problem of the introduction of \u2018me too\u2019 drugs, that is, drugs without signal advantage of any sort\u201d. [ 1 ]  Once a new drug class was discovered, other major drug companies made efforts to produce their own similar versions. Pharmacologist  Milton Silverman  and physician  Philip R. Lee  noted \"the great drug therapy era was marked not only by the introduction of new drugs in great profusion and by the launching of large promotional campaigns but also by the introduction of what are known as 'duplicative' or 'me-too' products\". [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5306", "text": "Between 1960 and 1962,  Estes Kefauver , then Senator of Tennessee, led a series of hearings enquiring about the pharmaceutical industry's motive to produce me-too drugs after it was noted that much of their time and resources were spent producing them. Subsequently, the FDA required drug companies to prove their drugs were safe and effective. [ 7 ]  In 1964,  Louis Lasagna  described me-too drugs as being \u201chard to justify putting into man at all, let alone on the market\u201d. [ 1 ]  Three years later, the term appeared in the  Oxford English Dictionary . [ 1 ]  In the early 1970s, Silverman and Lee reported that there were almost 100  tranquillisers , 130  antihistamines , greater than 270  antibiotics  and more than 200  sulfonamides . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5307", "text": "In 1994,  Desmond Laurence's  textbook  Clinical Pharmacology  referred to me-too as \"me-again\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5308", "text": "There is no agreed definition, however, several have been proposed, [ 1 ]  including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5309", "text": "Biosimilars  are compared with other biosimilars and are therefore not me-toos. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5310", "text": "Me-too drugs include  diazepam ,  ranitidine  and  esketamine . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5311", "text": "The first-in-class \u03b2-blocker pronethalol was developed by  James Black  at  ICI Pharmaceuticals . It was followed by  propranolol ,  sotalol ,  practolol ,  metoprolol ,  labetalol ,  acebutolol  and  bisoprolol . Successive differences between \u03b2-blockers have had a combined cumulative effect and are seen as \"innovative\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5312", "text": "15  benzodiazepines  were marketed in the UK between 1960 and 1982, of which seven were produced by Roche. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5313", "text": "The  proton-pump inhibitor   Nexium  by  AstraZeneca  is a me-too which was granted its patent by showing that it was effective for heartburn, not that it was better than its precursor,  Prilosec . [ 10 ]  It was shown to preserve revenues of Prilosec, whose U.S. patent expired in 2001. Considered a new drug by the FDA, Nexium was patented separately, sold for eight times the cost of its  generic   esomeprazole  and advertised as significantly better than its predecessor, a move the company received much criticism for, with a subsequent class action lawsuit filed against them. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5314", "text": "Both  Tagamet 's and  Zantac 's prices increased following the arrival of further me-too drugs  Pepcid  and  Axid . [ 4 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5315", "text": "Several me-toos followed the prototype of the  ace inhibitor ,  captopril , with  enalapril  being its first me-too. [ 1 ]  Most were as efficient as each other and had similar adverse effect profiles. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5316", "text": "When Merck's cholesterol-lowering statin Mevacor ( lovastatin ) was approved by the U.S.  Food and Drug Administration  (FDA) in 1987, the understanding of the link between cholesterol and heart disease was improving, and the potential market for the drug became significant. Subsequently, several other companies developed similar drugs: Merck developed Zocor ( simvastatin ) and Crestor ( rosuvastatin ),  Pfizer  developed Lipitor ( atorvastatin ),  Bristol-Myers Squibb  developed Pravachol ( pravastatin ), and  Novartis  developed Lescol ( fluvastatin ). [ 13 ] [ 14 ] [ 15 ]  Others include  pitavastatin  (Livalo). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5317", "text": "Imipramine  was the first-in-class of the tricyclic antidepressants.  Amitriptyline ,  Nortriptyline ,  Dosulepin  and  Doxepin  are some of the me-toos that followed. [ 1 ]  Several me-too  Selective serotonin reuptake inhibitors  have been developed for maintenance treatment in chronic depression. These include Paxil ( paroxetine ), Celexa ( citalopram ), Zoloft ( sertraline ), Lexapro ( escitalopram ) and Prozac ( fluoxetine ). [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5318", "text": "For example, Celexa is a mixture of a left-handed and right-handed version of the same compound (\"citalopram\"), but only the left-handed version (\"es-citalopram\") is biologically active. Lexapro, the \"me too\" drug released several years after Celexa thus extending the patent life, is a purified form of just the left-handed version (the \"es\" in \"es-citalopram\"). [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5319", "text": "Gilead Science's  Descovy  is a me-too drug of  Truvada , a popular Antiretroviral also used to prevent HIV infection in healthy people. Both versions are  prodrugs  that metabolize into the same active compound. Gilead has been accused in lawsuits of \"slow walking\" the development of the me-too drug; [ 18 ]  however, such lawsuits further a market perception the me-too drug is \"safer.\" This drives sales of the more expensive me-too drug when both drugs have virtually identical safety profiles. Similarly,  Valtrex , first FDA approved in 2001 to treat persistent herpes outbreaks is a prodrug of  acyclovir , first FDA approved in the mid-1980s. Valtrex metabolizes into acyclovir in the liver, [ 19 ]  but when it first entered the market, it cost many times than the generic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5320", "text": "In 2005, a report by the  International Policy Network  defended me-toos, describing their development as \"incremental improvements on already existing drugs\". [ 20 ]  The report stated:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5321", "text": "... this often represent(s) advances in safety and efficacy, along with providing new formulations and dosing options that significantly increase patient compliance. From an economic standpoint, expanding drug classes represent the possibility of lower drug prices as competition between manufacturers is increased. Additionally, pharmaceutical companies depend on incremental innovations to provide the revenue that will support the development of more risky \u201cblock-buster\u201d drugs. Policies aimed at curbing incremental innovation will ultimately lead to a reduction in the overall quality of existing drug classes and may ultimately curb the creation of novel drugs. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5322", "text": "This incremental innovation has led to some referring to me-toos as \"me-betters\". [ 14 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5323", "text": "Many physicians are unaware that me-toos are compared to placebos rather than pre-existing drugs. [ 22 ]  Me-toos are seen as patentable new drugs and therefore substantial profit makers, where innovative drugs may be more risky to develop. [ 13 ] [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5324", "text": "Between 1998 and 2003, the U.S. Food and Drug Administration (FDA) approved 487 drugs, of which 78 per cent appeared to have similar characteristics to pre-existing marketed drugs. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5325", "text": "More than 60% of medicines listed on the World Health Organization's essential list are me\u2010too drugs. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5326", "text": "In September 2019, half of  antibiotics  under clinical development were \u201cme-too\u201d drugs. At the beginning of 2020, the WHO stated that only two of the 50 antibiotics in clinical development are active against serious drug resistant gram-negative bacteria, and most are not significant \"upgrades\" of drugs. [ 26 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5327", "text": "Medication discontinuation  is the ceasing of a  medication  treatment for a patient by either the  clinician  or the patient themself. [ 1 ] [ 2 ]  When initiated by the clinician, it is known as  deprescribing . [ 3 ]  Medication discontinuation is an important medical practice that may be motivated by a number of reasons: [ 4 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5328", "text": "Unlike the prescribing of medications, appropriate discontinuation has not attracted nearly as much attention or interest. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5329", "text": "Medications may be stopped in the context of  end-of-life care , such as medications that may affect  risk factors  for future disease. Medications that may be stopped as part of discussions about end-of-life care include  antihypertensives , medications for  diabetes , and drugs for  high cholesterol . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5330", "text": "For people with a life-shortening or  terminal illness , such as a dementia, it is important to consider when to discontinue medications used to prevent future serious events.  The  Medication Appropriateness Tool for Comorbid Health conditions during Dementia  ( MATCH-D ) provides guidance for clinicians and consumers on how to manage medications. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5331", "text": "Drug discontinuation may cause  rebound effects  (return of the symptoms the drug relieved, and that, to a degree stronger than they were before treatment first began) and  withdrawal syndromes  (symptoms caused by the discontinuation by the drug itself)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5332", "text": "Drug discontinuation may be difficult to adjust to, owing to the long term use and the symbolism associated with ceasing medications, such as the decision to stop  chemotherapy . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5333", "text": "Recent research (Nixon & Vendel\u00f8, 2016) shows that General Practitioners (GPs) who actively consider discontinuation, are reluctant to do so, as they experience that the safest decision is to continue prescriptions, rather than discontinue them. In part this is due to the ambiguity about the appropriateness of discontinuing medication. The clinical guidelines available to GPs do not encourage discontinuation of medication, and thus, they offer GPs a weak frame for discontinuation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5334", "text": "Withdrawal of anti-hypertensive drugs in older people"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5335", "text": "The latest evidence does not have evidence of an effect due to discontinuing vs continuing medications used for treating elevated blood pressure or prevention of heart disease in older adults on all-case mortality and incidence of heart attack. [ 8 ]  The findings are based on low quality evidence suggesting it may be safe to stop anti-hypertensive medications. However, older adults should not stop any of their medications without talking to a healthcare professional. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5336", "text": "Membrane-mediated  anesthesia  or anaesthesia (UK) is a  mechanism of action  that involves an  anesthetic agent  exerting its  pharmaceutical  effects primarily through interaction with the  lipid bilayer membrane ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5337", "text": "The relationship between  volatile  ( inhalable )  general anesthetics  and the cellular  lipid  membrane has been well established since around 1900, based on the  Meyer-Overton Correlation . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  Since 1900 there have been extensive research efforts to characterize these membrane-mediated  effects  of anesthesia, leading to many  theories  but few answers. During the 1980s the focus of anesthetic research shifted from  membrane lipids  to  membrane proteins , [ 5 ] [ 6 ] [ 7 ]  where it currently remains. [ 8 ] [ 9 ] [ 10 ] [ 11 ]  Accordingly, the specific membrane-mediated anesthetic effects remain mostly undiscovered. [ 9 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5338", "text": "Recent research has demonstrated promising mechanisms of membrane- mediated  anesthetic action for both  general  and  Local anesthetics . These studies suggest that  t he anesthetic  binding site  in the membrane is within ordered lipids. This  binding  disrupts the function of the ordered lipids, forming  lipid rafts  that dislodge a membrane-bound  phospholipase  involved in a  metabolic pathway  that actives anesthetic-sensitive  potassium channels . [ 15 ] [ 16 ] [ 17 ]  Other recent studies show similar lipid-raft-specific anesthetic effects on  sodium channels . [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5339", "text": "See  Theories of general anaesthetic action  for a broader discussion of purely theoretical mechanisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5340", "text": "At the turn of the twentieth century, one of the most important anesthetic-based  theories  began to take shape. At the time, the research of both German  pharmacologist   Hans Horst Meyer  (1899) [ 1 ]  and British-Swedish  physiologist   Charles Ernest Overton  (1901) [ 2 ]  reached the same conclusion about  general anesthetics  and  lipids :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5341", "text": "There is a direct  correlation  between  anesthetic agents  and lipid  solubility . The more  lipophillic   the anesthetic  agent  is, the more  potent  the anesthetic agent is. [ 3 ] [ 8 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5342", "text": "This principle became known as the  Meyer-Overton Correlation . It originally compared the anesthetic  partition coefficient  in  olive oil  (X-axis) to the  effective dose  that induced anesthesia in 50% (i.e.,  EC50 ) of the  tadpole   research  subjects (Y-axis). [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Modern renditions of the Meyer-Overton  plot  usually compare olive oil partition coefficent of the  Inhalational  or  Intravenous   drug  ( X-axis ) to the  minimum alveolar concentration  (MAC) or the  effective dose  50 (i.e., ED50) of the anesthetic agent ( Y-axis ). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5343", "text": "Despite more than 175 years of  anesthetic  use and research, the exact connection between  phospholipids , the  bilayer membrane , and  general anesthetic agents  remains mostly unknown. [ 4 ] [ 9 ] [ 10 ]  Accordingly, the means of membrane-mediated anesthesia remain mostly theoretical. [ 4 ] [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5344", "text": "The Lateral Pressure Profile theory suggests that anesthetic agents partition into the  lipid bilayer , increasing the horizontal ( lateral )  pressure  on  proteins  imbedded in the membrane. The added pressure causes a  conformational change  in  protein structure , forcing the  neuronal   channel  into an open or closed  state  (e.g.,  hyperpolarization ) that generates the  Inhibitory  state of  general anesthesia  in the  central nervous system  (CNS). [ 20 ] [ 21 ] [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5345", "text": "This is the first hypothesis to explain the correlations of anesthetic potency with lipid bilayer  structural characteristics , describing both  mechanistic  and  thermodynamic  rationale for the effects of general anesthesia. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5346", "text": "Inhaled anesthetics  partition into the membrane and disrupt the function of ordered lipids. [ 15 ]  Membranes, like proteins, are composed of ordered and disordered regions. [ 14 ]  The ordered region of the membrane contains a  palmitate  binding site that drives the association of  palmitoylated  proteins to clusters of GM1 lipids (sometimes referred to as  lipid rafts ). Palmitate's binding to lipid rafts regulates the affinity of most proteins to lipid rafts. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5347", "text": "Inhaled anesthetics partition into the lipid membrane and disrupt the binding of palmitate to GM1 lipids (see figure). The anesthetic binds to a specific palmitate site nonspecifically. The clusters of GM1 lipids persist, but they lose their ability to bind palmitoylated proteins. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5348", "text": "Phospholipase D2 (PLD2) is a palmitoylated protein that is activated by  substrate presentation . [ 24 ]  Anesthetics cause PLD2 to move from GM1 lipids, where it lacks access to its substrate, to a  PIP2 domain  which has abundant PLD2 substrate. [ 23 ]  Animals with genetically depleted PLD2 were significantly resistant to anesthetics. The anesthetics xenon, chloroform, isofluorane, and propofol all activate PLD in cultured cells."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5349", "text": "Twik-related potassium channel ( TREK-1 ) is localized to ordered lipids through its interaction with PLD2. Displacement of the complex from GM1 lipids causes the complex to move to clusters. The product of PLD2,  phosphatidic acid  (PA) directly activates TREK-1. [ 25 ]  The anesthetic sensitivity of TREK-1 was shown to be through PLD2, and the sensitivity could be transferred to TRAAK, an otherwise anesthetic insensitive channel. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5350", "text": "The membrane mediated mechanism is still being investigated. Nonetheless, the GABAAR gamma subunit is palmitoylated and the alpha subunit binds to PIP2. When the agonist GABA binds to GABAAR it causes a translocation to thin lipids near PIP2. [ 26 ]  Anesthetic disruption of  Palmitate mediated localization  should therefore cause the channel to move the same as an agonist, but this has not yet been confirmed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5351", "text": "Endocytosis helps regulate the time an ion channel spends on the surface of the membrane. GM1 lipids are the site of endocytosis. The anesthetics hydroxychloroquine,  tetracaine , and  lidocaine  blocked entry of palmitoylated protein into the endocytic pathway. [ 27 ]  By blocking access to GM1 lipids, anesthetics block access to endocytosis through a membrane-mediated mechanism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5352", "text": "Local anesthetics disrupt ordered lipid domains and this can cause PLD2 to leave a lipid raft. [ 16 ]  They also disrupt protein interactions with PIP2. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5353", "text": "More than 100 years ago, a unifying theory of anesthesia was proposed based on the oil partition coefficient. In the 70s this concept was extended to the disruption of lipid partitioning. [ 28 ]  Partitioning itself is an integral part of forming the ordered domains in the membrane, and the proposed mechanism is very close to the current thinking, but the partitioning itself is not the target of the anesthetics. At clinical concentration, the anesthetics do not inhibit lipid partitioning. [ 15 ]  Rather they inhibit the order within the partition and/or compete for the palmitate binding site. Nonetheless, several of the early conceptual ideas about how disruption of lipid partitioning could affect an ion channel have merit."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5354", "text": "Occupational health concerns over the use of cannabis among workers are becoming increasingly important as cannabis becomes legal in more areas of the US. [ 1 ] [ 2 ]   [1]   Of note, employers have concerns of workers either coming to work acutely impaired or recent use of cannabis still being detected in the body. Employment issues such as  ADA  law as it relates to accommodations for cannabis, paying unemployment benefits or paying out workers compensation benefits and disability claims are all important issues. While federal law still prohibits use, employers in different states have taken different stances based on whether they are federal contractors, perform safety sensitive work or whether the cannabis use is acutely impairing the employee."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5355", "text": "Cannabis  is currently the most commonly used illicit drug in the world and one of the earliest plants cultivated by humans. Early evidence of cannabis use in medicine has been found in China and India for religious and medicinal uses. Archaeological research shows early civilization cultivation of hemp in India to create a variety of products from ropes, textiles and paper. In countries, such as  Nepal  and  China , cannabis seeds are still used today both as a pharmaceutical as well as a food enhancer. [ 3 ]  Lack of concentration, impaired learning and memory, alterations in thought formation, expression and sedation have been associated with cannabis use. Physiological signs include  tachycardia , dilated pupils with injected  conjunctiva , dry mouth and increased appetite Studies have also confirmed that impairment is related on a dose response relationship."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5356", "text": "As cannabis use increases and more states  legalize use in the US , there are concerns surrounding the use of cannabis and its effects on job performance and safety. [2]  There are also concerns that the concentration of  THC  have increased over the past 50 years, thereby increasing the effects of the drug. [ 4 ]  The  Controlled Substances Act  of 1970 currently lists cannabis as a Schedule 1 drug, deeming it to be a substance with high risk of dependence, abuse and no (supervised) medical uses. The  CATO  institute estimates that legalizing drugs would save $41 billion per year along with $46.7 billion in revenue, if taxed at the same rates as alcohol and tobacco. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5357", "text": "Employers and employees have faced new challenges in the workplace with the increasing legislation of cannabis. State law can have provisions, for an employer to refuse to hire based on marijuana use, under the concern of safety, productivity and company reputation. Companies that have \u201c safety sensitive work \u201d or include operating machinery or large vehicles are also free to institute a zero-tolerance policy for its employees. For the approximate 10 million  CDL  (Commercial Drivers Licenses) drivers in the USA, federal law requires they pass employer drug tests under the Omnibus Transportation Employee Safety Act of 1991."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5358", "text": "Individual states in response to the federal government differed in how they dealt with cannabis. California was the first state to pass medical marijuana in 1996, followed by 23 other states currently permitting the use of medical marijuana."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5359", "text": "In the case of U.S. v. Stacey among several others, the legality of cannabis use has been contested since citizens who argue for protection under state law, are always subject to federal charges [ 6 ]  While there has been some guidance from the Department of Justice to the DEA to reassess its priorities in the drug war and to target larger threats and substances, the interpretation is still subjective and has not prevented large scale raids on medical marijuana facilities across the country. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5360", "text": "California was the first state to pass medical marijuana in 1996, followed by 23 other states currently permitting the use of medical marijuana [ 7 ]  For the states that have legalized medical marijuana, employees and employers have had to face new challenges in the workplace. State law can have provisions, for an employer to refuse to hire based on marijuana use, under the concern of safety, productivity and company reputation. Companies that have a lot of \u201csafety sensitive work\u201d or include operating machinery or large vehicles are also free to institute a zero-tolerance policy for its employees. For the approximate 10 million CDL ( Commercial Drivers Licenses ) drivers in the USA, federal law requires they pass employer drug tests under the  Omnibus Transportation Employee Safety Act  of 1991."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5361", "text": "Drivers that use cannabis show impairment both in simulator and on the road tests, mainly on the abilities to \u201c..concentrate and maintain attention, estimate time and distance, and demonstrate coordination on divided attention tasks\u2014all important requirements for operating a motor vehicle\u201d [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5362", "text": "The Department of Transportation (DOT) has also stated in its Drug and Alcohol Testing Regulations that cannabis is not acceptable for any employee engaged in safety sensitive work. Currently, there are federal laws that give employers guidance and protection on how to ensure a drug free workplace despite the increase in cannabis use. According to the  National Association of Attorneys General  (NAAG), in Colorado the number of positive drug tests for marijuana went up by 20% between 2012-2013, compared to the national average increase of 5% [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5363", "text": "For those companies that have received federal grants and have federal contracts over $100,000, they follow  The Drug Free Workplace Act  of 1988, a comprehensive policy, which includes drug prevention methods, information about employee assistance programs and disciplinary consequences of drug use in the workplace [ 9 ]  Federal agencies are required to use the Substance Abuse and Mental health Services Administration ( SAMHSA ) procedures for testing and recommend private employers use the same criteria for consistency. [ 10 ]   The policy requires employees to report any criminal drug violations in the workplace to the employer within 5 calendar days which may subsequently result in discipline including termination, regardless of state law. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5364", "text": "The  Occupational and Safety Act of 1970  includes a  general duty clause  for employers to protect employees from exposure for those compounds with no regulated standards of safe exposure. It has been defined broadly as to \u201cmaintain conditions or adopt practices reasonably necessary and appropriate to protect workers on the job. [ 12 ]  The ADA prohibits employers from discriminating against disabled individuals, which is defined as \u201ca physical or mental impairment that substantially limits one or more major life activities, a person who has a history or record of such an impairment, or a person who is perceived by others as having such an impairment.\u201d"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5365", "text": "Employers under this law have an obligation to provide \u201creasonable accommodations\u201d to the disabled employee, so they may perform the essential duties of the job, as long as those accommodations don\u2019t pose an undue hardship on the employer\". [ 13 ]  The ADA section 12114(a) however states that these rights are not granted to employee or applicant who is currently engaging in the illegal use of drugs [ 13 ]  The ADA does not require employer coverage when the employee is engaging in the \u201cillegal use of drugs\u201d, including marijuana which is still illegal under the  Controlled Substance Act."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5366", "text": "Coats v. Dish Network LLC, held that a \u201cstate\u2019s lawful activities statute does not protect a worker\u2019s off-duty use of medical marijuana because this activity is not lawful under federal law\u201d under the ordinary meaning of \u201cpermitted by law\u201d [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5367", "text": "The  Federal Employees Compensation Act  (FECA) provides for the payment of workers\u2019 compensation benefits, including wages and medical benefits, to civilian officers and employees of all branches of the federal government, whereas state law has oversight over its own workers\u2019 compensation program"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5368", "text": "FECA  prohibits employees from receiving compensation when the injury \u201cwas proximately\u2026 caused by the intoxication by\u2026 illegal drugs.\u201d [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5369", "text": "Colorado Court of Appeals in Beinor v Industrial Claim Appeals [ 17 ]  agreed with the employer and held that unemployment insurance benefits could be withheld due to the violation of the employer\u2019s zero tolerance drug policy. Worker was a sweeper using cannabis legally outside of working hours. Colorado State statue \u201cdisqualifies an individual from receiving unemployment benefits after the presence of a controlled substance was not medically prescribed was found in the worker\u2019s system during worker hours.\u201d"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5370", "text": "Cannabis has unique  pharmacokinetics  and metabolism which makes it a challenge to drug test for acute impairment vs recent use.  THC  is deposited in fat and can be detectable in urine for up to a month or more. However, it is not always an indicator of acute impairment. Further there are privacy concerns, from invasive blood testing for compounds, under the  4th Amendment  of the US constitution. Variability in study designs, ethical dilemma of safety and productivity, work type and drug metabolism in users. When smoked, blood levels of THC immediately rise and are distributed primarily in the lungs and brain. THC is metabolized to the transient psychoactive substance THC-OH, which is finally converted to THC-COOH, the physiologically inactive metabolite.  The immediate euphoria and subsequent impairment from THC-OH, as suggested by older studies may last about 6 hours, with some limited studies showing impairment lasting as long as 24 to 48 hours [ 18 ]  Specific studies that assess driving and impairment show a return to \"...nonimpaired state within 3-6 hours.\u201c [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5371", "text": "The method of testing cannabis in urine can be misleading, due to the potential for interpreting a positive result for THC-COOH, as an indicator of acute impairment. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5372", "text": "FSMB ( Federal State Medical Boards ) after reviewing over 50 major studies in the field, have offered these 10 recommendations: [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5373", "text": "1)Thoroughly document patient\u2019s visit prior to considering cannabis use for those with good compliance. Information on the inadequacy of response to other treatment, comprehensive history and physical condition should be included."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5374", "text": "2) Don\u2019t treat close friends or family."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5375", "text": "3) Inform risks and benefits."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5376", "text": "4) Compliance Contract, concerns of diversion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5377", "text": "5) Regular Visits are recommended."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5378", "text": "6) No relationships with dispensaries or cannabis companies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5379", "text": "A large study in France of over 10,000 crashes, concluded an odds ratio of 2.18 for THC level less than 1\u00a0ng/ml up to 4.72 for THC 5\u00a0ng/ml for being involved in a crash. [ 20 ]   Some researchers such as  Donz\u00e9 N ,  M\u00e9n\u00e9trey  have considered categorizing impairment as the sum of THC, THC-OH and THC-COOH, which would be more accurate for assessing impairment since it would include the active metabolite; however, more research is needed along with better point of care detection. Some Norwegian studies have suggested that individuals with levels of 2-5\u00a0ng/mL experienced \u201cmoderate established impairment\u201d and levels of THC above 5 -10\u00a0ng/ml was likely to be severe impairment. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5380", "text": "The consensus from a meta-analysis study shows that serum levels of an average of 3.8 (ranging from 3.1 to 4.5) for oral cannabis and an average of 3.8 (ranging from 3.3 to 4.5) for smoker cannabis cause a similar impairment to a BAC of around 0.05g/dL, i.e. a 5\u00a0ng/mL cutoff would resemble the level of impairment allowed for alcohol under federal testing laws. [ 21 ]   However, since the presence of metabolites does not automatically indicate impairment, an immediate physical exam by a physician is advised to correlate findings clinically to diagnose impairment. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5381", "text": "Over-the-counter  ( OTC )  drugs  are  medicines  sold directly to a consumer without a requirement for a  prescription  from a healthcare professional, [ 1 ]  as opposed to  prescription drugs , which may be supplied only to consumers possessing a valid prescription. In many countries, OTC drugs are selected by a  regulatory agency  to ensure that they contain ingredients that are safe and effective when used without a  physician 's care. OTC drugs are usually regulated according to their  active pharmaceutical ingredient  (API) and strengths of final products. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5382", "text": "The term  over-the-counter  ( OTC ) refers to a medication that can be purchased without a medical prescription. [ 3 ]  In contrast,  prescription drugs  require a prescription from a doctor or other health care professional and should only be used by the prescribed individual. [ 4 ]  Some drugs may be legally classified as over-the-counter (i.e. no prescription is required), but may only be dispensed by a  pharmacist  after an assessment of the patient's needs or the provision of  patient education . Regulations detailing the establishments where drugs may be sold, who is authorized to dispense them, and whether a prescription is required vary considerably from country to country."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5383", "text": "As of 2011, around a third of older adults in the U.S. reportedly used OTC drugs, and this number is increasing. [ 5 ] [ 6 ] [ 7 ] [ 8 ]  By 2018, the prevalence of use by adults in the U.S. as first-line treatment for minor illnesses had reached 81%: however, there is some debate as to whether this figure relates to an actual improvement of health. [ 9 ] [ 1 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5384", "text": "In  Canada , there are four drug schedules: [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5385", "text": "All medications other than Schedule 1 may be considered an OTC drug, as they do not require prescriptions for sale. While the National Association of Pharmacy Regulatory Authorities provides recommendations on the scheduling of drugs for sale in Canada, each province may determine its own scheduling. [ 12 ]  The drugs found in each schedule may vary from province to province. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5386", "text": "In November 2016, India's Drug Consultative Committee announced it was embarking on establishing a definition of drugs which could be dispensed without a prescription. [ 1 ]  Prior to this, the general assumption was that any drug which did not fall into a prescription schedule could be purchased without a prescription. [ 1 ]   However, the needed definition had not been enacted by early 2018. The lack of a legal definition for OTC drugs has led to this  US$4 billion  market segment being effectively unregulated. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5387", "text": "In the  Netherlands , there are four categories: [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5388", "text": "A drug that is UA may be sold OTC but only by pharmacists. The drug can be on the shelves like any other product. Examples are  domperidone , 400\u00a0mg  ibuprofen  up to 50 tablets and  dextromethorphan . A drug that is UAD can also be sold at drugstores which are stores where no prescription can be filled. The drugs are usually on the shelves, and the store also sells items like toys, gadgets, perfumes and homeopathic products. The drugs in this category have limited risk and addiction potential. Examples are  naproxen  and  diclofenac  in small amounts,  cinnarizine , 400\u00a0mg ibuprofen up to 20 tablets and also 500\u00a0mg  paracetamol  up to 50 tablets. Drugs in the AV category can be sold at  supermarkets , gas stations, etc. and include only drugs with minimal risk to the public, like paracetamol up to 20 tablets, 200\u00a0mg ibuprofen up to 10 tablets,  cetirizine  and  loperamide ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5389", "text": "In the  United States , the manufacture and sale of OTC substances are regulated by the  Food and Drug Administration . The FDA requires that all \"new drugs\" obtain a  New Drug Application  (NDA) before entering interstate commerce, but the act exempts any drugs  generally recognized as safe and effective  (GRAS/E). [ 14 ]  To deal with the vast number of OTC drugs that were already on the market before the requirement that all drugs obtain an NDA, the FDA created the OTC monograph system to review classes of drugs and to categorize them as GRAS/E after review by expert panels. Certain classes of OTC drugs would not be required to obtain an NDA and could remain on the market if they conformed to the monograph guidelines for doses, labeling, and warnings finalized in the  Code of Federal Regulations [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5390", "text": "Thus, an OTC drug product is allowed to be marketed either (1) pursuant to an  FDA monograph  or (2) pursuant to an NDA for products that do not fit within a specific monograph. [ 16 ]  There is also the possibility that certain OTC drug products are marketed under the grandfathering provisions of the  Federal Food, Drug, and Cosmetic Act , but the FDA has never formally acknowledged that any legitimate grandfathered OTC drug exists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5391", "text": "Examples of OTC substances approved in the United States are sunscreens, anti-microbial and anti-fungal products, external and internal analgesics such as  lidocaine  and  aspirin ,  psoriasis  and  eczema  topical treatments, anti- dandruff  shampoos containing  coal tar , and other topical products with a therapeutic effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5392", "text": "The  Federal Trade Commission  regulates advertising of OTC products, in contrast to prescription drug advertising, which is regulated by the FDA. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5393", "text": "The FDA requires OTC products to be labeled with an approved \"Drug Facts\" label to educate consumers about their medications. The labels comply to a standard format and are intended to be easy for typical consumers to understand. Drug Facts labels include information on the product's  active ingredient(s) ,  indications  and purpose, safety warnings, directions for use, and  inactive ingredients . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5394", "text": "The 2020  Coronavirus Aid, Relief, and Economic Security Act  (CARES Act) includes reforms that modernize the way certain OTC drugs are regulated in the United States. [ 19 ] [ 20 ]  Many OTC monographs need to be updated but updating or changing an OTC monograph requires the slow and burdensome notice-and-comment rulemaking process. [ 19 ]  The CARES Act includes OTC monograph reform provisions that replace the rulemaking process with an administrative order process. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5395", "text": "An ill-defined third category of substances is products having over-the-counter status from the FDA while being simultaneously subject to other restrictions on sale. While they are legally classified as OTC drugs, they are typically stored behind the counter and are sold only in stores that are registered with their state. They may be unavailable in convenience and grocery stores that stock other non-restricted OTC medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5396", "text": "For example, many drugstores have moved products containing  pseudoephedrine , an OTC product, into locations where customers must ask a pharmacist for them. A prescription is not required; the change has been made in an effort to reduce  methamphetamine  production. Since the passage of the  Illinois Methamphetamine Precursor Control Act  and the subsequent federal  Combat Methamphetamine Epidemic Act of 2005 , the purchase of pseudoephedrine is restricted. Sellers of pseudoephedrine must obtain and record the identity of the purchaser and enforce  quantity restrictions . After initial attempts to control methamphetamine use (by requiring documentation of sale with government issued ID as well as limits on the quantity an individual could purchase) failed to realize meaningful reductions in methamphetamine use and production,  Mississippi  passed House Bill 512 in the State Senate on February 2, 2010 \"to require a prescription from a licensed medical professional to purchase over-the-counter medicines with pseudoephedrine,  ephedrine , or any other precursor chemical that can readily and illicitly be converted into  methamphetamine ,  methcathinone  or any active/scheduled analogs of  phenylethylamines / \u200b amphetamine .\" [ citation needed ]  However, products containing the substance are still OTC in most states, since no prescription is required."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5397", "text": "A similar regulation once applied to some forms of  emergency contraception . However, on February 25, 2014, the FDA approved generic one-pill emergency contraception products for unrestricted sale on the shelf. There is no age limit or need for ID to purchase. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5398", "text": "Furthermore, some  Schedule V  controlled substances may be classified as OTC products in certain states. Such drugs are sold without a prescription but are subject to record-keeping rules and quantity and/or age restrictions, and they must be dispensed by a  pharmacy . [ 22 ]  Finally, pharmacies frequently require a prescription for Schedule V drugs as a matter of policy, despite their OTC status according to applicable laws and regulations.  [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5399", "text": "In the United Kingdom, medication is governed by the Medicines Regulations 2012. Medication falls into one of three categories: [ 1 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5400", "text": "If it is not appropriate to sell a 'P' medication \u2013 i.e. the condition is not suitable for self-management and requires referral to a medical prescriber \u2013 then a sale should not occur and the pharmacist has a legal and professional obligation to refer this on to an appropriate service."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5401", "text": "Examples of these include some sleep aid tablets such as  diphenhydramine , human  deworming  tablets such as  mebendazole , painkillers with small amounts of  codeine  (up to 12.8\u00a0mg per tablet), and  pseudoephedrine . Medication available only with a prescription is marked somewhere on the box/container with [POM]. Pharmacy-only products are marked with [P]. A prescription is not required for [P] medicines, and pharmacy sales assistants are required by  Royal Pharmaceutical Society  codes to ask certain questions, which varies for what the customer says. If they ask for a specific product, the pharmacy assistant must ask \"Who is it for?\", \"How long have you had the symptoms?\", \"Are you allergic to any medication?\", \"Are you taking any medication?\" ('WHAM' questions). If a customer asks for a remedy, e.g., hay fever, then the '2WHAM questions' must be asked \"Who is it for?\", \"What are the symptoms?\", \"How long have you had the symptoms?\", \"Have you taken any action towards your symptoms?\", and \"Are you taking any other medication?\". It is with this information that the pharmacist can halt the sale, if need be. No [POM], [P] or [GSL] products that are stocked in a pharmacy can be sold, dispensed, or pre-made until a responsible pharmacist is signed in and on the premises. Some medication available in supermarkets and petrol stations is sold only in smaller packet sizes. Often, larger packs will be marked as [P] and available only from a pharmacy. Frequently, customers buying larger-than-usual doses of [P] medicines (such as  DXM , promethazine, codeine or  Gee's Linctus ) will be queried, due to the possibility of abuse. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5402", "text": "As a general rule, over-the-counter drugs have to be used primarily to treat a condition that does not require the direct supervision of a doctor and must be proven to be reasonably safe and well tolerated. [ 25 ]  OTC drugs are usually also required to have little or no abuse potential, although in some areas drugs such as  codeine  are available OTC (usually in strictly limited formulations or requiring paperwork or identification to be submitted during purchase). [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5403", "text": "Over time, often 3\u20136 years, drugs that prove themselves safe and appropriate as prescription medicines may be switched from prescription to OTC. [ citation needed ]  An example of this is  diphenhydramine  (Benadryl), an anti-histamine which once required a prescription but now is available OTC nearly everywhere. [ citation needed ]  More recent [ when? ]  examples are  cimetidine  and  loratadine  in the United States, and  ibuprofen  in Australia. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5404", "text": "It is somewhat unusual for an OTC drug to be withdrawn from the market as a result of safety concerns, rather than market forces, though it does happen occasionally. For example,  phenylpropanolamine  was removed from sale in the United States over concern regarding  strokes  in young women. [ 27 ]  A study has been done examining consumer's perceptions about the risk of and access to nonprescription medication. The study concluded that a small percentage of consumers prefer having access to medication over potential risks of taking non-prescribed medication. [ 28 ]   Ranitidine  was suspended in multiple markets due to concerns over the presence of the  carcinogen   N -nitrosodimethylamine  (NDMA). [ 29 ] [ 30 ] [ 31 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5405", "text": "In the United Kingdom, it was announced in February 2007 that  Boots the Chemist  would try over-the-counter sales of Viagra in stores in  Manchester, England  (previous available as prescription only). Men aged between 30 and 65 could buy four tablets after a consultation with a  pharmacist . [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5406", "text": "Overmedication  describes the excessive use of  over-the-counter  or  prescription medicines  for a person. Overmedication can have harmful effects, such as non-adherence or  interactions  with multiple prescription drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5407", "text": "Over-the-counter (OTC) medications are generally first-line therapies that people may choose to treat common acute illnesses, such as fevers, colds, allergies, headaches, or other pain. Many of these medications can be bought in retail pharmacies or grocery stores without a prescription. OTC medication overuse is most prevalent in adolescents and young adults. [ 1 ]  This overuse is common due to the relatively low cost, widespread availability, low perceived dangers, and internet culture associated with OTC medications. [ 2 ]  OTC medications may be combination formulations that contain multiple drugs. These combination formulations are often used with other substances, which complicates treatment for these types of overdoses. Furthermore, the easy access to information online can sometimes lead to self-diagnosis and self-medication, contributing to the potential for misuse and overuse."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5408", "text": "Overuse of  acetaminophen  is the leading cause of  liver failure  in the  Western world . [ 3 ]  The maximum daily limit of acetaminophen is 4 grams per day for someone with a healthy liver. It is also highly recommended to not go over the maximum daily limit. Exceeding the maximum daily limit could involve severe  liver toxicity , liver failure,  kidney failure , or even death. [ 4 ]  People who have poor liver function or with chronic alcohol use disorder should either limit or not ingest acetaminophen to prevent morbidities. [ 5 ]  Additionally, acetaminophen is an ingredient in many combination medications, increasing the risk of unintentional overdose. Consumers should read labels carefully and consult healthcare providers to ensure they are not consuming excessive doses. In cases of suspected overdose, immediate medical attention is needed to mitigate potential life-threatening consequences. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5409", "text": "Codeine  is an  opioid  and shares similarities to other opioid overuse. Many OTC medications for cough have formulations that contain codeine, which people may seek to overuse. The common effects of codeine include  miosis ,  respiratory depression ,  CNS depression , and decreased bowel motility. [ 6 ]  Despite the risk of death, dependence is another significant issue related to codeine overuse. Tolerance can cause users to use more opioid, leading to dependence, especially with chronic daily use of codeine. [ 1 ]  Additionally, the misuse of codeine-containing cough syrups has become a public health concern, as it can serve as a gateway to stronger opioids. [ citation needed ]  Education about the risks and signs of opioid addiction can play a role in prevention and early intervention."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5410", "text": "Dextromethorphan , also shortened to DXM, affects the  NMDA receptor  and serotonin receptors which is believed to give its psychoactive effects at high doses. Similarly to codeine, DXM comes primarily in formulations that contain other OTC medications and is not common to find DXM on its own. Moreso, people who use DXM tend to use it concomitantly with other substances such as alcohol,  hallucinogens ,   sedative drugs , and opioids. [ 1 ]  DXM has dose dependent psychoactive effects with lower dose leading to more restlessness and  euphoria  and higher doses causing hallucinations, delusional beliefs, paranoia, perceptual distortions,  ataxia , and out of body experiences. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5411", "text": "Diphenhydramine  is typically used for allergy relief, although it may be used to alleviate sleeping problems, anxiety, and overall restlessness. [ 7 ]  Effects may include euphoria, hallucinations, or  psychosis . [ 7 ]  The anticholinergic activity of diphenhydramine may lead to  tachycardia ,  dry mouth , blurred vision,  mydriasis ,  depression, and urinary retention. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5412", "text": "In 2020, purposeful overmedication with Benadryl (diphenhydramine) was a concern due to use of social media by teenagers in the United States, with the FDA issuing a public warning about the possibility of seizures, hallucinations, breathing difficulty or loss of consciousness. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5413", "text": "Pseudoephedrine ,  ephedrine  or  phenylpropanolamine  can be overused with the intent for weight loss or improving athletic performance, possibly causing  insomnia , diminished sense of fatigue, euphoria, and psychotic behavior. [ 1 ]  The habitual use of the medication has led to  dependence , with symptoms of restlessness, dysphoria, and distorted perceptions on withdrawal. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5414", "text": "Seniors (65 years old and up) are possible users of overmedication. [ 9 ]  Seniors are disproportionately affected by not only adverse drug events, but also  drug interactions  and more hospital admissions. [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5415", "text": "The term for individuals taking five or more medications is  polypharmacy , which commonly occurs in elderly people, increasing their risk of overmedication. [ 10 ]  Medical providers are generally hesitant to prescribe polypharmacy in the elderly due to the risk of harmful drug interactions. Concerns with polypharmacy and elderly groups are reduced medication adherence, increased fall risk, cognitive function impairment, and adverse drug reaction. [ 11 ]  Almost 75% of clinic visits result in people obtaining a written prescription. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5416", "text": "More careful prescribing practices could increase medication adherence in elderly people. [ 14 ] [ 15 ]  Single-pill combination formulations make it easier for a person to monitor medications. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5417", "text": "Opioids are used for pain management acutely or prescribed after a surgical procedure. While opioids aid in short- and long-term pain management, overprescription or constant opioid-exposure increases the risk for addiction. [ 16 ]  There is a rise within healthcare systems to manage prescription of opioids. [ 16 ]  Children prescribed opioids may become susceptible to the harms of addiction. [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5418", "text": "Reducing or withdrawing prescribed opioids, such as for people with chronic non-cancerous pain, using  either dose-reduction or stopping opioid prescriptions, may be effective, but standards are absent for managing withdrawal symptoms and deprescribing coprescription of sedatives. [ 19 ] [ 20 ]  Studies found a significant increase in opioid surplus disposal when individuals were provided with the necessary education or disposal kits. [ 21 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5419", "text": "As antibiotics inhibit bacterial infections, they are a commonly prescribed medication. Overuse of these medications over the years has contributed to reduced efficacy against certain bacteria due to  antimicrobial resistance , [ 23 ]  a global medical concern. [ 24 ]  Antibiotic overprescription is a potential problem in acute care, primary hospitals, and dental offices. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5420", "text": "Antibiotic-resistant bacterial infections are increasing. [ 23 ]  A systemic review of admitted  COVID-19  patients who were prescribed antibiotics showed that 80% of the admitted people were given antibiotics upon admission without confirmed bacterial coinfections. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5421", "text": "Physicians prescribe antibiotics for non-indicated diagnoses, such as viral infections, possibly cntributing to more antibiotic-resistant infections, greater adverse drug events, more drug-drug interactions, and deaths. [ 26 ]  Dentists may prescribe antibiotics for non-indicated conditions that could otherwise be treated with other interventions, according to clinical guidelines. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5422", "text": "Premedication  is using  medication  before some other  therapy  (usually  surgery  or  chemotherapy ) to prepare for that forthcoming therapy. Typical examples include premedicating with a  sedative  or  analgesic  before surgery; using  prophylactic (preventive)  antibiotics before surgery; and using  antiemetics  or  antihistamines  before chemotherapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5423", "text": "Premedication before chemotherapy for cancer often consists of drug regimens (usually 2  or more drugs, e.g.  dexamethasone ,  diphenhydramine  and  omeprazole ) given to a patient minutes to hours before the chemotherapy to avert side effects or   hypersensitivity  reactions (i.e. allergic reactions). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5424", "text": "Melatonin  has been found to be effective as a premedication in both adults and children due to its pharmacological properties of  hypnotic ,  antinociceptive  and  anticonvulsant  which produce effective  anxiolysis  and sedation. Unlike midazolam, melatonin does not impair psychomotor skills or adversely affect the quality of recovery. It has a faster recovery time compared to midazolam and has a reduced incidence of post-operative excitement and results in a reduction in dose required of  propofol  and  thiopental . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5425", "text": "Midazolam  is effective in children in reducing anxiety associated with separation from parents and induction of  anesthesia . [ 2 ]   Sufentanil  is also sometimes used as a premedication.  Clonidine  is becoming increasingly popular as a premedication for children. One drawback of clonidine is that it can take up to 45 minutes to take full effect. [ 3 ]  In children, clonidine has been found to be equal to and possibly superior to benzodiazepines as a premedication. It has a more favourable side effect profile. It also reduces the need for an  induction  agent. It improves post-operative pain relief, is better at inducing sedation at induction, reduces  agitated emergence , reduces shivering and  post-operative nausea and vomiting  and reduces post-operative delirium associated with  sevoflurane  anaesthesia.  Benzodiazepines  such as  midazolam  are more commonly used due largely to a lack of a marketing effort by the pharmaceutical companies. As a result, clonidine is becoming increasingly popular with  anesthesiologists . [ 4 ] [ 5 ]   Dexmedetomidine  and  atypical antipsychotic agents  are other premedications which are used particularly in very uncooperative children. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5426", "text": "Non-drug interventions for children include playing relaxing music, massages, reducing noise and controlling light to maintain the sleep wake cycle. [ 7 ]  Other non-pharmacological options for children who refuse or cannot tolerate premedication include clown doctors; low sensory stimulation and hand-held video games may also help reduce anxiety during induction of general anesthesia. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5427", "text": "Proprietary drug  are  chemicals  used for medicinal purposes which are formulated or manufactured under a name protected from competition through  trademark  or  patent . [ 1 ]  The invented drug is usually still considered proprietary even if the patent expired. [ 2 ]  When  a patent  expires,  generic drugs  may be developed and released legally. Some international and national  governmental organizations  have set up  laws  to enforce  intellectual property  to protect proprietary drugs, but some also highlight the importance of  public health  disregarding  legal regulations . [ 3 ] [ 4 ]  Proprietary drugs affect the world in various aspects including  medicine ,  public health  and  economy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5428", "text": "Not all proprietary drugs have their  generic replacements  available.  Biologics  are often produced by  in vivo  preparation and direct extraction of substances from  living organisms. [ 5 ]   Pharma  is not extensively involved in searching for ready-to-sell generic  biologics  due to the complexity of manufacture and hurdles in extraction processes. [ 6 ]  Besides  vaccines , these endogenous origin chemicals are prescribed to patients with severe conditions, such as complications including  asthma ,  rheumatoid arthritis , [ 7 ]  or  cancer . Patients taking a particular brand of  biologics  are unable to interchange between one and another to prevent underlying exposure to more side effects and/or suboptimal treatment. [ 6 ]  It is believed that  generic biopharmaceutical products  will not be released in the near future until all technical difficulties are overcome. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5429", "text": "The table below shows some examples of pharma and their past/current proprietary medications:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5430", "text": "Broadly defined as  drugs  that are marketed under  trade names  and have  patents , [ 15 ]  which can be a synonym of proprietary drugs in daily use. Strictly speaking, every  drug  with a  trade name  is a brand name drug, [ 16 ]  such as  Panadol , a  GSK  branded  paracetamol ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5431", "text": "Generic drugs  are  drugs  that have the same  active ingredient  with a patent-expired drug, and are virtually bio-equivalent. The official names are often used to market these drugs, which are called unbranded  generic drug , [ 17 ]  such as Panamax, a generic form of  paracetamol ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5432", "text": "A term specifically used to describe past proprietary drugs by referring to their off-patent status. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5433", "text": "To support scientific investigation and protect  intellectual properties ,  patents  are granted to companies and individuals who invented the drug. [ 19 ]  Most entities in the world have established corresponding agendas legally. Global and regional governmental organizations have various extents of advancements and approaches in their  intellectual property rights  protection  laws . Below are some examples for comparison:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5434", "text": "The Agreement on Trade-Related Aspects of Intellectual Property Rights  ( TRIPS Agreement ) [ 20 ]  set up in 1994 suggested a standard on  Intellectual Property Rights , which proprietary drug, a type of pharmaceutical and scientific inventions, is covered in this agreement. Basic principles such as the minimal duration of patent and part of the exclusive rights of  patent  owners are included by  WTO  member states in their respective  national regulations . By 5 years and 10 years after the effectiveness of  TRIPS Agreement ,  developed countries  and  developing countries  were required to comply with it. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5435", "text": "Trying to alleviate worldwide divide in  accessibility of medical resources , members from the  WTO  endorsed the  Doha Declaration  on the  TRIPS Agreement  and Public Health in 2001. The basics of this Declaration is that \"the TRIPS Agreement does not and should not prevent Members from taking measures to protect  public health \". [ 4 ]  It legalized the participating members to ignore the restriction from the  patent  of the proprietary medicine when they are controlling a significant  public health  crisis, namely  human immunodeficiency virus  ( HIV ),  malaria  and  tuberculosis . Thus, affordable  generic medicine  can be provided for the populations in the  developing countries  in emergency situations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5436", "text": "In the  United States , proprietary drugs are associated with two status:  patent  and  exclusivity .  Patent  is\u00a0managed by the  United States Patent and Trademark Office , [ 3 ]  granting inventors of new drugs rights for 20 years. [ 21 ]  It is open to all drugs, regardless of its research or commercialization status. [ 22 ]  To enjoy the benefits brought by  patenting , pharmaceutical companies are obliged to disclose all research data on that drug to the public for further progression. [ 23 ]   Exclusivity , given by  the U.S. Food and Drug Association  (FDA), means a period of time in which no other competitor drugs can be approved. [ 23 ]  Commercialized and clinically used drugs are the targets of exclusivity. The length of exclusivity depends on the nature of application, and ranges from one to seven years. [ 23 ]  Practically exclusivity is granted for proprietary drugs that have been granted with  patents , but it is not mandatory. Legalwise,  generic counterparts  have to wait for at least 2 decades for  patent  expiration to sell a copy . This system is said to aim for a balance between gaining  public access  to  generic drugs  and encouraging drug research and development. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5437", "text": "Despite the  US  having a legal system regarding to drug patenting, litigation have taken place. In the past, it is common for drug manufacturers challenging the validity of patents. [ 24 ]  In 2018,  Mylan  attempted to revoke the patent of  Symbicort  owned by  AstraZeneca  through the court. [ 25 ]  Now  pharma  suing on deliberately infringing  generic drugs  has become more prominent. [ 24 ]   AstraZeneca  then took follow-up actions against  Mylan  for premature submission of  Abbreviated New Drug Application  (ANDA) for generic  Symbicort  and won the  lawsuit . [ 25 ]  The introduction of  biopharmaceuticals  and the subsequent establishment of new drug laws may also bring more litigation. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5438", "text": "According to the  Patent  Law in India, drug can apply for a  patent  since 2005. [ 26 ]  Registering a drug for  patents  in  India  is more limiting than developed countries.  India  was removed from  the least developed member states  list of the  WTO  and is therefore no longer eligible for the waiver, [ 27 ]  it has modified its  patent  law [ 26 ]  to satisfy  TRIPS Agreement  with its  intellectual property rights   legal system . An Indian  patent  lasts for 20 years. [ 28 ]  To ensure the interest of public, a  compulsory license  can be issued by the government if a  pharma  is suspected for violating the  public health  principles. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5439", "text": "Introducing new drug  patenting  regulations after 35 years [ 29 ]  could possibly lead to today's disputes, such as the  Novartis v. Union of India  incident. Generic  Gleevec , a  formulation  that can substitute  Glivec , were distributed in the local market since 1993. [ 30 ]  Novartis had filed a  patent  for  Glivec  in 1997. [ 30 ]  An exclusive marketing right was also granted for  Novartis  in 2003 and the application were approved in 2005 . [ 30 ]  In 2013,  the Supreme Court of India  upheld the rejection of the patent application of  Glivec  by  Novartis , [ 31 ]  ending the 10-years battle between the proprietary drug tycoon and the local  patent law . Since 1993,  Novartis  has started to register  patent  for  Glivec  and its active ingredients worldwide without defeats. [ 31 ]  However,  the Supreme Court of India  rejected the  patent registration  of  Glivec  on 2006 [ 31 ]  according to the interpretations on the  patent law  and  TRIPS agreement  by the Court. By then, the local  generic drugs  in  India  are protected. [ 31 ]  This incident is referred as a challenge to the  intellectual property  laws. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5440", "text": "Patent cliff  refers to a dramatic dip in the revenue of a merchandise upon  patent expiry . [ 32 ]  It is a prominent phenomenon in the proprietary drug industry due to the vast gap of prices between the proprietary drug and the  generic drug . [ 33 ]  Since 2010, numerous pharmaceutical board busters have started to become off-patent. [ 34 ]  As seen in the figure below, the top five off-patent proprietary drug before 2017 have a combined lifetime sale of around US$588.4 Billion, [ 35 ]  which is enormous enough to surpass the bottom 5% countries'  GDP  in 2020. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5441", "text": "Figure 1: Five best-selling proprietary drug which lost their patents before 2017 [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5442", "text": "Proprietary drug is a substantial business protected by its respective  patent . They are usually sold at a higher price, to compensate for the  clinical trial  cost and sometimes for the  manufacturing  of new  technology . [ 37 ]  For example, an widely used average proprietary drug is 18 times more expensive than a common  generic drug . [ 33 ]   Lyrica , a recent off-patent  painkiller  for  nervous systems , had a sale of 5B USD in 2019, [ 38 ]  out of the 51.8B USD annual sale of the corresponding company. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5443", "text": "However, once the proprietary drug become off-patent, there will soon be immense competition from the  generic drugs  produced by their business rivals. [ 40 ]  As cheaper pharmaceutical alternatives are launched, the surge in supply disrupts the market  supply-and-demand  status. [ 34 ]  The declining dependence on the original proprietary drug will cause its sales decreases. On top of that, the original company usually will have their prices tuned down for improving competitiveness. [ 34 ]  Resulting in a significant drop of revenue of the proprietary drug. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5444", "text": "Below showed the graph which represented the yearly revenue of  Lipitor , a proprietary drug which lost its  patent  on 2011. [ 41 ]  As it can be seen, a significant  patent cliff  happened from 2011 to 2012(58.8% drop in yearly revenue) and it is very possibly due to its newly off-patent status. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5445", "text": "Figure 2: The yearly revenue of  Lipitor  by  Pfizer  (million US dollars) from 2004 to 2019 [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5446", "text": "Proprietary drug market is protected by its patent. As a result, its market exclusivity basis allows proprietary drugs to be highly profitable and commercially successful. [ 42 ]  Usually,  pharmaceutical research  is a lengthy, highly demanding, rarely successful, costly and risky investment. [ 43 ]  It is usually associated with a disinterested  merchandise  in the economic world. [ 43 ]  However, once a successful experimental drug candidate is registered as a proprietary drug product, the  patent  legally ensures a long-term dominance in the exclusive market which is free of imitative  generic drug . Generating a stable and considerable net income to cover the cost. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5447", "text": "The huge earning of the proprietary drug can circulate back to fund future  medical research . Providing more resources and manpower to the research and development of another drug candidates. [ 42 ]  As well as attracting new investments to the  pharmaceutical research  industry due to its exclusive market potential. They encourage efforts on  biopharmaceutical  innovations and newborn medical breakthroughs. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5448", "text": "Being required for successful  patent  registration, detailed  pharmaceutical formulations  of the proprietary drug are disclosed on its  patent  registration application, [ 45 ]  which promote the spillover of research efforts among the medical world. [ 46 ]  In order to inspect the safety and efficacy of the proprietary drug candidate, pharmaceutical companies need to list all  clinical trial  data and formulation method as detailed as possible to prove the drug candidate's validity to the patent registration committee. [ 45 ]  Once the  patent  is rewarded, these data will later be published on  medical literature  and  public domains  as common knowledge. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5449", "text": "Researchers can capitalise on the previous successes and establish their own project on top of the current statistics. These cooperatively help exploit more unknown drug candidates without repeating previous progresses. [ 46 ]  Speeding up future medical advancements. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5450", "text": "According to  World Health Organisation(WHO) ,  equitable access to medicines  refers to an affordable and reasonable ability for patients to get their required drug to achieve  health . [ 47 ]   WHO  member states shall fulfill their  moral responsibility  to improve the delivery of and access to the needed drugs. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5451", "text": "However, the  monopolisation  of some expensive proprietary drug in the market is hindering poor patients' access to their best available medications. [ 48 ]  Leading to suboptimal treatments of diseases and lowering of health standard of these patients. [ 48 ]  This phenomenon is very prominent in the underdeveloped countries which usually have a large proportion of underprivileged citizens. [ 48 ] [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5452", "text": "Some proprietary drugs(mainly speciality proprietary drug) are criticised for their price-gouging commercial tactics. [ 37 ] [ 50 ]  To illustrate, the world's most expensive drug,  Zolgensma , costs over US$2.1 million per year of treatment, which are generally considered as unaffordable. [ 51 ]  Since  Zolgensma  is the only approved drug for curing  Spinal Muscular Atrophy  in childhood, patients who cannot afford  Zolgensma  will be physically disabled for the rest of their lives. Creating inequity among patients with varying financial capacitances."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5453", "text": "According to the  TRIPS Agreement , the  term of patent  of the proprietary drug usually can last for 20 years counting from the filing date. [ 52 ]  After that, approved  generic drugs  can enter the market legally with fair competition. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5454", "text": "However, in order to achieve longer dominance in the market,  pharmaceutical manufacturer  (especially  big pharma ) may apply for  patent  extension or even new  patent  registration based on various reasons. [ 53 ]  Including modifying the formulations, dosage form or maneuvering legal system. [ 30 ] [ 54 ]  To illustrate,  AbbVie , a pharmaceutical tycoon, had attempted 247 proprietary drug  patent  extension applications for extending their exclusivity for 39 years in the  USA  on 2018 alone. [ 55 ]  Among them, 137 applications were successful in extending the  patent ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5455", "text": "The abusing of  patent  extension system leads to a much longer  terms of patent  than that stated in both local regulations and  TRIPS Agreement . [ 3 ] [ 53 ]  Providing a long period of competition-free market to their proprietary drug. It creates an unfair competition environment in the  pharmaceutical market . [ 53 ]  Since the  generic drug  companies are excluded from that particular market, they cannot release new pharmaceutical products for public use on the same field. [ 53 ]  Resulting enduring monopolisation of proprietary drug market by the  big pharma  which are already stockpiling proprietary drug. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5456", "text": "Royal Blood-Fresh  ( Korean :\u00a0 \ud608\uad81\ubd88\ub85c\uc815 ) is a  traditional Korean medicine  ( Koryo medicine )  health supplement  derived from  soybeans . [ 1 ]  It is manufactured in North Korea [ 2 ]  and is the most famous product sold by the North Korean company,  Pugang Pharmaceutic . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5457", "text": "It is marketed as a \"blood purifier\" and a preventative against  deep-vein thrombosis . [ 1 ]  It is marketed to foreigners during  Air Koryo  flights [ 3 ]  and has been sold at  Pyongyang Gwan , a North Korean restaurant in Hanoi, Vietnam. [ 4 ]  It has been dismissed outside of North Korea as a non-scientific \"miracle cure\". [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5458", "text": "In 2017, three Russian nationals were arrested in  South Korea  for selling North Korean drugs, which included Royal Blood-Fresh,  Kumdang-2 , and  Neo-Viagra-Y.R. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5459", "text": "The Seed  was a controversial  drug rehabilitation  program in the  United States  that operated between 1970 and 2001. [ 1 ]  Aimed at youths, the program was modeled after adult treatment programs, with its techniques having been compared to those of the cult  Synanon . [ 2 ]  In a 1974 U.S Senate report, its techniques were also compared to the  North Korean   brainwashing  technique used on  Prisoners of War  during the  Korean War . [ 3 ] [ 4 ]  At its height in the 1970s The Seed had locations in  Fort Lauderdale ,  Fort Myers ,  Dade County , [ 5 ]  and  St. Petersburg . [ 6 ] [ 7 ]  The organisation widely marketed itself as \"spectacularly successful\", \"teaching love\", and received wide press coverage. [ 8 ]   There was also a location in Cleveland, Ohio.  Art Barker and his entourage would travel back and forth a couple times a month."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5460", "text": "Following the release of the Senate report, along with criticisms from experts about the techniques and high suicide rate of the attendees, The Seed began to decline over the next two decades. By 2001, only the original Fort Lauderdale location remained, and the founder, Arthur Barker, retired and dissolved the organisation. [ 2 ]  Several other similar drug rehabilitation programs were founded in its image after The Seed's decline, most notably  Straight, Incorporated . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5461", "text": "Sepsivac  is a drug developed by  Cadila Pharmaceuticals  to treat  gram-negative   sepsis . \u00a0The active ingredient is heat-killed Mycobacterium w, a non-pathogenic strain of  Mycobacterium .  As an  immunomodulatory , it modulates the immune system of the body and hence significantly reduces mortality rate in patients with gram negative sepsis. Sepsivac is a drug developed by  CSIR  and Cadila Pharmaceuticals under New Millennium Indian Technology Leadership Initiative (NMITLI) programme. [ 1 ]  In many cases, Sepsivac has proven to provide effective care and relief to COVID patients. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5462", "text": "Sepsivac is approved by the  Drug Controller General of India  (DCGI) for treatment of  sepsis  or septic shock. [ 3 ] [ better\u00a0source\u00a0needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5463", "text": "In patients with sepsis, in response to an  infection , a lot of  pro-inflammatory  and  anti-inflammatory   cytokines  are generated in the body. However, some of the cytokines also cause inflammation in the organs of the body, which might be harmful.  Immunomodulator  drugs such as Sepsivac regulate this host immune response. [ 4 ]  Sepsivac is found to be safe in patients with no systematic side-effects. It can be used in combination with other treatments to manage a patient in critical care setting. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5464", "text": "Scientists at CSIR found similarities between the clinical characteristics of patients with gram-negative sepsis and  COVID-19 . In association with Cadila Pharmaceuticals, the researchers are now working on initiating a randomised, blinded, controlled  clinical trial  to evaluate Sepsivac's efficacy to reduce mortality in critically ill COVID-19 patients. [ 1 ]  The repurposed drug will boost the immunity of the body and limit the spread of COVID-19 and increase the recovery rate. [ 6 ]  The clinical trials will be conducted at national hospitals including  PGIMER Chandigarh ,  AIIMS New Delhi , and  AIIMS , Bhopal. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5465", "text": "A  sialogogue  (also spelled  sialagogue ,  ptysmagogue  or  ptyalagogue ) is a  substance , especially a  medication , that increases the flow rate of  saliva . [ 1 ]  The definition focuses on substances that promote  production or secretion of saliva  (proximal causation) rather than any food that is  mouthwatering  (distal causation that triggers proximal causation)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5466", "text": "Sialogogues can be used in the treatment of  xerostomia  (the subjective feeling of having a dry mouth), to stimulate any functioning  salivary gland  tissue to produce more saliva. Saliva has a bactericidal effect, so when low levels of it are secreted, the risk of  caries  increases. [ 2 ]  Not only this, but fungal infections such as oral  candidosis  also can be a consequence of low salivary flow rates. The  buffer  effect of saliva is also important, neutralising acids that cause tooth enamel demineralisation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5467", "text": "The following are used in dentistry to treat xerostomia: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5468", "text": "A tincture is prepared from the root of the pyrethrium ( pyrethrum ) or pellitory (a number of plants in the  Chrysanthemum  family). It is found growing in Levant and parts of Limerick and Clare in  Ireland . The root powder was used as flavouring in tooth powders in the past. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5469", "text": "Skin pop scars  are a cutaneous condition caused by intravenous drug abuse. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5470", "text": "This  dermatology  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5471", "text": "The  Solidarity trial for treatments  is a multinational  Phase III-IV clinical trial  organized by the  World Health Organization  (WHO) and partners to compare four untested treatments for hospitalized people with severe  COVID-19  illness. [ 1 ] [ 2 ]  The trial was announced 18 March 2020, [ 1 ]  and as of 6 August 2021, 12,000 patients in 30 countries had been recruited to participate in the trial. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5472", "text": "In May, the WHO announced an international coalition for simultaneously developing several candidate  vaccines  to prevent COVID-19 disease, calling this effort the  Solidarity trial for vaccines . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5473", "text": "The treatments being investigated are  remdesivir ,  lopinavir/ritonavir  combined, lopinavir/ritonavir combined with  interferon-beta , and  hydroxychloroquine  or  chloroquine . Hydroxychloroquine or chloroquine investigation was discontinued in June 2020 due to concluding that it provided no benefit. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5474", "text": "The trial intends to rapidly assess thousands of COVID-19 infected people for the potential efficacy of existing antiviral and  anti-inflammatory  agents not yet evaluated specifically for COVID-19 illness, a process called \"repurposing\" or \"repositioning\" an already-approved drug for a different disease. [ 2 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5475", "text": "The Solidarity project is designed to give rapid insights to key clinical questions: [ 2 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5476", "text": "Enrolling people with COVID-19 infection is simplified by gathering   informed consent , and capturing data on an online clinical trial platform (Castor EDC). [ 6 ] [ 2 ]  After the trial staff determine the drugs available at the hospital, the platform  randomizes  the hospitalized subject to one of the trial drugs or to the hospital standard of care for treating COVID-19. The trial physician records and submits follow-up information about the subject status and treatment, completing data input via the Castor EDC Platform. [ 6 ]  The design of the Solidarity trial is not  double-blind  \u2013 which is normally the standard in a high-quality clinical trial \u2013 but WHO needed speed with quality for the trial across many hospitals and countries. [ 2 ]  A global  safety monitoring board of WHO physicians  examine  interim results  to assist decisions on safety and effectiveness of the trial drugs, and alter the trial design or recommend an effective therapy. [ 2 ] [ 5 ]  A similar web-based study to Solidarity, called \"Discovery\", was initiated in March across seven countries by  INSERM  ( Paris ,  France ). [ 2 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5477", "text": "The Solidarity trial seeks to implement coordination across hundreds of hospital sites in different countries \u2013 including those with poorly-developed infrastructure for clinical trials \u2013 yet needs to be conducted rapidly. According to  John-Arne R\u00f8ttingen , chief executive of the  Research Council of Norway  and chairman of the Solidarity trial international  steering committee , the trial would be considered effective if therapies are determined to \"reduce the proportion of patients that need ventilators by, say, 20%, that could have a huge impact on our national health-care systems.\" [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5478", "text": "According to the WHO Director General, the aim of the trial is to \"dramatically cut down the time needed to generate robust evidence about what drugs work\", [ 9 ]  a process using an \"adaptive design\". [ 10 ] [ 11 ]  The Solidarity and European Discovery trials apply adaptive design to rapidly alter trial parameters when results from the four experimental therapeutic strategies emerge. [ 7 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5479", "text": "Adaptive designs within ongoing Phase III-IV clinical trials \u2013 such as the Solidarity and Discovery projects \u2013 may shorten the trial duration and use fewer subjects, possibly expediting decisions for early termination to save costs if interim results are negative. [ 7 ] [ 10 ] [ 11 ]  If the Solidarity project shows early evidence of success, design changes across the project's international locations can be made rapidly to enhance overall outcomes of affected people and hasten use of the therapeutic drug. [ 1 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5480", "text": "The individual or combined drugs being studied in the Solidarity and Discovery projects are already approved for other diseases. [ 2 ]  They are: [ 2 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5481", "text": "Due to safety concerns and evidence of  heart arrhythmias  leading to higher death rates, the WHO suspended the hydroxychloroquine arm of the Solidarity trial in late May 2020, [ 14 ] [ 15 ]  then reinstated it, [ 16 ]  then withdrew it again when an interim analysis in June showed that hydroxychloroquine provided no benefit to hospitalized people severely infected with COVID-19. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5482", "text": "In October 2020, the World Health Organization Solidarity trial produced an interim report concluding that its \"remdesivir, hydroxychloroquine, lopinavir and interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay.\" [ 17 ]  Gilead \u2013 the manufacturer of remdesivir \u2013 criticized the Solidarity trial methodology after it showed no benefit of the treatments, claiming that the international nature of the Solidarity trial was a weakness, whereas many experts regard the multinational study as a strength. [ 18 ]  Purchase agreements between the EU and Gilead for remdesivir and granting of its  Emergency Use Authorization  by the US FDA during October were questioned by Solidarity trial scientists as not based on positive clinical trial data, when the interim analysis of the Solidarity trial had found remdesivir to be ineffective. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5483", "text": "In January 2022, the Canadian component of the Solidarity trial reported that in-hospital people with COVID-19 treated with remdesivir had lower death rates (by about 4%) and reduced need for oxygen (less by 5%) and mechanical ventilation (less by 7%) compared to people receiving standard-of-care treatments. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5484", "text": "During March, funding for the Solidarity trial reached  US$108  million from 203,000 individual donations,  charitable organizations  and governments, with 45 countries involved in financing or trial management. [ 1 ] [ 20 ]  As of 1 July 2020, nearly 5,500 patients in 21 countries of 39 that have approval to recruit were recruited to participate in the trial. More than 100 countries in all 6 WHO regions have expressed interest in participating. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5485", "text": "The WHO has developed a multinational coalition of vaccine scientists defining a  Global Target Product Profile  (TPP) for COVID-19, identifying favorable attributes of safe and effective vaccines under two broad categories: \"vaccines for the long-term protection of people at higher risk of COVID-19, such as healthcare workers\", and other vaccines to provide rapid-response immunity for new outbreaks. [ 4 ]  The international TPP team was formed to 1) assess the development of the most promising candidate vaccines; 2) map candidate vaccines and their clinical trial worldwide, publishing a frequently-updated \"landscape\" of vaccines in development; [ 21 ]  3) rapidly evaluate and screen for the most promising candidate vaccines simultaneously before they are tested in humans; and 4) design and coordinate a multiple-site, international  randomized controlled trial  \u00a0\u2013  the Solidarity trial for vaccines [ 22 ]  \u00a0\u2013  to enable simultaneous evaluation of the benefits and risks of different vaccine candidates under clinical trials in countries where there are high rates of COVID-19 disease, ensuring fast interpretation and sharing of results around the world. [ 4 ]  The WHO vaccine coalition will prioritize which vaccines should go into Phase II and III clinical trials, and determine harmonized Phase III protocols for all vaccines achieving the  pivotal trial  stage. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5486", "text": "The WHO announced in August 2021 that it will roll out the next phase Solidarity trial under the name  Solidarity PLUS  trial in 52 countries. The trial will enroll hospitalized patients to test three new drugs for potential treatment of COVID-19. These drugs include  artesunate ,  imatinib  and  infliximab . The selection of these therapies was done by an independent expert panel of WHO. These drugs are already used for other indications: artesunate is used for malaria, imatinib for cancers, and infliximab, an  anti-TNF  agent is used for Crohn's Disease and rheumatoid arthritis. The drugs will be donated for the purpose of trial by their manufacturers. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5487", "text": "Sucrosomial iron  is a new  oral iron  preparation containing  ferric pyrophosphate  covered by  phospholipids  plus  sucrose   ester  of  fatty acid  matrix. This allows the molecule to be absorbed in the  gastrointestinal  tract by trans-cellular, para-cellular and M-cells independently of  hepcidin  and due to gastro-resistant properties, it does not cause the side effects such as gastric irritation which is commonly associated to oral iron. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5488", "text": "Targeted therapy  or  molecularly targeted therapy  is one of the major modalities of medical treatment ( pharmacotherapy ) for  cancer , [ 1 ]  others being  hormonal therapy  and  cytotoxic   chemotherapy . As a form of  molecular medicine , targeted therapy blocks the growth of  cancer cells  by interfering with specific targeted  molecules  needed for  carcinogenesis  and  tumor  growth, [ 2 ]  rather than by simply interfering with all  rapidly dividing cells  (e.g. with traditional  chemotherapy ). Because most agents for targeted therapy are  biopharmaceuticals , the term  biologic therapy  is sometimes synonymous with  targeted therapy  when used in the context of cancer therapy (and thus distinguished from chemotherapy, that is, cytotoxic therapy). However, the modalities can be combined;  antibody-drug conjugates  combine biologic and cytotoxic mechanisms into one targeted therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5489", "text": "Another form of targeted therapy involves the use of nanoengineered enzymes to bind to a tumor cell such that the body's natural cell degradation process can digest the cell, effectively eliminating it from the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5490", "text": "Targeted cancer therapies are expected to be more effective than older forms of treatments and less harmful to normal cells. Many targeted therapies are examples of  immunotherapy  (using immune mechanisms for therapeutic goals) developed by the field of  cancer immunology . Thus, as  immunomodulators , they are one type of  biological response modifiers ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5491", "text": "The most successful targeted therapies are chemical entities that target or preferentially target a protein or enzyme that carries a mutation or other genetic alteration that is specific to cancer cells and not found in normal host tissue. [ 3 ]  One of the most successful molecular targeted therapeutics is  imatinib , marketed as Gleevec, which is a kinase inhibitor with exceptional affinity for the oncofusion protein  BCR-Abl  which is a strong driver of tumorigenesis in  chronic myelogenous leukemia . Although employed in other indications, imatinib is most effective targeting BCR-Abl. Other examples of molecular targeted therapeutics targeting mutated oncogenes, include PLX27892 which targets mutant B-raf in melanoma."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5492", "text": "There are targeted therapies for  lung cancer ,  colorectal cancer ,  head and neck cancer ,  breast cancer ,  multiple myeloma ,  lymphoma ,  prostate cancer ,  melanoma  and other cancers. [ 1 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5493", "text": "Biomarkers are usually required to aid the selection of patients who will likely respond to a given targeted therapy. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5494", "text": "Co-targeted therapy involves the use of one or more therapeutics aimed at multiple targets, for example PI3K and MEK, in an attempt to generate a synergistic response [ 5 ]  and prevent the development of drug resistance. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5495", "text": "The definitive experiments that showed that targeted therapy would reverse the malignant phenotype of tumor cells involved treating Her2/neu transformed cells with monoclonal antibodies in vitro and in vivo by Mark Greene's laboratory and reported from 1985. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5496", "text": "Some have challenged the use of the term, stating that drugs usually associated with the term are insufficiently selective. [ 10 ]  The phrase occasionally appears in  scare quotes : \"targeted therapy\". [ 11 ]   Targeted therapies may also be described as \"chemotherapy\" or \"non-cytotoxic chemotherapy\", as \"chemotherapy\" strictly means only \"treatment by chemicals\". But in typical medical and general usage \"chemotherapy\" is now mostly used specifically for \"traditional\" cytotoxic chemotherapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5497", "text": "The main categories of targeted therapy are currently  small molecules  and  monoclonal antibodies ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5498", "text": "Many are  tyrosine-kinase inhibitors ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5499", "text": "Several are in development and a few have been licensed by the FDA and the European Commission. Examples of licensed monoclonal antibodies include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5500", "text": "Many  antibody-drug conjugates  (ADCs) are being developed. See also  antibody-directed enzyme prodrug therapy  (ADEPT)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5501", "text": "In the U.S., the  National Cancer Institute 's   Molecular Targets Development Program  (MTDP) aims to identify and evaluate molecular targets that may be candidates for drug development."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5502", "text": "Tetrodocain  ( Korean :  \ud14c\ud2b8\ub85c\ub3c4\uce74\uc778\uc8fc\uc0ac\uc57d ) is medical injection produced by the  Korea Jangsaeng Joint Venture Company  ( \uc870\uc120\uc7a5\uc0dd\ud569\uc601\ud68c\uc0ac ) in  North Korea . The injection was first claimed to be invented by the company in 2004. [ 1 ]  According to the state-run  Korean Central News Agency  (KCNA), the main ingredient of the injection is  tetrodotoxin , isolated from  puffer  poisons, and operates as an  anaesthetic . [ 2 ]  It has been sold for international export on sites based in Russia and China. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5503", "text": "KCNA described the medicine as efficacious in treating a wide range of diseases, including  cancer ,  tuberculosis , chronic  hepatitis ,  pancreatitis  and  HIV/AIDS . [ 4 ] [ 5 ]  These claims have been deemed to be either exaggerated or false. [ 3 ]  The North Korean government also marketed its use in  drug detoxification  from  narcotics  such as  opium ,  cocaine  and  heroin . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5504", "text": "North Korea released a supposed clinical research thesis about the usage of tetrodocain for anesthetics in 2015. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5505", "text": "This  North Korea -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5506", "text": "Pharmacogenomics , often abbreviated \"PGx,\" is the study of the role of the  genome  in  drug  response. Its name ( pharmaco-  +  genomics ) reflects its combining of  pharmacology  and  genomics . Pharmacogenomics analyzes how the genetic makeup of a patient affects their response to drugs. [ 1 ]  It deals with the influence of  acquired  and  inherited  genetic variation on drug response, by correlating DNA  mutations  (including  point mutations ,  copy number variations , and  structural variations ) with  pharmacokinetic  (drug  absorption ,  distribution ,  metabolism , and  elimination ),  pharmacodynamic  (effects mediated through a drug's  biological targets ), and/or  immunogenic  endpoints. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5507", "text": "Pharmacogenomics aims to develop rational means to optimize  drug therapy , with regard to the patients'  genotype , to achieve maximum efficiency with minimal  adverse effects . [ 5 ]  It is hoped that by using pharmacogenomics,  pharmaceutical drug  treatments can deviate from what is dubbed as the \"one-dose-fits-all\" approach. Pharmacogenomics also attempts to eliminate trial-and-error in prescribing, allowing physicians to take into consideration their patient's genes, the functionality of these genes, and how this may affect the effectiveness of the patient's current or future treatments (and where applicable, provide an explanation for the failure of past treatments). [ 6 ] [ 7 ]  Such approaches promise the advent of  precision medicine  and even  personalized medicine , in which drugs and drug combinations are optimized for narrow subsets of patients or even for each individual's unique genetic makeup. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5508", "text": "Whether used to explain a patient's response (or lack of it) to a treatment, or to act as a predictive tool, it hopes to achieve better treatment outcomes and greater efficacy, and reduce drug toxicities and adverse drug reactions (ADRs). For patients who do not respond to a treatment, alternative therapies can be prescribed that would best suit their requirements. In order to provide pharmacogenomic recommendations for a given drug, two possible types of input can be used:  genotyping , or  exome  or whole  genome   sequencing . [ 10 ]  Sequencing provides many more data points, including detection of mutations that prematurely terminate the synthesized protein (early  stop codon ). [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5509", "text": "The term  pharmacogenomics  is often used interchangeably with  pharmacogenetics . Although both terms relate to drug response based on genetic influences, there are differences between the two.  Pharmacogenetics  is limited to  monogenic  phenotypes (i.e., single gene-drug interactions).  Pharmacogenomics  refers to polygenic drug response phenotypes and encompasses  transcriptomics ,  proteomics , and  metabolomics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5510", "text": "Pharmacokinetics  involves the absorption, distribution, metabolism, and elimination of pharmaceutics. These processes are often facilitated by enzymes such as drug transporters or drug metabolizing enzymes (discussed in-depth below). Variation in DNA loci responsible for producing these enzymes can alter their expression or activity so that their functional status changes. An increase, decrease, or loss of function for transporters or metabolizing enzymes can ultimately alter the amount of medication in the body and at the site of action. This may result in deviation from the medication's  therapeutic window  and result in either toxicity or loss of effectiveness."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5511", "text": "The majority of clinically actionable pharmacogenetic variation occurs in genes that code for drug-metabolizing enzymes, including those involved in both  phase I  and  phase II  metabolism. The  cytochrome P450  enzyme family is responsible for metabolism of 70-80% of all medications used clinically. [ 11 ]   CYP3A4 ,  CYP2C9 ,  CYP2C19 , and  CYP2D6  are major CYP enzymes involved in drug metabolism and are all known to be highly polymorphic. [ 11 ]  Additional drug-metabolizing enzymes that have been implicated in pharmacogenetic interactions include  UGT1A1  (a  UDP-glucuronosyltransferase ),  DPYD , and  TPMT . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5512", "text": "Many medications rely on  transporters  to cross cellular membranes in order to move between body fluid compartments such as the blood, gut lumen, bile, urine, brain, and cerebrospinal fluid. [ 13 ]  The major transporters include the  solute carrier ,  ATP-binding cassette , and  organic anion transporters . [ 13 ]  Transporters that have been shown to influence response to medications include  OATP1B1  ( SLCO1B1 ) and breast cancer resistance protein (BCRP) ( ABCG2 ). [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5513", "text": "Pharmacodynamics  refers to the impact a medication has on the body, or its mechanism of action."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5514", "text": "Drug targets are the specific sites where a medication carries out its pharmacological activity. The interaction between the drug and this site results in a modification of the target that may include inhibition or potentiation. [ 15 ]  Most of the pharmacogenetic interactions that involve drug targets are within the field of  oncology  and include  targeted therapeutics  designed to address  somatic mutations  (see also  Cancer Pharmacogenomics ). For example,  EGFR  inhibitors like  gefitinib  (Iressa) or  erlotinib  (Tarceva) are only indicated in patients carrying specific mutations to  EGFR . [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5515", "text": "Germline mutations  in drug targets can also influence response to medications, though this is an emerging subfield within pharmacogenomics. One well-established gene-drug interaction involving a germline mutation to a drug target is  warfarin  (Coumadin) and  VKORC1 , which codes for  vitamin K epoxide reductase (VKOR) . Warfarin binds to and inhibits VKOR, which is an important enzyme in the vitamin K cycle. [ 18 ]  Inhibition of VKOR prevents  reduction  of  vitamin K , which is a  cofactor  required in the formation of  coagulation  factors  II ,  VII ,  IX  and  X , and inhibitors  protein C  and  S . [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5516", "text": "Medications can have off-target effects (typically unfavorable) that arise from an interaction between the medication and/or its metabolites and a site other than the intended target. [ 20 ]  Genetic variation in the off-target sites can influence this interaction. The main example of this type of pharmacogenomic interaction is  glucose-6-phosphate-dehydrogenase (G6PD) . G6PD is the enzyme involved in the first step of the  pentose phosphate pathway  which generates NADPH (from NADP). NADPH is required for the production of reduced  glutathione  in  erythrocytes  and it is essential for the function of  catalase . [ 21 ]  Glutathione and catalase protect cells from oxidative stress that would otherwise result in cell  lysis . Certain variants in  G6PD  result in  G6PD deficiency , in which cells are more susceptible to oxidative stress. When medications that have a significant oxidative effect are administered to individuals who are G6PD deficient, they are at an increased risk of erythrocyte lysis that presents as  hemolytic anemia . [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5517", "text": "The  human leukocyte antigen  (HLA) system, also referred to as the  major histocompatibility complex  (MHC), is a complex of genes important for the  adaptive immune system . Mutations in the HLA complex have been associated with an increased risk of developing hypersensitivity reactions in response to certain medications. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5518", "text": "The  Clinical Pharmacogenetics Implementation Consortium  (CPIC) is \"an international consortium of individual volunteers and a small dedicated staff who are interested in facilitating use of pharmacogenetic tests for patient care. CPIC\u2019s goal is to address barriers to clinical implementation of pharmacogenetic tests by creating, curating, and posting freely available, peer-reviewed, evidence-based, updatable, and detailed gene/drug clinical practice guidelines. CPIC guidelines follow standardized formats, include systematic grading of evidence and clinical recommendations, use standardized terminology, are peer-reviewed, and are published in a journal (in partnership with Clinical Pharmacology and Therapeutics) with simultaneous posting to cpicpgx.org, where they are regularly updated.\" [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5519", "text": "The CPIC guidelines are \"designed to help clinicians understand HOW available genetic test results should be used to optimize drug therapy, rather than WHETHER tests should be ordered. A key assumption underlying the CPIC guidelines is that clinical high-throughput and pre-emptive (pre-prescription) genotyping will become more widespread, and that clinicians will be faced with having patients\u2019 genotypes available even if they have not explicitly ordered a test with a specific drug in mind. CPIC's guidelines, processes and projects have been endorsed by several professional societies.\" [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5520", "text": "In February 2020 the  FDA  published the Table of Pharmacogenetic Associations. [ 24 ]  For the gene-drug pairs included in the table, \"the FDA has evaluated and believes there is sufficient scientific evidence to suggest that subgroups of patients with certain genetic variants, or genetic variant-inferred phenotypes (such as affected subgroup in the table below), are likely to have altered drug metabolism, and in certain cases, differential therapeutic effects, including differences in risks of adverse events.\" [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5521", "text": "\"The information in this Table is intended primarily for prescribers, and patients should not adjust their medications without consulting their prescriber. This version of the table is limited to pharmacogenetic associations that are related to drug metabolizing enzyme gene variants, drug transporter gene variants, and gene variants that have been related to a predisposition for certain adverse events. The FDA recognizes that various other pharmacogenetic associations exist that are not listed here, and this table will be updated periodically with additional pharmacogenetic associations supported by sufficient scientific evidence.\" [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5522", "text": "The FDA Table of Pharmacogenomic Biomarkers in Drug Labeling lists FDA-approved drugs with pharmacogenomic information found in the drug labeling. \"Biomarkers in the table include but are not limited to germline or somatic gene variants (polymorphisms, mutations), functional deficiencies with a genetic etiology, gene expression differences, and chromosomal abnormalities; selected protein biomarkers that are used to select treatments for patients are also included.\" [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5523", "text": "The  Pharmacogenomics Knowledgebase (PharmGKB)  is an \" NIH -funded resource that provides information about how human genetic variation affects response to medications. PharmGKB collects, curates and disseminates knowledge about clinically actionable gene-drug associations and genotype-phenotype relationships.\" [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5524", "text": "There are many commercial laboratories around the world who offer pharmacogenomic testing as a  laboratory developed test (LDTs) . The tests offered can vary significantly from one lab to another, including genes and alleles tested for, phenotype assignment, and any clinical annotations provided. With the exception of a few direct-to-consumer tests, all pharmacogenetic testing requires an order from an authorized healthcare professional. In order for the results to be used in a clinical setting in the  United States , the laboratory performing the test much be  CLIA -certified. Other regulations may vary by country and state."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5525", "text": "Direct-to-consumer  (DTC) pharmacogenetic tests allow consumers to obtain pharmacogenetic testing without an order from a prescriber. DTC pharmacogenetic tests are generally reviewed by the FDA to determine the validity of test claims. [ 28 ]  The FDA maintains a  list of DTC genetic tests  that have been approved."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5526", "text": "There are multiple ways to represent a pharmacogenomic  genotype . A commonly used  nomenclature  system is to report  haplotypes  using a star (*) allele (e.g.,  CYP2C19  *1/*2).  Single-nucleotide polymorphisms  (SNPs) may be described using their assignment reference SNP cluster ID (rsID) or based on the location of the  base pair  or  amino acid  impacted. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5527", "text": "In 2017 CPIC published results of an expert  survey  to standardize terms related to clinical pharmacogenetic test results. [ 30 ]  Consensus for terms to describe allele functional status,  phenotype  for drug metabolizing enzymes, phenotype for drug transporters, and phenotype for high-risk genotype status was reached."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5528", "text": "The list below provides a few more commonly known applications of pharmacogenomics: [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5529", "text": "Pharmacogenomics may be applied to several areas of medicine, including  pain management ,  cardiology ,  oncology , and  psychiatry . A place may also exist in  forensic pathology , in which pharmacogenomics can be used to determine the cause of death in drug-related deaths where no findings emerge using  autopsy . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5530", "text": "In  cancer treatment , pharmacogenomics tests are used to identify which patients are most likely to respond to certain  cancer drugs . In behavioral health, pharmacogenomic tests provide tools for physicians and care givers to better manage medication selection and side effect amelioration. Pharmacogenomics is also known as companion diagnostics, meaning tests being bundled with drugs. Examples include  KRAS  test with  cetuximab  and  EGFR  test with  gefitinib . Beside efficacy, germline pharmacogenetics can help to identify patients likely to undergo severe toxicities when given cytotoxics showing impaired detoxification in relation with genetic polymorphism, such as canonical 5-FU. [ 32 ]  In particular, genetic deregulations affecting genes coding for  DPD ,  UGT1A1 ,  TPMT ,  CDA  and  CYP2D6  are now considered as critical issues for patients treated with 5-FU/capecitabine, irinotecan, mercaptopurine/azathioprine, gemcitabine/capecitabine/AraC and tamoxifen, respectively. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5531", "text": "In  cardiovascular disorders , the main concern is response to drugs including  warfarin ,  clopidogrel ,  beta blockers , and  statins . [ 10 ]  In patients with CYP2C19, who take clopidogrel, cardiovascular risk is elevated, leading to  medication package insert  updates by regulators. [ 34 ]  In patients with  type 2 diabetes ,  haptoglobin  (Hp) genotyping shows an effect on cardiovascular disease, with Hp2-2 at higher risk and supplemental vitamin E reducing risk by affecting  HDL . [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5532", "text": "In psychiatry, as of 2010, research has focused particularly on  5-HTTLPR  and  DRD2 . [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5533", "text": "Initiatives to spur adoption by clinicians include the  Ubiquitous Pharmacogenomics (U-PGx)  program in  Europe  and the Clinical Pharmacogenetics Implementation Consortium (CPIC) in the United States. [ 37 ]  In a 2017 survey of European clinicians, in the prior year two-thirds had not ordered a pharmacogenetic test. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5534", "text": "In 2010,  Vanderbilt University Medical Center  launched Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment (PREDICT); [ 39 ]  in 2015 survey, two-thirds of the clinicians had ordered a pharmacogenetic test. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5535", "text": "In 2019, the largest private health insurer,  UnitedHealthcare , announced that it would pay for genetic testing to predict response to psychiatric drugs. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5536", "text": "In 2020,  Canada's  4th largest health and dental insurer,  Green Shield Canada , announced that it would pay for pharmacogenetic testing and its associated clinical decision support software to optimize and personalize mental health prescriptions. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5537", "text": "A potential role for pharmacogenomics is to reduce the occurrence of  polypharmacy : it is theorized that with tailored drug treatments, patients will not need to take several medications to treat the same condition. Thus they could potentially reduce the occurrence of  adverse drug reactions , improve treatment outcomes, and save costs by avoiding purchase of some medications. For example, maybe due to inappropriate prescribing,  psychiatric  patients tend to receive more medications than age-matched non-psychiatric patients. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5538", "text": "The need for pharmacogenomically tailored drug therapies may be most evident in a survey conducted by the Slone Epidemiology Center at  Boston University  from February 1998 to April 2007. The study elucidated that an average of 82% of adults in the United States are taking at least one medication (prescription or nonprescription drug, vitamin/mineral, herbal/natural supplement), and 29% are taking five or more. The study suggested that those aged 65 years or older continue to be the biggest consumers of medications, with 17-19% in this age group taking at least ten medications in a given week. Polypharmacy has also shown to have increased since 2000 from 23% to 29%. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5539", "text": "Case A \u2013 Antipsychotic adverse reaction [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5540", "text": "Patient A has schizophrenia. Their treatment included a combination of ziprasidone, olanzapine, trazodone and  benztropine . The patient experienced dizziness and sedation, so they were tapered off ziprasidone and olanzapine, and transitioned to quetiapine. Trazodone was discontinued. The patient then experienced excessive sweating, tachycardia and neck pain, gained considerable weight and had hallucinations. Five months later, quetiapine was tapered and discontinued, with ziprasidone re-introduced into their treatment, due to the excessive weight gain. Although the patient lost the excessive weight they had gained, they then developed muscle stiffness,  cogwheeling , tremors and night sweats. When benztropine was added they experienced blurry vision. After an additional five months, the patient was switched from ziprasidone to aripiprazole. Over the course of 8 months, patient A gradually experienced more weight gain and sedation, and developed difficulty with their gait, stiffness, cogwheeling and dyskinetic ocular movements. A pharmacogenomics test later proved the patient had a CYP2D6 *1/*41, which has a predicted phenotype of IM and CYP2C19 *1/*2 with a predicted phenotype of IM as well."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5541", "text": "Case B \u2013 Pain Management [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5542", "text": "Patient B is a woman who gave birth by caesarian section. Her physician prescribed codeine for post-caesarian pain. She took the standard prescribed dose, but she experienced nausea and dizziness while she was taking codeine. She also noticed that her breastfed infant was lethargic and feeding poorly. When the patient mentioned these symptoms to her physician, they recommended that she discontinue codeine use. Within a few days, both the patient's and her infant's symptoms were no longer present. It is assumed that if the patient had undergone a pharmacogenomic test, it would have revealed she may have had a duplication of the gene CYP2D6, placing her in the Ultra-rapid metabolizer (UM) category, explaining her reactions to codeine use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5543", "text": "Case C \u2013 FDA Warning on Codeine Overdose for Infants [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5544", "text": "On February 20, 2013, the  FDA  released a statement addressing a serious concern regarding the connection between children who are known as CYP2D6 UM, and fatal reactions to codeine following  tonsillectomy  and/or  adenoidectomy  (surgery to remove the tonsils and/or adenoids). They released their strongest Boxed Warning to elucidate the dangers of CYP2D6 UMs consuming codeine. Codeine is converted to morphine by CYP2D6, and those who have UM phenotypes are in danger of producing large amounts of morphine due to the increased function of the gene. The morphine can elevate to life-threatening or fatal amounts, as became evident with the death of three children in August 2012."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5545", "text": "Although there appears to be a general acceptance of the basic tenet of pharmacogenomics amongst physicians and healthcare professionals, [ 49 ]  several challenges exist that slow the uptake, implementation, and standardization of pharmacogenomics. Some of the concerns raised by physicians include: [ 50 ] [ 49 ] [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5546", "text": "Issues surrounding the availability of the test include: [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5547", "text": "Although other factors contribute to the slow progression of pharmacogenomics (such as developing guidelines for clinical use), the above factors appear to be the most prevalent. Increasingly substantial evidence and industry body guidelines for clinical use of pharmacogenetics have made it a population wide approach to precision medicine. Cost, reimbursement, education, and easy use at the point of care remain significant barriers to widescale adoption."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5548", "text": "There has been call to move away from race and ethnicity in medicine and instead use genetic ancestry as a way to categorize patients. [ 52 ]  Some  alleles  that vary in frequency between specific populations have been shown to be associated with differential responses to specific  drugs . As a result, some disease-specific guidelines only recommend pharmacogenetic testing for populations where high-risk alleles are more common [ 53 ]  and, similarly, certain insurance companies will only pay for pharmacogenetic testing for beneficiaries of high-risk populations. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5549", "text": "In the early 2000s, handling genetic information as exceptional, including legal or regulatory protections, garnered strong support. It was argued that genomic information may need special policy and practice protections within the context of electronic health records (EHRs). [ 55 ]  In 2008, the  Genetic Information Nondiscrimination Act (GINA)  was enacted to protect patients from health insurance companies discriminating against an individual based on genetic information. [ 56 ] [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5550", "text": "More recently it has been argued that  genetic exceptionalism  is past its expiration date as we move into a blended genomic/big data era of medicine, yet exceptionalism practices continue to permeate clinical healthcare today. [ 58 ] [ 59 ]  Garrison et al. recently relayed a call to action to update verbiage from genetic exceptionalism to genomic contextualism in that we recognize a fundamental duality of genetic information. [ 60 ]  This allows room in the argument for different types of genetic information to be handled differently while acknowledging that genomic information is similar and yet distinct from other health-related information. [ 60 ]  Genomic contextualism would allow for a case-by-case analysis of the technology and the context of its use (e.g., clinical practice, research, secondary findings)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5551", "text": "Others argue that genetic information is indeed distinct from other health-related information but not to the extent of requiring legal/regulatory protections, similar to other sensitive health-related data such as HIV status. [ 61 ]  Additionally, Evans et al. argue that the EHR has sufficient privacy standards to hold other sensitive information such as social security numbers and that the fundamental nature of an EHR is to house highly personal information. [ 58 ]  Similarly, a systematic review reported that the public had concern over privacy of genetic information, with 60% agreeing that maintaining privacy was not possible; however, 96% agreed that a direct-to-consumer testing company had protected their privacy, with 74% saying their information would be similarly or better protected in an EHR. With increasing technological capabilities in EHRs, it is possible to mask or hide genetic data from subsets of providers and there is not consensus on how, when, or from whom genetic information should be masked. [ 55 ] [ 62 ]   Rigorous protection and masking of genetic information is argued to impede further scientific progress and clinical translation into routine clinical practices. [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5552", "text": "Pharmacogenomics was first recognized by  Pythagoras  around 510 BC when he made a connection between the dangers of  fava bean  ingestion with  hemolytic anemia  and  oxidative stress . In the  1950s , this identification was validated and attributed to deficiency of  G6PD  and is called  favism . [ 64 ] [ 65 ]  Although the first official publication was not until 1961, [ 66 ]  the unofficial beginnings of this science were around the 1950s. Reports of prolonged paralysis and fatal reactions linked to genetic variants in patients who lacked  butyrylcholinesterase  ('pseudocholinesterase') following succinylcholine injection during anesthesia were first reported in 1956. [ 2 ] [ 67 ]  The term pharmacogenetics was first coined in 1959 by  Friedrich Vogel  of  Heidelberg ,  Germany  (although some papers suggest it was 1957 or 1958). [ 68 ]  In the late 1960s,  twin studies  supported the inference of genetic involvement in drug metabolism, with identical twins sharing remarkable similarities in drug response compared to fraternal twins. [ 69 ]  The term pharmacogenomics first began appearing around the 1990s. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5553", "text": "The first FDA approval of a pharmacogenetic test was in 2005 [ 9 ]  (for  alleles  in  CYP2D6  and  CYP2C19 )"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5554", "text": "Computational advances have enabled cheaper and faster sequencing. [ 70 ]  Research has focused on  combinatorial chemistry , [ 71 ]  genomic mining, omic technologies, and  high throughput screening ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5555", "text": "As the cost per genetic test decreases, the development of personalized drug therapies will increase. [ 72 ]  Technology now allows for genetic analysis of hundreds of target genes involved in medication metabolism and response in less than 24 hours for under $1,000.  This a huge step towards bringing pharmacogenetic technology into everyday medical decisions. Likewise, companies like  deCODE genetics , MD Labs Pharmacogenetics,  Navigenics  and  23andMe  offer genome scans. The companies use the same  genotyping  chips that are used in GWAS studies and provide customers with a write-up of individual risk for various traits and diseases and testing for 500,000 known SNPs. Costs range from $995 to $2500 and include updates with new data from studies as they become available. The more expensive packages even included a telephone session with a genetics counselor to discuss the results. [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5556", "text": "Pharmacogenetics has become a controversial issue in the area of  bioethics . Privacy and confidentiality are major concerns. [ 74 ]  The evidence of benefit or risk from a genetic test may only be suggestive, which could cause dilemmas for providers. [ 74 ] :\u200a145\u200a  Drug development may be affected, with rare genetic variants possibly receiving less research. [ 74 ]  Access and patient autonomy are also open to discussion. [ 75 ] :\u200a680"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5557", "text": "Journals:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5558", "text": "2HI4"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5559", "text": "1544"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5560", "text": "13077"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5561", "text": "ENSG00000140505"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5562", "text": "ENSMUSG00000032310"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5563", "text": "P05177"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5564", "text": "P00186"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5565", "text": "NM_000761"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5566", "text": "NM_009993"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5567", "text": "NP_000752"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5568", "text": "NP_034123"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5569", "text": "Cytochrome P450 1A2  (abbreviated  CYP1A2 ), a member of the  cytochrome P450  mixed-function oxidase system, is involved in the metabolism of  xenobiotics  in the human body. [ 5 ]  In humans, the CYP1A2 enzyme is encoded by the  CYP1A2   gene . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5570", "text": "CYP1A2 is a member of the  cytochrome P450  superfamily of enzymes. The cytochrome P450 proteins are  monooxygenases  which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. CYP1A2 localizes to the  endoplasmic reticulum  and its expression is induced by some  polycyclic aromatic hydrocarbons  (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. Other xenobiotic substrates for this enzyme include  caffeine , aflatoxin B1, and  paracetamol  (acetaminophen). The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5571", "text": "CYP1A2 also metabolizes  polyunsaturated fatty acids  into signaling molecules that have physiological as well as pathological activities. It has monoxygenase activity for certain of these fatty acids in that it metabolizes  arachidonic acid  to 19-hydroxyeicosatetraenoic acid (19-HETE) (see  20-Hydroxyeicosatetraenoic acid ) but also has  epoxygenase  activity in that it metabolizes  docosahexaenoic acid  to  epoxides , primarily 19 R ,20 S -epoxyeicosapentaenoic acid and 19 S ,20 R -epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and similarly metabolizes  eicosapentaenoic acid  to epoxides, primarily 17 R ,18 S - eicosatetraenoic acid  and 17 S ,18 R -eicosatetraenoic acid isomers (termed 17,18-EEQ). [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5572", "text": "19-HETE is an inhibitor of  20-HETE , a broadly active signaling molecule, e.g., it constricts  arterioles , elevates blood pressure, promotes  inflammation  responses, and stimulates the growth of various types of tumor cells; however the in vivo ability and significance of 19-HETE in inhibiting 20-HETE has not been demonstrated. The EDP ( epoxydocosapentaenoic acid ) and EEQ ( epoxyeicosatetraenoic acid ) metabolites have a broad range of activities. In various animal models and in vitro studies on animal and human tissues, they decrease hypertension and pain perception; suppress inflammation; inhibit  angiogenesis , endothelial cell migration and endothelial cell proliferation; and inhibit the growth and metastasis of human breast and prostate cancer cell lines. [ 9 ] [ 10 ] [ 11 ] [ 12 ]  It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of the  omega-3 fatty acids , docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids. [ 9 ] [ 12 ] [ 13 ]   EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation by  epoxide hydrolases , particularly  soluble epoxide hydrolase , and therefore act locally."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5573", "text": "CYP1A2 is not regarded as being a major contributor to forming the aforementioned epoxides [ 12 ]  but could act locally in certain tissues to do so."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5574", "text": "The authoritative list of star  allele  nomenclature for CYP1A2 along with activity scores is kept by PharmVar. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5575", "text": "Expression of CYP1A2 appears to be induced by various dietary constituents. [ 15 ]  Vegetables such as cabbages, cauliflower and broccoli are known to increase levels of CYP1A2. Lower activity of CYP1A2 in South Asians appears to be due to cooking these vegetables in curries using ingredients such as  cumin  and  turmeric , ingredients known to inhibit the enzyme. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5576", "text": "A single 2006 paper found CYP1A2 to be involved in the metabolization of  caffeine , and the presence of alleles that make this metabolization slow have been associated with an increased risk of nonfatal  myocardial infarction  for those who drink a lot of  coffee  (4 or more cups per day). [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5577", "text": "Following is a table of selected  substrates ,  inducers  and  inhibitors  of CYP1A2."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5578", "text": "Inhibitors of CYP1A2 can be classified by their  potency , such as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5579", "text": "Moderate"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5580", "text": "Weak"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5581", "text": "Unspecified potency :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5582", "text": "Moderate inducers: [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5583", "text": "Unspecified potency:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5584", "text": "2F9Q ,  3QM4 ,  3TBG ,  3TDA ,  4WNT ,  4WNU ,  4WNV ,  4WNW ,  4XRY ,  4XRZ"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5585", "text": "1565"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5586", "text": "56448"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5587", "text": "ENSG00000272532"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5588", "text": "ENSMUSG00000061740"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5589", "text": "P10635"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5590", "text": "Q9JKY7"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5591", "text": "NM_000106 NM_001025161"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5592", "text": "NM_001163472 NM_019823"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5593", "text": "NP_000097 NP_001020332"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5594", "text": "NP_001156944 NP_062797"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5595", "text": "Cytochrome P450 2D6  ( CYP2D6 ) is an  enzyme  that in humans is encoded by the  CYP2D6   gene .  CYP2D6  is primarily expressed in the  liver . It is also highly expressed in areas of the  central nervous system , including the  substantia nigra ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5596", "text": "CYP2D6, a member of the  cytochrome P450  mixed-function oxidase system, is one of the most important enzymes involved in the  metabolism  of  xenobiotics  in the body. In particular, CYP2D6 is responsible for the metabolism and  elimination  of approximately 25% of clinically used drugs, via the addition or removal of certain  functional groups \u00a0\u2013 specifically,  hydroxylation ,  demethylation , and  dealkylation . [ 5 ]   CYP2D6 also activates some  prodrugs . This enzyme also metabolizes several endogenous substances, such as  N,N-Dimethyltryptamine ,  hydroxytryptamines ,  neurosteroids , and both  m -tyramine  and  p -tyramine  which CYP2D6 metabolizes into  dopamine  in the brain and liver. [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5597", "text": "Considerable variation exists in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence, for drugs that are metabolized by CYP2D6 (that is, are CYP2D6  substrates ), certain individuals will eliminate these drugs quickly (ultrarapid metabolizers) while others slowly (poor metabolizers).  If a drug is metabolized too quickly, it may decrease the drug's  efficacy  while if the drug is metabolized too slowly, toxicity may result. [ 8 ]   So, the dose of the drug may have to be adjusted to take into account of the speed at which it is metabolized by CYP2D6. [ 9 ]  Individuals who exhibit an ultrarapid metabolizer phenotype, metabolize  prodrugs , such as  codeine  or  tramadol , more rapidly, leading to higher than therapeutic levels. [ 10 ] [ 11 ]  A case study of the death of an infant breastfed by an ultrarapid metabolizer mother taking codeine impacted postnatal pain relief clinical practices, but was later debunked. [ 12 ]  These drugs may also cause serious toxicity in ultrarapid metabolizer patients when used to treat other post-operative pain, such as after  tonsillectomy . [ 13 ] [ 14 ] [ 15 ]  Other drugs may function as  inhibitors  of CYP2D6 activity or  inducers  of CYP2D6 enzyme expression that will lead to decreased or increased CYP2D6 activity respectively.  If such a drug is taken at the same time as a second drug that is a CYP2D6 substrate, the first drug may affect the elimination rate of the second through what is known as a  drug-drug interaction . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5598", "text": "The gene is located on  chromosome 22q 13.1. near two cytochrome P450  pseudogenes  (CYP2D7P and CYP2D8P). [ 16 ]  Among them, CYP2D7P originated from CYP2D6 in a stem lineage of great apes and humans, [ 17 ]  the CYP2D8P originated from CYP2D6 in a stem lineage of  Catarrhine  and  New World monkeys ' stem lineage. [ 18 ]   Alternatively spliced  transcript variants encoding different  isoforms  have been found for this gene. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5599", "text": "CYP2D6 shows the largest  phenotypical  variability among the CYPs, largely due to  genetic   polymorphism . The  genotype  accounts for normal, reduced, and non-existent CYP2D6 function in subjects. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice. [ 20 ] \nThe CYP2D6 function in any particular subject may be described as one of the following: [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5600", "text": "A patient's CYP2D6 phenotype is often clinically determined via the administration of  debrisoquine  (a selective CYP2D6 substrate) and subsequent plasma concentration assay of the debrisoquine  metabolite  (4-hydroxydebrisoquine). [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5601", "text": "The type of CYP2D6 function of an individual may influence the person's response to different doses of drugs that CYP2D6 metabolizes. The nature of the effect on the drug response depends not only on the type of CYP2D6 function, but also on the extent to which processing of the drug by CYP2D6 results in a chemical that has an effect that is similar, stronger, or weaker than the original drug, or no effect at all. For example, if CYP2D6 converts a drug that has a strong effect into a substance that has a weaker effect, then poor metabolizers (weak CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects; conversely, if CYP2D6 converts a different drug into a substance that has a greater effect than its parent chemical, then ultrarapid metabolizers (strong CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects. [ 23 ]  Information about how human genetic variation of CYP2D6 affects response to medications can be found in databases such PharmGKB, [ 24 ]  Clinical Pharmacogenetics Implementation Consortium (CPIC). [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5602", "text": "The variability in metabolism is due to multiple different  polymorphisms  of the  CYP2D6   allele , located on  chromosome 22 . Subjects possessing certain allelic variants will show normal, decreased, or no CYP2D6 function, depending on the allele. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice. [ 20 ]  The current known alleles of CYP2D6 and their clinical function can be found in databases such as PharmVar. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5603", "text": "Ethnicity is a factor in the occurrence of CYP2D6 variability. The reduction of the liver cytochrome CYP2D6 enzyme occurs approximately in 7\u201310% in  white  populations, and is lower in most other ethnic groups such as  Asians  and  African-Americans  at 2% each. A complete lack of CYP2D6 enzyme activity, wherein the individual has two copies of the polymorphisms that result in no CYP2D6 activity at all, is said to be about 1-2% of the population. [ 27 ]  The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among  Middle Eastern  and  North African  populations. [ 28 ] [ 29 ]  In  Ethiopia , a particularly high percentage (30%) of the population are ultrametabolizers. As a result, the analgesic codeine is banned in Ethiopia due to the high rate of adverse events associated with ultrarapid metabolism of codeine in this population.  [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5604", "text": "Caucasians with European descent predominantly (around 71%) have the functional group of CYP2D6 alleles, producing extensive metabolism, while functional alleles represent only around 50% of the allele frequency in populations of Asian descent. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5605", "text": "This variability is accounted for by the differences in the prevalence of various  CYP2D6  alleles among the populations\u2013approximately 10% of whites are intermediate metabolizers, due to decreased CYP2D6 function, because they appear to have the one ( heterozygous ) non-functional  CYP2D6*4  allele, [ 32 ]  while approximately 50% of Asians possess the decreased functioning  CYP2D6*10  allele. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5606", "text": "Following is a table of selected  substrates ,  inducers  and  inhibitors  of CYP2D6. Where classes of agents are listed, there may be exceptions within the class."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5607", "text": "Inhibitors of CYP2D6 can be classified by their  potency , such as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5608", "text": "Strong"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5609", "text": "Unspecified potency"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5610", "text": "In  enzymology , a  dihydropyrimidine dehydrogenase (NADP+)  ( EC   1.3.1.2 ) is an  enzyme  that  catalyzes  the  chemical reaction"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5611", "text": "Thus, the two  substrates  of this enzyme are  5,6-dihydrouracil  and  NADP + , whereas its 3  products  are  uracil ,  NADPH , and  H + ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5612", "text": "In humans the enzyme is encoded by the  DPYD   gene . [ 1 ] [ 2 ]  It is the initial and rate-limiting step in pyrimidine catabolism. [ citation needed ]  It catalyzes the reduction of  uracil  and  thymine . [ 3 ]  It is also involved in the degradation of the chemotherapeutic drugs  5-fluorouracil  and  tegafur . [ 4 ]  It also participates in  beta-alanine metabolism  and  pantothenate and coa biosynthesis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5613", "text": "The  systematic name  of this enzyme class is  5,6-dihydrouracil:NADP+ 5-oxidoreductase .  Other names in common use include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5614", "text": "As of late 2007, 5  structures  have been solved for this class of enzymes, with  PDB  accession codes  1GT8 ,  1GTE ,  1GTH ,  1H7W , and  1H7X ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5615", "text": "The protein is a  pyrimidine  catabolic enzyme and the initial and rate-limiting factor in the pathway of  uracil  and  thymidine   catabolism . Genetic deficiency of this enzyme results in an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving  5-fluorouracil  chemotherapy. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5616", "text": "Click on genes, proteins and metabolites below to link to respective articles. [ \u00a7 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5617", "text": "This  EC 1.3   enzyme -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5618", "text": "The following is a list of countries by  pharmaceutical   exports ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5619", "text": "Global sales from exported drugs and medicines by country total US$371.3 billion in 2018. Overall the value of drugs and medicine exports grew by an average 5.80% for all exporting countries since 2014 when drugs and medicines shipments were valued at $344.1 billion. Year over year, there was a 7.9% uptick from 2017 to 2018."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5620", "text": "Among continents, European countries sold the highest dollar value worth of exported drugs and medicines during 2018 with shipments from Europe totaling $295.8 billion or 79.70% of the global total. In second place were Asian pharmaceutical exporters at 10.70% while 8.10% of worldwide drugs and medicine shipments originated from North America."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5621", "text": "Smaller percentages came from drugs and medicines suppliers in Latin America (0.7%) excluding Mexico but including the Caribbean, Oceania (0.5%) led by Australia and New Zealand, then Africa (0.2%)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5622", "text": "The 4-digit Harmonized Tariff System code prefixes for drugs and medicines are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5623", "text": "Below are the 15 countries that exported the highest dollar value worth of drugs and medicines during 2021."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5624", "text": "By value, the listed 15 countries shipped 85.3% of all exported drugs and medicine for 2021."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5625", "text": "Among the above countries, the fastest-growing exporters of drugs and medicines from 2019 to 2020 were: Slovenia (up 42.2%), Ireland (up 28.8%), India (up 13.5%) and Italy (up 11.2%)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5626", "text": "Those countries that posted the slowest gains year over year were: Switzerland (up 0.7%), Canada (up 1.6%), United Kingdom (up 1.6%), United States (up 1.8%) and Germany (up 6.5%). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5627", "text": "Data is for 2014, in billions of  United States dollars , as reported by  The Observatory of Economic Complexity . Currently the top ten countries are listed, which account for more than 75% of the total market value, estimated to be $US 354 billions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5628", "text": "Note: The total was calculated excluding the figures for individual member states (for this purpose these include the UK) in order to avoid double-counting."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5629", "text": "These are Wikipedia lists about the  pharmaceutical industry . The pharmaceutical industry develops, produces, and markets  drugs  or  pharmaceuticals   licensed  for use as  medications .  Pharmaceutical companies  are allowed to deal in  generic  or  brand  medications and medical devices. They are subject to a  variety of laws  and regulations regarding the production, testing, and  marketing of drugs ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5630", "text": "The  pharmaceutical industry  is a  medical  industry that discovers, develops, produces and markets pharmaceutical  goods  such as  medications  and  medical devices . Medications are then administered to (or  self-administered  by)  patients  for  curing  or  prevention  of  disease , as well as alleviating  symptoms  of illness or  injury . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5631", "text": "Pharmaceutical companies  may deal in  generic ,  branded , or both, within different contexts. Generic materials are without the involvement of  intellectual property , whereas branded materials are protected by  chemical patents . The industry's various subdivisions include distinct areas, such as manufacturing  biologics  or  total synthesis . The industry is subject to a  variety of laws and regulations  that govern the  patenting , efficacy testing,  safety evaluation , and  marketing  of these drugs. The global pharmaceutical market produced treatments worth a total of $1,228.45 billion in 2020. The sector showed a  compound annual growth rate  (CAGR) of 1.8% in 2021, including the effects of the  COVID-19 pandemic . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5632", "text": "In historical terms, the pharmaceutical industry as an intellectual  concept  arose in the middle to late 1800s in  nation-states  with  developed economies  such as  Germany ,  Switzerland , and the  United States . Some  businesses  engaging in synthetic  organic chemistry , such as several firms generating  dyestuffs  derived from  coal tar  on a large scale, were seeking out new applications of their artificial  materials  in terms of human  health . This trend to increased  capital investment  occurred in tandem with the scholarly study of  pathology  as a  field  advancing significantly, and a variety of businesses set up cooperative relationships with  academic   laboratories  evaluating human injury and disease. Examples of industrial companies with a pharmaceutical focus that have endured to this day after such distant beginnings include  Bayer  (based out of Germany) and  Pfizer  (based out of the U.S.). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5633", "text": "The modern era of the pharmaceutical industry began with local  apothecaries  that expanded their traditional role of distributing  botanical drugs  such as  morphine  and  quinine  to wholesale manufacture in the mid-1800s. Intentional  drug discovery  from plants began with the extraction of  morphine  \u2013 an  analgesic  and sleep-inducing agent \u2013 from  opium  by the German apothecary assistant  Friedrich Sert\u00fcrner  somewhere between 1803 and 1805.  Sert\u00fcrner later named this compound after the Greek god of dreams,  Morpheus . Multinational corporations including  Merck ,  Hoffman-La Roche , Burroughs-Wellcome (now part of  Glaxo Smith Kline ),  Abbott Laboratories ,  Eli Lilly  and  Upjohn  (now part of  Pfizer ) began as local apothecary shops in the mid-1800s. By the late 1880s, German dye manufacturers had perfected the purification of individual  organic compounds  from  tar  and other mineral sources and had also established rudimentary methods in  organic chemical synthesis . [ 4 ]  The development of synthetic chemical methods allowed scientists to systematically vary the structure of chemical substances, and growth in the emerging science of  pharmacology  expanded their ability to evaluate the biological effects of these structural changes. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5634", "text": "By the 1890s, the profound effect of  adrenal  extracts on many different tissue types had been discovered, setting off a search both for the mechanism of chemical signaling and efforts to exploit these observations for the development of new drugs. The blood pressure raising and vasoconstrictive effects of adrenal extracts were of particular interest to surgeons as  hemostatic  agents and as treatment for shock, and a number of companies developed products based on adrenal extracts containing varying purities of the active substance. In 1897,  John Abel  at the  Johns Hopkins University  identified the active principle as  epinephrine , which he isolated in an impure state as the sulfate salt. Industrial chemist  J\u014dkichi Takamine  later developed a method for obtaining epinephrine in a pure state, and licensed the technology to  Parke-Davis . Parke-Davis marketed epinephrine under the trade name  Adrenalin . Injected epinephrine proved to be especially efficacious for the acute treatment of  asthma  attacks, and an inhaled version was sold in the United States until 2011 ( Primatene Mist ). [ 5 ] [ 6 ]  By 1929 epinephrine had been formulated into an inhaler for use in the treatment of nasal congestion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5635", "text": "While highly effective, the requirement for injection limited the use of epinephrine [ clarification needed ]  and orally active derivatives were sought. A structurally similar compound,  ephedrine , was identified by Japanese chemists in the  Ma Huang  plant and marketed by  Eli Lilly  as an oral treatment for asthma. Following the work of  Henry Dale  and  George Barger  at  Burroughs-Wellcome , academic chemist  Gordon Alles  synthesized  amphetamine  and tested it in asthma patients in 1929. The drug proved to have only modest anti-asthma effects but produced sensations of exhilaration and palpitations. Amphetamine was developed by  Smith, Kline and French  as a nasal decongestant under the trade name  Benzedrine Inhaler.  Amphetamine was eventually developed for the treatment of  narcolepsy ,  post-encephalitic parkinsonism , and mood elevation in depression and other psychiatric indications. It received approval as a New and Nonofficial Remedy from the  American Medical Association  for these uses in 1937, [ 7 ]  and remained in common use for depression until the development of  tricyclic antidepressants  in the 1960s. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5636", "text": "In 1903,  Hermann Emil Fischer  and  Joseph von Mering  disclosed their discovery that diethylbarbituric acid, formed from the reaction of diethylmalonic acid, phosphorus oxychloride and urea, induces sleep in dogs. The discovery was patented and licensed to  Bayer pharmaceuticals , which marketed the compound under the trade name  Veronal  as a sleep aid beginning in 1904. Systematic investigations of the effect of structural changes on potency and duration of action led to the discovery of  phenobarbital  at Bayer in 1911 and the discovery of its potent anti-epileptic activity in 1912. Phenobarbital was among the most widely used drugs for the treatment of  epilepsy  through the 1970s, and as of 2014, remains on the World Health Organizations list of essential medications. [ 8 ] [ 9 ]  The 1950s and 1960s saw increased awareness of the addictive properties and abuse potential of barbiturates and amphetamines and led to increasing restrictions on their use and growing government oversight of prescribers. Today, amphetamine is largely restricted to use in the treatment of  attention deficit disorder  and phenobarbital in the treatment of  epilepsy . [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5637", "text": "In 1958,  Leo Sternbach  discovered the first  benzodiazepine ,  chlordiazepoxide  (Librium). Dozens of other benzodiazepines have been developed and are in use, some of the more popular drugs being  diazepam  (Valium),  alprazolam  (Xanax),  clonazepam  (Klonopin), and  lorazepam  (Ativan). Due to their far superior safety and therapeutic properties, benzodiazepines have largely replaced the use of barbiturates in medicine, except in certain special cases. When it was later discovered that benzodiazepines, like barbiturates, significantly lose their effectiveness and can have serious side effects when taken long-term,  Heather Ashton  researched benzodiazepine dependence and developed a protocol to discontinue their use. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5638", "text": "A series of experiments performed from the late 1800s to the early 1900s revealed that  diabetes  is caused by the absence of a substance normally produced by the pancreas. In 1869,  Oskar Minkowski  and  Joseph von Mering  found that diabetes could be induced in dogs by surgical removal of the pancreas. In 1921, Canadian professor  Frederick Banting  and his student Charles Best repeated this study and found that injections of pancreatic extract reversed the symptoms produced by pancreas removal. Soon, the extract was demonstrated to work in people, but development of insulin therapy as a routine medical procedure was delayed by difficulties in producing the material in sufficient quantity and with reproducible purity. The researchers sought assistance from industrial collaborators at Eli Lilly and Co. based on the company's experience with large scale purification of biological materials. Chemist  George B. Walden  of Eli Lilly and Company found that careful adjustment of the pH of the extract allowed a relatively pure grade of insulin to be produced. Under pressure from Toronto University and a potential patent challenge by academic scientists who had independently developed a similar purification method, an agreement was reached for non-exclusive production of insulin by multiple companies. Prior to the discovery and widespread availability of insulin therapy the life expectancy of diabetics was only a few months. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5639", "text": "The development of drugs for the treatment of infectious diseases was a major focus of early research and development efforts; in 1900, pneumonia, tuberculosis, and diarrhea were the three leading causes of death in the United States and mortality in the first year of life exceeded 10%. [ 13 ] [ 14 ] [ failed verification ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5640", "text": "In 1911  arsphenamine , the first synthetic anti-infective drug, was developed by  Paul Ehrlich  and chemist  Alfred Bertheim  of the Institute of Experimental Therapy in Berlin. The drug was given the commercial name Salvarsan. [ 15 ]  Ehrlich, noting both the general toxicity of  arsenic  and the selective absorption of certain dyes by bacteria, hypothesized that an arsenic-containing dye with similar selective absorption properties could be used to treat bacterial infections. Arsphenamine was prepared as part of a campaign to synthesize a series of such compounds, and was found to exhibit partially selective toxicity. Arsphenamine proved to be the first effective treatment for  syphilis , a disease untl then had been incurable and led inexorably to severe skin ulceration, neurological damage, and death. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5641", "text": "Ehrlich's approach of systematically varying the chemical structure of synthetic compounds and measuring the effects of these changes on biological activity was pursued broadly by industrial scientists, including  Bayer  scientists Josef Klarer, Fritz Mietzsch, and  Gerhard Domagk . This work, also based on the testing of compounds available from the German dye industry, led to the development of  Prontosil , the first representative of the  sulfonamide  class of  antibiotics . Compared to arsphenamine, the sulfonamides had a broader spectrum of activity and were far less toxic, rendering them useful for infections caused by pathogens such as  streptococci . [ 17 ]  In 1939, Domagk received the  Nobel Prize in Medicine  for this discovery. [ 18 ] [ 19 ]  Nonetheless, the dramatic decrease in deaths from infectious diseases that occurred prior to  World War II  was primarily the result of improved public health measures such as clean water and less crowded housing, and the impact of anti-infective drugs and vaccines was significant mainly after World War II. [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5642", "text": "In 1928,  Alexander Fleming  discovered the antibacterial effects of  penicillin , but its exploitation for the treatment of human disease awaited the development of methods for its large scale production and purification. These were developed by a U.S. and British government-led consortium of pharmaceutical companies during the world war. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5643", "text": "There was early progress toward the development of vaccines throughout this period, primarily in the form of academic and government-funded basic research directed toward the identification of the pathogens responsible for common communicable diseases. In 1885,  Louis Pasteur  and  Pierre Paul \u00c9mile Roux  created the first  rabies vaccine . The first  diphtheria vaccines  were produced in 1914 from a mixture of  diphtheria toxin  and  antitoxin  (produced from the serum of an inoculated animal), but the safety of the inoculation was marginal and it was not widely used. The United States recorded 206,000 cases of diphtheria in 1921, resulting in 15,520 deaths. In 1923, parallel efforts by  Gaston Ramon  at the Pasteur Institute and  Alexander Glenny  at the Wellcome Research Laboratories (later part of  GlaxoSmithKline ) led to the discovery that a safer vaccine could be produced by treating diphtheria toxin with  formaldehyde . [ 23 ]  In 1944,  Maurice Hilleman  of Squibb Pharmaceuticals developed the first  vaccine against Japanese Encephalitis . [ 24 ]  Hilleman later moved to  Merck , where he played a key role in the development of vaccines against  measles ,  mumps ,  chickenpox ,  rubella ,  hepatitis A ,  hepatitis B , and  meningitis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5644", "text": "Prior to the 20th century, drugs were generally produced by small scale manufacturers with little regulatory control over manufacturing or claims of safety and efficacy. To the extent that such laws did exist, enforcement was lax. In the United States, increased regulation of vaccines and other biological drugs was spurred by tetanus outbreaks and deaths caused by the distribution of contaminated smallpox vaccine and diphtheria antitoxin. [ 25 ]  The Biologics Control Act of 1902 required that federal government grant premarket approval for every biological drug and for the process and facility producing such drugs. This was followed in 1906 by the  Pure Food and Drugs Act , which forbade the interstate distribution of adulterated or misbranded foods and drugs. A drug was considered misbranded if it contained alcohol, morphine, opium, cocaine, or any of several other potentially dangerous or addictive drugs, and if its label failed to indicate the quantity or proportion of such drugs. The government's attempts to use the law to prosecute manufacturers for making unsupported claims of efficacy were undercut by a Supreme Court ruling restricting the federal government's enforcement powers to cases of incorrect specification of the drug's ingredients. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5645", "text": "In 1937 over 100 people died after ingesting \" Elixir Sulfanilamide \" manufactured by S.E. Massengill Company of Tennessee. The product was formulated in  diethylene glycol , a highly toxic solvent that is now widely used as antifreeze. [ 27 ]  Under the laws extant at that time, prosecution of the manufacturer was possible only under the technicality that the product had been called an \"elixir\", which literally implied a solution in ethanol. In response to this episode, the U.S. Congress passed  the Federal Food, Drug, and Cosmetic Act of 1938 , which for the first time required pre-market demonstration of safety before a drug could be sold, and explicitly prohibited false therapeutic claims. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5646", "text": "The aftermath of  World War II  saw an explosion in the discovery of new classes of antibacterial drugs [ 29 ]  including the  cephalosporins  (developed by Eli Lilly based on the seminal work of  Giuseppe Brotzu  and  Edward Abraham ), [ 30 ] [ 31 ]   streptomycin  (discovered during a Merck-funded research program in Selman Waksman's laboratory [ 32 ] ), the tetracyclines [ 33 ]  (discovered at Lederle Laboratories, now a part of  Pfizer ), erythromycin (discovered at Eli Lilly and Co.) [ 34 ]  and their extension to an increasingly wide range of bacterial pathogens. Streptomycin, discovered during a Merck-funded research program in Selman Waksman's laboratory at Rutgers in 1943, became the first effective treatment for tuberculosis. At the time of its discovery, sanitoriums for the isolation of tuberculosis-infected people were an ubiquitous feature of cities in developed countries, with 50% dying within 5 years of admission. [ 32 ] [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5647", "text": "A  Federal Trade Commission  report issued in 1958 attempted to quantify the effect of antibiotic development on American public health. The report found that over the period 1946\u20131955, there was a 42% drop in the incidence of diseases for which antibiotics were effective and only a 20% drop in those for which antibiotics were not effective. The report concluded that \"it appears that the use of antibiotics, early diagnosis, and other factors have limited the epidemic spread and thus the number of these diseases which have occurred\". The study further examined mortality rates for eight common diseases for which antibiotics offered effective therapy (syphilis, tuberculosis, dysentery, scarlet fever, whooping cough, meningococcal infections, and pneumonia), and found a 56% decline over the same period. [ 36 ]  Notable among these was a 75% decline in deaths due to tuberculosis. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5648", "text": "During the years 1940\u20131955, the rate of decline in the U.S.  death rate  accelerated from 2% per year to 8% per year, then returned to the historical rate of 2% per year. The dramatic decline in the immediate post-war years has been attributed to the rapid development of new treatments and vaccines for infectious disease that occurred during these years. [ 39 ] [ 21 ] \nVaccine development continued to accelerate, with the most notable achievement of the period being  Jonas Salk 's 1954 development of the polio vaccine under the funding of the non-profit  National Foundation for Infantile Paralysis . The vaccine process was never patented but was instead given to pharmaceutical companies to manufacture as a low-cost  generic . In 1960 Maurice Hilleman of  Merck Sharp & Dohme  identified the  SV40  virus, which was later shown to cause tumors in many mammalian species. It was later determined that SV40 was present as a contaminant in polio vaccine lots that had been administered to 90% of the children in the United States. [ 40 ] [ 41 ]  The contamination appears to have originated both in the original cell stock and in monkey tissue used for production. In 2004 the  National Cancer Institute  announced that it had concluded that SV40 is not associated with cancer in people. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5649", "text": "Other notable new vaccines of the period include those for measles (1962,  John Franklin Enders  of Children's Medical Center Boston, later refined by Maurice Hilleman at Merck), Rubella (1969, Hilleman, Merck) and mumps (1967, Hilleman, Merck) [ 43 ]  The United States incidences of rubella, congenital rubella syndrome, measles, and mumps all fell by >95% in the immediate aftermath of widespread vaccination. [ 44 ]  The first 20 years of licensed  measles vaccination  in the U.S. prevented an estimated 52 million cases of the disease, 17,400 cases of  mental retardation , and 5,200 deaths. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5650", "text": "Hypertension is a risk factor for atherosclerosis, [ 46 ]   heart failure , [ 47 ]   coronary artery disease , [ 48 ] [ 49 ]   stroke , [ 50 ]   renal disease , [ 51 ] [ 52 ]  and  peripheral arterial disease , [ 53 ] [ 54 ]  and is the most important  risk factor  for  cardiovascular   morbidity  and  mortality , in  industrialized countries . [ 55 ]  Prior to 1940 approximately 23% of all deaths among persons over age 50 were attributed to hypertension. Severe cases of hypertension were treated by surgery. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5651", "text": "Early developments in the field of treating hypertension included quaternary ammonium ion sympathetic nervous system blocking agents, but these compounds were never widely used due to their severe side effects, because the long-term health consequences of high blood pressure had not yet been established, and because they had to be administered by injection."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5652", "text": "In 1952 researchers at Ciba discovered the first orally available vasodilator,  hydralazine . [ 57 ]  A major shortcoming of hydralazine monotherapy was that it lost its effectiveness over time ( tachyphylaxis ). In the mid-1950s Karl H. Beyer, James M. Sprague, John E. Baer, and Frederick C. Novello of  Merck and Co.  discovered and developed  chlorothiazide , which remains the most widely used antihypertensive drug today. [ 58 ]  This development was associated with a substantial decline in the mortality rate among people with hypertension. [ 59 ]  The inventors were recognized by a Public Health  Lasker Award  in 1975 for \"the saving of untold thousands of lives and the alleviation of the suffering of millions of victims of hypertension\". [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5653", "text": "A 2009 Cochrane review concluded that thiazide antihypertensive drugs reduce the risk of death ( RR  0.89), stroke (RR 0.63), coronary heart disease (RR 0.84), and cardiovascular events (RR 0.70) in people with high blood pressure. [ 61 ]  In the ensuring years other classes of antihypertensive drug were developed and found wide acceptance in combination therapy, including loop diuretics (Lasix/ furosemide ,  Hoechst Pharmaceuticals , 1963), [ 62 ]   beta blockers  ( ICI Pharmaceuticals , 1964) [ 63 ]   ACE inhibitors , and  angiotensin receptor blockers . ACE inhibitors reduce the risk of new onset kidney disease [RR 0.71] and death [RR 0.84] in diabetic patients, irrespective of whether they have hypertension. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5654", "text": "Prior to the Second World war, birth control was prohibited in many countries, and in the United States even the discussion of contraceptive methods sometimes led to prosecution under  Comstock laws . The history of the development of oral contraceptives is thus closely tied to the  birth control movement  and the efforts of activists  Margaret Sanger ,  Mary Dennett , and  Emma Goldman . Based on fundamental research performed by  Gregory Pincus  and synthetic methods for progesterone developed by  Carl Djerassi  at  Syntex  and by  Frank Colton  at  G.D. Searle & Co. , the first oral contraceptive,  Enovid , was developed by G.D. Searle & Co. and approved by the FDA in 1960. The original formulation incorporated vastly excessive doses of hormones, and caused severe side effects. Nonetheless, by 1962, 1.2 million American women were on the pill, and by 1965 the number had increased to 6.5 million. [ 65 ] [ 66 ] [ 67 ] [ 68 ]  The availability of a convenient form of temporary contraceptive led to dramatic changes in social mores including expanding the range of lifestyle options available to women, reducing the reliance of women on men for contraceptive practice, encouraging the delay of marriage, and increasing pre-marital co-habitation. [ 69 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5655", "text": "In the U.S., a push for revisions of the FD&C Act emerged from Congressional hearings led by Senator  Estes Kefauver  of Tennessee in 1959. The hearings covered a wide range of policy issues, including advertising abuses, questionable efficacy of drugs, and the need for greater regulation of the industry. While momentum for new legislation temporarily flagged under extended debate, a new tragedy emerged that underscored the need for more comprehensive regulation and provided the driving force for the passage of new laws."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5656", "text": "On 12 September 1960, an American licensee, the William S. Merrell Company of Cincinnati, submitted a new drug application for Kevadon ( thalidomide ), a  sedative  that had been marketed in Europe since 1956. The FDA medical officer in charge of reviewing the compound,  Frances Kelsey , believed that the data supporting the safety of thalidomide was incomplete. The firm continued to pressure Kelsey and the FDA to approve the application until November 1961, when the drug was pulled off the German market because of its association with grave congenital abnormalities. Several thousand newborns in Europe and elsewhere suffered the  teratogenic  effects of thalidomide. Without approval from the FDA, the firm distributed Kevadon to over 1,000 physicians there under the guise of investigational use. Over 20,000 Americans received thalidomide in this \"study,\" including 624 pregnant patients, and about 17 known newborns suffered the effects of the drug. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5657", "text": "The  thalidomide  tragedy resurrected Kefauver's bill to enhance drug regulation that had stalled in Congress, and the  Kefauver-Harris Amendment  became law on 10 October 1962. Manufacturers henceforth had to prove to FDA that their drugs were effective as well as safe before they could go on the US market. The FDA received authority to regulate the advertising of prescription drugs and to establish  good manufacturing practices . The law required that all drugs introduced between 1938 and 1962 had to be effective. A collaborative study by the U.S. Food and Drug Administration and the National Academy of Sciences showed that nearly 40 percent of these products were not effective. A similarly comprehensive study of over-the-counter products began ten years later. [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5658", "text": "In 1971,  Akira Endo , a Japanese biochemist working for the pharmaceutical company Sankyo, identified  mevastatin  (ML-236B), a molecule produced by the fungus  Penicillium citrinum , as an inhibitor of HMG-CoA reductase, a critical enzyme used by the body to produce cholesterol.  Animal trials  showed very good inhibitory effect as in  clinical trials , however a long-term study in dogs found toxic effects at higher doses and as a result mevastatin was believed to be too toxic for human use. Mevastatin was never marketed, because of its adverse effects of tumors, muscle deterioration, and sometimes death in laboratory dogs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5659", "text": "P. Roy Vagelos , chief scientist and later CEO of  Merck & Co , was interested, and made several trips to Japan starting in 1975. By 1978, Merck had isolated  lovastatin  (mevinolin, MK803) from the fungus  Aspergillus terreus , first marketed in 1987 as Mevacor. [ 71 ] [ 72 ] [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5660", "text": "In April 1994, the results of a Merck-sponsored study, the  Scandinavian Simvastatin Survival Study , were announced. Researchers tested  simvastatin , later sold by Merck as Zocor, on 4,444 patients with high cholesterol and heart disease. After five years, the study concluded the patients saw a 35% reduction in their cholesterol, and their chances of dying of a heart attack were reduced by 42%. [ 74 ]  In 1995, Zocor and Mevacor both made Merck over US$1 billion. Endo was awarded the 2006  Japan Prize , and the  Lasker-DeBakey Clinical Medical Research Award  in 2008. For his \"pioneering research into a new class of molecules\" for \"lowering cholesterol,\" [ sentence fragment ] [ 75 ] [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5661", "text": "Since several decades, biologics have been rising in importance in comparison with small molecules treatments. The  biotech  subsector, animal health and the Chinese pharmaceutical sector have also grown substantially. On the organisational side, big international pharma corporations have experienced a substantial decline of their value share. Also, the core generic sector (substitutions for off-patent brands) has been downvalued due to competition. [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5662", "text": "Torreya estimated the pharmaceutical industry to have a market valuation of US$7.03 trillion by February 2021 from which US$6.1 trillion is the value of the publicly traded companies. Small Molecules modality had 58.2% of the valuation share down from 84.6% in 2003. Biologics was up at 30.5% from 14.5%. The valuation share of Chinese Pharma grew from 2003 to 2021 from 1% to 12% overtaking Switzerland who is now ranked number 3 with 7.7%. The United States had still by far the most valued pharmaceutical industry with 40% of global valuation. [ 78 ]  2023 was a year of layoffs for at least 10,000 people across 129 public biotech firms globally, albeit most small firms; this was a significant increase in reductions versus 2022 was in part due to worsening global financial conditions and a reduction in investment by \"generalist investors\". [ 79 ]  Private firms also saw a significant reduction in  venture capital  investment in 2023, continuing a downward trend started in 2021, which also led to a reduction in  initial public offerings  being floated. [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5663", "text": "A 2022 article articulated this notion succinctly by saying \"In the business of drug development, deals can be just as important as scientific breakthroughs\", typically referred to as pharmaceutical M&A (for mergers and acquisitions). [ 80 ]  It highlighted that some of the most impactful of the remedies of the early 21st Century were only made possible through M&A activities, specifically noting  Keytruda  and  Humira . [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5664", "text": "Drug discovery  is the process by which potential  drugs  are discovered or designed. In the past, most drugs have been discovered either by isolating the active ingredient from traditional remedies or by  serendipitous  discovery. Modern  biotechnology  often focuses on understanding the  metabolic pathways  related to a  disease  state or  pathogen , and manipulating these pathways using  molecular biology  or  biochemistry . A great deal of early-stage drug discovery has traditionally been carried out by universities and research institutions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5665", "text": "Drug development  refers to activities undertaken after a compound is identified as a potential drug in order to establish its suitability as a medication. Objectives of drug development are to determine appropriate  formulation  and  dosing , as well as to establish  safety . Research in these areas generally includes a combination of  in vitro  studies,  in vivo  studies, and  clinical trials . The cost of late stage development has meant it is usually done by the larger pharmaceutical companies. [ 81 ]  The pharmaceuticals and biotechnology industry spends more than 15% of its net sales for Research & Development which is in comparison with other industries by far the highest share. [ 82 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5666", "text": "Often, large multinational corporations exhibit  vertical integration , participating in a broad range of drug discovery and development, manufacturing and quality control, marketing, sales, and distribution. Smaller organizations, on the other hand, often focus on a specific aspect such as discovering drug candidates or developing formulations. Often, collaborative agreements between research organizations and large pharmaceutical companies are formed to explore the potential of new drug substances. More recently, multi-nationals are increasingly relying on  contract research organizations  to manage drug development. [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5667", "text": "Drug  discovery and development are very expensive; of all compounds investigated for use in humans only a small fraction are eventually  approved  in most nations by government-appointed medical institutions or boards, who have to approve new  drugs  before they can be marketed in those countries. In 2010 18 NMEs (New Molecular Entities) were approved and three  biologics  by the FDA, or 21 in total, which is down from 26 in 2009 and 24 in 2008. On the other hand, there were only 18 approvals in total in 2007 and 22 back in 2006. Since 2001, the Center for Drug Evaluation and Research has averaged 22.9 approvals a year. [ 84 ] \nThis approval comes only after heavy investment in  pre-clinical development  and  clinical trials , as well as a commitment to ongoing  safety monitoring . Drugs which fail part-way through this process often incur large costs, while generating no revenue in return. If the cost of these failed drugs is taken into account, the cost of developing a successful new drug ( new chemical entity , or NCE), has been estimated at US$1.3 billion [ 85 ]  (not including  marketing expenses ). Professors Light and Lexchin reported in 2012, however, that the rate of approval for new drugs has been a relatively stable average rate of 15 to 25 for decades. [ 86 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5668", "text": "Industry-wide research and investment reached a record $65.3 billion in 2009. [ 87 ]  While the cost of research in the U.S. was about $34.2 billion between 1995 and 2010, revenues rose faster (revenues rose by $200.4 billion in that time). [ 86 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5669", "text": "A study by the consulting firm  Bain & Company  reported that the cost for discovering, developing and launching (which factored in marketing and other business expenses) a new drug (along with the prospective drugs that fail) rose over a five-year period to nearly $1.7 billion in 2003. [ 88 ]  According to Forbes, by 2010 development costs were between $4 billion to $11 billion per drug. [ 89 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5670", "text": "Some of these estimates also take into account the  opportunity cost  of investing capital many years before revenues are realized (see  Time-value of money ). Because of the very long time needed for discovery, development, and approval of pharmaceuticals, these costs can accumulate to nearly half the total expense. A direct consequence within the pharmaceutical industry value chain is that major pharmaceutical multinationals tend to increasingly outsource risks related to fundamental research, which somewhat reshapes the industry ecosystem with biotechnology companies playing an increasingly important role, and overall strategies being redefined accordingly. [ 90 ]  Some approved drugs, such as those based on re-formulation of an existing  active ingredient  (also referred to as Line-extensions) are much less expensive to develop."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5671", "text": "In the United States, new pharmaceutical products must be approved by the  Food and Drug Administration  (FDA) as being both safe and effective. This process generally involves submission of an  Investigational New Drug  (IND) filing with sufficient pre-clinical data to support proceeding with human trials. Following IND approval,  three phases  of progressively larger human clinical trials may be conducted.  Phase I  generally studies  toxicity  using healthy volunteers.  Phase II  can include  pharmacokinetics  and  dosing  in patients, and  Phase III  is a very large study of efficacy in the intended patient population. Following the successful completion of Phase III testing, a  New Drug Application  is submitted to the FDA. The FDA reviews the data and if the product is seen as having a positive benefit-risk assessment, approval to market the product in the US is granted. [ 91 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5672", "text": "A fourth phase of post-approval surveillance is also often required due to the fact that even the largest clinical trials cannot effectively predict the prevalence of rare side-effects.  Postmarketing surveillance  ensures that after marketing the safety of a drug is monitored closely. In certain instances, its indication may need to be limited to particular patient groups, and in others the substance is withdrawn from the market completely."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5673", "text": "The FDA provides information about approved drugs at the Orange Book site. [ 92 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5674", "text": "In the UK, the  Medicines and Healthcare products Regulatory Agency  (MHRA) approves and evaluates drugs for use. Normally an approval in the UK and other European countries comes later than one in the USA. Then it is the  National Institute for Health and Care Excellence  (NICE), for England and Wales, who decides if and how the  National Health Service  (NHS) will allow (in the sense of paying for) their use. The  British National Formulary  is the core guide for pharmacists and clinicians."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5675", "text": "In many non-US western countries, a 'fourth hurdle' of  cost effectiveness analysis  has developed before new technologies can be provided. This focuses on the 'efficacy price tag' (in terms of, for example, the cost per  QALY ) of the technologies in question. In England and Wales NICE decides whether and in what circumstances drugs and technologies will be made available by the NHS, whilst similar arrangements exist with the  Scottish Medicines Consortium  in Scotland, and the  Pharmaceutical Benefits Advisory Committee  in Australia. A product must pass the threshold for cost-effectiveness if it is to be approved. Treatments must represent 'value for money' and a net benefit to society."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5676", "text": "There are  special rules  for certain rare diseases (\"orphan diseases\") in several major drug regulatory territories. For example, diseases involving fewer than 200,000 patients in the United States, or larger populations in certain circumstances are subject to the Orphan Drug Act. [ 93 ]  Because medical research and development of drugs to treat such diseases is financially disadvantageous, companies that do so are rewarded with tax reductions, fee waivers, and market exclusivity on that drug for a limited time (seven years), regardless of whether the drug is protected by patents."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5677", "text": "In 2011, global spending on prescription drugs topped $954 billion, even as growth slowed somewhat in Europe and North America. The United States accounts for more than a third of the global pharmaceutical market, with $340 billion in annual sales followed by the EU and Japan. [ 95 ]  Emerging markets such as China, Russia, South Korea and Mexico outpaced that market, growing a huge 81 percent. [ 96 ] [ 97 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5678", "text": "The top ten best-selling drugs of 2013 totaled $75.6 billion in sales, with the anti-inflammatory drug  Humira  being the best-selling drug worldwide at $10.7 billion in sales. The second and third best selling were Enbrel and Remicade, respectively. [ 98 ]  The top three best-selling drugs in the United States in 2013 were Abilify ($6.3 billion,) Nexium ($6 billion) and Humira ($5.4 billion). [ 99 ]  The best-selling drug ever,  Lipitor , averaged $13 billion annually and netted $141 billion total over its lifetime before Pfizer's patent expired in November 2011."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5679", "text": "IMS Health  publishes an analysis of trends expected in the pharmaceutical industry in 2007, including increasing profits in most sectors despite loss of some patents, and new 'blockbuster' drugs on the horizon. [ 100 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5680", "text": "Depending on a number of considerations, a company may apply for and be granted a  patent  for the drug, or the process of producing the drug, granting exclusivity rights typically for about 20 years. [ 101 ]  However, only after rigorous study and testing, which takes 10 to 15 years on average, will governmental authorities grant permission for the company to market and sell the drug. [ 102 ]  Patent protection enables the owner of the patent to recover the costs of research and development through high profit margins for the  branded  drug. When the patent protection for the drug expires, a  generic drug  is usually developed and sold by a competing company. The development and approval of generics is less expensive, allowing them to be sold at a lower price. Often the owner of the branded drug will introduce a generic version before the patent expires in order to get a head start in the generic market. [ 103 ]  Restructuring has therefore become routine, driven by the patent expiration of products launched during the industry's \"golden era\" in the 1990s and companies' failure to develop sufficient new blockbuster products to replace lost revenues. [ 104 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5681", "text": "In the U.S., the value of prescriptions increased over the period of 1995 to 2005 by 3.4 billion annually, a 61 percent increase.  Retail sales of prescription drugs  jumped 250 percent from $72 billion to $250 billion, while the average price of prescriptions more than doubled from $30 to $68. [ 105 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5682", "text": "Advertising is common in healthcare journals as well as through more mainstream media routes. In some countries, notably the US, they are allowed to advertise directly to the general public. Pharmaceutical companies generally employ salespeople (often called 'drug reps' or, an older term, 'detail men') to market directly and personally to physicians and other healthcare providers. In some countries, notably the US,  pharmaceutical companies also employ lobbyists  to influence politicians. Marketing of prescription drugs in the US is regulated by the federal  Prescription Drug Marketing Act of 1987 . The pharmaceutical marketing plan incorporates the spending plans, channels, and thoughts which will take the drug association, and its items and administrations, forward in the current scene."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5683", "text": "The book  Bad Pharma  also discusses the influence of drug representatives, how ghostwriters are employed by the drug companies to write papers for academics to publish, how independent the academic journals really are, how the drug companies finance doctors' continuing education, and how patients' groups are often funded by industry. [ 106 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5684", "text": "Since the 1980s, new methods of marketing for prescription drugs to consumers have become important. Direct-to-consumer media advertising was legalised in the FDA Guidance for Industry on Consumer-Directed Broadcast Advertisements."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5685", "text": "There has been increasing controversy surrounding pharmaceutical marketing and influence. There have been accusations and findings of influence on doctors and other health professionals through drug reps including the constant provision of marketing 'gifts' and biased information to health professionals; [ 107 ]  highly prevalent advertising in journals and conferences; funding independent healthcare organizations and health promotion campaigns; lobbying physicians and politicians (more than any other industry in the US [ 108 ] ); sponsorship of  medical schools  or nurse training; sponsorship of continuing educational events, with influence on the curriculum; [ 109 ]  and hiring physicians as paid consultants on medical advisory boards."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5686", "text": "Some advocacy groups, such as  No Free Lunch  and  AllTrials , have criticized the effect of drug marketing to physicians because they say it biases physicians to prescribe the marketed drugs even when others might be cheaper or better for the patient. [ 110 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5687", "text": "There have been related accusations of  disease mongering [ 111 ]  (over-medicalising) to expand the market for medications. An inaugural conference on that subject took place in Australia in 2006. [ 112 ]  In 2009, the Government-funded  National Prescribing Service  launched the \"Finding Evidence \u2013 Recognising Hype\" program, aimed at educating  GPs  on methods for independent drug analysis. [ 113 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5688", "text": "Meta-analyses have shown that psychiatric studies sponsored by pharmaceutical companies are several times more likely to report positive results, and if a drug company employee is involved the effect is even larger. [ 114 ] [ 115 ] [ 116 ]  Influence has also extended to the training of doctors and nurses in medical schools, which is being fought."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5689", "text": "It has been argued that the design of the  Diagnostic and Statistical Manual of Mental Disorders  and the expansion of the criteria represents an increasing medicalization of human nature, or \" disease mongering \", driven by drug company influence on psychiatry. [ 117 ]  The potential for direct  conflict of interest  has been raised, partly because roughly half the authors who selected and defined the DSM-IV psychiatric disorders had or previously had financial relationships with the pharmaceutical industry. [ 118 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5690", "text": "In the US, starting in 2013, under the Physician Financial Transparency Reports (part of the Sunshine Act), the Centers for Medicare & Medicaid Services has to collect information from applicable manufacturers and group purchasing organizations in order to report information about their financial relationships with physicians and hospitals. Data are made public in the Centers for Medicare & Medicaid Services website. The expectation is that relationship between doctors and Pharmaceutical industry will become fully transparent. [ 119 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5691", "text": "In a report conducted by  OpenSecrets , there were more than 1,100 lobbyists working in some capacity for the pharmaceutical business in 2017. In the first quarter of 2017, the health products and pharmaceutical industry spent $78 million on lobbying members of the United States Congress. [ 120 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5692", "text": "The pricing of pharmaceuticals is becoming a major challenge for health systems. [ 121 ]  A November 2020 study by the  West Health  Policy Center stated that more than 1.1 million  senior citizens  in the U.S.  Medicare  program are expected to die prematurely over the next decade because they will be unable to afford their prescription medications, requiring an additional $17.7 billion to be spent annually on avoidable medical costs due to health complications. [ 122 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5693", "text": "Ben Goldacre  has argued that regulators \u2013 such as the  Medicines and Healthcare products Regulatory Agency  (MHRA) in the UK, or the  Food and Drug Administration  (FDA) in the United States \u2013 advance the interests of the drug companies rather than the interests of the public due to revolving door exchange of employees between the regulator and the companies and friendships develop between regulator and company employees. [ 123 ]  He argues that regulators do not require that new drugs offer an improvement over what is already available, or even that they be particularly effective. [ 123 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5694", "text": "Others have argued that excessive regulation suppresses therapeutic innovation and that the current cost of regulator-required clinical trials prevents the full exploitation of new genetic and biological knowledge for the treatment of human disease. A 2012 report by the President's Council of Advisors on Science and Technology made several key recommendations to reduce regulatory burdens to new drug development, including 1) expanding the FDA's use of accelerated approval processes, 2) creating an expedited approval pathway for drugs intended for use in narrowly defined populations, and 3) undertaking pilot projects designed to evaluate the feasibility of a new, adaptive drug approval process. [ 124 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5695", "text": "Pharmaceutical fraud  involves deceptions which bring financial gain to a pharmaceutical company. It affects individuals and  public  and private insurers. There are several different schemes [ 125 ]  used to defraud the  health care system  which are particular to the pharmaceutical industry. These include: Good Manufacturing Practice (GMP) Violations, Off Label Marketing, Best Price Fraud, CME Fraud, Medicaid Price Reporting, and Manufactured Compound Drugs. [ 126 ]  Of this amount $2.5 billion was recovered through  False Claims Act  cases in FY 2010. Examples of fraud cases include the  GlaxoSmithKline  $3 billion settlement,  Pfizer  $2.3 billion settlement and  Merck & Co.  $650 million settlement. Damages from fraud can be recovered by use of the  False Claims Act , most commonly under the  qui tam  provisions which rewards an individual for being a \" whistleblower \", or  relator (law) . [ 127 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5696", "text": "Every major company selling atypical antipsychotics\u2014 Bristol-Myers Squibb ,  Eli Lilly and Company ,  Pfizer ,  AstraZeneca  and  Johnson & Johnson \u2014has either settled recent government cases, under the False Claims Act, for hundreds of millions of dollars or is currently under investigation for possible health care fraud. Following charges of illegal marketing, two of the settlements set records in 2009 for the largest criminal fines ever imposed on corporations. One involved Eli Lilly's antipsychotic  Zyprexa , and the other involved  Bextra , an anti-inflammatory medication used for arthritis. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic,  Geodon ; Pfizer settled that part of the claim for $301 million, without admitting any wrongdoing. [ 128 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5697", "text": "In July 2012,  GlaxoSmithKline  pleaded guilty to criminal charges and agreed to a $3 billion settlement of the largest health-care fraud case in the U.S. and the largest payment by a drug company. [ 129 ]  The settlement is related to the company's illegal promotion of prescription drugs, its failure to report safety data, [ 130 ]   bribing  doctors, and promoting medicines for uses for which they were not licensed. The drugs involved were  Paxil ,  Wellbutrin ,  Advair ,  Lamictal , and  Zofran  for off-label, non-covered uses. Those and the drugs  Imitrex ,  Lotronex ,  Flovent , and  Valtrex  were involved in the  kickback scheme . [ 131 ] [ 132 ] [ 133 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5698", "text": "The following is a list of the four largest settlements reached with pharmaceutical companies from 1991 to 2012, rank ordered by the size of the total settlement. Legal claims against the pharmaceutical industry have varied widely over the past two decades, including  Medicare and Medicaid fraud ,  off-label  promotion, and inadequate manufacturing practices. [ 134 ] [ 135 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5699", "text": "In May 2015, the  New England Journal of Medicine  emphasized the importance of pharmaceutical industry-physician interactions for the development of novel treatments, and argued that moral outrage over industry malfeasance had unjustifiably led many to overemphasize the problems created by financial conflicts of interest. The article noted that major healthcare organizations, such as National Center for Advancing Translational Sciences of the National Institutes of Health, the President's Council of Advisors on Science and Technology, the World Economic Forum, the Gates Foundation, the Wellcome Trust, and the Food and Drug Administration had encouraged greater interactions between physicians and industry in order to improve benefits to patients. [ 140 ] [ 141 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5700", "text": "In November 2020 several pharmaceutical companies announced successful trials of COVID-19 vaccines, with efficacy\nof 90 to 95% in preventing infection. Per company announcements and data reviewed by external analysts, these vaccines are priced at $3 to $37 per dose. [ 142 ]  The Wall Street Journal ran an editorial calling for this achievement to be recognized with a Nobel Peace Prize. [ 143 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5701", "text": "Doctors Without Borders  warned that high prices and monopolies on medicines, tests, and vaccines would prolong the pandemic and cost lives. They urged governments to prevent profiteering, using  compulsory licenses  as needed, as had already been done by Canada, Chile, Ecuador, Germany, and Israel. [ 144 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5702", "text": "On 20 February, 46 US lawmakers called for the US government not to grant monopoly rights when giving out taxpayer development money for any coronavirus vaccines and treatments, to avoid giving exclusive control of prices and availability to private manufacturers. [ 145 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5703", "text": "In the United States, the government signed agreements in which research and development or the building of manufacturing plants for potential COVID-19 therapeutics was subsidized. Typically, the agreement involved the government taking ownership of a certain number of doses of the product without further payment. For example, under the auspices of Operation Warp Speed in the United States, the government subsidized research related to COVID-19 vaccines and therapeutics at Regeneron, [ 146 ]  Johnson and Johnson, Moderna, AstraZeneca, Novavax, Pfizer, and GSK. Typical terms involved research subsidies of $400 million to $2 billion, and included government ownership of the first 100 million doses of any COVID-19 vaccine successfully developed. [ 147 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5704", "text": "American pharmaceutical company  Gilead  sought and obtained  orphan drug status  for  remdesivir  from the US  Food and Drug Administration  (FDA) on 23 March 2020. This provision is intended to encourage the development of drugs affecting fewer than 200,000 Americans by granting strengthened and extended legal monopoly rights to the manufacturer, along with waivers on taxes and government fees. [ 148 ] [ 149 ]  Remdesivir is a candidate for treating COVID-19; at the time the status was granted, fewer than 200,000 Americans had COVID-19, but numbers were climbing rapidly as the  COVID-19 pandemic  reached the US, and crossing the threshold soon was considered inevitable. [ 148 ] [ 149 ]  Remdesivir was developed by Gilead with over $79 million in U.S. government funding. [ 149 ]  In May 2020, Gilead announced that it would provide the first 940,000 doses of remdesivir to the federal government free of charge. [ 150 ]  After facing strong public reactions, Gilead gave up the \"orphan drug\" status for remdesivir on 25 March. [ 151 ]  Gilead retains 20-year remdesivir patents in more than 70 countries. [ 144 ]  In May 2020, the company further announced that it was in discussions with several generics companies to provide rights to produce remdesivir for developing countries, and with the Medicines Patent Pool to provide broader generic access. [ 152 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5705", "text": "Patents have been criticized in the developing world, as they are thought [ who? ]  to reduce access to existing medicines. [ 153 ]  Reconciling patents and universal access to medicine would require an efficient international policy of  price discrimination . Moreover, under the  TRIPS  agreement of the  World Trade Organization , countries must allow pharmaceutical products to be patented. In 2001, the WTO adopted the  Doha Declaration , which indicates that the TRIPS agreement should be read with the goals of public health in mind, and allows some methods for circumventing pharmaceutical monopolies: via  compulsory licensing  or  parallel imports , even before patent expiration. [ 154 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5706", "text": "In March 2001, 40 multi-national pharmaceutical companies brought litigation against  South Africa  for its  Medicines Act , which allowed the generic production of antiretroviral drugs (ARVs) for treating HIV, despite the fact that these drugs were on-patent. [ 155 ]  HIV was and is an  epidemic  in South Africa, and ARVs at the time cost between US$10,000 and US$15,000 per patient per year. This was unaffordable for most South African citizens, and so the South African government committed to providing ARVs at prices closer to what people could afford. To do so, they would need to ignore the patents on drugs and produce generics within the country (using a compulsory license), or import them from abroad. After international protest in favour of public health rights (including the collection of 250,000 signatures by  M\u00e9decins Sans Fronti\u00e8res ), the governments of several developed countries (including The Netherlands, Germany, France, and later the US) backed the South African government, and the case was dropped in April of that year. [ 156 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5707", "text": "In 2016, GlaxoSmithKline (the world's sixth largest pharmaceutical company) announced that it would be dropping its patents in poor countries so as to allow independent companies to make and sell versions of its drugs in those areas, thereby widening the public access to them. [ 157 ]  GlaxoSmithKline published a list of 50 countries they would no longer hold patents in, affecting one billion people worldwide."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5708", "text": "In 2011 four of the top 20 corporate charitable donations and eight of the top 30 corporate charitable donations came from pharmaceutical manufacturers. The bulk of corporate charitable donations (69% as of 2012) comes by way of non-cash charitable donations, the majority of which again were donations contributed by pharmaceutical companies. [ 158 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5709", "text": "Charitable programs and drug discovery & development efforts by pharmaceutical companies include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5710", "text": "ADEXA  is the  German   trade union  for all pharmaceutical employees, and also for trainees and students. ADEXA negotiates the salaries and working conditions in German public pharmacies with the employers\u2019 federations. The headquarters of the trade union is in  Hamburg ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5711", "text": "Pharmaceutical employees being organized in this trade union are entitled to all agreed conditions of pay and contract terms such as overtime pay, bonuses and extra holiday entitlement."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5712", "text": "For their members, ADEXA offers also legal advice and protection, lobbying, media representation and information concerning occupational politics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5713", "text": "In 1949, the Tarifgemeinschaft deutscher angestellter Apotheker was founded. [ 1 ]  In 1954, it was dissolved, and a new organisation, the Bundesverband der Angestellten in Apotheken, was founded as its successor. [ 2 ]  In 2004, it was renamed ADEXA. [ 3 ]  In 2012, ADEXA joined  EPhEU  (the European Association of Employed community Pharmacists in Europe. [ 4 ]  EPhEU is a network representing the interests of employed community pharmacists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5714", "text": "This  Hamburg -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5715", "text": "Obi Peter Adigwe  is a Nigerian pharmacist and a doctor of pharmaceutical policy. [ 1 ]  He was appointed the Director General of the  National Institute for Pharmaceutical Research and Development  (NIPRD) with effect from 10 August 2018  [ 2 ] [ 3 ]  by the former president of the Federal Republic of Nigeria,  Muhammadu Buhari . Before his appointment as NIPRD boss, he was the Executive Secretary of the Pharmaceutical Manufacturers Group of the Manufacturers' Association of Nigeria and holds a Doctor of Pharmaceutical Policy at the  University of Leeds , United Kingdom."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5716", "text": "Dr. Adigwe was the pioneer Head of the Health Policy Research and Development (HPRD) Unit at the  National Assembly (Nigeria) , where he formulated research and development strategies in Health Policy with a view to developing an Evidence-Based approach to Legislation and Policy formulation in Nigeria. He also developed innovative and contextual capacity-building modules for Healthcare Professionals, as well as coordinated research that contributed to Health System strengthening. He has a significant number of peer-reviewed publications including the first Knowledge Attitudes and Perceptions study on  Ebola  in  Nigeria , as well as a seminal paper on Rational Use of Medicines. While in the United Kingdom, he was the lead author of the article \u201cRewrite the Script for Non-medical Prescribing\u201d which contributed to prescribing policy reforms in the  Parliament of the United Kingdom ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5717", "text": "Throughout his career, Adigwe has pioneered a significant number of innovative research and developmental projects. He led teams that secured various high-profile grants including a Clinical Trials Grant from the  ECOWAS , an API Grant from  African Export\u2013Import Bank , a Drug Development Mega Grant from  Tertiary Education Trust Fund  and a  European Union  /  Government of Bulgaria  Grant supporting Local Production of Vaccines in the  Nigerian  setting. Based on the NIPRD study led by Dr Adigwe, the European Union  EU  announced the award of an \u20ac18m grant to Nigeria, [ 4 ]  as a catalyst for vaccines research."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5718", "text": "Dr. Obi Peter Adigwe has headed and served on numerous Committees and Expert Working Groups at both national and international levels, including the D8,  United Nations , World Health Organisation [WHO], The  African Union  and  ECOWAS . Dr. Adigwe was conferred with Nigeria's highest Productivity Award by the  President of Nigeria  in recognition of his hard work, productivity and excellence in National Developmental Initiatives. Adigwe is a Fellow of the Nigerian Academy of Pharmacy, as well as of the West African Institute of Public Health."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5719", "text": "Obi Adigwe attended  University of Jos , Jos, obtaining a bachelor's degree in pharmacy in 2000. He proceeded to the  University of Edinburgh , UK and obtained MSc in Global Health and Public Policy in 2008 and a Doctorate degree (PhD) in Pharmaceutical Policy from the  University of Leeds , UK, in 2012. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5720", "text": "Obi Adigwe started his career as a pharmacist at the  National Assembly (Nigeria) 's Pharmacy Department, FCT, Abuja Nigeria, in 2005 and remained there till 2007. He proceeded to become the Senior Project Officer at the Pharmacy Department Unit at  University of Leeds , United Kingdom, from 2010 to 2012. [ 6 ] \nFrom 2012 to 2015, he was the head of the Health Policy Research and Development Unit at the  National Assembly (Nigeria)  (NASS), FCT, Abuja, Nigeria, where he formulated research and development strategies across multiple policy areas and also authored write-ups to disseminate findings from research projects.\nOn 14 June 2022, Adigwe was reappointed as the Director General of  National Institute for Pharmaceutical Research and Development  (NIPRD). [ 7 ] \nAdigwe has mentored over 80 PhD and MSc candidates, and 100 Pharmacists. Adigwe has more than 82 scientific presentations. He chaired and contributed to the COVID-19 pandemic response, by providing an internationally acclaimed analysis that was recognized by the Nigerian Government and positioned the country on the Madagascan Covid Organics preparation. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5721", "text": "In  pharmaceuticals , an  adverse event  ( AE ) is any untoward medical occurrence in a patient or clinical investigation subject administered a  pharmaceutical product  and which does not necessarily have a  causal relationship  with this treatment. An adverse event can therefore be any unfavourable and unintended  symptom or sign  (including an abnormal laboratory finding) or  disease  temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5722", "text": "AEs in patients participating in  clinical trials  must be reported to the study sponsor and if required could be reported to the local  ethics committee . Adverse events categorized as \"serious\" (results in death, illness requiring hospitalization, events deemed life-threatening, results in persistent or significant incapacity, a  congenital anomaly  or medically important condition) must be reported to the regulatory authorities immediately, whereas non-serious adverse events are merely documented in the annual summary sent to the regulatory authority."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5723", "text": "The sponsor collects AE reports from the local researchers, and notifies all participating sites of the AEs at the other sites, as well as both the local investigators' and the sponsors' judgment of the seriousness of the AEs. This process allows the sponsor and all the local investigators access to a set of data that might suggest potential problems with the study treatment while the study is still ongoing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5724", "text": "All clinical trials have the potential to produce AEs. AEs are classified as serious or non-serious; expected or unexpected; and study-related, possibly study-related, or not study-related. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5725", "text": "For example, while a study that tests the effectiveness of a new blood pressure cuff for a period of 10 minutes might seem innocuous, the potential exists for the patient's skin to be irritated by the device. Patients in that study might also die during that 10-minute period. Both skin irritation and sudden death would be considered AEs. In this case, the skin irritation would be classified as not serious, unexpected, and possibly study-related. The death would be classified as serious and unexpected (unless the patient was already at death's door). The local researcher would use his/her medical judgment to determine whether the death could have been related to the study device."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5726", "text": "Both the skin irritation and the death are unexpected events, and should alert the researcher to the potential existence of a problem with the device (for instance, it could have malfunctioned and shocked the patient). The researcher would report these AEs to the local  Institutional Review Board  and to the sponsor, and await direction on whether to stop the study. If the researcher feels there is an imminent danger posed by the device, he or she can use medical discretion to stop patients from participating in the study."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5727", "text": "An adverse event can also be declared in the normal treatment of a patient which is suspected of being caused by the medication being taken or a medical device used in the treatment of the patient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5728", "text": "In Australia, 'Adverse EVENT' refers generically to medical errors of all kinds, surgical, medical or nursing related. The most recent available official study (1995) indicated 18,000 deaths per year are a result of hospital care. [ 3 ]  The Medical Error Action Group is lobbying for legislation to improve the reporting of AEs and through quality control, minimize the needless deaths."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5729", "text": "Researchers participating in a clinical trial must report all adverse events to the drug regulatory authority of the respective country where the drug or device is to be registered [e.g.   Food and Drug Administration  (FDA) if it is US].  Serious AEs  must be reported immediately; minor AEs are 'bundled' by the sponsor and submitted later."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5730", "text": "The type of method used to elicit AEs reported by individuals for evidence on likely adverse drug reactions (ADRs) influences the extent and nature of data. A 2018 review conducted found that some participants in clinical drug trials were asked simple open questions (i.e. 'how are you feeling?'), while in other trials, participants were given lengthy questionnaires about physical symptoms (i.e. 'do you experience muscle soreness or headaches?'. [ 4 ]  A 2022 review on adverse events in  Human challenge trials  found that reporting improved over time, but remains non-standardized in ways that make comparisons difficult. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5731", "text": "As there is a lack of consensus on how AEs should be assessed, there is a concern that the kinds of questions and the phrasing of questions may lead to measurement error and impede comparisons between studies and pooled analysis. However, Allen et al. [ 4 ]  concluded that the impact of the AE detected by different methods is unclear."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5732", "text": "Clinical trial results often report the number of grade 3 and grade 4 adverse events.\nGrades are defined: [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5733", "text": "The FDA provides a database for reporting of adverse  medical device  events called the  Manufacturer and User Facility Device Experience Database  (MAUDE)[1]. The data consist of voluntary reports since June 1993, user facility reports since 1991, distributor reports since 1993, and manufacturer reports since August 1996, and is open for public view. Two private companies have also recently started providing access to analyzed adverse event information: Clarimed provides adverse event information for medical devices and AdverseEvents provides adverse event data for drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5734", "text": "MAUDE is incomplete.    KFF Health News  of the  Kaiser Family Foundation  reported discovering a secret set of least 1.1 million adverse events hidden in a database not known to professionals familiar MAUDE [ 7 ]  Some device AEs reported to FDA can only be found in MDR Data Files of the Device Experience Network (DEN) or in Alternative Summary Report (ASR) data received by the FDA."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5735", "text": "Arven Pharmaceuticals  is a Turkish  pharmaceutical  corporation headquartered in  Istanbul  established as a subsidiary of Toks\u00f6z Group in 2013. Arven's primary focus is development and production of high-technology  inhaler  and  biotechnology  products. The company is specialized on difficult to make products. [ 1 ]  Arven is the first Turkish company developing biosimilars for global markets, including the US and EU. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5736", "text": "Arven has obtained a marketing authorization in 2016 for the biosimilar of  Filgrastim , marketed under Fraven, which is the first  biosimilar  drug, developed and manufactured from cell to final product in Turkey. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5737", "text": "Additionally, Arven is the first Turkish company to design and develop a patented  Dry Powder Inhaler  (DPI) device under Arvohaler trademark and globally introduced Cyplos ( salmeterol/fluticasone ) product inhaled with Arvohaler device. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5738", "text": "Some of the  ministry of health   foundations have visitations to the company for the vaccine manufacturing potential during  COVID-19 pandemic  period. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5739", "text": "In 2007 the Toks\u00f6z Group launched investments to contribute to the development of biotechnological products and the advancement of the pharmaceutical field in Turkey. A Biotechnology Division was first established in the Sanovel Silivri facility within the same year, and research and development work was initiated to produce Turkey's first biosimilar product. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5740", "text": "In the following years, the Toks\u00f6z Group brought together high-technology inhaler and biotechnology products under separate legal entity as\u201cArven \u0130la\u00e7 San ve Tic. A.\u015e.\u201d continuing its investments, the group then decided in 2013 to build a dedicated factory for manufacturing of Arvenproducts."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5741", "text": "As of 2020, Arven employs 200 staff in factory and R&D facility."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5742", "text": "The factory was built in the K\u0131rklareli Industrial Zoneclose to the western borders of Turkey and started operations by obtaining a manufacturing license from the Pharmaceutical and Medical Devices Agency of Turkey in 2017. Arven  K\u0131rklareli  factory was constructed on a 30,000-square-meter (320,000\u00a0sq\u00a0ft) area."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5743", "text": "The R&D facility in Selimpa\u015fa-Istanbul was established at the same time period with the manufacturing facility in K\u0131rklareli. R&D Center certificate was granted in 2017 by the Ministry of Industry, and started to develop new products. Arven R&D Center is currently carrying out research and development activities on inhaler (respiration) medicine and biosimilar drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5744", "text": "The research and development activity on biotechnological and biosimilar drugs are divided into two main groups: microbial drugs and mammalian cell culture-based drugs. The biotechnology team at Arven R&D center comprises Microbial Manufacturing, Mammalian Production, Biotechnology R&D and Biotechnology Quality Control divisions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5745", "text": "Biosimilar development project generally includes following basic steps:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5746", "text": "Characterization of the reference product,  cell line  development,  analytical  method development, process development, head-to-head  comparability  studies, manufacturing of the product at different scales for toxicology study and clinical trials, stability studies, animal studies, and phase 1 clinical trials."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5747", "text": "The facility is utilized for  upstream  processes, including  inoculation ,  fermentation , cell disruption and harvesting; and  downstream  processes, including advanced technology filtration and  chromatographic  purification techniques, and has the capacity to manufacture bulk products in controlled,  GMP  classified areas. Following the bulk manufacture of products, the final product is obtained through syringe filling under aseptic conditions in GMP areas using validated processes. It was the first GMP certificated-biotechnology manufacturing area in Turkey. Fraven, biosimilar of Filgrastim, is the first biosimilar drug developed from cell to the finished product in Turkey and was approved by Turkish Ministry of Health in April 2016. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5748", "text": "The manufacturing protocol of the product was successfully patented before the  European Patent Office . This success has also led company to move R&D projects to more complicated biomolecules, such as  monoclonal antibodies . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5749", "text": "Arven was the first Turkish pharmaceutical company to develop a medical device and corresponding anti-asthmatic product as a dry powder inhaler (DPI) complies with international guidelines and regulations including  WHO , ICH,  FDA  and  EMA . The company has new R&D projects on other inhalable molecules on the pipeline."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5750", "text": "Salmeterol with fluticasone propionate combined doses are manufactured as 50 mcg-500 mcg, 50 mcg-250 mcg and 50-100 mcg inhalation powder forms. [ 11 ]  Development of Cyplos Arvohaler products were started in 2006, authorization step in Turkey was completed in 2011 and the products were launched in 2012 to the Turkish market."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5751", "text": "Product development started with design and development of a plastic inhalation device (Arvohaler) in 2006 with a 100% percent of domestic capital in Turkey. While research and design studies were conducted internally by a team of people from R&D, IP and other related departments of Arven. Development stages were completed together with a local mold and device manufacturer having a clean room in Turkey."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5752", "text": "After the development stage today Arvohaler is a worldwide patented multi-unit dose dry powder inhalation (DPI) device developed by Arven. The device itself is protected in Turkey, EU, US and many other countries globally with a number of patent families."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5753", "text": "Arvohaler consists of 18 components, including 16 plastic parts and 2 stainless-steel springs. Whole material selections and documentation of the development stages were performed according to international guidelines and regulations including WHO, ICH, FDA and EMA."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5754", "text": "As a whole product; Cyplos Arvohaler is manufactured in DPI Production Unit located in Arven's GMP approved production facilities in clean room conditions. Production consists of subsequent stages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5755", "text": "Every stage of production and the finished product is controlled by in-process and chemical tests."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5756", "text": "The firm's main products are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5757", "text": "Arven has filed 571 patent applications before the  patent  offices since its foundation. 298 of the patents belong to the inhaler device(Arvohaler) and corresponding formulation technology inventions. Arven's innovator inhaler device, Arvohaler, succeeded to obtaining patent grants from  European Patent Office ,  USPTO ,  Japan Patent Office  and Chinese State Patent Office. Additionally, the first biotechnology drug patent application in Turkey was filed by Arven Pharmaceuticals. Arven has 23 European granted patents and ranked tenth among all of the Turkish companies in terms of number of registered European patents."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5758", "text": "Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients  is a book by the British physician and academic  Ben Goldacre  about the  pharmaceutical industry , its relationship with the medical profession, and the extent to which it controls academic research into its own products. [ 1 ]  It was published in the UK in September 2012 by the  Fourth Estate  imprint of  HarperCollins , and in the United States in February 2013 by  Faber and Faber ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5759", "text": "Goldacre argues in the book that \"the whole edifice of medicine is broken\", because the evidence on which it is based is systematically distorted by the pharmaceutical industry. [ n 1 ]  He writes that the industry finances most of the  clinical trials  into its own products and much of doctors' continuing education, that clinical trials are often conducted on small groups of unrepresentative subjects and negative data is routinely withheld, and that apparently independent academic papers may be planned and even  ghostwritten  by pharmaceutical companies or their contractors, without disclosure. [ 3 ]  Describing the situation as a \"murderous disaster\", he makes suggestions for action by patients' groups, physicians, academics and the industry itself. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5760", "text": "Responding to the book's publication, the  Association of the British Pharmaceutical Industry  issued a statement in 2012 arguing that the examples the book offers were historical, that the concerns had been addressed, that the industry is among the most regulated in the world, and that it discloses all data in accordance with international standards. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5761", "text": "In January 2013 Goldacre joined the  Cochrane Collaboration ,  British Medical Journal  and others in setting up  AllTrials , a campaign calling for the results of all past and current clinical trials to be reported. [ 6 ]  The British House of Commons  Public Accounts Committee  expressed concern in January 2014 that drug companies were still only publishing around 50 percent of clinical-trial results. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5762", "text": "Goldacre writes in the introduction of  Bad Pharma  that he aims to defend the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5763", "text": "Drugs are tested by the people who manufacture them, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques which are flawed by design, in such a way that they exaggerate the benefits of treatments. Unsurprisingly, these trials tend to produce results that favour the manufacturer. When trials throw up results that companies don't like, they are perfectly entitled to hide them from doctors and patients, so we only ever see a distorted picture of any drug's true effects. Regulators see most of the trial data, but only from early on in a drug's life, and even then they don't give this data to doctors or patients, or even to other parts of government. This distorted evidence is then communicated and applied in a distorted fashion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5764", "text": "In their forty years of practice after leaving medical school, doctors hear about what works through ad hoc oral traditions, from sales reps, colleagues or journals. But those colleagues can be in the pay of drug companies\u00a0\u2013 often undisclosed\u00a0\u2013 and the journals are too. And so are the patient groups. And finally, academic papers, which everyone thinks of as objective, are often covertly planned and written by people who work directly for the companies, without disclosure. Sometimes whole academic journals are even owned outright by one drug company. Aside from all this, for several of the most important and enduring problems in medicine, we have no idea what the best treatment is, because it's not in anyone's financial interest to conduct any trials at all. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5765", "text": "In \"Missing Data,\" Goldacre argues that the clinical trials undertaken by drug companies routinely reach conclusions favourable to the company. For example, in a 2007 journal article published in  PLOS Medicine , researchers studied every published trial on  statins , drugs prescribed to reduce  cholesterol  levels. In the 192 trials they looked at, industry-funded trials were 20 times more likely to produce results that favoured the drug. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5766", "text": "He writes that these positive results are achieved in a number of ways. Sometimes the industry-sponsored studies are flawed by design (for example by comparing the new drug to an existing drug at an inadequate dose), and sometimes patients are selected to make a positive result more likely. In addition, the data are analysed as the trial progresses. If the trial seems to be producing negative data it is stopped prematurely and the results are not published, or if it is producing positive data it may be stopped early so that longer-term effects are not examined. He writes that this  publication bias , where negative results remain unpublished, is endemic within medicine and academia. As a consequence, he argues, doctors may have no idea what the effects are of the drugs they prescribe. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5767", "text": "An example he gives of the difficulty of obtaining missing data from drug companies is that of  oseltamivir  (Tamiflu), manufactured by  Roche  to reduce the complications of  bird flu . Governments spent billions of pounds stockpiling this, based in large part on a meta-analysis that was funded by the industry.  Bad Pharma  charts the efforts of independent researchers, particularly  Tom Jefferson  of the  Cochrane Collaboration  Respiratory Group, to gain access to information about the drug. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5768", "text": "In the second chapter, the book describes the process as new drugs move from  animal testing  through  phase 1  ( first-in-man study ),  phase 2 , and  phase 3  clinical trials. Phase 1 participants are referred to as volunteers, but in the US are paid $200\u2013$400 per day, and because studies can last several weeks and subjects may volunteer several times a year, earning potential becomes the main reason for participation. [ 12 ]  Participants are usually taken from the poorest groups in society, and outsourcing increasingly means that trials may be conducted in countries with low wages by  contract research organizations  (CROs). The rate of growth for clinical trials in India is 20 percent a year, in Argentina 27 percent, and in China 47 percent, while trials in the UK have fallen by 10 percent a year and in the US by six percent. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5769", "text": "The shift to outsourcing raises issues about data integrity, regulatory oversight, language difficulties, the meaning of  informed consent  among a much poorer population, the standards of clinical care, the extent to which corruption may be regarded as routine in certain countries, and the ethical problem of raising a population's expectations for drugs that most of that population cannot afford. [ 13 ]  It also raises the question of whether the results of clinical trials using one population can invariably be applied elsewhere. There are both social and physical differences: Goldacre asks whether patients diagnosed with depression in China are really the same as patients diagnosed with depression in California, and notes that people of Asian descent metabolize drugs differently from Westerners. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5770", "text": "There have also been cases of available treatment being withheld during clinical trials.  In 1996 in Kano, Nigeria , the drug company  Pfizer  compared a new antibiotic during a  meningitis  outbreak to a competing antibiotic that was known to be effective at a higher dose than was used during the trial. Goldacre writes that 11 children died, divided almost equally between the two groups. The families taking part in the trial were apparently not told that the competing antibiotic at the effective dose was available from  M\u00e9decins Sans Fronti\u00e8res  in the next-door building. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5771", "text": "Chapter three describes the concept of \" regulatory capture ,\" whereby a regulator\u00a0\u2013 such as the  Medicines and Healthcare products Regulatory Agency  (MHRA) in the UK, or the  Food and Drug Administration  (FDA) in the United States\u00a0\u2013 ends up advancing the interests of the drug companies rather than the interests of the public. Goldacre writes that this happens for a number of reasons, including the  revolving door  of employees between the regulator and the companies, and the fact that friendships develop between regulator and company employees simply because they have knowledge and interests in common. The chapter also discusses  surrogate outcomes  and  accelerated approval , and the difficulty of having ineffective drugs removed from the market once they have been approved. [ 16 ]  He argues that regulators do not require that new drugs offer an improvement over what is already available, or even that they be particularly effective. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5772", "text": "\"Bad Trials\" examines the ways in which clinical trials can be flawed. Goldacre writes that this happens by design and by analysis, and that it has the effect of maximizing a drug's benefits and minimizing harm.\nThere have been instances of fraud, though he says these are rare. More common are what he calls the \"wily tricks, close calls, and elegant mischief at the margins of acceptability.\" [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5773", "text": "These include testing drugs on unrepresentative, \"freakishly ideal\" patients; comparing new drugs to something known to be ineffective, or effective at a different dose or if used differently; conducting trials that are too short or too small; and stopping trials early or late. [ 19 ]  It also includes measuring uninformative outcomes; packaging the data so that it is misleading; ignoring patients who drop out (i.e. using  per-protocol analysis , where only patients who complete the trial are counted in the final results, rather than  intention-to-treat analysis , where everyone who starts the trial is counted); changing the main outcome of the trial once it has finished; producing  subgroup analyses  that show apparently positive outcomes for certain tightly defined groups (such as Chinese men between the ages of 56 and 71), thereby hiding an overall negative outcome; and conducting \" seeding trials ,\" where the objective is to persuade physicians to use the drug. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5774", "text": "Another criticism is that outcomes are presented in terms of  relative risk reduction  to exaggerate the apparent benefits of the treatment. For example, he writes, if four people out of 1,000 will have a heart attack within the year, but on statins only two will, that is a 50 percent reduction if expressed as relative risk reduction. But if expressed as  absolute risk reduction , it is a reduction of just 0.2 percent. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5775", "text": "In chapter five Goldacre suggests using the  General Practice Research Database  in the UK, which contains the anonymized records of several million patients, to conduct  randomized trials  to determine the most effective of competing treatments. For example, to compare two statins,  atorvastatin  and  simvastatin , doctors would randomly assign patients to one or the other. The patients would be followed up by having data about their cholesterol levels, heart attacks, strokes and deaths taken from their computerized medical records. The trials would not be  blind \u00a0\u2013 patients would know which statin they had been prescribed\u00a0\u2013 but Goldacre writes that they would be unlikely to hold such firm beliefs about which one is preferable to the extent that it could  affect their health . [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5776", "text": "In the final chapter, Goldacre looks at how doctors are persuaded to prescribe \"me-too drugs,\" brand-name drugs that are no more effective than significantly cheaper off-patent ones. He cites as examples the statins atorvastatin (Lipitor, made by Pfizer) and simvastatin (Zocor), which he writes seem to be equally effective, or at least there is no evidence to suggest otherwise. Simvastatin came off patent several years ago, yet there are still three million prescriptions a year in the UK for atorvastatin, costing the  National Health Service  (NHS) an annual \u00a3165 million extra. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5777", "text": "He addresses the issue of  medicalization  of certain conditions (or, as he argues, of personhood), whereby pharmaceutical companies \"widen the boundaries of diagnosis\" before offering solutions.  Female sexual dysfunction  was highlighted in 1999 by a study published in the  Journal of the American Medical Association , which alleged that 43 percent of women were suffering from it. After the article appeared, the  New York Times  wrote that two of its three authors had worked as consultants for Pfizer, which at the time was preparing to launch  UK-414,495 , known as female  Viagra . The journal's editor said that the failure to disclose the relationship with Pfizer was the journal's mistake. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5778", "text": "The chapter also examines celebrity endorsement of certain drugs, the extent to which claims in advertisements aimed at doctors are appropriately sourced, and whether  direct-to-consumer advertising  (currently permitted in the US and New Zealand) ought to be allowed. [ 25 ]  It discusses how PR firms promote stories from patients who complain in the media that certain drugs are not made available by the funder, which in the UK is the NHS and the  National Institute for Health and Clinical Excellence  (NICE). Two breast-cancer patients who campaigned in the UK in 2006 for  trastuzumab  (Herceptin) to be available on the NHS were being handled by a law firm working for  Roche , the drug's manufacturer. The historian  Lisa Jardine , who was suffering from breast cancer, told the  Guardian  that she had been approached by a PR firm working for the company. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5779", "text": "The chapter also covers the influence of  drug reps , how  ghostwriters  are employed by the drug companies to write papers for academics to publish, how independent the academic journals really are, how the drug companies finance doctors' continuing education, and how patients' groups are often funded by industry. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5780", "text": "In the afterword and throughout the book, Goldacre makes suggestions for action by doctors, medical students, patients, patient groups and the industry. He advises doctors, nurses and managers to stop seeing drug reps, to ban them from clinics, hospitals and medical schools, to declare online and in waiting rooms all gifts and hospitality received from the industry, and to remove all drug company promotional material from offices and waiting rooms. (He praises the website of the  American Medical Student Association  \u2013 www.amsascorecard.org \u2013 which ranks institutions according to their  conflict-of-interest  policies, writing that it makes him \"feel weepy.\") He also suggests that regulations be introduced to prevent pharmacists from sharing doctors' prescribing records with drug reps. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5781", "text": "He asks academics to lobby their universities and academic societies to forbid academics from being involved in ghostwriting, and to lobby for \"film credit\" contributions at the end of every academic paper, listing everyone involved, including who initiated the idea of publishing the paper. [ 29 ]  He also asks for full disclosure of all past clinical trial results, and a list of academic papers that were, as he puts it, \"rigged\" by industry, so that they can be retracted or annotated. [ 30 ]  He asks drug company employees to become whistleblowers, either by writing an anonymous blog, or by contacting him. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5782", "text": "He advises patients to ask their doctors whether they accept drug-company hospitality or sponsorship, and if so to post details in their waiting rooms, and to make clear whether it is acceptable to the patient for the doctor to discuss his or her medical history with drug reps. Patients who are invited to take part in a trial are advised to ask, among other things, for a written guarantee that the trial has been publicly registered, and that the main outcome of the trial will be published within a year of its completion. He advises patient groups to write to drug companies with the following: \"We are living with this disease; is there anything at all that you're withholding? If so, tell us today.\" [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5783", "text": "The book was generally well received. The  Economist  described it as \"slightly technical, eminently readable, consistently shocking, occasionally hectoring and unapologetically polemical\". [ 33 ]   Helen Lewis  in the  New Statesman  called it an important book, [ 34 ]  while Luisa Dillner, writing in the  Guardian , described it as a \"thorough piece of investigative medical journalism\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5784", "text": "Andrew Jack wrote in the  Financial Times  that Goldacre is \"at his best in methodically dissecting poor clinical trials.\u00a0... He is less strong in explaining the complex background reality, such as the general constraints and individual slips of regulators and pharma companies' employees.\" Jack also argued that the book failed to reflect how many lives have been improved by the current system, for example with new treatments for HIV, rheumatoid arthritis and cancer. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5785", "text": "Max Pemberton , a psychiatrist, wrote in the  Daily Telegraph  that \"this is a book to make you enraged\u00a0... because it's about how big business puts profits over patient welfare, allows people to die because they don't want to disclose damning research evidence, and the tricks they play to make sure doctors do not have all the evidence when it comes to appraising whether a drug really works or not.\" [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5786", "text": "The  Association of the British Pharmaceutical Industry  (ABPI) replied in the  New Statesman  that Goldacre was \"stuck in a bygone era where pharmaceutical companies wine and dine doctors in exchange for signing on the dotted line\". [ 37 ]  The ABPI issued a press release, writing that the pharmaceutical industry is responsible for the discovery of 90 percent of all medicines, and that it takes an average of 10\u201312 years and \u00a31.1bn to introduce a medicine to the market, with just one in 5,000 new compounds receiving regulatory approval. This makes research and development an expensive and risky business. They wrote that the industry is one of the most heavily regulated in the world, and is committed to ensuring full transparency in the research and development of new medicines. They also maintained that the examples Goldacre offered were \"long documented and historical, and the companies concerned have long addressed these issues\". [ 5 ]  Goldacre argues in the book that \"the most dangerous tactic of all is the industry's enduring claim that these problems are all in the past\". [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5787", "text": "Humphrey Rang of the  British Pharmacological Society  wrote that Goldacre had chosen his target well and had produced some shocking examples of secrecy and dishonesty, particularly the nondisclosure of data on the antidepressant  reboxetine  (chapter one), in which only one trial out of seven was published (the published study showed positive results, while the unpublished trials suggested otherwise). He argued that Goldacre had gone \"over the top\" in devoting a whole chapter (chapter five) to recommending large clinical trials using electronic patient data from general practitioners, without fully pointing out how problematic these can be; such trials raise issues, for example, about informed consent and regulatory oversight. Rang also criticized Goldacre's style, describing the book as too long, repetitive, hyperbolic, and in places too conversational. He particularly objected to the line, \"medicine is broken\", calling it a \"foolish remark\". [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5788", "text": "Following the book's publication, Goldacre co-founded  AllTrials  with David Tovey, editor-in-chief of the  Cochrane Library , together with the  British Medical Journal ,  the Centre for Evidence-Based Medicine , and others in the UK, and  Dartmouth College 's  Geisel School of Medicine  and the  Dartmouth Institute for Health Policy and Clinical Practice  in the US. Set up in January 2013, the group campaigns for all past and current clinical trials to be registered and reported, for all treatments in use. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5789", "text": "The British House of Commons  Public Accounts Committee  produced a report in January 2014, after hearing evidence from Goldacre,  Fiona Godlee , editor-in-chief of the  British Medical Journal , and others, about the stockpiling of Tamiflu and the withholding of data about the drug by its manufacturer, Roche. The committee said it was \"surprised and concerned\" to learn that information from clinical trials is routinely withheld from doctors, and recommended that the Department of Health take steps to ensure that all clinical-trial data be made available for currently prescribed treatments. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5790", "text": "Ben Adams,  \"Goldacre takes ABPI to task over book snub\"   Archived  7 January 2014 at the  Wayback Machine ,  Pharma Times , 12 October 2012."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5791", "text": "Rajeev Syal,  \"Drug companies accused of holding back complete information on clinical trials\" ,  The Guardian , 3 January 2014."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5792", "text": "Staa, TP; Goldacre, B; Gulliford, M; Cassell, J; Pirmohamed, M; Taweel, A; Delaney, B; Smeeth, L (2012).  \"Pragmatic randomised trials using routine electronic health records: putting them to the test\" .  BMJ .  344 : e55.  doi : 10.1136/bmj.e55 .  PMC \u00a0 3934788 .  PMID \u00a0 22315246 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5793", "text": "For the 1999 study,  Laumann, EO; Paik, A; Rosen, RC (February 1999).  \"Sexual dysfunction in the United States: prevalence and predictors\" .  JAMA .  281  (6):  537\u2013 44.  doi : 10.1001/jama.281.6.537 .  PMID \u00a0 10022110 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5794", "text": "Denise Grady,  \"Sure, We've Got a Pill for That\" ,  The New York Times , 14 February 1999."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5795", "text": "Charlie Cooper,  \"Drugs companies 'routinely withhold results of medical trials' from doctors, researchers and patients\" ,  The Independent , 3 January 2014."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5796", "text": "Big Pharma: How the World's Biggest Drug Companies Control Illness  is a 2006 book by British journalist Jacky Law. The book examines how major  pharmaceutical companies  determine which  health care  problems are publicised and researched. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5797", "text": "Outlining the history of the  pharmaceutical industry , Law identifies what she says is the failure of a regulatory framework that assumes pharmaceutical companies always produce worthwhile products that society will want. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5798", "text": "Law has written about healthcare for 25 years, seven of them as associate editor of  Scrip Magazine , a monthly magazine for the drugs industry. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5799", "text": "Ike Iheanacho writes about the book that \"The author is clearly no great fan of the industry. But, refreshingly, she avoids the sort of lazy polemic that casts major pharmaceutical companies as an evil empire that continually foists its products on unwilling and unsuspecting healthcare professionals and patients.\" [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5800", "text": "Big Pharma conspiracy theories  are  conspiracy theories  that claim that  pharmaceutical companies as a whole , especially big  corporations , act in  dangerously secretive  and sinister ways that harm  patients . This includes concealing effective treatments, perhaps even to the point of intentionally causing and/or worsening a wide range of  diseases , in the pursuit of  higher profits  and/or other nefarious goals. The  general public  supposedly lives in a state of  ignorance , according to such claims. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5801", "text": "Some theories have incorporated the assertions that natural, alternative remedies to multiple  health  struggles are being suppressed, that  medications  for the treatment of  HIV/AIDS  are ineffective and harmful, that an effective cure for all  cancers  has been discovered but concealed from the public, that  vaccines for COVID-19  are ineffective, and that alternatively understood  cures  exist for  COVID-19  itself. In most cases, the conspiracy theorists have blamed pharmaceutical companies' search for increased  profit margins . A range of authors have shown these claims to be false, though some of these authors nevertheless maintain that other  criticisms of the pharmaceutical industry  are legitimate. [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5802", "text": "According to  Steven Novella , the use of  terminology  such as  Big Pharma  has come to connote a  demonized  form of the  pharmaceutical industry , described in an  emotional fashion , which exists disconnected from the real-life complexity of  business  history. [ 5 ]  Professor of writing Robert Blaskiewicz has written that conspiracy theorists use the term  Big Pharma  as \"shorthand for an abstract entity comprising corporations, regulators, NGOs, politicians, and often physicians, all with a finger in the trillion-dollar prescription pharmaceutical pie\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5803", "text": "According to Blaskiewicz, the Big Pharma conspiracy theory has four classic traits: first, the assumption that the conspiracy is perpetrated by a small malevolent cabal; secondly, the belief that the public at large is ignorant of the truth; thirdly, that its believers treat lack of evidence as evidence; and finally, that the arguments deployed in support of the theory are irrational, misconceived, or otherwise mistaken. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5804", "text": "In the 1970s and 1980s, the conspiracy theory was promoted by  Ann Wigmore  who held that diseases, including cancer and  HIV/AIDS , could be effectively treated with a  raw food diet . In this context, Wigmore believed that the pharmaceutical industry was part of a conspiracy to keep the population at large ill. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5805", "text": "Andr\u00e9 Picard  wrote in 2009 that the internet had radically changed the nature of popular scientific discourse from being infrequent and deferential to widespread and conspiracy based: scientific debate was often supplanted by dismissal of science as being \"part of some vast conspiracy\". In the conspiracist world view, \"Doctors, nurses, pharmacists, pharmacologists, biochemists, immunologists, geneticists and journalists are not to be trusted. They are all on the take\". [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5806", "text": "Research in Italy in 2016 found that nearly half the adult population believed that pharmaceutical companies hinder the development of effective medications to heal serious diseases, which according to the authors is a conspiracy theory, and that such beliefs were negatively correlated to mainstream religion while having anti-science and anti-elitism bases. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5807", "text": "The conspiracy theory has a variety of different specific manifestations. Each has different narratives, but they always cast \"Big Pharma\" as the villain of the piece. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5808", "text": "Since the beginning of the  AIDS epidemic , many dangerous hypotheses have been put forward to explain the origin and nature of the disease. One conspiracy theory claims that AIDS was created by the  US government  to control and/or wipe out  gays  and  African Americans . Also, there is a cure for HIV/AIDS that is withheld from the poor. [ 12 ] [ 13 ]  Other theories say that although the virus is harmful, the risks of  antiretroviral drugs  outweigh the benefits. The drugs are said to be toxins that are spread by doctors who have been corrupted by the pharmaceutical industry. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5809", "text": "In a 2006 column for  Harper's Magazine , journalist  Celia Farber  claimed that the antiretroviral drug  nevirapine  was part of a conspiracy by the \"scientific-medical complex\" to spread toxic drugs. [ 15 ]  Farber said that AIDS is not caused by HIV and that nevirapine had been unethically administered to pregnant women in clinical trials, leading to a fatality. [ 15 ]  Farber's theories and claims were refuted by scientists, but, according to researcher  Seth Kalichman , the resulting publicity represented a breakthrough moment for  AIDS denialism . [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5810", "text": "The former president of  South Africa ,  Thabo Mbeki , influenced by AIDS denier  Peter Duesberg , introduced policies that denied treatments to AIDS patients. According to estimates this led, among other things, to more than 300,000 people dying prematurely. [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5811", "text": "A recurring conspiracy theory claims that the pharmaceutical industry has a cure for  cancer , but suppresses it so that they can continue to make billions on the \"ineffective\" treatments currently given to cancer patients. [ 19 ]  This was believed by 27% of the American public according to a 2005 survey. [ 20 ]  The argument is that pharmaceutical companies are slowing down research for a comprehensive cure for cancer by developing high-profit, single-purpose treatments rather than focusing on a supposed cure-all for all cancers. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5812", "text": "Following the crash of  Voepass Linhas A\u00e9reas Flight 2283  in August 2024, social media posts appeared naming Leonardo Ferreira, a cancer researcher, as one of the passengers. The  Brazilian College of Radiology and Imaging Diagnosis  published an obituary and conspiracy theories spread about how big pharma had engineered the supposed death of somebody close to finding a breakthrough cancer cure. Ferreira confirmed he was not dead; nobody of that name was on the aircraft's passenger list. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5813", "text": "The idea that vaccines were created by the pharmaceutical industry to make people sick, or to alter  human DNA , [ 23 ] [ 24 ]  has been around for a long time but has been given new life during the COVID-19 pandemic. [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5814", "text": "The conspiracy theory that  vaccines make people autistic  can be traced back to a study published in  The Lancet  in February 1998. [ 27 ] [ 28 ]   Andrew Wakefield  claimed that there is a link between  MMR vaccine and autism . The study later  turned out to be fraudulent , and led to Wakefield being\u00a0struck off the medical register. The Lancet also withdrew the article. [ 29 ]  Although a number of studies have disproved the link between autism and vaccines, [ 30 ]  the conspiracy theory has survived in various forms, and it has been spread by, among others,  Donald Trump . [ 31 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5815", "text": "Other conspiracy theories suggest that vaccines are used to implant  microchips  for  surveillance  and  thought control . [ 33 ]  Among others, the  Bill & Melinda Gates Foundation  has been accused of wanting to microchip the world's population through global vaccination programs. [ 34 ] [ 35 ] [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5816", "text": "The  COVID-19 pandemic  is surrounded by a wide range of conspiracy theories, including the postulation that COVID-19 does not exist at all or is just a mild  flu . [ 37 ] [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5817", "text": "During the pandemic, there was a surge of conspiracies about  the origins of the disease , such as claiming that the virus was created in a laboratory. However, strong evidence suggests that the disease-causing virus,  SARS-CoV-2 , is a naturally evolved strain belonging to the  coronavirus subfamily . [ 39 ] [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5818", "text": "The 2020 video  Plandemic: The Hidden Agenda Behind Covid-19 , promotes the conspiracist claim that vaccines are \"a money-making enterprise that causes medical harm\". In the video, former research scientist  Judy Mikovits  spread the notion that \"Big Pharma\",  Bill Gates  and the  World Health Organization  led a conspiracy, in which they acted together as a \"circular cabal\" with the aim of killing Americans. [ 41 ]  The video was released on May 4, 2020, and garnered millions of views, making it one of the most widespread pieces of COVID-19 misinformation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5819", "text": "In the book  Natural Cures \"They\" Don't Want You to Know About , author  Kevin Trudeau  claims that there are all-natural cures for serious illnesses including  cancer ,  herpes ,  arthritis ,  AIDS ,  acid reflux disease ,  diabetes ,  multiple sclerosis ,  lupus ,  chronic fatigue syndrome ,  attention deficit disorder ,  muscular dystrophy , and that these are all being deliberately hidden and suppressed from the public by the  Food and Drug Administration , the  Federal Trade Commission , and major food and drug companies. [ 42 ]  The book has been the focus of much controversy since its publication, with widespread allegations of fraud. [ 43 ] [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5820", "text": "A common claim among proponents of the conspiracy theory is that pharmaceutical companies suppress negative research about their drugs by financially pressuring researchers and journals. Skeptic  Benjamin Radford , while conceding there is \"certainly a grain of truth\" to these claims, notes that there are in fact papers critical of specific drugs published in top journals on a regular basis. [ 3 ]  A prominent example noted by Radford is a systematic review published in the  British Medical Journal  showing that  paracetamol  is ineffective for lower back pain and has minimal effectiveness for  osteoarthritis . [ 3 ] [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5821", "text": "In his 2012 book  Bad Pharma ,  Ben Goldacre  heavily criticises the pharmaceutical industry but rejects any conspiracy theories. He argues that the problems are \"perpetrated by ordinary people, but many of them may not even know what they've done\". [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5822", "text": "Steven Novella  writes that while the pharmaceutical industry has a number of aspects which justly deserve criticism, the \"demonization\" of it is both cynical and intellectually lazy. [ 5 ]  He goes on to consider that overblown attacks on \"Big Pharma\" actually let the pharmaceutical industry \"off the hook\" since they distract from and tarnish more considered criticisms. [ 5 ]  He has also written, on  Skepticblog , about the general misunderstanding and sensationalizing of cancer research that typically accompanies a conspiratorial mindset. He points out that cures for cancer, rather than being hidden, are not the cures they are initially touted to be by the media and either result in a dead end, further research goals, or a decrease in the mortality rate for a specific type of cancer. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5823", "text": "Dave Roos and Oliver Childs have criticized the idea that holding back a cure for cancer would result in more profit than presenting one. [ 7 ] [ 8 ]  Dina Fine Maron further notes that this view largely ignores the fact that cancer is not a single disease but instead many, and the fact that large strides have been made in the fight against cancer. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5824", "text": "In 2016,  David Robert Grimes  published a research paper elaborating about the mathematical non-viability of conspiracy theories in general. [ 46 ]  He estimated that if there were a big pharma conspiracy to conceal a cure for cancer, it would be exposed after about 3.2 years due to the sheer number of people required to keep it secret. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5825", "text": "Biodollars , sometimes called  biobucks , is a term commonly used in business transactions between large  pharmaceutical  and smaller  biotechnology companies  to describe the total possible value of the transaction, excluding royalty payments.  While public announcements of these deals often state a single lump-sum figure as a representation of the entire deal-value, often only a small fraction of the amount is certain, while the remaining amount is highly uncertain. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5826", "text": "Common transactions in this industry are based on the grant of a  license  for products emerging from a  drug discovery  program or for a candidate drug that is already in  development  in exchange for money.  The risk for both parties is managed in the license agreement by spreading the payments over time, and making most of the payment contingent on sales through  royalty payments , and on reaching  milestones  such as completion of a  clinical trial phase , regulatory marketing approval in various jurisdictions, or a reaching some level of sales, through so-called \"milestone payments\".  The licensee may also agree to make payments to the licensor specifically to fund continued work on the licensed product (research funding). [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5827", "text": "Only the upfront payment and research funding are paid out when the deal is signed; the rest is all contingent and may never be paid or received. [ 1 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5828", "text": "Biosplice Therapeutics, Inc.  (formerly  Samumed, LLC ) is a private  biopharmaceutical  company based in  San Diego, California . [ 1 ]  It was founded in 2008 by  Osman Kibar . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5829", "text": "Samumed's products in development target novel components of the  Wnt signaling pathway . [ 3 ] [ 4 ] [ 5 ]  The company focuses on potential treatments for several diseases; its  osteoarthritis  program is its most advanced. [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5830", "text": "Biotechnology industry in Italy  is a highly innovative and fast-growing sector dedicated to research.\nAt the end of 2019, there are 696  biotech  companies active in Italy. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5831", "text": "The turnover exceeds 12\u00a0billion euros, the number of employees exceeds 13,000 units. Between 2017 and 2019, over 50 new innovative  start-ups  active in biotechnology were registered. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5832", "text": "In the laboratories of the IRBM Science Park a team of Italian and American researchers has developed the Chad3Ebola-Zaire anti-ebola vaccine, a monovalent adenovirus capable of neutralizing the \u00abZaire\u00bb strain of the virus, conceived and produced by OKAIROS, a biotech company founded by Prof. Riccardo Cortese, with whom IRBM set up the Advent equal joint venture."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5833", "text": "The research intensity of the biotech sector is significantly higher than that found for the  Italian industry  as a whole. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5834", "text": "A  black triangle  appearing after the trade name of a British  medicine  (or  vaccine ) indicates that the medication is new to the market, or that an existing medicine (or vaccine) is being used for a new reason or by a new route of administration. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5835", "text": "Examples of how it might appear:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5836", "text": "The black triangle also highlights the need for surveillance of any  Adverse Drug Reactions  (ADRs) that might arise from the use of a new medication. The  Medicines and Healthcare products Regulatory Agency  (MHRA) encourage anyone to voluntarily report ADRs (however minor) via the  Yellow Card Scheme  to gather more information and gain more understanding of a new medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5837", "text": "After a new medicine (or vaccine) has been brought to the market there is still a lot that can be learned about the drug from its widespread use. Similarly, if an existing drug is being used in a situation where it was not used before or if it is being given by a different route of administration much can still be learned about its new or modified use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5838", "text": "The black triangle label generally stays with the new drug (or new use of an existing drug) for at least 5 years, when it is reviewed, and after this time the black triangle label may or may not be discontinued."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5839", "text": "Blow-Fill-Seal , also spelled as  Blow/Fill/Seal , in this article abbreviated as  BFS , is an automated manufacturing process by which plastic containers, such as bottles or ampoules are, in a continuous operation, blow-formed, filled, and sealed. [ 1 ] [ 2 ]  It takes place in a sterile, enclosed area inside a machine, without human intervention, and thus can be used to  aseptically manufacture  sterile pharmaceutical or non-pharmaceutical liquid/semiliquid unit-dosage forms. [ 3 ] [ 4 ]  BFS is an advanced aseptic processing technology that is typically used for filling and packaging of certain sterile liquid formulations like  liquid ophthalmics ,  inhalational anesthetics , or  lavaging agents , but can also be used for  injectables , [ 1 ]   parenteral medicines , [ 5 ]  and several other liquid or semiliquid medications, [ 6 ]  with fill volumes ranging from 0.1...1000\u00a0cm\u00b3. [ 7 ] [ 8 ] [ 9 ]  Compared against traditional glass ampoules, BFS ampoules are inexpensive, lightweight, and shatterproof. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5840", "text": "BFS was developed in the early 1960s [ 11 ]  at Rommelag. [ 12 ]  In 1963, Gerhard Hansen applied for a patent on the BFS process. [ 13 ]  Originally, it was used for packaging of non-sterile products, such as non-sterile medical devices, food, and cosmetics. [ 10 ]  In the early 1970s, Rommelag's Bottelpack system was first used for packing large volume pharmaceutical solutions. [ 12 ]  By the late 1980s, BFS had been well-established in the packaging industry, especially for packaging pharmaceutical and healthcare products. [ 14 ]  During the 1980s and 1990s, BFS came into use for the now common small volume unit-dosage forms. [ 12 ]  Since the early 2000s, BFS has been emerging as the preferred packaging process for parenteral products. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5841", "text": "The BFS process functions similarly to conventional extrusion blow molding, and takes place within a BFS machine. [ 6 ]  First, a plastic polymer resin is heated to >160\u00a0\u00b0C and compressed to 35\u00a0MPa, [ 11 ] [ 15 ]  allowing it to be extruded in tubular form, [ 1 ]  and be taken over by an open two-part [ 16 ]  mold to form the container. Then, the mold closes which welds the bottom of the container. Simultaneously, the parison above the mold is cut, or the filling needles are placed in the parison head without the parison being cut (rotary BFS type). Next, a filling mandrel with blowing air function is placed in the neck area that seals the container. Sterile compressed air is then introduced through the filling mandrel to inflate and form the container. In the BFS process for smaller ampoules the compressed air system is avoided by using vacuum forming the container instead. After the BFS container has been formed, the desired liquid is filled into the container through the filling mandrel unit. Then, the filling mandrel unit is lifted off, and the head mold hermetically seals the container. Simultaneously, the head contour is formed by vacuum. In the last step, the mold opens and the finished container leaves the mold. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5842", "text": "One process cycle takes a few seconds. [ 11 ]  The process speed and thus process output largely depends upon the BFS container size and the BFS machinery dimensioning. For instance, in the early 2000s, Rommelag's 3012, 305, and 4010 M machines had outputs of approximately 4000, 8000, or 20,000 containers per hour. [ 17 ]  These machines have been succeeded by the Rommelag 312, 321, 360, 364 and 460 machines with output ranges of up to 35,000 containers per hour."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5843", "text": "The BFS processes is an aseptic filling process, which produces sterile products and thus needs to be sterile. [ 18 ]  Aseptic BFS machines must be designed in a way that prevents extraneous contamination. [ 19 ]  Thus, rotary-type BFS machines are placed in classified areas same as shuttle-type BFS machines (open parison), which have a cleanroom shroud  grade-A-compliant  provided with sterilised air and kept under overpressure. Automatic SIP programs are used to sterilise the BFS equipment and this avoids human interventions. Due to automatic start up and filling processes BFS machines require no human interaction during the actual BFS process. However, certain adjustments or interventions need to be carried out by personnel. Both particle and microbiological contamination monitoring are required in a BFS machine environment, as well as routine CIP/SIP processes. [ 20 ]  BFS machines are typically fitted with several different sterilising air filtration systems for the buffer air, support parison air and air shroud grade A air (if needed for shuttle machines, e. g. open parison type ones). [ 9 ]  Typically, the air is sterilised by filtration systems that have automatic filter integrity testing installed (i. e. automatic water intrusion or particle testing). The air systems are typically integrated into the SIP cycle of the BFS machine. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5844", "text": "The materials used in BFS packaging are usually  polyolefins , mainly  polyethylene  ( LDPE [ 22 ] [ 23 ]  or  HDPE ), [ 24 ]  and  polypropylene  (PP). [ 25 ] [ 26 ] [ 27 ]  These materials are robust and inert to ensure sterility and tightness during the product's shelf life. [ 5 ]  Diffusion tendencies can be reduced by using virgin polymers, but diffusion cannot be prevented entirely. This is due to the nature of polyolefins and their additives, if present. [ 25 ]  Several polyethylene suppliers have developed special EP or  USP  grade resin for BFS containers. Permeation into BFS containers and water loss may be an issue with some BFS resin. Therefore, in some applications, secondary packaging methods (laminate pouches) are used. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5845", "text": "BFS allows many different container designs, a consistent high process quality, a high process output, [ 7 ]  and is, compared against other packaging processes, inexpensive. [ 26 ]  In addition to that, BFS containers are lighter than glass containers, and shatterproof, which eases their transport. [ 10 ] [ 29 ]  Due to the single-dose nature of BFS containers, they are more convenient to use for patients. [ 30 ]  BFS technology assures high levels of sterility, [ 31 ] [ 32 ] [ 33 ]  especially compared against conventional filling, [ 34 ]  which is mainly achieved by the absence of human contact/interventions \u2013 a major source of contamination. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5846", "text": "BUKO Pharma-Kampagne  is an independent organization based in  Bielefeld ,  Germany , which watches over the marketing practices of German pharmaceutical companies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5847", "text": "It has gained wider recognition after being described in a bestselling novel,  The Constant Gardener  by  John le Carr\u00e9 . BUKO was mentioned explicitly in the author's afterword as a real counterpart to the novel's fictitious Hippo organisation (also based in Bielefeld, Germany)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5848", "text": "BUKO is partially financed by the  European Union  and mostly by private supporters."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5849", "text": "In early 1981 following a conference in  Geneva , co-sponsored by the  International Organization of Consumers Unions  and by  BUKO , it set up  Health Action International . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5850", "text": "This article about a medical organization or association is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5851", "text": "In the manufacture of pharmaceuticals,  encapsulation  refers to a range of  dosage forms \u2014techniques used to enclose medicines\u2014in a relatively stable shell known as a  capsule , allowing them to, for example, be taken orally or be used as  suppositories . The two main types of capsules are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5852", "text": "Both of these classes of capsules are made from aqueous solutions of  gelling agents , such as animal  protein  (mainly  gelatin ) or plant  polysaccharides  or their derivatives (such as  carrageenans  and modified forms of  starch  and  cellulose ). Other ingredients can be added to the gelling agent solution including  plasticizers  such as  glycerin  or  sorbitol  to decrease the capsule's hardness,  coloring agents ,  preservatives , disintegrants,  lubricants  and  surface treatment ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5853", "text": "Since their inception, capsules have been viewed by consumers as the most efficient method of taking medication. [ citation needed ]  For this reason, producers of drugs such as  OTC  analgesics wanting to emphasize the strength of their product developed the \"caplet\", a  portmanteau  of \"capsule-shaped tablet\", [ 1 ]  to tie this positive association to more efficiently produced  tablet  pills, as well as being an easier-to-swallow shape than the usual disk-shaped tablet medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5854", "text": "In 1833, Mothes and Dublanc were granted a patent for a method to produce a single-piece gelatin capsule that was sealed with a drop of gelatin solution. They used individual iron molds for their process, filling the capsules individually with a medicine dropper. Later on, methods were developed that used sets of plates with pockets to form the capsules. Although some companies still use this method, the equipment is no longer produced commercially. All modern soft-gel encapsulation uses variations of a process developed by  R. P. Scherer  in 1933. His innovation used a rotary die to produce the capsules. They were then filled by  blow molding . This method was high-yield, consistent, and reduced waste. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5855", "text": "Softgels can be an effective delivery system for oral drugs, especially poorly soluble drugs. This is because the fill can contain liquid ingredients that help increase the solubility or permeability of the drug across the membranes in the body. Liquid ingredients are difficult to include in any other solid dosage form, such as a tablet. Softgels are also highly suited to potent drugs (for example, where the dose is <100\u00a0\u03bcg), where the highly reproducible filling process helps ensure each softgel has the same drug content, and because the operators are not exposed to any drug dust during the manufacturing process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5856", "text": "In 1949, the Lederle Laboratories division of the  American Cyanamid Company  developed the \"Accogel\" process, allowing powders to be accurately filled into soft gelatin capsules."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5857", "text": "James Murdoch of London patented the two-piece telescoping gelatin capsule in 1847. [ 2 ]  The capsules are made in two parts by dipping metal pins in the gelling agent solution. The capsules are supplied as closed units to the pharmaceutical manufacturer. Before use, the two halves are separated, and the capsule is filled with powder or more normally pellets made by the process of extrusion and spheronization  (either by placing a compressed slug of powder into one half of the capsule or by filling one half of the capsule with loose powder) and the other half of the capsule is pressed on. With the compressed slug method, weight varies less between capsules. However, the machinery required to manufacture them is more complex. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5858", "text": "The powder or spheroids inside the capsule contains the  active ingredients  and any  excipients , such as  binders , disintegrants,  fillers ,  glidant , and preservatives."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5859", "text": "Gelatin capsules , informally called  gel caps  or  gelcaps , are composed of  gelatin  manufactured from the  collagen  of animal skin or bone. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5860", "text": "Vegetable capsules , introduced in 1989, [ 5 ]  are made from  cellulose , a structural component in plants. The main ingredient of vegetarian capsules is  hydroxypropyl methyl cellulose . In the 21st century, gelatin capsules are more broadly used than vegetarian capsules because the cost of production is lower. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5861", "text": "The process of encapsulation of hard gelatin capsules can be done on manual, semi-automatic, and automatic capsule filling machines. Hard gelatin capsules are manufactured by the dipping method which is dipping, rotation, drying, stripping, trimming, and joining. [ 6 ]  Softgels are filled at the same time as they are produced and sealed on the  rotary die  of a fully automatic machine. Capsule fill weight is a critical attribute in encapsulation and various real-time fill weight monitoring techniques such as  near-infrared spectroscopy  (NIR) and  vibrational spectroscopy  are used, as well as in-line weight checks, to ensure product quality. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5862", "text": "Volume is measured to the full line, which is customary to the top of the smaller-diameter body half. [ citation needed ]  After capping, some  ullage  volume (airspace) remains in the finished capsule."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5863", "text": "The  Clinical Practice Research Datalink  ( CPRD ) is an observational and interventional research service that operates as part of the  Department of Health and Social Care . It is jointly funded by the  National Institute for Health and Care Research  (NIHR) and the  Medicines and Healthcare products Regulatory Agency  (MHRA). CPRD is working closely with the extensive primary care, topic specific and comprehensive NIHR research networks and with  NHS Digital ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5864", "text": "The programme that would develop into the current organisation was initially developed by an Essex  general practitioner , Dr  Alan Dean , to facilitate day-to-day management of his own general practice, in collaboration with IT staff at the BATA shoe factory in East Tilbury near to his practice. Early programmers included a Czech programmer  Jan Boda . [ 1 ] [ 2 ]  In 1987 a  venture capital company  was set up, named Value Added Information Medical Products Ltd (VAMP) to recruit other practices and form an information base. The early development team of three, Marcella Devenish (formerly a midwife), Philip Lee-Warren (formerly a Senior Medical Laboratory Scientific Officer), under the leadership of Kieran O'Mally, developed further the computerised system using the  BOS Microcobol  development environment. During this period the number of UK practices using the software product IGP (Integrated General Practice) expanded from a few hundred to over two and a half thousand. In return for anonymous Healthcare data, VAMP Ltd offered GPs the cash equivalent of GBP 500 a month in order to build the VAMP research databank for research purposes. As of 1988, the VAMP research databank comprised 57 practices and 543,100 patients. [ 3 ]  This figure was doubled to 1.2 million in 1990. [ 4 ]  One year later, 970 practices allowed VAMP to access their data, while about 1000 practices had a straightforward maintenance agreement with VAMP. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5865", "text": "In November 1993, its parent company was acquired by  Reuters Health Information , which donated the database to the  Department of Health  in 1994, at which time it became General Practice Research Database (GPRD) and contained data from 650 practices (4.4 million active patients). At this time, there were two licensees of the data: Dr Alan Dean, and Professor  Hershel Jick . [ 6 ]  Then the database was operated by the  Office for National Statistics  until 1999, at which point the  Medicines Control Agency  (MCA) took over. This agency became the  Medicines and Healthcare products Regulatory Agency  (MHRA) on 1 April 2003 following a merger with the  Medical Devices Agency  (MDA).  Since then, use of the database has expanded within the  UK  and overseas.  The GPRD was run as a sub-division of the MHRA. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5866", "text": "Following initiatives by the Director, Dr John Parkinson, the utility of GPRD was dramatically enhanced by linkage to other datasets on an individual patient level. External datasets included the  Hospital Episode Statistics , death certificates, the national cancer registry and MINAP (cardiovascular disease) registry. Additionally the dataset became that of choice by the FDA and most major pharma companies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5867", "text": "In March 2011, The Government launched its \u2018Plan for Growth\u2019 which details steps needed to enable the British economy to become more internationally competitive. As part of this initiative The Government pledged to build a consensus on using e-health record data to create a unique position for the UK in health research."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5868", "text": "Following the announcement by the chancellor on the \"Plan for Growth\", a commissioned study entitled the \"Research Capability Programme\" was initiated with the aim of assessing the available research capabilities of the UK and future potential growth areas in this sector. An opportunity was identified for the collaboration of the Department of Health and the MHRA in creating a joint research service, based upon consolidating and expanding existing independent services. The new service, known as the CPRD has been developed to meet the expectations and criteria outlined by the \"Plan for Growth\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5869", "text": "On 29 March 2012, the Medicines and Healthcare products Regulatory Agency and the Department of Health's  National Institute for Health and Care Research  (NIHR) launched the Clinical Practice Research Datalink (CPRD). [ 10 ]   On the launch of CPRD,  Sir Kent Woods , Chief Executive of the MHRA said, \"The Clinical Practice Research Datalink will provide new data and research services that will improve the health of patients and also make the UK a world leader in life sciences research.\" [ 10 ]   David Willetts , Minister for Universities and Science, said, \"The UK is a world leader in life sciences, but both the research base and industry tell us that we could make better use of data in order to drive medical breakthroughs. The Clinical Practice Research Datalink will provide researchers with access to safeguarded data that respects patient confidentiality. This will give valuable insights into serious health conditions and ultimately help reduce the time it takes to develop new treatments.\" [ 10 ]  The GPRD became part of the data services provision from CPRD."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5870", "text": "At its launch in April 2012, CPRD was established as the new, England-wide NHS observational and interventional research service. It has built on the research developments of the GPRD, and also the Health Research Support Service (HRSS) previously managed by the NIHR Research Capability Program."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5871", "text": "CPRD remains housed within the Medicines and Healthcare products Regulatory Agency."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5872", "text": "The CPRD builds on its predecessors' capabilities and aims to provide a range of services and products in the areas of medical research and public health care. Fundamental to the work of the CPRD is the collection and linkage of anonymised data sets and provision of research services."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5873", "text": "The CPRD utilises the maximum benefit of linked data sets and the UK's health system to provide researchers with access to high quality anonymous primary and secondary health care data. The data collected allows researchers access to a wealth of information including;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5874", "text": "The NHS provides, free at the point of delivery, healthcare to a population of 52 Million in England. With access to the data sets of NHS in England, Wales, Scotland and Northern Ireland the CPRD can provide a population of potentially up to 64 Million patients in the UK. Further access and partnerships have been established to include data sets from other European countries. The linking of anonomysed primary care data with large data registries and related data sets means the CPRD can offer a huge array of data and information for the inclusion in medical research studies. This will include areas such as; prescription drugs uses and effect, long term patient treatment strategy, long-term health benefit studies, epidemic and pandemic studies and demographic health and welfare studies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5875", "text": "For example, an analysis of 100 million GP consultations using CPRD data in 2016 provided the first substantial evidence of the increase in GP clinical workload in England. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5876", "text": "The CPRD has a range of research experience and expertise including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5877", "text": "The CPRD provides consulting services for a range of research activities. Provided by an experienced internal team, the research service offers advice on research methodology and research governance as well as a host of other services. Drawing from its expertise and predecessors' experience the CPRD research team has built a reputation for conducting high-end research projects, from protocol development, gaining approvals for research, data analysis and report and publication writing. The research capacity is such that the CPRD has the resource and expertise to undertake research projects on behalf of customers or independently, for a variety of undertakings from the commercial regulatory, charitable and academic sectors. A huge range of studies from the CPRD and predecessors have been published and a list of published papers can be found at  CPRD Research"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5878", "text": "The CPRD offers a range of interventional research services to facilitate the running of clinical trials."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5879", "text": "The primary health care data collected by the CPRD is taken from participating  GP surgeries  in the  United Kingdom .  Personal identifiers are not collected, protecting the privacy of the individuals from whom the data comes. Data collected includes;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5880", "text": "The  co-pay  card appeared in 2005 as a means by which pharmaceutical marketers could, by offering an instantaneous rebate to patients, combat their challenges to prescription pharmaceuticals, including generic competition, lack of patient compliance and persistency, and an access to the physician population. As of January 2017, in the United States, coupon cards for more than 600 prescription medications are available. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5881", "text": "Based on the National Council for  Prescription Drug  Programs standard, all pharmacy software systems contain information fields for both a primary and secondary insurer to pay for patient's prescription."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5882", "text": "Typically, a patient will receive his/her co-pay card from their physician along with a prescription for the medicine.  The patient takes the card and prescription to a pharmacy where the pharmacist enters processing information into his/her pharmacy  management system  to submit a claim."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5883", "text": "If a patient has insurance, the pharmacist will key in the patient's insurance number in the  primary field  and an identifier from the co-pay card into the secondary insurer field.  Instantaneously the pharmacy benefit manager provides  coverage data , relaying the patient's out of pocket, or co-pay to the secondary insurer's benefit manager, who then provides a discount accordingly. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5884", "text": "An example:  A brand offers a co-pay card giving patients the opportunity to save up to $20 off each prescription fill.  A patient receives the co-pay card and visits their pharmacy.  The patient provides his/her insurance card and co-pay card to the pharmacist. The pharmacist enters information into his/her pharmacy management system from both cards.  The insurance benefit manager recognizes the drug as a TIER 3 brand for the patient and relays the patient co-pay to be $30.00.  The co-pay card benefit manager recognizes the $30.00 and covers the $20.00 of co-pay, leaving $10 for the patient to pay out of pocket.  Another patient without prescription insurance coverage follows the same process.  The co-pay card takes the primary insurer position where it recognizes the claim as that of a cash-paying patient and applies $20.00 discount to the patient's out-of-pocket costs. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5885", "text": "In most cases the  service provider  of the co-pay card program holds a reimbursement account for the  pharmaceutical marketing  client, which is used to remit to pharmacies the cost reductions through co-pay card programs.  The co-pay service provider remits to pharmacies every 14 to 28 days and deducts these remittances via this account."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5886", "text": "Some providers have attempted a variation on the original co-pay card by going to a magnetic strip swipe process, by which the card runs through both the pharmacy software and  financial software  (e.g. Visa/MasterCard and Debit networks)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5887", "text": "Debit cards  are another reimbursement method for co-pay in pharmacies because they offer real-time reimbursement of co-pay claims.  However, with new prompt-pay regulations for adjudicators, required for Medicare Part D and implemented by most PBMs, few pharmacies wait more than one week for reimbursement. Pharmacies used to prefer real-time Debit payments because they didn't require the pharmacies to carry the \"float\" of the 14 to 28 days payment cycles. This is no longer true."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5888", "text": "A  cold chain  is a  supply chain  that uses  refrigeration  to maintain perishable goods, such as pharmaceuticals, produce or other goods that are temperature-sensitive. [ 1 ]  Common goods, sometimes called  cool cargo, [ 2 ]  distributed in cold chains include fresh agricultural  produce , [ 3 ]  seafood,  frozen food ,  photographic film , chemicals, and  pharmaceutical products . [ 4 ]  The objective of a cold chain is to preserve the integrity and quality of goods such as pharmaceutical products or perishable good from production to consumption.  [ 5 ]   [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5889", "text": "A well functioning, or unbroken, cold chain requires uninterrupted sequence of refrigerated production, storage and distribution activities, along with associated equipment and logistics, which maintain a desired low-temperature interval to keep the safety and quality of perishable or sensitive products. Unlike other goods or merchandise, cold chain goods are  perishable  and always en-route towards end use or destination. Adequate cold storage, in particular, can be crucial to prevent   food loss and waste . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5890", "text": "Mobile  refrigeration  with  ice  from the  ice trade  began with  reefer ships  and  refrigerator cars  ( iceboxes  on wheels) in the mid-19th century. [ 8 ]  The term  cold chain  was first used in 1908. The first effective cold store in the UK opened in 1882 at  St Katharine Docks . [ 9 ]  It could hold 59,000 carcasses, and by 1911 cold storage capacity in London had reached 2.84 million carcasses. [ 9 ]  By 1930 about  a thousand refrigerated meat containers were in use which could be switched from road to railway. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5891", "text": "Mobile mechanical refrigeration was invented by  Frederick McKinley Jones , who co-founded  Thermo King  with entrepreneur Joseph A. \"Joe\" Numero. In 1938 Numero sold his Cinema Supplies Inc. movie sound equipment business to  RCA  to form the new entity, U.S. Thermo Control Company (later the  Thermo King Corporation ), in partnership with Jones, his engineer. Jones designed a portable air-cooling unit for trucks carrying perishable food, [ 10 ]  for which they obtained a patent on 12 July 1940, [ 11 ]  subsequent to a challenge to invent a refrigerated truck over a 1937 golf game by associates of Numero's, Werner Transportation Co. president Harry Werner, and United States Air Conditioning Co. president Al Fineberg, [ 12 ] [ 10 ] [ 11 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5892", "text": "This technology has been frequently in use since the 1950s, when it was most often used for preserving animal-based cells or tissue. As medical breakthroughs, such as in cancer treatment, have taken place, the demand for cold chain systems has grown. The  COVID-19 pandemic  and its associated  vaccinations , have caused vastly increased need. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5893", "text": "Cold chains are common in the food and  pharmaceutical  industries and also in some chemical shipments. One common temperature range for a cold chain in pharmaceutical industries is 2 to 8\u00a0\u00b0C (36 to 46\u00a0\u00b0F), but the specific temperature (and time at temperature) tolerances depend on the actual product being shipped. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5894", "text": "Unique to fresh produce cargoes, the cold chain requires to additionally maintain product specific environment parameters [ 3 ]  which include air quality levels (carbon dioxide, oxygen, humidity and others). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5895", "text": "The cold chain is used in the supply of  vaccines  to distant clinics in hot climates served by poorly developed transport networks. Vaccines can lose their efficacy if cold chain management fails. [ 15 ]  Disruption of a cold chain due to war may produce consequences similar to the  smallpox  outbreaks in the Philippines during the  Spanish\u2013American War , during which the distributed vaccines were inert due to lack of temperature control in transport. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5896", "text": "For vaccines, there are different types of cold chains. There is an ultralow, or deep freeze, cold chain for vaccines that require -70 degrees C, such as the Ebola and  Pfizer\u2013BioNTech COVID-19  vaccines, and some animal vaccines, such as those for chickens. Next the frozen chain requires -20 degrees C. Varicella and zoster vaccinations require this level. Then the refrigerated chain, which requires temperatures between two and eight degrees C. Most flu vaccinations only require refrigeration. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5897", "text": "In 2020, during the  COVID-19 pandemic , vaccines being developed may need  ultracold storage  and transportation temperatures as cold as \u221270\u00a0\u00b0C (\u221294\u00a0\u00b0F), requiring what has been referred to as a \"colder chain\" infrastructure. [ 18 ]  This creates some issues of distribution for the  Pfizer vaccine . It is estimated that only 25 to 30 countries in the world have the infrastructure for the required ultracold cold chain. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5898", "text": "The cold chain distribution process is an extension of the  good manufacturing practice  (GMP) environment that all drugs and biological products are required to follow, and are enforced by the various health regulatory bodies. As such, the distribution process must be validated to ensure that there is no negative impact to the safety, efficacy or quality of the drug substance. The GMP environment requires that all processes that might impact the safety, efficacy or quality of the drug substance must be  validated , including storage and distribution of the drug substance. [ 18 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5899", "text": "A cold chain can be managed by a  quality management system .  Temperature data loggers  and  RFID  tags help monitor the temperature history of the truck,  reefer container , warehouse, etc. and the temperature history of the product being shipped. [ 19 ]  They also can help determine the remaining  shelf life . [ 20 ]  Also, temperature sensors may need to be  National Institute of Standards and Technology  (NIST) traceable depending on the body monitoring the cold chain. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5900", "text": "This article incorporates text from a  free content  work. Licensed under CC BY-SA 3.0 ( license statement/permission ). Text taken from  The State of Food and Agriculture 2019. Moving forward on food loss and waste reduction, In brief\u200b , 24, FAO, FAO."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5901", "text": "Corporate Crime in the Pharmaceutical Industry  is a 1984 book on  corporate crime  and the  pharmaceutical industry  by  criminologist   John Braithwaite . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5902", "text": "The author writes from the perspective of a criminologist and not from a perspective of expertise in drug law or pharmacology. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5903", "text": "Various reviewers commented on the book. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5904", "text": "The author produced a follow-up book 30 years later titled,  Pharmaceuticals, Corporate Crime and Public Health . [ 5 ]  At the release of that new book a reviewer reconsidered the 1984 book in retrospect and reported that the book's ideas were still relevant. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5905", "text": "The book is  available  at the  Internet Archive ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5906", "text": "Critical Path Institute  (C-Path) is a non-profit organization created to improve the  drug development  process; its  consortia  include more than 1,600 scientists from government regulatory and research agencies,  academia , patient organizations, and bio-pharmaceutical companies. [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5907", "text": "The U.S.  Food and Drug Administration  (FDA) launched the  Critical Path Initiative  in 2004 to transform the way FDA-regulated medical products are developed, evaluated, and manufactured. [ 6 ]  C-Path was created as an independent organization to respond to the needs outlined in the FDA's initiative and with support and funding from the FDA,  Science Foundation Arizona , and the  Tucson, Arizona  community. It operates as a neutral third party to enable scientists from the regulated industry and international regulatory agencies to work together with scientists from academia and patient groups to improve the drug development process. [ 5 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5908", "text": "In the interest of national and global  public health , C-Path develops large databases of aggregated clinical trial data that can be used to study disease progression. These data are also used to develop and qualify  biomarkers  and clinical outcome assessment instruments that are shared with the greater community for use in drug development. C-Path also develops quantitative models to facilitate the design of efficient clinical trials. [ 5 ] [ 8 ] [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5909", "text": "C-Path programs are focused on reducing the time, cost, and risk of drug development and regulatory review. Where appropriate, C-Path forms consortia to improve the drug development process. [ 11 ] [ 12 ] [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5910", "text": "C-Path is headquartered in  Tucson, Arizona .  Raymond L. Woosley, M.D., Ph.D.  founded C-Path in 2005 and is President Emeritus. Kristen Swingle is currently C-Path's Interim President and Chief Operating Officer. The Board of Directors includes Robert M. Califf, Wainwright Fishburn, Timothy R Franson, Kay Holcombe, Jeffrey E Jacob, former Pfizer CFO  Alan Levin  and biochemist  Paula J. Olsiewski . [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5911", "text": "The  Drug Industry Documents Archive  (DIDA) is a digital archive of  pharmaceutical industry  documents created and maintained by the  University of California, San Francisco ,  Library  and Center for Knowledge Management.  DIDA is a part of the larger UCSF  Industry Documents Library  which includes the  Truth Tobacco Industry Documents .  The archive contains documents about pharmaceutical industry  clinical trials , publication of study results, pricing,  marketing , relations with physicians and drug company involvement in  continuing medical education ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5912", "text": "Most of the documents on DIDA were made public as a result of lawsuits against pharmaceutical companies  Parke-Davis ,  Warner-Lambert ,  Pfizer ,  Merck & Co. ,  Wyeth  and  Abbott Labs , among others.  DIDA was founded in 2005 with the support of a gift by Thomas Greene, the attorney for  David Franklin , whistleblower in United States ex rel. Franklin v. Parke-Davis, the case from which the first documents in the archive originated. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5913", "text": "Researchers as well as students, journalists, and the general public, use the archive to investigate the ways pharmaceutical companies market their products.  The  UCSF_Library  created this digital archive in an attempt to facilitate further research into the drug industry's practice of establishing close links with the medical community which has been shown to influence scientific research, drug approval, prescription practices, and ultimately, consumer health. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5914", "text": "DIDA contains:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5915", "text": "Documents come from a variety of sources including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5916", "text": "Drug Master File  or  DMF  is a document prepared by a  pharmaceutical  manufacturer and submitted solely at its discretion to the appropriate regulatory authority in the intended drug market. There is no regulatory requirement to file a DMF. However, the document provides the regulatory authority with confidential, detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs. Typically, a DMF is filed when two or more firms work in partnership on developing or manufacturing a drug product.  The DMF filing allows a firm to protect its  intellectual property  from its partner while complying with regulatory requirements for disclosure of processing details."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5917", "text": "Drug Master File (DMF) is a document containing complete information on an   Active Pharmaceutical Ingredient  (API) or finished drug  dosage form . It is known as European Drug Master File (EDMF) or Active Substance Master File (ASMF) and US-Drug Master file (US-DMF) in Europe and United States respectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5918", "text": "In the United States, DMFs are submitted to the  Food and Drug Administration  (FDA).  The Main Objective of the DMF is to support regulatory requirements and to prove the quality, safety and efficacy of the medicinal product for obtaining an  Investigational New Drug  Application (IND), a  New Drug Application  (NDA),As an  Abbreviated New Drug Application  (ANDA), another DMF, or an Export Application."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5919", "text": "In United States there are 5 types of Drug Master file: [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5920", "text": "The content and the format for drug master file used in United States differs from that used in European Countries to obtain market authorization (MA). The Main Objective of the EDMF is to support regulatory requirements of a medicinal product to prove its quality, safety and efficacy. This helps to obtain a Marketing Authorisation grant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5921", "text": "Drug nomenclature  is the  systematic naming  of  drugs , especially  pharmaceutical drugs . In the majority of circumstances, drugs have 3 types of names:  chemical names , the most important of which is the  IUPAC name ;  generic or nonproprietary names , the most important of which are  international nonproprietary names  (INNs); and trade names, which are  brand names . [ 1 ]  Under the INN system, generic names for drugs are constructed out of  affixes  and stems that classify the drugs into useful categories while keeping related names distinguishable. [ 2 ]  A marketed drug might also have a company code or  compound code . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5922", "text": "Drug names are often subject to legal regulation, including approval for new drugs (to avoid confusion with existing drugs) and on packaging to establish clear rules about  adulterants  and fraudulent or misleading labeling. A national  formulary [ 1 ]  is often designated to define drug names (and purity standards) for regulatory purposes. The legally approved names in various countries include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5923", "text": "The  World Health Organization  administers the  international nonproprietary name  list."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5924", "text": "A company or person developing a drug can apply for a generic (nonproprietary) name through their national formulary or directly to the WHO INN Programme. [ 4 ]  In order to minimize confusion, many of the national naming bodies have policies of maintaining harmony between national nonproprietary names and INNs. [ 2 ]  The European Union has mandated this harmonization for all member states [ 5 ]  In the United States, the developer applies to United States Adopted Name (USAN) Council, and a USAN negotiator applies to the INN on the developer's behalf. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5925", "text": "The chemical names are the  scientific names , based on the  molecular structure  of the drug. There are various systems of  chemical nomenclature  and thus various chemical names for any one substance. The most important is the  IUPAC name . Chemical names are typically very long and too complex to be commonly used in referring to a drug in speech or in prose documents. [ 1 ]  For example, \"1-(isopropylamino)-3-(1-naphthyloxy) propan-2-ol\" is a chemical name for  propranolol . Sometimes, a company that is developing a drug might give the drug a company code, [ 3 ]  which is used to identify the drug while it is in development. For example, CDP870 was  UCB 's company code for  certolizumab pegol ; UCB later chose \"Cimzia\" as its trade name. [ 1 ]  Many of these codes, although not all, have  prefixes that correspond to the company name ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5926", "text": "Generic names are used for a variety of reasons.  They provide a clear and unique identifier for active chemical substances, appearing on all drug labels, advertising, and other information about the substance. Relatedly, they help maintain clear differentiation between proprietary and nonproprietary aspects of reality, which people trying to sell proprietary things have an  incentive  to  obfuscate ; they help people  compare apples to apples . They are used in scientific descriptions of the chemical, in discussions of the chemical in the  scientific literature  and descriptions of  clinical trials . [ 2 ]  Generic names usually indicate via their stems what drug class the drug belongs to. [ 6 ]  For example, one can tell that  aciclovir  is an  antiviral drug  because its name ends in the  -vir  suffix."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5927", "text": "The earliest roots of  standardization  of generic names for drugs began with  city pharmacopoeias , such as the London, Edinburgh, Dublin, Hamburg, and Berlin Pharmacopoeias. The  fundamental advances in chemistry during the 19th century  made that era the first time in which what we now call  chemical nomenclature , a huge profusion of names based on atoms, functional groups, and molecules, was necessary or conceivable. In the second half of the 19th century and the early 20th, city pharmacopoeias were unified into  national pharmacopoeias  (such as the  British Pharmacopoeia ,  United States Pharmacopeia , Pharmacopoeia Germanica (PhG or PG), Italian Pharmacopeia, and  Japanese Pharmacopoeia ) and  national formularies  (such as the  British National Formulary , the  Australian Pharmaceutical Formulary , and the National Formulary of India). International pharmacopeias, such as the  European Pharmacopoeia  and the  International Pharmacopoeia  of the   World Health Organization  (WHO), have been the next level."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5928", "text": "In 1953 the WHO created the  International Nonproprietary Name  (INN) system, which issues INNs in various languages, including Latin, English, French, Spanish, Russian, Chinese, and Arabic. Several countries also have national-level systems for creating  generic drug  names, including the  British Approved Name  (BAN) system, the Australian Approved Name (AAN) system, the  United States Adopted Name  (USAN) system (which is mostly the same as the  United States Pharmacopeia  (USP) system), and the  Japanese Accepted Name  (JAN) system. At least several of these national-level Approved Name/Adopted Name/Accepted Name systems were not created until the 1960s, after the INN system already existed. In the 21st century, increasing  globalization  is encouraging maximal rationalization for new generic names for drugs, and there is an increasing expectation that new USANs, BANs, and JANs will not differ from new INNs without special justification."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5929", "text": "During the first half of the 20th century, generic names for drugs were often coined by  contracting  the chemical names into fewer syllables. Such contraction was partially, informally, locally standardized, but it was not universally consistent. In the second half of the 20th century, the nomenclatural systems moved away from such contraction toward the present system of stems and affixes that show chemical relationships."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5930", "text": "Biopharmaceuticals  have posed a challenge in nonproprietary naming because unlike smaller molecules made with  total synthesis  or  semisynthesis , there is less assurance of complete  fungibility  between products from different manufacturers. Just as  wine  may vary by  strain  of yeast and year of grape harvest, so each product can be subtly different because living organisms are an integral part of production. The WHO MedNet community continually works to augment its system for biopharmaceuticals to ensure continued fulfillment of the goals served by having nonproprietary names. [ 7 ]  In recent years the development of the Biological Qualifier system has been an example. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5931", "text": "The  prefixes  and  interfixes  have no pharmacological significance and are used to separate the drug from others in the same class.  Suffixes  or  stems  may be found in the middle or more often the end of the drug name, and normally suggest the action of the drug. Generic names often have suffixes that define what class the drug is. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5932", "text": "More comprehensive lists can be found in Appendix VII of the USP Dictionary or in the  WHO   INN  stembook. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5933", "text": "If the name of the drug solanezumab were to be broken down, it would be divided into two parts like this: solane-zumab. -Zumab is the suffix for humanized monoclonal antibody. [ 10 ]  Monoclonal antibodies by definition contain only a single antibody clone and have binding specificity for one particular epitope. [ 11 ]  In the case of solanezumab, the antibody is designed to bond to the  amyloid-\u03b2   peptides  which make up  protein plaques  on the  neurons  of people with  Alzheimer's disease ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5934", "text": "See also  Time release technology > List of abbreviations  for formulation suffixes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5935", "text": "For combination drug products\u2014those with two or more drugs combined into a single  dosage form \u2014single nonproprietary names beginning with \"co-\" exist in both  British Approved Name  (BAN) form and in a formerly maintained  USP  name called the pharmacy equivalent name (PEN). Otherwise the two names are simply both given, joined by hyphens or slashes. For example, suspensions combining  trimethoprim  and  sulfamethoxazole  are called either  trimethoprim/sulfamethoxazole  or co-trimoxazole. Similarly,  co-codamol  is  codeine - paracetamol  (acetaminophen), and co-triamterzide is  triamterene - hydrochlorothiazide . The USP ceased maintaining PENs, but the similar \"co\"-prefixed BANs are still current."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5936", "text": "Most commonly, a nonproprietary drug name has one widely agreed pronunciation in each language. For example,  doxorubicin  is consistently  / \u02cc d \u0252 k s o\u028a \u02c8 r u\u02d0 b \u026a s \u026a n /  in English. [ 12 ] [ 13 ]  Trade names almost always have one accepted pronunciation, because the sponsoring company who coined the name has an intended pronunciation for it."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5937", "text": "However, it is also common for a nonproprietary drug name to have two pronunciation variants, or sometimes three. For example, for  paracetamol , both  / \u02cc p \u00e6r \u0259 \u02c8 s i\u02d0 t \u0259 m \u0252 l /  and  / \u02cc p \u00e6r \u0259 \u02c8 s \u025b t \u0259 m \u0252 l / [ 13 ]  are common, and one  medical dictionary  gives  / p \u00e6 \u02cc r \u00e6 s \u026a \u02c8 t \u00e6 m \u0252 l / . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5938", "text": "Some of the variation comes from the fact that some stems and affixes have pronunciation variants. For example, the aforementioned third (and least common) pronunciation for  paracetamol  reflects the treatment of the  acet  affix as  / \u02c8 \u00e6 s \u026a t /  rather than  / \u0259 \u02c8 s i\u02d0 t /  (both are accepted for  acetyl [ 14 ] [ 12 ] )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5939", "text": "The  World Health Organization  does not give suggested pronunciations for its  INNs , but familiarity with the typical sounds and spellings of the stems and affixes often points to the widely accepted pronunciation of any given INN. For example,  abciximab  is predictably  / \u00e6 b \u02c8 s \u026a k s \u026a m \u00e6 b / , because for INNs ending in  -ciximab , the  / \u02c8 s \u026a k s \u026a m \u00e6 b /  sound is familiar. The  United States Pharmacopeia  gives suggested pronunciations for most  USANs  in its  USP Dictionary , which is published in annual editions.  Medical dictionaries  give pronunciations of many drugs that are both commonly used and have been commercially available for a decade or more, although many newer drugs or less common drugs are not entered. Pharmacists also have access to pronunciations from various  clinical decision support systems  such as  Lexicomp ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5940", "text": "For drugs that make it all the way through development, testing, and regulatory acceptance, the  pharmaceutical company  then gives the drug a  trade name , which is a standard term in the pharmaceutical industry for a  brand name  or  trademark  name. For example,  Lipitor  is  Pfizer 's trade name for  atorvastatin , a  cholesterol -lowering medication. Many drugs have multiple trade names, reflecting marketing in different countries, manufacture by different companies, or both. Thus the trade names for atorvastatin include not only Lipitor (in the U.S.) but also Atocor (in India)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5941", "text": "In the  scientific literature , there is a set of strong conventions for drug nomenclature regarding the  letter case  and placement of nonproprietary and  proprietary  names, as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5942", "text": "For example, the 2015  American Society of Hematology  (ASH) publication policies say, [ 15 ]  \"Non-proprietary (generic/scientific) names should be used and should be lowercase.\" [ 15 ]  ... \"[T]he first letter of the name of a proprietary drug should be capitalized.\" [ 15 ]  ... \"If necessary, you may include a proprietary name in parentheses directly following the generic name after its first mention.\" [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5943", "text": "Valid exceptions to the general pattern occur when a nonproprietary name starts a sentence (and thus takes a capital), when a proprietary name has  intercapping  (for example, GoLYTELY, MiraLAX), or when  tall-man letters  are used within nonproprietary names to prevent confusion of similar names (for example,  predniSONE  versus  predniSOLONE )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5944", "text": "Dublin Molecular Medicine Centre  (DMMC) was a charity set up in 2002, to create critical mass in molecular medicine research in Dublin, Ireland. Funding was provided by the  Higher Education Authority . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5945", "text": "The academic resources supporting the teaching hospitals include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5946", "text": "DMMC secured funding from the  Wellcome Trust  for a major clinical research centre to be led by Professor  Dermot P. Kelleher  for Dublin comprising two elements:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5947", "text": "Dublin Molecular Medicine Centre evolved to become Molecular Medicine Ireland which was established in 2008. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5948", "text": "The  electronic common technical document  ( eCTD ) is an interface and international specification for the  pharmaceutical industry  to  agency  transfer of regulatory information.\nThe specification is based on the  Common Technical Document  (CTD) format and was developed by the  International Council for Harmonisation  (ICH) Multidisciplinary Group 2 Expert Working Group (ICH M2 EWG)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5949", "text": "Version 2.0 of eCTD \u2013 an upgrade over the original CTD \u2013 was finalized on February 12, 2002, [ 1 ]  and version 3.0 was finalized on October 8 of the same year. [ 2 ]  As of August 2016 [update] , the most current version is 3.2.2, released on July 16, 2008. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5950", "text": "A Draft Implementation Guide (DIG) for version 4.0 of eCTD was released in August 2012. [ 4 ]  However, work stalled on the project. An additional Draft Implementation Guide was released in February 2015 [ 5 ]  The ICH and the FDA released draft specifications and guides in April 2016, and on May 13 there was an ICH \"teleconference\" to discuss the guidance and any queries or clarifications that might be necessary. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5951", "text": "On May 5, 2015, the  U.S. Food & Drug Administration  published a final, binding guidance document [ 7 ]  requiring certain submissions in electronic (eCTD) format within 24 months. The projected date for mandatory  electronic submissions  is May 5, 2017 for  New Drug Applications  (NDAs), Biologic License Applications (BLAs), Abbreviated New Drug Applications (ANDAs) and Drug Master Files (DMFs). [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5952", "text": "Health Canada  was a sponsor and an early adopter of the eCTD workflow, especially for its  Health Products and Food Branch  regulator, but as of April 2015 had not yet fully automated it. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5953", "text": "The E.U. and its  European Medicines Agency  began accepting eCTD submissions in 2003. [ 10 ]  In February 2015, the \"EMA announced it would no longer accept paper application forms for products applying to the centralized procedure beginning 1 July 2015.\" [ 11 ]  The EMA verified on that date that it would no longer accept \"human and veterinary centralised procedure applications\" and that all electronic application forms would have to be eCTD by January 2016. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5954", "text": "In November 2017,  China Food and Drug Administration (CFDA)  publishes draft eCTD structure for drug registration for public consultations. This is a big transition for China to move from paper submission to eCTD submissions. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5955", "text": "The  Japan   PhMDA  has been eCTD compliant at least since December 2017. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5956", "text": "The Electronic Common Technical Document Specification, the main ICH standard, largely determines the structure of an eCTD submission. [ 15 ]  However, additional specifications may be applied in national and continental contexts. In the United States, the  Food and Drug Administration  (FDA) layers additional specifications onto its requirements for eCTD submissions, including PDF, transmission, file format, and supportive file specifications. [ 16 ] [ 17 ]  In the European Union, the European Medicines Agency's EU Module 1 specification as well as other QA documents lay out additional requirements for eCTD submissions. [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5957", "text": "The eCTD has five modules:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5958", "text": "A  full table of contents  could be quite large."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5959", "text": "There are two categories of modules:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5960", "text": "The CTD defines the content only of the common modules. The contents of the Regional Module 1 are defined by each of the ICH  regions  (USA, Europe and Japan)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5961", "text": "The eCTD is a message specification for the transfer of files and metadata from a submitter to a receiver. The primary technical components are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5962", "text": "Each submission message constitutes one \"sequence\". A cumulative eCTD consists of one or more sequences. While a single sequence may be viewed with web browser and the ICH stylesheet provided, viewing a cumulative eCTD requires specialized eCTD viewers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5963", "text": "The top part of the directory structure is as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5964", "text": "The string  ctd-123456/0000  is just an example."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5965", "text": "This is the file  index.xml  in the  submission sequence number folder .\nFor example:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5966", "text": "The purpose of this file is twofold:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5967", "text": "Stylesheets that support the presentation and navigation should be included. They must be placed in the directory:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5968", "text": "See entry 377 in Appendix 4."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5969", "text": "DTDs must be placed in the directory:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5970", "text": "See entries 371\u201376 in Appendix 4.\nThey must follow a naming convention."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5971", "text": "The DTD of the backbone is in Appendix 8.\nIt must be placed in the above directory."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5972", "text": "The business process to be supported can be described as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5973", "text": "The  lifecycle management  is composed at least of:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5974", "text": "An  epedigree  (sometimes referred to as  e-pedigree  or  electronic pedigree ) is an  electronic document  which provides data on the history of a particular batch of a drug.  It satisfies the requirement for a  drug pedigree  while using a convenient electronic form."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5975", "text": "The  U.S. Food and Drug Administration  (FDA) in the 2006 Compliance Policy Guide for the  Prescription Drug Marketing Act  states that:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5976", "text": "\"A drug pedigree is a statement of origin that identifies each prior sale, purchase, or trade of a drug, including the date of those transactions and the names and addresses of all parties to them.\" [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5977", "text": "An epedigree  is simply an electronic document which satisfies the pedigree requirement.  The primary purpose of an epedigree is to protect consumers from any contaminated medicine or  counterfeit drugs ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5978", "text": "On January 5, 2007  EPCglobal  ratified the Pedigree Standard [ 2 ]  as an international standard that specifies an  XML  description of the life history of a product across an arbitrarily complex supply chain."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5979", "text": "As of 2008, most states have enacted some sort of pedigree requirement and many have also required an epedigree.  However, the existing epedigree requirements amount to little more than requiring that pharmaceutical supply chain companies be able to provide reports in formats such as  pdf , text files or  spreadsheets ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5980", "text": "The basic data elements of an original epedigree are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5981", "text": "As the product moves down the supply chain, each company is required to carry forward all previous epedigree information.  In this way, the final point of sale has the complete lineage of every unit."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5982", "text": "ePedigree laws were eventually replaced by a harmonized national standard called the  Drug Quality and Security Act ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5983", "text": "ePedigree laws were in a rapid state of flux with states changing the \"drop dead\" date for compliance with tracking and authentication years beyond the original dates set by Florida and California.  The definitive requirements will include serialization.  Companies that focus purely on achieving compliance will miss the opportunity to use regulation as a business driver.  The ability to track and serialize unit level saleable packages (e.g. bottle of 25 pills) not just cases or pallets can create business value in knowing exactly where their products are purchased can do the following: \n1) Minimize cost of chargebacks through 100% accurate adjudication. Chargebacks account for 2-15% of gross revenue for a pharmaceutical manufacturer.  \n2) Minimize risk by increasing accuracy in Medicare/Medicaid pricing calculations by fully knowing all fees, rebates, and chargebacks that should be applied to a specific unit sale.  Over $4B in fines have been handed down for improperly calculating Medicare/Medicaid pricing.  \n3) Limit liability of having to recall entire lots of product because a (non-serialized) shipment was stolen - see example:  [1] \n4) Achieve visibility for manufacturers in the labyrinth that is the wholesale distribution network to more accurately forecast demand and measure sales & marketing programs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5984", "text": "Although simple epedigree systems are an important first step, significant improvement in public safety would result from a more standardized and automated approach.  The larger and more difficult task of providing for an Automated Epedigree System has been suggested, but not required by any state.  Such a system would require fairly significant changes to  supply chain  companies' data interchanges and would certainly require advanced Track and Trace technology (with  bar codes  or  RFID ).  The requirements that come closest to an Automated Epedigree System have been proposed by California.  In March 2008, the California Board of Pharmacy (CBOP) published its \"E-Pedigree Requirements\" which are scheduled to go into effect in a phased approach between 2015 and 2017 (since abandoned).  CBOP has proposed an  XML  standard document and the law requires an \"interoperable electronic system\". [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5985", "text": "The  European Federation of Pharmaceutical Industries and Associations  (EFPIA) is a  Brussels -based trade association and  lobbying  organisation, founded in 1978 and representing the  pharmaceutical industry  operating in Europe. Through its membership of 36 national associations and 39 leading pharmaceutical companies, [ 1 ]  the EFPIA represents 1,900 European companies. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5986", "text": "EFPIA priorities include speeding up regulatory approval and reimbursement processes for new medicines, creating a strong science base in Europe, joining forces with key stakeholders on political issues concerning health and addressing safety concerns. EFPIA also includes specialised groups like Vaccines Europe [ 3 ]  who produce approximately 80% of vaccines used worldwide and European Biopharmaceutical Enterprises harness biotechnology to develop approximately one-fifth of new medicines."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5987", "text": "The Innovative Medicines Initiative (IMI) is a public-private partnership designed by the European Commission and EFPIA. It is a pan-European collaboration that brings together large biopharmaceutical companies, small- and medium-sized enterprises (SMEs), patient organisations, academia, hospitals and public authorities. The initiative aims to accelerate the discovery and development of better medicines by removing bottlenecks in the drug development process. It focuses on creating better methods and tools to improve and enhance the drug development process, rather than developing specific, new medicines."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5988", "text": "From 1991 to 1998  Emer Cooke  worked for the EFPIA. [ 4 ]  She became executive director of the  European Medicines Agency  (EMA), an  agency of the European Union  (EU) in charge of the evaluation and supervision of  medicinal products , in November 2020. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5989", "text": "In a session of the  Austrian Parliament   member of parliament   Gerald Hauser  on 1 April 2021 publicly criticised a potential  conflict of interest , by her allowing the controversial  Oxford\u2013AstraZeneca COVID-19 vaccine  to be approved, while having worked for the very same industry in the past as a lobbyist of the EFPIA. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5990", "text": "The  European Forum for Good Clinical Practices  (EFGCP) is a European think tank which works on the ethical, regulatory, and scientific framework of  clinical research  in  Europe . The EFGCP is committed to the development of the standards for the protection of human subjects and data quality in clinical trials, both in Europe and abroad."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5991", "text": "Expert Opinion on Therapeutic Patents  is a monthly  peer-reviewed   medical journal  covering  pharmaceutical  patent information across all therapy areas. Each review includes an \"expert opinion\" section, in which authors provide their personal view on the current status and future direction of the research discussed. The journal was established as  Current Opinion on Therapeutic Patents  in 1991, and changed to the current name in 1994. It is published by  Informa . The  editor-in-chief  is  Claudiu T. Supuran  ( University of Florence )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5992", "text": "The journal is abstracted and indexed in  Chemical Abstracts Service ,  Current Contents /Life Sciences,  EMBASE/Excerpta Medica ,  Index Medicus / Medline / PubMed , and the  Science Citation Index Expanded . According to the  Journal Citation Reports , the journal has a 2014  impact factor  of 4.297. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5993", "text": "This article about a  pharmacology   journal  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5994", "text": "See tips for writing articles about academic journals . Further suggestions might be found on the article's  talk page ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5995", "text": "Fire in the Blood  is a 2013  documentary film  by  Dylan Mohan Gray  depicting what it claims is the intentional obstruction of access to low-cost  antiretroviral drugs  used in the treatment of  HIV/AIDS  to people in  Africa  and other parts of the global south, driven by multinational pharmaceutical companies holding  patent  monopolies and various Western governments (above all those of the United States,  European Union  and Switzerland) consistently supporting these companies. The film claims that the battle against what it refers to as a \"genocidal blockade,\" which it estimates to have resulted in no less than ten to twelve million completely unnecessary deaths, was fought and (at least temporarily) won."}
{"_id": "WikiPedia_Pharmacology$$$corpus_5996", "text": "Fire in the Blood  features contributions from former US President  Bill Clinton , intellectual property activist  James Love , global health reporter  Donald McNeil, Jr.  of  The New York Times , HIV/AIDS treatment activist  Zackie Achmat , pioneering generic drug maker  Yusuf Hamied , former  Pfizer  executive-turned- whistleblower   Peter Rost , Ugandan AIDS  physician   Peter Mugyenyi , and  Nobel Prize -laureates  Desmond Tutu  and  Joseph Stiglitz . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5997", "text": "The film is narrated by  Academy Award -winning actor  William Hurt , who lent his voice to the film on a  pro bono  basis because he felt the story and subject matter were so important. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5998", "text": "In November 2013,  Fire in the Blood  set a new record for the longest theatrical run by a non-fiction feature film in India: five weeks. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_5999", "text": "In November 2018, Australian journalist and documentary filmmaker  John Pilger  included  Fire in the Blood  among his selection of \"26 landmark documentary films of the past seven decades.\" [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6000", "text": "Filmmaker  Dylan Mohan Gray  first learned of the issue in 2004, after he read an article in  The Economist  about the battle between pharmaceutical companies and the global public health community over access to lower-cost AIDS drugs for Africa. [ 6 ]  He decided to make the film three years later. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6001", "text": "The film was shot on four continents from March 2008 to the end of 2010, while editing was completed in 2012. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6002", "text": "The film was first released theatrically in Ireland on 21 February 2013, with the UK premiere the following day. It was released theatrically in the US on 7 September 2013 and in India on 11 October the same year, to outstanding reviews. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6003", "text": "The film was released on the  iTunes  UK Store in mid-2013, and worldwide on  VOD  via its website in 2014. It released in the UK and India on  DVD  in the first quarter of 2014."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6004", "text": "Thus far the film has been broadcast on  television  in the following countries, beginning in late 2013: Finland ( YLE ), Israel ( Yes (Israel) ), Norway ( NRK ), Spain ( TVE ), Switzerland ( SRF ), Austria ( ORF ), Poland ( Telewizja Polska ), Ireland ( TG4 ), Brazil ( Globosat ), Denmark ( DR ), the United States ( Audience Network ) and Japan ( NHK ). Transnational broadcasters include  AJE ,  Al Jazeera Arabic  and  Al Jazeera Balkans , along with  DStv  and GOtv across Sub-Saharan Africa as part of the \"AfriDocs\" initiative."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6005", "text": "Fire in the Blood  was the first Indian film to be selected for the World Cinema Documentary competition at the  Sundance Film Festival [ 9 ]  and subsequently participated in over 100 leading  film festivals  in dozens of countries all over the world. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6006", "text": "Fire in the Blood  received positive critical notices, both to its North American premiere at the 2013  Sundance Film Festival , as well as to its subsequent theatrical releases in Ireland,  Britain , the United States and India. [ 10 ] [ unreliable source? ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6007", "text": "The film  review aggregator  website  Rotten Tomatoes  has given  Fire in the Blood  a \"92% fresh\" rating based on 24 reviews as of January 2014. [ 16 ]  This ranks the film within the 5-10% best-reviewed films of 2013. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6008", "text": "Certain critics, such as Gary Goldstein of the  Los Angeles Times , while acknowledging the enormous importance of the topic, felt the film should have taken a more emotional approach to its \"incendiary subject\". [ 18 ]  The English critic  Philip French , in his review for  The Observer  described the film as \"quietly devastating\", praised Gray's choice in avoiding a  polemical  tone and allowing the material to speak for itself. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6009", "text": "Writing in  Sight & Sound , Ashley Clark called  Fire in the Blood  \"stirring\" and added \"Gray deserves credit for his own restraint... Such is the clarity of his ideological stance that any grandstanding would feel redundant.\" [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6010", "text": "David Rooney of  The Hollywood Reporter  echoed this view, stating that \"the admirable balance between impassioned argument and clear-sighted reporting in Dylan Mohan Gray's chronicle of the why and how makes  Fire in the Blood  indispensable viewing\", adding that the \"very smart\", \"extremely moving\" film is \"a shocking account of international trade terrorism sanctioned by Western governments\" and \"a powerful documentary that demands to be seen by as wide an audience as possible.\" [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6011", "text": "Author  John le Carr\u00e9  (who became involved with the issue of pharmaceutical company abuses while researching his landmark 2001 novel  The Constant Gardener ) called  Fire in the Blood  \"a blessing... full of conviction, passion and unanswerable argument\". [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6012", "text": "Australian-British journalist and documentary film maker,  John Pilger  wrote \" Fire in the Blood  is one of the most powerful, important and humane documentaries I have ever seen. It's the story of ordinary people standing up to unaccountable power. The struggle to save millions from the ravages of untreated HIV is revealed as a struggle against the new lords of the world, transnational corporations, their greed and lies. Genuine hope is rare these days -- you'll find it in this film.\" [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6013", "text": "Former (2001\u201306)  United Nations  Special Envoy for HIV/AIDS in Africa  Stephen Lewis  said \"I was enraged as I watched, thinking of those years I spent as the Envoy, watching people die...I rarely watch 'AIDS documentaries'; they're remarkably repetitive as a rule, largely uninspired and yielding almost nothing new. [Fire in the Blood] is in a wholly different category; a terrific, riveting documentary...dramatic, compelling, but most of all, wonderfully humane. [Gray is] a remarkably gifted documentary film-maker.\" [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6014", "text": "Special screenings of  Fire in the Blood  for policymakers have been held in such fora as the  United Nations  headquarters in  New York City  and  Vienna , the  European Parliament  in  Brussels , the  World Health Assembly  and  UNAIDS  headquarters in  Geneva , along with dedicated screenings for lawmakers in  Washington  and  New Delhi , and one hosted by the Indian Ministry of External Affairs (MEA) for ambassadors and consuls accredited to India."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6015", "text": "First Databank  ( FDB ) is a major provider of drug and medical device databases that help inform healthcare professionals to make decisions. [ 1 ]  FDB partners with information system developers to deliver useful medication- and medical device-related information to clinicians, business associates, and patients. FDB is part of Hearst and the Hearst Health network."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6016", "text": "First Databank was founded in 1977 as a company that published a quarterly magazine of drug prices. They were bought by  Hearst Corporation  in 1980. First Databank then evolved to become a provider of clinical and descriptive drug knowledge that is integrated into healthcare information systems globally. FDB has its headquarters in  San Francisco, California , and has other offices in  Indianapolis, Indiana ,  Exeter, England ,  Dubai, UAE  and  Hyderabad, India ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6017", "text": "The firm's drug databases support pharmacy dispensing, formulary management, drug pricing analysis, claims processing, computerized physician order entry (CPOE), electronic health records (EHR), electronic medical records (EMR), electronic prescribing (e-Prescribing), electronic medication administration records (EMAR), population health and telemedicine/telehealth."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6018", "text": "Beginning in 2011, First Databank's set of National Drug Codes (NDCs) have been integrated into RxNorm's standard clinical drug vocabulary that includes all medications available on the US market. [ 1 ]  RxNorm is produced and maintained by the  United States National Library of Medicine  (NLM)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6019", "text": "In 2017, FDB acquired Polygot Systems, which simplifies drug information for patients and translates that information into 21 languages. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6020", "text": "In 2018, FDB partnered with  PetIQ  to release the first veterinary medication database to provide information on pet medications structured for integration into pharmacy systems. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6021", "text": "Beginning in 2020, FDB partnered with  Amazon  and its  Alexa  devices to provide drug information and answer medication questions. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6022", "text": "During the  COVID-19 pandemic , FDB posted drug data (regarding  remdesivir ,  chloroquine , and  hydroxychloroquine ) and medical device-related coronavirus information to its website. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6023", "text": "In August 2021, the company announced a partnership with RxRevu to provide integrated decision support tools to improve patient access to care, delivering patient-specific pharmacy benefit information to  EHR  workflows via direct connections with pharmacy benefit managers. The technology displays accurate, real-time data at the point of prescribing, allowing physicians to find affordable alternatives for medications specific to a patient's health needs and insurance benefits. FDB will offer RxRevu's prescription cost and coverage solution to current and future hospital, health system, and EHR clients. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6024", "text": "First Databank's MedKnowledge provides prices, descriptions, and collateral clinical information on drugs approved by the US  Food and Drug Administration  (FDA), plus unapproved drugs, commonly used  over-the-counter drugs ,  herbal remedies , medical foods and nutritional supplements."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6025", "text": "First Databank has developed a drug ordering knowledge base that enables physicians to look up and order drugs. Drug orders are generated based on patient parameters such as age, weight, renal and hepatic impairment, thereby reducing lists of candidate drugs to a minimum. The database is expected to affect the number of  adverse drug reactions  and side effects at facilities that have adopted the electronic order entry systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6026", "text": "A web-based software tool that enables institution-specific modification of medication alerts using FDB MedKnowledge clinical modules based on clinician input, localized clinical experience, and other available evidence. The tool allows users to edit or turn off individual alerts, track all alert customizations and create an audit record, and view FDB updates in comparison with the user's own modifications. Users can load the results of their modifications directly into their medication  decision support system  for immediate use in the workflow. The approach follows the normal update process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6027", "text": "The FDB Prizm medical device database provides structured, categorized, and normalized information about medical device products that are implanted into patients; hospital and durable medical equipment; and medical supplies. The medical device content comes from a variety of sources such as the FDA, medical device manufacturers, and industry data pools. Also, it encompasses additional information from clinical, operational, and financial attributes and codes. Use of this database within supply chain and other information systems is designed to help decision makers to build and maintain device libraries, identify and document medical devices in case of recalls and adverse events, and group and analyze medical device utilization."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6028", "text": "Meducation comprises simplified medication instructions and medication regimen calendars using patient-specific information from the electronic health record (EHR). All material is written at a 5th to 8th grade reading level with supporting pictograms in more than 20 languages and is designed to help reduce medication errors and improve medication adherence for all patients. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6029", "text": "FDB Targeted Medication Warnings provides patient-specific clinical decision support (CDS) for medications and is integrated directly into the EHR workflow. This content uses lab results, risk scores, and other patient data to suggest clinical guidance that is most relevant to the patient context. The CDS derived from this solution provides specificity for clinical decisions and is linked to the related generic medication alerts which can be filtered out/customized using FDB AlertSpace. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6030", "text": "FDB Pet MedKnowledge is a comprehensive drug database with veterinary FDA approved medications, allowing veterinarians to access pet medication information whenever and wherever is needed. The service is modeled on the FDB MedKnowledge human medication database. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6031", "text": "A consumer coalition filed separate suits in a  Boston, Massachusetts federal court  against drug wholesaler  McKesson Corporation  and First Databank, accusing the companies of artificially inflating drug prices.  The lawsuits say that McKesson and FDB conspired from 2002 through 2005 to set the list prices artificially high.  The suit against First DataBank accused it of limiting its survey of wholesalers to a single company, McKesson. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6032", "text": "First Databank agreed to a settlement, tentatively approved by the federal court, in which it would not pay damages to the plaintiffs, but agreed to reduce  average wholesale prices  (AWPs) listed in its databases by five percent for about 2,033 drugs. [ 11 ]  McKesson chose to fight the suits."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6033", "text": "The settlement required First DataBank (FDB) to reduce the AWP mark-up from 1.25 to 1.20 times the Wholesale Acquisition Cost (WAC) for 1,442 NDCs identified in the litigation. FDB set the mark-up at 1.20 for all drugs independent of the litigation on September 26, 2009. The roll back of the WAC-to-AWP spread led to a 4% reduction in their AWP. FDB also stopped publishing AWP data on September 26, 2011, two years after the rollback adjustments were implemented. First DataBank continues to publish non-AWP drug pricing information, including WAC, Direct Price, and suggested wholesale price. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6034", "text": "A  generic drug  is a  pharmaceutical drug  that contains the same chemical substance as a drug that was originally protected by  chemical patents . Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active chemical substance is the same, the medical profile of generics is equivalent in performance compared to their performance at the time when they were patented drugs. [ 1 ] [ 2 ]  A generic drug has the same  active pharmaceutical ingredient  (API) as the original, but it may differ in some characteristics such as the manufacturing process,  formulation ,  excipients , color, taste, and packaging. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6035", "text": "Although they may not be associated with a particular company, generic drugs are usually subject to government regulations in the countries in which they are dispensed. They are labeled with the name of the manufacturer and a generic non-proprietary name such as the  United States Adopted Name  (USAN) or  International Nonproprietary Name  (INN) of the drug. A generic drug must contain the same  active ingredients  as the original brand-name formulation. The  U.S. Food and Drug Administration  (FDA) requires generics to be identical to or within an acceptable  bioequivalent  range of their brand-name counterparts, with respect to  pharmacokinetic  and  pharmacodynamic  properties. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6036", "text": "Biopharmaceuticals , such as  monoclonal antibodies , differ biologically from  small-molecule drugs .  Biosimilars  have active pharmaceutical ingredients that are almost identical to the original product and are typically regulated under an extended set of rules, but they are not the same as generic drugs as the active ingredients are not the same as those of their reference products. [ 4 ]  In most cases, generic products become available after the  patent  protections afforded to the drug's original developer expire. Once generic drugs enter the market, competition often leads to substantially lower prices for both the original brand-name product and its generic equivalents. In most countries, patents give 20 years of protection. However, many countries and regions, such as the  European Union  and the  United States , [ 5 ]  may grant up to five years of additional protection (\"patent term restoration\") if manufacturers meet specific goals, such as conducting  clinical trials  for  pediatric  patients. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6037", "text": "Manufacturers, wholesalers, insurers, and drugstores can all increase prices at various stages of production and distribution. [ 7 ]  In 2014, according to an analysis by the Generic Pharmaceutical Association, generic drugs accounted for 88 percent of the 4.3 billion prescriptions filled in the United States. [ 8 ] :\u200a2\u200a  \"Branded generics\" on the other hand are defined by the FDA and  National Health Service  as \"products that are (a) either novel dosage forms of off-patent products produced by a manufacturer that is not the originator of the molecule, or (b) a molecule copy of an off-patent product with a trade name.\" [ 9 ]  Since the company making branded generics can spend little on  research and development , it is able to spend on marketing alone, thus earning higher profits and driving costs down. [ 10 ]  For example, the largest revenues of  Ranbaxy , now owned by  Sun Pharma , came from branded generics. [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6038", "text": "Generic drug names are constructed using standardized  affixes  that distinguish drugs between and within classes and suggest their action. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6039", "text": "When a pharmaceutical company first markets a drug, it is usually under a  patent  that, until it expires, the company can use to exclude competitors by suing them for  patent infringement . [ 13 ]  Pharmaceutical companies that develop new drugs generally only invest in drug candidates with strong patent protection as a strategy to recoup their costs of  drug development  (including the costs of the drug candidates that fail) and to make a profit. [ 14 ]  The average cost to a brand-name company of discovering, testing, and obtaining regulatory approval for a new drug, with a  new chemical entity , was estimated to be as much as US$800 million in 2003 [ 15 ]  and US$2.6  billion  in 2014. [ 16 ]  Drug companies that bring new products have several  product line extension  strategies they use to extend their exclusivity, some of which are seen as gaming the system and labeled \" evergreening \" by critics, but at some point there is no patent protection available. [ 13 ]  For as long as a drug patent lasts, a brand-name company enjoys a period of market exclusivity, or  monopoly , in which the company is able to set the price of the drug at a level that maximizes profit. This profit often greatly exceeds the development and production costs of the drug, allowing the company to offset the cost of research and development of other drugs that are not profitable or do not pass clinical trials. [ 7 ]  The impact of loss of patent exclusivity on pharmaceutical products varies significantly across different product classes (e.g., biologics vs. small molecules), largely due to regulatory, legal and manufacturing hurdles associated with such products. Indeed, the greater degree of 'brand-brand' competitive dynamics seen in the biologics and complex generics space allows manufacturers of originators to better protect market share following loss of patent exclusivity. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6040", "text": "Large pharmaceutical companies often spend millions protecting their patents from generic competition. [ 7 ]  Apart from litigation, they may reformulate a drug or license a subsidiary (or another company) to sell generics under the original patent. Generics sold under license from the patent holder are known as  authorized generics . [ 18 ]  Generic drugs are usually sold for significantly lower prices than their branded equivalents and at lower  profit margins . [ 19 ]  One reason for this is that competition increases among producers when a drug is no longer protected by patents. [ 19 ]  Generic companies incur fewer costs in creating generic drugs\u2014only the cost of manufacturing, without the costs of  drug discovery  and  drug development \u2014and are therefore able to maintain  profitability  at a lower price. [ 19 ] [ 20 ] [ 21 ]  The prices are often low enough for users in less-prosperous countries to afford them. [ citation needed ]  Generic drug companies may also receive the benefit of the previous marketing efforts of the brand-name company, including advertising, presentations by drug representatives, and distribution of free samples. Many drugs introduced by generic manufacturers have already been on the market for a decade or more and may already be well known to patients and providers, although often under their branded name. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6041", "text": "India is a leading country in the world's generic drugs market, exporting US$20.0 billion worth of drugs in the 2019\u201320 (April\u2013March) year. [ 22 ]  India exports generic drugs to the United States and the European Union. [ 23 ]  also the according to market research community the Global Generic Drugs Market was evaluated US$465.96 million in 2021 and is expected to rise with a CAGR of 5.5% from 2022- 2028 during the forecast period. [ 24 ]  In the United Kingdom, generic drug pricing is controlled by the government's reimbursement rate. The price paid by pharmacists and doctors is determined mainly by the number of license holders, the sales value of the original brand, and the ease of manufacture. A typical price decay graph will show a \"scalloped\" curve, [ 25 ]  which usually starts at the brand-name price on the day of generic launch and then falls as competition intensifies. After some years, the graph typically flattens out at approximately 20% of the original brand price. In about 20% of cases, the price \"bounces\": Some license holders withdraw from the market when the selling price dips below their cost of goods, and the price then rises for a while until the license holders re-enter the market with new stock. [ 26 ] [ 27 ]  The NHS spent about \u00a34.3 billion on generic medicines in 2016\u201317. [ 28 ]  In 2012, 84 percent of prescriptions in the US were filled with generic drugs, [ 29 ]  and in 2014, the use of generic drugs in the United States led to US$254 billion in health care savings. [ 8 ] :\u200a2"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6042", "text": "In the mid-2010s the generics industry began transitioning to the end of an era of giant  patent cliffs  in the pharmaceutical industry; patented drugs with sales of around US$28 billion were set to come off patent in 2018, but in 2019 only about US$10 billion in revenue was set to open for competition, and less the next year. Companies in the industry have responded with  consolidation  or turning to try to generate new drugs. [ 30 ]  Most developed nations require generic drug manufacturers to prove that their formulations are bioequivalent to their brand-name counterparts. [ 31 ] [ 32 ] [ 33 ] [ 34 ] [ 35 ] [ 36 ]  Bioequivalence does not mean generic drugs must be exactly the same as the brand-name product (\"pharmaceutical equivalent\"). Chemical differences may exist; a different  salt  or  ester \u00a0may be used, for instance. Different inactive ingredients means that the generic may look different from the originator brand; [ 37 ]  however, the therapeutic effect of the drug must be the same (\"pharmaceutical alternative\"). [ citation needed ]  Most small molecule drugs are accepted as bioequivalent if their  pharmacokinetic  parameters of  area under the curve  (AUC) and  maximum concentration  (C max ) are within a 90%  confidence interval  of 80\u2013125%; most approved generics in the US are well within this limit. [ 38 ]  For more complex products\u2014such as  inhalers ,  patch delivery systems ,  liposomal preparations , or biosimilar drugs\u2014demonstrating pharmacodynamic or clinical equivalence is more challenging. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6043", "text": "Enacted in 1984, the  Drug Price Competition and Patent Term Restoration Act , informally known as the Hatch\u2013Waxman Act, standardized procedures for recognition of generic drugs.  In 2007, the FDA launched the Generic Initiative for Value and Efficiency (GIVE): [ 40 ]  an effort to modernize and streamline the generic drug approval process, and to increase the number and variety of generic products available. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6044", "text": "Before a company can market a generic drug, it needs to file an  Abbreviated New Drug Application  (ANDA) with the Food and Drug Administration, seeking to demonstrate therapeutic equivalence to a previously approved \"reference-listed drug\" and proving that it can manufacture the drug safely and consistently. [ 41 ]  For an ANDA to be approved, the FDA requires that the 90% confidence interval of the geometric mean test/reference ratios for the total drug exposure (represented by the area under the curve or AUC) and the maximum plasma concentration (Cmax) should fall within limits of 80\u2013125%. [ 42 ]  (This range is part of a statistical calculation, and does not mean that generic drugs are allowed to differ from their brand-name counterparts by up to 25 percent.) The FDA evaluated 2,070 studies conducted between 1996 and 2007 that compared the absorption of brand-name and generic drugs into a person's body. The average difference in absorption between the generic and the brand-name drug was 3.5 percent, comparable to the difference between two batches of a brand-name drug. [ 43 ] [ 44 ]  Non-innovator versions of biologic drugs, or biosimilars, require clinical trials for  immunogenicity  in addition to tests establishing bioequivalency. These products cannot be entirely identical because of batch-to-batch variability and their biological nature, and they are subject to extra rules. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6045", "text": "When an application is approved, the FDA adds the generic drug to its  Approved Drug Products with Therapeutic Equivalence Evaluations  list and annotates the list to show the equivalence between the reference-listed drug and the generic. The FDA also recognizes drugs that use the same ingredients with different bioavailability and divides them into therapeutic equivalence groups. [ 41 ]  For example, as of 2006,  diltiazem hydrochloride  had four equivalence groups, all using the same active ingredient, but considered equivalent only within each group. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6046", "text": "In order to start selling a drug promptly after the patent on innovator drug expires, a generic company has to file its ANDA well before the patent expires. This puts the generic company at risk of being sued for patent infringement, since the act of filing the ANDA is considered \"constructive infringement\" of the patent. [ 41 ]  In order to incentivize generic companies to take that risk the Hatch-Waxman act granted a 180-day administrative exclusivity period to generic drug manufacturers who are the first to file an ANDA. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6047", "text": "When faced with patent litigation from the drug innovator or patent holder, generic companies will often counter-sue, challenging the validity of the patent. [ 48 ] [ 49 ] [ 50 ] [ 51 ] [ 52 ]  Like any litigation between private parties, the innovator and generic companies may choose to settle the litigation. Some of these settlement agreements have been struck down by courts when they took the form of  reverse payment patent settlement  agreements, in which the generic company basically accepts a payment to drop the litigation, delaying the introduction of the generic product and frustrating the purpose of the Hatch\u2013Waxman Act. [ 53 ] [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6048", "text": "Innovator companies sometimes try to maintain some of the revenue from their drug after patents expire by allowing another company to sell an  authorized generic ; a 2011 FTC report found that consumers benefitted from lower costs when an authorized generic was introduced during the 180 day exclusivity period, as it created competition. [ 55 ] [ 56 ]  Innovator companies may also present arguments to the FDA that the ANDA should not be accepted by filing an  FDA citizen petition .  The right of individuals or organizations to petition the federal government is guaranteed by the First Amendment to the United States Constitution. [ 57 ]   For this reason, the FDA has promulgated regulations that provide, among other things, that at any time, any \"interested person\" can request that the FDA \"issue, amend, or revoke a regulation or order,\" and set forth a procedure for doing so. [ 58 ] [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6049", "text": "Some generic drugs are viewed with suspicion by doctors. For example,  warfarin  (Coumadin) has a narrow  therapeutic window  and requires frequent blood tests to make sure patients do not have a subtherapeutic or a toxic level. A study performed in  Ontario  showed that replacing Coumadin with generic warfarin was safe, [ 60 ]  but many physicians are not comfortable with their patients taking branded generic equivalents. [ 61 ]  In some countries (for example, Australia) where a drug is prescribed under more than one brand name, doctors may choose not to allow pharmacists to substitute a brand different from the one prescribed unless the consumer requests it. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6050", "text": "A series of scandals around the approval of generic drugs in the late 1980s shook public confidence in generic drugs; there were several instances in which companies obtained bioequivalence data fraudulently, by using the branded drug in their tests instead of their own product, and a congressional investigation found corruption at the FDA, where employees were accepting bribes to approve some generic companies' applications and delaying or denying others. [ 29 ] [ 63 ] [ 64 ] [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6051", "text": "In 2007,  North Carolina Public Radio 's  The People's Pharmacy  began reporting on consumers' complaints that generic versions of  bupropion  (Wellbutrin) were yielding unexpected effects. [ 66 ]  Subsequently,  Impax Laboratories 's 300\u00a0mg extended-release tablets, marketed by  Teva Pharmaceutical Industries , were withdrawn from the US market after the FDA determined in 2012 that they were not bioequivalent. [ 67 ] [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6052", "text": "Problems with the quality of generic drugs \u2013 especially those produced outside the United States \u2013 are widespread as of 2019. [ 69 ]  The FDA does infrequent \u2013 less than annual \u2013 inspections of production sites outside the United States. The FDA normally gives advance notice of inspections, which can lead to cover-ups of problems before inspectors arrive; inspections performed with little or no advance notice have produced evidence of serious problems at a majority of generic drug manufacturing sites in India and China. [ 69 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6053", "text": "Two women, each claiming to have suffered severe medical complications from a generic version of  metoclopramide , lost their Supreme Court appeal on June 23, 2011. In a 5\u20134 ruling in  PLIVA, Inc. v. Mensing , [ 70 ] [ 71 ]  the court held that generic companies cannot be held liable for information, or the lack of information, on the originator's label. [ 72 ] [ 73 ] [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6054", "text": "The  Indian government  began encouraging more drug manufacturing by Indian companies in the early 1960s, and with the Patents Act in 1970. [ 75 ]  The Patents Act removed composition patents for foods and drugs, and though it kept process patents, these were shortened to a period of five to seven years. The resulting lack of patent protection created a niche in both the Indian and global markets that Indian companies filled by reverse-engineering new processes for manufacturing low-cost drugs. [ 76 ]   The code of ethics issued by the  Medical Council of India  in 2002 calls for physicians to prescribe drugs by their generic names only. [ 77 ]  India is a leading country in the world's generic drugs market, with  Sun Pharmaceuticals  being the largest pharmaceutical company in India.  Indian generics companies exported US$17.3 billion worth of drugs in the 2017\u201318 (April\u2013March) year. In 1945\u20132017, bioequivalence studies were only required for generics of drugs that are less than four years old. Since 2017, all generic drugs of certain classes, irrespective of age, require bioequivalence to be approved. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6055", "text": "Generic drug production is a large part of the pharmaceutical industry in China. Western observers have said that China lacks administrative protection for patents. [ 79 ]  However, entry to the  World Trade Organization  has brought a stronger patent system. [ 80 ]  China remains the largest exporter of  active pharmaceutical ingredients , accounting for 40% of the world market per a 2017 estimate. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6056", "text": "Bioequivalence studies are required for new generic drugs starting from 2016, with older drugs planned as well. In addition,  in vitro  dissolution behavior is required to match. [ 82 ]  Since 2018, 44 classes of drugs are exempt from testing (requiring only a dissolution check), and 13 classes only require simplified testing. [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6057", "text": "As of 2021, several major companies traditionally dominate the generic drugs market, including  Viatris  (merger of  Mylan  and  Upjohn ),  Teva ,  Novartis'\u00a0Sandoz , and  Sun Pharma . [ 84 ]  Prices in traditional generic drugs have declined and newer companies such as India-based  Sun Pharma ,  Aurobindo Pharma , and  Dr. Reddy's Laboratories , as well as Canada-based  Apotex , have taken market share, which has led to a focus on  biosimilars ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6058", "text": "Generic pharmaceutical price decay  is what happens (in the UK) once the originator brand has lost its  patent exclusivity (patent expiry)  and generic versions of the originator brand have been launched. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6059", "text": "The number of license holders entering the market is controlled by the ease of manufacture and the number of companies making the  active pharmaceutical ingredient (API) . For many easy-to-manufacture solid dose tablets and capsules the manufacturing is done in India and China as the costs of production in these countries is significantly lower than in the US or Europe. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6060", "text": "On day one of generic launch the  first to market  the generic product usually gets more market share than late entrants. Both manufacturers (who make their own generic products) and license only holders (who use other companies to do the manufacturing) may be represented. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6061", "text": "If only one company is able to release a generic product into the UK market, the discount against the originator brand is likely to be small, and the price will usually follow the same trend as the brand price. However, in most cases more than one company will release stock at launch and they will compete for market share with other manufacturers and license holders. This means persuading chemists and dispensing doctors to purchase stock. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6062", "text": "As competition drives the price of the generic product down, the average price in the market typically follows a  scalloped curve  which will decline with time at a rate that is driven by the numbers of license holders and manufacturers. [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6063", "text": "Changes in the reimbursement price  drug tariff  will also serve to suppress this curve even more. [ 12 ] [ 13 ] [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6064", "text": "Generic substitution  was planned for the England, but this was rejected in late 2010. Generic substitution would have meant that a prescription written for a branded product by a doctor would result in a pharmacist giving the patient a generic medicine. On Thursday 14 October, the UK's Department of Health announced that it would not be proceeding with the proposals to implement generic substitution. Patient safety was cited as the primary reason for the rejection of this policy. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6065", "text": "In the case of more complex products, such as creams, inhalers and injectables, generic prices decay at a slower rate as fewer companies are able to make the product. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6066", "text": "In the UK, the M category of the drug tariff (reimbursement prices) is used to control the profits of chemists and to reduce the UK's health care tax burden. [ 18 ] [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6067", "text": "The rate of decay of most generic solid dose products has been shown to follow a predictable path and to have some similarity to the decay in price of other non pharmaceutical products. [ 21 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6068", "text": "Eventually price decline comes to and end and the price flattens out at approximately 20% of the original brand price."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6069", "text": "In about 20% of cases, the average price declines to a low point some months or years after generic launch, and then rises temporarily or  bounces   (Dead Cat Bounce) [ 23 ]  These bounces may then initiate the onset of longer term seasonality or recurrent annual price rises. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6070", "text": "Bounces happen when the average selling price falls below a license holder's manufacturing cost, making the product unprofitable. License holders and manufacturers then withdraw from the market, reducing the amount of competition and allowing the price to rise. They may later re-enter the market when higher prices make the product profitable once more. This usually forces the average price down again to levels lower than that seen before the start of the bounce."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6071", "text": "The reasoning behind why some products bounce whereas others do not, is thought to lie in the rapidity of the initial price decline. In these cases manufacturers and license holders either were not able to or did not forecast the levels to which the price might drop. \nThe period during which their product would be profitable was therefore not known, and the decline into unprofitably left them with stock which could only be sold at a loss. Additionally the product's expiry date might mean that it could not be stored until market prices recovered."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6072", "text": "Generic manufacturers and license holders believe that the  seasonality  induced by these bounces may be related to the time taken to manufacture a new product and gain  market access  (get the medicines onto chemist's shelves in the relevant country). The period between the high price peaks in the seasonality induced by price bounces has been shown to be approximately two years. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6073", "text": "It is possible for a product's price to be affected by seasonality in the absence of price bounces. This seasonality is caused by periods of intense competition in the UK market, and periods of calm with much less competition. In the UK traditionally employees  have taken holidays in April, August and January. This is caused by religious holidays like Christmas and Easter, and by spring, summer and winter school holidays."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6074", "text": "During holidays, wholesalers, license holders and manufacturers are less competitive than when employees are back at work. During the months when the majority of employees are at work, competing companies continually watch each other's prices and change their own selling prices on a daily or even hourly basis so as to maximize sales and profits."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6075", "text": "The pricing trends of some products are believed to be affected by disease patterns, such as the  hay fever  season in May and winter flu in November. It is also possible that the exchange rates between relevant currencies may be another factor in controlling generic prices. However the evidence for this is weak. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6076", "text": "After loss of exclusivity and generic launch the originator brand normally continues to hold at least some market share as either some doctors continue to prescribe the brand or as the originator  equalises  sales prices against the generic. [ 27 ] [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6077", "text": "Branded manufactures may build ongoing contracts with wholesalers so that the brand continues to be dispensed in pharmacies even though the prescriptions are generic. This means that an originator may offer an advantageous price to undercut the generic or  parallel import . Wholesalers gets a price and supply guarantee in exchange for taking the risk that they may be paying too much in the long term."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6078", "text": "Some companies offer 'branded generics' in the UK market. However, these are no longer common, and are not popular as their reimbursement price may be higher than the generic reimbursement price, costing the tax-payer more than a true generic. [ 29 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6079", "text": "Because the generic launch price is often at or close to the originator brand price, more profit can be made in the months following generic launch than in the months later in the product's life cycle. [ 31 ] [ 32 ] [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6080", "text": "Generic launch can only occur once all the patents on the originator brand have expired. These may include both product and process patents, and most products can get a further two years of patent life with a SPC  supplementary protection certificate  and a few may get a further six months with a  pediatric extension ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6081", "text": "Good documentation practice  (recommended to abbreviate as  GDocP  to distinguish from \"good  distribution  practice\" also abbreviated GDP) is a term in the pharmaceutical and medical device industries to describe standards by which  documents  are created and maintained. While some GDocP standards are  codified  by various  competent authorities , others are not but are considered  cGMP  (with emphasis on the \"c\", or \"current\"). Some competent authorities release or adopt  guidelines , and they may include non-codified GDocP expectations. While not law, authorities will inspect against these guidelines and cGMP expectations in addition to the legal requirements and make comments or observations if departures are seen. \nIn the past years, the application of GDocP is also expanding to cosmetic industry, excipient and ingredient manufacturers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6082", "text": "From the regulatory guidance above, additional expectations or allowances can be inferred by extension.  Among these are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6083", "text": "The competent authorities are empowered to inspect establishments to enforce the law and the interpretations of the law (e.g., the content of guidance documents and the cGMPs)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6084", "text": "Departures from GDocP that involved the regulator have included: documentation not contemporaneous, [ 11 ] [ 12 ]  use of  ditto marks , [ 13 ]  signature stamps., [ 14 ] [ 15 ]  obscured original data, [ 16 ]  Use of pencil, [ 16 ]  inaccurate records, [ 16 ]  and not dating changes. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6085", "text": "Current good manufacturing practices  ( cGMP ) are those conforming to the guidelines recommended by relevant agencies. Those agencies control the authorization and licensing of the manufacture and sale of  food  and  beverages , [ 1 ]   cosmetics , [ 2 ]   pharmaceutical products , [ 3 ]   dietary supplements , [ 4 ]  and  medical devices . [ 5 ]  These guidelines provide minimum requirements that a manufacturer must meet to assure that their products are consistently high in quality, from batch to batch, for their intended use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6086", "text": "Good Manufacturing Practice emerged in response to serious incidents of harm caused by contaminated, adulterated, or improperly manufactured products. Major incidents include: \ndeaths from  Elixir Sulfanilamide  in 1937,  thalidomide -induced birthdefects 1957\u20131961,  poliomyelitis  infections from  improperly prepared vaccines  in 1955, and  Dalkon Shield -induced  septicemia  in the 1970s."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6087", "text": "These incidents resulted in hundreds of deaths, infections, and birth defects. Complete timelines show the emergence of Good Manufacturing Practices alongside these incidents, starting from 1938 in the US and 1970s internationally. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6088", "text": "The rules that govern each industry may differ significantly; however, the main purpose of GMP is always to prevent harm from occurring to the end user. [ 2 ]  Additional tenets include ensuring the end product is free from contamination, that it is consistent in its manufacture, that its manufacture has been well documented, that personnel are well trained, and that the product has been checked for quality more than just at the end phase. [ 2 ]  GMP is typically ensured through the effective use of a  quality management system  (QMS). [ 1 ] :\u200a\"The Basis for GMP\",\u200a\u200a [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6089", "text": "Good manufacturing practice, along with  good agricultural practice ,  good laboratory practice  and  good clinical practice , are overseen by regulatory agencies in the United Kingdom, United States, Canada, various European countries, China, India and other countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6090", "text": "Good manufacturing practice guidelines provide guidance for manufacturing, testing, and quality assurance in order to ensure that a manufactured product is safe for human consumption or use. Many countries have legislated that manufacturers follow GMP procedures and create their own GMP guidelines that correspond with their legislation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6091", "text": "All guidelines follow a few basic principles: [ 2 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6092", "text": "Good manufacturing practice is recommended with the goal of safeguarding the health of consumers and patients as well as producing quality products. In the United States, a food or drug may be deemed \"adulterated\" if it has passed all of the specifications tests but is found to be manufactured in a facility or condition which violates or does not comply with current good manufacturing guideline."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6093", "text": "GMP standards are not prescriptive instructions on how to manufacture products. They are a series of performance based requirements that must be met during manufacturing. [ 9 ]  When a company is setting up its quality program and manufacturing process, there may be many ways it can fulfill GMP requirements. It is the company's responsibility to determine the most effective and efficient quality process that both meets business and regulatory needs. [ 1 ] :\u200a\"Decision Makers' Summary\",\u200a\u200a [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6094", "text": "Regulatory agencies have recently begun to look at more fundamental quality metrics of manufacturers than just compliance with basic GMP regulations.\u00a0US-FDA has found that manufacturers who have implemented quality metrics programs [ 10 ]  gain a deeper insight into employee behaviors that impact product quality."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6095", "text": "In its Guidance for Industry \"Data Integrity and Compliance With Drug CGMP\" US-FDA states \u201cit is the role of management with executive responsibility to create a quality culture where employees understand that [[data integrity [ 11 ] ]] is an organizational core value and employees are encouraged to identify and promptly report data integrity issues.\u201d [ 12 ]  Australia's Therapeutic Goods Administration has said that recent data integrity failures have raised questions about the role of quality culture in driving behaviors. [ 13 ]  In addition, non-governmental organizations such as the International Society for Pharmaceutical Engineering (ISPE) and the Parenteral Drug Association (PDA)\u00a0have developed information and resources to help pharmaceutical companies better understand why quality culture is important and how to assess the current situation within a site or organization. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6096", "text": "GMP is enforced in the United States by the U.S.  Food and Drug Administration  (FDA), under Title  21 CFR . The regulations use the phrase \"current good manufacturing practices\" (CGMP) to describe these guidelines. [ 15 ] [ 16 ] [ 17 ] [ 18 ]  Courts may theoretically hold that a product is  adulterated  even if there is no specific regulatory requirement that was violated as long as the process was not performed according to industry standards. [ 19 ]  However, since June 2007, a different set of CGMP requirements have applied to all manufacturers of  dietary supplements , with additional supporting guidance issued in 2010. [ 4 ]  Additionally, in the U.S., medical device manufacturers must follow what are called \"quality system regulations\" which are deliberately harmonized with  ISO  requirements, not necessarily CGMPs. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6097", "text": "The  World Health Organization  (WHO) version of GMP is used by pharmaceutical regulators and the  pharmaceutical industry  in over 100 countries worldwide, primarily in the developing world. [ 3 ]  The  European Union 's GMP (EU GMP) enforces similar requirements to WHO GMP, as does the FDA's version in the US. Similar GMPs are used in other countries, with Australia, Canada, Japan, Saudi Arabia, Singapore, Philippines], Vietnam and others having highly developed/sophisticated GMP requirements. [ 20 ]  In the United Kingdom, the Medicines Act (1968) covers most aspects of GMP in what is commonly referred to as \"The Orange Guide,\" which is named so because of the color of its cover; it is officially known as  Rules and Guidance for Pharmaceutical Manufacturers and Distributors . [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6098", "text": "Since the 1999 publication of  Good Manufacturing Practice for Active Pharmaceutical Ingredients , by the  International Conference on Harmonization  (ICH), GMPs now apply in those countries and trade groupings that are signatories to ICH (the EU, Japan and the U.S.), and applies in other countries (e.g., Australia, Canada, Singapore) which adopt ICH guidelines for the manufacture and testing of active raw materials. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6099", "text": "Within the European Union GMP inspections are performed by National Regulatory Agencies. GMP inspections are performed in Canada by the Health Products and Food Branch Inspectorate; [ 22 ]  in the United Kingdom by the  Medicines and Healthcare products Regulatory Agency  (MHRA); [ 23 ]  in the Republic of Korea (South Korea) by the  Ministry of Food and Drug Safety  (MFDS); [ 24 ]  in Australia by the  Therapeutic Goods Administration  (TGA); [ 25 ]  in Bangladesh by the Directorate General of Drug Administration (DGDA); [ 26 ]  in South Africa by the Medicines Control Council (MCC); [ 27 ]  in Brazil by the  National Health Surveillance Agency  (ANVISA); [ 28 ]  in India by state Food and Drugs Administrations (FDA), reporting to the  Central Drugs Standard Control Organization ; [ 29 ]  in Pakistan by the  Drug Regulatory Authority of Pakistan ; [ 30 ]  in Nigeria by  NAFDAC ; [ 31 ]  and by similar national organizations worldwide. Each of the  inspectorates  carries out routine GMP inspections to ensure that drug products are produced safely and correctly. Additionally, many countries perform pre-approval inspections (PAI) for GMP compliance prior to the approval of a new drug for marketing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6100", "text": "Regulatory agencies (including the FDA in the U.S. and regulatory agencies in many European nations) are authorized to conduct unannounced inspections, though some are scheduled. [ 15 ] [ 21 ] [ 24 ] [ 25 ] [ 26 ] [ 27 ] [ 29 ] [ 30 ] [ 31 ]  FDA routine domestic inspections are usually unannounced, but must be conducted according to 704(a) of the  Food, Drug and Cosmetic Act  (21 USCS \u00a7 374), which requires that they are performed at a \"reasonable time\". Courts have held that any time the firm is open for business is a reasonable time for an inspection. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6101", "text": "Other good-practice systems, along the same lines as GMP, exist:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6102", "text": "Collectively, these and other good-practice requirements are referred to as \" GxP \" requirements, all of which follow similar philosophies. Other examples include good guidance practice and good tissue practice."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6103", "text": "Healthy Skepticism Inc  is an international  non-profit organisation  whose main aim is to \"improve health by reducing harm from misleading  drug promotion \"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6104", "text": "Healthy Skepticism was founded in 1983 with the name Medical Lobby for Appropriate Marketing (MaLAM). It was begun by an  Australian  medical student,  Peter R. Mansfield ,  who had the idea for the organisation during his final year elective in  Bangladesh  in 1982. MaLAM initially focused on campaigning against questionable  marketing  practices in  developing countries . These included the promotion of  appetite  stimulants, tonics and  anabolic steroids  to parents of malnourished children. MaLAM was modelled on  Amnesty International  and wrote open letters to the international headquarters of  pharmaceutical companies  questioning them about specific advertisements. MaLAM letters were signed by supporters around the world and contributed to many improvements in drug marketing, several products being removed from the market and many  advertising  claims changed. [ 1 ] [ 2 ] [ 3 ]  MaLAM reported more than 450 alleged violations of the voluntary code of conduct of the drug industry in 1987, [ 4 ]  and also questioned drug advertisements in Australia during 1993 to 1997 with funding from the Australian federal government."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6105", "text": "In 2001, the organisation's name was changed to Healthy Skepticism and its work widened to include  research ,  education  and  advocacy  about misleading drug promotion in all countries. It has concentrated recently on raising awareness amongst  health professionals  of the influence that marketing techniques have on their decisions, and the psychological factors which make them vulnerable to that influence. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6106", "text": "In  biology  and other experimental sciences, an  in silico  experiment is one performed on a computer or via  computer simulation  software. The phrase is  pseudo-Latin  for 'in silicon' (correct  Latin :  in silicio ), referring to  silicon  in computer chips. It was coined in 1987 as an allusion to the  Latin phrases   in vivo ,  in vitro , and  in situ , which are commonly used in  biology  (especially  systems biology ).  The latter phrases refer, respectively, to experiments done in living organisms, outside living organisms, and where they are found in nature."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6107", "text": "The earliest known use of the phrase was by  Christopher Langton  to describe  artificial life , in the announcement of a workshop on that subject at the Center for Nonlinear Studies at the  Los Alamos National Laboratory  in 1987. [ 1 ] [ 2 ]  The expression  in silico  was first used to characterize biological experiments carried out entirely in a computer in 1989, in the workshop \"Cellular Automata: Theory and Applications\" in Los Alamos, New Mexico, by Pedro Miramontes, a mathematician from  National Autonomous University of Mexico  (UNAM),  presenting the report \" DNA  and  RNA  Physicochemical Constraints, Cellular Automata and Molecular Evolution\". The work was later presented by Miramontes as his  dissertation . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6108", "text": "In silico  has been used in  white papers  written to support the creation of bacterial genome programs by the Commission of the European Community. The first referenced paper where  in silico  appears was written by a French team in 1991. [ 4 ]  The first referenced book chapter where  in silico  appears was written by Hans B. Sieburg in 1990 and presented during a Summer School on Complex Systems at the Santa Fe Institute. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6109", "text": "The phrase  in silico  originally applied only to computer simulations that modeled natural or laboratory processes (in all the natural sciences), and did not refer to calculations done by computer generically."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6110", "text": "In silico study in medicine is thought to have the potential to speed the rate of discovery while reducing the need for expensive lab work and clinical trials.  One way to achieve this is by producing and screening drug candidates more effectively.  In 2010, for example, using the protein docking algorithm EADock (see  Protein-ligand docking ), researchers found potential inhibitors to an enzyme associated with cancer activity  in silico .  Fifty percent of the molecules were later shown to be active inhibitors  in vitro . [ 6 ] [ 7 ]   This approach differs from use of expensive  high-throughput screening  (HTS) robotic labs to physically test thousands of diverse compounds a day, often with an expected hit rate on the order of 1% or less, with still fewer expected to be real leads following further testing (see  drug discovery )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6111", "text": "As an example, the technique was utilized for a  drug repurposing  study in order to search for potential cures for  COVID-19  (SARS-CoV-2). [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6112", "text": "Efforts have been made to establish computer models of cellular behavior.  For example, in 2007 researchers developed an in silico model of  tuberculosis  to aid in drug discovery, with the prime benefit of its being faster than real time simulated growth rates, allowing phenomena of interest to be observed in minutes rather than months. [ 9 ]   More work can be found that focus on modeling a particular cellular process such as the growth cycle of  Caulobacter crescentus . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6113", "text": "These efforts fall far short of an exact, fully predictive computer model of a cell's entire behavior.  Limitations in the understanding of  molecular dynamics  and  cell biology , as well as the absence of available computer processing power, force large simplifying assumptions that constrain the usefulness of present in silico cell models."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6114", "text": "Digital genetic sequences  obtained from  DNA sequencing  may be stored in  sequence databases , be analyzed (see  Sequence analysis ), be digitally altered or be used as templates for creating new actual DNA using  artificial gene synthesis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6115", "text": "In silico computer-based modeling technologies have also been applied in:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6116", "text": "The UCSF  Industry Documents Library  (IDL) is a digital  archive  of internal tobacco, drug, food, chemical and fossil fuel corporate documents, acquired largely through litigation, which illustrate industry efforts to influence policies and regulations meant to protect  public health .  Created and maintained by the  UCSF Library , the mission of the UCSF Industry Documents Library is to \"identify, collect, curate, preserve, and make freely accessible internal documents created by industries and their partners which have an impact on public health, for the benefit and use of researchers, clinicians, educators, students, policymakers, media, and the general public at UCSF and internationally\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6117", "text": "The IDL includes the following archives:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6118", "text": "The  Influenza Antiviral Drug Search  was a  distributed computing  project that was running on the  BOINC  platform.  It is a project of the  University of Texas Medical Branch ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6119", "text": "The Influenza Antiviral Drug Search conducted millions of virtual  docking  experiments in order to discover compounds that may be suitable for real-world  clinical trials  to combat new or  drug resistant   strains  of  influenza  virus."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6120", "text": "One vulnerability of all influenza strains is that they need  viral neuraminidase ,  NS1 Influenza Protein  and  hemagglutinin  in order to infect a body.  A  chemical compound  that can disable one of these  molecules  has the potential to be an effective antiviral drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6121", "text": "This computing article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6122", "text": "The  Innovative Medicines Initiative  (IMI) is a European initiative to improve the competitive situation of the  European Union  in the field of  pharmaceutical research . The IMI is a joint initiative ( public-private partnership ) of the  DG Research  of the  European Commission , representing the European Communities, and the  European Federation of Pharmaceutical Industries and Associations  (EFPIA). IMI is laid out as a  Joint Technology Initiative  within the Seventh Framework Programme. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ]   Michel Goldman  was the first executive director, from September 2009 until December 2014. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6123", "text": "The Innovative Medicines Initiative is aimed towards removing research  bottlenecks  in the current  drug development  process. The IMI Joint Technology Initiative (IMI JTI), to be implemented by the IMI Joint Undertaking is meant to address these research bottlenecks. Its \u20ac2bn budget makes it the largest biomedical public-private partnership in the world."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6124", "text": "The funding scheme has been criticised, [ 10 ]  requiring universities to invest more money than with EU FP7 programs. Besides the non-competitive financial aspects of participation in IMI projects for academia, this criticism also discusses that intellectual property is freely flowing to industry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6125", "text": "The  Sixth Framework Programme's  research projects InnoMed AddNeuroMed and InnoMed PredTox acted as pilot projects establishing the feasibility of this particular public-private partnership. [ 11 ]  Since then, the IMI has had four funding rounds: the first call had the topic Safety, while the second call was about Efficacy. Projects for these two calls are ongoing. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6126", "text": "The IMI 2 started in 2014 and will run until 2024, while the IMI 1 is still running. Overall budget is \u20ac3.276 billion, taken for half from the European  Horizon 2020  program. Goals of that second calls are to improve clinical trials success rate, deliver clinical proof of concept, biomarkers and new medicines."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6127", "text": "In September 2014 IMI-TRAIN, an IMI/ENSO-funded education and training collaboration to support biomedical scientists and professionals, has been launched. IMI-TRAIN will serve as a collaboration platform for the currently IMI-funded education and training projects: [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6128", "text": "An  investigational device exemption  ( IDE ) allows an investigational device (i.e. a device that is the subject of a  clinical study [ 1 ] ) to be used in order to collect safety and effectiveness data required to support a  premarket approval  (PMA) application or a\n premarket notification  [510(k)] submission to  Food and Drug Administration  (FDA). [ 2 ]  Clinical studies are most often conducted to support a PMA. Only a small percentage of 510(k)'s require clinical data to support the application. Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6129", "text": "Clinical evaluation of devices that have not been cleared for  marketing  requires:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6130", "text": "An approved IDE permits a device to be shipped lawfully for the purpose of conducting investigations of the device without complying with other requirements of the  Food, Drug, and Cosmetic Act  that would apply to devices in commercial distribution. Sponsors need not submit a PMA or premarket notification, register their  establishment, or list the device while the device is under investigation. Sponsors of IDEs are also exempt from the Quality System (QS) Regulation except for the requirements for design control."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6131", "text": "A commercial sponsor of a significant risk device study must submit a complete IDE application to FDA. There are no preprinted forms for an IDE application; however, an IDE application must include certain required information. The sponsor must demonstrate in the application that there is reason to believe that the risks to human subjects from the proposed investigation are outweighed by the anticipated benefits to subjects and the importance of the knowledge to be gained, that the investigation is scientifically sound, and that there is reason to believe that the device as proposed for use will be effective."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6132", "text": "Klick  is a global group of companies in the area of health marketing and advertising."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6133", "text": "Klick was founded in 1997. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6134", "text": "The company introduced the  SymPulse  in 2017. Marketed as a \"tele-empathy\" device, it was designed to transmit the symptoms of  Parkinson's disease  to allow them to be felt and understood by care providers. [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6135", "text": "In 2021 it created \"Community Unity\", a video series with the Vaccine Confidence Project at the  London School of Hygiene & Tropical Medicine  which discusses frequently asked questions about the  COVID-19 vaccines . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6136", "text": "In 2006, Klick Health replaced its internal email systems with a new software program intended for messaging and project management. [ 1 ]  This program, named Genome, incorporates analytics to potentially improve productivity and has been associated with the agency's expansion. [ 7 ] [ 8 ]  Company co-founder Leerom Segal attributed these practices for Klick's low  turnover  rate of three percent, compared to seven percent across Canadian employers As of 2014 [update] . [ 9 ]  The system was marketed to external clients as SenseiOS. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6137", "text": "The organizational structure of Klick Health has not included a  human resources  department, which was a point of concern for some employees. [ 11 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6138", "text": "Its research and development division is Klick Labs. [ 12 ]  The division developed an AI program able to analyze people's voices to determine whether or not they have  type 2 diabetes . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6139", "text": "Klick Health is described by the  Yale School of Management  as the \"largest private health marketing company in the world\". [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6140", "text": "The  pharmaceutical lobby  refers to the representatives of  pharmaceutical drug  and  biomedicine  companies who engage in  lobbying  in favour of  pharmaceutical companies  and their products."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6141", "text": "The largest pharmaceutical companies and their two trade groups,  Pharmaceutical Research and Manufacturers of America  (PhRMA) and  Biotechnology Innovation Organization , lobbied on at least 1,600 pieces of legislation between 1998 and 2004. According to the non-partisan  OpenSecrets , pharmaceutical companies spent $900 million on lobbying between 1998 and 2005, more than any other industry. During the same period, they donated $89.9 million to federal candidates and political parties, giving approximately three times as much to  Republicans  as to  Democrats . [ 1 ]  According to the  Center for Public Integrity , from January 2005 through June 2006 alone, the pharmaceutical industry spent approximately $182 million on federal lobbying in the United States. [ 2 ]  In 2005, the industry had 1,274 registered lobbyists in Washington, D.C. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6142", "text": "A 2020 study found that, from 1999 to 2018, the pharmaceutical industry and health product industry together spent $4.7 billion lobbying the United States federal government, an average of $233 million per year. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6143", "text": "Critics of the pharmaceutical lobby argue that the drug industry's influence allows it to promote legislation friendly to drug manufacturers at the expense of patients. [ 5 ] [ failed verification ]  The lobby's influence in securing the passage of the  Medicare Prescription Drug, Improvement, and Modernization Act  of 2003 was considered a major and controversial [ according to whom? ]  victory for the industry, as it prevents the government from directly negotiating prices with drug companies who provide those prescription drugs covered by  Medicare . Price negotiations are instead conducted between manufacturers and the pharmacy benefit managers providing Medicare Part D benefits under contract with Medicare.  In 2010 the  Congressional Budget Office  estimated the average discount negotiated by pharmacy benefit managers at 14%. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6144", "text": "The high price of U.S. prescription drugs has been a source of ongoing controversy. Pharmaceutical companies state that the high costs are the result of pricey research and development programs. Critics point to the development of drugs having only small incremental benefit. [ 5 ] [ 7 ]  According to  Marcia Angell , former editor-in-chief of the  New England Journal of Medicine , \"The United States is the only advanced country that permits the pharmaceutical industry to charge exactly what the market will bear.\" [ 8 ]  In contrast, the  RAND Corporation  and authors from the  National Bureau of Economic Research  have argued that price controls stifle innovation and are economically counterproductive in the long term. [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6145", "text": "In 2021, during the height of COVID-19, vaccine makers increased lobbying and public-relations efforts to oppose  a proposal that would temporarily waive their patents  in Germany, Japan and other countries. This proposal would allow COVID-19 vaccine patents to be licensed to international vaccine makers or otherwise sold entirely. The Biden presidential administration in the U.S. supported the waiver proposal; however, pharmaceutical industry trade groups supported Germany, Japan, and other countries that expressed opposition. Pharmaceutical industry representatives have been lobbying members of Congress to pressure the Biden administration to reverse its support of the waiver, arguing that the patents protect its innovations. However, proponents of the proposal see the patent as giving companies a monopoly over sales of vaccines during a world crisis. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6146", "text": "Mean kinetic temperature  ( MKT ) is a simplified way of expressing the overall effect of  temperature  fluctuations during storage or transit of perishable goods. The MKT is used to predict the overall effect of temperature fluctuations on perishable goods.  It has more recently been applied to the  pharmaceutical industry ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6147", "text": "The mean kinetic temperature can be expressed as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6148", "text": "When the temperature readings are taken at the same interval (i.e.,  \n \n \n \n \n t \n \n 1 \n \n \n \n \n \n \n {\\displaystyle t_{1}\\,\\!} \n \n  =  \n \n \n \n \n t \n \n 2 \n \n \n \n \n \n \n {\\displaystyle t_{2}\\,\\!} \n \n  =  \n \n \n \n \u22ef \n \n \n {\\displaystyle \\cdots } \n \n  =  \n \n \n \n \n t \n \n n \n \n \n \n \n \n \n {\\displaystyle t_{n}\\,\\!} \n \n ), the above equation is reduced to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6149", "text": "A  medical science liaison  ( MSL ) is a  healthcare  consulting professional who is employed by  pharmaceutical ,  biotechnology , medical device, and managed care companies. Other job titles for medical science liaisons may include medical liaisons, clinical science liaisons, medical science managers, regional medical scientists, and regional medical directors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6150", "text": "The term \"MSL\" was originally trademarked by  Upjohn  as \"Education services \u2013 namely, initiation of drug studies in laboratory and clinical settings and development of workshops, symposia, and seminars for physicians, medical societies, specialty organizations, academicians, in concert, concerned with drug related medical topics\" in 1967 and with first use in commerce in 1967. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6151", "text": "As the number of MSL programs in healthcare increased, subsequent peer-reviewed journal publications and books became available to examine the emerging role of medical affairs [ 2 ] [ 3 ]  and the use of MSLs in an increasingly vertically integrated biotechnology industry. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6152", "text": "MSLs build relationships with key opinion leaders or  thought leaders  and  health care providers , providing critical windows of insight into the market and competition. Through such monitoring, MSLs can gain access to key influencers by interacting with national and regional societies and organizations. Moreover, as MSLs specialize in a particular therapeutic area and have scientific knowledge related to it. The educational background of MSLs consists primarily of MDs, DMSc, PharmD, and PhD professionals.  Other professions who work as MSLs include Physician Assistants and Nurses.  According to the program's advocates, the Board Certified Medical Affairs Specialist (BCMAS) program is the recognized MSL board certification for MSL professionals. [ 5 ]   They are now highly involved in activities related to  clinical trials . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6153", "text": "The medical science liaison role is varied and day-to-day activities include (but are not limited to); [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6154", "text": "The  Mexican barbasco trade  was the trade of the  diosgenin -rich  yam  species  Dioscorea mexicana ,  Dioscorea floribunda  and  Dioscorea composita  which emerged in Mexico in the 1950s as part of the  Mexican steroid industry . The trade consisted in Mexican  campesinos  harvesting the root in the jungle, selling it to middlemen who brought it to processing plants where the root was fermented and the diosgenin extracted and sold to pharmaceutical companies such as  Syntex  who used it to produce  synthetic hormones ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6155", "text": "The trade started when  Russell Marker , a chemist looking for a plant source from which to extract  diosgenin  and  saponin , traveled to  Veracruz  looking for the yam  Dioscorea mexicana  which he suspected might be suitable. He hired two Mexican campesinos to bring him exemplars of the  tuber . When he discovered that the root was indeed a significant source of diosgenin, he established Syntex, the first Mexican fine chemical company dedicated to producing  semisynthetic  hormones from Barbasco. Before this development, natural hormones were extracted from animal sources, such as urine from pregnant mares or women, or from bull testes; prices were consequently very high. With the development of the process of  Marker degradation  which allowed the production of hormones from vegetable  saponin  sources, Marker began a search for a plant  steroid  of the sapogenin class with a ring structure more like  progesterone . With the discovery of the chemical properties of the barbasco root, world market prices for steroids and other synthetic hormones plummeted, making them feasible for large-scale production of medicines for common ailments such as  arthritis  or  Addison's disease , and eventually as the basis for the  combined oral contraceptive pill . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6156", "text": "This development sparked a barbasco extraction industry centered on the barbasco-rich areas of southeastern Mexico, in Northern  Oaxaca , Southern  Veracruz  and  Puebla  states. Especially the area called  Chinantla  in Northern Oaxaca, around the cities of  Tuxtepec  and  Valle Nacional . The root was extracted in the wild by  barbasqueros , often poor  Indigenous   Chinantecs , who ventured into the jungle to dig out the tuber with digging sticks or with their bare hands. Before becoming used industrially, the tuber was used by  Chinantec  healers in northern  Oaxaca  as an  abortifacient  and in cures for aching joints. It was also used by Chinantecs as a poison for fishing in the  Papaloapan river . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6157", "text": "By the mid-1970s, 125,000 Mexican peasants depended on the barbasco trade for their livelihood, and ten tons of barbasco per week were extracted from the wild. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6158", "text": "Quickly, a system of middlemen appeared, as those who had enough means to pay  barbasqueros , started buying large quantities, often using a system of  debt peonage . They would start by giving the  barbasquero  a loan, which he or she would then have to pay off with barbasco. These middlemen would eventually establish  acopios , recollection and distribution centers where large quantities of barbasco are gathered and shipped on to the  beneficios , the processing plants. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6159", "text": "At the processing plants, the tuber is inspected, washed, chopped up, and mixed with water to produce a thick paste. The paste is then put into fermentation vats, where it remains for several days, after which it is taken out and sun-dried on a concrete floor, where it is turned by workers using rakes. In the process of drying, the paste crystallizes into diosgenin granules, also called flour. The flour is then bagged and sent to laboratories where the diosgenin content is measured and the price is calculated based on the diosgenin percentage, which varies from 4\u20136%. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6160", "text": "Knowledge of the uses and purposes of the barbasco tuber was highly stratified, and barbasqueros often did not know the true purpose of the root they were gathering; they were frequently told that it was used for soap. [ 5 ]  The acopio owners knew more about the process and eventually invented ways of improving the diosgenin concentration in roots collected by adding different solvents to the tubers before shipping them to the beneficios."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6161", "text": "In the late 1970s, populist President  Luis Echeverr\u00eda  sought to organize and nationalize the barbasco trade in order to provide more benefits to the barbasqueros and to the Mexican state. He established the organization PROQUIVEMEX (Productos Qu\u00edmicos Vegetales de M\u00e9xico). However, at this point, Mexico had lost its status as a world leader in the synthetic hormone market, and the barbasco trade was declining, just as the root was becoming depleted in the wild. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6162", "text": "Also during the 1970s, it became possible to produce steroids from soy  phytosterols , including  progesterone . This meant that barbasco was no longer necessary as a base product, and international reliance on Mexican yams stopped. Today, only a few communities in Northern Oaxaca continue to produce barbasco, and the few existing beneficios process only a few tons per year. In 1999, 65% of families in the municipio of  Santiago Jocotepec  depended on barbasco production, whereas in the municipios of  San Juan Lalana  it was 29.2%, in  San Felipe Usila  28.3%, and in  San Lucas Ojitl\u00e1n  24.4%. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6163", "text": "The relationship between water content and equilibrium relative humidity of a material can be displayed graphically by a curve, the so-called  moisture sorption isotherm . \nFor each  humidity  value, a  sorption isotherm  indicates the corresponding  water content  value at a given temperature. If the composition or quality of the material changes, then its sorption behaviour also changes. Because of the complexity of sorption process the isotherms cannot be determined explicitly by calculation, but must be recorded experimentally for each product. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6164", "text": "The relationship between water content and  water activity  (a w ) is complex. An increase in a w  is usually accompanied by an increase in water content, but in a non-linear fashion. This relationship between water activity and moisture content at a given temperature is called the moisture sorption isotherm. These curves are determined experimentally and constitute the fingerprint of a  food system . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6165", "text": "BET theory  (Brunauer-Emmett-Teller) provides a calculation to describe the physical adsorption of gas molecules on a solid surface.  Because of the complexity of the process, these calculations are only moderately successful; however,  Stephen Brunauer  was able to classify sorption isotherms into five generalized shapes as shown in Figure 2."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6166", "text": "He found that Type II and Type III isotherms require highly porous materials or desiccants, with first monolayer adsorption, followed by multilayer adsorption and finally leading to capillary condensation, explaining these materials high moisture capacity at high relative humidity. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6167", "text": "Care must be used in extracting data from isotherms, as the representation for each axis may vary in its designation. Brunauer provided the vertical axis as moles of gas adsorbed divided by the moles of the dry material, and on the horizontal axis he used the ratio of partial pressure of the gas just over the sample, divided by its partial pressure at saturation. More modern isotherms showing the sorption of water vapor, on the vertical axis, provide the ratio of the weight of water adsorbed  divided by its dry weight, or that ratio converted into a percentage. On the horizontal axis they provide relative humidity or water activity of the air presented to the material."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6168", "text": "Sorption Isotherms are named as such because the equilibrium established must be for a constant temperature and this temperature should be specified.  Normally, materials hold less moisture when they are hotter, and more moisture when they are colder.  Occasionally, a set of isotherms are provided on one graph that shows each curve at a different temperature. Such a set of adsorption isotherms is provided in Figure 3 as measured by Dini on a Type V silica gel. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6169", "text": "Molecular phenotyping  describes the technique of quantifying pathway reporter genes,  i.e.  pre-selected genes that are modulated specifically by metabolic and  signaling pathways , in order to infer activity of these pathways. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6170", "text": "In most cases, molecular phenotyping quantifies changes of pathway reporter  gene expression  to characterize modulation of pathway activities induced by perturbations such as therapeutic agents or stress in a cellular system  in vitro . In such contexts, measurements at early time points are often more informative than later observations because they capture the primary response to the perturbation by the cellular system. [ 3 ]  Integrated with quantified changes of  phenotype  induced by the perturbation, molecular phenotyping can identify pathways that contribute to the phenotypic changes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6171", "text": "Currently molecular phenotyping uses  RNA sequencing  and  mRNA  expression to infer pathway activities. Other technologies and readouts such as  mass spectrometry  and protein abundance or phosphorylation levels can be potentially used as well. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6172", "text": "Current data suggest that by quantifying pathway reporter  gene expression , molecular phenotyping is able to cluster compounds based on pathway profiles and dissect associations between pathway activities and disease  phenotypes  simultaneously. [ 5 ]  Furthermore, molecular phenotyping can be applicable to compounds with a range of binding specificities and is able to triage false positives derived from high-content screening assays. Furthermore, molecular phenotyping allows integration of data derived from  in vitro  and  in vivo  models as well as patient data into the drug discovery process. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6173", "text": "The  National Institute for Pharmaceutical Technology and Education  ( NIPTE ) is a  non-profit  scientific and research and development organization that was established in 2005 and incorporated in June 2007 in the State of  Indiana . [ citation needed ]  Its offices are currently located in  Minneapolis , Minnesota."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6174", "text": "NIPTE's current membership includes 18 leading schools and colleges of  pharmacy  and  chemical engineering  from the following universities:  University of Mississippi ,  Duquesne University ,  University of Rochester ,  Illinois Institute of Technology ,  Purdue University ,  Rutgers University ,  University of Puerto Rico ,  Long Island University ,  University of Connecticut ,  University of Texas at Austin ,  University of Iowa ,  University of Kentucky ,  University of Maryland ,  Texas A&M University ,  University of Michigan ,  University of Minnesota ,  University of Kansas  and  University of Wisconsin ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6175", "text": "The pharmaceutical industry is currently facing increased pricing pressures globally and rising  manufacturing  costs. Cost of Goods (COGS) for Brand-Name  pharmaceutical drugs  can be higher than 30% of the total sales revenues of these companies. In comparison, the percentage of sales revenues spent on  R&D  by these pharmaceutical companies is only 10-15%. For  generic drugs , COGS can be as high as 50% of their total sales revenues. [ 1 ]  Traditionally, pharmaceutical companies preferred to manufacture their own products internally. [ 2 ]  They were keen on \"making\" what they \"sold\" because it provided them with more control of the quality of their products. However, since the pressures to reduce cost these days are high, to save money, the pharmaceutical industry is increasingly outsourcing manufacturing to countries in Asia \u2013 where the regulatory standards are evolving and sometimes could lag several years behind the U.S. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6176", "text": "The science required to transform a new discovery to a marketable new  drug  has definitely not kept pace with advances on the drug discovery side. [ 4 ]  Pharmaceutical product development today is more of an art than science. Once the new drug discovery is made, product development and manufacturing are left to traditional \"tried and true\" practices. Marked advances in  chemistry ,  chemical engineering ,  computer modeling  & simulation,  instrumentation , analytical science, and product formulations that could be used to increase efficiency may also be more gainfully applied in pharmaceutical product development and manufacturing. The cost savings achievable by outsourcing can be easily exceeded by improving the science and technology for developing and manufacturing pharmaceutical products. Other industries, such as the  semiconductor  industry have examined their manufacturing technologies and have modernized them. This has allowed these industries to become more competitive and to have products of superior value. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6177", "text": "Manufacturing is a critical step in the chain of very complex events before a drug reaches the pharmacy shelves. When that critical link is broken, it opens the door for something like the  heparin  crisis. [ 5 ]  And heparin may just be the tip of the iceberg. The ultimate answer is not costly inspections of foreign manufacturing sites. [ 6 ]  If that remains the answer, the  U.S. Food and Drug Administration  (FDA) will need a lot more resources and millions of dollars from the  United States Congress  to ensure that all drugs and drug components manufactured in foreign countries are safe and effective. [ 7 ]  Our goal should be to improve the quality of pharmaceutical manufacturing such that drugs can be produced safely and cost-effectively no matter where they are produced. We need to build in manufacturing quality with front-end design \u2013 not back-end inspection. If the U.S. wants to increase medication safety and reduce the cost of drugs, it must invest in the basic science of drug development and manufacturing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6178", "text": "The  public/private partnership model  for drug discovery (known as the  NIH Roadmap ) shows success by spurring advances with strong basic science research investment. Between 1999 and 2006, research and development investments in the  United States  grew 5 times the initial investment while in  Europe  it grew 2.9 times. However, since 2006  Asia  has markedly outpaced the U.S. in the opening of new research sites for pharmaceuticals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6179", "text": "NIPTE's goal is to increase science and engineering-based understanding of this area such that novel state-of-the-art technologies can be developed and science-based regulations can be implemented. These technologies will also enable new drug discoveries to be brought to market faster with less variability, higher predictability of performance and at a significantly lower cost.\nNIPTE's research agenda [ citation needed ]  is to conduct fundamental and basic research that will:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6180", "text": "NIPTE has developed Strategic Roadmap for Research and Technology which outlines current and future challenges and proposed solutions in pharmaceutical science."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6181", "text": "NIPTE's membership includes leading schools and colleges of pharmacy and chemical and  pharmaceutical engineering , and has overlapping scientific interests with pharmaceutical scientists (e.g. American Association of Pharmaceutical Sciences)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6182", "text": "Current academic programs in pharmaceutical technology are disappearing despite the continued and growing needs of today's industry leading to too few good teacher/mentors and very few qualified graduates. NIPTE comprises leading educational institutions in the pharmaceutical science and engineering, NIPTE's goal is to create a \"pipeline\" of diverse talent that commences at the undergraduate level and continues throughout  graduate ,  postgraduate , and continuing education, augmenting the available workforce in academia, industry, and government. This goal is being addressed by developing and implementing an integrated Education and Training plan which incorporates NIPTE research programs. By that, NIPTE will create and deliver educational and training programs that will prepare the technical cadre needed by the industry and the FDA to implement and regulate new technologies. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6183", "text": "The  Newhouse Research Site  is a  drug research  facility situated 15 miles (24\u00a0km) east of  Glasgow  in central Scotland. It is located beside the  M8 motorway  in  Newhouse ,  North Lanarkshire . The site is an early  drug discovery  research centre with a track record of generating a succession of products in the areas of  anaesthesia  and  psychiatry . In 2007, the  Royal Society of Chemistry  Malcolm Campbell Memorial Prize was awarded to researchers for its work on a new anaesthesia drug,  sugammadex . [ 1 ] [ failed verification ]  It currently employs 250 scientists across a range of disciplines including  medicinal chemistry ,  molecular biology  and  drug metabolism . The site is currently the largest private drug discovery centre in  Scotland , and one of the biggest in the UK. [ 2 ] [ failed verification ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6184", "text": "The 20-acre (8.1\u00a0ha) campus was acquired by  Organon  in 1948 and has continued to grow throughout the years. [ 3 ] [ 4 ]  Scientists at the site are responsible for the invention of a succession of successful products, two of which have recently received approval. Organon was acquired by  Schering-Plough  in 2007, [ 5 ]  and the site was further expanded with the addition of one of the largest compound management facilities in the industry. [ 6 ]  Schering-Plough merged with  Merck  (known as MSD outside of North America) at the end of 2009. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6185", "text": "The site has a long history of research in the area of  neuromuscular blockers , which are commonly used during surgery, and was responsible for the identification of  rocuronium  as well as a number of other drugs. [ citation needed ]  In another major advance the reversal agent  sugammadex  was the first  selective relaxant binding agent  (SRBA) for Neuromuscular Block Reversal to be identified, [ 8 ]  and has recently entered the market in Europe. [ 9 ]  On the psychiatric front researchers at Newhouse supported the development of  mirtazepine , a novel  tetracyclic   anti-depressant  which has become widely prescribed throughout the world. More recently the site was closely involved in supporting the introduction of the  anti-psychotic   asenapine  which has just been launched for the treatment of  schizophrenia  and  bipolar disorder . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6186", "text": "The  osmotic-controlled release oral delivery system (OROS)  is an advanced  controlled release  oral drug delivery system in the form of a rigid  tablet  with a semi-permeable outer membrane and one or more small  laser drilled  holes in it. As the tablet  passes through the body , water is absorbed through the  semipermeable membrane  via  osmosis , and the resulting  osmotic pressure  is used to push the active  drug  through the laser drilled opening(s) in the tablet and into the  gastrointestinal tract . OROS is a trademarked name owned by  ALZA Corporation , which pioneered the use of osmotic pumps for oral drug delivery. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6187", "text": "Osmotic release systems have a number of major advantages over other controlled-release mechanisms. They are significantly less affected by factors such as  pH , food intake,  GI motility , and differing intestinal environments. Using an osmotic pump to deliver drugs has additional inherent advantages regarding control over drug delivery rates. This allows for much more precise drug delivery over an extended period of time, which results in much more predictable  pharmacokinetics . However, osmotic release systems are relatively complicated, somewhat difficult to manufacture, and may cause irritation or even blockage of the GI tract due to prolonged release of irritating drugs from the non-deformable tablet. [ 1 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6188", "text": "The Elementary Osmotic Pump (EOP) was developed by  ALZA  in 1974, and was the first practical example of an osmotic pump based drug release system for oral use. [ 1 ] [ 2 ] [ 10 ] [ 11 ] [ 12 ]  It was introduced to the market in the early 1980s in Osmosin ( indomethacin ) and Acutrim ( phenylpropanolamine ), but unexpectedly severe issues with GI irritation and cases of  GI perforation  led to the withdrawal of Osmosin. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6189", "text": "Merck & Co.  later developed the Controlled-Porosity Osmotic Pump (CPOP) with the intention of addressing some of the issues that led to Osmosin's withdrawal via a new approach to the final stage of the release mechanism. [ 1 ]  Unlike the EOP, the CPOP had no pre-formed hole in the outer shell for the drug to be expelled out of. Instead, the CPOP's semipermeable membrane was designed to form numerous small pores upon contact with water through which the drug would be expelled via osmotic pressure. The pores were formed via the use of a pH insensitive  leachable  or  dissolvable  additive such as  sorbitol . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6190", "text": "Both the EOP and CPOP were relatively simple designs, and were limited by their inability to deliver poorly  soluble  drugs. [ 1 ]  This led to the development of an additional internal \"push layer\" composed of material (a swellable  polymer ) that would expand as it absorbed water, which then pushed the drug layer (which incorporates a  viscous  polymer for suspension of poorly soluble drugs) out of the exit hole at a controlled rate. [ 1 ] [ 4 ]  Osmotic agents such as  sodium chloride ,  potassium chloride , or  xylitol  are added to both the drug and push layers to increase the  osmotic pressure . [ 1 ] [ 4 ] [ 5 ]  The initial design developed in 1982 by ALZA researchers was designated the Push-Pull Osmotic Pump (PPOP), and Procardia XL ( nifedipine ) was one of the first drugs to utilize this PPOP design. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6191", "text": "In the early 1990s, an ALZA-funded research program began to develop a new dosage form of  methylphenidate  for the treatment of children with  attention deficit hyperactivity disorder  (ADHD). [ 14 ]  Methylphenidate's short  half-life  required multiple doses to be administered each day to attain long-lasting coverage, which made it an ideal candidate for the OROS technology. Multiple candidate  pharmacokinetic  profiles were evaluated and tested in an attempt to determine the optimal way to deliver the drug, which was especially important given the puzzling failure of an existing extended-release formulation of methylphenidate (Ritalin SR) to act as expected. The zero-order (flat) release profile that the PPOP was optimal at delivering failed to maintain its efficacy over time, which suggested that acute tolerance to methylphenidate formed over the course of the day. This explained why Ritalin SR was inferior to twice-daily Ritalin IR, and led to the  hypothesis  that an ascending pattern of drug delivery was necessary to maintain clinical effect. Trials designed to test this hypothesis were successful, and ALZA subsequently developed a modified PPOP design that utilized an overcoat of methylphenidate designed to release immediately and rapidly raise serum levels, followed by 10 hours of first-order (ascending) drug delivery from the modified PPOP design. This design was called the Push-Stick Osmotic Pump (PSOP), and utilized two separate drug layers with different concentrations of methylphenidate in addition to the (now quite robust) push layer. [ 1 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6192", "text": "OROS medications include: [ 1 ] [ 3 ] [ 4 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6193", "text": "The  Pharmaceutical Accountability Foundation  (in Dutch  Stichting Farma Ter Verantwoording ) was established in  Amsterdam  in July 2018 to deal with pharmaceutical companies that demand excessive prices for medicines in the Netherlands. This followed a report by the  Raad voor de Volksgezondheid en Zorg \u00a0[ nl ]  in 2017. Wilbert Bannenberg, an epidemiologist, is the chairman. [ 1 ]  The group plans to deploy both health and pharmaceutical expertise and lawyers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6194", "text": "They have investigated 12 cases all with the same business model, which they describe as: \"buy an old, cheap product, get the old versions off the market, win orphan drug designation, and put up the price as high as you can.\" They say that European orphan drug legislation needs to be reformed. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6195", "text": "It plans to make a referral to the  Netherlands Authority for Consumers and Markets  in respect of the pricing policy of  Leadiant Biosciences  Ltd, formerly known as Sigma-Tau Rare Disease, for  chenodeoxycholic acid  which is used to treat about 60 children with  cerebrotendineous xanthomatosis  in the Netherlands. The company now sells this medicine at \u20ac140 per capsule, about \u20ac153,300 per patient per year. Previously it was sold under the name Chenofalk for the treatment of gallstones at a cost of \u20ac0.28 per capsule and used off label for the treatment of cerebrotendineous xanthomatosis.  Sigma-Tau  acquired the rights in 2008.  [ 3 ]  The  European Medicines Agency  approved chenodeoxycholic acid for the treatment of cerebrotendinous xanthomatosis. Leadiant, having secured orphan drug designation, and bought up rival suppliers, raised the price, as they were entitled to ten years market exclusivity in the European Union. Bannenberg claims that Leadiant is abusing its dominant market position. [ 4 ]  The  VU University Medical Center  are proposing to manufacture their own version at cost price, and this has been supported by Dutch health insurers. [ 5 ]  Leadiant has been compared to  Martin Shkreli . [ 6 ]  Bannanberg is quoted as saying \u201cThis may be legal but it\u2019s not socially acceptable.\u201d [ 7 ]  The foundation's complaints have been echoed by  Bruno Bruins , Minister for Medical Care. The track record of the  Netherlands Authority for Consumers and Markets  and previously of the Netherlands Competition Authority in the medicines sector has been described as poor.  [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6196", "text": "Under political pressure, the pharmaceutical companies in the Netherlands have been working on a code of conduct which they say will provide guarantees for responsible pricing, and keep speculators out of the door. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6197", "text": "In April 2020, Bannenberg said that the Netherlands' vulnerability to medicine shortages had been exposed by the  COVID-19 pandemic in the Netherlands  because the country was too dependent on medicines from low-wage countries and vaccines from big pharma. The Netherlands was not a priority for supply. He wanted to see more local production and different manufacturers, even if this meant that generic drugs would be more expensive. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6198", "text": "Pharmaceutical fraud  is when pharmaceutical companies engage in illegal,  fraudulent  activities to the detriment of patients and/or insurers. Examples include  counterfeit  drugs that do not contain the active ingredient, false claims in packaging and marketing, suppression of negative information regarding the efficacy or safety of the drug, and violating pricing regulations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6199", "text": "Pharma fraud refers to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6200", "text": "Because of a lack of regulation and enforcement, the quality, safety and efficacy of both imported and locally manufactured medicines in many developing countries cannot be guaranteed. Subsequently, smuggling and illegal importation of drugs are common. Substandard and counterfeit drugs are then not only sold in these countries but also exported or re-exported. [ 10 ]  According to the  World Customs Organization , counterfeit drugs are a $200 billion a year industry that kills hundreds of thousands of people annually. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6201", "text": "In the United States, there are several different schemes [ 12 ]  used to defraud the  health care system  which are particular to the pharmaceutical industry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6202", "text": "Involve fraud with the Good Manufacturing Practice (GMP) Regulations which require manufacturers to have adequately equipped manufacturing facilities, adequately trained personnel, stringent control over the manufacturing process, appropriate laboratory controls, complete and accurate records, reports, appropriate finished product examination, and so on. Certain violations of the Good Manufacturing Practice Regulations may be the basis for a False Claims Act lawsuit. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6203", "text": "Though physicians may prescribe drugs for off-label usage known as off-label marketing, the  Food and Drug Administration  (FDA) prohibits drug manufacturers from marketing or promoting a drug for a use that the FDA has not approved. A manufacturer illegally \u201cmisbrands\u201d a drug if the drug's labeling includes information about its unapproved uses. A drug is deemed misbranded unless its labeling bears adequate directions for use. The courts have agreed with the FDA that the  Food, Drug, and Cosmetic Act  (FDCA) requires information not only on how a product is to be used (e.g., dosage and administration), but also on all the intended uses of the product. In 2004, whistleblower  David Franklin  prevailed in a suit under the  False Claims Act  against  Warner-Lambert , resulting in a $430 million settlement in the  Franklin v. Parke-Davis  case. It was the  first off-label promotion case  successfully brought under the False Claims Act in U.S. history. Oral statements and materials presented at industry-support scientific and educational activities may provide evidence of a product's intended use. If these statements or materials promote a use that is inconsistent with the product's approved labeling, the product is misbranded under the FDCA for failure to bear labeling with adequate directions for all intended uses. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6204", "text": "A figure reported by the manufacturer to CMS in quarterly reports under the Medicaid Rebate Program, it is used to calculate the Medicaid reimbursement rate. It is defined as the lowest price available to any wholesaler, retailer, provider, health maintenance organization (HMO), nonprofit entity, or the government. BP excludes prices to the Indian Health Service (IHS), Department of Veterans Affairs (DVA), Department of Defense (DOD), the Public Health Service (PHS), 340B covered entities, Federal Supply Schedule (FSS), state pharmaceutical assistance programs, depot prices, and nominal pricing. BP includes cash discounts and free goods that are contingent upon purchase, volume discounts, and rebates. The fraud occurs as the manufacturer falsely self-reports its Best Price. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6205", "text": "In order to decrease the amounts owed to states under the  Medicaid Drug Rebate Program , some companies misrepresented material facts regarding the regulatory origin/status of their brand name drugs, the AMP, and/or the best price. Despite the Government's good faith reliance to charge manufacturers a unit rebate amount based upon the manufacturer's own representation of drug status, and price, some manufacturers have deceptively and fraudulently, breached their duty to deal honestly with the Government. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6206", "text": "FDA guidelines authorize pharmacists to \u201ccompound\u201d or mix medications only in response to a physician's valid prescription. This assumes, of course, that the physician intends that the medication be compounded. The regulations further require that the mixed or compounded medications are medically necessary and not commercially available. Illegal compounding includes compounding of ingredients such that the compounded drug is tantamount to commercially available medications, involving mass manufacturing of drugs under the guise of compounding."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6207", "text": "Federal law, including the Centers for Medicare and Medicaid Services (CMS) guidelines and the regulations of other Government Healthcare Programs, prohibit coverage of claims for \u201ccompounded\u201d medications when the claims are submitted by a company that is mass manufacturing large amounts of unapproved drugs in violation of the Federal Food, Drug and Cosmetic Act (FFDCA), under the guise of \u201ccompounding.\u201d [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6208", "text": "Kickbacks  are rewards such as cash, jewelry, free vacations, corporate sponsored retreats, or other lavish gifts used to entice medical professionals into using specific medical services. This could be a small cash kickback for the use of an MRI when not required, or a lavish doctor/patient retreat that is funded by a pharmaceutical company to entice the prescription and use of a particular drug. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6209", "text": "People engaging in this type of fraud are also subject to the federal Anti-Kickback statute."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6210", "text": "Drug discovery  and  development  requires the integration of multiple scientific and technological disciplines. These include  chemistry ,  biology ,  pharmacology ,  pharmaceutical technology  and extensive use of  information technology . The latter is increasingly recognised as  Pharmacoinformatics . Pharmacoinformatics relates to the broader field of  bioinformatics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6211", "text": "The main idea behind the field is to integrate different informatics branches (e.g. bioinformatics, chemoinformatics, immunoinformatics, etc.) into a single platform, resulting in a seamless process of drug discovery. The first reference of the term \"Pharmacoinformatics\" can be found in the year of 1993. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6212", "text": "The first dedicated department for Pharmacoinformatics was established at the  National Institute Of Pharmaceutical Education And Research , S.A.S. Nagar, India in 2003. [ 2 ]   This has been followed by different universities worldwide including a program by European universities named the  European Pharmacoinformatics Initiative  (Europin [ 3 ] )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6213", "text": "Pharmacoinformatics is also referred to as pharmacy informatics. According to the article \"Pharmacy Informatics: What You Need to Know Now\" by the University of Illinois at Chicago Pharmacoinformatics may be defined as: \u201cthe scientific field that focuses on medication-related data and knowledge within the continuum of healthcare systems. [ 4 ] \u201d It is the application of computers to the storage, retrieval and analysis of drug and prescription information. Pharmacy informaticists work with pharmacy information management systems that help the pharmacist safe decisions about patient drug therapies with respect to, medical insurance records, drug interactions, as well as prescription and patient information."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6214", "text": "Pharmacy informatics can be thought of as a sub-domain of the larger professional discipline of health informatics. Health informatics is the study of interactions between people, their work processes and engineered systems within health care with a focus on pharmaceutical care and improved patient safety. For example, the Health Information Management Systems Society (HIMSS) defines pharmacy informatics as, \"the scientific field that focuses on medication-related data and knowledge within the continuum of healthcare systems - including its acquisition, storage, analysis, use and dissemination - in the delivery of optimal medication-related patient care and health outcomes\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_6215", "text": "Pharmacometrics  is a field of study of the methodology and application of models for  disease  and  pharmacological   measurement . It uses mathematical models of  biology , pharmacology, disease, and  physiology  to describe and quantify interactions between  xenobiotics  and patients (human and non-human), including beneficial effects and adverse effects. [ 1 ]  It is normally applied to quantify drug, disease and trial information to aid efficient drug development, regulatory decisions and rational drug treatment in patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6216", "text": "Pharmacometrics uses models based on pharmacology, physiology, and disease for quantitative analysis of interactions between drugs and patients. This involves  Systems pharmacology ,  pharmacokinetics ,  pharmacodynamics  and  disease progression  with a focus on  populations  and  variability ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6217", "text": "Mould and Upton provide an overview of basic concepts in population modeling, simulation, and model-based drug development. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6218", "text": "A major focus of pharmacometrics is to understand variability in drug response. Variability may be predictable (e.g. due to differences in body weight or kidney function) or apparently unpredictable (a reflection of the current lack of knowledge)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6219", "text": "The term \"pharmacometrics\" first appeared in literature in the preface of the 1964 book \"Evaluation of Drug Activities: Pharmacometrics\" [ 3 ] :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6220", "text": "The sub-title of the book is, as far as we are aware, a  neologism , coined by one of us (A.L.B.), and the word is defined by the main title of the book, which could have been even more explicitly, if more verbosely, expressed as \"The Identification and the Comparative Evaluation, Qualitative and Quantitative, of Drug Activities\". The term has an etymological precedent in the now widely accepted \" Econometrics \". We hope it will prove useful for distinguishing the kind of measurement discussed and described in this book from what is nowadays called  bioassay ; although the same techniques sometimes serve for both, their objectives are not at all identical."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6221", "text": "However, the editors later state at the end of the preface:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6222", "text": "...we have learned with interest and humility that Dr. Karl Beyer, a vice-president of  Merck, Sharpe and Dohme , Rahway, New Jersey, U.S.A., and current president of the American Pharmacological Society, \"coined the word (Pharmacometrics) in the early '50s and has been using it in internal reports ever since\" (J. R. Vane, personal communication). Moreover, one of the laboratories in the pharmacological department of his Company is \"labeled 'Pharmacometrics'\"!\nWe do not know in exactly what sense Dr. Beyer has been using the word, though we find it difficult to think of any other legitimate one than that advanced above. We can only hope that he also thinks so and that its use in the title of this book may help to give it the wider currency that we believe it to deserve and all the \"priority\" rights to Dr. Beyer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6223", "text": "Pharmacokinetic  models are constructs aimed at characterizing the average pharmacokinetic behavior of a drug within a population. By incorporating inter-individual variability, these models provide insights into central tendencies and variabilities in drug responses across diverse patient groups. Their application extends to the optimization of dosing regimens at a population level."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6224", "text": "Pharmacodynamic  models focus on elucidating the intricate relationship between drug concentration and its effects on the body. This includes both the desired therapeutic effects and potential side effects. By delineating the time course of drug effects, these models contribute to the prediction of efficacy and adverse events, aiding in the identification of optimal dosing strategies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6225", "text": "Physiologically-Based Pharmacokinetic  models integrate physiological information to simulate drug behavior in various tissues and organs. These models consider organ-specific blood flow, tissue permeability, and drug properties, facilitating predictions of drug concentration at specific sites. PBPK models are instrumental in understanding complex drug behaviors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6226", "text": "Exposure-Response models establish the relationship between drug exposure and clinical response. They play a crucial role in determining the optimal therapeutic range and predicting the likelihood of efficacy or adverse events. These models guide dose individualization based on desired clinical outcomes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6227", "text": "Drug-Drug Interaction models explore the impact of interactions between different drugs on their pharmacokinetics or pharmacodynamics. These models help predict the effects of co-administered drugs on each other, aiding in the identification of potential risks and the adjustment of dosages in the presence of multiple medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6228", "text": "The natural time course of a disease is often dynamic, with the tendency to become worse without treatment. Disease progression models are mainly used to understand the relationship between treatment, biomarker changes and clinical outcomes. These models describe the disease trajectory, by observing the change in the biomarker level, or the other clinically relevant endpoint that reflects the disease status, over time. [ 4 ]  There are three key classes of disease progression models:  empirical , semi-mechanistic, and systems biology. [ 5 ]  Most of the disease progression models are empirical, describing disease trajectory rather than the physiological background of the disease. [ 6 ]  The simplest model that is used to describe disease progression is a  linear model  when the change of disease status over time is assumed to be constant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6229", "text": "Systems Pharmacology models integrate pharmacokinetics, pharmacodynamics, and systems biology to provide a comprehensive understanding of drug effects. By considering the intricate interplay between drugs, biological systems, and disease pathways, these models contribute to a holistic approach to drug development and personalized medicine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6230", "text": "Mechanistic models provide a detailed understanding of the underlying biological and physiological processes governing drug behavior. These models offer insights into the mechanisms influencing drug absorption, distribution, metabolism, and elimination, aiding in predicting drug responses in diverse scenarios."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6231", "text": "Trial models describe variations from the nominal trial protocol due to things such as patient dropout and lack of adherence to the dosing regimen."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6232", "text": "Historically, pharmacometrics has been represented in related clinical pharmacology and statistics organizations. A number of smaller local organizations in Europe, United States, and New Zealand/Australia held local meetings. In the early 1990s, The PAGE meeting was organized and has been held yearly since then, although no official organization was present. Ette and Williams have provided a historical context from which the evolution of pharmacometrics can be appreciated. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6233", "text": "In 2011, the  American Society of Pharmacometrics  (ASoP) was founded by a number of local American groups, and over 600 members worldwide joined ASoP within 6 months. In 2012, ASoP evolved to the  International Society of Pharmacometrics  (ISoP) to reflect the increasing number of international members. ISoP's growth continues and the society currently represents over 1000 members from almost 30 countries around the world. [ 8 ]  Regional groups include PAGE in Europe [ 9 ]  and PAGANZ in Australia and New Zealand. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6234", "text": "Pharmacometricians typically come from disciplines such as  Pharmacy ,  Clinical pharmacology ,  Statistics ,  Medicine , or  Engineering ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6235", "text": "The first professor of pharmacometrics was Mats Karlsson,  Uppsala University . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6236", "text": "The main journals that publish work in pharmacometrics are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6237", "text": "In Denmark (including  Greenland  and  Faroe Islands ),  pharmaconomists  ( Danish :  farmakonom ) are  experts in pharmaceuticals ( Danish :  l\u00e6gemiddelkyndig ) who have trained with a 3-year  tertiary degree .  Pharmaconomy  ( Danish :  farmakonomi ) describes either their professional practice or their training courses."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6238", "text": "The majority of the Danish pharmaconomists work at  community pharmacies  ( chemists' shops  or drug stores) and at  hospital pharmacies  and  hospitals ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6239", "text": "Some pharmaconomists work within the  chemical industry , the  pharmaceutical industry  and in  medical or clinical laboratories ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6240", "text": "Other pharmaconomists  teach  pharmacy students and pharmaconomy students at  colleges  or  universities , such as at the University of Copenhagen's  Faculty of Health and Medical Sciences  or at the Pharmakon\u2014Danish College of Pharmacy Practice."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6241", "text": "Pharmaconomists are also employed by the Danish  Ministry of Interior and Health ,  Danish Medicines Agency  and  Danish Association of Pharmacies ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6242", "text": "Some pharmaconomists do work as  pharmaceutical consultants ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6243", "text": "The 3 year higher education corresponds to 180  ECTS points (European Credit Transfer and Accumulation System) ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6244", "text": "During his or her  education  programme at  Pharmakon\u2014Danish College of Pharmacy Practice , the pharmaconomist student studies  human  and  animal   anatomy ,  physiology ,  pathology ,  pharmacology ,  pharmaconomy ,  pharmacy practice ,  pharmaceutics ,  toxicology ,  pharmacognosy ,  clinical pharmacy ,  pharmacotherapy ,  pharmaceutical sciences ,  chemistry ,  pharmaceutical chemistry ,  biochemistry ,  biology ,  microbiology ,  molecular biology ,  genetics ,  cytology ,  medicine ,  veterinary medicine ,  zoology ,  diagnosis ,  medical prescription ,  pharmacy law ,  medical sociology ,  patient safety ,  health care ,  psychology ,  psychiatry ,  pedagogy ,  communication ,  information technology (IT) ,  bioethics ,  medical ethics ,  safety ,  leadership ,  organization ,  logistics ,  economy ,  quality assurance (QA) ,  sales  and  marketing ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6245", "text": "There are two different professional groups with pharmaceutical education in Denmark:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6246", "text": "Due to his or her higher education as a  health professional , the pharmaconomist has by law the same  independent  competence in all Danish pharmacies as a pharmacist \u2014  i.e.  for example to dispense and check medical prescriptions, to counsel and advise  patients / customers  about the use of medicine/pharmaceuticals and to dispense, sell and provide  information  about medical prescriptions and about  prescription medicine  and  over-the-counter medicine (OTC) ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6247", "text": "The pharmaconomist also undertakes specialist and  managerial  operation of pharmacies and undertakes managerial  duty  service."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6248", "text": "The only difference by law is that only a pharmacist may  own  a Danish pharmacy \u2014 i.e. become a pharmacy owner."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6249", "text": "Like pharmacists, pharmaconomists can work as pharmacy managers and  HR managers  (or as chief pharmaconomists)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6250", "text": "The  Danish Association of Pharmaconomists  is a  trade union  who represents about 5,700 pharmaconomists in Denmark (i.e. 98% of all Danish pharmaconomists)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6251", "text": "The Danish title  farmakonom  (pharmaconomist) comes from the  Greek  \"pharmakon\" (meaning \"pharmaceuticals\") and \"nom\" (meaning \"expert in\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6252", "text": "In Denmark a pharmaconomist is also referred to as  l\u00e6gemiddelkyndig  (expert in pharmaceuticals).  L\u00e6gemiddelkyndig  comes from the Danish \"l\u00e6gemiddel\" (meaning \"pharmaceuticals\") and \"kyndig\" (meaning \"expert in\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6253", "text": "Pill prizes  are the idea put forth by  Joseph E. Stiglitz  when he wrote \"Prizes, not patents\", in order to address shortfalls of using  patents  from a pharmaceutical drug perspective. Patents are awarded to  inventors  and firms in order to promote  innovation  by providing  incentives  beyond traditional market incentives. Stiglitz is critical of patents and how they fail provide similar incentives to innovations which are not marketable to the normal  consumer society  while simply restricting information which is inefficient. Stiglitz provides the idea of  prizes  instead of patents to be awarded in order to further advance pharmaceutical solutions to global problems such as  AIDS ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6254", "text": "Patents essentially provide a temporary  monopoly  on a product to the first inventor or firm which comes up with the product. Patents vary in length but are designed to last long enough for the innovator to make a return on  investment . The nature of patents makes them an incentive so long as the product being invented is distributed to consumers through markets. While patented products are in the market, the producer can place any price on the product, regardless of the price of production which typically dictates prices in markets. If a product is not being distributed through markets then a patent cannot provide proper incentive for innovation. Patents do however provide gain through the restriction of information to others. Stiglitz identifies this as a problem of patents for the innovation of  drugs  and other products being distributed not with the purpose of making a  profit , but to solve global problems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6255", "text": "Offering a prize as opposed to a patent, according to Stiglitz, would address the lack of incentive for problems such as disease in  developing countries  and it would provide products immediately affordable instead of pending on a patent expiration. Awarding prizes offers a fixed amount appropriate for reimbursing research into drugs. Today, many drug companies spend much of money earned through patents on  marketing  and  advertising  as opposed to the research for the actual drugs  [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6256", "text": "Until  generic  versions of drugs reach the shelves, which occurs after a patent expires, the costs burden  consumers  due to prices not being dictated by the markets. [ 2 ]  These burdens are overwhelming in developing countries and Stiglitz suggests they be lowered by offering prizes instead of patents. Stiglitz discusses the idea of using  foreign aid  assistance funds to finance prizes as it would provide greater foreign aid than what funds are being used for currently. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6257", "text": "Psychiatry Under the Influence: Institutional Corruption, Social Injury, and Prescriptions for Reform  is a 2015 book by  Robert Whitaker  and Lisa Cosgrove. The book discusses the use of  psychiatric medication  in the United States and is critical of the  drug industry  influence on the field of  psychiatry . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6258", "text": "This article about a  psychology  book is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6259", "text": "The Regulatory Affairs Journal Pharma (RAJ Pharma)  is an  English language  international pharmaceutical information and analysis service published by  Informa plc . First published as a monthly print  magazinel  in 1992, it includes articles covering worldwide regulatory affairs within the pharmaceutical industry. The journal has now developed into   an online global  business intelligence  and analysis service. It provides daily news and analysis of developments in  regulation  of the  pharmaceutical industry  worldwide, including regulatory agencies and legislation, application requirements and guidelines,  patents  and  intellectual property , research and development, international  harmonisation , paediatric legislation,  pharmacovigilance  and  pharmacoeconomics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6260", "text": "Articles are written by a four-person in-house editorial team, sourced from locally based correspondents from around the world, and independent contributors from legal firms, pharmaceutical companies and regulatory agencies. [ 1 ]  The RAJ Pharma editorial board comprises a range of regulatory experts from industry and agencies alike. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6261", "text": "A sister publication,  RAJ Devices , covers regulatory affairs within the medical technology industry. It was established in 1995. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6262", "text": "This business magazine or journal-related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6263", "text": "See tips for writing articles about magazines . Further suggestions might be found on the article's  talk page ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6264", "text": "A  remote data entry  ( RDE ) system is a computerized system designed for the  collection of data  in electronic format. The term is most commonly applied to a class of software used in the  life sciences  industry for collecting patient data from participants in  clinical research  studies\u2014research of new drugs and/or medical devices."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6265", "text": "Typically, RDE systems provide:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6266", "text": "The development of RDE systems started in the mid- to late-1980s as software installed locally on  portable computers  with  modems .  It has largely been replaced by a newer generation of software called  electronic data capture , or EDC, that provides the same type of functionality over the Internet using web pages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6267", "text": "Sanatogen  was a \" brain tonic \" invented by the Bauer Chemical Company, in  Germany  in  1898  and sold worldwide [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6268", "text": "In the US it was advertised as a \"nerve revitaliser\". The medicine was prohibited in  Australia  in 1915 during   World War I  and a British-made substitute \"Sanagen\" was introduced to the Australian market the following year, claiming to be \"identical to Sanatogen\". The product became fashionable in  China  in the early 20th century and won the favour of many renowned people. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6269", "text": "The indications or uses for this product provided by the manufacturer were: \"Food tonic. A concentrated nutrient with tonic properties... easily digested and absorbed and is recommended as an effective means of reinforcing the daily diet of anaemic and convalescent patients.\" [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6270", "text": "The ingredients have been described as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6271", "text": "The product was marketed extensively in Europe and the US with such  slogans  as \"Endorsed by over 20,000 Physicians\". [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6272", "text": "In 1913 the product was at the centre of a  United States Supreme Court  case:  Bauer & Cie. v. O'Donnell . The product was also the subject of intellectual property litigation worldwide. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6273", "text": "The Sanatogen brand persists in the UK as a  fortified wine , with an alcohol content of 15%. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6274", "text": "Sanatogen is also the name of a modern  multivitamin  product manufactured by  Fisons  before being sold to  Roche , and later  Bayer . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6275", "text": "Scrip Intelligence (Scrip)  is an  English language  international  pharmaceutical  news, analysis and data service. First published as a weekly print  newsletter  in March 1972, Scrip included articles on side-effects, regulatory changes and  mergers and acquisitions ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6276", "text": "Scrip World Pharmaceutical News was initially published by advertising company  J Walter Thomson  but was bought by Dr Philip J Brown in 1976 for \u00a32000, who founded PJB Publishing. Brown sold Scrip, associated titles, and his company to  Informa  for \u00a3150 million in 2003. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6277", "text": "Scrip has now developed into an online global pharma news and analysis service. It provides daily news and analysis on the  biotechnology  and pharmaceutical industry including areas such as policy & regulation, business news,  research & development ,  generics ,  drug delivery , and  clinical trials ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6278", "text": "In 2022, Informa sold its Pharma Intelligence division, including  Scrip , to  Warburg Pincus . [ 4 ]  The business was renamed Citeline. Later in 2022, Citeline was acquired by Norstella."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6279", "text": "The Scrip readership has grown to over 100,000 worldwide, [ 5 ]  half of which are in Europe. Scrip is read by managers and executives working across all disciplines in pharmaceutical and biotech companies worldwide. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6280", "text": "Scrip has a large independent editorial team of 21. The journalists are based throughout the world in  Washington, D.C. ,  Tokyo ,  India , and  London  to ensure a global emphasis to the latest news stories."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6281", "text": "Sinecatechins  ( USAN , trade names  Veregen  and  Polyphenon E ) is a specific  water extract of green tea leaves  from  Camellia sinensis  that is the  active ingredient  in an ointment approved by the FDA in 2006 as a  botanical drug  to treat  genital warts . [ 1 ] [ 2 ] [ 3 ]   Sinecatechins are mostly  catechins , 55% of which is  epigallocatechin gallate . [ 4 ]   It was the first botanical drug approved by the US FDA. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6282", "text": "A  source document  is a document in which data collected for a clinical trial is first recorded. This data is usually later entered in the  case report form . The  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use  (ICH-GCP) guidelines define source documents as \"original documents, data, and records.\" [ 1 ]  Source documents contain source data, which is defined as \"all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.\" [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6283", "text": "The  Food and Drug Administration  (FDA) does not define the term \"source document\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6284", "text": "A  standard operating procedure  ( SOP ) is a set of step-by-step instructions compiled by an  organization  to help workers carry out routine operations. [ 1 ]  SOPs aim to achieve efficiency, quality output, and uniformity of performance, while reducing  miscommunication  and failure to comply with  industry regulations . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6285", "text": "Some  military  services (e.g., in the  U.S.  and the  UK ) use the term  standing operating procedure , [ 2 ]  since a military SOP refers to a unit's unique procedures, which are not necessarily standard to another unit. The word \"standard\" could suggest that only one (standard) procedure is to be used across all units. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6286", "text": "The term is sometimes used facetiously to refer to practices that are unconstructive, yet the norm. In the  Philippines , for instance, \"SOP\" is the term for pervasive corruption within the government and its institutions. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6287", "text": "In clinical research, the  International Council for Harmonisation  (ICH) defines SOPs as \"detailed, written instructions to achieve uniformity of the performance of a specific function\". SOPs usually get applied in pharmaceutical processing and for related clinical studies. There the focus is always set on repeated application of unchanged processes and procedures and its documentation, hence supporting the segregation of origins, causes and effects. Further application is with  triage , when limited resources get used according to an assessment on ranking, urgence and staffing possibilities. [ 5 ]   Study director is mainly responsible for SOPs. The Quality Assurance Unit are individuals who are responsible for monitoring whether the study report and tests are meeting the SOP. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6288", "text": "SOPs can also provide employees with a reference to common business practices, activities or tasks. New employees use an SOP to answer questions without having to interrupt supervisors to ask how an operation is performed. The international quality standard  ISO 9001  essentially requires the determination of processes (documented as standard operating procedures) used in any manufacturing process that could affect the quality of the product. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6289", "text": "Procedures are extensively employed to assist with working safely. They are sometimes called \"safe work methods statements\" (SWMS, pronounced as 'swims'). Their development is usually preceded by various methods of analyzing tasks or jobs to be performed in a workplace, including an approach called  job safety analysis , in which hazards are identified and their control methods described. Procedures must be suited to the literacy levels of the user, so the readability of procedures is important. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6290", "text": "Franco Stevanato (Executive Chairman of the Board of Directors)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6291", "text": "Stevanato Group  is an Italian multinational company headquartered in  Piombino Dese ,  Padua  \u2013  Italy . \nFounded in 1949, it is also active in the  glass tube  forming technology and inspection systems sector. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6292", "text": "The Group is the first worldwide producer of  insulin  cartridges for diabetes treatment [ 4 ]  and design and production of machinery for glass tubing converting."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6293", "text": "Nuova Ompi, the first company of the Group, was founded in  Venice  in 1949 by Giovanni Stevanato, father of the actual president  Sergio Stevanato . In 1959 the company moved to its current location: Piombino Dese, Padua \u2013 Italy.\nA second company (SPAMI) was established in 1971, specialized in the design and construction of high-speed precision machines and complete lines for the production and control of glass tube containers for pharmaceutical use.\nIn 1993 Stevanato Group purchased Alfamatic ( Latina, Italy ) and with the acquisition of Medical Glass ( Bratislava ) in 2005, the Group opened to the internationalization. \nIn 2007 the Group acquired Optrel ( Vicenza ), an Italian company specialized in the design and the construction of inspection machines for the pharmaceutical industry. In addition, Nuova Ompi launched the EZ-fill brand, starting with the production of sterile syringes. [ 5 ] \nIn 2008 a new production plant called \"Ompi North America\" was built in  Monterrey, Mexico . [ 6 ]  \nTwo years later the EZ-fill concept was extended to vials and cartridges. [ 7 ] \nIn 2012 the Group doubled the Monterrey plant started the construction of a new plant in  China  ( Zhangjiagang  -  Shanghai  area).\nIn 2013 the Group acquired InnoScan, a Danish manufacturer of inspection machines for the pharmaceutical industry.  In 2016 the Group acquired the Danish company SVM Automatik specialized in assembly, packaging and serialization solutions [ buzzword ]  for the pharmaceutical industry and the operative units of Balda Group, specialized in high quality and high precision plastic solutions [ buzzword ]  for diagnostic, pharmaceutical and medical device applications. In 2017 the third greenfield - Ompi do Brasil - plant was opened in  Sete Lagoas ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6294", "text": "Stevanato Group comprises two operational divisions: Pharmaceutical Systems with Ompi specialized in glass primary packaging and Balda, focused on specialty plastics and delivery devices; Engineering Systems with Spami, Optrel, InnoScan and SVM, specialized in glass processing, inspection systems, assembly, and packaging solutions. [ buzzword ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6295", "text": "Pharmaceutical Systems Division"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6296", "text": "With locations throughout the world (Italy, Slovakia, Germany, Mexico, USA, China, Brazil), the Pharmaceutical Systems Division produces both traditional products such as vials and ampoules, and strong growth products such as syringes and cartridges for   autoinjection systems . [ 8 ] \nWith the acquisition of the operative units of Balda, the division is also specialized now in high quality and high precision plastic solutions [ buzzword ] , developed and manufactured to meet customers\u2019 specific needs. Balda's healthcare segment is active in diagnostic, pharmaceutical and medical device applications. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6297", "text": "Engineering Systems Division"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6298", "text": "The Engineering Systems Division consists of SPAMI (with its brand Optrel), InnoScan and SVM Automatik.\nSpami designs and manufactures machinery for glass tubing converting for the production of vials, cartridges, syringes, ampoules and special devices.\nOptrel and InnoScan refer to the  visual inspection  area focused on the inspection machines market for the  pharmaceutical industry . [ 10 ] \nSVM Automatik is a company specialized in assembly, packaging and serialization solutions [ buzzword ]  for the pharmaceutical industry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6299", "text": "Nuova Ompi"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6300", "text": "Nuova Ompi is located in Piombino Dese (Padua) and Latina \u2013 Italy and produces pharmaceutical glass primary packaging for injectable use. It manufactures both bulk and sterile vials, cartridges, syringes. The company started supplying sterile syringes (EZ-fill Syringes) in 2007 and then it extended the ready-to-fill concept to vials and cartridges in 2010 (EZ-fill Vials & Cartridges)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6301", "text": "Medical Glass"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6302", "text": "Medical Glass was established in Bratislava in 1991 and acquired by the Group in 2005. Today it produces glass ampoules and vials."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6303", "text": "Ompi North America"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6304", "text": "The plant is located in Monterrey, Mexico. It was built in 2008 and doubled in 2012 in order to serve the American market with the support of the sales office situated in Newtown, Pennsylvania (USA)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6305", "text": "Ompi of China"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6306", "text": "The sales office is situated in Zhangjiagang, about 150\u00a0km from Shanghai. The greenfield facility construction started at the end of 2012 and the plant started production in November 2013."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6307", "text": "Ompi do Brasil"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6308", "text": "The plant is situated in Sete Lagoas, Minas Gerais, Brazil.  The greenfield facility construction started at the beginning of 2016 and the plant started production in June 2017."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6309", "text": "Balda Medical"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6310", "text": "Located in Bad Oeynhausen (Germany), it was founded in 1908 as a camera manufacturer and developed a focus on precision injection molding in the fifties. After a diversification in mobile telephony, medical and automotive, the company focused in the medical, healthcare, diagnostic and pharmaceutical segment. In 2016 it was acquired by Stevanato Group. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6311", "text": "Balda C. Brewer and Balda Precision"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6312", "text": "Based in Oceanside and Ontario (US), they have been acquired by Stevanato Group in 2016 and are specialized in injection molding for medical market and turning machine service supporting the Aerospace, Medical, Electronic and Consumer industries. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6313", "text": "SPAMI"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6314", "text": "The company refers to the Engineering Systems Division of the Group and was founded in 1971. It is located in Piombino Dese (Padua) \u2013 Italy. It produces glass tubing converting machines and inspection machines for pharmaceutical glass containers. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6315", "text": "InnoScan"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6316", "text": "The company joined the Group in 2013 and it produces high-speed inspection machines for the pharmaceutical industry. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6317", "text": "SVM"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6318", "text": "The Danish company SVM Automatik has been acquired by Stevanato Group in 2016. It is specialized in assembly, packaging and serialization solutions [ buzzword ]  for the pharmaceutical industry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6319", "text": "Ompi of America"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6320", "text": "The newest manufacturing site is in  Fishers, Indiana , United States.  The greenfield facility construction started at the beginning of 2021 for a 200,000-square foot facility in the Fishers Life Science and Innovation Park. [ 15 ]  The site opened in early 2024 and will serve the American market with ready-to-use (\"EZ-Fill\") [ 16 ]  syringes and vials. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6321", "text": "Tigers  (initially titled  White Lies ) [ 2 ]  is a 2014 Indian  drama film  directed by  Danis Tanovi\u0107 , and produced as a joint production between Cinema Time, French production company ASAP Films and  Sikhya Entertainment ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6322", "text": "The film is inspired by an episode in Pakistan during the 1990s, a repetition of the  Nestl\u00e9 baby milk scandal  in 1970s that occurred in developing countries. A Pakistani salesman named Syed Aamir Raza Hussain became a whistle-blower against his former employer  Nestl\u00e9 ; in 1999, two years after he left Nestl\u00e9, Hussain released a report in association with the non-profit organisation  International Baby Food Action Network , in which he alleged that Nestl\u00e9 was encouraging doctors to push its infant formula products over breastfeeding. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6323", "text": "The film features  Emraan Hashmi  in the leading role as Ayan, based on Hussain, a pharmaceutical representative in Pakistan who discovers his new company's baby formula has killed hundreds of children, after which he begins a lone and dangerous battle against the company. [ 4 ]  The film began filming in 2013 in  Punjab, India , and had its premiere in September 2014 at the  2014 Toronto International Film Festival . [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6324", "text": "The film faced multiple delays during its initial release. After Tanovic decided to fictionalise Raza's battle, he renamed Nestl\u00e9 as  Lasta  in the film and cast Hashmi after watching  Shanghai  (2012).  Tigers  was publicly released on the streaming platform  ZEE5  on 21 November 2018. [ 7 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6325", "text": "Tilray Brands, Inc.  is an American  pharmaceutical ,  cannabis -lifestyle and consumer packaged goods company, incorporated in the United States, headquartered in New York City. [ 1 ] [ 2 ]  Tilray also has operations in Canada, Australia, New Zealand, [ 3 ] [ 4 ]  and Latin America, [ 5 ]  with growing facilities in Germany and Portugal. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6326", "text": "In December 2020, the company announced a  merger  with  Aphria , and will operate under the Tilray name and its  ticker symbol  on  NASDAQ [ 8 ]  and the  Toronto Stock Exchange . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6327", "text": "Tilray also owns several breweries and is the 5th largest craft beer company in the US."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6328", "text": "Founded in 2014, Tilray was originally incorporated under the umbrella of Seattle-based  Privateer Holdings  and was one of Canada's first licensed producers. [ 10 ] [ 11 ]  At the end of 2014, it secured the first institutional investment in the cannabis industry from Founders Fund, a San Francisco-based venture capital fund. [ 10 ]  In 2016, it became the first cannabis company to conduct a clinical trial approved by Health Canada. [ 10 ]  The trial evaluated the therapeutic potential of medical cannabis. [ 10 ]  In January 2017, Tilray was certified for  good manufacturing practices . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6329", "text": "By October 2018, the company had raised $1.1 billion. [ 10 ]  In July 2018, it became the first cannabis company to trade publicly on a major U.S. stock exchange, [ 13 ]  opening on the  NASDAQ  exchange at a price of $17 per share, which increased in September 2018 to $214 per share, and then descended to $29 per share by August 2019. [ 14 ] [ 15 ]  The  IPO  raised  US$153  million. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6330", "text": "In September 2018, Tilray became the first Canadian cannabis company to legally export medical cannabis to the U.S. for a  clinical trial . [ 17 ]  In December 2018, the company signed a deal with  Novartis  subsidiary  Sandoz  to sell, distribute and co-brand Tilray's non-smokeable/non-combustible  medical cannabis  products in legal markets worldwide. [ 18 ]  On June 19, 2018, Tilray announced the launch of High Park Company which operates in the adult recreational cannabis market to establish unique adult-use brands in Canada. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6331", "text": "Since September 2022, Tilray has been licensed by the Polish and Italian Ministries of Health to import and distribute THC25 medical cannabis throughout Poland and Italy. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6332", "text": "In August 2023, Tilray acquired eight beverage brands in addition to the breweries of the brands from Anheuser-Busch for $85 million. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6333", "text": "In 2018, Tilray announced it had entered into global alliance with Sandoz, a division of Novartis to co-brand and distribute non-combustible medical cannabis products in global markets where it is legally authorized.  The Globe and Mail  dubbed this partnership as \u2018big-pharma\u2019s first foray into cannabis\u2019. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6334", "text": "Also in 2018, Tilray announced a $100-million joint venture with the world's largest brewer,  AbInBev  to research non-alcohol  tetrahydrocannabinol  (THC) and  cannabidiol  (CBD)-infused beverages, through their respective subsidiaries,  Labatt Breweries  and High Park Company. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6335", "text": "In 2019, Tilray signed a $250 million revenue-sharing deal with U.S. based brand company,  Authentic Brands Group , to leverage ABG brand names, such as  Juicy Couture ,  Greg Norman , and  Nine West  to create cannabis products. ABG has a portfolio of over 50 brands. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6336", "text": "In February 2019, Tilray acquired Manitoba Harvest, a hemp foods manufacturer, for $317 million from Compass Diversified Holdings. [ 25 ]  The acquisition allowed Tilray to use Manitoba Harvest's retail distribution network to enter the U.S. CBD market. [ 26 ]  Manitoba Harvest's products are available in approximately 13,000 U.S. stores and 3,600 in Canada. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6337", "text": "Also in 2019, Tilray entered into an agreement with Natura Naturals Holdings which owns 155,000 square feet of licensed cultivation  greenhouses  in  Leamington, Ontario . [ 27 ]  The acquisition doubled the cultivation ability of the company in Canada. [ 28 ]  In May 2020, Tilray announced closure of the High Park Gardens site (previously Natura Naturals) for  cost reductions . [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6338", "text": "In July 2019, Tilray acquired U.K.-based Smith & Sinclair to develop CBD-infused edibles. [ 30 ]  In August 2019, Tilray acquired Alberta cannabis retailer, Four20. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6339", "text": "On April 10, 2023, Tilray announced an agreement to acquire Hexo Corp. for approximately US$56 million. Hexo shareholders will receive 0.4352 of a share of Tilray common stock in exchange for each share held. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6340", "text": "On 15 December 2020, Aphria conducted a  reverse acquisition  of Tilray, creating the largest global cannabis company by revenue and geographic reach. [ 10 ] [ 8 ]  The  chief executive officer  (CEO) of Aphria, Irwin D. Simon, stated that the merger strategy was to capture Tilray's business assets and public trading exposure in the United States and its  free trade  abilities in Europe, enabling potential for becoming a global operation. [ 8 ]  Irwin was named as CEO and  chairman of the board  for the merged company, and Tilray CEO, Brendan Kennedy, will be a member of the  board of directors . [ 8 ]  The merged companies will keep Tilray's name and trade under the Tilray ticker symbol, TLRY, on the NASDAQ exchange. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6341", "text": "By combining assets, the new Tilray company will develop craft beer and cannabis-infused beverages in partnership with  Anheuser-Busch InBev , and have branded  hemp  and  cannabidiol  products. [ 8 ]  According to one source, the world market potential for cannabis products is $94 billion by 2025. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6342", "text": "Tilray also owns several breweries:  Montauk Brewing Company ,  Good Supply Beer ,  10 Barrel Brewing Company ,  Square Mile Cider Company , and  Truss Beverage Co. [ 33 ]  Tilray's beer division ranked No. 9 on the Brewers Association's annual report of the US nation's top craft companies based on beer sales volume in 2022. [ 34 ] [ 35 ] [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6343", "text": "Founded in 1999 in  Alpine, California , the Alpine Beer Company produced award-winning  sour beers . [ 37 ] [ 38 ]  The company would be acquired by the  Green Flash Brewing Company  in 2014 and continued existence as a brand. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6344", "text": "Founded in a former  ice factory  in 1998 to fill the niche of a  Long Island  focused  Microbrewery . [ 40 ]  The company's flagship \"Toasted Lager\" won a gold medal at the 2006  World Beer Cup  in the American-Style  Amber Lager  category. [ 41 ]  The company distributed their beer to 19 states and  Washington D.C.  before being purchased by Anheuser-Busch InBev on February 5, 2014, for nearly $24 million. Citing financial shortfall in part due to the  2023 Bud Light boycott , Anheuser-Busch sold the brand to Tilray in August 2023. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6345", "text": "Founded in  Breckenridge, Colorado  in 1990 as the state's third craft brewery before moving most of their production to  Denver  in 1992. [ 43 ] [ 44 ]  In 2010 the company merged with the Wynkoop Brewing Company and purchased the Phantom Canyon Brewing company to become the Breckenridge-Wynkoop LLC. [ 45 ]  In 2015 they moved to a new facility in  Littleton, Colorado  and was producing 70,000 barrels of beer per year. [ 46 ]  On December 22, 2015, Anheuser-Busch InBev announced its intent to purchase just Breckenridge Brewery from Breckenridge-Wynkoop LLC, splitting the companies with the purchase finalizing in 2016. [ 47 ]   Anheuser-Busch sold the brand to Tilray in August 2023. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6346", "text": "Founded in 2002 in  Vista, California  before moving to  San Diego  in 2011. [ 48 ]  The company operated a 44,000 barrel per year facility in San Diego in 2011, and a 100,000 barrel per year facility in  Virginia Beach, Virginia  in 2013. [ 49 ] [ 50 ]  By 2014 their beer was being sold in all 50 states, as well as internationally and they purchased the  Alpine Beer Company . [ 51 ] [ 39 ]  The company peaked in 2016 when it was the 37th largest producer of beer in the United States, afterwards the company began a rapid decline due to the rise of rival craft beer producers. [ 52 ]  In 2018 they cut distribution internationally and to 42 states and laid off 15% of their workforce and defaulted on their loans to construct the Virginia Beach facility. [ 53 ] [ 54 ]  The company would be sold to a group of private investors by the end of the year, who would sell the company to Tilray in 2020. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6347", "text": "Founded in  Seattle  in 1981, Redhook specializes in the production of  India pale ales . [ 56 ]  A founding member of the  Craft Brew Alliance , the company's distribution rights were bought by  Cisco Brewers  in 2018. [ 57 ]  In 2019 the Craft Brew Alliance, and its properties, were acquired by Anheuser-Busch InBev with Redhook operating as a brand. [ 58 ]  Anheuser-Busch sold the brand to Tilray in August 2023. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6348", "text": "A Belgian-Style, spiced  Witbeer  brand introduced as a seasonal beer by  Anheuser-Busch  in February 2006, however, the beer's popularity quickly grew and was used as a rival to  Molson Coors '  Blue Moon . The brand entered a decline following a failed rebranding effort in 2017 and, citing financial shortfall in part due to the  2023 Bud Light boycott , Anheuser-Busch sold the brand to Tilray in August 2023. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6349", "text": "A  craft brewery  founded in 1997 by Freddy Bensch and Kevin McNerney in  Atlanta ,  Georgia . [ 59 ]  SweetWater's beers are  unpasteurized  and distribution is limited to select states. SweetWater would be acquired by  Aphria  In November 2020 for $300 million. [ 60 ]  Later, in December 2020, Aphria merged with Tilray bringing SweetWater under Tilray's ownership. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6350", "text": "Founded in 1984 in  Portland, Oregon , the company primarily produced  Hefeweizen . [ 61 ]  In 2007 Widmer  and Redhook announced that they were going to merge to form the Craft Brewers Alliance, which was renamed to the  Craft Brew Alliance  in 2012. [ 62 ]   The goal of which was to offer smaller regional beers a national distribution network. In 2019 Widmer and the whole of the Craft Brew Alliance was bought by Anheuser-Busch InBev, with Widmer operating as a brand. [ 58 ]  Anheuser-Busch sold the brand to Tilray in August 2023. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6351", "text": "HiBall Energy was founded in 2005 by Todd Berardi and was based out of  San Francisco . They produced organic  energy drinks  and were purchased by Anheuser-Busch on July 20, 2017, in an effort to diversify into non-alcoholic beverages. Their products were low in sugar, produced with  fair-trade  ingredients, and were available at 14,000 locations prior to its acquisition by Anheuser-Busch. [ 63 ]  On May 19, 2023, Anheuser-Busch announced that they were discontinuing HiBall alongside their  box wine  brand  Babe Wine , stating that they will be focusing on their \"mega brands\" instead. This came despite HiBall having a dedicated consumer fan-base that heavily protested the discontinuation. An Anheuser-Busch spokesmen stated that the discontinuation had nothing to do with the  2023 Bud Light boycott . [ 64 ] [ 65 ]   Anheuser-Busch sold the HiBall brand to Tilray alongside seven of their beer brands in August 2023. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6352", "text": "In partnership with  University of Sydney ,  NSW Government , Chris O'Brien Lifehouse, Tilray participated in a  clinical trial  testing the efficacy and tolerability of medical cannabis as a possible treatment for the  side effects  of  chemotherapy . [ 67 ]  Led by  The Hospital for Sick Children , in Toronto, Canada, Tilray provided a  cannabidiol  (CBD) oil product available in Canada to test the efficacy and tolerability of medical cannabis oil as a possible treatment for pediatric epilepsy ( Dravet syndrome ). [ 68 ]  In partnership with the  University of British Columbia , Tilray provided medical cannabis products used to test medical cannabis as a possible treatment for  post-traumatic stress disorder . [ 69 ]  In partnership with the Grupo Espa\u00f1ol de Investigaci\u00f3n\u00a0en Neurooncolog\u00eda GEINO, in Spain, Tilray supplied medical cannabis products for the trial testing the efficacy and tolerability of medical cannabis as a possible treatment for  glioblastoma . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6353", "text": "In 2019, Tilray signed an agreement with Cannamedical Pharma GmbH to export $3.3 million worth of medical cannabis from its Portugal facility to Germany, marking Tilray's first export from Tilray Portugal Unipessoal, Lda. [ 70 ]  Tilray also has a research partnership with  Coimbra University  in Portugal. [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6354", "text": "In August 2019, Tilray announced a partnership with  New York University  to study the potential ability of CBD to treat  alcohol use disorder  and post-traumatic stress disorder. [ 72 ]  In partnership with New York University, Tilray supplied CBD for a clinical trial studying its possible efficacy for treating disorders caused by  breast cancer  treatments. [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6355", "text": "To ensure the best possible microbiological quality of medicinal cannabis flowers, treatment with ionizing radiation has become established worldwide to reduce bacterial counts. This is of great importance to protect patients, some of whom are highly vulnerable. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6356", "text": "Title 21 CFR Part 11  is the part of  Title 21  of the  Code of Federal Regulations  that establishes the United States  Food and Drug Administration  (FDA) regulations on electronic records and  electronic signatures  (ERES).  Part 11 , as it is commonly called, defines the criteria under which electronic records and electronic signatures are considered trustworthy, reliable, and equivalent to paper records (Title 21 CFR Part 11 Section 11.1 (a)). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6357", "text": "21 CFR, Part 11 applies to  drug makers ,  medical device  manufacturers,  biotech  companies,  biologics  developers,  CROs , and other FDA-regulated industries, with some specific exceptions. [ 2 ]  It requires that they implement controls, including audits, system validations,  audit trails , electronic signatures, and documentation for software and  systems  involved in processing the electronic data that FDA predicate rules require them to maintain. A predicate rule is any requirement set forth in the Federal Food, Drug and Cosmetic Act, the Public Health Service Act, or any FDA regulation other than Part 11. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6358", "text": "The rule also applies to submissions made to the FDA in electronic format (e.g., a  New Drug Application ) but not to paper submissions by electronic methods (i.e.,  faxes ).  It specifically does not require the 21 CFR Part 11 requirement for record retention for trackbacks by food manufacturers.  Most food manufacturers are not otherwise explicitly required to keep detailed records, but electronic documentation kept for  HACCP  and similar requirements must meet these requirements."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6359", "text": "Broad sections of the regulation have been challenged as \"very expensive and for some applications almost impractical\", [ 4 ]  and the FDA has stated in guidance that it will exercise enforcement discretion on many parts of the rule.  This has led to confusion on exactly what is required, and the rule is being revised. In practice, the requirements on access controls are the only part routinely enforced  [ citation needed ] .  The \"predicate rules\", which required organizations to keep records in the first place, are still in effect. If electronic records are illegible, inaccessible, or corrupted, manufacturers are still subject to those requirements."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6360", "text": "If a regulated firm keeps \"hard copies\" of all required records, those paper documents can be considered the authoritative document for regulatory purposes, and the computer system is not in scope for electronic records requirements\u2014though systems that control processes subject to predicate rules still require validation. [ 5 ]   Firms should be careful to make a claim that the \"hard copy\" of required records is the authoritative document. For the \"hard copy\" produced from electronic source to be the authoritative document, it must be a complete and accurate copy of the electronic source. The manufacturer must use the hard copy (rather than electronic versions stored in the system) of the records for regulated activities. The current technical architecture of computer systems increasingly makes the Part 11, Electronic Records; Electronic Signatures \u2014 Scope and Application for the complete and accurate copy requirement extremely mandatory. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6361", "text": "Various keynote speeches by FDA insiders early in the 21st century (in addition to high-profile audit findings focusing on computer system compliance) resulted in many companies scrambling to mount a defense against rule enforcement that they were procedurally and technologically unprepared for.  Many software and instrumentation vendors released Part 11 \"compliant\" updates that were either incomplete or insufficient to fully comply with the rule. Complaints about the wasting of critical resources, non-value added aspects, in addition to confusion within the drug, medical device, biotech/biologic and other industries about the true scope and enforcement aspects of Part 11 resulted in the FDA release of:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6362", "text": "This document was intended to clarify how Part 11 should be implemented and would be enforced.  But, as with all FDA guidances, it was not intended to convey the full force of law\u2014rather, it expressed the FDA's \"current thinking\" on Part 11 compliance.  Many within the industry, while pleased with the more limited scope defined in the guidance, complained that, in some areas, the 2003 guidance contradicted requirements in the 1997 Final Rule."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6363", "text": "In May 2007, the FDA issued the final version of their guidance on computerized systems in clinical investigations. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6364", "text": "This guidance supersedes the guidance of the same name dated April 1999; and supplements the guidance for industry on Part 11, Electronic Records; Electronic Signatures \u2014 Scope and Application and the Agency's international harmonization efforts when applying these guidances to source data generated at clinical study sites."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6365", "text": "FDA had previously announced that a new Part 11 would be released late 2006.  The Agency has since pushed that release date back.  The FDA has not announced a revised time of release.  John Murray, member of the Part 11 Working Group (the team at FDA developing the new Part 11), has publicly stated that the timetable for release is \"flexible\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6366", "text": "21 CFR Part 11 has the following benefits:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6367", "text": "The  UCSF Library  is the  library  of the  University of California, San Francisco . It is one of the world's foremost libraries in the  health sciences ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6368", "text": "The main branch (Kalmanovitz Library) is located at the Parnassus campus, with secondary locations at the  Mission Bay campus  in the Rutter Center and Mission Hall. Additionally, the library is affiliated with the ZSFG Library at the  Zuckerberg San Francisco General Hospital , the Fishbon Memorial Library at  UCSF Medical Center , the UCSF Fresno Medical Library at UCSF Fresno Medical Education Program, the UCSF Patient Health Library at Mount Zion Medical Center, the Medical Library at  Benioff Children's Hospital Oakland , and the Veterans Affairs Medical Center Library at the  San Francisco VA Medical Center ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6369", "text": "The main branch hosts artwork by  Hiroshige ,  Georges Mathieu ,  Helaman Ferguson , Fred Reichman,  R.C. Gorman ,  Bill Woodrow , Robert Cremean, and  Sarah Sze ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6370", "text": "The UCSF Archives and Special Collections is part of the UCSF Library located on the Parnassus campus in San Francisco, California. The UCSF archives serve as the official repository for the preservation of selected records, printed and born-digital materials, and realia generated by or about UCSF, including the School of Medicine, School of Nursing, School of Pharmacy, School of Dentistry, the Graduate Division, and the UCSF Medical Center. [ 1 ]  The archives also include rare and unique materials that support research and teaching in the history of the health sciences. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6371", "text": "The institutional archives were officially established in 1963 by UC President  Clark Kerr . He mandated the creation of both a records management system and an archives program at UCSF. The medical history rare book collection began in the 1930s, before the establishment of the institutional archives. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6372", "text": "Significant rare book collections and archival holdings include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6373", "text": "The UCSF  Industry Documents Library  (IDL) is a digital archive of internal tobacco, drug, food, chemical, and fossil fuel corporate documents, acquired largely through litigation, which illustrate industry efforts to influence policies and regulations meant to protect public health. The mission of the UCSF Industry Documents Library is to \"identify, collect, curate, preserve, and make freely accessible internal documents created by industries and their partners which have an impact on public health, for the benefit and use of researchers, clinicians, educators, students, policymakers, media, and the general public at UCSF and internationally\". [ 8 ]  The collection includes the   Truth Tobacco Industry Documents  and the  Drug Industry Document Archive . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6374", "text": "Wonder Drug: The Secret History of Thalidomide in America and Its Hidden Victims  is a nonfiction book authored by  Jennifer Vanderbes  and published by  Random House  in 2023. It tells the story of how  Frances Oldham Kelsey  of the  Food and Drug Administration  (FDA) found flaws in  thalidomide  research. Contrary to the initial opinion that the FDA declined the drug a license for  morning sickness  in pregnancy and the US was therefore spared the  thalidomide scandal , Vanderbes claims that the drug was still widely distributed there in the late 1950s and 1960s. As a result, many more babies were affected by  phocomelia  than originally believed. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6375", "text": "This article about a  medical book  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6376", "text": "Chirality  ( / k a\u026a \u02c8 r \u00e6 l \u026a t i / ) is a property of  asymmetry  important in several branches of science. The word  chirality  is derived from the  Greek   \u03c7\u03b5\u03af\u03c1  ( kheir ), \"hand\", a familiar chiral object."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6377", "text": "An object or a system is  chiral  if it is distinguishable from its  mirror image ; that is, it cannot be  superposed  (not to be confused with  superimposed ) onto it.  Conversely, a mirror image of an  achiral  object, such as a sphere, cannot be distinguished from the object. A chiral object and its mirror image are called  enantiomorphs  (Greek, \"opposite forms\") or, when referring to molecules,  enantiomers . A non-chiral object is called  achiral  (sometimes also  amphichiral ) and can be superposed on its mirror image."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6378", "text": "The term was first used by  Lord Kelvin  in 1893 in the second  Robert Boyle Lecture  at the  Oxford University Junior Scientific Club  which was published in 1894:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6379", "text": "I call any geometrical figure, or group of points, 'chiral', and say that it has chirality if its image in a plane mirror, ideally realized, cannot be brought to coincide with itself. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6380", "text": "Human  hands  are perhaps the most recognized example of chirality. The left hand is a non-superposable mirror image of the right hand; no matter how the two hands are oriented, it is impossible for all the major features of both hands to coincide across all axes. [ 2 ]  This difference in symmetry becomes obvious if someone attempts to shake the right hand of a person using their left hand, or if a left-handed glove is placed on a right hand. In mathematics,  chirality  is the property of a figure that is not identical to its mirror image."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6381", "text": "In  mathematics , a figure is chiral (and said to have chirality) if it cannot be mapped to its mirror image by  rotations  and  translations  alone.  For example, a right shoe is different from a left shoe, and clockwise is different from anticlockwise. See [ 3 ]  for a full mathematical definition."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6382", "text": "A chiral object and its mirror image are said to be enantiomorphs. The word  enantiomorph  stems from the Greek  \u1f10\u03bd\u03b1\u03bd\u03c4\u03af\u03bf\u03c2  ( enantios ) 'opposite' +  \u03bc\u03bf\u03c1\u03c6\u03ae  ( morphe ) 'form'.  A non-chiral figure is called achiral or amphichiral."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6383", "text": "The  helix  (and by extension a spun string, a screw, a propeller, etc.) and  M\u00f6bius strip  are chiral two-dimensional objects in three-dimensional ambient space. The J, L, S and Z-shaped  tetrominoes  of the popular video game  Tetris  also exhibit chirality, but only in a two-dimensional space."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6384", "text": "Many other familiar objects exhibit the same chiral symmetry of the human body, such as gloves, glasses (sometimes), and shoes. A similar notion of chirality is considered in  knot theory , as explained below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6385", "text": "Some chiral three-dimensional objects, such as the helix, can be assigned a right or left handedness, according to the  right-hand rule ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6386", "text": "In  geometry , a figure is achiral if and only if its  symmetry group  contains at least one  orientation-reversing  isometry.\nIn two dimensions, every figure that possesses an  axis of symmetry  is achiral, and it can be shown that every  bounded  achiral figure must have an axis of symmetry.\nIn three dimensions, every figure that possesses a  plane of symmetry  or a center of symmetry is achiral. There are, however, achiral figures lacking both plane and center of symmetry.\nIn terms of  point groups , all chiral figures lack an improper axis of rotation (S n ). This means that they cannot contain a center of inversion (i) or a mirror plane (\u03c3). Only figures with a point group designation of C 1 , C n , D n , T, O, or I can be chiral."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6387", "text": "A  knot  is called  achiral  if it can be continuously deformed into its mirror image, otherwise it is called chiral. For example, the  unknot  and the  figure-eight knot  are achiral, whereas the  trefoil knot  is chiral."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6388", "text": "In physics, chirality may be found in the  spin  of a particle, where the handedness of the object is determined by the direction in which the particle spins. [ 4 ]  Not to be confused with  helicity , which is the projection of the spin along the linear momentum of a subatomic particle, chirality is an intrinsic quantum mechanical property, like spin. Although both chirality and helicity can have left-handed or right-handed properties, only in the massless case are they identical. [ 5 ]  In particular for a massless particle the helicity is the same as the chirality while for an antiparticle they have opposite sign."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6389", "text": "The  handedness  in both chirality and helicity relate to the rotation of a particle while it proceeds in linear motion with reference to the human hands. The thumb of the hand points towards the direction of linear motion whilst the fingers curl into the palm, representing the direction of rotation of the particle (i.e. clockwise and counterclockwise). Depending on the linear and rotational motion, the particle can either be defined by left-handedness or right-handedness. [ 5 ]  A symmetry transformation between the two is called  parity . Invariance under parity by a  Dirac fermion  is called  chiral symmetry ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6390", "text": "Electromagnetic  waves can have handedness associated with their  polarization . Polarization of an  electromagnetic wave  is the property that describes the  orientation , i.e., the  time-varying  direction and  amplitude , of the  electric field   vector . For example, the electric field vectors of left-handed or right-handed  circularly polarized waves  form helices of opposite handedness in space."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6391", "text": "Circularly polarized waves of opposite handedness propagate through chiral media at different speeds ( circular birefringence ) and with different losses ( circular dichroism ). Both phenomena are jointly known as optical activity. Circular birefringence causes rotation of the polarization state of electromagnetic waves in chiral media and can cause a  negative index of refraction  for waves of one handedness when the effect is sufficiently large. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6392", "text": "While optical activity occurs in structures that are chiral in three dimensions (such as helices), the concept of chirality can also be applied in two dimensions.  2D-chiral  patterns, such as flat spirals, cannot be superposed with their mirror image by translation or rotation in two-dimensional space (a plane). 2D chirality is associated with directionally asymmetric transmission (reflection and absorption) of circularly polarized waves. 2D-chiral materials, which are also anisotropic and lossy exhibit different total transmission (reflection and absorption) levels for the same circularly polarized wave incident on their front and back. The asymmetric transmission phenomenon arises from different, e.g. left-to-right, circular polarization conversion efficiencies for opposite propagation directions of the incident wave and therefore the effect is referred to as circular conversion dichroism.\nLike the twist of a 2d-chiral pattern appears reversed for opposite directions of observation, 2d-chiral materials have interchanged properties for left-handed and right-handed circularly polarized waves that are incident on their front and back. In particular left-handed and right-handed circularly polarized waves experience opposite directional transmission (reflection and absorption) asymmetries. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6393", "text": "While optical activity is associated with 3d chirality and circular conversion is associated with 2d chirality, both effects have also been observed in structures that are not chiral by themselves. For the observation of these chiral electromagnetic effects, chirality does not have to be an intrinsic property of the material that interacts with the electromagnetic wave. Instead, both effects can also occur when the propagation direction of the electromagnetic wave together with the structure of an (achiral) material form a chiral experimental arrangement. [ 10 ] [ 11 ]  This case, where the mutual arrangement of achiral components forms a chiral (experimental) arrangement, is known as extrinsic chirality. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6394", "text": "Chiral mirrors are a class of metamaterials that reflect circularly polarized light of a certain helicity in a handedness-preserving manner, while absorbing circular polarization of the opposite handedness. [ 14 ]  However, most absorbing chiral mirrors operate only in a narrow frequency band, as limited by the causality principle. Employing a different design methodology that allows undesired waves to pass through instead of absorbing the undesired waveform, chiral mirrors are able to show good broadband performance. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6395", "text": "A  chiral molecule  is a type of  molecule  that has a non-superposable  mirror image . The feature that is most often the cause of chirality in molecules is the presence of an  asymmetric carbon atom . [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6396", "text": "The term \"chiral\" in general is used to describe the object that is non-superposable on its mirror image. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6397", "text": "In chemistry, chirality usually refers to molecules. Two mirror images of a chiral molecule are called  enantiomers  or optical  isomers . Pairs of enantiomers are often designated as \" right- \", \"left-handed\" or, if they have no bias, \"achiral\". As polarized light passes through a chiral molecule, the plane of polarization, when viewed along the axis toward the source, will be rotated clockwise (to the right) or anticlockwise (to the left). A right handed rotation is dextrorotary (d); that to the left is levorotary (l). The d- and l-isomers are the same compound but are called  enantiomers . An equimolar mixture of the two optical isomers, which is called a  racemic mixture , will produce no net rotation of polarized light as it passes through. [ 19 ]  Left handed molecules have l- prefixed to their names; d- is prefixed to right handed molecules. However, this  d-  and  l-  notation of distinguishing enantiomers does not say anything about the actual spatial arrangement of the ligands/substituents around the  stereogenic  center, which is defined as configuration. Another nomenclature system employed to specify configuration is Fischer convention. [ 20 ]  This is also referred to as the D- and L-system. Here the relative configuration is assigned with reference to D-(+)-Glyceraldehyde and L-(\u2212)-Glyceraldehyde, being taken as standard. Fischer convention is widely used in sugar chemistry and for \u03b1-amino acids. Due to the drawbacks of Fischer convention, it is almost entirely replaced by  Cahn-Ingold-Prelog convention , also known as the sequence rule or R and S nomenclature. [ 21 ] [ 22 ]  This was further extended to assign absolute configuration to  cis-trans  isomers with the E-Z notation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6398", "text": "Molecular chirality is of interest because of its application to  stereochemistry  in  inorganic chemistry ,  organic chemistry ,  physical chemistry ,  biochemistry , and  supramolecular chemistry ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6399", "text": "More recent developments in chiral chemistry include the development of chiral inorganic  nanoparticles  that may have the similar tetrahedral geometry as chiral centers associated with sp3 carbon atoms traditionally associated with chiral compounds, but at larger scale. [ 23 ] [ 24 ]    Helical and other symmetries of chiral  nanomaterials  were also obtained. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6400", "text": "All of the known life-forms show specific chiral properties in chemical structures as well as macroscopic anatomy, development and behavior. [ 26 ]  In any specific organism or evolutionarily related set thereof, individual compounds, organs, or behavior are found in the same single enantiomorphic form. Deviation (having the opposite form) could be found in a small number of chemical compounds, or certain organ or behavior but that variation strictly depends upon the genetic make up of the organism. From chemical level (molecular scale), biological systems show extreme stereospecificity in synthesis, uptake, sensing, metabolic processing. A living system usually deals with two enantiomers of the same compound in drastically different ways."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6401", "text": "In biology, homochirality is a common property of  amino acids  and  carbohydrates . The chiral  protein-making amino acids , which are translated through the ribosome from genetic coding, occur in the  L  form. However,  D -amino acids are also found in nature. The monosaccharides (carbohydrate-units) are commonly found in  D -configuration. DNA double helix is chiral (as any kind of  helix  is chiral), and  B-form of DNA  shows a right-handed turn."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6402", "text": "Sometimes, when two enantiomers of a compound are found in organisms, they significantly differ in their taste, smell and other biological actions. For example,(+)- Carvone  is responsible for the smell of  caraway  seed oil, whereas (\u2013)-carvone is responsible for smell of  spearmint  oil. [ 27 ]  However, it is a commonly held misconception that (+)-limonene is found in oranges (causing its smell), and (\u2013)-limonene is found in lemons (causing its smell). In 2021, after rigorous experimentation, it was found that all citrus fruits contain only (+)-limonene and the odor difference is because of other contributing factors. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6403", "text": "Also, for artificial compounds, including medicines, in case of  chiral drugs , the two enantiomers sometimes show remarkable difference in effect of their biological actions. [ 29 ]  Darvon ( dextropropoxyphene ) is a painkiller, whereas its enantiomer, Novrad ( levopropoxyphene ) is an anti-cough agent. In case of  penicillamine , the ( S -isomer is used in the treatment of primary chronic arthritis, whereas the ( R )-isomer has no therapeutic effect, as well as being highly toxic. [ 30 ]  In some cases, the less therapeutically active enantiomer can cause side effects. For example, ( S -naproxen is an analgesic but the ( R -isomer causes renal problems. [ 31 ]  In such situations where one of the enantiomers of a racemic drug is active and the other partner has undesirable or toxic effect one may switch from racemate to a single enantiomer drug for a better therapeutic value. [1]  Such a switching from a racemic drug to an enantiopure drug is called a  chiral switch ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6404", "text": "The naturally occurring plant form of alpha-tocopherol ( vitamin E ) is RRR-\u03b1-tocopherol whereas the synthetic form (all-racemic vitamin E, or dl-tocopherol) is equal parts of the stereoisomers RRR, RRS, RSS, SSS, RSR, SRS, SRR, and SSR with progressively decreasing biological equivalency, so that 1.36\u00a0mg of dl-tocopherol is considered equivalent to 1.0\u00a0mg of d-tocopherol. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6405", "text": "Macroscopic examples of chirality are found in the plant kingdom, the animal kingdom and all other groups of organisms. A simple example is the coiling direction of any climber plant, which can grow to form either a left- or right-handed helix."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6406", "text": "In anatomy, chirality is found in the imperfect mirror image symmetry of many kinds of animal bodies. Organisms such as  gastropods  exhibit chirality in their coiled shells, resulting in an asymmetrical appearance. Over 90% of gastropod species [ 33 ]  have  dextral  (right-handed) shells in their coiling, but a small minority of species and genera are virtually always  sinistral  (left-handed). A very few species (for example  Amphidromus perversus [ 34 ] ) show an equal mixture of dextral and sinistral individuals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6407", "text": "In humans, chirality (also referred to as  handedness  or  laterality ) is an attribute of humans defined by their unequal distribution of  fine motor skill  between the left and right  hands . An individual who is more  dexterous  with the right hand is called  right-handed , and one who is more skilled with the left is said to be  left-handed . Chirality is also seen in the study of  facial asymmetry  and is known as aurofacial asymmetry. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6408", "text": "According to the  Axial Twist theory ,  vertebrate  animals develop into a left-handed chirality. Due to this, the  brain is turned around  and the  heart  and  bowels  are turned by 90\u00b0. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6409", "text": "In the case of the health condition  situs inversus totalis , in which all the internal organs are flipped horizontally (i.e. the heart  placed slightly to the right  instead of the left), chirality poses some problems should the patient require a liver or heart transplant, as these organs are chiral, thus meaning that the blood vessels which supply these organs would need to be rearranged should a normal, non  situs inversus  ( situs solitus ) organ be required."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6410", "text": "In the monocot  bloodroot family , the species of the  genera   Wachendorfia  and  Barberetta  have only individuals that either have the style points to the right or the style pointed to the left, with both morphs appearing within the same populations. This is thought to increase  outcrossing  and so boost genetic diversity, which in turn may help to survive in a changing environment. Remarkably, the related genus  Dilatris  also has chirally dimorphic flowers, but here both morphs occur on the same plant. [ 37 ]  In  flatfish , the  summer flounder  or fluke are left-eyed, while  halibut  are right-eyed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6411", "text": "Homochirality  is a uniformity of  chirality , or handedness. Objects are chiral when they cannot be superposed on their mirror images. For example, the left and right hands of a human are approximately mirror images of each other but are not their own mirror images, so they are chiral. In  biology , 19 of the 20 natural  amino acids  are homochiral, being  L -chiral (left-handed), while  sugars  are  D -chiral (right-handed). [ 1 ]  Homochirality can also refer to  enantiopure  substances in which all the constituents are the same  enantiomer  (a right-handed or left-handed version of an atom or molecule), but some sources discourage this use of the term."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6412", "text": "It is unclear whether homochirality has a purpose; however, it appears to be a form of information storage. [ 2 ]  One suggestion is that it reduces  entropy  barriers in the formation of large organized molecules. [ 3 ]  It has been experimentally verified that amino acids form large aggregates in larger abundance from an  enantiopure  samples of the amino acid than from  racemic  (enantiomerically mixed) ones. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6413", "text": "It is not clear whether homochirality emerged before or after life, and many mechanisms for its origin have been proposed. [ 4 ]  Some of these models propose three distinct steps:  mirror-symmetry breaking  creates a minute enantiomeric imbalance,  chiral amplification  builds on this imbalance, and  chiral transmission  is the transfer of chirality from one set of molecules to another."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6414", "text": "Amino acids are the building blocks of  peptides  and  enzymes  while sugar-peptide chains are the backbone of  RNA  and  DNA . [ 5 ] [ 6 ]  In biological organisms, amino acids appear almost exclusively in the left-handed form ( L -amino acids) and sugars in the right-handed form (R-sugars). [ 7 ] [ verification needed ]  Since the enzymes catalyze reactions, they enforce homochirality on a great variety of other chemicals, including  hormones , toxins, fragrances and food flavors. [ 8 ] :\u200a493\u2013494\u200a   Glycine  is achiral, as are some other non- proteinogenic  amino acids that are either achiral (such as  dimethylglycine ) or of the  D  enantiomeric form."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6415", "text": "Biological organisms easily discriminate between molecules with different chiralities. This can affect physiological reactions such as smell and taste.  Carvone , a  terpenoid  found in  essential oils , smells like mint in its L-form and  caraway  in its R-form. [ 8 ] :\u200a494\u200a [ verification needed ]   Limonene  tastes like citrus when right-handed and pine when left-handed. [ 9 ] :\u200a168"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6416", "text": "Homochirality also affects the response to drugs.  Thalidomide , in its left-handed form, cures  morning sickness ; in its right-handed form, it causes birth defects. [ 9 ] :\u200a168\u200a  Unfortunately, even if a pure left-handed version is administered, some of it can convert to the right-handed form in the patient. [ 10 ]  Many drugs are available as both a  racemic mixture  (equal amounts of both chiralities) and an  enantiopure drug  (only one chirality). Depending on the manufacturing process, enantiopure forms can be more expensive to produce than stereochemical mixtures. [ 9 ] :\u200a168"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6417", "text": "Chiral preferences can also be found at a macroscopic level. Snail shells can be right-turning or left-turning helices, but one  form or the other is strongly preferred in a given species. In the edible snail  Helix pomatia , only one out of 20,000 is left-helical. [ 11 ] :\u200a61\u201362\u200a  The coiling of plants can have a preferred chirality and even the chewing motion of cows has a 10% excess in one direction. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6418", "text": "Theories for the origin of homochirality in the molecules of life can be classified as deterministic or based on chance depending on their proposed mechanism. If there is a relationship between cause and effect \u2014 that is, a specific chiral field or influence causing the mirror symmetry breaking \u2014 the theory is classified as deterministic; otherwise it is classified as a theory based on chance (in the sense of randomness) mechanisms. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6419", "text": "Another classification for the different theories of the origin of biological homochirality could be made depending on whether life emerged before the enantiodiscrimination step (biotic theories) or afterwards (abiotic theories). Biotic theories claim that homochirality is simply a result of the natural autoamplification process of life\u2014that either the formation of life as preferring one chirality or the other was a chance rare event which happened to occur with the chiralities we observe, or that all chiralities of life emerged rapidly but due to catastrophic events and strong competition, the other unobserved chiral preferences were wiped out by the preponderance and metabolic, enantiomeric enrichment from the 'winning' chirality choices. [ citation needed ]  If this was the case, remains of the extinct chirality sign should be found. Since this is not the case, nowadays biotic theories are no longer supported."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6420", "text": "The emergence of chirality consensus as a natural autoamplification process has also been associated with the  2nd law of thermodynamics . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6421", "text": "Deterministic theories can be divided into two subgroups: if the initial chiral influence took place in a specific space or time location (averaging zero over large enough areas of observation or periods of time), the theory is classified as local deterministic; if the chiral influence is permanent at the time the chiral selection occurred, then it is classified as universal deterministic. The classification groups for local determinist theories and theories based on chance mechanisms can overlap. Even if an external chiral influence produced the initial chiral imbalance in a deterministic way, the outcome sign could be random since the external chiral influence has its enantiomeric counterpart elsewhere."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6422", "text": "In deterministic theories, the enantiomeric imbalance is created due to an external chiral field or influence, and the ultimate sign imprinted in biomolecules will be due to it. Deterministic mechanisms for the production of non-racemic mixtures from racemic starting materials include: asymmetric physical laws, such as the  electroweak interaction  (via cosmic rays [ 15 ] ) or asymmetric environments, such as those caused by  circularly polarized  light,  quartz crystals , or the Earth's rotation, \u03b2-Radiolysis or the magnetochiral effect. [ 16 ] [ 17 ]  The most accepted universal deterministic theory is the electroweak interaction. Once established, chirality would be selected for. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6423", "text": "One supposition is that the discovery of an enantiomeric imbalance in molecules in the  Murchison meteorite  supports an extraterrestrial origin of homochirality: there is evidence for the existence of  circularly polarized light  originating from  Mie scattering  on aligned interstellar dust particles which may trigger the formation of an  enantiomeric excess  within chiral material in space. [ 11 ] :\u200a123\u2013124\u200a  Interstellar and near-stellar magnetic fields can align dust particles in this fashion. [ 19 ]  Another speculation (the Vester-Ulbricht hypothesis) suggests that fundamental chirality of physical processes such as that of the beta decay (see  Parity violation ) leads to slightly different half-lives of biologically relevant molecules."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6424", "text": "Chance theories are based on the assumption that \" Absolute asymmetric synthesis, i.e., the formation of enantiomerically enriched products from achiral precursors without the intervention of chiral chemical reagents or catalysts, is in practice unavoidable on statistical grounds alone \". [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6425", "text": "Consider the racemic state as a macroscopic property described by a binomial distribution; the experiment of tossing a coin, where the two possible outcomes are the two enantiomers is a good analogy. The discrete probability distribution  \n \n \n \n \n P \n \n p \n \n \n ( \n n \n , \n N \n ) \n \n \n {\\displaystyle P_{p}(n,N)} \n \n  of obtaining n successes out of  \n \n \n \n N \n \n \n {\\displaystyle N} \n \n  Bernoulli trials, where the result of each Bernoulli trial occurs with probability  \n \n \n \n p \n \n \n {\\displaystyle p} \n \n  and the opposite occurs with probability  \n \n \n \n q \n = \n ( \n 1 \n \u2212 \n p \n ) \n \n \n {\\displaystyle q=(1-p)} \n \n  is given by:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6426", "text": "P \n \n p \n \n \n ( \n n \n , \n N \n ) \n = \n \n \n \n ( \n \n \n N \n n \n \n \n ) \n \n \n \n \n p \n \n n \n \n \n ( \n 1 \n \u2212 \n p \n \n ) \n \n N \n \u2212 \n n \n \n \n \n \n {\\displaystyle P_{p}(n,N)={\\binom {N}{n}}p^{n}(1-p)^{N-n}} \n \n  ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6427", "text": "The discrete probability distribution  \n \n \n \n P \n ( \n N \n \n / \n \n 2 \n , \n N \n ) \n \n \n {\\displaystyle P(N/2,N)} \n \n  of having exactly  \n \n \n \n N \n \n / \n \n 2 \n \n \n {\\displaystyle N/2} \n \n  molecules of one chirality and   \n \n \n \n N \n \n / \n \n 2 \n \n \n {\\displaystyle N/2} \n \n  of the other, is given by:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6428", "text": "P \n \n 1 \n \n / \n \n 2 \n \n \n ( \n N \n \n / \n \n 2 \n , \n N \n ) \n = \n \n \n \n ( \n \n \n N \n \n N \n \n / \n \n 2 \n \n \n \n ) \n \n \n \n \n \n ( \n \n \n 1 \n 2 \n \n \n ) \n \n \n N \n \n / \n \n 2 \n \n \n \n \n ( \n \n \n 1 \n 2 \n \n \n ) \n \n \n N \n \n / \n \n 2 \n \n \n \u2248 \n \n \n \n 2 \n \n \u03c0 \n N \n \n \n \n \n \n \n {\\displaystyle P_{1/2}(N/2,N)={\\binom {N}{N/2}}\\left({\\frac {1}{2}}\\right)^{N/2}\\left({\\frac {1}{2}}\\right)^{N/2}\\approx {\\sqrt {\\frac {2}{\\pi N}}}} \n \n  ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6429", "text": "As in the experiment of tossing a coin, in this case, we assume both events ( \n \n \n \n L \n \n \n {\\displaystyle L} \n \n  or  \n \n \n \n D \n \n \n {\\displaystyle D} \n \n ) to be equiprobable,  \n \n \n \n p \n = \n q \n = \n 1 \n \n / \n \n 2 \n \n \n {\\displaystyle p=q=1/2} \n \n . The probability of having exactly the same amount of both enantiomers is inversely proportional to the square root of the total number of molecules  \n \n \n \n N \n \n \n {\\displaystyle N} \n \n . For one mol of a racemic compound,  \n \n \n \n N \n = \n \n N \n \n A \n \n \n \u2248 \n 6.022 \n \u22c5 \n \n 10 \n \n 23 \n \n \n \n \n {\\displaystyle N=N_{A}\\approx 6.022\\cdot 10^{23}} \n \n  molecules, this probability becomes  \n \n \n \n \n P \n \n 1 \n \n / \n \n 2 \n \n \n ( \n \n N \n \n A \n \n \n \n / \n \n 2 \n , \n \n N \n \n A \n \n \n ) \n \u2248 \n \n 10 \n \n \u2212 \n 12 \n \n \n \n \n {\\displaystyle P_{1/2}(N_{A}/2,N_{A})\\approx 10^{-12}} \n \n . The probability of finding the racemic state is so small that we can consider it negligible."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6430", "text": "In this scenario, there is a need to amplify the initial stochastic  enantiomeric excess  through any efficient mechanism of amplification. [ 4 ]  The most likely path for this amplification step is by  asymmetric autocatalysis . An autocatalytic chemical reaction is that in which the reaction product is itself a reactive, in other words, a chemical reaction is autocatalytic if the reaction product is itself the catalyst of the reaction. In asymmetric autocatalysis, the catalyst is a chiral molecule, which means that a chiral molecule is catalysing its own production. An initial enantiomeric excess, such as can be produced by polarized light, then allows the more abundant enantiomer to outcompete the other."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6431", "text": "In 1953,  Charles Frank  proposed a model to demonstrate that homochirality is a consequence of  autocatalysis . [ 21 ] [ 22 ]  In his model the  L  and  D  enantiomers of a chiral molecule are autocatalytically produced from an achiral molecule A"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6432", "text": "while suppressing each other through a reaction that he called  mutual antagonism"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6433", "text": "L \n + \n D \n \n \u2192 \n \n \n k \n \n d \n \n \n \n \n \u2205 \n . \n \n \n \n \n \n \n {\\displaystyle {\\begin{aligned}L+D\\xrightarrow {k_{d}} \\varnothing .\\\\\\end{aligned}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6434", "text": "In this model the racemic state is unstable in the sense that the slightest enantiomeric excess will be amplified to a completely homochiral state. This can be shown by computing the reaction rates from the  law of mass action :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6435", "text": "where  \n \n \n \n \n k \n \n a \n \n \n \n \n {\\displaystyle k_{a}} \n \n  is the rate constant for the autocatalytic reactions,  \n \n \n \n \n k \n \n d \n \n \n \n \n {\\displaystyle k_{d}} \n \n  is the rate constant for mutual antagonism reaction, and the concentration of A is kept constant for simplicity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6436", "text": "The analytical solutions for are found to be  \n \n \n \n [ \n L \n ] \n \n / \n \n [ \n D \n ] \n = \n [ \n L \n \n ] \n \n 0 \n \n \n \n / \n \n [ \n D \n \n ] \n \n 0 \n \n \n \n \n e \n \n k \n d \n ( \n [ \n L \n \n ] \n \n 0 \n \n \n \u2212 \n [ \n D \n \n ] \n \n 0 \n \n \n ) \n ( \n \n e \n \n \n k \n \n a \n \n \n t \n \n \n \u2212 \n 1 \n ) \n \n \n \n \n {\\displaystyle [L]/[D]=[L]_{0}/[D]_{0}\\,e^{kd([L]_{0}-[D]_{0})(e^{k_{a}t}-1)}} \n \n  . The ratio  \n \n \n \n [ \n L \n ] \n \n / \n \n [ \n D \n ] \n \n \n {\\displaystyle [L]/[D]} \n \n  increases at a more than exponential rate if  \n \n \n \n ( \n [ \n L \n \n ] \n \n 0 \n \n \n \u2212 \n [ \n D \n \n ] \n \n 0 \n \n \n ) \n \n \n {\\displaystyle ([L]_{0}-[D]_{0})} \n \n  is positive (and vice versa). Every starting conditions different to"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6437", "text": "[ \n L \n \n ] \n \n 0 \n \n \n = \n [ \n D \n \n ] \n \n 0 \n \n \n \n \n {\\displaystyle [L]_{0}=[D]_{0}} \n \n  lead to one of the asymptotes  \n \n \n \n [ \n L \n ] \n = \n 0 \n \n \n {\\displaystyle [L]=0} \n \n  or  \n \n \n \n [ \n D \n ] \n = \n 0 \n \n \n {\\displaystyle [D]=0} \n \n . Thus the equality of  \n \n \n \n [ \n L \n \n ] \n \n 0 \n \n \n \n \n {\\displaystyle [L]_{0}} \n \n  and  \n \n \n \n [ \n D \n \n ] \n \n 0 \n \n \n \n \n {\\displaystyle [D]_{0}} \n \n  and so of  \n \n \n \n [ \n L \n ] \n \n \n {\\displaystyle [L]} \n \n  and  \n \n \n \n [ \n D \n ] \n \n \n {\\displaystyle [D]} \n \n  represents a condition of unstable equilibrium, this result depending on the presence of the term representing mutual antagonism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6438", "text": "By defining the enantiomeric excess  \n \n \n \n e \n e \n \n \n {\\displaystyle ee} \n \n  as"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6439", "text": "the rate of change of enantiomeric excess can be calculated using  chain rule  from the rate of change of the concentrations of enantiomers  L  and  D ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6440", "text": "Linear stability analysis of this equation shows that the racemic state  \n \n \n \n e \n e \n = \n 0 \n \n \n {\\displaystyle ee=0} \n \n  is unstable. Starting from  almost everywhere  in the concentration space, the system evolves to a homochiral state."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6441", "text": "It is generally understood that autocatalysis alone does not yield to homochirality, and the presence of the mutually antagonistic relationship between the two enantiomers is necessary for the instability of the racemic mixture. However, recent studies show that homochirality could be achieved from autocatalysis in the absence of the mutually antagonistic relationship, but the underlying mechanism for symmetry-breaking is different. [ 4 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6442", "text": "There are several laboratory experiments that demonstrate how a small amount of one enantiomer at the start of a reaction can lead to a large excess of a single enantiomer as the product. For example, the Soai reaction is  autocatalytic . [ 24 ] [ 25 ]  If the reaction is started with some of one of the product enantiomers already present, the product acts as an  enantioselective  catalyst for production of more of that same enantiomer. [ 26 ]  The initial presence of just 0.2  equivalent  one enantiomer can lead to up to 93%  enantiomeric excess  of the product."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6443", "text": "Another study [ 27 ]  concerns the  proline  catalyzed  aminoxylation  of  propionaldehyde  by  nitrosobenzene . In this system, a small enantiomeric excess of catalyst leads to a large enantiomeric excess of product."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6444", "text": "Serine octamer clusters [ 28 ] [ 29 ]  are also contenders. These clusters of 8 serine molecules appear in mass spectrometry with an unusual homochiral preference, however there is no evidence that such clusters exist under non-ionizing conditions and amino acid phase behavior is far more prebiotically relevant. [ 30 ]  The recent observation that partial  sublimation  of a 10% enantioenriched sample of  leucine  results in up to 82% enrichment in the sublimate shows that enantioenrichment of amino acids could occur in space. [ 31 ]  Partial sublimation processes can take place on the surface of meteors where large variations in temperature exist. This finding may have consequences for the development of the  Mars Organic Detector  scheduled for launch in 2013 which aims to recover trace amounts of amino acids from the Mars surface exactly by a sublimation technique."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6445", "text": "A high asymmetric amplification of the  enantiomeric excess  of sugars are also present in the  amino acid  catalyzed asymmetric formation of  carbohydrates [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6446", "text": "One classic study involves an experiment that takes place in the laboratory. [ 33 ]  When  sodium chlorate  is allowed to  crystallize  from water and the collected crystals examined in a  polarimeter , each crystal turns out to be chiral and either the  L  form or the  D  form. In an ordinary experiment the amount of  L  crystals collected equals the amount of  D  crystals (corrected for statistical effects). However, when the sodium chlorate solution is stirred during the crystallization process the crystals are either exclusively  L  or exclusively  D . In 32 consecutive crystallization experiments 14 experiments deliver  D -crystals and 18 others  L -crystals. The explanation for this symmetry breaking is unclear but is related to  autocatalysis  taking place in the  nucleation  process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6447", "text": "In a related experiment, a crystal suspension of a racemic  amino acid  derivative continuously stirred, results in a 100% crystal phase of one of the enantiomers because the enantiomeric pair is able to equilibrate in solution  (compare with  dynamic kinetic resolution ). [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6448", "text": "Once a significant enantiomeric enrichment has been produced in a system, the transference of chirality through the entire system is customary. This last step is known as the chiral transmission step. Many strategies in  asymmetric synthesis  are built on chiral transmission. Especially important is the so-called  organocatalysis  of organic reactions by proline for example in  Mannich reactions ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6449", "text": "Some proposed models for the transmission of chiral asymmetry are polymerization, [ 35 ] [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ]  epimerization  [ 41 ] [ 42 ]  or copolymerization. [ 43 ] [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6450", "text": "There exists no theory elucidating correlations among  L -amino acids. If one takes, for example,  alanine , which has a small  methyl  group, and  phenylalanine , which has a larger  benzyl  group, a simple question is in what aspect,  L -alanine resembles  L -phenylalanine more than  D -phenylalanine, and what kind of mechanism causes the selection of all  L -amino acids, because it might be possible that alanine was  L  and phenylalanine was  D ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6451", "text": "It was reported [ 45 ]  in 2004 that excess racemic  D , L -asparagine  (Asn), which spontaneously forms crystals of either isomer during recrystallization, induces asymmetric resolution of a co-existing racemic amino acid such as  arginine  (Arg),  aspartic acid  (Asp),  glutamine  (Gln),  histidine  (His),  leucine  (Leu),  methionine  (Met),  phenylalanine  (Phe),  serine  (Ser),  valine  (Val),  tyrosine  (Tyr), and  tryptophan  (Trp). The  enantiomeric excess   ee = 100 \u00d7( L - D )/( L + D )  of these amino acids was correlated almost linearly with that of the inducer, i.e., Asn. When recrystallizations from a mixture of 12  D , L -amino acids (Ala, Asp, Arg, Glu, Gln, His, Leu, Met, Ser, Val, Phe, and Tyr) and excess  D , L -Asn were made, all amino acids with the same configuration with Asn were preferentially co-crystallized. [ 45 ]  It was incidental whether the enrichment took place in  L - or  D -Asn, however, once the selection was made, the co-existing amino acid with the same configuration at the \u03b1-carbon was preferentially involved because of thermodynamic stability in the crystal formation. The maximal ee was reported to be 100%. Based on these results, it is proposed that a mixture of racemic amino acids causes spontaneous and effective optical resolution, even if asymmetric synthesis of a single amino acid does not occur without an aid of an optically active molecule."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6452", "text": "This is the first study elucidating reasonably the formation of chirality from racemic amino acids with experimental evidences."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6453", "text": "This term was introduced by  Kelvin  in 1904, the year that he published his Baltimore Lecture of 1884. Kelvin used the term homochirality as a relationship between two molecules, i.e. two molecules are homochiral if they have the same chirality. [ 32 ] [ 46 ]  Recently, however, homochiral has been used in the same sense as  enantiomerically  pure. This is permitted in some journals (but not encouraged), [ 47 ] :\u200a342\u200a [ 48 ]  its meaning changing into the preference of a process or system for a single  optical isomer  in a pair of isomers in these journals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6454", "text": "In transportation infrastructure, a  bidirectional traffic  system divides travellers into two streams of traffic that flow in opposite directions. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6455", "text": "In the design and construction of tunnels, bidirectional traffic can markedly affect ventilation considerations. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6456", "text": "Microscopic traffic flow models  have been proposed for bidirectional automobile, pedestrian, and railway traffic. [ 3 ]  Bidirectional traffic can be observed in  ant  trails [ 4 ]  which have been researched for insight into human traffic models. [ 5 ]  In a  macroscopic theory  proposed by  Laval , the interaction between fast and slow vehicles conforms to the Newell kinematic wave model of moving  bottlenecks . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6457", "text": "In  air traffic control  traffic is normally separated by elevation, with east bound flights at odd thousand feet elevations and west bound flights at even thousand feet elevations (1000\u00a0ft \u2248 305m). Above 28,000\u00a0ft (~8.5\u00a0km) only odd flight levels are used, with FL 290, 330, 370, etc., for eastbound flights and FL 310, 350, 390, etc., for westbound flights. [ 7 ]  Entry to and exit from airports is always one-way traffic, as runways are chosen to allow aircraft to take off and land into the wind, to reduce ground speed. [ 8 ]  Even in no wind cases, a preferred calm wind runway and direction is normally chosen and used by all flights, to avoid collisions. [ 9 ]  In uncontrolled airports, airport information can be obtained from anyone at the airport. Traffic follows a specific traffic pattern, with designated entry and exits. Radio announcements are made, whether anyone is listening or not, to allow any other traffic to be aware of other traffic in the area. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6458", "text": "In the earliest days of railways in the  United Kingdom , most lines were built  double tracked  because of the difficulty of coordinating operations in pre- telegraphy  times."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6459", "text": "Most modern roads carry bidirectional traffic, although  one-way traffic  is common in dense urban centres. [ citation needed ]  Bidirectional traffic flow is believed to influence the rate of  traffic collisions . In an analysis of  head-on ,  rear-end , and lane-changing collisions based on the Simon-Gutowitz bidirectional traffic model, it was concluded that \"the risk of collisions is important when the density of cars in one lane is small and ... the other lane['s] is high enough,\" and that \"heavy vehicles cause an important reduction of traffic flow on the home lane and provoke an increase of the risk of car accident.\" [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6460", "text": "Bidirectional traffic is the most common form of flow observed in  trails , however, some larger pedestrian concourses exhibit multidirectional traffic. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6461", "text": "Bromochlorofluoroiodomethane  is a hypothetical  haloalkane  with all four stable  halogen  substituents present in it. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6462", "text": "This compound can be seen as a  methane  molecule, whose four  hydrogen  atoms are each replaced with a different  halogen  atom. As the mirror images of this molecule are not superimposable, the molecule has two  enantiomers .  As one of the simplest such molecules, it is often cited as the prototypical  chiral  compound. [ 2 ]  However, since there is no synthetic route known to produce bromochlorofluoroiodomethane, the related simple chiral compound  bromochlorofluoromethane  is used instead when such a compound is required for research."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6463", "text": "This article about  theoretical chemistry  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6464", "text": "This  stereochemistry  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6465", "text": "Bromochlorofluoromethane  or  fluorochlorobromomethane , is a chemical compound and  trihalomethane  derivative with the chemical formula  C H Br Cl F . As one of the simplest possible stable  chiral  compounds, it is useful for fundamental research into this area of chemistry. [ 1 ]  However, its relative instability to  hydrolysis , [ 2 ]  and lack of suitable  functional groups , made separation of the  enantiomers  of bromochlorofluoromethane especially challenging, [ 3 ]  and this was not accomplished until almost a century after it was first synthesised, in March 2005, though it has now been done by a variety of methods. [ 4 ] [ 5 ] [ 6 ] [ 7 ]  More recent research using bromochlorofluoromethane has focused on its potential use for experimental measurement of  parity violation , a major unsolved problem in  quantum physics . [ 8 ] [ 9 ] [ 10 ]  For example, the  S  enantiomer is predicted to be lower in energy by about  2.356 \u00d7 10 \u221216 \u00a0eV  (56.97\u00a0mHz), [ 11 ]  and the frequency of the  C \u2212 F  vibrational mode should be about 2.4\u00a0mHz lower for the  R -enantiomer. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6466", "text": "This article about a  hydrocarbon  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6467", "text": "Chemical compounds that come as mirror-image pairs are referred to by chemists as  chiral  or handed molecules. [ 1 ]  Each twin is called an  enantiomer . Drugs that exhibit handedness are referred to as  chiral drugs . Chiral drugs that are equimolar (1:1) mixture of enantiomers are called  racemic  drugs and these are obviously devoid of optical rotation. The most commonly encountered stereogenic unit, [ 2 ]  that confers  chirality  to drug molecules are stereogenic center. Stereogenic center can be due to the presence of tetrahedral tetra coordinate atoms (C,N,P) and pyramidal tricoordinate atoms (N,S). The word chiral describes the three-dimensional architecture of the molecule and does not reveal the stereochemical composition. Hence \"chiral drug\" does not say whether the drug is racemic (racemic drug), single enantiomer (chiral specific drug) or some other combination of stereoisomers. To resolve this issue  Joseph Gal  introduced a new term called  unichiral . [ 3 ] [ 4 ]  Unichiral indicates that the stereochemical composition of a chiral drug is homogenous consisting of a single enantiomer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6468", "text": "Many medicinal agents important to life are combinations of mirror-image twins. Despite the close resemblance of such twins, the differences in their biological properties can be profound. In other words, the component enantiomers of a racemic chiral drug may differ wildly in their pharmacokinetic, pharmacodynamic profile. [ 5 ] [ 6 ] [ 7 ] [ 8 ]  The tragedy of  thalidomide  illustrates the potential for extreme consequences resulting from the administration of a racemate drug that exhibits multiple effects attributable to individual enantiomers. [ 9 ]  With the advancements in chiral technology and the increased awareness about three-dimensional consequences of drug action and disposition emerged specialized field \"chiral pharmacology\". Simultaneously the chirality nomenclature system also evolved. A brief overview of chirality history and terminology/descriptors is given below. A detailed  chirality timeline  is not the focus of this article."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6469", "text": "Chirality can be traced back to 1812, when physicist  Jean-Baptiste Biot  found out about a phenomenon called \"optical activity.\" [ 10 ]   Louis Pasteur , a famous student of Biot's, made a series of observations that led him to suggest that the optical activity of some substances is caused by their molecular asymmetry, which makes nonsuperimposable mirror-images. In 1848, Pasteur grew two different kinds of crystals from the racemic sodium ammonium salt of tartaric acid. He was the first person to separate enantiomeric crystals by hand. [ 11 ]  In fact Pasteur laid the foundations of stereochemistry and chirality."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6470", "text": "In 1874,  Jacobus Henricus van 't Hoff  came up with the idea of an asymmetric carbon atom. He said that all optically active carbon compounds have an asymmetric carbon atom. [ 12 ]  In the same year,   Joseph Achille Le Bel  only used asymmetry arguments and talked about the asymmetry of the molecules as a whole instead of the asymmetry of each carbon atom. [ 13 ]  So,        Le Bel's idea could be seen as the general theory of stereoisomerism, while van 't Hoff's could be seen as a special case (restricted to tetrahedral carbon)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6471", "text": "Soon, scientists started to look into what chiral compounds meant for living things. In 1903, Cushny was the first person to show that enantiomers of a chiral molecule have different biological effects. [ 14 ]   Lord Kelvin  used the word \"chiral\" for the first time in 1904. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6472", "text": "This is to give an overview of the evolving chirality nomenclature system commonly employed to distinguish enantiomers of a chiral drug. In the beginning, enantiomers were distinguished based on their ability to rotate the plane of plane-polarized light. The enantiomer that rotates the plane-polarized light to the right is named \"dextro-rotatory\", abbreviated as  \"dextro\"  or  \"d\"  and the counterpart as  \"levo\"  or  \"l\" . A racemic mixture is denoted as \"(\u00b1)\",  \"rac\" , or  \"dl\" . Now the d/l system of naming based on optical rotation is falling into disuse."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6473", "text": "Later, the Fischer convention [ 16 ] [ 17 ]  was introduced to specify the configuration of a stereogenic center and uses the symbols D and L. The use of capital letters is to differentiate from the  \"d\"  /  \"l\"  notation (optical descriptor) described earlier. In this system, the enantiomers are named with reference to D- and L-glyceraldehyde which is taken as the standard for comparison. The structure of the chiral molecule should be represented in the Fischer projection formula. If the hydroxyl group attached to the highest chiral carbon is on the right-hand side it is referred to as D-series and if on the left-hand side it is called L-series. This nomenclature system has also become obsolete. But D-/L-system of naming is still employed to designate the configuration of amino acids and sugars. In general the D/L system of nomenclature is superseded by the Cahn-Ingold-Prelog (CIP) rule to describe the configuration of a stereogenic/chiral center."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6474", "text": "In the CIP or R/S convention, or sequence rule, the configuration, spatial arrangements of ligands/substituents around a chiral center, is labeled as either \"R\" or \"S\". [ 18 ] [ 2 ]  This convention is now almost worldwide in use and become a part of the  IUPAC  (International Union of Pure and Applied Chemistry) rules of nomenclature. In this approach: identify the chiral center, label the four atoms directly attached to the stereogenic center in question, assign priorities according to the sequence rule ( from 1 to 4), rotate the molecule until the lowest priority (number 4) substituent is away from the observer/viewer, draw a curve from number 1 to number 2 to number 3 substituent. If the curve is clockwise, the chiral center is of R-absolute configuration, \"R\" (Latin,  rectus  = right). If the curve is counterclockwise, the chiral center is of S-absolute configuration, \"S\" (Latin,  sinister  = left). Refer to figure, the Cahn-Ingold-Prelog rule."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6475", "text": "An overview of the nomenclature system is presented in the table below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6476", "text": "For many years scientists in  drug development  have been blind to the three-dimensional consequences of stereochemistry, chiefly due to the lack of technology for making enantioselective investigations. Besides the thalidomide tragedy, another event that raised the importance of issues of stereochemistry in drug research and development was the publication of a manuscript in 1984 entitled, \"Stereochemistry, a basis of sophisticated nonsense in pharmacokinetics and clinical pharmacology\" by Ari\u00ebns. [ 19 ]  This article, and the series of articles that followed, criticized the practice of conducting pharmacokinetic and pharmacodynamic studies on racemic drugs and ignoring the separate contributions of the individual enantiomers. [ 20 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ] [ 25 ]  These papers have served to crystallize some of the important issues surrounding racemic drugs and stimulated much discussion in industry, government and academia."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6477", "text": "As a result of these criticisms and the renewed awareness of the three-dimensional effects of drug action fueled by the exponential explosion of chiral technology emerged the new area \"stereo-pharmacology\". A more specific term is \"chiral pharmacology\", a phrase popularized by John Caldwell. [ 26 ]  This field has grown itself into a specialized discipline concerned with the three-dimensional aspects of drug action and disposition. This approach essentially views each version of the chiral twins as separate chemical species. To express the pharmacological activities of each of the chiral twins two technical terms have been coined,  eutomer  and  distomer . [ 27 ]  The member of the chiral twin that has greater physiological activity is referred to as the eutomer and the other one with lesser activity is referred to as distomer. It is generally understood that this reference is necessarily to a single activity being studied. The eutomer for one effect may well be the distomer when another is studied. The eutomer/distomer ratio is called the  eudysmic ratio . [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6478", "text": "The behavior of the chiral twins depends mainly on the nature of the environment (achiral/chiral) in which they are present. An achiral environment does not differentiate the molecular twins whereas a chiral environment does distinguish the left-handed version from the right-handed version. Human body, a classic bio-environment, is inherently handed as it is filled with chiral discriminators like amino acids, enzymes, carbohydrates, lipids, nucleic acids, etc. Hence when a racemic therapeutic gets exposed to biological system the component enantiomers will be acted upon stereoselectively. [ 29 ]   For drugs, chiral discrimination can take place either in the pharmacokinetic or pharmacodynamic phase."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6479", "text": "Easson and Stedman [ 30 ]  (1933) advanced a drug-receptor interaction model to account for the differential pharmacodynamic activity between enantiomeric pairs.  In this model the more active enantiomer (the eutomer) take part in a minimum of three simultaneous intermolecular interactions with the receptor surface (good fit), Figure. A., where as the less active enantiomer (distomer) interacts at two sites only (bad fit), Figure B. [Refer image for Figure: Easson-Stedman model]. Thus the \"fit\" of the individual enantiomers to the receptor site differs, as does the energy of interaction. This is a simplistic model but used to explain the biological discrimination between enantiomeric pairs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6480", "text": "In reality the drug-receptor interaction is not that simple, but this view of such complex phenomenon has provided major insights into the mechanism of action of drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6481", "text": "Racemic drugs are not  drug combinations  in the accepted sense of two or more co-formulated therapeutic agents, but combinations of isomeric substances whose pharmacological activity may reside predominantly in one specific enantiomeric form. In case of stereoselectivity in action only one of the components in the racemic mixture is truly active. The other isomer, the distomer, should be regarded as impurity or isomeric ballast, [ 31 ]  a term coined by Ari\u00ebns, not contributing to the effects aimed at. In contrast to the pharmacokinetic properties of an enantiomeric pair, differences in pharmacodynamic activity tend to be more obvious. There is a wide spectrum of possibilities of distomer actions, many of which are confirmed experimentally. [ 32 ] [ 33 ] [ 34 ]   Selected examples of the distomer actions (viz. equipotent, less active, inactive, antagonistic,  chiral inversion ) are presented in the table below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6482", "text": "Since there is a frequent large pharmacokinetic and pharmacodynamic differences between enantiomers of a chiral drug it is not surprising that enantiomers may result in stereoselective toxicity. They can reside in the pharmacologically active enantiomer (eutomer) or in the inactive one (distomer). [ 41 ] [ 42 ] [ 43 ]  The toxicologic differences between enantiomers of have also been demonstrated. The following are examples of some of the chiral drugs where their toxic/undesirable side-effects dwell almost in the distomer. This would seem to be a clear cut case of going for a  chiral switch ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6483", "text": "Penicillamine  is a chiral drug with one chiral center and exists as a pair of enantiomers. (S)-penicillamine is the eutomer with the desired antiarthritic activity while the (R)-penicillamine is extremely toxic. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6484", "text": "Ketamine is a widely used anaesthetic agent. It is a chiral molecule that is administered as a racemate. Studies show that (S)-(+)-ketamine is the active anaesthetic and the undesired side-effects (hallucination and agitation) reside in the distomer, (R)-(-)-ketamine. [ 45 ] [ 46 ] [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6485", "text": "The initial use of racemic dopa for the treatment of Parkinson's disease resulted in a number of adverse effects viz. nausea, vomiting, anorexia, involuntary movements and granulocytopenia. The use of L-dopa [the (S)-enantiomer] resulted in reducing the required dose, and adverse effects. The granulocytopenia was not observed with the single enantiomer. [ 48 ] [ 49 ] [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6486", "text": "The antitubercular agent Ethambutol contains two constitutionally symmetrical stereogenic centers in its structure and exists in three stereoisomeric forms. An enantiomeric pair (S,S)- and (R,R)-ethambutol, along with the achiral stereoisomer called  meso -form, it holds a diastereomeric relationship with the optically active stereoisomers. The activity of the drug resides in the (S,S)-enantiomer which is 500 and 12 fold more potent than the (R,R)-ethambutol and the  meso- form. The drug had initially been introduced for clinical use as the racemate and was changed to the (S,S)-enantiomer, as a result of optic neuritis leading to blindness. Toxicity is related to both dose and duration of treatment.  All the three stereoisomers were almost equipotent with respect to side effects. Hence the use of S,S)-enantiomer greatly enhanced the risk/benefit ratio. [ 51 ] [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6487", "text": "Thalidomide is a classical example highlighting the alleged role of chirality in drug toxicity. Thalidomide was a racemic therapeutic and prescribed to pregnant women to control nausea and vomiting. The drug was withdrawn from world market when it became evident that the use in pregnancy causes phocomelia (clinical conditions where babies are born with deformed hand and limbs). Later in late 1970s studies indicated that the (R)- enantiomer is an effective  sedative , the (S)-enantiomer harbors teratogenic effect and causes fetal abnormalities. [ 53 ] [ 54 ] [ 55 ]  Later studies established that under biological conditions the ( R) -thalidomide, good partner, undergoes an  in vivo  metabolic inversion to the ( S) -thalidomide, evil partner and vice versa. It is a  bidirectional  chiral   inversion . Hence the argument that the thalidomide tragedy could have been avoided by using a single enantiomer is ambiguous and pointless. [ 56 ] [ 57 ] [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6488", "text": "The salient features are presented in the table below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6489", "text": "Unichiral indicates configurationally homogeneous substance (i.e. made up of chiral molecules of one and the same configuration). Other commonly used synonyms are  enantiopure drugs  and enantiomerically pure drugs. Monochiral drugs has also been suggested as another synonym. [ 59 ]  Professor Eliel, Wilen, and Gal expressed their deep concern over the misuse of the term \"homochiral\" in articles to denote enantiomerically pure drugs, which is incorrect. [ 60 ] [ 61 ] [ 62 ]  Homochiral means objects or molecules of the same handedness. Hence should be used only for comparison of two or more objects of like \"chirality\". For instance, left hands of different individuals, or say R-naproxen and R-ibuprofen."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6490", "text": "Globally drug companies and regulatory agencies have an inclination towards the development of unichiral drugs as a consequence of the increased understanding of the differing biological properties of individual enantiomers of a racemic therapeutics.  Most of these unichiral drugs are the consequence of  chiral switch  approach. The table below list selected unichiral drugs used in drug therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6491", "text": "A company may go in for developing a racemic drug against an enantiomer by providing adequate reasoning. The rationale why a company might pursue developing racemic drugs [ 63 ] [ 64 ] [ 65 ]  could include expensive separation of enantiomers, eutomer racemizes in solution (e.g. oxazepam), [ 66 ]  activities of the enantiomeric pair are different but supplementary, distomer is inactive, but separation is exorbitant. Insignificant/low toxicity of the distomer, high therapeutic index, mutually beneficial, pharmacological activities of both the enantiomers, and if the development of an enantiomer takes huge amount of time for a drug of emergency need e.g., cancer, AIDS, etc."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6492", "text": "Chiral purity is a measure of the purity of a chiral drug. Other synonyms employed include  enantiomeric excess , enantiomer purity, enantiomeric purity, and optical purity. Optical purity is an obsolete term since today most of the chiral purity measurements are done using chromatographic techniques (not based on optical principles). Enantiomeric excess tells the extent (in\u00a0%) to which the chiral substance contains one enantiomer over the other. For a racemic drug the enantiomeric excess will be 0%. There are number of  chiral analysis  tools such as polarimetry, NMR spectroscopy with the use of chiral shift reagents, chiral GC (gas chromatography), chiral HPLC (high performance liquid chromatography), chiral TLC (thin-layer chromatography) [ 67 ]  and other chiral chromatographic techniques, that are employed to evaluate chiral purity. [ 68 ]  Assessing the purity of a unichiral drug or enantiopure drug is of great importance from a drug safety and efficacy perspective."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6493", "text": "Chiral  inversion  is the process of conversion of one  enantiomer  of a chiral molecule to its mirror-image version with no other change in the molecule. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6494", "text": "Chiral inversion happens depending on various factors (viz. biological-, solvent-, light-, temperature- induced, etc.) and the  energy barrier  energy barrier associated with the stereogenic element present in the chiral molecule. 2-Arylpropionic acid  nonsteroidal anti-inflammatory drugs  (NSAIDs) provide one of the best  pharmaceutical examples of chiral inversion.  Chirality  is attributed to a molecule due to the presence of a stereogenic element (viz. center, planar, helical, or axis). Many pharmaceutical drugs are chiral and have a labile (configurationally unstable) stereogenic element. Chiral compounds with  stereogenic center  are found to have high energy barriers for inversion and generally undergo biologically mediated chiral inversion.\u00a0 While compounds with  helical  or  planar chirality  have low energy barriers and chiral inversions are often caused by solvent, light, temperature. [ 5 ]  When this happens, the configuration of the chiral molecule may rapidly change reversibly or irreversibly depending on the conditions. The chiral inversion has been intensively studied in the context of the pharmacological and toxicological consequences. [ 6 ]  Other than NSAIDs, chiral drugs with different chemical structures can also show this effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6495", "text": "Chiral drugs  have different effects on the body depending on whether one enantiomer or both enantiomers act on different biological targets. As a result, chiral inversion can change how a pharmaceutical drug works in the body. From a pharmacological and toxicological point of view, it is very important to learn more about chiral inversion, the things that make it happen, and the tools used to figure out chiral inversion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6496", "text": "Essentially there are two types of chiral inversion, unidirectional and bidirectional. [ 7 ]  Inversion process is dependent on species and substrate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6497", "text": "It is well documented that (R)-enantiomers of profens in the presence of coenzyme A (CoA), adenosine triphosphate (ATP) and Mg +2  are converted to active (S)-forms. The pathways of chiral inversion is illustrated taking  ibuprofen  as the prototype, in the scheme below. [ 14 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6498", "text": "The pathway consists mainly of three steps:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6499", "text": "Because the acyl-CoA thioester (profenyl-CoA) changes the structure of triglycerides and phospholipids, metabolic chiral inversion may cause toxic effects. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6500", "text": "Chiral drugs with stereo-labile configuration are likely to undergo interconversion of the enantiomers that may be enzymatic (biological) or non-enzymatic. Enzyme-mediated conversion is the process of chiral inversion that happens in a living organism. Non-enzymatic inversion of drugs is important and relevant in the pharmaceutical manufacturing process. This may have impact on the shelf-life of a drug and the economic feasibility of the resolution. Inversion can also happen without enzymes when precolumn derivatization is used in enantioselective chromatographic separation techniques. Racemization can also happen in the acidic environment of the stomach and other bodily fluids."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6501", "text": "Enzyme-mediated (biological) chiral inversion of organic compounds is caused by highly chiral endogenous molecules found in receptors, enzymes, and other structures. [ 8 ]  While enzyme inhibitors suppress enzyme activity, enzyme inducers boost enzyme concentration and activity. The primary determinants of inter-individual variability in drug metabolism in humans are thought to include genetic polymorphism and a variety of other variables, including age, gender, biological conditions, pregnancy, illnesses, stress, nutrition, and drugs. For instance, Reichel et al. [ 26 ]  reported that a 2-arylpropionyl-coenzyme-A epimerase was molecularly cloned and expressed as a crucial enzyme in the inversion metabolism of ibuprofen. Ibuprofen's chiral inversion by enzymes has been documented in humans. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6502", "text": "The liver, gastrointestinal tract (GIT), lungs, kidney, and brain are among the tissues that participate in the chiral inversion of medicines. The liver has been shown to be the most crucial organ in the development of this mechanism. [ 28 ]   Although some studies contend that rat liver homogenates lack the enzymatic mechanisms necessary to invert the R-enantiomers of flurbiprofen, naproxen, suprofen, and ibuprofen, the liver may also be involved in the inversion of R-ibuprofen in rats. [ 15 ]  On the other hand, it was noted that certain medicines underwent chiral inversion without the involvement of the liver (hepatocytes). Although liver did not play a substantial role in the inversion of benoxaprofen, studies using benoxaprofen and ketoprofen show that one of the primary sites of inversion in rats is the GI tract. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6503", "text": "Chiral inversion is a very important part of designing and making drugs. Because this process can change how chiral drugs work in the body and can cause side effects that can be serious or even fatal. Traditionally, chiral inversions have been studied with NMR spectroscopy at different temperatures and chiroptical methods like polarimetry. But strong, complementary methods based on dynamic chromatography (GC, HPLC, SFC, CEC, and MEKC) and electrophoresis have been made and used to figure out how the enantiomeric composition of stereo-labile chiral compounds changes over time. [ 29 ]   Most of the time, liquid chromatographic methods are used to do enantioselective analysis of chiral drugs. When an analyte with one stereogenic center or axis is separated well, the chromatogram will show two peaks. But if the analyte is stereo-labile, the peaks tend to merge. [ 30 ]  How much coalescence there is will depend on how fast chiral inversion and enantioresolution happen. Over time, the peaks will merge into a flat area. Dynamic chromatography shows how the elution profile changes over time. This makes it useful for figuring out how pH, temperature, and solvents affect chiral inversion, which can happen on the stationary phase, in the injector, or in the detector. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6504", "text": "Multidimensional approaches have been used to improve separation and detection. Table below shows a list of common methods and experiments used to figure out chiral inversion. Any of these methods can then be used to determine chiral inversion. Which instrument is used to analyze a chiral compound depends on its physical and chemical properties (i.e., the solubility, vapor pressure, thermal and solvent stability, and detection). [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6505", "text": "For example, capillary electrophoresis or liquid chromatography could be used if the analyte can be ionized and has a high vapor pressure, but it is also soluble in polar solvents. [ 31 ]  On the other hand, gas chromatography is the best way to test a substance that is stable at high temperatures but has a low vapor pressure. When compared to gas or liquid chromatography, supercritical fluid chromatography is a better way to measure chiral inversion because it uses mass spectrometers and a green method. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6506", "text": "Enantiomers of a chiral drug often interact in an enantioselective way in a chiral environment. This may be offered by different biotic substances (viz. proteins, nucleic acids, phospholipids and oligosaccharides). They are made up of chiral building blocks that are put together in space in handed conformations. These biological targets function as receptors for the drug enantiomers. So, at the binding sites of these receptors, enantiomers will be seen as different chemical species. The three point attachment model (Easson & Stedman model) [ 33 ]  can be used to see how chiral discrimination works. Figure depicts how the enantiomers of a drug interact with receptors in a way that depends on the drug's shape. \nThis model was made for chiral drugs with a single stereogenic center. It says that there are three binding sites in the receptor (B', C' and D') that match the drug's pharmacophoric groups (B, C, D). A three-point fit (good fit) is possible for the eutomer at BB', CC' and DD'(Fig. A). Even though the distomer is the wrong enantiomer, it can fit either a one-point interaction (bad fit), or a two-point attachment (CC' and DD') with the same receptor site as shown in (Fig. B)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6507", "text": "Eutomer  is the version that works the way you want it to, and  distomer  is the version that doesn't work or works in a way you don't want it to. [ 34 ] [ 35 ]  Most of the time, the mirror-image versions have different binding affinities. In the eutomer, the ligands or moiety around a stereogenic element have more binding energy than in the distomer. When the eutomer goes through chiral inversion, it loses its ability to bind to a biological receptor. Because of these enantiospecific interactions, therapeutic and toxicological properties are enantioselective [ 27 ] [ 6 ]  So, the stereo-stability of chiral drugs may have big effects on the process of making new drugs, especially when it comes to how pharmaceutical, pharmacokinetic, and pharmacodynamic information is read and understood. At every stage of designing, making, and testing a drug for safety, chiral inversion must be taken into account."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6508", "text": "In the study of  abstract polytopes , a  chiral polytope  is a polytope that is as symmetric as possible without being mirror-symmetric, formalized in terms of the  action  of the  symmetry group  of the polytope on its  flags ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6509", "text": "The more technical definition of a chiral polytope is a polytope that has two orbits of  flags  under its  group of symmetries , with \nadjacent flags in different orbits. This implies that it must be  vertex-transitive ,  edge-transitive , and  face-transitive , as each vertex, edge, or face must be represented by flags in both orbits; however, it cannot be mirror-symmetric, as every mirror symmetry of the polytope would exchange some pair of adjacent flags. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6510", "text": "For the purposes of this definition, the symmetry group of a polytope may be defined in either of two different ways: it can refer to the symmetries of a polytope as a geometric object (in which case the polytope is called  geometrically chiral ) or it can refer to the symmetries of the polytope as a combinatorial structure (the automorphisms of an  abstract polytope ). Chirality is meaningful for either type of symmetry but the two definitions classify different polytopes as being chiral or nonchiral. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6511", "text": "Geometrically chiral polytopes are relatively exotic compared to the more ordinary regular polytopes. It is not possible for a geometrically chiral polytope to be convex, [ 3 ]  and many geometrically chiral polytopes of note are  skew ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6512", "text": "In three dimensions, it is not possible for a geometrically chiral polytope to have finitely many finite faces. For instance, the snub cube is vertex-transitive, but its flags have more than two orbits, and it is neither edge-transitive nor face-transitive, so it is not symmetric enough to meet the formal definition of chirality. The  quasiregular polyhedra  and their duals, such as the  cuboctahedron  and the  rhombic dodecahedron , provide another interesting type of near-miss: they have two orbits of flags, but are mirror-symmetric, and not every adjacent pair of flags belongs to different orbits. However, despite the nonexistence of finite chiral three-dimensional polyhedra, there exist infinite three-dimensional chiral  skew polyhedra  of types {4,6}, {6,4}, and {6,6}. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6513", "text": "In four dimensions, there are a geometrically chiral finite polytopes. One example is Roli's cube, a  skew polytope  on the skeleton of the  4-cube . [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6514", "text": "In  chemistry , a molecule or ion is called  chiral  ( / \u02c8 k a\u026a r \u0259l / ) if it cannot be superposed on its  mirror image  by any combination of  rotations ,  translations , and some  conformational  changes. This geometric property is called  chirality  ( / k a\u026a \u02c8 r \u00e6 l \u026a t i / ). [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The terms are derived from  Ancient Greek   \u03c7\u03b5\u03af\u03c1  ( cheir ) 'hand'; which is the  canonical  example of an object with this property."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6515", "text": "A chiral molecule or ion exists in two  stereoisomers  that are mirror images of each other, [ 5 ]  called  enantiomers ; they are often distinguished as either \"right-handed\" or \"left-handed\" by their  absolute configuration  or some other criterion. The two enantiomers have the same chemical properties, except when reacting with other chiral compounds. They also have the same  physical  properties, except that they often have opposite  optical activities . A homogeneous mixture of the two enantiomers in equal parts is said to be  racemic , and it usually differs chemically and physically from the pure enantiomers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6516", "text": "Chiral molecules will usually have a stereogenic element from which chirality arises. The most common type of stereogenic element is a stereogenic center, or stereocenter. In the case of organic compounds, stereocenters most frequently take the form of a carbon atom with four distinct (different) groups attached to it in a tetrahedral geometry. Less commonly, other atoms like N, P, S, and Si can also serve as stereocenters, provided they have four distinct substituents (including lone pair electrons) attached to them."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6517", "text": "A given stereocenter has two possible configurations (R and S), which give rise to stereoisomers ( diastereomers  and  enantiomers ) in molecules with one or more stereocenter. For a chiral molecule with one or more stereocenter, the enantiomer corresponds to the stereoisomer in which every stereocenter has the opposite configuration. An organic compound with only one stereogenic carbon is always chiral. On the other hand, an organic compound with multiple stereogenic carbons is typically, but not always, chiral. In particular, if the stereocenters are configured in such a way that the molecule can take a conformation having a plane of symmetry or an inversion point, then the molecule is achiral and is known as a  meso  compound ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6518", "text": "Molecules with chirality arising from one or more stereocenters are classified as possessing central chirality. There are two other types of stereogenic elements that can give rise to chirality, a stereogenic axis ( axial chirality ) and a stereogenic plane ( planar chirality ). Finally, the inherent curvature of a molecule can also give rise to chirality ( inherent chirality ). These types of chirality are far less common than central chirality.  BINOL  is a typical example of an axially chiral molecule, while  trans -cyclooctene  is a commonly cited example of a planar chiral molecule. Finally,  helicene  possesses helical chirality, which is one type of inherent chirality."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6519", "text": "Chirality is an important concept for  stereochemistry  and  biochemistry . Most substances relevant to  biology  are chiral, such as  carbohydrates  ( sugars ,  starch , and  cellulose ), all but one of the  amino acids  that are the building blocks of  proteins , and the  nucleic acids . Naturally occurring  triglycerides  are often chiral, but not always. In living organisms, one typically finds only one of the two enantiomers of a chiral compound. For that reason, organisms that consume a chiral compound usually can metabolize only one of its enantiomers. For the same reason, the two enantiomers of a chiral  pharmaceutical  usually have vastly different  potencies  or effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6520", "text": "The chirality of a molecule is based on the  molecular symmetry  of its conformations. A conformation of a molecule is chiral if and only if it belongs to the  C n ,  D n ,  T ,  O ,  I   point groups  (the chiral point groups). However, whether the molecule itself is considered to be chiral depends on whether its chiral conformations are persistent isomers that could be isolated as separated enantiomers, at least in principle, or the  enantiomeric  conformers rapidly interconvert at a given temperature and timescale through low-energy conformational changes (rendering the molecule achiral). For example, despite having chiral  gauche  conformers that belong to the  C 2  point group,  butane  is considered achiral at room temperature because rotation about the central C\u2013C bond rapidly interconverts the enantiomers (3.4 kcal/mol barrier). Similarly,  cis -1,2-dichlorocyclohexane consists of  chair conformers  that are nonidentical mirror images, but the two can interconvert via the cyclohexane chair flip (~10 kcal/mol barrier). As another example, amines with three distinct substituents (R 1 R 2 R 3 N:) are also regarded as achiral molecules because their enantiomeric pyramidal conformers rapidly undergo  pyramidal inversion ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6521", "text": "However, if the temperature in question is low enough, the process that interconverts the enantiomeric chiral conformations becomes slow compared to a given timescale.  The molecule would then be considered to be chiral at that temperature. The relevant timescale is, to some degree, arbitrarily defined: 1000 seconds is sometimes employed, as this is regarded as the lower limit for the amount of time required for chemical or chromatographic separation of enantiomers in a practical sense.  Molecules that are chiral at room temperature due to restricted rotation about a single bond (barrier to rotation \u2265 ca. 23 kcal/mol) are said to exhibit  atropisomerism ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6522", "text": "A chiral compound can contain no  improper axis of rotation  ( S n ), which includes planes of symmetry and inversion center. Chiral molecules are always dissymmetric (lacking  S n ) but not always asymmetric (lacking all symmetry elements except the trivial identity). Asymmetric molecules are always chiral. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6523", "text": "The following table shows some examples of chiral and achiral molecules, with the  Schoenflies notation  of the  point group  of the molecule. In the achiral molecules, X and Y (with no subscript) represent achiral groups, whereas X R  and X S  or Y R  and Y S  represent  enantiomers . Note that there is no meaning to the orientation of an  S 2  axis, which is just an inversion. Any orientation will do, so long as it passes through the center of inversion. Also note that higher symmetries of chiral and achiral molecules also exist, and symmetries that do not include those in the table, such as the chiral  C 3  or the achiral  S 4 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6524", "text": "An example of a molecule that does not have a mirror plane or an inversion and yet would be considered achiral is 1,1-difluoro-2,2-dichlorocyclohexane (or 1,1-difluoro-3,3-dichlorocyclohexane). This may exist in many conformers ( conformational isomers ), but none of them has a mirror plane. In order to have a mirror plane, the  cyclohexane  ring would have to be flat, widening the bond angles and giving the conformation a very high energy. This compound would not be considered chiral because the chiral conformers interconvert easily."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6525", "text": "An achiral molecule having chiral conformations could theoretically form a mixture of right-handed and left-handed crystals, as often happens with  racemic  mixtures of chiral molecules (see  Chiral resolution#Spontaneous resolution and related specialized techniques ), or as when achiral liquid  silicon dioxide  is cooled to the point of becoming chiral  quartz ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6526", "text": "A  stereogenic center  (or  stereocenter ) is an atom such that swapping the positions of two ligands (connected groups) on that atom results in a molecule that is stereoisomeric to the original.  For example, a common case is a  tetrahedral  carbon bonded to four distinct groups  a ,  b ,  c , and  d  (C abcd ), where swapping any two groups (e.g., C bacd ) leads to a stereoisomer of the original, so the central C is a stereocenter.  Many chiral molecules have point chirality, namely a single chiral stereogenic center that coincides with an atom. This stereogenic center usually has four or more bonds to different groups, and may be carbon (as in many biological molecules), phosphorus (as in many  organophosphates ), silicon, or a metal (as in many chiral  coordination compounds ). However, a stereogenic center can also be a trivalent atom whose bonds are not in the same plane, such as  phosphorus  in  P-chiral phosphines  (PRR\u2032R\u2033) and  sulfur  in  S-chiral sulfoxides  (OSRR\u2032), because a lone-pair of electrons is present instead of a fourth bond."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6527", "text": "Similarly, a stereogenic axis (or plane) is defined as an axis (or plane) in the molecule such that the swapping of any two ligands attached to the axis (or plane) gives rise to a stereoisomer.  For instance, the  C 2 -symmetric species   1,1\u2032-bi-2-naphthol  (BINOL) and 1,3-dichloro allene  have stereogenic axes and exhibit  axial chirality , while ( E )- cyclooctene  and many  ferrocene  derivatives bearing two or more substituents have stereogenic planes and exhibit  planar chirality ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6528", "text": "Chirality can also arise from isotopic differences between atoms, such as in the  deuterated   benzyl alcohol  PhCHDOH; which is chiral and optically active ([ \u03b1 ] D  = 0.715\u00b0), even though the non-deuterated compound PhCH 2 OH is not. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6529", "text": "If two enantiomers easily interconvert, the pure enantiomers may be practically impossible to separate, and only the racemic mixture is observable. This is the case, for example, of most amines with three different substituents (NRR\u2032R\u2033), because of the low  energy barrier  for  nitrogen inversion ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6530", "text": "When the optical  rotation  for an enantiomer is too low for practical measurement, the species is said to exhibit  cryptochirality ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6531", "text": "Chirality is an intrinsic part of the identity of a molecule, so the  systematic name  includes details of the  absolute configuration  ( R/S ,  D/L , or  other designations )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6532", "text": "Many biologically active molecules are chiral, including the naturally occurring  amino acids  (the building blocks of  proteins ) and  sugars ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6533", "text": "The origin of this  homochirality  in  biology  is the subject of much debate. [ 13 ]  Most scientists believe that Earth life's \"choice\" of chirality was purely random, and that if carbon-based life forms exist elsewhere in the universe, their chemistry could theoretically have opposite chirality. However, there is some suggestion that early amino acids could have formed in comet dust. In this case, circularly polarised radiation (which makes up 17% of stellar radiation) could have caused the selective destruction of one chirality of amino acids, leading to a selection bias which ultimately resulted in all life on Earth being homochiral. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6534", "text": "Enzymes , which are chiral, often distinguish between the two enantiomers of a chiral substrate. One could imagine an enzyme as having a glove-like cavity that binds a substrate. If this glove is right-handed, then one enantiomer will fit inside and be bound, whereas the other enantiomer will have a poor fit and is unlikely to bind."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6535", "text": "L -forms of amino acids tend to be tasteless, whereas  D -forms tend to taste sweet. [ 13 ]   Spearmint  leaves contain the  L -enantiomer of the chemical  carvone  or  R -(\u2212)-carvone and  caraway  seeds contain the  D -enantiomer or  S -(+)-carvone. [ 9 ]  The two smell different to most people because our olfactory  receptors  are chiral."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6536", "text": "Chirality is important in context of ordered phases as well, for example the addition of a small amount of an optically active molecule to a nematic phase (a phase that has long range orientational order of molecules) transforms that phase to a chiral nematic phase (or cholesteric phase). Chirality in context of such phases in polymeric fluids has also been studied in this context. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6537", "text": "Chirality is a symmetry property, not a property of any part of the periodic table. Thus many inorganic materials, molecules, and ions are chiral.  Quartz  is an example from the mineral kingdom. Such noncentric materials are of interest for applications in  nonlinear optics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6538", "text": "In the areas of  coordination chemistry  and  organometallic chemistry , chirality is pervasive and of practical importance. A famous example is  tris(bipyridine)ruthenium(II)  complex in which the three bipyridine ligands adopt a chiral propeller-like arrangement. [ 17 ]  The two enantiomers of complexes such as [Ru(2,2\u2032-bipyridine) 3 ] 2+  may be designated as \u039b (capital  lambda , the Greek version of \"L\") for a left-handed twist of the propeller described by the ligands, and \u0394 (capital  delta , Greek \"D\") for a right-handed twist (pictured). Also cf.  dextro- and levo- (laevo-) ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6539", "text": "Chiral ligands confer chirality to a metal complex, as illustrated by metal- amino acid  complexes. If the metal exhibits catalytic properties, its combination with a chiral ligand is the basis of  asymmetric catalysis . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6540", "text": "The term  optical activity  is derived from the interaction of chiral materials with polarized light. In a solution, the (\u2212)-form, or  levorotatory  form, of an optical isomer  rotates  the plane of a beam of  linearly polarized light   counterclockwise . The (+)-form, or  dextrorotatory  form, of an optical isomer does the opposite. The rotation of light is measured using a  polarimeter  and is expressed as the optical rotation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6541", "text": "Enantiomers can be separated by  chiral resolution . This often involves forming crystals of a salt composed of one of the enantiomers and an acid or base from the so-called  chiral pool  of naturally occurring chiral compounds, such as  malic acid  or the amine  brucine . Some racemic mixtures spontaneously crystallize into right-handed and left-handed crystals that can be separated by hand.  Louis Pasteur  used this method to separate left-handed and right-handed  sodium ammonium tartrate  crystals in 1849. Sometimes it is possible to seed a racemic solution with a right-handed and a left-handed crystal so that each will grow into a large crystal."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6542", "text": "Liquid chromatography (HPLC and TLC) may also be used as an analytical method for the direct separation of  enantiomers  and the control of enantiomeric purity, e.g.  active pharmaceutical ingredients  (APIs) which are chiral. [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6543", "text": "The rotation of plane polarized light by chiral substances was first observed by  Jean-Baptiste Biot  in 1812, [ 25 ]  and gained considerable importance in the  sugar industry , analytical chemistry, and pharmaceuticals.  Louis Pasteur  deduced in 1848 that this phenomenon has a molecular basis. [ 26 ] [ 27 ]  The term  chirality  itself was coined by  Lord Kelvin  in 1894. [ 28 ]  Different enantiomers or diastereomers of a compound were formerly called  optical isomers  due to their different optical properties. [ 29 ]  At one time, chirality was thought to be restricted to organic chemistry, but this misconception was overthrown by the resolution of a purely inorganic compound, a cobalt complex called  hexol , by  Alfred Werner  in 1911. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6544", "text": "In the early 1970s, various groups established that the  human olfactory organ  is capable of distinguishing chiral compounds. [ 9 ] [ 31 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6545", "text": "In  geometry , a figure is  chiral  (and said to have  chirality ) if it is not identical to its  mirror image , or, more precisely, if it cannot be mapped to its mirror image by  rotations  and  translations  alone. An object that is not chiral is said to be  achiral ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6546", "text": "A chiral object and its mirror image are said to be  enantiomorphs . The word  chirality  is derived from the Greek  \u03c7\u03b5\u03af\u03c1  (cheir), the hand, the most familiar chiral object; the word  enantiomorph  stems from the Greek  \u1f10\u03bd\u03b1\u03bd\u03c4\u03af\u03bf\u03c2  (enantios) 'opposite' +  \u03bc\u03bf\u03c1\u03c6\u03ae  (morphe) 'form'."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6547", "text": "Some chiral three-dimensional objects, such as the  helix , can be assigned a right or left  handedness , according to the  right-hand rule ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6548", "text": "Many other familiar objects exhibit the same chiral symmetry of the human body, such as gloves and shoes. Right shoes differ from left shoes only by being mirror images of each other. In contrast thin gloves may not be considered chiral if you can wear them  inside-out . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6549", "text": "The J-, L-, S- and Z-shaped  tetrominoes  of the popular video game  Tetris  also exhibit chirality, but only in a two-dimensional space. Individually they contain no mirror symmetry in the plane."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6550", "text": "A figure is achiral if and only if its  symmetry group  contains at least one  orientation-reversing  isometry. (In Euclidean geometry any  isometry  can be written as  \n \n \n \n v \n \u21a6 \n A \n v \n + \n b \n \n \n {\\displaystyle v\\mapsto Av+b} \n \n  with an  orthogonal matrix   \n \n \n \n A \n \n \n {\\displaystyle A} \n \n  and a vector  \n \n \n \n b \n \n \n {\\displaystyle b} \n \n . The  determinant  of  \n \n \n \n A \n \n \n {\\displaystyle A} \n \n  is either 1 or \u22121 then. If it is \u22121 the isometry is orientation-reversing, otherwise it is orientation-preserving."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6551", "text": "A general definition of chirality based on group theory exists. [ 2 ]  It does not refer to any orientation concept: an  isometry  is direct if and only if it is a product of squares of isometries, and if not, it is an indirect isometry. The resulting chirality definition works in spacetime. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6552", "text": "In two dimensions, every figure which possesses an  axis of symmetry  is achiral, and it can be shown that every  bounded  achiral figure must have an axis of symmetry. (An  axis of symmetry  of a figure  \n \n \n \n F \n \n \n {\\displaystyle F} \n \n  is a line  \n \n \n \n L \n \n \n {\\displaystyle L} \n \n , such that  \n \n \n \n F \n \n \n {\\displaystyle F} \n \n  is invariant under the mapping  \n \n \n \n ( \n x \n , \n y \n ) \n \u21a6 \n ( \n x \n , \n \u2212 \n y \n ) \n \n \n {\\displaystyle (x,y)\\mapsto (x,-y)} \n \n , when  \n \n \n \n L \n \n \n {\\displaystyle L} \n \n  is chosen to be the  \n \n \n \n x \n \n \n {\\displaystyle x} \n \n -axis of the coordinate system.) For that reason, a  triangle  is achiral if it is  equilateral  or  isosceles , and is chiral if it is  scalene ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6553", "text": "Consider the following pattern:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6554", "text": "This figure is chiral, as it is not identical to its mirror image:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6555", "text": "But if one prolongs the pattern in both directions to infinity, one receives an (unbounded) achiral figure which has no axis of symmetry. Its symmetry group is a  frieze group  generated by a single  glide reflection ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6556", "text": "In three dimensions, every figure that possesses a  mirror plane of symmetry   S 1 , an inversion center of symmetry  S 2 , or a higher  improper rotation  (rotoreflection)  S n  axis of symmetry [ 5 ]  is achiral. (A  plane of symmetry  of a figure  \n \n \n \n F \n \n \n {\\displaystyle F} \n \n  is a plane  \n \n \n \n P \n \n \n {\\displaystyle P} \n \n , such that  \n \n \n \n F \n \n \n {\\displaystyle F} \n \n  is invariant under the mapping  \n \n \n \n ( \n x \n , \n y \n , \n z \n ) \n \u21a6 \n ( \n x \n , \n y \n , \n \u2212 \n z \n ) \n \n \n {\\displaystyle (x,y,z)\\mapsto (x,y,-z)} \n \n , when  \n \n \n \n P \n \n \n {\\displaystyle P} \n \n  is chosen to be the  \n \n \n \n x \n \n \n {\\displaystyle x} \n \n - \n \n \n \n y \n \n \n {\\displaystyle y} \n \n -plane of the coordinate system. A  center of symmetry  of a figure  \n \n \n \n F \n \n \n {\\displaystyle F} \n \n  is a point  \n \n \n \n C \n \n \n {\\displaystyle C} \n \n , such that  \n \n \n \n F \n \n \n {\\displaystyle F} \n \n  is invariant under the mapping  \n \n \n \n ( \n x \n , \n y \n , \n z \n ) \n \u21a6 \n ( \n \u2212 \n x \n , \n \u2212 \n y \n , \n \u2212 \n z \n ) \n \n \n {\\displaystyle (x,y,z)\\mapsto (-x,-y,-z)} \n \n , when  \n \n \n \n C \n \n \n {\\displaystyle C} \n \n  is chosen to be the origin of the coordinate system.) Note, however, that there are achiral figures lacking both plane and center of symmetry. An example is the figure"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6557", "text": "which is invariant under the orientation reversing isometry  \n \n \n \n ( \n x \n , \n y \n , \n z \n ) \n \u21a6 \n ( \n \u2212 \n y \n , \n x \n , \n \u2212 \n z \n ) \n \n \n {\\displaystyle (x,y,z)\\mapsto (-y,x,-z)} \n \n  and thus achiral, but it has neither plane nor center of symmetry. The figure"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6558", "text": "also is achiral as the origin is a center of symmetry, but it lacks a plane of symmetry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6559", "text": "Achiral figures can have a  center axis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6560", "text": "A  knot  is called  achiral  if it can be continuously deformed into its mirror image, otherwise it is called a  chiral knot . For example, the  unknot  and the  figure-eight knot  are achiral, whereas the  trefoil knot  is chiral."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6561", "text": "A  chiral  phenomenon is one that is not identical to its  mirror image  (see the article on  mathematical chirality ). The  spin  of a  particle  may be used to define a  handedness , or helicity, for that particle, which, in the case of a massless particle, is the same as chirality. A   symmetry transformation  between the two is called  parity  transformation. Invariance under parity transformation by a  Dirac fermion  is called  chiral symmetry ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6562", "text": "The helicity of a particle is positive (\"right-handed\") if the direction of its  spin  is the same as the direction of its motion. It is negative (\"left-handed\") if the directions of spin and motion are opposite. So a standard  clock , with its spin vector defined by the rotation of its hands, has left-handed helicity if tossed with its face directed forwards."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6563", "text": "Mathematically,  helicity  is the sign of the projection of the  spin   vector  onto the  momentum   vector : \"left\" is negative, \"right\" is positive."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6564", "text": "The  chirality  of a particle is more abstract: It is determined by whether the particle transforms in a right- or left-handed  representation  of the  Poincar\u00e9 group . [ a ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6565", "text": "For massless particles \u2013  photons ,  gluons , and (hypothetical)  gravitons  \u2013 chirality is the same as  helicity ; a given massless particle appears to spin in the same direction along its axis of motion regardless of point of view of the observer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6566", "text": "For massive particles \u2013 such as  electrons ,  quarks , and  neutrinos  \u2013 chirality and helicity must be distinguished: In the case of these particles, it is possible for an observer to change to a  reference frame  moving faster than the spinning particle, in which case the particle will then appear to move backwards, and its helicity (which may be thought of as \"apparent chirality\") will be reversed. That is, helicity is a  constant of motion , but it is not  Lorentz invariant . Chirality is Lorentz invariant, but is not a constant of motion: a massive left-handed spinor, when propagating, will evolve into a right handed spinor over time, and vice versa."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6567", "text": "A  massless  particle moves with the  speed of light , so no real observer (who must always travel at less than the  speed of light ) can be in any reference frame where the particle appears to reverse its relative direction of spin, meaning that all real observers see the same helicity. Because of this, the direction of spin of massless particles is not affected by a change of inertial reference frame (a  Lorentz boost ) in the direction of motion of the particle, and the sign of the projection (helicity) is fixed for all reference frames: The helicity of massless particles is a  relativistic invariant  (a quantity whose value is the same in all inertial reference frames) which always matches the massless particle's chirality."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6568", "text": "The discovery of  neutrino oscillation  implies that  neutrinos have mass , so the  photon  is the only confirmed massless particle;  gluons  are expected to also be massless, although this has not been conclusively tested. [ b ]  Hence, these are the only two particles now known for which helicity could be identical to chirality, and only the  photon  has been confirmed by measurement. All other observed particles have mass and thus may have different helicities in different reference frames. [ c ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6569", "text": "Particle physicists have only observed or inferred left-chiral  fermions  and right-chiral antifermions engaging in the  charged weak interaction . [ 1 ]  In the case of the weak interaction, which can in principle engage with both left- and right-chiral fermions, only two left-handed  fermions  interact. Interactions involving right-handed or opposite-handed fermions have not been shown to occur, implying that the universe has a preference for left-handed chirality. This preferential treatment of one chiral realization over another violates parity, as first noted by  Chien Shiung Wu  in her famous experiment known as the  Wu experiment . This is a striking observation, since parity is a symmetry that holds for all other  fundamental interactions ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6570", "text": "Chirality for a  Dirac fermion   \u03c8  is defined through the  operator  \u03b3 5 , which has  eigenvalues  \u00b11; the eigenvalue's sign is equal to the particle's chirality: +1 for right-handed, \u22121 for left-handed. Any Dirac field can thus be projected into its left- or right-handed component by acting with the  projection operators   \u2060 1 / 2 \u2060 (1 \u2212  \u03b3 5 )  or  \u2060 1 / 2 \u2060 (1 +  \u03b3 5 )  on  \u03c8 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6571", "text": "The coupling of the charged weak interaction to fermions is proportional to the first projection operator, which is responsible for this interaction's  parity symmetry  violation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6572", "text": "A common source of confusion is due to conflating the  \u03b3 5 , chirality operator with the  helicity  operator. Since the helicity of massive particles is frame-dependent, it might seem that the same particle would interact with the weak force according to one frame of reference, but not another. The resolution to this paradox is that  the chirality operator is equivalent to helicity for massless fields only , for which helicity is not frame-dependent. By contrast, for massive particles, chirality is not the same as helicity, or, alternatively,  helicity is not Lorentz invariant, so there is no frame dependence of the weak interaction: a particle that couples to the weak force in one frame does so in every frame."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6573", "text": "A theory that is asymmetric with respect to chiralities is called a  chiral theory , while a non-chiral (i.e., parity-symmetric) theory is sometimes called a  vector theory . Many pieces of the  Standard Model  of physics are non-chiral, which is traceable to   anomaly cancellation  in chiral theories.  Quantum chromodynamics  is an example of a vector theory, since both chiralities of all quarks appear in the theory, and couple to gluons in the same way."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6574", "text": "The  electroweak theory , developed in the mid 20th century, is an example of a chiral theory. Originally, it assumed that  neutrinos were massless , and assumed the existence of only left-handed  neutrinos  and right-handed antineutrinos. After the observation of  neutrino oscillations , which imply that  neutrinos are massive  (like all other  fermions ) the revised  theories of the electroweak interaction  now include both right- and left-handed  neutrinos . However, it is still a chiral theory, as it does not respect parity symmetry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6575", "text": "The exact nature of the  neutrino  is still unsettled and so the  electroweak theories  that have been proposed are somewhat different, but most accommodate the chirality of  neutrinos  in the same way as was already done for all other  fermions ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6576", "text": "Vector  gauge theories  with massless Dirac fermion fields   \u03c8   exhibit chiral symmetry, i.e., rotating the left-handed and the right-handed components independently makes no difference to the theory. We can write this as the action of rotation on the fields:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6577", "text": "or"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6578", "text": "With  N   flavors , we have unitary rotations instead:  U( N ) L  \u00d7 U( N ) R ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6579", "text": "More generally, we write the right-handed and left-handed states as a projection operator acting on a spinor. The right-handed and left-handed projection operators are"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6580", "text": "and"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6581", "text": "Massive fermions do not exhibit chiral symmetry, as the mass term in the  Lagrangian ,    m \u03c8 \u03c8 ,  breaks chiral symmetry explicitly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6582", "text": "Spontaneous chiral symmetry breaking  may also occur in some theories, as it most notably does in  quantum chromodynamics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6583", "text": "The chiral symmetry transformation can be divided into a component that treats the left-handed and the right-handed parts equally, known as  vector symmetry , and a component that actually treats them differently, known as  axial symmetry . [ 2 ]  (cf.  Current algebra .) A scalar field model encoding chiral symmetry and its  breaking  is the  chiral model ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6584", "text": "The most common application is expressed as equal treatment of clockwise and counter-clockwise rotations from a fixed frame of reference."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6585", "text": "The general principle is often referred to by the name  chiral symmetry . The rule is absolutely valid in the  classical mechanics  of  Newton  and  Einstein , but results from  quantum mechanical  experiments show a difference in the behavior of left-chiral versus right-chiral  subatomic particles ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6586", "text": "Consider  quantum chromodynamics  (QCD) with two  massless   quarks   u  and  d  (massive fermions do not exhibit chiral symmetry). The Lagrangian reads"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6587", "text": "In terms of left-handed and right-handed spinors, it reads"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6588", "text": "(Here,  i  is the imaginary unit and  \n \n \n \n \n \n \n \n \u29f8 \n \n \n \n D \n \n \n \n {\\displaystyle \\displaystyle {\\not }D} \n \n  the  Dirac operator .)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6589", "text": "Defining"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6590", "text": "it can be written as"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6591", "text": "The Lagrangian is unchanged under a rotation of  q L  by any 2\u00d72 unitary matrix  L , and  q R  by any 2\u00d72 unitary matrix  R ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6592", "text": "This symmetry of the Lagrangian is called  flavor chiral symmetry , and denoted as  U(2) L  \u00d7 U(2) R .   It decomposes into"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6593", "text": "The singlet vector symmetry,  U(1) V ,  acts as"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6594", "text": "and thus invariant under  U(1)  gauge symmetry. This corresponds to  baryon number  conservation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6595", "text": "The singlet axial group   U(1) A   transforms as the following global transformation"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6596", "text": "However, it does not correspond to a conserved quantity, because the associated axial current is not conserved. It is explicitly violated by a  quantum anomaly ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6597", "text": "The remaining chiral symmetry  SU(2) L  \u00d7 SU(2) R  turns out to be  spontaneously broken  by a  quark condensate \n \n \n \n \n \n \u27e8 \n \n \n \n \n q \n \u00af \n \n \n \n \n R \n \n \n a \n \n \n \n q \n \n L \n \n \n b \n \n \n \u27e9 \n = \n v \n \n \u03b4 \n \n a \n b \n \n \n \n \n \n {\\displaystyle \\textstyle \\langle {\\bar {q}}_{\\text{R}}^{a}q_{\\text{L}}^{b}\\rangle =v\\delta ^{ab}} \n \n  formed through nonperturbative action of QCD gluons, into the diagonal vector subgroup  SU(2) V  known as  isospin . The  Goldstone bosons  corresponding to the three broken generators are the three  pions . \nAs a consequence, the effective theory of QCD bound states like the baryons, must now include mass terms for them, ostensibly disallowed by unbroken chiral symmetry. Thus, this  chiral symmetry breaking  induces the bulk of hadron masses, such as those for the  nucleons  \u2014 in effect, the bulk of the mass of all visible matter."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6598", "text": "In the real world, because of the nonvanishing and differing masses of the quarks,  SU(2) L  \u00d7 SU(2) R  is only an approximate symmetry [ 3 ]  to begin with, and therefore the pions are not massless, but have small masses: they are  pseudo-Goldstone bosons . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6599", "text": "For more  \"light\" quark species,  N   flavors   in general, the corresponding chiral symmetries are  U( N ) L  \u00d7 U( N ) R\u2032 ,  decomposing into"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6600", "text": "and exhibiting a very analogous  chiral symmetry breaking  pattern."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6601", "text": "Most usually,  N  = 3  is taken, the u, d, and s quarks taken to be light (the  eightfold way ), so then approximately massless for the symmetry to be meaningful to a lowest order, while the other three quarks are sufficiently heavy to barely have a residual chiral symmetry be visible for practical purposes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6602", "text": "In  theoretical physics , the  electroweak  model breaks  parity  maximally. All its  fermions  are chiral  Weyl fermions , which means that the charged  weak gauge bosons W +  and W \u2212  only couple to left-handed quarks and leptons. [ d ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6603", "text": "Some theorists found this objectionable, and so conjectured a  GUT  extension of the  weak force  which has new, high energy  W\u2032 and Z\u2032 bosons , which  do  couple with right handed quarks and leptons:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6604", "text": "to"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6605", "text": "Here,  SU(2) L  (pronounced \" SU(2)  left\") is  SU(2) W  from above, while  B\u2212L  is the  baryon number  minus the  lepton number . The electric charge formula in this model is given by"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6606", "text": "where  \n \n \n \n \u00a0 \n \n T \n \n \n 3 \n L \n \n \n \n \u00a0 \n \n \n {\\displaystyle \\ T_{\\rm {3L}}\\ } \n \n  and  \n \n \n \n \u00a0 \n \n T \n \n \n 3 \n R \n \n \n \n \u00a0 \n \n \n {\\displaystyle \\ T_{\\rm {3R}}\\ } \n \n  are the left and right  weak isospin  values of the fields in the theory."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6607", "text": "There is also the  chromodynamic   SU(3) C . The idea was to restore parity by introducing a  left-right symmetry . This is a  group extension  of  \n \n \n \n \n \n Z \n \n \n 2 \n \n \n \n \n {\\displaystyle \\mathbb {Z} _{2}} \n \n  (the left-right symmetry) by"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6608", "text": "to the  semidirect product"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6609", "text": "This has two  connected components  where  \n \n \n \n \n \n Z \n \n \n 2 \n \n \n \n \n {\\displaystyle \\mathbb {Z} _{2}} \n \n  acts as an  automorphism , which is the composition of an  involutive   outer automorphism  of  SU(3) C  with the interchange of the left and right copies of  SU(2)  with the reversal of  U(1) B\u2212L . It was shown by  Mohapatra  &  Senjanovic  (1975) [ 5 ]  that  left-right symmetry  can be  spontaneously broken  to give a chiral low energy theory, which is the Standard Model of Glashow, Weinberg, and Salam, and also connects the small observed neutrino masses to the breaking of left-right symmetry via the  seesaw mechanism ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6610", "text": "In this setting, the chiral  quarks"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6611", "text": "are unified into an  irreducible representation  (\"irrep\")"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6612", "text": "The  leptons  are also unified into an  irreducible representation"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6613", "text": "The  Higgs bosons  needed to implement the breaking of left-right symmetry down to the Standard Model are"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6614", "text": "This then provides three  sterile neutrinos  which are perfectly consistent with current [update]   neutrino oscillation  data. Within the seesaw mechanism, the sterile neutrinos become superheavy without affecting physics at low energies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6615", "text": "Because the left\u2013right symmetry is spontaneously broken, left\u2013right models predict  domain walls . This left-right symmetry idea first appeared in the  Pati\u2013Salam model  (1974) [ 6 ]  and Mohapatra\u2013Pati models (1975). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6616", "text": "Chirality timeline  presents a timeline of landmark events that unfold the developments happened in the field of  chirality ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6617", "text": "Many molecules come in two forms that are mirror images of each other, just like our hands. This type of molecule is called chiral. In nature, one of these forms is usually more common than the other. In our cells, one of these mirror images of a molecule fits \"like a glove,\" while the other may be harmful. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6618", "text": "In nature, molecules with chirality include  hormones ,  DNA ,  antibodies , and  enzymes . For example,  (R)-limonene  smells like oranges, while  (S)-limonene  smells like lemons. Both molecules have the same chemical formula, but their spatial orientations are different, which makes a big difference in their biological properties. Chiral molecules in the receptors in our noses can tell the difference between these things. Chirality affects biochemical reactions, and the way a drug works depends on what kind of enantiomer it is. Many drugs are chiral and it is important that the shape of the drug matches the shape of the cell receptor it is meant to affect. Mismatching will make the drug less effective, which could be a matter of life and death, as happened with  thalidomide  in the 1960s. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6619", "text": "It has long been known that structural factors, particularly chirality and stereochemistry, have a big impact on  pharmacological efficacy  and  pharmacokinetic behavior . Since more than a century ago, pertinent information pertaining to chirality has been accumulating in numerous fields, in particular, physics, chemistry and biology, at an accelerated rate, giving rise to more comprehensive and in-depth reasoning, conceptions, and ideas. [ 5 ] [ 6 ] [ 7 ] [ 8 ]  This page offers a chronology of significant contributions that have been made in the journey of chirality [1809 to 2021]."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6620", "text": "1958"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6621", "text": "Harold Scott MacDonald  \" Donald \"  Coxeter   CC   FRS   FRSC  (9 February 1907 \u2013 31 March 2003) [ 2 ]  was a British-Canadian  geometer  and mathematician. He is regarded as one of the greatest geometers of the 20th century. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6622", "text": "Coxeter was born in England and educated at the  University of Cambridge , with student visits to  Princeton University . He worked for 60 years at the  University of Toronto  in Canada, from 1936 until his retirement in 1996, becoming a full professor there in 1948. His many honours included membership in the  Royal Society of Canada , the  Royal Society , and the  Order of Canada ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6623", "text": "He was an author of 12 books, including  The Fifty-Nine Icosahedra  (1938) and  Regular Polytopes  (1947). Many concepts in geometry and  group theory  are named after him, including the  Coxeter graph ,  Coxeter groups ,  Coxeter's loxodromic sequence of tangent circles ,  Coxeter\u2013Dynkin diagrams , and the  Todd\u2013Coxeter algorithm ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6624", "text": "Coxeter was born in  Kensington , England, to Harold Samuel Coxeter and Lucy ( n\u00e9e \u00a0Gee ). His father had taken over the family business of Coxeter & Son, manufacturers of surgical instruments and compressed gases (including a mechanism for anaesthetising surgical patients with  nitrous oxide ), but was able to retire early and focus on sculpting and baritone singing; Lucy Coxeter was a portrait and landscape painter who had attended the  Royal Academy of Arts . A maternal cousin was the architect Sir  Giles Gilbert Scott . [ 4 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6625", "text": "In his youth, Coxeter composed music and was an accomplished pianist at the age of 10. [ 5 ]  He felt that  mathematics and music  were intimately related, outlining his ideas in a 1962 article on \"Music and Mathematics\" in the  Canadian Music Journal . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6626", "text": "He was educated at  King Alfred School, London , and  St George's School, Harpenden , where his best friend was John Flinders Petrie, later a mathematician for whom  Petrie polygons  were named. He was accepted at  King's College, Cambridge , in 1925, but decided to spend a year studying in hopes of gaining admittance to  Trinity College , where the standard of mathematics was higher. [ 2 ]  Coxeter won an entrance scholarship and went to Trinity in 1926 to read mathematics. There he earned his BA (as  Senior Wrangler ) in 1928, and his doctorate in 1931. [ 5 ] [ 6 ]  In 1932 he went to  Princeton University  for a year as a  Rockefeller Fellow , where he worked with  Hermann Weyl ,  Oswald Veblen , and  Solomon Lefschetz . [ 6 ]  Returning to Trinity for a year, he attended  Ludwig Wittgenstein 's seminars on the  philosophy of mathematics . [ 5 ]  In 1934 he spent a further year at Princeton as a Procter Fellow. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6627", "text": "In 1936 Coxeter moved to the University of Toronto. In 1938 he and  P. Du Val , H. T. Flather, and  John Flinders Petrie  published  The Fifty-Nine Icosahedra  with  University of Toronto Press . In 1940 Coxeter edited the eleventh edition of  Mathematical Recreations and Essays , [ 7 ]  originally published by  W. W. Rouse Ball  in 1892. He was elevated to  professor  in 1948. He was elected a Fellow of the  Royal Society of Canada  in 1948 and a  Fellow of the Royal Society  in 1950. He met  M. C. Escher  in 1954 and the two became lifelong friends; his work on geometric figures helped inspire some of Escher's works, particularly the  Circle Limit  series based on  hyperbolic   tessellations . He also inspired some of the innovations of  Buckminster Fuller . [ 6 ]  Coxeter,  M. S. Longuet-Higgins  and  J. C. P. Miller  were the first to publish the full  list of uniform polyhedra  (1954). [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6628", "text": "He worked for 60 years at the  University of Toronto  and published twelve books."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6629", "text": "Coxeter was a  vegetarian . He attributed his longevity to his vegetarian diet, daily exercise such as fifty press-ups and standing on his head for fifteen minutes each morning, and consuming a nightly cocktail made from  Kahl\u00faa  (a coffee liqueur),  peach schnapps , and  soy milk . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6630", "text": "Since 1978, the  Canadian Mathematical Society  have awarded the  Coxeter\u2013James Prize  in his honor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6631", "text": "He was made a  Fellow of the Royal Society  in 1950 and in 1997 he was awarded their  Sylvester Medal . [ 6 ]  In 1990, he became a Foreign Member of the  American Academy of Arts and Sciences [ 9 ]  and in 1997 was made a  Companion  of the  Order of Canada . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6632", "text": "In 1973 he received the  Jeffery\u2013Williams Prize . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6633", "text": "A  festschrift  in his honour,  The Geometric Vein , was published in 1982. It contained 41 essays on geometry, based on a symposium for Coxeter held at Toronto in 1979. [ 11 ]   A second such volume,  The Coxeter Legacy , was published in 2006 based on a Toronto Coxeter symposium held in 2004. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6634", "text": "The  Edinburgh Handedness Inventory  is a measurement scale used to assess the dominance of a person's right or left hand in everyday activities, sometimes referred to as  laterality . The inventory can be used by an observer assessing the person, or by a person self-reporting hand use. The latter method tends to be less reliable due to a person over-attributing tasks to the dominant hand."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6635", "text": "The Edinburgh Handedness Inventory was published in 1971 by Richard Carolus Oldfield [ 1 ]  and has been used in various scientific studies [ 2 ] [ 3 ]  as well as popular literature. [ 4 ]  According to Google Scholar it has been cited tens of thousands of times. Within the very substantial literature on handedness it is used far more than any rival, such as FLANDERS, or the Annett Hand Preference Questionnaire, which is not good at eliciting either-hand responses. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6636", "text": "Nevertheless, profound dissatisfaction with the Inventory has been expressed [ 6 ] [ 7 ]  and statistical analysis of the Inventory has shown that the two-handed items broom and box are poorly correlated with the other eight items, while drawing is too highly correlated with writing to add information. [ 8 ] [ 9 ]  A major revision has been published. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6637", "text": "An  enantiopure drug  is a pharmaceutical that is available in one specific  enantiomeric  form. Most biological molecules (proteins, sugars, etc.) are present in only one of many  chiral  forms, so different enantiomers of a  chiral drug  molecule bind differently (or not at all) to target  receptors . Chirality can be observed when the geometric properties of an object is not superimposable with its mirror image. Two forms of a molecule are formed (both mirror images) from a chiral carbon, these two forms are called enantiomers. One enantiomer of a drug may have a desired beneficial effect while the other may cause serious and undesired side effects, or sometimes even beneficial but entirely different effects. [ 1 ]  The desired enantiomer is known as an eutomer while the undesired enantiomer is known as the distomer. [ 2 ]  When equal amounts of both enantiomers are found in a mixture, the mixture is known as a racemic mixture. If a mixture for a drug does not have a 1:1 ratio of its enantiomers it is a candidate for an enantiopure drug. Advances in industrial chemical processes have made it economical for pharmaceutical manufacturers to take drugs that were originally marketed as a racemic mixture and market the individual enantiomers, either by specifically manufacturing the desired enantiomer or by  resolving  a  racemic mixture . On a case-by-case basis, the  U.S. Food and Drug Administration  (FDA) has allowed single enantiomers of certain drugs to be marketed under a different name than the racemic mixture. [ 3 ]  Also case-by-case, the United States Patent Office has granted patents for single enantiomers of certain drugs. The regulatory review for marketing approval (safety and efficacy) and for patenting (proprietary rights) is independent, and differs country by country."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6638", "text": "In 1848, Louis Pasteur became the first scientist to discover chirality and enantiomers while he was working with tartaric acid. During the experiments, he noticed that there were two crystal structures produced but these structures looked to be non-superimposable mirror images of each other; this observation of isomers that were non-superimposable mirror images became known as enantiomers. A couple years later, in 1857, Pasteur then discovered enantioselectivity when he noticed that the two enantiomer structures he had previously discovered metabolized at much different speeds. This suggested that one configuration was preferred over the other in vivo. As organic chemistry knowledge became more advanced, the discovery of enantioselectivity was used in the creation of enantiopure drugs. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6639", "text": "The formation of an enantiopure drug results from the separation of the enantiomers of a chiral drug. This separation was prompted when it was found that each enantiomer of a molecule can have different effects when used in drugs. This is because the body is very chiral selective reacting to each enantiomer differently and therefore producing different pharmaceutical effects. The use of a drug with a single enantiomer makes the drug more effective. Before a drug of a pure enantiomer can be formed, the two enantiomers must first be separated and tested. Three main techniques are used for this separation: capillary gas chromatography, high performance liquid chromatography, and capillary electrophoresis. Other technique such as chiral crystallization, enzyme-based kinetic separation, and enantioselective synthesis are also used. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6640", "text": "The body of living organisms are composed of many enantiopure chiral substances. For example, amino acids that make up the proteins in the body have the same configuration, L-absolute configuration. Because of this specificity, vital processes such as constructing proteins, rely on stereoselectivity to ensure that out of all the potential enantiomers available, the body is utilizing the correct enantiopure compound. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6641", "text": "Selectivity  is a very important part of organic synthesis. In scientific papers regarding synthesis, selectivity is often listed in data tables alongside percent yield and other reaction conditions. While selectivity is deemed important in scientific literature, it has been challenging to effectively implement selectivity in  drug development  and production. A major issue with selectivity in  pharmaceuticals  is that a large percentage of drug syntheses by nature are not selective reactions, racemic mixtures are formed as the products. Separating racemic mixtures into their respective enantiomers takes extra time, money, and energy. One way to separate enantiomers is to chemically convert them into species that can be separated: diastereomers.  Diastereomers , unlike enantiomers, have entirely different physical properties\u2014boiling points, melting points, NMR shifts, solubilities\u2014and they can be separated by conventional means such as  chromatography  or  recrystallization . This is a whole extra step in the synthesis process and not desirable from a manufacturing standpoint. [ 7 ]  As a result, a number of pharmaceuticals are synthesized and marketed as a racemic mixture of enantiomers in cases where the less-effective enantiomer is benign. However, by identifying and specifically purifying the enantiomer which effectively binds to its respective  binding site  in the body, less of the drug would be needed to achieve the desired effect. [ 8 ]  With the improvement of chiral technology, a rich repertoire of enantioselective chromatographic methods have become available for the separation of drug enantiomers on the analytical, [ 9 ]  preparative, [ 10 ]  and industrial scales. [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6642", "text": "According to the FDA, the stereoisomeric composition of a chiral drug should be known, and its effects should be well-characterized from pharmacologic, toxicologic, and clinical standpoints. In order to profile the different stereoisomers of enantiopure drugs, manufacturers are urged to develop quantitative assays for individual enantiomers in  in vivo  samples early in the development stage."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6643", "text": "Ideally, the main pharmacologic activities of the isomers should be compared in  in vitro  systems in animals. During instances when toxic findings are present beyond the natural extensions of the pharmacologic effects of the drug, toxicologic evaluation of the individual isomers in question must be completed. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6644", "text": "When drugs are covered under patent protection, only the pharmaceutical company that holds the patent is allowed to manufacture, market, and eventually profit from them. The lifetime of the patent varies between countries and also between drugs; in the United States, most drug patents last about twenty years. [ 14 ]  Once the patent has expired, the drug can be manufactured and sold by other companies - at which point, it is referred to as a  generic drug . Its availability on the market as a generic drug removes the monopoly of the patent holder, thereby encouraging competition and causing a significant drop in drug prices, which ensures that life-saving and important drugs reach the general population at fair prices. However, the company holding the initial patent may get a new patent by forming a new version of the drug that is significantly changed compared to the original compound. [ 15 ]  Patentability of different isomers has been controversial over the past ten years and there have been a number of related legal issues. In making their determinations, courts have looked at factors including: (i) Whether the racemate was known in the prior art. (ii) The difficulty in resolving the enantiomers. (iii) The  stereoselectivity  of the relevant receptor. (iv) Other secondary considerations of non-obviousness such as commercial success, unexpected results, and satisfaction of long-felt needs in the art. The decisions made regarding these issues have varied and there is no clear answer to the legality of patenting stereoisomers. These issues have been resolved on a case-by-case basis. [ 16 ]  With the number of current pharmaceuticals currently being marketed as  racemic mixtures , it is likely that patentability will continue to be debated in the near future."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6645", "text": "[ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6646", "text": "There are examples of common drugs, like ibuprofen, where the use of chiral switching has caused controversy. Ibuprofen is a racemic mixture where the S-enantiomer is known to play a major role in reducing inflammation as it inhibits COX-2 (cooxygenase 2) compared to the R-enantiomer; the fact that the S-enantiomer is stronger is what led to the chiral switching. But, when the racemic ibuprofen enters the body, a little over half of the R-enantiomers experience chiral inversion and transform into the favored S-enantiomer. This observation has led to a conclusion that the racemic and the S-enantiomer are potentially biologically equivalent. Because of this and the more recent evidence suggesting that the R-enantiomer may actually contribute to COX-2 inhibition, as well, but at a slower rate, there is still debate on whether or not the chiral switching seen in ibuprofen is really advantageous or if it is just to give patent protections to the manufacturers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6647", "text": "The following table lists pharmaceuticals that have been available in both  racemic  and single- enantiomer  form. These single-enantiomer drug switched from the respective racemic drug are referred to as  chiral switch ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6648", "text": "The following are cases where the individual enantiomers have markedly different effects:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6649", "text": "In  human biology ,  footedness  is the natural preference of one's left or right  foot  for various purposes. It is the foot equivalent of  handedness . While purposes vary, such as applying the greatest force in a certain foot to complete the action of kick as opposed to stomping, footedness is most commonly associated with the preference of a particular foot in the leading position while engaging in foot- or kicking-related sports, such as  association football  and  kickboxing . A person may thus be  left-footed ,  right-footed  or  ambipedal  (able to use both feet equally well)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6650", "text": "In  association football , the ball is predominantly struck by the foot. Footedness may refer to the foot a player uses to kick with the greatest force and skill. Most people are right-footed, kicking with the right leg. [ 1 ]  Capable left-footed footballers are rare and therefore quite sought after. [ 2 ]  As rare are \"two-footed\" players, who are equally capable with both feet. Such players make up only one sixth of players in the top professional leagues in Europe. [ 3 ]  Two-footedness can be learnt, a notable case being England international  Tom Finney , but can only be properly developed in the early years. [ 3 ]  In  Australian Rules Football , several players are equally adept at using both feet to kick the ball, such as  Sam Mitchell  and Charles Bushnell (footballer, retired). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6651", "text": "In  basketball , a sport composed almost solely of right-handed players, it is common for most athletes to have a dominant left leg which they would use when jumping to complete a right-hand layup. [ citation needed ]  Hence, left-handed basketball players tend to use their right leg more as they finish a left handed layup (although both right- and left-handed players are usually able to use both hands when finishing near the basket)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6652", "text": "In the  National Football League  (NFL)  placekickers  and  punters  who kick with their left leg are a relative rarity. As of the  2023 NFL season , only four of the league's 32 punters were left-footed.  [ 5 ]  The apparent advantage to punting with the left foot is that, because it is not as common,  return specialists  are not as experienced handling the ball spinning in the opposite direction. [ 6 ]  Left-footed placekickers are similarly uncommon."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6653", "text": "In  boardsports  (e.g., surfing, skateboarding and snowboarding), one stands erect on a single, lightweight board that slides along the ground or on water. The need for balance causes one to position the body perpendicular to the direction of motion, with one foot leading the other. As with handedness, when this task is repetitively performed, one tends to naturally choose a particular foot for the leading position."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6654", "text": "Boardsport riders are \"footed\" in one of two stances, generally called \"regular\" and \"goofy\". Riders will generally quickly choose a preferred stance that becomes permanently preferred. A \"regular\" stance indicates the left foot leading on the board with the right foot pushing, while a \"goofy\" stance leads with the right foot on the board, pushing with the left. [ 7 ]  Professionals seem to be evenly distributed between the stances. Practice can yield a high level of  ambidexterity  between the two stances, such that even seasoned participants of a boardsport have difficulty discerning the natural footedness of an unfamiliar rider in action."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6655", "text": "To increase the difficulty, variety, and aesthetic value of tricks, riders can ride \"switch stance\" (abbreviated to \"switch\"). For example, a goofy-footed skateboarder normally performs an  ollie  with the right foot forward, but a \"switch ollie\" would have the rider standing with the left foot at the front of the board. In sports where switch riding is common and expected, like  street skateboarding , riders have the goal of appearing natural at, and performing the same tricks in, both regular and goofy stances. Some sports like  kitesurfing  and  windsurfing  generally require the rider to be able to switch stance depending on the wind or travel direction rather than rider preference. Each time direction is changed, the stance changes. Snowboarders who ride switch may adopt a \"duck stance\", where the feet are mounted turned out, or pointed away from the mid-line of the body, typically at a roughly 15-degree angle. In this position, the rider will have the leading foot facing forward in either regular or switch stance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6656", "text": "When a rider rolls backwards, this is called \"riding  fakie \". A \"fakie\" trick is performed while riding backwards but taking off on the front foot. Although it is the same foot that jumps in one's traditional stance, it is normally the back foot. A rider can also land in the fakie position."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6657", "text": "While there are some parallels between switch stance and fakie, riding switch implies opening the shoulders more to face the direction headed, though not as much as in traditional stance, while fakie stance implies a slightly more backwards facing, closed shoulder posture. \""}
{"_id": "WikiPedia_Pharmacology$$$corpus_6658", "text": "Nollie  (nose ollie) is when the front foot takes off when one is riding in their normal stance, the same foot that jumps when doing tricks switch. In nollie position, the body and shoulders are facing forward as much as when riding in normal stance. Generally fakie and normal are done off the tail, whereas nollie and switch are done off the nose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6659", "text": "In skateboarding, most tricks that are performed riding backwards \u2014 with respect to the rider's preferred stance \u2014 are exclusively categorized as \"switch\" (in a switch stance) or as fakie, with the general rule that tricks off the  tail  are almost always described as fakie, and those off the nose are nollie. For example, a jump using the tail rolling backwards is a \"fakie  ollie \" (not a \"switch nollie\"), and a jump off the nose is a \"nollie\" (not a \"fakie nollie\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6660", "text": "Mongo foot refers to the use of the rider's front foot for pushing. Normally, a skateboarder will feel more comfortable using their back foot to push, while their front foot remains on the board. In the minority case of mongo-footed skateboarders, the opposite is true. Some skateboarders who do not push mongo in their regular stance may still push mongo when riding in switch stance, rather than push with their weaker back foot. Some well-known skaters who change between mongo and normal when pushing switch include Jacob Vance,  Stevie Williams , and  Eric Koston ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6661", "text": "Although its origins remain uncertain, it is widely believed that the term derives from the pejorative use of \" mongoloid \". [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6662", "text": "In  BMX , there is a  de facto  relationship between footedness and preferences of grinding position and of mid-air turning direction. The terms \"regular\" and \"goofy\" do not indicate a foot preference as in boardsports, but rather whether the rider's footedness has the usual relationship with their grinding and mid-air turning preferences. For example, consider the following classes of riders:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6663", "text": "Both classes are of equal size and would be considered \"regular\". \"Goofy\" would describe riders whose trick preferences do not match their footedness: a rider who prefers to grind on the opposite side as do most is considered a \"goofy grinder\"; one who prefers to turn the opposite direction in mid-air as do most is considered a \"goofy spinner\". Few riders have either goofy trait, but some riders may have both. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6664", "text": "In  human biology ,  handedness  is an individual's preferential use of one  hand , known as the  dominant hand , due to it being stronger, faster or more  dextrous . The other hand, comparatively often the weaker, less dextrous or simply less subjectively preferred, is called the  non-dominant hand . [ 2 ] [ 3 ] [ 4 ]  In a study from 1975 on 7,688 children in US grades 1\u20136, left handers comprised 9.6% of the sample, with 10.5% of male children and 8.7% of female children being left-handed. [ 5 ] [ 6 ] [ 7 ]  Overall, around 90% of people are right-handed. [ 8 ]  Handedness is often defined by one's writing hand, as it is fairly common for people to prefer to do a particular task with a particular hand. There are people with true  ambidexterity  (equal preference of either hand), but it is rare\u2014most people prefer using one hand for most purposes. However, in some cultures, the use of the left hand can be considered disrespectful."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6665", "text": "Most of the current research suggests that left-handedness has an  epigenetic  marker\u2014a combination of genetics, biology and the environment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6666", "text": "Because the vast majority of the population is right-handed, many devices are designed for use by right-handed people, making their use by left-handed people more difficult. [ 9 ]  In many countries, left-handed people are or were required to write with their right hands. However, left-handed people have an advantage in  sports  that involve aiming at a target in an area of an opponent's control, as their opponents are more accustomed to the right-handed majority. As a result, they are over-represented in  baseball ,  tennis ,  fencing , [ 10 ]   cricket ,  boxing , [ 11 ] [ 12 ]  and  mixed martial arts . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6667", "text": "Handedness may be measured behaviourally (performance measures) or through questionnaires (preference measures). The  Edinburgh Handedness Inventory  has been used since 1971 but contains some dated questions and is hard to score. Revisions have been published by Veale [ 19 ]  and by Williams. [ 20 ]  The longer Waterloo Handedness Questionnaire is not widely accessible. More recently, the Flinders Handedness Survey (FLANDERS) has been developed. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6668", "text": "Some non-human primates have a preferred hand for tasks, but they do not display a strong right-biased preference like modern humans, with individuals equally split between right-handed and left-handed preferences. When exactly a right handed preference developed in the human lineage is unknown, though it is known through various means that  Neanderthals  had a right-handedness bias like modern humans. Attempts to determine handedness of early humans by analysing the morphology of lithic artefacts have been found to be unreliable. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6669", "text": "There are several theories of how handedness develops."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6670", "text": "Handedness displays a complex inheritance pattern. For example, if both parents of a child are left-handed, there is a 26% chance of that child being left-handed. [ 23 ]  A large study of twins from 25,732 families by Medland et al. (2006) indicates that the  heritability  of handedness is roughly 24%. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6671", "text": "Two theoretical single-gene models have been proposed to explain the patterns of inheritance of handedness, by Marian Annett [ 25 ]  of the  University of Leicester , and by Chris McManus [ 23 ]  of  UCL ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6672", "text": "However, growing evidence from  linkage  and  genome-wide association  studies suggests that genetic variance in handedness cannot be explained by a single genetic  locus . [ 26 ] [ 27 ] [ 28 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ] [ 33 ] [ excessive citations ]  From these studies, McManus et al. now conclude that handedness is  polygenic  and estimate that at least 40  loci  contribute to the trait. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6673", "text": "Brandler et al. performed a  genome-wide association study  for a measure of relative hand skill and found that genes involved in the determination of  left-right asymmetry  in the body play a key role in handedness. [ 35 ]  Brandler and  Paracchini  suggest the same mechanisms that determine left-right asymmetry in the body (e.g.  nodal signaling  and  ciliogenesis ) also play a role in the development of  brain asymmetry \n(handedness being a reflection of brain asymmetry for motor function). [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6674", "text": "In 2019, Wiberg et al. performed a genome-wide association study and found that handedness was significantly associated with four loci, three of them in genes encoding proteins involved in brain development. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6675", "text": "Four studies have indicated that individuals who have had in-utero exposure to  diethylstilbestrol  (a synthetic  estrogen -based medication used between 1940 and 1971) were more likely to be left-handed over the clinical control group. Diethylstilbestrol animal studies \"suggest that estrogen affects the developing brain, including the part that governs sexual behavior and right and left dominance\". [ 38 ] [ 39 ] [ 40 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6676", "text": "Another theory is that  ultrasound  may sometimes affect the brains of unborn children, causing higher rates of left-handedness in children whose mothers receive ultrasound during pregnancy. Research suggests there may be a weak association between  ultrasound screening  (sonography used to check the healthy development of the fetus and mother) and left-handedness. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6677", "text": "Twin studies  indicate that genetic factors explain 25% of the variance in handedness, and environmental factors the remaining 75%. [ 43 ]  While the molecular basis of handedness  epigenetics  is largely unclear, Ocklenburg et al. (2017) found that asymmetric  methylation  of  CpG sites  plays a key role for  gene expression  asymmetries related to handedness. [ 44 ] [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6678", "text": "One common handedness theory is the brain hemisphere division of labor. In most people, the left side of the brain controls speaking. The theory suggests it is more efficient for the brain to divide major tasks between the hemispheres\u2014thus most people may use the non-speaking (right) hemisphere for perception and gross motor skills. As speech is a very complex motor control task, the specialised fine motor areas controlling speech are most efficiently used to also control fine motor movement in the dominant hand. As the right hand is controlled by the left hemisphere (and the left hand is controlled by the right hemisphere) most people are, therefore right-handed. The theory depends on left-handed people having a reversed organisation. [ 46 ]  However, the majority of left-handers have been found to have left-hemisphere language dominance\u2014just like right-handers. [ 47 ] [ 48 ]  Only around 30% of left-handers are not left-hemisphere dominant for language. Some of those have reversed brain organisation, where the verbal processing takes place in the right-hemisphere and visuospatial processing is dominant to the left hemisphere. [ 49 ]  Others have more ambiguous bilateral organisation, where both hemispheres do parts of typically lateralised functions. When tasks designed to investigate lateralisation (preference for handedness) are averaged across a group of left-handers, the overall effect is that left-handers show the same pattern of data as right-handers, but with a reduced asymmetry. [ 50 ]  This finding is likely due to the small proportion of left-handers who have atypical brain organisation. [ citation needed ]  The majority of the evidence comes from literature assessing oral language production and comprehension. When it comes to writing, findings from recent studies were inconclusive for a difference in lateralization for writing between left-handers and right-handers.  [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6679", "text": "Researchers studied fetuses in utero and determined that handedness in the womb was a very accurate predictor of handedness after birth. [ 52 ]  In a 2013 study, 39% of infants (6 to 14 months) and 97% of toddlers (18 to 24 months) demonstrated a hand preference. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6680", "text": "Infants have been observed to fluctuate heavily when choosing a hand to lead in grasping and object manipulation tasks, especially in one- versus two-handed grasping. Between 36 and 48 months, there is a significant decline in variability between handedness in one-handed grasping; it can be seen earlier in two-handed manipulation. Children of 18\u201336 months showed more hand preference when performing bi-manipulation tasks than with simple grasping. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6681", "text": "The decrease in handedness variability in children of 36\u201348 months may be attributable to preschool or kindergarten attendance due to increased single-hand activities such as writing and coloring. [ 54 ]  Scharoun and Bryden noted that right-handed preference increases with age up to the teenage years. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6682", "text": "The modern turn in handedness research has been towards emphasizing degree rather than direction of handedness as a critical variable. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6683", "text": "In his book  Right-Hand, Left-Hand , Chris McManus of  University College London  argues that the proportion of left-handers is increasing, and that an above-average quota of high achievers have been left-handed. He says that left-handers' brains are structured in a way that increases their range of abilities, and that the genes that determine left-handedness also govern development of the brain's language centers. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6684", "text": "Writing in  Scientific American , he states:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6685", "text": "Studies in the U.K., U.S. and Australia have revealed that left-handed people differ from right-handers by only one IQ point, which is not noteworthy ... Left-handers' brains are structured differently from right-handers' in ways that can allow them to process language, spatial relations and emotions in more diverse and potentially creative ways. Also, a slightly larger number of left-handers than right-handers are especially gifted in music and math. A study of musicians in professional orchestras found a significantly greater proportion of talented left-handers, even among those who played instruments that seem designed for right-handers, such as violins. Similarly, studies of adolescents who took tests to assess mathematical giftedness found many more left-handers in the population. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6686", "text": "Left-handers are overrepresented among those with lower cognitive skills and mental impairments, with those with  intellectual disability  being roughly twice as likely to be left-handed, as well as generally lower cognitive and non-cognitive abilities amongst left-handed children. [ 58 ]  Left-handers are nevertheless also overrepresented in high IQ societies, such as  Mensa . A 2005 study found that \"approximately 20% of the members of Mensa are lefthanded, double the proportion in most general populations\". [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6687", "text": "Ghayas & Adil (2007) found that left-handers were significantly more likely to perform better on  intelligence tests  than right-handers and that right-handers also took more time to complete the tests. [ 60 ]  In a systematic review and meta-analysis, Ntolka & Papadatou-Pastou (2018) found that right-handers had higher IQ scores, but that difference was negligible (about 1.5 points). [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6688", "text": "The prevalence of  difficulties  in left-right discrimination was investigated in a cohort of 2,720 adult members of  Mensa  and  Intertel  by Storfer. [ 62 ]  According to the study, 7.2% of the men and 18.8% of the women evaluated their left-right directional sense as poor or below average; moreover participants who were relatively ambidextrous experienced problems more frequently than did those who were more strongly left- or right-handed. [ 62 ]  The study also revealed an effect of age, with younger participants reporting more problems. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6689", "text": "Nelson, Campbell, and Michel studied infants and whether developing handedness during infancy correlated with language abilities in toddlers. In the article they assessed 38 infants and followed them through to 12 months and then again once they became toddlers from 18 to 24 months. They discovered that when a child developed a consistent use of their right or left hand during infancy (such as using the right hand to put the pacifier back in, or grasping random objects with the left hand), they were more likely to have superior language skills as a toddler. Children who became lateral later than infancy (i.e., when they were toddlers) showed normal development of language and had typical language scores. The researchers used  Bayley scales  of infant and toddler development to assess the subjects. [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6690", "text": "In two studies,  Diana Deutsch  found that left-handers, particularly those with mixed-hand preference, performed significantly better than right-handers in musical memory tasks. [ 64 ] [ 65 ]  There are also handedness differences in perception of musical patterns. Left-handers as a group differ from right-handers, and are more heterogeneous than right-handers, in perception of certain stereo illusions, such as the  octave illusion , the  scale illusion , and the  glissando illusion . [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6691", "text": "Studies have found a positive correlation between left-handedness and several specific physical and mental disorders and health problems, including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6692", "text": "As handedness is a highly heritable trait associated with various medical conditions, and because many of these conditions could have presented a Darwinian fitness challenge in ancestral populations, this indicates left-handedness may have previously been rarer than it currently is, due to natural selection. However, on average, left-handers have been found to have an advantage in fighting and competitive, interactive sports, which could have increased their reproductive success in ancestral populations. [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6693", "text": "In 2006, researchers from  Lafayette College  and  Johns Hopkins University  concluded that there was no statistically significant correlation between handedness and earnings for the general population, but among college-educated people, left-handers earned 10 to 15% more than their right-handed counterparts. [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6694", "text": "In a 2014 study published by the  National Bureau of Economic Research ,  Harvard  economist Joshua Goodman finds that left-handed people earn 10 to 12 percent less over the course of their lives than right-handed people. Goodman attributes this disparity to higher rates of emotional and behavioral problems in left-handed people. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6695", "text": "Interactive sports such as table tennis, badminton and cricket have an overrepresentation of left-handedness, while non-interactive sports such as swimming show no overrepresentation. Smaller physical distance between participants increases the overrepresentation. In  fencing , about half the participants are left-handed. [ 81 ]  In tennis, 40% of the  seeded players  are left-handed. [ 82 ]  The term  southpaw  is sometimes used to refer to a left-handed individual, especially in  baseball  and  boxing . [ 83 ]  Some studies suggest that right handed male athletes tend to be statistically taller and heavier than left handed ones. [ 84 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6696", "text": "Other, sports-specific factors may  increase or decrease  the advantage left-handers usually hold in one-on-one situations:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6697", "text": "One advantage is a left-handed catcher's ability to frame a right-handed pitcher's breaking balls. A right-handed catcher catches a right-hander's  breaking ball  across his body, with his glove moving out of the strike zone. A left-handed catcher would be able to catch the pitch moving into the strike zone and create a better target for the umpire."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6698", "text": "According to a meta-analysis of 144 studies, totaling 1,787,629 participants, the best estimate for the male to female  odds ratio  was 1.23, indicating that men are 23% more likely to be left-handed. For example, if the incidence of female left-handedness was 10%, then the incidence of male left-handedness would be approximately 12% (10% incidence of left-handedness among women multiplied by an odds ratio of 1:1.23 for women:men results in a 12.3% incidence of left-handedness among men). [ 94 ] [ clarification needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6699", "text": "Some studies examining the relationship between handedness and sexual orientation have reported that a disproportionate minority of homosexual people exhibit left-handedness, [ 95 ]  though findings are mixed. [ 96 ] [ 97 ] [ 98 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6700", "text": "A 2001 study also found that people assigned male at birth whose  gender identity  did not align with their assigned sex, were more than twice as likely to be left-handed than a clinical  control group  (19.5% vs. 8.3%, respectively). [ 99 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6701", "text": "Paraphilias  (atypical sexual interests) have also been linked to higher rates of left-handedness. A 2008 study analyzing the sexual fantasies of 200 males found \"elevated paraphilic interests were correlated with elevated non-right handedness\". [ 100 ]  Greater rates of left-handedness have also been documented among  pedophiles . [ 101 ] [ 102 ] [ 103 ] [ 104 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6702", "text": "A 2014 study attempting to analyze the biological markers of  asexuality  asserts that non-sexual men and women were 2.4 and 2.5 times, respectively, more likely to be left-handed than their heterosexual counterparts. [ 105 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6703", "text": "A study at  Durham University \u2014which examined mortality data for  cricketers  whose handedness was a matter of public record\u2014found that left-handed men were almost twice as likely to die in war as their right-handed contemporaries. [ 106 ]  The study theorised that this was because weapons and other equipment was designed for the right-handed. \"I can sympathise with all those left-handed cricketers who have gone to an early grave trying desperately to shoot straight with a right-handed Lee Enfield .303\", wrote a journalist reviewing the study in the cricket press. [ 107 ]  The findings echo those of previous American studies, which found that left-handed US sailors were 34% more likely to have a serious accident than their right-handed counterparts. [ 108 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6704", "text": "A high level of handedness (whether strongly favoring right or left) is associated with poorer  episodic memory , [ 109 ] [ 110 ]  and with poorer communication between brain hemispheres, [ 111 ]  which may give poorer emotional processing, although  bilateral stimulation  may reduce such effects. [ 112 ] [ 113 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6705", "text": "A high level of handedness is associated with a smaller  corpus callosum  whereas low handedness with a larger one. [ 114 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6706", "text": "Left-handedness is associated with better  divergent thinking . [ 115 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6707", "text": "Many tools and procedures are designed to facilitate use by right-handed people, often without realizing the difficulties incurred by the left-handed. John W. Santrock has written, \"For centuries, left-handers have suffered unfair discrimination in a world designed for right-handers.\" [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6708", "text": "Many products for left-handed use are made by specialist producers, although not available from normal suppliers. Items as simple as a knife ground for use with the right hand are less convenient for left-handers. There is a multitude of examples:  kitchen tools  such as knives, corkscrews and scissors,  garden tools , and so on. While not requiring a purpose-designed product, there are more appropriate ways for left-handers to tie shoelaces. [ 116 ]  There are companies that supply products designed specifically for left-handed use. One such is Anything Left-Handed, which in 1967 opened a shop in Soho, London; the shop closed in 2006, but the company continues to supply left-handed products worldwide by mail order. [ 117 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6709", "text": "Writing from left to right as in many languages, in particular, with the left hand covers and tends to smear (depending upon ink drying) what was just written. Left-handed writers have developed various ways of holding a pen for best results. [ 118 ]  For using a  fountain pen , preferred by many left-handers,  nibs  ground to optimise left-handed use (pushing rather than pulling across the paper) without scratching are available."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6710", "text": "McManus noted that, as the  Industrial Revolution  spread across Western Europe and the United States in the 19th century, workers needed to operate complex machines that were designed with right-handers in mind. This would have made left-handers more visible and at the same time appear less capable and more clumsy. Writing left-handed with a dip pen, in particular, was prone to blots and smearing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6711", "text": "Moreover, apart from inconvenience, left-handed people have historically been considered unlucky or even malicious for their difference by the right-handed majority. In many languages, including English, the word for the direction \"right\" also means \"correct\" or \"proper\". Throughout history, being left-handed was considered negative, or evil. [ 119 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6712", "text": "The Latin adjective  sinister  means  ' left '  as well as  ' unlucky ' , and this double meaning survives in European derivatives of Latin, including the English words  sinister  (meaning both 'evil' and 'on the bearer's left on a coat of arms') and  ambisinister  meaning 'awkward or clumsy with both or either hand'. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6713", "text": "There are many negative connotations associated with the phrase  left-handed : clumsy, awkward, unlucky, insincere, sinister, malicious, and so on. A \"left-handed compliment\" is one that has two meanings, one of which is unflattering to the recipient. In French,  gauche  means both  ' left '  and  ' awkward '  or  ' clumsy ' , while  droit(e)  ( cognate  to English  direct  and related to  adroit ) means both  ' right '  and  ' straight ' , as well as  ' law '  and the legal sense of  ' right ' . The name Dexter derives from the Latin for  ' right ' , as does the word  dexterity  meaning manual skill. As these are all very old words, they would tend to support theories indicating that the predominance of right-handedness is an extremely old phenomenon. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6714", "text": "Black magic  is sometimes referred to as the \" left-hand path \". [ 120 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6715", "text": "Before the development of fountain pens and other writing instruments,  children were taught to write with a  dip pen . While a right-hander could smoothly drag the pen across paper from left to right, a dip pen could not easily be pushed across by the left hand without digging into the paper and making blots and stains. [ 121 ]  Even with more modern pens, writing from left to right, as in many languages, with the left hand covers and can smear what was just written when moving across the line."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6716", "text": "Into the 20th and even the 21st century, left-handed children in  Uganda  were beaten by schoolteachers or parents for writing with their left hand, [ 122 ]  or had their left hands tied behind their backs to force them to write with their right hand. [ 123 ]  As a child, the future British king  George VI  (1895\u20131952) was naturally left-handed. He was forced to write with his right hand, as was common practice at the time. He was not expected to become king, so that was not a factor. [ 124 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6717", "text": "Until very recently [ when? ]  in  Taiwan , left-handed people were forced to switch to being right-handed, or at least switch to writing with the right hand. [ citation needed ]  Due to the importance of  stroke order , developed for the comfortable use of right-handed people, it is considered more difficult to write legible Chinese characters with the left hand than it is to write Latin letters, though difficulty is subjective and depends on the writer. [ 125 ] [ better\u00a0source\u00a0needed ]  Because writing when moving one's hand away from its side towards the other side of the body can cause smudging if the outward side of the hand is allowed to drag across the writing, writing in the  Latin alphabet  might possibly be less feasible with the left hand than the right under certain circumstances. Conversely, right-to-left alphabets, such as the Arabic and Hebrew, are generally considered easier to write with the left hand. [ citation needed ]  Depending on the position and inclination of the writing paper, and the writing method, the left-handed writer can write as neatly and efficiently or as messily and slowly as right-handed writers. Usually the left-handed child needs to be taught how to write correctly with the left hand, since discovering a comfortable left-handed writing method on one's own may not be straightforward. [ 126 ] [ 127 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6718", "text": "In the  Soviet school system , all left-handed children were forced to write with their right hand. [ 128 ] [ 129 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6719", "text": "International Left-Handers Day is held annually every August 13. [ 130 ]  It was founded by the Left-Handers Club in 1992, with the club itself having been founded in 1990. [ 130 ]  International Left-Handers Day is, according to the club, \"an annual event when left-handers everywhere can celebrate their sinistrality (left-handedness) and increase public awareness of the advantages and disadvantages of being left-handed.\" [ 130 ]  It celebrates their uniqueness and differences, who are from seven to ten percent of the world's population. Thousands of left-handed people in today's society have to adapt to use right-handed tools and objects. Again according to the club, \"in the U.K. alone there were over 20 regional events to mark the day in 2001 \u2013 including left-v-right sports matches, a left-handed tea party, pubs using left-handed corkscrews where patrons drank and played pub games with the left hand only, and nationwide 'Lefty Zones' where left-handers' creativity, adaptability and sporting prowess were celebrated, whilst right-handers were encouraged to try out everyday left-handed objects to see just how awkward it can feel using the wrong equipment.\" [ 130 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6720", "text": "Kangaroos  and other  macropod   marsupials  show a left-hand preference for everyday tasks in the wild. 'True' handedness is unexpected in marsupials however, because unlike  placental mammals , they lack a  corpus callosum . Left-handedness was particularly apparent in the red kangaroo ( Macropus rufus ) and the eastern gray kangaroo ( Macropus giganteus ). Red-necked (Bennett's) wallabies ( Macropus rufogriseus ) preferentially use their left hand for behaviours that involve fine manipulation, but the right for behaviours that require more physical strength. There was less evidence for handedness in  arboreal  species. [ 131 ]  Studies of dogs, horses, and domestic cats have shown that females of those species tend to be right-handed, while males tend to be left-handed. [ 132 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6721", "text": "Hyper\u2013Rayleigh scattering optical activity  ( / \u02c8 r e\u026a l i /   RAY -lee ), a form of  chiroptical harmonic scattering , is a  nonlinear optical  physical effect whereby chiral scatterers (such as nanoparticles or molecules) convert  light  (or other  electromagnetic radiation ) to higher frequencies via  harmonic generation  processes, in a way that the intensity of generated light depends on the chirality of the scatterers. \"Hyper\u2013Rayleigh scattering\" is a nonlinear optical counterpart to  Rayleigh scattering . \" Optical activity \" refers to any changes in light properties (such as intensity or polarization) that are due to  chirality ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6722", "text": "The effect was theoretically predicted in 1979, [ 1 ]  in a mathematical description of hyper Raman scattering optical activity. Within this theoretical model, upon setting the initial and final frequencies of light to the same value, the mathematics describe the hyper Rayleigh scattering optical activity. The theory was well in advance of its time, and the effect remained elusive for 40 years. Its author  David L. Andrews  referred to it as the \"impossible theory\". However, in January 2019, an experimental demonstration was reported by Ventsislav K. Valev and his team. [ 2 ] [ 3 ]  The team investigated the hyper Rayleigh scattering (at the  second harmonic generation  frequency) from chiral nanohelices made of silver. Valev and his team observed that the intensity of the hyper Rayleigh scattering light depended on the direction of circularly polarized light and that this dependence reversed with the chirality of the nanohelices. Valev's work unambiguously established that the effect is physically possible, opening the way for nonlinear chiroptical investigations of a variety of chiral light-scattering materials; including molecules, [ 4 ]  plasmonic metal nanoparticles [ 5 ]  and semiconductor nanoparticles. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6723", "text": "Hyper Rayleigh scattering optical activity (HRS OA) is arguably the most fundamental nonlinear chiral optical (chiroptical) effect; since other nonlinear chiroptical effects have additional requirements, which make them conceptually more involved, i.e. less fundamental. HRS OA is a scattering effect and therefore it does not require the frequency conversion process to be coherent, contrary to other nonlinear chiroptical effects, such as second harmonic generation circular dichroism [ 7 ]  or second harmonic generation optical rotation. [ 8 ]  Moreover, HRS OA is a  parametric process : the initial and final quantum mechanical states of the excited electron are the same. Because the excitation proceeds via  virtual states , there is no restriction on the frequency of incident light. By contrast, other nonlinear scattering effects, such as  two-photon circular dichroism  and hyper-Raman are non-parametric: they require real energy states that restrict the frequencies at which these effects can be observed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6724", "text": "Soon after the first demonstration of hyper Rayleigh scattering optical activity in metal nanoparticles, [ 3 ]  the effect was replicated in organic molecules, specifically aromatic oligoamide foldamers. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6725", "text": "Whereas the initial experimental demonstration of hyper-Rayleigh scattering optical activity was observed at the second harmonic of the illumination frequency of light, the effect is general and can be observed at higher harmonics. The first demonstration of hyper-Rayleigh scattering optical activity at the third harmonic was reported by Valev's team in 2021, from silver nanohelices. [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6726", "text": "In  chemistry ,  inherent chirality  is a property of asymmetry in molecules arising, not from a stereogenic or chiral center, but from a twisting of the molecule in 3-D space.   The term was first coined by Volker Boehmer in a 1994 review, to describe the chirality of  calixarenes  arising from their non-planar structure in 3-D space."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6727", "text": "This phenomenon was described as resulting from \"the absence of a place of symmetry or an inversion center in the molecule as a whole\". [ 1 ]  Boehmer further explains this phenomenon by suggesting that if an inherently chiral calixarene macrocycle were opened up it would produce an \"achiral linear molecule\". [ 1 ]  There are two commonly used notations to describe a molecules inherent chirality: cR/cS (arising from the notation used for classically chiral compounds, with  c  denoting curvature) and P/M. [ 2 ] [ irrelevant citation ]  Inherently chiral molecules, like their classically chiral counterparts, can be used in chiral host\u2013guest chemistry, enantioselective synthesis, and other applications. [ 3 ]   There are naturally occurring inherently chiral molecules as well.  Retinal, a chromophore in  rhodopsin . exists in solution as a racemic pair of enantiomers due to the curvature of an achiral polyene chain. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6728", "text": "After creating a series of traditionally chiral  calixarenes  (through the addition of a chiral substituent group on the top or bottom rim of the macrocycle,) the first inherently chiral calixarenes were synthesized in 1982, though the molecules were not yet described as such.  The inherently chiral calixarenes featured an XXYZ or WXYZ substitution pattern, such that the planar representation of the molecule does not show any chirality, and if the macrocycle were to be broken open, this would produce an achiral linear molecule. [ 5 ]   The chirality in these calixarenes is instead derived from the curvature of the molecule in space. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6729", "text": "Due to the initial lack of a formal definition after the initial conception, the term inherent chirality was utilized to describe a variety of chiral molecules that don't fall into other defined chirality types.  The first fully formulated definition of inherent chirality was published in 2004 by Mandolini and Schiaffino, (and later modified by Szumna): [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6730", "text": "inherent chirality arises from the introduction of a curvature in an ideal planar structure that is devoid of perpendicular symmetry planes in its bidimensional representation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6731", "text": "Inherent chirality has been known by a variety of names in the literature including bowl chirality (in fullerene fragments), intrinsic chirality, helicity (see section 3a) residual enantiomers (as applied to sterically hindered molecular propellers,) and cyclochirality (though this is often considered to be a more specific example and cannot be applied to all inherently chiral molecules). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6732", "text": "A simple example of inherent chirality is that of  corannulene  commonly referred to as \"bowl chirality\" in the literature.  The chirality of an unsubstituted corranulene (containing no classic stereogenic centers) cannot be seen in a 2D representation, but becomes clear when a 3D representation is evoked, as the C 5  symmetry of corranulenes provides the molecules with a source of chirality (figure 2.)  Racemization of these molecules is possible through an inversion of curvature, though some inherently chiral molecules have inversion barriers comparable to a classic chiral center. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6733", "text": "Some inherently chiral molecules contain  chirality planes , or planes within a given molecules across which the molecule is dissymmetric.  Paracyclophanes often contain chiral planes if the bridge across the phenylene unit is short enough, or if the phenylene contains another substituent, not in the bridge, that hinders rotation of the phenylene unit."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6734", "text": "Similar to chirality planes,  chirality axes  arise from an axis about which the spatial arrangement of substituents creates chirality.  This can be seen in helical molecules (see section 3a) as well as some alkenes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6735", "text": "Spiro compounds  (compounds with a twisted structure of two or more rings) can have inherent chirality at the spiroatom, due to the twisting of the achiral ring system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6736", "text": "Inherently chiral alkenes have been synthesized through the use of a \"buckle\" where in an achiral, linear alkene is forced into a chiral conformation.  Alkenes have no classical chirality, so generally, an external stereogenic center must be introduced.  However, by locking the alkene into a conformation through the use of an achiral buckle allows for the creation of an inherently chiral alkene.  Inherently chiral alkenes have been synthesized through the use of dialkoxysilanes, with a large enough racemization barrier that enantiomers have been isolated. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6737", "text": "The term  laterality  refers to the preference most  humans  show for one side of their  body  over the other. Examples include  left-handedness/right-handedness  and left/right- footedness ; it may also refer to the primary use of the left or right hemisphere in the brain. It may also apply to animals or plants. The majority of tests have been conducted on humans, specifically to determine the effects on  language ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6738", "text": "Most humans are  right-handed . Many are also right-sided in general (that is, they prefer to use their right  eye , right  foot  and right  ear  if forced to make a choice between the two). The reasons for this are not fully understood, but it is thought that because the left  cerebral hemisphere  of the  brain  controls the right side of the body, the right side is generally stronger; it is suggested that the  left cerebral hemisphere  is dominant over the right in most humans because in 90\u201392% of all humans, the left hemisphere is the  language  hemisphere."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6739", "text": "Human  cultures  are predominantly right-handed, and so the right-sided trend may be socially as well as biologically enforced. This is quite apparent from a quick survey of  languages . The  English  word \"left\" comes from the  Anglo-Saxon  word  lyft  which means \"weak\" or \"useless\". Similarly, the  French  word for left,  gauche , is also used to mean \"awkward\" or \"tactless\", and  sinistra , the  Latin  word from which the English word \"sinister\" was derived, means \"left\". Similarly, in many cultures the word for \"right\" also means \"correct\". The English word \"right\" comes from the Anglo-Saxon word  riht  which also means \"straight\" or \"correct.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_6740", "text": "This linguistic and social bias is not restricted to  European cultures : for example,  Chinese characters  are designed for right-handers to write, and no significant left-handed culture has ever been found in the world."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6741", "text": "When a person is forced to use the hand opposite of the hand that they would naturally use, this is known as  forced laterality , or more specifically  forced dextrality . A study done by the Department of Neurology at  Keele University ,  North Staffordshire Royal Infirmary  suggests that forced dextrality may be part of the reason that the percentage of left-handed people decreases with the higher age groups, both because the effects of pressures toward right-handedness are cumulative over time (hence increasing with age for any given person subjected to them) and because the prevalence of such pressure is decreasing, such that fewer members of younger generations face any such pressure to begin with. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6742", "text": "Ambidexterity  is when a person has approximately equal skill with both  hands  and/or both sides of the body. True ambidexterity is very rare. Although a small number of people can write competently with both hands and use both sides of their body well, even these people usually show preference for one side of their body over the other. However, this preference is not necessarily consistent for all activities. Some people may, for instance, use their right hand for  writing , and their  left hand  for playing  racket sports  and  eating [ 2 ]  ( see also:   cross-dominance )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6743", "text": "Also, it is not uncommon that people  preferring to use the right hand prefer to use the left leg , e.g. when using a shovel, kicking a ball, or operating control pedals. In many cases, this may be because they are disposed for left-handedness but have been trained for right-handedness, which is usually attached to learning and behavioural disorders (term usually so called as \" cross dominance \"). [ 3 ]  In the sport of  cricket , some players may find that they are more comfortable  bowling  with their left or right hand, but  batting  with the other hand."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6744", "text": "Approximate statistics, complied in 1981, are given below: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6745", "text": "Laterality of  motor  and sensory control has been the subject of a recent intense study and review. [ 5 ]  It turns out that the hemisphere of speech is the hemisphere of action in general and that the command hemisphere is located either in the right or the left hemisphere (never in both). Around 80% of people are left hemispheric for speech and the remainder are right hemispheric: ninety percent of right-handers are  left hemispheric for speech , but only 50% of left-handers are right hemispheric for speech (the remainder are left hemispheric). The  reaction time  of the neurally dominant side of the body (the side opposite to the major hemisphere or the command center, as just defined) is shorter than that of the opposite side by an interval equal to the interhemispheric transfer time. Thus, one in five persons has a handedness that is the opposite for which they are wired (per laterality of command center or brainedness, as determined by reaction time study mentioned above)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6746", "text": "Cerebral dominance  or  specialization  has been studied in relation to a variety of human functions. With speech in particular, many studies have been used as evidence that it is generally localized in the  left hemisphere . Research comparing the effects of  lesions  in the two hemispheres,  split-brain  patients, and  perceptual asymmetries  have aided in the knowledge of speech lateralization. In one particular study, the left hemisphere's sensitivity to differences in rapidly changing  sound cues  was noted (Annett, 1991). This has real world implication, since very fine  acoustic discriminations  are needed to comprehend and produce  speech signals . In an  electrical stimulation  demonstration performed by Ojemann and Mateer (1979), the exposed  cortex  was  mapped  revealing the same cortical sites were activated in  phoneme discrimination  and mouth movement sequences (Annett, 1991)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6747", "text": "As suggested by Kimura (1975, 1982), left hemisphere speech lateralization might be based upon a preference for movement sequences as demonstrated by  American Sign Language  (ASL) studies. Since ASL requires intricate  hand movements for language communication , it was proposed that skilled hand motions and speech require sequences of action over time. In  deaf  patients with a left hemispheric  stroke  and damage, noticeable losses in their abilities to sign were noted. These cases were compared to studies of normal speakers with  dysphasias  located at lesioned areas similar to the deaf patients. In the same study, deaf patients with right hemispheric lesions did not display any significant loss of signing nor any decreased capacity for motor sequencing (Annett, 1991)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6748", "text": "One theory, known as the acoustic laterality theory, the physical properties of certain speech sounds are what determine laterality to the left hemisphere.  Stop consonants , for example t, p, or k, leave a defined  silent period  at the end of words that can easily be distinguished. This theory postulates that changing sounds such as these are preferentially processed by the left hemisphere. As a result of the right ear being responsible for transmission to sounds to the left hemisphere, it is capable of perceiving these sounds with rapid changes. This right ear advantage in hearing and speech laterality was evidenced in  dichotic listening studies .  Magnetic imaging  results from this study showed greater left hemisphere activation when actual words were presented as opposed to pseudowords. [ 6 ]  Two important aspects of  speech recognition  are  phonetic cues , such as format patterning, and  prosody  cues, such as  intonation ,  accent , and emotional state of the speaker (Imaizumi, Koichi, Kiritani, Hosoi & Tonoike, 1998)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6749", "text": "In a study done with both  monolinguals  and  bilinguals , which took into account language experience,  second language proficiency , and onset of bilingualism among other variables, researchers were able to demonstrate left hemispheric dominance. In addition, bilinguals that began speaking a second language early in life demonstrated bilateral hemispheric involvement. The findings of this study were able to predict differing patterns of cerebral language lateralization in adulthood (Hull & Vaid, 2006)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6750", "text": "It has been shown that cerebral lateralization is a widespread phenomenon in the  animal kingdom . [ 7 ]  Functional and structural differences between left and right brain hemispheres can be found in many other vertebrates and also in invertebrates. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6751", "text": "It has been proposed that negative, withdrawal-associated emotions are processed predominantly by the right hemisphere, whereas the left hemisphere is largely responsible for processing positive, approach-related emotions. This has been called the \"laterality- valence  hypothesis\". [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6752", "text": "One sub-set of laterality in animals is limb dominance. Preferential limb use for specific tasks has been shown in species including chimpanzees, mice, bats, wallabies, parrots, chickens and toads. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6753", "text": "Another form of laterality is hemispheric dominance for processing conspecific vocalizations, reported for chimpanzees, sea lions, dogs, zebra finches and Bengalese finches. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6754", "text": "In mice ( Mus musculus ), laterality in paw usage has been shown to be a learned behavior (rather than inherited), [ 10 ]  due to which, in any population, half of the mice become left-handed while the other half becomes right-handed. The learning occurs by a gradual reinforcement of randomly occurring weak asymmetries in paw choice early in training, even when training in an unbiased world. [ 11 ] [ 12 ]  Meanwhile, reinforcement relies on short-term and long-term memory skills that are strain-dependent, [ 11 ] [ 12 ]  causing strains to differ in the degree of laterality of its individuals. Long-term memory of previously gained laterality in handedness due to training is heavily diminished in mice with absent corpus callosum and reduced hippocampal commissure. [ 13 ]  Regardless of the amount of past training and consequent biasing of paw choice, there is a degree of randomness in paw choice that is not removed by training, [ 14 ]  which may provide adaptability to changing environments."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6755", "text": "Domestic horses  ( Equus caballus ) exhibit laterality in at least two areas of neural organization, i.e. sensory and motor. In  thoroughbreds , the strength of motor laterality increases with age. Horses under 4 years old have a preference to initially use the right nostril during olfaction. [ 15 ]  Along with olfaction, French horses have an eye laterality when looking at novel objects. There is a correlation between their score on an emotional index and eye preference; horses with higher emotionality are more likely to look with their left eye. The less emotive French saddlebreds glance at novel objects using the right eye, however, this tendency is absent in the  trotters , although the emotive index is the same for both breeds. [ 16 ]   Racehorses  exhibit laterality in stride patterns as well. They use their preferred stride pattern at all times whether racing or not, unless they are forced to change it while turning, injured, or fatigued. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6756", "text": "In  domestic dogs  ( Canis familiaris ), there is a correlation between motor laterality and noise sensitivity - a lack of paw preference is associated with noise-related fearfulness. (Branson and Rogers, 2006) [ citation needed ]  Fearfulness is an undesirable trait in guide dogs, therefore, testing for laterality can be a useful predictor of a successful guide dog. Knowing a guide dog's laterality can also be useful for training because the dog may be better at walking to the left or the right of their blind owner. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6757", "text": "Domestic cats  ( Felis catus ) show an individual handedness when reaching for static food. In one study, 46% preferred to use the right paw, 44% the left, and 10% were ambi-lateral; 60% used one paw 100% of the time. There was no difference between male and female cats in the proportions of left and right paw preferences. In moving-target reaching tests, cats have a left-sided behavioural asymmetry. [ 19 ]  One study indicates that laterality in this species is strongly related to temperament. Furthermore, individuals with stronger paw preferences are rated as more confident, affectionate, active, and friendly. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6758", "text": "Chimpanzees  show right-handedness in certain conditions. This is expressed at the population level for females, but not males. The complexity of the task has a dominant effect on handedness in chimps. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6759", "text": "Cattle  use  visual/brain lateralisation  in their visual scanning of novel and familiar stimuli. [ 22 ]  Domestic cattle prefer to view novel stimuli with the left eye, (similar to horses, Australian magpies, chicks, toads and fish) but use the right eye for viewing familiar stimuli. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6760", "text": "Schreibers' long-fingered bat  is lateralized at the population level and shows a left-hand bias for climbing or grasping. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6761", "text": "Some types of  mastodon  indicate laterality through the fossil remains having differing tusk lengths. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6762", "text": "Marsupials  are fundamentally different from other mammals in that they lack a  corpus callosum . [ 25 ]  However, wild  kangaroos  and other  macropod   marsupials  have a left-hand preference for everyday tasks. Left-handedness is particularly apparent in the  red kangaroo  ( Macropus rufus ) and the  eastern gray kangaroo  ( Macropus giganteus ). The  red-necked wallaby  ( Macropus rufogriseus ) preferentially uses the left hand for behaviours that involve fine manipulation, but the right for behaviours that require more physical strength. There is less evidence for handedness in  arboreal  species. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6763", "text": "Parrots  tend to favor one foot when grasping objects (for example fruit when feeding). Some studies indicate that most parrots are left footed. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6764", "text": "The  Australian magpie  ( Gymnorhina tibicen ) uses both left-eye and right-eye laterality when performing anti-predator responses, which include  mobbing . Prior to withdrawing from a potential predator, Australian magpies view the animal with the left eye (85%), but prior to approaching, the right eye is used (72%). The left eye is used prior to jumping (73%) and prior to circling (65%) the predator, as well as during circling (58%) and for high alert inspection of the predator (72%). The researchers commented that \"mobbing and perhaps circling are agonistic responses controlled by the LE[left eye]/right hemisphere, as also seen in other species. Alert inspection involves detailed examination of the predator and likely high levels of fear, known to be right hemisphere function.\" [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6765", "text": "Yellow-legged gull  ( Larus michahellis ) chicks show laterality when reverting from a supine to prone posture, and also in pecking at a dummy parental bill to beg for food. Lateralization occurs at both the population and individual level in the reverting response and at the individual level in begging. Females have a leftward preference in the righting response, indicating this is sex dependent. Laterality in the begging response in chicks varies according to laying order and matches variation in egg  androgens  concentration.\n [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6766", "text": "Laterality determines the organisation of rainbowfish ( Melanotaenia  spp.) schools. These fish demonstrate an individual eye preference when examining their reflection in a mirror. Fish which show a right-eye preference in the mirror test prefer to be on the left side of the school. Conversely, fish that show a left-eye preference in the mirror test or were non-lateralised, prefer to be slightly to the right side of the school. The behaviour depends on the species and sex of the school. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6767", "text": "Three species of toads, the  common toad  ( Bufo bufo ),  green toad  ( Bufo viridis ) and the  cane toad  ( Bufo marinus ) show stronger escape and defensive responses when a model predator was placed on the toad's left side compared to their right side. [ 31 ]   Emei music frogs  ( Babina daunchina ) have a right-ear preference for positive or neutral signals such as a conspecific's advertisement call and white noise, but a left-ear preference for negative signals such as predatory attack. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6768", "text": "The  Mediterranean fruit fly  ( Ceratitis capitata ) exhibits left-biased population-level lateralisation of aggressive displays (boxing with forelegs and wing strikes) with no sex-differences. [ 33 ]  In ants,  Temnothorax albipennis  (rock ant) scouts show behavioural lateralization when exploring unknown nest sites, showing a population-level bias to prefer left turns. One possible reason for this is that its environment is partly maze-like and consistently turning in one direction is a good way to search and exit mazes without getting lost. [ 34 ]  This turning bias is correlated with slight asymmetries in the ants' compound eyes (differential ommatidia count). [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6769", "text": "Left-hand traffic  ( LHT ) and  right-hand traffic  ( RHT ) are the practices, in  bidirectional traffic , of keeping to the left side and to the right side of the road, respectively. They are fundamental to  traffic flow , and are sometimes called the  rule of the road . [ 1 ]  The terms right- and left-hand  drive  refer to the position of the driver and the  steering wheel  in the vehicle and are, in automobiles, the reverse of the terms right- and left-hand  traffic . The rule also includes where on the road a vehicle is to be driven, if there is room for more than one vehicle in one direction, and the side on which the vehicle in the rear overtakes the one in the front. For example, a driver in an LHT country would typically overtake on the right of the vehicle being overtaken."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6770", "text": "RHT is used in 165 countries and territories, mainly in the  Americas ,  Continental Europe , most of  Africa  and mainland  Asia  (except  South Asia ), while 75 countries use LHT, [ 2 ]  which account for about a sixth of the world's land area, a quarter of its roads, and about a third of its population. [ 3 ]  In 1919, 104 of the world's territories were LHT and an equal number were RHT. Between 1919 and 1986, 34 of the LHT territories switched to RHT. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6771", "text": "While many of the countries using LHT were part of the  British Empire , others such as  Indonesia ,  Japan ,  Nepal ,  Bhutan ,  Macao ,  Thailand ,  Mozambique  and  Suriname  were not, as well as formerly,  Sweden  and  Iceland , which have used RHT since  September 1967  and  late May 1968  respectively. Most of the countries that were part of the  French colonial empire  adopted RHT."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6772", "text": "Historical switches of traffic handedness have often been motivated by factors such as changes in political administration, a desire for uniformity within a country or with neighboring states, or availability and affordability of vehicles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6773", "text": "In LHT, traffic keeps left and cars usually have the steering wheel on the right (RHD: right-hand drive) and  roundabouts  circulate clockwise. RHT is the opposite: traffic keeps right, the driver usually sits on the left side of the car (LHD: left-hand drive), and roundabouts circulate anticlockwise."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6774", "text": "In most countries, rail traffic follows the handedness of the roads; but many of the countries that switched road traffic from LHT to RHT did not switch their trains. Boat traffic on  bodies of water  is RHT, regardless of location. Boats are traditionally piloted from the  starboard  side (and not the port side like RHT road traffic vehicles) to facilitate  priority to the right ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6775", "text": "Historically, many places kept left, while many others kept right, often within the same country. There are many myths that attempt to explain why one or the other is preferred. [ 5 ]  About 90 percent of people are  right-handed , [ 6 ]  and many explanations reference this. Horses are traditionally mounted from the left, and led from the left, with the reins in the right hand. So people walking horses might use RHT, to keep the animals separated. Also referenced is the need for pedestrians to keep their swords in the right hand and pass on the left as in LHT, for self-defence. It has been suggested that wagon-drivers whipped their horses with their right hand, and thus sat on the left-hand side of the wagon, as in RHT. Academic Chris McManus notes that writers have stated that in 1300,  Pope Boniface VIII  directed pilgrims to keep left; others suggest that he directed them to keep to the right, and there is no documented evidence to back either claim. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6776", "text": "The UK introduced LHT in the  East Africa Protectorate  (present-day  Kenya ), the  Protectorate of Uganda ,  Tanganyika  (formerly part of  German East Africa ; present-day  Tanzania ),  Rhodesia  (present-day  Zambia / Zimbabwe ),  Eswatini  and the  Cape Colony  (present-day  South Africa  and  Lesotho ), as well as in  British West Africa  (present-day Ghana, Gambia, Sierra Leone and Nigeria); [ 7 ]  former British West Africa, however, has now switched to RHT, as all its neighbours, which are former French colonies, use RHT. South Africa, formerly the Cape Colony, introduced LHT in former  German South West Africa , present-day  Namibia , after the end of  World War I ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6777", "text": "Sudan, formerly part of  Anglo-Egyptian Sudan , switched to RHT in 1973.  Most of its neighbours were RHT countries, with the exception of Uganda and Kenya, but since the independence of  South Sudan  in 2011, all of its neighbours drive on the right (including South Sudan, despite its land borders with two LHT countries). [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6778", "text": "Although  Portugal  switched to RHT in 1928, its  colony of Mozambique  remained LHT because it has land borders with former British colonies (with LHT)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6779", "text": "France introduced RHT in  French West Africa  and the  Maghreb , [ citation needed ]  where it is still used. Countries in these areas include  Mali ,  Mauritania ,  Ivory Coast ,  Burkina Faso ,  Benin ,  Niger ,  Morocco ,  Algeria , and  Tunisia . Other French former colonies that are RHT include  Cameroon ,  Central African Republic ,  Chad ,  Djibouti ,  Gabon , and the  Republic of the Congo ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6780", "text": "Rwanda  and  Burundi  are RHT but are considering switching to LHT (see \"Potential future shifts\" section below)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6781", "text": "In the late 18th century, right-hand traffic started to be introduced in the United States based on  teamsters ' use of large freight wagons pulled by several pairs of horses and without a driver's seat; the (typically right-handed)  postilion  held his whip in his right hand and thus sat on the left rear horse, and therefore preferred other wagons passing on the left so that he would have a clear view of other vehicles. [ 9 ] [ better\u00a0source\u00a0needed ]  The first keep-right law for  driving in the United States  was passed in 1792 and applied to the  Philadelphia and Lancaster Turnpike . [ 10 ]   Massachusetts  formalized RHT in 1821. [ 11 ]  However, the  National Road  was LHT until 1850, \"long after the rest of the country had settled on the keep-right convention\". [ 12 ]  Today the United States is RHT except the  United States Virgin Islands , [ 13 ]  which is LHT like many neighbouring islands."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6782", "text": "Some special-purpose vehicles in the United States, like certain postal service trucks, garbage trucks, and parking-enforcement vehicles, are built with the driver's seat on the right for safer and easier access to the curb. A common example is the  Grumman LLV , which is used nationwide by the  US Postal Service  and by  Canada Post ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6783", "text": "In Canada, the provinces of  Quebec  and  Ontario  were always RHT because they were created out of the former French colony of  New France . [ 14 ]  The province of  British Columbia  changed to RHT in stages from 1920 to 1923, [ 15 ] [ 16 ]   New Brunswick ,  Nova Scotia , and  Prince Edward Island  in 1922, 1923, and 1924 respectively, [ 17 ]  and the  Dominion of Newfoundland  (part of Canada since 1949) [ 18 ]  in 1947, in order to allow traffic (without side switch) to or from the United States. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6784", "text": "In the  West Indies , colonies and territories drive on the same side as their parent countries, except for the  United States Virgin Islands . Many of the island nations are former British colonies and drive on the left, including  Jamaica ,  Antigua and Barbuda ,  Barbados ,  Dominica ,  Grenada ,  Saint Kitts and Nevis ,  Saint Lucia ,  Saint Vincent and the Grenadines ,  Trinidad and Tobago , and  The Bahamas . However, most vehicles in The Bahamas, [ 20 ]   Cayman Islands , [ 21 ]   Turks and Caicos Islands [ 22 ]  and both the  British Virgin Islands , [ 23 ]  and the  United States Virgin Islands  are LHD due to their being imported from the United States. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6785", "text": "Brazil , a Portuguese colony until the early 19th century, had in the 19th and the early 20th century mixed rules, with some regions still on LHT, switching these remaining regions to RHT in 1928, the same year Portugal switched sides. [ 24 ]  Other Central and South American countries that later switched from LHT to RHT include Argentina, Chile, Panama, [ 25 ]  Paraguay, [ 26 ]  and Uruguay."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6786", "text": "Suriname , along with neighbouring  Guyana , are the only two remaining LHT countries in  South America . [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6787", "text": "LHT was introduced by the UK in  British India  (now  India ,  Pakistan ,  Myanmar , and  Bangladesh ),  British Malaya  and  British Borneo  (now  Malaysia , Brunei and Singapore), as well as  British Hong Kong . These countries, except Myanmar, are still LHT, as well as neighbouring countries  Bhutan  and  Nepal . Myanmar switched to RHT in 1970, [ 28 ]  although much of its infrastructure is still geared to LHT as its neighbours India, Bangladesh and  Thailand  use LHT. Most cars are used RHD vehicles imported from Japan. [ 29 ]   Afghanistan  was LHT until the 1950s, in line with Pakistan (former part of British India). [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6788", "text": "Although  Portuguese Timor  (present-day  East Timor ), which shares the island of  Timor  with  Indonesia , who is LHT, switched to RHT with  Portugal  in 1928, [ 1 ]  it switched back to LHT in 1976 during the  Indonesian occupation of East Timor ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6789", "text": "In the 1930s, parts of  China  such as the  Shanghai International Settlement ,  Canton  and Japanese-occupied  northeast China  used LHT. However, in 1946 the  Republic of China  made RHT mandatory in  China  (including  Taiwan ). Taiwan was LHT under  Japanese colonization  from 1895\u20131945.  Portuguese Macau  (present-day  Macau ) remained LHT, along with  British Hong Kong , despite being transferred to China in 1999 and 1997 respectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6790", "text": "Both  North Korea  and  South Korea  use RHT since 1946, after liberation from  Japanese colonialization . [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6791", "text": "The  Philippines  was mostly LHT during its  Spanish [ 32 ]  and  American  colonial periods, [ 33 ] [ 34 ]  as well as during the  Commonwealth era . [ 35 ]  During the  Japanese occupation , the Philippines remained LHT, [ 36 ]  as was required by the Japanese; [ 37 ]  but during the  Battle of Manila , the liberating American forces drove their tanks to the right for easier facilitation of movement. RHT was formalized in 1945 through a decree by president  Sergio Osme\u00f1a . [ 38 ]  Even though RHT was formalized, RHD vehicles such as public buses were still imported into the Philippines until a law passed banning the importation of RHD vehicles except in special cases. These RHD vehicles are required to be converted to LHD. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6792", "text": "Japan was never part of the British Empire, but its traffic also drives on the left. Although this practice goes back to the Edo period (1603\u20131868), it was not until 1872 \u2013 the year Japan's first railway was introduced, built with technical aid from the British \u2013 that this unwritten rule received official acknowledgment. Gradually, a massive network of railways and tram tracks was built, with all railway vehicles driven on the left-hand side. However, it took another half-century, until 1924, until left-hand traffic was legally mandated. Post- World War II   Okinawa  was ruled by the  United States Civil Administration of the Ryukyu Islands  until 1972, and was RHT until  6 a.m. the morning of 30 July 1978, when it switched back to LHT . [ 40 ]  The conversion operation was known as 730 ( Nana-San-Maru , which refers to the date of the changeover). Okinawa is one of only a few places to have changed from RHT to LHT in the late 20th century. While Japan drives on the left and most Japanese vehicles are RHD, imported vehicles (e.g. BMW, Mercedes-Benz, Porsche) are generally bought as LHD since LHD cars are considered to be status symbols. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6793", "text": "Vietnam  became RHT as part of  French Indochina , as did  Laos  and  Cambodia . In Cambodia, RHD cars, many of which were smuggled from Thailand, were banned in 2001, even though they accounted for 80% of vehicles in the country. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6794", "text": "In a study of the ancient traffic system of  Pompeii , Eric Poehler was able to show that drivers of carts drove in the middle of the road whenever possible. This was the case even on roads wide enough for two lanes. [ 43 ] :\u200a136\u200a  The wear marks on the kerbstones, however, prove that when there were two lanes of traffic, and the volume of traffic made it necessary to divide the lanes, the drivers always drove on the right-hand side. [ 43 ] :\u200a150\u2013155\u200a  These considerations can also be demonstrated in the archaeological findings of other cities in the  Roman Empire . [ 43 ] :\u200a218\u2013219"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6795", "text": "One of the first references in England to requiring traffic direction was an order by the London  Court of Aldermen  in 1669, requiring a man to be posted on  London Bridge  to ensure that \"all cartes going to keep on the one side and all cartes coming to keep on the other side\". [ 44 ]  It was later legislated as the  London Bridge Act 1756  ( 29 Geo. 2  c. 40), which required that \"all carriages passing over the said bridge from London shall go on the east side thereof\" \u2013 those going south to remain on the east, i.e. the left-hand side by direction of travel. [ 45 ]  This may represent the first statutory requirement for LHT. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6796", "text": "In the  Kingdom of Ireland , a law of 1793 (33 Geo. 3. c. 56 (I)) provided a ten- shilling  fine to anyone not driving or riding on the left side of the road within the  county of the city  of  Dublin , and required the local road overseers to erect written or printed notices informing road users of the law. [ 47 ]  The  Road in Down and Antrim Act 1798  (38 Geo. 3. c. 28 (I)) required drivers on the road from Dublin to  Donadea  to keep to the left. This time, the punishment was ten shillings if the offender was not the owner of the vehicle, or one  Irish pound  (twenty shillings) if he/she was. [ 48 ]  The  Grand Juries (Ireland) Act 1836  ( 6 & 7 Will. 4  c. 116) mandated LHT for the whole country, violators to be fined up to five shillings and imprisoned in default for up to one month. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6797", "text": "An oft-repeated story is that  Napoleon  changed the custom from LHT to RHT in France and the countries he conquered after the  French Revolution . Scholars who have looked for documentary evidence of this story have found none, and contemporary sources have not surfaced, as of 1999. [update] [ 4 ]  In 1827, long after Napoleon's reign, Edward Planta wrote that, in  Paris , \"The coachmen have no established rule by which they drive on the right or left of the road, but they cross and jostle one another without ceremony.\" [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6798", "text": "Rotterdam had no fixed rules until 1917, [ 51 ]  although the rest of the Netherlands was RHT. In May 1917 the police in Rotterdam ended traffic chaos by enforcing right hand traffic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6799", "text": "In Russia, in 1709, the Danish envoy under Tsar  Peter the Great  noted the widespread custom for traffic in Russia to pass on the right, but it was only in 1752 that  Empress Elizabeth  officially issued an edict for traffic to keep to the right. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6800", "text": "After the  Austro-Hungarian Empire  broke up, the resulting countries gradually changed to RHT. In  Austria ,  Vorarlberg  switched in 1921, [ 53 ]   North Tyrol  in 1930,  Carinthia  and  East Tyrol  in 1935, and the rest of the country in 1938. [ 54 ]  In  Romania ,  Transylvania , the  Banat  and  Bukovina  were LHT until 1919, while  Wallachia  and  Moldavia  were already RHT.  Partitions of Poland  belonging to the  German Empire  and the  Russian Empire  were RHT, while the former  Austrian Partition  changed in the 1920s. [ 55 ]  Croatia-Slavonia switched on joining the  Kingdom of Yugoslavia  in 1918, although  Istria  and  Dalmatia  were already RHT. [ 56 ]  The  switch in Czechoslovakia  from LHT to RHT had been planned for 1939, but was accelerated by the start of the  German occupation of Czechoslovakia  that year. [ 57 ]  Similarly, Hungary switched in 1941. West Ukraine was LHT, but the rest of Ukraine, having been part of the Russian Empire, was RHT. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6801", "text": "In Italy, it had been decreed in 1901 that each  province  define its own  traffic code , including the handedness of traffic, [ 58 ]  and the 1903  Baedeker  guide reported that the rule of the road varied by region. [ 5 ]  For example, in  Northern Italy , the provinces of  Brescia ,  Como ,  Vicenza , and  Ravenna  were RHT while nearby provinces of  Lecco ,  Verona , and  Varese  were LHT, [ 58 ]  as were the cities  Milan ,  Turin , and  Florence . [ 5 ]  In 1915,  allied  forces of  World War I  imposed LHT in areas of military operation, but this was revoked in 1918.  Rome  was reported by  Goethe  as LHT in the 1780s.  Naples  was also LHT although surrounding areas were often RHT. In cities, LHT was considered safer since pedestrians, accustomed to keeping right, could better see oncoming vehicular traffic. [ 58 ]  Finally, in 1923  Benito Mussolini  decreed that all LHT areas would gradually transition to RHT. [ 58 ]  In spite of this, some Italian heavy commercial vehicles were right-hand drive until the traffic code was changed in 1959. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6802", "text": "Portugal switched to RHT in 1928. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6803", "text": "Finland , formerly part of LHT Sweden, switched to RHT in 1858 as the  Grand Duchy of Finland  by Russian decree. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6804", "text": "Spain  switched to RHT in 1918, but not in the entire country. In  Madrid  people continued to drive on the left until 1924 when a national law forced drivers in Madrid switch to RHT. [ 60 ]   Madrid Metro  still uses LHT."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6805", "text": "Sweden  switched to RHT in 1967, having been LHT from about 1734 [ 61 ]  despite having land borders with RHT countries  Norway  and Finland, and approximately 90% of cars being left-hand drive (LHD). [ 62 ]   A referendum in 1955  overwhelmingly rejected a change to RHT, but, a few years later, the government ordered it and it occurred on Sunday, 3 September 1967 [ 63 ]  at 5\u00a0am. The accident rate then dropped sharply, [ 64 ]  but soon rose to near its original level. [ 65 ]  The day was known as H\u00f6gertrafikoml\u00e4ggningen, or  Dagen H  for short."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6806", "text": "When Iceland switched to RHT the following year, it was known as  H\u00e6gri dagurinn  or  H-dagurinn  (\"The H-Day\"). [ 66 ]  Most passenger cars in Iceland were already LHD."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6807", "text": "The United Kingdom is LHT, but two of its  overseas territories ,  Gibraltar  and the  British Indian Ocean Territory , are RHT. In the late 1960s, the British  Department for Transport  considered switching to RHT, but declared it unsafe and too costly for such a built-up nation. [ 67 ]  Road building standards, for motorways in particular, allow asymmetrically designed road junctions, where merge and diverge lanes differ in length. [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6808", "text": "Today, four countries in Europe continue to use LHT, all island nations: the United Kingdom,  Ireland  (formerly part of the UK),  Cyprus  and  Malta  (both former British colonies)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6809", "text": "Many former British colonies in the region have always been LHT, including Australia, New Zealand,  Fiji ,  Kiribati ,  Solomon Islands ,  Tonga , and  Tuvalu ; and nations that were previously administered by Australia:  Nauru  and  Papua New Guinea ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6810", "text": "Initially traffic was slow and very sparse, but, as early as 1856, a newspaper said, \"The cart was near to the right hand kerb. According to the rules of the road, it should have been on the left side. In turning sharp round a right-hand corner, a driver should keep away to the opposite side.\" That rule was codified when the first  Highway Code  was written in 1936. [ 69 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6811", "text": "Samoa , a former German colony, had been RHT for more than a century, but switched to LHT in 2009, [ 70 ]  making it the first territory in almost 30 years to change sides. [ 71 ]  The move was legislated in 2008 to allow Samoans to use cheaper vehicles imported from Australia, New Zealand, or Japan, and to harmonise with other South Pacific nations. A political party,  The People's Party , was formed by the group People Against Switching Sides (PASS) to protest against the change, with PASS launching a legal challenge; [ 72 ]  in April 2008 an estimated 18,000 people attended demonstrations against switching. [ 73 ]  The motor industry was also opposed, as 14,000 of Samoa's 18,000 vehicles were designed for RHT and the government refused to meet the cost of conversion. [ 71 ]  After months of preparation, the switch from right to left happened in an atmosphere of national celebration. There were no reported incidents. [ 3 ]  At 05:50 local time, Monday 7 September, a radio announcement halted traffic, and an announcement at 6:00 ordered traffic to switch to LHT. [ 70 ]  The change coincided with more restrictive enforcement of speeding and seat-belt laws. [ 74 ]  That day and the following were declared public holidays, to reduce traffic. [ 75 ]  The change included a three-day ban on alcohol sales, while police mounted dozens of checkpoints, warning drivers to drive slowly. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6812", "text": "Rwanda  and  Burundi , former Belgian colonies in  Central Africa , are RHT but are considering switching to LHT [ 76 ] [ 77 ]  like neighbouring members of the  East African Community  (EAC). [ 78 ]  A survey in 2009 found that 54% of Rwandans favoured the switch. Reasons cited were the perceived lower costs of RHD vehicles, easier maintenance and the political benefit of harmonising traffic regulations with other EAC countries. The survey indicated that RHD cars were 16% to 49% cheaper than their LHD counterparts. [ 79 ]  In 2014, an internal report by consultants to the Ministry of Infrastructure recommended a switch to LHT. [ 80 ]  In 2015, the ban on RHD vehicles was lifted; RHD trucks from neighbouring countries cost $1,000 less than LHD models imported from Europe. [ 81 ] [ 82 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6813", "text": "Although many LHT jurisdictions are on islands, there are cases where vehicles may be driven from LHT across a border into a RHT area. Such borders are mostly located in Africa and southern Asia. The  Vienna Convention on Road Traffic  regulates the use of foreign registered vehicles in the 78 countries that have ratified it."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6814", "text": "LHT Thailand has three RHT neighbours: Cambodia, Laos, and Myanmar. Most of its borders use a simple traffic light to do the switch, but there are also interchanges that enable the switch while keeping up a continuous flow of traffic. [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6815", "text": "There are six road border crossing points between Hong Kong and mainland China. In 2006, the daily average number of vehicle trips recorded at  Lok Ma Chau  was 31,100. [ 84 ]  The next largest is  Man Kam To , where there is no changeover system and the border roads on the mainland side  Wenjindu  intersect as one-way streets with a main road."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6816", "text": "The  Takutu River Bridge  (which links LHT Guyana and RHT Brazil [ 85 ] ) is the only border in the Americas where traffic changes sides."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6817", "text": "In RHT jurisdictions, vehicles are typically configured as  left hand drive  (LHD), with the  steering wheel  on the left side of the passenger compartment. In LHT jurisdictions, the reverse is true as the  right hand drive  (RHD) configuration. In most jurisdictions, the position of the steering wheel is not regulated, or explicitly permitted to be anywhere. [ 86 ]  The driver's side, the side closer to the centre of the road, is sometimes called the  offside , while the passenger side, the side closer to the side of the road, is sometimes called the  nearside . [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6818", "text": "Most  windscreen wipers  are preferentially designed to better clean the driver's side of the  windscreen  and thus have a longer wiper blade on the driver's side and wipe up from the passenger side to the driver's side. Thus on LHD configurations, they wipe up from right to left, viewed from inside the vehicle, and do the opposite on RHD vehicles. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6819", "text": "In both LHD and RHD vehicles, gear shifters are in the same position, and the shift patterns are not reversed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6820", "text": "Historically there was less consistency in the relationship of the position of the driver to the handedness of traffic. Most American cars produced before 1910 were RHD. [ 10 ]  In 1908  Henry Ford  standardised the  Model T  as LHD in RHT America, [ 10 ]  arguing that with RHD and RHT, the passenger was obliged to \"get out on the street side and walk around the car\" and that with steering from the left, the driver \"is able to see even the wheels of the other car and easily avoids danger.\" [ 88 ]  By 1915 other manufacturers followed Ford's lead, due to the popularity of the Model T. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6821", "text": "In specialised cases, the driver will sit on the nearside, or curbside. Examples include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6822", "text": "Generally, the convention is to mount a motorcycle on the left, [ 90 ]  and  kickstands  are usually on the left [ 91 ]  which makes it more convenient to mount on the safer kerbside [ 91 ]  as is the case in LHT. Some jurisdictions prohibit fitting a  sidecar  to a motorcycle's offside. [ 92 ] [ 93 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6823", "text": "In 2020, there were 160 LHD heavy goods vehicles in the UK involved in accidents (5%) for a total of 3,175 accidents, killing 215 people (5%) for a total of 4271. [ 94 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6824", "text": "It has been suggested that right-hand drive vehicles, and hence the left-hand traffic direction, are associated with greater safety. As most drivers are right-handed, the dominant right hand remains controlled on the steering wheel while the non-dominant left hand can manipulate gears. [ 95 ]  The right field of vision may also be more dominant, thereby permitting a superior view of oncoming traffic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6825", "text": "Some manufacturers primarily produce left-hand drive vehicles, due to the larger or nearer market for such vehicles. For such models supplied to left-hand traffic markets, in the right-hand drive configuration, the manufacturer may reuse the same  dashboard  configuration as is used in the left-hand drive models, with the steering column and pedals moved to the right-hand side. Oft-used controls (such as audio volume and fan controls) that were placed near the left-hand driver for ease of access, are now situated on the far side of the  center console  for the right-hand driver. This may make them more difficult to reach quickly or without looking away from the road ahead."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6826", "text": "In some cases, the manufacturer's dashboard design incorporates blanks and modular components, which permits the controls and underlying electronics to be rearranged to suit the right-hand drive model. This may be done in the factory, after import, or as an after-market modification."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6827", "text": "Most low-beam headlamps produce an asymmetrical light suitable for use on only one side of the road. Low beam headlamps in LHT jurisdictions throw most of their light forward-leftward; those for RHT throw most of their light forward-rightward, thus illuminating obstacles and road signs while minimising glare for oncoming traffic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6828", "text": "In Europe, headlamps approved for use on one side of the road must be adaptable to produce adequate illumination with controlled glare for temporarily driving on the other side of the road, [ 96 ] :\u200ap.13 \u00b65.8\u200a . This may be achieved by affixing masking strips or prismatic lenses to a part of the lens or by moving all or part of the headlamp optic so all or part of the beam is shifted or the asymmetrical portion is occluded. [ 96 ] :\u200ap.13 \u00b65.8.1\u200a  Some varieties of the  projector-type headlamp  can be fully adjusted to produce a proper LHT  or  RHT beam by shifting a lever or other movable element in or on the lamp assembly. [ 96 ] :\u200ap.12 \u00b65.4\u200a  Some vehicles adjust the headlamps automatically when the car's  GPS  detects that the vehicle has moved from LHT to RHT and vice versa. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6829", "text": "In Europe since early 1980s, [ 97 ]  cars must be equipped with one or two red  rear fog lamps . A single rear fog lamp must be located between the vehicle's longitudinal centreline and the outer extent of the driver's side of the vehicle. [ 98 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6830", "text": "ANCAP  reports that some RHD cars imported to Australia did not perform as well on crash tests as the LHD versions, although the cause is unknown, and may be due to differences in testing methodology. [ 99 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6831", "text": "In most countries rail traffic travels on the same side as road traffic. However, there are many instances of railways built using LHT British technology which remained LHT despite their nations' road traffic becoming RHT. Examples include:  Argentina ,  Belgium ,  Bolivia ,  Cambodia ,  China ,  Egypt ,  France ,  Iraq ,  Israel ,  Italy ,  Laos ,  Monaco ,  Morocco ,  Myanmar ,  Nigeria ,  Peru ,  Portugal ,  Senegal ,  Slovenia ,  Sweden ,  Switzerland ,  Taiwan ,  Tunisia ,  Uruguay  and  Venezuela . France is mainly LHT for trains except for the classic lines in  Alsace\u2013Lorraine , [ 100 ]  which were converted from LHT to RHT under German administration from 1870 to 1918. In North America, multi-track rail lines with  centralized traffic control  are typically signaled to allow operation on any track in both directions, and the side of operation will vary based on the railroad's specific operational requirements. [ 101 ]  In practice however, rail traffic is more often RHT.  Indonesia  is the only country in the world which has RHT for rails (even for newer rail systems such as the LRT and the MRT systems) and LHT for roads."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6832", "text": "Metro and light rail sides of operation vary and might not match railways or roads in their country. Some systems where the metro matches the side of the national rail network but not the roads include those in  Bilbao ,  Buenos Aires ,  Cairo ,  Catania ,  Jakarta ,  Lisbon ,  Lyon ,  Naples , and  Rome . A small number of cities, including  Madrid  and  Stockholm , originally ran on the same side as road traffic when the systems opened in 1919 and 1950 respectively, but had road traffic change in 1924 and 1967 respectively. Conversely, metros in France (except for the aforementioned Lyon) and mainland China run on the right just like roads, while mainline trains run on the left."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6833", "text": "A small number of systems have situational reasons to differ from the norm. On the  MTR  in Hong Kong, the section originally known as the  Ma On Shan line  (now part of the Tuen Ma line) runs on the right to make interchanging with the East Rail line easier, while the rest of the system runs on the left. On the  Seoul Metropolitan Subway , lines that integrate with Korail (except Line 3, which is disconnected from the rest of the network) run on the left, while the lines that are not run on the right. In  Nizhny Novgorod , Line 2 runs on the left due to the track layout when it first opened as a branch of Line 1. In  Lima , Line 1 runs entirely on the left, while Line 2 runs entirely on the right."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6834", "text": "Metro Line M1 in Budapest  is the only metro line to have switched sides. It originally ran on the left but switched to right hand-running during the line's reconstruction around 1973."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6835", "text": "Because trams frequently operate on roads, they generally operate on the same side as other road traffic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6836", "text": "Boats are traditionally piloted from  starboard  (the right-hand side) to facilitate  priority to the right . \nAccording to the  International Regulations for Preventing Collisions at Sea , water traffic is effectively RHT: a vessel proceeding along a narrow channel must keep to starboard, and when two power-driven vessels are meeting head-on both must alter course to starboard also."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6837", "text": "Typically, especially for larger vessels, a radio call will be made between two vessels, or with a  Vessel Traffic Service (VTS)  to co-ordinate if the vessels will pass \"green-to-green\" or \"red-to-red\". Marine traffic uses a system of green lighting for the starboard (right-hand) side and red for port (left-hand) side: to pass \"green-to-green\" the green (starboard, right-hand) side of the vessels will pass each other, essentially being left-hand traffic. Similarly, passing \"red-to-red\" means the red (port, left-hand) side of the vessels will pass each other, forming right-hand traffic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6838", "text": "In busy waterways, directional shipping lanes may be set up to facilitate handedness of traffic. For example, the  Strait of Dover  (Pas-de-Calais) on the  English Channel  uses RHT with North Sea-bound vessels following the French coast and Atlantic-bound vessels following the English coast."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6839", "text": "For aircraft the US  Federal Aviation Regulations  suggest RHT principles, both in the air and on water, and in aircraft with side-by-side cockpit seating, the pilot-in-command (or more senior flight officer) traditionally occupies the left seat. [ 102 ]  However, helicopter practice tends to favour the right hand seat for the pilot-in-command, particularly when flying solo. [ 103 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6840", "text": "Of the 195 countries currently recognised by the  United Nations , 141 use RHT and 54 use LHT on roads in general."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6841", "text": "A country and its territories and dependencies are counted as one. Whichever directionality is listed first is the type that is used in general in the traffic category."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6842", "text": "According to the  Vienna Convention on Road Traffic , which mostly covers Europe, if having a vehicle registered and legal to drive in one of the Convention countries, it is legal to drive it in any other of the countries, for visits and first year of residence after moving. This is regardless of whether it fulfils all the rules of the visitor countries. This convention does not affect rules on usage or registration of local vehicles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6843", "text": "Mefloquine , sold under the brand name  Lariam  among others, is a  medication  used to prevent or treat  malaria . [ 4 ]  When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. [ 4 ]  It can be used to treat mild or moderate malaria but is not recommended for severe malaria. [ 4 ]  It is taken  by mouth . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6844", "text": "Common side effects include vomiting, diarrhea, headaches, sleep disorders, and a rash. [ 4 ]  Serious side effects include potentially long-term mental health problems such as  depression ,  hallucinations , and  anxiety  and neurological side effects such as  poor balance ,  seizures , and  ringing in the ears . [ 4 ]  It is therefore not recommended in people with a history of mental health problems or  epilepsy . [ 4 ]  It appears to be safe during  pregnancy  and  breastfeeding . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6845", "text": "Mefloquine was developed by the United States Army in the 1970s and came into use in the mid-1980s. [ 5 ] [ 6 ] [ 7 ]  It is on the  World Health Organization's List of Essential Medicines . [ 8 ] [ 9 ]  It is available as a  generic medication . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6846", "text": "Mefloquine is used to both prevent and treat certain forms of malaria. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6847", "text": "Mefloquine is useful for the prevention of malaria in all areas except for those where parasites may have  resistance  to multiple medications, [ 11 ]  and is one of several anti-malarial medications recommended by the United States  Centers for Disease Control and Prevention  for this purpose. It is also recommended by the  Infectious Disease Society of America  for malaria prophylaxis as a first or second-line agent, depending on resistance patterns in the malaria found in the geographic region visited. [ 12 ] [ 13 ]  It is typically taken for one to two weeks before entering an area with malaria. [ 10 ]   Doxycycline  and  atovaquone/proguanil  provide protection within one to two days and may be better tolerated. [ 14 ] [ 15 ]  If a person becomes ill with malaria despite prophylaxis with mefloquine, the use of  halofantrine  and  quinine  for treatment may be ineffective. [ 16 ] :\u200a4"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6848", "text": "Mefloquine is used as a treatment for  chloroquine -sensitive or resistant  Plasmodium falciparum  malaria, and is deemed a reasonable alternative for uncomplicated chloroquine-resistant  Plasmodium vivax  malaria. [ 10 ] [ 16 ]  It is one of several drugs recommended by the United States' Centers for Disease Control and Prevention. [ 17 ] \nIt is not recommended for severe malaria infections, particularly infections from  P. falciparum , which should be treated with intravenous  antimalarials . [ 10 ] [ 16 ]  Mefloquine does not eliminate parasites in the liver phase of the disease, and people with  P. vivax  malaria should be treated with a second drug that is effective for the liver phase, such as  primaquine . [ 16 ] :\u200a4"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6849", "text": "Resistance  to mefloquine is common around the west border in  Cambodia  and other parts of Southeast Asia. [ 18 ]  The mechanism of resistance is by increase in  Pfmdr1  copy number. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6850", "text": "Common side effects include vomiting, diarrhea, headaches, and a rash. [ 4 ]  Severe side effects requiring hospitalization are rare, [ 11 ]  but include mental health problems such as  depression ,  hallucinations ,  anxiety  and neurological side effects such as  poor balance ,  seizures , and  ringing in the ears . [ 4 ]  Mefloquine is therefore not recommended in people with a history of  psychiatric disorders  or  epilepsy . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6851", "text": "In 2013, the U.S.  Food and Drug Administration  (FDA) added a  boxed warning  to the  prescription label  of mefloquine regarding the potential for neuropsychiatric side effects that may persist even after discontinuing administration of the medication. [ 20 ] [ 21 ]  In 2013 the FDA stated \"Neurologic side effects can occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent.\" [ 22 ]  Neurologic effects include  dizziness , loss of balance,  seizures , and  tinnitus . Psychiatric effects include  nightmares ,  visual hallucinations ,  auditory hallucinations ,  anxiety ,  depression , unusual behavior, and  suicidal ideations ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6852", "text": "Central nervous system events requiring hospitalization occur in about one in 10,000 people taking mefloquine for malaria prevention, with milder events (e.g., dizziness, headache,  insomnia , and vivid dreams) in up to 25%. [ 23 ]  When some measure of subjective severity is applied to the rating of adverse events, about 11\u201317% of travelers are incapacitated to some degree. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6853", "text": "Mefloquine may cause abnormalities with heart rhythms that are visible on  electrocardiograms . Combining mefloquine with other drugs that cause similar effects, such as quinine or  quinidine , can increase these effects. Combining mefloquine with halofantrine can cause significant increases in  QTc intervals . [ 16 ] :\u200a10"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6854", "text": "Mefloquine is contraindicated in those with a previous history of seizures or a recent history of psychiatric disorders. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6855", "text": "Available data suggests that mefloquine is safe and effective for use by pregnant women during all trimesters of pregnancy, [ 24 ]  and it is widely used for this indication. [ 25 ]  In pregnant women, mefloquine appears to pose minimal risk to the fetus, [ 25 ] [ 26 ]  and is not associated with increased risk of birth defects or miscarriages. [ 27 ]  Compared to other malaria chemoprophylaxis regimens, however, mefloqinone may produce more side effects in non-pregnant travelers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6856", "text": "Mefloquine is also safe and effective for use during breastfeeding, [ 24 ]  though it appears in breast milk in low concentrations. [ 11 ] [ 16 ] :\u200a9\u200a  The  World Health Organization  (WHO) gives approval for the use of mefloquine in the second and third trimesters of pregnancy and use in the first trimester does not mandate termination of pregnancy. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6857", "text": "Mefloquine is metabolized primarily through the liver. Its elimination in persons with impaired liver function may be prolonged, resulting in higher plasma levels and an increased risk of adverse reactions. The mean elimination plasma half-life of mefloquine is between two and four weeks. Total clearance is through the liver, and the primary means of excretion is through the bile and feces, as opposed to only 4% to 9% excreted through the urine. During long-term use, the plasma half-life remains unchanged. [ 28 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6858", "text": "Liver function tests should be performed during long-term administration of mefloquine. [ 30 ]  Alcohol use should be avoided during treatment with mefloquine. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6859", "text": "Specifically it is used as mefloquine hydrochloride."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6860", "text": "Mefloquine is a  chiral  molecule with two  asymmetric carbon  centres, which means it has four different  stereoisomers . The drug is currently manufactured and sold as a  racemate  of the ( R , S )- and ( S , R )-enantiomers by  Hoffmann-La Roche , a Swiss  pharmaceutical  company. Essentially, it is two drugs in one. Plasma concentrations of the (\u2013)-enantiomer are significantly higher than those for the (+)-enantiomer, and the pharmacokinetics between the two enantiomers are significantly different. The (+)-enantiomer has a shorter half-life than the (\u2013)-enantiomer. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6861", "text": "Mefloquine was formulated at  Walter Reed Army Institute of Research  (WRAIR) in the 1970s shortly after the end of the Vietnam war. Mefloquine was number 142,490 of a total of 250,000 antimalarial compounds screened during the study. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6862", "text": "Mefloquine was the first Public-Private Venture (PPV) between the US Department of Defense and a pharmaceutical company. WRAIR transferred all its phase I and phase II clinical trial data to Hoffman-LaRoche and  Smith Kline . FDA approval as a treatment for malaria was swift. Most notably, phase III safety and tolerability trials were skipped. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6863", "text": "The drug was first approved in Switzerland in 1984 by Hoffmann-LaRoche, [ 32 ]  who brought it to market with the name  Lariam . [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6864", "text": "However, mefloquine was not approved by the FDA for prophylactic use until 1989. This approval was based primarily on compliance, while safety and tolerability were overlooked. [ 5 ]  Because of the drug's very long half-life, the  Centers for Disease Control  originally recommended a mefloquine dosage of 250\u00a0mg every two weeks; however, this caused an unacceptably high malaria rate in the  Peace Corps  volunteers who participated in the approval study, so the drug regimen was switched to once a week. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6865", "text": "By 1991, Hoffman was marketing the drug on a worldwide basis. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6866", "text": "By the 1992  UNITAF , Canadian soldiers were being prescribed the drug  en masse . [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6867", "text": "By 1994, medical professionals were noting \"severe psychiatric side effects observed during prophylaxis and treatment with mefloquine\", and recommending that \"the absence of  contraindications  and minor side effects during an initial course of mefloquine should be confirmed before another course is prescribed.\" [ 35 ]  Other doctors at the  University Hospital of Zurich  noted in a case of \"a 47-year-old, previously healthy Japanese tourist\" who had severe neuropsychiatric side-effects from the drug that [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6868", "text": "The neuropsychiatric side effects of the antimalarial drug mefloquine are well documented. They include anxiety, depression, hallucinations, acute psychosis, and seizures. The incidence of these side effects is 1 in 13,000 with prophylactic use and 1 in 250 with therapeutic use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6869", "text": "The first randomized, controlled trial on a mixed population was performed in 2001. Prophylaxis with mefloquine was compared to prophylaxis with  atovaquone-proguanil . Roughly 67% of participants in the mefloquine arm reported greater than or equal to one adverse event, versus 71% in the atovaquone-proguanil arm. In the mefloquine arm, 5% of the users reported severe events requiring medical attention, versus 1.2% in the atovaquone-proguanil arm. [ 5 ] [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6870", "text": "In August 2009, Roche stopped marketing Lariam in the United States. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6871", "text": "Retired soldier  Johnny Mercer , who was later appointed Minister for Veterans Affairs by  Boris Johnson , told in 2015 that he had received \"a letter about once or twice a week\" about ill-effects from the drug. [ 39 ]  In July 2016, Roche took this brand off the market in Ireland. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6872", "text": "In 2006, the Australian military deemed mefloquine \"a third-line drug\" alternative, and over the five years from 2011 only 25 soldiers had been prescribed the drug, and only in cases of their intolerance for other alternatives. [ 38 ]  Between 2001 and 2012, 16,000 Canadian soldiers sent to Afghanistan were given the drug as a preventative measure. [ 38 ]  In 2013, the US Army banned mefloquine from use by its special forces such as the  Green Berets . [ 38 ]  In autumn 2016, the UK military followed suit with their Australian peers after a parliamentary inquiry into the matter revealed that it can cause permanent side effects and brain damage. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6873", "text": "In early December 2016, the German defence ministry removed mefloquine from the list of medications it would provide to its soldiers. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6874", "text": "In autumn 2016, Canadian  Surgeon General  Brigadier General  Hugh Colin MacKay  told a parliamentary committee that faulty science supported the assertion that the drug has indelible noxious side effects. An expert from  Health Canada  named  Barbara Raymond  told the same committee that the evidence she had read failed to support the conclusion of indelible side effects. [ 38 ]  Canadian soldiers who took mefloquine when deployed overseas have claimed they have been left with ongoing mental health problems. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6875", "text": "In 2020 the UK Ministry of Defence (MoD) admitted to a breach of duty regarding the use of Mefloquine. [ 41 ]  by acknowledging numerous instances of failure to assess the risks and warn of potential side effects of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6876", "text": "In June 2010, the first case report appeared of a  progressive multifocal leukoencephalopathy  being successfully treated with mefloquine. Mefloquine can also act against the  JC virus . Administration of mefloquine seemed to eliminate the virus from the patient's body and prevented further neurological deterioration. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6877", "text": "Mefloquine alters  cholinergic   synaptic transmission  through both postsynaptic  [ 43 ]  and presynaptic actions. [ 44 ]  The postsynaptic action to inhibit  acetylcholinesterase  changes transmission across synapses in the brain. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6878", "text": "Metachirality  is a stronger form of  chirality .\nIt applies to objects or systems that are chiral (not identical to their  mirror image ) and where, in addition, their mirror image has a  symmetry group  that differs from the symmetry group of the original object or system. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6879", "text": "Many familiar chiral objects, like the capital letter 'Z' embedded in the plane, are not metachiral.\nThe symmetry group of the capital letter 'Z' embedded in the plane consists of the  identity transformation  and a rotation over 180\u02da (a half turn).\nIn this case, the mirror image has the same symmetry group.\nIn particular, asymmetric objects (that only have the identity transformation as symmetry, like a human hand) are not metachiral,\nsince the mirror image is also asymmetric.\nIn general, two-dimensional objects and bounded three-dimensional objects are not metachiral."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6880", "text": "An example of a metachiral object is an infinite  helical staircase .\nA  helix  in 3D has a  handedness  (either left or right, like  screw thread ), whereby it differs from its mirror image.\nAn infinite helical staircase, however, does have symmetries:\n screw operations , that is, a combination of a  translation  and a  rotation .\nThe symmetry group of the mirror image of an infinite helical staircase also contains screw operations.\nBut they are of the opposite handedness and, hence,\nthe symmetry groups differ.\nNote, however, that these symmetry groups are  isomorphic ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6881", "text": "Of the 219  space groups , 11 are metachiral.\nA nice example of a metachiral spatial structure is the  K 4  crystal , [ 2 ]  also known as Triamond,\nand featured in the  Bamboozle  mathematical artwork. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6882", "text": "A  mirror image  (in a plane mirror) is a  reflected  duplication of an object that appears almost identical, but is reversed in the direction perpendicular to the mirror surface. As an  optical effect , it results from  specular reflection  off from surfaces of lustrous materials, especially a  mirror  or  water . It is also a concept in  geometry  and can be used as a  conceptualization  process for 3D structures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6883", "text": "In  geometry , the mirror image of an object or  two-dimensional figure  is the  virtual image  formed by  reflection  in a  plane mirror ; it is of the same size as the original object, yet different, unless the object or figure has  reflection symmetry  (also known as a  P-symmetry )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6884", "text": "Two-dimensional mirror images can be seen in the reflections of mirrors or other reflecting surfaces, or on a printed surface seen inside-out. If we first look at an object that is effectively two-dimensional (such as the writing on a card) and then turn the card to face a mirror, the object turns through an angle of 180\u00b0 and we see a left-right reversal in the mirror. In this example, it is the change in orientation rather than the mirror itself that causes the observed reversal. Another example is when we stand with our backs to the mirror and face an object that is in front of the mirror. Then we compare the object with its reflection by turning ourselves 180\u00b0, towards the mirror. Again we perceive a left-right reversal due to a change in our orientation. So, in these examples the mirror does not actually cause the observed reversals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6885", "text": "The concept of reflection can be extended to  three-dimensional  objects, including the inside parts, even if they are not  transparent . The term then relates to structural as well as visual aspects. A three-dimensional object is reversed in the direction perpendicular to the mirror surface. In physics, mirror images are investigated in the subject called  geometrical optics . More fundamentally in geometry and mathematics they form the principal objects of  Coxeter group  theory and  reflection groups ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6886", "text": "In chemistry, two versions ( isomers ) of a molecule, one a \"mirror image\" of the other, are called  enantiomers  if they are not \"superposable\" (the correct technical term, though the term \"superimposable\" is also used) on each other. That is an example of  chirality . In general, an object and its mirror image are called  enantiomorphs ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6887", "text": "If a point of an object has coordinates ( x ,  y ,  z ) then the image of this point (as reflected by a mirror in the  y ,  z  plane) has coordinates (\u2212 x ,  y ,  z ). Thus reflection is a reversal of the coordinate axis perpendicular ( normal ) to the mirror's surface. Although a plane mirror reverses an object only in the direction normal to the mirror surface, this turns the entire three-dimensional image seen in the mirror inside-out, so there is a  perception  of a left-right reversal. Hence, the reversal is somewhat misleadingly called a \"lateral inversion\". The perception of a left-right reversal is geometrically explained by the fact that a three-dimensional object seen in a mirror is an inside-out version of the actual object, like a glove stripped off the left hand and turned into a right-hand glove, but there is still some confusion about the explanation amongst psychologists. The psychology of the perceived left-right reversal is discussed in \"Much ado about mirrors\" by Professor  Michael Corballis  (see \"external links\", below)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6888", "text": "Reflection in a mirror  does  result in a change in  chirality , more specifically from a right-handed to a left-handed coordinate system (or vice versa). If one looks in a mirror two axes (up-down and left-right) coincide with those in the mirror, but  the third axis (front-back) is reversed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6889", "text": "If a person stands side-on to a mirror, left and right hands will be reversed  directly  by the mirror, because the person's left-right axis is then normal to the mirror plane. However, it is important to understand that there are  always  only two enantiomorphs, the object and its inside-out image. Therefore, no matter how the object is oriented towards the mirror, all the resulting images are fundamentally identical (as Corballis explains in his paper \"Much ado about mirrors\", mentioned above)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6890", "text": "In the picture of the mountain reflected in the lake (photograph top right), the reversal normal to the reflecting surface is obvious. Notice that there is no obvious front-back or left-right of the mountain. In the example of the urn and mirror (photograph to right), the urn is fairly symmetrical front-back (and left-right). Thus, no obvious reversal of any sort can be seen in the mirror image of the urn."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6891", "text": "A mirror image appears more obviously three-dimensional if the observer moves, or if the image is viewed using  binocular vision . This is because the relative position of objects changes as the observer's perspective changes, or is differently viewed with each eye. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6892", "text": "Looking through a mirror from different positions (but necessarily with the point of observation restricted to the halfspace on one side of the mirror) is like looking at the 3D mirror image of space; without further mirrors only the mirror image of the halfspace before the mirror is relevant; if there is another mirror, the mirror image of the other halfspace is too."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6893", "text": "A mirror does not just produce an image of what would be there without it; it also changes the light distribution in the halfspace in front of and behind the mirror. A mirror hanging on the wall makes the room brighter because additional light sources appear in the mirror image. However, the appearance of additional light does not violate the  conservation of energy  principle, because some light no longer reaches behind the mirror, as the mirror simply re-directs the light energy. In terms of the light distribution, the virtual mirror image has the same appearance and the same effect as a real, symmetrically arranged half-space behind a window (instead of the mirror). Shadows may extend from the mirror into the halfspace before it, and vice versa."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6894", "text": "In  mirror writing  a text is deliberately displayed as its mirror image, in order to be read through a mirror. For example, emergency vehicles such as  ambulances  or fire engines use mirror images in order to be read from a vehicle's  rear-view mirror . Some  movie theaters  also use mirror writing in a  Rear Window Captioning System  used to assist individuals with  hearing impairments  in watching films."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6895", "text": "In the case of two mirrors, in planes at an angle \u03b1, looking through both from the sector which is the intersection of the two halfspaces, is like looking at a version of the world rotated by an angle of 2\u03b1; the points of observations and directions of looking for which this applies correspond to those for looking through a frame like that of the first mirror, and a frame at the mirror image with respect to the first plane, of the second mirror. If the mirrors have vertical edges then the left edge of the field of view is the plane through the right edge of the first mirror and the edge of the second mirror which is on the right when looked at directly, but on the left in the mirror image."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6896", "text": "In the case of two parallel mirrors, looking through both at once is like looking at a version of the world which is translated by twice the distance between the mirrors, in the direction perpendicular to them, away from the observer. Since the plane of the mirror in which one looks directly is beyond that of the other mirror, one always looks at an oblique angle, and the translation just mentioned has not only a component away from the observer, but also one in a perpendicular direction. The translated view can also be described by a translation of the observer in opposite direction. For example, with a vertical  periscope , the shift of the world is away from the observer and down, both by the length of the periscope, but it is more practical to consider the equivalent shift of the observer: up, and backward."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6897", "text": "It is also possible to create a  non-reversing mirror  by placing two  first surface mirrors  at 90\u00ba to give an image which is not reversed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6898", "text": "Mirror life  (also called  mirror-image life ) is a hypothetical form of life with  mirror-reflected  molecular building blocks. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  The possibility of mirror life was first discussed by  Louis Pasteur . [ 6 ]  This alternative life form has never been discovered in nature, but efforts to build a mirror-image version of biology's molecular machinery are underway. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6899", "text": "In December 2024, a broad coalition of scientists, including leading synthetic biology researchers and Nobel laureates, warned that the creation of mirror life, including mirror bacteria, could cause \"unprecedented and irreversible harm\" to human health and ecosystems worldwide. [ 8 ] [ 9 ]  Its potential to escape immune defenses and invade natural ecosystems might lead to \"pervasive lethal infections in a substantial fraction of plant and animal species, including humans.\" Given these risks, the scientists concluded that mirror organisms should not be created without compelling evidence of safety. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6900", "text": "Many of the essential molecules for life on Earth can exist in two mirror-image forms, often called \"left-handed\" and \"right-handed\", where handedness refers to the direction in which polarized light skews when beamed through a pure solution of the molecule, but living organisms do not use both. [ 10 ]   RNA  and  DNA  contain only right-handed  sugars ;  proteins  are exclusively composed of left-handed  amino acids , although many bacteria and fungi are able to synthesise non-ribosomal peptides containing right-handed amino acids, as the example of  peptidoglycan synthesis  shows. This phenomenon is known as  homochirality . [ 11 ]  It is not known whether homochirality emerged before or after life, whether the building blocks of life must have this particular chirality, or indeed whether life needs to be homochiral. [ 12 ]  Protein chains built from amino acids of mixed chirality tend not to fold or function well, but mirror-image proteins have been constructed that have identical function but on substrates of opposite handedness. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6901", "text": "Advances in  synthetic biology , like  synthesizing viruses  since 2002,  partially synthetic bacteria  in 2010, and  synthetic ribosomes  in 2013, may lead to the possibility of fully synthesizing a living cell from small molecules, which could enable synthesizing mirror cells from mirrored versions ( enantiomers ) of life's building-block molecules. Some proteins have been synthesized in mirror-image versions, including  polymerase  in 2016. [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6902", "text": "Reconstructing regular lifeforms in mirror-image form, using the mirror-image (chiral) reflection of their cellular components, could be achieved by substituting left-handed amino acids with right-handed ones, in order to create mirror reflections of proteins, and likewise substituting right-handed with left-handed nucleic acids. [ 15 ]  Because the  phospholipids  of cell membranes are also chiral, American geneticist  George Church  proposed using an achiral fatty acid instead of mirror-image phospholipids for the membrane. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6903", "text": "Electromagnetic force (chemistry) is unchanged under such molecular reflection transformation ( P-symmetry ). There is a small alteration of weak interactions under reflection, which can produce very small corrections that theoretically favor the natural enantiomers of amino acids and sugars, [ 16 ]  but it is unknown if this effect is large enough to affect the functionality of mirror biomolecules or explain homochirality in nature. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6904", "text": "Mirror animals would need to feed on reflected food, produced by reflected plants. Mirror viruses would not be able to attack natural cells, just as natural viruses would not be able to attack mirror cells. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6905", "text": "Mirror life presents potential dangers. For example, a chiral-mirror version of  cyanobacteria , which only needs achiral nutrients and light for  photosynthesis , could take over Earth's ecosystem due to lack of natural enemies, disturbing the bottom of the food chain by producing mirror versions of the required sugars. [ 15 ]  Some bacteria can digest  L -Glucose ; exceptions like this would give some rare lifeforms an unanticipated advantage."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6906", "text": "Direct application of mirror-chiral organisms can be mass production of  enantiomers  (mirror-image) of molecules produced by normal life."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6907", "text": "The creation of a mirror human is the basis of the 1950 short story \" Technical Error \" by Arthur C. Clarke. [ 21 ]  In this story, a physical accident transforms a person into his mirror image, speculatively explained by travel through a fourth physical dimension. H. G. Wells'  The Plattner Story  (1896) is based on a similar idea."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6908", "text": "In the 1970  Star Trek  novel  Spock Must Die!  by James Blish, the science officer of the USS Enterprise is replicated in mirror form by a transporter mishap. He locks himself in the sick bay where he is able to synthesize mirror forms of basic nutrients needed for his survival. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6909", "text": "An alien machine that reverses chirality, and a blood-symbiont that functions properly only when in one chirality, were central to Roger Zelazny's 1976 novel  Doorways in the Sand . [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6910", "text": "On the titular planet of  Sheri S. Tepper 's 1989 novel  Grass , some lifeforms have evolved to use the right-handed isomer of  alanine . [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6911", "text": "In the  Mass Effect  series, chirality of amino acids in foodstuffs is discussed often in both dialogue and encyclopedia files."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6912", "text": "In the 2014 science fiction novel  Cibola Burn  by  James S. A. Corey , the planet Ilus has indigenous life with partially-mirrored chirality. This renders human colonists unable to digest native flora and fauna, and greatly complicates conventional farming. Consequently, the colonists have to rely upon  hydroponic farming  and food importation. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6913", "text": "In the 2017  Daniel Suarez  novel  Change Agent , an antagonist, Otto, nicknamed the \"Mirror Man\", is revealed to be a genetically-engineered mirror human. He views other humans with disdain and causes them to feel an inexplicable repulsion by his very presence. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6914", "text": "The concept is used during  Ryan North 's 2023 run on  Fantastic Four  as an existential threat towards the human population. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6915", "text": "Planar chirality , also known as 2D chirality, is the special case of  chirality  for two  dimensions ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6916", "text": "Most fundamentally, planar  chirality  is a  mathematical  term, finding use in  chemistry ,  physics  and related physical sciences, for example, in  astronomy ,  optics  and  metamaterials . Recent occurrences in latter two fields are dominated by  microwave  and  terahertz  applications as well as micro- and  nanostructured  planar interfaces for  infrared  and visible  light ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6917", "text": "This term is used in  chemistry  contexts, [ 2 ]  e.g., for a  chiral   molecule  lacking an  asymmetric carbon  atom, but possessing two non- coplanar  rings that are each dissymmetric and which cannot easily rotate about the  chemical bond  connecting them: 2,2'-dimethylbiphenyl is perhaps the simplest example of this case. Planar chirality is also exhibited by molecules like ( E )- cyclooctene , some di- or poly-substituted  metallocenes , and certain monosubstituted  paracyclophanes . Nature rarely provides planar chiral molecules,  cavicularin  being an exception."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6918", "text": "To assign the configuration of a planar chiral molecule, begin by selecting the pilot atom, which is the  highest priority  of the atoms that is not in the plane, but is directly attached to an atom in the plane. Next, assign the priority of the three adjacent in-plane atoms, starting with the atom attached to the pilot atom as priority 1, and preferentially assigning in order of highest priority if there is a choice. Then set the pilot atom to in front of the three atoms in question. If the three atoms reside in a clockwise direction when followed in order of priority, the molecule is assigned as R; when counterclockwise it is assigned as S. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6919", "text": "Papakostas  et al.  observed in 2003 that planar chirality affects the polarization of light diffracted by arrays of planar chiral microstructures, where large polarization changes of opposite sign were detected in light diffracted from planar structures of opposite handedness. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6920", "text": "The study of planar chiral  metamaterials  has revealed that planar chirality is also associated with an optical effect in non-diffracting structures: the directionally asymmetric transmission (reflection and absorption) of  circularly polarized  waves. Planar chiral metamaterials, which are also anisotropic and lossy exhibit different total transmission (reflection and absorption) levels for the same circularly polarized wave incident on their front and back.\nThe asymmetric transmission phenomenon arises from different, e.g. left-to-right, circular polarization conversion efficiencies for opposite propagation directions of the incident wave and therefore the effect is referred to as circular conversion dichroism.\nLike the twist of a planar chiral pattern appears reversed for opposite directions of observation, planar chiral metamaterials have interchanged properties for left-handed and right-handed circularly polarized waves that are incident on their front and back. In particular left-handed and right-handed circularly polarized waves experience opposite directional transmission (reflection and absorption) asymmetries. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6921", "text": "Achiral components may form a chiral arrangement. In this case, chirality is not an intrinsic property of the components, but rather imposed extrinsically by their relative positions and orientations. This concept is typically applied to experimental arrangements, for example, an achiral (meta)material illuminated by a beam of light, where the illumination direction makes the whole experiment different from its mirror image. Extrinsic planar chirality results from illumination of any periodically structured interface for suitable illumination directions. Starting from normal incidence onto a periodically structured interface, extrinsic planar chirality arises from tilting the interface around any axis that does not coincide with a line of mirror symmetry of the interface. In the presence of losses, extrinsic planar chirality can result in circular conversion dichroism, as described above. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6922", "text": "Conventional mirrors reverse the handedness of circularly polarized waves upon reflection. In contrast, a chiral mirror reflects circularly polarized waves of one handedness without handedness change [ dubious  \u2013  discuss ] , while absorbing circularly polarized waves of the opposite handedness. A perfect chiral mirror exhibits circular conversion dichroism with ideal efficiency. Chiral mirrors can be realized by placing a planar chiral metamaterial in front of a conventional mirror. [ 8 ]  The concept has been exploited in holography to realize independent holograms for left-handed and right-handed circularly polarized electromagnetic waves. [ 9 ]  Active chiral mirrors that can be switched between left and right, or chiral mirror and conventional mirror, have been reported. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6923", "text": "Racemic acid  is an old name for an optically inactive or  racemic  form of  tartaric acid . It is an equal mixture of two mirror-image  isomers  ( enantiomers ), optically active in opposing directions. Racemic acid does not occur naturally in grape juice, although L-tartaric acid does."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6924", "text": "Tartaric acid's sodium-ammonium  salt  is unusual among racemic mixtures in that during crystallization it can separate out into two kinds of crystals, each composed of one isomer, and whose macroscopic crystalline shapes are mirror images of each other. Thus,  Louis Pasteur  was able in 1848 to isolate each of the two enantiomers by laboriously separating the two kinds crystals using delicate tweezers and a hand lens. [ 1 ]  Pasteur announced his intention to resolve racemic acid in:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6925", "text": "while he presented his resolution of racemic acid into separate  optical  isomers in:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6926", "text": "In the latter paper, Pasteur sketches from natural concrete reality  chiral polytopes  quite possibly for the first time. The optical property of tartaric acid was first observed in 1832 by  Jean Baptiste Biot , who observed its ability to rotate  polarized light . [ 4 ] [ 5 ]  It remains unknown whether  Arthur Cayley  or  Ludwig Schl\u00e4fli , or other contemporary mathematicians who studied polytopes, knew of the French work."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6927", "text": "In two modern-day re-enactments performed in Japan of the Pasteur experiment, [ 6 ] [ 7 ]  it was established that the preparation of crystals was not very reproducible. The crystals deformed, but they were large enough to inspect with the naked eye (microscope not required)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6928", "text": "Sinistral  and  dextral , in some scientific fields, are the two types of  chirality  (\" handedness \") or  relative direction . The terms are derived from the  Latin  words for \"left\" ( sinister ) and \"right\" ( dexter ). Other disciplines use different terms (such as  dextro-  and  laevo-rotary  in  chemistry , or  clockwise  and  anticlockwise  in  physics ) or simply use left and right (as in  anatomy )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6929", "text": "Relative direction and chirality are distinct concepts. Relative direction is from the point of view of the observer; a completely symmetric object has a left side and a right side, from the observer's point of view, if the top and bottom and direction of observation are defined. Chirality, however, is observer-independent: no matter how one looks at a right-hand  screw thread , it remains different from a left-hand screw thread. Therefore, a symmetric object has sinistral and dextral directions arbitrarily defined by the position of the observer, while an asymmetric object that shows chirality may have sinistral and dextral directions defined by characteristics of the object, regardless of the position of the observer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6930", "text": "Because the coiled  shells  of  gastropods  are asymmetric, they possess a quality called  chirality \u2013the \"handedness\" of an asymmetric structure."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6931", "text": "Over 90% [ 1 ]  of gastropod species have shells in which the direction of the coil is  dextral  (right-handed). A small minority of species and genera have shells in which the coils are almost always  sinistral  (left-handed). Very few species show an even mixture of dextral and sinistral individuals (for example,  Amphidromus perversus ). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6932", "text": "The most obvious characteristic of  flatfish , other than their flatness, is their asymmetric morphology: both eyes are on the same side of the head in the adult fish. In some families of flatfish, the eyes are always on the right side of the body ( dextral  or right-eyed flatfish), and in others, they are always on the left ( sinistral  or left-eyed flatfish). Primitive  spiny turbots  include equal numbers of right- and left-sided individuals, and are generally more symmetric than other families. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6933", "text": "In  geology , the terms  sinistral  and  dextral  refer to the horizontal component of the movement of blocks on either side of a  fault  or the sense of movement within a  shear zone . These are terms of relative direction, as the movement of the blocks is described relative to each other when viewed from above. Movement is sinistral (left-handed) if the block on the other side of the fault moves to the left, or if straddling the fault the left side moves toward the observer. Movement is dextral (right-handed) if the block on the other side of the fault moves to the right, or if straddling the fault the right side moves toward the observer. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6934", "text": "In  chemistry , the term  supramolecular chirality  is used to describe  supramolecular assemblies  that are non-superposable on their mirror images."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6935", "text": "Chirality  in  supramolecular chemistry  implies the non-symmetric arrangement of molecular components in a non-covalent assembly. Chirality may arise in a  supramolecular   system if one of its component is chiral or if achiral components arrange in a non symmetrical way to produce a  supermolecule  that is chiral. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6936", "text": "[ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6937", "text": "Tartaric acid  is a white, crystalline  organic acid  that occurs naturally in many fruits, most notably in  grapes  but also in  tamarinds ,  bananas ,  avocados ,  and  citrus . [ 1 ]  Its  salt ,  potassium bitartrate , commonly known as cream of tartar, develops naturally in the process of  fermentation . Potassium bitartrate is commonly mixed with  sodium bicarbonate  and is sold as  baking powder  used as a  leavening agent  in food preparation. The acid itself is added to foods as an  antioxidant   E334  and to impart its distinctive sour taste.  Naturally occurring  tartaric acid is a useful raw material in  organic synthesis . Tartaric acid, an alpha-hydroxy- carboxylic acid , is  diprotic  and  aldaric  in acid characteristics and is a dihydroxyl derivative of  succinic acid ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6938", "text": "Tartaric acid has been known to  winemakers  for centuries. However, the chemical process for extraction was developed in 1769 by the  Swedish  chemist  Carl Wilhelm Scheele . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6939", "text": "Tartaric acid played an important role in the discovery of  chemical chirality . This property of tartaric acid was first observed in 1832 by  Jean Baptiste Biot , who observed its ability to rotate  polarized light . [ 5 ] [ 6 ]   Louis Pasteur  continued this research in 1847 by investigating the shapes of  sodium ammonium tartrate  crystals, which he found to be chiral. By manually sorting the differently shaped crystals, Pasteur was the first to produce a pure sample of levotartaric acid. [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6940", "text": "Naturally occurring form of the acid is  dextro tartaric\u00a0acid   or  L -(+)-tartaric\u00a0acid  (obsolete name  d -tartaric acid).  Because it is available naturally, it is cheaper than its  enantiomer  and the  meso isomer . The  dextro  and  levo  prefixes are archaic terms. [ 12 ]  Modern textbooks refer to the natural form as (2 R ,3 R )-tartaric acid  ( L -(+)-tartaric acid) , and its enantiomer as (2 S ,3 S )-tartaric acid  ( D -(-)-tartaric acid) .  The  meso  diastereomer is referred to as (2 R ,3 S )-tartaric acid or (2 S ,3 R )-tartaric acid."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6941", "text": "Tartaric acid in  Fehling's solution  binds to copper(II) ions, preventing the formation of insoluble hydroxide salts."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6942", "text": "The  L -(+)-tartaric acid isomer of tartaric acid is industrially produced in the largest amounts. It is obtained from  lees , a solid byproduct of fermentations. The former byproducts mostly consist of potassium bitartrate ( KHC 4 H 4 O 6 ). This potassium salt is converted to  calcium tartrate  ( CaC 4 H 4 O 6 ) upon treatment with  calcium hydroxide  ( Ca(OH) 2 ): [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6943", "text": "In practice, higher yields of calcium tartrate are obtained with the addition of  calcium sulfate .  Calcium tartrate is then converted to tartaric acid by treating the salt with aqueous sulfuric acid:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6944", "text": "Racemic tartaric acid can be prepared in a multistep reaction from  maleic acid . In the first step, the maleic acid is  epoxidized  by  hydrogen peroxide  using  potassium tungstate \u00a0[ de ]  as a catalyst. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6945", "text": "In the next step, the epoxide is hydrolyzed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6946", "text": "A mixture of racemic acid and  meso -tartaric acid is formed when  dextro -Tartaric acid is heated in water at 165\u00a0\u00b0C for about 2 days.  meso -Tartaric acid can also be prepared from dibromosuccinic acid using silver hydroxide: [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6947", "text": "meso -Tartaric acid can be separated from residual racemic acid by crystallization, the racemate being less soluble."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6948", "text": "L-(+)-tartaric acid, can participate in several reactions. As shown the reaction scheme below, dihydroxymaleic acid is produced upon treatment of L-(+)-tartaric acid with hydrogen peroxide in the presence of a  ferrous  salt."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6949", "text": "Dihydroxymaleic acid  can then be oxidized to  tartronic acid  with nitric acid. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6950", "text": "Important derivatives of tartaric acid include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6951", "text": "Tartaric acid is a  muscle   toxin , which works by inhibiting the production of  malic acid , and in high doses causes paralysis and death. [ 26 ]  The  median lethal dose  (LD 50 ) is about 7.5 grams/kg for a human, 5.3\u00a0grams/kg for rabbits, and 4.4\u00a0grams/kg for mice. [ 27 ]  Given this figure, it would take over 500\u00a0g (18\u00a0oz) to kill a person weighing 70\u00a0kg (150\u00a0lb) with 50% probability, so it may be safely included in many foods, especially sour-tasting  sweets . As a  food additive , tartaric acid is used as an  antioxidant  with  E number   E334 ;  tartrates  are other additives serving as antioxidants or  emulsifiers ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6952", "text": "When cream of tartar is added to water, a suspension results which serves to clean copper  coins  very well, as the tartrate solution can dissolve the layer of copper(II) oxide present on the surface of the coin. The resulting copper(II)-tartrate complex is easily soluble in water."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6953", "text": "Tartaric acid may be most immediately recognizable to wine drinkers as the source of \"wine diamonds\", the small  potassium bitartrate  crystals that sometimes form spontaneously on the  cork  or bottom of the bottle. These \"tartrates\" are harmless, despite sometimes being mistaken for broken glass, and are prevented in many wines through  cold stabilization  (which is not always preferred since it can change the wine's profile). The tartrates remaining on the inside of  aging barrels  were at one time a major industrial source of potassium bitartrate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6954", "text": "Tartaric acid plays an important role chemically, lowering the pH of fermenting \"must\" to a level where many undesirable spoilage bacteria cannot live, and acting as a preservative after  fermentation . In the mouth, tartaric acid provides some of the tartness in the wine, although  citric  and  malic acids  also play a role."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6955", "text": "Grapes and tamarinds have the highest levels of tartaric acid concentration. Other fruits with tartaric acid are  bananas ,  avocados ,  prickly pear  fruit,  apples ,  cherries ,  papayas ,  peaches ,  pears ,  pineapples ,  strawberries ,  mangoes   and  citrus fruits . [ 1 ] [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6956", "text": "Trace amounts of tartaric acid have been found in  cranberries  and other  berries . [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6957", "text": "Tartaric acid is also present in the leaves and pods of  Pelargonium  plants and  beans ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6958", "text": "Tartaric acid and its derivatives have a plethora of uses in the field of pharmaceuticals. For example, it has been used in the production of effervescent salts, in combination with citric acid, to improve the taste of oral medications. [ 22 ]  The potassium antimonyl derivative of the acid known as tartar emetic is included, in small doses, in  cough syrup  as an  expectorant ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_6959", "text": "Tartaric acid also has several applications for industrial use. The acid has been observed to  chelate  metal ions such as calcium and magnesium. Therefore, the acid has served in the farming and metal industries as a chelating agent for complexing micronutrients in soil  fertilizer  and for cleaning metal surfaces consisting of aluminium, copper, iron, and alloys of these metals, respectively. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6960", "text": "While tartaric acid is well-tolerated by humans and lab animals, an April 2021 letter to the editor of  JAVMA  hypothesized that the tartaric acid in grapes could be the cause of  grape and raisin toxicity in dogs . [ 30 ] [ 31 ]  Other studies have observed tartaric acid toxicity in kidney cells of dogs, but not in human kidney cells. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6961", "text": "In dogs, the tartaric acid of  tamarind  causes  acute kidney injury , which can often be fatal. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6962", "text": "A review identified a relationship between grape ingestion and illness, though the specific type or quantity of grapes that cause toxicity remains unclear. Grape ingestion commonly leads to gastrointestinal and/or renal issues, with treatment depending on the symptoms; outcomes can vary. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6963", "text": "Tendril perversion  is a geometric phenomenon sometimes observed in  helical  structures in which the direction of the helix transitions between left-handed and right-handed. [ 1 ]   [ 2 ]  Such a reversal of  chirality  is commonly seen in helical plant  tendrils  and  telephone handset  cords. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6964", "text": "The phenomenon was known to  Charles Darwin , [ 4 ]  who wrote in 1865,"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6965", "text": "A tendril ... invariably becomes twisted in one part in one direction, and in another part in the opposite direction\u00a0...\nThis curious and symmetrical structure has been noticed by several botanists, but has not been sufficiently\nexplained. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6966", "text": "The term \"tendril perversion\" was coined by  Alain Goriely  and Michael Tabor in 1998 based on the word  perversion  found in 19th-century science literature. [ 6 ] [ 7 ]  \"Perversion\" is a transition from one chirality to another and was known to  James Clerk Maxwell , who attributed it to  topologist   J. B. Listing . [ 4 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6967", "text": "Tendril perversion can be viewed as an example of  spontaneous symmetry breaking , in which the strained structure of the tendril adopts a  configuration of minimum energy  while preserving zero overall twist. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6968", "text": "Tendril perversion has been studied both experimentally and theoretically. Gerbode et al. have made experimental studies of the coiling of  cucumber  tendrils. [ 9 ] [ 10 ]  A detailed study of a simple model of the physics of tendril perversion was made by McMillen and Goriely in the early 2000s. [ 2 ]  Liu et al. showed in 2014 that \"the transition from a helical to a hemihelical shape, as well as the number of perversions, depends on the height to width ratio of the strip's cross-section.\" [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6969", "text": "Generalized tendril perversions were put forward by Silva et al., to include perversions that can be intrinsically produced in elastic filaments, leading to a multiplicity of geometries and dynamical properties. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6970", "text": "Thalidomide , sold under the brand names  Contergan  and  Thalomid  among others, is an  oral  medication used to treat a number of cancers (e.g.,  multiple myeloma ),  graft-versus-host disease , and many  skin disorders  (e.g., complications of  leprosy  such as  skin lesions ). [ 6 ] [ 7 ]  Thalidomide has been used to treat conditions associated with  HIV :  aphthous ulcers , HIV-associated  wasting syndrome , diarrhea, and  Kaposi's sarcoma , but increases in HIV viral load have been reported. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6971", "text": "Common side effects include  sleepiness ,  rash , and  dizziness . [ 6 ]  Severe side effects include  tumor lysis syndrome ,  blood clots , and  peripheral neuropathy . [ 8 ]  Thalidomide is a known human  teratogen  and carries an extremely high risk of severe, life-threatening birth defects if administered or taken during pregnancy. [ 6 ]  It causes skeletal deformities such as  amelia  (absence of legs and/or arms), absence of bones, and  phocomelia  (malformation of the limbs). A single dose of thalidomide, regardless of dosage, is enough to cause  teratogenic  effects. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6972", "text": "Thalidomide was first marketed in 1957 in West Germany, where it was available  over-the-counter . [ 9 ] [ 10 ]  When first released, thalidomide was promoted for  anxiety ,  trouble sleeping , \"tension\", and  morning sickness . [ 10 ] [ 11 ]  While it was initially thought to be safe in pregnancy,  concerns regarding birth defects  arose, resulting in its removal from the market in Europe in 1961. [ 9 ] [ 10 ]  The total number of infants severely harmed by thalidomide use during pregnancy is estimated at over 10,000, possibly 20,000, of whom about 40% died around the time of birth. [ 6 ] [ 10 ]  Those who survived had limb, eye, urinary tract, and heart problems. [ 9 ]  Its initial entry into the US market was prevented by  Frances Kelsey , a reviewer at the FDA. [ 11 ]  The birth defects caused by thalidomide led to the development of greater  drug regulation  and monitoring in many countries. [ 9 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6973", "text": "It was approved in the United States in 1998 for use as a treatment for cancer. [ 6 ]  It is on the  World Health Organization's List of Essential Medicines . [ 12 ]  It is available as a  generic medication . [ 8 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6974", "text": "Thalidomide is used as a first-line treatment for  multiple myeloma  in combination with  dexamethasone  or with  melphalan  and  prednisone  to treat acute episodes of  erythema nodosum leprosum , as well as for maintenance therapy. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6975", "text": "The bacterium that causes  tuberculosis  (TB) is related to  leprosy . Thalidomide may be helpful in some cases where  standard TB drugs  and  corticosteroids  are not sufficient to resolve severe inflammation in the brain. [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6976", "text": "It is used as a second-line treatment to manage  graft-versus-host disease  and  aphthous stomatitis  in children and has been prescribed for other conditions in children, including  actinic prurigo  and  epidermolysis bullosa ; the evidence for these uses is weak. [ 18 ]   It is recommended only as a third line treatment in graft-versus-host-disease in adults because of lack of efficacy and side effects observed in clinical trials. [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6977", "text": "Prescriptions of thalidomide are accompanied by strict measures to avoid any possibility of use during pregnancy, and thalidomide should be avoided in women wanting to conceive. [ 21 ]  In the United States, the prescribing doctor is required to ensure that  contraception  is being used and that regular pregnancy tests are taken. [ 15 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6978", "text": "Thalidomide  causes birth defects . [ 14 ] [ 15 ] [ 22 ] [ 23 ]  The U.S.  Food and Drug Administration  (FDA) and other regulatory agencies have approved marketing of the drug only with an auditable  risk evaluation and mitigation strategy  that ensures that people using the drug are aware of the risks and avoid pregnancy; this applies to both men and women, as the drug can be transmitted in  semen . [ 22 ] [ failed verification ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6979", "text": "There is a high risk that thalidomide can cause excessive  blood clots . There is also a high risk that thalidomide can interfere with the production of several types of new blood cells, creating a risk of infection via  neutropenia ,  leukopenia , and  lymphopenia , and risks that blood will not clot via  thrombocytopenia . There is also a risk of  anemia  via lack of red blood cells.  The drug can also damage nerves, causing potentially irreversible  peripheral neuropathy . [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6980", "text": "Thalidomide has several adverse cardiovascular effects, including risk of  heart attacks ,  pulmonary hypertension , and changes in heart rhythm, such as  syncope ,  bradycardia , and  atrioventricular block . [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6981", "text": "Thalidomide can cause  liver damage  and severe skin reactions like  Stevens\u2013Johnson syndrome . It tends to make people sleepy, which creates risk when driving and operating other machinery. As it kills cancer cells, it can cause  tumor lysis syndrome . Thalidomide can  prevent menstruation . [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6982", "text": "In addition, very common (reported in more than 10% of people) adverse effects include  tremor , dizziness, tingling, numbness, constipation, and  peripheral edema . [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6983", "text": "Common adverse effects (reported by 1\u201310% of people) include confusion, depressed mood, reduced coordination, heart failure, difficulty breathing, interstitial lung disease, lung inflammation, vomiting, dry mouth, rashes, dry skin, fever, weakness, and a sense of unwellness. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6984", "text": "There are no expected  pharmacokinetic  interactions between thalidomide and other medicines due to its neutral effects on  P-glycoprotein  and the  cytochrome P450  family.  It may interact with sedatives due to its sedative action and bradycardic agents, like beta-blockers, due to its bradycardia-inducing effects. The risk of  peripheral neuropathy  may be increased by concomitant treatment of thalidomide with other agents known to cause peripheral neuropathy. [ 24 ]  The risk of  venous thromboembolisms  with thalidomide seems to be increased when patients are treated with  oral contraceptives  or other cytotoxic agents (including  doxorubicin  and  melphalan ) concurrently. Thalidomide may interfere with various contraceptives, and hence it is advised that women of reproductive age use at least two different means of contraception to ensure that no child will be conceived while they are taking thalidomide. [ 14 ] [ 15 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6985", "text": "As of 2013, eighteen cases of overdoses had been reported with doses of up to 14.4\u00a0grams, none of them fatal. [ 24 ]  No specific antidote for overdose exists and treatment is purely  supportive . [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6986", "text": "The precise mechanism of action for thalidomide was not known until the twenty-first century, [ 25 ]  although efforts to identify thalidomide's  teratogenic  action generated more than 2,000 research papers and the proposal of 15 or 16 plausible mechanisms by 2000. [ 26 ]  The primary mechanism of action of thalidomide and its analogs in both their anti-cancer and teratogenic effects is now known to be as  cereblon   E3 ligase  modulators. [ 25 ] [ 27 ] [ 28 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6987", "text": "Thalidomide also binds to and acts as an  antagonist  of the  androgen receptor  and hence is a  nonsteroidal antiandrogen  of some capacity. [ 30 ]  In accordance, it can produce  gynecomastia  and  sexual dysfunction  as side effects in men. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6988", "text": "Thalidomide is provided as a  racemic mixture  of two  enantiomers ; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood. [ 22 ]  The (R)-enantiomer has the desired sedative effect while the (S)-enantiomer harbors embryo-toxic and teratogenic effects. Attempting to extract solely  R -thalidomide does not remove the risk of birth defects, as it was demonstrated that the \"safe\"  R -thalidomide undergoes an  in vivo   chiral inversion  to the \"teratogenic\"  S -thalidomide. Under biological conditions, the enantiomers interconvert ( bidirectional chiral inversion  \u2013 (R)- to (S)- and vice versa). [ 32 ] [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6989", "text": "Thalidomide is  racemic ; while  S -thalidomide is the bioactive form of the molecule, the individual enantiomers can  racemize  to each other due to the acidic hydrogen at the  chiral centre , which is the carbon of the  glutarimide  ring bonded to the  phthalimide   substituent . The racemization process can occur  in vivo . [ 5 ] [ 34 ] [ 35 ] [ 36 ]  The process of conversion of one enantiomer to its mirror-image version with no other change in the molecule is called chiral inversion. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6990", "text": "Celgene Corporation  originally synthesized thalidomide using a three-step sequence starting with  L -glutamic acid  treatment, but this has since been reformed by the use of  L -glutamine . [ 38 ]  As shown in the image below,  N -carbethoxyphthalimide (1) can react with  L -glutamine to yield  N -phthaloyl- L -glutamine (2). Cyclization of  N -phthaloyl- L -glutamine occurs using  carbonyldiimidazole , which then yields thalidomide (3). [ 38 ]  Celgene Corporation's original method resulted in a 31% yield of  S -thalidomide, whereas the two-step synthesis yields 85\u201393% product that is 99% pure. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6991", "text": "In 2023, it is reported that  phthalic anhydride  and  L -glutamine  under suitable conditions can react directly to form thalidomide. In the procedure, phthalic anhydride and  L -glutamine are grounded and added into  toluene  solvent. The solution, along with  triethylamine  and  acetic anhydride , is refluxed at ~110\u00b0C for 9 hours; after that the solution goes through a simple  vacuum filtration  procedure to obtain the product. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6992", "text": "In 1952, thalidomide was synthesised by  Chemical Industry Basel , but was found \"to have no effect on animals\" and was discarded on that basis. [ 40 ]   In 1957, it was acquired by  Chemie Gr\u00fcnenthal  in Germany. [ 40 ]  The German company had been established as a soap maker after World War II ended, to address the urgent market need for antibiotics. [ 41 ]   Heinrich M\u00fcckter [ 42 ]  was appointed to head the discovery program based on his experience working with the German army's antiviral research. While preparing  reagents  for the work, Mueckter's assistant Wilhelm Kunz isolated a by-product that was recognized by pharmacologist Herbert Keller as an analog of  glutethimide , a  sedative . The medicinal chemistry work turned to improving the lead compound into a suitable drug: the result was thalidomide. The toxicity was examined in several animals, and the drug was introduced in 1956 as a sedative, but it was never tested on pregnant women. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6993", "text": "Researchers at Chemie Gr\u00fcnenthal found that thalidomide was a particularly effective  antiemetic  that had an inhibitory effect on  morning sickness . [ 44 ]  On 1 October 1957, the company launched thalidomide and began marketing it under the trade name Contergan. [ 45 ] [ 46 ]  It was proclaimed a \"wonder drug\" for  insomnia , coughs, colds and headaches. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6994", "text": "During that period, the use of medications during pregnancy was not strictly controlled, and drugs were not thoroughly tested for potential harm to the  fetus . [ 44 ]  Thousands of pregnant women took the drug to relieve their symptoms. At the time of the drug's development, scientists did not believe any drug taken by a pregnant woman could pass across the  placental barrier  and harm the developing fetus. [ 48 ]  There soon appeared reports of abnormalities in children being born to mothers using thalidomide. In late 1959, it was noticed that  peripheral neuritis  developed in patients who took the drug over a period of time, and it was only after this point that thalidomide ceased to be provided over the counter. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6995", "text": "While initially considered safe, the drug was responsible for  teratogenic  deformities in children born after their mothers used it during pregnancies, prior to the third trimester. In November 1961, thalidomide was taken off the market due to massive pressure from the press and public. [ 50 ]  Experts estimate that thalidomide led to the death of approximately 2,000 children and serious birth defects in more than 10,000 children, with over half of them in West Germany. [ 51 ]  The regulatory authorities in  East Germany  never approved thalidomide. [ 52 ]  One reason for the initially unobserved side effects of the drug and the subsequent approval in West Germany was that at that time drugs did not have to be tested for teratogenic effects. They were tested for toxicity on rodents only, as was usual at the time. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6996", "text": "In the UK, the British pharmaceutical company  The Distillers Company  (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd (now part of  Diageo plc ), marketed thalidomide throughout the UK, Australia, and New Zealand, under the brand name Distaval, as a remedy for  morning sickness . Their advertisement claimed that \"Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child ... Outstandingly safe Distaval has been prescribed for nearly three years in this country.\" [ 52 ]  Globally, more pharmaceutical companies started to produce and market the drug under license from Chemie Gr\u00fcnenthal. By the mid-1950s, 14 pharmaceutical companies were marketing thalidomide in 46 countries under at least 37 different trade names. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6997", "text": "In the US, representatives from Chemie Gr\u00fcnenthal approached  Smith, Kline & French  (SKF), now  GlaxoSmithKline , with a request to market and distribute the drug in North America. A memorandum, rediscovered in 2010 in the archives of the FDA, shows that in 1956\u201357, as part of its in-licensing approach, Smith, Kline and French conducted animal tests and ran a clinical trial of the drug in the US involving 875 people, including pregnant women. [ 54 ]  In 1956, researchers involved in clinical trials at SKF noted that, even when used in very high doses, thalidomide could not induce sleep in mice. [ citation needed ]  When administered at doses 50 to 650 times larger than that claimed by Chemie Gr\u00fcnenthal to be \"sleep-inducing\", the researchers could still not achieve the hypnotic effect in animals that it had on humans. [ citation needed ]  After completion of the trial, and based on reasons kept hidden for decades, SKF declined to commercialize the drug. In 1958, Chemie Gr\u00fcnenthal reached an agreement with the William S. Merrell Company in Cincinnati, Ohio ( later Richardson-Merrell , now part of  Sanofi ), to market and distribute thalidomide throughout the US. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6998", "text": "The US FDA refused to approve thalidomide for marketing and distribution. However, the drug was distributed in large quantities for testing purposes, after the American distributor and manufacturer  Richardson-Merrell  had applied for its approval in September 1960. [ citation needed ]  The official in charge of the FDA review,  Frances Oldham Kelsey , did not rely on information from the company, which did not include any test results. Richardson-Merrell was called on to perform tests and report the results. The company demanded approval six times and was refused each time. The distribution for \"testing\" resulted in 17 children born in the US with thalidomide-induced malformations. Oldham Kelsey was awarded the  President's Award for Distinguished Federal Civilian Service  by President Kennedy in 1962 for not allowing thalidomide to be approved for sale in the US. She was also inducted into the  National Women's Hall of Fame  in 2000. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_6999", "text": "Canada's Food and Drug Directorate approved the sale of thalidomide by prescription in November 1960. [ 56 ]  There were many different forms sold: Kevadon, produced by the William S. Merrell Company seeking approval for its thalidomide product, was released on the market in April 1961, and the most common variant (Horner's Talimol) was put on the market on October 23 of the same year. [ 57 ]  Two months after Talimol went on sale, pharmaceutical companies sent physicians letters warning about the risk of birth defects. [ 57 ]  It was not until March 1962 that both drugs were banned from the Canadian market by the directorate, and soon afterward physicians were warned to destroy their supplies. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7000", "text": "In 1964, Israeli physician  Jacob Sheskin  administered thalidomide to a patient critically ill with  leprosy . The patient exhibited  erythema nodosum leprosum  (ENL), a painful skin condition, one of the complications of leprosy. The treatment was attempted despite the ban on thalidomide's use, and the results were favourable: the patient slept for hours and was able to get out of bed without aid upon awakening. A clinical trial studying the use of thalidomide in leprosy soon followed. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7001", "text": "Thalidomide has been used by Brazilian physicians as the drug of choice for the treatment of severe ENL since 1965, and by 1996, at least 33 cases of thalidomide embryopathy were recorded in people born in Brazil after 1965. [ 59 ]  Since 1994, the production, dispensing, and prescription of thalidomide have been strictly controlled, requiring women to use two forms of birth control and submit to regular pregnancy tests. Despite this, cases of thalidomide embryopathy continue, [ 60 ] [ 61 ]  with at least 100 cases identified in Brazil between 2005 and 2010. [ 62 ]  5.8 million thalidomide pills were distributed throughout Brazil in this time period, largely to poor Brazilians in areas with little access to healthcare, and these cases have occurred despite the controls. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7002", "text": "In 1998, the FDA approved the drug's use in the treatment of ENL. [ 63 ]  Because of thalidomide's potential for causing birth defects, the drug may be distributed only under tightly controlled conditions. The FDA required that  Celgene Corporation , which planned to market thalidomide under the brand name  Thalomid , establish a system for thalidomide education and prescribing safety (STEPS) oversight program. The conditions required under the program include limiting prescription and dispensing rights to authorized prescribers and pharmacies only, keeping a registry of all patients prescribed thalidomide, providing extensive patient education about the risks associated with the drug, and providing periodic pregnancy tests for women who take the drug. [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7003", "text": "In 2010, the  World Health Organization  stated that it did not recommend thalidomide for leprosy due to the difficulty of adequately controlling its use, and due to the availability of  clofazimine . [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7004", "text": "Shortly after the teratogenic properties of thalidomide were recognized in the mid-1960s, its anti-cancer potential was explored and two clinical trials were conducted in people with advanced cancer, including some people with multiple myeloma; the trials were inconclusive. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7005", "text": "Little further work was done with thalidomide in cancer until the 1990s. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7006", "text": "Judah Folkman  pioneered studies into the role of  angiogenesis  (the proliferation and growth of blood vessels) in the development of cancer, and in the early 1970s had shown that  solid tumors  could not expand without it. [ 66 ] [ 67 ]  In 1993 he surprised the scientific world by hypothesizing the same was true of  blood cancers , [ 68 ]  and the next year he published work showing that a  biomarker  of angiogenesis was higher in all people with cancer, but especially high in people with blood cancers, and other evidence emerged as well. [ 69 ]   Meanwhile, a member of his lab, Robert D'Amato, who was looking for  angiogenesis inhibitors , discovered in 1994 that thalidomide inhibited angiogenesis [ 70 ]  and was effective in suppressing tumor growth in rabbits. [ 71 ]  Around that time, the wife of a man who was dying of multiple myeloma and whom standard treatments had failed, called Folkman asking him about his anti-angiogenesis ideas. [ 67 ]   Folkman persuaded the patient's doctor to try thalidomide, and that doctor conducted a clinical trial of thalidomide for people with multiple myeloma in which about a third of the subjects responded to the treatment. [ 67 ]   The results of that trial were published in the New England Journal of Medicine in 1999. [ 67 ] [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7007", "text": "After further work was done by Celgene and others, in 2006 the US\u00a0Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for the treatment of newly diagnosed  multiple myeloma  patients. [ 67 ] [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7008", "text": "It was also evaluated whether thalidomide can be combined with melphalan and prednisone for patients with multiple myeloma. This combination of drugs probably increases the overall survival. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7009", "text": "In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with deformities, such as  phocomelia , as a consequence of thalidomide use. [ 75 ]  The severity and location of the deformities depended on how many days into the pregnancy the mother was before beginning treatment, with the time-sensitive window occurring approximately between day 20 and day 36 post-fertilisation. [ 51 ]  Thalidomide taken on the 20th day of pregnancy caused central brain damage, day 21 would damage the eyes, day 22 the ears and face, day 24 the arms, and leg damage would occur if taken up to day 28. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7010", "text": "It is not known exactly how many worldwide victims of the drug there have been, although estimates range from 10,000 to 20,000. [ 76 ]  Despite the side effects, thalidomide was sold in pharmacies in Canada until 1962. [ 57 ] [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7011", "text": "The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as the 1962  Kefauver Harris Amendment [ 85 ]   (US), 1965  Directive 65/65/EEC1  (EU), [ 86 ]  and the  Medicines Act 1968  (UK). [ 87 ] [ 88 ]  In the United States, the new regulations strengthened the FDA, among other ways, by requiring applicants to prove efficacy and to disclose all side effects encountered in testing. [ 75 ]  The FDA subsequently initiated the  Drug Efficacy Study Implementation  to reclassify drugs already on the market. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7012", "text": "In 1977 the US Federal Drug Administration published a clinical trial guideline that excluded women of \"childbearing potential\" from the early phases of most clinical trials, which in practice led to their exclusion from later trial phases as well. [ 89 ]  This 1977 FDA guideline was implemented in response to a protectionist climate caused by the thalidomide tragedy. [ 89 ]  In the 1980s, a US task force on women's health concluded that a lack of women's health research (in part due to the FDA guideline) had compromised the amount and quality of information available about diseases and treatments affecting women. [ 89 ]  This led to the National Institute of Health policy that women should, when beneficial, be included in clinical trials. [ 89 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7013", "text": "In the 1960s, thalidomide was successfully marketed as a safer alternative to  barbiturates . Due to a successful marketing campaign, thalidomide was widely used by pregnant women during the first trimester of pregnancy. However, thalidomide is a  teratogenic  substance, and a proportion of children born during the 1960s had thalidomide embryopathy (TE). [ 90 ]  Of these babies born with TE, \"about 40% of them died before their first birthday\". [ 91 ]  The surviving individuals are now middle-aged and they report experiencing challenges (physical, psychological, and socioeconomic) related to TE. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7014", "text": "Individuals born with TE frequently experience a wide variety of health problems secondary to their TE. These health conditions include both physical and psychological conditions. When compared to individuals of similar demographic profiles, those born with TE report less satisfaction with their quality of life and their overall health. [ 90 ]  Access to healthcare services can also be a challenge for these people, and women, in particular, have experienced difficulty in locating healthcare professionals who can understand and embrace their needs. [ 91 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7015", "text": "Brand names include Contergan, Thalomid, Talidex, Talizer, Neurosedyn, Distaval, and many others. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7016", "text": "Research efforts have been focused on determining how thalidomide causes birth defects and its other activities in the human body, efforts to develop safer analogs, and efforts to find further uses for thalidomide. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7017", "text": "The exploration of the  antiangiogenic  and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide  analogs . [ 92 ] [ 93 ]  Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as  lenalidomide , that are substantially more powerful and have fewer side effects\u00a0\u2014 except for greater  myelosuppression . [ 94 ]  In 2005, Celgene received FDA approval for  lenalidomide  (Revlimid) as the first commercially useful derivative. Revlimid is available only in a restricted distribution setting to avoid its use during pregnancy. Further studies are being conducted to find safer compounds with useful qualities. Another more potent analog,  pomalidomide , is now FDA-approved. [ 95 ]  Additionally,  apremilast  was approved by the FDA in March 2014. These  thalidomide analogs  can be used to treat different diseases, or used in a regimen to fight two conditions. [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7018", "text": "Interest turned to  pomalidomide , a  derivative  of thalidomide marketed by  Celgene . It is a very active anti-angiogenic agent [ 93 ]   and also acts as an  immunomodulator . Pomalidomide was approved in February 2013 by the FDA as a treatment for relapsed and refractory  multiple myeloma . [ 97 ]  It received a similar approval from the  European Commission  in August 2013, and is expected to be marketed in Europe under the brand name  Imnovid . [ 98 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7019", "text": "There is no conclusive evidence that thalidomide or  lenalidomide  is useful to bring about or maintain remission in Crohn's disease. [ 99 ] [ 100 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7020", "text": "Thalidomide was studied in a Phase II trial for  Kaposi's sarcoma , a rare soft-tissue cancer most commonly seen in the immunocompromised, that is caused by the  Kaposi's sarcoma-associated herpesvirus  (KSHV). [ 101 ] [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7021", "text": "Viedma ripening  or  attrition-enhanced deracemization  is a  chiral symmetry breaking  phenomenon observed in solid/liquid mixtures of enantiomorphous ( racemic conglomerate ) crystals that are subjected to  comminution . It can be classified in the wider area of  spontaneous symmetry breaking  phenomena observed in chemistry and physics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7022", "text": "It was discovered in 2005 by geologist Cristobal Viedma, who used glass beads and a magnetic stirrer to enable particle breakage of a racemic mixture of enantiomorphous  sodium chlorate  crystals in contact with their  saturated solution  in water. [ 1 ]  A  sigmoidal  ( autocatalytic ) increase in the solid-phase  enantiomeric excess  of the mixture was obtained, eventually leading to  homochirality , i.e. the complete disappearance of one of the  chiral  species. Since the original discovery, Viedma ripening has been observed in a variety of intrinsically chiral  organic compounds  that exhibit conglomerate  crystallization  and are able to inter-convert in the liquid via  racemization  reactions. [ 2 ]  It is also regarded as a potential new technique to separate  enantiomers  of chiral molecules in the pharmaceutical and fine chemical industries ( chiral resolution )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7023", "text": "The exact interplay of the mechanisms leading to deracemization in Viedma ripening is a subject of ongoing scientific debate. [ 3 ] [ 4 ]  It is, however, currently believed that for intrinsically chiral molecules, deracemization occurs via a combination of various phenomena:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7024", "text": "Two key assumptions often invoked to explain the mechanism is that: a) small fragments generated by breakage for each enantiomeric crystal population can maintain their chirality, even when they are smaller than the  critical radius  for  nucleation  (and are thus expected to dissolve) and b) small chiral fragments can undergo enantiospecific aggregation to larger particles of the same chirality. Using these two assumptions, it can be shown mathematically, [ 6 ]  that any stochastic even immeasurable asymmetry of one enantiomeric crystal population over the other can be amplified to homochirality in a random manner."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7025", "text": "In principle,  molecules  required for the generation of life, i.e.  amino acids  that combine to form  proteins  and  sugars  that form  DNA  molecules are all chiral and are thus able to adopt two mirror-image forms (often described as left- and right-handed), which from a chemical perspective are equally likely to exist. However, all biologically-relevant molecules known on earth are of a single handedness, even though their mirror images are also capable of forming similar molecules. The reason of the prevalence of  homochirality  in living organisms is currently unknown and is often connected to the  origin of life  itself. Whether homochirality emerged before or after life is currently unknown, but many researchers believe that homochirality could have been a result of amplification of extremely small chiral asymmetries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7026", "text": "Since Viedma ripening has been observed in biologically-relevant molecules, such as chiral amino acids [ 7 ]  it has been put forward by some as a possible contributing mechanism for chiral amplification in a prebiotic world. [ 8 ] [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7027", "text": "When Topology Meets Chemistry: A Topological Look At Molecular Chirality  is a book in  chemical graph theory  on the graph-theoretic analysis of  chirality  in molecular structures. It was written by  Erica Flapan , based on a series of lectures she gave in 1996 at the  Institut Henri Poincar\u00e9 , [ 1 ]  and was published in 2000 by the  Cambridge University Press  and  Mathematical Association of America  as the first volume in their shared Outlooks book series. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7028", "text": "A chiral molecule is a molecular structure that is different from its mirror image. This property, while seemingly abstract, can have big consequences in biochemistry, where the shape of molecules is essential to their chemical function, [ 3 ]  and where a chiral molecule can have very different biological activities from its mirror-image molecule. [ 4 ]   When Topology Meets Chemistry  concerns the mathematical analysis of molecular chirality."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7029", "text": "The book has seven chapters, beginning with an introductory overview and ending with a chapter on the chirality of  DNA  molecules. [ 2 ] \nOther topics covered through the book include the rigid geometric chirality of tree-like molecular structures such as  tartaric acid , and the stronger topological chirality of molecules that cannot be deformed into their mirror image without breaking and re-forming some of their molecular bonds. It discusses results of Flapan and Jonathan Simon on molecules with the molecular structure of  M\u00f6bius ladders , according to which every embedding of a M\u00f6bius ladder with an odd number of rungs is chiral while M\u00f6bius ladders with an even number of rungs have achiral embeddings. It uses the symmetries of graphs, in a result that the symmetries of certain graphs can always be extended to topological symmetries of three-dimensional space, from which it follows that  non-planar graphs  with no  self-inverse symmetry  are always chiral. It discusses graphs for which  every embedding is topologically knotted or linked . And it includes material on the use of  knot invariants  to detect topological chirality. [ 1 ] [ 2 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7030", "text": "The book is self-contained, and requires only an undergraduate level of mathematics. [ 3 ] [ 5 ]  It includes many exercises, [ 2 ]  making it suitable for use as a textbook at both the advanced undergraduate and introductory graduate levels. [ 1 ]  Reviewer Buks van Rensburg describes the book's presentation as \"efficient and intuitive\", and recommends the book to \"every mathematician or chemist interested in the notions of chirality and symmetry\". [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7031", "text": "In  physics ,  zilch  (or zilches) is a set of ten  conserved quantities  of the source-free  electromagnetic field , which were discovered by Daniel M. Lipkin in 1964. [ 1 ]  The name refers to the fact that the zilches are only conserved in regions free of  electric charge , and therefore have limited physical significance. One of the conserved quantities (Lipkin's   \n \n \n \n \n Z \n \n 0 \n \n \n \n \n {\\displaystyle Z^{0}} \n \n ) has an intuitive physical interpretation and is also known as  optical chirality ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7032", "text": "In particular, first, Lipkin observed that if he defined the quantities"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7033", "text": "The free  Maxwell equations  imply that  \n \n \n \n \n \u2202 \n \n 0 \n \n \n \n Z \n \n 0 \n \n \n + \n \u2207 \n \u22c5 \n \n Z \n \n = \n 0 \n \n \n {\\displaystyle \\partial _{0}Z^{0}+\\nabla \\cdot \\mathbf {Z} =0} \n \n ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7034", "text": "The precedent equation implies that the quantity  \n \n \n \n \u222b \n \n Z \n \n 0 \n \n \n \n \n d \n \n 3 \n \n \n x \n \n \n {\\displaystyle \\int Z^{0}\\,d^{3}x} \n \n  is constant. This time-independent quantity is one of the ten zilches discovered by Lipkin. Nowadays, the quantity  \n \n \n \n \u222b \n \n Z \n \n 0 \n \n \n \n \n d \n \n 3 \n \n \n x \n \n \n {\\displaystyle \\int Z^{0}\\,d^{3}x} \n \n  is widely known as  optical chirality  (up to a factor of 1/2). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7035", "text": "The quantity  \n \n \n \n \n \n Z \n \n \n 0 \n \n \n \n \n {\\displaystyle {Z}^{0}} \n \n  is the  spatial density  of optical chirality, while   \n \n \n \n \n Z \n \n \n \n {\\displaystyle \\mathbf {Z} } \n \n  is the  optical chirality flux . [ 2 ]  Generalizing the aforementioned differential conservation law for  \n \n \n \n \n Z \n \n 0 \n \n \n \n \n {\\displaystyle Z^{0}} \n \n , Lipkin found other nine conservation laws, all unrelated to the  stress\u2013energy tensor . He collectively named these ten conserved quantities the zilch (nowadays, they are also called the zilches [ 3 ] ) because of the apparent lack of physical significance. [ 1 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7036", "text": "The zilch is often described in terms of the zilch tensor,  \n \n \n \n \n Z \n \n \u03bd \n \u03c1 \n \n \n \u03bc \n \n \n \n \n {\\displaystyle Z_{\\nu \\rho }^{\\mu }} \n \n . The latter can be expressed using the  dual   electromagnetic tensor   \n \n \n \n \n \n \n \n F \n ^ \n \n \n \n \n \u03bc \n \u03bd \n \n \n = \n ( \n 1 \n \n / \n \n 2 \n ) \n \n \u03f5 \n \n \u03bc \n \u03bd \n \u03c1 \n \u03c3 \n \n \n \n F \n \n \u03c1 \n \u03c3 \n \n \n \n \n {\\displaystyle {\\hat {F}}^{\\mu \\nu }=(1/2)\\epsilon ^{\\mu \\nu \\rho \\sigma }F_{\\rho \\sigma }} \n \n  as\n \n \n \n \n \n Z \n \n \u03bd \n \u03c1 \n \n \n \u03bc \n \n \n = \n \n \n \n \n F \n ^ \n \n \n \n \n \u03bc \n \u03bb \n \n \n \n F \n \n \u03bb \n \u03bd \n , \n \u03c1 \n \n \n \u2212 \n \n F \n \n \u03bc \n \u03bb \n \n \n \n \n \n \n F \n ^ \n \n \n \n \n \u03bb \n \u03bd \n , \n \u03c1 \n \n \n \n \n {\\displaystyle Z_{\\nu \\rho }^{\\mu }={\\hat {F}}^{\\mu \\lambda }F_{\\lambda \\nu ,\\rho }-F^{\\mu \\lambda }{\\hat {F}}_{\\lambda \\nu ,\\rho }} \n \n . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7037", "text": "The zilch tensor is symmetric under the exchange of its first two  indices ,  \n \n \n \n \u03bc \n \n \n {\\displaystyle \\mu } \n \n  and  \n \n \n \n \u03bd \n \n \n {\\displaystyle \\nu } \n \n , while it is also  traceless  with respect to any two indices, as well as  divergence-free  with respect to any index. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7038", "text": "The conservation law  \n \n \n \n \n \u2202 \n \n \u03c1 \n \n \n \n Z \n \n \u03bc \n \u03bd \n \u03c1 \n \n \n = \n 0 \n \n \n {\\displaystyle \\partial _{\\rho }Z^{\\mu \\nu \\rho }=0} \n \n  means that the following ten quantities are time-independent:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7039", "text": "It was later demonstrated that Lipkin's zilch is part of an infinite number of zilch-like conserved quantities, a general property of free  fields . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7040", "text": "One of the zilches has been rediscovered. This is the zilch called \"optical chirality\", named by Tang and Cohen, since this zilch determines the degree of chiral asymmetry in the rate of excitation of a small chiral molecule by an incident electromagnetic field. [ 2 ] \nA further physical insight of optical chirality was offered in 2012; optical chirality is to the curl or time derivative of the electromagnetic field, what helicity, spin and related quantities are to the electromagnetic field itself. [ 6 ] \nThe physical interpretation of all zilches for topologically non-trivial electromagnetic fields was investigated in 2018. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7041", "text": "Since the discovery of the ten zilches in 1964, there is an important open mathematical question concerning their relation with symmetries. (Recently, the full answer to this question seems to have been found  [ 7 ] ). This is the question:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7042", "text": "What are the symmetries of the standard Maxwell action functional:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7043", "text": "S \n [ \n \n A \n \n \u03bc \n \n \n ] \n = \n \u2212 \n \n \n 1 \n 4 \n \n \n \u222b \n \n d \n \n 4 \n \n \n x \n \n F \n \n \u03bc \n \u03bd \n \n \n \n F \n \n \u03bc \n \u03bd \n \n \n \n \n {\\displaystyle S[A_{\\mu }]=-{\\frac {1}{4}}\\int d^{4}xF_{\\mu \\nu }F^{\\mu \\nu }}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7044", "text": "(with  \n \n \n \n \n F \n \n \u03bc \n \u03bd \n \n \n = \n \n \u2202 \n \n \u03bc \n \n \n \n A \n \n \u03bd \n \n \n \u2212 \n \n \u2202 \n \n \u03bd \n \n \n \n A \n \n \u03bc \n \n \n \n \n {\\displaystyle F_{\\mu \\nu }=\\partial _{\\mu }A_{\\nu }-\\partial _{\\nu }A_{\\mu }} \n \n  and  \n \n \n \n \n A \n \n \u03bc \n \n \n \n \n {\\displaystyle A_{\\mu }} \n \n  is the dynamical field variable) that give rise to the conservation of all zilches using  Noether's theorem . Until recently, the answer to this question had been given only for the case of optical chirality by Philbin in 2013. [ 8 ] \nThis open question was also emphasized by Aghapour, Andersson and Rosquist in 2020, [ 9 ] \nwhile these authors found the symmetries of the duality-symmetric Maxwell action underlying the conservation of all zilches. (Aghapour, Andersson and Rosquist did not find the symmetries of the standard Maxwell action, but they speculated that such symmetries should exist  [ 9 ] ).\nThere are also earlier works studying the conservation of zilch in the context of duality-symmetric electromagnetism, [ 10 ]  but the variational character of the corresponding symmetries was not established."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7045", "text": "The full answer to the aforementioned question seems to have been given for the first time in 2022, [ 7 ]  where the symmetries of the standard Maxwell action underlying the conservation of all zilches were found. According to this work, there is a hidden invariance algebra of free Maxwell equations in potential form that is related to the conservation of all zilches."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7046", "text": "The  Alcohol and Drugs History Society  ( ADHS ) is a scholarly organization whose members study the history of a variety of illegal, regulated, and unregulated  drugs  such as  opium ,  alcohol , and  coffee . Organized in 2004, the ADHS is the successor to a society with a more limited scope, the Alcohol and Temperance History Group, which existed for 25 years. The last ATHG president and the first ADHS president was Ian R. Tyrrell, Professor of History at the University of New South Wales, in Australia.  In July 2006 he was succeeded by  W.J. Rorabaugh , Professor of History at the University of Washington.  In July, 2008, David T. Courtwright, Professor of History at the  University of North Florida  became president.  In 2011 Joseph Spillane, Associate Professor of History at the University of Florida, succeeded him as president."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7047", "text": "The ADHS sponsors the academic journal  The Social History of Alcohol and Drugs: an Interdisciplinary Journal  (SHAD). The journal appears in both printed and electronic formats, published twice a year, in the winter and the summer. Starting in 2019, the journal was published by the University of Chicago Press. SHAD's editorial structure recently [ when? ]  changed and its current co-editors are David Herzberg (SUNY-Buffalo), Nancy Campbell (Rensselaer Polytechnic Institute), and Lucas Richert (University of Strathclyde). Its former editor-in-chief is Dan Malleck, from  Brock University ,  St. Catharines ,  Canada . Other former editors include Jim Mills, from  University of Strathclyde  in  Glasgow ,  Scotland ; W. Scott Haine, from  California , and the Reviews Editors are James Nicholls, from  Bath Spa University ,  England  and Alex Mold, from the London School of Hygiene and Tropical Medicine.  In November, 2009 it created an editorial board, which is populated by some of the most prominent alcohol and drugs history scholars in the world."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7048", "text": "The ADHS is affiliated with the  American Historical Association  and sponsors sessions at the January meetings of the AHA."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7049", "text": "The ADHS held an international conference in  Canada  in August 2007, with  Guelph University  (Ontario) as the host  The next international conference was in  2009 at  Glasgow ,  Scotland , with the  University of Strathclyde  as the host.  In 2011 an international conference was held at the State University of New York, Buffalo. In 2015 the ADHS met at Bowling Green State University in Ohio, USA. In 2017 there was an international conference at the University of Utrecht, The Netherlands. Shanghai will serve as host for the 2019 meeting."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7050", "text": "The  American College of Clinical Pharmacology\u00ae  ( ACCP ) is a national organization of  clinical pharmacology  healthcare professionals who seek to advance clinical pharmacology. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7051", "text": "In the 1960s, a group of physicians formulated the concept of an organization dedicated to a new branch of pharmacology that dealt with the effectiveness and safety of drugs in humans. As a result of their efforts, the American College of Clinical Pharmacology (ACCP) was founded on September 11, 1969. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7052", "text": "The mission is to improve health by optimizing  therapeutics  and to provide leadership and education that enables the generation, integration and translation of scientific knowledge to optimize research, development and utilization of medication. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7053", "text": "ACCP is governed by a  Board of Regents  elected by ACCP Members. The Board is advised by a network of ACCP committees. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7054", "text": "Levels of membership in ACCP are Retired, Student, Member and Fellow (FCP).  Fellowship  is the organization's way of noting outstanding achievement in the discipline. Fellows require specific credentials and are recommended by their peers and reviewed by the Board of Regents. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7055", "text": "The Journal of Clinical Pharmacology , published by ACCP is the main journal of the College.  Clinical Pharmacology in Drug Development  is another publication. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7056", "text": "The College organizes a number of annual meetings and has several committees. There are special programs for students and to promote the discipline in developing countries. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7057", "text": "ACCP promotes the rational use of medications in humans through research, development and regulation of medications, and education of healthcare professionals and patients on the optimal utilization of medications. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7058", "text": "ACCP is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7059", "text": "The  American Society for Pharmacology and Experimental Therapeutics  (ASPET) is a scientific society founded in late 1908 by  John Jacob Abel  of  Johns Hopkins University  (also the founder of the  American Society for Biochemistry and Molecular Biology ), with the aim of promoting the growth of pharmacological research. [ 1 ] [ 2 ]  Many society members are researchers in basic and clinical pharmacology who help develop disease-fighting medications and therapeutics. [ 3 ]  ASPET is one of the constituent societies of the  Federation of American Societies for Experimental Biology  (FASEB). [ 4 ]  The society's headquarters are in  Rockville, MD . The current president is Michael F. Jarvis. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7060", "text": "The society publishes three research journals and a review journal: the  Journal of Pharmacology and Experimental Therapeutics ,  Drug Metabolism and Disposition ,  Molecular Pharmacology , and  Pharmacological Reviews"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7061", "text": "Starting in 2012 these publications are only offered online. The society copublishes a wholly open access journal with the British Pharmacological Society and Wiley entitled  Pharmacology Research & Perspectives ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7062", "text": "ASPET also publishes a quarterly newsletter,  The Pharmacologist , and, from 2001 to 2011,  Molecular Interventions  magazine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7063", "text": "The society gives out several awards: [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7064", "text": "Travel awards to participate in its meetings are also given to students and postdocs. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7065", "text": "The  Association for Ocular Pharmacology and Therapeutics  ( AOPT ) is an organization that welcomes members from disciplines related to ocular pharmacology and its therapeutic applications. The mission of AOPT is the sustenance of a scientific network aiming the dissemination of knowledge in the field of  ocular disease ,  pharmacology  and  therapeutics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7066", "text": "AOPT was begun informally in the 1970s by Dr. George Chiou [ 1 ] [ 2 ]  as special sessions at the Federation of American Societies for Experimental Biology [ 3 ]  conferences. It grew to an official separate Symposium of Ocular Pharmacology meeting of academicians, clinicians, and pharmaceutical industry at Novi, Michigan in August 1993. [ 4 ]  The participants voted to charter the organization and this was accomplished the next year with the first AOPT meeting held in New Orleans, Louisiana in January 1995. The founding board comprised Drs. George Chiou (president), David Lee (vice-president), Hitoshi Shichi (treasurer), and Herbert Kaufman (trustee). During the early FASEB years, Chiou also established the  Journal of Ocular Pharmacology , now the  Journal of Ocular Pharmacology & Therapeutics . The history of AOPT is closely related to the Association for Research in Vision and Ophthalmology (ARVO). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7067", "text": "The mission of AOPT is to help researchers and eye-care professionals in their efforts toward the understanding and the treatment of eye diseases. AOPT scientific dissemination involves preclinical and clinical pharmacologists and researchers. Scientific dissemination is promoted through biennial meetings  [ 6 ]  and the  peer-reviewed journal :  Journal of Ocular Pharmacology and Therapeutics  ( JOPT )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7068", "text": "JOPT  is the official journal of AOPT. It is a multidisciplinary journal that covers the latest findings related to  pharmacodynamics  and  pharmacokinetics  of pharmaceuticals used in the treatment of ocular disorders. [ 7 ]   The journal is published 10 times per year.  This journal is peer reviewed with on line access prior to journal publication and it is available in 170 countries ( http://home.libertpub.com ).  The journal also publishes Special Issues.  The next one is \"N ext Generation Tissue Engineering:  Inspired Models for Ophthalmic Drug Discovery \".  (Ashwath Jayagopal and H\u00e9lo\u00efse Ragelle guest editors.  The current editor-in-chief of JOPT is  W. Daniel Stamer, PhD .(Duke University, Durham, NC  http://medschoolduke.edu/about-us/our-faculty/w-daniel-stamer  ) On line ISSN 1557-7732 with an impact factor of 1.782.  Affiliated with AOPT and ISOPT  Clinical  ( International Symposium on Ocular Pharmacology & Therapeutics Clinical) ( http://isopclinical.com )"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7069", "text": "AOPT has a diverse leadership and membership which include principal investigators, scientists, medical professionals, technicians, and students with an interest in ocular pharmacology and therapeutics. The directive committee and members come from academic institutions and private companies worldwide."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7070", "text": "[ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7071", "text": "Members of AOPT and societies in the field of eye research, gather every year at the annual  ARVO  meeting, in which the latest findings in vision and ophthalmology research are disseminated.\nSocieties in the field of eye research span from preclinical to clinical and a few of these societies are hereby listed:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7072", "text": "The  British Pharmacological Society  is the primary UK  learned society  for  pharmacologists , concerned with research into drugs and the ways in which they work. Members work in academia, industry, regulatory agencies, and the health services, and many are medically qualified. The Society covers the whole spectrum of pharmacology, including laboratory, clinical, and toxicological aspects. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7073", "text": "Clinical pharmacology is the medical speciality dedicated to promoting safe and effective use of medicines for patient benefit. Many  clinical pharmacologists  work as consultants in the  National Health Service  and many hold prominent positions in UK universities and in regulatory bodies, such as the Medicines and Healthcare products Regulatory Agency (MHRA) and the  National Institute of Health and Care Excellence  (NICE). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7074", "text": "The Society was founded in 1931, in Oxford, by a group of about 20 pharmacologists. [ 3 ]  They were brought together on the initiative of  Professor James Andrew Gunn , through a letter signed by Gunn,  Henry H. Dale , and  Walter E. Dixon , and sent to the heads of university departments of pharmacology and of institutions for pharmacological research in Great Britain, with proposals for the formation of a pharmacological club. There were favorable replies to this letter, and most of the recipients met in  Wadham College , Oxford, on the evening of 3 July 1931, the day before the meeting of the  Physiological Society . Gunn presided over the meeting. It was agreed that a Society should be founded, to meet at least once a year for the reading of papers on pharmacological subjects and discussions of questions of teaching and publications and to promote friendly relations between pharmacologists. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7075", "text": "The first female member of the society was  Mary Pickford  (1935), and other early eminent women members included  Marthe Vogt  and  Edith B\u00fclbring . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7076", "text": "The British Pharmacological Society publishes several works that promote pharmacology and clinical pharmacology:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7077", "text": "The office of president was formally created in 1999. Before that the role was taken by members of the society under titles such as secretary and general secretary. Since 2010, all previous general secretaries and presidents have been awarded the title  president emeritus ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7078", "text": "Secretary and treasurer"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7079", "text": "Secretary"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7080", "text": "General secretary"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7081", "text": "President"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7082", "text": "The society elects eminent, deceased contributors to the subject of pharmacology, whether or not they were members, to the Pharmacology Hall of Fame: [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7083", "text": "Members of the society awarded the  Nobel Prize in Physiology or Medicine  include Black, Dale and Vane. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7084", "text": "Fellowships (FBPhS) of the society are awarded to members who have made significant contributions to both the study of pharmacology and the Society. [ 15 ]  A full list of Fellows is available here. [ 16 ]  Honorary Fellowships (HonFBPhS) are awarded to member or non-members for distinguished and sustained leadership role in Pharmacology. Fellows and Honorary Fellows use the post-nominal FBPhS. Notable current honorary fellows include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7085", "text": "The Canadian Society for Pharmaceutical Research (CSPS) advocates for excellence in pharmaceutical research, promotes the allocation of research funds, seeks involvement in decision and policy making processes and provides a forum for early scientists. It was founded in 1997. The  Journal of Pharmacy and Pharmaceutical Sciences . [ 1 ] [ 2 ]  is the official journal of CSPS."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7086", "text": "The  Canadian Society of Pharmacology and Therapeutics  (CSPT;  French :  Soci\u00e9t\u00e9 Canadienne de Pharmacologie et de Th\u00e9rapeutique ) is an academic association whose mission is the promotion of research and education in  pharmacology  and  therapeutics  in Canada.  It  comprises graduate students, postdoctoral fellows, established investigators and clinical scientists working in academia, clinical practice, government, and industry.  Despite being based in Canada and having a majority of Canadian members, this is not a condition of membership, and the Society has members from all over the world. The CSPT is the Canadian member of the  International Union of Basic and Clinical Pharmacology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7087", "text": "The  European Association for Clinical Pharmacology and Therapeutics  (EACPT) is a  learned society  in the field of  clinical pharmacology . It is the leading society in Europe serving the European and global Clinical Pharmacology and Therapeutics community. It has its origins in a working party in the early 1980s under the auspices of the  World Health Organization  (WHO-Europe). Subsequently, a committee was created in 1993 chaired by Folke Sj\u00f6qvist [ 1 ]  with the remit to prepare the first congress of EACPT, held in Paris in 1995. [ 2 ]  At that congress the founding EACPT Council elected an Executive Committee with Sj\u00f6qvist as chairman, Michael Orme (United Kingdom) as Honorary Secretary, Jochen Kuhlmann (Germany) as Treasurer, and Giampaolo Velo (Italy) as Vice-Chairman, with 26 European countries as members through their home country clinical pharmacology society or section. [ 3 ]  The EACPT now includes all national organisations for clinical pharmacology in Europe and provides educational and scientific support for the more than 4000 individual professionals interested in Clinical Pharmacology and Therapeutics throughout the European region, with its congresses attended by a global audience."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7088", "text": "The EACPT promotes in Europe professional and ethical excellence and standards for clinical use of medicines and clinical research on drugs. The EACPT also aims to advise policy makers on how the specialty can contribute to human health and wealth. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7089", "text": "Activities of the EACPT include advice to policy makers and agencies in Europe, holding European congresses and workshops, and publishing policy papers, meeting reports, proceedings of congresses and constituent symposia, and contents of specific lectures. [ 5 ] [ 6 ]  The EACPT also holds Focus Meetings. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7090", "text": "Source: [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7091", "text": "Congresses [ 11 ]  are open to delegates from Europe and anywhere in the world, including health professionals, researchers, biotechnology and pharmaceutical industry professionals, regulators, policy makers, ethicists and others interested in drug discovery, and in clinical, cost-effectiveness and safety of medicines and related biomarkers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7092", "text": "The EACPT is led by an Executive Committee [ 22 ]  formed from a council of delegates from affiliated national societies [ 23 ]  for clinical pharmacology and  therapeutics . The EACPT also has key Working Groups for Research, Ethics and Regulatory Matters, Education and Young Pharmacologists. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7093", "text": "Clinical Therapeutics [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7094", "text": "The  European College of Neuropsychopharmacology  ( ECNP ) is a pan-European,  non-profit  scientific association that serves as a platform to exchange and promote research in the field of  neuropsychopharmacology . The ECNP \u201cis committed to ensuring that advances in the understanding of brain function and human behaviour are translated into better treatments and enhanced public health\u201d. [ 1 ]  The ECNP organises a number of activities to achieve this aim, such as a yearly congress, workshops, seminars, New Frontiers Meetings, publications ,  awards, supported talks and much more."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7095", "text": "In 1984 representatives of neuropsychopharmacological societies from across Europe suggested there might be room for a European structure. A meeting to discuss this plan further was held in Copenhagen in May 1985. It was decided that a European College of Neuropsychopharmacology would be founded. A Working Group was formed to plan of the association\u2019s inaugural scientific congress. This congress was held in Brussels in 1987. Around 500 people attended. [ 2 ] \nThe Working Group consisted of: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7096", "text": "In 1993 the College established a permanent secretariat in  Utrecht ,  Netherlands . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7097", "text": "The ECNP\u2019s executive organ is the Executive Committee. The Executive Committee consists of six officers (the president, vice- president, president-elect, past-president, secretary and treasurer) and a maximum of six councillors. The Executive Committee has a three year term. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7098", "text": "The  2019-2022 Executive Committee  consists of: [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7099", "text": "Martien Kas ,  The Netherlands , President \n Gitte Moos Knudsen ,  Denmark , Past-President  \n Andreas Reif ,  Germany , President-Elect \n Elisabeth Binder ,  Germany , Vice-President \n Catherine Harmer ,  United Kingdom , treasurer \n Suzanne Dickson ,  Sweden , Secretary"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7100", "text": "Councillors \n David Baldwin ,  United Kingdom \n Paolo Brambilla ,  Italy \n Iria Grande ,  Spain \n Iiris Hovatta ,  Finland  \nMarin Jukic,  Sweden \n Marion Leboyer ,  France"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7101", "text": "Chair Scientific Programme Committee \nJohn Cryan,  Ireland"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7102", "text": "Editor-in-chief  European Neuropsychopharmacology   ENP \n Eduard Vieta ,  Spain"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7103", "text": "Editor-in-chief  Neuroscience Applied \n Andreas Meyer-Lindenberg ,  Germany"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7104", "text": "Executive Director   \nAlexander Schubert,  The Netherlands"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7105", "text": "Past presidents are: [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7106", "text": "Gitte Moos Knudsen ,  Denmark  (2019-2022) \n Celso Arango ,  Spain  (2016-2019) \n Guy Goodwin ,  United Kingdom  (2013-2016) \n Joseph Zohar ,  Israel  (2010-2013) \n David Nutt ,  United Kingdom  (2007-2010) \nJulien Mendlewicz,  Belgium  (2004-2007) \nYves Lecrubier,  France  (2002-2004) \nJan M. van Ree,  Netherlands  (1998-2002) \nManfred Ackenheil,  Germany  (1995-1998) \nStuart A. Montgomery,  United Kingdom  (1992-1995) \nSalomon Z. Langer,  France  (1989-1992) \nCarl-Gerhard Gottfries,  Sweden  (1987-1989)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7107", "text": "The Executive Committee oversees the work of various sub-committees of the Executive Committees. These committees are staffed by scientists working in the field of  neuropsychopharmacology . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7108", "text": "Abstract and Poster Committee"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7109", "text": "The Abstract and Poster Committee oversees the abstract and poster process of the ECNP Congress."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7110", "text": "Award Committee"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7111", "text": "The Award Committee reviews applications for the ECNP Neuropsychopharmacology Award. The terms and criteria for this award, however, are set by the Executive Committee."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7112", "text": "Early Career Advisory Panel (ECAP)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7113", "text": "Six years ago ECNP founded the Early Career Advisory Panel (ECAP) to advise on the needs of future members of the College, to give input on development of Early Career Scientist activities and initiatives, to help generate activities for Early Career Scientists and clinicians, and to receive feedback on current activities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7114", "text": "Educational Committee"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7115", "text": "The Educational Committee is charged with propagating best practices in European applied neuroscience, from research methods and to clinical standards. As such, it oversees ECNP\u2019s training activities and educational programmes, especially for early career scientists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7116", "text": "Networks Board and Taskforce"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7117", "text": "Each ECNP Network is led by a Chair and a Co-chair. Chairs and Co-chairs of Networks and thematic working groups (TWGs) form the Networks Taskforce, which reports to the Networks Board and meets twice a year. The Networks Board guides the ECNP Networks."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7118", "text": "New Frontiers Programme Committee"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7119", "text": "The committee is responsible for developing the programme of the New Frontiers Meeting, held annually in Nice, France, and for guiding the ongoing discussion the meeting is designed to stimulate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7120", "text": "Workshop Committee"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7121", "text": "The Workshop Committee is charged with the organisation of the ECNP Workshop on Neuropsychopharmacology for Early Career Scientists in Europe, held annually in Nice, France."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7122", "text": "External Review Board of the ECNP"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7123", "text": "The External Review Board of the ECNP (formerly known as the Scientific Committee) was established in 2007 with the broad aim of overseeing the quality assurance of ECNP\u2019s governance and that of its activities.\n Nominating Committee"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7124", "text": "The Nominating Committee nominates candidates for the future Executive Committee (EC)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7125", "text": "Scientific Advisory Panel"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7126", "text": "The Scientific Advisory Panel (SAP) is ECNP\u2019s scientific sounding board, providing guidance and content advice in ECNP\u2019s key areas of scientific focus in disorders, interventions and methods."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7127", "text": "Scientific Programme Committee (ECNP Congress)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7128", "text": "The chair of the Scientific Programme Committee (SPC) is appointed by the Executive Committee for three consecutive ECNP Congresses. For each congress, the chair SPC submits a proposal of committee members to the Executive Committee for approval, taking into account scientific standing of potential candidates, as well as the overall geographical and disciplinary balance. The independent SPC is charged with ensuring that the programme is of a uniformly high standard and balanced across the field of applied and translational neuroscience."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7129", "text": "ECNP Workshop"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7130", "text": "ECNP Workshop on Clinical Research Methods"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7131", "text": "This Workshop aims at introducing early career clinicians (psychiatrists, clinical psychologists, etc) into research methodology and to promote a critical thinking approach to the scientific literature that is particularly relevant to clinical practice."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7132", "text": "ECNP New Frontiers Meeting"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7133", "text": "ECNP Negative Results Prize in Clinical Neuroscience"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7134", "text": "The ECNP Negative Results Prize in Clinical Neuroscience recognises those who have made exceptional contributions to CNS treatment development by publishing clinical research with negative findings."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7135", "text": "Best Negative Data Prize"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7136", "text": "The Best Negative Data Prize is a collaboration between ECNP and U.S.-based non-profit research organisation Cohen Veterans Bioscience to recognise published \u201cnegative\u201d scientific results or results of studies that do not confirm the expected outcome or original hypothesis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7137", "text": "ECNP Citation Prize"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7138", "text": "The ECNP Citation Prize recognises and encourage impactful original research in the ECNP journal,  European Neuropsychopharmacology (ENP) . It is awarded to the most cited research paper in the preceding two years."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7139", "text": "ECNP Neuropsychopharmacology Award"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7140", "text": "The ECNP Neuropsychopharmacology Award recognises exceptional research achievements in applied and translational neuroscience."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7141", "text": "ECNP Poster Award"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7142", "text": "Outstanding posters presented at the congress are awarded the ECNP Poster Award."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7143", "text": "ECNP Public Choice Poster Award"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7144", "text": "The best poster presented at the congress that is chosen by the public is awarded the ECNP Public Choice Poster Award."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7145", "text": "ECNP Seminar Award"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7146", "text": "ECNP confers two awards during each ECNP Seminar to help and encourage the most promising ECNP Seminar participants to visit the upcoming ECNP Congress."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7147", "text": "ECNP Excellence Award"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7148", "text": "The ECNP Excellence Award was established to encourage Early Career Scientists (ECS) resident in Europe and/or residents of a European Country with a Developing Country (CDE) to present a poster during the annual ECNP Congress."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7149", "text": "ECNP Rising Star Award"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7150", "text": "The ECNP Rising Star Award honours an Early Career Scientist whose research in applied and translational neuroscience has the potential to advance the science and treatment and prevention of brain disorders."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7151", "text": "The ECNP publishes:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7152", "text": "Alliance for Biomedical Research in Europe"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7153", "text": "Alliance for Biomedical Research \n European Brain Council  (EBC) (founder member) \n Federation of European Neuroscience Societies  (FENS) (founder member) \n International Society for CNS Clinical Trials and Methodology  (ISCTM)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7154", "text": "The  Federation of European Pharmacological Societies  (EPHAR) [ 1 ]  is a non-profit voluntary association established to advance research and education in the science of  pharmacology  and to promote co-operation between national/regional pharmacological societies in  Europe  and surrounding countries. It is an  umbrella organization  of currently 29 national societies for pharmacology and represents over 12,000 individual pharmacologists in Europe. Moreover it seeks to co-operate with other international organizations, especially the  International Union of Basic and Clinical Pharmacology  (IUPHAR) of which EPHAR is an associate member. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7155", "text": "The efforts in the 1990s to unite European economical and political forces had found their counterpart in formation of European scientific federations. One of those scientific federations is EPHAR that was founded at the XIth International Congress of Pharmacology in  Amsterdam  (The Netherlands) in 1990. The establishment of the federation was prepared by a steering committee formed in 1988 under the initiative of Rodolfo Paoletti. The steering committee, headed by B\u00f6rje Uvn\u00e4s, consisted of six members: Alasdair Breckenridge (UK), Flaminio Cattabeni (Italy), Gilles Fillion (France), Ove A. Nedergaard (Denmark), Rodolfo Paoletti (Italy), Hasso Scholz (Germany), B\u00f6rje Uvn\u00e4s (Sweden). EPHAR was recognized as an affiliate member of IUPHAR in 1994. Since 1990, the Federation has sponsored important scientific events. In particular, EPHAR has contributed in the organization of residential courses with a restricted number of participants (\"Molecular Biology in Pharmacology\", Milan, 1990; \"Neuroimmunomodulation in Pharmacology\", Paris, 1992; \"Electrophysiology in Pharmacology\", London, 1993). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7156", "text": "Pharmacology has developed into a multifaceted discipline extending from  molecular biology  at the one end to  clinical pharmacology  at the other. [ 4 ]  The necessity of collaborative efforts within all branches of  biological sciences , in the development and analysis of new  drugs , is the driving force of the activities of EPHAR. One challenge of this federation is the creation of new generations of pharmacologists with an analytical and broadminded attitude towards important aspects of modern medical biological sciences. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7157", "text": "The Federation seeks to achieve its objects by arranging instructional courses and training programs in matters connected with pharmacology, facilitating the exchange of scientific information between European pharmacologists (by encouraging the holding of joint meetings between European member societies), disseminating information and encouraging the participation to important activities organized by member societies. This will include the production of a calendar of the National and joint meetings of each European Society."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7158", "text": "Another important goal of the Federation is establishing common standards for basic courses in pharmacology, and fixing minimal standards for a European Pharmacologist Certificate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7159", "text": "The scientific dissemination is a fundamental step in progress and advance in research and education. For this reason, the most important scientific events established by the Federation are the EPHAR Congresses. They include plenary lectures, symposia, round tables, oral and poster communications devoted to the most recent advances in pharmacology and related sciences and therefore represented the adequate forum for discussing preclinical, clinical and therapeutic data. Particular emphasis was given to the impact of  biotechnologies  on  drug development  and to the identification of novel pharmacological approaches to  incurable   diseases . Sessions were also held on drug development, strategies for  research funding  and training of pharmacologists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7160", "text": "The EPHAR Congresses that have taken place since EPHAR\u2019s foundation are: [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7161", "text": "EPHAR supports activities, organized by its member societies that are intended to improve the cooperation among European pharmacologists. They are traditionally"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7162", "text": "One of these activities per year, for each country, is promoted by EPHAR. Calls for applications for these EPHAR-supported activities and the guidelines for these events are announced annually."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7163", "text": "Moreover EPHAR gives prizes to European young investigators in the field of pharmacology, the EPHAR Young Investigators Awards. So far, the following awards were given:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7164", "text": "The term of the EPHAR Executive Committees is four years."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7165", "text": "The present (2022\u20132026) Executive Committee is composed by the following members: [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7166", "text": "Past Presidents were:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7167", "text": "The National Societies members of EPHAR are (in alphabetical order):\n\u2022\tAustrian Pharmacological Society (\u00d6sterreichische Pharmakologische Gesellschaft) APHAR.\n\u2022\tBelgian Society of Fundamental and Clinical Physiology and Pharmacology. Soci\u00e9t\u00e9 Belge de Physiologie et de Pharmacologie Fondamentales et Cliniques. Belgisch Genootschap voor Fundamentele en Klinische Fysiologie en Farmacologie. \n\u2022\tAssociation of Pharmacologists of the Federation of Bosnia and Herzegovina. Udru\u017eenje Farmakologa Federacije Bosne i Hercegovine.\n\u2022\t British Pharmacological Society  (BPS).\n\u2022\tBulgarian Pharmacological Society.\n\u2022\tCroatian Pharmacological Society. Hrvatsko Dru\u0161tvo Farmakologa. (HDF). \n\u2022\tCzech Society for Experimental and Clinical Pharmacology and Toxicology. \u010cesk\u00e1 Spole\u010dnost pro Experiment\u00e1ln\u00ed a Klinickou Farmakologii a Toxicologii (\u010cSEKFT). \n\u2022\tDanish Society for Pharmacology, Toxicology and Medicinal Chemistry. Dansk Selskab for Farmakologi, Toksikologi og Medicinalkemi (DSFTM). \n\u2022\tDutch Pharmacological Society. Nederlands Vereniging voor Farmacologie (NVF)\n\u2022\tFinnish Pharmacological Society. Suomen Farmakologiyhdistys. (SFY). \n\u2022\tFrench Society of Pharmacology and Therapeutics. Soci\u00e9t\u00e9 Fran\u00e7aise de Pharmacologie et de Th\u00e9rapeutique. (SFPT).\n\u2022\tGerman Society of Pharmacology. Deutsche Gesellschaft f\u00fcr Pharmakologie. (DGP). \n\u2022\tHellenic (Greek) Society of Basic and Clinical Pharmacology. \u0395\u03bb\u03bb\u03b7\u03bd\u03b9\u03ba\u03ae \u0395\u03c4\u03b1\u03b9\u03c1\u03b5\u03af\u03b1 \u03a6\u03b1\u03c1\u03bc\u03b1\u03ba\u03b1\u03bb\u03bf\u03b3\u03af\u03b1\u03c2 (Ellinik\u00ed Etaire\u00eda Pharmakolog\u00edas). \n\u2022\tHungarian Society for Experimental and Clinical Pharmacology. Magyar Kis\u00e9rletes \u00e9s Klinikai Farmak\u00f3logiai T\u00e1rsas\u00e1g (MFT).\n\u2022\tIsrael Society for Physiology and Pharmacology (ISPP).\n\u2022\tSociet\u00e0 Italiana di Farmacologia (SIF). \n\u2022\tLatvian Society of Pharmacology. Latvijas Farmakolo\u0123ijas biedr\u012bba. (LFB).\n\u2022\tNorwegian Society for Pharmacology and Toxicology. Norsk Selskap for Farmakologi og Toksikologi. (NSFT). \n\u2022\tPharmacology Society of Malta.\n\u2022\tPolish Pharmacological Society. Polskie Towarzystwo Farmakologiczne. (PTST). \n\u2022\tPortuguese Pharmacological Society. Sociedade Portuguesa de Farmacologia (SPF).\n\u2022\tRussian Scientific Society of Pharmacology.\n\u2022\tSerbian Pharmacological Society. \u0421\u0440\u043f\u0441\u043a\u043e \u0424\u0430\u0440\u043c\u0430\u043a\u043e\u043b\u043e\u0448\u043a\u043e \u0414\u0440\u0443\u0448\u0442\u0432\u043e / Srpsko Farmakolo\u0161ko Dru\u0161tvo (\u0421\u0424\u0414 / SFD). \n\u2022\tSlovak Pharmacological Society. Slovensk\u00e1 Farmakologick\u00e1 Spolo\u010dnos\u0165 (SFaS). \n\u2022\tSlovenian Pharmacological Society. Slovensko Dru\u0161tvo Farmakologov. (SDF).\n\u2022\tSpanish Society of Pharmacology. Sociedad Espa\u00f1ola de Farmacolog\u00eda (SEF).\n\u2022\tSwedish Society for Pharmacology, Clinical Pharmacology and Therapeutics. Sektionen f\u00f6r L\u00e4kemedelsl\u00e4ra.\n\u2022\tSwiss Society of Pharmacology and Toxicology. Soci\u00e9t\u00e9 Suisse de Pharmacologie et de Toxicologie/ Schweizerische Gesellschaft f\u00fcr Pharmakologie und Toxikologie (SSPT/SGPT). \n\u2022\t Turkish Pharmacological Society. T\u00fcrk Farmakoloji Derne\u011fi  (TFD)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7168", "text": "EPHAR website:  http://www.ephar.org/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7169", "text": "The internet sites for each European pharmacological society, member of EPHAR, are hereby listed:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7170", "text": "\u2022\tAustria:  http://www.aphar.at/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7171", "text": "\u2022\tBelgium:  http://users.ugent.be/~jvdvoord/physiology&pharmacology/index.htm"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7172", "text": "\u2022\tCroatia:  http://pharma.mef.hr/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7173", "text": "\u2022 \tCzech Republic:  http://farmspol.cls.cz/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7174", "text": "\u2022\tDenmark  https://web.archive.org/web/20130903234249/http://dsftm.dk/index.php/en/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7175", "text": "\u2022\tNetherlands:  http://www.nvfarmaco.nl/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7176", "text": "\u2022\tFinland:  http://www.sfy.fi/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7177", "text": "\u2022\tFrance:  http://www.pharmacol-fr.org/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7178", "text": "\u2022\tGermany:  http://www.dg-pharmakologie.de/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7179", "text": "\u2022\tGreece:  https://web.archive.org/web/20131007085419/http://gsp.med.auth.gr/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7180", "text": "\u2022\tHungary:  http://www.mapharm.hu/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7181", "text": "\u2022\tItaly:  http://www.sifweb.org/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7182", "text": "\u2022\tNorway:  http://www.nsft.net/   Archived  2014-12-18 at the  Wayback Machine"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7183", "text": "\u2022\tPoland:  http://www.ptf.info.pl/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7184", "text": "\u2022\tSerbia:  http://www.sfarmd.org/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7185", "text": "\u2022\tSlovakia:  http://www.sfarm.sk/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7186", "text": "\u2022\tSpain:  http://www.socesfar.com/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7187", "text": "\u2022\tSweden  http://www.lakemedelslara.se/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7188", "text": "\u2022\tSwitzerland:  http://www.swisspharmtox.ch/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7189", "text": "\u2022\tTurkey:  http://www.tfd.org.tr/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7190", "text": "\u2022\tUnited Kingdom:  https://web.archive.org/web/20130410071823/http://www.bps.ac.uk/view/index.html"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7191", "text": "The  International Cannabinoid Research Society  ( ICRS ) is a  professional society  for scientific research in all fields of the  cannabinoids , based in  North Carolina , US. ICRS is one of the very few global non-profit medical societies or associations [ a ]  related to  cannabis  and  cannabinoids ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7192", "text": "The ICRS was formally incorporated as a scientific research society in 1992. [ 1 ]  Prior to that, early ICRS Symposia were organized by various researchers in the field since 1970. Membership in the Society has risen from 50 original members in its first year to 650+ members from all over the world."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7193", "text": "The International Cannabinoid Research Society is a:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7194", "text": "The mission of the ICRS is to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7195", "text": "Since 2019, [ 3 ]  the ICRS has partnered with  Mary Ann Liebert, Inc. Publishers  to produce the  academic journal   Cannabis and Cannabinoid Research ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7196", "text": "ICRS awards the \" Raphael Mechoulam  Award in Cannabinoid Research\" annually."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7197", "text": "The Society holds an annual meeting, not available to the media, [ 4 ]  which generally alternates between North America and Europe."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7198", "text": "The  International Union of Basic and Clinical Pharmacology  ( IUPHAR ) is a voluntary, non-profit association representing the interests of scientists in  pharmacology -related fields to facilitate  Better  Medicines  through Global Education and Research  around the world."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7199", "text": "Established in 1959 as a section of the International Union of Physiological Sciences, IUPHAR became an independent organization in 1966 [ 1 ]  and is a member of the  International Council for Science  (ICSU). [ 2 ]   The first World Congress of Pharmacology was held in  Stockholm ,  Sweden  in 1961 and subsequently held every three years.  After 1990 the World Congresses were moved to a four-year interval. [ 3 ]   These meetings present the latest pharmacological research, technology, and methodology, and provide a forum for international collaboration and exchange of ideas.  A General Assembly, consisting of delegates from all the member societies, is convened during the congresses so member societies have an opportunity to elect the Executive Committee and vote on matters concerning the governance and activities of the union."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7200", "text": "IUPHAR members are regional, national and special-interest societies  around the world. [ 4 ]  The various sections and committees are composed of individuals from  academia ,  pharmaceutical companies , and government organizations. IUPHAR resources are available to all members of the pharmacology-related societies that adhere to IUPHAR."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7201", "text": "IUPHAR is divided in sectional topics. The Division of Clinical Pharmacology, including 3 subcommittees of  Developing Countries , [ 5 ]   Geriatrics , [ 6 ]  and Pharmacoepidemiology and Pharmacovigilance, focuses on the needs and research tools for clinicians.  The Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) provides a uniform guideline for naming and classifying results from the  Human Genome Project , naming proteins derived from new sequences as functional receptors and ion channels. Sections specializing in various areas of pharmacology have been established, including  Drug Metabolism and Drug Transport , [ 7 ]   Education , [ 8 ]   Gastrointestinal Pharmacology , [ 9 ]   Immunopharmacology , [ 10 ]  Pharmacology of  Natural products , [ 11 ]   Neuropsychopharmacology , [ 12 ]   Pediatrics  Clinical Pharmacology [ 13 ]  and  Pharmacogenetics  and  Pharmacogenomics . [ 14 ]   Volunteers participate in the various sections and division according to their interests and training."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7202", "text": "A primary purpose of IUPHAR is providing global free access to a major, on-line repository of characterization data for  receptors , ion channels, enzyme target classes and  drugs  through the Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), established in 1987. The  Guide to Pharmacology  established in 2012 superseded the earlier IUPHAR-DB. This is a joint endeavor with the  British Pharmacological Society , and has been supported by the  Wellcome Trust . It includes all the  G protein -coupled receptors,  voltage-gated ion channels , 7TM receptors,  nuclear receptors ,  ligand-gated ion channels  and  Kinases  which are known to be in the  human genome . Where relevant, data on the rat and mouse  homologues  are presented to assist researchers and clinicians in developing and/or enhancing therapeutics for eventual medication in humans."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7203", "text": "NC-IUPHAR also promulgates standards of name  nomenclature  for research in pharmacology and the related disciplines."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7204", "text": "In general, IUPHAR offers individual pharmacologists free curriculum expertise, career development and job listings (the non-profit PharmacoCareers.org [ 15 ] ), research resources, and collaboration opportunities.  IUPHAR offers its member societies venues for participating in worldwide initiatives, publicizing member meetings and activities, nominating individuals for Young Investigator awards, and naming delegates to the quadrennial General Assemblies.  A biannual newsletter entitled  Pharmacology International  is published. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7205", "text": "As a  non-government organization  in official relations with the  World Health Organization  (WHO), IUPHAR representatives help shape international policy on  essential medicines , appropriate dose therapeutics for children, and  clinical pharmacology  core competencies among its many WHO-related activities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7206", "text": "The Division of Clinical Pharmacology compiled and released the Research in Humans Compendium, [ 17 ]  a free resource to provide the scientific community interested in human research with information on the design of research  protocols  to assess the effectiveness of a drug in a series of pathological conditions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7207", "text": "IUPHAR is involved in the development of pharmacology in  developing countries .  In conjunction with ICSU the Pharmacology for  Africa  (Phar f A) initiative was undertaken in 2006 to promote and organize pharmacology on the African continent.  The South African Society of Basic and Clinical Pharmacology is building a database and network of institutions and pharmacologists to create an infrastructure for training and funding pharmacologists.  The long-term goal is for the African continent to attain the necessary pharmacological knowledge and resources to address disease-related issues affecting the population.  As part of this mission, with the support of ICSU and the  American Society for Pharmacology and Experimental Therapeutics , the IUPHAR Education Section organized a series of workshops, mostly in Africa, to train young investigators on ethical laboratory practices, including the  three Rs of ethical use of animals ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7208", "text": "IUPHAR Pharmacology Education Project [ 18 ]  is a website developed by IUPHAR, with support from the American Society for Pharmacology and Experimental Therapeutics (ASPET), as a learning resource to support education and training in the pharmacological sciences. The materials are intended for use by students of pharmacology, clinical pharmacologists, and others interested in the pharmacological sciences. The stated aim is to produce a simple, attractive, easily searchable resource that will support students and teachers of the biomedical sciences, medicine, nursing and pharmacy. It is also intended as an introduction to some of the new data in the IUPHAR/BPS Guide to PHARMACOLOGY, particularly for those less familiar with such material."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7209", "text": "The early years of the 21st century will be focused on integrating basic and clinical research to implement  translational medicine  techniques more quickly.  The 9th World Conference on Clinical Pharmacology and Therapeutics in  Qu\u00e9bec City , Canada was the last IUPHAR meeting to present clinical pharmacology separately.  The World Congress of Basic and Clinical Pharmacology in  Copenhagen , Denmark on July 17\u201323, 2010 [ 19 ]  was the first integrated meeting.  The merging of these different approaches to the same discipline is to accelerate the introduction of improved therapeutics for humans."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7210", "text": "Educational components will be emphasized for both existing pharmacology programs as well as increasing and enhancing pharmacology training in developing countries.  This topic was a central theme of the 17th World Congress of Basic and Clinical Pharmacology (WCP2014) held July 13\u201318, 2014 in  Cape Town , South Africa. [ 20 ]   The 18th World Congress of Basic and Clinical Pharmacology (WCP2018) being held in Kyoto, Japan on July 1\u20136, 2018 will focus on drug development and therapeutics using new methodologies such as genome sequencing, stem cell biology, nanotechnology and systems biology. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7211", "text": "The  Safety Pharmacology Society  ( SPS ) is an organization that focuses on  safety pharmacology . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7212", "text": "The Safety Pharmacology Society was incorporated in 2000, [ 2 ]  at the time when the  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use  was issuing ICH S7A, a regulatory guidance covering safety pharmacology, and drafting ICH S7B, which is more specific to potential effects of new drugs on  cardiac repolarization . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7213", "text": "The Safety Pharmacology Society organizes an annual meeting in the fall, comprising invited speakers and posters. [ 4 ]  This meeting has alternated between North America and Europe."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7214", "text": "The  Society for Research on Nicotine and Tobacco  ( SRNT ) is an international  nonprofit organization  and  professional association  that studies and shares research on  nicotine  and  tobacco  use from a  public health  and scientific perspective. It is the largest organization focused on nicotine and tobacco, with members in 40 countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7215", "text": "The SRNT was founded in 1994. [ 1 ]  Work from SRNT members was noted in public discussion leading up to the  Family Smoking Prevention and Tobacco Control Act  in the United States [ 2 ]  and SRNT is cited as an expert source in the Act. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7216", "text": "The SRNT has its own official scientific journal,  Nicotine & Tobacco Research , founded in 1999 and published by  Oxford University Press ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7217", "text": "The SRNT also hosts SRNT University, a \"collection of organized, curated training, scientific articles, and tools and resources for people working in Nicotine & Tobacco Research and related professions.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_7218", "text": "The SRNT does not accept funding from the  tobacco industry . The organization does accept funding from  pharmaceutical companies  that make medications to help people quit smoking. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7219", "text": "The SRNT\u2019s work has been used by the  World Health Organization  and governments in setting policies on topics such as  tobacco advertising ,  taxation ,  smoke-free laws , and  smoking cessation . The SRNT has been particularly active in work on the  Tobacco Master Settlement Agreement  (adopted in 1998) in the United States and on the  WHO Framework Convention on Tobacco Control  (adopted on 2003)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7220", "text": "The society and its members have also been involved in the current debate on  tobacco harm reduction , [ 4 ]  the safety and prevalence of  e-cigarettes , [ 5 ]  and other  public health  issues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7221", "text": "In 2016, the Society began an annual Fellowship programme, designed to be \"prestigious but not elitist\". The first fellows were elected in 2017. Notable fellows include: [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7222", "text": "Uppsala Monitoring Centre  ( UMC ), located in  Uppsala ,  Sweden , is the field name for the  World Health Organization   Collaborating Centre  for International Drug Monitoring. UMC works by collecting, assessing and communicating information from member countries' national  pharmacovigilance  centres in regard to the benefits, harm, effectiveness and risks of drugs. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7223", "text": "Since 1978, responsibility for managing the WHO Programme for International Drug Monitoring has been carried by UMC. [ 2 ]  In the early years the staff consisted of just three pharmacists, Sten Olsson, Cecilia Biriell and Marie Lindquist, based at the Swedish  Medical Products Agency  (L\u00e4kemedelsverket); [ 3 ]  Currently over 150 staff work in central Uppsala. The founding chairman and acting Director was Professor \u00c5ke Liljestrand. From 1990 to 2009 the Director was Professor Ralph Edwards. [ 4 ]  In 2009, Dr. Marie Lindquist became the Director until her retirement in 2020. Herv\u00e9 Le Lou\u00ebt served from 2021 to 2022 and was succeeded by Peter Hjelmstr\u00f6m. The Head of Research is Dr. Niklas Nor\u00e9n."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7224", "text": "The work of the UMC is:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7225", "text": "The main focus and source of data in  pharmacovigilance  are reports of ICSRs (individual case safety reports) from healthcare providers and patients in member countries of the WHO Programme. A WHO global individual case safety report database ( VigiBase ) is maintained and developed on behalf of the WHO by UMC. [ 5 ]  UMC develops and provides several tools and classifications for use by organisations involved in drug safety, including the  WHO Drug Dictionary  \u2013 with a bridge to the  MedDRA  terminology and WHO ICD \u2013  tools for searching in the database, and a program for case report management, VigiFlow. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7226", "text": "UMC's research covers mainly three areas: data-driven discovery (especially statistical techniques), dis-proportionality analyses, interaction detection, patterns and duplicate case detection, safety surveillance and signaling (among which drug dependence and pediatric use) and benefit\u2014risk analysis. As of 2023 over 200 scientific articles in peer-reviewed journals were linked on the centre's website. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7227", "text": "UMC has been active in initiatives to improve communication in areas related to medicines safety since 1996. [ 8 ]  The centre has been active in presenting research in the medical literature which has included some seminal works in the field. [ 7 ]  The Uppsala centre has also published books in the field of drugs safety including a regular newsletter. [ 6 ]  In 2010 the 2nd edition of a crisis management guide was published, entitled 'Expecting the Worst', also translated into other languages. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7228", "text": "UMC's role in drug safety has not been without controversy for both medicines agencies and pharmaceutical companies, despite an open approach willing to engage with many parties in the pharmaceutical world. They are closely involved in outreach to developing countries and other areas where pharmacovigilance is not yet handled. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7229", "text": "An  anaesthetic machine  ( British English ) or  anesthesia machine  ( American English ) is a  medical device  used to generate and mix a fresh gas flow of medical gases and  inhalational anaesthetic  agents for the purpose of inducing and maintaining  anaesthesia . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7230", "text": "The machine is commonly used together with a  mechanical ventilator ,  breathing system ,  suction equipment , and  patient monitoring  devices; strictly speaking, the term \"anaesthetic machine\" refers only to the component which generates the gas flow, but modern machines usually integrate all these devices into one combined freestanding unit, which is colloquially referred to as the \"anaesthetic machine\" for the sake of simplicity. In the developed world, the most frequent type in use is the  continuous-flow anaesthetic machine  or \" Boyle's machine \", which is designed to provide an accurate supply of medical gases mixed with an accurate concentration of anaesthetic vapour, and to deliver this continuously to the patient at a safe  pressure  and flow. This is distinct from  intermittent-flow anaesthetic machines , which provide gas flow only on demand when triggered by the patient's own inspiration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7231", "text": "Simpler anaesthetic apparatus may be used in special circumstances, such as the  triservice anaesthetic apparatus , a simplified anaesthesia delivery system invented for the British  Defence Medical Services , which is light and portable and may be used for ventilation even when no medical gases are available. This device has unidirectional valves which suck in ambient air, which can be enriched with oxygen from a cylinder, with the help of a set of bellows."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7232", "text": "The original concept of continuous-flow machines was popularised by Boyle's anaesthetic machine, invented by the British anaesthetist  Henry Boyle  at  St Bartholomew's Hospital  in  London ,  United Kingdom , in 1917, although similar machines had been in use in France and the United States. [ 2 ]  Prior to this time, anaesthesiologists often carried all their equipment with them, but the development of heavy, bulky cylinder storage and increasingly elaborate airway equipment meant that this was no longer practical for most circumstances. Contemporary anaesthetic machines are sometimes still referred to  metonymously  as \"Boyle's machine\", and are usually mounted on anti-static wheels for convenient transportation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7233", "text": "Many of the early innovations in anaesthetic equipment in the United States, including the closed circuit carbon-dioxide absorber (a.k.a. the Guedel-Foregger Midget) and diffusion of such equipment to anaesthesiologists within the United States can be attributed to  Richard von Foregger  and  The Foregger Company ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7234", "text": "In anaesthesia, fresh gas flow is the mixture of medical gases and  volatile anaesthetic  agents which is produced by an anaesthetic machine and has not been recirculated. The flow rate and composition of the fresh gas flow is determined by the  anaesthetist . Typically the fresh gas flow emerges from the common gas outlet, a specific outlet on the anaesthetic machine to which the breathing attachment is connected. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7235", "text": "Open circuit forms of equipment, such as the Magill attachment, require high fresh gas flows (e.g. 7 litres/min) to prevent the patient from  rebreathing  their own expired carbon dioxide. Recirculating (rebreather) systems, use  soda lime  to absorb  carbon dioxide , in the scrubber, so that expired gas becomes suitable to re-use. With a very efficient recirculation system, the fresh gas flow may be reduced to the patient's minimum  oxygen  requirements (e.g. 250ml/min), plus a little volatile as needed to maintain the concentration of anaesthetic agent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7236", "text": "Increasing fresh gas flow to a recirculating breathing system can reduce carbon dioxide absorbent consumption. There is a cost/benefit trade-off between gas flow and use of adsorbent material when no inhalational anaesthetic agent is used which may have economic and environmental consequences. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7237", "text": "An  anesthetic vaporizer  ( American English ) or  anaesthetic vapouriser  ( British English ) is a device generally attached to an anesthetic machine which delivers a given concentration of a  volatile anesthetic  agent. It works by controlling the vaporization of anesthetic agents from liquid, and then accurately controlling the concentration in which these are added to the fresh gas flow. The design of these devices takes account of varying: ambient temperature, fresh gas flow, and agent  vapor pressure . There are generally two types of vaporizers: plenum and drawover. Both have distinct advantages and disadvantages. [ 5 ]  The  dual-circuit gas-vapor blender  is a third type of vaporizer used exclusively for the agent  desflurane ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7238", "text": "The plenum vaporizer is driven by  positive pressure  from the  anesthetic machine , and is usually mounted on the machine. The performance of the vaporizer does not change regardless of whether the patient is breathing spontaneously or is mechanically ventilated. The internal resistance of the vaporizer is usually high, but because the supply pressure is constant the vaporizer can be accurately  calibrated  to deliver a precise concentration of  volatile anesthetic  vapor over a wide range of fresh gas flows. [ 5 ]  The plenum vaporizer is an elegant device which works reliably, without external power, for many hundreds of hours of continuous use, and requires very little maintenance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7239", "text": "The plenum vaporizer works by accurately splitting the incoming gas into two streams. One of these streams passes straight through the vaporizer in the bypass channel. The other is diverted into the vaporizing chamber. Gas in the vaporizing chamber becomes fully  saturated  with volatile anesthetic vapor. This gas is then mixed with the gas in the bypass channel before leaving the vaporizer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7240", "text": "A typical volatile agent,  isoflurane , has a saturated  vapor pressure  of 32kPa (about 1/3 of an atmosphere). This means that the gas mixture leaving the vaporizing chamber has a  partial pressure  of isoflurane of 32kPa. At sea-level ( atmospheric pressure  is about 101kPa), this equates conveniently to a  concentration  of 32%. However, the output of the vaporizer is typically set at 1\u20132%, which means that only a very small proportion of the fresh gas needs to be diverted through the vaporizing chamber (this proportion is known as the splitting ratio). It can also be seen that a plenum vaporizer can only work one way round: if it is connected in reverse, much larger volumes of gas enter the vaporizing chamber, and therefore potentially toxic or lethal concentrations of vapor may be delivered. (Technically, although the dial of the vaporizer is calibrated in volume percent (e.g. 2%), what it actually delivers is a partial pressure of anesthetic agent (e.g. 2kPa))."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7241", "text": "The performance of the plenum vaporizer depends extensively on the saturated vapor pressure of the volatile agent. This is unique to each agent, so it follows that each agent must only be used in its own specific vaporizer. Several safety systems, such as the Fraser-Sweatman system, have been devised so that filling a plenum vaporizer with the wrong agent is extremely difficult. A mixture of two agents in a vaporizer could result in unpredictable performance from the vaporizer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7242", "text": "Saturated vapor pressure for any one agent varies with temperature, and plenum vaporizers are designed to operate within a specific temperature range. They have several features designed to compensate for temperature changes (especially cooling by  evaporation ). They often have a metal jacket weighing about 5\u00a0kg, which equilibrates with the temperature in the room and provides a source of heat. In addition, the entrance to the vaporizing chamber is controlled by a  bimetallic strip , which admits more gas to the chamber as it cools, to compensate for the loss of efficiency of evaporation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7243", "text": "The first temperature-compensated plenum vaporizer was the Cyprane 'FluoTEC'  Halothane  vaporizer, released onto the market shortly after Halothane was introduced into clinical practice in 1956."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7244", "text": "The drawover vaporizer is driven by  negative pressure  developed by the patient, and must therefore have a low resistance to gas flow. Its performance depends on the  minute volume  of the patient: its output drops with increasing minute ventilation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7245", "text": "The design of the drawover vaporizer is much simpler: in general it is a simple glass reservoir mounted in the breathing attachment. Drawover vaporizers may be used with any liquid volatile agent (including older agents such as  diethyl ether  or  chloroform , although it would be dangerous to use  desflurane ). Because the performance of the vaporizer is so variable, accurate calibration is impossible. However, many designs have a lever which adjusts the amount of fresh gas which enters the vaporizing chamber."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7246", "text": "The drawover vaporizer may be mounted either way round, and may be used in circuits where  re-breathing  takes place, or inside the circle breathing attachment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7247", "text": "Drawover vaporizers typically have no temperature compensating features. With prolonged use, the liquid agent may cool to the point where condensation and even frost may form on the outside of the reservoir. This cooling impairs the efficiency of the vaporizer. One way of minimising this effect is to place the vaporizer in a bowl of water."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7248", "text": "The relative inefficiency of the drawover vaporizer contributes to its safety. A more efficient design would produce too much anesthetic vapor. The output concentration from a drawover vaporizer may greatly exceed that produced by a plenum vaporizer, especially at low flows. For safest use, the concentration of anesthetic vapor in the breathing attachment should be continuously monitored."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7249", "text": "Despite its drawbacks, the drawover vaporizer is cheap to manufacture and easy to use. In addition, its portable design means that it can be used in the field or in  veterinary anesthesia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7250", "text": "The third category of vaporizer (the dual-circuit gas\u2013vapor blender) was created specifically for the agent  desflurane . [ 5 ]  Desflurane boils at 23.5\u00a0\u00b0C, which is very close to room temperature. This means that at normal  operating temperatures , the saturated vapor pressure of desflurane changes greatly with only small fluctuations in temperature. This means that the features of a normal plenum vaporizer are not sufficient to ensure an accurate concentration of desflurane. Additionally, on a very warm day, all the desflurane would boil, and very high (potentially lethal) concentrations of desflurane might reach the patient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7251", "text": "A desflurane vaporizer (e.g. the TEC 6 produced by  Datex-Ohmeda ) is heated to 39C and pressurized to 194kPa. [ 6 ]  It is mounted on the anesthetic machine in the same way as a plenum vaporizer, but its function is quite different. It evaporates a chamber containing desflurane using heat, and injects small amounts of pure desflurane vapor into the fresh gas flow. A  transducer  senses the fresh gas flow. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7252", "text": "A warm-up period is required after switching on. The desflurane vaporizer will fail if mains power is lost. Alarms sound if the vaporizer is nearly empty. An electronic display indicates the level of desflurane in the vaporizer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7253", "text": "The expense and complexity of the desflurane vaporizer have contributed to the relative lack of popularity of desflurane, although in recent years it is gaining in popularity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7254", "text": "Historically,  ether  (the first volatile agent) was first used by  John Snow 's inhaler (1847) but was superseded by the use of  chloroform  (1848). Ether then slowly made a revival (1862\u20131872) with regular use via  Curt Schimmelbusch 's \"mask\", a  narcosis  mask for dripping liquid ether. Now obsolete, it was a mask constructed of wire, and covered with cloth."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7255", "text": "Pressure and demand from  dental surgeons  for a more reliable method of administering ether helped modernize its delivery. In 1877,  Clover  invented an ether inhaler with a water jacket, and by the late 1899 alternatives to ether came to the fore, mainly due to the introduction of spinal anesthesia. Subsequently, this resulted in the decline of ether (1930\u20131956) use due to the introduction of  cyclopropane ,  trichloroethylene , and  halothane . By the 1980s, the anesthetic vaporizer had evolved considerably; subsequent modifications lead to a raft of additional safety features such as temperature compensation, a  bimetallic strip , temperature-adjusted splitting ratio and anti-spill measures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7256", "text": "The  breathing circuit  is the ducting through which the breathing gases flow from the machine to the patient and back, and includes components for mixing, adjusting, and monitoring the composition of the breathing gas, and for removing carbon dioxide."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7257", "text": "A modern anaesthetic machine includes at minimum the following components: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7258", "text": "Systems for monitoring the patient's  heart rate ,  ECG ,  blood pressure  and  oxygen saturation  may be incorporated, in some cases with additional options for monitoring  end-tidal carbon dioxide  and  temperature . [ 2 ]   Breathing systems  are also typically incorporated, including a manual  reservoir bag  for ventilation in combination with an  adjustable pressure-limiting valve , as well as an integrated mechanical ventilator, to accurately ventilate the patient during anaesthesia. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7259", "text": "Based on experience gained from analysis of mishaps, the modern anaesthetic machine incorporates several safety devices, including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7260", "text": "The functions of the machine should be checked at the beginning of every operating list in a \"cockpit-drill\". Machines and associated equipment must be maintained and serviced regularly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7261", "text": "Older machines may lack some of the safety features and refinements present on newer machines. However, they were designed to be operated without  mains electricity , using compressed gas power for the ventilator and suction apparatus. Modern machines often have  battery  backup, but may fail when this becomes depleted."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7262", "text": "The modern anaesthetic machine still retains all the key working principles of the Boyle's machine (a  British Oxygen Company  trade name) in honour of the British anaesthetist Henry Boyle. In India, however, the trade name 'Boyle' is registered with Boyle HealthCare Pvt. Ltd., Indore MP."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7263", "text": "Various regulatory and professional bodies have formulated checklists for different countries. [ 8 ]  Machines should be cleaned between cases as they are at considerable risk of contamination with  pathogens . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7264", "text": "The general term  nebulizer  refers to an apparatus that converts liquids into a fine mist. Nozzles also convert liquids into a fine mist, but do so by pressure through small holes. Nebulizers generally use gas flows to deliver the mist. The most common form of nebulizers are medical appliances such as  asthma inhalers  or paint spray cans.  Analytical nebulizers  are a special category in that their purpose is to deliver a fine mist to spectrometric instruments for elemental analysis. They are necessary parts of  inductively coupled plasma atomic emission spectroscopy  ( ICP-AES ),  inductively coupled plasma mass spectrometry  (ICP-MS), and  atomic absorption spectroscopy  (AAS)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7265", "text": "Analytical nebulizers are used in trace element analysis. This type of work plays an important role in areas of pharmaceutical and clinical study, biological, environmental and agricultural assessment and petroleum testing. They also have nuclear applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7266", "text": "Most analytical pneumatic nebulizers use the same essential principle ( induction ) to  atomize  the liquid: When gas at a higher pressure exits from a small hole (the orifice) into gas at a lower pressure, it forms a gas jet into the lower pressure zone, and pushes the lower pressure gas away from the orifice. This creates a current in the lower pressure gas zone, and draws some of the lower pressure gas into the higher pressure gas jet. At the orifice, the draw of the lower pressure gas creates considerable suction, the extent depending on the differential pressures, the size of the orifice, and the shape of the orifice and surrounding apparatus. In all pneumatic induction nebulizers, the suction near the orifice is utilized to draw the liquid into the gas jet. The liquid is broken into small droplets in the process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7267", "text": "Present induction pneumatic nebulizer designs fit into 5 categories: 1. Concentric: Liquid flow surrounded by a Gas flow or Gas flow surrounded by a Liquid flow; 2. Cross Flow: Gas flow at right angles to the Liquid flow; 3. Entrained: Gas and Liquid mixed in the system and emitted as a combined flow. 4. Babington and V Groove: Liquid is spread over a surface to decrease the surface tension, and passed over a gas orifice; 5. Parallel Path: Liquid is delivered beside a gas orifice and induction pulls the liquid into the gas stream."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7268", "text": "Newer non-induction nebulizers include 3 more categories: 6. Enhanced Parallel Path: Liquid is delivered beside a gas orifice and drawn into the gas stream by surface tension along a spout; 7: Flow Blurring: liquid is injected by pressure into a gas stream; 8. Vibrating Mesh: liquid is pushed through tiny holes by a vibrating ultrasonic plate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7269", "text": "Concentric nebulizers have a central capillary with the liquid and an outer capillary with the gas. The gas draws the liquid into the gas stream through induction, and the liquid is broken into a fine mist as it moves into the gas stream. In theory, the gas and liquid may be switched with the gas in the center and the liquid in the outer capillary, but generally they work better with the gas outside and the liquid inside. [ 1 ]  The first Canadian concentric patent was Canadian Patent #2405 of April 18, 1873. It was designed to deliver a better spray of oil into a burner. The design is larger but essentially the same as modern analytical nebulizers. The first one developed for spectrometers was a glass design developed by Dr. Meinhard of California in 1973. [ 2 ]  His design enabled early ICP users to have a consistent sample introduction nebulizer, but it plugged easily. Today many companies produce glass concentrics, and since 1997, Teflon concentrics have become available."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7270", "text": "Cross flow nebulizers have a gas capillary set at right angles to the liquid capillary. The gas is blown across the liquid capillary and this produces a low pressure that draws the liquid into the gas stream. Generally the suction is similar to what is produced in a concentric nebulizer. The benefit of a cross flow is that the liquid capillary have a larger inside diameter allowing for more particles to pass through without plugging the nebulizer. The disadvantage is that the mist is usually not as fine or as consistent. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7271", "text": "There are no analytical nebulizers at present using this technique, but some oil burners do. Mainly used in much older designs as newer concentrics and cross flows are much better and easier to make."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7272", "text": "V Groove nebulizers are similar to a cross flow in that the liquid is delivered in a capillary at right angles to the gas capillary, but the liquid is poured down a vertically orientated groove that flows past a gas orifice. The gas pulls the liquid into the gas flow and forms a fine mist. These allow for very large ID liquid capillaries, but have no suction and require a pump to feed the liquid to the device. They must be correctly orientated or they do not allow the liquid to flow past the gas stream. And their mist usually produces larger droplets than with concentrics or cross flows."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7273", "text": "This design was developed by John Burgener of Burgener Research Inc. Here, the gas stream and sample run through the nebulizer in parallel capillaries. At the tip of the nebulizer, the liquid is pulled into the gas stream and then dispersed into the chamber as a mist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7274", "text": "This design was developed by John Burgener of Burgener Research Inc. [ 4 ]  Here, the gas stream and sample run through the nebulizer in parallel capillaries. At the tip of the nebulizer, the liquid is pulled into the gas stream by surface tension along a spout dipping into the gas stream. This allows the gas to impact the liquid, and has the liquid interact in the center of the gas flow where the gas flow speed is highest, producing a better transfer of energy from the gas to the liquid, and producing a finer droplet size. The Burgener Mira Mist nebulizers are the main products using the Enhanced Parallel Path method."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7275", "text": "This is a new type of nebulizer which does not use induction to mix the sample and gas. Instead, pneumatic atomization is employed here, which results in the micro-mixing of fluids using a reflux cell. [ 5 ]  This means that there is a turbulent mixing of the liquid and gas which results in great sensitivity and is very efficient. The OneNeb is the only example of this sort."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7276", "text": "Since 2011, this variation on ultrasonic nebulizers has been available. There is a vibrating membrane which has micro holes in it. The sample enters through the back and is pushed through the holes as the membrane vibrates. This makes a fine mist with a droplet size proportional to the hole size. This method requires no gas flow, and is used in conjunction with a chamber. If the droplets are less than 5\u03bcm then they are too small to stick to the chamber walls and the chamber remains dry while 90\u2013100% of the sample makes it to the torch."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7277", "text": "The early history of medical nebulizers can be read  here . The development of analytical nebulizers since the introduction of the ICP / ICP-MS is seen below: [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7278", "text": "1970s Adjustable Cross flow (US patent #4,344,574) [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7279", "text": "1974 Meinhard Concentric"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7280", "text": "1978 V-groove (by Suddendorf and Boyer) (US Patent #4,206,160) [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7281", "text": "1980 Pillar and Post (by Garbarino and Taylor)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7282", "text": "1983 GMK Nebulizer: Glass Babington V-groove"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7283", "text": "1983 Meinhard C-type nebulizer"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7284", "text": "1983 Precision glassblowing (similar to Minehard A-type)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7285", "text": "1983 Jarrell Ash (Thermo) Sapphire V-groove"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7286", "text": "1983 Meddings' MAK: glass fixed cross flow"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7287", "text": "1984 Meinhard K-type: recessed inner capillary"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7288", "text": "1984 Glass Expansion begins making ICP glassware"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7289", "text": "1985 Burgener-Legere \u2013 first commercial teflon nebulizer \u2013 V-groove \u2013 no adjustable parts"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7290", "text": "1986 Direct injection micro nebulizer by Fassel, Rice & Lawrence (US patent #4,575,609) [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7291", "text": "1986 Hildebrand Grid nebulizer"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7292", "text": "Late 1980s Perkin Elmer Gem Tip cross flow"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7293", "text": "1988 CETAC Ultrasonic Nebs"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7294", "text": "1980s Cyclonic chambers"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7295", "text": "1987 Glass Expansion's first neb \u2013 the VeeSpray (ceramic V-groove)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7296", "text": "1989 Glass Expansion first concentric \u2013 the Conikal (machined instead of glass blown)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7297", "text": "1989 Noordermeer Glass V Groove (US patent #4,880,164) [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7298", "text": "1992 Glass Expansion \u2013 non salting Sea Spray"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7299", "text": "1993 Modified Lichte Glass V-Groove"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7300", "text": "1993 Burgener BTF \u2013 first Parallel Path Neb (US patent #5,411,208) [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7301", "text": "1994\u20131995 Main Burgener Parallel Path Nebs \u2013 BTS 50, BTN & T2002"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7302", "text": "Mid 1990s Perkin Elmer GemCone: Miniature V-Groove"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7303", "text": "With the introduction of the ICP-MS to the laboratory, the creation of micro nebulizers became a priority in order to deliver smaller amounts of sample at lower flow rates."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7304", "text": "1993 The Meinhard HEN (high efficiency nebulizer) was produced which handled very low flow rates but salted and plugged easily as a result. (25 times less sample than a standard Meinhard)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7305", "text": "1997 Cetac Microconcentric Nebulizer \u2013 first Teflon concentric 50, 100, 200 or 400 \u03bcL/min"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7306", "text": "1997 Meinhard Direct Injection HEN \u2013 (DIHEN) (US Patent #6,166,379) [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7307", "text": "1999 Elemental Scientific \u2013 PFA Concentric Nebs 20, 50, 100 or 400 \u03bcL/min"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7308", "text": "1999 Burgener Micro 1: Parallel Path"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7309", "text": "2000 Burgener Micro 3: Parallel Path"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7310", "text": "2001 Burgener Mira Mist: First Enhanced Parallel Path Nebulizer (US patent #6,634,572) [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7311", "text": "2004 Epond Typhoon: Glass Concentric"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7312", "text": "2005 Ingeniatrics OneNeb: Flow Blurring Technology"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7313", "text": "2010 Epond Lucida: Teflon Micro Concentric"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7314", "text": "2012 Burgener PFA 250: PFA Micro flow Enhanced Parallel Path Nebulizer"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7315", "text": "2010 \u2013 2013 Meinhard and Glass Expansion: Significant improvements in attachments and designs of glass concentrics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7316", "text": "AptarGroup, Inc.,  also known as  Aptar , is a United States\u2013based global manufacturer of consumer dispensing packaging and  drug delivery  devices. [ 7 ] [ 1 ]  The group has manufacturing operations in 18 countries. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7317", "text": "The company began as Werner Die & Stamping in Cary, Illinois, in 1946 and later incorporated as AptarGroup in 1992. [ 1 ] [ 9 ]  Aptar originally developed spray valves and pumps for consumer and household products. The company later began producing  nasal administration  and  pulmonary drug delivery  devices such as  nasal spray  systems and  metered-dose inhaler  valves. [ 9 ] [ 10 ] [ 11 ] [ 12 ]  Biotech and pharmaceutical companies use Aptar's different Unidose and Bidose devices for the single or two-shot intranasal delivery of different medicines. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7318", "text": "In 2016, Aptar announced that it provided the delivery system for Adapt Pharma's  Narcan . [ 14 ]  Narcan is a naloxone hydrochloride nasal spray used as an emergency treatment for opioid overdoses. [ 14 ]  Aptar's liquid spray drug delivery technology platform works as a ready-to-use, single-shot, unit-dose system for Narcan. It was the first  FDA  approved nasally administered, ready-to-use medication used to reverse the effects of an opioid overdose. [ 14 ]  Narcan does not require any assembly, medical training, or needle injection. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7319", "text": "In 2016, Aptar entered into an agreement with  Becton Dickinson & Company  to develop new self-injection devices. [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7320", "text": "Aptar entered into an agreement in 2016 with Propeller Health Partners to develop a digitally connected medication  inhaler . [ 18 ]  The company made an investment in Propeller Health Partners (now part of  Resmed ) in 2018. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7321", "text": "In July 2019, the FDA-approved Aptar Pharma's Unidose Powder System as the first intranasally-delivered, needle-free rescue treatment for severe  hypoglycemia . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7322", "text": "In 2020, during the  COVID-19 pandemic , Aptar invested in new tools to accelerate its molding equipment and assembly machines for pumps, but it still wasn't enough to keep up with demand. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7323", "text": "In 2012, Aptar acquired Stelmi, a manufacturer of  elastomer  primary packaging components. [ 21 ]  In 2016, Aptar acquired Mega Airless, a manufacturer of airless packaging solutions. [ 22 ]  In 2018, Aptar acquired CSP Technologies, a material science company that manufactures  active packaging  solutions. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7324", "text": "In June 2019, Aptar acquired two companies, Nanopharm and Gateway Analytical. [ 24 ]  In November 2019, the company acquired Noble International, which specializes in training devices and patient onboarding. [ 25 ]  In February 2020, Aptar acquired FusionPKG, a makeup packaging company. [ 26 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7325", "text": "In November 2020, the company acquired the digital respiratory health company Cohero Health. [ 28 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7326", "text": "In July 2021 Aptar acquired the digital therapeutics company, Voluntis (ENXTPA: ALVTX), and 80% of the equity interests of Weihai Hengyu Medical Products Co., Ltd., a Chinese manufacturer of elastomeric and plastic components used in injectable drug delivery. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7327", "text": "Aptar was named to  Barron's  list of the Top 100 Most Sustainable U.S. Companies in 2019, 2020, 2021, and 2022. [ 31 ] [ 32 ] [ 33 ] [ 34 ]  At the end of 2020, 85% of the company\u2019s global electricity use came from renewable sources. [ 35 ]  It was also named by  Newsweek  as one of America's Most Responsible Companies in 2021, [ 36 ]  2022, [ 37 ]  and 2023 [ 38 ]  and received an A score for climate change from the  Climate Disclosure Project . [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7328", "text": "In September 2019, the company announced a partnership with Loop, a shopping platform from  TerraCycle  that delivers products in reusable containers. [ 40 ]  The company made the  Forbes  Green Growth 50 List in 2021. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7329", "text": "Aquasomes  are self-assembling  nanoparticle  drug carrier systems composed of three layers: a  ceramic  core, an  oligomer  coat, and a loaded  biochemically active molecule . Aquasomes are utilized for targeted  drug delivery  to achieve specific therapeutic effects, and are  biocompatible ,  biodegradable , and stable. Due to their structure, aquasomes are capable of delivering several types of substrates, and can be used for applications such as delivery of  antigens ,  insulin , and  hemoglobin ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7330", "text": "Aquasomes were first investigated by Kossovsky et al. in 1996 in experiments proposing their use in antigen delivery, drug delivery, and hemoglobin delivery systems. [ 2 ]  This initial research described aquasomes as self-assembling, with a novel surface modification process allowing the immobilization of drugs on the surface. [ 2 ]  The research was intended to address the molecular denaturation of  polypeptide  pharmaceuticals. [ 2 ]  Kossovsky et al. suggested that this system would be able to combat physical and chemical degradative agents affecting bioactive molecules while preserving the molecular structure of the drug. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7331", "text": "Since this initial exploration, the understanding of the composition and applications of aquasomes has increased. After each individual layer is synthesized, aquasomes self-assemble into triple-layered particles. The tri-layer structure enables aquasomes to deliver and release poorly soluble drugs in a controlled manner. Delivery of these poorly soluble drugs within aquasomes increases their solubility, bioavailability, and stability. These drugs are  adsorbed  onto the surface of the aquasome, forming its third layer, which confers bioactive properties to the aquasome."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7332", "text": "Aquasomes form a three-layered structure, made of a  polyhydroxy   oligomer  coated core upon which the drug is loaded. The biochemically active molecules are able to interact with the coated core through different  Van der Waal forces ,  entropic forces , and  ionic  and  non-covalent bonds . [ 3 ]  The structure of aquasomes enables them to carry a variety of substrates (chemicals), facilitating applications such as protein and  peptide  delivery and protection, and the delivery of  nucleic acids  for  gene therapy  applications. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7333", "text": "Aquasomes\u2019 solid core, made of ceramic or  polymeric  material, is attributed to the structural stability of the nanoparticle itself, and can result in improved solubility and  biocompatibility  of the drug. [ 1 ]  Different core designs have also been shown to affect the controlled release properties of the drug molecule. A commonly used core material is the ceramic  calcium phosphate , which naturally occurs in the body. [ 1 ]   Hydroxyapatite , which is found in bone, is another commonly used core material. Hydroxyapatite cores have been shown to contribute to targeted delivery of encapsulated  hepatitis B  antigens intracellularly. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7334", "text": "The second layer of aquasomes is the  carbohydrate  coat, onto which the drug is adsorbed. Due to carbohydrate\u2019s action as a dehydroprotectant, [ definition needed ]  it has been shown to function as a natural stabilizer to preserve the conformation (shape) of  soft drugs . [ 1 ]  The dehydroprotectant property of the carbohydrate coat also enables protection of the biochemically active molecule from  dehydration  and  protein degradation . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7335", "text": "The size of aquasomes ranges from 60 to 300 nanometers, hence their characterization as a nanoparticle drug carrier. [ 2 ]  The nanoscale of aquasomes gives them a high surface area to volume ratio. The smaller the core, the higher the surface area to volume ratio, which increases the drug loading capacity of the aquasome. [ 3 ]  Aquasomes possess water-like properties due to the presence of the carbohydrate coating, enabling them to protect and preserve fragile biological molecules. The size of aquasome particles increases as a function of the ratio between the concentration of the core to the coat due to the availability of free surface core particles for the coating material. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7336", "text": "The  self-assembly  process of aquasomes into their tri-layer structure is achieved by non-covalent and ionic bonds, along with physicochemical properties of their components. Calcium phosphate nanoparticles are formed before the carbohydrate coat is  adsorbed  onto the surface of the core through  electrostatic interactions . Layers are then added to the structure to achieve desired size, while  crosslinked  polymers aid in further stabilization. The  sonication  process during the reaction of  disodium hydrogen phosphate  and  calcium chloride  to prepare calcium phosphate impacts the self-assembly process of aquasomes by increasing  surface free energy  of the core prepared. This assembly process allows the design of aquasomes for specific drug delivery applications. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7337", "text": "The structure of aquasomes can contribute to controlled drug release, drug stability, and intracellular targeting of the drug. Other commonly used nanoparticle drug delivery systems include  niosomes ,  liposomes , and  vesosomes , the compositions of which contribute to different properties of the resulting nanoparticle compared to aquasomes. Niosomes are composed of non-ionic  surfactants  and bilayer structures, allowing them to encapsulate  hydrophilic  and  hydrophobic  drugs. Liposomes are composed of  phospholipids  and a similar bilayer structure to niosomes, and can deliver toxic or poorly soluble drugs. Vesosomes have a core-shell structure similar to aquasomes, but contain a lipid bilayer core and a polymer shell, while aquasomes consist of a ceramic or polymeric core and a carbohydrate coat. Vesosomes are used for encapsulating  imaging agents  and aiding in imaging techniques such as  MRI .  [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7338", "text": "The three major units of aquasomes are fabricated together according to  self-assembly , a thermodynamically driven process that organizes subunits of a system in a manner that results in the lowest  Gibbs free energy  available, known as \u0394G. Self-assembly as a mixing process offers high accuracy and control over sizes on the nanometer scale, which is especially relevant for aquasomes, which exist on this size scale. The three layers of aquasomes can be synthesized differently using a variety of techniques depending on the intended functions or desired therapeutic effects. [ 1 ]  The general scheme of aquasome fabrication involves a sequential synthesis of a  nanocrystalline  core, followed by a  polyhydroxy  coating, and finished with integration of bioactive molecules. Throughout this process, several intermittent steps are included that involve selective filtering and purification to remove byproducts while isolating the desired products for further processing. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7339", "text": "The core of an aquasome can be made from either ceramic or  polymeric  materials. Examples of such polymers include  acrylates  and  gelatin . However, because ceramic materials are more ordered due to their naturally occurring crystalline structure, they are more often preferred as the material type for the core. [ 1 ]  Some of the most common ceramic materials used in the formation of an aquasome core include  tin oxide ,  calcium phosphate , and even  diamond . Another characteristic that ceramic materials provide is enhanced binding of the carbohydrate layer due to the high  surface energy  present on the orderly surface. The binding affinity of the carbohydrate layer also reduces  surface tension  for its bond to the ceramic core. [ 2 ]  The first aquasomes fabricated with a nanocrystalline core using ceramic material are detailed in Kossovsky et al. in 1996. [ 2 ]  Calcium phosphate ceramic nanoparticles ( brushite ) were first prepared via the method of solution precipitation and  sonication . [ 2 ]  Precipitation methods are the most common techniques employed when synthesizing the core of an aquasome as they offer control over the homogeneity and purity of the precipitated products, which are important design features in the core structure. [ 1 ]  Once the cores are prepared, they are separated by  centrifugation  and then washed to remove any  salt  byproducts from the solution precipitation process. Finally, the washed cores are passed through a  Millipore filter  to selectively isolate core particles of a certain size. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7340", "text": "After synthesizing and purifying the core, the carbohydrate layer is added to its surface. Common coating materials are typically  polyhydroxy   oligomers  such as  cellobiose ,  citrate ,  lactose , and  sucrose . [ 2 ]  This layer seems to be important for the properties of aquasomes, as it influences several drug characteristics including adsorption, molecular stability, and conformation (shape), and acts as a dehydroprotectant. [ 1 ] [ definition needed ]  The addition of the carbohydrate layer to the surface of the nanocrystalline core is commonly carried out by passive adsorption through incubation [ clarification needed ]  and  sonication . Similar to the processing of the core, the carbohydrate layer is subjected to centrifugation, washing, and further sonification followed by heated air drying. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7341", "text": "Finally, the bioactive molecule of interest is loaded into the carbohydrate layer. This process typically occurs through either  lyophilization  or passive adsorption, and the fully functionalized aquasome is then characterized. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7342", "text": "Solution precipitation as a core synthesis technique produces homogenous-sized nanoparticles, which can be advantageous in controlling specific physical properties such as  surface tension  and  packing density  of the atoms in a  crystalline lattice  structure. [ 1 ]  The most common methods of characterizing nanoparticle size distribution and morphology of the core in aquasomes include  scanning electron microscopy  (SEM) and  transmission electron microscopy  (TEM). [ citation needed ]  In a study by Kommimeni et al. in 2012, researchers employed TEM to verify that the ceramic particles were spherical and also in the acceptable nano-range for aquasomes. [ 6 ]  The carbohydrate coating size can also be characterized using SEM and TEM, but  Fourier-transform infrared spectroscopy  (FTIR) is commonly utilized to check for the presence of the coat. [ citation needed ]  In a study by Kommimeni et al. in 2020, FTIR was used to confirm the presence of the coating by analyzing the IR spectra bands that correspond to the functional groups of either the core or the sugar coat. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7343", "text": "The bioactive drug loaded onto the aquasome can be characterized in a variety of ways depending on the molecular classification of the drug. In Kossovsky et al. in 1996, which studied the effect of insulin as the bioactive drug of interest, immunogold labeling was employed. Through this technique, the different binding efficiencies of carbohydrate coatings for insulin were able to be observed. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7344", "text": "The structure of aquasomes enables dual drug delivery, or the delivery of two drugs simultaneously. This practice aims to enhance the therapeutic efficiency and reduce the side effects of the drugs delivered. Such systems can be useful in treating patients suffering from multiple diseases. Challenges in dual drug delivery include independently controlling release rates of each of the drugs loaded in the system. In a 2019 study by Damera et al., aquasomes were used to deliver  bovine serum albumin  (BSA) in combination with one of three therapeutic drugs ( Coumarin 153 ,  Warfarin , and  Ibuprofen ), allowing release of a  bioactive  molecule and a  hydrophobic  drug simultaneously. [ 7 ]  Damera et al. suggested that dual drug delivery was enabled by the bioactive molecule layer of the aquasome being BSA. This BSA layer interacted with the hydrophobic therapeutic drugs, and the strength of the binding interactions was shown to affect the release behaviors of the drugs. Dual drug delivery with aquasomes thus shows promise for treatment of patients with coexisting diseases alongside  hypoalbuminemia , as the albumin from BSA can treat the hypoalbuminemia while the additional drug treats the disease. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7345", "text": "Aquasomes have been explored as carriers for  hemoglobin  throughout the body. In a 2002 study by Khopade, Khopade, and Jain, aquasomes were used to act as red blood cell substitutes with hemoglobin attached to the  oligomer  surface. Aquasomes in this application demonstrated minimal toxicity while obtaining a hemoglobin content of 80%, supplying blood and oxygen in a manner similar to regular red blood cells. [ 8 ]  Hemoglobin aquasomes with spherical  hydroxyapatite  cores have been shown to retain oxygen- affinity  and  cooperativity  for 30 days in rats in vivo, causing no red blood cell  hemolysis  or  blood coagulation , demonstrating potential capability as effective oxygen transporters. Additionally, aquasomes protected hemoglobin from degradation while maintaining hemoglobin function. Future exploration of aquasomes as hemoglobin carriers may explore controlled release of the aquasomes themselves to mimic typical oxygen release properties to aid in biomedical applications that require specific targeting and delivery of hemoglobin. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7346", "text": "Aquasomes with  calcium phosphate  ceramic cores may be useful for the pharmaceutical administration of substrates such as  insulin  where drug action is  conformationally specific . In a 2000 study by Cherian et al.,  disaccharides  such as  trehalose  were used to coat the core before insulin was loaded onto the coated cores via  adsorption . [ 9 ]  Albino rats were used as test subjects to test these aquasome insulin formulations, and the efficiency of different carbohydrate coat molecules on the aquasome was explored.  Pyridoxal-5-phosphate -coated particles were shown to lower blood glucose levels more efficiently when compared to trehalose- or  cellobiose -coated particles, which may be due to their differences in structural stability. [ 9 ]  The use of these nanoparticles for the delivery of insulin in vivo in rabbits demonstrated that insulin-bearing aquasomes showed slower release and prolonged activity compared to standard insulin solution. [ 9 ]  Similar to their role in carrying hemoglobin, the carbohydrate layer of aquasomes may be responsible for the ability to protect insulin from degradation when injected subcutaneously as in the albino rats tested. Aquasomes were also shown to release insulin in controlled manners, mimicking the typical release of insulin from the  pancreas . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7347", "text": "A potential challenge of aquasome-based drug delivery could be toxicity due to burst release of drugs if poorly absorbed on the carbohydrate coat. [ 1 ]  Aquasomes can also be expensive to formulate, particularly due to their step-by-step synthesis. Careful attention is needed during aquasome production to tune the thickness of each layer, and  leaching  and  aggregation  may occur during prolonged storage of aquasomes. A physiological challenge aquasomes present is that upon their entry into the bloodstream, they may be taken up nonspecifically, [ definition needed ]  leading to  opsonization  and  phagocytic clearance  by the immune system. To prevent this, aquasome surfaces can be coated with  polyethylene glycol  (PEG) to block  opsonin  binding through  steric hindrance ; however, the effect of PEGylation on aquasome drug release has not been sufficiently explored to enable clinical applications. [ 1 ]   Polymer degradation  in different physiological environments can change the stability and drug loading of aquasomes over time, as their surface properties directly impact drug release. Aquasomes may also be challenging to scale up and prepare as it is difficult to ensure consistent formulation quality. More research is needed to demonstrate both the efficiency and safety of aquasomes in clinical use. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7348", "text": "Further advances in aquasome research require additional investigation of their  in vivo  drug release and targeting. Applications such as delivery of  dithranol  for the treatment of  psoriasis  and oral delivery of  bromelain  for the treatment of inflammatory diseases such as cancer show promising results  in vitro  and  ex vivo . However, such applications have been unexplored in vivo, limiting their clinical use. Applications using aquasomes as carriers of hemoglobin, vaccines, and insulin have been tested in vivo in small animal models such as rats, mice, and rabbits, but current literature lacks in vivo testing in more advanced animal models, preventing their use as treatments for human conditions. Aquasomes are promising drug delivery mechanisms due to their ability to stabilize and transport a variety of substrates while allowing for controlled drug release. Prior to expanding the clinical applications of aquasomes, the gap existing in current literature will need to be filled by further investigating immune clearance of aquasomes, exploring additional surface modifications such as PEGylation, and expanding in vivo drug testing. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7349", "text": "An  autoinjector  (or  auto-injector ) is a  medical device  for injection of a premeasured  dose  of a particular  drug . Most autoinjectors are one-use,  disposable ,  spring -loaded  syringes  ( prefilled syringes ). By design, autoinjectors are easy to use and are intended for self-administration by patients, administration by untrained personnel, or easy use by healthcare professionals; they can also overcome the hesitation associated with self-administration using a needle. [ 1 ]  The site of injection depends on the drug, but it typically is administered into the  thigh  or the  buttocks . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7350", "text": "Autoinjectors are  sharps waste . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7351", "text": "Automatic syringes are known since  the 1910s, [ 2 ]  and many spring-loaded devices with needle protectors were patented in the first half of the 20th century, [ 3 ]  but it was not until 1970s when they became economically feasible to mass-produce (simple  syrettes  were used instead before). In 2023 an  open source  autoinjector was developed that could be digitally replicated with a low cost desktop  3D printer . [ 4 ]  It was tested against the then current standard (ISO 11608\u20131:2022) [ 5 ]  for needle-based injection systems and found to cost less than mass manufactured systems. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7352", "text": "Designs exist for both  intramuscular  and  subcutaneous injection . Disposable autoinjectors commonly use a pre-loaded spring as a power source. This spring and the associated mechanical components form a one-shot  linear actuator . [ citation needed ]  When triggered the actuator drives a three-step sequence: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7353", "text": "Some injectors are triggered by simply pushing the nose ring against the injection site. In these designs, the protective cap is the primary safety. Other designs use a safety mechanism similar to  nail guns : The injection is triggered by pushing the nose ring against the injection site and simultaneously, while applying pressure, pushing a trigger button at the rear end of the device. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7354", "text": "Since spent autoinjectors contain a  hypodermic needle , they pose a potential biohazard to waste management workers. Hence the protective cap is designed not only to protect the drug and keep the needle  sterile  but also to provide adequate sharps waste confinement after disposal. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7355", "text": "Injectors intended for application through layers of clothing may feature an adjustable injection depth. Other typical features include: A drug inspection window, a color-coded spent indicator, and an audible click after the injection has finished. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7356", "text": "Military uses include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7357", "text": "Another design has a shape and size of a  smartphone  which can be put into a pocket. This design also has a retractable needle and automated voice instructions to assist the users on how to correctly use the autoinjector. The \"Auvi-Q\" epinephrine autoinjector uses this design. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7358", "text": "A newer variant of the autoinjector is the gas  jet autoinjector , which contains a cylinder of pressurized gas and propels a fine jet of liquid through the skin without using a needle. This has the advantage that patients who fear needles are more accepting of using these devices. The autoinjector can be reloaded, and various doses or different drugs can be used, although the only widespread application to date has been for the administration of  insulin  in the treatment of  diabetes . [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7359", "text": "The  bifurcated needle  is a narrow steel rod, approximately 5\u00a0cm (2\u00a0in) long with two prongs at one end. [ 1 ]  It was designed to hold one dose of reconstituted freeze-dried  smallpox vaccine  between its prongs. [ 2 ]  Up to one hundred vaccinations can be given from one vial of the reconstituted vaccine. The established technique for smallpox vaccination is to dip the needle in the vaccine, and then perpendicularly puncture a person's upper arm fifteen times rapidly in a small circular area. Though skin in the area should be clean, use of an alcohol swab is optional and if used the skin must be allowed to fully dry to avoid deactivation of the live virus vaccine. The punctures should remain in an area approximately 5 mm in diameter. The needle is then disposed of. When done correctly a trace of blood appears at the vaccination site within 10 to 20 seconds after the procedure. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7360", "text": "The bifurcated needle was created as a more efficient and cost effective alternative to the  jet injector  previously in use. It was invented in 1965 by Dr.  Benjamin Rubin , working at Wyeth Laboratories, and was the primary instrument used during the  World Health Organization 's 1966\u20131977 campaign to  eradicate smallpox . [ 5 ]  Rubin estimated that it was used to administer 200 million vaccinations per year during the final years of the campaign. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7361", "text": "Bioprinting drug delivery  is a method for producing  drug delivery  vehicles. It uses  3D printing  of  biomaterials . Such vehicles are biocompatible, tissue-specific  hydrogels  or implantable devices. 3D bioprinting prints cells and biological  molecules  to form tissues, organs, or biological materials in a scaffold-free manner that mimics living human tissue. The technique allows targeted disease treatments with scalable and complex geometry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7362", "text": "This technique was first developed in the 1950s as patients with incurable diseases sought  organ transplantations  beyond those available from donors. Organ transplantation showed limitations with immune responses and organ rejection. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7363", "text": "Techniques that have been studied include bioprinting hydrogels with various  bio-ink  (cell-laden microgel) materials and bioprinting implantable devices that mimic specific tissues or biological functions. Applications include promoting wound healing by delivering  antibiotics , anti-inflammatory treatments, or drugs that promote  cell differentiation  and  cell proliferation , providing anticancer treatments directly to tumors, and promoting/inhibiting  angiogenesis  and  vascularization  to treat cancer, arterial diseases, heart diseases, and arthritis. In addition, implants can be printed in unique shapes and forms to deliver drugs directly to targeted tissues. One approach adds a fourth dimension, which allows the materials to conform, by folding/unfolding, to release drugs in a more controlled manner. Bioprinting allows for biocompatible, biodegradable, universal, and personalized delivery vehicles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7364", "text": "Layer-by-layer printing of biochemicals and living cells requires precise placement and viable materials. The basic technology of a bioprinter starts with data taken from  computer-assisted design  ( CAD ) or a similar program, uses motion control systems to control the X/Y/Z axis direction drive mechanisms along with a material control system for the bio-ink printhead, and deposits material into a 3D construct. [ 2 ]  Bioprinting can be done by material jetting, material extrusion, or vat polymerization. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7365", "text": "Material jetting, sometimes referred to as  fused deposition modeling  (FDM), is a method that involves depositing cells using  piezoelectric /thermal ink-jetting, acoustic wave jetting,  electrohydrodynamic jetting , or laser-induced forward transfer (LIFT). [ 3 ]  Piezoelectric/thermal ink-jetting uses the same non-contact process as desktop  inkjet printers  by pressuring material into a nozzle that expels droplets. Acoustic wave jetting uses acoustic radiation force to produce droplets; electrohydrodynamic jetting uses electric voltage to form droplets; and LIFT is replaces nozzles with a laser and generates a high-pressure bubble that propels droplets. [ 3 ]  These methods provide precise placement of the bioink and enable scaffold-free bioprinting."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7366", "text": "Another method of bioprinting is extrusion. This is a mechanical method that uses motors to drive a piston. Extrusion is based on the rate of the motor's displacement, where the difference between the piston-driven pressure and  ambient pressure  drives the material through an angular turn of a rotary screw. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7367", "text": "Vat polymerization printing (VPP) uses a cell-hydrogel suspension. The constructs are formed layer-by-layer through laser curing in  stereolithography  (SLA) or UV  digital light processing  (DLP) into the vat of a photopolymer using a micromirror device. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7368", "text": "Hydrogels  are three-dimensional polymeric networks that can maintain their structure while absorbing large amounts of water or biological fluids. Hydrogels can be made of many different synthetic polymers or natural polysaccharides. These have been widely studied due to their similarities to the human  extracellular matrix  (ECM) and their ability to encapsulate drugs. They are mainly printed using jetting and extrusion. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7369", "text": "A common polysaccharide used in biomedical hydrogel applications is  alginate , a naturally occurring polyanionic  copolymer . [ 1 ]  The structure and high water absorption of alginate provides a tissue environment that closely mimics human soft tissue. In addition, it is an ideal candidate for biomedical applications due to its natural biodegradability and biocompatibility. This hydrogel leverages the delivery of drugs, protects drugs with encapsulation, and allows for tunable drug release and degradability"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7370", "text": "To construct alginate hydrogels, a series of negatively and positively charged polyelectrolytes are assembled layer-by-layer. Alginate is used as the matrix in bio-ink that is extruded from the bioprinter's syringe with increasing shear, resulting in a tough hydrogel with low  viscosity . Depending on the surrounding medium, alginate has the potential to form two different types of gels. Low-pH alginate shrinks and produces a viscous acidic gel, holding onto encapsulated drugs. Once the pH increases, such as inside an intestinal tract, alginate turns into a viscose gel that allows drug dissolution and release. This process allows for a controlled and sustained release to specific tissues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7371", "text": "One 2018 study used alginate-based hydrogels combined with the growth factor  platelet-rich plasma  (PRP) to develop a bio-ink with personalized biological factors. The plasms was extracted from specific patients, then mixed with the alginate solution. The solution was coated with  calcium chloride   agarose  gel. The result was a hydrogel disk that had decreased the risk of immune responses from the patient. The disk showed potential for promoting  mesenchymal stem cells  and  endothelial  cells in tissue healing. The study reported that PRP and alginate hydrogel bio-ink could be used by any bioprinter to produce personalized drug delivery therapies. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7372", "text": "The hydrogel can be loaded with any drug, and target any tissue. The low toxicity and controllable factors of alginate make it a suitable candidate for hydrogel incorporation. Alginate hydrogels have been used to deliver  bortezomib , an anticancer drug,  tetracycline hydrochloride  and  silver sulfadiazine , which are hydrophobic antibiotics, and  simvastatin , which promotes local stem cell differentiation. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7373", "text": "Another bio-ink is low molecular weight self-assembling  peptide -based materials. Peptide-based hydrogels are candidates for bio-inks since they resemble the ECM. In addition, their mechanical strength and stiffness of up to 40 kPa allow for strong and rigid hydrogels. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7374", "text": "A 2019 study used the \"helical coiling of  micelles  induced by disulfide crosslinking in a lyotropic peptide  liquid crystal \" to produce a printable hydrogel. They reported that the tripeptide self-assembled into a viscous solution of aligned micelles at high pH values that could be transformed into a self-supporting hydrogel when the cross-linking of the  sulfhydryl  group of the side chain peptides increased the  storage modulus  of the solution. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7375", "text": "These self-assembling peptides provide beneficial organization and strength. In addition, their resemblance to the native cellular microenvironment and tunable mechanical strength allow them to support the proliferation of human stem cells. Using self-assembling peptides to print hydrogels provides drug delivery vehicles that represent the ECM and potentially differentiate primary cells into organotypic structures and deliver antimicrobial, anti-inflammatory, anticancer, and wound healing drugs. [ 6 ] [ 7 ]  Specifically, hydrogels made of such peptides have been studied to encapsulate  chemotherapy  drugs that can disassemble and release the loaded drug under the stimulation of tumor environments, providing an alternative to typical chemotherapy that inevitably damages healthy cells, while killing cancer cells. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7376", "text": "Common protein-based bio-inks include  collagen ,  keratin ,  gelatin , and silk. These proteins are advantageous since they are in the ECM and display good cytocompatibility, biocompatibility, and biodegradability. They are all derived from natural sources, are isolated with different methods, and have various advantages and disadvantages. Collagen is typically printed using extrusion or SLA and provides good structural responses and esion for cells. [ 9 ] [ 10 ] [ 11 ]  Silk is printed using digital light processing, and provides strength and robustness. One disadvantage of silk is its potential to conform in response to high shear forces. [ 9 ] [ 10 ] [ 11 ] [ 12 ]  Gelatin is printed using extrusion and provides good cellular affinity, however, its covalent crosslinking-based stabilization requires chemical reactions that are not cytocompatible. [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ]  Overall, protein-based bio-inks are abundant, inexpensive, biocompatible, and biodegradable, and are in common use for 3D bioprinting. Advantages of protein-based bio-inks over synthetic bio-inks include their similarity to human host tissue and their ability to match their degradation rate with the regeneration of host tissue."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7377", "text": "Multiple protein applications use bio-inks for 3D printing. A 2014 study bioprinted cell-laden methacrylated gelatin (GelMA) hydrogels at concentrations ranging from 7 to 15% with varying cell densities. [ 14 ]  The study used \"direct-write bioprinting of cell-laden photolabile ECM-derived hydrogels\". [ 14 ]  They reported a direct correlation between printability and hydrogel mechanical properties. A commercially available bioprinter dispensed the GelMA hydrogel fibers using  digital light processing  since GelMA is  photosensitive . The hydrogels provided cell viability for at least eight days. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7378", "text": "Other research includes gelatin-sulfonated skin composite tissue to deliver cells to open wounds by seeding matrices. [ 15 ] [ 16 ]  Doing this helps wounds to heal faster and more efficiently. Gelatin hydrogels have successfully delivered  fluorescein , a hydrophobic molecule, and  microRNA  to promote  osteogenic  cell differentiation. [ 13 ]  Silk has successfully delivered  aspirin , an anti-inflammatory drug that aids in wound dressing, and  gentamicin , an antibiotic that also aids in wound dressing. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7379", "text": "Another bio-ink that has been successful in producing drug delivery systems via bioprinting is cellulosic nanomaterials.  Cellulose -based bio-inks are accessible, inexpensive, biodegradable, biocompatible, and stiff. A polysaccharide is obtained from the biosynthesis of plants and bacteria. It is extracted from raw materials with mechanical shearing actions and biological treatments, such as  hydrolysis , resulting in highly structured nanofibrils. Cellulose materials are defined by their high viscosity and shear-thinning behavior. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7380", "text": "One 2015 study used nanocellulose bio-inks as wound dressings. Extrusion produced porous structures with ionic  calcium chloride  cross-linking. These porous hydrogels were reported to support bacterial growth and incorporate and release antimicrobial drugs. These structures provide strong, moist environments that are ideal for delivering drugs to tissues that require wound healing aid. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7381", "text": "Non-hydrogel delivery systems implants are printed in the same manner as hydrogels. A 2022 study used SLA 3D printing to produce an implant to deliver drugs to the ear. 0.5%  levofloxacin  was added to a flexible resin. Mechanical and  in vitro  tests measured levofloxacin release. The results showed no interaction between the resin and the drug, the resistance of the implant without compromise, and high antimicrobial activity. Antibiotics were delivered directly to the inner ear to address infection. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7382", "text": "Researchers studied a printed bladder device for intravesical drug delivery. [ 20 ]  Intravesical instillation provides an alternative to oral medication and delivers high drug concentrations to specific sites. Studies reported the use indwelling bladder devices with an elastic polymer bio-ink to deliver  lidocaine hydrochloride  directly to the target site."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7383", "text": "One study deposited perfusable vascular structures with a cell-responsive bio-ink that consisted of GelMA, sodium alginate, and poly(ethylene glycol)-tetra-acrylate (PEGTA). [ 21 ]  The study reported that this supported the spreading and proliferation of encapsulated endothelial and stem cells, leading to the formation of perfusable vessels. These may lead to the application of vascularized tissue constructs in organ transplantation and repair. Bioprinting vascular structures may lead to treatments for cancer, arterial disease, heart disease, and arthritis by regulating vascularization and  angiogenesis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7384", "text": "Cellulose nanofibrils have been used as a bio-ink for non-hydrogel applications. A 2017 study evaluated the use of bioprinting cellulose as drug-loaded implants. Researchers used FDM to evaluate drug release behavior. Fluorescent dye quinine was used to visualize the distribution of drugs in the implants. Quinine filaments were loaded into bio-printed cellulose implants and then incubated to observe their drug-release behaviors. The study reported showed that around 5% of the quinine was released from the cellulose implant over 100 days. Using cellulose nanofibrils might provide implants with customizable shapes and controlled release of loaded drugs via FDM. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7385", "text": "One study added a fourth dimension to the devices, which allows printed objects to change their shapes and functions as external factors are applied, broadening the range of biomedical applications as cellular self-organization becomes possible. [ 23 ]  This technique allows for more advanced control of drug release. Studies have reported results in the use of responsive materials and bio-inks. Responsive materials can reshape in response to stimuli, such as transforming via self-folding, assembling, and disassembling. Certain bio-inks have been reported to undergo maturation with cellular coating, self-organization, and matrix deposition."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7386", "text": "Examples include a self-folding hydrogel  in vitro  model for  ductal carcinoma . [ 24 ]  The study attempted to create a self-folding curved hydrogel microstructure to mimic the geometry of ducts and  acini  within  mammary glands . The researchers used microstructures composed of poly(ethylene glycol)-diacrylate (PEGDA) and copolymerized the PEGDA to synthesize microstructures with increased cell adherence. Curved and tubular structures were fabricated via bioprinting, and the proliferation of cells on the outer surface, along with encapsulation of cells on the inner surface, was observed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7387", "text": "4D printing with thermally actuating hydrogels was reported to be relatively fast and reversible with skeletal muscle-like linear actuation in tough hydrogel materials that control the flow of water. [ 25 ]  Other examples include the usage of water absorption [ 26 ]  and thermal shape memory [ 27 ]  to demonstrate shape change. A 2015 study considered a 4D-printed capsule system that could release drugs on-demand at specific locations with a core-shell hydrogel. [ 28 ]  A 2014 study evaluated thermo-responsive poly(propylene fumarate) (PPF)-based system that released drugs in a controlled manner for treating the gastrointestinal tract. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7388", "text": "A  bong  (also known as a  water pipe ) is a filtration device generally used for smoking  cannabis ,  tobacco , or other herbal substances. [ 1 ]   In the bong shown in the photo, the smoke flows from the lower port on the left to the upper port on the right."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7389", "text": "In construction and function, a bong is similar to a  hookah , except smaller and especially more portable. A bong may be constructed from any air- and water-tight vessel by adding a bowl and stem apparatus (or slide) [ 2 ]  which guides air downward to below water level whence it bubbles upward (\"bubbler\") during use. To get fresh air into the bong and harvest the last remaining smoke, a hole known as the \"carburetor\", \"carb\", \"choke\", \"bink\", \"rush\", \"shotty\", \"kick hole\", or simply \"hole\", somewhere on the lower part of the bong above water level, is first kept covered during the smoking process, then opened to allow the smoke to be drawn into the respiratory system. On bongs without such a hole, the bowl and/or the stem are removed to allow air from the hole that holds the stem."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7390", "text": "Bongs have been in use by the  Hmong  in  Laos  and  Thailand , as well all over Africa, for centuries. [ 3 ]  One of the earliest recorded uses of the word in the West is in the McFarland Thai-English Dictionary, published in 1944, which describes one of the meanings of  bong  in the Thai language as, \"a bamboo waterpipe for smoking kancha, tree, hashish, or the hemp-plant\". A January 1971 issue of the  Marijuana Review  also used the term."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7391", "text": "The word  bong  is an adaptation of the  Thai  word  bong  or  baung  ( Thai :  \u0e1a\u0e49\u0e2d\u0e07 ,  [b\u0254\u0302\u014b] ), which refers to a cylindrical  wooden  tube,  pipe , or  container  cut from  bamboo , and which also refers to the bong used for smoking."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7392", "text": "Excavations of a  kurgan  in Russia in 2013 revealed that  Scythian  tribal chiefs used gold vessels 2400 years ago to smoke cannabis and opium. The kurgan was discovered when construction workers were clearing land for the construction of a power line. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7393", "text": "During the reign of  Emperor Akbar , physician Hakim Abul Fath invented the waterpipe in  India , and discovered tobacco. Abul suggested that tobacco \"smoke should be first passed through a small receptacle of water so that it would be rendered harmless\". [ 5 ]  Other sources also show evidence of the invention of the waterpipe in  China  during the late  Ming dynasty  (16th century), along with tobacco, through Persia and the  Silk Road . [ citation needed ]  By the  Qing dynasty , it became the most popular method to smoke tobacco, but became less popular since the Republic era. While typically employed by commoners, the water pipe is known to have been preferred by  Empress Dowager Cixi  over snuff bottles or other methods of intake. According to the  Imperial Household Department , she was buried with at least three water pipes; some of her collections can be seen in the  Palace Museum ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7394", "text": "The water pipe employed since the Qing dynasty can be divided into two types: the homemade bamboo bong commonly made and used by country people, and a more elegant metal version employed by Chinese merchants, urbanites, and nobility. Metal utensils are typically made out of bronze or brass, the nobility version of silver and decorated with jewels. Typically, the metal version is made out of the following components:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7395", "text": "During a smoking session, the user may keep all equipment inside the rack and just hold the entire assembly (rack, pipe, and container) in one hand, lighting the bowl with a slow-burning paper wick (\u7eb8\u7164) lit over a coal stove.\nUnlike in North America and the Southern Hemisphere, the water pipe is typically employed by older generations. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7396", "text": "The water can trap some heavier particles and water-soluble molecules, preventing them from entering the smoker's airways. [ 6 ]  The mechanics of a bong are compared to those of a laboratory  gas washing  bottle. The user puts their mouth at the top and places the cannabis in the tube, as shown in the picture."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7397", "text": "Bongs are often either  glass  or  plastic  that use a bowl, stem, and water to produce smoke. Most glass bongs are made from heat resistant  borosilicate glass , allowing the bong to withstand repeated use and heat exposure without breaking. After the bowl has been packed and water has been inserted into the bong, the substance is lit and the smoke is drawn through water to produce a smoother smoke than other methods of smoking do. [ 7 ]  To smoke a bong, the smoker must inhale in the bong so bubbles containing smoke begin to come from the stem. Once the bong has a fair amount of smoke built up, either the carb is uncovered or the stem is separated from the bong, allowing the remaining smoke to be inhaled."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7398", "text": "However, a 2000  NORML - MAPS  cannabis study found that \"water pipes filter out more psychoactive  THC  than they do other tars, thereby requiring users to smoke more to reach their desired effect\". [ 8 ]  In the study, smoke from cannabis supplied by the  NIDA  was drawn through a number of smoking devices and analyzed. This study looked at the tar to cannabinoid ratio in the gas in output by various bongs, as well as unfiltered and filtered joints, and vaporizers. The results showed that only vaporizers produced a better tar to cannabinoid ratio than unfiltered joints, but that within the cannabinoids produced, even vaporizers warped the ratio of THC (the psychoactive component of the smoke) to  CBN  (capable of producing medical benefits but is not psychoactive) in favor of CBN. This showed an unfiltered joint had the best tar to THC ratio of all, and bongs were actually seriously detrimental in this respect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7399", "text": "MAPS [ 9 ]  also reviewed a study that examined the effects and composition of water-filtered and non-filtered  cannabis  and  tobacco smoke . It found that when  alveolar   macrophages  were exposed to unfiltered smoke, their ability to fight bacteria was reduced, unlike exposure to water-filtered smoke. It also found substantial epidemiological evidence of a lower incidence of  carcinoma  among tobacco smokers who used water-pipes, as opposed to  cigarettes ,  cigars , and regular  pipes . \"It appears that water filtration can be effective in removing components from cannabis smoke that are known toxicants... The effectiveness of toxicant removal is related to the smoke's water contact area.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_7400", "text": "Specially designed water pipes, incorporating particulate filters and gas-dispersion  frits , would likely be most effective in this regard; the gas-dispersion frit serves to break up the smoke into very fine bubbles, thereby increasing its water-contact area. [ 9 ]  These frits are commonly referred to as  diffuser  for the way that they diffuse (or disperse) the smoke as it exits the downstem, and usually consist of small holes or slats at the end of the downstem. This study suggests that a bong's smoke is less harmful than unfiltered smoke."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7401", "text": "Bongs that are cleaned regularly eliminates yeast, fungi, bacteria and pathogens that can cause several symptoms that vary from allergy to lung infection. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7402", "text": "It has been reported that it is possible to taste the chemicals in the water from a plastic water bottle left sitting in a hot car because \"...chemicals have leached into the contents of the bottle.\" [ 11 ]  It was also reported that it is possible to imagine that this process of chemicals leaching into water occurring with \"...a homemade water bottle bong where the bottle is routinely heated up.\" [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7403", "text": "It was also reported that \"According to  Cancer Research UK , plastic bottles heated up to 60\u00b0C contain unhealthy levels of toxic chemicals.\" [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7404", "text": "In the  United States , under the Federal Drug Paraphernalia Statute, which is part of the  Controlled Substances Act , it is illegal to sell, transport through the mail, transport across state lines, import, or export drug paraphernalia. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7405", "text": "In countries where marijuana and hashish are illegal, some retailers specify that bongs are intended for use with tobacco in an attempt to circumvent laws against selling drug paraphernalia. While technically \"bong\" does not mean a device used for smoking mainly cannabis, drug-related connotations have been formed with the word itself (partly due to punning with Sanskrit  bhangah  \"hemp\"). Thus for fear of the law many  head shops  will not serve customers who use the word \"bong\" or \"bongs\", or any other word typically associated with illegal drug use. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7406", "text": "Some  brand name  bong manufacturers (notably RooR) have sought to curb the  counterfeit  market for their products by suing stores accused of selling fake merchandise. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7407", "text": "Breast milk-mediated drug delivery  refers to the use of  breast milk  to transport a pharmaceutical compound, protein, or other treatment to achieve a desired effect. Delivery of these substances via milk provides an oral alternative for transport of a compound to the gut, specifically in infants. Breast milk-mediated drug delivery provides a way for pharmaceuticals and proteins to travel through the  gastrointestinal system  of an infant while minimizing the potential for irritation within gastrointestinal tissue."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7408", "text": "There are multiple routes that a treatment can enter into the breast milk. One route is through a  breastfeeding  mother. When a mother that is  lactating  receives a treatment including but not limited to  prescription medication ,  over-the-counter medications , or  herbal remedies , these compounds can make their way into the mother\u2019s milk and are subsequently delivered to an infant via breastfeeding. [ 1 ]  The amount of treatment transferred into the milk depends on the substance, but it is noted that these compounds can have an effect on the infant consuming the breast milk. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7409", "text": "A common method for intended addition of treatment into breast milk involves the use of donor breast milk in combination with the compound of interest for treatment. Addition of  antibiotics ,  oligosaccharides ,  cytokines , or selected proteins into donor breast milk for consumption can have a variety of effects on the patient consuming it, typically an infant. [ 2 ] [ 3 ] [ 4 ]  This method has also been studied for use in adults, specifically for the delivery of poorly water-soluble drugs. [ 5 ] [ 6 ]  While this method allows for the highest level of modularity among breast milk treatments, the effects of these treatments on various factors such as the  microbiome  of the milk base must be acknowledged to limit potential side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7410", "text": "Other novel technologies for drug delivery via breast milk involve the use of external objects to mediate the addition of compounds into the milk being consumed. One of these technologies is a  nipple shield . A nipple shield is placed onto the nipple of a breastfeeding mother, releasing treatment into the milk as the mother breastfeeds an infant. [ 7 ]  Many of these novel technologies still require testing for efficacy and safety before any potential commercial application."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7411", "text": "Breast milk fortification refers to the addition of nutrients such as proteins, oligosaccharides, or cytokines into breast milk to supplement the natural contents of the milk. [ 2 ] [ 3 ] [ 4 ]  This practice is common in babies that have been born prematurely, with a major goal of this practice being growth promotion. [ 8 ]  These infants do not receive enough nutrients for proper growth and development from a normal breastfeeding regimen, potentially leading to neural and/or cognitive impairment. [ 8 ] [ 9 ]  Thus, supplementation of breast milk with proteins, calcium, phosphate, and other nutrients can help to remedy this issue. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7412", "text": "Studies have shown that human milk fortification can improve the short-term growth of infants, though future research is needed to determine long term growth effects. [ 10 ]  There is variation with results from case to case, however. The nonstandard concentration of proteins across different mothers\u2019 breast milk can lead to issues when pinpointing the amount of nutrients an infant is receiving. [ 8 ]  While there is a standard fortification level used in most cases, \u201cAdjustable Fortification and \u201cTargeted Fortification\u201d are being researched as ways to provide targeted individual fortification to suit the needs of each individual being treated. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7413", "text": "One particular compound that can be used to fortify breast milk is  Human Milk Oligosaccharide . These prebiotics are found naturally in human breast milk, and provide a variety of health benefits to newborns, including modulation of the immune system, fighting  viral infections , and promoting epithelial cell maturation. [ 3 ]  These prebiotics, which have been confirmed to be safe and tolerable for infants, are a leading candidate for breast milk fortification."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7414", "text": "Antibiotics can be added into breast milk as a preventative measure for the development of infections such as Subsequent Late Onset Sepsis and Necrotizing Enterocolitis. [ 11 ]  Antibiotic treatment is a very common treatment for premature babies, though dosing regimen and treatment length tend to be \u201carbitrary\u201d. [ 11 ]  While potentially detrimental to the health of the gut microbiome if given in excess, the administration of antibiotics within breast milk can help to prevent infection in newborns. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7415", "text": "Antibiotics are used as the most common treatment for prematurely born infants in  Neonatal Intensive Care Units  \u2013 used as a preventative measure for infection. These treatments usually contain empirical antibiotics and are often given to infants that do not show signs of  bacterial infection . [ 13 ]  Studies are currently being performed to determine the optimal length of treatment for infants to prevent infection while maintaining gut health, specifically in the microbiome. [ 11 ] [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7416", "text": "Stability of milk-drug formulations is another factor that contributes to the effectiveness of antibiotic addition into breast milk. Many orally delivered antibiotics show poor solubility in aqueous environments, leading to increased research into lipid-based drug delivery systems. [ 6 ]  Milk formulations, which contain varying levels of natural lipids, have been shown to increase delivery efficacy of antibiotic compounds, while maintaining stability and integrity of the colloidal structure that makes up milk. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7417", "text": "Addition of carefully selected compounds into breast milk have been shown to not only stimulate growth within an infant, but also help to prevent infections from forming, specifically in the gut. Babies born very prematurely are at high risk for these infections, particularly  necrotizing enterocolitis . [ 14 ]  Necrotizing enterocolitis is an intestinal condition that develops in some premature babies, and is characterized by  inflammation , bacterial infection, potential intestinal injury, and in extreme cases, death. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7418", "text": "The development of necrotizing enterocolitis has also been linked to the microbiome of the gut in the affected population. [ 11 ] [ 12 ]  High levels of antibiotic administration have been shown to reduce the variety of bacteria present within the gut microbiome, and this lower level of diversity found in these infants can increase their susceptibility to necrotizing enterocolitis. [ 11 ]  Studies have indicated that time of administration of antibiotics as well as type of antibiotic can impact the incidence of the condition. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7419", "text": "Prevention of necrotizing enterocolitis in premature infants is mainly achieved through the addition of predetermined compounds into donor breast milk that is fed to premature infants at risk for the condition. Compounds such as  immunoglobulins  have been shown to reduce Necrotizing Enterocolitis incidence, as well as severity in those that still develop the condition. [ 2 ]  Studies have shown that the addition of  IgA  and  IgG  into a premature infant\u2019s feed can lower the incidence of the disease in the population of infants that are at the highest risk for the condition (very premature, low birth weight). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7420", "text": "One of the main issues surrounding breast milk-mediated drug delivery is the uncertainty of the composition of the milk acting as the vessel for the treatment. Since every breastfeeding mother experiences different external conditions such as diet and environment, as well as differences in genetics, breast milk from every mother will have a different composition, making it difficult to create replicable treatments from infant to infant. [ 8 ]  Donor breast milk encounters this same issue, with infant formula acting as a potential avenue for stabilization of treatment levels."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7421", "text": "Improper administration of antibiotics into an infant\u2019s gastrointestinal system can increase the susceptibility of infants to gut infections. This is due to the lowered diversity and viability of organisms found within the gut, also known as the microbiome. [ 11 ] [ 12 ]  Especially prevalent in  preterm infants , this deviation from a healthy microbiome can lead to adverse effects during the beginning of an infant\u2019s life. These infants may be predisposed to conditions such as Necrotizing Enterocolitis due to higher growth of pathogenic bacteria within the gut, as well as a lower count of commensal bacteria growth. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7422", "text": "New breast milk-mediated therapies are still in development, aiming to take advantage of properties that are unique to this form of treatment. One such technology is the use of  exosomes  found in milk to transport molecules such as  mRNA ,  DNA , and proteins to an area of interest. [ 15 ]  This research proposes the use of milk, as a scalable source of exosomes for a method of targeted drug delivery with higher efficacy than standard oral methods. [ 15 ]  These novel therapies may provide a way to achieve a low-cost method to deliver drugs with poor water solubility into the body, with potential use as a low-cost alternative. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7423", "text": "Cell encapsulation  is a possible solution to  graft rejection  in tissue engineering applications.  Cell  microencapsulation  technology involves  immobilization  of cells within a polymeric  semi-permeable membrane . It permits the bidirectional  diffusion  of molecules such as the influx of oxygen, nutrients,  growth factors  etc. essential for cell  metabolism  and the outward diffusion of waste products and  therapeutic  proteins.  At the same time, the semi-permeable nature of the membrane prevents immune cells and  antibodies  from destroying the encapsulated cells, regarding them as foreign invaders."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7424", "text": "Cell encapsulation could reduce the need for long-term use of  immunosuppressive drugs  after an  organ transplant  to control side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7425", "text": "In 1933 Vincenzo Bisceglie made the first attempt to encapsulate cells in polymer membranes. He demonstrated that  tumor  cells in a polymer structure transplanted into pig  abdominal  cavity remained viable for a long period without being rejected by the  immune system . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7426", "text": "Thirty years later in 1964, the idea of encapsulating cells within ultra thin polymer membrane microcapsules so as to provide immunoprotection to the cells was then proposed by  Thomas Chang  who introduced the term \" artificial cells \" to define this concept of bioencapsulation. [ 2 ]  He suggested that these artificial cells produced by a drop method not only protected the encapsulated cells from immunorejection but also provided a high surface-to-volume relationship enabling good mass transfer of oxygen and nutrients. [ 2 ] \nTwenty years later, this approach was successfully put into practice in small animal models when alginate-polylysine-alginate (APA) microcapsules immobilizing xenograft  islet  cells were developed. [ 3 ]  The study demonstrated that when these microencapsulated islets were implanted into  diabetic  rats, the cells remained viable and controlled  glucose  levels for several weeks.\nHuman trials utilising encapsulated cells were performed in 1998. [ 4 ] [ 5 ] [ 6 ]  Encapsulated cells expressing a cytochrome P450 enzyme to locally activate an anti-tumour prodrug were used in a trial for advanced, non-resectable pancreatic cancer. Approximately a doubling of survival time compared to historic controls was demonstrated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7427", "text": "Questions could arise as to why the technique of encapsulation of cells is even required when therapeutic products could just be injected at the site. An important reason for this is that the encapsulated cells would provide a source of sustained continuous release of therapeutic products for longer durations at the site of implantation. Another advantage of cell microencapsulation technology is that it allows the loading of non-human and genetically modified cells into the polymer matrix when the availability of donor cells is limited. [ 7 ]  Microencapsulation is a valuable technique for local, regional and oral delivery of therapeutic products as it can be implanted into numerous tissue types and organs. For prolonged  drug delivery  to the treatment site, implantation of these drug loaded  artificial cells would be more cost effective in comparison to direct drug delivery. Moreover, the prospect of implanting artificial cells with similar chemical composition in several patients irrespective of their leukocyte antigen could again allow reduction in costs. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7428", "text": "The potential of using cell microencapsulation in successful clinical applications can be realized only if several requirements encountered during the development process are optimized such as the use of an appropriate  biocompatible  polymer to form the mechanically and chemically stable semi-permeable matrix, production of uniformly sized microcapsules, use of an appropriate immune-compatible polycations cross-linked to the encapsulation polymer to stabilized the capsules, selection of a suitable cell type depending on the situation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7429", "text": "The use of the best biomaterial depending on the application is crucial in the development of drug delivery systems and tissue engineering. The polymer  alginate  is very commonly used due to its early discovery, easy availability and low cost but other materials such as cellulose sulphate,  collagen ,  chitosan ,  gelatin  and  agarose  have also been employed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7430", "text": "Several groups have extensively studied several natural and synthetic polymers with the goal of developing the most suitable biomaterial for cell microencapsulation. [ 8 ] [ 9 ]  Extensive work has been done using alginates which are regarded as the most suitable biomaterials for cell microencapsulation due to their abundance, excellent biocompatibility and   biodegradability  properties. Alginate is a natural polymer which can be extracted from seaweed and  bacteria [ 10 ]  with numerous compositions based on the isolation source. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7431", "text": "Alginate is not free from all criticism. Some researchers believe that alginates with high-M content could produce an  inflammatory  response [ 11 ] [ 12 ]  and an abnormal cell growth [ 13 ]  while some have demonstrated that  alginate  with high-G content lead to an even higher cell overgrowth [ 14 ] [ 15 ]  and inflammatory reaction in vivo as compared to intermediate-G alginates. [ 16 ] [ 17 ] \nEven ultrapure alginates may contain  endotoxins , and  polyphenols  which could compromise the biocompatibility of the resultant cell microcapsules. [ 15 ] [ 18 ] [ 19 ]  It has been shown that even though purification processes successfully lower endotoxin and polyphenol content in the processed alginate, it is difficult to lower the protein content [ 18 ]  and the purification processes could in turn modify the properties of the biomaterial. [ 19 ]  Thus it is essential that an effective purification process is designed so as to remove all the contaminants from alginate before it can be successfully used in clinical applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7432", "text": "Researchers have also been able to develop alginate microcapsules with an altered form of alginate with enhanced biocompatibility and higher resistance to osmotic swelling. [ 20 ] [ 21 ]  \nAnother approach to increasing the biocompatibility of the membrane biomaterial is through surface modification of the capsules using  peptide  and protein molecules which in turn controls the proliferation and rate of differentiation of the encapsulated cells. One group that has been working extensively on coupling the amino acid sequence Arg-Gly-Asp (RGD) to alginate hydrogels demonstrated that the cell behavior can be controlled by the RGD density coupled on the alginate gels. Alginate microparticles loaded with myoblast cells and functionalized with RGD allowed control over the growth and differentiation of the loaded cells. [ 22 ] [ 23 ]  \nAnother vital factor that controls the use of cell microcapsules in clinical applications is the development of a suitable immune-compatible polycation to coat the otherwise highly porous alginate beads and thus impart stability and immune protection to the system. [ 24 ]   Poly-L-lysine  is the most commonly used polycation but its low biocompatibility restricts the successful clinical use of these PLL formulated microcapsules which attract inflammatory cells thus inducing necrosis of the loaded cells. [ 25 ]  Studies have also shown that alginate-PLL-alginate (APA) microcapsules demonstrate low mechanical stability and short term durability. Thus several research groups have been looking for alternatives to PLL and have demonstrated promising results with poly-L-ornithine [ 26 ]  and poly(methylene-co-guanidine) hydrochloride [ 27 ]  by fabricating durable microcapsules with high  and controlled mechanical strength for cell encapsulation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7433", "text": "Several groups have also investigated the use of  chitosan  which is a naturally derived polycation as a potential replacement for PLL to fabricate alginate-chitosan (AC) microcapsules for cell delivery applications. [ 28 ] [ 29 ]  However, studies have also shown that the stability of this AC membrane is again limited [ 30 ] [ 31 ]  and one group demonstrated that modification of this alginate-chitosan microcapsules with  genipin , a naturally occurring iridoid glucosid from gardenia fruits, to form genipin cross-linked alginate-chitosan (GCAC) microcapsules could augment stability of the cell loaded microcapsules. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7434", "text": "Collagen, a major protein component of the ECM, provides support to tissues like skin, cartilage, bones, blood vessels and ligaments and is thus considered a model scaffold or matrix for tissue engineering due to its properties of biocompatibility,  biodegradability  and ability to promote cell binding. [ 32 ]  This ability allows chitosan to control distribution of cells inside the polymeric system. Thus, Type-I collagen obtained from animal tissues is now successfully being used commercially as tissue engineered biomaterial for multiple applications. [ 33 ]  Collagen has also been used in nerve repair [ 34 ]  and bladder engineering. [ 27 ]   Immunogenicity  has limited the applications of collagen. Gelatin has been considered as an alternative for that reason. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7435", "text": "Gelatin  is prepared from the denaturation of  collagen  and many desirable properties such as  biodegradability , biocompatibility, non-immunogenity in physiological  \nenvironments, and easy processability make this polymer a good choice for tissue engineering applications. [ 36 ]  It is used in engineering tissues for the skin, bone and cartilage and is used commercially for skin replacements. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7436", "text": "Chitosan  is a polysaccharide composed of randomly distributed \u03b2-(1-4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It is derived from the N-deacetylation of  chitin  and  has been used for several applications such as  drug delivery , [ 38 ]  space-filling implants [ 39 ]  and in wound dressings. [ 40 ]  However, one drawback of this polymer is its weak mechanical properties  and is thus often combined with other polymers  such  collagen  to form a polymer with stronger mechanical properties for cell encapsulation applications. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7437", "text": "Agarose  is a  polysaccharide   derived from seaweed used for nanoencapsulation of cells and the cell/agarose suspension [ 42 ]   can be modified to form  microbeads by reducing the temperature during preparation. [ 43 ]  However, one drawback with the microbeads so obtained is the possibility of cellular protrusion through the  polymeric  matrix wall after formation of the capsules."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7438", "text": "Cellulose sulphate is derived from cotton and, once processed appropriately, can be used as a biocompatible base in which to suspend cells. When the poly-anionic cellulose sulphate solution is immersed in a second, poly-cationic solution (e.g. pDADMAC), a semi-permeable membrane is formed around the suspended cells as a result of gelation between the two poly-ions. Both mammalian cell lines and bacterial cells remain viable and continue to replicate within the capsule membrane in order to fill-out the capsule. As such, in contrast to some other encapsulation materials, the capsules can be used to grow cells and act as such like a mini-bioreactor. The biocompatible nature of the material has been demonstrated by observation during studies using the cell-filled capsules themselves for implantation as well as isolated capsule material. [ 44 ]  Capsules formed from cellulose sulphate have been successfully used, showing safety and efficacy, in clinical and pre-clinical trials in both humans and animals, primarily as anti-cancer treatments, but also exploring possible uses for gene therapy or antibody therapies. [ 4 ] [ 45 ] [ 46 ] [ 47 ] [ 48 ]  Using cellulose sulphate it has been possible to manufacture encapsulated cells as a pharmaceutical product at large scale and fulfilling Good Manufacturing Process (cGMP) standards. This was achieved by the company  Austrianova  in 2007. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7439", "text": "The use of an ideal high quality biomaterial with the inherent properties of biocompatibility is the most crucial factor that governs the long term efficiency of this technology. An ideal biomaterial for cell encapsulation should be one that is totally  biocompatible , does not trigger an immune response in the host and does not interfere with cell  homeostasis  so as to ensure high cell viability. [ 50 ]  However, one major limitation has been the inability to reproduce the different biomaterials and the requirements to obtain a better understanding of the chemistry and biofunctionality of the biomaterials and the  microencapsulation  system. [ 42 ]   Several studies demonstrate that surface modification of these cell containing microparticles allows control over the growth and cellular differentiation. [ 42 ] [ 51 ]  of the encapsulated cells. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7440", "text": "One study proposed the use of  zeta potential  which measures the  electric charge  of the microcapsule as a means to predict the interfacial reaction between microcapsule and the surrounding tissue and in turn the biocompatibility of the delivery system. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7441", "text": "A fundamental criterion that must be established while developing any device with a  semi-permeable membrane  is to adjust the permeability of the device in terms of entry and exit of molecules. [ 54 ] [ 55 ]  It is essential that the cell microcapsule is designed with uniform thickness and should have a control over both the rate of molecules entering the capsule necessary for cell viability and the rate of  therapeutic  products and waste material exiting the capsule membrane. Immunoprotection of the loaded cell is the key issue that must be kept in mind while working on the permeability of the encapsulation membrane as not only immune cells but also  antibodies  and  cytokines  should be prevented entry into the microcapsule which in fact depends on the pore size of the biomembrane. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7442", "text": "It has been shown that since different cell types have different metabolic requirements, thus depending on the cell type encapsulated in the membrane the permeability of the membrane has to be optimized. [ 56 ]  Several groups have been dedicated towards the study of membrane permeability of cell microcapsules [ 51 ] [ 52 ] [ 57 ]  and although the role of permeability of certain essential elements like oxygen has been demonstrated, [ 58 ]  the permeability requirements of each cell type are yet to be determined."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7443", "text": "Sodium Citrate is used for degradation of alginate beads after encapsulation of cells. [ 59 ]  In order to determine viability of the cells or for further experimentation. Concentrations of approximately 25mM are used to dissolve the alginate spheres and the solution is spun down using a centrifuge so the sodium citrate can be removed and the cells can be collected."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7444", "text": "It is essential that the microcapsules have adequate membrane strength (mechanical stability) to endure physical and  osmotic stress  such as during the exchange of nutrients and waste products. The microcapsules should be strong enough and should not rupture on implantation as this could lead to an immune rejection of the encapsulated cells. [ 55 ]  For instance, in the case of  xenotransplantation , a tighter more stable membrane would be required in comparison to  allotransplantation . Also, while investigating the potential of using APA microcapsules loaded with bile salt hydrolase (BSH) overproducing active  Lactobacillus  plantarum 80 cells, in a simulated  gastro intestinal tract  model for oral delivery applications, the mechanical integrity and shape of the microcapsules was evaluated. It was shown that APA microcapsules could potentially be used in the oral delivery of live bacterial cells. [ 60 ]  However, further research proved that the GCAC microcapsules possess a higher mechanical stability as compared to APA microcapsules for oral delivery applications. [ 61 ]  Martoni et al. were experimenting with bacteria-filled capsules that would be taken by mouth to reduce serum cholesterol. \nThe capsules were pumped through a series of vessels simulating the human GI tract to determine how well the capsules would survive in the body. Extensive research into the mechanical properties of the biomaterial to be used for cell microencapsulation is necessary to determine the durability of the microcapsules during production and especially for in vivo applications where a sustained release of the therapeutic product over long durations is required.\nvan der Wijngaart et al. [ 57 ]  grafted a solid, but permeable, shell around the cells to provide increased mechanical strength."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7445", "text": "Droplet-based microfluidics can be used to generate microparticles with repeatable size. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7446", "text": "Eletrospraying is used to create alginate spheres by pumping an alginate solution through a needle. A source of high voltage usually provided by a clamp attached to the needle is used to generate an electric potential with the alginate falling from the needle tip into a solution that contains a ground.  Calcium chloride is used as cross linking solution in which the generated capsules drop into where they harden after approximately 30 minutes. Beads are formed from the needle due to charge and surface tension. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7447", "text": "The diameter of the microcapsules is an important factor that influences both the immune response towards the cell microcapsules as well as the mass transport across the capsule membrane. Studies show that the cellular response to smaller capsules is much lesser as compared to larger capsules [ 63 ]  and in general the diameter of the cell loaded microcapsules should be between 350-450\u00a0\u03bcm so as to enable effective diffusion across the semi-permeable membrane. [ 64 ] [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7448", "text": "The cell type chosen for this technique depends on the desired application of the cell microcapsules. The cells put into the capsules can be from the patient ( autologous  cells), from another donor (allogeneic cells) or from other species (xenogeneic cells). [ 66 ]  The use of autologous cells in microencapsulation therapy is limited by the availability of these cells and even though xenogeneic cells are easily accessible, danger of possible transmission of  viruses , especially  porcine  endogenous  retrovirus  to the patient restricts their clinical application, [ 67 ]  and after much debate several groups have concluded that studies should involve the use of allogeneic instead of xenogeneic cells. [ 68 ]  Depending on the application, the cells can be genetically altered to express any required protein. [ 69 ]  However, enough research has to be carried out to validate the safety and stability of the expressed gene before these types of cells can be used."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7449", "text": "This technology has not received approval for clinical trial because of the high immunogenicity of cells loaded in the capsules. They secrete  cytokines  and produce a severe  inflammatory  reaction at the implantation site around the capsules, in turn leading to a decrease in viability of the encapsulated cells. [ 15 ] [ 70 ]  One promising approach being studied is the administration of anti-inflammatory drugs to reduce the immune response produced due to administration of the cell loaded microcapsules. [ 71 ] [ 72 ]  Another approach which is now the focus of extensive research is the use of  stem cells  such as mesenchymal stem cells for long term cell microencapsulation and cell therapy applications in hopes of reducing the immune response in the patient after implantation. [ 73 ]  Another issue which compromises long term viability of the microencapsulated cells is the use of fast proliferating cell lines which eventually fill up the entire system and lead to decrease in the  diffusion  efficiency across the semi-permeable membrane of the capsule. [ 69 ]  A solution to this could be in the use of cell types such as  myoblasts  which do not proliferate after the microencapsulation procedure."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7450", "text": "Probiotics  are increasingly being used in numerous dairy products such as ice cream, milk powders, yoghurts, frozen dairy desserts and cheese due to their important health benefits. But, low viability of probiotic  bacteria  in the food still remains a major hurdle. The  pH , dissolved oxygen content, titratable acidity, storage temperature, species and strains of associative fermented dairy product organisms and concentration of lactic and acetic acids are some of the factors that greatly affect the probiotic viability in the product. [ 74 ] [ 75 ] [ 76 ]  As set by  Food and Agriculture Organization  (FAO) of the United Nations and the  World Health Organization  (WHO), the standard in order to be considered a health food with probiotic addition, the product should contain per gram at least 10 6 -10 7   cfu  of  viable  probiotic bacteria. [ 77 ]  It is necessary that the bacterial cells remain stable and healthy in the manufactured product, are sufficiently  viable  while moving through the upper digestive tract and are able to provide positive effects upon reaching the intestine of the host. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7451", "text": "Cell microencapsulation technology has successfully been applied in the food industry for the encapsulation of live probiotic bacteria cells to increase viability of the bacteria during processing of dairy products and for targeted delivery to the gastrointestinal tract. [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7452", "text": "Apart from dairy products, microencapsulated probiotics have also been used in non-dairy products, such as  TheresweetTM  which is a  sweetener . It can be used as a convenient vehicle for delivery of encapsulated  Lactobacillus  to the intestine although it is not itself a dairy product."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7453", "text": "The potential of using  bioartificial pancreas , for treatment of  diabetes mellitus , based on encapsulating  islet  cells within a semi permeable membrane is extensively being studied by scientists. These devices could eliminate the need for of  immunosuppressive drugs  in addition to finally solving the problem of shortage of organ donors. The use of microencapsulation would protect the islet cells from immune rejection as well as allow the use of animal cells or genetically modified insulin-producing cells. [ 80 ]  It is hoped that development of these islet encapsulated microcapsules could prevent the need for the insulin injections needed several times a day by type 1 diabetic patients. [ 66 ]  The  Edmonton protocol  involves implantation of human islets extracted from cadaveric donors and has shown improvements towards the treatment of type 1 diabetics who are prone to  hypoglycemic  unawareness. [ 81 ]  However, the two major hurdles faced in this technique are the limited availability of donor organs and with the need for  immunosuppresents  to prevent an immune response in the patient's body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7454", "text": "Several studies have been dedicated towards the development of bioartificial pancreas involving the immobilization of islets of Langerhans inside polymeric capsules. The first attempt towards this aim was demonstrated in 1980 by Lim et al. where xenograft islet cells were encapsulated inside alginate polylysine microcapsules and showed significant in vivo results for several weeks. [ 3 ]  It is envisaged that the implantation of these encapsulated cells would help to overcome the use of immunosuppressive drugs and also allow the use of xenograft cells thus obviating the problem of donor shortage."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7455", "text": "The polymers used for islet microencapsulation are alginate, [ 82 ]  chitosan, [ 83 ]   polyethylene glycol  (PEG), [ 84 ]  agarose, [ 85 ]  sodium cellulose sulfate and water-insoluble  polyacrylates  with alginate and PEG being commonly used polymers.  \nWith successful in vitro studies being performed using this technique, significant work in clinical trials using microencapsulated human islets is being carried out. In 2003, the use of alginate/PLO microcapsules containing islet cells for pilot phase-1 clinical trials was permitted to be carried out at the University of Perugia by the Italian Ministry of Health. [ 54 ]  In another study, the potential of clinical application of PEGylation and low doses of the immunosuppressant  cyclosporine  A were evaluated. The trial which began in 2005 by Novocell, now forms the phase I/II of clinical trials involving implantation of islet allografts into the  subcutaneous  site. [ 86 ]  However, there have been controversial studies involving human clinical trials where Living Cell technologies Ltd demonstrated the survival of functional xenogeneic cells transplanted without immunosuppressive medication for 9.5 years. [ 87 ]  However, the trial received harsh criticism from the International Xenotransplantation Association as being risky and premature. [ 88 ] \nHowever, even though clinical trials are under way, several major issues such as biocompatibility and immunoprotection need to be overcome. [ 89 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7456", "text": "Potential alternatives to encapsulating isolated islets (of either allo- or xenogeneic origin) are also being explored. Using sodium cellulose sulphate technology from  Austrianova Singapore  an islet cell line was encapsulated and it was demonstrated that the cells remain viable and release insulin in response to glucose. [ 90 ]  In pre-clinical studies, implanted, encapsulated cells were able to restore blood glucose levels in diabetic rats over a period of 6 months. [ 91 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7457", "text": "The use of cell encapsulated microcapsules towards the treatment of several forms of  cancer  has shown great potential. One approach undertaken by researchers is through the implantation of microcapsules containing genetically modified cytokine secreting cells. An example of this was demonstrated by Cirone et al. when genetically modified  IL-2 cytokine  secreting   non- autologous  mouse  myoblasts  implanted into mice showed a delay in the  tumor  growth with an increased rate of survival of the animals. [ 92 ]  However, the efficiency of this treatment was brief due to an immune response towards the implanted microcapsules. \nAnother approach to cancer suppression is through the use of angiogenesis inhibitors to prevent the release of  growth factors  which lead to the spread of tumors. The effect of implanting microcapsules loaded with xenogenic cells genetically modified to secrete  endostatin , an  antiangiogenic  drug which causes  apoptosis  in  tumor  cells, has been extensively studied. [ 93 ] [ 94 ]  However, this method of local delivery of microcapsules was not feasible in the treatment of patients with many tumors or in  metastasis  cases and has led to recent studies involving systemic implantation of the capsules. [ 95 ] [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7458", "text": "In 1998, a murine model of pancreatic cancer was used to study the effect of implanting genetically modified  cytochrome P450  expressing feline  epithelial  cells encapsulated in cellulose sulfate polymers for the treatment of solid tumors. [ 97 ]  The approach demonstrated for the first time the application of  enzyme  expressing cells to activate chemotherapeutic agents. On the basis of these results, an encapsulated cell therapy product, NovaCaps, was tested in a phase I and II clinical trial for the treatment of pancreatic cancer in patients [ 98 ] [ 99 ]  and has recently been designated by the European medicines agency (EMEA) as an orphan drug in Europe. A further phase I/II clinical trial using the same product confirmed the results of the first trial, demonstrating an approximate doubling of survival time in patients with stage IV pancreatic cancer. [ 100 ]  In all of these trials using cellulose sulphate, in addition to the clear anti-tumour effects, the capsules were well tolerated and there were no adverse reactions seen such as immune response to the capsules, demonstrating the biocompatible nature of the cellulose sulphate capsules. In one patient the capsules were in place for almost 2 years with no side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7459", "text": "These studies show the promising potential application of cell microcapsules towards the treatment of cancers. [ 42 ]  However, solutions to issues such as immune response leading to inflammation of the surrounding tissue at the site of capsule implantation have to be researched in detail before more clinical trials are possible."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7460", "text": "Numerous studies have been dedicated towards the development of effective methods to enable  cardiac  tissue regeneration in patients after  ischemic  heart disease. An emerging approach to answer the problems related to ischemic tissue repair is through the use of stem cell-based therapy. [ 101 ]  However, the actual mechanism due to which this stem cell-based therapy has generative effects on cardiac function is still under investigation. Even though numerous methods have been studied for cell administration, the efficiency of the number of cells retained in the beating heart after implantation is still very low. A promising approach to overcome this problem is through the use of cell microencapsulation therapy which has shown to enable a higher cell retention as compared to the injection of free  stem cells  into the heart. [ 102 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7461", "text": "Another strategy to improve the impact of cell based encapsulation technique towards cardiac regenerative applications is through the use of genetically modified stem cells capable of secreting angiogenic factors such as  vascular endothelial growth factor  (VEGF) which stimulate  neovascularization  and restore  perfusion  in the damaged ischemic heart. [ 103 ] [ 104 ]  An example of this is shown in the study by Zang et al. where genetically modified xenogeneic CHO cells expressing VEGF were encapsulated in alginate-polylysine-alginate microcapsules and implanted into rat myocardium. [ 105 ]  It was observed that the encapsulation protected the cells from an immunoresponse for three weeks and also led to an improvement in the cardiac tissue post- infarction  due to increased angiogenesis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7462", "text": "The use of monoclonal antibodies for therapy is now widespread for treatment of cancers and inflammatory diseases. Using cellulose sulphate technology, scientists have successfully encapsulated antibody producing hybridoma cells and demonstrated subsequent release of the therapeutic antibody from the capsules. [ 45 ] [ 46 ]  The capsules containing the hybridoma cells were used in pre-clinical studies to deliver neutralising antibodies to the mouse retrovirus FrCasE, successfully preventing disease."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7463", "text": "Many other medical conditions have been targeted with encapsulation therapies, especially those involving a deficiency in some biologically derived protein. One of the most successful approaches is an external device that acts similarly to a  dialysis machine , only with a reservoir of pig  hepatocytes  surrounding the semipermeable portion of the blood-infused tubing. [ 106 ]   This apparatus can remove toxins from the blood of patients suffering severe  liver failure . Other applications that are still in development include cells that produce  ciliary-derived neurotrophic factor  for the treatment of  ALS  and  Huntington's disease ,  glial-derived neurotrophic factor  for  Parkinson's disease ,  erythropoietin  for  anemia , and  HGH  for  dwarfism . [ 107 ]  In addition, monogenic diseases such as haemophilia, Gaucher's disease and some  mucopolysaccharide disorders  could also potentially be targeted by encapsulated cells expressing the protein that is otherwise lacking in the patient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7464", "text": "Cervical drug delivery  is a route of carrying drugs into the body through the  vagina  and  cervix . This is a form of localized drug delivery that prevents the drugs from impacting unintended areas of the body, which can lower side effects of toxic drugs such as  chemotherapeutics .\u00a0Cervical drug delivery has specific applications for a variety of female health issues: treatment of  cervical cancer , pregnancy prevention, STD prevention, and STD treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7465", "text": "Viscous  mucus  secreted by glands in the cervix presents a unique environment for drug delivery.\u00a0 Due to its ability to retain substances and slowly release them, it holds potential to be used as a natural, noninvasive drug delivery system.\u00a0 The mucus can act as a reservoir for compounds that destroy pathogens. [ 1 ] \u00a0 However, the cervical mucus also presents a barrier to drug delivery as it can be really thick, making it difficult to permeate the mucus barrier. [ 2 ]  The mechanisms for penetration and bioactivity of the cervical mucus must be understood to utilize the mucus\u2019s potential as a drug delivery system. [ 1 ]   Due to the changes in viscosity and water content of the mucus during the stages of the  menstrual cycle , this poses a particularly complex consideration. [ 3 ]   For example, the cervical mucus will be thicker when a woman is not  ovulating  in order to prevent sperm from being able to penetrate the mucus barrier, which also in turn makes in more difficult for penetration of drug delivery systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7466", "text": "The vaginal environment is slightly acidic, with  pH  ranging from 3.8 - 4.5 based on multiple factors such as age, natural bacteria, and stage of menstrual cycle. [ 4 ] \u00a0 Due to the variety in possible pH values, this poses an interesting consideration for drug delivery.\u00a0 Absorption and release of drugs is often influenced by pH, so if the pH is changing through the menstrual cycle, different combinations could be needed at different times to achieve the most effective drug delivery system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7467", "text": "Some  hormonal birth control  methods utilize cervical drug delivery methods.\u00a0 The earliest example of such dates to 1850 Ancient Egypt when acadia gum was inserted into the vagina, releasing  spermicidal  components. [ 5 ] \u00a0 Examples in the modern era include  vaginal rings  and  intrauterine devices  (IUDs) that release hormones into the reproductive system to prevent fertilization.  Vaginal rings are plastic ring-shaped devices that are inserted into the vaginal canal and slowly release hormones such as estradiol or progestin.  Hormonal IUDs are T-shaped devices inserted into the uterus, releasing progestin over extended periods of time. These hormones work to thicken the cervical mucus to prevent sperm from penetrating and reaching the  fallopian tubes . [ 6 ]   Copper IUDs are another form of intrauterine devices that release copper ions instead of hormones.  The copper ions are toxic to sperm and therefore prevents successful fertilization. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7468", "text": "The most common application of cervical drug delivery is for treatment of cervical cancer. Due to the direct route provided through the use of cervical drug delivery mechanisms, it proves to be the most effective route with the lowest number of side effects. [ 8 ] \u00a0 The localized treatment has been suggested as ideal as cancer is treated with highly toxic compounds, such as chemotherapeutics.  The more contained the exposure to these compounds can be, the less negative impacts the patient will endure.  Treatment can be delivered in the form of  nanoparticles , vaginal gels, or films and reach the cervix quickly for ideal response. [ 9 ]  Vaginal gels are easily administered into the vaginal canal to reach the cervix due to low viscosity at room temperature.  When inserted into the body which has a higher temperature, the gels become more viscous, allowing them to reside longer at the cervix and have more sustained release. [ 8 ]   Vaginal films are very thin films inserted into the vagina to release a compound.  They can be maintained for six hours in cervical mucus, meaning they hold potential to treat cervical cancer caused by  Human Papilloma Virus . [ 9 ]  Nanoparticle systems take advantage of the size of nanoparticles  to encapsulate the drugs and pass through the mucus barrier. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7469", "text": "Cervical drug delivery serves as a route for compounds to prevent and treat  sexually transmitted diseases  (STDs). Prevention of STDs for women can be achieved by administering preventative compounds into the vaginal canal prior to intercourse. One method researched is the use of a CAP technology that remains stable in the vaginal environment, but breaks down in the presence of human semen, releasing a drug to destroy STDs. [ 10 ]  This application of cervical drug delivery would be useful for prevention of STDs in women without interfering with the bodily environment until there is potential for infection.\u00a0 STDs can also be treated through cervical drug delivery methods.  Antibiotics for STD treatment are often administered into the vagina in the form of creams or gels."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7470", "text": "Hormones to increase fertility are also often delivered through the cervical route.  While this is less common than applications for birth control, it essentially utilizes the same concepts.  Hormones influence the natural menstrual cycle, so instead of using hormones that prevent ovulation, hormones are used to encourage ovulation, such as follicle-stimulation hormones (FSH) and luteinizing hormones (LH).  Fertility lubricants are the most common example of fertility treatments delivered through the cervical route.  These lubricants are designed to mimic a pH and viscosity that is conducive for sperm to reach the fallopian tube. [ 11 ] [ 12 ]  Studies are being done to combine the properties of fertility lubricants with fertility increasing hormones to lead to more direct and efficient treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7471", "text": "Vaginal rings are most commonly used for birth control purposes but can also be used to release compounds that treat and prevent STDs as well. The rings come in one standard size that fits most women [ 13 ]  and are made of flexible materials that contain the desired compound, whether that be hormones for birth control or other compounds for STD treatment.\u00a0These substances are then slowly released over an extended period of time, typically a month.\u00a0 This is a convenient drug delivery method because they can easily be inserted and removed and do not prohibit intercourse.  For birth control purposes, the vaginal ring is removed after 3 week and a new one is inserted a week later.  Vaginal rings are also often used to treat symptoms of menopause, and these rings are replaced after a 3 month use. [ 14 ]   STD prevention and treatment through the use of vaginal rings is a newer application of such a device, but holds an advantage as a low maintenance option for women in areas with less access to regular healthcare. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7472", "text": "Vaginal  suppositories  are forms of medications that are inserted into the vagina in a solid form, but melt from body heat to release the substances. [ 16 ] \u00a0 Common uses for them are to treat yeast or bacterial infections.\u00a0 Hormones are often delivered in this form for treatment of  menopausal  or menstrual related issues.\u00a0 Spermicide can also be delivered as a suppository when inserted prior to intercourse for birth control purposes.  Insertion of vaginal suppositories uses a mechanism and applicator similar to that of a  tampon .  If there is no applicator available, they can be inserted with two fingers pushing them into the vaginal canal as far as is comfortable."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7473", "text": "Vaginal gels are forms of medication that are water-based.\u00a0 They are applied using a plastic applicator to distribute the gel throughout the length of the vaginal canal.\u00a0 These gels tend to have release kinetics that are fast acting, which makes them useful for treatment of irritations.\u00a0 Antibiotics are often distributed in the form of a gel for treatment of common infections, including sexually transmitted infections (STIs).\u00a0 The gels also have the benefit of being lubricating, which grants additional relief to symptoms of dryness and itching that is common with vaginal infections. Gels that are in the form of liposomal structure have been shown to retain substances for extensive periods of time, making them useful for slow release of drugs administered through the cervical drug delivery route [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7474", "text": "Vaginal films are soluble, thin sheets of medication that are inserted into the vagina where they dissolve and release the substances.\u00a0 Typical uses include delivery of contraceptive substances or antibiotics for infections. These films are inserted by simply pushing them into the vagina with one\u2019s fingers.\u00a0 There they dissolve quickly upon interaction with natural vaginal fluids. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7475", "text": "Bioadhesives  are substances that naturally stick to live tissue.\u00a0 Currently, studies are being done on bioadhesives adhering to cervical mucous membranes to allow for an extended release period.\u00a0 The drug would be released with mucus to create a localized treatment with high effectiveness. This is anticipated to be highly useful for treatment of cervical cancer.  Bioadhesives can come in multiple forms, such as films, tablets, or gels. [ 19 ] [ 18 ]   The appeal of bioadhesives is that they take advantage of the mucous environment surrounding the cervix and utilize it to benefit the drug delivery mechanism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7476", "text": "Coiled-coil drug delivery systems  refer to  drug delivery  systems utilizing  coiled-coil   motifs  capable of delivering disease-treating therapies, imaging agents, and vaccines to patients systemically or  specifically . These systems are a form of  peptide therapeutics  and are capable of being engineered and finely tuned into different types of drug delivery vehicles (such as  liposomes ,  nanoparticle drug carriers ,  polymer hybrid drug carriers ,  micelles , etc.) based on the specific application required. The goal of a coiled-coil drug delivery system is to deliver cargo such as medication, imaging agents, biological molecules, or vaccines efficiently and specifically, in order to maximize the  therapeutic efficacy  and minimize  unwanted side effects . This is achieved through fine-tuning the factors affecting the coiled coil\u2019s  oligomerization , resulting in modular systems that are highly specific for the intended application."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7477", "text": "Coiled-coil motifs make up 10% of all  protein  sequences, [ 1 ]  and are utilized naturally by various proteins in both  prokaryotes  and  eukaryotes  to achieve diverse cellular functions. Coupled with the simple  helical  structure of coiled coils which has been widely studied and reported on in literature, engineered coiled coil drug delivery systems are capable of improving drug  pharmacokinetics , reducing unintentional  toxicity  during delivery, delivering drugs in a specific manner,  controlling cargo release , and maintaining high  stability  through transport in the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7478", "text": "Coiled-coil research began in 1953 when Dr.  Francis Crick  first reported on the theory behind the packing formation of  \u03b1-helices  in  fibrous proteins  at the time, which he proposed to consist of alpha helices composed of  heptad  repeats, or seven-residue repeats (a-b-c-d-e-f-g), whereby 2 or more alpha helices twist around each other similar to the strands of a rope. [ 2 ]  In 1972, Dr. Robert Hodges and his colleagues confirmed Dr. Crick\u2019s hypothesis upon sequencing  tropomyosin , further discovering that the heptad repeat consists of two hydrophobic residues at the a and d positions, which stabilize coiled coils and are their basis for formation. This confirmation formed the basis for designing engineered coiled-coil proteins to further investigate and better understand coiled-coil interactions, structures, functions, oligomerization, and other properties. [ 3 ] [ 4 ] [ 5 ] [ 6 ]  Later in 1991, Dr. O\u2019Shea and colleagues obtained the first high-resolution image of a two-stranded coiled-coil at a resolution of 1.8\u00c5. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7479", "text": "Dr. Hodges was the first to suggest the use of coiled coils in a drug delivery system in 1996 when he proposed a two-stage targeting and delivery system based on  heterodimerization , whereby a drug would be conjugated to chain 1 and an antibody would be conjugated to chain 2, such that chains 1 and 2 would form a heterodimeric coiled coil. In this system, the antibody conjugate would hypothetically be delivered first such that it binds to the target location, followed by the administration of the drug conjugate, whose chain 1 would dimerize with the antibody chain 2, resulting in targeted drug delivery. [ 8 ]  Since then, hundreds of investigations have been reported in the literature discussing novel drug delivery systems consisting of various coiled coil  supramolecular assemblies , such as fibers, hydrogels, and nanostructures. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7480", "text": "Typically, a coiled-coil motif consists of 2-7 alpha helix strands coiled together, each of which consists of a 7-residue repeat (a-b-c-d-e-f-g) called a heptad. Heptads are unique in that positions a, d are occupied by  hydrophobic residues  \u2013 typically  Leu ,  Ile , or  Val . [ 9 ]  Positions e, g are typically occupied by charged or  polar residues  \u2013 typically  Lys  or  Glu . Through this pattern, individual helices become  amphipathic , such that when oligomerized, a hydrophobic core forms between the a, d residues of the helices, along with interhelical  ionic interactions  that aid in stabilizing the oligomer that forms between the e and g residues of the helices (see figure 1). The number of heptads in a molecule is variable and can be modified based on specific applications of coiled-coil systems. For example, sequences with fewer heptads consisting of a, d hydrophobic residues can prove to be more stable than sequences with more heptads containing a mixture of polar and non-polar residues at the same positions. [ 5 ]  Thus, the hydrophobic core of a coiled-coil motif is considered a dominant factor affecting the  stability  of the motif. Additionally, the hydrophobic core residues affect the  specificity  of the coiled-coil motif, such that the specific pairs of a, d residues determine the number of alpha helices that compose the coiled-coil system. For example, in the case of the GCN4 leucine zipper protein, mutants with the a, d pair of I, L resulted in a two-stranded coiled-coil, while a pair of I, I resulted in a three-stranded coiled-coil and a pair of L, I resulted in a four-stranded coiled coil. [ 10 ]  Thus, the oligomerization selectivity can be tuned on a coiled-coil motif by choosing the appropriate amino acid residues in positions a, d."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7481", "text": "The polar residues on positions e, g of a heptad also contribute to the stability and specificity of the coiled-coil motif due to the electrostatic interactions such as  salt bridges  with e, g residues on other heptads, though to a lesser extent compared to residues in the a, d positions. [ 9 ]  However, e, g residues are capable of conferring  heterospecific  properties to a coiled-coil motif, such that a system can be designed whereby strands prefer hetero-oligomerize as opposed to homo-oligomerize. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7482", "text": "Coiled coils may be either left-handed or right-handed coils \u2013 although the majority of coiled-coil proteins found in nature consist of heptads and are left-handed since the handedness of coiled coils opposes the handedness of the alpha helices that comprise them. [ 11 ]  Right-handed coils have been reported in the literature to contain 11 residue repeats known as  undecad  repeats (a-b-c-d-e-f-g-h-i-j-k) or 15 residue repeats known as  pentadecad  repeats (a-b-c-d-e-f-g-h-i-j-k-l-m-n-o), both of which could feature larger hydrophobic cores and larger cavities that would be useful in drug delivery systems to load larger cargo. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7483", "text": "Coiled-coils are used as non-covalent  polymer-drug conjugates  to link  drugs  to  polymer backbones . The goal of these types of systems is to attach multiple drugs to a non-toxic backbone such that drugs can be stably transported throughout the body and  released at a controlled rate  once at the target location.  Doxorubicin ,  paclitaxel , and  campothecin  are examples of drugs typically used with polymer-drug conjugate systems. Hetero-dimeric coiled-coils motifs can be utilized in such systems, whereby one strand would be conjugated to the polymer backbone network, while the other strand would be conjugated to the drug of choice. The coiled-coils would then oligomerize, followed by the  administration of the drug system  into the body, whereby the stability of the coiled-coil in physiological conditions would ensure the intact delivery of the drug to the target. Upon  cellular uptake  at the target site, coiled-coil system would be exposed to a decrease in  pH  associated with the acidic environments of  endosomes  and  lysosomes , triggering the  dissociation  of the coiled-coils, resulting in drug release. Dr. Harm-Anton Klok and colleagues were the first to investigate the usage of coiled coils as linkers in polymer-drug conjugate systems, whereby they utilized the parallel heterodimeric E3/K3 coiled-coil system (known for its stability at physiological pH and dissociation at pH 5, resulting in E3 homotrimers along with K3 unimers [ 12 ] [ 13 ] ) to link cargo to a p oly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) -based polymer backbone. Klok et al. proved the intracellular uptake of cargo via  endocytosis , along with cargo release as a result of coiled-coil dissociation. Dr. Ond\u0159ej Van\u011bk and colleagues utilized the same E3/K3-PHPMA system to attach an antibody to the polymer backbone to target the delivery of the drug system, which was successful in vitro. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7484", "text": "Coiled-coil polymer hybrid drug delivery systems can also be used in drug-free macromolecular therapeutic (DFMT) applications, whereby a coiled-coil-based system would be used to induce  apoptosis  in target cells. Specifically, Dr.  Jind\u0159ich Kope\u010dek  and colleagues attempted to induce apoptosis in  CD20 -positive  non-Hodgkin's lymphoma   B-cells  by mimicking the induction of apoptosis typically caused by the recognition of secondary antibodies to the CD20 antigen. In this case, apoptosis was induced upon the oligomerization of a PHMPA copolymer-conjugated coil to the anti-CD20 FAB fragment-conjugated coil (which would recognize and bind CD20). [ 15 ] \u00a0The coiled-coil motifs used in this system were the  anti-parallel  heterodimeric CCE/CCK coiled coils, which consist of  pentaheptad  repeats. This system was found to be successful at inducing apoptosis in those cells  in vitro , providing an alternative to the anti-CD20 antibody drug  Rituximab . Further studies have shown the efficacy of this system in vivo whereby malignant B-cells implanted in the  bone marrow  of mice were eradicated completely. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7485", "text": "Coiled-coils can be used to create  nanoparticle drug delivery systems  capable of delivering drugs or other biological molecules with increased targeting and controlled release due to their biocompatibility, stability, and targeting properties. Self-assembled cage-like particles (SAGE) utilize coiled-coils along with  disulfide linkers  to create hollow  nanoparticles  of diameters in the range of 100nm. [ 17 ]  SAGE consists of two separate coiled-coil motifs: a ~20 residue heptad homotrimer motif (CC-Tri3) and a ~20 residue heptad heterodimer motif (CC-Di-A / CC-Di-B). Each CC-Tri3 would be bound to either a CC-Di-A or a CC-Di-B via a disulfide linker, such that each time CC-Di-A and CC-Di-B would oligomerize together, hexagonal networks would form with pores of 5-6nm in diameter: CC-Di-A \u2013 CC-Tri3 \u2013 CC-Di-A \u2013 CC-Di-b \u2013 CC-Tri3 \u2013 CC-Di-B. Self-assembly would result in further oligomerization between the heterodimer motifs, which would eventually result in the formation of a hollow nanoparticle sphere. The final diameter of the nanoparticle would depend on the length linker used, along with the size of the coiled-coil motifs used. [ 17 ] \u00a0SAGE has been applied in the field of  antigen delivery , whereby Dr. Andrew Davidson and colleagues modified 3 SAGE systems described above with the antigenic peptides  tetanus toxoid ,  ovalbumin , and  hemagglutinin  individually. The investigators found that SAGE systems were nontoxic  in vivo , and were capable of eliciting  CD4 T cell  and B cell responses in the case of the tetanus toxoid and ovalbumin systems while eliciting a CD8 T cell response with the hemagglutinin system. [ 18 ]  \u00a0 Some advantages to using SAGE systems for antigen presentation include the ability to remain stable and functional after functionalization with cargo, the ability to modify and tune  cellular uptake  properties, and the modularity of the platform which could potentially be used to present multiple antigens at the same time, resulting in increased  antigen immunogenicity . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7486", "text": "Another type of coiled-coil nanoparticle system is the self-assembling protein nanoparticles (SAPN). SAPN differs from SAGE in that SAPN utilizes trimeric and  pentameric  coiled-coil motifs. [ 19 ]  This change results in the self-assembly of a symmetrical  polyhedral  16nm  nanoparticle  composed of 60 monomer building blocks. The small size of SAPN allows the nanoparticle system to resemble viruses in shape and size, which is beneficial to antigen presentation. [ 9 ] \u00a0Specifically, SAPN has been utilized by Dr. David Lanar and colleagues to develop a P. falciparum malaria vaccine whereby B and CD8-T cell epitopes of the disease were modified into the SAPN coiled-coil motifs. In vivo results showed that a long-lasting immune response was generated in the mice for up to 13 months, capable of preventing malaria infection in vaccine-treated mice. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7487", "text": "Convection-enhanced delivery  ( CED ) is method of drug delivery in which the drug is delivered into the brain using  bulk flow  rather than conventional diffusion. This is done by utilizing  catheters  inserted into the target region of the brain and utilizing pressure to deliver the therapeutic to a target region. CED has been used to delivery drugs to the  central nervous system  (CNS) for diseases such as  cancer ,  epilepsy , and  Parkinson's disease . [ 1 ] [ 2 ] [ 3 ]  CED has been used to deliver drugs to the CNS for its ability to bypass the  blood\u2013brain barrier  (BBB) and target specific regions for targeted treatment, but current techniques using CED have failed to progress past clinical trials due to a variety of physical limitations associated with CED itself."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7488", "text": "The blood brain barrier (BBB) has historically proved to be a very difficult obstacle to overcome when aiming to deliver a drug to the brain. In order to overcome the difficulties in delivering therapeutic levels of drug past the BBB, drugs had to either be  lipophilic  molecules with a molecular weight below 600 Da or be transported across the BBB using some sort of  cellular transport system . [ 4 ]  In the 1990s, a research group led by Edward Oldfield at the  National Institutes of Health  proposed utilizing CED to deliver drugs and molecules too big to bypass the BBB to the brain. [ 5 ]  CED is also useful to delivery drugs that have poor diffusive properties and allows for targeted placement of the catheter used to deliver the drugs. A vast majority of current clinical studies using CED are currently using CED as a method to treat  brain tumors  that are inoperable or have shown little response to conventional therapies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7489", "text": "CED is a method of drug delivery in which a pressure gradient is created at the tip of a catheter to use bulk flow rather than diffusion to delivery drugs into the brain. Diffusion has been limited by the diffusivity of the tissue, and can be expressed using Fick's law,  \n \n \n \n J \n = \n \u2212 \n D \n \u2207 \n C \n \n \n {\\displaystyle J=-D\\nabla C} \n \n , where J is diffusion, D is the diffusivity of the targeted tissue, and  \n \n \n \n \u2207 \n C \n \n \n {\\displaystyle \\nabla C} \n \n  is the concentration gradient of the drug. Diffusion is can only be modified by the concentration gradient of a drug, meaning that in order to deliver drug to large parts of a tissue, high concentrations of a drug are needed in order to promote diffusion, which can result in toxicity. In comparison, bulk flow is limited only by Darcy's law, defined as  \n \n \n \n v \n = \n \u2212 \n K \n \u2207 \n p \n \n \n {\\displaystyle v=-K\\nabla p} \n \n , where v is velocity, K is the hydraulic conductivity of the molecule, and  \n \n \n \n \u2207 \n p \n \n \n {\\displaystyle \\nabla p} \n \n  is the pressure gradient. Using bulk flow to deliver a drug can mean a drug can be delivered further into a target tissue with higher pressure, resulting in lower concentrations and less risk of drug toxicity. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7490", "text": "To perform a CED treatment, catheters are inserted through burr holes drilled into the skull. Treatments can use multiple catheters for a single delivery if that is required. The catheters are inserted into the interstitial space of the brain using image guidance. Once the catheters are placed at the desired site, the catheters are connection to an infusion pump which is used to create the pressure gradient for bulk flow. Infusion rates are typically set to 0.1-10 \u03bcL/min and the drug is delivered into the interstitial space, displacing any extracellular fluid. [ 5 ]  CED can result in delivery of drug centimeters deep into the tissue from the delivery site, rather than the millimeters deep that would result from delivery of drugs via diffusion. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7491", "text": "Current clinical trials exploring the use of CED to date have not resulted in any FDA approved treatments. These clinical trials have mostly been focused on using CED to treat glioblastoma and only two studies have been able to progress to stage 3 clinical trials. The first study began in 2004 and was comparing the efficacy of  cintredekin besudotox  delivered using CED and  gliadel  for the treatment of glioblastoma multiform. [ 7 ]  Results from this study showed similar survival rates between the two groups, but patients who were given CED treatment had higher rates of  pulmonary emboli . The second stage 3 clinical trial began in 2008 and was delivering  trabedersen  via CED to treat anaplastic astrocytoma  glioblastoma . [ 8 ]  This trial was terminated early due to the inability to recruit enough trial participants and efficacy of CED in this treatment was not established. These two studies have been the only major clinical trials which have compared the efficacy of CED treatment to current clinical standards for treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7492", "text": "While CED clinical trials have primarily explored treating brain tumors, other conditions involving the brain have also been investigated in clinical trials. To date there have been 2 registered clinical trials, both in stage 1, which aim to use CED to treat Parkinson's disease. The first trial, which was registered in 2009, was withdrawn in 2017 for unknown reasons. [ 9 ]  The other clinical trial, which reached completion in 2022, delivered an  adenovirus  (AAV2) encoding for a  glial cell line derived neurotropic growth factor  (GDNF) directly into the brain using CED. [ 10 ]  GDNF is known to protect neurons which produce dopamine. Parkinson's disease has been shown to decrease the amount of dopamine which can be produced in the brain, so researchers hope to be able to decrease the side effects of Parkinson's disease by protecting neurons which produce dopamine. While results from this study have not been published as of April 2022, the pre-clinical research done in a Parkinson's disease model rhesus monkey showed that CED treatment with AAV2-GDNF resulted in neurological improvement without significant side effects. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7493", "text": "Even though current clinical trials have not yet resulted in an FDA approved treatment, there is still plenty of research being done on delivering different types of therapeutics and treating different diseases being done. One of these areas of research is the visualization of the region of treatment. One research group was able visualize the regions of the brain that received drug from bulk flow mixing the desired drug with  Gd-DTPA , a common  MRI contrast agent . [ 12 ]  This allowed researchers to immediately take an MRI post CED treatment to assess if the drug was reaching the targeted area. Research has also tagged nanocarriers of their therapeutic with the MRI contrast  gadoteridol  for real time treatment imaging. [ 13 ]  Other than MRI contrasts, it has been shown to be possible to tag a therapeutic microcarrier with a radiolabeled or fluorescent molecule that can then be excited during imaging. The biggest limitation of this drug distribution visualization is that this technique only works  ex vivo.  One research group was able to optimize their liposomal design using this technique, showing the usefulness of this technique. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7494", "text": "While a common use of CED is to directly deliver drugs to the brain, it is also possible to deliver non-chemical therapeutics, such as proteins or growth factors, using CED. There are several types of microcarriers which have been used for CED, including nanospheres, nanoparticles, liposomes, micelles, and dendrites. [ 15 ]  Nanocarriers have several unique benefits for delivering therapeutics compared to conventional drug solutions. Firstly, nanocarriers can be modified to create an optimal carrier for the system that is being developed. These modifications can include tagging them for imaging, size, charge,  osmolarity ,  viscosity , and changes in surface coating. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7495", "text": "The other large area of research being done currently on CED is the translation of CED from being used for brain tumors to other brain diseases. The primary conditions being researched for non-cancerous treatments include Parkinson's disease and epilepsy. Animal model research using CED to deliver therapeutics to the brain to treat Parkinson's disease have shown 3 promising therapeutics for treatment. Researchers for these therapeutics have typically used adenovirus carriers for therapeutics since many drugs used to treat Parkinson's disease currently are not chemical based but rather gene therapy or protein based. [ 16 ]  Current research areas focus on using GDNF, a growth factor which protects dopamine producing brain cells,  glutamic acid decarboxylase  (GAD), which is another therapeutic that helps to protect dopamine producing brain cells, and  neurturin , which is a GDNF homolog. [ 16 ]  Another reported use of CED is in the treatment of epilepsy. Current epilepsy treatments are too large to pass through the BBB, so utilizing CED to delivery these drugs is currently one of the only ways to target the brain. The two primary antiepileptic drugs (AEDs) being delivered using CED in research are  conotoxin   N-type calcium channel  antagonists and  botulinum neurotoxins . [ 2 ]  Results from these studies showed promise in reducing the risk of seizures for up to 5 days when treated with calcium channel antagonists and up to 50 days when using botulinum  neurotoxins   [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7496", "text": "While there has been promise in the use of CED to delivery drugs directly into the brain, there are some drawbacks with it. A vast majority of studies to date have failed to have consistent delivery from patient to patient for technical reasons surrounding the usage of CED. Incorrect placement of catheters can result in a less effective treatment with increased risks of leaks from the brain into other parts of the central nervous system (CNS). Another, more common occurrence is the incidence or reflux of the drug back into the catheter. Reflux can cause leakage into unintended areas as well as decrease the true volume of drug delivered. [ 6 ]  CED catheter improvements are currently being researched, with some research groups modifying the tips of the catheters to prevent reflux. The design of a balloon tipped catheter for use in CED has been proposed, and results showed that drug was successfully delivered into the brain using the balloon tipped catheter without any complication. [ 19 ]  Other proposed designs include the utilization of catheters with multiple exit sites, catheters with porous tips, and catheters with tips that are smaller than the rest of the catheter. [ 20 ]  New catheter designs also aim to allow for a greater flow rate while still minimizing the risk of reflux. [ 13 ]  These improvements to the technical limitations of CED aim to help researchers determine efficacy of a treatment without worrying about failed treatments due to limitations in the equipment of CED. With this in mind, there is a fast growing tech company in Baltimore, Maryland named CraniUS LLC, for which is inventing, designing and engineering the world's first fully-implantable, MRI-compatible, wirelessly-charged, bluetooth-enabled, high-profile craniofacial implant device to provide neurosurgical patients a safe option for receiving direct and chronic medicine delivery to their brain via convection-enhanced delivery; using a novel embedded, microfluidic-pump system and easy port-access system for repeated, transcutaneous filling. |url= http://www.CraniUSmed.com"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7497", "text": "A  cream  is a preparation usually for application to the  skin .  Creams for application to  mucous membranes  such as those of the  rectum  or  vagina  are also used.  Creams may be considered  pharmaceutical  products, since even cosmetic creams are manufactured using techniques developed by  pharmacy  and unmedicated creams are highly used in a variety of skin conditions (dermatoses).  The use of the  finger tip unit  concept may be helpful in guiding how much topical cream is required to cover different areas."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7498", "text": "Creams are semi-solid  emulsions  of oil and water.  They are divided into two types: oil-in-water (O/W) creams which are composed of small droplets of oil dispersed in a continuous water phase, and water-in-oil (W/O) creams which are composed of small droplets of water dispersed in a continuous oily phase.  Oil-in-water creams are more comfortable and cosmetically acceptable as they are less greasy and more easily washed off using water.  Water-in-oil creams are more difficult to handle but many  drugs  which are incorporated into creams are  hydrophobic  and will be released more readily from a water-in-oil cream than an oil-in-water cream.  Water-in-oil creams are also more moisturising as they provide an oily barrier which reduces water loss from the  stratum corneum , the outermost layer of the skin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7499", "text": "Creams are semisolid dosage forms containing more than 20% water or volatile components and typically less than 50% hydrocarbons, waxes, or polyols as vehicles. [ 1 ]  They may also contain one or more drug substances dissolved or dispersed in a suitable cream base. This term has traditionally been applied to semisolids that possess a relatively fluid consistency formulated as either water-in-oil (e.g.,  cold cream ) or oil-in-water (e.g.,  fluocinolone acetonide  cream) emulsions. However, more recently the term has been restricted to products consisting of oil-in-water emulsions or aqueous microcrystalline dispersions of  long-chain fatty acids  or alcohols that are water washable and more cosmetically and aesthetically acceptable. Creams can be used for administering drugs via the vaginal route (e.g.,  Triple Sulfa  vaginal cream). Creams are also used to treat  sun burns ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7500", "text": "There are four main ingredients of the cold cream: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7501", "text": "There are many types of preparations applied to a body surface, such as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7502", "text": "Cypher  is a brand of  drug-eluting coronary stent  from  Cordis Corporation , a  Cardinal Health  company. During a balloon  angioplasty , the stent is inserted into the artery to provide a \"scaffold\" to open the artery. An anti-rejection-type medication,  sirolimus , helps to limit the overgrowth of normal cells while the artery heals which reduces the chance of re-blockage in the treated area known as  restenosis , and reduces the chances that another procedure is required. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7503", "text": "The Cypher stent was approved for use by the FDA in 2003. [ 2 ]  Following claims of inconsistent manufacturing processes and poor sales,  Johnson & Johnson  have announced that it will stop selling Cypher stents by the end of 2011. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7504", "text": "A  dermal patch  or  skin patch  is a  medicated   adhesive  patch placed on  human skin  to deliver a medication into the skin. This is in contrast to a  transdermal patch , which delivers the medication through the skin and into the  bloodstream ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7505", "text": "In 2016, a study from the University of Nottingham was published describing the first  synthetic  spider silk  that is functionally identical to naturally spun spider silk. Using non-natural methionine analog L-azidohomoalanine (L-Aha) and genetically modified E-Coli cells, self-assembling proteins under the conditions needed to create the filament were produced. These conditions had been researched years earlier by J. Johansson and co-workers studying the production of spider silk proteins. The proteins used in the study are a miniaturized version of the silk monomers found in nature that behave the same way; because of the modifications, they were able to express functionalized regions of the protein 4RepCT, which is a self-assembling recombinant dragline silk protein, derived from the nursery-web spider along the axis of the filament. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7506", "text": "Methods of functionalizing the 4RepCT protein have been successful, but not in the way of reliably producing a stable protein functionalization in biologic environments that can also be tuned and modified. Genetic fusion of functional peptide sequences to silk genes and chemical conjugation of functional molecules onto amino acid side chains are the only two methods currently known to achieve a functionalized 4RepCT protein with tunable functionality. The first approach has the advantage that post-translational manipulation of the silk is minimized. Unfortunately, genetic manipulation is challenging due to the high GC (guanine-cytosine) content of the gene which leads to transcription errors. This method also limits the prevalence of functional binding sites to a single ligand-binding site per 25 kDa 4RepCT silk protein. Large adaptor proteins such as antibodies can be used to display more binding sites, but it isn't considered a feasible solution. This method has been shown to produce 4RepCT proteins that have a higher cell adhesion than natural spidroin proteins and have varied antimicrobial properties. The second method, chemical modification of the silk proteins should result in the covalent attachment of several copies of a wide range of organic and organometallic ligands using robust or sensitive linkers depending on the application. The challenge with this method is it is difficult to make the modification of the 4RepCT protein site-specific. Specific site targeting requires the residues to also be modified to be accessible and chemically bioorthogonal to the rest of the silk protein. Cytosine residues are commonly used for this type of conjugation through a Michael addition, but they tend to undergo exchange reactions which makes them unstable for long durations in a biological environment. These two methods are rather outdated but have been useful in validating the fact that 4RepCT can be tuned in the important areas of cellular adhesion, antimicrobial potency, and the type of molecule or drug attached to it. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7507", "text": "Later azide functional groups were conjugated to the N-terminal of a dragline silk protein using EDC/NHS coupling, yielding glycopolymer-conjugated films with enhanced cell adhesion and DNA-silk chimeras with controllable micro-architectures. Armed with this, the researchers in this study investigated the incorporation of\u00a03 L-Aha residues into 4RepCT, yielding  \n \n \n \n 4 \n R \n e \n p \n C \n \n T \n \n 3 \n A \n h \n a \n \n \n \n \n {\\displaystyle 4RepCT^{3Aha}} \n \n . The azide side chains of L-Aha allow highly specific and efficient site-specific conjugation to a lot different of functional molecules via Staudinger ligation with phosphine reagents, and Copper (I)-catalysed azide-alkyne cycloaddition ( CuAAC ) or Strain promoted azide-alkyne cycloaddition ( SPAAC ) in click reactions. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7508", "text": "CuAAC and SPAAC are both common click reactions which are often interchangeable in click chemistry. It is well known that intracellular Cu(I) is cytotoxic, which means CuAAC is not as common as SPAAC click reactions for research leading to in-vivo applications. The researchers for this study decided to use CuAAC, despite the purpose of this research to have in-vivo applications, for a few reasons. First, the likelihood for copper to be bound by the  \n \n \n \n 4 \n R \n e \n p \n C \n \n T \n \n 3 \n A \n h \n a \n \n \n \n \n {\\displaystyle 4RepCT^{3Aha}} \n \n  protein is low due to the presence of only 2 glutamic acid residues and no histidine residues (two residues with a high affinity for Cu(I)). These residues are present in the thioredoxin; which is the solubilizing fusion partner conjugated to the 4RepCT protein during synthesis. However, this does not cause issues since the thioredoxin is removed in order to trigger the self-assembly reaction with thrombin which results in fiber formation. This removal of the Cu(I) laden thioredoxin removes virtually all copper from the silk structure. The researchers also, through a buffer containing EDTA and by utilizing THPTA (which stabilizes the copper ions), rinsed the fibers resulting in further removal of Cu(I) leaving a <0.1\u00a0% by weight trace of copper ions. Secondly, CuAAC outperforms SPAAC in click reactions where proteins with a high cytosine content, such as 4RepCT, are present. The SPAAC process, in the presence of proteins like 4RepCT, will often create \u2018clicks\u2019 in off-target sites resulting in the ligand conjugating to the wrong part of the protein and rendering the protein essentially useless. In order to maximize the number of functional sites along the fiber, CuAAC is preferred. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7509", "text": "This study demonstrated the CuAAC mediated conjugation of  \n \n \n \n 4 \n R \n e \n p \n C \n \n T \n \n 3 \n A \n h \n a \n \n \n \n \n {\\displaystyle 4RepCT^{3Aha}} \n \n  with two different fluorophores and the antibiotic levofloxacin, showcasing the potential of covalently functionalized recombinant spider silk proteins as biomaterials with enhanced properties. The researchers were able to successfully conjugate  \n \n \n \n 4 \n R \n e \n p \n C \n \n T \n \n 3 \n A \n h \n a \n \n \n \n \n {\\displaystyle 4RepCT^{3Aha}} \n \n  with alkyne fluorophores, proving the protein can be functionalized through an azide group while conjugated to the axis of the silk fiber. Their results showed not only an intense uniform fluorescence along the fiber axis but also an intense uniform composite fluorescence when the fiber was decorated with two different fluorophores in a 1:1 ratio. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7510", "text": "To prove the functional azide group could be decorated with a clinically relevant molecule, the researchers attempted to decorate the fiber with glycidyl propargyl ether (an acid-labile linker) and bound Levofloxacin (a gram-positive targeting antibiotic) to it using an ester bond between the epoxide carboxylate groups respectively. They conducted an inhibition zone assay with the functionalized silk fibers against E. Coli NCTC 12242 bacteria where each factor level contained LB media. Their results showed a successful functionalization of the Levofloxacin decorated fiber which maintained an antibiotic persistence across a 3.5\u00a0cm radius for 120 hours and a cell density ~50% of other factor levels (LB media only, unfunctionalized silk, and Levofloxacin doped silk) with p \u2264 0.01. A maximum sustained release of Levofloxacin from the fiber of 5 days was achieved. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7511", "text": "Spider silk is one of the earliest known dermal patches. Primarily used for wound binding, the glycoprotein adhesive found on the capture spiral silk, as well as the protein structure of the fiber itself, has mild antibacterial properties. The silk, acting as a local antiseptic, reduced the rate of sepsis and chronic illness. The silk's viscoelastic properties and high tensile strength and toughness aided wound healing in a way similar to surgical tape."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7512", "text": "Despite its superiority to current methods of large-surface-area wound care\u2014gauze wrapping, honey vinegar treatments, and systemic antibiotics\u2014and popular dermal patch uses, spider silk has not found its way into clinical practice. Historically the main reason for this is the difficulty of farming, and harvesting the silk. Unlike silkworms, that spin silk for several easy-to-replicate conditions, spiders spin silk for specific purposes such as catching prey, difficult to replicate in laboratory conditions. In addition, spiders generally tend to be cannibalistic, so breeding sufficient numbers becomes difficult. Forced silking yields unsuitable silks. The most popular proposed use case for dermal applications are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7513", "text": "Research shows  silkworm  silk does not possess any inherent antibiotic characteristics, bio-mimicking mechanical properties, and can cause fatal respiratory allergic reactions in some people. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7514", "text": "A 2020 study found that recombinantly produced spider silk proteins self-assemble at the liquid-air interface of a standing solution, forming protein permeable, super strong and ultra flexible membranes. The unforced self-assembly creates a nanofibrilar membrane which supports cell growth. A confluent layer of human skin cells forms within three days, and would be suitable for direct delivery to a patient. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7515", "text": "As silkworm silk is potentially fatal to humans when in contact with vasculature, there is no approved dermal patch, or dermal patch-like, application for silkworm silk."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7516", "text": "Dextran drug delivery systems  involve the use of the natural glucose polymer  dextran  in applications as a  prodrug ,  nanoparticle ,  microsphere ,  micelle , and  hydrogel   drug carrier  in the field of targeted and controlled drug delivery. According to several  in vitro  and animal research studies, dextran carriers reduce off-site toxicity and improve local drug concentration at the target tissue site. [ 1 ]  This technology has significant implications as a potential strategy for delivering therapeutics to treat cancer, cardiovascular diseases, pulmonary diseases, bone diseases, liver diseases, colonic diseases, infections, and HIV. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7517", "text": "Although there are many  FDA  approved natural polymeric-based drug carriers available for clinical use, dextran has failed to obtain any clinical applications. Research must address several challenges and obstacles associated with dextran before it can become a viable, clinically approved drug delivery strategy. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7518", "text": "Dextran has many favorable properties that make it an ideal candidate for applications as a drug delivery system. As a natural polymer, dextran is  biocompatible  and  biodegradable  in the human body. Dextran can also be chemically modified to produce derivatives at a low cost, which can address a few of the undesirable characteristics including its low mechanical strength and uncontrollable hydration rate [4]. This natural glucose polymer has excellent water solubility and prolonged circulation in the blood as well. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7519", "text": "Dextran prodrugs are chemically linked drug-polymer complexes in which enzymatic processes and  hydrolysis   in vivo  cause the drug to become pharmacologically active. Therapeutic agents can be linked to dextran via an  ester  bond which can be hydrolyzed slowly by  esterases  to produce sustained, stable drug release. Drug-dextran complexes can also be formed by chemical linkage through an amide bond, which is hydrolyzed by amidase. Prodrugs coupled by amide bonds provide much slower drug release than by ester bonds. Succinic acid and glutaric acid carboxyl groups, amino acids, pH and reductivity sensitive  disulfide bonds , and click chemistry are also methods of coupling drugs to dextran. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7520", "text": "These drug-polymer complexes have advantages such as longer drug half-life and improved targeted drug delivery. Dextran prodrugs have potential applications in the treatment of liver diseases, pulmonary diseases, colonic diseases, and cancer. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7521", "text": "Dextran nanoparticles are 1-100 nm sized particles with drug encapsulation capability. The high surface area of these nanoparticles allows more drugs to be loaded and encapsulated, leading to higher drug concentrations at the target site. The small size of these particles also encourages cellular uptake, which makes dextran nanoparticles a potential effective drug delivery system for targeting tumor cells. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7522", "text": "Dextran has indirect applications in nanoparticles as a coating.  Iron oxide  nanoparticles coated with dextran can be loaded with the  microRNA  miR-29a to selectively target breast cancer cells and down-regulate anti-apoptotic genes leading to successful breast cancer treatment. [ 6 ]  Dextran-coated iron oxide nanoparticles loaded with heparinase-like antisense nucleic acid effectively target uterine cancer cells and inhibit tumor growth. Supermagnetic nanospheres composed of iron oxide coated with dextran can be loaded with doxorubicin to effectively target tumor cells and limit off-site toxicity. Gold magnetic nanoparticles coated with dextran can effectively target desired tissue sites with the aid of an externally applied magnetic field. [ 1 ]  Dextran coatings can further improve the drug targeting capability of other types of nanoparticles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7523", "text": "Dextran conjugates are also utilized in nanoparticle drug delivery system formulations. Nanoparticles composted of dextran and stearic acid with a  polyethylene glycol  (PEG) coating can be loaded with antiviral drugs and be effectively internalized by cells. This nanosystem has the advantages of providing protection against immune responses and providing stability to the encapsulated drug. This technology has applications in the treatment of HIV and AIDS. [ 7 ]  Dextran can be grafted with folic acid to develop doxorubicin-loaded nanoparticles. Dextran-folic acid nanoparticles effectively target tumors, reduce off-site toxicity, and prolong blood circulation. Dextran- spermine  nanoparticles loaded with doxorubicin can achieve targeted and sustained drug release in tumors. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7524", "text": "Dextran nanoparticles have advantages such as increased drug-loading capacity, improved cellular uptake, reduce off-site toxicity, and increase local drug concentrations at the target tissue site. The current research indicates that dextran nanoparticles can potentially have applications in the delivery of anti-tumor therapeutics. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7525", "text": "Dextran microspheres are 1 to 250 micrometer sized polymeric particles that can encapsulate drugs. Microspheres composed of dextran have several advantages as a drug delivery system including controlled drug release, localized drug concentration, and reduced adverse reactions. Controlled drug release by these dextran microparticles is achieved by degradation, which is the breakdown of chemical bonds in the molecular structure of the polymeric network. [ 1 ]  Dextran microspheres are formulated in many forms including native dextran, dextran as a cross-linker, dextran conjugates, and chemically modified dextran. [ 1 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7526", "text": "Dextran can be used as a standalone material in microspheres. Dextran microspheres can provide controlled drug release in gastric and intestinal pH environments, which is ideal for targeting of the colon. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7527", "text": "One application of the glucose polymer dextran in microsphere compositions is as a cross-linker. Dextran and oxidized dextran can be used to crosslink gelatin microspheres to reduce gelatin dissolution, which slows the drug release rate. These dextran/gelatin microspheres can be used to provide slow-release of TRAPP-Br, which is a cancer therapeutic. [ 8 ]  Hydrogel microspheres synthesized by using porous chitosan polyelectrolyte complex with dextran sulfate as a cross-linker can deliver hydrophobic drugs to the intestines with high efficacy. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7528", "text": "Dextran can be conjugated with other materials to synthesize microspheres. Dextran grafted with PLGA forms microspheres that can provide effective delivery of insulin in diabetic patients. Dextran/chitosan microspheres efficiently deliver recombinant bone morphogenic protein (rhBMP-2) for the treatment of bone diseases. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7529", "text": "Microspheres can also be developed by chemically modifying dextran. Acetated dextran can be modified with amine groups and grafted with heparin to form microspheres that provide protamine-stimulated, targeted drug release for the delivery of therapeutics to treat cardiovascular diseases. [ 9 ]  Dextran modified with an octyl- group creates microspheres that provide extended release of doxorubicin, which is an antitumor therapeutic. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7530", "text": "Dextran-based microspheres can encapsulate a variety of drugs and provide therapeutic delivery in the treatment of diseases such as cancer, colonic diseases, bone diseases, and cardiovascular diseases. [ 1 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7531", "text": "Dextran micelles are 10 to 100 nm sized amphiphilic polymeric particles which have the advantages of avoiding drug clearance by the kidneys and traveling through blood vessels. [ 1 ]  The core of these micelles are hydrophobic, allowing for loading of hydrophobic drugs into the micelle. The outer shell of the particles is hydrophilic, which allows for long circulation times in the blood. [ 5 ]  Dextran can be conjugated with other materials to form polymeric micelles including stearic acid and cholesterol to further improve sustained release of the loaded hydrophobic drug. The size of the micelles can be controlled by altering the ratio of stearic acid to dextran. [ 5 ]  Dextran micelles can also be formed from conjugation with  polycaprolactone ,  folic acid ,  retinoic acid , and  PLGA . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7532", "text": "Dextran micelles can be synthesized and modified to be stimuli-responsive. These stimuli include pH, temperature, and redox conditions. [ 10 ]  Micelles composed of dextran grafted with deoxycholic acid or polycaprolactone via a disulfide bond are responsive to a redox environment. Dextran micelles conjugated with cholesterol exhibit pH responsiveness when modified with histidine. [ 1 ]  Dextran-benzimidazole conjugate micelles also exhibit pH-responsiveness. [ 10 ]  When the polymeric micelles encounter these stimuli, release of the drug from the hydrophobic core is triggered by various mechanisms depending on the stimuli and the conjugated material. Stimuli-responsive dextran grafted micelles decrease off-site drug toxicity and increase localized drug concentration in the target site. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7533", "text": "Dextran micelles and dextran copolymer micelles can be loaded with a variety of hydrophobic drugs such as doxorubicin, rapamycin, and paclitaxel, indicating a significant application in the delivery of anti-cancer therapeutics. [ 1 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7534", "text": "Dextran hydrogels and dextran conjugate hydrogels are heavily cross-linked polymeric networks that have a strong affinity for water. These gels have soft, elastic physical properties and are biocompatible and biodegradable. [ 1 ]  Dextran hydrogels have also been shown to be stable and safe  in vivo . [ 2 ]  Glucose-based polymeric gels have the advantage of being able to be chemically or physically modified to improve targeted drug delivery. [ 1 ]  Swelling is one mechanism by which drugs are released from the dextran hydrogels. Swelling can be reduced by increasing the molecular weight of dextran, leading to a slower drug diffusion rate out of the hydrogel. Swelling can also be lessened by increasing the amount of the conjugated species and introducing ethanol during the cross-linking reaction. [ 2 ] [ 3 ]  Degradation of chemical linkages in the dextran hydrogels is another mechanism by which drugs are released from the polymeric matrices. An increase in degradation of the dextran hydrogel leads to an increase in drug release rate. Degradation of dextran hydrogels specifically is caused by dextranases, which are microbial enzymes mostly located in the colon. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7535", "text": "The colon is an ideal target for dextran hydrogel drug delivery systems due to the presence of dextranases. Dextran can be cross-linked with diisocyanate to form a hydrogel that can be loaded with hydrocortisone to treat swelling or inflammation in the colon. [ 3 ]  Hydrogels can also be synthesized from crosslinking  epichlorohydrin  (ECH) with dextran. Dextran-ECH hydrogels can be loaded with salmon calcitonin (sCT) to treat bone diseases. Dextran-ECH hydrogels loaded with sCT achieved comparable release rates to other polymeric hydrogels in the colon. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7536", "text": "Dextran conjugate hydrogels can also target other desirable sites. Paclitaxel-loaded dextran-sericin hydrogels can effectively target tumor growth in mice. Hydrogels composed of translocator protein (TSPO) ligands conjugated to dextran have the potential to induce apoptosis in tumor cells via the TSPO receptor on the mitochondria. [ 1 ]  Dextran/polyacrylamide hydrogels with covalently bound silver nanoparticles can effectively release ornidazole to treat infections. Dextran conjugated with oligolactide chains through a disulfide bond can form hydrogels that have potential applications in cancer treatment drug delivery systems. Dextran hydrogels that release drugs in response to an external electrical field can also be synthesized. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7537", "text": "Dextran hydrogel and dextran conjugate hydrogel drug delivery systems have a variety of applications. These gels can be used to release therapeutics to treat cancer, swelling, inflammation, bone diseases, and infections. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7538", "text": "Dextran has yet to be approved for any clinical uses in drug delivery due to a wide variety of limitations including heterogeneity, undesirable side effects, and unknown biological pathways. Changes in the molecular weight of dextran have been shown to alter biological activity, indicating a need for separation and purification processes to ensure batch homogeneity. Dextran, although considered relatively safe and nontoxic  in vivo , exhibits a few side effects with the most notable being thrombocytopenia and liver toxicity. The exact biological mechanisms by which dextran-based drug delivery systems act on the drug target must be elucidated as well. [ 4 ]  Dextran-based drug delivery systems have an enormous potential for clinical use in the treatment of a variety of disease states."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7539", "text": "Digital medicine  refers to the application of advanced digital technologies, such as  artificial intelligence , machine learning, and big data analytics, to improve patient outcomes and healthcare delivery. It involves the integration of technology and medicine to facilitate the creation, storage, analysis, and dissemination of health information, with the aim of enhancing clinical decision-making, improving patient care, and reducing costs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7540", "text": "Digital medicine encompasses a wide range of disciplines, including techbio, healthtech, and biomedical engineering. It involves the use of digital tools and platforms to collect, store, and analyze patient data, including electronic health records, genomic data, and medical imaging. This data can then be used to develop new analytics and treatment approaches, personalize healthcare interventions, and optimize healthcare delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7541", "text": "Digital medicine is evidence-based, and its approach is rooted in rigorous scientific research and clinical evidence. It is designed to augment and complement traditional medical practices, providing physicians and other healthcare professionals with the tools and resources they need to make more informed decisions and provide better care to patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7542", "text": "Digital medicine is sometimes confused with similar disciplines, including the broader category of  digital health , as well as  digital therapeutics , another digital health subset. Digital health offerings use digital technologies to enhance human health in some capacity but often lacking the required evidence base to qualify as digital medicine. [ 1 ]  Within this broader category, programs that include a prescription medication with an ingestible sensor component are considered digital medicines. By contrast, digital therapeutics are associated mainly with web-based health management tools and stand-alone health apps, generally without a prescription medication element. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7543", "text": "The ingestible sensor component associated with digital medicines was originally approved in 2012 by the U.S. Food and Drug Administration (FDA) through the Center for Devices and Radiological Health via a de novo pathway for novel, low-risk medical devices. [ 3 ]  This approval has been accompanied by FDA 510(k) clearances. [ 3 ]  The ingestible sensor is CE marked in Europe. [ 4 ]  A New Drug Application for the first fully integrated pharmaceutical with ingestible sensor component,  Otsuka Pharmaceutical 's ABILIFY MYCITE\u00ae (aripiprazole with Proteus ingestible sensor), was approved by the FDA in November 2017. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7544", "text": "With its approval of the  digital pill , the FDA confirmed that the review of digital medicines includes assessment of the ingestible device component, and that no additional safety and efficacy data is required for the original pharmaceutical. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7545", "text": "Digital medicines are being used for a variety of conditions in commercial and clinical settings. Medications with ingestible sensors are being prescribed in the treatment areas of  hypertension ,  diabetes ,  hypercholesterolemia ,  heart failure ,  Hepatitis C ,  mental health ,  HIV ,  TB  and  organ transplantation . [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7546", "text": "In January 2016, Barton Health became the first institution to commercially offer digital medicines to patients with  chronic medical conditions . [ 9 ]  In 2016, Children's Health in Dallas, Texas became the first to commercially use digital medicines with  pediatric  patients. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7547", "text": "Bioethicists have expressed concerns around technologies that log and share information about patients\u2019 medication-taking behavior. [ 11 ]   These concerns exist from the perspective of both individual and collective patient rights. However, proponents note that participation in digital medicine programs are voluntary, comply with all applicable laws and standards, and protect patient data in accordance with applicable state and federal privacy regulations, as with other data generated and stored in electronic medical records. [ 12 ]   Experts add that digital medicine programs show promise as a solution to  medication adherence , and help physicians more accurately titrate dosages and determine how well the medication worked. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7548", "text": "A  douche  is a term for a device used to introduce a stream of water into the body for medical or hygienic reasons, or for the stream of water itself. Douche usually refers to vaginal irrigation, the rinsing of the  vagina , but it can also refer to the rinsing of any body cavity. A douche bag is a piece of equipment for douching\u2014a bag for holding the fluid used in douching. To avoid transferring intestinal bacteria to the vagina, the same bag must not be used for both an  enema  and a vaginal douche."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7549", "text": "Douching after sexual intercourse is not an effective form of  birth control . [ 1 ]  Additionally, douching is associated with a number of health problems, including  cervical cancer ,  pelvic inflammatory disease ,  endometritis , and increased risk of  sexually transmitted infections . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7550", "text": "The word's first known use is in 1766.  Douche  came into English via  French , from  Italian :  doccia  \"conduit pipe\" and  docciare  \"pour by drops\" to douche, from  doccia  water pipe, probably back-formation from  doccione  conduit, from  Latin :  duction- ,  ductio  means of conveying water, from  ducere  to lead. [ 3 ] [ failed verification ]  In French today it means  shower , as it does in many European languages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7551", "text": "Vaginal douches  may consist of water, water mixed with  vinegar , or even  antiseptic  chemicals. Douching has been touted as having a number of supposed but unproven benefits. In addition to promising to clean the vagina of unwanted odors, it can also be used by women who wish to avoid smearing a sexual partner's penis with menstrual blood while having  sexual intercourse during menstruation . In the past, douching was also used after intercourse as a method of  birth control , though it is not effective (see below)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7552", "text": "Many health-care professionals state that douching is dangerous, as it interferes with both the vagina's normal self-cleaning and with the natural bacterial culture of the vagina, and it might spread or introduce infections. Douching is implicated in a wide variety of dangers, including: adverse pregnancy outcomes including  ectopic pregnancy ,  low birth weight , preterm labor,  preterm birth , and  chorioamnionitis ; serious gynecologic outcomes, including increased risk of  cervical cancer ,  pelvic inflammatory disease ,  endometritis , and increased risk for  sexually transmitted infections , including  HIV ; it also predisposes women to develop  bacterial vaginosis  (BV), [ 4 ]  which is further associated with adverse pregnancy outcomes and increased risk of sexually transmitted infections. [ 5 ]  Due to this, the  U.S. Department of Health and Human Services  strongly discourages douching, citing the risks of irritation, bacterial vaginosis, and pelvic inflammatory disease (PID). Frequent douching with water may result in an imbalance of the  pH  of the vagina, and thus may put women at risk for possible vaginal infections, especially yeast infections. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7553", "text": "In May 2003, a randomized, controlled, multi-center study was conducted with 1827 women ages 18\u201344 who were regular users of a douche product and who had been treated recently for a sexually transmitted bacterial infection or bacterial vaginosis. Women were randomly assigned to use either a newly designed and marketed douche product or a soft cloth towelette. There was little or no indication of a greater risk of PID among women assigned to use the douche product (versus soft cloth towelette). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7554", "text": "Antiseptics used during douching disturb the natural balance of bacteria in the vagina and can cause infections. [ 8 ]  Unclean douching equipment may introduce foreign bodies into the vagina. Douching may also wash bacteria into the  uterus  and  fallopian tubes , causing fertility problems. [ 9 ]  For these reasons, the practice of douching is now strongly discouraged except when ordered by a physician for medical reasons. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7555", "text": "Douching after intercourse is estimated to reduce the chances of conception by only about 30%. [ 10 ]  In comparison, proper male  condom  use reduces the chance of conception by as much as 98%. [ 11 ]  In some cases douching may force the  ejaculate  further into the vagina, increasing the chance of pregnancy. A review of studies by researchers at the  University of Rochester Medical Center  (N.Y.) showed that women who douched regularly and later became pregnant had higher rates of  ectopic pregnancy ,  infections , and low birth weight infants than women who only douched occasionally or who never douched. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7556", "text": "A 1995 survey quoted in the  University of Rochester  study found that 27% of U.S. women age 15 to 44 douched regularly, but that douching was more common among  African-American  women (over 50%) than among white women (21%), [ 8 ]  and frequent douching contributes to more frequent bacterial vaginosis among African-American women than the average. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7557", "text": "Medical doctor  Harriet Hall  writes that not only can douching change the  pH  of the vagina and lead to infections, \"There is no need ... to cleanse the vagina. It cleanses itself\". [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7558", "text": "Douchebag  and its variants, or simply  douche , [ 13 ] [ 14 ]  are  pejorative  terms [ 14 ]  referring to an arrogant, obnoxious, or despicable person. [ 15 ]  The slang usage of the term originated in the 1960s. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7559", "text": "A  drip chamber , also known as  drip bulb , is a device used to allow gas (such as  air ) to rise out from a fluid so that it is not passed downstream. It is commonly employed in delivery systems of  intravenous therapy  and acts to prevent  air embolism . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7560", "text": "The use of a drip chamber also allows an estimate of the rate at which fluid is administered. For a fluid of a given  viscosity , drips from a hole of known size will be of nearly identical volume, and the number of drips in a minute can be counted to gauge the rate of flow. In this instance the rate of flow is usually controlled by a clamp on the infusion tubing; this affects the resistance to flow. However, other sources of resistance (such as whether the vein is kinked or compressed by the patient's position) cannot be so directly controlled and a change in position may change the rate of flow leading to inadvertently rapid or slow infusion. Where this might be problematic an  infusion pump  can be used which gives a more accurate measurement of flow rate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7561", "text": "Drip chambers can be classified into macro-drip (about 10 to 20  gtts /ml) and micro-drip (about 60 gtts/ml) based on their drop factors. For a given drip chamber (when the fluid drips from the hole into the chamber) drop factor means number of drops per ml of the IV fluid. Flow rate can be calculated with the help of the observations from the drip chamber and its drop factor. The unit of flow rate is gtts/min, where gtts means  guttae  (Latin plural noun meaning \u201cdrops\u201d)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7562", "text": "Drug packaging  (or  pharmaceutical packaging ) is process of packing  pharmaceutical preparations  for distribution, and the physical  packaging  in which they are stored. It involves all of the operations from production through  drug distribution  channels to the end consumer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7563", "text": "Pharmaceutical packaging is highly regulated but with some variation in the details, depending on the country of origin  or the region. Several common factors can include:  assurance of patient safety, assurance of the efficacy of the drug through the intended  shelf life , [ 1 ]  uniformity of the drug through different production lots, thorough documentation of all materials and processes, control of possible migration of packaging components into the drug, control of degradation of the drug by oxygen, moisture, heat, light exposure etc., prevention of  microbial  contamination, sterility, etc. Packaging is often involved in dispensing, dosing, and use of the pharmaceutical product. Communication of proper use and cautionary labels are also regulated. Packaging is an integral part of pharmaceutical product. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7564", "text": "Pharmaceutical packaging can often be thought of by the segment in the distribution system being encountered and by the functions needed by the user of the package.   Packaging requirements are different. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7565", "text": "Bulk pharmaceuticals can be shipped to another pharmaceutical company for further processing, to a  contract packager  for forming unit packs, to international customers, etc.               Bulk shipments might be in fiber drums (with plastic liners),  bulk boxes ,  corrugated boxes  with liners,  intermediate bulk containers , and other  shipping containers ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7566", "text": "Smaller bulk packs can be shipped to pharmacies, particularly compounding pharmacies.  The liquids or powders can be measured and put into primary packages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7567", "text": "Shipments to medical professionals could be at hospitals, nursing homes, veterinarians, dentists, etc.    These packaged  pharmaceuticals are intended to be dispensed and administered by professionally trained and certified personnel."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7568", "text": "Drugs under prescription control are sent to pharmacies in  multi-packs  of unit packs or in bottles containing many hundreds of capsules.     Typically  a pharmacist prepares the final form of the unit pack or places a lower count of capsules in a small bottle for the customer.  In a pharmacy, pharmacists are available to answer questions and to ensure that proper documentation is provided.  Internet pharmacies mail the prescribed drugs to the customer; boxes or mailing envelopes are used.  Child resistant packaging is often required on the unit packs; if requested, a pharmacist is allowed put drugs in a bottle with easy open features."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7569", "text": "Over-the-counter drugs are sold in drug stores, grocery stores, and diverse retail outlets.  Usually the package needs to have all the usage information available.  Packages often need to have  tamper resistant  features and  child-resistant packaging ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7570", "text": "Usually the packaging and labeling of  dietary supplements ,  homeopathic  drugs, and  folk medicines  are not regulated.  Some producers voluntarily follow the regulations for over-the-counter drugs or regional  Pharmacopoeias ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7571", "text": "The wide variety of pharmaceutical solids, liquids, and gasses are packaged in a wide variety of packages.  Some of the common primary packages are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7572", "text": "Formed solid  unit doses  of pharmaceuticals ( capsules ,  suppositories ,   tablets , etc.) are commonly packed in blister packs.  In Europe about 85% of solid unit doses are packed in blister packs with only about 20% in North America. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7573", "text": "Blister packs are pre-formed plastic/paper/foil packaging used for formed solid drugs.  The primary component of a blister pack is a cavity or pocket made from a thermoformed plastic. This usually has a backing of  paperboard  or a lidding seal of  aluminum foil  or  plastic film . Blister packs are useful for protecting drugs against external factors, such as humidity and contamination for extended periods of time."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7574", "text": "Blister packing machinery is readily available and is suited to validation processes. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7575", "text": "Bottles are commonly used for liquid pharmaceuticals as well as formed tablets and capsules.   Glass is most common for liquids because it is inert and has excellent barrier properties.   Various types of plastic bottles are used both by drug producers as well as by pharmacists in a pharmacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7576", "text": "Prescription bottles have been around since the 19th century. [ 7 ]  Throughout the 19th and 20th centuries, prescription medication bottles were called  medicinal bottles . [ 7 ]  There are many styles and shapes of prescription bottles. [ 7 ]  Bottles would often include cotton to cushion powdery, breakable pills. In modern times, pills are coated, and thus the inclusion of a cotton ball is no longer necessary. The U.S.  National Institute of Health  recommends consumers remove any cotton balls from opened pill bottles, as cotton balls may attract moisture into the bottle. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7577", "text": "Prescription bottles come in several different colors, the most common of which being orange or light brown due to its ability to prevent  ultraviolet light  from degrading the potentially photosensitive contents through  photochemical reactions , while still letting enough visible light through for the contents to be easily visible. Other common colors include: Clear (for compounds that don't degrade in light), blue, dark brown, green, and various opaque hues. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7578", "text": "Many pharmaceutical products are sensitive to heat or cold. Controlled distribution systems and sometimes  cold chains  are  required."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7579", "text": "A mail order or  online pharmacy  usually ships orders by mail services or by small parcel carrier.  The shipment is not temperature-controlled and it may sit in a  mail box  upon delivery.  Conditions can include high or low temperatures outside of the recommended storage conditions for certain products. For example, the  USFDA  found that the temperature in a steel mailbox painted black could reach 136\u00a0\u00b0F (58\u00a0\u00b0C) in full sun while the ambient air temperature was 101\u00a0\u00b0F (38\u00a0\u00b0C). [ 10 ]   Insulated mailing envelopes are sometimes used."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7580", "text": "Larger shipments are sent in  insulated shipping containers  with  dry ice  or  gel packs . A digital  temperature data logger  or a  time temperature indicator  is often enclosed to monitor the temperature inside the container for its entire shipment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7581", "text": "Many dry pharmaceuticals are sensitive to moisture.  Tablets may become unstable and the drug may degrade.  High barrier packaging (including seals) is necessary but, by itself, is often not enough.\n Shelf life  of a moisture-sensitive drug can be extended by means of desiccants. [ 11 ] \nSeveral types of dessicants are available; the type and quantity need to be matched to the particular drug and package.  One common method is to include a small packet of dessicant in a bottle.  Other methods of including desiccants attached to the inner surface or in the material have recently been developed. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7582", "text": "Counterfeit drugs are a serious problem. People can potentially ingest useless or dangerous drugs without their knowledge. Custom package seals,  authentication  labels,  holograms , and  security printing  can be valued parts of an entire security system. [ 14 ]  They help verify that enclosed drugs are what the package says they are. Drug counterfeiters, however, often work with package counterfeiters, some of whom can be sophisticated. No packaging system is completely secure."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7583", "text": "Medication packaging includes a document that provides information about that drug and its use. In the US, this information is overseen by the Center for Drug Research and Evaluation (CDER), a branch of the Food and Drug Administration (FDA).  For  prescription medications , the insert is  technical , and provides information for  medical professionals  about how to prescribe the drug. Package inserts for prescription drugs often include a separate document called a \"patient package insert\" with information written in  plain language  intended for the  end-user  -- the person who will take the drug or administer the drug to another person. Inserts for  over-the-counter medications  are also written plainly. [ 15 ] [ 16 ] [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7584", "text": "In the US the document is called \"prescribing information\" or the \" package insert \" (PI) and layperson's document is called the \"patient package insert\" (PPI). [ 15 ]   In Europe the technical document is called the \"summary of product characteristics\" and the document for end-users is called the \"package leaflet\". [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7585", "text": "The bottle or box also has information printed on it, intended for the person taking the medication. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7586", "text": "All aspects of pharmaceutical production, including packaging, are tightly controlled and have regulatory requirements.   Uniformity, cleanliness ( washdown ), sterility, and other requirements are needed to maintain  Good Manufacturing Practices ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7587", "text": "Product safety management is vital.  A complete  Quality Management System  must be in place.  Validation involves collecting documentary evidence of all aspects of compliance. [ 20 ]   Hazard analysis and critical control points  is a methodology which has been proven useful. [ 21 ]   Quality assurance extends beyond the packaging operations through distribution and cold chain management; Good  distribution  practice is often a regulatory requirement.  Track and trace  systems are usually required."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7588", "text": "With a large portion of  pharmaceutical packaging being outsourced to  contract packagers ,  additional demand is being placed on specialty areas, i.e. specialty dosage forms. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7589", "text": "A  drug-eluting stent  (DES) is a tube made of a mesh-like material used to treat  narrowed arteries  in medical procedures both mechanically (by providing a supporting scaffold inside the artery) and pharmacologically (by slowly releasing a pharmaceutical compound). A DES is inserted into a narrowed  artery  using a delivery catheter usually inserted through a larger artery in the groin or wrist. The stent assembly has the DES mechanism attached towards the front of the stent, and usually is composed of the collapsed stent over a collapsed polymeric balloon mechanism, the balloon mechanism is inflated and used to expand the meshed stent once in position. The stent expands, embedding into the occluded artery wall, keeping the artery open, thereby improving blood flow. The mesh design allows for stent expansion and also for new healthy vessel endothelial cells to grow through and around it, securing it in place. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7590", "text": "A DES is different from other types of  stents  in that it has a coating that delivers medication directly into the blood vessel wall. The stent slowly releases a drug to prevent the growth of scar tissue and new obstructive plaque material which caused the original blood vessel stenosis, this clogging of a stent is termed  restenosis . A DES is fully integrated with a  catheter  delivery system and is viewed as one integrated  medical device . [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7591", "text": "DESs are commonly used in the treatment of narrowed arteries in the heart ( coronary artery disease ), but also elsewhere in the body, especially the legs ( peripheral artery disease ). [ 7 ]  Over the last three decades,  coronary stenting  has matured into a primary minimally invasive treatment tool in managing CAD. [ 8 ]  Coronary artery stenting is inherently tied to  percutaneous coronary intervention  (PCI) procedures. PCI is a minimally invasive procedure performed via a catheter (not by open-chest surgery), it is the medical procedure used to place a DES in narrowed coronary arteries.  PCI procedures are performed by an  interventional cardiologist  using  fluoroscopic imaging  techniques to see the location of the required DES placement. PCI uses larger peripheral arteries in the arms or the legs to thread a catheter/DES device through the arterial system and place the DES in the narrowed coronary artery or arteries. [ 7 ]  Multiple stents are often used depending on the degree of blockage and the number of diseased coronary arteries that are being treated. [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7592", "text": "A drug-eluting stent (DES) is a small mesh tube that is placed in the arteries to keep them open in the treatment of  vascular disease . The stent slowly releases a drug to block  cell proliferation  (a biological process of cell growth and division), thus preventing the arterial narrowing ( stenosis ) that can occur after stent implantation. While such stents can be used in various arteries throughout the body, they are commonly placed in the  coronary arteries  to treat  coronary heart disease . [ 11 ] [ 12 ] [ 13 ] [ 14 ]  DES products are integrated medical devices and are part of a  percutaneous coronary intervention  (PCI) delivery system. [ 15 ] [ 16 ] [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7593", "text": "DES is a medical device with several key properties: it functions as a structural scaffold, physically keeping an artery open to ensure blood flow; the device has specific drug delivery features, and the chosen drug is critical for its effectiveness. The drug, the hallmark compenent of the device, is selected for its suitability in inhibiting  restenosis  and its  pharmacokinetics . Apart from the drug, the materials used in the fabrication of the device are also essential and are carefully chosen for their  biocompatibility  and durability in a biological environment, such as human blood; these materials must also withstand the constant motion of the heart's beat and be suitable for future patient imaging using  magnetic resonance imaging  (MRI) technologies, which employ high  magnetic fields . [ 15 ] [ 16 ] [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7594", "text": "Other components, such as the catheter design, also play significant roles in the device's overall functionality and effectiveness. [ 15 ] [ 16 ] [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7595", "text": "DES are typically composed of metal alloys, most commonly  stainless steel  or  cobalt-chromium , but can also be made of other materials such as platinum-chromium or  nickel-titanium . The stent is often coated with a  polymer  to control the release of drugs. The role of polymers in drug delivery is significant as they regulate the rate at which the drug is released into the surrounding tissue. [ 19 ] [ 20 ]  There are also polymer-free stents where the drug is directly coated on the stent or contained in reservoirs within the stent. [ 21 ] [ 22 ] [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7596", "text": "The design of the stent includes  struts , which are thin wire structures that make up the stent frame. The strut thickness can influence the stent's performance, with thinner struts generally being associated with lower  restenosis  rates and reduced  thrombosis  risk. [ 25 ] [ 26 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7597", "text": "Most DES are balloon-expandable, meaning they are mounted on a balloon catheter and expand when the balloon is inflated. [ 27 ] [ 28 ]  There are also self-expanding stents, which automatically expand when deployed. The very first stent, introduced in 1986, was of this type. [ 29 ] [ 30 ] [ 31 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7598", "text": "The stent tube mesh is initially collapsed onto the catheter\u2014in this collapsed state, it is small enough to be passed though relatively narrow arteries and then expanded in its destination place, pushing firmly to the diseased artery wall. [ 33 ] [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7599", "text": "The pharmaceutical compounds that DES emit are  antiproliferative  agents such as  sirolimus ,  everolimus ,  zotarolimus ,  paclitaxel  and  biolimus . These drugs help prevent the arterial narrowing that can occur after stent implantation. [ 35 ] [ 36 ] [ 37 ]  These drugs are also used for other purposes, that involve moderating the  immune system  or treating cancer. They work by inhibiting cell growth. In DES, they are used in very small amounts and for a short time, and only in the area where the stent is placed. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7600", "text": "There is a distinction between  coronary stents  and peripheral stents. [ 7 ]  While both are used to prevent the narrowing of arteries, coronary stents are specifically for the  coronary arteries , while peripheral stents are for any other arteries in the body. [ 39 ] [ 40 ] [ 41 ]  Peripheral stents are mostly  bare metal  ones; some peripheral DES, of the self-expanding type, are used in arteries of the legs. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7601", "text": "Bioresorbable  DES are made of materials that can be absorbed by the body over time, potentially reducing potential long-term complications associated with permanent stents. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7602", "text": "Atherosclerosis is a chronic disease that affects the large and medium-sized arteries. It is characterized by the accumulation of calcium, fats (such as cholesterol) and other substances in the innermost layer of the endothelium, a layer of cells that line the interior surface of blood vessels. Atherosclerosis is considered to be the most common form of arteriosclerosis, which refers to the loss of arterial elasticity caused by thickening and stiffening of blood vessels. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7603", "text": "Atherosclerosis can begin as early as childhood with the development of small \"fatty streaks\" within arteries. These streaks are essentially deposits of fat. Over time, these initial lesions grow larger and become thicker, forming atheromas (atherosclerotic plaques). [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7604", "text": "Drug-eluting stents (DESs) are used in the treatment of atherosclerosis in both coronary interventions and peripheral arterial interventions: [ 45 ] [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7605", "text": "DESs are used in the management of atherosclerosis in both coronary and peripheral arterial interventions. [ 7 ]  They help improve blood flow and reduce the risk of restenosis, thereby improving patient outcomes. The use of DESs is accompanied by appropriate medical therapy and lifestyle modifications to manage atherosclerosis effectively. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7606", "text": "Stenosis of blood vessels refers to the narrowing of the blood vessels, which can restrict blood flow to the organs and tissues. [ 20 ]  This condition is often caused by the buildup of fatty deposits in the arteries, a process also called atherosclerosis. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7607", "text": "In the context of stents, stenosis is a significant concern. Stents are inserted into a narrowed artery during a procedure known as angioplasty. The stents help to open up the narrowed artery and improve blood flow. However, over time, the treated artery can close up again, a condition known as restenosis. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7608", "text": "Restenosis, or in-stent restenosis, is a blockage or narrowing that comes back in the portion of the artery previously treated with a stent. [ 20 ]  Restenosis tends to happen three to six months after the procedure. [ 20 ]  Restenosis is even more likely to occur if a stent would not have been used. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7609", "text": "When restenosis occurs, another procedure may be needed to correct the problem, such as the placement of a DES [ 20 ] [ 55 ]  that gradually release a drug compound that suppresses cellular growth, thereby reducing the potential for blockage within the stent area itself. [ 20 ] [ 55 ]  This therapy significantly reduces the occurrence of adverse events post-stenting. [ 20 ] [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7610", "text": "Technically, a DES in a mesh tube implant devices that is used in angioplasty procedures to treat stenosis of blood vessels and prevent restinosis: the stent, which elutes drugs, is implanted into the blood vessel to help keep the vessel open and improve blood flow. [ 56 ] [ 57 ] [ 58 ]  Specifically, drug-eluting stents are used in the treatment of various medical conditions usually at the site of stenotic or occlusive arterial lesions, but one of the primary medical uses is in the treatment of coronary artery disease. [ 59 ]  Stents are inserted into narrowed coronary arteries, where the narrowing is primarily caused by atherosclerosis. Stents are then expanded to open up the narrowed artery. Such stents gradually release a drug compound that suppresses  cellular growth , into the newly stented area, thereby reducing the potential for blockage within the stent area itself. [ 59 ]  Such blockage is termed in-stent restenosis (ISR). This in-stent blockage is most often caused by excessive  cell proliferation  or  thrombi  (blood clots).  Anticoagulation therapy  (blood thinners), has become a standard treatment following the placement of DES. This therapy significantly reduces the occurrence of adverse events post-stenting. [ 60 ] [ 61 ] [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7611", "text": "DESs have played a transformative role in the management of coronary artery disease. These stents are tiny, flexible mesh tubes employed during percutaneous coronary intervention (PCI) to address narrowed coronary arteries. What sets them apart is their special coating, which incorporates a drug delivery system that enables controlled release of medication over a specific period, typically within the first 30 to 45 days following implantation. This medication aids in inhibiting the formation of scar tissue within the stent and subsequent re-narrowing of the blood vessel. [ 63 ] [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7612", "text": "PCI is a minimally invasive procedure. It involves the placement of a drug-eluting stent (DES) in a coronary artery. This procedure, previously known as  angioplasty  with a stent, is considered non-surgical as it is performed through a small puncture in a peripheral artery, avoiding the need to open the chest wall. While bleeding from the puncture site was once a concern, advancements in PCI practices have mitigated this issue through the use of pressure bands and arterial closure systems. Modern DES/PCI procedures are generally painless, although some mild discomfort may be experienced. [ 65 ] [ 66 ] [ 67 ]  In PCI, multiple DES are sometimes implanted within a single patient; the decision to use multiple stents is typically contingent on the extent of the coronary artery disease present and the number of diseased coronary arteries that require treatment. [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7613", "text": "DESs have emerged as the primary therapeutic approach for managing symptomatic peripheral arterial disease (PAD). These specialized stents are now widely utilized in the treatment of peripheral arterial occlusive disease (PAOD), a condition that shares similarities with coronary artery disease but affects the peripheral arteries. By deploying DESs, healthcare professionals can effectively address and alleviate the complications associated with PAOD, enhancing patient outcomes and quality of life. [ 68 ] [ 69 ] [ 51 ]  The use of DESs in peripheral arterial interventions has shown encouraging results in terms of primary patency (PP) and target lesion  revascularization  (TLR) compared with bare-metal stents (BMSs). [ 70 ] [ 71 ] [ 52 ] [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7614", "text": "Different types of DESs are available on the market, each with different concentrations of drugs and showing varying efficacy. [ 52 ] [ 53 ]  Among the different DESs,  sirolimus -eluting stents and  everolimus -eluting stents were found to be more effective than  paclitaxel -eluting stents. [ 52 ] [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7615", "text": "PCI and stent placement are considered when someone shows signs of reduced blood flow in the arteries that supply the heart or when tests, such as different types of coronary artery imaging, show a blockage in those arteries. [ 72 ] [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7616", "text": "Symptoms can include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7617", "text": "In a medical setting, it's not very useful for doctors to rely solely on what people say about where their pain comes from or how it feels, because the way people describe chest pain caused by reduced blood flow to the heart can vary greatly and may not match what is typically taught in medical education or described in books and articles. [ 75 ] [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7618", "text": "DES is not recommended in some cases as it may do more harm than good. DES is not suitable:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7619", "text": "Bleeding disorders make DES unsuitable because of the need for anticoagulation drugs (blood thinners) during the procedure and in post-stenting aftercare. Other factors that could rule out the use of stents include a history of in-stent blockage, bleeding problems, complex or unsuitable coronary anatomy, or a short life expectancy due to other serious medical conditions. [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7620", "text": "Stent placement risks include bleeding, allergic reactions to the contrast agents used to visualize the coronary arteries, and myocardial infarction. With  percutaneous coronary intervention  (PCI), the requirement for emergency  coronary artery bypass graft (CABG) surgery  has decreased as better practices have been introduced. [ 81 ]   In some situations, coronary stenting is permitted in hospitals without cardiac surgery facilities, [ 82 ]  but such permission remains controversial because of the rare but unpredictable risk of coronary artery perforation. [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7621", "text": "A complication of coronary stenting is stent thrombosis (blood clots). This occurs when a new clot forms within the stent and occludes blood flow, causing a heart attack. [ 84 ] [ 85 ] [ 86 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7622", "text": "DES were designed to specifically combat issues of restenosis that occurred with older bare-metal stents (BMS). [ 70 ] [ 87 ]  Though less frequent with drug-eluting stents, restenosis can still occur. [ 88 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7623", "text": "Since the advent of DES technology, the incidence of ISR has significantly decreased. [ 89 ] [ 90 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7624", "text": "DES have been shown to be superior to BMS in reducing short-term complications of stenting in  saphenous vein  grafts. [ 91 ]  However, the use of DESs in  bypass grafts  was not their originally intended use nor within the scope of originally regulatory approval ( US FDA ,  European Medicines Agency , etc.). The practice of using a medical device or drug in a way not specified in the original or current approved labeling is often referred to as \" off-label \" use. [ 92 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7625", "text": "In regions were cardiac stenting has become commonplace, think tanks and advocacy groups express concern about the overzealous use of stents, [ 93 ]  because patients who received stents for unapproved reasons [ 94 ] [ 95 ]  often have worse outcomes compared to patients who received stents for approved uses. [ 96 ] [ 97 ] [ 98 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7626", "text": "People who receive a coronary stent have different needs depending on their medical condition. Some patients are actually having a heart attack and need immediate life-saving emergency care. Other patients are at high risk of having a heart attack in the very near future. For people from each of these groups, PCI procedures may vary slightly, with particular modifications as to how they are sedated, pain management, and broader  intensive care  issues such as breathing support. [ 99 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7627", "text": "Many people who are not in critical care situations are usually fully awake during the PCI procedure and DES placement, but they receive local anesthetic at the site of catheter entry, to ensure there is no pain. Different sedation and pain management practices are used by different medical institutions and practitioners, but patient comfort is always a primary consideration. [ 100 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7628", "text": "The catheter/stent system is inserted into the body by piercing a peripheral artery (an artery in the arm or leg) and moved through the arterial system to deliver the DES into the blocked coronary artery. The stent is then expanded to widen (open) blocked or narrowed coronary arteries (narrowed by plaque buildup), caused by a condition called atherosclerosis. Peripheral arterial access is usually through the femoral (upper leg) or the radial artery (arm/wrist) and less often done through the brachial or ulnar artery (wrist/arm). [ 101 ] [ 102 ]  In the past, controlling bleeding at the point of arterial access after the procedure was a problem.  Modern arterial pressure bands and arterial closure systems now exist, which have helped control bleeding after the procedure, but it is still a concern. [ 103 ] [ 104 ] [ 105 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7629", "text": "Modern catheter/stent systems are integrated medical devices, made of a guidewire, catheter, balloon, and stent. The stent tube mesh is initially collapsed onto the balloon of the device, and it is small enough to be passed through relatively narrow peripheral arteries. When in position, the balloon is inflated by introducing physiological saline, and this pushes the overlaying stent firmly into the diseased artery wall, inflation time and pressure are recorded during this placement procedure. After placement, the balloon is deflated, and the device is removed from the body, leaving the expanded stent in place and opening up the artery. [ 67 ] [ 106 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7630", "text": "The interventional cardiologist decides how to treat the blockage in the best way during the PCI/DES placement, based on real-time data. The cardiologist uses imaging data provided by both  intravascular ultrasound  (IVUS), and  fluoroscopic  imaging (combined with a  radiopaque  dye). During the procedure, the information obtained from these two sources enables the cardiologist to track the path of the catheter-DES device as it moves through the arterial blood vessels. This information also helps determine both the location and characteristics of any plaque causing narrowing in the arteries. Data from these two techniques is used to correctly position the stent and to obtain detailed information relating to the coronary arterial anatomy. Given that this anatomy varies greatly among individuals, having this information becomes a prerequisite for effective treatment. The obtained data is recorded on video and may be used in cases when further treatment is needed. [ 107 ] [ 108 ] [ 109 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7631", "text": "For many people the stenting procedure does not require staying in the hospital for any extended time period, most people leave the hospital the same day. Much of the time immediately after the stenting is spent in a recovery area to make sure the access site is not bleeding and to ensure vital signs are stable. [ 110 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7632", "text": "In most hospital settings, the interventional cardiologist who performed the procedure will speak directly with the patient/family and give them information about how things went, and follow-up instructions. The nursing staff will keep an eye on the person's condition and use tools like ECG to monitor their heart. To prevent a blood clot from forming in the stent, medications are given right after the procedure. One common medication is  plavix , which is a potent blood thinner that comes as a pill. Other medicines that thin the blood are also used, and it's typical to combine  aspirin  with  plavix . [ 111 ]  For people who have had a heart attack, the length of hospitalization is dependent on the degree of heart muscle damage caused by the event. [ 112 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7633", "text": "A catheter with DES is a medical device, so people who receive it are given a medical device card. This card has information on the implanted DES and a medical device serial number. This information is important for future medical procedures, because it helps the doctors to know what type of device is in the person's body. Some arterial closure systems, which are devices that help to seal the access site after the procedure, are also medical devices and have their own informational cards. [ 113 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7634", "text": "The access site is the place where the catheter enters the artery in the arm or leg. There is usually soreness and bruising at this site. This bruising and soreness usually get better after a week or so. People are advised to rest for a week or two and not to lift heavy things. This is mainly to make sure the access site heals well. It is normal to have follow-up appointments with a cardiologist or a primary care provider/general practitioner within a week or two of the procedure. [ 114 ] [ 115 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7635", "text": "People who get a coronary stent usually have more check-ups every three to six months for the first year, but this can vary. They usually do not need to have another  coronary angiography , which is a test that uses a special dye and X-rays to see the arteries of the heart. If the doctors suspect that the heart disease is getting worse, they can prescribe a stress test, which is a test that measures how the heart works during physical activity. People who have symptoms or show signs of reduced blood flow to the heart in a stress test may need to have a diagnostic cardiac re-catheterization. [ 116 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7636", "text": "After PCI-stenting procedures, physical examinations are important. People who have a high risk of complications or more complex coronary problems may need to have angiography. This may be the case even if the results of non-invasive stress tests, which are tests that measure how the heart works during physical activity, appear normal. [ 117 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7637", "text": "Cardiac rehabilitation activities depend on many factors, but mainly on how much the heart muscle was damaged before the PCI/DES procedure. Many people who have this procedure have not had a heart attack, and their hearts may be fine. Others may have had a heart attack and their hearts may have trouble pumping oxygen-rich blood to the body. Rehabilitation activities are tailored to each person's needs. [ 118 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7638", "text": "DES are an improvement over older BMS devices as they reduce the chances of in-stent blockages. This reduces the incidence of serious post-stenting events such as, angina occurrence or recurrence, heart attacks, and death. They also reduce the likelihood of requiring another PCI procedure to open a blockage caused by the actual stent. [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7639", "text": "The major benefit of drug-eluting stents (DES) when compared to bare-metal stents (BMS) is the prevention of in-stent restenosis (ISR). [ 70 ]  Restenosis is a gradual re-narrowing of the stented segment that occurs most commonly between 3\u201312 months after stent placement. [ 119 ]  High rates of restenosis associated with BMS prompted the development of DES, which resulted in a reduction of ISR incidence to around 5-10%. [ 120 ]  Continued development of newer generation DES have resulted in the near-elimination of BMS from clinical practice. [ 121 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7640", "text": "A key benefit of DES usage compared to BMS is a lower incidence of repeat revascularization procedures (re-stenting, invasive bypass surgeries etc.). Revascularization procedures are treatments that restore blood flow to parts of the heart that are not getting enough blood, a problem called ischemia. This can happen because of plaque buildup in the arteries of the heart, which can narrow or block them. [ 122 ]  Rates of repeat revascularizations and stent thrombosis (blood clots) are significantly lower in those who received DES compared to BMS. [ 120 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7641", "text": "Newer generations of DES devices have substantially improved safety outcomes, specifically regarding stent thrombosis, recurrent  myocardial infarctions , and death. [ 122 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7642", "text": "There are a number of very detailed medical device design considerations for DES products, these considerations are included in submissions for approval to regulatory authorities such as the US FDA: [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7643", "text": "The drug choice is a critical design element and determining its true effectiveness in inhibiting  neointimal  growth due to the proliferation of smooth muscle cells that would cause restenosis can be a design challenge. Much of the  neointimal hyperplasia  seems to be caused by inflammation. [ 123 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7644", "text": "Vascular stents are classified by the US as class III medical devices, [ 124 ]  meaning that they pose the highest risk to patients and are subject to both general and  premarket approval , which requires clinical trials and scientific evidence of safety and effectiveness, as well as rigorous mechanical testing. [ 125 ]  During the mechanical testing process, universal testing machines induce bending, stretching, twisting, and putting pressure on vascular stents from various angles. [ 124 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7645", "text": "The specific properties of each type of stent and its intended use depend on the results of testing, and vice versa: different types of stents may need different or additional tests based on where they will be placed in the body and what they will be used for. Some of these additional tests might include checking how well the stent can withstand being crushed or bent out of shape, its resistance to getting kinks in it, whether it resists corrosion or damage over time, as well as making sure any coatings on the device remain intact. [ 124 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7646", "text": "Pharmacological therapy  for coronary artery disease may be indicated instead of or in addition to invasive treatment. For those requiring  percutaneous coronary intervention  or surgery, medical therapy should be viewed as complementary to revascularization procedures, rather than an opposing strategy.  Coronary artery bypass graft  (CABG) surgery is an alternative to percutaneous coronary intervention (PCI) with drug-eluting stents (DES) for patients with ischemic left ventricular systolic dysfunction (LVSD). CABG is associated with lower risks of all-cause mortality, repeat revascularization, and myocardial infarction compared to PCI. However, there is no significant difference between the two procedures in terms of cardiovascular mortality, stroke, major adverse cardiovascular and cerebrovascular events, and ventricular tachycardia. [ 126 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7647", "text": "The first procedure to treat blocked  coronary arteries  was  coronary artery bypass graft  surgery (CABG), wherein a section of vein or artery from elsewhere in the body is used to bypass the diseased segment of the coronary artery. In 1977,  Andreas Gr\u00fcntzig  introduced  percutaneous transluminal coronary angioplasty  (PTCA), also called balloon angioplasty, in which a catheter was introduced through a peripheral artery and a balloon expanded to dilate the narrowed segment of the artery. [ 127 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7648", "text": "As equipment and techniques improved, the use of PTCA rapidly increased, and by the mid-1980s, PTCA and CABG were being performed at equivalent rates. [ 128 ]  Balloon angioplasty was generally effective and safe, but restenosis was frequent, occurring in about 30\u201340% of cases, usually within the first year after dilation. In about 3% of balloon angioplasty cases, failure of the dilation and acute or threatened closure of the coronary artery (often because of dissection) prompted emergency CABGs. [ 128 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7649", "text": "Charles Theodore Dotter  and  Melvin Judkins  had proposed using prosthetic devices inside arteries in the leg to maintain blood flow after dilation as early as 1964. [ 129 ]   In 1986, Puel and Sigwart implanted the first coronary stent in a human patient. [ 130 ]  Several trials in the 1990s showed the superiority of stent placement over balloon angioplasty.  Restenosis was reduced because the stent acted as a scaffold to hold open the dilated segment of the artery. Acute closure of the coronary artery (and the requirement for emergency CABG) was reduced, because the stent repaired dissections of the arterial wall. By 1999, stents were used in 84% of  percutaneous  coronary interventions (i.e., those done via a catheter, and not by open-chest surgery). [ 130 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7650", "text": "Early difficulties with coronary stents included a risk of early  thrombosis  (clotting) resulting in occlusion of the stent. [ 128 ]  Coating stainless steel stents with other substances such as platinum or gold did not eliminate this problem. [ 130 ]  High-pressure balloon expansion of the stent to ensure its full apposition to the arterial wall, combined with drug therapy using aspirin and another inhibitor of  platelet  aggregation (usually  ticlopidine  or clopidogrel) nearly eliminated this risk of early stent thrombosis. [ 128 ] [ 130 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7651", "text": "Though it occurred less frequently than with balloon angioplasty or other techniques, stents nonetheless remained vulnerable to restenosis, caused almost exclusively by neointimal tissue growth (tissue formation in the inner 'tube'  structure of the artery). To address this issue, developers of drug-eluting stents used the devices themselves as a tool for delivering medication directly to the arterial wall.  While initial efforts were unsuccessful, the release (elution) of drugs with certain specific physicochemical properties from the stent was shown in 2001 to achieve high concentrations of the drug locally, directly at the target lesion, with minimal systemic side effects. [ 131 ]   As currently used in clinical practice, \"drug-eluting\" stents refers to metal stents that elute a drug designed to limit the growth of neointimal scar tissue, thus reducing the likelihood of stent  restenosis . [ 132 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7652", "text": "The first type of DES to be approved by the  European Medicines Agency  (EMA) and the  US Food and Drug Administration  (FDA) were sirolimus-eluting stents (SES), which release a natural product called  sirolimus , [ 133 ]  an immunosuppressant drug. [ 134 ]  SES were shown to reduce the need for repeat procedures and improve the outcomes of patients with coronary artery disease. [ 135 ] [ 136 ] [ 137 ]  The sirolimus-eluting Cypher stent received CE mark approval in Europe in 2002, and then underwent a larger trial to demonstrate its safety and effectiveness for the US market. [ 138 ] [ 139 ] [ 140 ]  The trial, published in 2003, enrolled 1058 patients with more complex lesions and confirmed the superiority of SES over bare metal stents in terms of angiographic and clinical outcomes. [ 141 ] [ 142 ] [ 143 ] [ 144 ]  Based on these results, the Cypher stent received FDA approval and was released in the US in 2003. [ 130 ]  The FDA approval process for DES involves submitting an investigational device exemption (IDE) application to conduct clinical trials under 21 CFR Part 812, and then a premarket approval (PMA) application to obtain marketing authorization under 21 CFR Part 8144. The FDA assigns the primary review responsibility to the Center for Devices and Radiological Health (CDRH), but also consults with the Center for Drug Evaluation and Research (CDER) for the drug component of the combination product."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7653", "text": "The second type of DES to be approved by the EMA and the FDA were paclitaxel-eluting stents (PES), which release another natural product called  paclitaxel . PES also reduced the need for repeat procedures and improved the outcomes of patients with different types of lesions and risk factors. The paclitaxel-eluting Taxus stent received FDA approval and was launched in the US in 2004, [ 145 ]  after a series of trials that compared it with a bare metal stent in various settings. The trials showed a significant reduction in target lesion revascularization and major adverse cardiac events with the Taxus stent at 9 and 12 months. Both SES and PES use natural products as the active agents to prevent the recurrence of blockages in the arteries. [ 146 ]  These DES have changed the practice of interventional cardiology and have become the preferred treatment for many patients with coronary artery disease. [ 146 ] [ 147 ] [ 148 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7654", "text": "The initial rapid acceptance of DES led to their peak usage in 2005, accounting for 90% of all stent implantations, but concerns about late stent thrombosis led to a decrease in DES usage in late 2006. Subsequent studies reassured the medical community about their safety, showing that while DES may have a slightly higher risk for very late stent thrombosis, they significantly reduce target vessel revascularization without increasing the incidence of death or myocardial infarction; these reassurances led to a resurgence in DES utilization, although it did not reach the peak usage rates seen in early 2006. [ 149 ] [ 150 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7655", "text": "The concept of using absorbable (also called biodegradable, bioabsorbable or bioresorbable) [ 151 ]  materials in stents was first reported in 1878 by Huse who used magnesium wires as ligatures to halt the bleeding in vessels of three patients. Despite extensive search, the full name of this pioneer in the field remains elusive. [ 151 ] [ 152 ]  In 20th century, a resorbable stent tested in humans was developed by the Igaki Medical Planning Company in Japan and was constructed from poly-L-lactic acid (a form of  polylactic acid ); they published their initial results in 2000. [ 153 ]  The German company  Biotronik  developed a  magnesium  absorbable (bioresorbable) stent and published clinical results in 2007. [ 153 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7656", "text": "The first company to bring a bioresorbable stent to market was  Abbott Vascular  which received European marketing approval in September 2012; the second was Elixir which received its CE mark in May 2013. [ 154 ] [ 155 ] [ 156 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7657", "text": "Despite the initial promise, the first-generation bioresorbable stents, such as the Absorb bioresorbable stent by Abbott, faced significant challenges in their performance. In comparison to current-generation drug-eluting stents, numerous trials revealed that these first-generation bioresorbsble stents exhibited poor outcomes. Specifically, they showed high rates of stent thrombosis (cases where an implanted coronary stent caused a thrombotic occlusion), target-lesion myocardial infarction (heart attack occurring at the site of the treated lesion), and target vessel revascularization (the need for further procedures to restore blood flow in the treated artery). In 2017, Abbott pulled its bioabsorbable stent, Absorb, from the European market after negative press regarding the device. [ 157 ]   Boston Scientific  also announced termination of its Renuvia bioresorbable coronary stent program as studies showed higher risk of serious adverse events. [ 158 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7658", "text": "Currently, fully bioresorbable stents do not play a significant role in coronary interventions. [ 159 ] [ 160 ] [ 161 ]  While various manufacturers are proposing new stents and continuing their development, [ 162 ]  it remains uncertain whether they will have a substantial impact, unless there will be more data from their clinical trials. As of now, these stents are not widely utilized in practice. [ 163 ] [ 164 ] [ 159 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7659", "text": "Due to challenges in developing resorbable stents, many manufacturers have focused efforts on targeting or reducing drug release through bioabsorbable-polymer coatings. Boston Scientific's Synergy bioabsorbable polymer stent has been shown potential to reduce the length of dual antiplatelet therapy post-implantation. [ 165 ]   MicroPort's  Firehawk target eluting stent has been shown to be non-inferior to traditional drug-eluting stents while using one-third of the amount of equivalent drug. [ 166 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7660", "text": "As for the materials used to make a DES, the first DES products available for treating patients were stainless steel alloys composed of iron, nickel, and chromium and were based on existing bare metal stents. [ 123 ]  These stents were hard to visualize with medical imaging, posed a risk of causing allergic responses, and were difficult to deliver. Subsequent new alloys were used, namely  cobalt-chrome  and platinum chrome, with improved performance.  Bioresorbable stents  have been developed in which the stent itself dissolves over time. [ 58 ]  Materials explored for use include  magnesium ,  polylactic acid ,  polycarbonate  polymers, and  salicylic acid  polymers. [ 153 ]   Resorbable stents have held the promise of providing an acute treatment that would eventually allow the vessel to function normally, without leaving a permanent device behind. [ 167 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7661", "text": "For the coating of DES, one to three or more layers of  polymer  can be used: a base layer for adhesion, a main layer that holds and elutes (releases) the drug into the arterial wall by contact transfer, and sometimes a top coat to slow down the release of the drug and extend its effect. The first few drug-eluting stents to be licensed used durable coatings. The first generation of coatings appears to have caused immunological reactions at times, and some possibly led to thrombosis. This has driven experimentation and the development of new coating approaches. [ 154 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7662", "text": "A research direction for a DES is to improve the material from which a device is made. The first-generation DES were made of stainless steel, while contemporary DES mainly consist of different kinds of alloys such as cobalt chromium and platinum chromium. In the current generation DES, thinner struts are employed than in the first-generation DES with preserved radial strength and radio-opacity. The lower strut thickness is believed to be associated with better stent-related outcomes including target lesion revascularization, myocardial infarction, and stent thrombosis. [ 168 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7663", "text": "Another area of research for DES focuses on polymers. The current generation DES includes both durable polymer-coated stents and biodegradable polymer-coated stents. It has been reported that the presence of a durable polymer in the body over a long period can lead to chronic inflammation and neoatherosclerosis. To address this potential limitation, researchers have developed biodegradable polymer DES as an alternative solution. [ 168 ] [ 169 ] [ 170 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7664", "text": "Scientists are also studying different drugs that could be used in DES to prevent restenosis. These drugs, which have immunosuppressive [ 134 ]  and anti-cancer properties, aim to inhibit the growth of smooth muscle cells. Additionally, there is a specific type of stent that features an extra layer of anti-CD4 antibodies on its struts. This additional layer is positioned on top of the polymer coating and aims to capture circulating endothelial progenitor cells. The goal behind this design is to promote improved healing of the blood vessel lining, known as the  endothelium . [ 168 ] [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7665", "text": "A potential research focus for DES is the application of a polymer-free DES in clinical practice: moving away from polymer-based DES and instead using either a polymer-free DES or a drug-coated coronary stent. In the case of the polymer-free DES, it utilizes an abluminal coating of probucol to control the release of sirolimus. On the other hand, the drug-coated coronary stent has a micro-structured abluminal surface that allows for direct application of an anti-restenotic drug. [ 168 ] [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7666", "text": "As of 2023 [update]  there are over 20 different types of drug-eluting stents available, with differences in features and characteristics. [ 171 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7667", "text": "The economic evaluation of DES has been a topic of extensive research. [ 172 ]  In 2007, the overall incremental cost-effectiveness ratio in Europe was \u20ac98,827 per quality-adjusted life-years gained. Avoiding one revascularization with DES would cost \u20ac4,794, when revascularization with BMS costs \u20ac3,2606. [ 173 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7668", "text": "There were controversies related to the use of DES. In 2012, a  meta-analysis  of clinical trial data [ 174 ]  showed no benefit of the use of DES for people with stable coronary artery compared to treatment with drugs, yet,  The New York Times  interviewed David Brown, an author of the analysis, who said that more than half of patients with stable  coronary artery disease  were implanted with stents without even trying drug treatment and that he believed this happened because hospitals and doctors wanted to make more money. [ 175 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7669", "text": "The interview sparked a debate among cardiologists, researchers, and patients about the appropriateness and effectiveness of DES for stable coronary artery disease: some agreed with the study's findings and questioned the overuse of stents, [ 176 ] [ 177 ] [ 178 ]  while others criticized the study's methods and limitations and defended the benefits of stents, arguing that the interviewee's statement was \"outrageous and defamatory\" and that he was \"insulting the integrity of the entire profession. [ 179 ] [ 180 ] [ 181 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7670", "text": "In 2013 the Times of India reported that DES were widely overused and that Indian distributors used profits from high  markups  on DES to bribe doctors to use them. [ 182 ] [ 183 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7671", "text": "In 2014 an investigation by the  Maharashtra  Food and Drug Administration found that high markups and bribery related to DES was still widespread. [ 184 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7672", "text": "There have been several patent disputes related to drug-eluting stents. In one of them, Boston Scientific Corporation (BSC) has been found guilty of infringing upon a patent awarded to the University of Texas at Arlington in 2003 and licensed to TissueGen. [ 185 ] [ 186 ] [ 187 ]  This patent involves technology developed by TissueGen founder Kevin Nelson, during his time as a faculty member at the University. The technology is designed to deliver drugs through an extruded fiber within an implanted vascular stent. As a result, BSC has been ordered to pay $42 million in lost royalties to both TissueGen and the University [ 185 ] [ 186 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7673", "text": "Drug-eluting stents have been associated with legal and ethical controversies, and there have been related class action lawsuits. In 2014, the former owners of St. Joseph Medical Center in Maryland settled a class action lawsuit for $37 million with hundreds of patients who received unnecessary DES implantation. The lawsuit alleged that Dr. Mark Midei, a cardiologist at the center, falsified the degree of coronary artery stenosis to justify the use of DES, exposing the patients to increased risks of thrombosis, bleeding, and infection. Another DES manufacturer, Cordis Corporation, a subsidiary of Johnson & Johnson, was involved in lawsuits from people who suffered adverse events from the Cypher Stent, a stainless-steel DES coated with sirolimus, [ 188 ] [ 189 ]  an immunosuppressant drug. [ 134 ]  The Cypher Stent was approved by the FDA in 2003, but soon after, the FDA issued a Safety Warning following 290 reports of subacute thrombosis and at least 60 deaths related to the device. [ 188 ] [ 189 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7674", "text": "Dry shampoo  otherwise known as hybrid shampoo is a type of  shampoo  which reduces  hair greasiness  without the need for water. It is in powder form and is typically administered from an  aerosol  can. Dry shampoo is often based on  corn starch  or rice starch. [ citation needed ]  In addition to cleansing hair, it can also be used as a tool for hair-styling as it can create volume, help tease hair, keep  bobby pins  in place, and be used in place of  mousse  in wet hair. [ 1 ]  Dry shampoo proponents attest that daily wash-and-rinse with detergent shampoo can strip away natural oils from hair. [ 2 ]  However, others attest that spraying dry shampoo every day will lead to a build-up of product that can dull hair color and irritate the scalp, arguing that the scalp needs regular cleansing and  exfoliating  to get rid of  bacteria , remove dead skin cells, and stay healthy. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7675", "text": "The powders within dry shampoo are meant to absorb the  sebum  in hair, which is excreted from  sebaceous glands  and can give hair a greasy appearance when the oil is overproduced. By absorbing the oils, the greasy appearance of the hair is improved; however, the absorbed oils and powders remain in the scalp, so the hair may appear clean but feel unclean to the user. [ 4 ]  The user may need to wash their hair with traditional  shampoos  to actually remove the oils and dry shampoo powder in order for the scalp and hair to feel and appear clean."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7676", "text": "Throughout history, people have used powder-based products similar to dry shampoo to cleanse and improve the appearance of hair. Evidence suggests that people in Asia used clay powder to clean their hair as early as the late 15th century. [ 5 ]  During the  Elizabethan era , a lack of regular bathing made clay powders popular among women to cleanse their hair of excess dirt and oil. Some powders were even colored for decorative purposes. [ 6 ]  Powders were also used by 18th-century British and American elites to absorb the oils in hair and wigs at a time when long hair was a marker of masculine privilege. [ 7 ]  The first written reference of dry shampoo in the United States is from the late 1700s, when starches were used to deodorize and alter the color of wigs. [ 8 ]  Other early mentions of dry shampoo include foam substances used by barbers to clean hair in the late 1800s. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7677", "text": "The first commercially produced dry shampoo was sold in the 1940s, but the product existed before that. By the early 1940s, the Stephanie Brooke Company of Jersey City, New Jersey had developed Minipoo, the first brand of commercially produced dry shampoo powder. Minipoo was marketed to women and children for use in scenarios such as \"surprise dates\" or when they were sick in bed, according to the  Smithsonian 's  National Museum of American History . [ 10 ]  Since 1790, 71 patents have been filed for dry shampoo products in the United States. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7678", "text": "Dry shampoo is generally composed of a carrier agent containing an active powder. [ 12 ]  Normally,  starch  is used as the active powder. When the powder is sprayed onto hair, the carrier agent evaporates while the starch remains attached. While the active powder can be replaced with other substances such as  activated carbon  and  alumina , these substances are generally not used due to their inability to biodegrade. In particular, activated carbon and alumina leave behind a residue that is difficult to remove. [ 13 ]  Presently,  oryza sativa  starch and  cetrimonium chloride  are the most common starches used in dry shampoos. Dry shampoo in the form of aerosol also often contains a propellant ingredient. [ 14 ]  The propellant used in dry shampoo usually consists of  butane ,  isobutane , and  propane , which makes up 70\u201390% of the total composition. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7679", "text": "Dry shampoos often contain  anionic surfactants  that do not dissolve in water. The surfactant molecules have a hydrophilic portion as well as a hydrophobic portion to bind with water and oils. Surfactants such as detergents rely heavily on micelle formations.  Amphiphile  molecules organize into small clusters of micelles with the hydrocarbon non-polar ends facing inwards. [ 15 ]  When dry shampoo is applied, amphiphile molecules surround suspended oil drops which then can be removed. The anionic substances often leave a form of calcium salts, which are not soluble, in the hair strands that causes hair to be dry and tangled. The alkaline residue may also cause hair and skin irritations. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7680", "text": "Dry shampoo can be administered as a powder, where all the ingredients of dry shampoo are combined together and applied to the scalp with the hand, or through the aerosol form where the dry shampoo is sprayed directly onto the head. In the aerosol form, the powders comprising the dry shampoo are dispersed throughout pressurized gas inside a can; when the release is pressed, the pressurized gas and powders inside are released, forming the aerosol that lands on the head or scalp. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7681", "text": "This product has also been made at home, in addition to being purchased in stores.  DIY  dry shampoos usually have some sort of starch base, which is one of the key products in commercially produced dry shampoos, and often contains  essential oils  for scent. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7682", "text": "Herbal powder shampoos are another form of dry shampoo. As a natural hair-care product, they tend to have fewer negative side effects than traditional mass-market shampoos, and contain a dry powder mixture of  aloe vera  and other plant byproducts to reduce skin, eye, and scalp irritation from  surfactants . [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7683", "text": "Clay  has been used throughout history as a form of dry shampoo. The  Rhassoul  clay, also known as red clay, originating from Morocco is traditionally used as a leave-in shampoo and conditioner. Due to its high absorbance of sebum, clay is often used as a remedy for  dandruff  and  seborrhea . Such properties of clay stem from its colloidal particle size and crystalline structure. Even though clay is generally considered to be a natural non-toxic material, it should not be stored in metal containers due to its retention of heavy metals. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7684", "text": "In addition to the liquid shampoos, there are dry shampoos available for pets with fur. The waterless-foaming shampoo is applied directly into the fur of the pet without the need to pre-wet or rinse the pet after application. These shampoos often contain a combination of detergents, antimicrobial agents, and surfactants. Certain conditioners may also contain additional agents such as  Melaleuca  oil for the treatment of fleas. [ 21 ]  The foaming component of the shampoo comes from a pressurized gas such as carbon dioxide mixing with a foaming liquid. Once the foam is applied to the fur, the foam needs to be worked in vigorously before being wiped off."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7685", "text": "The product is applied to the scalp or roots of the hair, either through aerosol form or directly applying the powder, the powder within the product is allowed to sit on the hair for an extended period of time, and then the powder is massaged or brushed through the scalp. [ 22 ]  Allowing the product to sit in the hair before brushing it out allows more time for the product to absorb the sebum oils in the hair and brushing out the product would reduce the powder's potentially noticeable appearance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7686", "text": "A  dry-powder inhaler  ( DPI ) is a device that delivers medication to the lungs in the form of a dry powder.  DPIs are commonly used to treat  respiratory diseases  such as  asthma ,  bronchitis ,  emphysema  and  COPD  although DPIs (such as  inhalable insulin ) have also been used in the treatment of  diabetes mellitus . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7687", "text": "DPIs are an alternative to the aerosol-based inhalers commonly called  metered-dose inhaler  (or MDI). The DPIs may require some procedure to allow a measured dose of powder to be ready for the patient to take. The medication is commonly held either in a capsule for manual loading or in a proprietary form inside the inhaler. Once loaded or actuated, the operator puts the mouthpiece of the inhaler into their mouth and takes a sharp, deep inhalation (ensuring that the medication reaches the lower parts of the lungs), holding their breath for 5\u201310 seconds."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7688", "text": "There are a variety of such devices. The dose that can be delivered is typically less than a few tens of milligrams in a single breath since larger powder doses may lead to provocation of  cough ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7689", "text": "Most DPIs rely on the force of patient inhalation to entrain powder from the device and subsequently break-up the powder into particles that are small enough to reach the lungs. [ 2 ]  For this reason, insufficient patient inhalation flow rates may lead to reduced dose delivery and incomplete deaggregation of the powder, leading to unsatisfactory device performance. Thus, most DPIs have a minimum inspiratory effort that is needed for proper use and it is for this reason that such DPIs are normally used only in older children and adults."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7690", "text": "While DPIs are commonly used in the treatment of lung-based disorders, their use requires dexterity to complete the required sequential steps to achieve application of these devices. Incorrect completion of one or more steps in the use of a DPI can substantially reduce the delivery of the administrated medication and consequently its effectiveness and safety. Numerous studies have demonstrated that between 50 and 100% of patients do not use their inhaler devices correctly, with patients often unaware that they are using their inhaled medication incorrectly. [ 3 ] [ 4 ]  Incorrect inhaler technique has been associated with poorer outcomes. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7691", "text": "Some powder inhalers use  lactose  to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7692", "text": "It has been suggested that such  lactose  may be harmful to  lactose intolerant  people, [ 6 ]   and some doctors advise patients not to use lactose containing DPIs [ 7 ]  to minimize the risk of hypersensitivity reactions. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7693", "text": "DPI medication must be stored in a dry place in a temperature of not more than 25\u00a0\u00b0C (77\u00a0\u00b0F) and humidity between 40 and 50% in a sealed packaging, since exposure of the powder to moisture degrades the ability of the device to disperse its medication as a fine powder upon inhalation. Some medication also needs photo protection."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7694", "text": "A  dual therapy stent  is a  coronary artery stent  that combines the technology of an  antibody -coated  stent  and a  drug-eluting stent . [ 1 ]  Currently, second-generation  drug-eluting stents  require long-term use of  dual-antiplatelet therapy , which increases the risk of major bleeding occurrences in patients. [ 2 ]  Compared to  drug-eluting stents , dual therapy stents have improved vessel regeneration and cell proliferation capabilities. [ 1 ] [ 2 ]  As a result, dual therapy stents were developed to reduce the long-term need for  dual-antiplatelet therapy . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7695", "text": "The COMBO stent is the first and only dual therapy stent that addresses the challenges of vessel healing in  drug-eluting stents . [ 4 ]  This stent is an  anti-CD34 antibody -coated and  sirolimus -eluting bioresorbable stent. [ 2 ]  The COMBO stent combines the  Genous  stent's  endothelial cell  capture technology with an antiproliferative, biodegradable  sirolimus  drug elution. [ 5 ]  The COMBO stent has received  CE Mark approval . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7696", "text": "The field of  interventional cardiology  began in the 20th century with the development of the  plain old balloon angioplasty . [ 4 ]  However, this procedure carried risks of promoting  platelet aggregation , tearing, arterial recoil, and  restenosis . [ 4 ]  Thus, coronary artery stents were created to prevent  restenosis  after  balloon dilation . [ 4 ]  There are three types of stents:  bare-metal stents  (BMS),  drug-eluting stents  (DES), and bioresorbable vascular scaffolds (BRS). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7697", "text": "The first stents created were bare-metal stents where they were made from stainless steel and had poor flexibility. Despite its reduced rates of  restenosis  compared to  plain old balloon angioplasty , it still had high rates of  stent thrombosis  and required a high dosage of  blood thinners . [ 4 ]  This led to the development of  drug-eluting stents  to act as local drug delivery and vascular scaffold platform to reduce  in-stent restenosis . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7698", "text": "Antiproliferative drugs  like  sirolimus  and  paclitaxel  were used in the first-generation  drug-eluting stents  to inhibit the migration of  vascular smooth muscle cells  and  restenosis . [ 4 ] [ 1 ]  The first implanted  drug-eluting stent  occurred in 1999, which revolutionized the course of  interventional cardiology . [ 1 ]  However, despite the  drug-eluting stents  superiority over the  bare-metal stents , drug-eluting stent implantation had possible concerns over  platelet aggregation  and significant  blood clotting  in a localized area. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7699", "text": "As a result, improvements in the stent material, strut thickness, polymer, and drug choice led to the development of  second-generation drug-eluting stents  that showcased overall clinical enhancements to its predecessor. [ 4 ] [ 1 ]  The new stent used more biocompatible molecules like  zotarolimus  and  everolimus  with quicker drug elution. [ 4 ]  However, despite these improvements, concerns persisted on the risk of  stent thrombosis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7700", "text": "The development of dual therapy stents resulted from the health risks of long-term use of  dual antiplatelet therapy  from  drug-eluting stents . [ 2 ]   Drug-eluting stents  inhibit the growth of  endothelial cells  and  vascular smooth muscle cells , which are essential for in-stent endothelialization. [ 1 ]  Due to inhibition of vital vascular system cells, this causes risk of stent thrombosis, and, thus, patients with  drug-eluting stents  are required to use  dual antiplatelet therapy  for approximately 12 months. [ 2 ]  Although long term use of  dual antiplatelet therapy  research showcases reduced risk of cardiovascular deaths, it has increased occurrences of major bleeding events, which has challenges for patients with  bleeding disorders . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7701", "text": "The COMBO dual therapy stent is the first and only dual therapy stent presently developed. [ 1 ]  The COMBO dual therapy stent combines the  anti-CD34 antibody  coating of the  Genous Stent  with antiproliferative  sirolimus  elution. [ 1 ]  The  sirolimus  drug reduces the risk of  stent restenosis  through inhibiting the formation of  neointima  while the  anti-CD34 antibody  coating reverses the inhibition of local  endothelial cells  from the  sirolimus  elution. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7702", "text": "The predecessor of the biotechnology used to create a dual therapy stent was the development of the  Genous stent . [ 1 ]  The  Genous stent  is a coronary artery stent coated with  anti-CD3 monoclonal antibodies  that bind with circulating endothelial cells to the stent. [ 7 ]  The coated stent promotes the formation of an  endothelial layer , which protects against  thrombosis  and reduces  restenosis . [ 7 ]   Furthermore, the Genous stent promotes coronary vascular repair response and reduces  neointimal hyperplasia  after stent implantation. [ 8 ]   Although the Genous stent promotes rapid vessel healing, it did not decrease the rate of target lesion failure compared to  drug-eluting stents , which increases the risk of  restenosis  and  stent  failure. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7703", "text": "The COMBO stent is a pro-healing stent with  sirolimus  drug elution and anti-CD3 monoclonal antibodies that has enhanced degree of endothelization. [ 10 ]  The stent has an abluminal, facing vessel wall, bioabsorbable coating that continuously releases  sirolimus  and a luminal  anti-CD34 antibody  cell capture coating. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7704", "text": "The COMBO stent's enhanced endothelization is due to the  sirolimus  drug that reduces the risk of stent  restenosis  and the  Genous stent 's  anti-CD3 antibodies  capture biotechnology. [ 8 ]  The COMBO stent reduces not only the rate of  stent restenosis  but also the need for  dual antiplatelet therapy , which enables high-risk patient groups like patients who are under long-term  anticoagulation regimens  or patients with  bleeding disorders  to use this type of stent. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7705", "text": "Ear drops  are a form of  topical medication  for the ears used to treat  infection, inflammation ,  impacted ear wax   and  local anesthesia . They are commonly used for short-term treatment and can be purchased with or without a prescription. Before using ear drops, refer to the package insert or consult a health professional for the amount of drops to use and the duration of treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7706", "text": "Prior to using the medication, refer to package label for specific instructions or ask a local pharmacist. Check to make sure a  tamper-evident  seal is intact and the medication is not expired. Let a health care provider know of any drug allergies to any medications or other ingredients in the medication. Let a healthcare provider know what was prescribed and what over the counter medications, vitamins, supplements, and herbal supplements are being taken with this medication. If pregnant, planning to become pregnant, or breastfeeding, make sure to inform a healthcare before using any medications. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7707", "text": "Always wash hands with soap and water for 30 seconds prior to administering ear drops and after administering."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7708", "text": "For adults and teenagers: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7709", "text": "For children under 3: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7710", "text": "For children 3 and over: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7711", "text": "Eye drops can generally be used safely in the ears, but ear drops should never be used in the eyes. [ 4 ]  Prescribers must specifically indicate the use of eye drops for ear drops on the prescription; do not make this substitution without consulting a medical provider."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7712", "text": "Side effects from using ear drops used to remove ear wax are uncommon, but may result in discomfort, irritation, or pain. [ 5 ]  Antibiotic ear drops may cause ear discomfort, pain, or itching. [ 1 ]  When cold ear drops are used, it may cause brief but severe dizziness and/or vertigo. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7713", "text": "If a dose is missed, do not double up at the next administration to catch up and the dose can be administered when recalled. Additionally if it is close to the next dose, skip that missed dose and resume as normal. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7714", "text": "Although ear drops typically contain preservatives that slow the growth of bacteria and other microorganisms, this does not offer long term protection from contamination. The shelf life of ear drops varies with products generally needing to be discarded within 4 weeks after opening. [ 10 ] [ 11 ]  With proper use and storage, ear drops should remain effective and safe until the expiration date printed in the medication package insert."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7715", "text": "Ear wax, also known as  cerumen , protects the ear from dust, bacteria, and small objects from entering and damaging the ear. It also provides a coating to protect the skin inside the ear canal from irritation from water during showers and water activities. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7716", "text": "However, some individuals have more active glands which can produce more ear wax. That can lead to a build up and block the ear canal causing hearing loss, noises in the ear, sensation of ear is plugged and full, and earache. [ 6 ]  The excess ear wax may also harden causing an impaction and discomfort. Healthcare providers recommend against reaching into the ears to clean it because the ear wax may be pushed even deeper into the ear canal. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7717", "text": "Drops to safely break up earwax are available over-the-counter and are labeled 'otic' drops. [ 12 ]  Products in this category contain carbamide peroxide, which dissolves some of the  earwax . Some common brands include Auro and Debrox. When carbamide peroxide ear drops are applied to the ear canal, there may hear some fizzing as a result of the reaction with the earwax. Drops should be used according to the package instructions (typically recommended maximum of 4 days) or as directed by a healthcare provider. If the blockage has worsened or not improved, consult a doctor. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7718", "text": "Another method to break up earwax is by using body temperature water. While having the head upright, straighten the ear canal by gently pulling the upper outer ear back and up. Then use a syringe (do not use jet irrigator that is designed for teeth cleaning) [ 6 ]  to aim a small gentle stream of water at the ear canal wall next to the ear wax to be removed. Next, tilt the head to allow water to drain and repeat if necessary.  After removing the ear wax, allow the ear to dry thoroughly. Adding a few drops of alcohol in the ear may help to dry the ear. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7719", "text": "Do not use irrigation or ear drops if there is a hole in the ear drum or had recent ear surgery to prevent damage or infection in the ears. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7720", "text": "Otitis externa, also known as  swimmer's ear , is an inflammation (infectious or non-infectious) of the external auditory canal. [ 14 ]  Risk factors include retained water in the outer ear, particularly due to swimming, humidity, trauma or external devices, dermatologic conditions, or scratching the ear canal that may lead to bacterial growth. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7721", "text": "Otitis externa can generally be prevented by keeping the ear canal dry and/or applying ear drops labeled for swimmer's ear (typically a dilution of isopropyl and glycerin) after exposure to water to assist with keeping the ear canal dry. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7722", "text": "Treatment of otitis externa is centered around antibiotic ear drops and pain control (e.g.  acetaminophen ,  non-steroidal anti-inflammatory drugs , and opioids including  oxycodone  or  hydrocodone ). Antibiotic ear drops are generally safe and well-tolerated. Some studies have demonstrated that the addition of topical steroids to antibiotic ear drops provides quicker pain relief, but these results are conflicting. [ 17 ]  Symptoms of uncomplicated otitis externa typically improve within 48 hours of initiating antibiotics. If pain does not improve within 48 to 72 hours of antibiotic therapy, individuals should consult their provider to confirm the diagnosis. [ 17 ]  Common antibiotic ear drops for treating otitis externa include: [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7723", "text": "Bacterial ear infections are treated with antibiotics; local administration is preferred over systemic delivery due to increased antibiotic concentration and lack of systemic side effects. [ 18 ]  Antibiotic ear drops are much faster at killing the bacteria. [ 19 ]  Ear drops work faster since the medication directly goes to the site of infection whereas oral antibiotics enter the bloodstream first. [ 19 ]  Some commonly used antibiotics include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7724", "text": "Antibiotics for ear infections are prescribed for infections that are recurrent or difficult for the body to clear. Antibiotic ear drops should be used as prescribed. Do not stop the use of medication even if the infection appears cleared because remaining bacteria can cause the infection to return. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7725", "text": "Otic analgestic-anesthetic are drops that can help alleviate swelling, pain and congestion caused by middle ear inflammation. However, these ear drops do not treat the infections because they do not contain any antibiotic properties. [ 24 ]  A common over-the-counter product sold as  Auralgan  contained  antipyrine  (analgesic) and  benzocaine  (anesthetic). It was prescribed alone or with an antibiotic ear drop to help manage an ear infection. However, Auralgran was reformulated without meeting the FDA requirements to be reapproved and was removed from the market in July 2, 2015. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7726", "text": "There is some literature to suggest that anesthetic ear drops helped with acute pain. This study was conducted in Australia in 2008 in a hospital emergency room. It included 63 children who were between the ages of 3 and 17 who presented to the emergency department reporting of ear pain. Children were randomized such that 32 received placebo and 31 children received topical  lignocaine  prior to being offered an oral pain medication. The study showed that a topical pain medication was helpful while waiting for an oral pain medication to be effective. [ 26 ]  There is another small study conducted in England and  Wales  that reported that an analgestic-anesthetics could reduce the amount of antibiotics being used in children. While the study did show evidence of less antibiotic use, it did not meet the sample size goal of  96 participants. Additionally did not evaluate if pain relief was linked to reduced antibiotic use. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7727", "text": "An   elixir  is a sweet liquid used for medical purposes, to be taken orally and intended to cure one's illness. [ 1 ]  When used as a  pharmaceutical preparation , an elixir contains at least one  active ingredient  designed to be taken orally."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7728", "text": "The word was introduced in late  Middle English , through  Latin  from the  Arabic   \u0627\u0644\u0625\u0643\u0633\u064a\u0631  ( al-\u02beiks\u012br ), which in turn is the  Arabization  of the  Ancient Greek   \u03be\u03ae\u03c1\u03b9\u03bf\u03bd  ( x\u0113rion )  ' powder for drying wounds '  (from  \u03be\u03b7\u03c1\u03cc\u03c2  ( x\u0113ros )  ' dry ' ). [ 1 ]  For centuries,  elixir  primarily meant an ingredient used in  alchemy , either referring to a liquid which purportedly converts lead to gold, or a substance or liquid which is believed to cure all ills and  give eternal life ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7729", "text": "These are used as  solvents  or vehicles for the preparation of medicated elixirs. Active ingredients are dissolved in a 15\u2013\u206050% by volume solution of  ethyl alcohol :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7730", "text": "These include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7731", "text": "Daily non-alcoholic non-caffeinated 'vitamin drinks' have been popular in East Asia since the 1950s, with  Oronamin  from  Otsuka Pharmaceutical  perhaps the market leader. Packaged in brown light-proof bottles, these drinks have the reputation of being enjoyed by old men and other health-conscious individuals. Counterparts exist in South Korea and China."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7732", "text": "Western  energy drinks  typically have caffeine and are targeted at a younger demographic, with colorful labels and printed claims of increased athletic/daily performance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7733", "text": "See  Patent medicine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7734", "text": "An elixir is a  hydro - alcoholic  solution of at least one active ingredient. The alcohol is mainly used to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7735", "text": "The lowest alcoholic quantity that will dissolve completely the active ingredient(s) and give a clear solution is generally chosen. High concentrations of alcohol give burning taste to the final product."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7736", "text": "An elixir may also contain the following  excipients :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7737", "text": "Elixirs should only be stored in a tightly closed, light resistant container away from direct heat and sunlight."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7738", "text": "An  emulsion  is a  mixture  of two or more  liquids  that are normally  immiscible  (unmixable or unblendable) owing to liquid-liquid  phase separation . Emulsions are part of a more general class of two-phase systems of  matter  called  colloids . Although the terms  colloid  and  emulsion  are sometimes used interchangeably,  emulsion  should be used when both phases, dispersed and continuous, are liquids. In an emulsion, one liquid (the dispersed  phase ) is  dispersed  in the other (the continuous phase). Examples of emulsions include  vinaigrettes , homogenized  milk , liquid  biomolecular condensates , and some  cutting fluids  for  metal working ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7739", "text": "Two liquids can form different types of emulsions. As an example, oil and water can form, first, an oil-in-water emulsion, in which the oil is the dispersed phase, and water is the continuous phase. Second, they can form a water-in-oil emulsion, in which water is the dispersed phase and oil is the continuous phase. Multiple emulsions are also possible, including a \"water-in-oil-in-water\" emulsion and an \"oil-in-water-in-oil\" emulsion. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7740", "text": "Emulsions, being liquids, do not exhibit a static internal structure. The droplets dispersed in the continuous phase (sometimes referred to as the \"dispersion medium\") are usually assumed to be  statistically distributed  to produce roughly spherical droplets."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7741", "text": "The term \"emulsion\" is also used to refer to the photo-sensitive side of  photographic film . Such a  photographic emulsion  consists of  silver halide  colloidal particles dispersed in a  gelatin  matrix.  Nuclear emulsions  are similar to photographic emulsions, except that they are used in particle physics to detect high-energy  elementary particles ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7742", "text": "A fluid system in which liquid droplets are dispersed in a liquid."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7743", "text": "Note 1 : The definition is based on the definition in ref. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7744", "text": "Note 2 : The droplets may be amorphous, liquid-crystalline, or any mixture thereof."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7745", "text": "Note 3 : The diameters of the droplets constituting the  dispersed phase usually range from approximately 10\u00a0nm to 100\u00a0\u03bcm; i.e., the droplets may exceed the usual size limits for  colloidal  particles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7746", "text": "Note 4 : An emulsion is termed an oil/water (o/w) emulsion if the dispersed phase is an organic material and the  continuous phase  is water or an aqueous solution and is termed water/oil (w/o) if the dispersed phase is water or an aqueous solution and the continuous phase is an organic liquid (an \"oil\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7747", "text": "Note 5 : A w/o emulsion is sometimes called an inverse emulsion. The term \"inverse emulsion\" is misleading, suggesting incorrectly that the emulsion has properties that are the opposite of those of an emulsion. Its use is, therefore, not recommended. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7748", "text": "The word \"emulsion\" comes from the Latin  emulgere  \"to milk out\", from  ex  \"out\" +  mulgere  \"to milk\", as milk is an emulsion of fat and water, along with other components, including  colloidal   casein  micelles (a type of secreted  biomolecular condensate ). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7749", "text": "Emulsions contain both a dispersed and a continuous phase, with the boundary between the phases called the \"interface\". [ 5 ]  Emulsions tend to have a cloudy appearance because the many  phase interfaces   scatter  light as it passes through the emulsion. Emulsions appear  white  when all light is scattered equally. If the emulsion is dilute enough, higher-frequency (shorter-wavelength) light will be scattered more, and the emulsion will appear  bluer \u00a0\u2013 this is called the \" Tyndall effect \". [ 6 ]  If the emulsion is concentrated enough, the color will be distorted toward comparatively longer wavelengths, and will appear more  yellow . This phenomenon is easily observable when comparing  skimmed milk , which contains little fat, to  cream , which contains a much higher concentration of milk fat. One example would be a mixture of water and oil. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7750", "text": "Two special classes of emulsions\u00a0\u2013  microemulsions  and nanoemulsions, with droplet sizes below 100\u00a0nm\u00a0\u2013 appear translucent. [ 8 ]  This property is due to the fact that light waves are scattered by the droplets only if their sizes exceed about one-quarter of the wavelength of the incident light. Since the  visible spectrum  of light is composed of wavelengths between 390 and 750  nanometers  (nm), if the droplet sizes in the emulsion are below about 100\u00a0nm, the light can penetrate through the emulsion without being scattered. [ 9 ]  Due to their similarity in appearance, translucent nanoemulsions and microemulsions are frequently confused. Unlike translucent nanoemulsions, which require specialized equipment to be produced, microemulsions are spontaneously formed by \"solubilizing\" oil molecules with a mixture of  surfactants , co-surfactants, and co- solvents . [ 8 ]  The required surfactant concentration in a microemulsion is, however, several times higher than that in a translucent nanoemulsion, and significantly exceeds the concentration of the dispersed phase. Because of many undesirable side-effects caused by surfactants, their presence is disadvantageous or prohibitive in many applications. In addition, the stability of a microemulsion is often easily compromised by dilution, by heating, or by changing pH levels. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7751", "text": "Common emulsions are inherently unstable and, thus, do not tend to form spontaneously. Energy input\u00a0\u2013 through shaking, stirring,  homogenizing , or exposure to power  ultrasound [ 10 ] \u00a0\u2013 is needed to form an emulsion. Over time, emulsions tend to revert to the stable state of the phases comprising the emulsion. An example of this is seen in the separation of the oil and vinegar components of  vinaigrette , an unstable emulsion that will quickly separate unless shaken almost continuously. There are important exceptions to this rule\u00a0\u2013 microemulsions are  thermodynamically  stable, while translucent nanoemulsions are  kinetically  stable. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7752", "text": "Whether an emulsion of oil and water turns into a \"water-in-oil\" emulsion or an \"oil-in-water\" emulsion depends on the volume fraction of both phases and the type of emulsifier (surfactant) (see  Emulsifier , below) present. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7753", "text": "Emulsion stability refers to the ability of an emulsion to resist change in its properties over time. [ 12 ] [ 13 ]  There are four types of instability in emulsions:  flocculation ,  coalescence ,  creaming / sedimentation , and  Ostwald ripening . Flocculation occurs when there is an attractive force between the droplets, so they form flocs, like bunches of grapes. This process can be desired, if controlled in its extent, to tune physical properties of emulsions such as their flow behaviour. [ 14 ]  Coalescence occurs when droplets bump into each other and combine to form a larger droplet, so the average droplet size increases over time. Emulsions can also undergo creaming, where the droplets rise to the top of the emulsion under the influence of  buoyancy , or under the influence of the  centripetal force  induced when a  centrifuge  is used. [ 12 ]  Creaming is a common phenomenon in dairy and non-dairy beverages (i.e. milk, coffee milk,  almond milk , soy milk) and usually does not change the droplet size. [ 15 ]  Sedimentation is the opposite phenomenon of creaming and normally observed in water-in-oil emulsions. [ 5 ]  Sedimentation happens when the dispersed phase is denser than the continuous phase and the gravitational forces pull the denser globules towards the bottom of the emulsion. Similar to creaming, sedimentation follows  Stokes' law ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7754", "text": "An appropriate surface active agent (or surfactant) can increase the kinetic stability of an emulsion so that the size of the droplets does not change significantly with time. The stability of an emulsion, like a  suspension , can be studied in terms of  zeta potential , which indicates the repulsion between droplets or particles. If the size and dispersion of droplets does not change over time, it is said to be stable. [ 16 ]  For example, oil-in-water emulsions containing  mono- and diglycerides  and milk protein as surfactant showed that stable oil droplet size over 28 days storage at 25\u00a0\u00b0C. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7755", "text": "The stability of emulsions can be characterized using techniques such as light scattering, focused beam reflectance measurement, centrifugation, and  rheology . Each method has advantages and disadvantages. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7756", "text": "The kinetic process of destabilization can be rather long\u00a0\u2013 up to several months, or even years for some products. [ 18 ]  Often the formulator must accelerate this process in order to test products in a reasonable time during product design. Thermal methods are the most commonly used \u2013 these consist of increasing the emulsion temperature to accelerate destabilization (if below critical temperatures for phase inversion or chemical degradation). [ 19 ]  Temperature affects not only the viscosity but also the interfacial tension in the case of non-ionic surfactants or, on a broader scope, interactions between droplets within the system. Storing an emulsion at high temperatures enables the simulation of realistic conditions for a product (e.g., a tube of sunscreen emulsion in a car in the summer heat), but also accelerates destabilization processes up to 200 times. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7757", "text": "Mechanical methods of acceleration, including vibration, centrifugation, and agitation, can also be used. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7758", "text": "These methods are almost always empirical, without a sound scientific basis. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7759", "text": "An  emulsifier  is a substance that stabilizes an emulsion by reducing the oil-water  interface tension . Emulsifiers are a part of a broader group of compounds known as  surfactants , or \"surface-active agents\". [ 21 ]  Surfactants are compounds that are typically  amphiphilic , meaning they have a polar or  hydrophilic  (i.e., water-soluble) part and a non-polar (i.e., hydrophobic or  lipophilic ) part. Emulsifiers that are more soluble in water (and, conversely, less soluble in oil) will generally form oil-in-water emulsions, while emulsifiers that are more soluble in oil will form water-in-oil emulsions. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7760", "text": "Examples of food emulsifiers are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7761", "text": "In food emulsions, the type of emulsifier greatly affects how emulsions are structured in the stomach and how accessible the oil is for gastric  lipases , thereby influencing how fast emulsions are digested and trigger a  satiety  inducing  hormone  response. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7762", "text": "Detergents  are another class of surfactant, and will interact physically with both  oil  and  water , thus stabilizing the interface between the oil and water droplets in suspension. This principle is exploited in  soap , to remove  grease  for the purpose of  cleaning . Many different emulsifiers are used in  pharmacy  to prepare emulsions such as  creams  and  lotions . Common examples include  emulsifying wax ,  polysorbate 20 , and  ceteareth 20 . [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7763", "text": "Sometimes the inner phase itself can act as an emulsifier, and the result is a nanoemulsion, where the inner state disperses into \" nano-size \" droplets within the outer phase. A well-known example of this phenomenon, the \" ouzo effect \", happens when water is poured into a strong alcoholic  anise -based beverage, such as  ouzo ,  pastis ,  absinthe ,  arak , or  raki . The anisolic compounds, which are soluble in  ethanol , then form nano-size droplets and emulsify within the water. The resulting color of the drink is opaque and milky white."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7764", "text": "A number of different chemical and physical processes and mechanisms can be involved in the process of emulsification: [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7765", "text": "Oil-in-water emulsions are common in food products:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7766", "text": "Water-in-oil emulsions are less common in food, but still exist:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7767", "text": "Other foods can be turned into products similar to emulsions, for example  meat emulsion  is a suspension of meat in liquid that is similar to true emulsions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7768", "text": "In  pharmaceutics ,  hairstyling ,  personal hygiene , and  cosmetics , emulsions are frequently used. These are usually oil and water emulsions but dispersed, and which is continuous depends in many cases on the  pharmaceutical formulation . These emulsions may be called  creams ,  ointments ,  liniments  (balms),  pastes ,  films , or  liquids , depending mostly on their oil-to-water ratios, other additives, and their intended  route of administration . [ 26 ] [ 27 ]  The first 5 are  topical   dosage forms , and may be used on the surface of the  skin ,  transdermally ,  ophthalmically ,  rectally , or  vaginally . A highly liquid emulsion may also be used  orally , or may be  injected  in some cases. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7769", "text": "Microemulsions are used to deliver  vaccines  and kill  microbes . [ 28 ]  Typical emulsions used in these techniques are nanoemulsions of  soybean oil , with particles that are 400\u2013600\u00a0nm in diameter. [ 29 ]  The process is not chemical, as with other types of  antimicrobial  treatments, but mechanical. The smaller the droplet the greater the  surface tension  and thus the greater the force required to merge with other  lipids . The oil is emulsified with detergents using a  high-shear mixer  to stabilize the emulsion so, when they encounter the lipids in the  cell membrane  or envelope of  bacteria  or  viruses , they force the lipids to merge with themselves. On a mass scale, in effect this disintegrates the membrane and kills the pathogen. The soybean oil emulsion does not harm normal human cells, or the cells of most other  higher organisms , with the exceptions of  sperm cells  and  blood cells , which are vulnerable to nanoemulsions due to the peculiarities of their membrane structures. For this reason, these nanoemulsions are not currently used  intravenously  (IV). The most effective application of this type of nanoemulsion is for the  disinfection  of surfaces. Some types of nanoemulsions have been shown to effectively destroy  HIV-1  and  tuberculosis  pathogens on non- porous  surfaces."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7770", "text": "Emulsifying agents are effective at extinguishing fires on small, thin-layer spills of flammable liquids ( class B fires ). Such agents encapsulate the fuel in a fuel-water emulsion, thereby trapping the flammable vapors in the water phase. This emulsion is achieved by applying an  aqueous  surfactant solution to the fuel through a high-pressure nozzle. Emulsifiers are not effective at extinguishing large fires involving bulk/deep liquid fuels, because the amount of emulsifier agent needed for extinguishment is a function of the volume of the fuel, whereas other agents such as  aqueous film-forming foam   need cover only the surface of the fuel to achieve vapor mitigation. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7771", "text": "Emulsions are used to manufacture polymer dispersions \u2013 polymer production in an emulsion 'phase' has a number of process advantages, including prevention of coagulation of product. Products produced by such polymerisations may be used as the emulsions \u2013 products including primary components for glues and paints. Synthetic  latexes  (rubbers) are also produced by this process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7772", "text": "Engineered chimeric antigen receptor (CAR)-T cell delivery  is the methodology by which clinicians introduce the cancer-targeting therapeutic system of the  CAR-T cell  to the human body. CAR-T cells, which utilizes genetic modification of human  T-cells  to contain antigen binding sequences in addition to the receptor systems  CD4  or  CD8 , are useful in direct targeting and elimination of cancer cells through  cytotoxicity ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7773", "text": "CAR-T cell delivery involves many varying modalities for implementation, spurring innovative biomedical research to address these modalities. These delivery mechanisms serve to address the limitations of CAR-T cells in translational experimentation and clinical trials, including shelf-life, off-target effects, and  tumor infiltration . [ 1 ]  As of April 2023, six CAR-T cell therapies are clinically approved by the  FDA , all of which target  hematologic  (blood-based) cancers, including  multiple myeloma  and  B-cell leukemias . [ 2 ] [ 3 ]  Novel engineered compound-based delivery methods, some of which are in clinical trials, aim to address limitations related to CAR-T cell delivery with the focus to target non-blood based cancers. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7774", "text": "The classic method of administration of CAR-T cells to cancers within the human body is through intravenous (IV)  central line  infusion. [ 6 ]  This infusion allows the CAR-T cells to enter the body\u2019s  cardiovascular system , entering the circulation (systemically) amongst developing hematologic cancers. This facilitates the final step in generation and implementation of both autologous and allogeneic CAR-T cell therapy. While this delivery method is reliable for hematologic cancers, as demonstrated by successful clinical trials and FDA regulation, systemic delivery may result in an increase in autoimmune overload, leading to toxic disorders such as  cytokine release syndrome  (CRS). [ 1 ]  Discrimination between healthy and malignant cancer cells may additionally result in  aplasia , or extremely low or absent amounts of healthy blood cells. [ 7 ]  Thus, clinically recommended dosage amounts are in place for current CAR-T cell therapies. [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ]  Current methods exploring ways to improve such complications have been introduced recently by researchers, including \u201coff-switches\u201d to turn off CAR-T cells after initial therapies and further genetic modification to avoid immune rejection. [ 1 ] [ 7 ] [ 15 ] [ 16 ]  While systemic delivery is important for targeting hematologic cancers, it remains inefficient at targeting  solid, or non-circulatory, cancerous tumors . Therefore, regional, or localized targeting strategies utilizing CAR-T cells have arisen in pre-clinical research. [ 4 ] [ 5 ] [ 17 ] [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7775", "text": "Solid tumors, which typically take the form of neoplasms in  epithelial cells  or in bones, tissue, or  adipose  (fat), are different than hematologic cancers in that they form a mass of cells, thereby maintaining multiple layers of protection. [ 20 ]  Because CAR-T cells attack cancerous cells at a surface level, this leaves the CAR-T cells vulnerable to cancerous cell resistance, which renders the CAR-T cell inefficient. [ 21 ] [ 22 ]  In recent years, cellular and genetic engineering methods have been explored by researchers to overcome layered protection of solid tumors, in addition to other challenges that have been presented in the advent of CAR-T cell delivery such as  in-situ  editing and manufacturing, negative  immune responses , and  biocompatibility  of delivery structures. [ 4 ] [ 5 ] [ 17 ] [ 23 ] [ 24 ] [ 25 ] [ 26 ]  Some of the methodologies used to suspend and deliver CAR-T cells include  hydrogel  and polymeric gel-based delivery systems,  thin polymeric films , and  microneedle  patches. Most of these devices, currently still in the pre-clinical phase, are intended to be injected or surgically inserted directly into the solid tumor mass. While initial clinical trials have been unsuccessful due to relatively inefficient delivery as compared to direct injection and high  immunosuppression , recent research has shown promise in overcoming these barriers. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7776", "text": "Gel-based delivery of CAR-T cells involves implantation or injection of a hydrogel or polymer gel into the target solid tumor. These gels suspend CAR-T cells in various ways through manipulation of cell-specific chemistry or by fixing the cells in a polymeric matrix. One strength of gel-based delivery is that these systems are functionally  biodegradable , so once the CAR-T cells have been administered, the depot does not stay in the body, reducing immunosuppressive conditions or tumor resistance. [ 24 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7777", "text": "One of the earliest examples of this methodology developed by Luo et al. in 2020 consisted of a layered hydrogel microchip that facilitated CAR-T survival from immunosuppressive elements of the tumor system which could be injected into the tumor. [ 28 ]  In addition, this system was able to take advantage of the  hypoxic  (low oxygen) conditions of the tumor by additionally containing oxygen-releasing agents that when released with  interleukin-15  (IL-15)  cytokines  could cause tumor cell death. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7778", "text": "Two recent examples utilizing gel-based delivery towards specific cancers include targeted  fibrin  gel-based delivery to  glioblastoma  and modified CAR-T cell hydrogel complexes to  retinoblastoma . [ 29 ] [ 30 ]  In the glioblastoma-targeting system, Ogunnaike et al. used CAR-T cells loaded in a fibrin matrix, which undergoes in-situ  polymerization  upon mixture of  fibrinogen  and  thrombin  (as part of the coagulation cascade). In addition, the CAR-T cells were modified to target the  B7-H3  antigen, present on some forms of cancer including glioblastoma. [ 29 ] [ 31 ]  In the retinoblastoma-targeting system, Wang et al. fabricated CAR-T cells specific to the  GD2  ganglioside, specific to retinoblastoma, and suspended them into an IL-15/ chitosan - polyethylene glycol  (PEG) hydrogel suspension, effectively targeting the tumor via injection. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7779", "text": "Additionally, researchers have developed hydrogel-based systems that limit further growth and proliferation of tumors, such as the  hyaluronic acid  hydrogel system developed by Hu et al. [ 32 ]  This system, which targets  melanoma  through targeting the  CSPG4  antigen, was shown to slowly but efficiently release IL-15 and CAR-T cells from a cross-linked hyaluronic acid matrix and  poly(lactic-co-glycolic acid)  (PLGA) nanoparticle suspension intratumorally. [ 32 ]  In addition, the system utilized anti- PDL1  antibody delivery, increasing platelet release of programmed cell death molecules onto the tumors, killing them. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7780", "text": "Sustained delivery and long-term retention of CAR-T cells through hydrogel systems has also been developed, as shown by Grosskopf et al., to address controlled release of CAR-T cells onto tumors. [ 33 ]  In this system, the researchers crosslinked a combination of dodecyl-modified  hydroxypropyl methylcellulose  (HPMC-C12) and PEG- poly(lactic acid)  (PLA) nanoparticles to form the hydrogel, then mixed CAR-T cells and IL-15 into the matrix. [ 33 ]  The sustained release profiles showed promise in tumor suppression treatments due to the slow release duration profiles. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7781", "text": "Codelivery of CAR-T cells with other  agonists , such as  stimulator of interferon (IFN) genes  (STING), remain a popular new method of administration of CAR-T cells to solid tumors. [ 34 ]  Smith et al. developed a  silica  nanoparticle based coating conjugated with  lipid  film to suspend CAR-T cells and select antibodies onto an  alginate  polymer scaffold. This system was tested in mouse  pancreatic cancer  and melanoma models, and showed expansion of CAR-T cells at the tumor site, increasing the therapeutic efficiency."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7782", "text": "There are still challenges with these delivery systems, however, as they have limitations on CAR-T cell suspension amounts, host-specific immunogenic responses, and have been performed primarily in mouse models. [ 24 ] [ 28 ] [ 33 ]  Regardless, hydrogel-based CAR-T delivery systems have shown promise in translational experimentations towards solid tumor targeting."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7783", "text": "Thin-film targeting has emerged as an alternative method of CAR-T cell delivery to solid tumors, utilizing metal-based microfilms made of  nitinol , an alloy of nickel and titanium, a composite commonly used in  stents . [ 17 ] [ 35 ]  One such example using these nitinol scaffolds was developed by Coon et al., whereby the researchers suspended CAR-T cells into pores laden throughout the film, combined with fibrin. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7784", "text": "Upon implantation, the CAR-T cells would release from the film, but remain within the site of the tumor due to engineered antibody attraction of the film. [ 35 ]  This caused increased localization and duration of CAR-T therapy to the tumor site as compared to intravenous or local injection of CAR-T cells. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7785", "text": "Microneedle patches have been used previously as a minimally-invasive, distributive system to release drugs across certain body systems, most notably on the skin. [ 36 ]  Microneedles patches have been used recently as a method of CAR-T cell release to solid tumor cancers such as melanoma and pancreatic cancer. [ 23 ] [ 37 ]  Using a porous PLGA microneedle-shaped scaffold, Li et al. developed a system to suspend and release CAR-T cells. [ 37 ]  An advantage of this method is that the patch could be inserted on the surface of the tumor, allowing for surface-targeting of CAR-T cells upon release. Additionally, the needles would penetrate into the solid tumor, allowing for a distribution of CAR-T cells release along the interior axis of the tumor. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7786", "text": "Production of CAR-T cells involve removal of T cells via an extraction process known as  leukapheresis , followed by cell culture with  viral vectors  containing ingredients needed to construct the chimeric system. [ 2 ] [ 38 ] [ 39 ]  These methodologies, while important, have been shown to be expensive and time-consuming. [ 21 ] [ 40 ]  Recent advances in research have introduced \u201cscaffold factories\u201d to program, produce, and release autologous CAR-T cells into the body after implantation. [ 41 ] [ 42 ] [ 43 ] [ 44 ]  These \u201cscaffold factories\u201d have shown to function in targeting hematologic cancers and show promise in future research to target solid tumors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7787", "text": "One method of in-situ generation involves the injection of  lentiviral vectors , containing genetic information relating to targeting of CD4 antigens directly to  lymphocytes  in conjugation with the CAR gene, allowing for the construction of this system within the body, as shown by Agarwal et al. [ 41 ]  Another method of in-situ generation involves the manufacture polymeric  nanocarriers  to carry genes involved in the development of the CAR-T cell. [ 44 ]  Smith et al. used poly(\u03b2-amino ester) (PBAE) particles laden with  polyglutamic acid  (PGA),  nuclear localization signals , and T-cell targeting fragments to deliver CAR genes to T cells for translation into CAR-T cells. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7788", "text": "These advances have led to the investigation and development of a novel system for manufacturing CAR-T cells known as Multifunctional Alginate Scaffold for T Cell Engineering and Release (MASTER). [ 43 ]  These alginate scaffolds, which are highly porous, are embedded with  azide ,  cyclooctyne -conjugated targeting antibodies, CAR-based  retroviral  vectors, and  mononuclear  blood cells. The azide and cyclooctyne-conjugated particles undergo a rapid  click chemistry  reaction, whereby when implanted, alongside introduction of the blood cells, the scaffold will generate CAR-T cells. This system was shown to be long-lasting and biodegradable, factors that are important for long suppression of cancers. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7789", "text": "An  epinephrine autoinjector  (or  adrenaline autoinjector , also known by the  trademark   EpiPen ) is a medical device for injecting a measured dose or doses of  epinephrine  (adrenaline) by means of  autoinjector  technology. It is most often used for the treatment of  anaphylaxis . The first epinephrine autoinjector was brought to market in 1983."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7790", "text": "Epinephrine autoinjectors are hand-held devices carried by those who have severe allergies; the  epinephrine  delivered by the device is an emergency treatment for  anaphylaxis . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7791", "text": "When anaphylaxis is suspected, epinephrine solution should be given as soon as possible as an  intramuscular injection , in the middle of the outer side of the thigh, which corresponds to the location of the  vastus lateralis muscle . [ 3 ]  The injection may be repeated every 5 to 15 minutes if there is insufficient response. [ 4 ]  A second dose is needed in 16\u201335% of episodes with more than two doses rarely required; in around 80% of the cases where a second dose is administered, it is by a medical professional. [ 4 ]   It is not clear which are the  people who might need a second injection at the outset. [ 4 ]  The intramuscular route is preferred over  subcutaneous  administration because the latter may have delayed absorption. [ 4 ] [ 5 ]  Minor adverse effects from epinephrine include  tremors , anxiety, headaches, and  palpitations . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7792", "text": "The epinephrine in autoinjectors expires after one year. [ 2 ]   A study in rabbits showed that intramuscular epinephrine has decreased effectiveness  after it expires; that study also recommended that if the drug in an expired device has not started to precipitate (if the solution is not cloudy and has no particles in it) using the expired device is better than no injection at all in an emergency situation. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7793", "text": "The devices contain a fixed dose of epinephrine and a spring-loaded needle (or, in the case of AuviQ, a CO 2 -driven needle) that exits the tip or edge of the device and penetrates the recipient's skin, to deliver the medication via  intramuscular injection . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7794", "text": "People to whom epinephrine autoinjectors are prescribed need to be trained how to use the specific device prescribed. [ 1 ] [ 4 ]   The rate of unintentional injections using these devices is unknown but a 2009 review found that the rate is increasing. [ 7 ]   Unintentional injections are delivered to a finger or thumb around 90% of the time; they cause intense pain locally but usually completely resolve. [ 7 ]   The cause of unintentional injections has been attributed to design flaws, where the device is mistaken for a pen or the user mistakes which end of the device contains the needle. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7795", "text": "The  European Medicines Agency  conducted a review of the safety of devices then on the market and found several factors that determine whether the devices successfully deliver drug into muscle, including \"needle length, the thickness of fat under the skin, the way the auto-injector works (e.g., if it is spring loaded or not), the angle at which the device is placed on the skin and the force used to activate the device as well as how well the user follows the instructions for injection.\" [ 8 ]   It found that how well the user was trained was the most important factor determining successful delivery, and requested companies to develop better training materials for doctors and people to whom the devices are prescribed. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7796", "text": "In 2013, emergency physician  Seth C. Hawkins  and coauthors published a technique for obtaining multiple additional doses of epinephrine from used, single dose autoinjectors EpiPen and Adrenaclick. It was emphasized this was an emergency adaptation of the intended design for austere environments when no additional epinephrine was available. [ 9 ]  In 2016, Robinson and Lareau published a similar technique adapted to used AuviQ autoinjectors. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7797", "text": "Autoinjectors  were originally developed for the rapid administration of  nerve gas  antidotes in kits like the  Mark I NAAK . The first modern epinephrine autoinjector, the EpiPen, was invented in the mid-1970s at Survival Technology in  Bethesda , Maryland, US by  Sheldon Kaplan [ 11 ] [ 12 ]  and was first approved for marketing by the FDA in 1987. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7798", "text": "One of the people who helped in making the EpiPen was Richard B. Toren. He had the idea to use this technology for allergic reactions because his daughter was allergic to bees and had to carry around a complex kit if she was ever stung. He then helped to slightly alter the technology in order to create EpiPen's current design. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7799", "text": "In 1996, Survival Technology merged with a company called Brunswick Biomedical and the new company was called  Meridian Medical Technologies . [ 15 ]  In 1997, Dey, a subsidiary of  Merck KGaA , acquired the exclusive right to market and distribute the EpiPen. [ 16 ] [ 17 ]  In 1998 there was a recall of one million EpiPens, the second such recall in a year. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7800", "text": "In 2001 Meridian and Dey introduced a two-pack version of the EpiPen; at that time the device had $23.9 million in annual sales and accounted for 75% of the market in the United States. [ 19 ]   In 2002  King Pharmaceuticals  acquired Meridian for $247.8 million in cash; [ 17 ]  the deal was completed in January 2003. [ 20 ]  Kaplan continued to improve his designs over the years, filing for example US Patent 6,767,336 in 2003. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7801", "text": "In 2003, Hollister-Stier received approval from the FDA to market an epinephrine autoinjector called Twinject that could deliver two shots of epinephrine, which it had spent ten years developing. [ 22 ] [ 23 ] [ 24 ]   In 2005, it sold the product to Verus Pharmaceuticals, [ 22 ]  which launched the product the same year. [ 25 ]   In March 2008, Sciele Pharma acquired Twinject from Verus [ 26 ]  and later that year, Sciele was acquired by Shionogi. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7802", "text": "In 2007,  Mylan  acquired the right to market the EpiPen from  Merck KGaA  as part of a larger transaction. [ 28 ]  At that time annual sales were around $200 million [ 29 ]  and the EpiPen had about 90% of the market. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7803", "text": "In 2009, Mylan and King started marketing a new version of EpiPen with the same basic mechanism but a stronger spring, better safety features, and clearer markings and instructions; an expert for NBC News estimated that the cost to redesign the device and packaging may have been \"several million dollars\" and the cost to retool the manufacturing process may have \"run into the double-digit millions.\" [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7804", "text": "In 2009,  Teva Pharmaceuticals  filed an  ANDA  to market a generic EpiPen in collaboration with Antares Pharma Inc, a maker of injection systems; Pfizer and King sued them for infringing US Patent 7,449,012 that was due to expire in 2025; [ 32 ]  Pfizer, Mylan, and Teva settled in April 2012 in a deal that allowed Teva to start selling the device in mid-2015, pending FDA approval. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7805", "text": "In 2009, Intelliject, a US startup developing a new epinephrine autoinjector, licensed their product to  Sanofi . [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7806", "text": "King was acquired by  Pfizer  in 2010 for $3.6 billion in cash. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7807", "text": "In 2010, Sciele/Shionogi faced a recall of Twinject devices [ 36 ]  and launched Adrenaclick, a modified version of the Twinject that could deliver only one dose. [ 37 ] [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7808", "text": "In 2010, European regulators approved Twinject, [ 39 ]  and also approved a new epinephrine autoinjector made by  ALK  and sold under the brand name Jext. [ 40 ] [ 41 ]  Jext was launched in the European Union in September 2011. [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7809", "text": "Also in 2010, Shionogi authorized Greenstone, the  authorized generics  division of Pfizer, [ 44 ] [ 45 ]  to begin selling an authorized generic of Adrenaclick. [ 46 ] [ 47 ]   The media noted that Pfizer, through Greenstone, was marketing a generic epinephrine autoinjector when Pfizer acquired King later that year. [ 48 ]   At that time, King and Mylan's EpiPen had 91% of the global market share for epinephrine autoinjectors and 96% of the US market. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7810", "text": "In 2010, Pfizer and King sued  Novartis ' Sandoz generic unit for patent infringement after Sandoz submitted an ANDA to sell a generic EpiPen. [ 49 ]  In response, Sandoz challenged the validity of the patents, and as of July 2016 this litigation was ongoing. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7811", "text": "In 2011, Pfizer and King sued Intelliject and Sanofi after the companies filed a 505(b)(2) [ 51 ]   New Drug Application  for the product, then known as \"e-cue\"; [ 52 ]  Pfizer, Mylan and Sanofi settled in 2012 under a deal that allowed the device to enter the market no earlier than November 2012, pending FDA approval. [ 53 ]  In August 2012, the FDA approved the autoinjector, called \"Auvi-Q\" after the FDA required a name change from \"e-cue\". [ 54 ]  The device is equipped with a sound chip to provide electronic voice instructions to guide the user in the proper use of the device. [ 55 ] [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7812", "text": "In 2012, Mylan launched a program called  EpiPen4Schools  to sell EpiPens in bulk and with discounts to schools; to participate in the program schools had to agree not to buy epinephrine autoinjectors from any other company for a year. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7813", "text": "In December 2012, the  National Association of State Boards of Education  launched a policy initiative designed to \"help state boards of education as they develop student health policies regarding anaphylaxis and epinephrine auto-injector access and use\", and advocated for state laws protecting school from legal liability for stocking and using epinephrine autoinjectors.   Gayle Conelly Manchin , mother of Mylan's CEO,  Heather Bresch , had become president of the association in 2010, and shortly after had discussed donations from her \"daughter's company\" to the association.  Manchin had been appointed to the West Virginia state school board by her husband  Joe Manchin , then-governor of the state, in 2012. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7814", "text": "In 2012, Shionogi, the manufacturer of Adrenaclick and Twinject, announced it would stop making them; [ 34 ]  it had sold the rights to the NDA to a company called Amedra Pharmaceuticals. [ 59 ] [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7815", "text": "In June 2013, Amedra relaunched Adrenaclick. [ 61 ]  and at the same time, Lineage Therapeutics launched its authorized generic version of Adrenaclick. [ 62 ]  Lineage was a wholly owned subsidiary of Amedra that had acquired the rights to the Adrenaclick authorized generic from Greenstone/Pfizer. [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7816", "text": "After successful lobbying from Mylan, [ 29 ]  in 2013, the \"School Access to Emergency Epinephrine Act\" became law after passing Congress with broad and bipartisan support; it protected anyone from liability if they administered epinephrine to a child in a school (previously, only trained professionals or the affected person were allowed to administer the drug, and were open to liability), and it provided some financial incentives for schools that didn't already stock epinephrine autoinjector to start stocking them. [ 64 ]   Joe Manchin, the father of Mylan's CEO, was a senator at that time. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7817", "text": "In January 2015 Mylan filed a  citizen petition  with the FDA raising concerns about TEVA's ANDA application to market a generic EpiPen and filed an additional supplement later in May; the FDA rejected the petition in June. [ 65 ] [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7818", "text": "In March 2015,  Impax Laboratories  acquired the parent company of Amedra and Lineage, and placed Amedra and the Adrenaclick in its Impax Specialty Pharma division; at the same time it acquired Lineage, which it placed, along with its generic version of Adrenaclick, in its Impax Generics division. [ 67 ] [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7819", "text": "In May 2015, the Emerade epinephrine autoinjector developed by the Swedish company Medeca was approved in Sweden and Germany; [ 69 ]   it had been approved in the UK in 2013. [ 70 ]    Also in 2015  Valeant , which had licensed the rights from Medeca, abandoned its efforts to get Emerade approved in the US. [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7820", "text": "In October 2015, Auvi-Q and Allerject devices were voluntarily recalled by Sanofi in North America. [ 72 ] [ 73 ]  The reason stated by Sanofi was that the products had been found to potentially have inaccurate dosage delivery, which may include failure to deliver drug. [ 74 ]   In February 2016, Sanofi terminated its license to manufacture and market the Auvi-Q, leaving Kal\u00e9o (Intelliject was renamed) to consider how and whether to re-introduce the device. [ 75 ] [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7821", "text": "The EpiPen had 89% of the market for epinephrine autoinjectors in 2015; [ 57 ]  in the first half of the year it had about 85% share and Auvi-Q had about 10% share. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7822", "text": "In March 2016, Teva's ANDA for a generic EpiPen, which had already faced several delays, was rejected by the FDA. [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7823", "text": "In 2015 Mylan had about $1.5 billion in sales of EpiPens, which accounted for 40% of Mylan's profit. [ 29 ]  Mylan had maintained about a 90% market share since it had acquired the product, and had continually raised the price of EpiPens starting in 2009: in 2009, the wholesale price of two EpiPens was about $100; by July 2013, the price was about $265; in May 2015, it was around $461; and in May 2016, the price rose again to around $609, [ 28 ]  around a 500% jump from the price in 2009. [ 78 ]   The cost of the drug and device to Mylan as of 2016 was about $35. [ 31 ]  In the summer of 2016, as parents prepared to send their children back to school and went to pharmacies to get new EpiPens, people began to express outrage at the cost of the EpiPen and Mylan was widely and harshly criticized. [ 79 ] [ 80 ]     In September 2016, the New York State Attorney General began an investigation into Mylan's  EpiPen4Schools  program in New York to determine if the program's contracts violated  antitrust law [ 81 ]  and the West Virginia State Attorney General opened an investigation into whether Mylan had given the state the correct discount under the  Medicaid Drug Rebate Program  and subpoenaed the company when it refused to provide the documentation the state requested. [ 82 ]  In October 2016, Mylan announced a $465M settlement with the  US Department of Justice  over rebates paid by Mylan to states under the  Medicaid Drug Rebate Program . [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7824", "text": "On 5 September 2017, FDA posted a warning letter to the manufacturer, Meridian Medical Technologies. The agency warned Meridian Medical for failing to investigate problems with the devices, recall bad batches, and follow-up on problems found. According to the FDA, the manufacturer of EpiPen devices failed to address known malfunctions in its auto-injectors even as hundreds of customer complaints rolled in and failures were linked to deaths. During an inspection, Meridian employees told inspectors that they weren't allowed to disassemble and investigate complain samples, because they were allowed to do if only it was \u201capproved by management\u201d. [ 84 ] [ 85 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7825", "text": "On 16 August 2018 the FDA approved the first generic EpiPen from Teva Pharmaceuticals. [ 86 ] [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7826", "text": "In an effort to address the supply shortage of EpiPens, [ 88 ]  on August 21, 2018 the FDA approved extending the expiration dates on some products by four months. [ 89 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7827", "text": "The Sandoz division of  Novartis  announced on 9 July 2019 the availability of Symjepi, a manual epinephrine injection as an alternative to autoinjectors, in 0.3\u00a0mg and 0.15\u00a0mg versions. [ 90 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7828", "text": "As of 2015, the following epinephrine autoinjectors were available in various parts of Europe: Adrenalina WZF, Adrenaline (epinephrine) 1 in 1000 solution for injection BP auto-injector, Altellus, Anapen, Emerade, EpiPen, Fastjekt, FastPen, and Jext. [ 91 ]  As of 2018, three branded products were available in the United States: Adrenaclick, Auvi-Q, and EpiPen. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7829", "text": "As of 2020, three brands of autoinjectors are available in Canada: Allerject, Emerade, and EpiPen. [ 92 ]  One generic autoinjector has been approved by  Health Canada  but is not marketed. [ 93 ]  From 2015 to 2020 the only autoinjector marketed in Canada was EpiPen and production issues led to supply shortages during that period. [ 94 ] [ 95 ] [ 96 ]  During a 2018 shortage of EpiPens,  Health Canada  temporarily permitted the importation of Auvi-Q autoinjectors from the United States. [ 97 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7830", "text": "As of 2005, epinephrine autoinjectors were not available in most of the developing world. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7831", "text": "As of May 2019 [update] , in Canada the wholesale cost of a single EpiPen is approximately  CA$95.00 . [ 93 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7832", "text": "As of September 2016 [update] , two EpiPens cost around $100 in France and at maximum 10\u20ac for members of the statutory health insurance in Germany. [ 43 ] [ 98 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7833", "text": "As of September 2016 [update] , two Jext autoinjectors cost users about \u00a38.50 (US$11.64) in Britain, and the National Health Service pays around \u00a348 (US$65.75) in order to make them available; that price was about 17 percent less than 2013. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7834", "text": "Supplies of 150 microgram adrenaline auto-injectors were said to be \u201ccritical\u201d in the United Kingdom in October 2018.  Community pharmacists were told to prioritise supplies for children weighing 25\u00a0kg or less.   Mylan  identified shortages because of manufacturing problems in May 2018. [ 99 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7835", "text": "In October 2016 the CEO of  Mylan  testified to Congress that Pfizer/King charged Mylan about $34.50 for one EpiPen. [ 31 ]  The devices deliver about $1 worth of drug. [ 29 ] [ clarification needed ]  In September 2016, a Silicon Valley engineering consultancy performed a teardown analysis of the EpiPen and estimated the manufacturing and packaging costs at about $10 for a two-pack. [ 100 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7836", "text": "The EpiPen, manufactured by Meridian Medical Technologies, and marketed by Mylan, has dominated the market. [ 57 ]  In 2007 when Mylan acquired the rights to market the product, annual sales of all epinephrine autoinjectors were about $200 million and EpiPen had around 90% of the market; in 2015 the market size was around $1.5 billion and Mylan still had about 90% of the market. [ 30 ] [ 57 ]  Mylan raised the price from around $100 for a package of two EpiPens in 2007 to around $600 in 2016. [ 78 ]  In the United Kingdom, an EpiPen costs \u00a326.45 as of 2015. [ 101 ]  In Canada they are about 120 CAD each. [ 102 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7837", "text": "Mylan acquired the right to market the EpiPen line of epinephrine autoinjector devices from  Merck KGaA  as part of their 2007 deal. [ 28 ]   Heather Bresch , Mylan's CEO, saw an opportunity to increase sales in the US through marketing and advocacy, and the company launched a marketing campaign to increase awareness of the dangers of  anaphylaxis  for people with severe allergies that made the  EpiPen  brand as identified with epinephrine autoinjectors as  Kleenex  is for facial tissue; the company also successfully lobbied the FDA to broaden the label to include risk of anaphylaxis and in parallel, successfully lobbied Congress to generate legislation making EpiPens available in public places like  defibrillators  are, and hired the same people that  Medtronic  had worked with on defibrillator legislation to do so. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7838", "text": "Mylan's efforts to maintain its market dominance were aided when  Sanofi 's competing product was recalled in November 2015 and further when  Teva 's generic competitor was rejected by the FDA in March 2016. [ 103 ]  By the first half of 2015, sales of EpiPen accounted for 40% of Mylan's profit. [ 29 ]  Those profits were also due in part to Mylan's continually raising the price of EpiPens starting in 2009: in 2007, the wholesale price of two EpiPens was about $100; the price was about the same in 2009; by July 2013, the price was about $265; in May 2015, it was around $461; and in May 2016, the price rose again to around $609, [ 28 ]  around a 500% jump from the price in 2009. [ 78 ]  The last price increase sparked widespread outrage in the late summer as parents prepared to send their children back to school and went to pharmacies to get new EpiPens. [ 79 ] [ 80 ]   Some Americans responded to the high price by buying EpiPens online from pharmacies outside the US, [ 104 ] [ 105 ]  forgoing new EpiPens and relying on their expired EpiPen, [ 104 ]  or forgoing an autoinjector altogether and having their children carry pre-loaded syringes. [ 106 ] [ 107 ]  Former Mylan CEO, Heather Bresch testified before the U.S. Senate Special Committee on Aging to argue that the price change was \"fair\". [ 108 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7839", "text": "In response to criticism, Mylan increased financial assistance available for some patients to purchase EpiPens, [ 109 ]  a gesture that was called a \"classic public relations move\" by Harvard Medical School professor Aaron Kesselheim. [ 110 ]  The up to $300 saving cards can be used only by a small number of people who need the drug, and no one on  Medicaid . They do nothing about the high price which is still being paid by insurers, who ultimately pass the cost on to consumers. [ 110 ]   In October 2016, Mylan announced a settlement with the  US Department of Justice  over rebates paid by Mylan to states under the  Medicaid Drug Rebate Program . [ 83 ]   Questions had been raised by Congress and others about why EpiPen had been classified as a generic rather a proprietary product in the program since 1997; generic drugs have lower rebates (13%) than proprietary drugs (23%), and price hikes for generic drugs cannot be passed onto states, and a common form of  pharmaceutical fraud  involves misclassifying proprietary drugs as generic under the program. [ 111 ]   Under the agreement, Mylan agreed to pay a $465 million payment and to a sign a  corporate integrity agreement  requiring it to perform better in the future; [ 83 ]  the settlement also resolved cases brought by states related to the rebates. [ 112 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7840", "text": "As of August 2016 [update] , the  authorized generic  of Adrenaclick cost $142 at retail stores. [ 107 ] [ 113 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7841", "text": "In September 2016, a group of  hackers  called the  Four Thieves Vinegar  published a video and documents describing what they call an EpiPencil, an autoinjector which can be built using off-the-shelf parts, for a claimed price tag of about $30. [ 114 ]  At its core is a repurposed insulin autoinjector. [ 115 ]  This device has not been subject to any validation by regulatory agencies. [ 114 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7842", "text": "Ethosomes  are  phospholipid   nanovesicles  used for dermal and  transdermal delivery  of molecules. Ethosomes were developed by Touitou et al.,1997, as additional novel lipid carriers composed of ethanol, phospholipids, and water. They are reported to improve the skin delivery of various drugs. Ethanol is an efficient permeation enhancer that is believed to act by affecting the intercellular region of the stratum corneum. Ethosomes are soft malleable vesicles composed mainly of phospholipids, ethanol (relatively high concentration), and water. These soft vesicles represent novel vesicles carriers for enhanced delivery through the skin. The size of the ethosomes vesicles can be modulated from tens of nanometers to microns. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7843", "text": "Ethosomes are mainly composed of multiple, concentric layers of flexible  phospholipid bilayers , with a relative high concentration of  ethanol  (20-45%),  glycols  and water. [ 2 ] [ 3 ]  Their overall structure has been confirmed by  31 P-NMR ,  EM  and  DSC . [ citation needed ]  They have high penetration of the  horny layer of the skin , which enhances the permeation of encapsulated drugs. The mechanism of permeation enhancement is attributed to the overall properties of the system. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7844", "text": "Because of their unique structure, ethosomes are able to efficiently encapsulate and deliver into the skin highly  lipophilic  molecules such as  testosterone ,  cannabinoids  and  ibuprofen , as well as  hydrophilic  drugs such as  clindamycin phosphate ,  buspirone hydrochloride . They have been studied for the transdermal and intradermal delivery of  peptides ,  steroids ,  antibiotics ,  prostaglandins ,  antivirals  and  anti-pyretics . [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ]  The components used to make ethosomes are already approved for pharmaceutical and  cosmetic  use and the formulated vesicles are stable when stored. [ citation needed ]  They can be incorporated in various pharmaceutical formulations such as  gels ,  creams ,  emulsions  and sprays. [ citation needed ]  They're consequently being developed for  pharmaceutical  and  cosmeceutical  products. [ 17 ] [ 18 ] [ 19 ] [ 20 ] [ 21 ] [ 22 ] [ 23 ]  Ethosomal systems compare favourably to alternative carriers for quantity and depth of molecule delivery. [ 24 ] [ 25 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7845", "text": "Exhalation delivery systems  ( EDS ) deliver medications to the  internal nose . Developed in 2006, [ 1 ]  EDS devices use the patient's exhaled breath to propel medication, such as steroids, [ 1 ]  into the nasal cavities. The method can deliver medication deeper into the nasal passages than intranasal sprays, [ 1 ]  and at a lower pressure than nasal irrigation methods. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7846", "text": "Using EDS to deliver  fluticasone  (EDS-FLU) to patients with  nasal polyps  has been shown to reduce the need for surgery. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7847", "text": "This  pulmonology  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7848", "text": "Extra-amniotic administration  is a  route of administration  to the space between the  fetal membranes  and  endometrium  inside the  uterus  of a  pregnant  woman."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7849", "text": "It can be used to administer drugs affecting  uterus  motility, such as  oxytocin  and  prostaglandins , e.g. in  labor induction  or  medical abortion . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7850", "text": "Eye drops  or  eyedrops  are  liquid drops  applied directly to the surface of the  eye  usually in small amounts such as a single drop or a few drops. Eye drops usually contain  saline  to match the  salinity  of the eye. Drops containing only saline and sometimes  a lubricant are often used as artificial  tears  to treat  dry eyes  or simple  eye irritation  such as itching or  redness . Eye drops may also contain one or more medications to treat a wide variety of  eye diseases . Depending on the condition being treated, they may contain  steroids ,  antihistamines ,  sympathomimetics ,  beta receptor blockers ,  parasympathomimetics ,  parasympatholytics ,  prostaglandins ,  nonsteroidal anti-inflammatory drugs  (NSAIDs),  antibiotics ,  antifungals , or  topical anesthetics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7851", "text": "Eye drops have less of a risk of side effects than do oral medicines, and such risk can be minimized by occluding the  lacrimal punctum  (i.e. pressing on the inner corner of the eye) for a short while after instilling drops."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7852", "text": "Prior to the development of single-use pre-loaded sterile plastic applicators, eye drops were administered using an  eye dropper , a glass pipette with a rubber bulb."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7853", "text": "Although most bottles of eye drops contain preservatives to inhibit contamination once opened, these will not prevent contamination indefinitely. Ophthalmologists recommend keeping bottles for no longer than three months after opening. [ 1 ]  Eye drops that contain no preservatives are usually packaged in single-use tubes.  Dispensers typically oversize the drops; the human eye can only handle about 25 microlitres. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7854", "text": "Different pharmacological classes of eye drops can be recognized by patients by their different colored tops. For instance, the tops to dilating drops are a different color than anti-allergy drops."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7855", "text": "Eyes drops sometimes do not have medications in them and are only lubricating and tear-replacing solutions. There is a wide variety of  artificial tear  eye drops that provide different surface healing strategies. One can find bicarbonate ions,  hypotonicity , high  viscosity  gels and ointments, and non-preserved types. They all act differently and therefore, one may have to try different artificial tears to find the one that works the best. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7856", "text": "Steroid and antibiotic eye drops are used to treat eye  infections . They also have  prophylactic  properties and are used to prevent infections after eye surgeries. They should be used for the entire time prescribed without interruptions. The infection may relapse if the use of the medication is stopped. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7857", "text": "Antibiotic eye drops are prescribed when infection  conjunctivitis  is caused by bacteria but not when it is caused by a virus. In the case of allergic conjunctivitis, artificial tears can help dilute irritating allergens present in the tear film. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7858", "text": "Some eye drops may contain  histamine antagonists  or  nonsteroidal anti-inflammatory drug  (NSAIDs), which suppress the optical mast cell responses to allergens including (but not limited to) aerosolized dust particles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7859", "text": "Eye drops used in managing  glaucoma  help the eye's  fluid  to drain better and decrease the amount of fluid made by the eye which decreases eye pressure. They are classified by their active ingredient and they include:  prostaglandin analogs ,  beta blockers , alpha agonists, and  carbonic anhydrase inhibitors . There are also combination drugs available for those patients who require more than one type of medication. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7860", "text": "These make the eye's  pupil  widen to maximum, to let an  optometrist  have the best view inside the  eyeball  behind the iris. Afterwards in sunny weather they can cause dazzling and  photophobia  until the effect of the  mydriatic  has worn off."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7861", "text": "In some countries including  Russia  and  Italy , Tropicamide, a mydriatic eye drop, is used to some degree as an inexpensive recreational drug. [ 7 ]  Like other anticholinergics, when taken recreationally, tropicamide acts as a deliriant. When injected intravenously, as is most often the case, the tropicamide may cause problems such as slurred speech, unconsciousness, unresponsiveness, hallucinations, kidney pain, dysphoria, hyperthermia, tremors, suicidal tendency, convulsions, psychomotor agitation, tachycardia and headache. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7862", "text": "Syringe designed saline drops (e.g. Wallace Cameron Ultra Saline Minipod) are distributed in modern  needle-exchange programmes  as they can be used efficiently either by injection or ophthalmic (if the drug is potent in small doses) route of administer which is compared to intravenous use; by demonstration, the elimination of latanoprost acid from plasma is rapid (half-life 17 minutes) after either ophthalmic or intravenous administration. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7863", "text": "Steroid and antibiotic eye drops may cause stinging for one or two minutes when first used and if stinging continues, medical advice should be sought. Also, one should tell their doctor if vision changes occur or if they experience persistent  sore throat ,  fever , easy  bleeding  or  bruising  when using drops with  chloramphenicol . Also, one should be aware of symptoms of an allergic reaction, such as:  rash ,  itching ,  swelling ,  dizziness , and trouble breathing. [ 4 ]  Long term steroid use can cause many adverse effects including steroid-induced  glaucoma  and  cataract . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7864", "text": "Prostaglandin analogs may cause changes in  iris  color and  eyelid  skin, growth of  eyelashes , stinging,  blurred vision , eye redness, itching, and burning. Beta blockers' side effects include  low blood pressure , reduced  pulse rate ,  fatigue , shortness of breath, and in rare occasions, reduced  libido  and  depression . Alpha agonists can cause burning or stinging, fatigue,  headache ,  drowsiness ,  dry mouth  and  nose , and also they have a higher likelihood of allergic reaction. Carbonic anhydrase inhibitors may cause stinging, burning, and eye discomfort. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7865", "text": "Lubricant eye drops may cause some side effects and one should consult a doctor if pain in the eye or changes in vision occur.  Furthermore, when redness occurs but lasts more than 3 days, one should immediately consult a doctor. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7866", "text": "EyePoint Pharmaceuticals Inc.  (formerly  pSivida Corporation ) is a  Watertown, Massachusetts  company specialising in the application of  microelectromechanical systems  (MEMS) and  nanotechnology  to drug delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7867", "text": "pSivida obtained  porous silicon  technology from the British government  Defence Evaluation and Research Agency  (DERA, now  QinetiQ ). [ citation needed ]  QinetiQ continues to be a strategic partner. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7868", "text": "In June 2004, pSivida acquired full ownership of pSiMedica. [ 1 ]  In April 2018, pSivida purchased eye products firm Icon Bioscience. [ 3 ] [ 4 ]  Afterwards, it rebranded to its current name of EyepOint Pharmaceuticals, Inc. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7869", "text": "This United States manufacturing company\u2013related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7870", "text": "Fumigatory boxes  were described in the 19th century as prophylactic or curative medical devices designed to use smoke or vapor to restore health or help prevent the spread of infectious or contagious diseases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7871", "text": "Fumigatory boxes were sometimes used to combat the spread of infectious diseases such as the  plague . One version used in 1837 in Turkey was described as a wooden box approximately 8 feet tall by 3 feet wide (about 2.4 m by 1 m).  At the bottom was a one-foot (30\u00a0cm) tall chamber in which the ingredients of the prophylactic were burned in a dish. Before entering a residence or public building, the clothed subject was to stand inside the box with his or her face protruding through an opening to avoid suffocation, while the rest of his or her body and clothing were engulfed in the smoke produced by the burning disinfectant.  Its purpose was to inhibit the spread of the virulent epidemic then decimating  Constantinople  and its environs.  Although the government ordered such devices installed outside all government buildings, they were often ignored by the populace. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7872", "text": "Another version was designed by Dr. Gales, an  apothecary  at the  Hospital St. Louis  in Paris, in 1812 or shortly thereafter. It had the naked subject seated on a chair in a wooden box, with the patient's entire head exposed through an opening at the box's top. The opening around the patient's neck was sealed so fumes could not escape. There were three chambers at the bottom of this box, the top one containing  sulfur  which was heated by a fire in a chamber below. A bottom chamber caught the ashes.  The sulfurous fumes rose through many small holes drilled through the floor of the patient compartment. If necessary, fumes could be applied directly to the head or face by means of a flexible hose attached to the main compartment. The purpose of this type of fumigatory box was curative or palliative rather than prophylactic, used as a treatment for ailments including  rheumatism  and  psoriasis , not to prevent the spread of disease. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7873", "text": "A third type of fumigatory box was described at the turn of the 20th century as being used to fumigate imported plants on their arrival in Jamaica, to prevent the importation of plant diseases or pests. Plants were placed in the box for one hour and one vial of  cyanide  was released per 300 cubic feet (8.5 cubic meters) of space inside the fumigatory box. For delicate plants, one half the dose for one half-hour was recommended. [ 4 ]  Similar devices, often called fumigation chambers, are still sometimes used. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7874", "text": "A  gel  is a  semi-solid  that can have properties ranging from soft and weak to hard and tough. [ 1 ] [ 2 ]  Gels are defined as a substantially dilute  cross-linked  system, which exhibits no flow when in the steady state, although the liquid phase may still diffuse through this system. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7875", "text": "Gels are mostly liquid  by mass , yet they behave like solids because of a three-dimensional cross-linked network within the liquid. It is the cross-linking within the fluid that gives a gel its structure (hardness) and contributes to the adhesive stick ( tack ). In this way, gels are a dispersion of molecules of a liquid within a solid medium. The word  gel  was coined by 19th-century Scottish chemist  Thomas Graham  by  clipping  from  gelatine . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7876", "text": "The process of forming a gel is called  gelation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7877", "text": "Gels consist of a solid three-dimensional network that spans the volume of a liquid medium and ensnares it through  surface tension  effects. This internal network structure may result from physical bonds such as polymer chain entanglements (see  polymers )  (physical gels) or  chemical bonds  such as  disulfide  bonds (see  thiomers ) (chemical gels), as well as  crystallites  or other junctions that remain intact within the extending fluid. Virtually any fluid can be used as an extender including water ( hydrogels ), oil, and air ( aerogel ). Both by weight and volume, gels are mostly fluid in composition and thus exhibit densities similar to those of their constituent liquids. Edible jelly is a common example of a hydrogel and has approximately the density of water."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7878", "text": "Polyionic polymers are polymers with an ionic functional group. The ionic charges prevent the formation of tightly coiled polymer chains. This allows them to contribute more to  viscosity  in their stretched state, because the stretched-out polymer takes up more space. This is also the reason gel hardens. See  polyelectrolyte  for more information."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7879", "text": "A  colloidal  gel consists of a  percolated  network of particles in a fluid medium, [ 5 ]  providing  mechanical properties , [ 6 ]  in particular the emergence of elastic behaviour. [ 7 ]  The particles can show attractive interactions through  osmotic depletion  or through polymeric links. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7880", "text": "Colloidal gels have three phases in their lifespan: gelation, aging and collapse. [ 9 ] [ 10 ]  The gel is initially formed by the assembly of particles into a space-spanning network, leading to a phase arrest. In the aging phase, the particles slowly rearrange to form thicker strands, increasing the elasticity of the material. Gels can also be collapsed and separated by external fields such as gravity. [ 11 ]  Colloidal gels show linear response rheology at low amplitudes. [ 12 ]  These materials have been explored as candidates for a drug release matrix. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7881", "text": "A  hydrogel  is a network of polymer chains that are hydrophilic, sometimes found as a  colloidal  gel in which water is the dispersion medium. A three-dimensional solid results from the hydrophilic polymer chains being held together by cross-links. [ clarification needed ]  Because of the inherent cross-links, the structural integrity of the hydrogel network does not dissolve from the high concentration of water. [ 14 ]  Hydrogels are highly  absorbent  (they can contain over 90% water) natural or synthetic polymeric networks.\nHydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content. As responsive \" smart materials ,\" hydrogels can encapsulate chemical systems which upon stimulation by external factors such as a change of pH may cause specific compounds such as glucose to be liberated to the environment, in most cases by a  gel-sol transition  to the liquid state. [ 15 ]  Chemomechanical polymers are mostly also hydrogels, which upon stimulation change their volume and can serve as  actuators  or  sensors . The first appearance of the term 'hydrogel' in the literature was in 1894. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7882", "text": "An  organogel  is a  non-crystalline ,  non-glassy  thermoreversible ( thermoplastic ) solid material composed of a  liquid   organic  phase entrapped in a three-dimensionally cross-linked network. The liquid can be, for example, an  organic solvent ,  mineral oil , or  vegetable oil . The  solubility  and  particle  dimensions of the structurant are important characteristics for the  elastic  properties and firmness of the organogel. Often, these systems are based on  self-assembly  of the structurant molecules. [ 17 ] [ 18 ]  (An example of formation of an undesired thermoreversible network is the occurrence of wax crystallization in  petroleum . [ 19 ] )"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7883", "text": "Organogels have potential for use in a number of applications, such as in  pharmaceuticals , [ 20 ]  cosmetics, art conservation, [ 21 ]  and food. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7884", "text": "A  xerogel   / \u02c8 z \u026a\u0259r o\u028a \u02cc d\u0292 \u025b l /  is a solid formed from a gel by drying with unhindered shrinkage. Xerogels usually retain high porosity (15\u201350%) and enormous surface area (150\u2013900 m 2 /g), along with very small  pore  size (1\u201310\u00a0nm). When  solvent  removal occurs under  supercritical  conditions, the network does not shrink and a highly porous, low-density material known as an  aerogel  is produced. Heat treatment of a xerogel at elevated temperature produces viscous  sintering  (shrinkage of the xerogel due to a small amount of viscous flow) which results in a denser and more robust solid, the density and porosity achieved depend on the sintering conditions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7885", "text": "Nanocomposite hydrogels [ 23 ] [ 24 ]  or hybrid hydrogels, are highly hydrated polymeric networks, either physically or covalently crosslinked with each other and/or with nanoparticles or nanostructures. [ 25 ]  Nanocomposite hydrogels can mimic native tissue properties, structure and microenvironment due to their hydrated and interconnected porous structure. A wide range of nanoparticles, such as carbon-based, polymeric, ceramic, and metallic  nanomaterials  can be incorporated within the hydrogel structure to obtain nanocomposites with tailored functionality. Nanocomposite hydrogels can be engineered to possess superior physical, chemical, electrical, thermal, and biological properties. [ 23 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7886", "text": "Many gels display  thixotropy  \u2013 they become fluid when agitated, but resolidify when resting.\nIn general, gels are apparently solid, jelly-like materials. It is a type of  non-Newtonian fluid .\nBy replacing the liquid with gas it is possible to prepare  aerogels , materials with exceptional properties including very low density,  high specific surface areas , and excellent thermal insulation properties."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7887", "text": "A gel is in essence the mixture of a polymer network and a  solvent  phase. Upon stretching, the network  crosslinks  are moved further apart from each other. Due to the polymer strands between crosslinks acting as  entropic springs , gels demonstrate elasticity like  rubber  (which is just a polymer network, without solvent). This is so because the  free energy  penalty to stretch an  ideal polymer  segment  \n \n \n \n N \n \n \n {\\displaystyle N} \n \n  monomers of size  \n \n \n \n b \n \n \n {\\displaystyle b} \n \n  between crosslinks to an  end-to-end distance   \n \n \n \n R \n \n \n {\\displaystyle R} \n \n  is approximately given by [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7888", "text": "This is the origin of both gel and  rubber elasticity . But one key difference is that gel contains an additional solvent phase and hence is capable of having significant volume changes under  deformation  by taking in and out solvent. For example, a gel could swell to several times its initial volume after being immersed in a solvent after equilibrium is reached. This is the phenomenon of gel swelling. On the contrary, if we take the swollen gel out and allow the solvent to evaporate, the gel would shrink to roughly its original size. This gel volume change can alternatively be introduced by applying external forces. If a uniaxial compressive  stress  is applied to a gel, some solvent contained in the gel would be squeezed out and the gel shrinks in the applied-stress direction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7889", "text": "To study the gel mechanical state in equilibrium, a good starting point is to consider a cubic gel of volume  \n \n \n \n \n V \n \n 0 \n \n \n \n \n {\\displaystyle V_{0}} \n \n  that is stretched by factors  \n \n \n \n \n \u03bb \n \n 1 \n \n \n \n \n {\\displaystyle \\lambda _{1}} \n \n ,  \n \n \n \n \n \u03bb \n \n 2 \n \n \n \n \n {\\displaystyle \\lambda _{2}} \n \n  and  \n \n \n \n \n \u03bb \n \n 3 \n \n \n \n \n {\\displaystyle \\lambda _{3}} \n \n  in the three orthogonal directions during swelling after being immersed in a solvent phase of initial volume  \n \n \n \n \n V \n \n s \n 0 \n \n \n \n \n {\\displaystyle V_{s0}} \n \n . The final deformed volume of gel is then  \n \n \n \n \n \u03bb \n \n 1 \n \n \n \n \u03bb \n \n 2 \n \n \n \n \u03bb \n \n 3 \n \n \n \n V \n \n 0 \n \n \n \n \n {\\displaystyle \\lambda _{1}\\lambda _{2}\\lambda _{3}V_{0}} \n \n  and the total volume of the system is  \n \n \n \n \n V \n \n 0 \n \n \n + \n \n V \n \n s \n 0 \n \n \n \n \n {\\displaystyle V_{0}+V_{s0}} \n \n , that is assumed constant during the swelling process for simplicity of treatment. The swollen state of the gel is now completely characterized by stretch factors  \n \n \n \n \n \u03bb \n \n 1 \n \n \n \n \n {\\displaystyle \\lambda _{1}} \n \n ,  \n \n \n \n \n \u03bb \n \n 2 \n \n \n \n \n {\\displaystyle \\lambda _{2}} \n \n  and  \n \n \n \n \n \u03bb \n \n 3 \n \n \n \n \n {\\displaystyle \\lambda _{3}} \n \n  and hence it is of interest to derive the  deformation free energy  as a function of them, denoted as  \n \n \n \n \n f \n \n gel \n \n \n ( \n \n \u03bb \n \n 1 \n \n \n , \n \n \u03bb \n \n 2 \n \n \n , \n \n \u03bb \n \n 3 \n \n \n ) \n \n \n {\\displaystyle f_{\\text{gel}}(\\lambda _{1},\\lambda _{2},\\lambda _{3})} \n \n . For analogy to the historical treatment of  rubber elasticity  and mixing free energy,  \n \n \n \n \n f \n \n gel \n \n \n ( \n \n \u03bb \n \n 1 \n \n \n , \n \n \u03bb \n \n 2 \n \n \n , \n \n \u03bb \n \n 3 \n \n \n ) \n \n \n {\\displaystyle f_{\\text{gel}}(\\lambda _{1},\\lambda _{2},\\lambda _{3})} \n \n  is most often defined as the free energy difference after and before the swelling normalized by the initial gel volume  \n \n \n \n \n V \n \n 0 \n \n \n \n \n {\\displaystyle V_{0}} \n \n , that is, a free energy difference density. The form of  \n \n \n \n \n f \n \n gel \n \n \n ( \n \n \u03bb \n \n 1 \n \n \n , \n \n \u03bb \n \n 2 \n \n \n , \n \n \u03bb \n \n 3 \n \n \n ) \n \n \n {\\displaystyle f_{\\text{gel}}(\\lambda _{1},\\lambda _{2},\\lambda _{3})} \n \n  naturally assumes two contributions of radically different physical origins, one associated with the  elastic deformation  of the polymer network, and the other with the  mixing  of the network with the solvent. Hence, we write [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7890", "text": "We now consider the two contributions separately. The polymer elastic deformation term is independent of the solvent phase and has the same expression as a rubber, as derived in the Kuhn's theory of  rubber elasticity :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7891", "text": "where  \n \n \n \n \n G \n \n 0 \n \n \n \n \n {\\displaystyle G_{0}} \n \n  denotes the  shear modulus  of the initial state. On the other hand, the mixing term  \n \n \n \n \n f \n \n mix \n \n \n ( \n \n \u03bb \n \n 1 \n \n \n , \n \n \u03bb \n \n 2 \n \n \n , \n \n \u03bb \n \n 3 \n \n \n ) \n \n \n {\\displaystyle f_{\\text{mix}}(\\lambda _{1},\\lambda _{2},\\lambda _{3})} \n \n  is usually treated by the  Flory-Huggins free energy  of  concentrated polymer solutions   \n \n \n \n f \n ( \n \u03d5 \n ) \n \n \n {\\displaystyle f(\\phi )} \n \n , where  \n \n \n \n \u03d5 \n \n \n {\\displaystyle \\phi } \n \n  is polymer volume fraction. Suppose the initial gel has a polymer volume fraction of  \n \n \n \n \n \u03d5 \n \n 0 \n \n \n \n \n {\\displaystyle \\phi _{0}} \n \n , the polymer volume fraction after swelling would be  \n \n \n \n \u03d5 \n = \n \n \u03d5 \n \n 0 \n \n \n \n / \n \n \n \u03bb \n \n 1 \n \n \n \n \u03bb \n \n 2 \n \n \n \n \u03bb \n \n 3 \n \n \n \n \n {\\displaystyle \\phi =\\phi _{0}/\\lambda _{1}\\lambda _{2}\\lambda _{3}} \n \n  since the number of monomers remains the same while the gel volume has increased by a factor of  \n \n \n \n \n \u03bb \n \n 1 \n \n \n \n \u03bb \n \n 2 \n \n \n \n \u03bb \n \n 3 \n \n \n \n \n {\\displaystyle \\lambda _{1}\\lambda _{2}\\lambda _{3}} \n \n . As the polymer volume fraction decreases from  \n \n \n \n \n \u03d5 \n \n 0 \n \n \n \n \n {\\displaystyle \\phi _{0}} \n \n  to  \n \n \n \n \u03d5 \n \n \n {\\displaystyle \\phi } \n \n ,  a polymer solution of concentration  \n \n \n \n \n \u03d5 \n \n 0 \n \n \n \n \n {\\displaystyle \\phi _{0}} \n \n  and volume  \n \n \n \n \n V \n \n 0 \n \n \n \n \n {\\displaystyle V_{0}} \n \n  is mixed with a pure solvent of volume  \n \n \n \n ( \n \n \u03bb \n \n 1 \n \n \n \n \u03bb \n \n 2 \n \n \n \n \u03bb \n \n 3 \n \n \n \u2212 \n 1 \n ) \n \n V \n \n 0 \n \n \n \n \n {\\displaystyle (\\lambda _{1}\\lambda _{2}\\lambda _{3}-1)V_{0}} \n \n  to become a solution with polymer concentration  \n \n \n \n \u03d5 \n \n \n {\\displaystyle \\phi } \n \n  and volume  \n \n \n \n \n \u03bb \n \n 1 \n \n \n \n \u03bb \n \n 2 \n \n \n \n \u03bb \n \n 3 \n \n \n \n V \n \n 0 \n \n \n \n \n {\\displaystyle \\lambda _{1}\\lambda _{2}\\lambda _{3}V_{0}} \n \n . The free energy density change in this mixing step is given as"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7892", "text": "where on the right-hand side, the first term is the  Flory\u2013Huggins  energy density of the final swollen gel, the second is associated with the initial gel and the third is of the pure solvent prior to mixing. Substitution of  \n \n \n \n \u03d5 \n = \n \n \u03d5 \n \n 0 \n \n \n \n / \n \n \n \u03bb \n \n 1 \n \n \n \n \u03bb \n \n 2 \n \n \n \n \u03bb \n \n 3 \n \n \n \n \n {\\displaystyle \\phi =\\phi _{0}/\\lambda _{1}\\lambda _{2}\\lambda _{3}} \n \n  leads to"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7893", "text": "Note that the second term is independent of the stretching factors  \n \n \n \n \n \u03bb \n \n 1 \n \n \n \n \n {\\displaystyle \\lambda _{1}} \n \n ,  \n \n \n \n \n \u03bb \n \n 2 \n \n \n \n \n {\\displaystyle \\lambda _{2}} \n \n  and  \n \n \n \n \n \u03bb \n \n 3 \n \n \n \n \n {\\displaystyle \\lambda _{3}} \n \n  and hence can be dropped in subsequent analysis. Now we make use of the  Flory-Huggins  free energy for a polymer-solvent solution that reads [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7894", "text": "where  \n \n \n \n \n v \n \n c \n \n \n \n \n {\\displaystyle v_{c}} \n \n  is monomer volume,  \n \n \n \n N \n \n \n {\\displaystyle N} \n \n  is polymer strand length and  \n \n \n \n \u03c7 \n \n \n {\\displaystyle \\chi } \n \n  is the  Flory-Huggins  energy parameter. Because in a network, the polymer length is effectively infinite, we can take the limit  \n \n \n \n N \n \u2192 \n \u221e \n \n \n {\\displaystyle N\\to \\infty } \n \n  and  \n \n \n \n f \n ( \n \u03d5 \n ) \n \n \n {\\displaystyle f(\\phi )} \n \n  reduces to"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7895", "text": "Substitution of this expression into  \n \n \n \n \n f \n \n mix \n \n \n ( \n \n \u03bb \n \n 1 \n \n \n , \n \n \u03bb \n \n 2 \n \n \n , \n \n \u03bb \n \n 3 \n \n \n ) \n \n \n {\\displaystyle f_{\\text{mix}}(\\lambda _{1},\\lambda _{2},\\lambda _{3})} \n \n  and addition of the network contribution leads to [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7896", "text": "This provides the starting point to examining the swelling equilibrium of a gel network immersed in solvent. It can be shown that gel swelling is the competition between two forces, one is the  osmotic pressure  of the polymer solution that favors the take in of solvent and expansion, the other is the restoring force of the polymer network  elasticity  that favors shrinkage. At equilibrium, the two effects exactly cancel each other in principle and the associated  \n \n \n \n \n \u03bb \n \n 1 \n \n \n \n \n {\\displaystyle \\lambda _{1}} \n \n ,  \n \n \n \n \n \u03bb \n \n 2 \n \n \n \n \n {\\displaystyle \\lambda _{2}} \n \n  and  \n \n \n \n \n \u03bb \n \n 3 \n \n \n \n \n {\\displaystyle \\lambda _{3}} \n \n  define the equilibrium gel volume. In solving the force balance equation, graphical solutions are often preferred."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7897", "text": "In an alternative, scaling approach, suppose an  isotropic  gel is stretch by a factor of  \n \n \n \n \u03bb \n \n \n {\\displaystyle \\lambda } \n \n  in all three directions. Under the  affine network  approximation, the mean-square  end-to-end distance  in the gel increases from initial  \n \n \n \n \n R \n \n 0 \n \n \n 2 \n \n \n \n \n {\\displaystyle R_{0}^{2}} \n \n  to  \n \n \n \n ( \n \u03bb \n \n R \n \n 0 \n \n \n \n ) \n \n 2 \n \n \n \n \n {\\displaystyle (\\lambda R_{0})^{2}} \n \n  and the elastic energy of one stand can be written as"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7898", "text": "where  \n \n \n \n \n R \n \n ref \n \n \n \n \n {\\displaystyle R_{\\text{ref}}} \n \n  is the mean-square fluctuation in end-to-end distance of one strand. The modulus of the gel is then this single-strand elastic energy multiplied by strand number density  \n \n \n \n \u03bd \n = \n \u03d5 \n \n / \n \n N \n \n b \n \n 3 \n \n \n \n \n {\\displaystyle \\nu =\\phi /Nb^{3}} \n \n  to give [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7899", "text": "This modulus can then be equated to  osmotic pressure  (through differentiation of the free energy) to give the same equation as we found above."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7900", "text": "Consider a  hydrogel  made of  polyelectrolytes  decorated with  weak acid  groups that can ionize according to the reaction"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7901", "text": "is immersed in a salt solution of physiological concentration. The degree of  ionization  of the  polyelectrolytes  is then controlled by the  \n \n \n \n \n pH \n \n \n \n {\\displaystyle {\\text{pH}}} \n \n  and due to the charged nature of  \n \n \n \n \n \n H \n \n \n + \n \n \n \n \n {\\displaystyle {\\text{H}}^{+}} \n \n  and  \n \n \n \n \n \n A \n \n \n \u2212 \n \n \n \n \n {\\displaystyle {\\text{A}}^{-}} \n \n ,  electrostatic interactions  with other ions in the systems. This is effectively a reacting system governed by  acid-base equilibrium  modulated by electrostatic effects, and is relevant in  drug delivery , sea water  desalination  and  dialysis  technologies. Due to the elastic nature of the gel, the dispersion of  \n \n \n \n \n \n A \n \n \n \u2212 \n \n \n \n \n {\\displaystyle {\\text{A}}^{-}} \n \n  in the system is constrained and hence, there will be a partitioning of salts ions and  \n \n \n \n \n \n H \n \n \n + \n \n \n \n \n {\\displaystyle {\\text{H}}^{+}} \n \n  inside and outside the gel, which is intimately coupled to the  polyelectrolyte  degree of ionization. This ion partitioning inside and outside the gel is analogous to the partitioning of ions across a semipemerable membrane in classical  Donnan  theory, but a membrane is not needed here because the gel volume constraint imposed by network elasticity effectively acts its role, in preventing the macroions to pass through the fictitious membrane while allowing ions to pass. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7902", "text": "The coupling between the ion partitioning and polyelectrolyte ionization degree is only partially by the classical  Donnan  theory. As a starting point we can neglect the electrostatic interactions among ions. Then at equilibrium, some of the weak acid sites in the gel would dissociate to form  \n \n \n \n \n \n A \n \n \n \u2212 \n \n \n \n \n {\\displaystyle {\\text{A}}^{-}} \n \n that electrostatically attracts positive charged  \n \n \n \n \n \n H \n \n \n + \n \n \n \n \n {\\displaystyle {\\text{H}}^{+}} \n \n  and salt cations leading to a relatively high concentration of  \n \n \n \n \n \n H \n \n \n + \n \n \n \n \n {\\displaystyle {\\text{H}}^{+}} \n \n  and salt cations inside the gel. But because the concentration of  \n \n \n \n \n \n H \n \n \n + \n \n \n \n \n {\\displaystyle {\\text{H}}^{+}} \n \n  is locally higher, it suppresses the further ionization of the acid sites. This phenomenon is the prediction of the classical Donnan theory. [ 31 ]  However, with electrostatic interactions, there are further complications to the picture. Consider the case of two adjacent, initially uncharged acid sites  \n \n \n \n \n HA \n \n \n \n {\\displaystyle {\\text{HA}}} \n \n  are both dissociated to form  \n \n \n \n \n \n A \n \n \n \u2212 \n \n \n \n \n {\\displaystyle {\\text{A}}^{-}} \n \n . Since the two sites are both negatively charged, there will be a charge-charge repulsion along the backbone of the polymer than tends to stretch the chain. This energy cost is high both elastically and electrostatically and hence suppress ionization. Even though this ionization suppression is qualitatively similar to that of Donnan prediction, it is absent without electrostatic consideration and present irrespective of ion partitioning. The combination of both effects as well as gel elasticity determines the volume of the gel at equilibrium. [ 30 ]  Due to the complexity of the coupled acid-base equilibrium, electrostatics and network elasticity, only recently has such system been correctly recreated in  computer simulations . [ 30 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7903", "text": "Some species secrete gels that are effective in parasite control. For example, the  long-finned pilot whale  secretes an enzymatic gel that rests on the outer surface of this animal and helps prevent other organisms from establishing colonies on the surface of these whales' bodies. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7904", "text": "Hydrogels  existing naturally in the body include  mucus , the  vitreous humor  of the eye,  cartilage ,  tendons  and  blood clots . Their viscoelastic nature results in the soft tissue component of the body, disparate from the mineral-based hard tissue of the skeletal system. Researchers are actively developing synthetically derived tissue replacement technologies derived from hydrogels, for both temporary  implants  (degradable) and permanent implants (non-degradable). A review article on the subject discusses the use of hydrogels for  nucleus pulposus  replacement, cartilage replacement, and  synthetic tissue  models. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7905", "text": "Many substances can form gels when a suitable  thickener or gelling agent  is added to their formula. This approach is common in the manufacture of a wide range of products, from foods to paints and adhesives."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7906", "text": "In fiber optic communications, a soft gel resembling  hair gel  in viscosity is used to fill the plastic tubes containing the fibers. The main purpose of the gel is to prevent water intrusion if the buffer tube is breached, but the gel also buffers the fibers against mechanical damage when the tube is bent around corners during installation, or flexed. Additionally, the gel acts as a processing aid when the cable is being constructed, keeping the fibers central whilst the tube material is extruded around it."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7907", "text": "In  polymer chemistry ,  gelation  ( gel transition ) is the formation of a  gel  from a system with  polymers . [ 1 ] [ 2 ]   Branched polymers  can form  links  between the chains, which lead to progressively larger polymers. As the linking continues, larger branched polymers are obtained and at a certain extent of the reaction, links between the polymer result in the formation of a single  macroscopic molecule . At that point in the reaction, which is defined as  gel point , the system loses fluidity and  viscosity  becomes very large. The onset of gelation, or gel point, is accompanied by a sudden increase in viscosity. [ 3 ]  This \"infinite\" sized polymer is called the gel or network, which does not dissolve in the solvent, but can swell in it. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7908", "text": "Gelation is promoted by  gelling agents .\nGelation can occur either by physical linking or by chemical  crosslinking . While the physical gels involve physical bonds, chemical gelation involves covalent bonds. The first quantitative theories of chemical gelation were formulated in the 1940s by  Flory and Stockmayer . Critical percolation theory was successfully applied to gelation in 1970s. A number of growth models (diffusion limited aggregation, cluster-cluster aggregation, kinetic gelation) were developed in the 1980s to describe the kinetic aspects of aggregation and gelation. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7909", "text": "It is important to be able to predict the onset of gelation, since it is an irreversible process that dramatically changes the properties of the system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7910", "text": "According to the  Carothers equation  number-average degree of polymerization  \n \n \n \n D \n \n P \n \n n \n \n \n \n \n {\\displaystyle DP_{n}} \n \n  is given by"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7911", "text": "D \n \n P \n \n n \n \n \n = \n \n \n 2 \n \n 2 \n \u2212 \n p \n . \n \n f \n \n a \n v \n \n \n \n \n \n \n \n {\\displaystyle DP_{n}={\\frac {2}{2-p.f_{av}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7912", "text": "where  \n \n \n \n p \n \n \n {\\displaystyle p} \n \n  is the extent of the reaction and   \n \n \n \n \n f \n \n a \n v \n \n \n \n \n {\\displaystyle f_{av}} \n \n  is the average functionality of reaction mixture. For the gel  \n \n \n \n D \n \n P \n \n n \n \n \n \n \n {\\displaystyle DP_{n}} \n \n  can be considered to be infinite, thus the critical extent of the reaction at the gel point is found as"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7913", "text": "p \n \n c \n \n \n = \n \n \n 2 \n \n f \n \n a \n v \n \n \n \n \n \n \n {\\displaystyle p_{c}={\\frac {2}{f_{av}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7914", "text": "If   \n \n \n \n p \n \n \n {\\displaystyle p} \n \n  is greater or equal to   \n \n \n \n \n p \n \n c \n \n \n \n \n {\\displaystyle p_{c}} \n \n , gelation occurs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7915", "text": "Flory and Stockmayer used a statistical approach to derive an expression to predict the gel point by calculating when  \n \n \n \n D \n \n P \n \n n \n \n \n \n \n {\\displaystyle DP_{n}} \n \n  approaches infinite size. The statistical approach assumes that (1) the reactivity of the functional groups of the same type is the same and independent of the molecular size and (2) there are no intramolecular reactions between the functional groups on the same molecule. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7916", "text": "Consider the polymerization of bifunctional molecules  \n \n \n \n A \n \u2212 \n A \n \n \n {\\displaystyle A-A} \n \n ,  \n \n \n \n B \n \u2212 \n B \n \n \n {\\displaystyle B-B} \n \n  and multifunctional  \n \n \n \n \n A \n \n f \n \n \n \n \n {\\displaystyle A_{f}} \n \n , where  \n \n \n \n f \n \n \n {\\displaystyle f} \n \n  is the functionality. The extends of the functional groups are   \n \n \n \n \n p \n \n A \n \n \n \n \n {\\displaystyle p_{A}} \n \n and  \n \n \n \n \n p \n \n B \n \n \n \n \n {\\displaystyle p_{B}} \n \n , respectively. The ratio of all A groups, both reacted and unreacted, that are part of branched units, to the total number of A groups in the mixture is defined as  \n \n \n \n \u03c1 \n \n \n {\\displaystyle \\rho } \n \n . This will lead to the following reaction"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7917", "text": "A \n \u2212 \n A \n + \n B \n \u2212 \n B \n + \n \n A \n \n f \n \n \n \u2192 \n \n A \n \n f \n \u2212 \n 1 \n \n \n \u2212 \n ( \n B \n \u2212 \n B \n A \n \u2212 \n A \n \n ) \n \n n \n \n \n B \n \u2212 \n B \n A \n \u2212 \n \n A \n \n f \n \u2212 \n 1 \n \n \n \n \n {\\displaystyle A-A+B-B+A_{f}\\rightarrow A_{f-1}-(B-BA-A)_{n}B-BA-A_{f-1}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7918", "text": "The probability of obtaining the product of the reaction above is given by  \n \n \n \n \n p \n \n A \n \n \n [ \n \n p \n \n B \n \n \n ( \n 1 \n \u2212 \n \u03c1 \n ) \n \n p \n \n A \n \n \n \n ] \n \n n \n \n \n \n p \n \n B \n \n \n \u03c1 \n \n \n {\\displaystyle p_{A}[p_{B}(1-\\rho )p_{A}]^{n}p_{B}\\rho } \n \n , since the probability that a B group reach with a branched unit is  \n \n \n \n \n p \n \n B \n \n \n \u03c1 \n \n \n {\\displaystyle p_{B}\\rho } \n \n  and the probability that a B group react with non-branched A is  \n \n \n \n \n p \n \n B \n \n \n ( \n 1 \n \u2212 \n \u03c1 \n ) \n \n \n {\\displaystyle p_{B}(1-\\rho )} \n \n ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7919", "text": "This relation yields to an expression for the extent of reaction of A functional groups at the gel point"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7920", "text": "p \n \n c \n \n \n = \n \n \n 1 \n \n { \n r \n [ \n 1 \n + \n \u03c1 \n ( \n f \n \u2212 \n 2 \n ) \n ] \n \n } \n \n 1 \n \n / \n \n 2 \n \n \n \n \n \n \n \n {\\displaystyle p_{c}={\\frac {1}{\\{r[1+\\rho (f-2)]\\}^{1/2}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7921", "text": "where r is the ratio of all A groups to all B groups. If more than one type of multifunctional branch unit is present and average  \n \n \n \n f \n \n \n {\\displaystyle f} \n \n  value is used for all monomer molecules with functionality greater than 2."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7922", "text": "Note that the relation does not apply for reaction systems containing monofunctional reactants and/or both A and B type of branch units."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7923", "text": "Gelation of polymers can be described in the framework of the  Erd\u0151s\u2013R\u00e9nyi model  or the  Lushnikov model , which answers the question when a  giant component  arises. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7924", "text": "The structure of a gel network can be conceptualised as a random graph. This analogy is exploited to calculate the gel point and gel fraction for monomer precursors with arbitrary types of functional groups. Random graphs can be used to derive analytical expressions for simple polymerisation mechanisms, such as step-growth polymerisation, or alternatively, they can be combined with a system of rate equations that are integrated numerically."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7925", "text": "Hindustan Syringes & Medical Devices  is one of the major world firms manufacturing  medical syringes  and one of the few producing a special type of syringe suitable for making efficient use of the  Pfizer\u2013BioNTech COVID-19 vaccine . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7926", "text": "The  New Delhi  factories have been producing 2.5 billion syringes a year, increasing their capacity because of the  coronavirus pandemic . Two thirds of the capacity is for the market in India but there is global demand, increased by stockpiling, from the US and Europe where investment focused on the vaccine development rather than syringe manufacture. The  United Nations  is also being supplied for the  COVAX  programme. [ 2 ] [ 1 ]  Before the pandemic, global production was about 16 billion syringes per annum but only 5 to 10 percent were used for vaccination and immunisation. Now 8 to 10 billion vaccination syringes are required. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7927", "text": "To make best use of the Pfizer\u2013BioNTech vaccine a dose no larger than 0.3  millilitres  is required which allows six or even seven doses to be extracted from each  vial . The device must also be a  low dead space syringe  so scarcely anything is left in the syringe after injection and the syringe itself must break after use so that there is no possibility of repeated use spreading infection. [ 1 ]  For this reason Japan ordered 15 million syringes at the beginning of 2021 and deliveries started within a month. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7928", "text": "Hindustan Syringes & Medical Devices was established in 1957 [ 4 ]  and is a family run business. In 1995 new machines were required for an increase in production and so private capital was needed. The latest ramping up could be achieved very quickly because no further investment was required. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7929", "text": "A  hypodermic needle  (from  Greek  \u1f51\u03c0\u03bf- ( hypo-  = under), and \u03b4\u03ad\u03c1\u03bc\u03b1 ( derma  = skin)) is a very thin, hollow tube with one sharp tip. It is one of a category of medical tools which enter the skin, called  sharps . [ 1 ]  It is commonly used with a  syringe , a hand-operated device with a plunger, to  inject  substances into the body (e.g.,  saline solution , solutions containing various drugs or liquid medicines) or extract fluids from the body (e.g., blood). Large-bore hypodermic intervention is especially useful in catastrophic blood loss or treating  shock ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7930", "text": "A hypodermic needle is used for rapid delivery of liquids, or when the injected substance cannot be ingested, either because it would not be  absorbed  (as with  insulin ), or because it would harm the  liver . It is also useful to deliver certain medications that cannot be delivered orally due to vomiting. There are many possible  routes  for an injection, with  intramuscular  (into a  muscle ) and  intravenous  (into a  vein ) being the most common. A hypodermic syringe has the ability to retain liquid and blood in it up to years after the last use and a great deal of caution should be taken to use a new syringe every time."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7931", "text": "The hypodermic needle also serves an important role in research environments where sterile conditions are required.  The hypodermic needle significantly reduces contamination during  inoculation  of a sterile  substrate . The hypodermic needle reduces contamination for two reasons: First, its surface is extremely smooth, which prevents airborne  pathogens  from becoming trapped between irregularities on the needle's surface, which would subsequently be transferred into the media (e.g.  agar ) as contaminants; second, the needle's surface is extremely sharp, which significantly reduces the diameter of the hole remaining after puncturing the membrane and consequently prevents microbes larger than this hole from contaminating the substrate. [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7932", "text": "The ancient  Greeks  and  Romans  knew injection as a method of medicinal delivery from observations of snakebites and poisoned weapons. [ 6 ]  There are also references to \"anointing\" and \"inunction\" in the  Old Testament  as well as the works of  Homer , but injection as a legitimate medical tool was not truly explored until the 17th century. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7933", "text": "Christopher Wren  performed the earliest confirmed experiments with crude hypodermic needles, performing intravenous injection into dogs in 1656. [ 7 ]  These experiments consisted of using animal bladders (as the syringe) and goose quills (as the needle) to administer drugs such as  opium  intravenously to dogs. Wren and others' main interest was to learn if medicines traditionally administered orally would be effective intravenously. In the 1660s,  Johann Daniel Major  of  Kiel  and  Johann Sigismund Elsholtz  of  Berlin  were the first to experiment with injections in humans. [ 6 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7934", "text": "The 19th century saw the development of medicines that were effective in small doses, such as opiates and strychnine. This spurred a renewed interest in direct, controlled application of medicine. \"Some controversy surrounds the question of priority in hypodermic medication.\" [ 9 ]  Irish physician  Francis Rynd  is generally credited with the first successful injection in 1844, in the  Meath Hospital  in  Dublin ,  Ireland . [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7935", "text": "Alexander Wood 's main contribution was the all-glass syringe in 1851, which allowed the user to estimate dosage based on the levels of liquid observed through the glass. [ 12 ]  Wood used hypodermic needles and syringes primarily for the application of localized, subcutaneous injection (localized anesthesia) and therefore was not as interested in precise dosages. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7936", "text": "Simultaneous to Wood's work in Edinburgh,  Charles Pravaz  of Lyon also experimented with sub-dermal injections in sheep using a syringe of his own design. Pravaz designed a hypodermic needle measuring 3\u00a0cm (1.18\u00a0in) long and 5\u00a0mm (0.2\u00a0in) in diameter; it was made entirely of silver. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7937", "text": "Charles Hunter , a London surgeon, is credited with the coining of the term \"hypodermic\" to describe subcutaneous injection in 1858. The name originates from two Greek words:  hypo , \"under\", and  derma , \"skin\". Furthermore, Hunter is credited with acknowledging the systemic effects of injection after noticing that a patient's pain was alleviated regardless of the injection's proximity to the pained area. [ 7 ] [ 8 ]  Hunter and Wood were involved in a lengthy dispute over not only the origin of the modern hypodermic needle, but also because of their disagreement as to the medicine's effect once administered. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7938", "text": "Dr. Francis Rynd  used the first \"Hollow Needle\" as a hypodermic syringe on Ms. Margaret Cox in Ireland on June 3rd, 1844. Dr. Wood can be largely credited with the popularization and acceptance of injection as a medical technique, as well as the widespread use and acceptance of the hypodermic needle. The basic technology of the hypodermic needle has stayed largely unchanged since the 19th century, but as the years progressed and medical and chemical knowledge improved, small refinements have been made to increase safety and efficacy, with needles being designed and tailored for very particular uses. Hypodermic needles remain essential to large volume administration or exchange in settings of trauma or dialysis. The trend of needle specification for use began in the 1920s, particularly for the administration of insulin to diabetics. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7939", "text": "The onset of World War II spurred the early development of partially disposable syringes for the administration of  morphine  and  penicillin  on the battlefield. Development of the  fully disposable  hypodermic needle was spurred on in the 1950s for several reasons. The  Korean War  created blood shortages and in response disposable, sterile syringes were developed for collecting blood. The widespread  immunization against polio  during the period required the development of a fully disposable syringe system. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7940", "text": "The 1950s also saw the rise and recognition of cross-contamination from used needles. This led to the development of the first fully disposable plastic syringe by New Zealand pharmacist Colin Murdoch in 1956. [ 15 ]  This period also marked a shift in interest from needle specifications to general sterility and safety. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7941", "text": "The 1980s saw the  rise of the HIV epidemic  and with it renewed concern over the safety of cross-contamination from used needles. New safety controls were designed on disposable needles to ensure the safety of medical workers in particular. These controls were implemented on the needles themselves, such as retractable needles, but also in the handling of used needles, particularly in the use of  hard-surface disposal receptacles  found in every medical office today. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7942", "text": "By 2008, all-plastic needles were in production and in limited use. One version was made of  Vectra (plastic)   aromatic   liquid crystal polymer  tapered from 1.2\u00a0mm at the hub to 0.72\u00a0mm at the tip (equivalent to 22 gauge metal needle), with an ID/OD ratio of 70%. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7943", "text": "Hypodermic needles are normally made from a  stainless-steel  or  Niobium  tube [ 17 ]  through a process known as  tube drawing  where the tube is drawn through progressively smaller  dies  to make the needle. The end of the needle is  bevelled  to create a sharp pointed tip, letting the needle easily penetrate the skin. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7944", "text": "The main system for measuring the diameter of a hypodermic needle is the  Birmingham gauge  (also known as the Stubs Iron Wire Gauge); the  French gauge  is used mainly for catheters. Various needle lengths are available for any given gauge. Needles in common medical use range from 7 gauge (the largest) to 34 (the smallest). 21-gauge needles are most commonly used for drawing blood for testing purposes, and 16- or 17-gauge needles are most commonly used for blood donation, as the larger luminal cross-sectional area results in lower fluid shear, reducing harm to red blood cells while also allowing more blood to be collected in a shorter time. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7945", "text": "Although reusable needles remain useful for some scientific applications, disposable needles are far more common in medicine. Disposable needles are embedded in a plastic or aluminium hub that attaches to the syringe barrel by means of a press-fit or twist-on fitting. These are sometimes referred to as \"Luer Lock\" connections, referring to the trademark  Luer-Lok . The male and female luer lock and hub\u2014produced by pharmaceutical equipment manufacturers\u2014are two of the most critical parts of disposable hypodermic needles. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7946", "text": "Hypodermic needles are usually used by medical professionals ( dentists ,  phlebotomists ,  physicians ,  pharmacists ,  nurses ,  paramedics ), but they are sometimes used by patients themselves. This is most common with  type one diabetics , who may require several  insulin  injections a day. [ 21 ]  It also occurs with patients who have  asthma  or other severe  allergies . Such patients may need to take  desensitization  injections or they may need to carry injectable medicines to use for first aid in case of a severe allergic reaction. In the latter case, such patients often carry a syringe loaded with  epinephrine  (e.g.  EpiPen ), [ 22 ]   diphenhydramine  (e.g.  Benadryl ), or  dexamethasone . Rapid injection of one of these drugs may stop a severe allergic reaction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7947", "text": "Multiple sclerosis  patients may also treat themselves by injection; several MS therapies, including various  interferon  preparations, are designed to be self-administered by subcutaneous or intramuscular injection. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7948", "text": "Transgender  people may also inject their own  hormone replacement therapy , using either  intramuscular injection  or  subcutaneous injection  methods."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7949", "text": "Hypodermic needles are also used for  erotic piercing . [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7950", "text": "It is estimated that anywhere from nearly 3.5 to 10% of the world's population may have a  phobia  of needles (trypanophobia), [ 25 ]  and it is much more common in children, ages 5\u201317. Topical anesthetics can be used to desensitize the area where the injection will take place to reduce pain and discomfort. [ 26 ]  For children, various techniques may be effective at reducing distress or pain related to needles. [ 27 ]  Techniques include: distraction,  hypnosis , combined  cognitive behavioral therapy , and breathing techniques. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7951", "text": "Immunoliposome therapy  is a targeted drug delivery method that involves the use of  liposomes  (artificial lipid bilayer vesicles) coupled with monoclonal  antibodies  to deliver therapeutic agents to specific sites or tissues in the body. [ 1 ]  The antibody modified liposomes target tissue through cell-specific antibodies with the release of drugs contained within the assimilated liposomes. [ 1 ]  Immunoliposome aims to improve drug stability, personalize treatments, and increased drug efficacy. [ 1 ]  This form of therapy has been used to target specific cells, protecting the encapsulated drugs from degradation in order to enhance their stability, to facilitate sustained drug release and hence to advance current traditional  cancer  treatment. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7952", "text": "Alec D. Bangham  discovered liposomes in the 1960s as spherical vesicles made of a phospholipid bilayer that houses hydrophilic cores. [ 2 ]  The liposomes were then studied to uncover the properties of biological membranes and a hydration method was discovered to prepare artificial liposomes from 1968 to 1975. [ 2 ]  Since then, multiple methods of preparing liposomes have been utilized and their characteristics (physical and chemical) have been studied. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7953", "text": "Monoclonal antibodies  are proteins that stick to specific  antigens  that tag specific cells and can be synthesized in the lab. [ 3 ]  They were first generated in 1975 and have since advanced to being used for immunotherapy. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7954", "text": "Immunolipsomes were developed utilizing both of these components. [ 1 ]  The first anticancer drug made with this method was  doxorubicin  (DOX) in the 1990s. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7955", "text": "The core structure of immunoliposomes is a  lipid bilayer . This lipid bilayer forms a hydrophilic core, which provides stable encapsulation for a therapeutic payload. [ 5 ]  Common lipids used are  phosphatidylcholine  (PC),  phosphatidylethanolamine  (PE), and  cholesterol . [ 5 ]  The lipid bilayer is surface modified through conjugation using monoclonal antibodies for specific recognition of the target cells or tissues of interest. [ 5 ]  The core of the immunoliposome contains the therapeutic payload, which can be anything from small drugs, nucleic acids, peptides, or imaging agents. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7956", "text": "There are often stabilizers and excipients present for formulation, stability, and functionality. [ 5 ]  Some include  polyethylene glycol  (PEG), antioxidants to prevent degradation of lipids, and buffering agents for optimal pH. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7957", "text": "Immunoliposomes are created when antibodies are conjugated to liposomes. [ 6 ]  One way to do this is through covalent bonds between the antibody (or its fragment) and the lipid. [ 6 ]  Another way is through chemical modification of antibodies so they have a higher affinity for the liposome. [ 6 ]  \u201cIn general, the conjugation methodology is based on three main reactions; a reaction between activated carboxyl groups and amino groups which yields an amide bond, a reaction between pyridyl dithiols and thiols which yields disulfide bonds, and a reaction between  maleimide  derivatives and thiols, which yields  thioether  bonds.\u201d  [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7958", "text": "Amine groups are found throughout an antibody and are used as a target due to their easy steric accessibility and modification. An overview of this reaction is found in  Figure 2 . Most often amine groups found on lysine are covalently bonded to  carboxyl groups  of  glutamic  and  aspartic acid  on formed liposomes using certain agents. A two step process is utilized where the first step uses 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide to create an amine reactive product from the carboxyl group. [ 6 ]  This product is a target for a nucleophilic attack by the amine but it hydrolyzes quickly, so EDC is added to stabilize it. As seen in the  Figure 2 , the intermediate can lead to the desired stable amide bond by chance or the recreation of a carboxyl group. [ 6 ]  To create more of the desired carboxyl-amine bond, N-hydroxysulfosuccinimide (sulfo-NHS) is added to form another intermediate that is an NHS ester. [ 6 ]  The second step to this reaction is for the antibodies to use the N-terminus of the lipid to covalently conjugate by creating an amide bond via displacement of sulfo-NHS groups. [ 6 ]  This leads to the final product of an antibody conjugated to a liposome to create an immunoliposome. This process is highly efficient and effective while maintaining the biological activity of the antibody. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7959", "text": "Another process of creating immunoliposomes is by using a thiol group and creating a thioether bond. [ 6 ]  The sulfhydryl group is a key player can is found in cysteine bridges on proteins and reagents like  Traut\u2019s reagents , SATA, and Sulfo-LC-SPDP. [ 6 ]  The reduction or hydrolysis of these groups generates thiol groups that create antibody conjugation to lipids. [ 6 ]  There are multiple methods of this process, and one uses the crosslinking agent SATA as shown in  Figure 3 . [ 6 ]  The ester end of SATA reacts with amino groups in proteins to form an amide link and a molecule with a protected sulfhydryl group. [ 6 ]  In order to continue the reaction, this group must be freed which is done by adding hydroxylamine. The following step is to add a chemical that can be an anchor between the lipid and the thiol group. Some examples of molecules that are capable of being this anchor are maleimide, iodoacetyl groups or 2-pyridyldithiol groups. [ 6 ]  Ultimately, these steps create an antibody-enzyme conjugate that has been formulated using a thiol group. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7960", "text": "Immunoliposomes use similar functionality as liposomes with the added measure of conjugating monoclonal antibodies and their fragments to the liposomes. [ 6 ]  The use of antibodies allow for easy targeting as they can recognize many different types of antigens. [ 6 ]  Diseased cells typically contain more antigens than healthy cells, which is how antibodies are able to appropriately target certain extracellular domains (depending on antigen overexpression) and kill diseased cells. [ 6 ]  Liposomal drug delivery combined with antibodies as a targeting ligand are what help immunoliposomes function as an effective drug carrier. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7961", "text": "Once the immunoliposomes deliver the appropriate drugs to the targeted cells, they can enter the cell using either selective uptake of liposomes by endocytosis or liposome release near the targeted cell. [ 6 ]  Because of antibody conjunction, the cellular uptake amount is increased for immunoliposomes allowing greater drug entry into diseased cells. [ 6 ]  To control when a drug is released, immunoliposomes are being developed that can sense stimuli. This stimuli can come from the microenvironment of a tumor using factors such as reduced pH, temperature, and enzyme levels. [ 6 ]  External stimuli like light, heat, magnetic fields, or ultrasound can also act as a trigger for drug release. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7962", "text": "Immunoliposomes can target a wide variety of cell options. This can be split into two main types commonly known as intravascular and extravascular space as seen in  Figure 4 . [ 7 ]  Intravascular cells are more accessible during circulation and include  erythrocytes ,  myeloid cells ,  lymphocytes ,  neutrophils , etc. [ 7 ]  Extravascular cells are located on tissue  parenchymal  or  stromal  cells. [ 7 ]  Because immunoliposomes have many antibody copies, they contain a higher avidity than just one antibody alone allowing for effective targeting against cancer cells and some drug resistant cells. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7963", "text": "Immunoliposome applications use its ability to act as a drug delivery system and release specific drug components to target cells. This mechanism can be specifically highlighted in cancer cell targeting and through nutrient delivery systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7964", "text": "The most common use of immunoliposomes is to target cancer cells using different antibodies.  Folate receptors  and  transferrin receptors  are typically overexpressed on cancer cells, so immunoliposomes will target these corresponding ligands. [ 8 ]  Folate receptors dictate tumor cell specificity and have been seen to be expressed in multiple inflammatory diseases including  psoriasis ,  Crohn\u2019s disease ,  atherosclerosis , and  rheumatoid arthritis  making folate-targeted immunoliposomes an efficient drug carrier to deliver antiinflammatory drugs. [ 8 ]  Transferrin receptors help with the iron demand in proliferating cancer cells and allow for formation of transferrin receptor-targeted anticancer therapies. [ 8 ]   EGFR  (epidermal growth factor) is a tyrosine kinase receptor overexpressed in solid tumors such as colorectal, non small-cell lung cancer, squamous cell carcinoma, and breast cancer making it another target receptor for immunoliposomes. [ 8 ]  Some cancers create tumors that have multiple different receptors being overexpressed or utilize cancer stem cells, which allow for differentiation of numerous cancer types, so to combat this, dual-targeting immunoliposomes are being created to target multiple ligands and increase therapeutic efficacy. [ 9 ]  A study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Valrubicin-loaded immunoliposomes (Val-ILs) as a novel nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7965", "text": "Immunoliposomes can also be used as nutrient delivery systems to help stimulate brain activity. The effective transport of certain nutrients to the  hypothalamus  in order to regulate brain activity is currently a huge problem. [ 11 ]  The  leptin  gene is used to regulate feedback loops and send signals from the adipose tissue to the hypothalamus. [ 11 ]  Using this physiological function of leptin, immunoliposome nutrient delivery systems can be integrated into the body to help with nutrition transport to the brain as seen in  Figure 5 . [ 11 ]  Transferrin receptors have high expression at the BBB ( blood brain barrier ) and can be used as targets for immunoliposomes to transport p-glycoprotein substances. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7966", "text": "Immunoliposomes have many possible applications as described above and have certain advantages in new research and ideas. [ 6 ]  Some advantages being researched include immunoliposomes targeting specific molecules in the body. [ 6 ]  In preclinical testing, they can be environmentally responsive to specific conditions of temperature, pH, enzymes, redox reactions, magnetic energy, and light to release drugs. [ 6 ]  This conditional ability allows immunoliposomes to focus on specific target areas which can be beneficial for drug delivery. [ 6 ]  Increased targeting allows the possibility for decreased systemic toxicity while increasing drug concentration at a certain site. [ 6 ]  Even with this advantage of immunoliposomes, there are some challenges in their application."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7967", "text": "The success of immunoliposomes during in vivo testing has been shown by multiple groups including Meeroekyai et al 2023 [ 12 ]  and animal testing has been successful in groups such as Refaat et al 2022. [ 13 ]  However, they struggle to thrive in higher level and clinical testing. [ 6 ]  This challenge stems from the variability and lack of understanding of tumors, pharmacokinetics, and large scale production of immunoliposomes. For example, tumors vary but typically have increased vascular permeability and decreased lymphatic drainage which lead to the EPR effect. EFR is the enhanced permeability and retention effect in which drug carriers depend on but the effect and environment can vary in solid tumors. [ 14 ]  This varying environment makes it hard to predict how the immunoliposome acts and quantify its pharmacokinetics. [ 6 ]  Additionally, it has been a concern that the animal models used in preclinical testing will not reflect the same effect in humans. [ 6 ]  Because of this idea, despite any preclinical success, there is a concern to test in humans due to unknown risks. For environmentally responsive immunoliposomes, more modification and purification steps are required to produce the final product. This increase in complexity for immunoliposomes and their behavior also increases costs. [ 6 ]  Another challenge to marketability and clinical research is the difficulty of scaling up the production of immunoliposomes. The procedure and use of small quantities in the laboratory make upscaling the production a challenge that has not been focused upon. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7968", "text": "Liposomal medicine research for cancer therapy has increased over the years as an alternative to conventional cancer treatment. [ 15 ]  There is an interest in liposomal medicine because it features targeted drug delivery while mitigating the damage to healthy cells and tissues. [ 15 ]  One of the combination products under liposome therapy that is being researched for cancer therapy applications is immunoliposome therapy. [ 15 ]  Other research areas in liposome combination therapy include  photodynamic therapy , photothermal agents,  radiotherapy , and gas therapy agents. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7969", "text": "A immunoliposome therapy clinical study that was completed was conducted by the  Swiss Group for Clinical Cancer Research from 2006 to 2009 . [ 16 ]  The study was a phase II clinical trial that looked at the combination of commercially sold  Doxorubicin  with  bevacizumab , a monoclonal antibody that blocks tumor growth. [ 16 ]  The therapy was used to treat patients with locally recurrent or  metastatic breast cancer . [ 16 ]  Out of the 43 patients, 16 had grade 3 palmar-plantar erythrodysesthesia, one had grade 3 mucositis, and one severe cardiotoxicity, according to the study. [ 16 ]  As a result, the combination therapy demonstrated higher than anticipated toxicity while only having modest therapeutic effect. [ 16 ]  These results concluded that, although immunoliposome therapy has promise, there is still more research needed before translating into commercial products. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7970", "text": "There are several liposome medicines currently available commercially, which helps set the regulatory pathway for immunoliposome therapies. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7971", "text": "As immunoliposome therapy has progressed in research, big market players in pharmaceutical research and manufacturing have invested in the development of these therapies. [ 15 ]  A relevant example of this is a  phase I/II trial  that examined the effectiveness of PDS0101 in combination with  pembrolizumab , an immune checkpoint inhibitor (sold under the brand name  Keytruda ). [ 17 ]  The study is funded by PDS Biotechnology and in partnership with  Merck . [ 18 ]  The purpose of the study is to determine the effectiveness of PDS0101 + pembrolizumab in shrinking tumors in patients with virus-related  oropharyngeal cancer  tumors in humans. [ 15 ]  PDS0101 is a peptide-based vaccine that aids in the immune response to kill tumor cells. [ 15 ]  The study also relies on pembrolizumab monoclonal antibodies to help the body's immune system attack the cancer and interfere with the spread of tumor cells. [ 15 ]  \nAlthough immunoliposome therapy exhibits clinical and commercial promise, there are several known challenges in the translation from laboratory studies to clinical studies and ultimately to commercialization. [ 15 ]  One obstacle is that immunoliposome therapy is limited by having a short half-life and retention time once it reaches the tumor microenvironment. [ 15 ]  Additionally, immunoliposome therapies are often individualized which requires close clinical monitoring and comprehensive evaluation methods. [ 15 ]  From a biochemical perspective, other challenges that immunoliposome therapies face are drug instability due to the phospholipid bilayer and the known possibility for  hepatotoxicity . [ 15 ]  From a manufacturing perspective, designing liposome drug delivery systems at an industrial scale can present a challenge due to the complexity of these drug release mechanisms and their related biosafety. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7972", "text": "Though immunoliposomes serve as a possible advancement, there are other therapies similar to it that trail on the role of targeted drug delivery systems. [ 19 ]  One example of such therapy is Immune Polymeric  nanoparticles , which are similar to liposomes but consist of small particles composed of biodegradable polymers. [ 19 ]  These nanoparticles similarly encapsulate drugs and can function to enhance specificity towards targeted diseased cells with peptide ligands. [ 19 ]  Another type is Targeting  Antibody Drug Conjugates , which combine monoclonal antibodies with the cytotoxicity of chemotherapy drugs. [ 20 ]  This specific type is catered towards cancer cells expressing a specific target antigen. [ 20 ]  They are well-tolerated by the body as they are biodegradable, eliminating many potential toxicity factors, and proving to be a possible new model for therapeutics. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7973", "text": "An  infusion pump   infuses  fluids,  medication  or  nutrients  into a  patient's   circulatory system . It is generally used  intravenously , although  subcutaneous ,  arterial  and  epidural  infusions are occasionally used."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7974", "text": "Infusion pumps can administer fluids in ways that would be impractically expensive or unreliable if performed manually by nursing staff.  For example, they can administer as little as 0.1 mL per hour injections (too small for a drip), injections every minute, injections with repeated  boluses  requested by the patient, up to maximum number per hour (e.g. in  patient-controlled analgesia ), or fluids whose volumes vary by the time of day."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7975", "text": "Because they can also produce quite high but controlled  pressures , they can inject controlled amounts of fluids subcutaneously (beneath the skin), or epidurally (just within the surface of the  central nervous system  \u2013 a very popular local spinal  anesthesia  for  childbirth )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7976", "text": "The  user interface  of pumps usually requests details on the type of infusion from the technician or nurse that sets them up:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7977", "text": "To get the entire dose of antibiotics into the patient, the \"volume to be infused\" or VTBI must be programmed for at least 30 CCs more than is in the medication bag; failure to do so can potentially result in up to half of the antibiotic being left in the IV tubing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7978", "text": "Some pumps offer modes in which the amounts can be scaled or controlled based on the time of day.  This allows for  circadian cycles  which may be required for certain types of medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7979", "text": "There are two basic classes of pumps.  Large volume pumps can pump   fluid replacement  such as  saline solution , medications such as  antibiotics  or nutrient solutions large enough to feed a patient.  Small-volume pumps infuse  hormones , such as  insulin , or other medicines, such as  opiates ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7980", "text": "Within these classes, some pumps are designed to be portable, others are designed to be used in a hospital, and there are special systems for charity and battlefield use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7981", "text": "Large-volume pumps usually use some form of  peristaltic pump .  Classically, they use computer-controlled rollers compressing a silicone-rubber tube through which the medicine flows.  Another common form is a set of fingers that press on the tube in sequence."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7982", "text": "Small-volume pumps usually use a  computer -controlled motor turning a screw that pushes the plunger on a syringe."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7983", "text": "The classic medical improvisation for an infusion pump is to place a  blood pressure  cuff around a bag of fluid.  The battlefield equivalent is to place the bag under the patient.  The pressure on the bag sets the infusion pressure.  The pressure can actually be read-out at the cuff's indicator.  The problem is that the flow varies dramatically with the cuff's pressure (or patient's weight), and the needed pressure varies with the administration route, potentially causing risk when attempted by an individual not trained in this method."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7984", "text": "Places that must provide the least-expensive care often use pressurized infusion systems.  One common system has a purpose-designed plastic \"pressure bottle\" pressurized with a large disposable plastic syringe.  A combined  flow restrictor , air filter and drip chamber helps a nurse set the flow.  The parts are reusable, mass-produced  sterile  plastic, and can be produced by the same  machines that make plastic soft-drink bottles and caps.  A pressure bottle, restrictor and chamber requires more nursing attention than electronically controlled pumps.  In the areas where these are used, nurses are often volunteers, or very inexpensive."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7985", "text": "The restrictor and high pressure helps control the flow better than the improvised schemes because the high pressure through the small restrictor orifice reduces the variation of flow caused by patients' blood pressures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7986", "text": "An air filter is an essential safety device in a pressure infusor, to keep air out of the patients' veins.  Small bubbles could cause harm in arteries, but in the veins they pass through the heart and leave in the patients' lungs. The air filter is just a membrane that passes gas but not fluid or  pathogens . When a large air bubble reaches it, it bleeds off."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7987", "text": "Some of the smallest infusion pumps use  osmotic  power.  Basically, a bag of salt solution absorbs water through a membrane, swelling its volume.  The bag presses medicine out.  The rate is precisely controlled by the salt concentrations and pump volume.  Osmotic pumps are usually recharged with a syringe."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7988", "text": "Spring-powered clockwork infusion pumps have been developed, and are sometimes still used in veterinary work and for ambulatory small-volume pumps.  They generally have one spring to power the infusion, and another for the alarm bell when the infusion completes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7989", "text": "Battlefields often have a need to perfuse large amounts of fluid quickly, with dramatically changing blood pressures and patient condition.  Specialized infusion pumps have been designed for this purpose, although they have not been deployed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7990", "text": "Many infusion pumps are controlled by a small  embedded system .  They are carefully designed so that no single cause of failure can harm the patient.  For example, most have batteries in case the wall-socket power fails.  Additional hazards are uncontrolled flow causing an  overdose , uncontrolled lack of flow, causing an underdose, reverse flow, which can siphon blood from a patient, and air in the line, which can cause an  air embolism ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7991", "text": "Elastomeric pumps , also known as balloon pumps or ball pumps, rely on the gradual contraction of an internal elastomeric reservoir to deliver medication at a pre-determined flow rate over several hours or days. These pumps do not require electricity and offer simplicity and portability, making them suitable for administering various medications, including antibiotics, in situations where continuous, low-rate infusion is required. These features make them useful for infusions in outpatient settings, such as  outpatient parenteral antibiotic therapy  (OPAT). However, due to their limited features and programmability, they are not suitable for all medications or flow rates. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7992", "text": "The range of safety features varies widely with the age and make of the pump.  A state of the art pump in 2003 [update]  might have had the following safety features:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7993", "text": "By 2019  intravenous smart pumps were being introduced. They could include wireless connectivity, drug libraries, profiles of care areas, and soft and hard limits. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7994", "text": "Infusion pumps have been a source of multiple patient safety concerns, and problems with such pumps have been linked to more than 56,000 adverse event reports from 2005 to 2009, including at least 500 deaths. [ 4 ]  As a result, the U.S.  Food and Drug Administration  (FDA) has launched a comprehensive initiative to improve their safety, called the Infusion Pump Improvement Initiative. [ 5 ]   The initiative proposed stricter regulation of infusion pumps.  It cited software defects, user interface issues, and mechanical or electrical failures as the main causes of adverse events."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7995", "text": "An  inhaler  ( puffer ,  asthma pump  or  allergy spray ) is a medical device used for delivering medicines into the  lungs  through the work of a person's breathing. This allows medicines to be delivered to and absorbed in the lungs, which provides the ability for targeted medical treatment to this specific region of the body, as well as a reduction in the side effects of oral medications. There are a wide variety of inhalers, and they are commonly used to treat numerous medical conditions with  asthma  and  chronic obstructive pulmonary disease  (COPD) being among the most notable. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7996", "text": "Some of the common types of inhalers include  metered-dose inhalers ,  dry powder inhalers , soft mist inhalers, and  nebulizers . Each device has advantages and disadvantages and can be selected based on individually specific patient needs, as well as age, pathological conditions, coordination, and lung function. [ 2 ]  Proper education on inhaler use is important to ensure that inhaled medication creates its proper effects in the lungs. [ 3 ]  Using a spacer can ensure that more medicine reaches the lungs, [ 4 ] [ 5 ]  thus providing the most optimal treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_7997", "text": "Inhalers are designed to deliver medication directly to the lungs through a person's own breathing. This may benefit a patient by providing medicines directly to areas of disease, allowing medication to take a greater effect on its intended target, and limit side effects of medications when administered locally. [ 1 ]  Inhalers are used in a variety of different medical conditions with  diseases of the lungs  and  respiratory system  being among the most common. Individuals with these diseases/conditions need medications designed to decrease airway inflammation and obstruction to allow for easier and comfortable breathing. [ 6 ]  Antibiotic medications have even been developed for inhalers to allow for direct delivery to areas of infection within the lungs. [ 7 ]  Two of the most common conditions that warrant inhaler therapy are  asthma  and  chronic obstructive pulmonary disease . [ 6 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7998", "text": "Asthma  is a condition of intermittent  airway obstruction  due to  inflammatory  processes in the lungs. Inhaled medications are used to calm down the inflammation present in the lungs and allow for relief of the airway obstruction. Common inhaled medications used for treatment of asthma include long term inhalational steroidal  anti-inflammatory drugs  (most commonly  inhaled corticosteroids , also called ICS) and fast-relieving bronchodilators such as  salbutamol  (known commonly as \"Ventolin\") and  salmeterol . These medications allow for patients to have relief of airway obstruction symptoms and reduced inflammation. [ 6 ]  If some people are unable to use inhalers,  non-steroidal anti-inflammatory drugs  (NSAIDs) may be used, but with caution since they may cause immunological  hypersensitivity  to NSAIDs, resulting in respiratory-related symptoms such as  bronchospasms , acute  asthma exacerbation , and severe asthma morbidity. [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_7999", "text": "COPD is an obstructive lung disease due to long-term damage to the airways of the lungs. The long-term damage leads to the inability of the airways to open properly, causing  airway obstruction . Inhaled medications allow patients to see improvement in symptoms and better function of daily living. Some commonly used inhaled medications in patient's with COPD are  ipratroprium ,  salmeterol , and  corticosteroids . [ 8 ]  Inhalers that combine two or three different medications including inhaled corticosteroids, long-active muscarinic medications (LAMA) and long acting beta2 agonists (LABA) for treating COPD may be associated with improvements in some quality of life variables and small improvements in lung function and respiratory symptoms, however, may also be associated with an increase in the risk of pneumonia. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8000", "text": "The most common type of inhaler is the pressurized  metered-dose inhaler  (MDI) which is made up of 3 standard components- a metal canister, plastic actuator, and a metering valve. The medication is typically stored in solution in a pressurized canister that contains a propellant or suspension. The MDI canister is attached to a plastic, hand-operated actuator. On activation, the metered-dose inhaler releases a fixed dose of medication in  aerosol  form through the actuator and into a patient's lungs. [ 12 ]   These devices require significant coordination as a person must discharge the medication at or near the same time that they inhale in order for the medication to be effective. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8001", "text": "Dry powder inhalers  release a metered or device-measured dose of powdered medication that is inhaled through a DPI device. This device usually contains a chamber in which the powdered medication is deposited prior to each dosage. [ 3 ]  The powder can then be inhaled with a quick breath. [ 1 ]   This allows for medication to be delivered to the lungs without the need for use of propellant/suspension. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8002", "text": "Soft mist inhalers release a light mist containing medication without the need for a propellant/suspension. Upon pressing a button, the inhaler creates a mist of medication, allowing for inhalation into the lungs. SMIs suspend inhaled medications for roughly 1.2 seconds, which is longer than the average MDI inhaler suspension time period.  This requires less coordination when using and may be helpful for young patients or patients that find the MDI inhalers difficult to use. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8003", "text": "Nebulizers  are designed to deliver medications over an extended period of time over multiple breaths through a mouthpiece or face mask.  They generate a continuous mist with aerosolized medication, allowing a patient to breathe normally and receive medications. [ 13 ]   They are commonly used in infants and toddlers requiring inhaled medications or in patients in the hospital who require inhaled medications. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8004", "text": "The smart-inhaler is an inhaler that will automatically update an app with information that includes the time of day, air quality, and how many times it has been used through sensor technology on the device. [ 14 ]  The first smart-inhaler was approved in 2019 by the FDA, its purpose is to track patient use of the device and some other circumstantial factors that could affect the effectiveness of the dosage. [ 14 ]  This information is sent via Bluetooth to a mobile device app, and is later shared with their physician to determine what kind of things can trigger issues with asthma and other problems. [ 14 ]  This technology presents a great way to cut down on medical costs associated with asthma and also help patients better manage their condition with fewer emergencies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8005", "text": "The Teva ProAir Digihaler was the first FDA approved smart inhaler. [ 15 ]  It shows how effective the device is at aiding patients in using the proper dose amount for their asthma. In a study published by the European Respiratory Journal, the ProAir Digihaler accurately identified when patients were using their inhalers and whether they were effectively administering the dose in a 370 patient trial with the device. [ 15 ]  This study further gives an overview on the technology regarding applications and devices that help aid in the tracking and medication management for asthma and other lung conditions. Another study showed that smart inhalers accurately recorded all doses administered by patients with their technology, which signifies their importance in providing accurate dosage information to patients and their physicians. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8006", "text": "In 2009, the FDA banned the use of inhalers that use  chlorofluorocarbons  (CFC) as  propellants . In their place, inhalers now use  hydrofluoroalkane  (HFA). HFA is not environmentally inert as it is a  greenhouse gas  but it does not affect the  ozone layer . [ 17 ]  While some people with asthma and advocacy groups contend that HFA inhalers are not as effective, [ 18 ]  published clinical studies indicate CFC and HFA inhalers are equally effective in controlling asthma. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8007", "text": "While the impact of CFCs from inhalers on the ozone layer had been minuscule (dwarfed by industrial processes using CFCs), the FDA in its interpretation of the  Montreal Protocol  mandated the switch in propellants. [ 17 ]  Patients expressed concern about the high price of the HFA inhalers as there were initially no generic versions, whereas generic CFC inhalers had been available. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8008", "text": "It is important to use proper techniques when administering medications through inhalers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8009", "text": "Proper use of inhalers often involves initial  deep breathing  (which involves mostly the  diaphragm 's movements), and then rapid breathing [ 20 ]  (which involves most of the muscles of respiration, such as external and internal  intercostal muscles [ 21 ] ) during intake of one or more puffs from the inhalers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8010", "text": "Improper use of inhalers is very common, can lead to distribution of the medicine into the mouth or throat where it cannot create its desired effect and may cause harm. [ 1 ] [ 22 ] [ 23 ]  Education on the correct use of inhalers for delivery of medications is a commonly cited topic in medical studies and a great deal of thought has been put into how best to help people learn to use their inhalers effectively. [ 24 ] [ 3 ]  Below is a description of proper inhaler technique for each different type of inhaler as well as a helpful video explaining what the text states."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8011", "text": "Spacer is placed at the mouthpiece of a meter-dosed inhaler while keeping mouth at the end of the spacer. After pressing the canister of the inhaler, the medicine will linger inside the spacer, allowing for the user of the inhaler to directly absorb medicine into their lungs. [ 25 ]  Deep breathing is done to be ready for the delivery of the medicine to the lungs; this minimizes need for coordination of breathing with inhaler activation. [ 1 ]  Cleanage of the spacer regularly with warm soapy water is recommended. [ 25 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8012", "text": "If inhaler is used everyday, the inhaler usually has to be primed the first time using a new cartridge, but it may need to be primed again if it has not been used in multiple days. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8013", "text": "If using inhaled corticosteroids, one should wash the mouth out directly after use of an inhaler. This helps to prevent  mouth infections  that can occur due to  immunosuppressant  effects of corticosteroids. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8014", "text": "In the United States, pharmaceutical manufacturers use legal and regulatory strategies to keep inhaler prices artificially high. There has been little innovation in inhaler technology for decades \u2014 the most recent drug to be approved by the FDA for treating asthma or COPD via a novel  target of action  was  Ipratropium bromide  in 1986. Since then, manufacturers have used small changes to drug delivery mechanisms, or have switched active ingredients from one inhaler device to another (a strategy known as a \" device hop \") to keep patents active. This has the effect of limiting competition, keeping inhalers expensive. [ 26 ]  Because of high prices, patients sometimes skip doses or give up using their inhalers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8015", "text": "The idea of directly delivering medication into the lungs was based on ancient traditional cures that involved the use of aromatic and medicinal vapors. These did not involve any special devices beyond the apparatus used for burning or heating to produce fumes. Early inhalation devices included one devised by John Mudge in 1778. It had a pewter mug with a hole allowing attachment of a flexible tube. Mudge used it for the treatment of coughs using opium. These devices evolved with modifications by Wolfe, Mackenzie (1872) and better mouth attachments such as by Beigel in 1866. Many of these early inhalers needed heat to vaporize the active chemical ingredient. The benefits of forced expiration and inspiration to treat asthma were noted by J. S. Monell in 1865. Chemicals used in inhalers included ammonia, chlorine, iodine, tar, balsams, turpentine camphor and numerous others in combinations. [ 27 ]   Julius Mount Bleyer  used a variation in 1890 in New York. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8016", "text": "In 1968, Robert Wexler of  Abbott Laboratories  developed the Analgizer, a disposable inhaler that allowed the self-administration of  methoxyflurane   vapor  in air for  analgesia . [ 29 ]  The Analgizer consisted of a  polyethylene  cylinder 5\u00a0inches long and 1\u00a0inch in diameter with a 1\u00a0inch long mouthpiece. The device contained a rolled  wick  of  polypropylene   felt  which held 15\u00a0 milliliters  of methoxyflurane."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8017", "text": "Because of the simplicity of the Analgizer and the  pharmacological  characteristics of methoxyflurane, it was easy for patients to self-administer the drug and rapidly achieve a level of  conscious analgesia  which could be maintained and adjusted as necessary over a period of time lasting from a few minutes to several hours. The 15\u00a0milliliter supply of methoxyflurane would typically last for two to three hours, during which time the user would often be partly  amnesic  to the sense of pain; the device could be refilled if necessary. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8018", "text": "The Analgizer was found to be safe, effective, and simple to administer in  obstetric  patients during childbirth, as well as for patients with  bone fractures  and  joint dislocations , [ 30 ]  and for dressing changes on  burn  patients. [ 31 ]  When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent  adverse effect  on  Apgar scores . [ 30 ]  All  vital signs  remain normal in obstetric patients, newborns, and injured patients. [ 30 ]  The Analgizer was widely utilized for analgesia and  sedation  until the early 1970s, in a manner that foreshadowed the  patient-controlled analgesia   infusion pumps  of today. [ 32 ] [ 33 ] [ 34 ] [ 35 ]  The Analgizer inhaler was withdrawn in 1974, but use of methoxyflurane as a sedative and analgesic continues in Australia and New Zealand in the form of the  Penthrox inhaler . [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8019", "text": "An  injector pen  (also called a  medication pen ) is a device used for injecting medication  under the skin . First introduced in the 1980s, injector pens are designed to make injectable medication easier and more convenient to use, thus increasing  patient adherence . The primary difference between injector pens and traditional vial and syringe administration is the easier use of an injector pen by people with low dexterity, poor vision, or who need portability to administer medicine on time. Injector pens also decrease the fear or adversity towards self-injection of medications, which increases the likelihood that a person takes the medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8020", "text": "Injector pens are commonly used for medications that are injected repeatedly by a person over a relatively short period of time, especially  insulin and insulin analogs  used in the treatment of diabetes (called  insulin pens ). Many other medications are also available as injector pens, including other injectable medicines for diabetes, high cholesterol, migraine prevention, and other  monoclonal antibodies . Studies have shown injector pens to be at least as effective as vial and syringe administration, and surveys have shown that a vast majority of people would prefer an injector pen over vial and syringe administration if one was available. After a slow uptake in the United States, injector pens have surpassed vial and syringe administration of insulin in  type 2 diabetes ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8021", "text": "The primary goal of injector pens is to increase  patient adherence  by making it easier and more convenient for people to use injectable therapy. This is especially problematic with injectable medications given the extra work associated with an injection, as well as the potential aversion to self-injecting medication. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8022", "text": "Injector pens increase patient adherence by increasing the ease of self-administering injectable medication, as well as the portability of injection medication. [ 2 ]  Furthermore, injector pens are easier to handle and use than vials and syringes, making them useful in people with low dexterity, cognitive or visual impairment, or those who worry about being able to properly use a vial and syringe. [ 2 ]  For medications which do not follow standard dosage in all people, injector pens may be designed to enable easier and more accurate administration of an exact dose, whereas a vial and syringe requires the person to prepare the correct dose themselves. [ 2 ]  Injector pens may also remove stigma or fear around the use of injection medication in public environments, such as insulin before a meal at a restaurant. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8023", "text": "Combination injector pens which include multiple medications used to treat a disease are designed to reduce the number of injections a person must use to administer their medications. [ 3 ]  The reduction in number of injections required may decrease the risk of non-adherence due to forgetfulness or unwillingness to self-inject medication. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8024", "text": "An injector pen consists of a chamber or cartridge of medication, a tip to attach a needle, and a piston or plunger to inject the dose. [ 4 ]  Some pens, including most insulin pens, include dials to adjust the dose of the injection before each administration. [ 2 ]  Dials enable more accurate dose measuring than traditional vial and syringe administration, especially for low doses of insulin. [ 2 ]  Injector pens which have dials to adjust dosages may also include a clicking sound or other method to confirm the dose adjustment. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8025", "text": "Some pens may include a cartridge filled with medication which can be replaced when empty to enable reuse of the pen itself, whereas other pens are designed to be disposed of after their prefilled chamber is depleted. [ 2 ]  Injector pens designed for single use may also be  autoinjectors , which do not require the user to press a plunger to inject the dose. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8026", "text": "All injector pens other than those designed for single use require the use of single-use replaceable pen needles for each injection. These pen needles come in various lengths to accommodate varying depths of subcutaneous tissue under the top of the skin. [ 5 ]  Pen needles are designed for single use  subcutaneous injection  of medication and are not designed to be reused for more than one administration. [ 6 ]  The needles are generally manufactured with an outer protective plastic shell, which is used by a person to attach the needle to the pen, and an inner plastic shell protecting the needle itself. Instruction on how to properly attach and use needles is the responsibility of the doctor or  pharmacist  to ensure proper use. [ 2 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8027", "text": "Today, pen needles are manufactured at shorter needle lengths than required for typical vial and syringe administration, which decreases the pain associated with injection. [ 2 ]  They are available in multiple lengths and  gauge of needle , including 3.5mm, 4mm, 5mm, and 8mm lengths, and 31 through 34 gauge. [ 8 ]  Over time, needles have also had bevels designed which decrease the force required to penetrate the skin, which decreases the pain associated with injection and may increase the acceptability of self-injection. [ 8 ]  Furthermore, pen needles are designed for insertion at a 90-degree angle to the skin, as opposed to normal syringes which are designed to be injected at an angle. Pen needles generally do not require pinching of the skin for proper administration, unlike historically used syringes. [ 9 ]  Pen needles should be disposed of properly after each use, preferably in a purpose-made sharps container, to prevent injury from accidental contact after use. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8028", "text": "Injector pens are an alternative to the manufacture of medication for injection in vials containing either liquid or a powder to which a  diluent  such as sterile water is added. When a vial is used as a means of storage, the end-user must use a syringe to \"draw up\" or remove the medication from the vial to prepare it for administration. The end user must then perform a series of actions to insert the needle of the syringe under the skin, and depress the plunger on the syringe to inject the dose. This requires dexterity which may make it difficult to accurately or completely administer the appropriate doses of medications. [ 2 ]  Injector pens remove some of the complications of syringes by allowing the pen to be \"pushed\" against the skin at a 90-degree angle (removing the need to inject at a proper angle as is the case with syringes), as well as by replacing a long, thin plunger of a syringe with a simple button which is depressed and held to inject the dose. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8029", "text": "Many  insulin analogs  and  GLP-1 agonists  for diabetes treatment are available as injector pens. [ 2 ]  As with insulin vials, some insulin pens are made with higher concentrations including U-200, U-300, and U-500. Different concentration insulin products may not have the same  pharmacokinetic  properties as other strengths. [ 10 ]  The higher concentrations are used to lessen the volume of the injection, and allow the same dose of insulin to be injected with less force. [ 10 ]  In some cases, these medications may be combined into one pen to be administered daily, for example  insulin degludec with liraglutide [ 6 ]  and  insulin glargine with lixisenatide . [ 11 ]  Combination products are available in fixed-dose ratios and are generally dosed by units of insulin, which will administer a proportional amount of the GLP-1 agonist as well. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8030", "text": "Another class of medication commonly available as an injector pen is  monoclonal antibodies . Due to the molecular size of monoclonal antibodies, they must be administered via injection. Examples of monoclonal antibodies available or studied as injector pens include  adalimumab , [ 13 ]   secukinumab , [ 14 ]  and  alirocumab . [ 15 ]   CGRP antagonists  which are monoclonal antibodies, used for the prevention of migraines, are also available as injector pens. [ 16 ]  Other monoclonal antibodies designed for home use may also be manufactured as injector pens. [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8031", "text": "Some medications are formulated as injector pens to quicken the onset of action of the medication. This includes  epinephrine , which when used to treat  anaphylaxis  must work as soon as possible. [ 19 ]  Contrary to most other injector pens, epinephrine injector pens are designed to administer the medication via  intramuscular injection . [ 19 ]  Another medication formulated as an injector pen to ensure quick onset of action is  glucagon  for hypoglycemia. [ 20 ]  Other medications normally administered orally are also available or have been studied as injector pens, either due to different  pharmacokinetic  properties when administered via injection, or for those who cannot take oral medications. This includes  methotrexate  for  juvenile idiopathic arthritis [ 21 ]  and  sumatriptan  for treatment of migraines. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8032", "text": "Most injector pens are designed for subcutaneous injection just under the skin, but some are designed for injection into muscle. The desired injection site and the skin profile at the injection site will determine what needle length is appropriate for a person to use. [ 23 ]  For products with included needles, such as epinephrine pens, different brands may have different included needle lengths, which must be taken into account. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8033", "text": "Multiple studies have shown that many people prefer the use of injector pens over other forms of injectable medication, such as vial and syringe. [ 2 ]  Injector pens in general have also been shown to be at least as effective therapeutically as other injection methods. [ 2 ]  One study of the use of injector pens for insulin administration found that the chance a person initiated on insulin continued therapy for at least 12 months was higher with insulin pens than with vial and syringe administration. [ 2 ]  The same study found that the increase in adherence to therapy resulted in increased short-term pharmacy costs (i.e. for the pens/needles) but resulted in an overall decrease in healthcare costs related to diabetes. [ 2 ]  Insulin pens have also been shown to provide a higher quality of life than traditional injection methods. [ 2 ]  A 2011 systematic review which examined preference of insulin pens over vial and syringe administration found that in almost all studies and surveys a majority of people preferred insulin pens. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8034", "text": "The effectiveness of an injector pen can also depend on the technique used to inject. After fully pressing the plunger button to activate the pen, the button must continue to be held for about 10 seconds to ensure the dose is administered before removing the pen needle from the skin and finally releasing the button. [ 23 ]  Failure to use the pen as instructed may result in medication leakage and administration of a lower dose than was intended. [ 23 ]  Another administration problem which may impact effectiveness of an injector pen is  lipohypertrophy  of the subcutaneous tissue near the injection site. For this reason, it is recommended to rotate the injection site every administration. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8035", "text": "The first injector pen was introduced in 1985, by  Novo Nordisk  to administer insulin products. [ 25 ]  After their introduction, insulin pens had a slow adoption in the United States, with only 2% of insulin being injected via pen in 1999. A major barrier to adoption in the United States was the increased up-front cost of insulin pens compared to traditional injections. [ 26 ]  Pen adoption in the United States accelerated after studies showed that the higher up-front cost of insulin pens was offset by the increase in compliance, which decreased overall healthcare costs. [ 27 ]  Historically, pen needles were manufactured in lengths up to 12.7mm. Over time, pen needles designed for insulin pens have become shorter, and a 4mm long needle is considered sufficient for most people to administer subcutaneously correctly. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8036", "text": "In 1989, an injector pen form of  human growth hormone  was licensed in New Zealand. [ 28 ]  In the US, a pen form of  octreotide  was approved by the FDA in 2020, under the brand name  Bynfezia . [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8037", "text": "Intranasal drug delivery  occurs when particles are inhaled into the nasal cavity and transported directly into the nervous system. Though pharmaceuticals can be injected into the nose, some concerns include injuries, infection, and safe disposal. Studies demonstrate improved  patient compliance  with inhalation. Treating brain diseases has been a challenge due to the  blood brain barrier . Previous studies evaluated the efficacy of delivery therapeutics through intranasal route for brain diseases and mental health conditions. Intranasal administration is a potential route associated with high drug transfer from nose to brain and drug  bioavailability . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8038", "text": "Drug delivery  is a process of administering therapeutics to treat human diseases. The first drug delivery system is often dated to the 1950s, when Smith Kline & French Laboratories introduced the Spansule technology. [ 2 ]  Between 1950s and 1980s, there were four drug release systems developed for oral and transdermal applications: dissolution, diffusion, osmosis, and ion-exchange controlled release. [ 3 ]  Later in the 1980s, the  Lupron Depot  technology further advanced the field by offering zero-order and long-term release systems. The intranasal route gained interest towards the end of the 20th century with treating cardiovascular and respiratory diseases. During the late 1980s, William Frey II studied the intranasal route for treating brain diseases. Ever since, it has become a potential route for nose-to-brain delivery. [ medical citation needed ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8039", "text": "The nasal cavity is highly vascularized, allowing efficient transfer of molecules directly to the nervous system. Compared to other administration routes, nasal drug delivery increases bioavailability and reduces systemic exposure risks. The nasal cavity\u2019s slightly acidic environment and enzymes can affect drug degradation, making delivery systems with neutral to acidic pH ideal. The respiratory region, with its large surface area and high vascularization, is the primary site for drug absorption into systemic circulation. Targeting the olfactory region enhances nose-to-brain drug delivery, as particles can travel via the olfactory nerve to the brain. This route offers potential for treating brain diseases and mental health conditions. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8040", "text": "The blood-brain barrier (BBB) is a semipermeable membrane that separates the blood from the brain\u2019s interstitial fluid. It is formed by tight junctions between endothelial cells, astrocytes, and pericytes in the brain\u2019s capillaries, and has high electrical resistance. The BBB is crucial for protecting the brain from pathogens and toxic substances, maintaining homeostasis, and preventing alterations to neuronal functions. However, some diseases can damage the BBB, causing leakage. Research suggests that increasing intake of vitamins and antioxidants, as well as reducing stress, can help restore the BBB. Due to its selective nature, the BBB restricts the passive diffusion of solutes, large and hydrophilic molecules, and immune factors, making it challenging to deliver pharmaceuticals directly to the brain. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8041", "text": "Neurodegenerative diseases  occur from loss of neuronal structure and function. This progressive degeneration of neurons is irreversible.  Alzheimer's  is a neurodegenerative disease that begins with short-term memory loss progressing to loss of control over heartbeat and breathing. It has been over 100 years since Alois Alzheimer first presented the world disease to the world in 1906. There is evidence for the efficacy of intranasal delivery to treat Alzheimer's. Intranasal delivery of insulin showed greater memory improvement in patients with Alzheimer's than in healthy individuals. [ 7 ]  Increased microglial activation inflammation are characteristics of Alzheimer's. Animal studies show intranasal administration of pro-resolving lipid mediators decreased both factors, slowing  pathogenesis  of this disease. [ 8 ]  Delivering a novel peptide via intranasal route reduced amyloid beta plaques, a defining trait of Alzheimer's and enhanced cognitive functions. [ 9 ]  Intranasal delivery of anti-Alzheimer's drug dispersed through hydrogel in rabbits demonstrated higher bioavailability compared to oral tablets. [ 10 ]  MiR132 is an RNA molecule that regulates neuronal morphology and maintains survival. This molecule is downregulated with Alzheimer's. A study administered PEG-PLA  nanoparticles  loaded with this miRNA to mice through the nasal route. This novel therapy showed increased expression of miR132 and improved memory function. [ 11 ]  To strengthen the effectiveness of intranasal delivery, there are studies to develop permeation enhancers to better improve drug transport across the blood brain barrier. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8042", "text": "Abnormal cell growth and formation of mass in the brain tissue or nearby regions may cause brain cancer. Constant headaches, seizures, and blurred vision are common symptoms.  Glioblastoma  (GBM) is the most fast-growing and deadliest brain tumor. Though the main cause of glioblastoma remains unknown, it originates when  astrocytes  mutate and multiply uncontrollably forming tumors in the frontal and temporal lobes of the brain. The challenge with current therapeutics is to initiate tumor cell apoptosis with no toxic effects to healthy brain tissue. Nanoparticles loaded with chemotherapeutics delivered through the intranasal route show promising results in treating glioblastoma.  PLGA -based nanoparticles loaded with  paclitaxel  or  doxorubicin  conjugated with a  RGD sequence  targeted the glioblastoma microenvironment and reduced tumor volume through cell death. [ 13 ] [ 14 ]  MicroRNA-21 (miR-21) inhibits pro-apoptotic genes increasing progression of glioblastoma. Self-assembling nanoparticles produced with anti-tumor peptides were administered intranasally and reduced miR-21 levels increasing tumor cell apoptosis. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8043", "text": "Infection, head injury, or strokes can cause sudden bursts of neuronal activity leading to abnormal behaviors, muscle movement, and mood changes. This condition is known as seizure.  Epilepsy  is characterized by recurring seizures. Some possible causes of epilepsy include imbalance or disruption of  neurotransmitters , strokes, or brain injury. Intranasal delivery of  carbamazepine  nanoparticles increase antiepileptic drug bioavailability. [ 16 ]  Administering a self-assembling hydrogel with neuroactive drugs to treat Parkinson's disease appears to be biocompatible, low in toxicity, and have a good recovery capacity. Nasal delivery of this gel demonstrated increased drug concentration in the brain. [ 17 ]   Oxytocin  is a hormone which is observed to alleviate anxiety symptoms in people with autism. Intranasal administration indicated efficient transfer of pharmacologically active oxytocin from nasal cavity to brain. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8044", "text": "Similar to Alzheimer's,  Parkinson's  is the most common neurodegenerative disease associated with balance and coordination issues, muscle stiffness, and tremors. During the early 1800s, James Parkinson medically defined this disease. A study observed improvement in locomotor abilities in rats with Parkinson's after intranasal delivery of conjugated mitochondrial systems. [ 19 ]  Another study demonstrated delivery of neuroactive drugs in a hydrogel increased residence times in the nasal cavity and concentration in the brain. [ 20 ]  Administering therapeutics combined with nanocarriers is shown to directly transfer drugs to the target cells and enhance accumulation. The observed effects include improved neuronal signaling and locomotion. [ 21 ]  Furthermore, intranasal delivery of biodegradable nanoparticles surface-modified with  lactoferrin  increase accumulation in the brain and cellular uptake. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8045", "text": "Characterized by loss of  neuroplasticity , depression is a common mood disorder causing persistent negative emotions and changes in lifestyle. Intranasal delivery of  relaxin-3  mimetics demonstrated significant anti-depressant activity in behavior paradigms of rat models. [ 23 ]   Delivering a  thermoresponsive  hydrogel loaded with berberine intranasally exhibited high bioavailability in hippocampus and anti-depressant activity. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8046", "text": "Anxiety can impair hippocampus function which increases risk of depression and dementia.  Anxiolytic  effects were observed in animal models post-intranasal delivery of a loaded polymeric nanoparticles. [ 25 ]  Another study indicated intranasal delivery of  neuropeptide Y  lowered anxiety in rats. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8047", "text": "Anorexia nervosa  (AN) is a common eating disorder characterized by low intake of food from fear of weight gain. Several complications are associated with this chronic disorder such as fatigue, insomnia, and low blood pressure. Intranasal administration of oxytocin in patients with AN significantly lowered food anticipation and eating concern. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8048", "text": "Uncontrolled and continuous use of a substance, drugs or alcohol, is known as substance use disorder. Substances can interfere with neuronal signaling and potentially disrupt the brain circuit. Addiction to these substances impairs thinking, behavior, and other biological functions. Intranasal delivery of insulin is associated with improvement in brain metabolic activities and alleviate impulsivity. [ 28 ]   Opioid  addiction is prevalent and associated with many substance abuse deaths. A study observed high biodistribution in the brain and reduction in opioid overdose in rats administered with  naloxone -loaded lipid nanoparticles. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8049", "text": "Witnessing a devastating or terrifying situation can lead to  post-traumatic stress disorder  (PTSD). This mental health condition triggers anxiety, depression, and extreme fear with memories. Intranasal administration of temperature-sensitive hydrogels loaded with PTSD medications showed enhanced brain targeting effects and tissue distribution. [ 30 ]  Similarly, another study observed anti-PTSD effects with intranasal administration of loaded hydrogels. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8050", "text": "Schizophrenia  is a chronic mental health condition caused by changes in brain chemistry and structure. Genetics and environment are hypothesized to play a key role in development of this disorder. Research suggests impaired gene expression or chemical imbalance may impact this condition. Anxiety can increase risk of schizophrenia and symptoms include hallucinations, disorganized speech, and abnormal behavior. Davunetide (NAP) is a segment of activity-dependent neuroprotective protein (ADNP). ADNP is reported be downregulated with schizophrenia. A study observed decreased hyperactivity in mice when treated with NAP via the intranasal route. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8051", "text": "Migraine  occurs with episodes of intense headache causing nausea and throbbing pain. Stress and hormonal changes can be a trigger migraine. A nasal spray containing sumatriptan demonstrated a significant reduction of migraine pain. Further clinical studies of intranasal administration of  sumatriptan  (ST) can help evaluate efficacy and safety of such delivery systems. [ 33 ]  Since its approval by the FDA in 2021, dihydroergotamine mesylate has been administered through nasal sprays to treat migraines. [ 34 ] [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8052", "text": "Nanoparticles are drug delivery systems ranging from 1\u20131000\u00a0nm in diameter. Lipid-based and polymer-based nanocarriers are commonly used for nose-to-brain delivery as they exert high stability, solubility, and adherence. [ 36 ]  Exosomes and dendrimers are other potential nanocarriers. Nanosystems can be synthesized either using physical or chemical methods. A few physical methods include evaporation-condensation reaction and laser ablation. Irradiation, microemulsion, and chemical reduction are common chemical techniques to develop nanoparticles. Sonication, electroporation, and incubation are common methods to load drugs into nanocarriers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8053", "text": "Coating these nanosystems with mucoadhesive agents, stimulus-sensitive materials, or antibodies can enhance biocompatibility, clearance rates, specificity, and bioavailability. Penetration and absorption enhancers can significantly increase the overall efficacy of the system. Imaging studies along with measurement of drug transfer efficiency and bioavailability can further support the role of these drug delivery systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8054", "text": "Lipid-based nanoparticles (LNP) can deliver molecules with low toxicity and controlled release. Liposomes, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and nanoemulsions are examples."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8055", "text": "Liposomes are made up of phospholipids forming spherical vesicles. This property enables liposomes to exhibit high biocompatibility and biodegradability. Studies report potential application of liposomes to treat brain diseases due to increased retention and absorption in nasal cavity, and high brain biodistribution. [ 37 ]  A previous study developed a  cationic  liposome loaded with mRNA and green fluorescent protein  (GFP) . Intranasal delivery of this formulation in murine models demonstrated high brain biodistribution and expression of mRNA-GFP. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8056", "text": "Solid lipid nanoparticles (SLNs) are made up of solid lipids forming a matrix and stabilized by  surfactants . They exhibit high physical stability and remain in solid state at different temperatures. Based on a study, intranasal delivery of SLNs loaded with  rivastigmine tartrate  (RT) exhibited no toxicity, stability, and improved bioavailability. [ 39 ]  Sometimes burst release may occur due to rigidity and less flexibility in shape."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8057", "text": "Nanostructured lipid carriers (NLC) are synthesized by a mixture of solid and aqueous lipids. NLC's are developed from SLNs, thus referred to as second generation LNPs. Intranasal administration of NLC loaded with  curcumin  (CRM) increased biodistribution and concentration in brain after emerging as a potential system for brain cancer. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8058", "text": "Small colloidal systems made of  micelles  containing oil, aqueous phases, and emulsifiers are called nanoemulsions. Intranasal delivery of gel nanoemulsion loaded with  temozolomide  is observed to exhibit sustained release and better permeation from nose to brain to treat glioblastoma. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8059", "text": "Polymer-based nanoparticles can be made from either natural or synthetic sources. Nanospheres and nanocapsules are polymeric nanoparticle systems. Natural polymers can be found in the environment or human body. On the other hand, synthetic polymers do not occur naturally and are artificially developed polymers with chemical modifications. Natural polymer-based nanoparticles can be made up of chitosan,  hyaluronic acid , alginate, and gelatin. Natural polymers exhibit excellent biocompatibility and biodegradability, and low toxicity. Synthetic polymer-based nanoparticles can consist of poly (glycolic acid) (PGA), poly (lactic acid) (PLA), and poly(L-lactide-co-glycolide) (PLGA)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8060", "text": "A study evaluated chitosan nanoparticles loaded with an anti-epileptic drug,  phenytoin  (PHT), to treat epilepsy. Observations suggested high stability, sustained release, and bioavailability when these particles where administered via the intranasal route. [ 42 ]  Similarly, administering PLGA nanoparticles loaded  lamotrigine  (LTG), polymer-based nanoparticle, showed better permeation through BBB and higher bioavailability. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8061", "text": "Exosomes are vesicular structures containing genetic information. Recently, exosomes are being utilized as drug carriers. These systems are observed to be stable, specific, and safe. Moreover, delivery of exosomes shows less immunogenic affects. Further surface modifications and conjugation with liposomes enhances the therapeutic effects. Based on a previous study, intranasal delivery of exosomes loaded with a  Stat3  inhibitor reduced brain inflammation and slowed brain tumor growth. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8062", "text": "Dendrimers are polymeric macromolecules with a branched network similar to a tree structure. Generally, they are spherical and homogeneous. Surface charge and molecule chemistry can play crucial role with drug interaction and release. Poly(amidoamine) ( PAMAM ) dendrimers are the most commonly used system. A study investigated potential application of dendrimer-based formulation of  haloperidol . Intranasal administration showed improved targeting, and solubility as well as high concentrations in the brain. [ 45 ]  Drugs can be loaded in dendrimers through formulation and nanoconstruct. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8063", "text": "For drug delivery systems to bypass the blood brain barrier, modifications of physiochemical properties can enhance safety and efficacy. Size, surface charge, and  lipophilicity  play a major role in substance bypassing the blood brain barrier. Smaller, positively charged, or more lipophilic molecules enhance efficacy of nose-to-brain delivery. Decrease in delivery system size increases permeation. As the membrane is negatively charged, a particle with positive surface charge interacts electrostatically which enhances  bioadhesion . Carriers with more lipophilicity exert better  mucoadhesion  and residence time. Drug system pH, solubility, and hydrogen bonding potential are other physiochemical properties which should be evaluated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8064", "text": "An  intrauterine device  ( IUD ), also known as an  intrauterine contraceptive device  ( IUCD  or  ICD ) or  coil , [ 3 ]  is a small, often T-shaped  birth control  device that is inserted into the  uterus  to prevent  pregnancy . IUDs are a form of  long-acting reversible contraception  (LARC). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8065", "text": "Users are more satisfied with  contraceptive implants  such as IUDs than any other birth control method. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8066", "text": "IUDs are safe and effective in adolescents as well as those who have not previously had children. [ 6 ] [ 7 ]  Once an IUD is removed, even after long-term use, fertility returns to normal rapidly. [ 8 ]   Copper  devices have a failure rate of about 0.8%, while hormonal ( levonorgestrel ) devices fail about 0.2% of the time within the first year of use. [ 9 ]  In comparison,  male sterilization  and  male condoms  have a failure rate of about 0.15% and 15%, respectively. [ 10 ]  Copper IUDs can also be used as  emergency contraception  within five days of unprotected sex. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8067", "text": "Although  copper IUDs  may increase menstrual bleeding and result in painful cramps, [ 12 ]   hormonal IUDs  may reduce menstrual bleeding or stop  menstruation  altogether. [ 13 ]  However, women can have daily spotting for several months after insertion, and it can take up to three months for there to be a 90% decrease in bleeding with hormonal IUDs. [ 14 ]  Cramping can be treated with  NSAIDs . [ 15 ]  More serious potential complications include expulsion (2\u20135%) and rarely perforation of the uterus (less than 0.7%). [ 13 ] [ 15 ]  IUDs do not affect  breastfeeding  and can be inserted immediately after delivery. [ 13 ]  They may also be used immediately after an  abortion . [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8068", "text": "The use of IUDs increased within the United States from 0.8% in 1995 to 7.2% from the period of 2006 to 2014. [ 18 ] [ 19 ]  The use of IUDs as a form of birth control dates from the 1800s. [ 1 ]  A previous model known as the  Dalkon shield  was associated with an increased risk of  pelvic inflammatory disease  (PID). However, current models do not affect PID risk in women without  sexually transmitted infections  during the time of insertion. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8069", "text": "IUDs primarily work by preventing  fertilization . [ 21 ]  The progestogen released from hormonal IUDs mainly works by thickening the cervical mucus, preventing sperm from reaching the fallopian tubes. Hormonal IUDs may also sometimes prevent ovulation. [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8070", "text": "Copper IUDs do not contain any hormones, but release copper ions, which are toxic to sperm. They also cause the uterus and fallopian tubes to produce a fluid that contains white blood cells, copper ions, enzymes, and  prostaglandins , which is also toxic to sperm. [ 22 ]  The very high effectiveness of copper-containing IUDs as emergency contraceptives implies they may also act by preventing  implantation  of the  blastocyst . [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8071", "text": "The types of intrauterine devices available, and the names they go by, differ by location. In the United States, there are two types available: [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8072", "text": "The  WHO   ATC  labels both copper and hormonal devices as IUDs. In the United Kingdom, there are more than 10 different types of copper IUDs available. In the United Kingdom, the term  IUD  refers only to these copper devices. Hormonal intrauterine contraception is labeled with the term  intrauterine system  (IUS). [ 27 ] [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8073", "text": "levonorgestrel"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8074", "text": "-Prevents ovulation at times"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8075", "text": "-Emergency contraception"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8076", "text": "-Lighter periods after 3 months; some users experience  amenorrhea"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8077", "text": "Most copper IUDs have a  T-shaped frame that is wound around with pure electrolytic copper wire and/or has copper collars (sleeves). The arms of the frame hold the IUD in place near the top of the uterus. The  Paragard  TCu 380a measures 32\u00a0mm (1.26\") horizontally (top of the T), and 36\u00a0mm (1.42\") vertically (leg of the T). Copper IUDs have a first year failure rate ranging from 0.1 to 2.2%. [ 34 ]  They work by damaging sperm and disrupting their motility so that they are not able to join an egg. Specifically, copper acts as a spermicide within the uterus by increasing levels of copper ions, prostaglandins, and white blood cells within the uterine and tubal fluids. [ 12 ] [ 35 ]  The increased copper ions in the cervical mucus inhibit the sperm's motility and viability, preventing sperm from traveling through the cervical mucus, or destroying it as it passes through. [ 36 ]  Copper can also alter the endometrial lining, and while studies show that while this alteration can prevent implantation of a fertilized egg (\" blastocyst \"), it cannot disrupt one that has already been implanted. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8078", "text": "Advantages of the copper IUD include its ability to provide  emergency contraception  up to five days after unprotected sex. It is the most effective form of emergency contraception available. [ 38 ]  It works by preventing fertilization or implantation but does not affect already implanted embryos. [ 37 ]  It contains no hormones, so it can be used while breastfeeding, and fertility returns quickly after removal. [ 39 ] \nCopper IUDs also last longer and are available in a wider range of sizes and shapes than hormonal IUDs. [ 14 ]  Disadvantages include the possibility of heavier menstrual periods and more painful cramps. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8079", "text": "IUDs that contain gold or silver also exist. [ 27 ] [ 40 ]  Other shapes of IUD include the so-called U-shaped IUDs, such as the Load and Multiload, and the frameless IUD that holds several hollow cylindrical minuscule copper beads. It is held in place by a suture (knot) to the  fundus of the uterus . It is mainly available in China and Europe. A framed copper IUD called the  IUB SCu300  coils when deployed and forms a three-dimensional spherical shape. It is based on a  nickel titanium  shape memory alloy core. [ 41 ]  In addition to copper, noble metal, and progestogen IUDs, women in China can get copper IUDs with  indomethacin . This non-hormonal compound reduces the severity of menstrual bleeding, and these coils are popular. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8080", "text": "Inert IUDs do not have a  bioactive  component. They are made of inert materials like  stainless steel  (such as the stainless steel ring (SSR), a flexible ring of steel coils that can deform to be inserted through the cervix) or  plastic  (such as the Lippes Loop, which can be inserted through the cervix in a  cannula  and takes a trapezoidal shape within the uterus). They are less effective than copper or hormonal IUDs, with a side effect profile similar to copper IUDs. Their primary mechanism of action is inducing a local  foreign body reaction , which makes the uterine environment hostile both to  sperm  and to  implantation  of an embryo. [ 43 ]  They may have higher rates of preventing pregnancy after fertilization, instead of before fertilization, compared to copper or hormonal IUDs. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8081", "text": "Inert IUDs are not yet approved for use in the United States, UK, or Canada. In China, where IUDs are the most common form of contraception, copper IUD production replaced inert IUD production in 1993. [ 45 ]  However, as of 2008, the most common IUD used by immigrants presenting to Canadian clinics for removal of IUDs placed in China was still the SSR. Because the SSR has no string for removal, it can present a challenge to healthcare providers unfamiliar with IUD types not available in their region. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8082", "text": "Hormonal IUDs (referred to as intrauterine systems in the UK) work by releasing a small amount of  levonorgestrel , a  progestin . Each type varies in size, amount of levonorgestrel released, and duration. The primary mechanism of action is making the inside of the uterus uninhabitable for sperm. [ 47 ]  They can also thin the endometrial lining and potentially impair implantation, but this is not their usual function. [ 48 ] [ 49 ]  Because they thin the endometrial lining, they can also reduce or even prevent menstrual bleeding. As a result, they are used to treat  menorrhagia  (heavy  menses ), once pathologic causes of menorrhagia (such as  uterine polyps ) have been ruled out. [ 50 ]  In a 10-year study, the levonorgestrel coil was found to be as effective as oral medicines (tranexamic acid, mefenamic acid, combined oestrogen\u2013progestogen or progesterone alone); the same proportion of women had not had surgery for heavy bleeding and had similar improvements in their quality of life. [ 51 ] [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8083", "text": "The progestin released by hormonal IUDs primarily acts locally; use of Mirena results in much lower systemic progestin levels than other very-low-dose  progestogen only contraceptives . [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8084", "text": "Regardless of IUD type, there are some potential side effects that are similar for all IUDs. Some of these side effects include bleeding pattern changes, expulsion,  pelvic inflammatory disease  (especially in the first 21 days after insertion), and rarely uterine perforation. A small probability of pregnancy remains after IUD insertion, and when it occurs, there is a greater risk of  ectopic pregnancy . [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8085", "text": "IUDs with progestogen confer an increased risk of  ovarian cysts , [ 55 ]  and IUDs with copper confer an increased risk of heavier periods.  Mirena  lists among its side effects mental health changes including nervousness, depressed mood, or mood swings. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8086", "text": "Menstrual cup  companies recommend that women with IUDs who are considering using menstrual cups should consult with their gynecologists before use. There have been rare cases in which women using IUDs dislodged them when removing their menstrual cups, however, this can also happen with tampon use. [ 57 ]  Despite reports, as of 2023, there is no scientific agreement on whether using a menstrual cup increases the risk of IUD expulsion; more rigorous studies are needed. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8087", "text": "Unlike condoms, the IUD does not protect against sexually transmitted infections. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8088", "text": "Modern IUDs do not lead to infertility or make it harder for a woman to become pregnant, and fertility typically returns within days of removal. Some prior studies found an association between infertility and the  Dalkon Shield , an early IUD design which is no longer available. [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8089", "text": "Modern IUDs do not cause increased infection, though the earlier Dalkon Shield may have, because it contained multifilament strings, which provided bacteria a space to grow and move up the string. IUDs manufactured after 2008 use monofilament strings in order to prevent this from happening. [ 61 ]  However, as with any medical intervention, IUDs can lead to increased risk of infection immediately after the insertion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8090", "text": "According to the  U.S. Medical Eligibility Criteria for Contraceptive Use , published by the  CDC , women and adolescents under the age of 20 and women who have not given birth are classified in category 2 for IUD use, mainly due to \"the risk for expulsion from nulliparity and for STDs from sexual behavior in younger age groups.\" According to the CDC, benefits generally outweigh the risks, and IUDs are recommended for young and nulliparous women, although more careful attention may be required. Women over age 20 and those who have previously given birth are placed in category 1, meaning no special concerns are placed on use. [ 62 ] [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8091", "text": "Some women experience  amenorrhea , or lack of menstruation while using an IUD. Menstruation occurs when a woman has not become pregnant and the uterus sheds its lining in preparation for the next cycle. IUDs tend to thin the lining of the uterus, leading to less menses by volume or a lack of menstruation altogether. There is a condition known as  polycystic ovarian syndrome  (PCOS) which causes women to miss their periods and can lead to an increased risk of endometrial cancer. [ 64 ]  However, an IUD causes the endometrial lining of a uterus to thin, which is the opposite of what occurs with PCOS."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8092", "text": "The main mechanisms of action of IUDs occur prior to fertilization, by preventing sperm from ever reaching the egg. [ 65 ]  The copper-bearing IUD acts as a spermicide, killing or impairing sperm so they cannot reach the egg. IUDs that contain progestin cause the cervical mucus to thicken, which stops sperm from entering the uterus."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8093", "text": "It is difficult to predict what a woman will experience during IUD insertion or removal. Some women describe the insertion as cramps, some as a pinch, and others do not feel anything. Only 9% of  nulliparous  women considered the procedure painless, 72% moderately painful, and 17% experience substantial pain with insertion that needs active management. [ 66 ]  Approximately 11% of parous women feel similar pain. [ 67 ]  In such cases,  NSAIDs  can be effective when given in response to post-insertion pain, but have no significant effect when given prophylactically. [ 67 ]  Topical lidocaine has been found as an effective pain management drug when applied before the procedure. [ 68 ]  The use of intrauterine lidocaine (paracervical block) is underutilized in the United States as an effective method to reduce pain associated with insertion. [ 69 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8094", "text": "IUD insertion can occur at multiple timepoints in a woman's reproductive lifespan:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8095", "text": "During the insertion procedure, health care providers use a  speculum  to find the  cervix  (the opening to the uterus), pinch the cervix to stabilize it open with a  tenaculum , [ 75 ]  and then use an insertion device to place the IUD in the uterus. The insertion device goes through the cervix. The procedure itself, if uncomplicated, should take no more than five to ten minutes. [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8096", "text": "A  suction cervical stabilizer  can be used in place of the standard tenaculum to hold the cervix open during the IUD insertion procedure. [ 77 ]  Suction cervical stabilizers, such as The Carevix\u2122 Suction Cervical Stabilizer,  [ 78 ]  may reduce pain associated with the insertion procedure.  [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8097", "text": "For immediate postpartum insertion, the IUD is inserted following the removal of the  placenta  from the  uterus . The uterus is larger than baseline following birth, which has important implications for insertion. After vaginal deliveries, insertions can be done using placental forceps, a longer inserter specialized for postpartum insertions, or manually, where the provider uses their hand to insert the IUD in the uterus. After cesarean deliveries, the IUD is placed in the uterus with forceps or manually during surgery prior to suturing the uterine incision. [ 74 ] [ 71 ] [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8098", "text": "Generally, the removal is uncomplicated and reported to be not as painful as the insertion because there is no instrument that needs to go through the cervix. [ 81 ]  This process requires the health care provider to find the cervix with a speculum and then use ring forceps, which only go into the vagina, to grasp the IUD strings and then pull the IUD out."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8099", "text": "IUD placement and removal can be taught both by manufacturers and other training facilities. [ 82 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8100", "text": "The history of intrauterine devices dates back to the early 20th century. Unlike modern intrauterine devices, early interuterine (from Latin  inter- , meaning \"between\", as opposed to  intra- ) devices crossed both the vagina and the uterus, causing a high rate of pelvic inflammatory disease. The first IUD was developed in 1909 by the German physician Richard Richter, of Waldenburg. His device was made of silkworm gut and was not widely used. [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8101", "text": "Ernst Gr\u00e4fenberg , another German physician (after whom the  G-spot  is named), created the first Ring IUD,  Gr\u00e4fenberg's ring , made of silver filaments. His work was suppressed during the Nazi regime, when contraception was considered a threat to Aryan women. [ 83 ]  He moved to the United States, where his colleagues H. Hall and M. Stone took up his work after his death and created the stainless steel Hall-Stone Ring. A Japanese doctor named Tenrei Ota also developed a silver or gold IUD called the Precea or Pressure Ring. [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8102", "text": "Jack Lippes helped begin the increase of IUD use in the United States in the late 1950s. In this time,  thermoplastics , which can bend for insertion and retain their original shape, became the material used for first-generation IUDs. Lippes also devised the addition of the monofilament nylon string, which facilitates IUD removal. His trapezoid shape Lippes Loop IUD became one of the most popular first-generation IUDs. In the following years, many different shaped plastic IUDs were invented and marketed. [ 83 ]  These included the infamous  Dalkon Shield , whose poor design caused bacterial infection and led to thousands of lawsuits. Although the Dalkon shield was removed from the market, it had a lasting, negative impact on IUD use and reputation in the United States. [ 84 ]   Lazar C. Margulies  developed the first plastic IUD using thermoplastics in the 1960s. [ 85 ]  His innovation allowed insertion of the IUD into the uterus without the need to dilate the  cervix . [ 86 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8103", "text": "The invention of the copper IUD in the 1960s brought with it the capital T-shaped design used by most modern IUDs. U.S. physician Howard Tatum determined that the 'T' shape would work better with the shape of the uterus, which forms a 'T' when contracted. He predicted this would reduce rates of IUD expulsion. [ 83 ]  Together, Tatum and Chilean physician Jaime Zipper discovered that copper could be an effective spermicide and developed the first copper IUD, TCu200. Improvements by Tatum led to the creation of the TCu380A ( ParaGard ), which is currently the preferred copper IUD. [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8104", "text": "The hormonal IUD was also invented in the 1960s and 1970s; initially the goal was to mitigate the increased menstrual bleeding associated with copper and inert IUDs. The first model, Progestasert, was conceived of by Antonio Scommegna and created by Tapani J. V. Luukkainen, but the device only lasted for one year of use. [ 84 ]  Progestasert was manufactured until 2001. [ 87 ] [ unreliable medical source? ]  One commercial hormonal IUD which is currently available, Mirena, was also developed by Luukkainen and released in 1976. [ 83 ]  The manufacturer of the Mirena,  Bayer AG , became the target of multiple lawsuits over allegations that Bayer failed to adequately warn users that the IUD could pierce the uterus and migrate to other parts of the body. [ 88 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8105", "text": "In  China , the use of IUDs by state health services was part of the government's efforts to limit birth rates. From 1980 to 2014, 324 \u00a0 million women were inserted with IUDs, in addition to the 107 \u00a0 million who had  tubal ligation . Women who refused could lose their government employment and their children could lose access to  public schools . [ citation needed ]  The IUDs inserted in this way were modified such that they could not be removed in a doctor's office (meant to be left indefinitely), and  surgical removal  is usually needed. [ 89 ]  Until the mid-1990s, the state-preferred IUD was a  stainless steel  ring, [ 90 ] [ 91 ]  which had a higher rate of  complications  compared to other types of IUD. It gave rise to the  idiom   sh\u00e0nghu\u00e1n  ( \u4e0a\u73af ), meaning \"insert a loop\". Nowadays, the IUDs include T and V shapes, the former being the most common and easiest to remove."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8106", "text": "To implement the  two-child policy , the government announced that IUD-removals would be paid for by the government. [ 89 ]  IUD removals are free for women \"who are allowed to have another child\" (see  one-child policy ) or \"who cannot continue to have the IUD for health reasons.\" [ 92 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8107", "text": "In the United States, the price of an IUD may range from $0 to $1,300. [ 93 ]   [ clarification needed ]  The price includes medical exams, insertion, and follow-up visits.\nUnder the Affordable Care Act, most insurance plans are required to cover all forms of birth control, including IUDs, although they may not cover all IUD brands. [ 94 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8108", "text": "Among birth control methods, IUDs, along with other  contraceptive implants , result in the greatest satisfaction among users. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8109", "text": "A study found that female family planning providers choose LARC methods more often (41.7%) than the general public (12.1%). [ 95 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8110", "text": "Mechanism of action Copper-releasing IUCs When used as a regular or emergency method of contraception, copper-releasing IUCs act primarily to prevent fertilization. Emergency insertion of a copper IUC is significantly more effective than the use of ECPs, reducing the risk of pregnancy following unprotected intercourse by more than 99%. 2,3  This very high level of effectiveness implies that emergency insertion of a copper IUC must prevent some pregnancies after fertilization. Emergency contraceptive pills To make an informed choice, women must know that ECPs\u2014like the birth control pill, patch, ring, shot, and implant, 76 and even like breastfeeding 77 \u2014prevent pregnancy primarily by delaying or inhibiting ovulation and inhibiting fertilization, but may at times inhibit implantation of a fertilized egg in the endometrium. However, women should also be informed that the best available evidence indicates that ECPs prevent pregnancy by mechanisms that do not involve interference with post-fertilization events. ECPs do not cause abortion 78  or harm an established pregnancy. Pregnancy begins with implantation according to medical authorities such as the US FDA, the National Institutes of Health 79  and the American College of Obstetricians and Gynecologists (ACOG). 80 Ulipristal acetate (UPA).  One study has demonstrated that UP can delay ovulation. 81 ... Another study found that UPA altered the endometrium, but whether this change would inhibit implantation is unknown. 82 p. 122: Progestin-only emergency contraceptive pills.  Early treatment with ECPs containing only the progestin levonorgestrel has been shown to impair the ovulatory process and luteal function. 83\u201387 p. 123: Combined emergency contraceptive pills.  Several clinical studies have shown that combined ECPs containing ethinyl estradiol and levonorgestrel can inhibit or delay ovulation. 107\u2013110"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8111", "text": "How does EC work? In 2002, a judicial review ruled that pregnancy begins at implantation, not fertilisation. 8  The possible mechanisms of action should be explained to the patient as some methods may not be acceptable, depending on individual beliefs about the onset of pregnancy and abortion. Copper-bearing intrauterine device (Cu-IUD). Copper is toxic to the ovum and sperm and thus the copper-bearing intrauterine device (Cu-IUD) is effective immediately after insertion and works primarily by inhibiting fertilisation. 9\u201311  A systematic review on mechanisms of action of IUDs showed that both pre- and postfertilisation effects contribute to efficacy. 11 If fertilisation has already occurred, it is accepted that there is an anti-implantation effect, 12,13 Levonorgestrel (LNG). The precise mode of action of levonorgestrel (LNG) is incompletely understood but it is thought to work primarily by inhibition of ovulation. 16,17 Ulipristal acetate (UPA). UPA's primary mechanism of action is thought to be inhibition or delay of ovulation. 2"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8112", "text": "Mechanism of action The contraceptive action of all IUDs is mainly in the intrauterine cavity. Ovulation is not affected, and the IUD is not an abortifacient. 58\u201360  It is currently believed that the mechanism of action for IUDs is the production of an intrauterine environment that is spermicidal. Nonmedicated IUDs depend for contraception on the general reaction of the uterus to a foreign body. It is believed that this reaction, a sterile inflammatory response, produces tissue injury of a minor degree but sufficient to be spermicidal. Very few, if any, sperm reach the ovum in the fallopian tube. The progestin-releasing IUD adds the endometrial action of the progestin to the foreign body reaction. The endometrium becomes decidualized with atrophy of the glands. 65  The progestin IUD probably has two mechanisms of action: inhibition of implantation and inhibition of sperm capacitation, penetration, and survival."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8113", "text": "Intravesical drug delivery  is the  delivery of medications  directly into the  bladder  by  urinary catheter . This method of drug delivery is used to directly target diseases of the bladder such as  interstitial cystitis  and  bladder cancer , but currently faces obstacles such as low drug retention time due to washing out with urine and issues with the low permeability of the bladder wall itself. Due to the advantages of directly targeting the bladder, as well as the effectiveness of  permeability enhancers , advances in intravesical  drug carriers , and  mucoadhesive , intravesical drug delivery is becoming more effective and of increased interest in the medical community."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8114", "text": "Delivering drugs directly to the target bladder site allows for maximizing drug delivery while minimizing  systemic effects .  \nDelivering the treatment directly to the site allows for more effective dosages to be given since high concentrations of drug in the bladder can be reached. [ 1 ]  This becomes especially important when patients have a  urinary bladder disease  that is  drug resistant . The delivery of drugs directly to the bladder is a large improvement over systemic delivery which only allows a small fraction of the drug to reach the bladder, causing lower concentrations of drug leading to systemic treatments being ineffective. [ 1 ]  The smaller fraction of drug reaching its target with systemic delivery means more drugs must be administered which can lead to problems with systemic  toxicity . This is not the case when drug is administered directly to the bladder."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8115", "text": "The layer of the bladder which comes into contact with urine, the urothelium (the  transitional epithelium  of the bladder, is a mostly impermeable barrier which stops molecules in the urine from being reabsorbed and prevents molecules from being secreted directly into the bladder as well. [ 1 ]   The bladder\u2019s impermeability means that any drug delivered intravesical will not absorb into the bloodstream well through the bladder wall, causing fewer systemic effects. This impermeability also causes treatment of bladder diseases to be more difficult to treat as drugs do not absorb well into the bladder wall. Intravesical drug delivery has been identified as an ideal way to treat most urinary disorders, including bladder tumors and  bladder cancers ,  interstitial cystitis , and  urinary incontinence . [ 1 ] [ 2 ] \n [ 3 ] [ 4 ] [ 5 ]  There is currently a lack of interest in treating  urinary tract infections  using intravesical delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8116", "text": "While intravesical delivery shows distinct advantages over systemic drug delivery it has several problems to overcome. When giving a drug intravesically it is  diluted  by urine and washed out when urine is voided. [ 1 ] [ 2 ] [ 3 ]  Additionally, the low permeability of the urothelium which lines the bladder creates a hurdle that must be overcome if the bladder wall needs to be treated. [ 3 ]  These issues create the need for more frequent dosing, which causes urinary catheter site irritation and compliance issues with treatments. [ 2 ]  \nIntravesical drug dilution occurs as urine accumulates in the bladder, lowering the concentration of drug in the bladder as overall volume increases. The  voiding  of drug with urine when using traditional drug formulations in the bladder has become a hurdle to overcome as well, since  residence time  of the drug inside the bladder is directly tied to the treatment\u2019s  efficacy . [ 1 ]  Creating  formulations  which adhere to the bladder wall has been targeted as one way to improve intravesical dug efficacy,. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  The low adherence of drugs to the bladder wall and low permeability into the bladder wall contributes to low drug retention in the bladder. [ 1 ]  When modifying drug formulations for intravesical delivery gels or  viscosity  increasing formulations are sometimes used to increase retention, though this can cause issues with  urethra obstruction , an additional hurdle in intravesical drug delivery. [ 2 ]  \nPermeability issues with the bladder wall can be attributed to the urothelium, the lining of the bladder wall made up of  umbrella cells , intermediate cells, and basal cells.,. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  The impermeability can be attributed to the umbrella cells which form tight junctions with each other to make up the innermost layer of the urothelium and have the ability to change shape to adapt to the bladder\u2019s varying size. [ 1 ] [ 2 ]  The umbrella cells are covered in a dense layer of plaques which further prevents the absorption of particles through the urothelium and a layer of  mucin  composed of  glycosaminoglycans  (GAGs) which prevents both hydrophobic and negatively charged molecules from adhering to the bladder wall. [ 1 ] [ 4 ]  Overcoming the impermeability of the mucin layer and the urothelium is a large focus of many intravesical drug formulations, and is key to an efficacious intravesical treatment [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8117", "text": "The main ways researchers are currently overcoming the problems in intravesical drug delivery are through developing formulations using  mucoadhesives ,  nanoparticles ,  liposomes , polymeric  hydrogel , expandable delivery devices, and electromotive drug administration. [ 1 ] [ 2 ] [ 3 ]  These methods each serve to improve retention time, drug permeability through the urothelium, or some combination of the two."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8118", "text": "Enhancing Drug retention can be achieved through changing formulation and delivery device. Often drug retention and permeability enhancement are tied, as drugs which permeate the urothelium will suffer fewer effects from urine dilution and voiding. Two of the most common methods to improve drug retention are by using a  mucoadhesive  formulation or using polymeric  hydrogels  that form in the bladder, or  in situ  gelling hydrogels. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8119", "text": "Mucoadhesive formulations can be made with both  biopolymers  and  synthetic polymers , and usually contain polymers that are  hydrophilic  and can form many  hydrogen bonds  with the  GAG-mucin . [ 1 ]  Positively charged molecules typically make far better mucoadhesive as the mucin layer is negatively charged. [ 6 ]  By forming these bonds, the mucoadhesive, and the drug it carries, can maintain sustained contact with the bladder wall, enhancing retention of the drug in the bladder. Among mucoadhesive materials  Chitosan  often stands out due to its  biocompatibility ,  biodegradability , and permeability enhancing factors. [ 3 ]  In experiments with chitosan, it has been shown that the mucoadhesive properties of a molecule likely increase as the  molecular weight  is increased. [ 7 ]  Studies have also found that the modification of chitosan formulations with  thiomers , which can form covalent bonds with mucus, can significantly improve the mucoadhesion of the chitosan formulations [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8120", "text": "Polymeric  hydrogels  for intravesical drug delivery take advantage of characteristics of the bladder or urine to gel, or may use external manipulation to cause the hydrogel to form. [ 1 ] [ 9 ]  These gels can take advantage of pH or temperature differences, or external input like  UV  lasers, to form gels inside the bladder after instillation of the formulation in liquid form. [ 9 ]  If these gels are made to be mucoadhesive they stick to the bladder wall and do not wash out or cause urethral obstruction. Polymeric hydrogels have also been formulated to float on top of the urine to avoid wash out and obstruction without having to adhere to the bladder wall. [ 10 ]  Drawbacks of using polymeric hydrogel formulations include the concern of urethral obstruction, the varying conditions of the urine which make pH or ionic controlled gelling formulations less controlled, and the  bladder wall inflammation  which can occur with mucoadhesive polymeric hydrogels. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8121", "text": "Enhancing drug permeability can be done through physical or chemical methods, and is also achieved through  nanoparticle  and  liposome   drug carriers . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  Physical methods include electromotive drug administration, radiofrequency-induced chemotherapeutic effect, and conductive hyperthermic  chemotherapy , but electromotive drug administration seems to be the most prevalent in recent research and clinical trial focus. [ 1 ] [ 2 ] [ 3 ] [ 5 ] [ 11 ]  Chemical methods revolve around adding a chemical agent to enhance drug uptake and increase permeability. To enhance drug permeability through physical or chemical methods both the  mucin layer  and the  umbrella cells  of the urothelium must undergo a structural or chemical change. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8122", "text": "Electromotive drug administration utilizes a small  electric current  flowing across the bladder wall between two  electrodes , one on the skin and one placed inside the bladder via  catheterization , to enhance permeability of  aqueous  solutions. [ 1 ] [ 2 ] [ 3 ]  Electromotive drug administration best enhances  ionized  formulations, which diffuse poorly using standard  passive diffusion . [ 3 ]  This allows it to potentially assist in the delivery of many drugs that usually perform poorly in the bladder without having to change their formulations heavily. Across multiple studies and clinical trials electromotive drug administration has been shown to increase the uptake of many drugs, showing potential use in  bladder cancer ,  urinary incontinence ,  urinary cystitis  and pain management. [ 1 ] [ 2 ] [ 3 ] [ 5 ]  Cost of  local anesthesia  for bladder distention using electromotive drug administration in combination with  lidocaine  has been shown to be cheaper and more practical than  general anesthesia  or  spinal anesthesia . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8123", "text": "To enhance the permeability of the bladder wall, specifically the urothelium, to drugs administered locally to the bladder four chemical agents are most commonly used:  DMSO ,  protamine sulphate ,  Hyaluronidase , and  chitosan . DMSO is already widely used to directly treat urinary cystitis due to its  anti-inflammatory  and  antibacterial  properties. [ 1 ] [ 3 ]  DMSO can penetrate tissues without causing any damage to them. [ 1 ] [ 3 ]  This property of DMSO made it of particular interest as a chemical enhancer and it has been shown to increase the uptake of several chemotherapeutics used intravesically. [ 12 ]  Protamine sulphate causes disruption to the mucus layer of the urothelium and can cause large disruption of bladder permeability which can be modified by adding  defibrotide . [ 1 ] [ 3 ]  Hyaluronidase breaks down  Hyaluronic acid , a GAG molecule important to the  mucin layer , causing enhanced permeability of the mucin layer to drugs administered concurrently with hyaluronidase. [ 1 ]  Conversely, hyaluronic acid can be used to treat  interstitial cystitis  as it helps to repair damaged mucin layers. [ 3 ]  Chitosan is thought to function as a permeability enhancer by binding to the mucin layer and negatively affecting tight junctions between  umbrella cells  in the urothelium. [ 1 ]  It has been shown that chitosan increases bladder wall permeability but its effectiveness as a permeability enhancer decreases as calcium ion concentration increases. [ 13 ]  Chemically enhancing bladder permeability can lead to negative side effects such as  incontinence , pain, and uncontrolled leakage of molecules other than intended drug from the urine into the bladder wall. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8124", "text": "Nanoparticle  and  liposome   drug carrier  formulations allow for increased drug uptake, especially in the case of liposomes which allow for greater uptake via  endocytosis . [ 1 ] [ 2 ] [ 3 ] [ 5 ]  Liposomes generally must be shielded via modification with a  Polyethylene glycol  molecule to overcome issues with instability and  aggregation  in urine. [ 4 ]  Nanoparticle and Liposome drug carriers can be loaded into a  in situ  forming hydrogel to gain the advantages of mucoadhesive properties [ 4 ]  Empty liposomes by themselves have been noted to improve interstitial cystitis, most likely due to formation of a lipid film on damaged urothelium. [ 3 ] [ 5 ]  The variety of types of nanoparticles which can be made to carry drugs in intravesical formulations, combined with the tunability of many of these particles in regards to drug loading and release rates makes nanoparticles and liposomes a highly versatile and useful tool in intravesical drug delivery. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8125", "text": "A  jet injector  is a type of medical  injecting   syringe  device used for a method of drug delivery known as  jet injection . A narrow, high- pressure  stream of liquid is made to penetrate the outermost layer of the skin (stratum corneum) to deliver medication to targeted underlying tissues of the  epidermis  or dermis (\"cutaneous\" injection, also known as classical \" intradermal \" injection), fat (\"subcutaneous\" injection), or muscle (\"intramuscular\" injection)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8126", "text": "The jet stream is usually generated by the pressure of a piston in an enclosed liquid-filled chamber. The piston is usually pushed by the release of a compressed metal spring, although devices being studied may use piezoelectric effects and other novel technologies to pressurize the liquid in the chamber.  The springs of currently marketed and historical devices may be compressed by operator muscle power, hydraulic fluid, built-in battery-operated motors, compressed air or gas, and other means. Gas-powered and hydraulically powered devices may involve hoses that carry compressed gas or hydraulic fluid from separate cylinders of gas, electric air pumps, foot-pedal pumps, or other components to reduce the size and weight of the hand-held part of the system and to allow faster and less-tiring methods to perform numerous consecutive vaccinations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8127", "text": "Jet injectors were used for mass  vaccination , and as an alternative to needle syringes for  diabetics  to inject  insulin . However, the  World Health Organization  no longer recommends jet injectors for vaccination due to risks of disease transmission. [ 1 ]  Similar devices are used in other industries to inject grease or other fluid."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8128", "text": "The term \" hypospray \", although better known from its usage in the 1960s television show  Star Trek , is attested in the medical literature as early as 1956. [1]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8129", "text": "A jet injector, also known as a jet gun injector, air gun, or pneumatic injector, is a medical instrument that uses a high-pressure jet of liquid medication to penetrate the skin and deliver medication under the skin without a needle. Jet injectors can be single-dose or multi-dose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8130", "text": "Throughout the years jet injectors have been redesigned to overcome the risk of carrying contamination to successive subjects. To try to stop the risk, researchers placed a single-use protective cap over the reusable nozzle. The protective cap was intended to act as a shield between the reusable nozzle and the patient's skin. After each injection the cap would be discarded and replaced with a sterile one. These devices were known as protector cap needle-free injectors or PCNFI. [ 2 ]  A safety test by Kelly and colleagues (2008) [ 3 ]  found a PCNFI device failed to prevent contamination. After administering injections to  hepatitis B  patients, researchers found hepatitis B had penetrated the protective cap and contaminated the internal components of the jet injector, showing that the internal fluid pathway and patient-contacting parts cannot safely be reused."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8131", "text": "Researchers developed a new jet injection design by combining the drug reservoir, plunger and nozzle into a single-use disposable cartridge. The cartridge is placed onto the tip of the jet injector and, when activated, a rod pushes the plunger forward. This device is known as a disposable-cartridge jet injector (DCJI). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8132", "text": "The International Standards Organization recommended abandoning the use of the name \"jet injector\", which is associated with a risk of cross-contamination and rather refer to newer devices as \"needle-free injectors\". [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8133", "text": "Since the late 1970s, jet injectors have been increasingly used by diabetics in the United States. These devices have all been spring-loaded. At their peak, jet injectors accounted for 7% of the injector market. Currently, the only model available in the United States is the Injex 23.  In the United Kingdom, the Insujet has recently entered the market. As of June 2015, the Insujet is available in the UK and a few select countries. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8134", "text": "Researchers from the  University of Twente  in the Netherlands patented a Jet Injection System, comprising a microfluidic device for jet ejection and a laser-based heating system. A continuous laser beam \u2013 also called a continuous-wave laser \u2013 heats the liquid to be administered, which is launched in a droplet form across the epidermis and slows down into the tissue below. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8135", "text": "Since the jet injector breaks the barrier of the skin, there is a risk of blood and biological material being transferred from one user to the next. Research on the risks of cross-contamination arose immediately after the invention of jet injection technology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8136", "text": "There are three inherent problems with jet injectors:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8137", "text": "Splash-back refers to the jet stream penetrating the outer skin at a high velocity, causing the jet stream to ricochet backward and contaminate the nozzle. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8138", "text": "Instances of splash-back have been published by several researchers. Samir Mitragrotri visually captured splash-back after discharging a multi-use nozzle jet injector using high-speed  microcinematography . [ 7 ]  Hoffman and colleagues (2001) also observed the nozzle and internal fluid pathway of the jet injector becoming contaminated. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8139", "text": "Fluid suck-back occurs when blood left on the nozzle of the jet injector is sucked back into the injector orifice, contaminating the next dose to be fired. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8140", "text": "The CDC has acknowledged that the most widely used jet injector in the world, the Ped-O-Jet, sucked fluid back into the gun. \"After injections, they [CDC] observed fluid remaining on the Ped-O-Jet nozzle being sucked back into the device upon its cocking and refilling for the next injection (beyond the reach of alcohol swabbing or acetone swabbing),\" stated Dr. Bruce Weniger. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8141", "text": "Retrograde flow happens after the jet stream penetrates the skin and creates a hole, if the pressure of the jet stream causes the spray, after mixing with tissue fluids and blood, to rebound back out of the hole, against the incoming jet stream and back into the nozzle orifice. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8142", "text": "This problem has been reported by numerous researchers. [ 10 ] [ 11 ] [ 8 ] [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8143", "text": "Hepatitis B  can be transmitted by less than one nanolitre [ 14 ]  so makers of injectors must ensure there is no cross-contamination between applications. The  World Health Organization  no longer recommends jet injectors for vaccination due to risks of disease transmission. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8144", "text": "Numerous studies have found cross-infection of diseases from jet injections.  An experiment using  mice , published in 1985, showed that jet injectors would frequently transmit the viral infection  lactate dehydrogenase elevating virus  (LDV) from one mouse to another. [ 15 ]  Another study used the device on a calf, then tested the fluid remaining in the injector for blood. Every injector they tested had detectable blood in a quantity sufficient to pass on a virus such as hepatitis B. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8145", "text": "From 1984 to 1985, a weight-loss clinic in Los Angeles administered  human chorionic gonadotropin  (hCG) with a Med-E-Jet injector. A CDC investigation found 57 out of 239 people who had received the jet injection tested positive for hepatitis B. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8146", "text": "Jet injectors have also been found to inoculate bacteria from the environment into users. In 1988 a podiatry clinic used a jet injector to deliver  local anaesthetic  into patients' toes. Eight of these patients developed infections caused by  Mycobacterium chelonae . The injector was stored in a container of water and disinfectant between use, but the organism grew in the container. [ 17 ]  This species of bacteria is sometimes found in tap water, and had been previously associated with infections from jet injectors. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8147", "text": "Laser-assisted drug delivery  (LADD) is a drug delivery technique commonly used in the dermatology field that involves lasers. As skin acts as a protective barrier to the environment, the absorption of topical products through the epidermis is limited; thus, different drug delivery modalities have been employed to improve the efficacy of these treatments. The use of lasers in LADD has been shown to enhance the penetration of drugs transdermal, leading to a higher absorption rate, limited systemic effects, and reduced duration of treatment. Although this technique has evolved in the past decade due to its efficacy through scientific research and clinical practice, there remain some limitations regarding the safety aspect that needs to be taken into consideration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8148", "text": "Skin is the largest organ in the human body that acts as the primary protective barrier against the external environment. It provides protection against ultraviolet light, trauma, pathogens, microorganisms, and toxins, sensory perception, temperature regulation, and immunity. [ 1 ]  There are primarily three layers of skin, which include the outer epidermis, followed by the dermis and subcutaneous tissue, or hypodermis. [ 1 ]  Skin is used as the target for drug delivery as it is a convenient route of drug administration, and the large area allows for different placements on the skin for transdermal delivery [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8149", "text": "Transdermal delivery is a non-invasive method commonly assisted in transporting topical products into intact and healthy skin. The substances initially penetrate through the stratum corneum, which is the outermost layer of the epidermis, then diffuse into the deeper epidermis and dermis layers for a systemic effect. [ 2 ]  Although transdermal drug delivery presents several advantages as compared to other conventional modalities such as oral and parenteral routes, [ 2 ] [ 3 ] [ 4 ] [ 5 ]  the complexity of the skin barrier limits the methodology to reach its full potential."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8150", "text": "Various technologies have been developed to enhance the permeability of transdermal drugs, which can be divided into passive or chemical and active or physical methods. The passive approach involves the optimization of drug and vehicle interaction that could modify the stratum corneum structure or the addition of penetration enhancers for better absorption rates. [ 2 ]  Some of the limitations of this approach include lag time in drug release, low efficiency, and skin irritation. [ 2 ]  The active approach involves ultrasound, electrical stimulation, thermal approach, and mechanical approach. [ 2 ]  These techniques facilitate the transportation of drugs by using energy as a driving force. Within the thermal approach, laser-assisted drug delivery is a common and effective method that has been used to increase the efficiency of transdermal drug delivery by selectively destroying the chromophores of interest using light waves."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8151", "text": "There are different types of lasers used in LADD, and they can be categorized into four main groups: (1) fully ablative lasers, (2) ablative fractional lasers (AFL), (3) non-ablative fractional lasers (NAFL), and (4) non-ablative dermal remodeling lasers. [ 6 ]  Common fully ablative lasers, including carbon dioxide (CO\u2082, wavelength peak 10,600 nm) and erbium-doped yttrium aluminum garnet (Er:YAG, wavelength peak 2940 nm), target water as their chromophore where all water-containing tissues within the epidermis are ablated. [ 7 ]  With its high wavelength peak, CO\u2082 laser has a high absorption rate of water and adipose tissues; whereas the wavelength of Er:YAG allows for the precise ablation of water and minimizes heat generation. [ 8 ]  The mechanism of AFL is similar to fully ablative lasers but when used fractionally, they create multiple vertical columns on the skin surface, which are also called microscopic treatment zones (MTZ) and allow for a more quantitatively controllable usage in LADD. [ 8 ]  NAFL are also fractionated lasers that produce MTZ, but as they are non-ablative, there is no ablation of the epidermis and instead, they use light energy to damage the dermis layer. [ 9 ]  Non-ablative dermal remodeling lasers include all types of lasers with a chromophore that is different from water as used in the previous groups. Common lasers within this group are neodymium-doped YAG laser (Nd: YAG, wavelength peak 1064 nm and 1320 nm), pulsed dye laser (wavelength ranges from 585 to 600 nm), and intense pulsed laser (IPL, wavelength ranges from 500 to 1200 nm). [ 9 ]  In general, with its high efficiency and rapid recovery time, AFL is the more common modality used for LADD, especially in the dermatology field. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8152", "text": "Lipophilic substances have shown to have a greater ability to cross the epidermis, thus, the efficiency of LADD is more remarkable when using hydrophilic substances. [ 6 ] [ 11 ]  Liquid and gel formulations of drugs also are proven to cross the channels created from the fractional lasers more easily as compared to oily formulations such as creams or ointments. [ 6 ]  Common drugs used in LAPP include but are not limited to 5-aminolaevulinic (5-ALA), 5-aminolevulinate (MAL), methotrexate (MTX), imiquimod, 5-fluorouracil (5-FU), timolol, triamcinolone acetonide (TAC), bimatoprost, tretinoin, pimecrolimus, poly-L-lactic acid (PLLA), analgesics, minoxidil (MXD), diphencyprone (DPCP), vitamin C, small interfering RNA (siRNA), vaccine, and antibodies. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8153", "text": "The efficiency of LADD with the selected laser settings is dependent upon the different characteristics associated with individual patients. The dermatological condition, the properties of the skin, and the surface area are taken into consideration to determine the eligibility of the patients for certain lasers and provide optimal treatments for each patient. For example, hydrated skin has a higher affinity for absorption of oily substances; skin atrophy that is associated with solar elastosis is more likely to produce pathological scarring under high laser intensity; hair areas have a higher absorption rate; older patients are more prone to adverse effects such as atrophy, erosion, ulceration, and will require longer recovery time. [ 6 ]  Not all patients are candidates for LADD as this method is intensified as compared to conventional topical treatment. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8154", "text": "A vast majority of pre-clinical work on LADD focuses on AFL based on its translational characteristics in clinical settings. These studies utilized mostly either porcine or murine skin as their disease model."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8155", "text": "Within the dermatology field, porcine skin has been used as a disease model for testing the efficacy of LADD  in vivo . Haedersdal et al. pre-treated porcine skin with CO 2 -AFL before the application of MAL photodynamic therapy (PDT), creating single MTZs that increased porphyrin fluorescence uniformly up to 1.5 mm from the ablated channels. [ 14 ]  This demonstrated that for MAL, pre-treatment of AFL with MTZs spacing at 3-mm intervals, covering less than 1% surface of the area, was useful for the entire lesion. [ 7 ]  Similarly, Bachhav et al. showed that the increased numbers of MTZs from Er:YAG laser did not affect the absorption of lidocaine into either the epidermis or dermis, and thus, higher fluences of laser were not proportionally correlated to the absorption rate. [ 15 ]  AFL pre-treatment of porcine skin also has also shown to enhance the delivery of MAL at deeper layers of the skin, [ 15 ]  increase surface fluorescence from MAL as compared to non-AFL pre-treated skin, [ 16 ]  and induce higher fluorescence of 5-ALA as compared to MAL for deeper structure. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8156", "text": "Besides porcine skin, murine skin has also been used for testing the efficacy of LADD. A study performed on murine skin has shown that the penetration of 5-FU through skin increased 36 to 133-fold after pre-treatment with fully ablative Q-switched ruby, CO 2 , or Er:YAG lasers. [ 18 ]  Likewise, delivery of imiquimod in both murine and porcine skin increased up to 65-fold and 127-fold, after one and four passes of low-fluence fractional Er:YAG laser, respectively. [ 19 ]  As a result, with LADD, a dose of 0.4% imiquimod was equivalent to a topically applied dose of 5% imiquimod, [ 19 ]  which implied that a lower dosage of drug could be used with similar clinical outcomes. Besides topical drugs, Chen et al. showed that the treatment of fractional CO 2  on murine skin increased 8- to 15-fold the delivery of ovalbumin vaccine, along with an enhanced production of ovalbumin specific antibodies at 2 weeks. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8157", "text": "LADD has been implemented in clinical practice to support the absorption of topical agents into the skin, representative drugs include 5-ALA, MAL, 5-FU, corticosteroid, vitamin, and lidocaine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8158", "text": "LADD has been used in adjunction to photodynamic therapy (PDT) as a pre-treatment, which has shown to enhance the absorption of these drugs into the skin. 5-ALA and MAL are common photosensitizers that are used in PDT to treat different skin diseases such as actinic keratoses (AK), Bowen\u2019s disease, and superficial cell carcinoma. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8159", "text": "Lim et al. (2014) utilized nonablative fractional laser Er:YAG to pre-treat twelve treatment areas on the back of 10 healthy males, followed by the incubation of 5-ALA. [ 21 ]  The results showed that pre-treated areas had higher level of porphyrin fluorescence as compared to non-pretreated areas, which indicated that LADD enhanced 5-ALA skin penetration. In another study, Jang et al. (2013) pre-treated 29 AK patients with an ablative CO 2  fractional laser, followed by 5-ALA-PDT treatment with varying incubation times. [ 22 ]  The pre-treatment of laser showed improvement of clinical outcomes even with the short incubation time, with 70.6% of the AK lesions had a complete clinical response to PDT."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8160", "text": "In a randomized study, Choi et al. used both conventional MAL-PDT and a combination of AFL (Er:YAG) and MAL-PDT to treat 93 AK patients. [ 23 ]  The group treated with a combination of LADD and PDT showed higher clinical response rate of 91.7% as compared to conventional MAL-PDT group with clinical response rate of 65.6% after three months, and results were persistent after a twelve-month follow-up. In another randomized study with 21 patients with Bowen\u2019s disease, the clearance rate of the lesions after 3 months was higher with pre-treatment of one session of ablative fractional Er:YAG followed by MAL-PDT (93.8%) as compared to two sessions of conventional MAL-PDT (73.1%), and with lower recurrence rates (6.7% versus 31.6%). [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8161", "text": "5-FU is a common drug which is used to treat cancer and certain skin diseases, such as AK and certain types of nonmelanoma skin cancers. In a case study of 28 patients, including 16 superficial basal cell carcinomas and 14 squamous cell carcinomas  in situ , pre-treatment of a single pass of CO 2 -AFL followed by a single application of 5-FU showed histological clearance of 100% squamous cell carcinomas  in situ  and 71% of the superficial basal cell carcinomas. [ 25 ]  In a case report study, a patient with multiple Bowen\u2019s disease lesions was selected for a half-side study, one was treated with Er:YAG laser followed by a topical treatment of 5-FU and the other was treated with only 5-FU cream. [ 26 ]  The legions treated with LADD showed accelerated clinical and histologic response as compared to conventional 5-FU, with no recurrences of lesions after 9 months. In another study, Wenande et al. (2021) showed that CO 2 -AFL enhanced the efficiency of cisplatin and 5-FU treatment for 20 patients with basal cell carcinoma, with 94.7% patients showed clinical clearance. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8162", "text": "Triamcinolone acetonide (TAC) is a common corticosteroid used as a therapeutic strategy for hypertrophic scars and keloids. [ 28 ]  In a case study, Waibel et al. used CO 2 -AFL to assist topical TAC delivery to treat 15 patients with hypertrophic and restrictive cutaneous scars. The results showed that significant improvement of the scars was observed after 6 months, with the most impacts on texture. [ 29 ]  Similarly, in a pilot study, either CO 2 -AFL or radiofrequency was used in adjunction with ultrasound-assisted TAC to treat alopecia areata, a disease associated with hair loss. [ 30 ]  All patients showed complete response after the treatment and specifically, the use of LADD with CO 2 -AFL showed complete response of patients after a single session as compared to a required of three and six sessions for radiofrequency."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8163", "text": "Vitamin C and E are important substances that show antioxidant effects against UV radiation. Transdermal delivery after topical application of these vitamins has been facilitated with LADD. Lee et al. (2003) showed that the application of either nonablative fractional Er:YAG or CO 2  lasers improved the transdermal penetration of vitamin C significantly. [ 31 ]  In a split face comparison study regarding UV-induced skin aging, Trelles et al. treated 14 patients with conventional CO 2 -AFL on one side and CO 2 -AFL along with the application of vitamin C and E on the other side. [ 32 ]  As a result, the combination of LADD and vitamins demonstrated a 79% reduction in fine lines as compared to a 69% reduction for AFL-treated side without the delivery of vitamins."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8164", "text": "Local anesthesia is used widely for dermatological surgeries via topical products or injections. As topical agents have a long incubation time for drug penetration and injections are associated with pain, LADD has been applied to the field for advancing the efficacy of anesthesia. Lidocaine is a local anesthetic cream used to prevent and treat pain. Increase dermal absorption and transdermal bioavailability of lidocaine were seen when using in conjunction with LADD, specifically AFL. Yun et al. demonstrated that 5% lidocaine cream applied after Er:YAG-AFL for a full resurfacing procedure showed significant lower pain score after the first pass of resurfacing, but there were only half of the patients were able to tolerate the second pass. [ 33 ]  Nevertheless, this indicated that LADD showed an enhancement of lidocaine penetration through the stratum corneum. Similarly, in a double-blind randomized controlled trial with 320 healthy volunteers, the patients were either pre-treated with Er:YAG-AFL followed by 4% lidocaine or treated with topical 4% lidocaine alone before cannulation. [ 34 ]  The results showed a 62% reduction in pain with the use of LADD as compared to conventional topical lidocaine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8165", "text": "When applying LADD in clinical settings, safety is an imperative factor that needs to be considered. As mentioned above, there are different lasers with distinct properties that could be implemented for patients. However, radiation of any type will damage human tissue to some extent. Some potential adverse events that are laser-induced include erythema, edema, scabbing, blistering, and pigmentary changes, especially at higher intensity and densities. [ 35 ] [ 36 ] [ 37 ]  Regarding intralesional therapies for scarring, telangiectasia, hypopigmentation, and skin atrophy have been observed in multiple studies as side effects of LADD. [ 35 ] [ 38 ] [ 39 ] [ 40 ] [ 41 ]  In LADD application for management of pigmentary condition, there are some pigment-related adverse effects such as worsening of melasma, [ 42 ] [ 43 ]  and hyperpigmentation in vitiligo. [ 44 ] [ 45 ]  While LADD improves the dermal infiltration of different medications, the skin also has heightened local reaction when exposed to the substances and external environment. [ 46 ]  In several studies about AFL-assisted delivery of MAL-photodynamic therapy, there are intensified local cutaneous responses, including burning sensation, pain, edema, pruritus, purpura, and transient pigmentary changes. [ 47 ] [ 48 ] [ 49 ] [ 50 ] [ 51 ] [ 52 ]  Furthermore, exposing the underlying dermis and vasculature to the outside environment also increases the risk of infection. [ 26 ]  AFL-assisted delivery of 5-FU, steroids, and MAL have shown elevated bacterial infections. [ 53 ] [ 54 ] [ 28 ] [ 55 ] [ 56 ]  In general, most LADD safety concerns are related to local reactions similar to that of laser therapy, and are generally well-tolerated with some exceptions. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8166", "text": "Current studies support the use of LADD in adjunction with topical products in treating dermatological diseases, but these studies are limited in sample size and lack of long-term follow-up outcomes. Larger randomized controlled trials with a wide variety of topical drugs are required to validate the efficacy and side effects of LADD before this technique could be employed as a standard of treatment. Besides its application in drug delivery, the prospect of using LADD to improve the transdermal delivery of vaccines, promote wound healing, correct genetic sequence, and as a complement to inflammatory dermatoses and cosmetic indications is being investigated [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8167", "text": "Liniment  (from  Latin :  linere , meaning \"to  anoint \"), also called  embrocation  and  heat rub , is a medicated topical preparation for application to the skin. Some liniments have a viscosity similar to that of water; others are  lotion  or balm; still, others are in  transdermal patches , soft solid sticks, and sprays. Liniment usually is rubbed into the skin, which the active ingredients penetrate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8168", "text": "Liniments are typically sold to relieve pain and stiffness, such as from  muscular   aches  and  strains , and  arthritis . These are typically formulated from  alcohol ,  acetone , or similar quickly evaporating  solvents  and contain  counterirritant  aromatic chemical compounds, such as  methyl salicylate ,  benzoin resin ,  menthol , and  capsaicin . They produce a feeling of warmth within the  muscle  of the area they are applied to, typically acting as  rubefacients  via a counterirritant effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8169", "text": "Methyl salicylate , which is the  analgesic  ingredient in some heat rubs, can be toxic if used in excess. [ 1 ]   Heating pads  are also not recommended for use with heat rubs, because the added warmth may cause overabsorption of the active ingredients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8170", "text": "Liniments are commonly used on horses following exercise, applied either by rubbing on full-strength, especially on the legs; or applied in a diluted form, usually added to a bucket of water and sponged on the body. They are used in hot weather to help cool down a horse after working, the alcohol cooling through rapid evaporation, and counterirritant oils dilating capillaries in the skin, increasing the amount of blood releasing heat from the body. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8171", "text": "Many horse liniment formulas in diluted form have been used on humans, though products for horses which contain  DMSO  are not suitable for human use, as DMSO carries the topical product into the bloodstream. [ 17 ]  Horse liniment ingredients such as menthol,  chloroxylenol , or iodine are also used in different formulas in products used by humans. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8172", "text": "Absorbine , a horse liniment product manufactured by  W.F. Young, Inc. , was reformulated for humans and marketed as Absorbine Jr. [ 19 ]   The company also acquired other liniment brands including Bigeloil and RefreshMint. [ 20 ]   The equine version of Absorbine is sometimes used by humans, [ 21 ]  though, anecdotally, its benefits in humans may be because the smell of menthol releases  serotonin , or due to a  placebo effect . [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8173", "text": "Earl Sloan  was a US entrepreneur who made his initial fortune selling his father's horse liniment formula beginning in the period following the Civil War. Sloan's liniment with capsicum as a key ingredient was also marketed for human use. He later sold his company to the predecessor of  Warner\u2013Lambert , which was purchased in 2000 by  Pfizer . [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8174", "text": "Lip balm  or  lip salve  is a  wax -like substance applied to the lips to moisturize and relieve  chapped  or dry lips,  angular cheilitis ,  stomatitis , or  cold sores . Lip balm often contains   beeswax  or  carnauba wax ,  camphor ,  cetyl alcohol ,  lanolin ,  paraffin , and  petrolatum , among other ingredients. Some varieties contain dyes, flavor, fragrance,  phenol ,  salicylic acid , and  sunscreen ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8175", "text": "The primary purpose of lip balm is to provide an occlusive layer on the lip surface to seal moisture in lips and protect them from external exposure. Dry air, cold temperatures, and wind all have a drying effect on skin by drawing moisture away from the body. Lips are particularly vulnerable because the skin is so thin, and thus they are often the first to present signs of dryness. Occlusive materials like waxes and  petroleum jelly  prevent moisture loss and maintain lip comfort while flavorings, colorants, sunscreens, and various medicaments can provide additional, specific benefits. Lip balms are produced from bee wax and natural candelilla and carnauba waxes. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8176", "text": "Lip balm can be applied by a finger to the lips, or in a  lipstick -style tube from which it can be applied directly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8177", "text": "In 2022, the global lip balm market was valued at US$732.76 mln. The market is predicted to grow at a rate of 9.28% within the next five years and is likely to reach US$1247.74 mln by 2027. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8178", "text": "Production for lip balms includes the following stages: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8179", "text": "Since 40 BC, the Egyptians made treatment for lip care, which was made with a mixture of beeswax, olive oil, and animal fat. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8180", "text": "In the 1800s,  Lydia Maria Child  recommended earwax as a treatment for cracked lips in her highly-popular book,  The American Frugal Housewife .  Child observed that, \"Those who are troubled with cracked lips have found this earwax remedy successful when others have failed. It is one of those sorts of cures, which are very likely to be laughed at; but I know of its having produced very beneficial results.\" [ 5 ]  The invention of the lip balm was first formally invented in the 1880s by physician  Charles Brown Fleet [ 6 ]  though its origins may be traced to  earwax . [ 7 ]  Fleet later named his lip balm product \" ChapStick \". [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8181", "text": "In 1872, chemist  Robert Chesebrough  discovered and sampled a new petroleum jelly, initially describing it as a \"natural, waxy ingredient, rich in minerals from deep within the earth\" which could be used as a solution for skin repair. He then distributed his product under the name \"Wonder Jelly\" before shortly changing it to \"Vaseline\". [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8182", "text": "In the early 1880s, Charles Brown Fleet created ChapStick. [ 8 ]  However, due to the lack of sales, Fleet sold his formula and rights to ChapStick to John Morton in 1912 for $5, who saw the marketing potential in the brand. [ 4 ]  After making the purchase, Morton commissioned Frank Wright, Jr. to create a design for the logo of ChapStick for $15 in 1936. [ 4 ]  In 1972, ChapStick tubes concealing hidden microphones were used during the  Watergate scandal . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8183", "text": "In 1937, Alfred Woelbing created  Carmex  to treat cold sores in Milwaukee, though the occurrence of  World War 2  would slow the production and sales due to the lack of  lanolin . In 1980, Carmex underwent a product change by converting its packaging into squeezable tubes. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8184", "text": "In 1973,  Bonne Bell  created the first flavored lip balm and marketed the company as Lip Smackers. The company would later collaborate on various different-flavored lip balms including  Dr. Pepper  in 1975,  The Wrigley Company  in 2004, and  The Coca-Cola Company  in 2006. Bonne Bell also collaborated with  Disney  to produce lip balms with various princess characters in 2010. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8185", "text": "In 1991, Burt Shavitz and Roxanne Quimby created their first beeswax based lip balm solution through their company,  Burt's Bees . [ 13 ]  In 2020, it was reported that Burt's Bees had used 50 percent of recycled material to package various products and that 100 percent of the products were recyclable. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8186", "text": "In 2011,  Evolution of Smooth  (or commonly known as EOS) created a spherical-shaped lip balm as well as describing its 95% organic ingredients. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8187", "text": "With the gradual legalization of cannabis in the United States, some companies have produced lip balms containing doses of  THC  or  CBD  oil. The lip balms were infused with a low dosage of THC in order to prevent the occurrence of any psychoactive or related effect.  [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8188", "text": "According to a report, professor Brad Rohu states that it is natural for the lips to feel dry. [ 15 ]  The exposure to environments with cold, dry, or windy weather can directly cause the chapping of the lips as well as behaviors such as lip licking or  mouth breathing . [ 16 ]  These factors may directly contribute to an increased amount of lip balm usage. According to dermatologist Amy Derick, those who have expressed dependencies on lip balm have developed a desire of how the lips feel after application. She also mentions that the variety of lip balm flavor may also directly cause lip balm dependency as a person may want to lick their lips to taste the flavor, which may consequentially remove the lip balm coating from the lips. This may also leave saliva on the lips which can dry up and make the lips feel even more dry than they initially were. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8189", "text": "Some physicians have suggested that certain types of lip balm can be addictive or contain ingredients that actually cause drying, [ 18 ]  though, it has been debated by many professionals. Lip balm manufacturers sometimes state in their FAQs that there is nothing addictive in their products or that all ingredients are listed and approved by the  FDA .  Snopes  found the claim that there are substances in  Carmex  that are irritants necessitating reapplication, such as ground glass, to be false. [ 19 ]  However, some experts such as dermatologist Dr. Cynthia Bailey state that some ingredients in lip balm directly causes sensitive lip skin which may lead to addiction. [ 20 ]  Dermatology professor Marcia Driscoll also adds onto this argument by stating that aroma ingredients found in flavored or scented lip balms have the potential to irritate skin. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8190", "text": "The human lips have an inadequate capability of holding moisture as well as an imperfect lip barrier function. [ 22 ]  The  Journal of the American Academy of Dermatology  performed a study in order to determine whether consistent use of lip balm would enhance the overall quality of the lips. The study used 32 female participants within the ages of 20 to 40 years and the participants had mild to moderate dried lips without any history of health-related complications. The participants underwent a procedure in which no lip treatment was provided on the first 3 days, then 2 weeks of consistent lip balm usage, and then a period of no treatment for 3 days. The study determined the quality of the lips based on the physical details and appearance throughout the study. The study showed a direct improvement of the physical details of the lips except for lip cracking during the second week of treatment and after the period of no treatment. The study also showed that hydration of the lips lasted for approximately 8 hours after usage and the lip balm improved the lip barrier function despite discontinued usage. The study concluded that lip balms assist the hydration of the lips which consequentially improves the lip barrier function and the quality. [ 23 ]  This study was completely funded by  Burt's Bees , a lip balm company."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8191", "text": "In 2015, German consumer watchdog  Stiftung Warentest  analyzed cosmetics containing mineral oils. After developing a new detection method they found high concentrations of Mineral Oil Aromatic Hydrocarbons (MOAH) and even polyaromatics in products containing mineral oils with Vaseline products containing the most MOAH of all tested cosmetics (up to 9%). [ 24 ]  The  European Food Safety Authority  sees MOAH and polyaromatics as possibly carcinogenic. [ 24 ]  Based on the results, Stiftung Warentest warns not to use Vaseline or any product that is based on mineral oils for lip care."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8192", "text": "In 2019, a research report conducted by the  Statista Research Department  concluded that ChapStick was the leading lip balm brand in the United States with an approximate unit sale of 55.8 million. Carmex was the second leading brand with approximately 35.2 million units sold and Burt's Bees being the third leading brand with approximately 32.3 million units sold. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8193", "text": "Beezin' is a trend dating back to 2013 in which a person applies  Burt's Bees  brand lip balm onto the eyelids. [ 26 ]  The practice is done in order to feel a sensation of being high or drunk, and even to increase the desired effects of alcohol and other substances. [ 27 ]  In 2022, Beezin' became a viral trend on the social media platform  TikTok . [ 28 ]  Some ingredients, including peppermint oil, are known to be eye irritants which can cause an unintentional inflammatory response which may require treatment and may also cause dermatitis on the eyelids. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8194", "text": "A  liposome  is a small artificial  vesicle , spherical in shape, having at least one  lipid bilayer . [ 2 ]  Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, [ 2 ]  liposomes can be used as  drug delivery  vehicles for  administration  of  pharmaceutical drugs  and  nutrients , [ 3 ]  such as  lipid nanoparticles  in  mRNA vaccines , and  DNA vaccines .  Liposomes can be prepared by disrupting biological membranes (such as by  sonication )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8195", "text": "Liposomes are most often composed of  phospholipids , [ 4 ]  especially  phosphatidylcholine , and  cholesterol , [ 2 ]  but may also include other lipids, such as those found in  egg  and  phosphatidylethanolamine , as long as they are compatible with  lipid bilayer  structure. [ 5 ]  A liposome design may employ surface  ligands  for attaching to desired cells or tissues. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8196", "text": "Based on vesicle structure, there are seven main categories for liposomes: multilamellar large (MLV), oligolamellar (OLV), small unilamellar (SUV), medium-sized unilamellar (MUV), large unilamellar (LUV), giant unilamellar (GUV) and multivesicular vesicles (MVV). [ 6 ]  The major types of liposomes are the multilamellar vesicle (MLV, with several  lamellar phase   lipid bilayers ), the small  unilamellar liposome  vesicle (SUV, with one  lipid bilayer ), the large unilamellar vesicle (LUV), and the cochleate vesicle. A less desirable form is multivesicular liposomes in which one vesicle contains one or more smaller vesicles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8197", "text": "Liposomes should not be confused with  lysosomes , or with  micelles  and  reverse micelles . [ 8 ]  In contrast to liposomes, micelles typically contain a monolayer of fatty acids or surfactants. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8198", "text": "The word  liposome  derives from two Greek words:  lipo  (\"fat\") and  soma  (\"body\"); it is so named because its composition is primarily of phospholipid."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8199", "text": "Liposomes were first described by British hematologist  Alec Douglas Bangham [ 10 ] [ 11 ] [ 12 ]  in 1961 at the Babraham Institute, in Cambridge\u2014findings that were published 1964. The discovery came about when Bangham and R. W. Horne were testing the institute's new  electron microscope  by adding  negative stain  to dry phospholipids. The resemblance to the  plasmalemma  was obvious, and the microscopic pictures provided the first evidence that the cell membrane is a bilayer lipid structure. The following year, Bangham, his colleague Malcolm Standish, and  Gerald Weissmann , an American physician, established the integrity of this closed, bilayer structure and its ability to release its contents following detergent treatment (structure-linked latency). [ 13 ]  During a Cambridge pub discussion with Bangham, Weissmann first named the structures \"liposomes\" after something which laboratory had been studying, the lysosome: a simple organelle whose structure-linked latency  could be disrupted by detergents and streptolysins. [ 14 ]  Liposomes are readily distinguishable from micelles and hexagonal lipid phases through negative staining transmission electron microscopy. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8200", "text": "Bangham, with colleagues Jeff Watkins and Standish, wrote the 1965 paper that effectively launched what would become the liposome \"industry.\" Around that same time, Weissmann joined Bangham at the Babraham. Later, Weissmann, then an emeritus professor at New York University School of Medicine, recalled the two of them sitting in a Cambridge pub, reflecting on the role of lipid sheets in separating the cell interior from its exterior milieu. This insight, they felt, would be to cell function what the discovery of the double helix had been to genetics. As Bangham had been calling his lipid structures \"multilamellar smectic mesophases,\" or sometimes \"Banghasomes,\" Weissmann proposed the more user-friendly term liposome. [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8201", "text": "A liposome has an aqueous solution core surrounded by a  hydrophobic  membrane, in the form of a  lipid bilayer ;  hydrophilic   solutes  dissolved in the core cannot readily pass through the bilayer. Hydrophobic chemicals associate with the bilayer. This property can be utilized to load liposomes with hydrophobic and/or hydrophilic molecules, a process known as encapsulation. [ 18 ]  Typically, liposomes are prepared in a solution containing the compound to be trapped, which can either be an aqueous solution for encapsulating hydrophilic compounds like proteins, [ 19 ] [ 20 ]  or solutions in organic solvents mixed with lipids for encapsulating hydrophobic molecules.\nEncapsulation techniques can be categorized into two types: passive, which relies on the stochastic trapping of molecules during liposome formation, and active, which relies on the presence of charged lipids or transmembrane ion gradients. [ 18 ] \nA crucial parameter to consider is the \"encapsulation efficiency,\" which is defined as the amount of compound present in the liposome solution divided by the total initial amount of compound used during the preparation. [ 21 ] \nIn more recent developments, the application of liposomes in  single-molecule experiments  has introduced the concept of \"single entity encapsulation efficiency.\" This term refers to the probability of a specific liposome containing the required number of copies of the compound. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8202", "text": "To deliver the molecules to a site of action, the lipid bilayer can fuse with other bilayers such as the  cell membrane , thus delivering the liposome contents; this is a complex and non-spontaneous event, however, [ 23 ]  that does not apply to nutrients and drug delivery. By preparing liposomes in a solution of  DNA  or  drugs  (which would normally be unable to  diffuse  through the membrane) they can be (indiscriminately) delivered past the lipid bilayer. [ 24 ]  Liposomes can also be designed to deliver drugs in other ways. Liposomes that contain low (or high)  pH  can be constructed such that dissolved aqueous drugs will be  charged  in solution (i.e., the pH is outside the drug's  pI  range). As the pH naturally neutralizes within the liposome ( protons  can pass through some membranes), the drug will also be neutralized, allowing it to freely pass through a membrane. These liposomes work to deliver drug by  diffusion  rather than by direct cell fusion. However, the efficacy of this pH regulated passage depends on the physiochemical nature of the drug in question (e.g. pKa and having a basic or acid nature), which is very low for many drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8203", "text": "A similar approach can be exploited in the biodetoxification of drugs by injecting empty liposomes with a transmembrane pH gradient. In this case the vesicles act as sinks to scavenge the drug in the blood circulation and prevent its toxic effect. [ 25 ] \nAnother strategy for liposome drug delivery is to target  endocytosis  events. Liposomes can be made in a particular size range that makes them viable targets for natural  macrophage   phagocytosis . These liposomes may be  digested  while in the macrophage's  phagosome , thus releasing its drug. Liposomes can also be decorated with  opsonins  and  ligands  to activate endocytosis in other cell types."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8204", "text": "Regarding pH-sensitive liposomes, there are three mechanisms of drug delivery intracellularly, which occurs via endocytosis. [ 26 ]  This is possible because of the acidic environment within endosomes. [ 26 ]  The first mechanism is through the destabilization of the liposome within the endosome, triggering pore formation on the endosomal membrane and allowing diffusion of the liposome and its contents into the cytoplasm. [ 26 ]  Another is the release of the encapsulated content within the endosome, eventually diffusing out into the cytoplasm through the endosomal membrane. [ 26 ]  Lastly, the membrane of the liposome and the endosome fuse together, releasing the encapsulated contents onto the cytoplasm and avoiding degradation at the lysosomal level due to minimal contact time. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8205", "text": "Certain anticancer drugs such as  doxorubicin  (Doxil) and  daunorubicin  may be administered encapsulated in liposomes. Liposomal  cisplatin  has received  orphan drug  designation for pancreatic cancer from EMEA. [ 27 ]  A study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Valrubicin-loaded immunoliposomes (Val-ILs) as a novel nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death.  [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8206", "text": "The use of liposomes for transformation or  transfection  of DNA into a host cell is known as  lipofection ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8207", "text": "In addition to gene and drug delivery applications, liposomes can be used as carriers for the delivery of dyes to textiles, [ 29 ]  pesticides to plants, enzymes and nutritional supplements to foods, and cosmetics to the skin. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8208", "text": "Liposomes are also used as outer shells of some microbubble  contrast agents  used in  contrast-enhanced ultrasound ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8209", "text": "Until recently, the clinical uses of liposomes were for  targeted drug delivery , but new applications for the oral delivery of certain dietary and nutritional supplements are in development. [ 31 ]   This new application of liposomes is in part due to the low absorption and  bioavailability  rates of traditional oral dietary and nutritional tablets and capsules.  The low oral bioavailability and absorption of many nutrients is clinically well documented. [ 32 ]  Therefore, the natural encapsulation of  lypophilic  and  hydrophilic  nutrients within liposomes would be an effective method of bypassing the destructive elements of the  gastric system  and  small intestines  allowing the encapsulated nutrient to be efficiently delivered to the cells and tissues. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8210", "text": "The term  nutraceutical  combines the words  nutrient  and  pharmaceutical , originally coined by Stephen DeFelice, who defined nutraceuticals as \u201cfood or part of a food that provides medical or health benefits, including the prevention and/or treatment of a disease\u201d. [ 34 ]  However, currently, there is no conclusive definition of nutraceuticals yet, to distinguish them from other food\u2010derived categories, such as food (dietary) supplements, herbal products, pre\u2010 and probiotics,  functional foods , and fortified foods. [ 35 ]  Generally, this term is used to describe any product derived from food sources which is expected to provide health benefits additionally to the nutritional value of daily food. A wide range of nutrients or other substances with nutritional or physiological effects (EU Directive 2002/46/EC) might be present in these products, including  vitamins ,  minerals ,  amino acids ,  essential fatty acids ,  fibres  and various plants and herbal extracts. Liposomal nutraceuticals contain bioactive compounds with health-promoting effects. The encapsulation of bioactive compounds in liposomes is attractive as liposomes have been shown to be able to overcome serious hurdles bioactives would otherwise encounter in the gastrointestinal (GI) tract upon oral intake. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8211", "text": "Certain factors have far-reaching effects on the percentage of liposome that are yielded in manufacturing, as well as the actual amount of realized liposome entrapment and the actual quality and long-term stability of the liposomes themselves. [ 37 ]  They are the following: (1) The actual manufacturing method and preparation of the liposomes themselves; (2) The constitution, quality, and type of raw  phospholipid  used in the formulation and manufacturing of the liposomes; (3) The ability to create homogeneous liposome particle sizes that are stable and hold their encapsulated payload. These are the primary elements in developing effective liposome carriers for use in dietary and nutritional supplements."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8212", "text": "The choice of liposome preparation method depends, i.a., on the following parameters: [ 38 ] [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8213", "text": "Useful liposomes rarely form spontaneously. They typically form after supplying enough energy to a dispersion of (phospho)lipids in a polar solvent, such as water, to break down multilamellar aggregates into oligo- or unilamellar bilayer vesicles. [ 5 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8214", "text": "Liposomes can hence be created by  sonicating  a dispersion of amphipatic lipids, such as  phospholipids , in water. [ 8 ]  Low  shear rates  create multilamellar liposomes. The original aggregates, which have many layers like an onion, thereby form progressively smaller and finally  unilamellar liposomes  (which are often unstable, owing to their small size and the sonication-created defects). Sonication is generally considered a \"gross\" method of preparation as it can damage the structure of the drug to be encapsulated. Newer methods such as extrusion, micromixing [ 40 ] [ 41 ] [ 42 ]  and Mozafari method [ 43 ]  are employed to produce materials for human use. Using lipids other than  phosphatidylcholine  can greatly facilitate liposome preparation. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8215", "text": "Further advances in liposome research have been able to allow liposomes to avoid detection by the body's immune system, specifically, the cells of  reticuloendothelial system  (RES). These liposomes are known as \" stealth liposomes \". They were first proposed by G. Cevc and G. Blume [ 44 ]  and, independently and soon thereafter, the groups of L. Huang and  Vladimir Torchilin [ 45 ]  and are constructed with PEG ( Polyethylene Glycol ) studding the outside of the membrane. The PEG coating, which is  inert  in the body, allows for longer circulatory life for the drug delivery mechanism. Studies have also shown that PEGylated liposomes elicit anti-IgM antibodies, thus leading to an enhanced blood clearance of the liposomes upon re-injection, depending on lipid dose and time interval between injections. [ 46 ] [ 47 ]  In addition to a PEG coating, some stealth liposomes also have some sort of biological species attached as a ligand to the liposome, to enable binding via a specific expression on the targeted drug delivery site. These targeting ligands could be  monoclonal antibodies  (making an  immunoliposome ),  vitamins , or specific  antigens , but must be accessible. [ 48 ]  Targeted liposomes can target certain cell type in the body and deliver drugs that would otherwise be systemically delivered. Naturally toxic drugs can be much less systemically toxic if delivered only to diseased tissues.  Polymersomes , morphologically related to liposomes, can also be used this way. Also morphologically related to liposomes are highly deformable vesicles, designed for non-invasive transdermal material delivery, known as  transfersomes . [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8216", "text": "Liposomes are used as models for artificial cells."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8217", "text": "Liposomes can be used on their own or in combination with traditional antibiotics as neutralizing agents of bacterial toxins. Many bacterial toxins evolved to target specific lipids of the host cells membrane and can be baited and neutralized by liposomes containing those specific lipid targets. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8218", "text": "A study published in May 2018 also explored the potential use of liposomes as \"nano-carriers\" of fertilizing nutrients to treat malnourished or sickly plants. Results showed that these synthetic particles \"soak into plant leaves more easily than naked nutrients\", further validating the utilization of nanotechnology to increase crop yields. [ 51 ] [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8219", "text": "Machine learning  has started to contribute to liposome research. For example,   deep learning  was used to monitor a multistep  bioassay  containing sucrose-loaded and nucleotides-loaded liposomes interacting with a lipid membrane-perforating  peptide . [ 53 ]   Artificial neural networks  were also used to optimize formulation parameters of  leuprolide   acetate  loaded liposomes [ 54 ] \nand to predict the particle size and the  polydispersity  index of liposomes. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8220", "text": "A  liposome  extruder  is a device that prepares cell membranes,  exosomes  and also generates nanoscale liposome formulations. [ 1 ] [ 2 ]  The liposome extruder employs the track-etched  membrane  to filter huge particles and achieve sterile filtration. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8221", "text": "A  liposome  is made up of  phospholipid bilayers , with the liposome being a spherical vesicle. Phospholipid bilayers have both  hydrophobic  and  hydrophilic  properties, which are important characteristics of  cell membranes . [ 5 ]  The hydrophobic ends of phospholipid molecules are constrained [ clarification needed ] , often to each other, creating spherical liposomes that are smaller when the hydrophobic ends are exposed to a solution that is aqueous in nature. The preparation of liposomes results in the formation of the liposome extruder [ clarification needed ] . A liposome extruder is characterized by the uniform, narrow size distribution of its output, and has a particle-size control mechanism that is highly precise. Complex, toxic, injectable products such as the  antifungal  liposomal  Amphotericin B , or the liposomal  cytotoxic   anticancer agents   doxorubicin ,  paclitaxel ,  irinotecan ,  Adriamycin , and  cytarabine  contain liposomes which are prepared using the liposome extruder. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8222", "text": "The technology for extruding liposomes relies on the performance and structural characteristics of the  lipid bilayers  in the liposomal  phospholipids . [ how? ] [ clarification needed ] [ 7 ]  An external extrusion force pushes the vesicles of liposomes that are large through the polycarbonate membranes with pore sizes that are specific when the  transition temperature  of the phospholipids rises slightly due to the change in operating temperature [ further explanation needed ] . Re- polymerization  of the multiple compartments pr liposomes that are large in particle size occurs, [ 8 ] [ 9 ]  and smaller liposomes are created due to the rupturing of the membrane [ which? ]  pores. Extrusion of liposomes occurs at a uniform size, based on the pore size in the  polycarbonate   membrane . [ 10 ]  This happens when the big vesicles are passed through the  cell membrane  with a nanopore size specified in size several times [ 10 ]  due to the extrusion of polycarbonate membranes having uniform and vertical nanopore distribution on the surface of the membrane. [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8223", "text": "Liposome extruders are applied in the formulation of liposomes of homogeneous size distributions. [ 3 ] [ 13 ] [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8224", "text": "This type of liposome extruder is primarily used in research laboratories, as it can process mini-sample volumes between 0.25 ml and 2.5 ml. The hand-driven liposome extruders are further categorized into liposome extruders with a thermal-jacketed option and liposome extruders under ambient temperature. They are operated by manually by  pushing a plunger. Liposome extruders under ambient temperature can be fitted with a cooling jacket to regulate temperatures during liposome extrusion. [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8225", "text": "Jacketed liposome extruders are applied in laboratories and in pilot-scale research phases. They process volumes between 2 mL and 3 L. The jacketed extruders are fitted with barrels [ clarification needed ]  to regulate the temperatures of the samples. To drive this extruder, a compressed nitrogen cylinder is used. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8226", "text": "Online liposome extruders process volumes of between 2 ml and 20L. They are driven by a high-pressure electric pump, making them appropriate for use in pilot-scale liposome production. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8227", "text": "A multiple liposome extruder system is fitted with pressure and temperature sensors and a control panel to regulate liposome production. it processes capacities of between 1L and 200L. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8228", "text": "Lotion  is a low- viscosity  topical preparation intended for application to the  skin . By contrast,  creams  and  gels  have higher viscosity, typically due to lower water content. [ 1 ] [ 2 ]   Lotions are applied to external skin with bare hands, a brush, a clean cloth, or  cotton wool ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8229", "text": "While a lotion may be used as a medicine delivery system, many lotions, especially  hand lotions  and  body lotions  and lotion for  allergies  are meant instead to simply smooth, moisturize, soften and, sometimes, perfume the skin. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8230", "text": "Some skincare products, such as  sunscreen  and  moisturizer , may be available in multiple formats, such as lotions, gels, creams, or sprays."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8231", "text": "Dermatologists can prescribe lotions to treat or prevent skin diseases. [ 1 ]  It is not unusual for the same drug ingredient to be formulated into a lotion,  cream  and  ointment . Creams are the most convenient of the three but inappropriate for application to regions of hairy skin such as the scalp, while a lotion is less viscous and may be readily applied to these areas (many medicated  shampoos  are in fact lotions). Historically, lotions also had an advantage in that they may be spread thinly compared to a cream or ointment and may economically cover a large area of skin, but product research has steadily eroded this distinction.  Non-comedogenic  lotions are recommended for use on acne prone skin. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8232", "text": "Lotions can be used for the delivery to the skin of medications such as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8233", "text": "Since health care workers must wash their hands frequently to prevent disease transmission, hospital-grade lotion is recommended to prevent skin  dermatitis  caused by frequent exposure to cleaning agents in the soap. [ 5 ]  A 2006 study found that application of hospital-grade lotion after hand washing significantly reduced skin roughness and dryness. [ 6 ] [ failed verification ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8234", "text": "Care must be taken not to use consumer lotions in a hospital environment, as the  perfumes  and  allergens  may be a danger to those who are immunodeficient or with allergies. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8235", "text": "Most cosmetic lotions are  moisturizing lotions , although other forms, such as  tanning lotion , also exist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8236", "text": "Cosmetic lotions may be marketed as anti-aging lotions, which can also be classified as a cosmetic in many cases, and may contain fragrances. The  Food and Drug Administration  voiced concern about lotions not classified as drugs that advertise anti-aging or anti-wrinkle properties. [ 7 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8237", "text": "Most lotions are oil-in-water  emulsions  using a substance such as  cetearyl alcohol  to keep the emulsion together, but water-in-oil lotions are also formulated. The key components of a skin care lotion, cream or gel emulsion (that is mixtures of oil and water) are the  aqueous  and oily phases, an  emulsifier  to prevent separation of these two phases, and, if used, the  drug  substance or substances. Various other ingredients such as  fragrances ,  glycerol ,  petroleum jelly ,  dyes ,  preservatives ,  proteins  and stabilizing agents are commonly added to lotions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8238", "text": "Manufacturing lotions and creams can be completed in two cycles:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8239", "text": "A typical oil-in-water manufacturing process may be:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8240", "text": "Depending on their composition, lotions can be comedogenic, meaning that they can result in the increased formation of  comedones  (clogged hair follicles). [ 10 ]  People who are prone to  acne  or forming comedones often prefer lotions that are designed to be non-comedogenic (not causing outbreaks). [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8241", "text": "All topical products, including lotions, can result in the  percutaneous (through the skin) absorption  of their ingredients. Though this has some use as a route of drug administration, it more commonly results in unintended  side effects . For example, medicated lotions such as  diprolene  are often used with the intention of exerting only  local effects , but absorption of the drug through the skin can occur to a small degree, resulting in systemic side effects such as  hyperglycemia  and  glycosuria . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8242", "text": "Absorption through the skin is increased when lotions are applied and then covered with an  occlusive  layer, when they are applied to large areas of the body, or when they are applied to damaged or broken skin. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8243", "text": "Lotions containing some aromas or food additives may trigger an immune reaction or even cause users to develop new allergies. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8244", "text": "There is currently no regulation over use of the term \"hypoallergenic\", and even pediatric skin products with the label were found to still contain allergens. [ 13 ]  Those with  eczema  are especially vulnerable to an allergic reaction with lotion, as their compromised skin barrier allows preservatives to bind with and activate immune cells. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8245", "text": "The  American Academy of Allergy, Asthma, and Immunology  released a warning in 2014 that natural lotion containing ingredients commonly found in food (such as goats milk, cow's milk, coconut milk, or oil) may introduce new allergies, and an allergic reaction when those foods are later consumed. [ 12 ]  A 2021 study found that \"frequent skin moisturization in early life might promote the development of food allergy, most likely through transcutaneous sensitization\". [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8246", "text": "Magnetic  nanoparticle -based drug delivery  is a means in which magnetic particles such as  iron oxide nanoparticles  are a component of a delivery vehicle for magnetic  drug delivery , due to the simplicity with which the particles can be drawn to (external)  magnetopuissant targets . [ 1 ] [ 2 ]  Magnetic nanoparticles can impart imaging and  controlled release  capabilities to drug delivery materials such as  micelles ,  liposomes , and polymers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8247", "text": "Molecular magnets  (single-molecule magnets) are a platform that incorporates insoluble (toxic) drugs into biocompatible carrier materials, without adding magnetic  iron oxide nanoparticles  which might adversely affect patients susceptible to  iron overdose . The drawbacks in conventional magnetic drug delivery methods can be overcome by switching from typical  iron oxide nanoparticles  to ones based on molecular magnets, such as  Fe(salen) -based \" anticancer nanomagnet \" with proven cancer-fighting ability. [ 3 ] [ 4 ] [ 5 ]  However, insoluble drugs including Fe(salen) also have some inherent drawbacks, such as poor water solubility, loss of magnetic activity in solvents, and potential cytotoxicity when accumulated in tissues and organs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8248", "text": "As an alternative synthetic method of magnetic drug delivery, a \"non-iron oxide\"-based smart delivery platform has been very recently developed by  self-assembly  of the Fe(salen) drugs into nano-cargoes encapsulated by a  smart polymer , exhibiting bio-safe multifunctional magnetic capabilities, including  MRI , magnetic field- and pH-responsive heat-releasing  hyperthermia  effects, and controlled release. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8249", "text": "Magnetic nanoparticle drug delivery  is the use of external or internal magnets to increase the accumulation of  therapeutic  elements contained in  nanoparticles  to fight pathologies in specific parts of the body. It has been applied in  cancer treatments ,  cardiovascular diseases , and  diabetes . Scientific researches revealed that magnetic drug delivery can be made increasingly useful in clinical settings."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8250", "text": "The development of magnetic nanoparticle drug delivery started with  Paul Ehrlich 's concept of a \"magic bullet\". [ 1 ]  The concept was built during the 1970s with the application of the anticancer drug  doxorubicin  in animal models. The first successful clinical trial of the process occurred in 1996. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8251", "text": "The use of magnetic nanoparticles for drug delivery results in the accumulation of therapeutic elements at a disease site to increase their therapeutic effects as well as limit side-effects at non-target loci. There are many factors that act as variables to accumulation including blood circulation, adherence of therapeutic elements, diffusion of therapeutic elements, bodily response to increased concentrations of these particles, etc. [ 3 ]  Tumor hypoxia is one of the largest challenges regarding cancer drug delivery as tumors grow faster than  vasculature , making initial targeting increasingly important in treatment. This tumor environment drives considerable attention towards magnetic nanoparticles as treatment modalities allowing faster and efficient delivery of drugs and treatment. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8252", "text": "Fundamentally, pulsatile artificial capillaries made to mimic blood flow show that the flow force of the  capillaries  inhibits accumulation of nanoparticles on a magnet downstream, but the magnetic force of the upstream magnet overcomes the force of flow to result in larger accumulation. As a result, for near-surface disease states, magnets should be placed downstream of the disease locus, and for intra-surface disease states, magnets should be placed upstream of the disease locus to maximize accumulation. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8253", "text": "Magnetic nanoparticles for therapeutic applications are selected based on their properties determined by the nanoparticle composition which can be divided into three main groups - metal only,  metal alloy , or metal oxide nanoparticles. Some key properties of magnetic nanoparticles include a large specific surface area, desirable biocompatibility, presence without causing disease or eliciting  immune response , and superparamagnetism. [ 5 ]  Magnetic nanoparticles are influenced by an external magnetic field due to the magnetic moment found within the network unit. The external magnetic field is necessary for transport and activation of these nanoparticles. Therefore, when a drug is attached/encased in magnetic nanoparticles, these particles will be targeted using an external magnetic field to guide and concentrate the drug at desired disease locus. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8254", "text": "Design of magnetic nanoparticles for clinical application requires careful evaluation of the effects of surface modification, size, and shape on its magnetic properties. Ferromagnetic properties of nanoparticles have been used in magnetic drug delivery systems. This is important, as ferromagnetism is described as the coercivity of particles to form macro-materials on permanent magnets. The macro-materials include  iron ,  cobalt , and  nickel ; these elements retain their magnetic properties when a magnet is removed, which is why they accumulate on the permanent magnets. [ 3 ]  Iron oxides, such as Fe\u2082O\u2084 and Fe\u2083O\u2084 in particular, play a key role in magnetic nanoparticle drug delivery. The particle sizes typically range from 3 nm to 30 nm. Overall, these iron oxides display good magnetic properties, lower toxicity, and high stability against degradation. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8255", "text": "For example, a Fe3-\u03b4O4 core-shell is used as a carrier for drug delivery. The designed magnetic nanoparticle-based structure displayed biocompatibility, the formation of a covalent bond between the carrier and drug, and  glutathione -responsive drug release which prevents early drug release and increases bioavailability. Furthermore, the presence of magnetic nanoparticles in this drug delivery method allows for its response to external magnetic fields for functionalization. [ 7 ]  The combination of superparamagnetic iron oxide (SPIO) and polyethylene glycol (PEG) used as drug carriers for doxorubicin are influenced by external magnetism. In vivo SPIO-PEG-D under a magnetic field leads to greater tumor accumulation of therapeutic elements, shows lower tumor size, and reduces  cardiotoxicity  and  hepatotoxicity  in the magnetic field.  Doxorubicin  is known for being extremely toxic, and SPIO-PEG shows potential for use as a nanoparticle carrier for reduced toxicity in the periphery. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8256", "text": "Coating defines the biocompatibility of the therapeutic agent and its ability to travel in the body. When the agent is not biocompatible, it will quickly be excreted from the body, and there will be magnetic accumulation or off-target therapeutic effects. [ 4 ]  The use of organic or inorganic coating molecules increases the  half-life  of the nanocarrier by delaying its clearance by the  reticuloendothelial system   (RES). This delay occurs because the coating overcomes the pH, hydrophobicity, and surface charge of the magnetic nanoparticles. Additionally, coating allows molecules to covalently bind to specific molecules, such as ligands, proteins, or antibodies, which provides binding specificity to target tissues. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8257", "text": "A common structure of coating includes the core-shell structure. In this structure, metal oxide cores are coated with biocompatible materials which allows for increased control and biocompatibility. [ 6 ]  The most common coatings used for optimum response involve the use of  polysaccharides  like  dextran  and polymers like  polyethylene glycol . [ 4 ] [ 9 ]  Furthermore, carbon coatings have proved to be biocompatible and have high capacity for absorption into cells. Even  polyaniline  with anti-cancer agent  epirubicin  can be used for tumor exploration of the brain. Polyethyleneimine has displayed high cellular accumulation and low toxicity. This coating was found to have poor pharmacokinetic properties when used alone, but with magnetic field induction, it was found to accumulate on tumors at clinically significant rates. [ 4 ]  Silica coatings increase the external surface area to assist in binding and are heat resistant. There are various coatings used to prevent leaching of the magnetic core of the nanoparticles; these coatings have a significant salt concentration with a slightly alkaline (basic) pH. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8258", "text": "Polyethylene glycol (PEG) is an example of a hydrophilic coating that has been used as a biocompatible targeting modality. Hydrophilic PEG interacts beneficially with the physiological environment to improve biocompatibility by preventing opsonization on the surface of the particles, thus increasing circulation time from minutes to hours, or even days, for magnetic nanoparticles. MRI shows prolonged\u00a0 PEG circulation and increased SPIO-PEG-D particle accumulation within the tumor with magnetic guidance. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8259", "text": "Coating not only provides hydrophilic and hydrophobic properties but can also contribute to temperature- and pH-dependent properties. Particular substances, such as PNG, provide these two properties, allowing unique and efficient delivery of drugs. This also enables greater control of release, as body temperature allows a greater amount of drug released, while physiological pH allows a lower amount of drug released. [ 10 ]  Other coating options for similar pH-dependent properties include the hydrogel chitosan that is crosslinked to a polymer coating. [ 11 ]  These coating choices have displayed positive results in delivery of anticancer drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8260", "text": "The small sizes of magnetic nanoparticles allow them to target a variety of targets of different sizes for different purposes. These sizes range from targeting a small cell (10-100 \u03bcm), a virus (20-45 nm), a protein (5-50 nm), or a gene (2 nm wide and 10-100 nm long). If these magnetic nanoparticles are coated correctly, they can interact with and enter body structures, allowing adequate delivery of a drug. Additionally, using magnetic nanoparticles in drug delivery has remote control capability. This occurs through the external magnetic field gradient that is associated with the magnetic field's permeability within human tissue. With the application of this remote control, accumulation and transfer of the magnetic nanoparticles is promoted, which has been especially useful in the delivery of anticancer drugs to specific tumor tissues. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8261", "text": "Another advantage of drug delivery using magnetic nanoparticles is the personability of magnet placement depending on disease state location. [ 3 ]  While this may also be a limitation, it can be effective if the resources can be used for personally tailored medicine reception. Additionally, a major advantage of magnetic nanoparticles is that they can be visualized with ultrasound and/or MRI imaging. [ 1 ] [ 8 ] [ 9 ]  Increase in cellular uptake of SPIO-PEG-D was linked to distinguishable darker differences in  MRI  and increased tumor visibility. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8262", "text": "Limitations of magnetic drug delivery can range from their inherent magnetic properties to interactions with bodily barriers. When magnetic nanoparticles are in the bloodstream, they have high solubility and ionic strength, allowing them to interact with plasma proteins, stimulating the immune system to further inhibit their function. Additionally, the proportion of the nanoparticle size to the target tissue has shown limitations in effective drug delivery, especially in the kidneys and the brain. Intracellular barriers include the removal of the magnetic nanoparticles from the target membrane by ligand-dependent endocytosis followed by separation via acidification in the endosome chamber. Other barriers to consider are the depth of the target tissue, vascular sources, body weight, the speed and amount of blood flow to the target tissue, distance from the field source, injection route, and tumor volume. However, the use of magnetic nanoparticles is more effective when used in near-surface tissues that have slower blood flow, allowing for diffusion and/or endocytosis of nanoparticles into the tissue. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8263", "text": "Another limitation involves the accumulation of nanoparticles only 5 mm away from an external magnet. [ 3 ]  An accumulation distance of 5 mm may not be sufficient in larger applications of magnetic drug delivery. This may be effective enough for sites in closer proximity to the surface of the body, but when the site of interest is deeper within tissue, then the advantage of using magnetic nanoparticles for delivery decreases exponentially. It has been proposed to implant magnets within the body to overcome this limitation. [ 4 ]  Magnet location placement can be upstream or downstream of the location of the disease for maximum accumulation. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8264", "text": "Another question arises from the subject of cellular uptake. While the use of a magnetic field may guide particles to therapeutic sites, it is not an indicator of cellular uptake of particles. This raises questions regarding the effect, if any, of the therapeutic element on the effector area. Generally, nanoparticles efficiently cross cell barriers; however, this can change in the presence of other processes. Promise has been shown with the use of PEG coating. Hydrophilic coatings have shown enhanced cellular uptake at tumor cells with the use of a magnetic field. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8265", "text": "Another concern arises regarding the biotoxicity of magnetic nanoparticles. It is difficult to say for certain that all magnetic nanoparticles are toxic due the large variety of magnetic particles that can be used. The nanoparticles size, biodegradability, composition, and dosage are a few of the properties impacting this concern. However, it has been shown that magnetic nanoparticles that are either inhaled to enter the lungs or are swallowed and enter the gastrointestinal tract have unsatisfactory impacts on the body. PEG, linear neutral polyether coatings have a tendency to lose their targeting capabilities in response to their \"immune stealthing\" function. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8266", "text": "Most magnetic nanoparticle applications in clinical settings are used for cancer therapies. Magnetic nanoparticles have the ability to target the specific locus of the tumor, use a decreased amount of drug to treat the tumor, and result in decreased off-target effects of the drug. [ 1 ]  The most common method of introducing magnetic nanoparticles into the body is through  intravenous  injection; from the site of injection, the nanoparticles travel through the bloodstream. They eventually migrate to the target site with the use of external or implanted magnetic forces. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8267", "text": "A pH/magnetic field dual responsive drug loaded nanomicelle was developed for targeted magnetothermal synergistic chemotherapy of cancer. In this drug delivery system, after the drug reaches the target site and tumor cell uptake is complete, an external magnetic field is applied causing a magnetothermal effect, raising the tumor cells' temperature and further promoting drug uptake. This nanocarrier system aims to improve drug stability, control drug release, and improve tumor targeting efficacy. This approach has shown increased treatment efficacy over traditional chemotherapy and has not demonstrated any noticeable biotoxicity. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8268", "text": "Cardiovascular disease treatment presents as another application of magnetic nanoparticle drug delivery. Atherosclerosis cardiovascular disease is a buildup of plaque in the inner lining of the arteries, and there are models on how magnetic nanoparticle drug delivery could be used as a treatment. However there have not been any in vivo or in vitro studies of magnetic nanoparticles being used to deliver drugs to the arteries to effectively reduce inflammation. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8269", "text": "Other potential applications of magnetic nanoparticles are brain imaging and drug delivery past the  blood-brain barrier  (BBB) using biodegradable magnetic iron oxide nanoparticles. The scope of this application is the treatment of central nervous system (CNS) disorders by functioning as contrast agents and drug carriers. To cross the BBB, these nanoparticles are designed by creating specificity to the BBB; this is achieved by designing the surface of the nanoparticles to be engrafted to ligands, antibodies, small molecules, cell-penetrating peptides, or conjugated RNA to target specific receptors situated along the BBB in order to facilitate entry. As opposed to methods of drug delivery that result in drugs being removed from the cerebrospinal fluid (CSF) or being degraded, magnetic nanoparticle delivery presents an opportunity to protect therapeutics as well as encourage more efficient delivery following the introduction of the nanoparticles. Magnetic nanoparticles can also be used in conjunction with imaging modalities like  ultrasound  to improve imaging. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8270", "text": "The use of nanoparticles in ophthalmic drug delivery is also being explored in clinical research. Magnetic nanoparticles inserted into rats'  corneas  or administered in an eye drop solution showed high adhesion to the target site. However, the exact mechanism by which the adhesion occurred is still being researched. When the rats were exposed to a bacterial substance that should induce  keratitis  of the cornea, the amount of inflammation in the treatment group of rats (received the eye drops after exposure) was inhibited. [ 14 ]  Magnetic nanoparticles have also been used in hyperthermic therapy of cancer, cell purification, biosensing, and immunocytochemical tests. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8271", "text": "In the  United States military , the  Mark I NAAK , or  MARK I Kit , ( \"Nerve Agent Antidote Kit\" ) is a dual-chamber  autoinjector : Two anti- nerve agent  drugs\u2014 atropine sulfate  and  pralidoxime chloride \u2014each in injectable form, constitute the kit. The kits are only effective against the nerve agents  tabun  (GA),  sarin  (GB),  soman  (GD) and  VX ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8272", "text": "Typically, U.S. servicemembers are issued three MARK I Kits when operating in circumstances where chemical weapons are considered a potential hazard. Along with the three kits are issued one  CANA  (Convulsive Antidote, Nerve Agent) for simultaneous use. (CANA is the drug  diazepam  or  Valium , an anticonvulsant.) Both of these kits are intended for use in \"buddy aid\" or \"self aid\" administration of the drugs prior to  decontamination  and delivery of the patient to definitive medical care for the condition."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8273", "text": "A newer model, the  ATNAA  (Antidote Treatment Nerve Agent Auto-Injector), [ 1 ]  has both the atropine and the pralidoxime in one syringe, allowing for simplified administration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8274", "text": "The use of a Mark 1 or ATNAA kit inhibits the nerve agents' purpose, thereby reducing the number of fatal casualties in the advent of chemical warfare. The kits should only be administered if nerve agents have been absorbed or inhaled."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8275", "text": "A  metered-dose inhaler  ( MDI ) is a device that delivers a specific amount of medication to the  lungs  in the form of a short burst of aerosolized medicine that is usually self-administered by the patient via inhalation. It is the most commonly used delivery system for treating  asthma ,  chronic obstructive pulmonary disease  (COPD) and other respiratory diseases. The medication in a metered dose inhaler is most commonly a  bronchodilator ,  corticosteroid  or a combination of both for treating asthma and COPD. Other medications less commonly used but also administered by MDI are mast cell stabilizers, such as  cromoglicate  or  nedocromil ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8276", "text": "A metered-dose inhaler consists of three major components: the canister, which is produced in aluminum or stainless steel by means of  deep drawing , where the formulation resides; the metering valve, which allows a metered quantity of the formulation to be dispensed with each actuation; and an actuator (or mouthpiece) which enables the patient to operate the device and directs the aerosol into the patient's lungs. [ 1 ] [ 2 ]  The formulation comprises the drug, a liquefied gas propellant and, in many cases, stabilizing  excipients . The actuator contains the mating discharge nozzle and generally includes a dust cap to prevent contamination."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8277", "text": "To use the inhaler, the patient presses down on the top of the canister, with their thumb supporting the lower portion of the actuator. Actuation of the device releases a single metered dose of the formulation, which contains the medication either dissolved or suspended in the propellant. Breakup of the volatile propellant into droplets, followed by rapid evaporation of these droplets, results in the generation of an aerosol consisting of micrometer-sized medication particles that are then inhaled. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8278", "text": "Metered-dose inhalers are only one type of  inhaler , but they are the most commonly used type. The replacement of  chlorofluorocarbons  propellants with  hydrofluoroalkanes  (HFA) resulted in the redesign of metered-dose inhalers in the 1990s. For one variety of  beclomethasone  inhalers, this redesign resulted in considerably smaller aerosol particles being produced and increased in potency by a factor of 2.6. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8279", "text": "Before the invention of the MDI, asthma medication was delivered using a fragile and unreliable squeeze bulb  nebulizer . [ 7 ]   The relatively crude nature of these devices also meant that the particles that they generated were relatively large, too large for effective drug delivery to the lungs. [ 2 ]   Nonetheless, these nebulizers paved the way for inhalation drug delivery, inspiring the MDI."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8280", "text": "MDIs were first developed in 1955 by Riker Laboratories, now a subsidiary of  3M Healthcare . [ 7 ]   At that time, MDIs represented a convergence of two relatively new technologies, the  CFC  propellant and the Meshburg metering valve, originally designed for dispensing perfume. [ 8 ]  The initial design by Riker used a glass canister coated with vinyl plastic to improve its resilience. [ 7 ]   By 1956, Riker had developed two MDI-based products, the Medihaler-Ept containing  epinephrine  and the Medihaler-Iso containing  Isoprenaline . [ 2 ]   Both products are  agonists  that provide short-term relief from asthma symptoms and have now largely been replaced in asthma treatment by  salbutamol , which is more selective."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8281", "text": "Metered-dose inhalers are sometimes used with add-on devices referred to as holding chambers or spacers, tubes attached to the inhaler that act as a reservoir or holding chamber and reduce the speed at which the aerosol enters the mouth. They serve to hold the medication that is sprayed by the inhaler. This makes it easier to use the inhaler and helps ensure that more of the medication gets into the lungs instead of just into the mouth or the air. Proper use of a spacer can make an inhaler more effective in delivering medicine. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8282", "text": "Spacers can be especially helpful to adults and children who find a regular metered dose inhaler hard to use. People who use corticosteroid inhalers should use a spacer to prevent getting the medicine in their mouth, where  oral yeast infections  and  dysphonia  can occur. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8283", "text": "The deposition of the content of drug formulation on the canister surface can result in a shorter shelf life of an MDI  inhaler . Applying a suitable surface coating to the components helps to extend this shelf life. Over the years, various coating processes have been developed that can be applied to both the canister and valve to protect the contents from deposition and degradation.\nGas plasma processing is an industrial technique carried out in a vacuum to coat the entire MDI  inhaler . It involves constant or pulsed gas excitation by radio frequency (RF) or the microwave field to produce an energetic plasma. This coating ensures that the drug formulation does not stick to the interior wall of the MD  inhaler  and results in the patient receiving the prescribed dose of medication, extending the product's shelf-life."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8284", "text": "A metered dose inhaler contains enough medication for a certain number of actuations (or \"puffs\") printed on the canister.  Even though the inhaler may continue to work beyond that number of uses, the amount of medication delivered may not be correct. It is important to keep track of the number of times an inhaler is used so that it can be replaced after its recommended number of uses. For this reason, several regulatory authorities have requested that manufacturers add a dose counter or dose indicator to the actuator. Several inhalation products are now sold with a dose counter-actuator. Depending on the manufacturer and the product, inhalers are sold as a complete unit or the individual canister as a refill prescription."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8285", "text": "While MDIs are commonly used in the treatment of lung-based disorders, their use requires dexterity to complete the required sequential steps to achieve the application of these devices. Incorrect completion of one or more steps in using an MDI can substantially reduce the delivery of the administered medication and, consequently, its effectiveness and safety. Numerous studies have demonstrated that between 50-100% of patients do not use their inhaler devices correctly, with patients often unaware that they are using their inhaled medication incorrectly. [ 11 ] [ 12 ]  Incorrect inhaler technique has been associated with poorer outcomes. [ 12 ] [ 13 ]  Incorrect maintenance and cleaning of metered dose inhalers is also an issue identified by many users, highlighting the need for clear guidance for patients prescribed MDIs. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8286", "text": "One of the most crucial components of an MDI is its propellant. The propellant provides the force to generate the aerosol cloud and is also the medium where the active component must be suspended or dissolved. Propellants in MDIs typically make up more than 99% of the delivered dose, [ 16 ]  so the properties of the propellant dominate more than any other individual factor.  This is often overlooked in literature and in industry because so few propellants are used, and their contribution is often taken for granted.  Suitable propellants must pass a stringent set of criteria, and they must:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8287", "text": "In the early days of MDIs, the most commonly used propellants were the  chlorofluorocarbons   CFC-11 ,  CFC-12  and  CFC-114 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8288", "text": "In 2008, the  Food and Drug Administration  announced that inhalers using  chlorofluorocarbons  as a propellant, such as  Primatene Mist , could no longer be manufactured or sold as of 2012. [ 19 ]  This followed from U.S. decision to agree to the 1987  Montreal Protocol  on Substances that deplete the ozone layer. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8289", "text": "Hydrofluorocarbon  propellants have replaced CFC propellants. [ 21 ]  Concerns about the use of  hydrofluorocarbon  propellants have, however, since arisen since these compounds are potent  greenhouse gases ; propellants released during the use of a single inhaler result in a greenhouse footprint equivalent to greenhouse gases released during a 180-mile car journey. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8290", "text": "Phospholipids  are important natural  surfactant  lipids. [ 23 ]  used to enhance penetration and bioavailability. [ 24 ]  Phospholipids reduce the high  surface tension  forces at the air-water interface within the  alveoli , thereby reducing the pressure needed to expand the lungs. Thus, commercially available formulations of phospholipids have been designed to spread rapidly over an air-aqueous interface, thereby reducing what is otherwise a very high surface tension of water."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8291", "text": "For ease of identification, many MDI's are colour-coded"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8292", "text": "Microbial drug delivery  is an emerging form of drug administration characterized by the use of  commensal   microbes  that have been  genetically modified  to produce medications for  chronic diseases  in  humans . [ 1 ] [ 2 ] [ 3 ]  Only proteinaceous  drugs  can be produced by microbes, as  DNA  encodes for  protein . Research into microbial drug delivery refers to this  route of administration  as  topical , since the microbes release the drug directly to the surface of affected  tissues , namely the  gastrointestinal (GI) epithelium . [ 1 ] [ 2 ]  Microbial drug delivery is not currently used as a standard route of drug administration due to its experimental nature. During  clinical trials , it has been used to treat forms of  inflammatory bowel disease  (IBD). [ 2 ] [ 3 ]  The most prominently studied vehicles of microbial drug administration are the  bacterial   species ,  Lactococcus lactis  and  Bacteroides ovatus . [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8293", "text": "The usage of  recombinant  microbes (i.e. microorganisms designed to contain DNA from two or more different species) has applications in treating chronic diseases. [ 1 ] [ 2 ] [ 3 ]  In 2006, Braat  et al . implemented microbial drug delivery with  L. lactis  in clinical trials, successfully treating  Crohn's disease  (CD), a form of IBD that causes  inflammation  and  ulceration  in the  intestines . In this study, a recombinant strain of  L. lactis  containing  complementary DNA  (cDNA) for the human  interleukin-10  (IL-10)  gene  was used to treat CD with IL-10, an anti-inflammatory  cytokine . [ 2 ] [ 3 ]  Patients consumed capsules containing the microbe to populate the intestines and received therapeutic doses of IL-10 directly from the recombinant bacteria. [ 3 ]  As this route of administration is experimental, it is currently not available as a standard treatment option."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8294", "text": "In a 2013  animal study  with  B. ovatus  as the vehicle for microbial drug delivery, researcher Zaed Hamady suggested that recombinant strains of  B. ovatus  containing  transforming growth factor-beta  (TGF-\u03b2) and  keratinocyte growth factor -2 (KGF-2) are ready for clinical trials. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8295", "text": "The  L. lactis  mechanism of microbial drug delivery described in the 2006 study of Braat  et al.  uses a form of recombinant  L. lactis  (LL-Thy12) which has replaced the gene, Thy12, with the gene for human IL-10. Removal of Thy12, which encodes for the production of  thymidine , causes  L. lactis  to become dependent on dietary thymidine to maintain live colonies in the gut. [ 2 ] [ 3 ]  The addition of the IL-10 gene allows for the production of human IL-10 to decreases gut inflammation. [ 3 ]   Secretion  of IL-10 from  L. lactis  in the gut is considered to be a topical administration of the drug to the epithelium, permitting healing in local tissues damaged by inflammation. [ 2 ] [ 3 ]  The administration of IL-10 topically avoids  systemic effects , such as  immunosuppression  in non-target tissues. [ 2 ]  When using LL-Thy12, IL-10 secretion is dependent on the quantity of live LL-Thy12 in the GI tract. As the presence of dietary thymidine increases the quantity of LL-Thy12, the drug production increases proportionately. Reductions in dietary thymidine kill LL-Thy12, decreasing the production of IL-10. [ 2 ] [ 3 ]  There is a delay of approximately 72-hours between a change in thymidine dosage and the production of IL-10. [ 1 ]  Due to LL-Thy12\u2019s dependence on thymidine, they will die upon exiting the body through  defecation . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8296", "text": "B. ovatus  has been used in animal studies as a mode of microbial drug delivery due to its  xylanase   operon . [ 1 ]  Operons exist in bacteria to control  gene expression  and are composed of a DNA sequence containing an  operator  followed by the genes of interest. The operator in the xylanase operon prevents  transcription  of genes when bound to a  repressor protein . The  B. ovatus  xylanase operon only functions in the presence of the starch,  xylan , which removes the repressor and enables production of whichever proteins correlate with the genes located after the operator. [ 1 ]  For microbial drug delivery, the genes after the operator include those inserted as part of the genetic modification.  Xylan is non- digestible  to human  gastric acid  or  digestive enzymes , so a predictable quantity of dietary xylan will reach the recombinant  B. ovatus  in the gut, hypothetically allowing for a precise quantity of drug to be produced by the recombinant  B. ovatus . [ 1 ]  In  mice , recombinant  B. ovatus  strains containing genes for  growth factors  TGF-\u03b2 and KGF-2 within the xylanase operon have successfully treated  ulcerative colitis  (UC). [ 1 ]  The secreted drugs from  B. ovatus  are applied topically to the epithelial lining, affecting local tissues rather than acting systemically. Systemic administration of these growth factors could otherwise cause  tumors  and increased  vascularization  of tissues. [ 1 ]  When administered microbially, TGF-\u03b2 and KGF-2 facilitate tissue repair only in the colon where they are released. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8297", "text": "Safety is a major factor in the efficacy of microbial drug delivery. Depending on the type of drug being administered, a certain level of control is required for effective and safe treatment of colonic diseases. [ 1 ]  The  L. lactis  system has a 72-hour delay between ingesting thymidine and activating IL-10 production, while the  B. ovatus  system allows the drug to be produced once xylan reaches the bacteria. [ 1 ]  Regarding IL-10 secretions in  L. lactis , the delay is acceptable for treatment of IBD, [ 1 ] [ 2 ] [ 3 ]  however any drug that requires a precise dosage and timing may necessitate  B. ovatus  for controlling drug output. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8298", "text": "The safety of microbial drug delivery is tied to the microbes\u2019 commensal capability and instance of  pathogenesis . A highly pathogenic microbe would not be suitable for medical treatment due to an inherent  infection  risk.  L. lactis  is considered by the  Food and Drug Administration  (FDA) to be  generally recognized as safe  (GRAS), [ 4 ]  as it is commonly found in widely consumed  dairy  products, suggesting its safety in medical treatment. [ 2 ] [ 3 ]   B. ovatus  is naturally found in 10% of healthy human  colons , [ 5 ]  demonstrating safety in its compatibility with the human gut microbiota; [ 1 ]  however,  Bacteroides  species are known in some cases to cause infections, typically resulting from  surgery in the GI tract . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8299", "text": "Concerns regarding the containment of recombinant microbes in the gut have been addressed through safety mechanisms in both  L. lactis  and  B. ovatus . [ 1 ] [ 2 ] [ 3 ]  Containment refers to the inability of microbes to colonize the external environment, where they may have unknown consequences. LL-Thy12 will die upon removal from the body, as they depend on dietary thymidine for survival. [ 2 ] [ 3 ]   B. ovatus  is naturally an  obligate anaerobe , so any recombinant strain is expected to die in the presence of oxygen once removed from the body. [ 1 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8300", "text": "Microneedles (MNs) are medical tools used for microneedling, primarily in drug delivery, disease diagnosis, and collagen induction therapy. Known for their minimally invasive and precise nature, MNs consist of arrays of micro-sized needles ranging from 25\u03bcm to 2000\u03bcm. Although the concept of microneedling was first introduced in the 1970s, its popularity has surged due to its effectiveness in drug delivery and its cosmetic benefits."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8301", "text": "Since the 2000s, there has been discoveries on new fabrication materials of MNs, like silicon, metal and polymer. Alongside with materials, a variety of MNs types (solid, hollow, coated, hydrogel) has also been developed to possess different functions. The research on MNs has led to improvements in different aspects, including instruments and techniques, yet adverse events are possible in MNs users."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8302", "text": "Microneedle patches  or  Microarray patches  are micron-scaled medical devices used to administer  vaccines , drugs, and other therapeutic agents. [ 2 ]  While  microneedles  were initially explored for  transdermal  drug delivery applications, their use has been extended for the intraocular, vaginal, transungual, cardiac, vascular, gastrointestinal, and intracochlear delivery of drugs. [ 3 ] [ 4 ] [ 5 ]  Microneedles are constructed through various methods, usually involving  photolithographic  processes or micromolding. [ 6 ]  These methods involve  etching  microscopic structure into resin or silicon in order to cast microneedles. Microneedles are made from a variety of material ranging from  silicon ,  titanium ,  stainless steel , and  polymers . [ 7 ] [ 1 ]  Some  microneedles  are made of a drug to be delivered to the body but are shaped into a needle so they will penetrate the skin. The microneedles range in size, shape, and function but are all used as an alternative to other delivery methods like the conventional  hypodermic needle  or other  injection  apparatus. Stimuli-responsive microneedles are advanced devices that respond to environmental triggers such as temperature, pH, or light to release therapeutic agents. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8303", "text": "Microneedles are usually applied through even single needle or small arrays. The arrays used are a collection of microneedles, ranging from only a few microneedles to several hundred, attached to an applicator, sometimes a patch or other solid stamping device. The arrays are applied to the skin of patients and are given time to allow for the effective administration of drugs. Microneedles are an easier method for physicians as they require less training to apply and because they are not as hazardous as other needles, making the administration of drugs to patients safer and less painful while also avoiding some of the drawbacks of using other forms of  drug delivery , such as risk of infection, production of hazardous waste, or cost. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8304", "text": "The concept of microneedles was first derived from the use of large hypodermic needles in the 1970s, [ 10 ]  but it only became prominent in the 1990s as microfabrication manufacturing technology developed. [ 10 ]  Later, the concept of MNs finally came into experimentation in 1994 when  Orentreich  discovered the insertion of tri-beveled needles to the skin could possibly stimulates the release of  fibrous strand. [ 10 ] [ 11 ]   The investigation on MNs\u2019 potential to improve transdermal drug delivery gradually raised public awareness of MNs. [ 10 ]  Since then, there has been massive research conducted on MNs, contributing to the development of different materials, types, and fabrication methods of MNs. Application and adverse events are explored. [ 12 ]  In the 2000s, clinical trials on MNs\u2019 use in drug delivery began. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8305", "text": "Microneedles were first mentioned in a 1998 paper by the research group headed by  Mark Prausnitz  at the  Georgia Institute of Technology  that demonstrated that microneedles could penetrate the uppermost layer ( stratum corneum ) of the  human skin  and were therefore suitable for the  transdermal delivery  of therapeutic agents. [ 13 ]  Subsequent research into microneedle drug delivery has explored the medical and cosmetic applications of this technology through its design. This early paper sought to explore the possibility of using microneedles in the future for vaccination. Since then researchers have studied microneedle delivery of  insulin ,  vaccines ,  anti-inflammatories , and other pharmaceuticals. In dermatology, microneedles are used for scarring treatment with skin rollers. As mentioned before, microneedles have also been explored for local targeted drug delivery at other  drug delivery  sites, such as the gastrointestinal, ocular, vascular etc., of which, ocular, vaginal and gastrointestinal have shown increasingnly convincing outcomes where they serve as a more efficient, localised drug delivery system, without the drawbacks of systemic exposure/toxicity. [ 14 ] [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8306", "text": "The major goal of any microneedle design is to penetrate the skin's outermost layer, the  stratum corneum  (10-15\u03bcm). [ 17 ]  Microneedles are long enough to cross the stratum corneum but not so long that they stimulate nerves which are located deeper in the tissues and therefore cause little to no pain. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8307", "text": "Research has shown that there is a limit on the type of drugs that can be delivered through intact skin. Only compounds with a relatively low molecular weight, like the common allergen nickel (130  Da ), [ 18 ]  can penetrate the skin. Compounds that weigh more than 500 Da cannot penetrate the skin. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8308", "text": "Microneedles (MNs) consist of micro-sized needles arrays that are made of various materials exhibiting different characteristics and are suitable in the synthesis of different types of MNs. The selection of materials for formation of MNs greatly depends on the strength of skin penetration, manufacturing method, and rate of drug release. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8309", "text": "Silicon  is the first material used for the production of MNs. [ 12 ]  While the flexible nature of silicon allows easy manufacture of different sizes and types of MNs, silicon MNs can easily fracture during insertion in the skin. [ 19 ]  On the contrary, MNs made of metals like  stainless steel ,  titanium , and  aluminum , are non-toxic and possess strong mechanical properties to penetrate the skin without breakage. [ 12 ] [ 19 ]  Nevertheless, metal MNs may cause allergic effects in some patients and it creates non-biodegradable wastes. [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8310", "text": "Polymer  is also regarded as a promising material for MNs due to its good  biocompatibility  and low toxicity. [ 12 ] [ 19 ]  Water-soluble polymers are more commonly used within the big polymer group and MNs tip breaking is more likely compared to MNs made of silicon and metal. [ 12 ] [ 19 ]  Therefore, polymer is a more suitable material for dissolving MNs or hydrogel-forming MNs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8311", "text": "Since their conceptualization in 1998, several advances have been made in terms of the variety of types of microneedles that can be fabricated. The 5 main types of microneedles are solid, hollow, coated, dissolvable/dissolving, and  hydrogel -forming. [ 2 ]  The distinct characteristic of each type of MNs allow a variety of clinical applications, including diagnosis and treatment. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8312", "text": "Micro-sized needles in a microneedles (MNs) device can be as short as 25\u03bcm or even 2000\u03bcm in length depending on their types. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8313", "text": "Solid MNs are the first type of MNs fabricated and are the most commonly used. [ 21 ]  Hard solid MNs have sharp tips that pierce through and form pores on the  stratum corneum . [ 12 ] [ 21 ]  A drug patch will then be applied to the skin for drug to be absorbed slowly and passively through numerous micropores. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8314", "text": "This type of array is designed as a two part system; the microneedle array is first applied to the skin to create microscopic wells just deep enough to penetrate the outermost layer of skin, and then the drug is applied via  transdermal patch . Solid microneedles are already used by dermatologists in  collagen induction therapy , a method which uses repeated puncturing of the skin with microneedles to induce the  expression  and deposition of the  proteins   collagen  and  elastin  in the  skin . [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8315", "text": "Solid MNs help increase the permeability and absorption of drugs. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8316", "text": "Hollow MNs are designed with a hole at the tip and a hollow capacity that store drugs. [ 21 ]  Upon MNs insertion, stored drug is directly injected into the  dermis  and this effectively facilitates the absorption of either large-molecular or large-dosage drug. [ 12 ] [ 21 ]  Yet, a portion of the drug can be leaked or clogged and it may hinders the overall drug administration. [ 12 ]  Since the delivery of the drug depends on the flow rate of the microneedle, this type of array could become clogged by excessive swelling or flawed design. [ 17 ]  This design also increases the likelihood of buckling under the pressure and therefore failing to deliver any drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8317", "text": "Coated MNs are fabricated by coating drug solution over solid MNs and the thickness of the drug layer can be adjusted depending on the amount of drug to be administered. [ 12 ] [ 23 ]  A benefit of coated MNs is that less amount of drug is needed as compared to other drug administration route. [ 12 ] [ 21 ] [ 23 ]  This is because the layer of drug will quickly dissolve and delivered into the  systemic circulation  directly across the skin. [ 21 ] [ 23 ]  The solid MNs which are removed afterwards may be contaminated by left-over drugs and the reuse of those MNs raise the concern of  cross-infection  between patients. [ 12 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8318", "text": "Coated microneedles are often covered in other  surfactants  or thickening agents to assure that the drug is delivered properly. [ 17 ]  Some of the chemicals used on coated microneedles are known irritants. While there is risk of local inflammation to the area where the array was, the array can be removed immediately with no harm to the patient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8319", "text": "Dissolving MNs are mostly composed of water-soluble drugs that enable the dissolution of MN tips when inserted into skin. [ 12 ] [ 23 ] [ 1 ]  This is a one-step approach which does not require the removal of MNs and is convenient for long-term therapy. [ 12 ] [ 21 ]  However, incomplete insertion and delay dissolution is observed with the use of dissolving MNs. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8320", "text": "This polymer would allow the drug to be delivered into the skin and could be broken down once inside the body. Pharmaceutical companies and researchers have begun to study and implement polymers such as  Fibroin , a silk-based protein that can be molded into structures like microneedles and dissolved once in the body. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8321", "text": "The primary material for the fabrication of hydrogel-forming microneedles (HFMs) is  hydrophilic  polymer that encloses drugs. [ 21 ] [ 25 ]  This material draws water from  interstitial fluid  in the stratum corneum and results in  polymer  swelling and release of drug. [ 21 ] [ 25 ]  Besides, the hydrophilic features of HFMs allow readily uptake of interstitial fluid that could be used for disease diagnosis. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8322", "text": "The most abundant transdermal drug administration route currently is via  hypodermic needles ,  transdermal patches , and topical creams. [ 21 ]  However, these routes have limited therapeutic effects because stratum corneum serves as a barrier that reduces the entry of  drug molecules into the systemic circulation and target tissues. [ 21 ]  The invention of MNs have retained the benefits of both hypodermic needles and transdermal patches while minimizing their cons. [ 12 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8323", "text": "Compared to hypodermic needles, MNs provide a pain-free administration. [ 11 ] [ 12 ]  MNs are able to penetrate through the  epidermis , but not any deeper to compress on nerve-ends to produce pain responses. [ 11 ] [ 12 ]  The superficial penetration also lessen the infection risk. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8324", "text": "Compared to transdermal patches, MNs are proven to be effective in producing micropores on the epidermis. The micropores facilitate the absorption of large molecules, like  calcein  and  insulin , by 4 times via  in-vitro  skin models. [ 11 ]  In addition, MNs' direct drug delivery to systemic circulation avoided the first-pass effect in the liver. [ 27 ]  Significantly increasing the drug  bioavailability , and the fast absorption into the systemic circulation also allowed a fast onset of action. Therefore, MNs could benefit diabetes treatment as common oral delivery would lead to a significant loss of insulin from degradation in the liver ( first-pass effect ) and insulin molecules are too large to be absorbed using common transdermal patches. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8325", "text": "Furthermore, the high precision of MNs also allows drug reaching to localized tissues precisely, for instance, intradermal layers for cancer or the eye for ophthalmic disorder. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8326", "text": "MNs are suitable for vaccination with their capability to deliver macromolecules and maintain a slow and sustained release of vaccine agents by using both coated and dissolving MNs. [ 26 ]  In addition, MNs' biodegradability minimizes biohazardous waste, unlike hypodermic needles. [ 12 ] [ 26 ]  The application of MNs in vaccination would benefit people who avoid vaccination due to  trypanophobia  (fear of needles in medical settings). [ 26 ] As of 2024, it has been found to generate an immune response similar to injection of measles and rubella vaccine. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8327", "text": "Disease diagnosis and monitoring of  therapeutic efficacy  is possible by detecting several  biomarkers  in body fluid. However, current tissue fluid extraction methods are pain-inducing, and it may take up to hours or days for samples to be analyzed in medical laboratories. [ 12 ]  MNs could collect body fluid in an almost painless manner, and it could provide immediate diagnosis when combined with a sensor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8328", "text": "MNs allow penetration through the epidermis but not long enough to compress nerves in deeper layers, and thus, they are minimally invasive and almost painless. MNs' precision also allow the extraction of fluid surrounding diseased tissues, which may contain higher concentration of different biomarkers and specific biomarkers that are not present in the systemic circulation. [ 29 ]  These fluids provide more clinically significant and accurate values than those extracted from the systemic circulation, subsequently lowering the chances of underestimation of disease severity, especially for localized diseases. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8329", "text": "Furthermore, MNs are capable of providing (near) real-time diagnosis, and it is easily administrated with simple procedures. [ 30 ]  Thus, MNs are potential candidates for  Point-of-care (PoC) testing  which could be conducted bedside. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8330", "text": "Hollow MNs and hydrogel MNs could be used to diagnose and monitor several diseases including  Cataracts ,  Diabetes ,  Cancer , and  Alzheimer\u2019s disease . [ 12 ] [ 29 ]  For instance, hollow glass MNs and hydrogel MNs could extract skin interstitial fluid for the detection of glucose levels. [ 12 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8331", "text": "In the field of  dermatology , MNs are more commonly known as collagen induction therapy. The therapy induces dermis regeneration via repetitive perforation of the skin using sterilized MNs. [ 31 ]  The repetitive penetration through the stratum corneum forms micropores, and these physical traumas to the skin sequentially stimulate the  wound-healing  cascade and expression of  collagen  and  elastin  in the  dermis . [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8332", "text": "By making use of the human natural regeneration properties, microneedling could be used alone to treat scars, wrinkles, and skin  rejuvenation , or in combination therapy with topical  tretinoin  and  vitamin C  for enhanced effect. [ 11 ] [ 31 ]  Recent research has expanded the possibilities of MNs to treat  pigmentation disorder ,  actinic keratosis , and promote hair growth in patients of  androgenetic alopecia  and  alopecia areata . [ 11 ] [ 31 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8333", "text": "MNs have been diverged into different forms, including Dermapen and Dermarollers. Dermarollers are hand-held rollers equipped with a total of 192 solid steel micro-sized needles arranged into 24 arrays, lengths ranging from 0.5-1.5mm. [ 31 ] [ 33 ]  With the growing popularity of microneedling, MNs have also been commodified into home care Dermarollers, which are similar to medical dermarollers, except that the needles are shorter (0.15mm). [ 33 ]  This is a more budget-friendly device that allows individuals to perform microneedling at home."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8334", "text": "There are many advantages to the use of microneedles, the most prominent being the improved comfort of patients.  Needle phobia  can affect both adults and children, and sometimes can lead to fainting. The benefit of microneedle arrays is that they reduce anxiety that patients have when confronted with a hypodermic needle. In addition to improving psychological and emotional comfort, microneedles have been shown to be substantially less painful than conventional injections. [ 17 ]  Some studies recorded children's views on blood sampling with microneedles and found patients were more willing when prompted with a less painful procedure than traditional sampling with needles. Microneedles are beneficial to physicians as well, since they produce less hazardous waste than needles and are generally easier to use. Microneedles are also less expensive than needles as they require less material and the material used is cheaper than the materials in hypodermic needles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8335", "text": "Microneedles present a new opportunity for home and community-based healthcare. One of the biggest drawbacks of traditional needles is the hazardous waste that they produce, making disposal a serious concern for doctors and hospitals. For patients who require regular administration of medication at home, disposal can become an environmental concern is needles are placed in the trash. Dissolvable or swelling microneedles would provide those who are limited in their ability to seek hospital care with the ability to safely administer drugs in the comfort of their homes, although disposal of solid or hollow microneedles could still pose a  needle-stick  or  blood borne pathogen  infection risk. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8336", "text": "Another benefit of microneedles is their lower rates of  microbial  invasion into delivery sites. [ 1 ] [ 17 ]  Traditional injection methods can leave puncture wounds for up to 48 hours post-treatment. This leaves a large window of opportunity for harmful bacteria to enter into the skin. Microneedles only damage the skin to a depth of 10-15\u03bcm, making it difficult for bacteria to enter the bloodstream and giving the body a smaller wound to repair. [ 6 ]  Further research is required to determine the types of bacteria able to breach the shallow puncture site of microneedles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8337", "text": "There are some concerns about how physicians can be sure that all of the drug or vaccine has entered the skin when microneedles are applied. Hollow and coated microneedles both possess the risk that the drug will not properly enter the skin and will not be effective. Both of these types of microneedles can leak [ 34 ] [ 17 ]  onto a person's skin either by damage of the microneedle or incorrect application by the physician. This is why it is essential that physicians are trained how to properly apply the arrays."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8338", "text": "Another concern is that incorrectly applied arrays could leave foreign material in the body. Although there is a lower risk of infection associated with microneedles, the arrays are more fragile than a typical hypodermic needle due to their small size and thus have a chance of breaking off and remaining in the skin. Some of the material used to construct the microneedles, such as titanium, cannot be absorbed by the body and any fragments of the needles would cause irritation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8339", "text": "There is a limited amount of literature available on the subject of microneedle drug delivery, as current research is still exploring how to make effective needles. In terms of design and manufacture, low drug loading is a key barrier towards reaching the clinics. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8340", "text": "Apart from procedural pain, some common post-treatment  adverse events  (AEs) of MNs include temporary discomfort,  erythema  (skin redness), and  edema . [ 11 ] [ 36 ]  Pinpoint bleeding, itching, irritation, and bruising are also possible in some cases. [ 11 ] [ 36 ]  However, most of the adverse side effects are not long-lasting and could be resolved spontaneously within 24 hours after the treatment, making MNs a rather safe tool. [ 36 ] [ 37 ]  Photoprotection and minimal exposure to chemicals irritants  are often advised for an effective recovery and lowered chance of skin inflammation. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8341", "text": "Severe risks may be possible if there are technical errors during the procedure. For example, the usage of non-sterile tools might result in post-inflammatory  hyperpigmentation , systemic  hypersensitivity , local infections, etc. [ 11 ]  Moreover, if excess pressure is used over a bony prominence, it could lead to \u201cTram-track scarring\u201d. [ 36 ]  But this could be avoided by using smaller needles and prevent over-pressurizing on top of these areas. [ 36 ]  In addition, if the patient is allergic to the either the drug used or the material of MNs,  contact dermatitis  is possible. [ 11 ]  Therefore, clinicians should be cautious towards patients with high risks of allergy. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8342", "text": "Molecule-based magnets  ( MBMs ) or  molecular magnets  are a class of materials capable of displaying  ferromagnetism  and other more complex magnetic phenomena. This class expands the materials properties typically associated with magnets to include low density,  transparency ,  electrical insulation , and low-temperature fabrication, as well as combine magnetic ordering with other properties such as  photoresponsiveness . Essentially all of the common magnetic phenomena associated with conventional transition-metal magnets and  rare-earth magnets  can be found in molecule-based magnets. [ 1 ] [ 2 ]  Prior to 2011, MBMs were seen to exhibit \"magnetic ordering with  Curie temperature  (T c ) exceeding room temperature\". [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8343", "text": "The first synthesis and characterization of MBMs was accomplished by Wickman and co-workers in 1967. This was a diethyldithiocarbamate-Fe(III) chloride compound. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8344", "text": "In February 1992, Gatteschi and  Sessoli  published on MBMs with particular attention to the fabrication of systems in which stable  organic radicals  are coupled to  metal ions . [ 6 ]  At that date, the highest Tc on record was measured by  SQUID magnetometer  as 30K. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8345", "text": "The field exploded in 1996 with the publication of the book \"Molecular Magnetism: From Molecular Assemblies to the Devices\". [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8346", "text": "In February 2007, de Jong et al. grew thin-film  TCNE  MBM in situ, [ 9 ]  while in September 2007, photoinduced magnetism was demonstrated in a TCNE organic-based magnetic semiconductor. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8347", "text": "The June 2011 issue of  Chemical Society Reviews  was devoted to MBMs. In the editorial, written by Miller and Gatteschi, are mentioned  TCNE  and above-room-temperature magnetic ordering along with many other unusual properties of MBMs. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8348", "text": "The mechanism by which molecule-based magnets stabilize and display a net magnetic moment is different than that present in traditional metal- and ceramic-based magnets. For metallic magnets, the unpaired electrons align through  quantum mechanical  effects (termed exchange) by virtue of the way in which the electrons fill the orbitals of the  conductive band . For most oxide-based ceramic magnets, the unpaired electrons on the metal centers align via the intervening  diamagnetic  bridging oxide (termed  superexchange ). The magnetic moment in molecule-based magnets is typically stabilized by one or more of three main mechanisms: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8349", "text": "In general, molecule-based magnets tend to be of low dimensionality. Classic magnetic alloys based on iron and other ferromagnetic materials feature  metallic bonding , with all atoms essentially bonded to all nearest neighbors in the  crystal lattice . Thus, critical temperatures at which point these classical magnets cross over to the ordered magnetic state tend to be high, since interactions between spin centers is strong. Molecule-based magnets, however, have spin bearing units on molecular entities, often with highly directional bonding. In some cases, chemical bonding is restricted to one dimension (chains). Thus, interactions between spin centers are also limited to one dimension, and ordering temperatures are much lower than metal/alloy-type magnets. Also, large parts of the magnetic material are essentially diamagnetic, and contribute nothing to the net magnetic moment. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8350", "text": "In 2015  oxo-dimeric   Fe(salen) -based magnets (\"anticancer nanomagnets\") in a water suspension were shown to demonstrate intrinsic room temperature ferromagnetic behavior, as well as antitumor activity, with possible medical applications in  chemotherapy , [ 11 ] [ 12 ] [ 13 ] [ 14 ]   magnetic drug delivery ,  magnetic resonance imaging  (MRI), and magnetic field-induced local  hyperthermia therapy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8351", "text": "Molecule-based magnets comprise a class of materials which differ from conventional magnets in one of several ways. Most traditional magnetic materials are comprised purely of metals (Fe, Co, Ni) or metal oxides (CrO 2 ) in which the unpaired electrons spins that contribute to the net  magnetic moment  reside only on metal atoms in d- or f-type orbitals. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8352", "text": "In molecule-based magnets, the structural building blocks are molecular in nature. These building blocks are either purely  organic molecules ,  coordination compounds  or a combination of both. In this case, the unpaired electrons may reside in d or f orbitals on isolated metal atoms, but may also reside in highly localized s and p orbitals as well on the purely organic species. Like conventional magnets, they may be classified as hard or soft, depending on the magnitude of the  coercive field . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8353", "text": "Another distinguishing feature is that molecule-based magnets are prepared via low-temperature solution-based techniques, versus high-temperature metallurgical processing or electroplating (in the case of  magnetic thin films ). This enables a chemical tailoring of the molecular building blocks to tune the magnetic properties. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8354", "text": "Specific materials include purely organic magnets made of organic radicals for example p-nitrophenyl nitronyl nitroxides, [ 15 ]  decamethylferrocenium tetracyanoethenide, [ 16 ]  mixed coordination compounds with bridging organic radicals, [ 17 ]   Prussian blue  related compounds, [ 18 ]  and  charge-transfer complexes . [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8355", "text": "Molecule-based magnets derive their net moment from the cooperative effect of the spin-bearing molecular entities, and can display bulk  ferromagnetic  and  ferrimagnetic  behavior with a true  critical temperature . In this regard, they are contrasted with  single-molecule magnets , which are essentially superparamagnets (displaying a blocking temperature versus a true critical temperature). This  critical temperature  represents the point at which the materials switches from a simple paramagnet to a bulk magnet, and can be detected by ac susceptibility and  specific heat  measurements. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8356", "text": "Mouthwash ,  mouth rinse ,  oral rinse , or  mouth bath [ 1 ]  is a liquid which is held in the mouth passively or swirled around the mouth by contraction of the perioral muscles and/or movement of the head, and may be  gargled , where the head is tilted back and the liquid bubbled at the back of the mouth."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8357", "text": "Usually mouthwashes are  antiseptic  solutions intended to reduce the microbial load in the mouth, although other mouthwashes might be given for other reasons such as for their  analgesic ,  anti-inflammatory  or  anti-fungal  action. Additionally, some rinses act as saliva substitutes to neutralize acid and keep the mouth moist in  xerostomia  (dry mouth). [ 2 ] [ 3 ]  Cosmetic mouthrinses temporarily control or reduce bad breath and leave the mouth with a pleasant taste. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8358", "text": "Rinsing with water or mouthwash after brushing with a  fluoride toothpaste  can reduce the availability of salivary fluoride. This can lower the anti-cavity re-mineralization and antibacterial effects of fluoride. [ 5 ] [ 6 ] [ 7 ]  Fluoridated mouthwash may mitigate this effect or in high concentrations increase available fluoride, but is not as cost-effective as leaving the fluoride toothpaste on the teeth after brushing. [ 5 ]  A group of experts discussing post brushing rinsing in 2012 found that although there was clear guidance given in many public health advice publications to \"spit, avoid rinsing with water/excessive rinsing with water\" [ 8 ]  they believed there was a limited evidence base for best practice. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8359", "text": "Common use involves rinsing the mouth with about  20\u201350  ml   (0.7\u20131.7\u00a0 US\u00a0fl\u00a0oz )  of mouthwash. The wash is typically swished or gargled for about half a minute and then spat out. Most companies suggest not drinking water immediately after using mouthwash. In some brands, the  expectorate  is stained, so that one can see the bacteria and debris. [ 10 ] [ 11 ] [ 12 ] \nMouthwash should not be used immediately after brushing the teeth so as not to wash away the beneficial fluoride residue left from the toothpaste. Similarly, the mouth should not be rinsed out with water after brushing. Patients were told to \"spit don't rinse\" after toothbrushing as part of a  National Health Service  campaign in the UK. [ 13 ]  A fluoride mouthrinse can be used at a different time of the day to brushing. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8360", "text": "Gargling is where the head is tilted back, allowing the mouthwash to sit in the back of the mouth while exhaling, causing the liquid to bubble. Gargling is practiced in Japan for perceived prevention of viral infection. One commonly used way is with  infusions  or  tea . In some cultures, gargling is usually done in private, typically in a  bathroom  at a sink so the liquid can be rinsed away. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8361", "text": "Serious harm and even death can quickly result from ingestion due to the high alcohol content and other substances harmful to ingestion present in some brands of mouthwash. [ 15 ]  Zero percent alcohol mouthwashes do exist, as well as many other formulations for different needs (covered in the above sections)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8362", "text": "These risks may be higher in toddlers and young children if they are allowed to use toothpaste and/or mouthwash unsupervised, where they may swallow it. Misuse in this way can be avoided with parental admission or supervision and by using child-safe forms or a children's brand of mouthwash."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8363", "text": "Surrogate alcohol  use such as ingestion of mouthwash is a common cause of death among homeless people during winter months, because a person can feel warmer after drinking it. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8364", "text": "The most-commonly-used mouthwashes are commercial antiseptics, which are used at home as part of an  oral hygiene  routine. Mouthwashes combine ingredients to treat a variety of oral conditions. Variations are common, and mouthwash has no standard formulation, so its use and recommendation involves concerns about  patient safety . Some manufacturers of mouthwash state that their antiseptic and antiplaque mouthwashes kill the  bacterial plaque  that causes  cavities ,  gingivitis , and  bad breath . It is, however, generally agreed that the use of mouthwash does not eliminate the need for both  brushing  and  flossing . [ 17 ] [ 18 ] [ 19 ]  The  American Dental Association  asserts that regular brushing and proper flossing are enough in most cases, in addition to regular dental check-ups, although they approve many mouthwashes. [ 20 ] \nFor many patients, however, the mechanical methods could be tedious and time-consuming, and, additionally, some local conditions may render them especially difficult. Chemo\u00adthera\u00adpeutic agents, including mouthwashes, could have a key role as adjuncts to daily home care, preventing and controlling supra\u00adgingival plaque, gingivitis and oral malodor. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8365", "text": "Minor and transient side effects of mouthwashes are very common, such as  taste disturbance , tooth staining,  sensation of a dry mouth , etc. Alcohol-containing mouthwashes may make dry mouth and halitosis worse, as they dry out the mouth. [ 22 ] [ 23 ]  Soreness, ulceration and redness may sometimes occur (e.g.,  aphthous stomatitis  or  allergic contact stomatitis ) if the person is allergic or sensitive to mouthwash ingredients, such as preservatives, coloring, flavors and fragrances. Such effects might be reduced or eliminated by diluting the mouthwash with water, using a different mouthwash (e.g. saltwater), or foregoing mouthwash entirely."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8366", "text": "Prescription mouthwashes are used prior to and after oral surgery procedures, such as  tooth extraction , or to treat the pain associated with  mucositis  caused by  radiation therapy  or  chemotherapy . They are also prescribed for  aphthous ulcers , other  oral ulcers , and other mouth pain. [ 24 ]  \"Magic mouthwashes\" are prescription mouthwashes  compounded  in a  pharmacy  from a list of ingredients specified by a doctor. [ 25 ] [ 26 ]  Despite a lack of evidence that prescription mouthwashes are more effective in decreasing the pain of oral  lesions , many patients and prescribers continue to use them. There has been only one  controlled study  to evaluate the  efficacy  of magic mouthwash; it shows no difference in efficacy between the most common magic-mouthwash formulation, on the one hand, and commercial mouthwashes (such as  chlorhexidine ) or a  saline / baking soda  solution, on the other. Current guidelines suggest that saline solution is just as effective as magic mouthwash in pain relief and in shortening the healing time of oral mucositis from cancer therapies. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8367", "text": "The first known references to mouth rinsing is in  Ayurveda [ 27 ]  for treatment of gingivitis. [ 28 ]  Later, in the  Greek  and  Roman  periods, mouth rinsing following mechanical cleansing became common among the upper classes, and  Hippocrates  recommended a mixture of salt,  alum , and vinegar. [ 29 ]  The Jewish  Talmud , dating back about 1,800 years, suggests a cure for gum ailments containing \"dough water\" and olive oil. [ 30 ]  The ancient Chinese had also gargled salt water, tea and wine as a form of mouthwash after meals, due to the antiseptic properties of those liquids. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8368", "text": "Before Europeans came to the Americas, Native North American and Mesoamerican cultures used mouthwashes, often made from plants such as  Coptis trifolia . [ 32 ]  Peoples of the Americas used salt water mouthwashes for sore throats, and other mouthwashes for problems such as  teething  and mouth ulcers. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8369", "text": "Anton van Leeuwenhoek , the famous 17th century  microscopist , discovered living organisms (living, because they were mobile) in deposits on the teeth (what we now call  dental plaque ). He also found organisms in water from the canal next to his home in Delft. He experimented with samples by adding vinegar or brandy and found that this resulted in the immediate immobilization or killing of the organisms suspended in water. Next he tried rinsing the mouth of himself and somebody else with a mouthwash containing vinegar or brandy and found that living organisms remained in the dental plaque. He concluded\u2014correctly\u2014that the mouthwash either did not reach, or was not present long enough, to kill the plaque organisms. [ 33 ] \nIn 1892, German  Richard Seifert  invented mouthwash product  Odol , which was produced by company founder  Karl August Lingner  (1861\u20131916) in  Dresden . [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8370", "text": "That remained the state of affairs until the late 1960s when Harald Loe (at the time a professor at the  Royal Dental College  in  Aarhus , Denmark) demonstrated that a  chlorhexidine  compound could prevent the build-up of dental plaque. The reason for chlorhexidine's effectiveness is that it strongly adheres to surfaces in the mouth and thus remains present in effective concentrations for many hours. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8371", "text": "Since then commercial interest in mouthwashes has been intense and several newer products claim effectiveness in reducing the build-up in dental plaque and the associated severity of gingivitis, in addition to fighting bad breath. Many of these solutions aim to control the volatile sulfur compound\u2013creating anaerobic bacteria that live in the mouth and excrete substances that lead to bad breath and unpleasant mouth taste. [ 11 ] [ 10 ] [ 36 ] [ 37 ] [ 38 ]  For example, the number of mouthwash variants in the United States of America has grown from 15 (1970) to 66 (1998) to 113 (2012). [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8372", "text": "Research in the field of  microbiotas  shows that only a limited set of microbes cause tooth decay, with most of the bacteria in the human mouth being harmless. Focused attention on cavity-causing bacteria such as  Streptococcus mutans  has led research into new mouthwash treatments that prevent these bacteria from initially growing. While current mouthwash treatments must be used with a degree of frequency to prevent this bacteria from regrowing, future treatments could provide a viable long-term solution. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8373", "text": "A clinical trial and laboratory studies have shown that alcohol-containing mouthwash could reduce the growth of  Neisseria gonorrhoeae  in the pharynx. [ 41 ] [ 42 ]  However, subsequent trials have found that there was no difference in gonorrhoea cases among men using daily mouthwash compared to those who did not use mouthwash for 12 weeks. [ 43 ] [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8374", "text": "Alcohol is added to mouthwash not to destroy bacteria but to act as a carrier agent for essential active ingredients such as menthol, eucalyptol and thymol, which help to penetrate plaque. [ 45 ]  Sometimes a significant amount of  alcohol  (up to 27% vol) is added, [ 46 ]  as a carrier for the  flavor , to provide \"bite\". [ 47 ] [ unreliable medical source? ]  Because of the alcohol content, it is possible to fail a  breathalyzer  test after rinsing, although breath alcohol levels return to normal after 10 minutes. [ 48 ]  In addition, alcohol is a  drying agent , which encourages bacterial activity in the mouth, releasing more malodorous volatile sulfur compounds. Therefore, alcohol-containing mouthwash may temporarily worsen  halitosis  in those who already have it, or, indeed, be the sole cause of halitosis in other individuals. [ 49 ]  Alcohol in mouthwashes may act as a  carcinogen  (cancer-inducing agent) in some cases  (see:  Oral cancer \u00a7\u00a0Alcohol ) . [ 50 ]  Many newer brands of mouthwash are alcohol-free, not just in response to consumer concerns about oral cancer, but also to cater for religious groups who abstain from alcohol consumption."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8375", "text": "In painful oral conditions such as  aphthous stomatitis , analgesic mouthrinses (e.g.  benzydamine  mouthwash, or \"Difflam\") are sometimes used to ease pain, commonly used before meals to reduce discomfort while eating."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8376", "text": "Benzoic acid  acts as a buffer. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8377", "text": "Betamethasone  is sometimes used as an anti-inflammatory, corticosteroid mouthwash. It may be used for severe inflammatory conditions of the oral mucosa such as the severe forms of aphthous stomatitis. [ 51 ] :\u200a209"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8378", "text": "Cetylpyridinium chloride  containing mouthwash (e.g. 0.05%) is used in some specialized mouthwashes for halitosis. [ 52 ]  Cetylpyridinium chloride mouthwash has less anti-plaque effect than chlorhexidine and may cause staining of teeth, or sometimes an oral burning sensation or  ulceration . [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8379", "text": "Chlorhexidine digluconate  is a chemical antiseptic and is used in a 0.05\u20130.2% solution as a mouthwash. [ 54 ] [ 11 ] [ 45 ] [ 55 ]  There is no evidence to support that higher concentrations are more effective in controlling dental plaque and gingivitis. [ 56 ]  A randomized clinical trial conducted in Rabat University in  Morocco  found better results in  plaque  inhibition when chlorohexidine with alcohol base 0.12% was used, when compared to an alcohol-free 0.1% chlorhexidine mouthrinse. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8380", "text": "Chlorhexidine has good  substantivity  (the ability of a mouthwash to bind to hard and soft tissues in the mouth). [ 53 ]  It has anti-plaque action, and also some anti-fungal action. [ 53 ]  It is especially effective against Gram-negative  rods . [ 53 ]  The proportion of  Gram-negative  rods increase as  gingivitis  develops, so it is also used to reduce gingivitis. [ 56 ] [ 58 ]  It is sometimes used as an adjunct to prevent dental caries and to treat  periodontal disease , [ 53 ]  although it does not penetrate into periodontal pockets well. [ 59 ]  Chlorhexidine mouthwash alone is unable to prevent plaque, so it is not a substitute for regular toothbrushing and flossing. [ 59 ]  Instead, chlorhexidine mouthwash is more effective when used as an adjunctive treatment with toothbrushing and flossing. [ 56 ]  In the short term, if toothbrushing is impossible due to pain, as may occur in  primary herpetic gingivostomatitis , chlorhexidine mouthwash is used as a temporary substitute for other oral hygiene measures. [ 59 ]  It is not suited for use in  acute necrotizing ulcerative gingivitis , however. [ 59 ]  Rinsing with  chlorhexidine  mouthwash before and after a tooth extraction may reduce the risk of a  dry socket . [ 60 ]  Other uses of chlorhexidine mouthwash include prevention of oral candidiasis in  immunocompromised  persons, [ 59 ]  treatment of  denture-related stomatitis , mucosal ulceration/erosions and  oral mucosal  lesions, general burning sensation [ 56 ]  and many other uses. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8381", "text": "Chlorhexidine mouthwash is known to have minor adverse effects. [ 60 ]  Chlorhexidine binds to  tannins , meaning that prolonged use in persons who consume coffee, tea or red wine is associated with extrinsic staining (i.e. removable staining) of teeth. [ 53 ]  A systematic review of commercial chlorhexidine products with anti-discoloration systems (ADSs) found that the ADSs were able to reduce tooth staining without affecting the beneficial effects of chlorhexidine. [ 61 ]  Chlorhexidine mouthwash can also cause taste disturbance or alteration. [ 56 ]  Chlorhexidine is rarely associated with other issues like overgrowth of enterobacteria in persons with  leukemia , desquamation, irritation, and  stomatitis  of oral mucosa, [ 53 ] [ 60 ]  salivary gland pain and swelling, and hypersensitivity reactions including anaphylaxis. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8382", "text": "Hexetidine [ 45 ]  also has anti-plaque, analgesic, astringent and anti-malodor properties, but is considered an inferior alternative to chlorhexidine. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8383", "text": "In dilute concentrations,  chlorine dioxide  is an ingredient that acts as an antiseptic agent in some mouthwashes. [ 63 ] [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8384", "text": "In traditional  Ayurvedic medicine , the use of oil mouthwashes is called \"Kavala\" (\"oil swishing\") or \"Gandusha\", [ 27 ] [ 65 ]  and this practice has more recently been re-marketed by the  complementary and alternative medicine  industry as \" oil pulling \". [ 27 ]  Its promoters claim it works by \"pulling out\" \"toxins\", which are known as  ama  in Ayurvedic medicine, and thereby reducing  inflammation . [ 66 ]  Ayurvedic literature claims that oil pulling is capable of improving oral and systemic health, including a benefit in conditions such as  headaches ,  migraines ,  diabetes mellitus ,  asthma , [ 27 ]  and  acne , as well as  whitening teeth . [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8385", "text": "Oil pulling has received little study and there is little evidence to support claims made by the technique's advocates. [ 65 ]  When compared with chlorhexidine in one small study, it was found to be less effective at reducing oral bacterial load, [ 68 ] [ 69 ]  and the other health claims of oil pulling have failed scientific verification [ 65 ]  or have not been investigated. [ 65 ]  There is a report of  lipid pneumonia  caused by accidental inhalation of the oil during oil pulling. [ 70 ] [ 71 ] [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8386", "text": "The mouth is rinsed with approximately one tablespoon of oil for 10\u201320 minutes then spat out. [ 65 ] [ 67 ]   Sesame oil ,  coconut oil  and  ghee  are traditionally used, [ 67 ]  but newer oils such as  sunflower oil  are also used. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8387", "text": "Phenolic compounds  and  monoterpenes  include  essential oil  constituents that have some antibacterial properties, [ 45 ] [ 73 ]  such as  eucalyptol , [ 14 ]   eugenol , [ 45 ]   hinokitiol , [ 74 ]   menthol , [ 75 ]   phenol , [ 45 ]  or  thymol . [ 45 ] \n Essential oils  are oils which have been extracted from plants. Mouthwashes based on  essential oils  could be more effective than traditional mouthcare as  anti-gingival  treatments. [ 73 ] [ 76 ]  They have been found effective in  reducing halitosis , and are being used in several commercial mouthwashes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8388", "text": "Anti-cavity mouthwashes contain  fluoride  compounds (such as  sodium fluoride ,  stannous fluoride , or  sodium monofluorophosphate ) to protect against  tooth decay . [ 77 ] [ 78 ]  Fluoride-containing mouthwashes are used as prevention for dental caries for individuals who are considered at higher risk for tooth decay, whether due to xerostomia related to salivary dysfunction or side effects of medication, to not drinking fluoridated water, or to being physically unable to care for their oral needs (brushing and flossing), and as treatment for those with dentinal hypersensitivity, gingival recession/ root exposure."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8389", "text": "Flavoring agents  include sweeteners such as  sorbitol ,  sucralose ,  sodium saccharin , and  xylitol , which stimulate salivary function due to their sweetness and taste and helps restore the mouth to a neutral level of acidity. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8390", "text": "Xylitol rinses double as a bacterial inhibitor, [ 79 ]  and have been used as substitute for alcohol to avoid dryness of mouth associated with alcohol. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8391", "text": "Hydrogen peroxide  can be used as an oxidizing mouthwash (e.g. Peroxyl, 1.5%). [ 59 ] [ 80 ]  It kills anaerobic bacteria, and also has a mechanical cleansing action when it froths as it comes into contact with debris in mouth. [ 59 ]  It is often used in the short term to treat  acute necrotising ulcerative gingivitis . [ 59 ]  Side effects can occur with prolonged use, including  hypertrophy  of the  lingual papillae . [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8392", "text": "Enzymes  and non-enzymatic proteins, such as  lactoperoxidase ,  lysozyme , and  lactoferrin , have been used in mouthwashes (e.g.,  Biotene ) to reduce levels of oral bacteria, and, hence, of the acids produced by these bacteria. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8393", "text": "Oral  lidocaine  is useful for the treatment of  mucositis  symptoms ( inflammation  of  mucous membranes ) induced by radiation or chemotherapy. [ 82 ]  There is evidence that lidocaine anesthetic mouthwash has the potential to be systemically absorbed, when it was tested in patients with oral mucositis who underwent a bone marrow transplant. [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8394", "text": "Methyl salicylate  functions as an antiseptic, antiinflammatory, and analgesic agent, a flavoring, and a fragrance. [ 49 ]  Methyl salicylate has some anti-plaque action, but less than chlorhexidine. [ 53 ]  Methyl salicylate does not stain teeth. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8395", "text": "Nystatin  suspension is an  antifungal  ingredient used for the treatment of  oral candidiasis . [ 84 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8396", "text": "A randomized clinical trial found promising results in controlling and reducing  dentine hypersensitivity  when potassium oxalate mouthwash was used in conjugation with toothbrushing. [ 85 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8397", "text": "A 2005 study found that gargling three times a day with simple water or with a  povidone-iodine  solution was effective in preventing  upper respiratory infection  and decreasing the severity of symptoms if contracted. [ 86 ]  Other sources attribute the benefit to a simple placebo effect. [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8398", "text": "PVP-I in general covers \"a wider virucidal spectrum, covering both enveloped and nonenveloped viruses, than the other commercially available antiseptics\", [ 88 ]  which also includes the novel  SARS-CoV-2  virus. [ 89 ] [ 90 ] [ 91 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8399", "text": "Sanguinarine -containing mouthwashes are marketed as anti-plaque and anti-malodor treatments. [ 53 ]  Sanguinarine is a toxic alkaloid herbal extract, obtained from plants such as  Sanguinaria canadensis  (bloodroot),  Argemone mexicana  (Mexican prickly poppy), and others. [ 53 ]  However, its use is strongly associated with the development of  leukoplakia  (a white patch in the mouth), usually in the buccal sulcus. [ 53 ] [ 92 ]  This type of leukoplakia has been termed \"sanguinaria-associated keratosis\", and more than 80% of people with leukoplakia in the  vestibule of the mouth  have used this substance. Upon stopping contact with the causative substance, the lesions may persist for years. Although this type of leukoplakia may show  dysplasia , the potential for  malignant  transformation is unknown. [ 93 ]  Ironically, elements within the complementary and alternative medicine industry promote the use of sanguinaria as a therapy for cancer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8400", "text": "Sodium bicarbonate  is sometimes combined with salt to make a simple homemade mouthwash, indicated for any of the reasons that a saltwater mouthwash might be used. Pre-mixed mouthwashes of 1% sodium bicarbonate and 1.5% sodium chloride in  aqueous solution  are marketed, although pharmacists will easily be able to produce such a formulation from the base ingredients when required. Sodium bicarbonate mouthwash is sometimes used to remove viscous saliva and to aid visualization of the oral tissues during examination of the mouth. [ 51 ] :\u200a4"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8401", "text": "Saline has a mechanical cleansing action and an antiseptic action, as it is a  hypertonic  solution in relation to bacteria, which undergo  lysis . The heat of the solution produces a therapeutic increase in blood flow ( hyperemia ) [ 59 ]  to the surgical site, promoting healing. [ 1 ]  Hot saltwater mouthwashes also encourage the draining of  pus  from  dental abscesses . [ 94 ]  In contrast, if heat is applied on the side of the face (e.g., hot water bottle) rather than inside the mouth, it may cause a dental abscess to drain extra-orally, which is later associated with an area of  fibrosis  on the face  (see:  Cutaneous sinus of dental origin ) . [ 95 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8402", "text": "Saltwater mouthwashes are also routinely used after oral surgery, to keep food debris out of healing wounds and to prevent infection. Some oral surgeons consider saltwater mouthwashes the mainstay of wound cleanliness after surgery. [ 95 ]  In dental extractions, hot saltwater mouthbaths should start about 24 hours after a dental extraction. [ 95 ]  The term  mouth bath  implies that the liquid is passively held in the mouth, rather than vigorously swilled around (which could dislodge a blood clot). Once the blood clot has stabilized, the mouthwash can be used more vigorously. [ 95 ]  These mouthwashes tend to be advised for use about 6 times per day, especially after meals (to remove food from the socket). [ 95 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8403", "text": "Sodium lauryl sulfate  (SLS) is used as a foaming agent in many oral hygiene products, including many mouthwashes. Some may suggest that it is probably advisable to use mouthwash at least an hour after brushing with toothpaste when the toothpaste contains SLS, since the anionic compounds in the SLS  toothpaste  can deactivate cationic agents present in the mouthwash. [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8404", "text": "Sucralfate  is a mucosal coating agent, composed of an aluminum salt of sulfated  sucrose . [ 97 ]  It is not recommended for use in the prevention of  oral mucositis  in head and neck cancer patients receiving  radiotherapy  or  chemoradiation , due to a lack of efficacy found in a well-designed,  randomized controlled trial . [ 97 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8405", "text": "Tetracycline  is an antibiotic which may sometimes be used as a mouthwash in adults (it causes red staining of teeth in children). It is sometimes use for herpetiforme ulceration (an uncommon type of aphthous stomatitis), but prolonged use may lead to oral candidiasis, as the fungal population of the mouth overgrows in the absence of enough competing bacteria. [ 51 ] :\u200a209\u200a  Similarly, minocycline mouthwashes of 0.5% concentrations can relieve symptoms of  recurrent aphthous stomatitis . [ 98 ]   Erythromycin  is similar. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8406", "text": "A 4.8%  tranexamic acid  solution is sometimes used as an  antifibrinolytic  mouthwash to prevent bleeding during and after oral surgery in persons with  coagulopathies  (clotting disorders) or who are taking  anticoagulants  (blood thinners such as  warfarin ). [ 99 ] :\u200a473"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8407", "text": "Triclosan  is a non-ionic chlorinate bisphenol antiseptic found in some mouthwashes. [ 100 ]  When used in mouthwash (e.g. 0.03%), there is moderate substantivity, broad spectrum anti-bacterial action, some anti-fungal action, and significant anti-plaque effect, especially when combined with a  copolymer  or  zinc citrate . [ 53 ]  Triclosan does not cause staining of the teeth. [ 53 ]  The safety of triclosan has been questioned. [ 101 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8408", "text": "Astringents  like zinc chloride provide a pleasant-tasting sensation and shrink tissues. [ 102 ]   Zinc , when used in combination with other antiseptic agents, can limit the buildup of  tartar . [ 103 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8409", "text": "A  Murphy drip  is a  rectal infusion  apparatus to administer the medical procedure of  proctoclysis , also known as rectoclysis. [ 2 ] [ 3 ]  During the procedure, an end of the Murphy drip is inserted into the  rectum  and large quantities of liquid are infused into the rectum drop by drop. [ 4 ]  Prior to fluids or medicines being given  intravenously , the Murphy drip and  hypodermoclysis  were the prime routes to administer fluids such as for  replacement  when patients could not be fed by mouth. [ 5 ]  American surgeon  John Benjamin Murphy  introduced the drip method of  saline  infusion per rectum in the treatment of  peritonitis . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8410", "text": "The Murphy drip was invented by  Wisconsin  surgeon  John Benjamin Murphy , for the purpose of administering a proctoclysis for  hydration  and replenishment of  electrolytes , via a  sodium  and  calcium chloride  solution. This would be used when administration by mouth was not possible because of the condition of the patient. [ 7 ]  The Murphy drip was described in the April 1909 issue of the  Journal of the American Medical Association . [ 8 ]  By as early as July 1928, the Murphy drip was considered an auxiliary method of injection behind  intravenous therapy  and  subcutaneous injection , the two principal methods of  injection  at that time. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8411", "text": "The Murphy drip can be used for administering drugs by this route and the apparatus is also used in conjunction with a  catheter  for  bladder  irrigation.\nThe term can even be applied to apparatus used to administer fluids intravenously. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8412", "text": "A curious anecdote involving the Murphy drip is related by  Walter Lord  in his book on the  Battle of Midway . On 4 June 1942 Pharmacist's Mate Edwin Miller was stationed on Sand Island (part of the  Midway Atoll ) and was making ready for the expected Japanese attack. Miller prepared undrinkably strong coffee which, he claimed, was to be used in an \"old fashioned\" treatment for  shock  \u2013 administration of  strong coffee through the rectum  via a Murphy drip. When the attack got underway, Miller was joined by his commanding officer and doctor in charge, Lieutenant Commander A. E. Ady, who did not appear to know the medical purpose of the coffee and asked for some to be poured. Miller thought that it would be amusing to let his commander drink it, but made the mistake of also drinking some himself. Dr. Ady continued to tell jokes throughout the attack. Miller, however, paid for his practical joke and was sick. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8413", "text": "A description of a Murphy drip set-up is contained in the 1932  Kansas Supreme Court  legal case  Ratliffe v. Wesley Hospital and Nurses' Training School: [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8414", "text": "On February 14, 1929, \"Dr. Horn directed the nurse to use the proctoclysis, known as the \u201cMurphy drip.\u201d While the operation was in progress a student nurse in the employ of the hospital prepared the room for the return of the appellant. The proctoclysis set was a part of the equipment of the hospital and was assembled and placed at or near the foot of the bed by the student nurse. The proctoclysis set consists of a standard which is an iron pole setting on a tripod containing hooks at intervals, and on these hooks by means of a chain, tape, string, or piece of gauze is hung a can containing hot water and soda solution. From this can a tube extends which is inserted in the rectum of the patient to whom the proctoclysis is administered. It was necessary to keep the solution hot in order that it would have a body temperature after dropping through the tube and entering the body. ... It was not unusual for the vessel holding the water to be fastened to the standard by gauze, string, or other bandage, although a part of the vessels were equipped with chains.\" [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8415", "text": "A  nanocell  is a  drug delivery  platform consisting of a polymer-bound chemotherapeutic drug combined with a lipid-bound anti-angiogenesis drug. Nanocells are currently being developed in the lab of Shiladitya Sengupta of  MIT ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8416", "text": "Angiogenesis , or the formation of new  blood vessels , plays a major role in the development of a  tumor .  After a tumor has grown to about the size of a cubic millimeter, its core becomes  hypoxic , and it begins to release growth factors to recruit new blood vessels that will supply it with oxygen.  Inhibiting angiogenesis has been investigated as a means of preventing tumor growth but has not proven to be fully successful, for tumor cells cut off from the blood supply can eventually develop \u201creactive resistance\u201d to hypoxia.  These resistant cancer cells could be killed by  chemotherapeutic  drugs, but once the vasculature to the tumor has been cut off, there is no way for chemotherapy to be delivered.  Nanotechnology offers a way to deliver chemotherapeutic drugs and anti-angiogenic drugs in the same vehicle so that as the blood supply is shut off, chemotherapy is present to prevent any hypoxia-resistant cells from proliferating."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8417", "text": "Labs at MIT are in the process of developing nanocells capable of delivering both types of drugs.  Each nanocell is between 120 and 200 _m in diameter and can be thought of as \u201ca balloon within a balloon.\u201d  Inside each nanocell is a chemotherapeutic drug covalently bound to a polymer, and on the surface of each cell is a lipid coat containing an anti-angiogenic drug.  The technology makes use of the fact that a tumor's blood vessels have pores 600 _m in diameter and are much leakier than normal blood vessels, which have pores only around 50 _m in diameter.  The nanocells circulate in the blood, and because of their size, they leak out of blood vessels only in tumors.  Once there, the nanocells are degraded by enzymes produced by the tumor.  Work remains to be done to win clinical approval for the technology, but results from Sengupta's lab indicate that the nanocells are more effective and less toxic than traditional chemotherapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8418", "text": "Nanoneedles  may be conical or tubular needles in the  nanometre  size range, made from silicon or boron-nitride with a central bore of sufficient size to allow the passage of large molecules, or solid needles useful in  Raman spectroscopy ,  light emitting diodes  (LED) and  laser diodes ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8419", "text": "In 2005 the Research Institute for Cell Engineering at Japan's  National Institute of Advanced Industrial Science and Technology  (AIST) and  Tokyo University of Agriculture and Technology  used nanoneedles controlled by an  atomic force microscope  (AFM) to penetrate the nucleus of living cells and insert molecules of nucleic acid, proteins or possibly to carry out cell surgery. The technique can accurately establish the position of the needle by monitoring the force exerted. Cells to be used for tracking, diagnosing, and treatment of illness may be removed from the body and replaced after being injected. The 100  nm  diameter needles were cut from silicon AFM tips using focused  ion beam etching . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8420", "text": "In 2009, researchers at the  University of Illinois  produced a 50\u00a0nm diameter boron-nitride nanoneedle with a thin coating of gold, suitable for biophysical research. Its diameter allows easy penetration of cell walls in order to deliver organic matter or fluorescent  quantum dots  into the cytoplasm or the nucleus. It may also be used as electrochemical probe or optical  biosensor  in a cellular environment. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8421", "text": "The  University of California, Berkeley  in 2008 produced  gallium arsenide  (GaAs) nanoneedles which emit extremely bright light, though  not yet lasers , when  optically pumped . With a length of 3-4 micrometres, they taper to tips of 2-5\u00a0nm across. In addition to  optoelectronic  devices, the needles will be useful in atomic force microscopy (AFM), and can be easily grown in arrays. Such AFM arrays, besides producing near-atomic resolution images of surfaces, could lead to new forms of data storage by direct manipulation of atoms. The needles may also find a use in tip-enhanced Raman spectroscopy, a process in which molecular energy levels are measured by comparing the frequency of incident light with that of outgoing light. A sharp needle tip allows for a more precise examination of the sample, down perhaps to that of single molecules. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8422", "text": "Research at the department of NanoMedicine and Biomedical Engineering at the  University of Texas  in 2010 created a new type of nanoneedle using silicon. A solution of  hydrogen peroxide  produces porous needles - their porosity is controlled along their length by altering the concentration of peroxide over time. The coloured porous needles are constructed to biodegrade over a predictable period, and have a surface area 120 times that of equivalent solid wires, making them useful as drug-delivery vehicles. Since porous silicon does not harm cells, the needles may also be used to tag cells and monitor chemical reactions. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8423", "text": "A note of caution was sounded by Martin A. Philbert, professor of  toxicology  at the  University of Michigan, Ann Arbor .  \"The ability to manipulate nanometer-scale materials at the molecular level holds the promise of conferring specificity of cellular delivery and the reduction of collateral nuisance injury to neighboring cells. In the context of environmental health, the scientific community will have to pay close attention to those physicochemical properties of engineered nanomaterials that defeat or circumvent normal cellular processes and lend themselves to indiscriminate penetration of biological barriers, tissues, and cellular systems.\"   [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8424", "text": "Nanoparticle drug delivery  systems are engineered technologies that use  nanoparticles  for the targeted delivery and controlled release of therapeutic agents. The modern form of a  drug delivery  system should minimize side-effects and reduce both dosage and dosage frequency. Recently, nanoparticles have aroused attention due to their potential application for effective drug delivery. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8425", "text": "Nanomaterials  exhibit different chemical and physical properties or biological effects compared to larger-scale counterparts that can be beneficial for drug delivery systems. Some important advantages of nanoparticles are their high surface-area-to-volume ratio, chemical and geometric tunability, and their ability to interact with biomolecules to facilitate uptake across the  cell membrane . The large surface area also has a large affinity for drugs and small molecules, like ligands or antibodies, for targeting and controlled release purposes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8426", "text": "Nanoparticles refer to a large family of materials both organic and inorganic. Each material has uniquely tunable properties and thus can be selectively designed for specific applications. Despite the many advantages of nanoparticles, there are also many challenges, including but not exclusive to:  nanotoxicity , biodistribution and accumulation, and the clearance of nanoparticles by human body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8427", "text": "The  National Institute of Biomedical Imaging and Bioengineering  has issued the following prospects for future research in nanoparticle drug delivery systems:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8428", "text": "The development of new drug systems is time-consuming; it takes approximately seven years to complete fundamental research and development before advancing to preclinical animal studies. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8429", "text": "Nanoparticle drug delivery focuses on maximizing drug efficacy and minimizing cytotoxicity. Fine-tuning nanoparticle properties for effective drug delivery involves addressing the following factors. \nThe surface-area-to-volume ratio of nanoparticles can be altered to allow for more ligand binding to the surface. [ 4 ]  Increasing ligand binding efficiency can decrease dosage and minimize nanoparticle toxicity. Minimizing dosage or dosage frequency also lowers the mass of nanoparticle per mass of drug, thus achieving greater efficiency. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8430", "text": "Surface functionalization of nanoparticles is another important design aspect and is often accomplished by  bioconjugation  or passive adsorption of molecules onto the nanoparticle surface. By functionalizing nanoparticle surfaces with ligands that enhance drug binding, suppress immune response, or provide targeting/controlled release capabilities, both a greater efficacy and lower toxicity are achieved. Efficacy is increased as more drug is delivered to the target site, and toxic side effects are lowered by minimizing the total level of drug in the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8431", "text": "The composition of the nanoparticle can be chosen according to the target environment or desired effect. For example,  liposome-based nanoparticles  can be biologically degraded after delivery, [ 6 ]  thus minimizing the risk of accumulation and toxicity after the therapeutic cargo has been released."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8432", "text": "Metal nanoparticles, such as gold nanoparticles, have optical qualities(also described in  nanomaterials ) that allow for less invasive imaging techniques. [ 7 ]  Furthermore, the photothermal response of nanoparticles to optical stimulation can be directly utilized for tumor therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8433", "text": "Current nanoparticle drug delivery systems can be cataloged based on their platform composition into several groups: polymeric nanoparticles, inorganic nanoparticles, viral nanoparticles, lipid-based nanoparticles, and nanoparticle albumin-bound (nab) technology. Each family has its unique characteristics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8434", "text": "Polymeric nanoparticles are synthetic polymers with a size ranging from 10 to 100\u00a0nm. Common synthetic polymeric nanoparticles include polyacrylamide, [ 8 ]  polyacrylate, [ 9 ]  and chitosan. [ 10 ]  Drug molecules can be incorporated either during or after polymerization. Depending on the polymerization chemistry, the drug can be covalently bonded, encapsulated in a hydrophobic core, or conjugated electrostatically. [ 9 ] [ 11 ]  Common synthetic strategies for polymeric nanoparticles include microfluidic approaches, [ 12 ]  electrodropping, [ 13 ]  high pressure homogenization, and emulsion-based interfacial polymerization. [ 14 ] \nPolymer  biodegradability  is an important aspect to consider when choosing the appropriate nanoparticle chemistry. Nanocarriers composed of biodegradable polymers undergo hydrolysis in the body, producing biocompatible small molecules such as lactic acid and glycolic acid. [ 15 ] \nPolymeric nanoparticles can be created via self assembly or other methods such as particle replication in nonwetting templates (PRINT) which allows customization of composition, size, and shape of the nanoparticle using tiny molds. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8435", "text": "Dendrimers  are unique hyper-branched synthetic polymers with monodispersed size, well-defined structure, and a highly functionalized terminal surface. They are typically composed of synthetic or natural amino acid, nucleic acids, and carbohydrates. Therapeutics can be loaded with relative ease onto the interior of the dendrimers or the terminal surface of the branches via electrostatic interaction, hydrophobic interactions, hydrogen bonds, chemical linkages, or covalent conjugation. [ 17 ] [ 18 ] [ 16 ]  Drug-dendrimer conjugation can elongate the half-life of drugs. Currently, dendrimer use in biological systems is limited due to dendrimer toxicity [ 19 ]  and limitations in their synthesis methods. [ 20 ]  Dendrimers are also confined within a narrow size range (<15\u00a0nm) and current synthesis methods are subject to low yield. The surface groups will reach the de Gennes dense packing limit at high generation level, which seals the interior from the bulk solution \u2013 this can be useful for encapsulation of hydrophobic, poorly soluble drug molecules. The seal can be tuned by intramolecular interactions between adjacent surface groups, which can be varied by the condition of the solution, such as pH, polarity, and temperature, a property which can be utilized to tailor encapsulation and controlled release properties. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8436", "text": "Inorganic nanoparticles have emerged as highly valuable functional building blocks for drug delivery systems due to their well-defined and highly tunable properties such as size, shape, and surface functionalization. Inorganic nanoparticles have been largely adopted to biological and medical applications ranging from imaging and diagnoses to drug delivery. [ 22 ]  Inorganic nanoparticles are usually composed of inert metals such as gold and titanium that form nanospheres, however, iron oxide nanoparticles have also become an option."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8437", "text": "Quantum dots  (QDs), or inorganic semiconductor nanocrystals, have also emerged as valuable tools in the field of bionanotechnology because of their unique size-dependent optical properties and versatile surface chemistry. Their diameters (2 - 10\u00a0nm) are on the order of the exciton Bohr radius, resulting in quantum confinement effects analogous to the \" particle-in-a-box \" model. As a result, optical and electronic properties of quantum dots vary with their size: nanocrystals of larger sizes will emit lower energy light upon fluorescence excitation. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8438", "text": "Surface engineering of QDs is crucial for creating nanoparticle\u2013biomolecule hybrids capable of participating in biological processes. Manipulation of nanocrystal core composition, size, and structure changes QD photo-physical properties Designing coating materials which encapsulate the QD core in an organic shell make nanocrystals biocompatible, and QDs can be further decorated with biomolecules to enable more specific interaction with biological targets. The design of inorganic nanocrystal core coupled with biologically compatible organic shell and surface ligands can combine useful properties of both materials, i.e. optical properties of the QDs and biological functions of ligands attached. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8439", "text": "While application of inorganic nanoparticles in bionanotechnology shows encouraging advancements from a materials science perspective, the use of such materials in vivo is limited by issues related with toxicity, biodistribution and  bioaccumulation . Because metal inorganic nanoparticle systems degrade into their constituent metal atoms, challenges may arise from the interactions of these materials with biosystems, and a considerable amount of the particles may remain in the body after treatment, leading to buildup of metal particles potentially resulting in toxicity. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8440", "text": "Recently, however, some studies have shown that certain nanoparticle environmental toxicity effects aren't apparent until nanoparticles undergo transformations to release free metal ions. Under aerobic and anaerobic conditions, it was found that copper, silver, and titanium nanoparticles released low or insignificant levels of metal ions. This is evidence that copper, silver, and titanium NP are slow to release metal ions, and may therefore appear at low levels in the environment. [ 26 ]  Additionally, nanoshell coatings significantly protect against degradation in the cellular environment and also reduce QDs toxicity by reducing metal ion leakage from the core. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8441", "text": "Organic nanocrystals consist of pure drugs and surface active agents required for stabilization. They are defined as carrier-free submicron colloidal drug delivery systems with a mean particle size in the nanometer range. The primary importance of the formulation of drugs into nanocrystals is the increase in particle surface area in contact with the dissolution medium, therefore increasing bioavailability. A number of drug products formulated in this way are on the market. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8442", "text": "One of the issues faced by drug delivery is the solubility of the drug in the body; around \n40% of newly detected chemicals found in drug discovery are poorly soluble in water. [ 28 ]  This low solubility affects the bioavailability of the drug, meaning the rate at which the drug reaches the circulatory system and thus the target site. Low bioavailability is most commonly seen in oral administration, which is the preferred choice for drug administration due to its convenience, low costs, and good patient practice. [ 28 ]  A measure to improve poor bioavailability is to inject the drugs in a solvent mixture with a solubilizing agent. [ 29 ]  However, results show this solution is ineffective, with the solubilizing agent demonstrating side-effects and/or toxicity. \nNanocrystals used for drug delivery can increase saturation solubility and dispersion velocity. Generally, saturation solubility is thought to be a function of temperature, but it is also based on other factors, such as crystalline structure and particle size, in regards to nanocrystals. The Ostwald-Freundlich equation below shows this relationship:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8443", "text": "l \n o \n g \n ( \n \n \n \n C \n \n s \n \n \n \n C \n \n \u03b1 \n \n \n \n \n ) \n = \n \n \n \n 2 \n \u03c3 \n V \n \n \n 2.303 \n R \n T \n \u03c1 \n r \n \n \n \n \n \n {\\displaystyle log({\\frac {C_{s}}{C_{\\alpha }}})={\\frac {2\\sigma V}{2.303RT\\rho r}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8444", "text": "Where  C s  is the saturation solubility of the nanocrystal,  C \ud835\udefc  is the solubility of the drug at a non-nano scale,  \u03c3  is the interfacial tension of the substance,  V  is the molar volume of the particle,  R  is the gas constant,  T  is the absolute temperature,  \ud835\udf0c  is the density of the solid, and  r  is the radius. [ 28 ]  The advantage of nanocrystals is that they can improve oral adsorption, bioavailability, action onset and reduces intersubject variability. \nConsequently, nanocrystals are now being produced and are on the market for a variety of purposes ranging from antidepressants to appetite stimulants. Nanocrystals can be produced using two different ways: the top-down method or the bottom-up method. Bottom-up technologies are also known as nanoprecipitation. This technique involves dissolving a drug in a suitable solvent and then precipitating it with a non-solvent. On the other hand, top-down technologies use force to reduce the size of a particle to nanometers, usually done by milling a drug. Top-down methods are preferred when working with poorly soluble drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8445", "text": "A disadvantage of using nanocrystals for drug delivery is nanocrystal stability. Instability problems of nanocrystalline structures derive from thermodynamic processes such as particle aggregation, amorphization, and bulk crystallization. Particles at the nanoscopic scale feature a relative excess of Gibbs free energy, due to their higher surface area to volume ratio. To reduce this excess energy, it is generally favorable for aggregation to occur. Thus, individual nanocrystals are relatively unstable by themselves and will generally aggregate. This is particularly problematic in top-down production of nanocrystals. Methods such as high-pressure homogenization and bead milling, tend to increase instabilities by increasing surface areas; to compensate, or as a response to high pressure, individual particles may aggregate or turn amorphous in structure. [ 30 ]  Such methods can also lead to the reprecipitation of the drug by surpassing the solubility beyond the saturation point (Ostwald ripening). [ 31 ] \nOne method to overcome aggregation and retain or increase nanocrystal stability is by use of stabilizer molecules. These molecules, which interact with the surface of the nanocrystals and prevent aggregation via ionic repulsion or steric barriers between the individual nanocrystals, include surfactants and are generally useful for stabilizing suspensions of nanocrystals. [ 30 ]  Concentrations of surfactants that are too high, however, may inhibit nanocrystal stability and enhance crystal growth or aggregation. It has been shown that certain surfactants, upon reaching a critical concentration, begin to self-assemble into micelles, which then compete with nanocrystal surfaces for other surfactant molecules. With fewer surface molecules interacting with the nanocrystal surface, crystal growth and aggregation is reported to occur at increased amounts. [ 32 ]  Use of surfactant at optimal concentrations reportedly allows for higher stability, larger drug capacity as a carrier, and sustained drug release. [ 30 ]  In a study using PEG as a stabilizer was found that nanocrystals treated with PEG enhanced accumulation at tumor sites and had greater blood circulation, than those not treated with PEG. [ 33 ] \nAmorphization can occur in top-down methods of production. With different intramolecular arrangements, amorphization of nanocrystals leads to different thermodynamic and kinetic properties that affect drug delivery and kinetics. Transition to amorphous structures is reported to occur through production practices such as spray drying, lyophilization, and mechanical mechanisms, such as milling. [ 30 ]  This amorphization has been reportedly observed with or without the presence of stabilizer in a dry milling process. Using a wet milling process with surfactant, however significantly reduced amorphization, suggesting that solvent, in this case water, and surfactant could inhibit amorphization for some top-down production methods that otherwise reportedly facilitate amorphization. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8446", "text": "Liposomes  are spherical vesicles composed of synthetic or natural phospholipids that self-assemble in aqueous solution in sizes ranging from tens of nanometers to micrometers. [ 16 ]  The resulting vesicle, which has an aqueous core surrounded by a hydrophobic membrane, can be loaded with a wide variety of hydrophobic or hydrophilic molecules for therapeutic purposes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8447", "text": "Liposomes are typically synthesized with naturally occurring phospholipids, mainly  phosphatidylcholine .  Cholesterol  is often included in the formulation to adjust the rigidity of the membrane and to increase stability. The molecular cargo is loaded through liposome formation in aqueous solution, solvent exchange mechanisms, or pH gradients methods. [ 35 ]  Various molecules can also be chemically conjugated to the surface of the liposome to alter recognition properties. One typical modification is conjugating polyethyleneglycol (PEG) to the vesicle surface. The hydrophilic polymer prevents recognition by macrophages and decreases clearance. The size, surface charge, and bilayer fluidity also alter liposome delivery kinetics. [ 36 ] \nLiposomes diffuse from the bloodstream into the interstitial space near the target site. As the cell membrane itself is composed of phospholipids, liposomes can directly fuse with the membrane and release the cargo into the cytosol, or may enter the cell through phagocytosis or other active transport pathways.\nLiposomal delivery has various advantages. Liposomes increase the solubility, stability, and uptake of drug molecules. Peptides, polymers, and other molecules can be conjugated to the surface of a liposome for targeted delivery. Conjugating various ligands can facilitate binding to target cells based on the receptor-ligand interaction. Altering vesicle size and surface chemistry can also be tuned to increase circulation time.\nVarious FDA-approved liposomal drugs are in clinical use in the US. The anthracycline drug doxorubicin is delivered with phospholipid-cholesterol liposomes to treat AIDS-related Kaposi sarcoma and multiple myeloma with high efficacy and low toxicity. [ 37 ]  Many others are undergoing clinical trials, and liposomal drug delivery remains an active field of research today, with potential applications including nucleic acid therapy, brain targeting, and tumor therapy. [ 38 ] [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8448", "text": "Viruses can be used to deliver genes for genetic engineering or gene therapy. Commonly used viruses include adenoviruses, retroviruses, and various bacteriophages. The surface of the viral particle can also be modified with ligands to increase targeting capabilities. While viral vectors can be used to great efficacy, one concern is that may cause off-target effects due to its natural tropism. This usually requires replacing the proteins causing virus-cell interactions with chimeric proteins. [ 40 ] \nIn addition to using viruses, drug molecules can also be encapsulated in protein particles derived from the viral capsid, or virus-like particles (VLPs). VLPs are easier to manufacture than viruses, and their structural uniformity allows VLPs to be produced precisely in large amounts. VLPs also have easy-to-modify surfaces, allowing the possibility for targeted delivery. There are various methods of packaging the molecule into the capsid; most take advantage of the capsid's ability to self-assemble. One strategy is to alter the pH gradient outside the capsid to create pores on the capsid surface and trap the desired molecule. Other methods use aggregators such as leucine zippers or polymer-DNA amphiphiles to induce capsid formation and capture drug molecules. It is also possible to chemically conjugate of drugs directly onto the reactive sites on the capsid surface, often involving the formation of amide bonds. \nAfter being introduced to the organism, VLPs often have broad tissue distribution, rapid clearance, and are generally non-toxic. It may, however, like viruses, invoke an immune response, so immune-masking agents may be necessary. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8449", "text": "Nanoparticle albumin-bound technology utilizes the protein albumin as a carrier for hydrophobic chemotherapy drugs through noncovalent binding. Because albumin is already a natural carrier of hydrophobic particles and is able to transcytose molecules bound to itself, albumin composed nanoparticles have become an effective strategy for the treatment of many diseases in clinical research."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8450", "text": "An ideal drug delivery system should have effective targeting and controlled release. The two main targeting strategies are passive targeting and active targeting. Passive targeting depends on the fact that tumors have abnormally structured blood vessels that favor accumulation of relatively large macromolecules and nanoparticles. This so-called  enhanced permeability and retention effect  (EPR) [ 42 ]  allows the drug-carrier be transported specifically to the tumor cells. Active targeting is, as the name suggests, much more specific and is achieved by taking advantage of receptor-ligand interactions at the surface of the cell membrane. [ 43 ]  Controlled drug release systems can be achieved through several methods. Rate-programmed drug delivery systems are tuned to the diffusivity of active agents across the membrane. [ 44 ]  Another delivery-release mechanism is activation-modulated drug delivery, where the release is triggered by environmental stimuli. The stimuli can be external, such as the introduction of a chemical activators or activation by light or electromagnetic fields, or biological - such as pH, temperature, and osmotic pressure which can vary widely throughout the body. [ 45 ] [ 46 ] [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8451", "text": "For polymeric nanoparticles, the induction of stimuli-responsiveness has usually relied heavily upon well-known polymers that possess an inherent stimuli-responsiveness. Certain polymers that can undergo reversible phase transitions due to changes in temperature or pH have aroused interest. [ 48 ] \nArguably the most utilized polymer for activation-modulated delivery is the thermo-responsive polymer poly(N-isopropylacrylamide). It is readily soluble in water at room temperature but precipitates reversibly from when the temperature is raised above its lower critical solution temperature (LCST), changing from an extended chain conformation to a collapsed chain. [ 49 ]  This feature presents a way to change the hydrophilicity of a polymer via temperature. \nEfforts also focus on dual stimuli-responsive drug delivery systems, which can be harnessed to control the release of the encapsulated drug. For example, the triblock copolymer of poly(ethylene glycol)-b-poly(3-aminopropyl-methacrylamide)-b-poly(N-isopropylacrylamide) (PEG-b-PAPMA-b-PNIPAm) can self-assemble to form micelles, possessing a core\u2013shell\u2013corona architecture above the lower critical solution temperature. It is also pH responsive. Therefore, drug release can be tuned by changing either temperature or pH conditions. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8452", "text": "Drug delivery strategies of inorganic nanoparticles are dependent on material properties. The active targeting of inorganic nanoparticle drug carriers is often achieved by surface functionalization with specific ligands of nanoparticles. For example, the inorganic multifunctional nanovehicle (5-FU/Fe3O4/\u03b1ZrP@CHI-FA-R6G) is able to accomplish tumor optical imaging and therapy simultaneously. [ 51 ]  It can be directed to the location of cancer cells with sustained release behavior. \nStudies have also been done on gold nanoparticle responses to local near-infrared (NIR) light as a stimuli for drug release. In one study, gold nanoparticles functionalized with double-stranded DNA encapsulated with drug molecules, were irradiated with NIR light. The particles generated heat and denatured the double-stranded DNA, which triggered the release of drugs at the target site. [ 52 ] \nStudies also suggest that a porous structure is beneficial to attain a sustained or pulsatile release. Porous inorganic materials demonstrate high mechanical and chemical stability within a range of physiological conditions. [ 53 ]  The well-defined surface properties, such as high pore volume, narrow pore diameter distribution, and high surface area allow the entrapment of drugs, proteins and other biogenic molecules with predictable and reproducible release patterns. [ 54 ] [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8453", "text": "Some of the same properties that make nanoparticles efficient drug carriers also contribute to their toxicity. For example, gold nanoparticles are known to interact with proteins through surface adsorption, forming a  protein corona , which can be utilized for cargo loading and immune shielding. However, this protein-adsorption property can also disrupt normal protein function that is essential for homeostasis, especially when the protein contains exposed sulfur groups. [ 56 ]  The photothermal effect, which can be induced to kill tumor cells, may also create reactive oxygen species that impose oxidative stress on surrounding healthy cells. Gold nanoparticles of sizes below 4-5\u00a0nm fit in DNA grooves which can interfere with transcription, gene regulation, replication, and other processes that rely on DNA-protein binding. Lack of  biodegradability  for some nanoparticle chemistries can lead to accumulation in certain tissues, thus interfering with a wide range of biological processes. [ 57 ]  Currently, there is no regulatory framework in the United States for testing nanoparticles for their general impact on health and on the environment. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8454", "text": "Nasal sprays  are used to deliver medications  locally  in the  nasal cavities  or  systemically . They are used locally for conditions such as  nasal congestion  and  allergic rhinitis . In some situations, the  nasal delivery route  is preferred for systemic therapy because it provides an agreeable alternative to injection or pills. Substances can be assimilated extremely quickly and directly through the nose. [ 1 ] [ unreliable medical source? ]  Many pharmaceutical drugs exist as nasal sprays for systemic administration (e.g.  sedative -analgesics, treatments for  migraine ,  osteoporosis  and  nausea ). Other applications include  hormone replacement therapy , treatment of  Alzheimer's disease  and  Parkinson's disease . Nasal sprays are seen as a more efficient way of transporting drugs with potential use in crossing the blood\u2013brain barrier."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8455", "text": "Antihistamines  work by competing for receptor sites to block the function of histamine, thereby reducing the inflammatory effect. Antihistamine nasal sprays include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8456", "text": "Corticosteroid  nasal sprays can be used to relieve the symptoms of  sinusitis ,  hay fever , allergic rhinitis and non-allergic (perennial) rhinitis. They can reduce inflammation and histamine production in the nasal passages, and have been shown to relieve  nasal congestion ,  runny nose , itchy nose and  sneezing . [ 2 ]  Side effects may include  headaches ,  nausea  and  nose bleeds . [ citation needed ]  Corticosteroid nasal sprays include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8457", "text": "Saline  sprays are typically non medicated. A mist of  saline solution  containing  sodium chloride  is delivered to help moisturize dry or irritated nostrils. This is a form of  nasal irrigation . They can also relieve nasal congestion and remove airborne irritants such as pollen and dust thereby providing sinus allergy relief."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8458", "text": "Three types of nasal sprays preparations of sodium chloride are available including hypertonic (3% sodium chloride or  sea water ), isotonic (0.9% sodium chloride) and hypotonic (0.65% sodium chloride). Isotonic solutions have the same salt concentration as the human body, whereas hypertonic solutions have a higher salt content and hypotonic solutions have a lower salt content. Isotonic saline nasal sprays are commonly used in infants and children to wash out the thick  mucus  from the nose in case of  allergic rhinitis . Hypertonic solutions may be more useful at drawing moisture from the  mucous membrane  and relieving nasal congestion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8459", "text": "Natural nasal sprays that include chemical complexes derived from plant sources such as  ginger ,  capsaicin  and  tea-tree oil  are also available. There is however no trial-verified evidence that they have a measurable effect on symptoms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8460", "text": "Decongestant  nasal sprays are available  over-the-counter  in many countries. They work to very quickly open up nasal passages by constricting blood vessels in the lining of the nose. Prolonged use of these types of sprays can damage the delicate mucous membranes in the nose. This causes increased inflammation, an effect known as  rhinitis medicamentosa  or the  rebound effect . Decongestant nasal sprays are advised for short-term use only, preferably 5 to 7 days at maximum. Some doctors advise to use them 3 days at maximum. A recent clinical trial has shown that a corticosteroid nasal spray may be useful in reversing this condition. [ 3 ]  Topical nasal decongestants include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8461", "text": "Combination use of two medications as nasal spray preparation has been frequently prescribed by doctors. [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8462", "text": "List of some combination nasal sprays:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8463", "text": "In some countries, Dymista is marketed by  Viatris  after Upjohn merged with Mylan to create Viatris. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8464", "text": "In 2022, the combination azelastine/fluticasone was the 299th most commonly prescribed medication in the United States, with more than 300,000 prescriptions. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8465", "text": "A  nasal vaccine  is a  vaccine  administered through the nose that stimulates an immune response without an injection. It induces immunity through the  inner surface of the nose , a surface that naturally comes in contact with many  airborne microbes . [ 1 ]  Nasal vaccines are emerging as an alternative to injectable vaccines because they do not use needles and can be introduced through the mucosal route. Nasal vaccines can be delivered through nasal sprays to prevent respiratory infections, such as  influenza ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8466", "text": "Nasal inoculation dates as far back as the 17th century in China during the  Kangxi Emperor \u2019s reign. Documentation during this period indicates that the Kangxi Emperor vaccinated his family, army, and others for mild smallpox. Manuals detailing vaccination techniques at the time all focused on sending smallpox up the nose of the individual being vaccinated. Although other vaccination techniques were developed using an infected individual\u2019s scabs, a common method was to place a cotton swab with the fluid from an infected person\u2019s pustule up the nose. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8467", "text": "Following smallpox, influenza became a prominent focus for nasal vaccine development. The first  live attenuated influenza vaccine (LAIV)  in the form of a nasal spray was created in Russia by the  Institute of Experimental Medicine  in 1987. This nasal vaccine development was based on the Russian backbone of LAIV while nasal vaccines since then have been based on other LAIV backbones. [ 3 ]  The first nasal influenza vaccine was released in the United States in 2001 but was taken off the market due to toxicity concerns.  FluMist , one of the most prominent nasal LAIVs, was released in 2003 as nasal LAIVs continued developing. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8468", "text": "Anthrax  attacks at the beginning of the 21st century caused a demand for nasal vaccine development. As anthrax is an airborne substance that can be inhaled, a nasal vaccine has the potential to be used to protect individuals from the effects it can have on the respiratory system. [ 5 ]  Following the  September 11, 2001 terrorist attacks  in the United States, several individuals at news stations and U.S. senators died after being sent letters with anthrax as an act of bioterrorism. [ 6 ]  Nasal vaccine research and development against anthrax was encouraged by the U.S. government in an effort to vaccinate troops. [ 5 ] [ 7 ]   BioThrax , the current anthrax vaccine that is licensed and administered in the United States, requires up to five intramuscular injections and annual boosters; research within the past decade has developed an alternative nasal vaccine that follows the path of infection for anthrax and induces both humoral and cellular immune responses. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8469", "text": "The  global COVID-19 pandemic  led to a rise in nasal vaccines against coronavirus. International efforts for vaccine development occurred as countries such as  India ,  Iran ,\u00a0 Russia , and  China  created nasal COVID-19 vaccines. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8470", "text": "Nasal vaccines are a subsection of mucosal immunization as they use a mucosal route for vaccine delivery. As many pathogens can enter the body through the nose, nasal vaccines take advantage of this mechanism to deliver the vaccine. The nose has multiple lines of defense to prevent pathogens from entering further into the body. Nasal hairs are the first defense as they are at the entrance of the nose and prevent large particles from entering. The mucus layer in the nasal cavity can trap smaller particles that get past the nose hairs. [ 8 ]  The nasal cavity has a large vascularization network so particles can go through the epithelial layer and directly enter the bloodstream. [ 9 ]  Intruding particles will interact with the mucosal immune system if they reach the nasal mucosa. The mucosal immune system is composed of lymphoid tissue, B cells, T cells, and antigen-presenting cells. These different types of cells work together to identify intruding particles and trigger an immune response. [ 8 ]  Nasal vaccines must overcome these barriers and get clearance to deliver the viral antigen to patients. [ 4 ]  Nasal vaccines must overcome these barriers and get clearance to deliver the viral antigen to patients. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8471", "text": "Nasal vaccines can come in different forms such as solutions (liquids), powders, gels, and solid inserts. The most prevalent type of nasal vaccine in research and clinical application is solutions due to its ease of use. Although solutions are usually pipetted into test subjects\u2019 nostrils when conducting animal trials for nasal vaccines, nasal sprays are considered the most practical approach for mass human vaccination using nasal vaccines. [ 8 ]  A nasal spray is able to bypass the initial layers of the nasal mucosa and deliver the vaccine particles directly to the mucoadhesive layer. [ 11 ]  The antigen in the nasal vaccine can then trigger an immune response and prevent infection due to nasal vaccines\u2019 accessibility to the immune system. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8472", "text": "Nasal sprays are commonly used for delivering drugs in addition to vaccines. Decongestant drugs are often directly delivered to the nose through nasal sprays. Cold and allergy medication can be administered using nasal sprays for local delivery by bypassing nasal hairs and being introduced to the nasal cavity. Intranasal administration can have less drug degradation compared to oral administration because of direct particle delivery. Peptide drugs used for hormone treatments can be delivered nasally through nasal sprays instead of orally to retain particle integrity. Nasal sprays can also be used to deliver diabetes treatment, steroids, and intranasal oxytocin to induce labor. Nasal administration is also used to deliver anesthetics and sedatives due to direct access to the mucosal immune system and bloodstream. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8473", "text": "The  olfactory epithelium  makes up approximately 7% of the surface area of the nasal cavity and is connected to the olfactory bulb in the brain. Drugs and vaccines can be delivered to the brain past the  blood-brain barrier  through olfactory nerve cells. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8474", "text": "Compared to injectable vaccines, nasal vaccines can be advantageous because they are safe, painless, and easy to use. Nasal vaccines do not require a needle, which eliminates pain from needlestick injuries and safety concerns due to cross-contamination and needle disposal. Some studies also show that intranasal vaccines can generate cross-reactive antibodies that could lead to cross-protection. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8475", "text": "The live attenuated influenza vaccine (LAIV) in the form of a nasal spray was one of the first nasal vaccines released on the market. Nasal spray LAIVs have been used since the late 1980s as an alternative to the injectable influenza vaccine. [ 3 ]  Nasal influenza vaccines have become popular as they reduce the risk of intramuscular injuries from administration and are painless. They can also be given more easily to patients because they do not require a needle."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8476", "text": "The most prominent nasal LAIV is FluMist, which was released in 2003. [ 4 ]  FluMist, officially known as FluMist Quadrivalent in the United States and Fluenz in Europe, is known to be the only flu vaccine on the market that does not use a needle. [ 15 ]  All nasal LAIVs for recent flu seasons (2022-2023) are considered quadrivalents because \u201cthey are designed to protect against four types of flu viruses: an influenza A(H1N1) virus, an influenza A(H3N2) virus and two influenza B viruses.\u201d [ 16 ]  Although injectable and nasal LAIVs are presented as options for yearly vaccination against influenza, FluMist was pulled off of the United States market from 2016 to 2018 due to its inefficiency against a common influenza strain in children. Since then, FluMist has been reformulated and has re-entered the market. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8477", "text": "The active ingredients in nasal LAIVs are grown in fertilized chicken eggs. The practice of growing viruses in chicken eggs is common in vaccine production because these viruses need to be grown inside cells. [ 18 ]  Virus fluid from the incubated chicken eggs is extracted and killed for the viral antigen to be purified for LAIV production. [ 19 ]  Similar to other vaccines, nasal LAIVs contain ingredients in addition to the viral antigen. Stabilizers such as gelatine, arginine hydrochloride, monosodium glutamate, and sucrose are commonly used in vaccines to assure the vaccines are still effective during and after production, transportation, and storage as well as delivery. [ 20 ] [ 21 ]  Stabilizers are especially important for nasal vaccines as proteases and amino-peptidase in the mucosal membrane can degrade proteins and peptides in vaccines. [ 4 ]  Research continues to improve nasal LAIVs as influenza affects nearly 9 million people. [ 22 ]  As influenza changes slightly each year, continuous research on new strains can improve vaccine efficiency. Research on nasal vaccine development for nontypeable  Haemophilus influenzae  shows that the vaccine binding to surface proteins prevented biofilm formation. As a result, this vaccine can have the potential to treat ear infections caused by biofilm from influenza infection. [ 23 ]  New components like \u03b1-galactosylceramide (\u03b1-GalCer) are also being researched to be used as nasal vaccines against influenza. Since \u03b1-GalCer induced immune responses when immunized with a replication-deficient live adenovirus, there is evidence that nasal LAIVs can be co-immunized with other treatments against influenza. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8478", "text": "Prior to the 2020 global COVID-19 pandemic, animal studies in 2004 on African green monkeys tested a SARS-associated coronavirus (SARS-CoV) vaccine and showed that these monkeys did not emit the virus from their upper respiratory tract after being infected. [ 25 ]  Since then, several intranasal COVID-19 vaccines have been developed with the onset of the COVID-19 pandemic.  inCOVACC ,  Razi Cov Pars ,  Sputnik , and  Convidicia  are nasal COVID-19 vaccines that were developed throughout the world to improve vaccine availability and reduce the spread of COVID-19.  [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8479", "text": "In August 2020, during the  COVID-19 pandemic , studies in mice and monkeys demonstrated that protection from the  new coronavirus  might be obtained through the nasal route. Another study postulated that if a  COVID-19 vaccine  could be given by a spray in the nose, people might be able to vaccinate themselves. [ 26 ]  Research about the main characteristics of nasal spray vaccines that can affect the efficiency of vaccine delivery for COVID-19 indicates that the spray cone angle can impact the delivery efficiency; droplet initial velocity and composition did not have as much of an impact on nasal vaccine efficiency as the spray cone angle. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8480", "text": "India and China approved  inCOVACC  and  Convidecia , respectively, to be used as boosters for those who have already received at least two COVID-19 vaccine doses. [ 28 ]  Although nasal COVID-19 vaccine research continues in the United States, lack of government funding could prevent this research from moving on to human trials to get approval for public administration. [ 29 ]  Privately funded research for nasal COVID-19 vaccines is starting to reach clinical trials; a nasal COVID-19 vaccine by Blue Lake Biotechnology has started its Phase 1 clinical trials as of late February 2023. Scientists speculate that nasal vaccines might have an advantage over other types of vaccines because they provide immune defense at the site of administration. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8481", "text": "Species other than humans use nasal vaccines to prevent diseases. Intranasal vaccines are used on dogs for  Bordetella bronchiseptica  to prevent  infectious tracheobronchitis  (ITB). ITB, commonly known as kennel cough, typically spreads in highly populated environments such as kennels and dog shelters. Consistent vaccination against ITB using an intranasal vaccine can create an immune response to protect the vaccinated dog. Consistent vaccination against ITB using an intranasal vaccine can create an immune response to protect the vaccinated dog. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8482", "text": "Cattle receive nasal vaccines against diseases such as  bovine herpesvirus 1 , parainfluenza type 3, and bovine rhinotracheitis virus. [ 32 ] [ 33 ]  As all three of these viruses are related to respiratory infection, using an intranasal route can bring the vaccine directly to the respiratory system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8483", "text": "Recent discoveries indicate that rainbow trout have a previously unknown lymphoid structure in their nasal cavity. This structure allows them to have fast innate and adaptive responses to nasal vaccines. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8484", "text": "Current research is exploring new technologies and developments to improve nasal vaccine delivery methods. Particle size and characteristics have become a focus of research as smaller particles can travel more easily to reach the epithelial layer of the nasal cavity compared to larger particles.  Nanoparticles  and nanosystems are being researched to optimize nasal delivery. Coated nanoparticles are an area of focus due to their properties to induce immune effects. Glycol chitosan-coated nanoparticles induced more of an immune response compared to the other types of nanoparticles. [ 35 ]  Nanocarriers designed based on the characteristics of the nasal epithelium can be used to deliver nasal vaccines and can therefore make nasal vaccination more accessible. [ 36 ]  Polymeric nanosystems are also being developed to deliver vaccines to target sites while preventing them from degrading; current research is focused on understanding the material and physical properties of biodegradable materials to be used in nanosystems to improve vaccine efficacy. [ 37 ]  Research on the movement of nasal vaccine particles is focused on developing more effective ways for these vaccines to enter the body. An animal study on mice tested how a nasal vaccine can bypass issues with entry into the nasal epithelium by taking advantage of ciliary movement. The results indicated that tubulin tyrosine ligase-like family member 1 (Ttll1) knockout mice had higher levels of the vaccine antigen compared to the hetero mice. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8485", "text": "In  medicine , a  nebulizer  ( American English ) [ 1 ]  or  nebuliser  ( British English ) [ 2 ]  is a  drug delivery device  used to administer medication in the form of a mist inhaled into the lungs. Nebulizers are commonly used for the treatment of  asthma ,  cystic fibrosis ,  COPD  and other  respiratory diseases  or disorders. They use  oxygen ,  compressed air  or  ultrasonic  power to break up solutions and suspensions into small  aerosol  droplets that are inhaled from the mouthpiece of the device. An aerosol is a mixture of gas and solid or liquid particles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8486", "text": "Various asthma guidelines, such as the Global Initiative for Asthma Guidelines [GINA], the British Guidelines on the management of Asthma, The Canadian Pediatric Asthma Consensus Guidelines, and United States Guidelines for Diagnosis and Treatment of Asthma each recommend  metered dose inhalers  in place of nebulizer-delivered therapies. [ 3 ] \nThe European Respiratory Society acknowledge that although nebulizers are used in hospitals and at home they suggest much of this use may not be evidence-based. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8487", "text": "Recent evidence shows that nebulizers are no more effective than  metered-dose inhalers  (MDIs) with spacers. [ 5 ]   An MDI with a spacer may offer advantages to children who have acute asthma. [ 3 ] [ 6 ] [ 5 ]  Those findings refer specifically to the treatment of asthma and not to the efficacy of nebulisers generally, as for COPD for example. [ 5 ]  For COPD, especially when assessing exacerbations or lung attacks, there is no evidence to indicate that MDI (with a spacer) delivered medicine is more effective than administration of the same medicine with a nebulizer. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8488", "text": "The  European Respiratory Society  highlighted a risk relating to droplet size reproducibility caused by selling nebulizer devices separately from nebulized solution. They found this practice could vary droplet size 10-fold or more by changing from an inefficient nebulizer system to a highly efficient one. [ 4 ] [ 5 ] \nTwo advantages attributed to nebulizers, compared to MDIs with spacers (inhalers), are their ability to deliver larger dosages at a faster rate, especially in acute asthma; however, recent data suggests actual lung deposition rates are the same. In addition, another trial found that a MDI (with spacer) had a lower required dose for clinical result compared to a nebulizer. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8489", "text": "Beyond use in chronic lung disease, nebulizers may also be used to treat acute issues like the inhalation of toxic substances. One such example is the treatment of inhalation of toxic  hydrofluoric acid  (HF) vapors. [ 8 ]   Calcium gluconate  is a first-line treatment for HF exposure to the skin. By using a nebulizer, calcium gluconate is delivered to the lungs as an aerosol to counteract the toxicity of inhaled HF vapors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8490", "text": "The lung deposition characteristics and efficacy of an aerosol depend largely on the particle or droplet size. Generally, the smaller the particle the greater its chance of peripheral penetration and retention. However, for very fine particles below 0.5\u00a0\u03bcm in diameter there is a chance of avoiding deposition altogether and being exhaled. In 1966 the Task Group on Lung Dynamics, concerned mainly with the hazards of inhalation of environmental toxins, proposed a model for deposition of particles in the lung. This suggested that particles of more than 10\u00a0\u03bcm in diameter are most likely to deposit in the mouth and throat, for those of 5\u201310\u00a0\u03bcm diameter a transition from mouth to airway deposition occurs, and particles smaller than 5\u00a0\u03bcm in diameter deposit more frequently in the lower airways and are appropriate for pharmaceutical aerosols. [ 9 ] \nNebulizing processes have been modeled using  computational fluid dynamics . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8491", "text": "The most commonly used nebulizers are jet nebulizers, which are also called \"atomizers\". [ 11 ]  Jet nebulizers are connected by tubing to a supply of compressed gas, usually  compressed air  or  oxygen  to flow at high velocity through a liquid medicine to turn it into an  aerosol  that is inhaled by the patient. Currently there seems to be a tendency among physicians to prefer prescription of a  pressurized Metered Dose Inhaler  (pMDI) for their patients, instead of a jet nebulizer that generates a lot more noise (often 60\u00a0dB during use) and is less portable due to a greater weight. However, jet nebulizers are commonly used in hospitals for patients who have difficulty using inhalers, such as in serious cases of respiratory disease, or severe asthma attacks. [ 12 ]  The main advantage of the jet nebulizer is related to its low operational cost. If the patient needs to inhale medicine on a daily basis the use of a pMDI can be rather expensive. Today several manufacturers have also managed to lower the weight of the jet nebulizer to just over half a kilogram (just under one and a half pounds), and therefore started to label it as a portable device. Compared to all the competing inhalers and nebulizers, the noise and heavy weight is still the biggest draw back of the jet nebulizer. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8492", "text": "The medical company  Boehringer Ingelheim  also invented a device named  Respimat  Soft Mist Inhaler in 1997. This new technology provides a metered dose to the user, as the liquid bottom of the inhaler is rotated clockwise 180 degrees by hand, adding a buildup tension into a spring around the flexible liquid container. When the user activates the bottom of the inhaler, the energy from the spring is released and imposes pressure on the flexible liquid container, causing liquid to spray out of 2 nozzles, thus forming a soft mist to be inhaled. The device features no gas propellant and no need for battery/power to operate. The average droplet size in the mist was measured to 5.8 micrometers, which could indicate some potential efficiency problems for the inhaled medicine to reach the lungs. Subsequent trials have proven this was not the case. Due to the very low velocity of the mist, the Soft Mist Inhaler in fact has a higher efficiency compared to a conventional pMDI. [ 14 ]  In 2000, arguments were launched towards the European Respiratory Society (ERS) to clarify/expand their definition of a nebulizer, as the new Soft Mist Inhaler in technical terms both could be classified as a \"hand driven nebulizer\" and a \"hand driven pMDI\". [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8493", "text": "Ultrasonic wave nebulizers were invented in 1965 [ 16 ]  as a new type of portable nebulizer. The technology inside an ultrasonic wave nebulizer is to have an  electronic oscillator  generate a high frequency  ultrasonic wave , which causes the mechanical vibration of a  piezoelectric  element. This vibrating element is in contact with a liquid reservoir and its high frequency vibration is sufficient to produce a vapor mist [ 17 ]  via  ultrasonic atomization . As they create aerosols from ultrasonic vibration instead of using a heavy air compressor, they only have a weight around 170 grams (6.0\u00a0oz). Another advantage is that the ultrasonic vibration is almost silent. Examples of these more modern type of nebulizers are:  Omron  NE-U17 and Beurer Nebulizer IH30. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8494", "text": "A new significant innovation was made in the nebulizer market around 2005, with creation of the ultrasonic Vibrating Mesh Technology (VMT). With this technology a mesh/membrane with 1000\u20137000 laser drilled holes vibrates at the top of the liquid reservoir, and thereby pressures out a mist of very fine droplets through the holes. This technology is more efficient than having a vibrating piezoelectric element at the bottom of the liquid reservoir, and thereby shorter treatment times are also achieved. The old problems found with the ultrasonic wave nebulizer, having too much liquid waste and undesired heating of the medical liquid, have also been solved by the new vibrating mesh nebulizers. Available VMT nebulizers include: Pari eFlow, [ 19 ]   Respironics  i-Neb, [ 20 ]  Beurer Nebulizer IH50, [ 21 ]  and Aerogen Aeroneb. [ 22 ]  As the price of the ultrasonic VMT nebulizers is higher than models using previous technologies, most manufacturers continue to also sell the classic jet nebulizers. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8495", "text": "Nebulizers accept their medicine in the form of a liquid solution, which is often loaded into the device upon use.  Corticosteroids  and  bronchodilators  such as  salbutamol  ( albuterol   USAN ) are often used, and sometimes in combination with  ipratropium . The reason these pharmaceuticals are inhaled instead of ingested is in order to target their effect to the  respiratory tract , which speeds onset of action of the medicine and reduces side effects, compared to other alternative intake routes. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8496", "text": "Usually, the aerosolized medicine is inhaled through a tube-like mouthpiece, similar to that of an  inhaler . The mouthpiece, however, is sometimes replaced with a face mask, similar to that used for inhaled  anesthesia , for ease of use with young children or the elderly. Pediatric masks are often shaped like animals such as fish, dogs or dragons to make children less resistant to nebulizer treatments. Many nebulizer manufacturers also offer pacifier attachments for infants and toddlers. But mouthpieces are preferable if patients are able to use them since face-masks result in reduced lung delivery because of aerosol losses in the nose. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8497", "text": "After use with corticosteroid, it is theoretically possible for patients to develop a  yeast infection  in the mouth ( thrush ) or hoarseness of voice ( dysphonia ), although these conditions are clinically very rare. To avoid these adverse effects, some clinicians suggest that the person who used the nebulizer should rinse his or her mouth. This is not true for bronchodilators; however, patients may still wish to rinse their mouths due to the unpleasant taste of some bronchodilating drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8498", "text": "The first \"powered\" or pressurized inhaler was invented in France by Sales-Girons in 1858. [ 24 ]  This device used pressure to atomize the liquid medication. The pump handle is operated like a bicycle pump. When the pump is pulled up, it draws liquid from the reservoir, and upon the force of the user's hand, the liquid is pressurized through an atomizer, to be sprayed out for inhalation near the user's mouth. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8499", "text": "In 1864, the first steam-driven nebulizer was invented in Germany. This inhaler, known as \"Siegle's steam spray inhaler\", used the  Venturi principle  to atomize liquid medication, and this was the very beginning of nebulizer therapy. The importance of droplet size was not yet understood, so the efficacy of this first device was unfortunately mediocre for many of the medical compounds. The Siegle steam spray inhaler consisted of a spirit burner, which boiled water in the reservoir into steam that could then flow across the top and into a tube suspended in the pharmaceutical solution. The passage of steam drew the medicine into the vapor, and the patient inhaled this vapor through a mouthpiece made of glass. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8500", "text": "The first pneumatic nebulizer fed from an electrically driven gas (air) compressor was invented in the 1930s and called a Pneumostat. With this device, a medical liquid (typically  epinephrine chloride , used as a bronchial muscle relaxant to reverse constriction). [ 28 ]  As an alternative to the expensive electrical nebulizer, many people in the 1930s continued to use the much more simple and cheap hand-driven nebulizer, known as the Parke-Davis Glaseptic. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8501", "text": "In 1956, a technology competing against the nebulizer was launched by Riker Laboratories ( 3M ), in the form of pressurized  metered-dose inhalers , with Medihaler-iso ( isoprenaline ) and Medihaler-epi ( epinephrine ) as the two first products. [ 30 ]  In these devices, the drug is cold-fill and delivered in exact doses through some special metering valves, driven by a gas propellant technology (i.e.  Freon  or a less environmentally damaging HFA). [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8502", "text": "In 1964, a new type of electronic nebulizer was introduced: the \"ultrasonic wave nebulizer\". [ 31 ]  Today the nebulizing technology is not only used for medical purposes. Ultrasonic wave nebulizers are also used in  humidifiers , to spray out water aerosols to moisten dry air in buildings. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8503", "text": "Some of the first models of  electronic cigarettes  featured an ultrasonic wave nebulizer (having a  piezoelectric  element vibrating and creating high-frequency  ultrasound  waves, to cause vibration and atomization of liquid  nicotine ) in combination with a  vapouriser  (built as a  spray nozzle  with an electric  heating element ). [ 32 ]  The most common type of electronic cigarettes currently sold, however, omit the ultrasonic wave nebulizer, as it was not found to be efficient enough for this kind of device. Instead, the electronic cigarettes now use an electric vaporizer, either in direct contact with the absorbent material in the \"impregnated atomizer,\" or in combination with the nebulization technology related to a \"spraying jet atomizer\" (in the form of liquid droplets being out-sprayed by a high-speed air stream, that passes through some small venturi injection channels, drilled in a material absorbed with nicotine liquid). [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8504", "text": "An  Ommaya reservoir  is an intraventricular  catheter  system that can be used for the aspiration of  cerebrospinal fluid  or for the delivery of drugs (e.g.  chemotherapy ) into the  cerebrospinal fluid . It consists of a  catheter  in one  lateral ventricle  attached to a reservoir implanted under the scalp. It is used to treat brain tumors, leukemia/lymphoma or  leptomeningeal  disease by  intrathecal  drug administration.   In the  palliative care  of terminal cancer, an Ommaya reservoir can be inserted for  intracerebroventricular injection  (ICV) of morphine. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8505", "text": "It was originally invented in 1963 by  Ayub K. Ommaya , a Pakistani-American  neurosurgeon ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8506", "text": "In January 2017, researchers at University of Texas Southwestern Medical Centre used an Ommaya reservoir to measure the  intracranial pressure  that is regularly observed in astronauts in  zero-gravity  conditions. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8507", "text": "An  orally disintegrating tablet  or  orally dissolving tablet  ( ODT ) is a drug  dosage form  available for a limited range of  over-the-counter  (OTC) and  prescription  medications. ODTs differ from traditional  tablets  in that they are designed to be dissolved on the tongue rather than swallowed whole. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ]  The ODT serves as an alternative dosage form for patients who experience  dysphagia  (difficulty in swallowing) or for where compliance is a known issue and therefore an easier dosage form to take ensures that medication is taken. Common among all age groups, dysphagia is observed in about 35% of the general population, as well as up to 60% of the elderly institutionalized population  [ 12 ] [ 13 ]  and 18-22% of all patients in long-term care facilities\n [ 14 ]  ODTs may have a faster onset of effect than tablets or capsules, and have the convenience of a tablet that can be taken without water. During the last decade, ODTs have become available in a variety of therapeutic markets, both OTC and by prescription."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8508", "text": "Tablets designed to dissolve on the buccal (cheek)  mucous membrane  were a precursor to the ODT. This dosage form was intended for drugs that yield low  bioavailability  through the digestive tract but are inconvenient to administer parenterally, such as steroids and narcotic analgesics. [ 15 ]  Absorption through the cheek allows the drug to bypass the digestive tract for rapid systemic distribution. Not all ODTs have buccal absorption and many have similar absorption and bioavailability to standard oral dosage forms with the primary route remaining GI absorption. However, a fast disintegration time and a small tablet weight can enhance absorption in the buccal area. The first ODTs disintegrated through  effervescence  rather than dissolution, and were designed to make taking vitamins more pleasant for children. [ 16 ]  This method was adapted to pharmaceutical use with the invention of microparticles containing a drug, which would be released upon effervescence of the tablet and swallowed by the patient. [ 17 ]  Dissolution became more effective than effervescence through improved manufacturing processes and ingredients (such as the addition of  mannitol  to increase binding and decrease dissolution time). [ 18 ]   Catalent Pharma Solutions  (formerly Scherer DDS) in the U.K., Cima Labs and Fuisz Technologies (whose founder  Richard Fuisz  went on to pioneer orally soluble films, a separate but related dosage form) in the U.S. and  Takeda Pharmaceutical Company  in Japan led the development of ODTs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8509", "text": "The first ODT form of a drug to get approval from the  U.S. Food and Drug Administration  (FDA) was a  Zydis  ODT formation of Claritin ( loratadine ) in December 1996. [ 19 ]  It was followed by a Zydis ODT formulation of Klonopin ( clonazepam ) in December 1997, [ 20 ]  and a Zydis ODT formulation of Maxalt ( rizatriptan ) in June 1998. [ 21 ]  The regulatory condition for meeting the definition of an orally disintegrating tablet is  USP  method 701 for Disintegration. FDA guidance issued in Dec 2008 is that ODT drugs should disintegrate in less than 30 seconds. [ 22 ]  This practice is under review by the FDA as the fast disintegration time of ODTs makes the disintegration test too rigorous for some of the ODT formulations that are commercially available."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8510", "text": "The processes used to manufacture orally disintegrating tablets include loose compression tabletting, a process which is not very different than the manufacturing method used for traditional tablets and  lyophilization  processes. In loose compression, ODTs are compressed at much lower forces (4 \u2013 20  kN ) than traditional tablets.  However, since ODTs are compressed at very low forces due to the need for them to be soft enough to disintegrate rapidly in the mouth, issues of material sticking to the  die  walls can be challenging.  Typically, as in most tablet blends, lubricants such as  magnesium stearate  are added to the blend to reduce the amount of material that may stick to the die wall.  Differences may be the use of disintegrating aids, such as  crospovidone , and binding agents that aid in  mouth feel , such as microcrystalline  cellulose .  Primarily, ODTs contain some form of sugar such as  mannitol , which typically serves as the major  diluent  of the ODTs, and is also the primary contributor to the smooth and creamy mouth feel of most ODTs. Lyophilized ODT  formulations may use proprietary technologies but can produce a tablet that has a faster disintegration rate, for example the  Zydis  ODT typically dissolves in the mouth in less than 5 seconds without water and Lyophilized Freeze drying tablets - ODT typically dissolves in the mouth in few seconds depending on the molecules and strength."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8511", "text": "ODTs are available in HPDE bottles (Parcopa) or individually sealed in  blister packs  to protect the tablets from damage, moisture, and oxidation.  Because ODTs are soft in nature, the ability to successfully package an ODT in a bottle is difficult. However, CIMA Labs markets their Durasolv ODT as being able to be placed into bottle for commercial sale, while CIMA's Orasolv is marketed for blisters only.   Zydis  ODT tablets manufactured by  Catalent Pharma Solutions  and Lyophilized Freeze drying tablets manufactured by Galien-LPS are delivered in a  blister pack . The differences between the two CIMA products are proprietary, however, the primary difference is expected to be the use of microcrystalline cellulose (MCC), such as Avicel PH101, in the Durasolv product.  MCC serves multiple purposes in an ODT but in the case of CIMA's products, it acts as a binder, increasing the internal strength of the tablet and making it more robust for packaging in bottles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8512", "text": "(Naloxone is included because it deters abuse. Naloxone is poorly absorbed into the body when used by mouth or as an ODT. However, when the pill is crushed and/or filtered and  injected intravenously , naloxone blocks the effects of buprenorphine.)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8513", "text": "Ved Parkash et al. note the following advantages of ODTs:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8514", "text": "Ved Parkash et al. lists the following disadvantages of ODTs:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8515", "text": "An  oxygen concentrator  is a device that concentrates the  oxygen  from a gas supply (typically ambient air) by selectively removing nitrogen to supply an oxygen-enriched product gas stream. They are used industrially, to provide  supplemental oxygen  at high altitudes, and as  medical devices  for  oxygen therapy . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8516", "text": "Oxygen concentrators are used widely for oxygen provision in healthcare applications, especially where liquid or pressurized oxygen is too dangerous or inconvenient, such as in homes or portable clinics, and can also provide an economical source of oxygen in industrial processes, where they are also known as oxygen gas generators or  oxygen generation plants . Two methods in common use are  pressure swing adsorption  and  membrane gas separation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8517", "text": "Pressure swing adsorption (PSA) oxygen concentrators use a  molecular sieve  to adsorb gases and operate on the principle of  rapid pressure swing adsorption  of atmospheric  nitrogen  onto  zeolite  minerals at high pressure.  This type of adsorption system is therefore functionally a nitrogen scrubber, allowing the other atmospheric gases to pass through, leaving oxygen as the primary gas remaining. PSA technology is a reliable and economical technique for small to mid-scale oxygen generation.  Cryogenic separation is more suitable at higher volumes. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8518", "text": "Gas separation across a membrane is a pressure-driven process, where the driving force is the difference in pressure between inlet of raw material and outlet of product. The membrane used in the process is a generally non-porous layer, so there will not be a severe leakage of gas through the membrane. The performance of the membrane depends on permeability and selectivity. Permeability is affected by the penetrant size. Larger gas molecules have a lower diffusion coefficient. The membrane gas separation equipment typically pumps gas into the membrane module and the targeted gases are separated based on difference in diffusivity and solubility. For example, oxygen will be separated from the ambient air and collected at the upstream side, and nitrogen at the downstream side. As of 2016, membrane technology was reported as capable of producing 10 to 25 tonnes of 25 to 40% oxygen per day. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8519", "text": "Home medical oxygen concentrators were invented in the early 1970s, with the manufacturing output of these devices increasing in the late 1970s.  Union Carbide  Corporation and  Bendix Corporation  were both early manufacturers. Before that era, home medical oxygen therapy required the use of heavy high-pressure oxygen cylinders or small cryogenic liquid oxygen systems. Both of these delivery systems required frequent home visits by suppliers to replenish oxygen supplies. In the United States, Medicare switched from fee-for-service payment to a flat monthly rate for home oxygen therapy in the mid-1980s, causing the durable medical equipment (DME) industry to rapidly embrace concentrators as a way to control costs. This reimbursement change dramatically decreased the number of primary high pressure and liquid oxygen delivery systems in use in homes in the United States at that time. Oxygen concentrators became the preferred and most common means of delivering home oxygen. The number of manufacturers entering the oxygen concentrator market increased greatly as a result of this change.  Union Carbide  Corporation invented the  molecular sieve  in the 1950s, which made these devices possible.  It also invented the first cryogenic liquid home medical oxygen systems in the 1960s."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8520", "text": "Oxygen concentrators using  pressure swing adsorption  (PSA) technology are used widely for oxygen provision in healthcare applications, especially where liquid or pressurized oxygen is too dangerous or inconvenient, such as in homes or portable clinics. For other purposes, there are also concentrators based on  nitrogen separation membrane  technology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8521", "text": "An oxygen concentrator takes in air and removes nitrogen from it, leaving an oxygen-enriched gas for use by people requiring medical oxygen due to low oxygen levels in their blood. [ 4 ]  Oxygen concentrators provide an economical source of oxygen in industrial processes, where they are also known as oxygen gas generators or  oxygen generation plants ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8522", "text": "These oxygen concentrators utilize a  molecular sieve  to adsorb gases and operate on the principle of  rapid pressure swing adsorption  of atmospheric  nitrogen  onto  zeolite  minerals at high pressure.  This type of adsorption system is therefore functionally a nitrogen scrubber, allowing the other atmospheric gases to pass through, leaving oxygen as the primary gas remaining. PSA technology is a reliable and economical technique for small- to mid-scale oxygen generation.  Cryogenic separation is more suitable at higher volumes, and external delivery generally more suitable for small volumes. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8523", "text": "At high pressure, the porous zeolite  adsorbs  large quantities of nitrogen because of its large surface area and chemical characteristics. The oxygen concentrator compresses air and passes it over zeolite, causing the zeolite to adsorb the nitrogen from the air.  It then collects the remaining gas, which is mostly oxygen, and the nitrogen desorbs from the zeolite under the reduced pressure to be vented."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8524", "text": "An oxygen concentrator has an air compressor, two cylinders filled with zeolite pellets, a pressure-equalizing reservoir, and some valves and tubes. In the first half-cycle, the first cylinder receives air from the compressor, which lasts about 3 seconds. During that time, the pressure in the first cylinder rises from atmospheric to about 2.5 times normal atmospheric pressure (typically 20 psi/138 kPa gauge, or 2.36 atmospheres absolute) and the zeolite becomes saturated with nitrogen. As the first cylinder reaches near pure oxygen (there are small amounts of argon, CO 2 , water vapour,  radon , and other minor atmospheric components) in the first half-cycle, a valve opens and the oxygen-enriched gas flows to the pressure-equalizing reservoir, which connects to the patient's oxygen hose. At the end of the first half of the cycle, there is another valve position change so that the air from the compressor is directed to the second cylinder. The pressure in the first cylinder drops as the enriched oxygen moves into the reservoir, allowing the nitrogen to be desorbed back into gas. Partway through the second half of the cycle, there is another valve position change to vent the gas in the first cylinder back into the ambient atmosphere, keeping the concentration of oxygen in the pressure-equalizing reservoir from falling below about 90%. The pressure in the hose delivering oxygen from the equalizing reservoir is kept steady by a pressure-reducing valve."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8525", "text": "Older units cycled for a period of about 20 seconds and supplied up to 5 litres per minute of 90+% oxygen. Since about 1999, units capable of supplying up to 10 L/min have been available."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8526", "text": "Classic oxygen concentrators use two-bed molecular sieves; newer concentrators use multi-bed molecular sieves. The advantage of the multi-bed technology is the increased availability and redundancy, as the 10 L/min molecular sieves are staggered and multiplied on several platforms. With this, over 960 L/min can be produced. The ramp-up time \u2014 the elapsed time until a multi-bed concentrator is producing oxygen at >90% concentration \u2014 is often less than 2 minutes, much faster than simple two-bed concentrators. This is a big advantage in mobile emergencies. The option to fill standard oxygen cylinders (e.g., 50 L at 200 bar = 10,000 L each) with high-pressure boosters, to ensure automatic failover to previously filled reserve cylinders and to ensure the oxygen supply chain, e.g., in case of power failure, is given with those systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8527", "text": "In  membrane gas separation , membranes act as a permeable barrier, which different compounds move across at different rates or do not cross at all."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8528", "text": "Gas mixtures can be effectively separated by  synthetic membranes  made from polymers such as  polyamide  or  cellulose acetate , or from ceramic materials. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8529", "text": "While polymeric membranes are economical and technologically useful, they are bound by their performance, known as the Robeson limit (permeability must be sacrificed for selectivity and vice versa). [ 7 ]  This limit affects polymeric membrane use for CO 2  separation from flue gas streams, since mass transport becomes limiting and CO 2  separation becomes very expensive due to low permeabilities. Membrane materials have expanded into the realm of  silica ,  zeolites ,  metal-organic frameworks , and  perovskites , due to their strong thermal and chemical resistance as well as high tunability (ability to be modified and functionalized), leading to increased permeability and selectivity.  Membranes  can be used for separating gas mixtures, where they act as a permeable barrier through which different compounds move across at different rates or don't move at all. The membranes can be nanoporous, polymer, etc., and the gas molecules penetrate according to their size,  diffusivity , or solubility."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8530", "text": "Gas separation across a membrane is a pressure-driven process, where the driving force is the difference in pressure between inlet of raw material and outlet of product. The membrane used in the process is a generally non-porous layer, so there will not be a severe leakage of gas through the membrane. The performance of the membrane depends on permeability and selectivity. Permeability is affected by the penetrant size. Larger gas molecules have a lower diffusion coefficient. The polymer chain flexibility and free volume in the polymer of the membrane material influence the diffusion coefficient, as the space within the permeable membrane must be large enough for the gas molecules to diffuse across. The solubility is expressed as the ratio of the concentration of the gas in the polymer to the pressure of the gas in contact with it. Permeability is the ability of the membrane to allow the permeating gas to diffuse through the material of the membrane as a consequence of the pressure difference over the membrane, and can be measured in terms of the permeate flow rate, membrane thickness and area, and the pressure difference across the membrane. The selectivity of a membrane is a measure of the ratio of permeability of the relevant gases for the membrane. It can be calculated as the ratio of permeability of two gases in binary separation. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8531", "text": "The membrane gas separation equipment typically pumps gas into the membrane module, and the targeted gases are separated based on difference in diffusivity and solubility. For example, oxygen will be separated from the ambient air and collected at the upstream side and nitrogen at the downstream side. As of 2016, membrane technology was reported as capable of producing 10 to 25 tonnes of 25 to 40% oxygen per day. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8532", "text": "Medical oxygen concentrators are used in hospitals or at home to concentrate oxygen for patients. [ 8 ]  PSA generators provide a cost-efficient source of  oxygen . They are a safer, [ 9 ]  less expensive, [ 10 ]  and more convenient  alternative to tanks of cryogenic oxygen or pressurised cylinders. They can be used in various industries, including medical, pharmaceutical production, water treatment, and glass manufacture."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8533", "text": "PSA generators are particularly useful in remote or inaccessible parts of the world or mobile  medical facilities  ( military hospitals , disaster facilities). [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8534", "text": "Since the early 2000s, many companies have produced portable oxygen concentrators. [ 13 ]  Typically, these devices produce the equivalent of one to five liters per minute of continuous oxygen flow and they use some version of pulse flow or \"demand flow\" to deliver oxygen only when the patient is inhaling. [ 14 ]  They can also provide pulses of oxygen either to provide higher intermittent flows or to reduce power consumption."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8535", "text": "Research into oxygen concentration is ongoing, and modern techniques suggest that the amount of adsorbent required by medical oxygen concentrators can be potentially \"reduced by a factor of three while offering ~10\u201320% higher oxygen recovery compared to a typical commercial unit.\" [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8536", "text": "The FAA has approved the use of portable oxygen concentrators on commercial airlines. [ 16 ]  However, users of these devices should check in advance as to whether a particular brand or model is permitted on a particular airline. [ 17 ]  Unlike in commercial airlines, users of aircraft without  cabin pressurization  need oxygen concentrators that are able to deliver enough flowrate even at high altitudes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8537", "text": "Usually, \"demand,\" or pulse-flow, oxygen concentrators are not used by patients while they sleep. There have been problems with the oxygen concentrators not being able to detect when the sleeping patient is inhaling.  Some larger portable oxygen concentrators are designed to operate in a continuous-flow mode in addition to pulse-flow mode. Continuous-flow mode is considered safe for night use when coupled with a  CPAP  machine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8538", "text": "Repurposed medical oxygen concentrators or specialized industrial oxygen concentrators can be made to operate  small   oxyacetylene  or other fuel gas cutting, welding, and  lampworking  torches. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8539", "text": "Oxygen is widely needed for the oxidation of different chemicals for industrial purposes. Previously, these industries purchased oxygen cylinders in large numbers to meet their requirements, but it was very expensive, and oxygen cylinders were not always available in the market."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8540", "text": "Oxygen is needed here for the bleaching of paper pulp with the help of the oxidation process to make the paper white. \nMoreover, lignin present in the wood is removed by the delignification process, which also needs oxygen."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8541", "text": "Huge furnaces are needed to melt the raw materials that combine to form glass. Oxygen flares up the furnace's fire to burn at a higher temperature needed for the production of glass."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8542", "text": "Oxygen is needed for the oxidation of different chemicals to form the desired chemical substances. Waste chemical products are burnt down and destroyed in the incinerator with the help of oxygen; thus, the continuous supply of a bulk amount of oxygen is essential, which is possible only by a PSA oxygen generator."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8543", "text": "In both clinical and emergency-care situations, oxygen concentrators have the advantage of not being as dangerous as  oxygen cylinders , which can, if ruptured or leaking, greatly increase the combustion rate of fire. As such, oxygen concentrators are particularly advantageous in  military  or  disaster  situations, where oxygen tanks may be dangerous or unfeasible."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8544", "text": "Oxygen concentrators are considered sufficiently foolproof to be supplied to individual patients as a prescription item for use in their homes. Typically they are used as an adjunct to  CPAP  treatment of severe  sleep apnea . There also are other medical uses for oxygen concentrators, including  COPD  and other respiratory diseases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8545", "text": "People who depend upon oxygen concentrators for home care may have life-threatening emergencies if the electricity fails during a  natural disaster . [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8546", "text": "Industrial processes may use much higher pressures and flows than medical units. To meet that need, another process, called  vacuum swing adsorption  (VSA), has been developed by  Air Products . This process uses a single low-pressure blower and a valve that reverses the flow through the blower so that the regeneration phase occurs under a vacuum. Generators using this process are being marketed to the  aquaculture  industry. Industrial oxygen concentrators are often available in a much wider range of capacities than medical concentrators."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8547", "text": "Industrial oxygen concentrators are sometimes referred to as oxygen  generators  within the oxygen and ozone industries to distinguish them from medical oxygen  concentrators . The distinction is used in an attempt to clarify that industrial oxygen concentrators are not  medical devices  approved by the  Food and Drug Administration  (FDA) and they are not suitable for use as bedside medical concentrators. However, applying the oxygen generator nomenclature can lead to confusion. The term oxygen  generator  is a misnomer in that the oxygen is not  generated  as it is with a  chemical oxygen generator , but rather it is concentrated from the air."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8548", "text": "Non-medical oxygen concentrators can be used as feed gas to a medical oxygen system, such as the oxygen system in a hospital, though governmental approval is required, such as by the FDA, and additional filtering is generally required."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8549", "text": "The  COVID-19 pandemic  increased the demand for oxygen concentrators. During the pandemic  open source  oxygen concentrators were developed, locally manufactured \u2013 with prices below imported products \u2013 and used, especially during  a COVID-19 pandemic wave in India . [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8550", "text": "An  oxygen mask  is a mask that provides a method to transfer  breathing oxygen gas  from a storage tank to the  lungs . Oxygen masks may cover only the nose and mouth (oral nasal mask) or the entire face (full-face mask). They may be made of  plastic ,  silicone , or  rubber .\nIn certain circumstances, oxygen may be delivered via a  nasal cannula  instead of a mask."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8551", "text": "Medical plastic oxygen masks are used primarily by medical care providers for  oxygen therapy  because they are disposable and so reduce cleaning costs and infection risks. Mask design can determine accuracy of oxygen delivered with many various medical situations requiring treatment with oxygen."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8552", "text": "Oxygen is naturally occurring in room air at 21% and higher percentages are often essential in medical treatment. Oxygen in these higher percentages is classified as a drug with too much oxygen being potentially harmful to a patient's health, resulting in oxygen dependence over time, and in extreme circumstances patient blindness. For these reasons oxygen therapy is closely monitored. Masks are light in weight and attached using an elasticated headband or ear loops. They are transparent for allowing the face to be visible for patient assessment by healthcare providers, and reducing a sensation of claustrophobia experienced by some patients when wearing an oxygen mask. The vast majority of patients having an operation will at some stage wear an oxygen mask; they may alternatively wear a nasal cannula but oxygen delivered in this way is less accurate and restricted in concentration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8553", "text": "The global disposable oxygen masks market, according to Altus Market Research, has the potential to grow by US$1.1 billion between 2019 and 2023. The market's growth pace will also pick up speed throughout this time. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8554", "text": "Silicone and rubber oxygen masks are heavier than plastic masks. They are designed to provide a good seal for long-duration use by  aviators , medical research subjects, and  hyperbaric chamber  and other patients who require administration of pure oxygen, such as  carbon monoxide poisoning  and  decompression sickness  victims. Dr.  Arthur H. Bulbulian  pioneered the first modern viable oxygen mask, worn by World War II pilots and used by hospitals. [ 2 ]   Valves  inside these tight-fitting masks control the flow of gases into and out of the masks, so that rebreathing of exhaled gas is minimised."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8555", "text": "Hoses or tubing connect an oxygen mask to the oxygen supply. Hoses are larger in diameter than tubing and can allow greater oxygen flow. When a hose is used it may have a ribbed or corrugated design to allow bending of the hose while preventing twisting and cutting off the oxygen flow. The quantity of oxygen delivered from the storage tank to the oxygen mask is controlled by a valve called a  regulator . Some types of oxygen masks have a breathing bag made of plastic or rubber attached to the mask or oxygen supply hose to store a supply of oxygen to allow deep breathing without waste of oxygen with use of simple fixed flow regulators."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8556", "text": "An early 1919 high-altitude oxygen system used a vacuum flask of liquid oxygen to supply two people for one hour at 15,000\u00a0ft (4,600\u00a0m). The liquid passed through several warming stages before use, as expansion when it evaporated, and absorbed  latent heat of vaporization , would make the gasified oxygen so cold that it could cause instant  frostbite  of the lungs. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8557", "text": "The first successful creation for the oxygen mask was by Armenian born  Dr. Arthur Bulbulian , in the field of facial prosthetics, in 1941. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8558", "text": "Many designs of aviator's oxygen masks contain a microphone to transmit speech to other crew members and to the aircraft's radio. Military aviators' oxygen masks have face pieces that partially cover the sides of the face and protect the face against flash burns, flying particles, and effects of a high speed air stream hitting the face during emergency evacuation from the aircraft by  ejection seat  or  parachute . They are often part of a  pressure suit  or intended for use with a  flight helmet ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8559", "text": "Three main kinds of oxygen masks are used by  pilots  and crews who fly at high altitudes: continuous flow, diluter demand, and pressure demand. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8560", "text": "In a  continuous-flow system , oxygen is provided to the user continuously. It does not matter if the user is exhaling or inhaling as oxygen is flowing from the time the system is activated. Below the oxygen mask is a rebreather bag that collects oxygen during exhalation and as a result allows a higher flow rate during the inhalation cycle. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8561", "text": "Diluter-demand  and  pressure-demand  masks supply oxygen only when the user inhales. [ 6 ]  They each require a good seal between the mask and the user's face."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8562", "text": "In a  diluter-demand system,  as the altitude increases (ambient pressure, and therefore the partial pressure of ambient oxygen, decreases), the oxygen flow increases such that the partial pressure of oxygen is roughly constant. Diluter-demand oxygen systems can be used up to 40,000\u00a0ft (12,000\u00a0m). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8563", "text": "In a  pressure-demand system , oxygen in the mask is above ambient pressure, permitting breathing above 40,000 feet (12,000\u00a0m). [ 5 ]  Because the pressure inside the mask is greater than the pressure around the user's torso, inhalation is easy, but exhalation requires more effort. Aviators are trained in pressure-demand breathing in  altitude chambers . Because they seal tightly, pressure-demand-type oxygen masks are also used in hyperbaric oxygen chambers and for oxygen breathing research projects with standard oxygen regulators. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8564", "text": "Supplemental oxygen is needed for flying more than 30 minutes at cabin pressure altitudes of 12,500 feet (3,800\u00a0m) or higher, pilots must use oxygen at all times above 14,000 feet (4,300\u00a0m) and each occupant must be provided supplemental oxygen above 15,000 feet (4,600\u00a0m). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8565", "text": "Most  commercial aircraft  are fitted with oxygen masks for use when cabin pressurization fails. [ 8 ] [ 9 ]  In general, commercial aircraft are  pressurized  so that the cabin air is at a pressure equivalent to no more than 8,000 feet (2,400\u00a0m) altitude (usually somewhat lower altitude), where one can breathe normally without an oxygen mask. If the oxygen pressure in the cabin drops below a safe level, risking  hypoxia , compartments containing the oxygen masks will open automatically, either above or in front of the passenger and crew seats, and in the lavatories."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8566", "text": "In the early years of commercial flight, before  pressurized cabins  were invented, airliner passengers sometimes had to wear oxygen masks during routine flights."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8567", "text": "Firefighters  and  emergency service  workers use full face masks that provide breathing air as well as eye and face protection. [ 10 ]  These masks are typically attached to a tank carried upon the back of the wearer and are called  self-contained breathing apparatuses  (SCBA). [ 11 ]  Open circuit SCBAs do not normally supply oxygen, as it is not necessary and constitutes an easily avoidable fire hazard. Rebreather SCBAs usually supply oxygen as this is the lightest and most compact option, and uses a simpler mechanism than other types of rebreather."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8568", "text": "Specialized full-face masks that supply oxygen or other  breathing gases  are used by  astronauts  to remove nitrogen from their blood before  space walks  (EVA). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8569", "text": "Specialized snout masks which supply oxygen to revive family  pets  have been donated to  fire departments . [ 12 ] [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8570", "text": "Divers only use pure oxygen for  accelerated decompression , or from oxygen  rebreathers  at shallow depths where the risk of acute  oxygen toxicity  is acceptable. Oxygen supply during in-water decompression is via rebreather,  open circuit diving regulator ,  full-face mask  or  diving helmet  which has been prepared for  oxygen service . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8571", "text": "Oxygen supply to divers in  decompression chambers  is preferably through a built-in breathing system, which uses an oxygen mask plumbed into supply and exhaust hoses which supply oxygen from outside the chamber, and discharge the exhaled oxygen-rich gas outside the chamber, using a system equivalent to two  demand valves , one upstream of the diver, to supply oxygen on demand, and the other downstream, to exhaust exhaled gas on demand, so that the oxygen partial pressure in the chamber is limited to relatively safe levels. If oxygen masks are used that discharge into the chamber, the chamber air must be replaced frequently to keep the oxygen level within safe operating limits. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8572", "text": "Anesthesia masks are face masks that are designed to administer  anesthetic  gases to a patient through inhalation. Anesthesia masks are either made of anti-static silicone or rubber, as a static electricity spark may ignite some anesthetic gases. They are either black rubber or clear silicone. Anesthesia masks fit over the mouth and nose and have a double hose system. One hose carries inhaled anesthetic gas to the mask and the other brings exhaled anesthetic gas back to the machine. Anesthesia masks have 4 point head strap harnesses to securely fit on the head to hold the mask in place as the anaesthetist controls the gases and oxygen inhaled."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8573", "text": "Oxygen masks are used by  climbers  of high peaks such as  Mount Everest . [ 17 ]  Because of the severe cold and harsh conditions oxygen masks for use at extreme altitude must be robust and effective. The oxygen storage tanks used with the masks (called oxygen bottles) are made of lightweight, high-strength metals and are covered in high-strength fiber such as  kevlar . These special oxygen bottles are filled with oxygen at a very high pressure which provides a longer time duration of oxygen for breathing than standard pressure oxygen bottles. These systems are generally only used above 7,000 metres (23,000\u00a0ft)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8574", "text": "In recent years oxygen mask systems for high-altitude climbing which pump oxygen constantly have been increasingly replaced by systems supplying oxygen on demand via  nasal cannulas . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8575", "text": "Oxygen helmets are used in  hyperbaric oxygen  chambers for oxygen administration. [ 2 ]  They are transparent, lightweight plastic helmets with a seal that goes around the wearer's neck that looks like a  space suit   helmet . They offer a good visual field. Light weight plastic hoses provide oxygen to the helmet and remove exhaled gas to the outside of the chamber. Oxygen helmets are often preferred for oxygen administration in hyperbaric oxygen chambers for children and patients that are uncomfortable wearing an oxygen mask. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8576", "text": "Medical oxygen masks are held in place by medical personnel or the user by hand, or they may be fitted with a lightweight elastic headband so the mask can be removed quickly. Full-face masks are secured by several straps. Tightly fitting oxygen masks are secured at four points by two head straps. Aviators' masks are often equipped with \"quick don\" harnesses that allow those in pressurized aircraft to rapidly don the masks in emergencies. Military aviators' oxygen masks are secured to flight helmets with quick-release systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8577", "text": "In  physics , a  paste  is a substance that behaves as a  solid  until a sufficiently large load or  stress  is applied, at which point it flows like a  fluid . In  rheological  terms, a paste is an example of a  Bingham plastic   fluid ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8578", "text": "Pastes typically consist of a  suspension  of  granular material  in a background fluid.  The individual grains are jammed together like  sand  on a  beach , forming a disordered,  glassy  or  amorphous  structure, and giving pastes their solid-like character.  It is this \"jamming together\" that gives pastes some of their most unusual properties; this causes paste to demonstrate properties of  fragile matter ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8579", "text": "Examples include  starch  pastes,  toothpaste ,  mustard , and  putty ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8580", "text": "In pharmacology,  paste  is a basic  pharmaceutical form . It consists of a fatty base (e.g.,  petroleum jelly ) and at least 25% of a solid substance (e.g.,  zinc oxide ). Pharmaceutical pastes are typically intended for external application to the skin. They are usually thick and do not melt at physiologic temperatures. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8581", "text": "This  material -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8582", "text": "A  pessary  is a prosthetic device inserted into the  vagina  for structural and pharmaceutical purposes. It is most commonly used to treat  stress urinary incontinence  to stop urinary leakage and to treat  pelvic organ prolapse  to maintain the location of organs in the pelvic region. [ 1 ]  It can also be used to administer medications locally in the vagina or as a method of  contraception ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8583", "text": "Pessaries come in different shapes and sizes, so it is important that individuals be fitted for them by health care professionals to avoid any complications. [ 1 ]  However, there are a few instances and circumstances that allow pessaries to be purchased without a prescription or without seeking help from a health care professional. [ 2 ]  Some side effects may occur if pessaries are not sized properly or regularly maintained, but with the appropriate care, pessaries are generally safe and well tolerated. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8584", "text": "Early use of pessaries dates back to the ancient Egyptians, as they described using pessaries to treat pelvic organ prolapse. [ 3 ]  The term 'pessary' itself, is derived from the Ancient Greek word 'pess\u00f3s', meaning round stone used for games. [ 4 ] [ 5 ]  Pessaries are even mentioned in the oldest surviving copy of the Greek medical text,  Hippocratic Oath , as something that physicians should never administer for the purposes of an abortion: \"Similarly I will not give to a woman a pessary to cause abortion.\" [ 6 ]  The earliest documented pessaries were natural products. For example, Greek physicians  Hippocrates  and  Soranus  described inserting half of a pomegranate into the vagina to treat prolapse. [ 3 ]  It was not until the 16th century that the first purpose-made pessaries were made. [ 5 ]  For instance, in the late 1500s,  Ambroise Par\u00e9  was described as making oval pessaries from hammered brass and waxed cork. Nowadays, pessaries are generally made from silicone and are well tolerated and effective among patients who need them. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8585", "text": "The most common use for pessaries is to treat pelvic organ prolapse. A pelvic organ prolapse can occur when the muscles and tissues surrounding the bladder, uterus, vagina, small bowel, and rectum stop working properly to hold the organs in place and the organs begin to drop outside the body. The most common cause of such prolapse is childbirth, usually multiple births.  Obesity , long-term respiratory problems,  constipation , pelvic organ cancers, and  hysterectomies  can all be causes for pelvic organ prolapses as well. [ 7 ]  Some signs and symptoms include feeling pressure in the pelvic area, lower back pain, painful intercourse, urinary incontinence, a feeling that something is out of place, constipation, or bleeding from the vagina. [ 7 ]  Pessaries are manual devices that are inserted into the vagina to help support and reposition descended pelvic organs, which helps to prevent the worsening of prolapse, helps with symptom relief, and can delay or prevent the need for surgery. [ 3 ] [ 5 ]  Further, pessaries can be used for surgery preparation as a way to maintain prolapse without progression. [ 3 ]  This is especially useful when a surgery may need to be delayed. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8586", "text": "Stress urinary incontinence is leakage of urine that is caused by sudden pressure on the bladder. It occurs during activities that increase the amount of pressure on the bladder such as coughing, sneezing, laughing, and exercising. [ 8 ]  The pressure causes opening of the  sphincter muscles  which usually help prevent urine leakage. Stress urinary incontinence is a common medical problem especially in women as about 1 in 3 women are affected by this condition at some point in their lives. [ 8 ]   Pessaries are considered a safe non-surgical treatment option for stress urinary incontinence as it can control the urine leakage by pushing the  urethra  closed. Pessaries can be removed any time. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8587", "text": "Some additional uses for pessaries are for an  incarcerated uterus , prevention of  preterm birth  and an incompetent  cervix . [ 3 ] [ 10 ]  In early pregnancy the  uterus  can be displaced, which can lead to pain and rectal and urinary complications. [ 3 ]  A pessary can be used to treat this condition and support the uterus. [ 3 ]  Preterm birth is when babies are born prematurely, which puts the baby at increased risk for complications and even death. Currently, the use of pessaries to help prevent preterm birth is an ongoing area of research. [ 10 ]  The use of pessaries for an incompetent cervix is not commonly practiced today, but they have been used in the past. [ 3 ]  Specifically, an incompetent cervix is when the cervix begins to open up prematurely. [ 11 ]  This can lead to a preterm birth or even a miscarriage. Pessaries can be used to correctly position the cervix, increasing the success of pregnancy. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8588", "text": "A  therapeutic pessary  is a medical device similar to the outer ring of a  diaphragm . Therapeutic pessaries are used to support the  uterus ,  vagina ,  bladder , or  rectum . [ 12 ]  Pessaries are most commonly used for pelvic organ prolapse and considered a good treatment option for women who need or desire non-surgical management or future pregnancy. [ 12 ]  It is used to treat  prolapse of uterine , vaginal wall ( vaginal vault ), bladder ( cystocele ), rectum ( rectocele ), or small bowel ( enterocele ). It is also used to treat  stress urinary incontinence . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8589", "text": "There are different types of pessaries but most of them are made out of silicone\u2014a harmless and durable material. [ 14 ]  Pessaries are mainly categorized into two types, supporting pessaries and space-occupying pessaries. [ 5 ]  Support pessaries function by supporting the prolapse and space-occupying pessaries by filling the vaginal space. [ 3 ]  There are also lever type pessaries. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8590", "text": "Ring with support pessaries  are the supporting type. [ 5 ]  These are often used as a first-line treatment and used for earlier stage prolapse since individuals can easily insert and remove them on their own without a doctor's help. These can be easily folded in half for insertion. [ 12 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8591", "text": "Gellhorn pessaries  are considered a type of supporting and space-occupying pessary. [ 5 ]  These resemble the shape of a mushroom and are used for more advanced pelvic organ prolapse. [ 5 ] [ 14 ]  These are less preferred than ring with support pessaries due to difficulty with self-removal and insertion. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8592", "text": "Marland pessaries  are another type of supporting pessary. [ 12 ]  These are used to treat pelvic organ prolapse as well as stress urinary incontinence. [ 12 ]  These pessaries have a ring at their base and a wedge-shaped ridge on one side. [ 14 ]  Although these pessaries are less likely to fall out than standard ring with support pessaries, individuals find it difficult to insert or remove them on their own. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8593", "text": "Donut pessaries  are considered space-occupying pessaries. [ 5 ]  These are used for more advanced pelvic organ prolapse including cystocele or rectocele as well as a second or third-degree uterine prolapse. [ 12 ]  Due to its shape and size, it is one of the hardest ones to insert and remove. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8594", "text": "Cube pessaries  are space-occupying pessaries in the shape of a cube that are available in 7 sizes. The pessary is inserted into the vagina and kept in place by the suction of its 6 surfaces to the vaginal wall. Cube pessaries must be removed before sexual intercourse and replaced daily. [ 5 ]  Cube pessaries are generally used as a last resort only if the individuals cannot retain any other pessaries. [ 3 ]  This is due to undesirable side effects such as vaginal discharge and erosion of the vaginal wall. [ 3 ] [ 5 ]  In order to remove the cube pessary, the suction must be broken by grasping the device. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8595", "text": "Gehrung pessaries  are space-occupying pessaries that are similar to the Gellhorn pessaries. [ 3 ]  They are silicone devices that are placed into the vagina and used for second or third degree (more severe) uterine prolapse. These contain metal and should be removed prior to any MRI, ultrasound or X-rays. They can also be used to help with stress urinary incontinence such as urine leaks during exercising or coughing. These types of pessaries need to be fitted by a health care professional to ensure proper size. Once placed it should not move when standing, sitting, or squatting. It should be cleaned with mild soap and warm water every day or two. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8596", "text": "Hodge pessaries  are a type of lever pessary. Although these can be used for mild  cystocele  and stress urinary incontinence, they are not commonly used. Smith, and Risser pessaries are other types of lever pessaries and they differ in shape. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8597", "text": "Treating vaginal yeast infections is one of the most common uses of pharmaceutical pessaries. They are also known as vaginal  suppositories , which are  inserted into the vagina  and are designed to dissolve at body temperature. They usually contain a single use antifungal agent such as  clotrimazole . Oral antifungal agents are also available. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8598", "text": "Pessaries can also be used in a similar way to help induce labor for women who have overdue expected delivery dates or who experience premature rupture of membranes.  Prostaglandins  are usually the medication used in these kinds of pessaries in order to relax the cervix and promote contractions. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8599", "text": "According to  Pliny the Elder , pessaries were used as birth control in ancient times. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8600", "text": "Occlusive pessaries are most commonly used for contraception. Also known as a contraceptive cap, they work similar to a diaphragm as a barrier form of contraception. They are inserted into the vagina and block sperm from entering the uterus through the cervix. The cap must be used in conjunction with a spermicide in order to be effective in preventing pregnancy. When used correctly the cap is thought to be 92\u201396% effective. These caps are reusable but come in different sizes. It is recommended for anyone attempting this form of contraception to be fitted for the correct size by a trained health care professional. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8601", "text": "The stem pessary, a type of occlusive pessary, was an early form of the  cervical cap . Shaped like a dome, it covered the cervix, and a central rod or \"stem\" entered the uterus through the external orifice of the uterus, also known as the cervical canal or the  os , to hold it in place. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8602", "text": "When pessaries are used correctly, they are tolerated well for pelvic organ prolapse or stress urinary incontinence. [ 22 ]  However, pessaries are still a foreign device that is inserted into the vagina, so side effects can occur. [ 23 ]  Some more common side effects include vaginal discharge and odor. [ 12 ]  Vaginal discharge and odor may be associated with  bacterial vaginosis , characterized by an overgrowth of naturally occurring bacteria in the vagina. [ 24 ]  These symptoms can be treated with the appropriate medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8603", "text": "More serious side effects include  fistula  formation between the vagina and rectum or the vagina and bladder, or erosion, or thinning, of the vaginal wall. [ 12 ]  Fistula formation is rare, but erosion of the vaginal wall occurs more frequently. Low estrogen production can also increase the risk of vaginal wall thinning. [ 25 ]  For individuals with pessaries that are not fitted for them,  herniations  of the cervix and uterus can occur through the opening of the pessary. This can lead to tissue necrosis in the cervix and uterus. [ 23 ]  To prevent these side effects, individuals can be fitted properly for their pessaries and undergo routine follow-up visits with their health care professionals to ensure the individual has the correct pessary size and no other complications. [ 12 ]  In addition, those with an increased risk of vaginal wall thinning can be prescribed estrogen to prevent erosion and prevent these complications. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8604", "text": "If pessaries are not used properly or not maintained periodically, more serious complications can occur. For example, the pessary can become embedded into the vagina, which makes it harder to remove. Estrogen can decrease the inflammation of the vaginal walls and promote skin cells in the vagina to mature, so use of estrogen cream can allow removal of the pessary more easily. [ 23 ]  In rare cases, pessaries would need to be removed through surgical procedures. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8605", "text": "To prevent complications, individuals should not use pessaries if they have characteristics that exclude them from this method of therapy.  Contraindications  to pessary use include current infections in the pelvis or vagina, or allergies to the material of the pessary (which can be silicone or latex). [ 13 ]  In addition, individuals should not be fitted for a pessary if they are less likely to properly maintain their pessary."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8606", "text": "Gholam A. Peyman  (born 1 January 1937) is an  Iranian American   ophthalmologist ,  retina  surgeon, and inventor. He is best known for his invention of  LASIK  eye surgery, [ 2 ]  a vision correction procedure designed to allow people to see clearly without glasses. He was awarded the first US patent for the procedure in 1989."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8607", "text": "Peyman was born in  Shiraz ,  Iran . At the age of 19, he moved to Germany to begin his medical studies. He received his MD at the  University of Freiburg  in 1962. [ citation needed ]  He completed his internship at St. Johannes Hospital in Duisburg, Germany in 1964 and at Passaic General Hospital in  Passaic, New Jersey  in 1965. [ citation needed ]  Peyman completed his residency in ophthalmology and a retina fellowship at the University of Essen, Essen Germany, in 1969 and an additional postdoctoral fellowship in retina at the  Jules Stein Eye Institute , UCLA School of Medicine in Los Angeles in 1971. Peyman held the position of assistant professor of ophthalmology at the  UCLA  School of Medicine from 1971 and served as associate professor and then professor of ophthalmology and ocular oncology at the  Illinois Eye and Ear Infirmary ,  University of Illinois at Chicago  during 1971\u20131987. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8608", "text": "Peyman held a joint appointment at the School of Medicine and also at the Neuroscience Center of Excellence at the Louisiana State University Medical University Medical Center in New Orleans during 1987\u20132000. During 1998-2000 Peyman held the Prince Abdul Aziz Bin Ahmed Bin Abdul Aziz Al Saud Chair in Retinal Diseases. During 2000\u20132006, Peyman served as professor of ophthalmology, ocular oncology and co-director, Vitreo-Retinal Service,  Tulane University School of Medicine  in New Orleans. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8609", "text": "During 2006\u20132007, he was professor of ophthalmology at the  University of Arizona, Tucson , with a cross appointment at  University of Arizona College of Optical Sciences . He has been emeritus professor of ophthalmology at Tulane University since 2009. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8610", "text": "Peyman is currently professor of basic medical sciences at the  University of Arizona College of Medicine \u2013 Phoenix  & Optical engineering at the University of Arizona in Tucson.\nPeyman was awarded in 2013 an honoree doctorate degree from the  National University of Cordoba  in  Argentina . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8611", "text": "At the  Illinois Eye and Ear Infirmary , Peyman, because of his interest in the effects of lasers on tissues in the eye, began evaluating the potential use of a CO 2  laser to modify corneal refraction in rabbits. No prior study had existed on this concept. The laser was applied to the surface of the cornea using different patterns. This laser created significant scarring. His conclusions at that time were: 1) one has to wait for the development of an ablative laser and 2) one should not ablate the surface of the cornea but, instead, the ablation should take place under a flap in order to prevent scarring, pain and other undesirable sequelae. Peyman published the first article on this subject in 1980. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8612", "text": "In late 1982, he read an article from IBM Laboratories, published in  Laser Focus , describing the photo-ablative properties of an excimer laser on organic material. This was very exciting information, but, unfortunately, Peyman did not have access to this laser, which at the time was new and very expensive. By 1985 and beyond, many investigators were interested in ablating the corneal surface. However, because of his previous experience with the CO 2  laser, Peyman wanted to avoid surface ablation in order to prevent potential corneal scarring and the pain associated with the removal of the corneal epithelium, necessary to expose the surface of the cornea. Therefore, in July 1985, he applied for a patent that described a method of modifying corneal refractive errors using laser ablation under a corneal flap. This US patent was accepted after two revisions and issued in June, 1989. Peyman performed a number of experimental studies evaluating the effect of various excimer lasers in collaboration with Physics Department of the University of Helsinki, Finland. Since he had purchased an Erb-Yag laser in the U.S., he evaluated the concept using this laser  in vivo  in rabbit and primate eyes and described the creation of a hinged corneal flap to enable the ablation to be performed on the exposed corneal bed, thus reducing the potential for postoperative scarring and pain. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8613", "text": "Always aware of the potential limitations of his invention, Peyman devoted considerable time and effort in subsequent years to ameliorating them. In order to improve the risk/benefit considerations of the LASIK procedure, he invented in 2004 and patented a broad range of ablative and non-ablative inlays to be placed under the surgically created corneal flap (US Patent 6,702,807). These inlays offered many potential advantages over the standard LASIK technique, the most significant of which is that the inlay procedure is reversible. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8614", "text": "However, their ablation was not predictable. In October 2009, Peyman invented and applied for a patent on a method of preventing corneal implant rejection, which was approved in 2017 (US Patent 9,681,942).  It consisted of forming a Lasik flap in the cornea, raising the flap, inserting a lamellar cornea under the flap so as to overlie the exposed stromal tissue. The inlay is ablated with wavefront guided excimer laser, to correct the refractive errors of the eye, applying a cross linking solution to the inlay and stromal tissue of the cornea, replacing the corneal flap and cross linking the inlay with UV radiation, killing the cellular elements in the inlay and its surrounding cornea, preventing cellular migration in the inlay and its rejection or encapsulation by the host corneal cells.  This new procedure is now called \u201cMesoick\u201d (Meso means Inside, Implant, Crosslinking Keratomileusis (US Patent 9,037,033). This creates an immune privileged cell free space that does not initiate an immune response to an implant. A synthetic, crosslinked organic or polymeric lens can be implanted in the corneal pocket to compensate for the patient's refractive error. The implant can be exchanged as the eye grows or refractive need dictates. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8615", "text": "Peyman has been granted 200 US  Patents [ 8 ]  covering a broad range of novel medical devices, intra-ocular drug delivery, surgical techniques, as well as new methods of diagnosis and treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8616", "text": "Development of direct intraocular drug delivery and Vitrectomy"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8617", "text": "Surgical removal of intraocular tumors"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8618", "text": "This technology enables an ophthalmologist to treat a patient located in another location e.g. another city by a laser system controlled remotely, via the internet, using a sophisticated secure system in a non-contact fashion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8619", "text": "Development of precision thermotherapy in oncology \nTherapy of malignant tumors in early-stage along with imaging and immune therapy and precision localized drug delivery:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8620", "text": "Tele-laser system and tele- medicine with a novel Dynamic Identity recognition"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8621", "text": "Macular degeneration"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8622", "text": "Intravitreal slow-release Rock inhibitors alone or in combination with Anti-VEGF"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8623", "text": "Artificial Retina Stimulation"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8624", "text": "Quantum dots and Optogenetic for artificial retinal and brain stimulation and gene therapy"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8625", "text": "Gene therapy with non-viral nanoparticles and CRISPR"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8626", "text": "Adaptic optic phoropter for automated vision correction and Tunable light field camera in use for VR and AR technology"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8627", "text": "Among other awards and honors, Peyman has received the  National Medal of Technology and Innovation  (2012), [ 18 ]  the Waring Medal of the  Journal of Refractive Surgery  (2008), [ 19 ]  and the  American Academy of Ophthalmology 's Lifetime Achievement Award (2008) [ 20 ]  He was named a fellow of the  National Academy of Inventors  in 2013. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8628", "text": "Photosensitizers  are light absorbers that alter the course of a  photochemical reaction .  They usually are  catalysts . [ 1 ]   They can function by many mechanisms, sometimes they donate an electron to the substrate, sometimes they abstract a hydrogen atom from the substrate. At the end of this process, the photosensitizer returns to its  ground state , where it remains chemically intact, poised to absorb more light. [ 2 ] [ 3 ] [ 4 ]  One branch of chemistry which frequently utilizes photosensitizers is  polymer chemistry , using photosensitizers in reactions such as  photopolymerization , photocrosslinking, and  photodegradation . [ 5 ]  Photosensitizers are also used to generate prolonged excited electronic states in organic molecules with uses in  photocatalysis ,  photon upconversion  and  photodynamic therapy . Generally, photosensitizers absorb  electromagnetic radiation  consisting of  infrared radiation ,  visible light radiation , and  ultraviolet radiation  and transfer absorbed energy into neighboring molecules. This absorption of light is made possible by photosensitizers' large  de-localized \u03c0-systems , which lowers the energy of  HOMO and LUMO  orbitals to promote  photoexcitation . While many photosensitizers are organic or organometallic compounds, there are also examples of using semiconductor  quantum dots  as photosensitizers. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8629", "text": "Photosensitizers absorb light (h\u03bd) and transfer the energy from the  incident light  into another nearby molecule either directly or by a chemical reaction.  Upon absorbing  photons  of radiation from incident light, photosensitizers transform into an excited  singlet state . The single electron in the excited  singlet state  then flips in its intrinsic spin state via  Intersystem crossing  to become an excited  triplet state . Triplet states typically have longer lifetimes than excited singlets. The prolonged lifetime increases the probability of interacting with other molecules nearby. Photosensitizers experience varying levels of efficiency for intersystem crossing at different wavelengths of light based on the internal electronic structure of the molecule. [ 2 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8630", "text": "For a molecule to be considered a photosensitizer:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8631", "text": "It is important to differentiate photosensitizers from other  photochemical  interactions including, but not limited to,  photoinitiators ,  photocatalysts ,  photoacids  and  photopolymerization . Photosensitizers utilize light to enact a chemical change in a substrate; after the chemical change, the photosensitizer returns to its initial state, remaining chemically unchanged from the process.  Photoinitiators  absorb light to become a reactive species, commonly a  radical  or an  ion , where it then reacts with another chemical species. These photoinitiators are often completely chemically changed after their reaction.  Photocatalysts  accelerate chemical reactions which rely upon light. While some photosensitizers may act as photocatalysts, not all photocatalysts may act as photosensitizers.  Photoacids  (or photobases) are molecules which become more acidic (or basic) upon the absorption of light. Photoacids increase in acidity upon absorbing light and thermally reassociate back into their original form upon relaxing.  Photoacid generators  undergo an irreversible change to become an acidic species upon light absorption.  Photopolymerization  can occur in two ways. Photopolymerization can occur directly wherein the monomers absorb the incident light and begin polymerizing, or it can occur through a photosensitizer-mediated process where the photosensitizer absorbs the light first before transferring energy into the monomer species. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8632", "text": "Photosensitizers have existed within natural systems for as long as  chlorophyll  and other light sensitive molecules have been a part of plant life, but studies of photosensitizers began as early as the 1900s, where scientists observed photosensitization in biological substrates and in the treatment of cancer. Mechanistic studies related to photosensitizers began with scientists analyzing the results of chemical reactions where photosensitizers  photo-oxidized  molecular oxygen into peroxide species. The results were understood by calculating quantum efficiencies and fluorescent yields at varying wavelengths of light and comparing these results with the yield of  reactive oxygen species . However, it was not until the 1960s that the electron donating mechanism was confirmed through various  spectroscopic  methods including reaction-intermediate studies and  luminescence  studies. [ 8 ] [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8633", "text": "The term photosensitizer does not appear in scientific literature until the 1960s. Instead, scientists would refer to photosensitizers as sensitizers used in photo-oxidation or photo-oxygenation processes. Studies during this time period involving photosensitizers utilized organic photosensitizers,  consisting of  aromatic hydrocarbon  molecules, which could facilitate synthetic chemistry reactions. However, by the 1970s and 1980s, photosensitizers gained attraction in the scientific community for their role within biologic processes and enzymatic processes. [ 12 ] [ 13 ]  Currently, photosensitizers are studied for their contributions to fields such as energy harvesting,  photoredox catalysis  in synthetic chemistry, and cancer treatment. [ 11 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8634", "text": "There are two main pathways for photosensitized reactions. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8635", "text": "In Type I photosensitized reactions, the photosensitizer is excited by a light source into a triplet state. The excited, triplet state photosensitizer then reacts with a substrate molecule which is not molecular oxygen to both form a product and reform the photosensitizer. Type I photosensitized reactions result in the photosensitizer being quenched by a different chemical substrate than molecular oxygen. [ 2 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8636", "text": "In Type II photosensitized reactions, the photosensitizer is excited by a light source into a triplet state. The excited photosensitizer then reacts with a ground state,  triplet oxygen  molecule. This excites the oxygen molecule into the singlet state, making it a  reactive oxygen species . Upon excitation, the  singlet oxygen  molecule reacts with a substrate to form a product. Type II photosensitized reaction result in the photosensitizer being quenched by a ground state oxygen molecule which then goes on to react with a substrate to form a product. [ 2 ] [ 17 ] [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8637", "text": "Photosensitizers can be placed into 3 generalized domains based on their molecular structure. These three domains are organometallic photosensitizers, organic photosensitizers, and nanomaterial photosensitizers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8638", "text": "Organometallic photosensitizers contain a metal atom chelated to at least one organic  ligand . The photosensitizing capacities of these molecules result from electronic interactions between the metal and ligand(s).  Popular electron-rich metal centers for these complexes include  Iridium ,  Ruthenium , and  Rhodium . These metals, as well as others, are common metal centers for photosensitizers due to their highly filled  d-orbitals , or high  d-electron  counts, to promote  metal to ligand charge transfer  from pi-electron accepting ligands. This interaction between the metal center and the ligand leads to a large continuum of orbitals within both the  highest occupied molecular orbital  (HOMO) and the  lowest unoccupied molecular orbital  (LUMO) which allows for excited electrons to switch multiplicities via intersystem crossing. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8639", "text": "While many organometallic photosensitizer compounds are made synthetically, there also exists naturally occurring,  light-harvesting  organometallic photosensitizers as well. Some relevant naturally occurring examples of organometallic photosensitizers include  Chlorophyll A  and  Chlorophyll B . [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8640", "text": "Organic photosensitizers are carbon-based molecules which are capable of photosensitizing. The earliest studied photosensitizers were aromatic hydrocarbons which absorbed light in the presence of oxygen to produce reactive oxygen species. [ 22 ]  These organic photosensitizers are made up of highly  conjugated  systems which promote  electron delocalization . Due to their high conjugation, these systems have a smaller gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) as well as a continuum of orbitals within the HOMO and LUMO. The smaller  band gap  and the continuum of orbitals in both the  conduction band  and the  valence band  allow for these materials to enter their triplet state more efficiently, making them better photosensitizers. Some notable organic photosensitizers which have been studied extensively include benzophenones, methylene blue, rose Bengal, flavins, pterins [ 23 ]  and others. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8641", "text": "Colloidal  quantum dots  are nanoscale  semiconductor  materials with highly tunable optical and electronic properties. Quantum dots photosensitize via the same mechanism as organometallic photosensitizers and organic photosensitizers, but their nanoscale properties allow for greater control in distinctive aspects. Some key advantages to the use of quantum dots as photosensitizers includes their small, tunable  band gap  which allows for efficient transitions to the triplet state, and their insolubility in many solvents which allows for easy retrieval from a synthetic reaction mixture. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8642", "text": "Nanorods , similar in size to quantum dots, have tunable optical and electronic properties. Based on their size and material composition, it is possible to tune the maximum absorption peak for nanorods during their synthesis. This control has led to the creation of photosensitizing nanorods. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8643", "text": "Photodynamic therapy  utilizes Type II photosensitizers to harvest light to degrade  tumors  or cancerous masses. This discovery was first observed back in 1907 by  Hermann von Tappeiner  when he utilized  eosin  to treat skin tumors. [ 11 ]  The photodynamic process is predominantly a noninvasive technique wherein the photosensitizers are put inside a patient so that it may accumulate on the tumor or cancer. When the photosensitizer reaches the tumor or cancer, wavelength specific light is shined on the outside of the patient's affected area. This light (preferably  near infrared  frequency as this allows for the penetration of the skin without acute toxicity) excites the photosensitizer's electrons into the triplet state. Upon excitation, the photosensitizer begins transferring energy to neighboring ground state triplet oxygen to generate excited  singlet oxygen . The resulting excited oxygen species then selectively degrades the tumor or cancerous mass. [ 25 ] [ 26 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8644", "text": "In February 2019, medical scientists announced that  iridium  attached to  albumin , creating a photosensitized molecule, can penetrate  cancer cells  and, after being irradiated with light (a process called  photodynamic therapy ), destroy the cancer cells. [ 27 ] [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8645", "text": "In 1972, scientists discovered that chlorophyll could absorb sunlight and transfer energy into electrochemical cells. [ 29 ]  This discovery eventually led to the use of photosensitizers as sunlight-harvesting materials in solar cells, mainly through the use of photosensitizer dyes.  Dye Sensitized Solar cells  utilize these photosensitizer dyes to absorb photons from  solar light  and transfer energy rich electrons to the neighboring  semiconductor  material to generate electric energy output. These dyes act as  dopants  to semiconductor surfaces which allows for the transfer of light energy from the photosensitizer to electronic energy within the semiconductor. These photosensitizers are not limited to dyes. They may take the form of any photosensitizing structure, dependent on the semiconductor material to which they are attached. [ 16 ] [ 14 ] [ 30 ] [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8646", "text": "Via the absorption of light, photosensitizers can utilize triplet state transfer to reduce small molecules, such as water, to generate Hydrogen gas. As of right now, photosensitizers have generated hydrogen gas by splitting water molecules at a small, laboratory scale. [ 32 ] [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8647", "text": "In the early 20th century, chemists observed that various aromatic hydrocarbons in the presence of oxygen could absorb wavelength specific light to generate a peroxide species. [ 12 ]  This discovery of oxygen's reduction by a photosensitizer led to chemists studying photosensitizers as  photoredox catalysts  for their roles in the catalysis of  pericyclic reactions  and other  reduction  and  oxidation  reactions. Photosensitizers in synthetic chemistry allow for the manipulation of electronic transitions within molecules through an externally applied light source. These photosensitizers used in redox chemistry may be organic, organometallic, or nanomaterials depending on the physical and spectral properties required for the reaction. [ 16 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8648", "text": "Photosensitizers that are readily incorporated into the external tissues can increase the rate at which reactive oxygen species are generated upon exposure to UV light (such as UV-containing sunlight). Some photosensitizing agents, such as St. John's Wort, appear to increase the incidence of inflammatory skin conditions in animals and have been observed to slightly reduce the minimum tanning dose in humans. [ 34 ] [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8649", "text": "Some examples of photosensitizing medications (both investigatory and approved for human use) are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8650", "text": "A  Ramsden emulsion , sometimes named  Pickering emulsion , is an  emulsion  that is stabilized by solid particles (for example  colloidal   silica ) which adsorb onto the  interface  between the water and oil  phases . Typically, the emulsions are either water-in-oil or oil-in-water emulsions, but other more complex systems such as water-in-water, oil-in-oil, water-in-oil-in-water, and oil-in-water-in-oil also do exist. Pickering emulsions were named after  S.U. Pickering , who described the phenomenon in 1907, although the effect was first recognized by  Walter Ramsden  in 1903. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8651", "text": "If oil and water are mixed and small oil droplets are formed and dispersed throughout the water (oil-in-water emulsion), eventually the droplets will  coalesce  to decrease the amount of energy in the system. However, if solid particles are added to the mixture, they will bind to the surface of the interface and prevent the droplets from coalescing, making the emulsion more stable."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8652", "text": "Particle properties such as  hydrophobicity , shape, and size, as well as the  electrolyte  concentration of the continuous phase and the volume ratio of the two phases can have an effect on the stability of the emulsion. The particle\u2019s  contact angle  to the surface of the droplet is a characteristic of the hydrophobicity of the particle. If the contact angle of the particle to the interface is low, the particle will be mostly  wetted  by the droplet and therefore will not be likely to prevent coalescence of the droplets. Particles that are partially hydrophobic are better stabilizers because they are partially wettable by both liquids and therefore bind better to the surface of the droplets. The optimal contact angle for a stable emulsion is achieved when the particle is equally wetted by the two phases (i.e. 90\u00b0 contact angle). The stabilization energy is given by"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8653", "text": "where r is the particle radius,  \n \n \n \n \n \u03b3 \n \n O \n W \n \n \n \n \n {\\displaystyle \\gamma _{OW}} \n \n  is the interfacial tension, and  \n \n \n \n \n \u03b8 \n \n O \n W \n \n \n \n \n {\\displaystyle \\theta _{OW}} \n \n  is the contact angle of the particle with the interface."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8654", "text": "When the contact angle is approximately 90\u00b0, the energy required to stabilize the system is at its minimum. [ 3 ] \nGenerally, the phase that preferentially wets the particle will be the continuous phase in the emulsion system. The most common type of Ramsden emulsions are oil-in-water emulsions due to the hydrophilicity of most organic particles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8655", "text": "One example of a Ramsden-stabilized emulsion is homogenized milk. The milk protein ( casein ) units are adsorbed at the surface of the milk fat globules and act as  surfactants . The casein replaces the milkfat globule membrane, which is damaged during homogenization. Other examples of emulsions where Ramsden particles may be the stabilizing species are for example detergents, low-fat chocolates, mayonnaises and margarines."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8656", "text": "Ramsden emulsions have gained increased attention and research interest during the last 20 years when the use of traditional  surfactants  was questioned due to environmental, health and cost issues. Synthetic  nanoparticles  as Ramsden emulsion stabilizers with well-defined sizes and compositions have been the primarily particles of interest until recently when also natural organic particles have gained increased attention. They are believed to have advantages such as cost-efficiency and degradability, and are issued from renewable resources. [ 4 ]  \nPickering emulsions find applications for  enhanced oil recovery [ 5 ]  or  water remediation . [ 6 ]  Certain Pickering emulsions remain stable even under gastric conditions and show an extraordinary resistance against gastric  lipolysis , [ 7 ]  facilitating their use for controlled lipid digestion and satiation [ 8 ]  or oral delivery systems. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8657", "text": "Additionally, it has been demonstrated that the stability of the Ramsden emulsions can be improved by the use of amphiphilic \" Janus particles \", namely particles that have one hydrophobic and one hydrophilic side, due to the higher adsorption energy of the particles at the liquid-liquid interface. [ 10 ]  This is evident when observing  emulsion stabilization using polyelectrolytes ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8658", "text": "It is also possible to use  latex  particles for Ramsden stabilization and then fuse these particles to form a permeable shell or capsule, called a colloidosome. [ 11 ]  Moreover, Ramsden emulsion droplets are also suitable templates for  micro-encapsulation  and the formation of closed, non-permeable capsules. [ 12 ]  This form of encapsulation can also be applied to water-in-water emulsions (dispersions of phase-separated aqueous polymer solutions), and can also be reversible. [ 13 ] \nPickering-stabilized microbubbles may have applications as ultrasound  contrast agents . [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8659", "text": "Pill-splitting  refers to the practice of splitting a  tablet  or  pill  to provide a lower dose of the active ingredient, or to obtain multiple smaller doses, either to reduce cost or because the pills available provide a larger dose than required. Many pills that are suitable for splitting ( aspirin  tablets for instance) come pre-scored so that they may easily be halved."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8660", "text": "The practice is also referred to as tablet scoring. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8661", "text": "It is unsafe to split some  prescription medications . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8662", "text": "A pill-splitter is a simple and inexpensive device to split medicinal pills or  tablets , comprising some means of holding the tablet in place, a blade, and usually a compartment in which to store the unused part. The tablet is positioned, and the blade pressed down to split it. With care it is often possible to cut a tablet into  quarters . Also available as consumer items are  multiple pill splitters , which cut numerous round or oblong pills in one operation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8663", "text": "A  drug manufacturer  may score pills with a  groove  to both indicate that a pill may be split and to aid the practice of splitting pills. When manufacturers do create grooves in pills, the groove must be consistent for consumers to be able to use them effectively. Many manufacturers choose to not use grooves. The United States government  Center for Drug Evaluation and Research  makes the following recommendations for manufacturers when scoring pills with grooves: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8664", "text": "In the U.S. \"uniformity of dosage units\" is defined by the  United States Pharmacopeia  (USP), which describes itself as \"the official public standards-setting authority for all prescription and over-the-counter medicines, dietary supplements, and other healthcare products manufactured and sold in the United States.\" [ 4 ]  More than 140 countries develop or rely upon US pharmaceutical standards according to the USP."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8665", "text": "The USP standard for dosage uniformity expresses statistical criteria in the complex language of  sampling protocols .  The pharmaceutical dosage literature sometimes boils this down as requiring a  standard deviation  in dosage weight of less than 6%, which roughly corresponds to the weaker rule-of-thumb offered for public consumption that the vast majority of dosage units should be within 15% of the dosage target.  \"Dosage unit\" is a technical term which covers oral medications (tablets, pills, capsules), as well as non-oral delivery methods. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8666", "text": "A 2002 study of pill-splitting as conducted in four American long-term care facilities determined that 15 of the 22 dispensed prescriptions evaluated (68%) had fragment weight variance in excess of USP standards. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8667", "text": "Pill-splitting can be used to save money on pharmaceutical costs, as many prescription pharmaceuticals are sold at prices less than proportional to the dose.  For example, a 10\u00a0mg tablet of a drug might be sold for the same or nearly the same price as a 5\u00a0mg tablet. Splitting 10\u00a0mg tablets allows the patient to purchase half the number of tablets at a lower price than the same weight of 5\u00a0mg tablets."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8668", "text": "Both specialist and generalist physicians are not sufficiently aware of and do not communicate with patients about the cost to them of medication. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8669", "text": "Randall Stafford of the  Stanford School of Medicine  published a study in 2002 of common prescription medications in the United States in which he evaluates pill splitting for \"potential cost savings and clinical appropriateness\".  The study identifies eleven prescription medications that satisfied the study criteria, based on the American pharmaceutical cost structure, pill formulation, and dosages of the time. [ 8 ]   Most of the medications listed in the table from the psychiatric drug class are  antidepressants ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8670", "text": "Not all tablets split equally well.  In a 2002 study,  Paxil ,  Zestril  and  Zoloft  split cleanly with 0% rejects.   Glucophage  was described as a hard tablet, requiring significant force, causing tablet halves to fly.   Glyburide  exhibited very poor splitting with many splitting into multiple pieces.   Hydrodiuril  and  Oretic  crumbled.   Lipitor  did not split cleanly, and the coating peeled.  The diamond shaped  Viagra  tablets made location of the midline difficult.  The worst result reported was Oretic 25\u00a0mg in which 60% of tablets failed to split to within 15% of target weight. [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8671", "text": "Some drugs have a few different uses, and are usually sold in different packages and different doses for different applications. The price for some applications may be very different from that for other purposes. [ citation needed ]  One example is  Minoxidil , which is well known as a hair-growth stimulant; the same drug under the name  Loniten  is used for blood pressure control in much larger doses at a much lower price per unit weight. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8672", "text": "The  Food and Drug Administration  (FDA) has called pill splitting \"risky\". [ 11 ]  At the same time, the FDA approves the manufacture of pills which are intended to be split. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8673", "text": "Splitting pills may result in uneven splitting and creating pieces which will not deliver accurate dosage. [ 11 ]  Pills which are split might not be correctly halved, making the cut pieces unequal in size. [ 11 ]  Some pills are difficult to split. [ 11 ]  Some pills (particularly some  time release drugs ) [ 12 ]  are unsafe to split, and there could be mistakes in identifying when pills should not be split. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8674", "text": "In a  California  court filing dated April 2001,  Trial Lawyers for Public Justice  (TLPJ) brought a class-action lawsuit against  Kaiser Permanente  ( Timmis v. Kaiser Permanente ) on the grounds that \"Kaiser's mandatory pill-splitting policy endangers patients' health solely to enhance the HMO's profits\" in violation of the  California Unfair Competition Law  (UCL) and the  California Consumer Legal Remedies Act  (CLRA). [ 13 ] [ 14 ]  In December 2004, the  California Court of Appeal  affirmed the trial court ruling that Kaiser's policy did not violate UCL or CLRA, noting the suit had failed to present evidence that the policy was unsafe. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8675", "text": "Polystyrene  is a synthetic hydrocarbon polymer that is widely adaptive and can be used for a variety of purposes in drug delivery. These methods include  polystyrene  microspheres, nanoparticles, and solid foams. In the biomedical engineering field, these methods assist researchers in drug delivery, diagnostics, and imaging strategies. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8676", "text": "A common group of medication that utilizes a combination of polystyrene and sulfonate functional groups are  polystyrene sulfonates . [ 3 ]  This medication is primarily used to treat  hyperkalemia , a condition that results from an increased blood potassium level. [ 3 ]   FDA  approved equivalents of polystyrene sulfonates are KIONEX, KALEXATE, and SPS. While these are the only current FDA approved drug that utilizes polystyrene, polystyrene sees a number of applications in other pharmacological contexts with nanoparticles and microspheres."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8677", "text": "Polystyrene integrated solid foams are not commonly used in biomedical applications but have shown promise as a new drug delivery vehicle. The manipulation of the porous foam networks is a fundamental component in solid foam dosing \u2013 affecting variables such as dissolution,  adsorption , and drug diffusion. [ 4 ]  Solid foam structures are particularly attractive due to the predictability in drug release profiles through the highly tunable porosity and high surface area of these foams. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8678", "text": "The process of creating these structures is typically a hassle, requiring multiple step processes in order to synthesis a foam of desired properties. [ 4 ]  However, polystyrene solid foams have been created through simpler methods such as  extrusion  from a blowing agent or polystyrene bead expansion. [ 4 ]  While these methods are typically utilized for insulation or similar industry uses, this production method has also seen use in drug delivery applications [5]. Polystyrene solid foams can also be produced through emulsions. [ 4 ]  An  emulsion  can be created through the combination of two immiscible liquids. [ 4 ]  While many methods are used to create emulsion, Canal et al. used a unique method known as phase inversion temperature (PIT). [ 4 ]  PIT utilizes phase transitions to produce highly concentrated amounts of emulsion quickly. [ 4 ]  Through changes in temperature, solubility, and low interfacial tension, PIT is able to efficiently promote emulsion. [ 4 ]  The porosity of these solid foams is able to be fine-tuned, showing promise for osteogenic and therapeutic applications. [ 4 ]  For example, proposed osteogenic applications include the promotion of bone integration. [ 4 ]  The study conducted by Canal et al., utilized polystyrene solid foams as a drug delivery method to evaluate the drug release profile of  ketoprofen . [ 4 ]  Researchers have stated that understanding the release profile for various drugs with polystyrene solid foams could significantly improve treatment outcomes for many disease states."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8679", "text": "Nanoparticles  have been used in drug delivery for applications such as diagnosis and treatment of diseases, with polymeric nanoparticles gaining significant traction as a carrier of drugs or  biomolecules  over the last few decades. [ 5 ] [ 6 ] [ 7 ]  These structures are extremely small, having a diameter < 100\u00a0nm. [ 6 ]  The high surface to volume ratio allows nanoparticles to display properties that are different than their bulk material in biological systems. [ 7 ]  These properties have been the sole reason of their use in physiological environments. [ 7 ]  While the structure of nanoparticles is straightforward, the efficacy of nanoparticles is affected by variables such as size and surface modifications which determines their overall biocompatibility and biological interaction. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8680", "text": "Polystyrene nanoparticles are the model nanoparticle used for drug delivery applications because they are easy to synthesize in varying sizes. Size is an important factor in cellular uptake rates, which is important for specific pathways such as the endocytic pathway. In a study conducted by Rejman et al., researchers were able to show that polystyrene nanoparticles with diameters of 50\u00a0nm and 100\u00a0nm were internalized faster than nanoparticles with diameters of 200\u00a0nm and 500\u00a0nm. [ 2 ] [ 8 ]  Internalization is vital in understanding the impact the designed nanoparticles are having on the target cells. [ 2 ]  Nanoparticle internalization depends on a couple of key factors such as nanoparticle size, cell type, and time. [ 2 ]  Nanoparticles of larger size are typically internalized through processes such as  phagocytosis  or  micropinocytosis . [ 2 ]  Smaller nanoparticles are typically internalized through processes such as macro-pinocytosis, phagocytosis, clathrin-mediated endocytosis, caveolae-mediated endocytosis, and clathrin-and caveolae-independent pathways. [ 2 ]  The diversity in pathways is one of the greatest challenges with utilizing these nanoparticles since a case-by-case approach is typically required to maximize the entry pathways. [ 2 ]  To measure nanoparticle internalization, techniques such as fluorescence activated cell sorting/scanning (FACS), inductively coupled plasma (ICP) mass spectroscopy, confocal laser scanning microscopy (CLSM), and imaging flow cytometry (IFC) are utilized, each offering their own advantages and disadvantages. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8681", "text": "The main advantage of polystyrene nanoparticles is their biocompatibility, which allows them to be used broadly for biomedical devices and the study of bio-nano interactions. [ 6 ] [ 7 ]  Furthermore, their ability to not degrade in cellular environments proves to be an asset in biomedical applications. [ 7 ]  A unique property of polystyrene nanoparticles, like some other polymers, is their ability to fuse with proteins. [ 6 ]  When proteins bind to the surface of the nanoparticle, a protein corona is formed. [ 6 ]  A protein corona encapsulates the identity of the nanoparticle, and the properties of the corona can be manipulated based on the physical properties of the nanoparticle. [ 6 ]  The corona can be defined as \u201csoft\u201d or \u201chard\u201d depending on bonding strength and surface-bound protein exchange rate. [ 6 ]  As such, a soft protein corona is defined by nanoparticles that are loosely bound and proteins that are easily exchangeable. [ 6 ]  In contrast, a hard protein corona has nanoparticles that are tightly bound and proteins that are not as easily exchangeable. [ 6 ]  These kinetics are vital in understanding how nanoparticles will respond in biological fluid. [ 6 ] [ 9 ]  The hardness of the protein corona plays a role in the Vroman effect, a principle that describes how proteins with higher affinities replace proteins of lower affinity [8], [11]. The Vroman effect is influenced by protein concentration relative to the surface area and diffusion coefficients. [ 6 ] [ 9 ]  Overall, this affects the protein surface binding affinity. For example, Ehrenburg et al. have shown that fibrinogen presence rapidly declines with polystyrene nanoparticles containing functional groups, such as COOH and CH 3 . [ 10 ]  This allows a protein such as albumin, with a lower affinity, to adsorb and become replaced by fibrinogen. [ 10 ]  Overall, polymeric nanoparticles that can fuse with proteins have a significant advantage over other polymeric nanoparticles due to this versatility in biological interaction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8682", "text": "Certain properties of polystyrene nanoparticles can be modified depending on the scenario. For instance, the surface of polystyrene nanoparticles can be manipulated by surface oxidation, which creates a surface that is highly receptive with cell cultures. These surface-level modifications also express a lower polydispersity index and can create stable colloids in biological liquid. [ 11 ]  Similarly, the surface of these nanoparticles can be treated with  ethylene oxide  or  UV irradiation  for sterilization purposes. [ 7 ]  Due to the emphasis on biocompatibility, Loos et al. have utilized polystyrene nanoparticles as a model to analyze how different surface properties affect biomedical variables. [ 7 ]  Overall, it was determined that a strong understanding of surface properties is vital to manipulate parameters such as  pharmacokinetics , biocompatibility, and tissue and cell affinity. [ 7 ]  \u00a0In a study conducted by Lundqvist et al., the protein corona was studied with three surface modified polystyrene (plain, carboxyl-modified, and amine-modified) nanoparticles of two different sizes (50\u00a0nm and 100\u00a0nm). [ 12 ]  This study ultimately showed that surface corona properties are also affected by size and surface composition. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8683", "text": "Polystyrene nanoparticles have been used in various applications such as cancer treatment. [ 1 ]  The primary issue associated with treating cancer is that many chemotherapies suffer from poor penetration into tumor cells. [ 1 ]  In a study conducted by Larina et al., researchers utilized polystyrene nanoparticles in conjunction with ultrasound radiation to influence tumor regression. [ 1 ]  They proposed a method of utilizing ultrasound-induced cavitation to enhance drug delivery to cancer cells. [ 1 ]  Nanoparticles have typically been used in these applications because they are able to accumulate in these tumor sites actively or passively. [ 1 ]  For this application, since cavitation is an important factor, polystyrene nanoparticles were used since their presence allows cavitation to occur at lower pressure intensities. [ 1 ]  Within mice models, their study found that ultrasound irradiation and polystyrene nanoparticles with a combination of 5-FU injections showed strong levels of tumor inhibition and total tumor regression. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8684", "text": "The effect of polystyrene nanoparticles on various cell lines have also been researched. [ 13 ]  Application with human gastric adenocarcinoma cell (AGS) lines has been studied due to these cells being the first line of contact with nanoparticles from ingestion. [ 13 ]  The goal of the study by Forte et al. was a further understanding of nanoparticle interaction with biological systems by studying the kinetic uptake of polystyrene nanoparticle uptake by AGS cells. [ 13 ]  Just as previous studies have shown, it was concluded that the primary factors that influence drug delivery strategies are the size and concentration of these nanoparticles. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8685", "text": "Polystyrene nanoparticle composites have also been the focus of literature due to their adaptability. Composites are useful since the properties for the constituent materials can be combined in a way that is unlike the original components. [ 14 ]  This is extremely relevant in drug delivery applications to fine tune specific parameters case-by-case. In a study conducted by Lim et al., a composite of mono-disperse Fe 3 O 4  and polystyrene nanoparticles were utilized for cardiac myocyte treatment via magnetic targeting. [ 14 ]  Other polystyrene composites have been created with silica nanoparticles. [ citation needed ]  These materials are attractive for a number of reasons such as having low toxicity, being able to control its particle size, strong chemical and thermal stability, biocompatibility, and degradability in physiological environments. [ citation needed ]  Since many of these properties are already present in polystyrene nanoparticles (i.e.,  biocompatibility  and particle size), these structures only enhance its effect in biological environments. [ citation needed ]  As a result, composites such as these have seen increased use a mode of drug delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8686", "text": "Microspheres  (or microparticles) are a group of small spherical particles that typically have a diameter ranging from 1\u00a0\u03bcm to 1000\u00a0\u03bcm. [ citation needed ]  While microspheres can be created through natural or synthetic purposes, synthetic polymer microspheres offer useful advantages over other options. [ citation needed ]  The most common types of polymeric microspheres are  polyethylene  and polystyrene; however, polystyrene microspheres are especially useful in biomedical applications because they are able to actively facilitate cell sorting and  immunoprecipitation . [ citation needed ]  This results in proteins and ligands adsorbing readily, similar to polystyrene nanoparticles. Polystyrene microparticles are also  hydrophobic  meaning that they will not swell when exposed to a biological environment. [ citation needed ]  Microspheres are applicable with a myriad of drug delivery applications (e.g.,  ophthalmic , gene, intra-tumoral, local, oral, nasal, gastrointestinal, peroral, vaginal, transdermal, and colonic drug delivery). [ citation needed ]  Polystyrene microspheres have also seen use in magnetic and radiolabeled microspheres. [ 15 ]  Similarly, model microspheres such as carboxylated polystyrene microspheres have been used for many studies due to high ligand conjugation through carbodiimide chemistry. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8687", "text": "The way that microspheres are prepared can influence their physical properties. Preparation methods such as  precipitation polymerization , seed polymerization, microemulsion, and dispersion polymerization have been used in the past to create polystyrene microspheres. [ 16 ]  Precipitation polymerization is a robust method of polymer synthesis where a monomer and initiator are dissolved in a solvent. [ 16 ]  This method is advantageous due to low viscosities, clean surfaces, low solid content, and irregular geometries, factors which are beneficial in physiological environments. [ 16 ]  Seed polymerization is a preparation method used to create core-shell emulsions. [ 16 ]  These structures have good stability and narrow particle size distribution, however, due to a long and complex preparation process there is a high likelihood of monomers becoming embedded inside the particles. [ 16 ]  Microemulsions are a method of creating emulsions through an emulsifier. [ 16 ]  By creating particles with microbubbles, this method can create particles that have similar particle size and stability. [ 16 ]  Dispersion polymerization is a method of creating particles with similar size with the advantage of being easy to perform and operate. [ 16 ]  With this method, particle size can easily be modified by manipulating the concentrations of stabilizer, co-monomer, and water. [ 16 ] [ 17 ]  Due to these reasons, dispersion polymerization has become one of the primary methods of polystyrene microsphere synthesis. [ 16 ]  Each of these methods offer their own advantages and disadvantages and are chosen for microsphere synthesis accordingly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8688", "text": "Polystyrene microspheres have previously been used for  serological tests  (i.e.,  rheumatoid arthritis ,  disseminated lupus erythematous , and  pregnancy tests ). [ 18 ]  Saravanan et al. have shown that polystyrene microspheres can be used for controlled drug delivery applications with  ibuprofen . [ 18 ]  One of the biggest limitations associated with drug delivery is that intravenously injected drug carriers (e.g., microspheres and  liposomes ) become trapped by mononuclear phagocyte system (MGS) cells. [ 19 ]  This limitation is important to overcome for the progression of treatment outcomes for diseases such as  AIDS  and  tuberculosis  which primarily rely on the macrophage response system. [ 19 ]  A study by Makino et al. delved into the required size and surface modifications required for alveolar macrophages to uptake polystyrene microspheres. [ 19 ]  It was shown that microspheres with a softer surface were more accessible to alveolar macrophages. [ 19 ]  Moreover, primary amine groups were also shown to be more effective over carboxyl groups. [ 19 ]  As a result, polystyrene microspheres have seen increased use a mode of drug delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8689", "text": "One of the most important factors to consider is the toxicity of the polystyrene particles. Many  in vitro  studies have been conducted to understand how these structures can affect reactive oxygen species generation and cell viability. [ 6 ] [ 20 ]  Overall, these studies showed that polystyrene nanoparticles did not affect cell viability. [ 6 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8690", "text": "Similarly, it is important to consider polystyrene toxicity in human models. The use of polystyrene has been under scrutiny by various international and local agencies due to the effects of polystyrene on the environment. As a result, there has always been a cause for concern for how polystyrene can affect human health. The  Environmental Protection Agency (EPA)  and studies conducted by Mutti et al. claim that the chronic toxicity of styrene is 300ppm (1,000\u00a0\u03bcg/m 3 ). [ 6 ] [ 21 ]  Within the polymer industry, these levels typically don't go over 20ppm. [ 6 ] [ 21 ]  Furthermore, the FDA reports that the admissible daily intake (ADI) is 90,000\u00a0\u03bcg/person/day. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8691", "text": "Reduction-sensitive nanoparticles  (RSNP) consist of  nanocarriers  that are chemically responsive to  reduction . Drug delivery systems using RSNP can be loaded with different drugs that are designed to be released within a concentrated reducing environment, such as the tumor-targeted microenvironment. Reduction-Sensitive Nanoparticles provide an efficient method of targeted drug delivery for the improved controlled release of medication within localized areas of the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8692", "text": "Nanoparticles  are small in size with maximized surface area and have an enhanced level of solubility; these elements result in an improved bioavailability. [ 1 ] [ 2 ]  Reduction-Sensitive Nanoparticles are nanoparticles that are responsive to reduction signaling environments. Redox-Sensitive Nanoparticles can be responsive to signaling through a reduction activation or an oxidative activation. Therefore, degradation of chemical bonds can be either activated through  oxidants  or  reductants  in the localized area. The cleavage/degradation of chemical bonds will enable the drugs loaded within the nanoparticle to be released into the body. Depending on the activation mechanism, Redox-Sensitive Nanoparticles can be associated with Reduction-Sensitive Nanoparticles if the chemical activation method is through reduction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8693", "text": "Nanoparticle Drug Loading is dependent on the mass ratio of the drug being loaded and the drug-loaded nanoparticle. [ 3 ]  Variations necessary to consider are the pore volume size, the surface, shape, and charge of the nanoparticle. The mode of drug loading will depend on the type of drug being administered, which will vary depending on the illness that is treated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8694", "text": "One of the limitations of nanoparticles for drug delivery is the insufficient or slow release of drugs. The rate of release is a critical element to identify how slowed drug release could limit the proper concentration of treatment. If the drug is not administered in concentrations high enough it could result in undertreatment of tumor cells with little to no effect. Concentration thresholds must be met to initiate cell death amongst tumor cells. However, the uncontrolled release of treatment could also permit adverse side effects. RSNPs have improved rates of drug release which improves the medication concentrations that can be administered to a specific area."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8695", "text": "RSNPs consist of reduction or redox-sensitive bonds. After administration in the body, the RSNP will eventually come into contact with the  tumor microenvironment  (TME). Nanoparticles can be synthesized to activate when exposed to selective characteristics of the tumor microenvironments. TMEs depict unique characteristics that create a differing microenvironment in comparison to healthy tissue. Thus, nanoparticles can be designed to react to the unique elements of TMEs such as the formation of a reducing environment. The reducing abilities of the TMEs are due to the expression of reducing agents. [ 4 ]  RSNPs are formulated to express reduction-sensitive bonds that are cleaved when exposed to reducing agents. After the reduction occurs the degradation of the nanoparticles commences and the loaded drugs begin to release."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8696", "text": "The physicochemical characteristics of nanoparticles are inclusive of the size, shape, chemical composition, stability, topography, surface charge, and surface area. [ 5 ]  Deviations of these characteristics can be impacted by the classification of the nanoparticle. For example, the RSNP can be classified as a polymeric, micelle, or lipid-polymeric hybrid. [ 6 ] [ 7 ]  The reduction sensitivity of nanoparticles is reliant on the reduction-responsive chemical structures infused into the nanoparticle. Reduction occurs when the number of electrons increases in a chemical species. Reduction sensitive nanoparticles depict high plasma stability and quick responsiveness/activation. [ 2 ]  The reducing environment of tumor cells is greatly impacted by the oxidation and reduction states of  NADPH /NADP+ and  Glutathione . [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8697", "text": "For the effective application of RSNPs, the physicochemical characteristics of the tumor microenvironment must also be considered. The characteristics depicted by the TME are  tumor hypoxia ,  angiogenesis ,  metabolism ,  acidosis ,  reactive oxygen species  (ROS), etc. [ 4 ]  The elements of the tumor microenvironment can affect the reduction-inducing environment. Tumor cells abnormally regulate  redox  homeostasis leading to differences in the redox balance and increases in ROS levels. Research trends have shown that increased levels of ROS are correlated with high levels of antioxidant activity, such as intracellular GSH. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8698", "text": "Glutathione (GSH) or \u03b3-glutamyl-cysteinyl-glycine is a critical biological reducing agent for drug delivery applications; it creates an effective reducing environment in the  cytosol  and  nucleus  of a cell. [ 8 ] [ 9 ]  Glutathione is an  antioxidant  that is naturally produced in the liver and takes part in tissue building, tissue repair, immune responses, chemical production, and protein production. GSH is also a significant signaler of cell differentiation, proliferation, apoptosis, and ferroptosis. [ 9 ]  Furthermore, the glutathione concentration in the tumor microenvironment is reportedly at least four times higher compared to regular tissue. This is due to the high metabolic needs of tumor cells; for example, the rapid proliferation rates of tumor cells. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8699", "text": "The over-expression of nicotinamide adenine dinucleotide phosphate NADPH can lead to higher ROS levels. NADPH has a lower concentration than GSH in the reducing environment. [ 9 ]  NADPH is an electron donor that exists among all organisms; additionally, the NADPH is used as a source of reduction to drive anabolic reactions and redox balances. The reduction and oxidation states of NADPH/NADP+ will influence the reduced responsiveness of the environment. Cancer cells express a unique NADPH homeostasis due to the adaptive alterations of signaling pathways and metabolic enzymes. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8700", "text": "Redox-Sensitive Nanoparticles with  Disulfide bonds  are commonly observed in medical research. RSNP can consist of disulfide bonds that are cleaved and introduced to a reduction condition. Additionally, the reduction of glutathione results in the formation of sulfhydryl groups. [ 8 ] [ 9 ]  In large concentrations of GSH, the disulfide bonds are capable of being cleaved. Following the activation process, the degradation of the drug carrier results in the drug release. These linkages are commonly used between hydrophilic and hydrophobic segments in copolymers. Moreover, RSNP's hydrophilic shells will degrade in response to the reducing environment. The disulfide bonds are used as linkers and cross-linking agents. Disulfide bonds can be expressed attached to the side chains, the backbone, on the surface, and as linkages between moieties. [ 9 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8701", "text": "Disulfide bonds can also act as cross-linking agents in micelles nanoparticles. Micelles lack the structural stability as a nanocarrier for drug delivery. The lack of stability can result in the loss of drugs after administration and before reaching the infected area. This occurrence can potentially cause adverse side effects from the improper release of medication. Disulfide bonds can be used as crosslinked structures to increase the structural stability of micelle nanocarriers. In general, these crosslinks are located in the shell or the core of micelles nanoparticles. [ 9 ] [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8702", "text": "Redox-Sensitive Nanoparticles with  Diselenide  bonds share comparable reduction responsiveness to disulfide bonds. Diselenide consists of two selenium atoms along with an additional element or radical. Diselenide bonds are dynamic covalent bonds that can be exchange between molecules. Diselenide bonds have an estimated bond energy of 172 kJ/mol, and disulfide bonds have estimated bond energy of 268 kJ/mol; the lower bond energy holds a higher potential to design an increased sensitive redox-responsive delivery. [ 9 ]  Diselenide bonds have been observed to be attached to hydrophobic parts of amphiphilic triblocks or hyperbranched copolymers to create micelles. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8703", "text": "Succinimide-thioether linkages express sensitivity to reducing environments and can be cleaved as a result. Succinimide-thioether bonds show slower rates of release in comparison to disulfide bonds; however, succinimide-thioether nanoparticles are still sensitive to the reducing environment and are cleaved by GSH for fast intracellular release. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8704", "text": "Nanoparticles with Trimethyl Benzoquinone have demonstrated responsiveness to reduced environments. The experiments that have been conducted testing TMBQ are limited in observing the full scope of TMBQ nanoparticles in delivery systems. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8705", "text": "The synthesis of reduction sensitive nanoparticles is dependent on the mechanism subtype of the nanoparticle. Additionally, the synthesis can vary within subtype classes depending on how the different reduction sensitive bonds are expressed. The deviations of RSNPs can range from attachments to the backbone, side chains, on the surface, etc. Research has been conducted with reduction sensitivity mechanisms using polymeric, lipid-polymer hybrids, and micelles nanoparticles. The production methods would be dependent on the delivery method design for the nanoparticle. Polymeric nanoparticle synthesis occurs from the addition of electrolyte-saturated or a nonelectrolyte-saturated solution with a water-miscible solvent; additionally, the mixture should be constantly stirred. Lipid micelles are formed by amphiphilic molecules through self-assembly. Lipid-polymer hybrids have multiple synthesis methods which consist of the single-step method, the two-step method, nanoprecipitation, emulsification-solvent evaporation, and a non-conventional two-step method. [ 6 ] [ 7 ] [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8706", "text": "Reduction Sensitive Nanoparticles provide a mode of localized drug delivery by targeting elements of the tumor microenvironment. RSNP has the advantages of high stability when adhering to hydraulic degradation, fast responsiveness to the intracellular reducing environment, and drug release occurs in the cytosol and cell nucleus. Furthermore, drug release in the cytosol and cell nucleus has shown the potential to effectively administer treatment of more potent and poorly soluble anticancer drugs. [ 16 ]  The quick-release of RSNPs has the potential to offer an effective treatment for multidrug-resistant tumors. This addresses an important limitation of nanoparticles. Nanoparticle drug delivery often exhibits slow drug release. The slow release can lead the nanomedicine to be released at low concentrations; moreover, these limited concentrations inhibit the cell death of the tumor cells. Polymeric RSNPs have shown improved solubility, stability, biocompatibility, and decreased drug toxicity; for example, carbohydrate polymers. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8707", "text": "The effectiveness of reduction-sensitive nanoparticles is dependent on the responsiveness of the RSNP throughout the body. The microtumor and inflammatory environments contain higher concentrations of reducing agents in contrast to healthy cells; however, healthy cells still express GSH and NADPH. RSNPs are designed to be receptive to higher concentrations of reducing agents for the ability to distinguish between cancer cells and healthy cells. Furthermore, the other limitations are dependent on other characterizations, such as the type of nanoparticle; For example, micelles nanoparticles' lower levels of physical stability which can lead to drug loss and release in unwanted locations. Additionally, polymeric nanoparticles cannot effectively target the tumor and often undergo drug release too early. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8708", "text": "Reduction Sensitive Nanoparticles are used as nanomedicines for drug delivery. As nanocarriers, RSNP can be loaded with drugs for disease therapeutics. [ 18 ]  This is commonly observed in the use of tumor and cancer treatments. Cancer cells create reducing environments that are used for RSNP activation. RSNPS can also increase the penetration of cancer treatment to the cancer cells. Specific applications include, but are not limited to Breast Cancer, Liver Cancer (hepatoma), Melanoma, Lung Cancer, Malignant Glioma, Ovarian Cancer, Cervical Cancer, Subcutaneous EAT, Pancreatic Cancer, Colon Cancer, Prostate Cancer, etc. [ 2 ] [ 8 ] [ 19 ] [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8709", "text": "The development of RSNP for inflammatory diseases has been explored to a lesser extent. Regardless, in more recent years reduction-sensitive and redox-sensitive nanoparticles have gained more momentum in the realm of inflammatory diseases. Further advances have demonstrated Research has been conducted to evaluate the potential of RSNP as a therapeutic for inflammatory bowel disease. The activation mechanism consisted of pH and redox sensitivity. The outcomes of the experiment demonstrated higher selectivity to the reducing potential; therefore establishing the promising potential of RSNPs for the treatment of inflammatory bowel disease. [ 22 ]  Other studies have demonstrated potential applications as activatable magnetic resonance  contrast agents . These proposed agents would help detect and monitor the treatment of inflammatory diseases by applying redox dysregulation. [ 23 ] [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8710", "text": "A  relative analgesia machine  is used by  dentists  to induce inhalation  sedation  in their patients. It delivers a mixture of  nitrous oxide  (\"laughing gas\") and  oxygen . A relative analgesia machine is simpler than an  anaesthetic machine , as it does not feature the additional  medical ventilator  and  anaesthetic vaporiser , which are only needed for administration of  general anesthetics . Instead the relative analgesia machine is designed for the light form of  anaesthesia  with nitrous oxide, where the patient is less sensitive to pain but remains fully conscious. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8711", "text": "Reverse smoking  is a kind of  smoking  where the burnt end of a hand rolled tobacco leaf is put in the mouth rather than the unlit end of the cigar. [ 1 ]  It is practiced in some parts of  Andhra Pradesh, India ,  Lusaka, Zambia  and the  Philippines . While conventional smoking is more prevalent among men, [ 2 ]  studies suggest that reverse smoking is a more common among women than men. [ 3 ] [ 4 ]  Reverse smoking is considered to be a risk factor for  oral cancer . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8712", "text": "Reverse smoking may cause a pre-malignant version of  Stomatitis nicotina , [ 6 ]  also called \"smoker's palate\", characterized by melanin depigmentation and epithelial thinning. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8713", "text": "This  health -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8714", "text": "A  safety syringe  is a  syringe  with a built-in safety mechanism to reduce the risk of  needlestick injuries  to healthcare workers and others. The  needle  on a safety syringe can be detachable or permanently attached. On some models, a  sheath  is placed over the needle, whereas in others the needle retracts into the barrel.  Safety needles [ 1 ]  serve the same functions as safety syringes, but the protective mechanism is a part of the needle rather than the syringe. Legislation requiring safety syringes or equivalents has been introduced in many nations since needlestick injuries and re-use prevention became the focus of governments and safety bodies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8715", "text": "There are many types of safety syringes available on the market. [ 2 ]  Auto Disable (AD) syringes are designed as a single use syringe, with an internal mechanism blocking the barrel once depressed so it cannot be depressed again.  The other type of syringe with a re-use prevention feature is the breaking plunger syringe. An internal mechanism cracks the syringe when the plunger is fully depressed to prevent further use. These syringes are only effectively disabled with a full depression of the plunger; users can avoid activating the re-use prevention feature and re-use the syringe."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8716", "text": "The more effective safety syringes have reuse and needlestick prevention features.  A sheath or hood slides over the needle after the injection is completed with a Needlestick Prevention Syringe, which also has a re-use prevention feature (either an auto disable mechanism or breaking plunger).  Retractable syringes use either manual or spring-loaded retraction to withdraw the needle into the barrel of the syringe.  Some brands of spring-loaded syringes can have a splatter effect, where blood and fluids are sprayed off the  cannula  from the force of the retraction.  Manual retraction syringes are generally easier to depress because there is no resistance from a spring."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8717", "text": "Traditional glass syringes can be re-used once  disinfected . Plastic body syringes have become more popular in recent years because they are disposable. Unfortunately, improper disposal methods and re-use are responsible for transferring  blood borne diseases ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8718", "text": "Of the 55 cases documented by the  CDC  of (non- sex work ) occupational transmission of  HIV , 90% were from contaminated needles that pierced the skin. [ 3 ]  The direct cost of needlestick injuries was calculated in a recent study to be between $539 and $672 million US dollars. [ clarification needed ] [ 4 ]  That includes only lab tests, treatment, service and \"other\"; [ clarification needed ]  it does not take into account lost time and wages for employers and individuals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8719", "text": "Two lawyers,  Mike Weiss  and Paul Danzinger, were approached in 1998 by an inventor, Thomas Shaw, who was having trouble selling a safety syringe developed to protect health care workers from accidentally being infected by dirty needles. The problems were due to  monopolistic  actions of a major industry needle maker and hospital group purchasing organizations. The case was settled before trial for $150 million. [ 6 ]  This was portrayed by the 2011 movie  Puncture . [ 7 ]  Shaw's attempts to get his retractable needle accepted by health care facilities were covered in a 2010  Washington Monthly  article. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8720", "text": "\u2022 Washington Monthly, Jul/Aug 2010,   \"Dirty Medicine\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_8721", "text": "A  self-microemulsifying drug delivery system  ( SMEDDS ) is a  drug delivery  system that uses a  microemulsion  achieved by chemical rather than mechanical means.  That is, by an intrinsic property of the drug formulation, rather than by special mixing and handling.  It employs the familiar  ouzo effect  displayed by  anethole  in many  anise -flavored  liquors .  Microemulsions have significant potential for use in drug delivery, and SMEDDS (including so-called \"U-type\" microemulsions) are the best of these systems identified to date. [ 1 ]   SMEDDS are of particular value in increasing the absorption of  lipophilic  drugs taken by mouth."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8722", "text": "SMEDDS in research or development include formulations of the drugs  anethole trithione , [ 2 ]   oridonin , [ 3 ] [ 4 ] [ 5 ]   curcumin , [ 6 ]   vinpocetine , [ 7 ] [ 8 ]   tacrolimus , [ 9 ] [ 10 ] [ 11 ]   mitotane ,  berberine hydrochloride , [ 12 ]   nobiletin , [ 13 ]   piroxicam , [ 14 ] [ 15 ]  anti- malaria  drugs  beta-artemether [ 16 ]  and  halofantrine , [ 17 ] [ 18 ]  anti- HIV  drug  UC 781 , [ 19 ] [ 20 ]   nimodipine , [ 21 ] [ 22 ]   exemestane , [ 23 ]  anti- cancer  drugs  9-nitrocamptothecin  (9-NC) [ 24 ]   paclitaxel , [ 25 ] [ 26 ]  and  seocalcitol , [ 27 ] [ 28 ]   alprostadil  ( intraurethral  use), [ 29 ]   probucol , [ 18 ] [ 30 ]   itraconazole , [ 31 ]   fenofibrate , [ 32 ]   acyclovir , [ 33 ]   simvastatin , [ 34 ] [ 35 ]   xibornol , [ 36 ]   silymarin , [ 37 ] [ 38 ]   alpha-asarone , [ 39 ]   enilconazole , [ 19 ]   puerarin  (an  isoflavone  found in  Pueraria lobata ), [ 40 ] [ 41 ] [ 42 ] [ 43 ]   atorvastatin , [ 44 ] [ 45 ] [ 46 ]   heparin , [ 47 ]   carvedilol , [ 48 ]   ketoconazole , [ 49 ]   gentamicin , [ 50 ]   labrasol , [ 51 ]   flurbiprofen , [ 52 ]   celecoxib , [ 53 ]   danazol , [ 54 ]   cyclosporine , [ 55 ]  and  idebenone . [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8723", "text": "Actual applications of  Self-microemulsifying drug delivery system'  (SMEDDS) remain rare. The first drug marketed as a SMEDDS was  cyclosporin , and it had significantly improved bioavailability compared with the conventional solution. In the last decade, several SMEDDS loaded with antiviral drugs ( ritonavir ,  saquinavir ) were tested for treatment of HIV infection, but the relative improvement in clinical benefit was not significant. The SMEDDS formulation of  ritonavir  (soft capsules) has been withdrawn in some countries. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8724", "text": "Within the last years SMEDDS were also utilized for the oral administration of biologics. Due to ion pairing with appropriate surfactants  [ 58 ]  these mainly hydrophilic macromolecular drugs can be incorporated in the lipophilic phase of SMEDDS. Provided that the oily droplets being formed in the gut are sufficiently stable towards lipases, [ 59 ]  can permeate the mucus gel layer in sufficient quantities  [ 60 ]  and exhibit permeation enhancing properties  [ 61 ]  the oral bioavailability of various biologics can be strongly improved  [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8725", "text": "SMEDDS offer numerous advantages: spontaneous formation, ease of manufacture, thermodynamic stability, and improved solubilization of bioactive materials. [ 1 ]   Improved solubility contributes to faster release rates and greater bioavailability.  For many drugs taken by mouth, faster release rates improve the drug acceptance by consumers. Greater bioavailability means that less drug need be used; this may lower cost, and does lower the stomach irritation and toxicity of drugs taken by mouth."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8726", "text": "For oral use, SMEDDS may be formulated as liquids or solids, the solids packaged in capsules or tablets. Limited studies comparing these report that in terms of bioavailability liquid SMEDDS are superior to solid SMEDDS, [ 21 ]  which are superior to conventional tablets. [ 21 ] [ 42 ] [ 47 ]   Liquid SMEDDS have also shown value in injectable (IV and urethral) formulations and in a topical (oral) spray. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8727", "text": "Shampoo  ( / \u0283 \u00e6 m \u02c8 p u\u02d0 / ) is a  hair care  product, typically in the form of a  viscous  liquid, that is formulated to be used for cleaning (scalp)  hair . Less commonly, it is available in solid bar format. (\" Dry shampoo \" is a separate product.) Shampoo is used by applying it to wet hair, massaging the product in the hair, roots and scalp, and then rinsing it out. Some users may follow a shampooing with the use of  hair conditioner ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8728", "text": "Shampoo is typically used to remove the unwanted build-up of  sebum  (natural oils) in the hair without stripping out so much as to make hair unmanageable. Shampoo is generally made by combining a  surfactant , most often  sodium lauryl sulfate  or  sodium laureth sulfate , with a co-surfactant, most often  cocamidopropyl betaine  in water. The  sulfate  ingredient acts as a  surfactant , trapping oils and other contaminants, similarly to  soap ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8729", "text": "Shampoos are marketed to people with hair. There are also shampoos intended for animals that may contain  insecticides  or other  medications  to treat skin conditions or  parasite  infestations such as  fleas ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8730", "text": "In the  Indian subcontinent , a variety of herbs and their extracts have been used as shampoos since ancient times. The first origin of shampoo came from the  Indus Valley Civilization . A very effective early shampoo was made by boiling  Sapindus  with dried  Indian gooseberry  (amla) and a selection of other herbs, using the strained extract. [ citation needed ]   Sapindus , also known as soapberries or soapnuts, a tropical tree widespread in India, is called  ksuna  (Sanskrit: \u0915\u094d\u0937\u0941\u0923) [ 1 ]  in ancient Indian texts and its fruit pulp contains  saponins  which are a natural surfactant. The extract of soapberries creates a lather which Indian texts called  phenaka  (Sanskrit: \u092b\u0947\u0928\u0915). [ 2 ]  It leaves the hair soft, shiny and manageable. Other products used for hair cleansing were shikakai ( Acacia concinna ),  hibiscus  flowers, [ 3 ] [ 4 ]  ritha ( Sapindus mukorossi ) and arappu ( Albizzia amara ). [ 5 ]   Guru Nanak , the founder and the first  Guru  of  Sikhism , made references to soapberry tree and soap in the 16th century. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8731", "text": "Cleansing the hair and body massage (champu) during one's daily bath was an indulgence of early colonial traders in India. When they returned to Europe, they introduced the newly learned habits, including the hair treatment they called shampoo. [ 7 ]   The word  shampoo  entered the English language from the  Indian subcontinent  during the  colonial era . [ 8 ]  It dated to 1762 and was derived from the  Hindi  word  c\u0101\u0303p\u014d  ( \u091a\u093e\u0901\u092a\u094b ,  pronounced   [t\u0283\u00e3\u02d0po\u02d0] ), [ 9 ] [ 10 ]  itself derived from the  Sanskrit  root  chapati  ( \u091a\u092a\u0924\u093f ), which means 'to press, knead, or soothe'. [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8732", "text": "Sake Dean Mahomed , an Indian traveller, surgeon, and entrepreneur, is credited with introducing the practice of  shampoo  or \"shampooing\" to Britain. In 1814, Mahomed, with his Irish wife Jane Daly, opened the first commercial \"shampooing\" vapour masseur bath in England, in  Brighton . He described the treatment in a local paper as \"The Indian Medicated Vapour Bath (type of Turkish bath), a cure to many diseases and giving full relief when everything fails; particularly Rheumatic and paralytic, gout, stiff joints, old sprains, lame legs, aches and pains in the joints\". [ 13 ]  This medical work featured testimonies from his patients, as well as the details of the treatment made him famous. The book acted as a marketing tool for his unique baths in Brighton and capitalised on the early 19th-century trend for seaside spa treatments. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8733", "text": "During the early stages of shampoo in  Europe , English  hair stylists  boiled shaved  soap  in  water  and added  herbs  to give the hair shine and  fragrance . Commercially made shampoo was available from the turn of the 20th century. A 1914 advertisement for Canthrox Shampoo in  American Magazine  showed young women at camp washing their hair with Canthrox in a lake; magazine advertisements in 1914 by  Rexall  featured Harmony Hair Beautifier and Shampoo. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8734", "text": "In 1900, German perfumer and hair-stylist Josef Wilhelm Rausch developed the first liquid hair washing soap and named it \"Champooing\" in Emmishofen, Switzerland. Later, in 1919, J.W. Rausch developed an antiseptic chamomile shampooing with a pH of 8.5. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8735", "text": "In 1927, liquid shampoo was improved for mass production by German inventor  Hans Schwarzkopf  in Berlin; his name became a shampoo brand sold in Europe."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8736", "text": "Originally,  soap  and shampoo were very similar products; both containing the same naturally derived  surfactants , a type of  detergent . Modern shampoo as it is known today was first introduced in the 1930s with  Drene , the first shampoo using synthetic surfactants instead of soap."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8737", "text": "Early shampoos used in  Indonesia  were made from the  husk  and  straw  ( merang ) of  rice . The husks and straws were burned into ash, and the ashes (which have  alkaline  properties) are mixed with water to form  lather . The ashes and lather were scrubbed into the hair and rinsed out, leaving the hair clean, but very dry. Afterwards,  coconut oil  was applied to the hair in order to moisturize it. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8738", "text": "Filipinos  have been traditionally using  gugo  before commercial shampoos were sold in stores. The shampoo is obtained by soaking and rubbing the bark of the vine  Gugo  ( Entada phaseoloides ), [ 18 ] [ 19 ]  producing a lather that cleanses the scalp effectively.  Gugo  is also used as an ingredient in  hair tonics . [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8739", "text": "Certain  Native American  tribes used extracts from North American plants as hair shampoo; for example the  Costanoans  of present-day coastal  California  used extracts from the  coastal woodfern ,  Dryopteris expansa . [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8740", "text": "Before  quinoa  can be eaten the  saponin  must be washed out from the grain prior to cooking. Pre-Columbian  Andean  civilizations used this soapy by-product as a shampoo. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8741", "text": "Shampoos can be classified into four main categories: [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8742", "text": "Shampoo is generally made by combining a  surfactant , most often  sodium lauryl sulfate  or  sodium laureth sulfate , with a co-surfactant, most often  cocamidopropyl betaine  in  water  to form a thick, viscous liquid. Other essential ingredients include salt ( sodium chloride ), which is used to adjust the viscosity, a  preservative  and  fragrance . [ 24 ] [ 25 ]  Other ingredients are generally included in shampoo formulations to maximize the following qualities:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8743", "text": "Many shampoos are  pearlescent . This effect is achieved by the addition of tiny flakes of suitable materials, e.g.  glycol distearate , chemically derived from  stearic acid , which may have either animal or vegetable origins. Glycol distearate is a wax. Many shampoos also include  silicone  to provide conditioning benefits."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8744", "text": "In the United States, the  Food and Drug Administration  (FDA) mandates that shampoo containers accurately list ingredients on the products container. The government further regulates what shampoo manufacturers can and cannot claim as any associated benefit. Shampoo producers often use these regulations to challenge marketing claims made by competitors, helping to enforce these regulations. While the claims may be substantiated, however, the testing methods and details of such claims are not as straightforward. For example, many products are purported to protect hair from damage due to  ultraviolet radiation . While the ingredient responsible for this protection does block UV, it is not often present in a high enough concentration to be effective. The North American Hair Research Society has a program to certify functional claims based on third-party testing. Shampoos made for treating medical conditions such as  dandruff [ 29 ]  or  itchy scalp  are regulated as  OTC  drugs [ 30 ]  in the US marketplace."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8745", "text": "In the European Union, there is a requirement for the anti-dandruff claim to be substantiated as with any other advertising claim, but it is not considered to be a medical problem. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8746", "text": "A number of contact  allergens  are used as ingredients in shampoos, and  contact allergy  caused by shampoos is well known. [ 31 ]   Patch testing  can identify ingredients to which patients are allergic, after which a physician can help the patient find a shampoo that is free of the ingredient to which they are allergic. [ 31 ] [ 32 ]  The US bans 11 ingredients from shampoos, Canada bans 587, and the EU bans 1328. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8747", "text": "Cosmetic companies have developed shampoos specifically for those who have  dandruff . These contain  fungicides  such as  ketoconazole ,  zinc pyrithione  and  selenium disulfide , which reduce loose dander by killing  fungi  like  Malassezia furfur .  Coal tar  and  salicylate  derivatives are often used as well.\nAlternatives to medicated shampoos are available for people who wish to avoid synthetic fungicides. Such shampoos often use  tea tree oil ,  essential oils  or herbal extracts. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8748", "text": "Many companies have also developed color-protection shampoos suitable for colored hair; some of these shampoos contain gentle cleansers according to their manufacturers.  Shampoos for color-treated hair are a type of moisturizing shampoo. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8749", "text": "Shampoo for  infants  and young children is formulated so that it is less irritating and usually less prone to produce a stinging or burning sensation if it were to get into the eyes. [ 23 ]  For example,  Johnson's Baby  Shampoo advertises under the premise of \"No More Tears\". This is accomplished by one or more of the following formulation strategies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8750", "text": "The distinction in 4 above does not completely surmount the controversy over the use of shampoo ingredients to mitigate eye sting produced by other ingredients, or the use of the products so formulated. The considerations in 3 and 4 frequently result in a much greater multiplicity of surfactants being used in individual baby shampoos than in other shampoos, and the detergency or foaming of such products may be compromised thereby. The monoanionic sulfonated surfactants and viscosity-increasing or foam stabilizing alkanolamides seen so frequently in other shampoos are much less common in the better baby shampoos."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8751", "text": "Sulfate-free shampoos are composed of natural ingredients and free from both  sodium lauryl sulfate  and  sodium laureth sulfate . [ 35 ]  These shampoos use alternative surfactants to cleanse the hair."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8752", "text": "Shampoo intended for animals may contain  insecticides  or other medications for treatment of skin conditions or  parasite  infestations such as  fleas  or  mange . These must never be used on humans. While some human shampoos may be harmful when used on animals, any human haircare products that contain active ingredients or drugs (such as zinc in anti-dandruff shampoos) are potentially toxic when ingested by animals. Special care must be taken not to use those products on pets. Cats are at particular risk due to their instinctive method of grooming their fur with their tongues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8753", "text": "Shampoos that are especially designed to be used on  pets , commonly  dogs  and  cats , are normally intended to do more than just clean the pet's  coat  or skin. Most of these shampoos contain ingredients which act different and are meant to treat a skin condition or an  allergy  or to fight against  fleas ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8754", "text": "The main ingredients contained by pet shampoos can be grouped in insecticidals, antiseborrheic, antibacterials, antifungals,  emollients ,  emulsifiers  and  humectants . Whereas some of these ingredients may be efficient in treating some conditions, pet owners are recommended to use them according to their  veterinarian 's indications because many of them cannot be used on cats or can harm the pet if it is misused.\nGenerally, insecticidal pet shampoos contain  pyrethrin ,  pyrethroids  (such as permethrin and which may not be used on cats) and  carbaryl . These ingredients are mostly found in shampoos that are meant to fight against parasite infestations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8755", "text": "Antifungal shampoos are used on pets with yeast or  ringworm  infections. These might contain ingredients such as  miconazole ,  chlorhexidine ,  providone iodine ,  ketoconazole  or  selenium sulfide  (which cannot be used on cats)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8756", "text": "Bacterial infections in pets are sometimes treated with antibacterial shampoos. They commonly contain  benzoyl peroxide ,  chlorhexidine , povidone iodine,  triclosan ,  ethyl lactate , or sulfur."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8757", "text": "Antipruritic  shampoos are intended to provide relief of itching due to conditions such as atopy and other allergies. [ 36 ]  These usually contain colloidal  oatmeal ,  hydrocortisone ,  Aloe vera , pramoxine hydrochloride,  menthol ,  diphenhydramine , sulfur or salicylic acid. These ingredients are aimed to reduce the inflammation, cure the condition and ease the symptoms at the same time while providing comfort to the pet."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8758", "text": "Antiseborrheic shampoos are those especially designed for pets with scales or those with excessive oily coats. These shampoos are made of sulfur,  salicylic acid , refined  tar  (which cannot be used on cats),  selenium sulfide  (cannot be used on cats) and benzoyl peroxide. All these are meant to treat or prevent seborrhea oleosa, which is a condition characterized by excess oils. Dry scales can be prevented and treated with shampoos that contain sulfur or salicylic acid and which can be used on both cats and dogs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8759", "text": "Emollient shampoos are efficient in adding oils to the skin and relieving the symptoms of a dry and itchy skin. They usually contain oils such as  almond ,  corn ,  cottonseed ,  coconut ,  olive ,  peanut , Persia,  safflower ,  sesame ,  lanolin ,  mineral  or  paraffin oil . The emollient shampoos are typically used with emulsifiers as they help distributing the emollients. These include ingredients such as  cetyl alcohol ,  laureth-5 ,  lecithin , PEG-4 dilaurate,  stearic acid ,  stearyl alcohol ,  carboxylic acid ,  lactic acid ,  urea ,  sodium lactate ,  propylene glycol ,  glycerin , or  polyvinylpyrrolidone ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8760", "text": "Although some of the pet shampoos are highly effective, some others may be less effective for some condition than another. Yet, although natural pet shampoos exist, it has been brought to attention that some of these might cause  irritation  to the skin of the pet. Natural ingredients that might be potential allergens for some pets include  eucalyptus ,  lemon  or  orange  extracts and  tea tree oil . [ citation needed ]  On the contrary, oatmeal appears to be one of the most widely skin-tolerated ingredients that is found in pet shampoos. Most ingredients found in a shampoo meant to be used on animals are safe for the pet as there is a high likelihood that the pets will lick their coats, especially in the case of cats."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8761", "text": "Pet shampoos which include  fragrances ,  deodorants  or colors may harm the skin of the pet by causing inflammations or irritation. Shampoos that do not contain any unnatural additives are known as  hypoallergenic  shampoos and are increasing in popularity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8762", "text": "Solid shampoos or shampoo bars can either be soap-based or use other plant-based surfactants, such as sodium cocoyl isethionate or sodium coco-sulfate combined with oils and waxes. Soap-based shampoo bars are high in pH (alkaline) compared to human hair and scalps, which are slightly acidic. Alkaline pH increases the friction of the hair fibres which may cause damage to the hair cuticle, making it feel rough and drying out the scalp. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8763", "text": "Stiff, non-pourable clear gels to be squeezed from a tube were once popular forms of shampoo, and can be produced by increasing a shampoo's  viscosity . This type of shampoo cannot be spilled, but unlike a solid, it can still be lost down the drain by sliding off wet skin or hair."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8764", "text": "Shampoos in the form of pastes or creams were formerly marketed in jars or tubes. The contents were wet but not completely dissolved. They would apply faster than solids and dissolve quickly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8765", "text": "Antibacterial shampoos are often used in  veterinary  medicine for various conditions, [ 38 ] [ 39 ]  as well as in humans before some  surgical procedures . [ 40 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8766", "text": "Closely associated with  environmentalism , the \" no poo \" movement consists of people rejecting the societal norm of frequent shampoo use. Some adherents of the no poo movement use  baking soda  or  vinegar  to wash their hair, while others use diluted honey. Further methods include the use of raw eggs (potentially mixed with salt water), rye flour, or chickpea flour dissolved in water. Other people use nothing or rinse their hair only with conditioner. [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8767", "text": "In the 1970s, ads featuring  Farrah Fawcett  and  Christie Brinkley  asserted that it was unhealthy not to shampoo several times a week. This mindset is reinforced by the greasy feeling of the scalp after a day or two of not shampooing. Using shampoo every day removes  sebum , the oil produced by the scalp. This causes the  sebaceous glands  to produce oil at a higher rate, to compensate for what is lost during shampooing. According to Michelle Hanjani, a dermatologist at Columbia University, a gradual reduction in shampoo use will cause the sebum glands to produce at a slower rate, resulting in less grease in the scalp. [ 44 ]  Although this approach might seem unappealing to some individuals, many people try alternate shampooing techniques like baking soda and vinegar in order to avoid ingredients used in many shampoos that make hair greasy over time. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8768", "text": "Whereas the use of baking soda for hair cleansing has been associated with hair damage and skin irritation, likely due to its high pH value and exfoliating properties, honey, egg, rye flour, and chickpea flour hair washes seem gentler for long-term use. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8769", "text": "Silicone gel sheeting (SGS)  has been an effective reduction and preventive scar therapy since 1980. [ 1 ]  It was first discovered to be used in treating scars by Perkins in Australia and New Zealand, and first discussed in the thesis of Karen Quinn, a British biomedical engineering student, in 1985. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8770", "text": "It is now considered the first-line prevention and treatment for  hypertrophic  and  keloid  scars by occlusion and then hydration of the scar tissue. [ 3 ]  Silicone gel is made of medical-grade silicone polymers. [ 4 ]  Silicone gel sheet consists of a soft, semi-occlusive sheet and a membrane that increases the durability of the sheet. [ 3 ]  The sheet has a solid rubber-like appearance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8771", "text": "Although the mechanism of action of silicone gel sheeting remains partially unknown, its efficacy is confirmed by many clinical trials, [ 5 ]  and is similar to silicone gel. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8772", "text": "Silicone gel sheeting is the gold-standard and non-invasive treatment for hypertrophic and keloid scars.  During skin injury repair, dermal cells proliferate and migrate from the skin tissue to the wound, producing collagen and causing contraction of the placement dermis. [ 5 ]  These scars are proliferative due to chronic inflammation and overproduction of abnormal collagen. [ 7 ]  Common clinical presentations of these scars are raised, thickened, red, or dark-colored. [ 4 ]  Patients may also experience pain and itching. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8773", "text": "Hypertrophic scars  are elevated scars that remain in the region of the original lesion [ 9 ]  following mechanical traumas, burns, and necrotizing infections. [ 10 ]  These scars typically develop in locations under tension, such as shoulders, ankles, knees, and the neck. [ 8 ]  Hypertrophic scars are generally confined to the boundaries of the original wound and tend to diminish over time. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8774", "text": "Keloids  grow extensively beyond the wound margins and tend to persist or even worsen over time. [ 11 ]  They are relatively difficult to treat due to their high risk of recurrence. [ 9 ]  Keloids are more common in people with darker skin tones [ 12 ]  and often occur in individuals with a genetic predisposition. [ 13 ]  Keloids are the most extreme type of scarring since minor wounds such as insect bites or piercings can all lead to an elevated tissue area. Patients may experience psychological trauma if their scars are not well-controlled. [ 8 ]  Therefore, the prevention of wound formation is crucial to them. They should avoid undergoing any unnecessary invasive procedures or cosmetic surgeries. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8775", "text": "The beneficial effects of silicone gel sheeting on the treatment and prevention of these two scars have been confirmed. [ 10 ]  Since most patients develop hypertrophic and keloid scars within 3 months after surgery or injury, the silicone gel sheeting therapy should be started in the early repair phase to achieve an optimal therapeutic effect. The maturity of scars takes over a year; therefore, silicone treatment is also effective in scars aged over 12 months. [ 15 ]  The therapy usually requires 6 to 12 months of constant wear to achieve optimum results. Recent data suggest that the combination of silicone gel sheeting and pressure therapy can improve post-traumatic scar healing. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8776", "text": "The sheet should not be used on open wounds. [ 16 ] [ 17 ]  The sheet is reusable with proper cleaning though it should be replaced when it starts to deteriorate. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8777", "text": "The exact mechanism of action of silicone gel sheeting has not been fully studied. Currently, many proposed mechanisms explain the efficacy of such treatment, including the occlusion and hydration effect, increased body surface temperature, polarized electric charge, immunological effects, etc. [ 9 ]  The occlusion and hydration effect is the most studied mechanism of action."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8778", "text": "Silicone gel sheets occlude and hydrate the  stratum corneum  of the treated skin area. The  stratum corneum  normally conserves water and acts as a barrier to microbial infection. Its function can be disrupted by wound formation. The stratum corneum of hypertrophic scars and keloids absorbs more water than normal skin, depleting the water supply from the  stratum corneum . Excessive dehydration of  keratinocytes  stimulates cytokine production, leading to increased  collagen  production. [ 18 ] [ 5 ]  After applying the sheet, the rate of water loss via evaporation of the treated skin area is half of the untreated area. Therefore, the sheet prevents the drying up of  stratum corneum , and thus further  collagen  production. Collagen production exacerbates the growth of  hypertrophic scars  and  keloids  and thus should be avoided. [ 9 ] [ 5 ]  Hydrating a scar over a prolonged period can also relieve symptoms such as itching and pain. Such an effect is likely due to decreased capillary activity and thus local collagen deposition. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8779", "text": "Applying silicone gel sheeting causes a slight increase in surface temperature. Increased temperature intensifies the activity of  collagenase , an enzyme that breaks down  collagen . Since excessive collagen production leads to scar formation, increased levels of  collagenase  may help reduce the risk of scar formation. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8780", "text": "Silicone-related products can reduce the growth factor production of  fibroblasts  in hypertrophic scars and keloids. [ 19 ]  However, the relevance is unclear as silicone products do not have direct contact with dermal fibroblasts but with the  epidermis  only. Possible relevance may be due to the initiation of a signaling cascade by the epidermis. Through the signaling cascade, the epidermis regulates dermal fibroblast extracellular matrix production. Delayed epithelialization, which raises the risk of hypertrophic scar formation, is less likely to happen. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8781", "text": "A negative  static electric charge  is formed by friction between the silicone gel sheet and the skin. The charge induces collagen realignment, aiding the elimination of the scar. [ 18 ]  Moreover, the negative electric field leads to the polarization of scar tissues and thus scar shrinkage. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8782", "text": "Silicone gel sheeting has remained the first-line therapy stated by international clinical recommendations on scar management. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8783", "text": "Scar measurements studied in most clinical trials include color ( vascularisation  and pigmentation), thickness (height: clinical and histological), relief (surface irregularities), pliability (tissue elasticity), and surface area (scar contraction or expansion). [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8784", "text": "Scar elevation index is commonly used to indicate scar improvement. It measures the height of scar tissue compared to the normal surrounding skin. [ 21 ]  Studies show the effectiveness of silicone gel sheeting in minimizing scar elevation index. [ 22 ]  Another physical measure is the pliability of the scar tissue, which is also improved by silicone gel sheeting. [ 23 ]  Scar improvement is generally measured by size reduction, appearance, and calming effect. Silicone gel sheeting addresses the 3 requirements well among scar treatments. [ 5 ]  Several randomized controlled trials were carried out to assess the effectiveness. Silicone gel sheeting produces a statistically significant reduction in scar thickness and color amelioration. Therefore, it is an evidence-based non-invasive preventive treatment. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8785", "text": "Results of comparative studies on the effectiveness of silicone gel sheeting and silicone gel do not show significant differences between the two. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8786", "text": "Another non-invasive treatment is compression therapy, in which patients wear  pressure garments  to control the growth of scars. Pressure garments apply mechanical pressure to the surface of the scar, reducing the supply of blood and oxygen to the scar tissue. Formation of excessive scar tissue is thus prevented. The combination of silicone gel sheeting and compression therapy has been proven to be more effective than using the sheet alone. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8787", "text": "Patients who find the non-invasive treatments ineffective may choose to undergo invasive treatments such as intralesional injections of  corticosteroids , surgical excision of the scars, and  radiotherapy . [ 26 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8788", "text": "Common side effects of silicone gel sheets include itchiness,  rash , maceration of the skin, and malodor. [ 28 ]  These symptoms are generally well-tolerated and can be minimized by rinsing the area properly daily. Patients who suffer from these side effects should wash the treated area and the silicone gel sheets with mild soap since the dirt or bacteria on the sheets may irritate the scar. [ 16 ] \u00a0In tropical climates with high humidity, excessive moisture underneath the gel may lead to heat rash and uncomfortable sensations in patients. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8789", "text": "Silicone gel sheets are usually made of medical silicone polymers such as  polysiloxane  and  polydimethylsiloxane , along with  silicon dioxide  and volatile components. The long-chain silicone polymers form cross-linking with silicon dioxide and spread as a thin sheet. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8790", "text": "They are either flesh color (most common) or clear and come as either a single large rectangle sheet or a roll. Available size varies with brands."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8791", "text": "[ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8792", "text": "In  pharmaceutics , sink condition is a term mostly related to the  dissolution testing  procedure."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8793", "text": "It means using a sheer volume of  solvent , usually about 5 to 10 times greater than the volume present in the  saturated solution  of the targeted chemical (often the  API , and sometimes the  excipients ) contained in the  dosage form  being tested. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8794", "text": "During the  dissolution testing , \"sink condition\" is a mandatory requirement, otherwise when the concentration begins to get too close to the  saturation point , even though the  total soluble amount  still remains constant, the  dissolution rate  will gradually begin to reduce in significant amounts, enough to corrupt the  test  results. . [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8795", "text": "Small molecule  drug conjugates  or  SMDC s are built with three modules: a targeting  ligand , a linker and a drug payload [ citation needed ] . The targeting ligands consist of low molecular weight, high-affinity ligands that are precisely linked to potent drugs. The linkers are designed to be stable in the bloodstream and then release the active drug from the targeting ligand when the SMDC is taken up by the diseased cell. The  drug payloads  are highly active molecules that are too toxic to be administered in their untargeted forms at therapeutic dose levels [ citation needed ] . This modular approach allows varying targeting ligands, linker systems and drug payloads and generate SMDCs for different diseases. [ 1 ] \nThe most advanced SMDC is  vintafolide , a derivative of the anti-mitotic chemotherapy drug  vinblastine   which is chemically linked to  folic acid . [ 2 ]  Potent, bioactive natural products like triptolide that inhibit mammalian transcription has been recently reported as a glucose conjugate for targeting hypoxic cancer cells with increased glucose transporter expression. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8796", "text": "SMDCs are currently being developed by  Endocyte  for treating  cancer , inflammatory diseases and kidney disease, as well as a companion imaging agent that is created by replacing the potent drug with an  imaging agent . [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8797", "text": "Smoking  is a practice in which a substance is  combusted  and the resulting  smoke  is typically  inhaled  to be  tasted  and absorbed into the  bloodstream  of a person. Most commonly, the substance used is the dried  leaves  of the  tobacco  plant, which have been rolled with a small rectangle of paper into an elongated cylinder called a  cigarette . Other forms of smoking include the use of a  smoking pipe  or a  bong ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8798", "text": "Smoking is primarily practised as a  route of administration  for  psychoactive chemicals  because the  active substances  within the burnt dried plant leaves vaporize and can be airborne-delivered into the  respiratory tract , where they are rapidly absorbed into the bloodstream of the  lungs  and then reach the  central nervous system . In the case of  tobacco smoking , these active substances are a mixture of  aerosol  particles that includes the pharmacologically active alkaloid  nicotine , which stimulates the  nicotinic acetylcholine receptors  in the  brain . Other notable active substances inhaled via smoking include  tetrahydrocannabinol  (from  cannabis ),  morphine  (from  opium ) and  cocaine  (from  crack )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8799", "text": "Smoking is one of the most common forms of  recreational drug use . Tobacco smoking is the most popular form, being practised by over one billion people globally, of whom the majority are in the  developing countries . [ 1 ]  Less common drugs for smoking include  cannabis  and  opium . Some of the substances are classified as hard  narcotics , like  heroin , but the use of these is very limited as they are usually not commercially available. Cigarettes are primarily industrially manufactured but also can be hand-rolled from loose tobacco and  rolling paper . Other smoking implements include  pipes ,  cigars ,  bidis ,  hookahs , and bongs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8800", "text": "Smoking has negative health effects , because smoke inhalation inherently poses challenges to various  physiologic  processes such as  respiration . Smoking tobacco is among the leading causes of many diseases such as  lung cancer ,  heart attack ,  COPD ,  erectile dysfunction , and  birth defects . [ 1 ]  Diseases related to tobacco smoking have been shown to kill approximately half of long-term smokers when compared to average mortality rates faced by non-smokers. Smoking caused over five million deaths a year from 1990 to 2015. [ 2 ]  Non-smokers account for 600,000 deaths globally due to  second-hand smoke . [ 3 ]  The health hazards of smoking have caused many countries to institute high taxes on tobacco products, publish advertisements to discourage use, limit advertisements that promote use, and provide help with quitting for those who do smoke. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8801", "text": "Smoking can be dated to as early as 5000 BCE, and has been recorded in many different cultures across the world. Early smoking evolved in association with religious ceremonies; as offerings to deities; in cleansing rituals; or to allow  shamans  and priests to alter their minds for purposes of divination or spiritual enlightenment. After the European exploration and conquest of the Americas, the practice of smoking tobacco quickly spread to the rest of the world. In regions like India and Sub-Saharan Africa, it merged with existing practices of smoking (mostly of cannabis). In Europe, it introduced a new type of social activity and a form of drug intake which previously had been unknown."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8802", "text": "Perception surrounding smoking has varied over time and from one place to another: holy and sinful, sophisticated and vulgar, a  panacea  and deadly health hazard. In the last decade of the 20th century, smoking came to be viewed in a decidedly negative light, especially in Western countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8803", "text": "The history of smoking dates back to as early as 5000 BCE for shamanistic rituals. [ 4 ]  Many ancient civilizations, such as the Babylonian and Chinese, burnt incense as a part of religious rituals, as did the  Israelites  and the later Catholic and Orthodox Christian churches. Smoking in the Americas probably had its origins in the incense-burning ceremonies of  shamans  but was later adopted for pleasure, or as a social tool. [ 5 ]  The smoking of tobacco, as well as various  hallucinogenic  drugs, was used to achieve trances and to come into contact with the spirit world."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8804", "text": "Substances such as  cannabis , clarified butter ( ghee ), fish offal, dried snake skins and various pastes molded around  incense  sticks dates back at least 2000\u00a0years. Fumigation ( dhupa ) and fire offerings ( homa ) are prescribed in the  Ayurveda  for medical purposes, and have been practiced for at least 3,000\u00a0years while smoking,  dhumrapana  (literally \"drinking smoke\"), has been practiced for at least 2,000\u00a0years. Before modern times these substances have been consumed through  pipes , with stems of various lengths or  chillums . [ 6 ]  Archaeological findings also show the existence of pipes to smoke  opium  in  Cyprus  and  Crete  as soon as the  Bronze Age . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8805", "text": "Cannabis smoking was common in the Middle East before the arrival of tobacco, and was early on a common social activity that centered around the type of water pipe called a  hookah . Smoking, especially after the introduction of tobacco, was an essential component of Muslim society and culture and became integrated with important traditions such as weddings, funerals and was expressed in architecture, clothing, literature and poetry. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8806", "text": "Cannabis smoking was introduced to  Sub-Saharan Africa  through  Ethiopia  and the east African coast by either Indian or Arab traders in the 13th century or earlier and spread on the same trade routes as those that carried coffee, which originated in the highlands of Ethiopia. [ 9 ]  It was smoked in  calabash  water pipes with  terracotta  smoking bowls, apparently an  Ethiopian  invention which was later conveyed to eastern, southern and central Africa."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8807", "text": "Reports from the first European explorers and conquistadors to reach the Americas tell of rituals where native priests smoked themselves into such high degrees of intoxication that it is unlikely that the rituals were limited to just tobacco. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8808", "text": "In 1612, six years after the settlement of  Jamestown ,  John Rolfe  was credited as the first settler to successfully grow tobacco as a  cash crop . The demand quickly grew as tobacco, referred to as \"golden weed\", revived the  Virginia Company  from its failed expeditions in search for gold in the Americas. [ 11 ]  In order to meet demands from the old world, tobacco was grown in succession, quickly depleting the land. This became a motivator to settle west into the unknown continent, and likewise an expansion of tobacco production. [ 12 ]   Indentured servants  became the primary labor force up until  Bacon's Rebellion , from which the focus turned to  slavery . [ 13 ]  This trend abated following the  American Revolution  as slavery became regarded as unprofitable. However the practice was revived in 1794 with the invention of the cotton gin. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8809", "text": "A Frenchman named  Jean Nicot  (from whose name the word nicotine is derived) introduced tobacco to  France  in 1560. From France tobacco spread to England. The first report documents an English sailor in Bristol in 1556, seen \"emitting smoke from his nostrils\". [ 15 ]  Like tea, coffee and opium, tobacco was just one of many intoxicants that was originally used as a form of medicine. [ 16 ]  Tobacco was introduced around 1600 by French merchants in what today is modern-day  The Gambia  and  Senegal . At the same time caravans from  Morocco  brought tobacco to the areas around  Timbuktu  and the Portuguese brought the commodity (and the plant) to southern Africa, establishing the popularity of tobacco throughout all of Africa by the 1650s."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8810", "text": "Soon after its introduction to the  Old World , tobacco came under frequent criticism from state and religious leaders.  Murad IV , sultan of the  Ottoman Empire  1623\u201340 was among the first to attempt a smoking ban by claiming it was a threat to public morality and health. The  Chongzhen Emperor  of China issued an edict banning smoking two years before his death and the overthrow of the  Ming dynasty . Later, the  Manchu  rulers of the  Qing dynasty , would proclaim smoking \"a more heinous crime than that even of neglecting archery\". In  Edo period  Japan, some of the earliest tobacco plantations were scorned by the  sh\u014dgun  as being a threat to the military economy by letting valuable farmland go to waste for the use of a recreational drug instead of being used to plant food crops. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8811", "text": "Religious leaders have often been prominent among those who considered smoking immoral or outright blasphemous. In 1634, the  Patriarch of Moscow and all Rus'  forbade the sale of tobacco and sentenced men and women who flouted the ban to have their nostrils slit and their backs whipped until skin came off their backs. The Western church leader  Pope Urban VII  likewise condemned smoking in a papal bull of 1590. Despite many concerted efforts, restrictions and bans were almost universally ignored. When  James VI and I , a staunch anti-smoker and the author of  A Counterblaste to Tobacco , tried to curb the new trend by enforcing a whopping 4000% tax increase on tobacco in 1604, it proved a failure, as London had some 7,000 tobacco sellers by the early 17th century. Later, scrupulous rulers would realise the futility of smoking bans and instead turned tobacco trade and cultivation into lucrative government monopolies. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8812", "text": "By the mid-17th century every major civilization had been introduced to tobacco smoking and in many cases had already assimilated it into its culture, despite the attempts of many rulers to stamp the practice out with harsh penalties or fines. Tobacco, both product, and plant followed the major trade routes to major ports and markets, and then on into the hinterlands. The English language term  smoking  was coined in the late 18th century; before then the practice was referred to as  drinking smoke . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8813", "text": "Tobacco and cannabis were used in Sub-Saharan Africa, much like elsewhere in the world, to confirm social relations, but also created entirely new ones. In what is today  Congo , a society called Bena Diemba (\"People of Cannabis\") was organized in the late 19th century in Lubuko (\"The Land of Friendship\"). The Bena Diemba were collectivist pacifists that rejected alcohol and herbal medicines in favor of cannabis. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8814", "text": "The growth remained stable until the  American Civil War  in the 1860s, from which the primary labor force transition from slavery to  sharecropping . This compounded with a change in demand, lead to the industrialization of tobacco production with the cigarette.  James Albert Bonsack , a craftsman, in 1881 produced a machine to speed the production of cigarettes. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8815", "text": "In the 19th century, the practise of smoking opium became widespread in  China . Previously, opium had only been ingested via consumption, and then only for its medicinal properties (opium was an  anaesthetic ). The narcotic was also outlawed in China sometime in the early 18th century due the societal issues it caused. Due to a massive trade imbalance, however, foreign merchants started to smuggle opium into China via  Canton , to the chagrin of the Chinese authorities. Attempts by Chinese official  Lin Zexu  to eliminate the trade led to the outbreak of the  First Opium War . The Chinese defeat in the First and  Second Opium Wars  resulted in the legalization of the importation of opium into China. [ 21 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8816", "text": "Opium smoking later spread with  Chinese immigrants  and spawned many infamous  opium dens  in  Chinatowns  around South and Southeast Asia, Europe and the Americas. In the latter half of the 19th century, opium smoking became popular in the artistic community in Europe, especially Paris; artists' neighborhoods such as  Montparnasse  and  Montmartre  became virtual \"opium capitals\". While opium dens that catered primarily to emigrant Chinese continued to exist in Chinatowns around the world, the trend among the European artists largely abated after the outbreak of World War I. [ 21 ]  The consumption of Opium abated in China during the  Cultural Revolution  in the 1960s and 1970s. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8817", "text": "Many people have been critical about tobacco use since it gained popularity. In 1798, Dr.  Benjamin Rush  (early American physician, signer of the  Declaration of Independence ,  Surgeon General  under  George Washington , and anti-tobacco activist) was \"against the habitual use of tobacco\" because he believed it (a) \"led to a desire for strong drink,\" (b) \"was injurious both to health and morals,\" (c) \"is generally offensive to\" nonsmokers, (d) \"produces a want of respect for\" nonsmokers, and (e) \"always disposes to unkind and unjust behavior towards them.\" [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8818", "text": "With the modernization of cigarette production compounded with the increased life expectancies during the 1920s, adverse health effects began to become more prevalent. [ 1 ]  In Germany, anti-smoking groups, often associated with anti-liquor groups, [ 25 ]  first published advocacy against the consumption of tobacco in the journal  Der Tabakgegner  (The Tobacco Opponent) in 1912 and 1932. In 1929,  Fritz Lickint  of Dresden, Germany, published a paper containing formal statistical evidence of a lung cancer\u2013tobacco link. During the  Great Depression ,  Adolf Hitler  condemned his earlier smoking habit as a waste of money, [ 26 ]  and later with stronger assertions. This movement was further strengthened with Nazi reproductive policy as women who smoked were viewed as unsuitable to be wives and mothers in a German family. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8819", "text": "The movement in Nazi Germany did reach across enemy lines during the Second World War, as anti-smoking groups quickly lost popular support. [ clarification needed ]  By the end of the Second World War, American cigarette manufacturers quickly reentered the German black market. Illegal smuggling of tobacco became prevalent, [ 28 ]  and leaders of the Nazi anti-smoking campaign were assassinated. [ 29 ]  As part of the  Marshall Plan , the United States shipped free tobacco to Germany; with 24,000 tons in 1948 and 69,000\u00a0tons in 1949. [ 28 ]  Per capita yearly cigarette consumption in  post-war Germany  steadily rose from 460 in 1950 to 1,523 in 1963. [ 30 ]  By the end of the 20th century, anti-smoking campaigns in Germany were unable to exceed the effectiveness of the Nazi-era climax in the years 1939\u201341 and German tobacco health research was described by  Robert N. Proctor  as \"muted\". [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8820", "text": "In the UK and the US, an increase in lung cancer rates, formerly \"among the rarest forms of disease\", was noted by the 1930s, but its cause remained unknown and even the credibility of this increase was sometimes disputed as late as 1950. For example, in Connecticut, reported age-adjusted incidence rates of lung cancer among males increased 220% between 1935\u201339 and 1950\u201354. In the UK, the share of lung cancer among all cancer deaths in men increased from 1.5% in 1920 to 19.7% in 1947. Nevertheless, these increases were questioned as potentially caused by increased reporting and improved methods of diagnosis. Although several carcinogens were already known at the time (for example,  benzo[a]pyrene  was isolated from coal tar and demonstrated to be a potent carcinogen in 1933), none were known to be contained in adequate quantities in  tobacco smoke . [ 31 ]   Richard Doll  in 1950 published research in the  British Medical Journal  showing a close link between smoking and lung cancer. [ 32 ]  Four years later, in 1954 the  British Doctors Study , a study of some 40 thousand doctors over 20 years, confirmed the link, based on which the government issued advice that smoking and lung cancer rates were related. [ 33 ] [ 34 ]  In 1964 the United States  Surgeon General 's Report on Smoking and Health demonstrated the relationship between smoking and cancer. [ 35 ]  Further reports confirmed this link in the 1980s and concluded in 1986 that  passive smoking  was also harmful. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8821", "text": "As scientific evidence mounted in the 1980s, tobacco companies claimed  contributory negligence  as the adverse health effects were previously unknown or lacked substantial credibility. Health authorities sided with these claims up until 1998, from which they reversed their position. The  Tobacco Master Settlement Agreement , originally between the four largest US tobacco companies and the Attorneys General of 46 states, restricted certain types of tobacco advertisement and required payments for health compensation; which later amounted to the largest civil settlement in United States history. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8822", "text": "From 1965 to 2006, rates of smoking in the United States have declined from 42% to 20.8%. [ 38 ]  A significant majority of those who quit were professional, affluent men. Despite this decrease in the prevalence of consumption, the average number of cigarettes consumed per person per day increased from 22 in 1954 to 30 in 1978. This paradoxical event suggests that those who quit smoked less, while those who continued to smoke moved to smoke more light cigarettes. [ 39 ]  This trend has been paralleled by many industrialized nations as rates have either leveled-off or declined. In the  developing countries , however, tobacco consumption continues to rise at 3.4% in 2002. [ 40 ]  In Africa, smoking is in most areas considered to be modern, and many of the strong adverse opinions that prevail in the West receive much less attention. [ 41 ]  Today  Russia  leads as the top consumer of tobacco followed by  Indonesia ,  Laos ,  Ukraine ,  Belarus ,  Greece ,  Jordan , and  China . [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8823", "text": "At the global scale, initial ideas of an international convention towards the prevention of tobacco had been initiated in the World Health Assembly (WHA) in 1996. [ 43 ]  In 1998, along with the successful election of  Dr. Gro Harlem Brundtland  as the Director-General, the  World Health Organization  set tobacco control as its leading health concern and has begun a program known as the  Tobacco Free Initiative  (TFI) in order to reduce rates of consumption in the developing world. However, it was not until 2003 that the Framework Convention on Tobacco Control (FCTC) was accepted in WHA and entered into force in 2005. FCTC marked a milestone as the first international treaty concerning a global health issue that aims to combat tobacco in multiple aspects including tobacco taxes, advertisement, trading, environmental affects, health influences, etc. [ 44 ]  The birth of this evidence-based and systematic approach has resulted in the reinforcement of tobacco taxes and the implementation of smoke-free laws in 128 countries that led to the decrease of smoking prevalence in developing nations. [ 45 ]  In Nepal, \"Smokers are not selfish\", a  health campaign  lasting two weeks is started on the occasion of  Valentine day  and  Vasant panchami  to motiviate individuals to quit smoking as a sacrifice for their loved ones and making it a meaningful decision of life. This campaign is attracting public attention. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8824", "text": "In the early 1980s, organized international trafficking of  cocaine  grew. However, overproduction and tighter legal enforcement for the illegal product caused drug dealers to convert the powder to \"crack\" \u2013 a solid, smokable form of cocaine that could be sold in smaller quantities to more people. [ 47 ]  This trend abated in the 1990s as increased police action coupled with a robust economy caused many potential consumers to give up or fail to take up the habit. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8825", "text": "Recent years shows an increase in the consumption of vaporized heroin,  methamphetamine  and  Phencyclidine  (PCP). Along with a smaller number of  psychedelic drugs  such as  Changa ,  DMT ,  5-Meo-DMT , and  Salvia divinorum . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8826", "text": "The most popular type of substance that is smoked is  tobacco . There are many different tobacco cultivars which are made into a wide variety of mixtures and brands. Tobacco is often sold flavored, often with various fruit aromas, something which is especially popular for use with water pipes, such as  hookahs . The second most common substance that is smoked is  cannabis , made from the flowers or leaves of  Cannabis sativa  or  Cannabis indica . The substance is considered illegal in most countries in the world and in the countries that tolerate public consumption, it is sometimes only pseudo-legal. Despite this, a considerable percentage of the adult population in many countries have tried it with smaller minorities doing it on a regular basis. Since cannabis is illegal or only tolerated in many jurisdictions, there is no industrial mass-production of cigarettes, meaning that the most common form of smoking is with hand-rolled cigarettes (often called  joints ) or with pipes. Water pipes are also fairly common; water pipes used for cannabis include designs known as bongs and bubblers, among others."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8827", "text": "A few other recreational drugs are smoked by smaller minorities. Most of these substances are  controlled , and some are considerably more intoxicating than either tobacco or cannabis. These include  crack cocaine , heroin,  methamphetamine  and  PCP . A small number of  psychedelic drugs  are also smoked, including  DMT ,  5-Meo-DMT , and  Salvia divinorum ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8828", "text": "Even the most primitive form of smoking requires tools of some sort to perform. This has resulted in a staggering variety of smoking tools and paraphernalia from all over the world. Whether tobacco, cannabis, opium or herbs, some form of receptacle is required along with a source of fire to light the mixture. The most common today is by far the cigarette, consisting of a mild inhalant strain of tobacco in a tightly rolled tube of paper, usually manufactured industrially and including a  filter , or hand-rolled with loose tobacco. Other popular smoking tools are various  pipes  and cigars."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8829", "text": "A less common but increasingly popular alternative to smoking is vaporizers, which use hot air convection to deliver the substance without combustion, which may reduce health risks. A portable vaporization alternative appeared in 2003 with the introduction of  electronic cigarettes , battery-operated, cigarette-shaped devices which produce an aerosol intended to mimic the smoke from burning tobacco, delivering nicotine to the user without some of the harmful substances released in tobacco smoke."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8830", "text": "Other than actual smoking equipment, many other items are associated with smoking;  cigarette cases ,  cigar boxes ,  lighters ,  matchboxes ,  cigarette holders , cigar holders,  ashtrays ,  silent butlers ,  pipe cleaners , tobacco cutters, match stands, pipe tampers, cigarette companions and so on. Some examples of these have become valuable  collector items  and particularly ornate and antique items can fetch high prices."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8831", "text": "Smoking is one of the leading  preventable causes of deaths  globally and is the cause of over 8 million deaths annually, 1.2 million of which are non-smokers who die due to  second-hand smoke . [ 49 ]  In the United States, about 500,000 deaths per year are attributed to smoking-related diseases and a recent study [ as of? ]  estimated that as much as one-third of China's male population will have significantly shortened lifespans due to smoking. [ 50 ]  Male and female smokers lose an average of 13.2 and 14.5 years of life, respectively. [ 51 ]  At least half of all lifelong smokers die earlier as a result of smoking. [ 52 ] [ 53 ]  The risk of dying from lung cancer before age 85 is 22.1% for a male smoker and 11.9% for a female current smoker, in the absence of competing causes of death. The corresponding estimates for lifelong nonsmokers are a 1.1% probability of dying from lung cancer before age 85 for a man of European descent, and a 0.8% probability for a woman. [ 54 ]  Smoking just one cigarette a day results in a risk of  coronary heart disease  that is halfway between that of a heavy smoker and a non-smoker. [ 55 ] [ 56 ]  The  non-linear   dose\u2013response relationship  may be explained by smoking's effect on  platelet aggregation . [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8832", "text": "Among the diseases that can be caused by smoking are vascular  stenosis , lung cancer, [ 58 ]   heart attacks [ 59 ]  and  chronic obstructive pulmonary disease  (COPD). [ 60 ]  Smoking during pregnancy may cause ADHD to a fetus. [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8833", "text": "Smoking is a risk factor strongly associated with  periodontitis  and  tooth loss . [ 62 ]  The effects of smoking on  periodontal tissues  depend on the number of cigarettes smoked daily and the duration of the habit. A study showed that smokers had 2.7 times and former smokers 2.3 times greater probabilities to have established periodontal disease than non\u2010smokers, independent of age, sex and plaque index, [ 63 ]  however, the effect of tobacco on periodontal tissues seems to be more pronounced in men than in women. [ 63 ]  Studies have found that smokers had greater odds for more severe dental bone loss compared to non\u2010smokers; [ 64 ]  also, people who smoke and drink  alcohol  heavily have much higher  risk  of developing  oral  cancer  (mouth and lip) compared with people who do neither. [ 65 ]  Smoking can also cause  milanosis  in the mouth. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8834", "text": "Smoking has been also associated with oral conditions including  dental caries ,  dental implant failures ,  premalignant lesions , and  cancer . [ 67 ]  Smoking can affect the immune-inflammatory processes which may increase susceptibility to infections; it can alter the oral mycobiota and facilitate colonization of the oral cavity with fungi and pathogenic molds. [ 68 ] [ 69 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8835", "text": "Many governments are trying to deter people from smoking with anti-smoking campaigns in mass media stressing the harmful long-term effects of smoking.  Passive smoking , or secondhand smoking, which affects people in the immediate vicinity of smokers, is a major reason for the enforcement of  smoking bans . These are laws enforced to stop individuals from smoking in indoor public places, such as bars, pubs and restaurants, thus reducing nonsmokers' exposure to secondhand smoke. A common concern among legislators is to discourage smoking among minors and many states have passed laws against selling tobacco products to underage customers (establishing a  smoking age ). Many developing countries have not adopted anti-smoking policies, leading some to call for anti-smoking campaigns and further education to explain the negative effects of ETS (Environmental Tobacco Smoke) in developing countries. [ citation needed ]   Tobacco advertising  is also sometimes regulated to make smoking less appealing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8836", "text": "Despite the many bans, European countries still hold 18 of the top 20 spots, and according to the ERC, a market research company, the heaviest smokers are from Greece, averaging 3,000 cigarettes per person in 2007. [ 70 ]  Rates of smoking have leveled off or declined in the developed world but continue to rise in developing countries. Smoking rates in the United States have dropped by half from 1965 to 2006, falling from 42% to 20.8% in adults. [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8837", "text": "The effects of addiction on society vary considerably between different substances that can be smoked and the indirect social problems that they cause, in great part because of the differences in legislation and the enforcement of narcotics legislation around the world. Though nicotine is a highly addictive drug, its effects on cognition are not as intense or noticeable as other drugs such as cocaine, amphetamines or any of the  opiates  (including heroin and  morphine ). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8838", "text": "Smoking is a risk factor in  Alzheimer's disease . [ 72 ]  While smoking more than 15 cigarettes per day has been shown to worsen the symptoms of  Crohn's disease , [ 73 ]  smoking has been shown to actually lower the prevalence of  ulcerative colitis . [ 74 ] [ 75 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8839", "text": "Smokers are 30-40% more likely to develop  type 2 diabetes  than non-smokers, and the risk increases with the number of cigarettes smoked. [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8840", "text": "Inhaling the vaporized gas form of substances into the lungs is a quick and very effective way of delivering drugs into the bloodstream (as the gas diffuses directly into the pulmonary vein, then into the heart and from there to the brain) and affects the user within less than a second of the first inhalation. The lungs consist of several million tiny bulbs called  alveoli  that altogether have an area of over 70 m 2  (about the area of a tennis court). This can be used to administer useful medical as well as recreational drugs such as aerosols, consisting of tiny droplets of a medication, or as gas produced by burning plant material with a psychoactive substance or pure forms of the substance itself. Not all drugs can be smoked, for example the sulphate derivative that is most commonly inhaled through the nose, though purer free base forms of substances can, but often require considerable skill in administering the drug properly. The method is also somewhat inefficient since not all of the smoke will be inhaled. [ 79 ]  The inhaled substances trigger chemical reactions in nerve endings in the brain due to being similar to naturally occurring substances such as  endorphins  and  dopamine , which are associated with sensations of pleasure. The result is what is usually referred to as a \"high\" that ranges between the mild stimulus caused by  nicotine  to the intense euphoria caused by heroin,  cocaine  and  methamphetamines . [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8841", "text": "Inhaling smoke into the lungs, no matter the substance, has adverse effects on one's health. [ citation needed ]  The incomplete combustion produced by burning plant material, like tobacco or cannabis, produces  carbon monoxide , which impairs the ability of blood to carry oxygen when inhaled into the lungs. There are several other toxic compounds in tobacco that constitute serious health hazards to long-term smokers from a whole range of causes; vascular abnormalities such as  stenosis , lung cancer, heart attacks, strokes,  impotence , low birth weight of infants born by  smoking mothers . 8% of long-term smokers develop the characteristic set of facial changes known to doctors as  smoker's face . [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8842", "text": "Tobacco smoke is a complex mixture of over 5,000 identified chemicals, of which 98 are known to have specific  toxicological  properties. [ 82 ]  The most important chemicals  causing cancer  are those that produce  DNA damage  since such damage appears to be the primary underlying cause of cancer. [ 83 ]  Cunningham et al. [ 84 ]  combined the microgram weight of the compound in the smoke of one cigarette with the known  genotoxic  effect per microgram to identify the most  carcinogenic  compounds in cigarette smoke. The seven most important carcinogens in tobacco smoke are shown in the table, along with DNA alterations they cause."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8843", "text": "Most tobacco smokers begin during adolescence or early adulthood. Smoking has elements of risk-taking and rebellion, which often appeal to young people. The presence of high-status models and peers may also encourage smoking. Because teenagers are influenced more by their peers than by adults, [ 93 ]  attempts by parents, schools, and health professionals at preventing people from trying cigarettes are not always successful."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8844", "text": "Smokers often report that cigarettes help relieve feelings of stress. However, the stress levels of adult smokers are slightly higher than those of nonsmokers. Adolescent smokers report increasing levels of stress as they develop regular patterns of smoking, and  smoking cessation  leads to reduced stress. Far from acting as an aid for mood control, nicotine dependency seems to exacerbate stress. This is confirmed in the daily mood patterns described by smokers, with normal moods during smoking and worsening moods between cigarettes. Thus, the apparent relaxant effect of smoking only reflects the reversal of the tension and irritability that develop during nicotine depletion. Dependent smokers need nicotine to remain feeling normal. [ 94 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8845", "text": "In the mid-20th century psychologists such as  Hans Eysenck  developed a personality profile for the typical smoker of that period;  extraversion  was associated with smoking, and smokers tended to be sociable, impulsive, risk taking, and excitement-seeking individuals. [ 95 ]  Although personality and social factors may make people likely to smoke, the actual habit is a function of  operant conditioning . During the early stages, smoking provides pleasurable sensations (because of its action on the  dopamine  system) and thus serves as a source of  positive reinforcement . After an individual has smoked for many years, the avoidance of withdrawal symptoms and  negative reinforcement  become the key motivations. Like all addictive substances, the amount of exposure required to become dependent on nicotine can vary from person to person."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8846", "text": "In terms of the  Big Five personality traits , research has found smoking to be correlated with lower levels of  agreeableness  and  conscientiousness , as well as higher levels of  extraversion  and  neuroticism . [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8847", "text": "Education and counselling by physicians of children and adolescents has been found to be effective in decreasing the risk of tobacco use. [ 97 ]  Systematic reviews show that psychosocial interventions can help women stop smoking in late pregnancy, reducing low birthweight and preterm births. [ 98 ]  A 2016 Cochrane review showed that the combination of medication and behavioural support was more effective than minimal interventions or usual care. [ 99 ]  Another Cochrane review \"suggests that neither reducing smoking to quit nor quitting abruptly results in superior quit rates; people could therefore be given a choice of how to quit, and support provided to people who would specifically like to reduce their smoking before quitting.\" [ 100 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8848", "text": "Smoking, primarily of tobacco, is an activity that is practiced by some 1.1\u00a0billion people, and up to 1/3 of the adult population. [ 107 ]  The image of the smoker can vary considerably, but is very often associated, especially in fiction, with individuality and aloofness. [ citation needed ]  Even so, smoking of both tobacco and cannabis can be a social activity which serves as a reinforcement of social structures and is part of the cultural rituals of many and diverse social and ethnic groups. Many smokers begin smoking in social settings and the offering and sharing of a cigarette is often an important rite of initiation or simply a good excuse to start a conversation with strangers in many settings; in bars,  night clubs , at work or on the street. Lighting a cigarette is often seen as an effective way of avoiding the appearance of idleness or mere loitering. For adolescents, it can function as a first step out of childhood or as an act of rebellion against the adult world. Also, smoking can be seen as a sort of camaraderie. It has been shown that even opening a packet of cigarettes, or offering a cigarette to other people, can increase the level of dopamine (the \"happy feeling\") in the brain, and it is doubtless that people who smoke form relationships with fellow smokers, in a way that only proliferates the habit, particularly in countries where smoking inside public places has been made illegal. [ citation needed ]  Other than recreational drug use, it can be used to construct identity and a development of self-image by associating it with personal experiences connected with smoking. The rise of the modern anti-smoking movement in the late 19th century did more than create awareness of the hazards of smoking; it provoked reactions of smokers against what was, and often still is, perceived as an assault on personal freedom and has created an identity among smokers as rebels or outcasts, apart from non-smokers:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8849", "text": "There is a new Marlboro land, not of lonesome cowboys, but of social-spirited urbanites, united against the perceived strictures of public health. [ 108 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8850", "text": "The importance of tobacco to soldiers was early on recognized as something that could not be ignored by commanders. By the 17th century allowances of tobacco were a standard part of the naval rations of many nations and by World War I cigarette manufacturers and governments collaborated in securing tobacco and cigarette allowances to soldiers in the field. It was asserted that regular use of tobacco while under duress would not only calm the soldiers but allow them to withstand greater hardship. [ 109 ]  Until the mid-20th century, the majority of the adult population in many Western nations were smokers and the claims of anti-smoking activists were met with much skepticism, if not outright contempt. Today the movement has considerably more weight and evidence of its claims, but a considerable proportion of the population remains steadfast smokers. [ 110 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8851", "text": "Smoking has been accepted into culture, in various art forms, and has developed many distinct, and often conflicting or mutually exclusive, meanings depending on time, place and the practitioners of smoking.  Pipe smoking , until recently one of the most common forms of smoking, is today often associated with solemn contemplation, old age and is often considered quaint and archaic. [ citation needed ]  Cigarette smoking, which did not begin to become widespread until the late 19th century, has more associations of  modernity  and the faster pace of the industrialized world. Cigars have been, and still are, associated with  masculinity , power and is an iconic image associated with the stereotypical capitalist. In fact, some evidence suggests that men with higher than average testosterone levels are more likely to smoke. [ 111 ]  Smoking in public has for a long time been something reserved for men and when done by women has been associated with  promiscuity . In Japan during the  Edo period , prostitutes and their clients would often approach one another under the guise of offering a smoke; the same was true for 19th-century Europe. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8852", "text": "The earliest depictions of smoking can be found on Classical Mayan pottery from around the 9th century. The art was primarily religious in nature and depicted deities or rulers smoking early forms of cigarettes. [ 112 ]  Soon after smoking was introduced outside of the Americas it began appearing in painting in Europe and Asia. The painters of the  Dutch Golden Age  were among the first to paint portraits of people smoking and still lifes of pipes and tobacco. For southern European painters of the 17th century, a pipe was much too modern to include in the preferred motifs inspired by mythology from Greek and Roman antiquity. At first smoking was considered lowly and was associated with peasants. [ 113 ]  Many early paintings were of scenes set in taverns or brothels. Later, as the  Dutch Republic  rose to considerable power and wealth, smoking became more common amongst the affluent and portraits of elegant gentlemen tastefully raising a pipe appeared. Smoking represented pleasure, transience and the briefness of earthly life as it, quite literally, went up in smoke. Smoking was also associated with representations of both the sense of smell and that of taste."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8853", "text": "In the 18th century smoking became far more sparse in painting as the elegant practice of taking  snuff  became popular. Smoking a pipe was again relegated to portraits of lowly commoners and country folk and the refined sniffing of shredded tobacco followed by sneezing was rare in art. When smoking appeared it was often in the exotic portraits influenced by  Orientalism . Many proponents of  postcolonialism  controversially believe this portrayal was a means of projecting an image of European superiority over its colonies and a perception of the male dominance of a feminized Orient. Proponents believe the theme of the exotic and alien \"Other\" escalated in the 19th century, fueled by the rise in the popularity of  ethnology  during the  Enlightenment . [ 114 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8854", "text": "In the 19th century smoking was common as a symbol of simple pleasures; the pipe smoking \"noble savage\", solemn contemplation by Classical Roman ruins, scenes of an artist becoming one with nature while slowly toking a pipe. The newly empowered middle class also found a new dimension of smoking as a harmless pleasure enjoyed in smoking saloons and libraries. Smoking a cigarette or a cigar would also become associated with the  Bohemian , someone who shunned the conservative middle class values and displayed his contempt for conservatism. But this was a pleasure that was to be confined to a male world; women smokers were associated with prostitution and smoking was not considered an activity fit for proper ladies. [ 115 ]  It was not until the start of the 20th century that smoking women would appear in paintings and photos, giving a chic and charming impression.  Impressionists  like  Vincent van Gogh , who was a pipe smoker himself, would also begin to associate smoking with gloom and  fin-du-si\u00e8cle  fatalism.\nWhile the symbolism of the cigarette, pipe and cigar respectively were consolidated in the late 19th century, it was not until the 20th century that artists began to use it fully; a pipe would stand for thoughtfulness and calm; the cigarette symbolized modernity, strength and youth, but also nervous anxiety; the cigar was a sign of authority, wealth and power. The decades following World War II, during the apex of smoking when the practice had still not come under fire by the growing anti-smoking movement, a cigarette casually tucked between the lips represented the young rebel, epitomized in actors like  Marlon Brando  and  James Dean  or mainstays of advertising like the  Marlboro Man . It was not until the 1970s when the negative aspects of smoking began to appear, yielding the image of the unhealthy lower-class individual, reeking of cigarette smoke and lack of motivation and drive, which was especially prominent in art inspired or commissioned by anti-smoking campaigns. [ 116 ]  In his painting \"Holy Smokes\", artist  Brian Whelan  pokes fun at the smoking debate and its newly found focus on morality and guilt."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8855", "text": "Ever since the era of  silent films , smoking has had a major part in film symbolism. In the hard-boiled  film noir  crime thrillers, cigarette smoke often frames characters and is frequently used to add an aura of mystique or  nihilism . One of the forerunners of this symbolism can be seen in  Fritz Lang 's  Weimar era   Dr Mabuse, der Spieler , 1922 ( Dr Mabuse, the Gambler ), where men mesmerized by card playing smoke cigarettes while gambling."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8856", "text": "Female smokers in film were also early on associated with a type of sensuous and seductive sexuality, most notably personified by German film star  Marlene Dietrich . Similarly, actors like  Humphrey Bogart  and  Audrey Hepburn  have been closely identified with their smoker persona, and some of their most famous portraits and roles have involved them being haloed by a mist of cigarette smoke. Hepburn often enhanced the glamor with a cigarette holder, most notably in the film  Breakfast at Tiffany's . Smoking could also be used as a means to subvert censorship, as two cigarettes burning unattended in an ashtray were often used to suggest sexual activity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8857", "text": "Since World War II, smoking has gradually become less frequent on screen as the obvious health hazards of smoking have become more widely known. With the anti-smoking movement gaining greater respect and influence, conscious attempts not to show smoking on screen are now undertaken in order to avoid encouraging smoking or giving it positive associations, particularly for family films. [ 117 ]  Smoking on screen is more common today among characters who are portrayed as anti-social or even criminal. [ 118 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8858", "text": "According to a 2019 study, the introduction of television in the United States led to a substantial increase in smoking, in particular among 16\u201321-year-olds. [ 119 ]  The study suggested \"that television increased the share of smokers in the population by 5\u201315 percentage points, generating roughly 11 million additional smokers between 1946 and 1970.\" [ 119 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8859", "text": "Just as in other types of fiction, smoking has had an important place in literature and smokers are often portrayed as characters with great individuality, or outright eccentrics, something typically personified in one of the most iconic smoking literary figures of all,  Sherlock Holmes . Other than being a frequent part of short stories and novels, smoking has spawned endless eulogies, praising its qualities and affirming the author's identity as a devoted smoker. Especially during the late 19th century and early 20th century, a panoply of books with titles like  Tobacco: Its History and associations  (1876),  Cigarettes in Fact and Fancy  (1906) and  Pipe and Pouch: The Smokers Own Book of Poetry  (1905) were written in the UK and the US. The titles were written by men for other men and contained general tidbits and poetic musings about the love for tobacco and all things related to it, and frequently praised the refined bachelor's life.  The Fragrant Weed: Some of the Good Things Which Have been Said or Sung about Tobacco , published in 1907, contained, among many others, the following lines from the poem  A Bachelor's Views  by Tom Hall that were typical of the attitude of many of the books:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8860", "text": "So let us drink To her, \u2013 but think Of him who has to keep her; And  sans  a wife Let's spend our life In bachelordom, \u2013 it's cheaper."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8861", "text": "These works were all published in an era before the cigarette had become the dominant form of tobacco consumption and pipes, cigars, and chewing tobacco were still commonplace. Many of the books were published in novel packaging that would attract the learned smoking gentleman.  Pipe and Pouch  came in a leather bag resembling a tobacco pouch and  Cigarettes in Fact and Fancy  (1901) came bound in leather, packaged in an imitation cardboard cigar box. By the late 1920s, the publication of this type of literature largely abated and was only sporadically revived in the later 20th century. [ 121 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8862", "text": "There have been few examples of tobacco in music in early modern times, though there are occasional signs of influence in pieces such as  Johann Sebastian Bach 's  Enlightening Thoughts of a Tobacco-Smoker . [ 122 ]  However, from the early 20th century and onwards smoking has been closely associated with popular music.  Jazz  was from early on closely intertwined with the smoking that was practiced in the venues where it was played, such as bars, dance halls, jazz clubs and even brothels. The rise of jazz coincided with the expansion of the modern tobacco industry, and in the United States also contributed to the spread of cannabis. The latter went under names like \"tea\", \"muggles\" and \"reefer\" in the jazz community and was so influential in the 1920s and 30s that it found its way into songs composed at the time such as  Louis Armstrong 's  Muggles ,  Larry Adler 's  Smoking Reefers , and  Don Redman 's  Chant of The Weed . The popularity of marijuana among jazz musicians remained high until the 1940s and 50s, when it was partially replaced by the use of heroin. [ 123 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8863", "text": "Another form of modern popular music that has been closely associated with cannabis smoking is  reggae , a style of music that originated in  Jamaica  in the late 1950s and early 60s. Cannabis, or  ganja , is believed to have been introduced to Jamaica in the mid-19th century by Indian immigrant labor and was primarily associated with Indian workers until it was appropriated by the  Rastafari movement  in the middle of the 20th century. [ 124 ]  The Rastafari considered cannabis smoking to be a way to come closer to God, or  Jah , an association that was greatly popularized by reggae icons such as  Bob Marley  and  Peter Tosh  in the 1960s and 70s. [ 125 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8864", "text": "Estimates claim that smokers cost the U.S. economy $97.6 billion a year in lost productivity and that an additional $96.7 billion is spent on public and private health care combined. [ 126 ]  This is over 1% of the  gross domestic product . A male smoker in the United States that smokes more than one pack a day can expect an average increase of $19,000 just in medical expenses over the course of his lifetime. A U.S. female smoker that also smokes more than a pack a day can expect an average of $25,800 additional healthcare costs over her lifetime. [ 127 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8865", "text": "In  chemistry , a  solution  is defined by  IUPAC  as \"A liquid or solid phase containing more than one substance, when for convenience one (or more) substance, which is called the solvent, is treated differently from the other substances, which are called solutes. When, as is often but not necessarily the case, the sum of the mole fractions of solutes is small compared with unity, the solution is called a dilute solution. A superscript attached to the \u221e symbol for a property of a solution denotes the property in the limit of infinite dilution.\" [ 1 ]  One important parameter of a solution is the  concentration , which is a measure of the amount of solute in a given amount of solution or solvent. The term \" aqueous solution \" is used when one of the solvents is  water . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8866", "text": "Homogeneous  means that the components of the mixture form a single phase.  Heterogeneous  means that the components of the mixture are of different phase. The properties of the mixture (such as concentration, temperature, and density) can be uniformly distributed through the volume but only in absence of diffusion phenomena or after their completion. Usually, the substance present in the greatest amount is considered the solvent. Solvents can be gases, liquids, or solids. One or more components present in the solution other than the solvent are called solutes. The solution has the same  physical state  as the solvent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8867", "text": "If the solvent is a  gas , only gases (non-condensable) or vapors (condensable) are dissolved under a given set of conditions. An example of a gaseous solution is  air  (oxygen and other gases dissolved in nitrogen). Since interactions between gaseous molecules play almost no role, non-condensable gases form rather trivial solutions. In the literature, they are not even classified as solutions, but simply addressed as homogeneous  mixtures  of gases. The  Brownian motion  and the permanent molecular agitation of gas molecules guarantee the homogeneity of the gaseous systems. Non-condensable gaseous mixtures (e.g., air/CO 2 , or air/xenon) do not spontaneously demix, nor sediment, as distinctly stratified and separate gas layers as a function of their  relative density .  Diffusion  forces efficiently counteract  gravitation  forces under normal conditions prevailing on Earth. The case of condensable vapors is different: once the  saturation vapor pressure  at a given temperature is reached, vapor excess condenses into the  liquid state ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8868", "text": "Liquids  dissolve gases, other liquids, and solids.  An example of a dissolved gas is  oxygen  in water, which allows fish to breathe under water.  An examples of a dissolved liquid is ethanol in water, as found in  alcoholic beverages .  An example of a dissolved solid is sugar water, which contains dissolved  sucrose ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8869", "text": "If the solvent is a  solid , then gases, liquids, and solids can be dissolved."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8870", "text": "The ability of one  compound  to dissolve in another compound is called  solubility . [ clarification needed ]  When a liquid can completely dissolve in another liquid the two liquids are  miscible . Two substances that can never mix to form a solution are said to be  immiscible ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8871", "text": "All solutions have a positive  entropy  of mixing. The interactions between different molecules or ions may be energetically favored or not. If interactions are unfavorable, then the  free energy  decreases with increasing solute concentration. At some point, the energy loss outweighs the entropy gain, and no more solute particles [ clarification needed ]  can be dissolved; the solution is said to be  saturated . However, the point at which a solution can become saturated can change significantly with different environmental factors, such as  temperature ,  pressure , and contamination. For some solute-solvent combinations, a  supersaturated  solution can be prepared by raising the solubility (for example by increasing the temperature) to dissolve more solute and then lowering it (for example by cooling)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8872", "text": "Usually, the greater the temperature of the solvent, the more of a given solid solute it can dissolve. However, most gases and some compounds exhibit solubilities that decrease with increased temperature. Such behavior is a result of an  exothermic   enthalpy of solution . Some  surfactants  exhibit this behaviour. The solubility of liquids in liquids is generally less temperature-sensitive than that of solids or gases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8873", "text": "The physical properties of compounds such as  melting point  and  boiling point  change when other compounds are added. Together they are called  colligative properties . There are several ways to quantify the amount of one compound dissolved in the other compounds collectively called  concentration . Examples include  molarity ,  volume fraction , and  mole fraction ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8874", "text": "The properties of  ideal solutions  can be calculated by the  linear combination  of the properties of its components. If both solute and solvent exist in equal quantities (such as in a 50%  ethanol , 50% water solution), the concepts of \"solute\" and \"solvent\" become less relevant, but the substance that is more often used as a solvent is normally designated as the solvent (in this example, water)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8875", "text": "In principle, all types of liquids can behave as solvents: liquid  noble gases , molten metals, molten salts, molten covalent networks, and molecular liquids. In the practice of chemistry and biochemistry, most solvents are molecular liquids. They can be classified into  polar and non-polar , according to whether their molecules possess a permanent  electric dipole moment . Another distinction is whether their molecules can form  hydrogen bonds  ( protic  and aprotic solvents).  Water , the most commonly used solvent, is both polar and sustains hydrogen bonds."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8876", "text": "Salts dissolve in polar solvents, forming positive and negative ions that are attracted to the negative and positive ends of the solvent molecule, respectively. If the solvent is water,  hydration  occurs when the charged solute ions become surrounded by water molecules. A standard example is aqueous saltwater. Such solutions are called  electrolytes . Whenever salt dissolves in water  ion association  has to be taken into account."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8877", "text": "Polar solutes dissolve in polar solvents, forming polar bonds or hydrogen bonds. As an example, all alcoholic beverages are  aqueous solutions  of  ethanol . On the other hand, non-polar solutes dissolve better in non-polar solvents. Examples are hydrocarbons such as  oil  and  grease  that easily mix, while being incompatible with water."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8878", "text": "An example of the immiscibility of oil and water is a leak of petroleum from a damaged tanker, that does not dissolve in the ocean water but rather floats on the surface."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8879", "text": "Sonophoresis  also known as  phonophoresis , is a method that utilizes  ultrasound  to enhance the delivery of topical medications through the  stratum corneum , to the  epidermis  and  dermis . Sonophoresis allows for the enhancement of the permeability of the skin along with other modalities, such as  iontophoresis , to deliver drugs with lesser side effects. Currently, sonophoresis is used widely in  transdermal   drug delivery , but has potential applications in other sectors of drug delivery, such as the delivery of drugs to the eye and brain."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8880", "text": "Sonophoresis, also known as  phonophoresis , was dated back all the way to the 1950s in its first mention in a published report. [ 1 ]  This report showcased that a  hydrocodone  injection yielded better outcomes for  bursitis  when combined with an ultrasound massage. [ 2 ]  Following this, a series of publications from several investigators showed the increased therapeutic effect when combining ultrasound with  hydrocortisone  injections for various other disease states, further demonstrating the novelty of sonophoresis. [ 2 ]  However, while some researchers provided evidence that ultrasound had a positive effect on the transdermal permeation of drugs, others contradicted this information by displaying research that showed no quantitative effect using ultrasound. [ 2 ]  These early studies mainly investigated the combination of therapeutics with high-frequency sonophoresis (HFS), which can be categorized into frequencies greater than 0.7\u00a0MHz. [ 1 ]  High frequency sonophoresis usually includes a range between 0.7 \u2013 16\u00a0MHz. [ 1 ]  Studies evolved and HFS was continually studied for four decades until a greater understanding of a mechanism of action,  cavitation , was discovered. [ 1 ]  Cavitational effects are inversely proportional to the frequency of the ultrasound applied, which led to further studies of low-frequency sonophoresis (LFS) for use in transdermal drug delivery due to studies showing greater efficacy in enhancing skin permeability in comparison to HFS. [ 1 ]  Low-frequency sonophoresis usually includes a range between 20 and 100\u00a0kHz. [ 1 ]  For this reason, currently HFS focuses on topical applications for penetration through the stratum corneum, whereas LFS focuses on transdermal drug delivery applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8881", "text": "Ultrasonic  sonicators  generate ultrasound waves, which is a longitudinal compression wave, by converting electrical energy into mechanical energy by deformation of  piezoelectric  crystals in response to an electric field. [ 1 ] [ 3 ]  The frequency of the waves generated by this method can range from 20\u00a0kHz up to 3\u00a0MHz. [ 3 ]  The ultrasound waves generated from this device allow for penetration through biological tissue by molecular oscillation of the biological tissue they travel through. [ 1 ] [ 3 ]  The amplitude of the wave can be modified by manipulating the displacement of the ultrasound horn for each half cycle as they are proportional."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8882", "text": "The primary purpose of phonophoresis is to assist in transdermal drug delivery, usually with the help of a coupling agent or medium. Transdermal drug delivery sometimes does not permeate the skin to reach a targeted area within the body because of the  stratum corneum  layer of the skin, a layer that prevents foreign substances from penetrating the body. [ 4 ] [ 5 ] [ 6 ]  Transdermal drug delivery is patient-compliance, [ 7 ]  usually avoids  digestive system  degradation, [ 8 ]  and has the ability to use drugs with short  half-lives . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8883", "text": "While increased skin permeability is seen through sonophoresis, the precise mechanisms to describe sonophoresis are yet to be fully discovered. However, there are several important mechanisms that have been identified that contribute to the phenomenon of sonophoresis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8884", "text": "Cavitation is generally determined to be the dominant mechanism that drives sonophoresis. It can be described as the distortion, expansion, and contraction of gas bubbles in a liquid medium. [ 10 ]  The frequency of the ultrasound waves helps determine the bubble parameters, such as size and shape. There exist two types of cavitation, stable and transient. Stable cavitation is when cavitation bubbles persist over many acoustic pressure cycles without collapsing. On the other hand, transient cavitation is where these cavitation bubbles uncontrollably and rapidly grow and decay over many acoustic pressure cycles. [ 1 ]  However, while cavitation is considered the primary mechanism for sonophoresis, the gas bubbles that contribute to cavitation are generated by a process termed rectified diffusion. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8885", "text": "Rectified diffusion is the process where cavitation bubbles experience growth. [ 1 ]  The growth of these bubbles occurs by encountering a negative pressure half cycle, expanding the gas inside the bubble. Similarly, the gas bubble will dramatically decay in size when encountering the other positive half of the pressure cycle. [ 1 ]  There are further factors that manipulate the oscillation of the bubbles\u2019 size, such as temperature and composition of the gas and liquid phases. Depending on the dramatization of the oscillation from previously mentioned factors, stable or transient cavitation occurs. A rapid process will lead to transient cavitation bubbles, whereas a slower process will lead to stable cavitation bubbles. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8886", "text": "An important consideration when transferring energy to a patient would be the thermal energy generated from heating of the biological tissue due to energy losses from the ultrasound waves. It has been shown that increases in temperature can increase skin permeability through several factors. [ 1 ]  Two factors are increased kinetic energy and diffusivity of drugs, which allow for compounds to pass through the stratum corneum. Moreover, hair follicles and sweat glands are dilated, allowing for more points of entry for compounds. The enhanced circulation of blood that comes as a result of increased temperature from ultrasound parameters also allows for better diffusion of compounds. [ 1 ]  While the intensity and duty cycle of the ultrasound are directly proportional to the corresponding thermal effects, surprisingly thermal effects are not a considerable mechanism for HFS in ranges from 1 \u2013 2 degrees Celsius. [ 1 ]  However, once larger temperature changes are observed, such as an excess of 10 degrees Celsius, permeant transport was increased. [ 1 ]  When it comes to LFS, thermal effects are an important consideration on the side of safety. Thermal effects need to be minimized at higher amplitudes, as burns and  necrosis  of tissues can occur due to exposure to high, sustained temperatures. [ 1 ]  A simple solution to counteract sustained exposure to high temperatures is to periodically replace the coupling agent every so often. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8887", "text": "While sonophoresis alone is able to increase the permeability of skin by several factors depending on the procedure and the drug being delivered, a synergistic combination of sonophoresis with other enhancers, such as iontophoresis and  electroporation , has shown greater enhancement as well as increased safety in reduction of individual enhancer parameters. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8888", "text": "Iontophoresis is similar to sonophoresis as it is a method for transdermal drug delivery but does so by applying a  voltage  gradient across the skin. Since there are differences in pathways between iontophoresis and sonophoresis, a combination of these two methods allows for greater enhancement. [ 2 ]  For example, Le et al. displayed, for the case of  heparin , that a combination of iontophoresis and sonophoresis resulted in a 56-fold enhancement of heparin flux in comparison to sonophoresis having a 3-fold enhancement and iontophoresis having a 15-fold enhancement. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8889", "text": "Electroporation allows the cell membrane to open up after applying an  electric field . By applying short, high voltage pulses to the stratum corneum, the lipid structure will become disorganized and allow enhancement of drug delivery. [ 3 ]  There are currently very few reports of the combination of these modalities being used together. However, in these reports, there is mention that the  transdermal  enhancement created by the combination was greater than the sum of the individual enhancers, suggesting that electroporation and sonophoresis work together synergistically. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8890", "text": "Phonophoresis can be performed using two main methods: The first is simultaneous treatment, where the drug can be applied at the same time as the ultrasound. The second method is pretreatment, where the  ultrasound  is used briefly before drug delivery. [ 8 ] [ 9 ] [ 13 ] [ 7 ]  This is to ensure that the skin is permeable prior to the drug being applied."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8891", "text": "When using an ultrasound, cavities will develop due to the pressure change. Stable cavitation describes the repetitive oscillations of a cavity bubble, while inertial cavitation describes the collapse of a cavity bubble. [ 8 ]  If the developed cavities fall apart, the effect on the  stratum corneum   lipids  will increase the permeability of the skin. [ 9 ] [ 6 ]  These areas of increased permeability are often called localized transport regions, where there is lower  electrical resistivity . [ 14 ]  One potential method is to use cavitation seed at the surface of the skin. [ 15 ]  Another potential method is to use ultrasound-responsive liquid-core nuclei (URLN). [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8892", "text": "Low-frequency ultrasound is seen as the optimal level of ultrasound frequency. This is typically characterized as 20 to 100\u00a0kHz (sometimes 18 to 100\u00a0kHz). [ 7 ]  Low frequency makes cavitation more likely. For reference, high frequency ultrasound is typically in the range of 1 to 3\u00a0MHz. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8893", "text": "The drug should be able to work together with the coupling agent. [ 9 ]  In a 2019 study, they used the drug  diclofenac  in coordination with  thiocolchioside  gel to treat patients who suffer from  acute lower back pain . [ 16 ]  An application of a drug serving as a coupling agent is the use of  piroxicam  gel mixtures and  dexamethasone sodium phosphate  gel mixtures to treat patients who suffer from  carpal tunnel syndrome . [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8894", "text": "Various conditions that can be addressed include  cervical spine  pain, [ 18 ]  acute lower back pain, [ 16 ]   carpal tunnel syndrome , [ 17 ]  muscle injury, [ 19 ]   rheumatoid arthritis , [ 20 ]  and  venous thrombosis . [ 5 ]  Examples of drugs that have been used with sonophoresis include  hydrocortisone ,  mannitol ,  dexamethasone , and  lidocaine . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8895", "text": "Several products have been marketed to use phonophoresis for transdermal drug delivery. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8896", "text": "A potential future application of phonophoresis is to use it with vaccines, as phonophoresis is considered a less painful alternative to needles. [ 14 ] [ 9 ] [ 7 ] [ 4 ]  Another potential use is in cancer therapeutics; one such application that has been explored is the delivery of  cisplatin  for patients who have  cervical cancer . [ 21 ]  Genetic skin diseases and  wound healing  may be assisted by phonophoresis. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8897", "text": "Regarding high frequency sonophoresis (HFS), the future potential is very similar to its usage in the past. Many of the treatments involving HFS are topical and regional. [ 1 ]  Commonly used drugs in these topical applications include anti-inflammatory medications such as  cortisol  and  dexamethasone . However, there has been a notable shift towards using  non-steroidal anti-inflammatory drugs  (NSAIDs), such as  ibuprofen  and  ketoprofen . [ 1 ]  NSAIDs commonly cause  gastrointestinal  side effects such as nausea and heartburn, which can all be bypassed by delivering NSAIDs using sonophoresis. [ 1 ]  With its credible safety and useful ability in penetrating the stratum corneum, HFS remains an incredibly versatile option for delivering drugs topically. Low frequency sonophoresis (LFS), on the other hand, has a variety of applications that can be built upon in the future. Since LFS is not restricted by its ability to deliver molecules of varying sizes, drugs such as  proteins ,  nanoparticles , and  vaccines  are all possible targets. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8898", "text": "In previous literature, it has been demonstrated that ocular delivery of drugs can be achieved with high efficacy and minimal invasion. With 20\u00a0kHz ultrasound waves at an average temporal intensity of 2 W/cm^2applied every second, the permeability of drugs with varying  lipophilicity  were investigated, such as  atenolol  and  carteolol , increased by 2.6 and 2.8-fold respectively. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8899", "text": "Topical  gene therapy  is another area for investigation in combination with sonophoresis.  Since there exists a need to enhance gene transfer into cells, sonophoresis has the ability to achieve higher  transfection  rate through acoustic cavitation. [ 23 ]  Additionally, there is the advancement of using  microbubbles  with a  contrast agent  to diagnostically image the brain, as LFS and cavitation allows for disruption of the  blood brain barrier . [ 24 ]  Gene therapy using ultrasound and microbubbles is also being investigated for ocular disease. [ 25 ]  In cardiovascular disease, for example, the efficiency of gene therapy can be improved by  ultrasound targeted microbubble destruction  where a gene-loaded microbubble can be burst to release its contents. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8900", "text": "Research being done on sonophoresis is poorly standardized. For example, the emission of ultrasound waves further away from the source results in a greater beam area, which drastically changes the ultrasound energy at the targeted area. [ 3 ]  More challenges surround the cost of the actual ultrasound devices used in sonophoresis in more clinical settings. There still yet exists a low-cost device with high efficacy. [ 27 ]  Additionally the precise mechanisms as to how sonophoresis works is currently yet to be discovered. Further research into the mechanisms, and the dominant mechanisms, can allow for better optimization of sonophoresis parameters, which will increase the efficacy of treatments."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8901", "text": "Areas of sonophoretic research include the application of various drugs, dual-frequency sonophoresis, combined transdermal drug delivery techniques, and the use of nanoparticles to carry drugs. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8902", "text": "At an optimal frequency, phonophoresis will be painless and have minimal to no risk. The heat that is emitted from ultrasound use can also be damaging to the surface of the skin, [ 13 ]  and cavitation can potentially lead to tissue damage. [ 13 ]   Nanoparticle toxicity  is another potential risk. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8903", "text": "Conventional  drug delivery  is limited by the inability to control dosing, target specific sites, and achieve targeted permeability. Traditional methods of delivering therapeutics to the body experience challenges in achieving and maintaining maximum therapeutic effect while avoiding the effects of drug toxicity. Many drugs that are delivered orally or parenterally do not include mechanisms for sustained release, and as a result they require higher and more frequent dosing to achieve any therapeutic effect for the patient. [ 1 ]  As a result, the field of drug delivery systems developed into a large focus area for pharmaceutical research to address these limitations and improve quality of care for patients. Within the broad field of drug delivery, the development of  stimuli-responsive drug delivery systems  has created the ability to tune drug delivery systems to achieve more controlled dosing and targeted specificity based on material response to exogenous and endogenous stimuli."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8904", "text": "Endogenous stimuli consist of chemical, biological, and physical stimuli that occur naturally in the body, such as changes in pH, temperature, enzymatic action, pressure, and shear forces. More specifically, endogenous chemical stimuli include environmental pH, redox reactions, and chemical gradients, each of which are typically out of physiological range or unique to a specific or diseased tissue, which provides the ability to achieve target specificity using these particular stimuli for release. [ 2 ]  Researchers have worked to develop numerous types of drug delivery systems that harness a response to endogenous chemical stimuli to achieve targeted delivery and controlled release of drug into a specific environment. These chemically responsive drug delivery systems can be created using a wide variety of materials and carriers, including lipid, protein, or polymeric materials to create degradable scaffolds or depots and micelles and nanoparticles. [ 3 ]  An example of this includes the engineering of biopolymeric nanospheres that are triggered to release an encapsulated therapeutic when they enter the tumor microenvironment due to the drop in pH associated with the tumor microenvironment. Many of these systems rely on the application and manipulation of  click chemistry  to achieve stimulated response [ 2 ]  The field of endogenous chemical-responsive systems has developed greatly within the last 20 years and continues to grow as researchers determine new applications for the field, including the development of chemically responsive systems for diagnostic purposes. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8905", "text": "Endogenous chemical stimuli-responsive drug delivery systems are important in the field of drug delivery because of their ability to harness chemical phenomena within the body to overcome traditional therapeutic release limitations such as temporal release and tissue permeability. These drug delivery systems can be applied both as diagnostic and treatment tools for diseases like cancer to achieve long-term action and maximize the therapeutic effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8906", "text": "While the study of drug delivery methods and techniques has been around for centuries, the modern field of drug delivery we know today was not introduced until the 1960s, when the concept of controlled drug delivery systems was introduced by Judah Folkman, MD of Harvard. [ 4 ]  He first introduced the idea of a prolonged drug release system as a means of constant rate delivery while experimenting with anesthetic gases and arterio-venous shunts on mice [ 4 ]  This inspired the formation of a company called ALZA by a chemist named Alejandro Zaffaroni, whose primary focus was on the development of drug carrying systems that would increase the specificity and efficacy of drugs. [ 1 ]  The introduction of this concept led to the development of the field we know today, with macro scale delivery devices being developed in the 1970s and 1980s before moving into more focused development of microscale and nanoscale devices in the late 1980s onward. [ 4 ]  The concept of stimuli-responsive drug delivery systems can actually be seen as ahead of this time, since the first pH-responsive drug coating was used in the late 1950s in Europe. [ 4 ]  These coatings were used on drugs delivered to the stomach, so that they would protonate and dissolve at low pH to release drug. [ 4 ]  The development of stimuli-responsive drug carriers was not popularized until the mid-1980s by researchers at Utah University, who created thermally-responsive drug delivery systems. [ 4 ]   Since the eruption of this field, substantial research has been conducted to tune stimuli-responsive drug delivery systems despite several limitations. As of 2013, a redox-responsive therapy targeting metastatic breast cancer had been approved by the FDA but was not yet currently in use. [ 1 ]  Much work is still being done to continue the development of this field in hopes of one day making stimuli-responsive drug delivery systems commonplace in medical practice."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8907", "text": "pH responsive drug delivery systems respond to the environmental pH of a tissue, which, when existing within a certain acidic range, can lead to structural and chemical changes of the drug delivery system. These changes can include conformational changes and surface interactions that can lead to the degradation or swelling/shrinking of the drug carrier. [ 1 ]  pH responsive drug delivery systems are possible because of the tendency of diseased or cancerous tissues to maintain a lower pH value than is physiologically normal due to high rates of tumor cell metabolism (normal: 7.4, lower range: 5.0-6.5). [ 2 ] [ 5 ]  These systems are governed by hydrophilic and hydrophobic interactions of self-assembled drug carriers within a certain pH range. [ 2 ]  These hydrophilic and hydrophobic interactions can cause the destabilization of these systems, which lead to conformational changes that cause the drug carrier to breakdown or degrade. As a result, the drug is released from the system. pH responsive drug delivery systems are typically synthesized from pH-responsive polymers that have been conjugated with ionic residues that change charge based on the pH of the environment. [ 1 ]  Systems used with pH-responsive polymers include implantable hydrogels and micro- and nanoparticles. pH-responsive drug delivery systems are particularly suitable for the design of chemotherapeutic delivery systems due to the naturally low pH found in tumor microenvironments, but can be applied in other disease settings where the pH of the varies from physiological pH. The highly targeted and controlled release ability, as well as their broad applications, make pH-responsive drug delivery systems some of the most well-researched and sought after clinical solutions in stimuli-responsive drug delivery. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8908", "text": "Redox responsive drug delivery systems rely on the natural reduction-oxidation reactions that occur in the body and the availability of reducing or oxidative-agents in the extracellular and intracellular space. [ 2 ]  In redox-stimulated responses, drug carriers enter the intracellular space through endocytosis and are destabilized by intracellular concentrations of reducing agents, leading to their disassembly and the delivery of the therapeutic intracellularly. [ 2 ]  For example, the use of redox stimulated drug delivery is primarily attributed to the high intracellular concentration of glutathione (GSH) as compared to the much lower extracellular concentration of GSH. [ 6 ]  GSH acts as a reducing agent in redox reactions, allowing it to cleave bonds like disulfide bonds. The increased level of GSH in tumor cells combined with its ability to cleave disulfide bonds has led to the development of drug delivery systems, such as polymeric micelles, synthesized with disulfide bonds that are subsequently cleaved by intracellular GSH, which cause the breakdown of the micelle and the intracellular release of the encapsulated therapeutic. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8909", "text": "Gradient responsive drug delivery systems are stimulated to deliver therapeutics through contact with an endogenous chemical gradient. When the system comes into contact with its specific chemical gradient, increased concentration of the chemical can lead to the conformational change or degradation of a drug carrier to allow drug release. [ citation needed ]  Gradient responsive systems also include gradients created by pH or redox reactants."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8910", "text": "pH-responsive drug delivery systems are very popular subjects of research for their variability in application. Deviations from physiological pH occur in numerous disease states including infection, inflammation, and cancer, which makes this stimulus one of the most widely researched in the field of endogenous chemically responsive drug delivery systems. [ 3 ]  Applications of pH-responsive drug delivery systems include the synthesis of pH-responsive polymers into carriers like hydrogels, micelles, and micro- and nanovesicles. [ 3 ]  pH-responsive polymers can be selected for certain applications based on characteristics like the drug concentration, number of ionizable groups, and the type of carrier being used. Examples of widely used pH-responsive polymers include but are not limited to: poly(acrylamide), poly(acrylic acid), and poly(methacrylic acid) [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8911", "text": "Redox-responsive drug delivery systems are also widely studied for a variety of applications, in particular their use in targeting cancer due to the increased levels of GSH in cancerous cells. Redox-responsive drug delivery systems are also used in the delivery of DNA and siRNA for gene therapy. [ 2 ]  Redox-responsive drug carriers are primarily synthesized as micelles or polymersomes and are highly stable because they contain a high amount of cross-linking [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8912", "text": "Gradient-responsive drug delivery systems do not have a substantial body of research as of yet. The primary applications of gradient-responsive drug delivery systems are usually referenced as pH or redox gradients, as opposed to the gradients of other hormones or factors found naturally in the body. Aside from pH and redox gradients, there are no published works on gradient-responsive drug delivery systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8913", "text": "There are many limitations that exist within the field of endogenous chemically responsive drug delivery systems that prevent many of these products from approved to be used in a clinical setting. One of the primary challenges of endogenous chemically responsive drug delivery is the inability to address or overcome patient heterogeneity. Patient heterogeneity describes the naturally-occurring difference between patient biology, such as differences in tumor pH for the same cancer and blood concentrations of redox reagents. [ 1 ]  The targeting of many chemical properties in pathological tissues is also restricted by a small range of fluctuation of the chemical property, which prevents researchers from being able to safely and specifically target that diseased tissue and stimulus due to small windows of sensitivity that have yet to be optimized. [ 5 ] [ 13 ]  \nOther important limitations to consider include the formulation of the drug carrier, which can affect the clearance rate and biodistribution of the drug carrier and decrease therapeutic efficacy due to size, shape, or effective penetration of the tissue by the drug carrier. [ 5 ] [ 13 ]  Biocompatibility and toxicity of the drug carrier formulation also poses a significant challenge to the development of the field, so future studies need to be conducted using inherently biocompatible materials to ensure feasibility and safety of these proposed delivery systems. Finally, cost of production and the scalability of the creation of stimuli responsive drug delivery systems remains an enormous barrier between the development and clinical use of these delivery systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8914", "text": "Stretch-triggered drug delivery  is a method of controlled  drug delivery  stimulated by mechanical forces. The most commonly used materials for stretch-triggered autonomous drug release systems are  hydrogels  and  elastomers . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8915", "text": "This method of drug delivery falls in the category of  stimuli-responsive drug delivery systems  which include  pH ,  temperature , and  redox -responsive systems. Mechanical forces occur naturally throughout the human body therefore, stretch-triggered drug delivery systems may be used to autonomously deliver medications to the body when needed. The use of autonomous drug release systems reduces outcomes such as delays in receiving treatment and inaccurate dosages. [ 1 ]  Autonomous drug release systems induced by stretch apply to drugs such as  antimicrobial agents , cardiovascular medication, and  anticancer drugs . [ 1 ]   Theranostic agents  are also applicable to this drug delivery system, allowing for simultaneous treatment and diagnosis of diseases. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8916", "text": "Compression ,  tension , and  shear  are the three main types of mechanical stimuli. [ 3 ] [ 4 ]  Compression force is when an object experiences forces from two sides, going in opposite directions, causing it to become compacted. Tensile force is when an object experiences forces from two sides, pointing in opposite directions, causing it to stretch. Shear forces are when an object experiences forces that are parallel and are going in opposite directions.  Ultrasound  and  magnetic fields  are also examples of mechanical forces. [ 5 ]  Depending on the mechanical stimuli, a different material may improve the desired results. [ 2 ]  The human body is exposed to mechanical forces on or within  bones, organs, joints, blood vessels, and cartilage. [ 1 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8917", "text": "There are naturally occurring mechanical forces in the human body such as increased stress within blood vessels due to  atherosclerotic plaque . [ 4 ]  The naturally occurring mechanical forces in the body enable the self-administration of medications. [ 3 ]  Motion-triggered drug delivery of anticancer therapy is achievable through the natural forces generated by organ movements. [ 7 ]  Research has been conducted on contact lenses that are pre-loaded with  glaucoma medication  that is released by the stretch of the contact lens during natural eye movements. [ 6 ]  The movement of joints has been used to trigger the release of  antibacterial drugs  into the body. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8918", "text": "Stretch-triggered drug delivery has a variety of applications. Intracellular  transfection  can be achieved through drug-delivery systems that are responsive to mechanical stimuli. [ 3 ]  Drug release can be controlled by triggers due to forces experienced by the body from daily motions. [ 4 ]  Mechanical triggers have been applied to polymers to release 2-furylcarbonil derivatives which then trigger the release of molecular cargo. [ 8 ]  An application of stretch-triggered drug delivery systems is the delivery of chemotherapy triggered by  esophageal  stent expansion. [ 4 ]  Also, the incorporation of several drugs into stretch-triggered autonomous drug release systems is a possibility, allowing drugs to be released by the same or different signals. [ 1 ]  Stretch-triggered drug delivery is also applied to nanoparticle-loaded stretchable  elastomers  that release drugs due to their expanded surface area. [ 7 ]  Stretch-triggered drug delivery has been applied to the cardiovascular system through the use of drug-loaded hydrogels that lead to increased  vascularization . [ 5 ]  A research study demonstrated that  quinine -loaded hydrogels resulted in restricted growth of bacteria as a result of exposure to stretching. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8919", "text": "Due to the limited research on mechanical force-responsive drug delivery systems, the effects of mechanical forces on cells remain unclear. [ 10 ]  Current research on stretch-triggered drug delivery systems mostly involves  in vitro  studies, therefore, extensive  in-vivo  studies are required to further improve knowledge in this subject. [ 10 ] [ 4 ]  A limitation of current technology is the release of drugs in the absence of tensile triggers and a limit of loading agents. [ 4 ]   Transdermal  drug delivery systems may include stretch-triggered technology but these devices are typically used for long-term administration, making drug reloading a topic of concern. [ 11 ]  Issues of environmental impact are also a concern when it comes to transdermal drug delivery due to the material's lack of ability to biodegrade and associated electronic waste. [ 11 ]  An area of interest regarding drug delivery devices that use naturally occurring triggers is the variability of  physiological  parameters between people. [ 11 ]  This makes it difficult to set a standard of what will trigger this technology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8920", "text": "In  chemistry , a  suspension  is a  heterogeneous mixture  of a  fluid  that contains  solid   particles  sufficiently large for  sedimentation . The particles may be  visible  to the  naked eye , usually must be larger than one  micrometer , and will eventually  settle , although the  mixture  is only classified as a suspension when and while the particles have not settled out."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8921", "text": "A suspension is a heterogeneous mixture in which the  solid  particles do not  dissolve , but get suspended throughout the bulk of the  solvent , left floating around freely in the medium. [ 1 ]  The internal phase (solid) is dispersed throughout the external phase (fluid) through mechanical  agitation , with the use of certain  excipients  or suspending agents."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8922", "text": "An example of a suspension would be sand in water. The suspended particles are visible under a  microscope  and will settle over time if left undisturbed. This distinguishes a suspension from a  colloid , in which the  colloid  particles are smaller and do not settle. [ 2 ]  Colloids and suspensions are different from  solution , in which the dissolved substance (solute) does not exist as a solid, and solvent and solute are homogeneously mixed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8923", "text": "A suspension of liquid droplets or fine solid particles in a gas is called an  aerosol . In the  atmosphere , the suspended particles are called  particulates  and consist of fine dust and  soot  particles,  sea salt ,  biogenic  and  volcanogenic   sulfates ,  nitrates , and  cloud  droplets."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8924", "text": "Suspensions are classified on the basis of the  dispersed phase  and the  dispersion medium , where the former is essentially solid while the latter may either be a solid, a liquid, or a gas."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8925", "text": "In modern chemical process industries,  high-shear mixing technology  has been used to create many novel suspensions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8926", "text": "Suspensions are unstable from a thermodynamic point of view but can be kinetically stable over a longer period of time, which in turn can determine a suspension's shelf life. This time span needs to be measured in order to provide accurate information to the consumer and ensure the best product quality."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8927", "text": "\"Dispersion stability refers to the ability of a dispersion to resist change in its properties over time.\" [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8928", "text": "Dispersion  of solid particles in a liquid."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8929", "text": "Note : Definition based on that in ref. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8930", "text": "Multiple light scattering coupled with vertical scanning is the most widely used technique to monitor the dispersion state of a product, hence identifying and quantifying  destabilization  phenomena. [ 6 ] [ 7 ] [ 8 ] [ 9 ]  It works on concentrated dispersions without dilution. When light is sent through the sample, it is back scattered by the particles. The backscattering intensity is directly proportional to the size and volume fraction of the dispersed phase. Therefore, local changes in concentration ( sedimentation ) and global changes in size ( flocculation ,  aggregation ) are detected and monitored. Of primary importance in the analysis of stability in particle suspensions is the value of the  zeta potential  exhibited by suspended solids. This parameter indicates the magnitude of interparticle electrostatic repulsion and is commonly analyzed to determine how the use of  adsorbates  and pH modification affect particle repulsion and suspension stabilization or destabilization."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8931", "text": "The kinetic process of destabilisation can be rather long (up to several months or even years for some products) and it is often required for the formulator to use further accelerating methods in order to reach reasonable development time for new product design. Thermal methods are the most commonly used and consists in increasing temperature to accelerate destabilisation (below critical temperatures of phase and degradation). Temperature affects not only the viscosity, but also interfacial tension in the case of non-ionic surfactants or more generally interactions forces inside the system. Storing a dispersion at high temperatures enables simulation of real life conditions for a product (e.g. tube of sunscreen cream in a car in the summer), but also to accelerate destabilisation processes up to 200 times including vibration,  centrifugation  and agitation are sometimes used. They subject the product to different forces that pushes the particles / film drainage. However, some emulsions would never coalesce in normal gravity, while they do under artificial gravity. [ 10 ]  Moreover, segregation of different populations of particles have been highlighted when using centrifugation and vibration. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8932", "text": "Common examples of suspensions include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8933", "text": "A  syrette  is a single-use device for injecting liquid through a needle. It is similar to a  syringe  except that it has a sealed  squeeze tube  instead of a rigid tube and  piston . It was developed by the  pharmaceutical manufacturer  E.R. Squibb & Sons (eventually merged into the current day  Bristol-Myers Squibb ) just prior to World War II (WWII). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8934", "text": "In WWII, the  morphine  syrette was included in first aid kits. It had a wire loop with a guard at the end of a hollow needle that was used to break a seal where the needle was attached to the tube. The wire loop was then removed and the needle was inserted under the skin at a shallow angle and the tube slowly squeezed from the sealed end (see  subcutaneous injection ). [ 2 ]  After injection the used tube was often pinned to the receiving soldier's collar to inform others of the dose administered. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8935", "text": "The syrette was adopted for use by the  United States Army  in 1940. [ 1 ]  The US military also distributed  atropine  in syrettes. [ citation needed ]  Chemical treatment was subsequently distributed in  autoinjector  form. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8936", "text": "A  syringe  is a simple  reciprocating pump  consisting of a  plunger  (though in modern syringes, it is actually a  piston ) that fits tightly within a cylindrical tube called a barrel. The plunger can be linearly pulled and pushed along the inside of the tube, allowing the syringe to take in and expel liquid or gas through a discharge  orifice  at the front (open) end of the tube.  The open end of the syringe may be fitted with a  hypodermic needle , a  nozzle  or  tubing  to direct the flow into and out of the barrel.  Syringes are frequently used in  clinical medicine  to administer  injections , infuse  intravenous therapy  into the bloodstream, apply compounds such as  glue  or  lubricant , and draw/measure liquids. There are also  prefilled syringes  (disposable syringes marketed with liquid inside)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8937", "text": "The word \"syringe\" is derived from the  Greek  \u03c3\u1fe6\u03c1\u03b9\u03b3\u03be ( syrinx , meaning \"Pan flute\", \"tube\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8938", "text": "Medical syringes include disposable and  safety syringes , injection pens, needleless injectors, insulin pumps, and specialty needles. [ 2 ]  Hypodermic syringes are used with  hypodermic needles  to  inject  liquid or gases into body tissues, or to remove from the body. Injecting of air into a  blood vessel  is hazardous, as it may cause an  air embolism ; preventing embolisms by removing air from the syringe is one of the reasons for the familiar image of holding a hypodermic syringe pointing upward, tapping it, and expelling a small amount of liquid before an injection into the  bloodstream ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8939", "text": "The  barrel  of a syringe is made of plastic or glass, usually has graduated marks indicating the volume of fluid in the syringe, and is nearly always transparent. Glass syringes may be  sterilized  in an  autoclave . Plastic syringes can be constructed as either two-part or three-part designs. A three-part syringe contains a plastic plunger/ piston  with a rubber tip to create a seal between the piston and the barrel, where a two-part syringe is manufactured to create a perfect fit between the plastic plunger and the barrel to create the seal without the need for a separate synthetic rubber piston. Two-part syringes have been traditionally used in  European countries  to prevent introduction of additional materials such as silicone oil needed for lubricating three-part plungers. [ 3 ]  Most modern medical syringes are plastic because they are cheap enough to dispose of after being used only once, reducing the risk of spreading  blood-borne diseases . Reuse of needles and syringes has caused spread of diseases, especially  HIV  and  hepatitis , among intravenous drug users. Syringes are also commonly reused by diabetics, as they can go through several in a day with multiple daily insulin injections, which becomes an affordability issue for many. Even though the syringe and needle are only used by a single person, this practice is still unsafe as it can introduce bacteria from the skin into the bloodstream and cause serious and sometimes lethal infections. [ 4 ]  In medical settings, single-use needles and syringes effectively reduce the risk of cross-contamination. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8940", "text": "Medical syringes are sometimes used without a needle for orally administering liquid medicines to young children or animals, or milk to small young animals, because the dose can be measured accurately and it is easier to squirt the medicine into the subject's mouth instead of coaxing the subject to drink out of a measuring spoon."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8941", "text": "Syringes come with a number of designs for the area in which the blade locks to the syringe body. Perhaps the most well known of these is the  Luer lock , which simply twists the two together."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8942", "text": "Bodies featuring a small, plain connection are known as slip tips and are useful for when the syringe is being connected to something not featuring a screw lock mechanism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8943", "text": "Similar to this is the catheter tip, which is essentially a slip tip but longer and tapered, making it good for pushing into things where there the plastic taper can form a tight seal. These can also be used for rinsing out wounds or large abscesses in veterinary use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8944", "text": "There is also an eccentric tip, where the nozzle at the end of the syringe is not in the centre of the syringe but at the side. This causes the blade attached to the syringe to lie almost in line with the walls of the syringe itself and they are used when the blade needs to get very close to parallel with the skin (when injecting into a surface vein or artery for example)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8945", "text": "Syringes for  insulin  users are designed for standard U-100 insulin.  The dilution of insulin is such that 1 mL of insulin fluid has 100 standard \"units\" of insulin. [ 6 ]   A typical insulin vial may contain 10\u00a0mL, for 1000 units."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8946", "text": "Insulin syringes are made specifically for a patient to inject themselves, and have features to assist this purpose when compared to a syringe for use by a healthcare professional:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8947", "text": "U-100 syringe sizes and markings"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8948", "text": "There are needle syringes designed to reload from a built-in tank (container) after each injection, so they can make several or many injections on a filling. These are not used much in human medicine because of the risk of cross-infection via the needle. An exception is the personal  insulin   autoinjector  used by  diabetic  patients and in dual-chambered syringe designs intended to deliver a prefilled saline flush solution after the medication. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8949", "text": "Venom extraction syringes are different from standard syringes, because they usually do not puncture the wound. The most common types have a plastic nozzle which is placed over the affected area, and then the syringe piston is pulled back, creating a vacuum that allegedly sucks out the venom. Attempts to treat snakebites in this way are specifically advised against, as they are ineffective and can cause additional injury. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8950", "text": "Syringes of this type are sometimes used for extracting  human botfly  larvae from the skin. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8951", "text": "An oral syringe is a  measuring instrument  used to accurately measure doses of liquid  medication , expressed in  millilitres  (mL).  They do not have threaded tips, because no needle or other device needs to be screwed onto them.  The contents are simply squirted or sucked from the syringe directly into the mouth of the person or animal."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8952", "text": "Oral syringes are available in various sizes, from 1\u201310 mL and larger. An oral syringe is typically purple in colour to distinguish it from a standard injection syringe with a luer tip. [ 24 ]  The sizes most commonly used are 1 mL, 2.5 mL, 3 mL, 5 mL and 10 mL. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8953", "text": "A dental syringe is used by  dentists  for the injection of an  anesthetic . [ 26 ]  It consists of a  breech-loading  syringe fitted with a sealed cartridge containing an anesthetic solution."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8954", "text": "In 1928,  Bayer  Dental developed, coined and produced a sealed cartridge system under the registered trademark Carpule \u00ae . The current trademark owner is  Kulzer Dental   GmbH ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8955", "text": "The carpules have long been reserved for  anesthetic  products for dental use. It is practically a bottomless flask. The latter is replaced by an  elastomer  plug that can slide in the body of the cartridge. This plug will be pushed by the plunger of the syringe. The neck is closed with a rubber cap. The dentist places the cartridge directly into a  stainless steel  syringe, with a double-pointed (single-use) needle. The tip placed on the cartridge side punctures the capsule and the piston will push the product. There is therefore no contact between the product and the ambient air during use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8956", "text": "The ancillary tool (generally part of a  dental engine ) used to supply water, compressed air or mist (formed by combination of water and compressed air) to the oral cavity for the purpose of irrigation (cleaning debris away from the area the dentist is working on), is also referred to as a dental syringe or a dental irrigation nozzle."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8957", "text": "A 3-way syringe/nozzle has separate internal channels supplying air, water or a mist created by combining the pressurized air with the waterflow. The syringe tip can be separated from the main body and replaced when necessary."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8958", "text": "In the UK and Ireland, manually operated hand syringes are used to inject  lidocaine  into patients' gums. [ 27 ] [ 28 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8959", "text": "A dose-sparing syringe is one which minimises the amount of liquid remaining in the barrel after the plunger has been depressed. These syringes feature a combined needle and syringe, and a protrusion on the face of the plunger to expel liquid from the needle hub. Such syringes were particularly popular during the  COVID-19 pandemic  as vaccines were in short supply. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8960", "text": "In some jurisdictions, the sale or possession of hypodermic syringes may be controlled or prohibited without a prescription, [ 30 ]  due to its potential use with illegal  intravenous drugs . [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8961", "text": "The syringe has many non-medical applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8962", "text": "Medical-grade  disposable hypodermic syringes are often used in research laboratories for convenience and low cost. Another application is to use the needle tip to add liquids to very confined spaces, such as washing out some scientific apparatus. They are often used for measuring and transferring solvents and reagents where a high precision is not required.  Alternatively, microliter syringes can be used to measure and dose chemicals very precisely by using a small diameter capillary as the syringe barrel."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8963", "text": "The  polyethylene  construction of these disposable syringes usually makes them rather chemically resistant. There is, however, a risk of the contents of the syringes leaching plasticizers from the syringe material. Non-disposable glass syringes may be preferred where this is a problem. Glass syringes may also be preferred where a very high degree of precision is important (i.e.  quantitative chemical analysis ), because their  engineering tolerances  are lower and the plungers move more smoothly. In these applications, the transfer of  pathogens  is usually not an issue."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8964", "text": "Used with a long needle or  cannula , syringes are also useful for transferring fluids through rubber  septa  when atmospheric  oxygen  or  moisture  are being excluded. Examples include the transfer of air-sensitive or  pyrophoric  reagents such as  phenylmagnesium bromide  and  n -butyllithium  respectively. Glass syringes are also used to inject small samples for  gas chromatography  (1 \u03bcl) and  mass spectrometry  (10 \u03bcl). Syringe drivers may be used with the syringe as well."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8965", "text": "Some  culinary  uses of syringes are injecting liquids (such as  gravy ) into other foods, or for the manufacture of some  candies ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8966", "text": "Syringes may also be used when  cooking  meat to enhance flavor and texture by injecting juices inside the meat, and in  baking  to inject filling inside a  pastry . It is common for these syringes to be made of stainless steel components, including the barrel. Such facilitates easy disassembly and cleaning."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8967", "text": "Syringes are used to refill  ink cartridges  with  ink  in  fountain pens ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8968", "text": "Common workshop applications include injecting  glue  into tight spots to repair joints where disassembly is impractical or impossible; and injecting lubricants onto working surfaces without spilling."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8969", "text": "Sometimes a large hypodermic syringe is used without a needle for very small baby  mammals  to  suckle  from in artificial rearing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8970", "text": "Historically, large pumps that use reciprocating motion to pump water were referred to as syringes.  Pumps of this type were used as early  firefighting  equipment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8971", "text": "There are fountain syringes where the liquid is in a bag or can and goes to the nozzle via a pipe. In earlier times,  clyster  syringes were used for that purpose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8972", "text": "Loose  snus  is often applied using modified syringes. The nozzle is removed so the opening is the width of the chamber. The snus can be packed tightly into the chamber and plunged into the upper lip. Syringes, called portioners, are also manufactured for this particular purpose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8973", "text": "A  tablet  (also known as a  pill ) is a  pharmaceutical  oral dosage form ( oral solid dosage , or OSD) or solid unit dosage form. Tablets may be defined as the solid unit dosage form of medication with suitable  excipients . It comprises a mixture of active substances and excipients, usually in  powder  form, that are pressed or compacted into a solid dose. The main advantages of tablets are that they ensure a consistent dose of medicine that is easy to consume."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8974", "text": "Tablets are prepared either by moulding or by  compression .  The excipients can include  diluents ,  binders  or granulating agents,  glidants  (flow aids) and  lubricants  to ensure efficient tabletting;  disintegrants  to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive or aid in visual identification of an unknown tablet. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet's appearance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8975", "text": "Medicinal tablets were originally made in the shape of a disk of whatever colour their components determined, but are now made in many shapes and colours to help distinguish different medicines. Tablets are often imprinted with symbols, letters, and numbers, which allow them to be identified, or a groove to allow splitting by hand. Sizes of tablets to be swallowed range from a few millimetres to about a centimetre."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8976", "text": "The compressed tablet is the most commonly seen  dosage form  in use today. About two-thirds of all  prescriptions  are dispensed as solid dosage forms, and half of these are compressed tablets. A tablet can be formulated to deliver an accurate dosage to a specific site in the body; it is usually taken orally, but can be administered  sublingually ,  buccally ,  rectally  or  intravaginally . The tablet is just one of the many forms that an oral drug can take such as  syrups ,  elixirs ,  suspensions , and  emulsions ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8977", "text": "Pills are thought to date back to around 1500 BC. [ 1 ]  Earlier medical recipes, such as those from 4000 BC, were for liquid preparations rather than solids. [ 1 ]  The first references to pills were found on papyruses in ancient Egypt and contained bread dough, honey, or grease. Medicinal ingredients, such as plant powders or spices, were mixed in and formed by hand to make little balls, or pills.\nIn ancient Greece, such medicines were known as  katapotia  (\"something to be swallowed\"), and the Roman scholar Pliny, who lived from 23 to 79 AD, first gave a name to what we now call pills, calling them  pilula . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8978", "text": "Pills have always been difficult to swallow, and efforts have been made to make them go down easier. In mediaeval times, people coated pills with slippery plant substances. Another approach, used as recently as the 19th century, was to gild them in gold and silver, although this often meant that they would pass through the digestive tract with no effect. [ 1 ]  In the 1800s, sugar coating and gelatin coating were invented, as were  gelatin capsules . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8979", "text": "In 1843, the British painter and inventor  William Brockedon  was granted a patent for a machine capable of \"Shaping Pills, Lozenges, and Black Lead by Pressure in Dies\". The device was capable of compressing powder into a tablet without the use of an adhesive. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8980", "text": "A pill was originally defined as a small, round, solid pharmaceutical  oral   dosage form  of medication.  The word's etymology  reflects the historical concepts of grinding the ingredients with a  mortar and pestle  and rolling the resultant paste or dough into lumps to be dried. Today, in its strict sense, the word  pill  still refers specifically to tablets (including caplets) rather than  capsules  (which were invented much later), but because a simple  hypernym  is needed to intuitively cover all such oral dosage forms, the broad sense of the word  pill  is also widely used and includes both tablets and capsules \u2014 colloquially, any solid oral form of medication falls into the \"pill\" category (see  pill \u00a7 Usage notes )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8981", "text": "An early example of a pill comes from ancient Rome. They were made of zinc carbonates,  hydrozincite  and  smithsonite . The pills were used for sore eyes and were found aboard a Roman ship that wrecked in 140 BC. However, these tablets were meant to be pressed on the eyes, not swallowed. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8982", "text": "A caplet is a smooth, coated, oval-shaped medicinal tablet in the general shape of a  capsule . Many caplets have an indentation running down the middle, so they may be split in half more easily. [ 5 ]  Consumers have viewed capsules as the most effective way to take medication ever since they first appeared. For this reason, producers of drugs such as  OTC  analgesics wanting to emphasize the strength of their product developed the \"caplet\", a  portmanteau [ 6 ]  of  capsule-shaped tablet , [ 7 ] [ 8 ]  in order to tie this positive association to more efficiently produced tablet pills as well as being an easier-to-swallow shape than the usual disk-shaped tablet."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8983", "text": "An  orally disintegrating tablet  or orodispersible tablet (ODT), is a drug  dosage form  available for a limited range of over-the-counter (OTC) and  prescription  medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8984", "text": "In the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. Mixed particle sized powders may separate during the manufacturing process due to differing particle densities. This can result in tablets with non-uniform concentrations of drug or active pharmaceutical ingredient (API), resulting in uneven dosage between tablets, but  granulation  should prevent this."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8985", "text": "Some APIs may be compressed into tablets as pure substances, but this is rarely the case; most formulations include pharmacologically inactive ingredients ( excipients ):"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8986", "text": "Tablets can be made in virtually any shape, although the requirements of patients and tableting machines mean that most are round, oval, or capsule-shaped. More unusual shapes have been manufactured, but patients find these harder to swallow, and they are more vulnerable to chipping or manufacturing problems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8987", "text": "Tablet diameter and shape are determined by the machine tooling used to produce them; a die plus an upper and a lower punch are required. This is called a station of tooling. The amount of tablet material and the placement of the punches in relation to one another during compression determine the thickness. Once this is done, we can measure the corresponding pressure applied during compression. The shorter the distance between the punches, the greater the pressure applied during compression, and sometimes the harder the tablet. Tablets need to be hard enough that they do not break up in the bottle, yet friable enough that they disintegrate in the gastric tract."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8988", "text": "Tablets need to be strong enough to resist the stresses of packaging, shipping, and handling by the pharmacist and patient.  The mechanical strength of tablets is assessed using a combination of simple failure and erosion tests, and more sophisticated engineering tests. The simpler tests are often used for quality control purposes, whereas the more complex tests are used during the design of the formulation and manufacturing process in the research and development phase.  Standards for tablet properties are published in the various international pharmacopeias (USP/NF, EP, JP, etc.).  The hardness of tablets is the principal measure of mechanical strength.  Hardness is tested using a  tablet hardness tester .  The units for hardness have evolved since the 1930s but are commonly measured in kilograms per square centimetre. Models of testers include the Monsanto (or Stokes) Hardness Tester from 1930, the Pfizer Hardness Tester from 1950, the Strong Cob Hardness Tester and the Heberlain (or Schleeniger) Hardness Tester."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8989", "text": "Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall, as well as between granules, which helps in uniform filling of the die."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8990", "text": "Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8991", "text": "In the tablet pressing process, the appropriate amount of active ingredient must be in each tablet.  Hence, all the ingredients should be well mixed. If a sufficiently homogenous mix of the components cannot be obtained with simple blending processes, the ingredients must be granulated prior to compression to assure an even distribution of the active compound in the final tablet. Two basic techniques are used to granulate powders for compression into tablets: wet granulation and dry granulation.  Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression (\"DC\"). Direct compression is desirable as it is quicker. There is less processing, equipment, labor, and energy consumption. However, DC is difficult when a formulation has a high content of poorly compressible active ingredients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8992", "text": "Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture.  The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems but may not be suitable for drugs which are degraded by hydrolysis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8993", "text": "Low shear wet granulation processes use very simple mixing equipment, and can take a considerable time to achieve a uniformly mixed state.  High shear wet granulation processes use equipment that mixes the powder and liquid at a very fast rate, and thus speeds up the manufacturing process. Fluid bed granulation is a multiple-step wet granulation process performed in the same vessel to pre-heat, granulate, and dry the powders.  It is used because it allows close control of the granulation process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8994", "text": "Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor. Dry granulation equipment offers a wide range of pressures to attain proper densification and granule formation. Dry granulation is simpler than wet granulation, therefore the cost is reduced. However, dry granulation often produces a higher percentage of fine granules, which can compromise the quality or create yield problems for the tablet. Dry granulation requires drugs or excipients with cohesive properties, and a 'dry binder' may need to be added to the formulation to facilitate the formation of granules."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8995", "text": "Hot melt extrusion is utilized in pharmaceutical solid oral dose processing to enable delivery of drugs with poor solubility and  bioavailability . Hot melt extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier increasing dissolution rates and bioavailability. The process involves the application of heat, pressure and agitation to mix materials together and 'extrude' them through a die. Twin-screw high shear extruders blend materials and simultaneously break up particles. The extruded particles can then be blended and compressed into tablets or filled into capsules. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8996", "text": "After granulation, a final lubrication step is used to ensure that the tableting blend does not stick to the equipment during the tableting process.  This usually involves low shear blending of the granules with a powdered lubricant, such as  magnesium stearate  or  stearic acid ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8997", "text": "Whatever process is used to make the tableting blend, the process of making a tablet by powder compaction is very similar.  First, the powder is filled into the die from above.  The mass of powder is determined by the position of the lower punch in the die, the cross-sectional area of the die, and the powder density.  At this stage, adjustments to the tablet weight are normally made by repositioning the lower punch.  After die filling, the upper punch is lowered into the die and the powder is uniaxially compressed to a porosity of between 5 and 20%.  The compression can take place in one or two stages (main compression, and, sometimes, pre-compression or tamping) and for commercial production occurs very fast (500\u201350  mg  per tablet). Finally, the upper punch is pulled up and out of the die (decompression), and the tablet is ejected from the die by lifting the lower punch until its upper surface is flush with the top face of the die.  This process is repeated for each tablet."}
{"_id": "WikiPedia_Pharmacology$$$corpus_8998", "text": "Common problems encountered during tablet manufacturing operations include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_8999", "text": "Consequently, permanent consistency checks are required during the manufacturing process. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9000", "text": "Tablet formulations are designed and tested using a laboratory machine called a Tablet Compaction Simulator or Powder Compaction Simulator. This is a computer controlled device that can measure the punch positions, punch pressures, friction forces, die wall pressures, and sometimes the tablet internal temperature during the compaction event. Numerous experiments with small quantities of different mixtures can be performed to optimise a formulation. Mathematically corrected punch motions can be programmed to simulate any type and model of production tablet press. Initial quantities of active pharmaceutical ingredients are very expensive to produce, and using a Compaction Simulator reduces the amount of powder required for product development."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9001", "text": "Tablet presses , also called tableting machines, range from small, inexpensive bench-top models that make one tablet at a time (single-station presses), with only around a half-ton pressure, to large, computerized, industrial models (multi-station rotary presses) that can make hundreds of thousands to millions of tablets an hour with much greater pressure. The tablet press is an essential piece of machinery for any pharmaceutical and nutraceutical manufacturer. Tablet presses must allow the operator to adjust the position of the lower and upper punches accurately, so that the tablet weight, thickness and density/hardness can each be controlled. This is achieved using a series of cams, rollers, or tracks that act on the tablet tooling (punches).  Mechanical systems are also incorporated for die filling, and for ejecting and removing the tablets from the press after compression.  Pharmaceutical tablet presses are required to be easy to clean and quick to reconfigure with different tooling, because they are usually used to manufacture many different products.\nThere are two main standards of tablet tooling used in pharmaceutical industry: American standard TSM and European standard EU. TSM and EU configurations are similar to each other but cannot be interchanged. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9002", "text": "Modern tablet presses reach output volumes of up to 1,700,000 tablets per hour. These huge volumes require frequent in-process quality control for the tablet weight, thickness and hardness. Due to efforts to reduce rejects rates and machine down-time, automated tablet testing devices are used on-line with the tablet press or off-line in the IPC-labs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9003", "text": "Many tablets today are coated after being pressed. Although sugar-coating was popular in the past, the process has many drawbacks. Modern tablet coatings [ 13 ]  are  polymer  and  polysaccharide  based, with  plasticizers  and  pigments  included. Tablet coatings must be stable and strong enough to survive the handling of the tablet, must not make tablets stick together during the coating process, and must follow the fine contours of embossed characters or logos on tablets. Coatings are necessary for tablets that have an unpleasant taste, and a smoother finish makes large tablets easier to swallow. Tablet coatings are also useful to extend the shelf-life of components that are sensitive to moisture or oxidation. Special coatings (for example with pearlescent effects) can enhance brand recognition."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9004", "text": "If the active ingredient of a tablet is sensitive to acid, or is irritant to the stomach lining, an  enteric coating  can be used, which is resistant to  stomach  acid, and dissolves in the less acidic area of the intestines. Enteric coatings are also used for medicines that can be negatively affected by taking a long time to reach the  small intestine , where they are absorbed. Coatings are often chosen to  control the rate of dissolution  of the drug in the gastrointestinal tract. Some drugs are absorbed better in certain parts of the digestive system. If this part is the stomach, a coating is selected that dissolves quickly and easily in acid. If the rate of absorption is best in the large intestine or colon, a coating is used that is acid resistant and dissolves slowly to ensure that the tablet reaches that point before dispersing. To measure the disintegration time of the tablet coating and the tablet core, automatic disintegration testers are used which are able to determine the complete disintegration process of a tablet by measuring the rest height of the thickness with every upward stroke of the disintegration tester basket."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9005", "text": "There are two types of coating machines used in the pharmaceutical industry: coating pans and automatic coaters. [ 14 ]  Coating pans are used mostly to sugar coat pellets. Automatic coaters are used for all kinds of coatings; they can be equipped with a remote control panel, a dehumidifier, and dust collectors. An explosion-proof design is required for applying coatings that contain alcohol."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9006", "text": "It is sometimes necessary to split tablets into halves or quarters. Tablets are easier to break accurately if scored, but there are devices called  pill-splitters  which cut unscored and scored tablets. Tablets with special coatings (for example, enteric coatings or  controlled-release  coatings) should not be broken before use, as this exposes the tablet core to the digestive juices, circumventing the intended delayed-release effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9007", "text": "Target-controlled infusion  ( TCI ) automates the dosing of intravenous drugs during surgery.  After the  anesthetist  sets the desired parameters in a computer and presses the start button, the system controls the  infusion pump , while being monitored by the anesthetist. [ 1 ]   TCI is as safe and effective as manually controlled infusion. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9008", "text": "TCI can be sub-classified according to the  target . The suffix 'e' as in  TCIe  indicates that the target is the effect site, in most cases, the central nervous system or brain. Alternatively, the suffix 'p' denotes plasma, indicating that the device implementing the TCI model is to target the blood plasma. There are important differences in relation to the time taken for  effect site equilibration . Studies have demonstrated the clinical safety of the effect-site target model. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9009", "text": "Popular TCI models exist for  Propofol  and the synthetic opioid  Remifentanil . The models are based on  pharmacokinetic  studies and use software embedded in the  infusion device . For  propofol  the Marsh and Schnider models are available and the Minto model is commonly used for  remifentanil . In 2017, a project to emulate the TCI models in the  python  language was published on  GitHub ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9010", "text": "TCI has been used in clinical settings since 1996, initially with  propofol . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9011", "text": "Thin-film drug delivery  uses a  dissolving film  or  oral drug strip  to administer  drugs  via absorption in the mouth ( buccally  or  sublingually ) and/or via the small intestines ( enterically ).  A film is prepared using  hydrophilic  polymers that rapidly dissolves on the tongue or buccal cavity,  delivering  the drug to the  systemic circulation  via  dissolution  when contact with  liquid  is made."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9012", "text": "Thin-film drug delivery has emerged as an advanced alternative to the traditional  tablets ,  capsules  and liquids often associated with  prescription  and  OTC  medications.  Similar in size, shape and thickness to a  postage stamp , thin-film strips are typically designed for  oral administration , with the user placing the strip on or under the tongue (sublingual) or along the inside of the cheek (buccal). These drug delivery options allow the medication to bypass the first pass metabolism thereby making the medication more bioavailable. [ citation needed ]  As the strip dissolves, the drug can enter the blood stream enterically, buccally or sublingually. Evaluating the systemic  transmucosal  drug delivery, the  buccal mucosa  is the preferred region as compared to the sublingual mucosa."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9013", "text": "Different buccal delivery products have been marketed or are proposed for certain diseases like  trigeminal neuralgia ,  M\u00e9ni\u00e8re's disease ,  diabetes , and  addiction . [ citation needed ]   There are many commercial non-drug product to use thin films like Mr. Mint and  Listerine PocketPaks   breath freshening strips . Since then, thin-film products for other breath fresheners, as well as a number of cold, flu, anti-snoring and gastrointestinal medications, have entered the marketplace. There are currently [ when? ]  several projects in development that will deliver prescription drugs using the thin-film  dosage form . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9014", "text": "Formulation of oral drug strips involves the application of both aesthetic and performance characteristics such as strip-forming polymers,  plasticizers , active pharmaceutical ingredient, sweetening agents,  saliva  stimulating agent, flavoring agents, coloring agents, stabilizing and thickening agents. From the regulatory perspectives, all  excipients  used in the formulation of oral drug strips should be approved for use in oral pharmaceutical  dosage  forms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9015", "text": "The polymer employed should be non-toxic, non-irritant and devoid of leachable impurities. It should have good wetting and spreadability property. The polymer should exhibit sufficient peel, shear and tensile strengths. The polymer should be readily available and should not be very expensive. Film obtained should be tough enough so that there won't be any damage while handling or during transportation. Combination of  microcrystalline   cellulose  and  maltodextrin  has been used to formulate Oral Strips of piroxicam made by hot melt extrusion technique.  Pullulan  has been the most widely used film former (used in Listerine PocketPak, Benadryl, etc.)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9016", "text": "Plasticizer is a vital ingredient of the OS formulation. It helps to improve the flexibility and reduces the brittleness of the strip. Plasticizer significantly improves the strip properties by reducing the glass transition temperature of the polymer.  Glycerol ,  Propylene glycol , low molecular weight  polyethylene glycols ,  phthalate  derivatives like  dimethyl ,  diethyl  and  dibutyl phthalate ,  Citrate  derivatives such as tributyl, triethyl, acetyl citrate,  triacetin  and  castor oil  are some of the commonly used plasticizer excipients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9017", "text": "Since the size of the dosage form has limitation, high-dose molecules are difficult to be incorporated in OS. Generally 5%w/w to 30%w/w of active pharmaceutical ingredients can be incorporated in the oral strip. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9018", "text": "An important aspect of thin film drug technology is its taste and color. The sweet taste in formulation is more important in case of  pediatric  population. Natural sweeteners as well as artificial sweeteners are used to improve the flavor of the mouth dissolving formulations for the flavors changes from individual to individual. Pigments such as titanium dioxide is  incorporated for coloring."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9019", "text": "The stabilizing and thickening agents are employed to improve the  viscosity  and consistency of dispersion or solution of the strip preparation solution or suspension before casting. Drug content uniformity is a requirement for all dosage forms, particularly those containing low dose highly potent drugs. To uniquely meet this requirement, thin film formulations contain uniform dispersions of drug throughout the whole manufacturing process. [ 3 ]   Since this criterion is essential for the quality of the thin film and final pharmaceutical dosage form, the use of Laser Scanning Confocal Microscopy (LSCM) was recommended to follow the manufacturing process. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9020", "text": "An increasing number of film-based therapeutics are in development, including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9021", "text": "Other molecules like sildenafil citrate, tadalafil, methylcobalamin and vitamin D 3  are also developed by IntelGenx Zim Laboratories Ltd."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9022", "text": "Thiolated  polymers  \u2013 designated  thiomers  \u2013 are functional  polymers  used in  biotechnology  product development with the intention to prolong mucosal drug residence time and to enhance absorption of  drugs . The name thiomer was coined by  Andreas Bernkop-Schn\u00fcrch  in 2000. [ 1 ]  Thiomers have  thiol  bearing  side chains . [ 2 ] [ 3 ]  Sulfhydryl ligands of low molecular mass are  covalently  bound to a polymeric backbone consisting of mainly  biodegradable  polymers, such as  chitosan , [ 4 ] [ 5 ]   hyaluronic acid , [ 6 ]   cellulose  derivatives, [ 7 ]   pullulan , [ 8 ] [ 9 ]   starch , [ 10 ]   gelatin , [ 11 ]   polyacrylates , [ 12 ]   cyclodextrins , [ 13 ] [ 14 ]  or  silicones . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9023", "text": "Thiomers exhibit properties potentially useful for  non-invasive  drug delivery via oral, ocular, nasal, vesical,  buccal  and vaginal routes. Thiomers show also potential in the field of  tissue engineering  and  regenerative medicine . Various thiomers such as thiolated chitosan [ 16 ]  and thiolated hyaluronic acid [ 17 ]  are commercialy available as scaffold materials. Thiomers can be directly compressed to tablets or given as solutions. [ 18 ] [ 19 ]   In 2012, a second generation of thiomers \u2013 called \"preactivated\" or \"S-protected\" thiomers \u2013 were introduced. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9024", "text": "In contrast to thiomers of the first generation, preactivated thiomers are stable towards  oxidation  and display comparatively higher  mucoadhesive  and  permeation enhancing  properties. [ 21 ]  Approved thiomer products for human use are for example eyedrops for treatment of  dry eye syndrome  or adhesive gels for treatment of nickel allergy. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9025", "text": "Thiomers are capable of forming disulfide bonds with cysteine substructures of the mucus gel layer covering mucosal membranes. Because of this property they exhibit up to 100-fold higher mucoadhesive properties in comparison to the corresponding unthiolated polymers. [ 23 ] [ 24 ] [ 25 ]  Because of their mucoadhesive properties, thiolated polymers are an effective tool in the treatment of diseases such as dry eye, dry mouth, and dry vagina syndrome where dry mucosal surfaces are involved. [ 26 ] [ 27 ] [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9026", "text": "Various polymers such as  poloxamers  exhibit in situ gelling properties. Because of these properties they can be administered as liquid formulations forming stable gels once having reached their site of application. An unintended rapid elimination or outflow of the formulation from mucosal membranes such as the ocular, nasal or vaginal mucosa can therefore be avoided. Thiolated polymers are capable of providing a comparatively more pronounced increase in viscosity after application, as an extensive crosslinking process by the formation of disulfide bonds between the polymer chains due to oxidation takes place. This effect was first described in 1999 by Bernkop-Schn\u00fcrch et al. [ 29 ]  for polymeric excipients. In case of thiolated chitosan, for instance, a more than 10,000-fold increase in viscosity within a few minutes was shown. [ 30 ]  These high in situ gelling properties can also be used for numerous further reasons such as for parenteral formulations, [ 31 ]  as coating material [ 32 ]  or for food additives [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9027", "text": "Due to a sustained drug release, a prolonged therapeutic level of drugs exhibiting a short elimination  half-life  can be maintained. Consequently the frequency of dosing can be reduced contributing to an improved compliance. The release of drugs out of polymeric carrier systems can be controlled by a simple diffusion process. So far the efficacy of such delivery systems, however, was limited by a too rapid disintegration and/or erosion of the polymeric network. [ 34 ]  By using thiolated polymers this essential shortcoming can be overcome. Because of the formation of inter- and intrachain disulfide bonds during the swelling process, the stability of the polymeric drug carrier matrix is strongly improved. Hence, a controlled drug release for numerous hours is guaranteed. There are numerous drug delivery systems making use of this technology. [ 35 ] [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9028", "text": "Due to the binding of metal ions being essential for various enzymes to maintain their enzymatic activity, thiomers are potent reversible enzyme inhibitors. Many non-invasively administered drugs such as therapeutic peptides or nucleic acids are degraded on the mucosa by membrane bound enzymes, strongly reducing their bioavailability. In case of oral administration, this \u2018enzymatic barrier\u2019 is even more pronounced as an additional degradation caused by luminally secreted enzymes takes place. Because of their capability to bind zinc ions via thiol groups, thiomers are potent inhibitors of most membrane bound and secreted zinc-dependent enzymes. Due to this enzyme inhibitory effect, thiolated polymers can significantly improve the bioavailability of non-invasively administered drugs [ 41 ] [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9029", "text": "In vitro , thiomers were shown to have antimicrobial activity towards Gram-positive bacteria. [ 44 ] [ 45 ]  In particular, N-acyl thiolated chitosans show great potential as highly efficient, biocompatible and cost-effective antimicrobial compounds. [ 46 ]  Metabolism and mechanistic studies are under way to optimize these thiomers for clinical applications. Because of their antimicrobial activity, thiolated polymers are also used as coatings that avoid bacterial adhesion. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9030", "text": "Thiomers are able to reversibly open tight junctions. The responsible mechanism seems to be based on the inhibition of protein tyrosine phosphatase being involved in the closing process of tight junctions. [ 48 ]  Due to thiolation the permeation enhancing effect of polymers such as  polyacrylic acid  or chitosan can be up to 10-fold improved. [ 49 ] [ 50 ] [ 51 ]  In comparison to most low molecular weight permeation enhancers, thiolated polymers offer the advantage of not being absorbed from the mucosal membrane. Hence, their permeation enhancing effect can be maintained for a comparatively longer period of time and systemic toxic side effects of the auxiliary agent can be excluded."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9031", "text": "Thiomers are able to reversibly inhibit efflux pumps. Because of this property the mucosal uptake of various efflux pump substrates such as anticancer drugs, antimycotic drugs and antiinflammatory drugs can be tremendously improved. [ 52 ] [ 53 ] [ 54 ]  The postulated mechanism of efflux pump inhibition is based on an interaction of thiolated polymers with the channel forming transmembrane domain of various efflux pumps such as P-gp and multidrug resistance proteins (MRPs). P-gp, for instance, exhibits 12 transmembrane regions forming a channel through which substrates are transported outside of the cell. Two of these transmembrane domains \u2013 namely 2 and 11 \u2013 exhibit on position 137 and 956, respectively, a cysteine subunit. Thiomers seem to enter in the channel of P-gp and likely form subsequently one or two disulfide bonds with one or both cysteine subunits located within the channel. Due to this covalent interaction the allosteric change of the transporter being essential to move drugs outside of the cell might be blocked. [ 55 ] [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9032", "text": "Thiomers have the ability to form complexes with different metal ions, especially divalent metal ions, due to their thiol groups. Thiolated chitosans, for instance, were shown to effectively absorb nickel ions. [ 57 ] [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9033", "text": "As thiolated polymers exhibit biocompatibility, cellular mimicking properties and efficiently support proliferation and differentiation of various cell types, they are used as scaffolds for tissue engineering. [ 59 ] [ 60 ] [ 61 ] [ 62 ]  Furthermore thiolated polymers such as thiolated hyaluronic acid [ 63 ]  and thiolated chitosan [ 64 ]  were shown to exhibit wound healing properties."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9034", "text": "A  throat lozenge  (also known as a  cough drop ,  sore throat sweet ,  troche ,  cachou ,  pastille  or  cough sweet ) is a small, typically medicated tablet intended to be dissolved slowly in the mouth to temporarily stop coughs, lubricate, and soothe irritated tissues of the  throat  (usually due to a  sore throat  or  strep throat ), possibly from the  common cold  or  influenza . Cough tablets have taken the name  lozenge , based on their original shape, a diamond."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9035", "text": "Lozenges may contain  benzocaine , an  anaesthetic , or  eucalyptus oil .  Non-menthol throat lozenges generally use either  zinc gluconate glycine  or  pectin  as an  oral demulcent . Several brands of throat lozenges contain  dextromethorphan ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9036", "text": "Other varieties such as  Halls  contain  menthol ,  peppermint oil  and/or  spearmint  as their  active ingredient (s).  Honey  lozenges are also available."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9037", "text": "The purpose of the throat lozenge is to calm the irritation that may be felt in the throat while swallowing, breathing, or even drinking certain fluids. However, one study found that excessive use of menthol cough drops can prolong coughs rather than relieve them. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9038", "text": "Candies to soothe the throat date back to 1000\u00a0BC in  Egypt 's  Twentieth Dynasty , when they were made from honey flavored with  citrus , herbs, and spices. [ citation needed ]  In the 19th century, physicians discovered  morphine  and  heroin , which suppress coughing at its source\u2014the brain.  Popular formulations of that era included  Smith Brothers  Cough Drops, first advertised in 1852, and  Luden's , created in 1879. Concern over the risk of  opioid dependence  led to the development of alternative medications. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9039", "text": "A  tincture  is typically an  extract  of plant or animal material  dissolved  in  ethanol  (ethyl alcohol).  Solvent  concentrations of 25\u201360% are common, but may run as high as 90%. [ 1 ]  In  chemistry , a tincture is a  solution  that has ethanol as its solvent. In  herbal medicine , alcoholic tinctures are made with various ethanol concentrations, which should be at least 20% alcohol for preservation purposes. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9040", "text": "Other solvents for producing tinctures include  vinegar ,  glycerol  (also called glycerine),  diethyl ether  and  propylene glycol , not all of which can be used for internal consumption. Ethanol has the advantage of being an excellent solvent for both acidic and basic (alkaline) constituents. A tincture using glycerine is called a  glycerite . Glycerine is generally a poorer solvent than ethanol. Vinegar, being acidic, is a better solvent for obtaining alkaloids but a poorer solvent for acidic components. For individuals who choose not to ingest alcohol, non-alcoholic extracts offer an alternative for preparations meant to be taken internally."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9041", "text": "Low  volatility  substances such as  iodine  and  mercurochrome  can also be turned into tinctures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9042", "text": "Tinctures are often made of a combination of  ethyl alcohol  and water as solvents, each dissolving constituents the other is unable to, or weaker at. Varying their proportions can also produce different levels of constituents in the final extraction. As an  antimicrobial , alcohol also acts as a preservative."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9043", "text": "A downside of using alcohol as a solvent is that ethanol has a tendency to  denature  some organic compounds, reducing or destroying their effectiveness. This tendency can also have undesirable effects when extracting botanical constituents, such as  polysaccharides . Certain other constituents, common among them  proteins , can become irreversibly denatured, or \"pickled\" by the alcohol. Alcohol can also have damaging effects on some aromatic compounds."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9044", "text": "Ether and  propylene glycol  based tinctures are not suitable for internal consumption, although they are used in preparations for external use, such as personal care creams and  ointments ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9045", "text": "Some examples that were formerly common in medicine [ 3 ]  include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9046", "text": "Examples of spirits include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9047", "text": "Toothpaste  is a paste or gel  dentifrice  used with a  toothbrush  to clean and maintain the aesthetics and health of  teeth . Toothpaste is used to promote  oral hygiene : it is an abrasive that aids in removing  dental plaque  and food from the teeth, assists in suppressing  halitosis , and delivers  active ingredients  (most commonly  fluoride ) to help prevent tooth decay ( dental caries ) and gum disease ( gingivitis ). [ 1 ]  Owing to differences in composition and fluoride content, not all toothpastes are equally effective in maintaining oral health. The decline of  tooth decay  during the 20th century has been attributed to the introduction and regular use of fluoride-containing toothpastes worldwide. [ 2 ] [ 3 ]  Large amounts of swallowed toothpaste can be poisonous. [ 4 ]  Common colors for toothpaste include white (sometimes with colored stripes or green tint) and blue."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9048", "text": "Since 5000 BCE, the  Egyptians  made a tooth powder, which consisted of powdered ashes of ox hooves, myrrh, powdered and burnt eggshells, and  pumice . The  Greeks , and then the  Romans , improved the recipes by adding abrasives such as crushed bones and oyster shells. [ 5 ]  In the 9th century, Iraqi musician and fashion designer  Ziryab  invented a type of toothpaste, which he popularized throughout  Islamic Spain . The exact ingredients of this toothpaste are unknown, but it was reported to have been both \"functional and pleasant to taste\". [ 6 ]  It is not known whether these early toothpastes were used alone, were to be rubbed onto the teeth with rags, or were to be used with early toothbrushes, such as  neem-tree  twigs and  miswak . During Japan's  Edo period , inventor  Hiraga Gennai's   Hika rakuyo  (1769) contained advertisements for  Sosekiko , a \"toothpaste in a box.\" [ 7 ]  Toothpastes or powders came into general use in the 19th century."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9049", "text": "Toothpastes are generally useful to maintain dental health. Toothpastes containing fluoride are effective at preventing tooth decay. [ 2 ] [ 8 ] [ 9 ]  Toothpastes may also help to control and remove plaque build-up, promoting healthy gums. A 2016 systematic review indicated that using toothpaste when brushing the teeth does not necessarily impact the level of plaque removal. [ 10 ]  However, the active ingredients in toothpastes are able to prevent dental diseases with regular use. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9050", "text": "Toothpastes are derived from a variety of components, the three main ones being abrasives, fluoride, and detergent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9051", "text": "Abrasives constitute 8-20% of a typical toothpaste. [ 11 ]  These insoluble particles are designed to help remove plaque from the teeth. [ 12 ]  The removal of plaque inhibits the accumulation of tartar ( calculus ) helping to minimize the risk of gum disease. [ 13 ]  Representative abrasives include particles of  aluminum hydroxide  (Al(OH) 3 ),  calcium carbonate  (CaCO 3 ),  magnesium carbonate  (MgCO 3 ),  sodium bicarbonate , various  calcium hydrogen phosphates , various  silicas  and  zeolites , and  hydroxyapatite  (Ca 5 (PO 4 ) 3 OH)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9052", "text": "After the  Microbead-Free Waters Act of 2015 , the use of  microbeads  in toothpaste has been discontinued in the US, [ 14 ]  however since 2015 the industry has shifted toward instead using  FDA -approved \"rinse-off\"  metallized-plastic   glitter  as their primary  abrasive agent . [ 15 ] [ 16 ] [ 17 ]  Some brands contain powdered white  mica , which acts as a mild abrasive, and also adds a cosmetic glittery shimmer to the paste. The polishing of teeth removes stains from tooth surfaces, but has not been shown to improve dental health over and above the effects of the removal of  plaque  and Calculus. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9053", "text": "Abrasives, like the dental polishing agents used in dentists' offices, also cause a small amount of enamel erosion which is termed \"polishing\" action. The abrasive effect of toothpaste is indicated by its  RDA  value. Toothpastes with RDA values above 250 are potentially damaging to the surfaces of teeth. The  American National Standards Institute  and  American Dental Association  considers toothpastes with an RDA below 250 to be safe and effective for a lifetime of use. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9054", "text": "Fluoride  in various forms is the most popular and effective active ingredient in toothpaste to prevent cavities. [ 12 ]  Fluoride is present in small amounts in plants, animals, and  some natural water sources . The additional fluoride in toothpaste has beneficial effects on the formation of dental enamel and bones.  Sodium fluoride  (NaF) is the most common source of fluoride, but  stannous fluoride  (SnF 2 ), and  sodium monofluorophosphate  (Na 2 PO 3 F) are also used. [ 12 ]   At similar fluoride concentrations, toothpastes containing stannous fluoride have been shown to be more effective than toothpastes containing sodium fluoride for reducing the incidence of dental caries and  dental erosion , [ 20 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ]  as well as reducing  gingivitis . [ 25 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ]  Some stannous fluoride-containing toothpastes also contain ingredients that allow for better stain and calculus removal. [ 30 ]  A systematic review revealed stabilised stannous fluoride-containing toothpastes had a positive effect on the reduction of plaque, gingivitis and staining, with a significant reduction in  calculus  and halitosis compared to other toothpastes. [ 31 ]  Furthermore, numerous clinical trials have shown gluconate chelated stannous fluoride toothpastes possess superior protection against dental erosion and  dentine hypersensitivity  compared to other fluoride-containing and fluoride-free toothpastes. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9055", "text": "Much of the toothpaste sold in the United States has 1,000 to 1,100 parts per million fluoride. In European countries, such as the UK or Greece, the fluoride content is often higher; a sodium fluoride content of 0.312% w/w (1,450  ppm  fluoride) or stannous fluoride content of 0.454% w/w (1,100 ppm fluoride) is common. All of these concentrations are likely to prevent  tooth decay , according to a 2019  Cochrane review . [ 9 ]  Concentrations below 1,000 ppm are not likely to be preventive, and the preventive effect increases with concentration. [ 9 ]  Clinical trials support the use of high fluoride (5,000 ppm fluoride) dentifrices, for prevention of root caries in elderly adults by reducing the amount of plaque accumulated, decreasing the number of  mutans streptococci  and  lactobacilli  and possibly promoting calcium fluoride deposits to a higher degree than after the use of traditional fluoride containing dentifrices. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9056", "text": "Many, although not all, toothpastes contain  sodium lauryl sulfate (SLS)  or related  surfactants  (detergents). SLS is found in many other personal care products as well, such as  shampoo , and is mainly a  foaming agent , which enables uniform distribution of toothpaste, improving its cleansing power. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9057", "text": "Triclosan , an antibacterial agent, is a common toothpaste ingredient in the United Kingdom. Triclosan or  zinc chloride  prevent gingivitis and, according to the American Dental Association, helps reduce  tartar  and  bad breath . [ 1 ] [ 33 ]  A 2006 review of clinical research concluded there was evidence for the effectiveness of 0.30% triclosan in reducing plaque and gingivitis. [ 34 ]   Another Cochrane review in 2013 has found that triclosan achieved a 22% reduction in plaque, and in gingivitis, a 48% reduction in  bleeding gums . However, there was insufficient evidence to show a difference in fighting  periodontitis  and there was no evidence either of any harmful effects associated with the use of triclosan toothpastes for more than 3 years. The evidence relating to plaque and gingivitis was considered to be of moderate quality while for periodontitis was low quality. [ 35 ]  Recently, triclosan has been removed as an ingredient from well-known toothpaste formulations. This may be attributed to concerns about adverse effects associated with triclosan exposure. Triclosan use in cosmetics has been positively correlated with triclosan levels in human tissues, plasma and breast milk, and is considered to have potential neurotoxic effects. [ 36 ]  Long-term studies are needed to substantiate these concerns."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9058", "text": "Chlorhexidine  is another antimicrobial agent used in toothpastes; however, it is more commonly added in  mouthwash  products. [ 37 ]   Sodium laureth sulfate , a foaming agent, is a common toothpaste ingredient that also possesses some antimicrobial activities. [ 38 ]  There are also many commercial products available in the market containing different  essential oils ,  herbal  ingredients (e.g.  chamomile ,  neem ,  chitosan ,  Aloe vera ), and natural or plant extracts (e.g.  hinokitiol ). [ 39 ]  These ingredients are claimed by the manufacturers to fight plaque, bad breath and prevent  gum disease . A 2020 systematic metareview found that herbal toothpastes are as effective as non-herbal toothpastes in reducing dental plaque at shorter period of follow-up (4 weeks). [ 40 ]  However, this evidence comes from low-quality studies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9059", "text": "The stannous ( tin ) ion, commonly added to toothpastes as stannous fluoride or  stannous chloride , has been shown to have antibacterial effects in the mouth. Research has shown that stannous fluoride-containing toothpaste inhibits extracellular polysaccharide ( EPS ) production in a multispecies  biofilm  greater than sodium fluoride-containing toothpaste. [ 41 ]  This is thought to contribute to a reduction in plaque and gingivitis when using stannous fluoride-containing toothpastes when compared to other toothpastes, and has been evidenced through numerous clinical trials. [ 25 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ]  In addition to its antibacterial properties, stabilised stannous fluoride toothpastes have been shown to protect against dental erosion and dentine hypersensitivity, making it a multifunctional component in toothpaste formulations. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9060", "text": "Toothpaste comes in a variety of  colors  and  flavors , intended to encourage use of the product. The three most common flavorants are  peppermint ,  spearmint , and  wintergreen . Toothpaste flavored with peppermint-anise oil is popular in the Mediterranean region. These flavors are provided by the respective oils, e.g. peppermint oil. [ 18 ]  More exotic flavors include Anethole  anise ,  apricot ,  bubblegum ,  cinnamon ,  fennel ,  lavender ,  neem ,  ginger ,  vanilla ,  lemon ,  orange , and  pine . Alternatively, unflavored toothpastes exist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9061", "text": "Chemical repair ( remineralization ) of early tooth decay is promoted naturally by  saliva . [ 42 ]  However, this process can be enhanced by various remineralisation agents. [ 43 ]  Fluoride promotes remineralization, but is limited by bioavailable calcium. [ 44 ]  Casein phosphopeptide stabilised amorphous calcium phosphate (CPP-ACP) is a toothpaste ingredient containing bioavailable calcium that has been widely researched to be the most clinically effective remineralization agent that enhances the action of saliva and fluoride. [ 45 ] [ 46 ] [ 47 ] [ 48 ]  Peptide-based systems, hydroxyapatite nanocrystals and a variety of  calcium phosphates  have been advocated as remineralization agents; however, more clinical evidence is required to substantiate their effectiveness. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9062", "text": "Agents are added to suppress the tendency of toothpaste to dry into a powder. Included are various sugar alcohols, such as  glycerol ,  sorbitol , or  xylitol , or related derivatives, such as  1,2-propylene glycol  and  polyethyleneglycol . [ 49 ]   Strontium chloride  or  potassium nitrate  is included in some toothpastes to reduce sensitivity. Two systemic meta-analysis reviews reported that  arginine , and  calcium sodium phosphosilicate \u2013 CSPS containing toothpastes are also effective in alleviating dentinal hypersensitivity respectively. [ 50 ] [ 51 ]  Another randomized clinical trial found superior effects when both formulas were combined. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9063", "text": "Sodium polyphosphate is added to minimize the formation of tartar. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9064", "text": "Chlorohexidine mouthwash has been popular for its positive effect on controlling plaque and gingivitis, [ 53 ]  however, a systemic review studied the effects of Chlorhexidine toothpastes and found insufficient evidence to support its use, tooth surface discoloration was observed as a side effect upon using it, which is considered a negative side effect that can affect patients' compliance. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9065", "text": "Sodium hydroxide , also known as lye or caustic soda, is listed as an inactive ingredient in some toothpaste, for example Colgate Total."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9066", "text": "A systematic review reported two out of ten studies by the same authors on the same population showed toothpastes with xylitol as an ingredient were more effective at preventing dental caries in permanent teeth of children than toothpastes containing fluoride alone. Furthermore, xylitol has not been found to cause any harmful effects. However, further investigation into the efficacy of toothpastes containing xylitol is required as the currently available studies are of low quality and high risk of bias. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9067", "text": "Fluoride-containing toothpaste can be acutely toxic if swallowed in large amounts, [ 56 ] [ 57 ]  but instances are exceedingly rare and result from prolonged and excessive use of toothpaste (i.e. several tubes per week). [ 58 ]  Approximately 15\u00a0mg/kg body weight is the acute lethal dose, even though as small amount as 5\u00a0mg/kg may be fatal to some children. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9068", "text": "The risk of using fluoride is low enough that the use of full-strength toothpaste (1350\u20131500 ppm fluoride) is advised for all ages. However, smaller volumes are used for young children, for example, a smear of toothpaste until three years old. [ 57 ]  A major concern of  dental fluorosis  is for children under 12 months ingesting excessive fluoride through toothpaste. Nausea and vomiting are also problems which might arise with topical fluoride ingestion. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9069", "text": "The inclusion of sweet-tasting but toxic  diethylene glycol  in Chinese-made toothpaste led to a recall in 2007 involving multiple toothpaste brands in several nations. [ 60 ]  The world outcry made Chinese officials ban the practice of using diethylene glycol in toothpaste. [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9070", "text": "Reports have suggested triclosan, an active ingredient in many kinds of toothpastes, can combine with  chlorine  in tap water to form  chloroform . [ 62 ]  An animal study revealed the chemical might modify hormone regulation, and many other lab researches proved bacteria might be able to develop resistance to triclosan in a way which can help them to resist antibiotics also. [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9071", "text": "PEG  is a common ingredient in some of the formulas of toothpastes; it is a hydrophilic  polymer  that acts as a  dispersant  in toothpastes. Also, it is used in many cosmetic and pharmaceutical formulas, for example: ointments, osmotic  laxatives , some of the  nonsteroidal anti-inflammatory drugs , other medications and household products. [ 64 ]   However, 37 cases of PEG  hypersensitivity  (delayed and immediate) to PEG-containing substances have been reported since 1977, [ 65 ]  suggesting that they have unrecognized allergenic potential. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9072", "text": "With the exception of toothpaste intended to be used on pets such as dogs and cats, and toothpaste used by  astronauts , most toothpaste is not intended to be swallowed, and doing so may cause  nausea  or  diarrhea . Tartar fighting toothpastes have been debated. [ 66 ]   Sodium lauryl sulfate (SLS) has been proposed to increase the frequency of  mouth ulcers  in some people, as it can dry out the protective layer of oral tissues, causing the underlying tissues to become damaged. [ 67 ]  In studies conducted by the university of Oslo on  recurrent aphthous ulcers , it was found that SLS has a denaturing effect on the oral  mucin  layer, with high affinity for proteins, thereby increasing epithelial permeability. [ 68 ]  In a double-blind cross-over study, a significantly higher frequency of  aphthous ulcers  was demonstrated when patients brushed with an SLS-containing versus a detergent-free toothpaste. Also patients with  Oral Lichen Planus  who avoided SLS-containing toothpaste benefited. [ 69 ] [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9073", "text": "After using toothpaste,  orange juice  and other fruit juices are known to have an unpleasant taste if consumed shortly afterwards.  Sodium lauryl sulfate , used as a surfactant in toothpaste, alters taste perception. It can break down  phospholipids  that inhibit taste receptors for sweetness, giving food a bitter taste. In contrast, apples are known to taste more pleasant after using toothpaste. [ 71 ]  Distinguishing between the hypotheses that the bitter taste of orange juice results from stannous fluoride or from sodium lauryl sulfate is still an unresolved issue and it is thought that the  menthol  added for flavor may also take part in the alteration of taste perception when binding to lingual  cold receptors . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9074", "text": "Many toothpastes make whitening claims. Abrasion is the principal way that toothpaste removes stains, and toothpastes that are not marketed as whitening can still remove stains by abrasion. [ 72 ]  Some of these toothpastes contain peroxide, the same ingredient found in tooth bleaching gels. Whitening toothpaste cannot alter the natural color of teeth or reverse discoloration by penetrating surface stains or decay. To remove surface stains, whitening toothpaste may include abrasives to gently polish the teeth or additives such as  sodium tripolyphosphate  to break down or dissolve stains. When used twice a day, whitening toothpaste typically takes two to four weeks to make teeth appear whiter. Whitening toothpaste is generally safe for daily use, but excessive use might damage tooth enamel. [ 73 ]  A recent systematic review in 2017 concluded that nearly all dentifrices that are specifically formulated for tooth whitening were shown to have a beneficial effect in reducing extrinsic stains, irrespective of whether or not a chemical discoloration agent was added. [ 74 ]  However, the whitening process can permanently reduce the strength of the teeth, as the process scrapes away a protective outer layer of enamel. [ 75 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9075", "text": "Herbal toothpastes are marketed to consumers who wish to avoid some of the artificial ingredients commonly found in regular toothpastes. The ingredients found in so-called natural toothpastes vary widely but often include  baking soda ,  aloe ,  eucalyptus oil ,  myrrh ,  camomile ,  calendula , neem,  toothbrush tree , plant extract (strawberry extract), and essential oils. Many herbal toothpastes do not contain fluoride or  sodium lauryl sulfate . [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9076", "text": "A 2020 meta-analysis showed some evidence for the efficacy of herbal toothpaste, albeit from poor quality studies. [ 40 ]  According to a study by the  Delhi Institute of Pharmaceutical Sciences and Research , many of the herbal toothpastes being sold in India were adulterated with  nicotine . [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9077", "text": "Charcoal  has also been incorporated in toothpaste formulas; however, there is no evidence to determine its safety and effectiveness, and the American Dental Association does not recommend its use. [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9078", "text": "In the United States toothpaste is regulated by the U.S.  Food and Drug Administration  as a  cosmetic , except for ingredients with a medical purpose, such as fluoride, which are regulated as  drugs . [ 77 ]  Drugs require scientific studies and FDA approval in order to be legally marketed in the United States, but cosmetic ingredients do not require pre-approval, except for color additives. The FDA does have labelling and requirements and bans certain ingredients. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9079", "text": "Striped toothpaste was invented by Leonard Marraffino in 1955. The patent (US patent  2,789,731 , issued 1957) was subsequently sold to  Unilever , which marketed the novelty under the Stripe brand-name in the early 1960s. This was followed by the introduction of the Signal brand in Europe in 1965 (UK patent 813,514). Although Stripe was initially very successful, it never again achieved the 8% market share that it cornered during its second year."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9080", "text": "Marraffino's design, which remains in use for single-color stripes, is simple. The main material, usually white, sits at the crimp end of the toothpaste tube and makes up most of its bulk. A thin pipe, through which that carrier material will flow, descends from the nozzle to it. The stripe-material (this was red in Stripe) fills the gap between the carrier material and the top of the tube. The two materials are not in separate compartments, but they are sufficiently  viscous  that they will not mix. When pressure is applied to the toothpaste tube, the main material squeezes down the thin pipe to the nozzle. Simultaneously, the pressure applied to the main material causes pressure to be forwarded to the stripe material, which thereby issues out through small holes (in the side of the pipe) onto the main carrier material as it is passing those holes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9081", "text": "In 1990, Colgate-Palmolive was granted a patent (USPTO  4,969,767 ) for two differently colored stripes. In this scheme, the inner pipe has a cone-shaped plastic guard around it, and about halfway up its length. Between the guard and the nozzle-end of the tube is a space for the material for one color, which issues out of holes in the pipe. On the other side of the guard is space for second stripe-material, which has its own set of holes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9082", "text": "In 2016,  Colgate -Palmolive was granted a patent (USPTO  U.S. patent 20,160,228,347 ) for suitable sorts of differently colored toothpastes to be filled directly into tubes to produce a striped mix without any separate compartments. This required adjustment of the different components' behavior ( rheology ) so that stripes are produced when the tube is squeezed. [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9083", "text": "Striped toothpaste should not be confused with layered toothpaste. Layered toothpaste requires a multi-chamber design (e.g. USPTO  5,020,694 ), in which two or three layers extrude out of the nozzle. This scheme, like that of pump dispensers (USPTO  4,461,403 ), is more complicated (and thus, more expensive to manufacture) than either the Marraffino design or the Colgate designs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9084", "text": "The iconic depiction of a wave-shaped blob of toothpaste sitting on a toothbrush is called a \"nurdle\". [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9085", "text": "Tooth powders for use with toothbrushes came into general use in the 19th century in Britain. Most were homemade, with chalk, pulverized brick, or salt as ingredients. An 1866 Home Encyclopedia recommended pulverized charcoal, and cautioned that many patented tooth powders that were commercially marketed did more harm than good."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9086", "text": "Arm & Hammer  marketed a baking soda-based toothpowder in the United States until approximately 2000, and  Colgate  currently markets toothpowder in India and other countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9087", "text": "An 18th-century American and British toothpaste recipe called for burned bread. Another formula around this time called for  dragon's blood  (a resin), cinnamon, and burned  alum . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9088", "text": "In 1873 the Colgate company began the mass production of aromatic toothpaste in jars. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9089", "text": "By 1900, a paste made of  hydrogen peroxide  and  baking soda  was recommended for use with toothbrushes. Pre-mixed toothpastes were first marketed in the 19th century, but did not surpass the popularity of tooth-powder until  World War I ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9090", "text": "Together with  Willoughby D. Miller ,  Newell Sill Jenkins  developed the first toothpaste containing  disinfectants , branded as  Kolynos . [ 82 ]  The name is a combination of two Greek words, meaning \"beautifier\" and \"disease preventer\". [ 83 ]  Numerous attempts to produce the toothpaste by pharmacists in Europe proved uneconomic. After returning to the US, he continued experimenting with  Harry Ward Foote  (1875\u20131942), professor of chemistry at  Sheffield Chemical Laboratory  of  Yale University . [ 84 ]  After 17 years of development of Kolynos and clinical trials, Jenkins retired and transferred the production and distribution to his son  Leonard A. Jenkins , who brought the first toothpaste tubes on the market on April 13, 1908. Within a few years the company expanded in North America, Latin America, Europe and the Far East. A branch operation opened in London in 1909. In 1937, Kolynos was produced in 22 countries and sold in 88 countries. Kolynos has been sold mainly in South America and in Hungary. Colgate-Palmolive took over the production of  American Home Products  in 1995 at a cost of one billion US dollars. [ 85 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9091", "text": "Fluoride  was first added to toothpastes in the 1890s. Tanagra, containing  calcium fluoride  as the active ingredient, was sold by  Karl F. Toellner Company , of  Bremen , Germany, based upon the early work of chemist  Albert Deninger . [ 86 ]  An analogous invention by  Roy Cross , of  Kansas City, Missouri , was initially criticized by the American Dental Association (ADA) in 1937. Fluoride toothpastes developed in the 1950s received the ADA's approval. To develop the first ADA-approved fluoride toothpaste,  Procter & Gamble  started a research program in the early 1940s. In 1950, Procter & Gamble developed a joint research project team headed by  Joseph C. Muhler  at  Indiana University  to study new toothpaste with fluoride. In 1955, Procter & Gamble's  Crest  launched its first  clinically proven  fluoride-containing toothpaste. On August 1, 1960, the ADA reported that \"Crest has been shown to be an effective anticavity (decay preventative) dentifrice that can be of significant value when used in a conscientiously applied program of oral hygiene and regular professional care.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_9092", "text": "In 1980, the Japanese company, Sangi Co., Ltd., launched APADENT, the world's first remineralizing toothpaste to use a nano-form of hydroxyapatite, the main component of tooth enamel, rather than fluoride, to remineralize areas of mineral loss below the surface of tooth enamel (incipient caries lesions). After many years of laboratory experiments and field trials, [ 87 ]  its hydroxyapatite ingredient was approved as an active anti-caries agent by the Japanese Ministry of Health in 1993, and given the name Medical Hydroxyapatite to distinguish it from other forms of hydroxyapatite used in toothpaste, such as dental abrasives."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9093", "text": "In 2006,  BioRepair  appeared in Europe with the first European toothpaste containing synthetic  hydroxylapatite  as an alternative to fluoride for the remineralization and reparation of  tooth enamel . The \"biomimetic hydroxylapatite\" is intended to protect the teeth by creating a new layer of synthetic enamel around the tooth instead of hardening the existing layer with fluoride that chemically changes it into  fluorapatite . [ 88 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9094", "text": "Toothpaste is usually dispensed via a collapsible tube or with a more rigid pump. Several traditional and innovative designs have been developed. [ 89 ]   The dispenser must be matched to the flow properties of the toothpaste. [ 90 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9095", "text": "In 1880, Doctor  Washington Sheffield  of  New London, CT  manufactured toothpaste into a collapsible tube,  Dr. Sheffield's Creme Dentifrice . He had the idea after his son traveled to Paris and saw painters using paint from tubes. In  York  in 1896, Colgate-Palmolive Dental Cream was packaged in collapsible tubes imitating Sheffield. The original collapsible toothpaste tubes were made of  lead . [ 91 ] [ 92 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9096", "text": "Topical cream formulation  is an  emulsion  semisolid dosage form that is used for skin external application. Most of the topical cream formulations contain more than 20 per cent of water and  volatiles  and/or less than 50 per cent of  hydrocarbons ,  waxes , or  polyethylene glycols  as the vehicle for external skin application. [ 1 ]  In a topical cream formulation, ingredients are dissolved or dispersed in either a  water-in-oil (W/O) emulsion  or an  oil-in-water (O/W) emulsion . [ 2 ]  The topical cream formulation has a higher content of oily substance than  gel , but a lower content of oily ingredient than  ointment . Therefore, the viscosity of topical cream formulation lies between  gel  and  ointment . [ 1 ]  The  pharmacological effect  of the topical cream formulation is confined to the skin surface or within the skin. [ 3 ]  Topical cream formulation penetrates through the skin by transcellular route, intercellular route, or trans-appendageal route. [ 4 ]  Topical cream formulation is used for a wide range of diseases and conditions, including  atopic dermatitis  (eczema),  psoriasis ,  skin infection ,  acne , and  wart . [ 5 ]   Excipients  found in a topical cream formulation include  thickeners ,  emulsifying agents ,  preservatives ,  antioxidants , and  buffer agents . [ 6 ] [ 7 ]  Steps required to manufacture a topical cream formulation include excipient dissolution, phase mixing, introduction of  active substances , and  homogenization  of the product mixture. [ 2 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9097", "text": "Human skin can be divided, from outside to inside, into the  stratum corneum , viable  epidermis ,  dermis , and underlying  hypodermis . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9098", "text": "The  stratum corneum  is typically 10\u201320 \u03bcm thick and consists of extracellular lipid-surrounded  corneocytes . The lipophilic environment of the stratum corneum can serve as a reservoir for certain highly lipophilic molecules.  Keratin  found in the stratum corneum may provide great affinity with certain drugs. Both of these interactions can play a role in drug accumulation in the stratum corneum and the local drug action on skin disease. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9099", "text": "Below the stratum corneum is the viable  epidermis . The viable epidermis is usually 50\u2013100 \u03bcm thick. It includes immunologically sensitive cells (e.g.  Langerhans cells ), and metabolically active cells (e.g.  keratinocytes ,  melanocytes ,  merkel cells ). Melanocytes are involved in  melanoma   pathogenesis . As a result, drugs treating melanoma need to be administered to the lower epidermis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9100", "text": "The  dermis  lies next to the epidermis. It is a 1\u20132\u00a0mm layer mainly composed of  fibroblasts  and  immune cells  (e.g. dermal  dendritic cells ,  macrophages ,  T cells ,  mast cells ) in a  collagen  and  elastic fiber  extracellular matrix. [ 5 ]  These immune cells play important roles in  parasitic infections ,  psoriasis  induction,  tumor progression , dermal inflammation,  angiogenesis ,  wound healing ,  tissue remodeling ,  skin sensitization , and tolerance. [ 10 ]  Therefore, the regional accumulation of drugs in the dermis is necessary for the prevention and treatment of these local skin diseases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9101", "text": "The  hair follicle  is an  invagination  of epidermis cells deep into the dermis. The follicular route is critical in the topical delivery of particle-based formulations and hydrophilic, high-molecular-weight drugs. The follicular route provides benefits such as deeper  penetration , prolonged residence duration, faster entry into the skin, and site-specific targeting. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9102", "text": "Beneath these layers lies the  hypodermis , which is composed of  adipose tissue ,  fascia , as well as larger lymphatic and blood vessels. For joint and muscle disease treatment, topically applied drugs such as  non-steroidal anti-inflammatory drugs  (NSAIDs) can penetrate the  subcutaneous tissue  or even deeper tissues in the hypodermis. [ 12 ]  Drugs are primarily delivered into the underlying muscle by direct penetration without prior entry into the systemic circulation to prevent unintended side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9103", "text": "In general, there are three possible routes for drug administration into or across the skin. The first one is the  transcellular  route, where the drugs are required to pass through both lipid matrix and dead  corneocytes  of the  stratum corneum . The second one is the intercellular route, where the drugs only have to pass through lipid domains between  corneocytes . The third one is the trans-appendageal route, where the drugs are transported by  hair follicles ,  sebaceous glands , or  sweat glands . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9104", "text": "The most common route for drug delivery into the skin is the intercellular route. Multiple steps are involved. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9105", "text": "Excipient  has a significant impact on the final product performance, manufacturability, and stability. Therefore, the selection of excipients has to be carefully considered during topical cream formulation design."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9106", "text": "In topical cream formulations, oily compounds act as active substance carriers. They also serve as skin penetration enhancers and  consistency  or  viscosity  modifiers. The oily excipients may influence cream viscosity, drug  solubility , physical stability, drug release performance, and transport into the skin. Oily compounds commonly used in cream formulations include saturated and unsaturated  fatty acids /fatty acid  esters ,  hydrocarbons , and  polyols ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9107", "text": "Topical cream formulations consist of the oily phase and water phase. As the two phases are immiscible, in the absence of thickeners and emulsifying agents, molecules in the topical cream formulation will form droplets. Rapid aggregation of droplets within each phase will eventually lead to  phase separation . Physical stability is determined by the mitigation ability to these physical instability phenomena."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9108", "text": "Thickeners  increase cream viscosity and thus reduce dispersed droplets' mobility. They hinder the separation of phases, thereby increases the physical stability of the cream. For example, the inclusion of  methylcellulose  and  paraffin  reduces dispersed droplets' mobility in an oil-in-water emulsion and water-in-oil emulsion respectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9109", "text": "Emulsifying agents  can reduce the  interfacial tension  between the two phases, thus retards phase separation. Ionic  surfactants  are used in oil-in-water emulsions, whereas nonionic surfactants are used in both oil-in-water and water-in-oil formulations. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9110", "text": "Oils and fats used in topical cream formulations are susceptible to  oxidation  by atmospheric oxygen or microorganism action. The stability against oxidation can be enhanced by the introduction of  antioxidants . The selection of antioxidants and their concentration can only be determined by testing their effectiveness on the final product, according to pharmacopoeial information. The efficiency of antioxidants depends on their compatibility with other excipients and oil/water  partition coefficient ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9111", "text": "Oxidations from microbiological source influence the physicochemical properties of the emulsion, resulting in color and odor changes, fat and oil  hydrolysis , pH changes in the aqueous phase, or phase separation of the cream. Oil-in-water creams are more susceptible to microbial contamination. Therefore,  preservatives  are included to prevent any microorganism growth. Preservatives suitable for topical cream formulations must present a broad spectrum of bactericidal activity, low  logP , compatibility with other excipients, stability, and effectiveness over a wide range of pH and temperatures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9112", "text": "By buffering any potential pH change,  buffer agents  can provide chemical stability and ensure the physical compatibility of the topical cream formulation. They ensure that the formulation can deliver the correct amount of drug to the therapeutic application site, is free from microbial contamination, and physically unchanged since the manufacturing day. Nonetheless, buffer agents need to be carefully added to avoid undesirable effects on physical stability. For example, buffer agents may influence the  rheological  behavior. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9113", "text": "During the production of the topical cream formulation, the first step is to dissolve excipients in the phase in which they are soluble. The initial mixing temperature of both phases should be high enough to ensure intimate liquid mixing and avoid premature solidification of the oily phase by the colder water. The aqueous phase should be warmed to a temperature slightly higher than the oily phase."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9114", "text": "The second step is the mixing of both the aqueous phase and the oily phase by adding either the dispersed phase to the continuous phase, or the continuous phase to the dispersed phase. The effect of the addition order and the addition rate on the drug product quality should be evaluated during process development."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9115", "text": "The third step is the introduction of the active substances into the mixture. Some active pharmaceutical ingredients can be dissolved at high temperatures but  recrystallize  during the cooling stage after mixing. To prevent recrystallization, the active substances can be carried to the cooled down cream base via a powder induction system or through slurry addition. The active substances are simultaneously mixed into the cream base."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9116", "text": "The last step is the  homogenization  stage.  Agitators , mechanical mixers, rotor stators,  homogenizers , or ultrasonic devices can be employed to ensure uniform excipient  dispersion  and droplet size reduction. Critical variables of the homogenization equipment include time, temperature, and mechanical energy. Critical parameters must be controlled to produce products of consistent quality. [ 2 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9117", "text": "A wide spectrum of drugs is available as topical cream formulations. Therefore, topical cream formulations are used to treat many skin diseases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9118", "text": "and  Immunomodulatory  Agents"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9119", "text": "Cream, together with  gel  and  ointment , are semisolid dosage forms intended for topical application. [ 16 ]  They have different appearances, advantages, disadvantages, and applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9120", "text": "Topical gels  are a  topical  drug delivery  dosage form  commonly used in cosmetics and treatments for skin diseases because of their advantages over cream and ointment. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  They are formed from a mixture of  gelator , solvent, active drug, and other excipients, and can be classified into  organogels  and  hydrogels . [ 1 ] [ 5 ] [ 6 ] [ 7 ]  Drug formulation and preparation methods depend on the properties of the gelators, solvents, drug and excipients used. [ 1 ] [ 2 ] [ 5 ] [ 3 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9121", "text": "A  gel  refers to the semi-"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9122", "text": "solid, 3-dimensional matrix formed from an interspersed system of colloidal particles or the permeation of a solvent into an entwined polymer chain network. [ 1 ] [ 2 ] [ 5 ] [ 3 ] [ 8 ]  Pharmaceutical gels are formed by adding a  gelator  (gelling agent) to the solvent  [ 5 ] [ 6 ]  and active ingredient mixture."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9123", "text": "Gelators used in gel formulation can be small molecules with low molecular weight or polymers (synthetic, semi-synthetic or natural). [ 5 ] [ 7 ]  The solvent that is used as a dispersion medium can be aqueous, organic, inorganic, or a system of different solvents. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9124", "text": "Topical gels are used as a contact or transport medium for active drugs to act on [ 4 ]  or through the skin. [ 9 ]  The active drug molecules are entwined into the 3D mesh of the gel and delivered to the site of action."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9125", "text": "Gels have certain special properties that put them apart from other dosage forms, in terms of swelling,  syneresis ,  ageing ,  rigidity  and  rheology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9126", "text": "Gels can be classified through a variety of criteria such as their nature of the  colloidal  phase, nature of the solvent used and physical nature."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9127", "text": "This is the most widely used classification of gels. They are classified into two main groups by the nature of the solvent: organogels and hydrogels."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9128", "text": "Organogels  are not as commonly used as mediums for drugs or vaccines when compared to other gel classes. [ 5 ]  This is due to the untested or pharmaceutically unacceptable solvents and gelators commonly used in organogel synthesis. [ 5 ]  Organogels that are used pharmaceutically include  microemulsion -based gels and lecithin gels. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9129", "text": "Some manufacturers decide to use organogels as a medium for drug delivery due to its potentially  emollient  effect. Some organogels contain bases composed of  oleaginous  substances. [ 1 ] [ 6 ]  These bases can help retain skin moisture through the formation of an occlusive layer on the area of application. [ 1 ] [ 6 ]  This occlusive layer traps moisture, allowing hydration of the skin and providing an emollient effect. [ 1 ] [ 6 ] [ 10 ]  This emollient effect is particularly helpful in formulation of topical gels for patients with dry and irritated skin. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9130", "text": "Hydrogels  have a high water content, [ 7 ]  with some hydrogels containing up to 90% water. [ 5 ]  Active drugs and other substances dispersed as  colloids  or dissolved in water can be easily taken up by hydrogels. [ 5 ]  Hydrogels are  biocompatible . [ 5 ] [ 7 ]  They also swell to a greater volume than organogels when in contact with water and other natural liquids. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9131", "text": "Hydrogels can be used as drug delivery vehicles, for  transdermal  application,  ophthalmic  drug delivery, [ 11 ]  cancer treatment  [ 12 ]  or for  wound dressing . [ 7 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9132", "text": "As a type of water based formulation, hydrogels are generally less greasy and are easier to be removed than oil-based formulations like organogels. [ 6 ]  Examples of hydrogels include aluminum oxide gels, and  bentonite magma . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9133", "text": "Drugs administered through topical application can act locally or systemically. [ 1 ] [ 6 ]  However, the drug molecules must first be retained in and penetrate the surface layer of the  skin . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9134", "text": "Absorption of the drug through the skin surface is a passive process of  diffusion . [ 1 ] [ 9 ]  Skin penetration of the drug can take place by  passive diffusion  directly through the  epidermis  (via  transcellular  or  intercellular  routes), or absorption through  shunt routes  (diffusion through  hair follicles  and  sweat glands ). [ 1 ] [ 6 ] [ 10 ]  Initially, drug absorption may take place via the transfolliar route. After the drug reaches a steady state, transepidermal absorption may replace transfolliar absorption as the main pathway for absorption. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9135", "text": "Drug absorption through the skin varies depending on the concentration gradient between the surface of the skin and the body, [ 1 ] [ 14 ]  with a higher rate of absorption resulting from a greater concentration gradient. [ 6 ] [ 14 ]  The rate of drug absorption can be maintained at a constant level by ensuring that the drug concentration at the surface of the skin remains consistently and substantially greater than that in the body. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9136", "text": "The rate of penetration of the drug across the skin barrier depends on the physiological factors, physicochemical properties of the drug, and gel characteristics. [ 1 ] [ 6 ]  Physiological factors include skin properties, [ 3 ] [ 1 ] [ 2 ]  size of application area, frequency and force of application. [ 1 ] [ 6 ]  Physicochemical properties of the drug include drug solubility, attraction to the skin and  metabolism . [ 3 ] [ 1 ] [ 6 ] [ 10 ]  Gel characteristics include stability,  thermodynamic activity , and  occlusive  properties. [ 3 ] [ 1 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9137", "text": "Following penetration through the skin barrier, the drug may permeate through deeper skin tissues and reach the blood capillaries in the  dermis . [ 6 ] [ 9 ]  It may then proceed to enter the  systemic circulation  for systemic effect. [ 1 ] [ 6 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9138", "text": "Formulation of topical gels is determined by important factors such as appearance, odor, spreadability, extrudability, viscosity, pH, texture, microbial contamination potential and  bioavailability . [ 1 ]  The components of the vehicle should serve to make the skin surface more penetrable to the drug. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9139", "text": "Characteristics of the gel such as  consistency  and  viscosity  are affected by formulation design. [ 3 ]  Consistency and viscosity affect the adhesion and retention property of the gel, and are important in ensuring the gel is retained at the site of application and effective delivery of the drug. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9140", "text": "The ingredients in topical gel formulation can be broadly categorized into four types: gelator, solvent, drug, and excipients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9141", "text": "Gelators  serve as stabilizers and thickeners, thickening the gel solution while simultaneously maintaining the gel\u2019s flexible nature. [ 8 ]  When dispersed through the solvent as a colloid, gelators offer a stable internal structure to the gel. [ 8 ]  Gelators are usually chosen based on their affinity for the solvent and the purpose of the gel. [ 5 ]  The nature of the gelators used determines the rigidity of the gel. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9142", "text": "There are many types of gelators, of which  carbomers  are more frequently used due to their ability to thicken gels across a wide range of pH. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9143", "text": "Gelators can be classified by polymer types, namely natural, semi-synthetic and synthetic polymers. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9144", "text": "Natural gelators include  tragacanth , [ 6 ]   gelatin ,  collagen , [ 4 ]  and  guar gum ; semi-synthemic gelators include  methylcellulose  and other cellulose derivatives; [ 5 ] [ 8 ] [ 6 ]  while synthetic gelators include  carbomers , [ 6 ]   polyvinyl alcohol ,  polyethylene  and its copolymers. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9145", "text": "Solvents are usually chosen based on the applications of the gel. [ 5 ]  They can be  hydrophilic ,  lipophilic , or  organic . [ 5 ]  Individual solvents can be used alone or as a mixture. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9146", "text": "Some examples of solvents include  purified water , [ 3 ]   glycerin ,  glycols ,  alcohols ,  sucrose ,  toluene , and  mineral oils . [ 5 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9147", "text": "Topical  delivery is often used for drugs that are easily degraded in the  GI tract , or are highly susceptible to  hepatic first pass effect . [ 1 ] [ 2 ]  Even if the drug has to be administered for long periods of time or can induce  adverse drug reactions  in parts of the body other than the target location, it can still be formulated as a topical gel. [ 1 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9148", "text": "There are a number of physicochemical and biological properties that determine whether a drug is suitable for being delivered topically through a gel dosage form."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9149", "text": "Physicochemical properties:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9150", "text": "The drug must:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9151", "text": "Biological properties:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9152", "text": "Excipients  are materials inert to the drug, which are added into dosage forms to improve the overall quality of the dosage form. [ 14 ]  Some examples include  antioxidants ,  sweetening agents ,  stabilizers ,  dispersing agents ,  penetration enhancers ,  buffers  and  preservatives . [ 5 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9153", "text": "Penetration enhancers  are excipients that can increase skin permeability. [ 1 ] [ 6 ]  Many classes of excipients can be used as penetration enhancers, such as  glycerin ,  sulfoxides  and related analogues,  pyrrolidines ,  fatty acid  and  ethanol ,  surfactants  etc. [ 1 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9154", "text": "Buffers  can be added to control the pH of aqueous or hydroalcoholic based gels. [ 3 ] [ 9 ]  Examples of buffers include  phosphate  and  citrate . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9155", "text": "Preservatives  are important for their  antimicrobial  action, [ 5 ] [ 3 ]  and are especially important in formulation of hydrogels. [ 5 ]  Examples of preservatives include  parabens  and  phenolics . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9156", "text": "Antioxidants  are used to prevent gel ingredients from being  oxidised . [ 3 ]  When choosing the antioxidant to be used, it is important to consider the nature of the solvent. [ 3 ]  Since the solvent of most gels are aqueous in nature, water-soluble antioxidants are more commonly used. [ 3 ] Some common examples include  sodium metabisulphite  and sodium formaldehyde sulfoxylate. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9157", "text": "Sweetening agents are only used in gels that are designed to be used in the oral cavity such as dental gels. [ 3 ]  Examples include  sucrose ,  glycerol ,  sorbitol  and liquid  glucose . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9158", "text": "The process of gel formation involves finding a balance between the concentrations of the gelator and the solvent. [ 5 ]  When adding a gelator to the solvent, the mixture remains in liquid state. [ 5 ]  As the concentration of the gelator increases to a certain critical concentration (gelling point),  gelation  occurs through swelling to form the semi-solid gel. [ 5 ]  Further increasing the concentration of the gelator\u00a0beyond the gelling point will increase gel viscosity. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9159", "text": "The exact gelling point varies depending on the properties of the gelator and the solvent, such as structure uniformity, molecular weight of the polymer, and flexibility of the polymer chain. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9160", "text": "Generally, gels are prepared by firstly dissolving the soluble excipients in the solvent. [ 5 ] [ 3 ]  The solution is then mixed using a mechanical stirrer. [ 3 ]  After that, the gelator is added slowly to the stirred mixture in order to avoid aggregation. [ 3 ]  Then, the mixture is continuously stirred until the polymer dissolves and a gel gradually forms. [ 3 ]  The gel is allowed to settle for one to two days before the final consistency of the gel can be reached. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9161", "text": "The exact method of preparing gels depends on the properties of the formulation ingredients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9162", "text": "Topical gels are commonly used as  sustained release dosage forms . [ 5 ] [ 9 ]  Usage of the sustained release dosage form reduces the administration of recurrent doses while maintaining  serum  dose levels at the therapeutic range (difference between toxic and therapeutic doses), hence improving  patient compliance . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9163", "text": "Some topical gels are fast release gels, which are highly absorbent and can swell rapidly. [ 5 ]  These fast release gels can be used to treat acute disorders."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9164", "text": "Topical gels are also used as  lubricants , or carriers for pharmaceutical agents. [ 5 ]  They can be used as vehicles for different purposes, via different routes of administration, such as dental,  dermatological [ 15 ] l , [ 16 ] [ 17 ]   ophthalmic , [ 11 ]  intranasal, vaginal, rectal and others. [ 5 ] [ 1 ] [ 2 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9165", "text": "Topical gels are commonly used in cosmetics, which include shampoos,  dentifrices , skin and hair care formulations and fragrance products, [ 1 ] [ 2 ]  and can be used to treat scalp inflammation. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9166", "text": "Topical gels can be used to deliver  anti-inflammatory   steroids  to the scalp in treatment of scalp inflammations. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9167", "text": "Examples of Commercially available topical gels.   [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9168", "text": "The texture of topical gels is less greasy as it contains a higher proportion of water compared with cream and  ointment . [ 3 ] [ 1 ] [ 2 ] [ 8 ]  These gels have an excellent spreading property and cooling effect due to solvent evaporation, and also has a higher retention time on the skin. [ 5 ] [ 3 ] [ 1 ] [ 2 ] [ 8 ]  Topical gels are more stable than creams and ointments, and can adhere well to the site of application. [ 5 ] [ 2 ]  They form an occlusive layer on the application site that can act as a form of protection. [ 5 ]  They can be washed off easily and are nontoxic due to their unique composition and structure. [ 5 ] [ 2 ] [ 6 ]  They have minimal side effects due to their localized effect. [ 1 ]  Topical gels are convenient and easy to apply. [ 2 ] [ 6 ]  The topical mode of action of topical gels is also  non-invasive . [ 1 ] [ 6 ]  These favorable factors of topical gels improve patient  compliance  and  tolerability . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9169", "text": "The formulation and manufacturing processes of topical gels are relatively simpler and more cost effective than other semisolid dosage forms. [ 5 ] [ 1 ] [ 8 ]  The release profile of the gel can be modified by altering the properties of the gelator, allowing for continuous drug delivery. [ 1 ]  Topical gels are also eco-friendly,  biocompatible  and  biodegradable . [ 5 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9170", "text": "The drug can penetrate deeply into the skin  [ 2 ]  and be directly delivered to the target site, as the topical application allows it to avoid  hepatic first pass metabolism . [ 1 ] [ 2 ] [ 8 ] [ 6 ]  Difficulties in gastrointestinal absorption caused by pH, enzymatic activity and drug-food interactions can be minimized, while at the same time avoiding GI irritation. [ 1 ] [ 2 ] [ 6 ]  The topical dosage form allows stable and continuous drug delivery to the site of application, [ 2 ]  while having a faster drug release than ointments and creams. [ 1 ]  All these can increase the drug\u2019s  bioavailability  in the body. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9171", "text": "There may be  flocculation  in some gels, which may produce an unstable gel. [ 5 ] [ 8 ]  The  rheology  of some gels are easily altered by environmental factors such as temperature and humidity, [ 5 ]  resulting in stricter storage requirements.  Syneresis  of the gel may occur during storage, causing the gel to shrink unpredictably or even dry out. [ 5 ] [ 3 ]  The gelators may precipitate and  salt out , and some drugs may degrade in gel formulation due to the other ingredients present in the formulation. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9172", "text": "Some additives and gelators added into the formulation may cause irritation problems, [ 5 ] [ 8 ]  such as skin irritation,  dermatitis  or  allergic conditions . [ 2 ]  The increased water content in gels increases the chances of microbial or fungal attack, [ 5 ] [ 8 ]  which may contaminate the gel, making it unsuitable for use. Considering the direct route of administration, drugs must be very small in size to have an effective plasma concentration for action. The particle size and other properties of the drug may also affect its absorption through the  skin  barrier, [ 2 ]  resulting in an unreliable effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9173", "text": "Transdermal implants , or  dermal piercings , are a form of  body modification  used both in a  medical  and  aesthetic  context that, in contrast to  subdermal implants , consist of an object placed partially below and partially above the  skin , thus  implanted   trans dermal. Two techniques are prevalent using  post -like and microdermal implants respectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9174", "text": "Although the skin around such implants generally heals as if it were a  piercing , in the body piercing community, these types of modification are commonly called fairly \"heavy\" due to the complexity of the procedure, but the potential  social implications  either."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9175", "text": "When the procedure is done using a  post -like implant, an incision is made a small distance from the site. The skin is then lifted and the implant is passed through. Then, a hole is opened at the site for it to pass through, and it is moved so that the top part fills the hole. The implants used for this are generally small and not textured in any way except rounding."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9176", "text": "If a more graphic implant is desired, it is generally done in two parts. First, the base is inserted the same way a single-part would be, except that the base implant is threaded. It may either stick out like a bolt, or be inward like a nut. When this is done, the top half is screwed on. This type is usually done for spikes and/or horns."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9177", "text": "In any case, the part of the implant which passes under the skin generally is somewhat large and has holes. The skin will grow into them, making it more permanent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9178", "text": "Microdermal implants  are a form of  body modification  which gives the aesthetic appearance of a transdermal implant, without the complications of the much more complicated surgery associated with transdermal implants. [ 1 ] [ unreliable source? ]  Microdermals are single point piercings which are a sort of surface piercing. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9179", "text": "Microdermal implants can be placed practically anywhere on the surface of the  skin  on the body, but are different from conventional  piercings  in that they are composed of two components: an anchor, which is implanted underneath the skin, with a step protruding from (or flush with) the surface of the surrounding skin, and the changeable  jewellery , which is screwed into the threaded hole in the step of the anchor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9180", "text": "They should not be implanted in hands, feet, wrists, collarbones or any area where it is not flat or that is near a joint. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9181", "text": "The procedure is usually performed using a dermal punch or needle. When a dermal piercing is done with a punch, the pouch is made in a different way. When using a needle, the pouch is made by separating the skin. When using a dermal punch, the pouch is made by removing a bit of tissue. A microdermal punch is less painful and therefore commonly used. The process starts by identifying the point of piercing on the sterilized area that will be marked with a surgical marker. The microdermal punch is then used to remove skin tissues. The anchor is then placed under the skin and a piece of jewelry is placed using surgical forceps. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9182", "text": "A  metered-dose transdermal spray  ( MDTS ) delivers a  drug  to the surface of the skin and is absorbed into the circulation on a sustained basis. It works in a similar manner to a  transdermal patch  or  topical gel . The drug is delivered by a device placed gently against the skin and triggered, causing it to release a light spray containing a proprietary formulation of the drug that quickly dries on the skin to form an invisible drug depot. As it would be from a patch, the drug is then absorbed steadily for a predetermined amount of time."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9183", "text": "Transfersome  is a proprietary drug delivery technology, an artificial  vesicle  designed to exhibit the characteristics of a  cell vesicle  suitable for controlled and potentially targeted drug delivery. Some evidence has shown efficacy for its use for drug delivery without causing skin irritation, [ 1 ]  potentially being used to treat skin cancer. [ 2 ]  Transfersome is made by the German company IDEA AG."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9184", "text": "Ultrasound-triggered drug delivery using stimuli-responsive hydrogels  refers to the process of using  ultrasound  energy for inducing drug release from  hydrogels  that are sensitive to acoustic stimuli. This method of approach is one of many  stimuli-responsive drug delivery-based systems  that has gained traction in recent years due to its demonstration of localization and specificity of disease treatment. Although recent developments in this field highlight its potential in treating certain diseases such as  COVID-19 , there remain many major challenges that need to be addressed and overcome before more related biomedical applications are clinically translated into standard of care."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9185", "text": "Hydrogels are three dimensional structures consisting of hydrophilic  polymers  (i.e., polymers, colloids, etc.) that form networks through cross-linking processes. The macromolecules involved in the formation of hydrogels are able to absorb and retain large amounts of water and other aqueous substances. Since its discovery in 1960, [ 1 ]  hydrogels have become a crucial component in biomedical research and applications. A few examples of hydrogel use include organ regeneration, [ 2 ]   wound healing , [ 3 ] [ 4 ] [ 5 ]  and  drug delivery . [ 6 ] [ 7 ]  Hydrogels are generally classified based on the following characteristics: material, crosslinking mechanism, physical structure, electric charge, and response to stimuli. [ 8 ]  Synthesis of hydrogels are developed from a combination or isolated forms of natural and synthetic polymers. [ 2 ] [ 9 ]  The main examples of natural polymers used to derive hydrogels include polysaccharides, [ 9 ]  polypeptides, [ 10 ]  and polynucleotides. [ 5 ]  Several known examples of synthetic polymeric constituents include poly (vinyl alcohol) ( PVA ), [ 7 ] [ 9 ] [ 11 ]  poly (acrylic acid) ( PAA ), [ 7 ] [ 9 ] [ 11 ]  and poly (2-hydroxyethyl methacrylate) ( PHEMA ). [ 9 ] [ 11 ] [ 12 ] [ 13 ]  The crosslinking mechanism of the hydrophilic macromolecules are driven by covalent bonding, resulting in a physical- or chemical-type hydrogel. Physical hydrogels contain reversible matrices of hydrogen and non-covalent bonds, while chemical hydrogels are composed of irreversible matrices that are molecularly held together by covalent bonds. Used as another parameter in characterizing gels,  electric charge  (also referred to as ionic character) describes the ability of the macromolecules to drive swelling behavior. Hydrogels classified based on this property fall under three main categories: cationic, anionic, and amphoteric. Bawa et al. demonstrated that cationic gels swell in acidic environments but remain condensed in basic environments. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9186", "text": "Since traditional hydrogels were able to encapsulate and carry materials, research into drug-loaded hydrogels began to expand in the field of drug delivery. Dubbed as \u201csmart hydrogels\u201d or \u201cstimuli-responsive hydrogels\u201d, these gels are able to dynamically respond to external or internal stimuli in addition to possessing similar swelling-deswelling properties of traditional hydrogels. Various examples of external stimuli that have been used to control smart hydrogels in drug delivery systems include temperature, [ 10 ] [ 12 ] [ 13 ] [ 15 ] [ 16 ] [ 17 ]  pH, [ 12 ] [ 13 ] [ 15 ] [ 16 ] [ 17 ]  light, [ 10 ] [ 12 ] [ 15 ] [ 16 ]  ultrasound, [ 15 ] [ 16 ]  and enzymes. [ 18 ]  Additional considerations in designing smart hydrogels involve fundamental understanding of  bond strength , molecular weight, degree of polymerization, polymer structure, and molecular assembly. [ 17 ] [ 19 ]  The bond strength describes the cross-linking strength of the hydrogel, which is considered in designing drug release mechanisms of hydrogel-based platforms. Scientific understanding of the molecular weight of gels is taken into account when loading drugs of increasing weight. [ 20 ]  Similar to conventional hydrogels, the polymeric chain (or backbone) of the smart hydrogels is derived from  polysaccharides ,  polypeptides , and polynucleotides. Examples of natural polymers include  alginate , [ 21 ] [ 22 ] [ 23 ]   chitosan , [ 6 ] [ 17 ] [ 24 ] [ 25 ]   cellulose , [ 6 ] [ 13 ]   gelatin , [ 13 ]   fibrin , [ 17 ]  and  collagen . [ 26 ]  Hydrogel size and type are the two main properties considered in designing hydrogels when seeking the optimal delivery route for drug administration. [ 27 ]  Various examples of hydrogel type designs include  nanoparticles , [ 13 ] [ 28 ]   nanogels , [ 16 ] [ 28 ] [ 29 ]  and microgels. [ 29 ]  For example, El-Sherbiny et al. proposed gelatin-based hydrogel nanoparticles that were stimulated by magnetic forces. [ 30 ]  Other variables considered in hydrogel design include safety, biodegradability, [ 31 ]  drug loading capacity, and on-demand control of drug release [23]. The main safety concerns in formulating hydrogels include bacterial infection [ 32 ]  and biocompatibility. [ 26 ]  The final parameter considered in developing hydrogels for drug delivery systems revolve around the embedded payload within the hydrogel. [ 33 ]  Cells, proteins, and therapeutic drugs are the main payloads used in hydrogel-based drug delivery platforms. [ 34 ]  In one example of payload use, Jiang et al. demonstrated the stimulated release of  gallic acid  from chitin-based hydrogel via ultrasound induction. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9187", "text": "According to the Moyano et al., ultrasound refers to vibrational mechanical waves with frequencies greater than 20 kilohertz (kHz). [ 35 ]  Ultrasound is traditionally used for imaging, monitoring, and diagnosing a broad range of conditions in the medical field. Various examples of ultrasound modalities include Doppler ultrasound, focused ultrasound, and echocardiography. The key component of using most ultrasound devices is a transducer that consists of an array of piezoelectric crystals. The atoms within these crystals vibrate under electrical current stimulation, converting this electrical energy into mechanical, in this case, high acoustic or ultrasonic energy. When the sonicating transducer is directed at the human body, the resulting sound pressure waves produced by the transducer will pass through the dermal layer and reach the tissue where the waves are reflected (or echoed) back to the transducer and converted back into electrical signals for image reconstruction. Tissue characteristics such as density affect the intensity of the reflected sound waves. Other parameters such as beam frequency, equipment components, and imaging settings contribute towards the resolution of the ultrasound application. Ultrasound has also been used for therapeutic purposes because it is non-invasiveness, able to provide deeper tissue penetration, and safely localize application of acoustic energy. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9188", "text": "While ultrasound modalities are generally considered safe, extreme levels of human exposure to ultrasound can increase injury risk. [ 35 ]  In the US, the  Food and Drug Administration  (FDA) guidelines, [ 34 ]  the maximum allowed exposure to ultrasound for use is defined by the following key parameters:  mechanical index , [ 36 ]  thermal index, [ 37 ]  spatial-peak temporal-peak intensity, [ 38 ]  spatial-peak pulse-average power, [ 39 ]  and spatial-peak temporal-average power. [ 34 ]  Mechanical index (MI) is a unitless metric that is used to measure the acoustic power output from ultrasound use. Since the MI is inversely proportional to the ultrasonic beam frequency, the MI will be lower at higher frequencies. The thermal index (TI) describes the risk of increasing the temperature of the tissue being sonicated by ultrasound. A solution to decreasing TI involves the reduction of the time that the sonicating transducer is focused on the targeted area. [ 37 ]  The spatial-peak temporal-peak (SPTP) power refers to the highest intensity output of the ultrasound beam during implementation. The spatial-peak pulse-average (SPPA) power is a measure of the maximum intensity output averaged over the duration of ultrasound use in. The spatial-peak temporal-average power describes the measure of the highest intensity output generated by the repeating pulse of the ultrasound beam over a period of time."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9189", "text": "Due to the sonication capability of ultrasound and drug-release property of smart hydrogels, there has been scientific interest in controlling the release of the payload from hydrogels. [ 10 ]  Focusing and directing acoustic energy (that can convert to thermal or mechanical energy [ 36 ] [ 40 ] ) towards smart hydrogels, implanted within tissue at times, induces a hydrogel response that results in the release of the embedded payload. Although hydrogels that are sensitive to mechanical pressure are generally used in ultrasound-triggered drug delivery platforms, hydrogels that respond to changes in temperature have also been used for these systems. [ 10 ]  \u00a0For example, Makhmalzadeh et al. proposed an ultrasound-triggered drug delivery method involving the use of thermo-responsive hydrogels loaded with  silibinin , a cancer drug for treating melanoma. [ 16 ] [ 41 ]  At low temperatures, these thermo-responsive hydrogels exist in liquid form but following ultrasonication, they transition into a gel state. [ 16 ] [ 25 ]  Although ultrasound- and thermo-sensitive hydrogels are responsive to certain ultrasound modalities, they differ in how they respond to external stimuli. Ultrasound-responsive hydrogels are capable of being stimulated by more than one type of stimulation force through ultrasound. [ 42 ]  Conversely, thermo-responsive hydrogels, as the name specifies, can only respond to the thermal forces induced by ultrasound. [ 13 ]  Despite this, thermo-responsive hydrogels have been widely used in cancer-based drug delivery systems. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9190", "text": "Of the existing ultrasound modalities, focused ultrasound has been used extensively in drug delivery research. [ 33 ] [ 34 ]  High-Intensity Focused Ultrasound (HIFU) and Low-Intensity Focused Ultrasound are the two main techniques used in inducing drug release from smart hydrogels. [ 43 ]  Current HIFU applications are used for ablating tumors located at increased depths. [ 44 ]  Since HIFU is able to invoke high temperatures, they have been used for cancer therapy by stimulating drug release from smart hydrogels via thermolysis mechanisms. [ 45 ]  In regard to the use of ultrasound- and thermo-responsive hydrogels for drug delivery, HIFU is able to stimulate both types of hydrogels. [ 45 ]  In one study related to cancer therapy, HIFU exhibited high efficiency inducing nanovaccine release from hydrogel-based carriers. [ 46 ]  Although HIFU has been studied in various capacities, this technique can cause irreparable damage to healthy tissue. [ 31 ]  Therefore, LIFU has been the conventional method for use in hydrogel responsive drug delivery platforms. In other areas of the biomedical field, LIFU has been used for stimulation such as bone regeneration in  tissue engineering  applications. [ 47 ] [ 48 ]  Due to its lower generated acoustic power output, LIFU is preferred over HIFU in biomedical applications involving neuromodulation [ 49 ]  and other brain-related procedures. [ 50 ]  Studies have shown that LIFU has proven to be a cost-effective and non-invasive method for hydrogel-based drug delivery. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9191", "text": "The underlying drug-releasing mechanism induced by focused ultrasound onto ultrasound-sensitive hydrogels is based on mechanical or thermal effects. [ 19 ] [ 31 ] [ 45 ]  Mechanical-based ultrasound sonication mechanisms refer to the conversion of acoustic energy into mechanical energy with various types that include acoustic cavitation force, [ 31 ] [ 45 ]  or oscillation force. [ 36 ]  Generally, applying mechanical pressure to a responsive hydrogel loaded with drugs causes the hydrogel to deform. This deformation reduces the structural integrity of the hydrophobic core, allowing for the release of the drug payload. [ 43 ]  Both ultrasound- and thermo- responsive hydrogels are capable of carrying various embedded carriers of drug payloads which include metal-organic framework, [ 52 ]  nanoparticles, [ 23 ] [ 28 ]  and liposomes. [ 53 ]  Although many studies have demonstrated the irreversible compression of hydrogels induced under ultrasound, Goncalves et al. designed hydrogel-based nanoparticles that were capable of \u201cself-healing\u201d, meaning they were able to return to their original form following drug release from its depot. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9192", "text": "Acoustic cavitation forces, specifically, have been used in conjunction with ultrasound-responsive hydrogels for drug delivery. This type of mechanical force refers to the formation, growth, and destruction of bubble occurs that results in the generation of acoustic energy. There are varying degrees of cavitation which divided into three groups:  sonoporation , [ 15 ]  stable cavitation, [ 3 ] [ 15 ] [ 36 ]  and inertial cavitation. [ 19 ] [ 36 ]  Sonoporation refers to the process of using ultrasound to open pores (or permeability) of cellular membranes to allow substances of interest to enter into the targeted cell. In cases where  microbubbles  are coated with hydrogels, these embedded carrier systems undergo stable cavitation and inertial cavitation. [ 36 ]  Stable cavitation characterizes vapor bubbles that oscillate within its own equilibrium, while inertial cavitation describes bubbles that generate a net growth each time the bubble expands and results in the bubble collapsing violently. Severe cavitation increases the risk of damage to tissue and drug degradation. [ 3 ] [ 7 ]  Other forces generated by ultrasound that is used in several hydrogel-based platforms are hyperthermia [ 36 ] [ 45 ]  and radiation. [ 36 ]  These forces are generally created by HIFU as they generate high levels of heat. Thus, guidelines established by the FDA help ensure the safe use of ultrasound in all biomedical applications, inclusive of drug delivery systems, based on the scientific understanding of these mechanical forces."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9193", "text": "In regard to tissues, ultrasound is generally used for imaging and monitoring tissue pathologies. [ 34 ]  Due to its ability to penetrate through tissue easily, [ 25 ]  ultrasound has been widely studied and developed for drug delivery applications in the field of tissue engineering. In order for hydrogels to release drugs at the targeted location, they must be injected or implanted within the tissue. Injection of hydrogels is usually preferred over implantation due to its minimal invasiveness, [ 2 ] [ 6 ] [ 25 ]  reduced healing time following the procedure, [ 47 ]  and biocompatibility. [ 54 ]  In one study, Liu et al. proposed a novel design of injectable  chemotaxis  hydrogels to help promote the migration of bone marrow mesenchymal cells for cartilage repair. [ 55 ]  Other examples of using smart hydrogels and ultrasound in tissue engineering applications include cartilage repair, [ 55 ]  bone repair, [ 47 ] [ 56 ]  and wound healing. [ 3 ]  The design of these drug delivery platforms is specific to each tissue type and its intended use. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9194", "text": "In the field of  cancer , ultrasound is commonly used for helping health care professionals detect and develop a diagnosis in affected patients. [ 34 ]  In the context of drug delivery, ultrasound has been used for a wide variety of therapeutic applications which include but are not limited to melanoma, [ 16 ]  ovarian cancer, [ 7 ] [ 16 ]  and breast cancer. [ 16 ] [ 21 ]  Hydrogels are generally used in designing these drug delivery platforms due to minimal invasiveness (if injected) and its ability to carry a different cancer drugs. These hydrogel-based systems are also paired with chemotherapy treatments. [ 45 ]  Cancer drugs used in this drug delivery platforms include  doxorubicin , [ 6 ] [ 21 ] [ 40 ]   mitoxantrone , [ 22 ]   paclitaxel , [ 16 ] [ 57 ]  silibinin, [ 16 ] [ 57 ]  and  cisplatin . [ 16 ] [ 57 ]  In a cancer therapy study, Baghbani et al. proposed a method of pairing ultrasound with doxorubicin-loaded alginate-stabilized perfluorohexane (PFH) nanodroplets. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9195", "text": "Although it is generally used in combination with cancer therapeutic treatments, [ 16 ]  gene therapy has become a topic of interest in the drug delivery field. Gene therapy refers to the insertion of genes into a biological system in an attempt to add or modify mutated genes for therapeutic benefit. In order to attain high  transgene  expression, the  electrostatic  interaction between the gene and hydrogel polymer and the controlled release of the drug payload from the hydrogel is necessary. [ 36 ]  Several gene therapy drugs used in hydrogel-based drug delivery systems include CRISPR/Cas9, [ 58 ]   siRNA , [ 40 ] [ 59 ]  and other RNA-based drugs. [ 59 ]  In a gene therapy study, Han et al. proposed a focused ultrasound-responsive hydrogel-based system for delivering siRNA nanoparticles to the targeted tumor site [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9196", "text": "The main challenge for future ultrasound-triggered hydrogel responsive delivery systems is to develop safer guidelines for using HIFU to take advantage of its benefits. In doing so, this will lead to improvements on FDA guidelines for ultrasound use. Therefore, the use of LIFU or lower acoustic energy intensity settings is suggested as the conventional method for decreasing injury risk, specifically damage to healthy tissue, until then. [ 34 ]  Focused ultrasound continues to be the primary type of ultrasound technique used in drug delivery systems. Another challenge presented in using ultrasound for inducing drug release from smart hydrogels in delivery platforms is inappropriate drug administration and unexpected complications. [ 31 ]  Currently, on-demand drug release from ultrasound-responsive hydrogels is still difficult to fully control when only using ultrasound. Yeingst et al. suggested that future hydrogel-based delivery platforms will be designed based on the drug payload to optimize the interaction between the ultrasound and stimuli-responsive hydrogel. [ 34 ]  Future development of drug delivery systems will continue to incorporate ultrasound and smart hydrogel designs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9197", "text": "Uniject  is a disposable, pre-filled, single-use  syringe  which was developed to promote vaccination in developing countries. It was developed by  PATH  as part of the solution to the problem of delivering vaccines to areas which have insufficient medical workers to meet the needs of traditional, doctor-mediated vaccination programs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9198", "text": "The Uniject was invented by PATH in 1987. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9199", "text": "In 2003 PATH accepted a  Tech Award  from  The Tech Museum of Innovation  for its development of the Uniject. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9200", "text": "To activate the device, the user would first shake the device to homogenize the liquid suspension. Then, the  tamper-evident  seal would be twisted. After that, with \"a firm, rapid motion\" the needle shield would be pushed into the port until the \"gap between the needle shield and port closes completely\". [ 3 ]  To actually use the device, the needle shield needs to be removed, exposing the needle. The user would then push the needle into the skin. Almost simultaneously, the reservoir would be pushed down in a similar motion to opening a  blister pack  or using a syrette, dispensing the medication through the needle into the skin. [ original research ]  The device, once used, should be considered  sharps waste ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9201", "text": "The introduction of the Uniject has been called \"the greatest single leap forward in the battle against tetanus\" [ 4 ]  because it has allowed tetanus vaccines to be used in places which were previously inaccessible to health programs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9202", "text": "A  unilamellar liposome  is a spherical  liposome , a  vesicle , bounded by a single bilayer of an  amphiphilic   lipid  or a mixture of such lipids, containing aqueous solution inside the chamber. Unilamellar liposomes are used to study biological systems and to mimic cell membranes, and are classified into three groups based on their size: small unilamellar liposomes/vesicles (SUVs) that with a size range of 20\u2013100\u00a0nm, large unilamellar liposomes/vesicles (LUVs) with a size range of 100\u20131000\u00a0nm and giant unilamellar liposomes/vesicles (GUVs) with a size range of 1\u2013200\u00a0\u03bcm. [ 1 ]  GUVs are mostly used as models for biological membranes in research work. [ 2 ]  Animal cells are 10\u201330\u00a0\u03bcm and plant cells are typically 10\u2013100\u00a0\u03bcm. Even smaller cell organelles such as mitochondria are typically 1\u20132\u00a0\u03bcm. Therefore, a proper model should account for the size of the specimen being studied. [ 1 ]  In addition, the size of vesicles dictates their  membrane curvature  which is an important factor in studying fusion proteins. SUVs have a higher membrane curvature and vesicles with high membrane curvature can promote membrane fusion faster than vesicles with lower membrane curvature such as GUVs. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9203", "text": "The composition and characteristics of the cell membrane varies in different cells (plant cells, mammalian cells, bacterial cells, etc). In a membrane  bilayer , often the composition of the phospholipids is different between the inner and outer leaflets. Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and sphingomyelin are some of the most common lipids most animal cell membranes. These lipids are widely different in charge, length, and saturation state. The presence of unsaturated bonds (double bonds) in lipids for example, creates a kink in acyl chains which further changes the lipid packing and results in a looser packing. [ 4 ] [ 5 ]  Therefore, the composition and sizes of the unilamellar liposomes must be chosen carefully based on the subject of the study."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9204", "text": "Each  lipid bilayer  structure is comparable to  lamellar phase  lipid organization in  biological membranes , in general. In contrast,  multilamellar liposomes  (MLVs), consist of many concentric amphiphilic lipid bilayers analogous to onion layers, and MLVs may be of variable sizes up to several micrometers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9205", "text": "There are several methods to prepare unilamellar liposomes and the protocols differ based on the type of desired unilamellar vesicles. Different lipids can be bought either dissolved in  chloroform  or as  lyophilized  lipids. In the case of lyophilized lipids, they can be solubilized in chloroform. Lipids are then mixed with a desired molar ratio. Then chloroform is evaporated using a gentle stream of nitrogen (to avoid oxygen contact and oxidation of lipids) at room temperature. A  rotary evaporator  can be used to form a homogeneous layer of liposomes. This step removes the bulk of chloroform. To remove the residues of trapped chloroform, lipids are placed under vacuum from several hours to overnight. Next step is re-hydration where the dried lipids are re-suspended in the desired buffer. Lipids can be vortexed for several minutes to insure that all the lipid residues get re-suspended. SUVs can be obtained in via two methods. Either by  sonication  (for instance with 1 second pulses in 3\u00a0Hz cycles at a power of 150 W) or by extrusion. In extrusion method, the lipid mixture is passed through a membrane for 10  or more times. [ 6 ] [ 7 ]  Depending on the size of the membrane, either SUVs or LUVs can be obtained. Keeping vesicles under argon and away from oxygen and light can extend their lifetime."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9206", "text": "Natural swelling: in this method soluble lipids in chloroform are pipetted on a Teflon ring. The chloroform is allowed to evaporate and the ring is then placed under the vacuum for several hours. Next the aqueous buffer is added gently over the Teflon ring and lipids are allowed to naturally swell to form GUVs overnight. the disadvantage of this method is that a large amount of multilamellar vesicles and lipid debris are formed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9207", "text": "Electroformation: In this method lipids are placed on a conductive cover glass (indium tin oxide or ITO coated glass) or on Pt wires instead of a Teflon ring and after vacuuming, buffer is placed on the dried lipids and it is sandwiched using a second conductive cover glass. Next an electrical field with certain frequency and voltage is applied which promotes formation of GUVs. For polyunsaturated lipids, this technique can induce a significant oxidation effect on the vesicles. [ 8 ]  Nevertheless, it is a very common and reliable technique to generate GUVs. Modified approaches exist that employ gel-assisted swelling (agarose-assisted swelling or PVA-assisted swelling) for the formation of GUVs under more biologically relevant conditions. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9208", "text": "A variety of methods exist to encapsulate biological reactants within GUVs by using water-oil interfaces as a scaffold to assemble lipid layers. This allows the use GUVs as cell-like membrane containers for the in vitro recreation (and investigation) of biological functions. [ 10 ]  These encapsulation methods include microfluidic methods, which allow for a high-yield production of vesicles with consistent sizes. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9209", "text": "Phospholipid   liposomes  are used as targeted  drug delivery  systems. [ 12 ]   Hydrophilic  drugs can be carried as solution inside the SUVs or MLVs and  hydrophobic  drugs can be incorporated into  lipid bilayer  of these liposomes. If injected into circulation of human/animal body, MLVs are preferentially taken up  phagocytic cells , and thus drugs can be targeted to these cells. For general or overall delivery, SUVs may be used. For topical applications on skin, specialized lipids like phospholipids and   sphingolipids  may be used to make drug-free liposomes as moisturizers, and with drugs such as  for anti-ultraviolet radiation applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9210", "text": "In biomedical research, unilamellar liposomes are extremely useful to study biological systems and mimicking cell functions. [ 1 ] [ 10 ]  As a living cell is very complicated to study, unilamellar liposomes provide a simple tool to study membrane interaction events such as  membrane fusion , protein localization in the plasma membrane, study ion channels, etc."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9211", "text": "Vaginal rings  (also known as  intravaginal rings , or  V-Rings ) are polymeric  drug delivery  devices designed to provide controlled release of drugs for  intravaginal administration  over extended periods of time.  The ring is inserted into the  vagina  and provides contraception protection. Vaginal rings come in one size that fits most people."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9212", "text": "Several vaginal ring products are currently available, including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9213", "text": "A number of other vaginal ring products are also in development."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9214", "text": "The combined hormonal contraceptive vaginal ring is self-administered once a month. Leaving the ring in for three weeks slowly releases hormones into the body, mainly  vaginally administered estrogens  and/or  progestogens  (a group of hormones including  progesterone ) - the same hormones used in birth control pills. [ 4 ]  These hormones work mostly by stopping ovulation and thickening the cervical mucus, creating a barrier preventing sperm from fertilizing an egg. [ 4 ]  They could theoretically affect implantation but no evidence shows that they do. [ 5 ]  Worn continuously for three weeks followed by a week off, each vaginal ring provides anywhere from one month (NuvaRing) to one year (Annovera and Progering) of birth control. For continuous-use contraception, users can also choose to wear the vaginal ring for the full four week cycle. This manner of contraception will eliminate monthly periods. [ 6 ]  Throughout the additional week, the serum hormone levels will remain in the contraceptive range. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9215", "text": "When compared with combined hormonal pills, the combined hormonal vaginal ring offers potentially better cycle control and treatment of  heavy menstrual bleeding . [ 8 ]  However, both methods are effective short-term treatments in the reproductive age group. Vaginal rings may lead to increased normal vaginal secretions, decreased body weight, reduced symptoms of  PMS , and occasionally cases of  vaginitis , device-related problems and  leukorrhea . [ 4 ] [ 7 ] [ 8 ]  Because they release estrogen, vaginal rings have an increased risk of heart attack, stroke, and other serious side effects. [ 6 ]  Additionally, certain medicines and supplements, such as the antibiotic  rifampin , the anti-fungal  griseofulvin , anti-seizure medicines,  St. John's wort , and  HIV  medicines, may compromise the effectiveness of vaginal rings. [ 6 ]  Vaginal rings do not protect users from  sexually transmitted diseases . The only contraceptive measures that does so are latex or polyurethane  condoms . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9216", "text": "The  contraceptive vaginal ring  has a failure rate of 0.3% when used as prescribed and 9% when used typically. [ 7 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9217", "text": "The correlation between breast cancer and the use of vaginal rings is under investigation, but recent literature suggests that the hormones used in vaginal rings has little, if any, relation to the risk of developing breast cancer. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9218", "text": "Vaginal rings are easily inserted and removed. [ 10 ]  Vaginal walls hold them in place. Although their exact location within the vagina is not critical for clinical efficacy, rings commonly reside next to the  cervix , and the deeper the placement in the vagina, the less likely the ring will be felt. [ 6 ] [ 7 ]  Rings are typically left in place during intercourse, and most couples report no interference or discomfort. In many cases, neither partner feels the presence of the ring. [ 11 ]  Rings can be removed prior to intercourse, but, in the case of the contraceptive NuvaRing, only for one to three hours to maintain efficacy of birth control. If the ring is out for more than 48 hours, back up contraception is necessary for seven days. [ 6 ]  It typically takes between one and two months for a user's cycle to return to normal after the use of a vaginal ring is stopped. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9219", "text": "A  vaporizer  or  vaporiser , colloquially known as a  vape , is a device used to vaporize substances for  inhalation . Plant substances can be used, commonly  cannabis ,  tobacco , or other herbs or blends of  essential oil . [ 1 ]  However, they are most commonly filled with a combination  propylene glycol ,  glycerin , and drugs such as  nicotine  (e.g. extract from tobacco) or  tetrahydrocannabinol  as a liquid solution. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9220", "text": "Vaporizers contain various forms of extraction chambers including straight bore,  venturi , or sequential venturi, and are made of materials such as metal or glass. The extracted vapor may be collected in an inflatable bag, or inhaled directly through a hose or pipe. When used properly, cooler temperatures due to lack of combustion [ 3 ]  result in significantly more efficient extraction of the ingredients. Hence, the irritating and harmful effects of smoking are heavily reduced, [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ]  as is its  secondhand smoke ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9221", "text": "Cannabis flower is commonly consumed using a dry herb vaporizer. The cannabis may be heated in a chamber via indirect flame exposure or an electrical heating element, allowing users to inhale the resulting vapor. The temperatures reached are cooler than the combustion temperature of cannabis, which is around 230\u2013315\u00a0\u00b0C (445\u2013600\u00a0\u00b0F). [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9222", "text": "Vaporizing is more efficient than  smoking , because approximately 30% of  THC  in cannabis or hashish cigarettes is destroyed by  pyrolysis  during smoking. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9223", "text": "Cannabis is also consumed via the vaporization of  cannabis concentrates  or oils that have been extracted from the plant, commonly referred to as \"dabbing\". Users typically employ a torch to heat a small cup shaped quartz or titanium attachment on a bong before dabbing the oil onto the heated surface and inhaling the vapors through the bong. [ 11 ]  This route of consumption is generally much more potent than smoking or vaporizing marijuana flower due to the increased concentration of cannabinoids. Users typically report that the effects of dabbing are much more intense than regular cannabis, while also being shorter lived. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9224", "text": "Cannabis concentrate is also commonly used in e-cigarette style vaporizer pens in the form of liquid containers known as cartridges. A  battery  connected to the  atomizer  is used to heat the cannabis oil, creating a vapor that is inhaled by the user. Cartridges typically contain different preparations of cannabis oil mixed with  cannabinoids ,  terpenes ,  solvents  (primarily  Propylene glycol  and  Glycerol ) used for thinning,  fatty acids , and  flavonoids . Natural or artificial terpenes are frequently added by manufacturers to enhance flavor, often using blends that mimic popular  cannabis strains  or sugary foods such as candy or  pastries . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9225", "text": "Of the studies that have investigated cannabis vaporization, few have addressed the quality of the vapor extracted and delivered; instead, studies usually focus on the mode of usage of the vaporizers. However, those that have addressed vapor quality have demonstrated promising results. Such studies suggest that the absence of combustion results in an aerosol that contains significantly lower amounts of harmful substances found in smoke, such as  tar ,  carbon monoxide , and carcinogenic compounds known as  polynuclear aromatic hydrocarbons  (PAH). [ 14 ] [ 9 ] [ 15 ]  One study found that cannabis smoke contains 111 compounds (including several carcinogenic PAHs) in addition to the cannabinoids, whereas only 3 additional compounds were identified in cannabis vapor, other than the cannabinoids. [ 9 ]  This suggests that the vaporization of cannabis may be a safer alternative to combusted cannabis. [ 16 ]  On the other hand, a study in the UK (where cannabis is illegal) found that some illicitly distributed cannabis vaporizers contained harmful levels of  xylazine , an animal  sedative  which can lead to overdose. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9226", "text": "An electronic cigarette is a handheld  battery -powered vaporizer that simulates  smoking  by providing some of the behavioral aspects of smoking, including the hand-to-mouth action of smoking, but without  combusting  tobacco. [ 18 ]  Using an e-cigarette is known as \"vaping\" and the user is referred to as a \"vaper.\" [ 19 ]  Instead of  cigarette smoke , the user inhales an  aerosol , commonly called  vapor . [ 20 ]  E-cigarettes typically have a  heating element  that atomizes a  liquid solution  called  e-liquid . [ 21 ]  E-cigarettes may be automatically activated by taking a puff; [ 22 ]  others turn on manually by pressing a button. [ 19 ]  Some e-cigarettes look like  traditional cigarettes , [ 23 ]  but they come in many variations. [ 19 ]  Most versions are reusable, though some are disposable. [ 24 ]  There are first-generation, [ 25 ]  second-generation, [ 26 ]  third-generation, [ 27 ]  and fourth-generation devices. [ 28 ]  E-liquids usually contain  propylene glycol ,  glycerin ,  nicotine ,  flavorings , additives, and differing amounts of contaminants. [ 29 ]   E-liquids are also sold without propylene glycol, [ 30 ]  nicotine, [ 31 ]  or flavors.  [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9227", "text": "The benefits and the  health risks of e-cigarettes  are uncertain. [ 33 ] [ 34 ] [ 35 ]  There is tentative evidence they may help people quit smoking, [ 36 ]  although they have not been proven to be more effective than  smoking cessation  medicine. [ 37 ]  There is concern with the possibility that non-smokers and children may start nicotine use with e-cigarettes at a rate higher than anticipated than if they were never created. [ 38 ]  Following the possibility of  nicotine addiction  from e-cigarette use, there is concern children may start smoking cigarettes. [ 38 ]  Youth who use e-cigarettes are more likely to go on to smoke cigarettes. [ 39 ] [ 40 ]  Their part in  tobacco harm reduction  is unclear, [ 41 ]  while another review found they appear to have the potential to lower tobacco-related death and disease. [ 42 ]  Regulated US  Food and Drug Administration   nicotine replacement products  may be safer than e-cigarettes, [ 41 ]  but e-cigarettes are generally seen as safer than combusted  tobacco products . [ 43 ] [ 44 ]  It is estimated their safety risk to users is similar to that of  smokeless tobacco . [ 45 ]  The long-term effects of e-cigarette use are unknown. [ 46 ] [ 47 ] [ 48 ]  The risk from  serious adverse events  was reported in 2016 to be low. [ 49 ]  Less serious  adverse effects  include abdominal pain, headache, blurry vision, [ 50 ]  throat and mouth irritation, vomiting, nausea, and coughing. [ 51 ]  Nicotine itself is associated with some health harms. [ 52 ] \nIn 2019 and 2020, an  outbreak of severe lung illness throughout the US has been linked to the use of contaminated black market THC vape cartridges . [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9228", "text": "Vaporizers can be used to inhale other recreational drugs as well. A wide variety can be consumed this way, either dissolved in e-liquid or vaporized directly. [ 54 ]  The use of e-cigarettes to inhale the  psychedelic drug   DMT  has been reported. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9229", "text": "Studies have shown that vaporizing cannabis exposes the user to lower levels of harmful substances than smoking cannabis. [ 9 ] [ 56 ] [ 57 ] [ 58 ]  These findings are important for it is estimated that 10\u201320% of patients with  chronic pain ,  multiple sclerosis ,  epilepsy , and  HIV / AIDS  have admitted to smoking cannabis for therapeutic purposes.  For patients, a study found that smoking cannabis sativa reduced daily pain by 34%, a statistically significant amount. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9230", "text": "In a study published in the  Journal of Psychopharmacology  in May 2008, it was stated that vaporizers were a \"suitable method for the administration of THC\". [ 60 ]  A 2007 study by the  University of California, San Francisco , published in the  Journal of the American Academy of Neurology , found that \"there was virtually no exposure to harmful combustion products using the vaporizing device\". [ 7 ]  A 2006 study performed by researchers at  Leiden University  found that vaporizers were \"safe and effective  cannabinoid  delivery system(s)\". The study stated that the amount of THC delivered by vaporizers were equivalent to the amount delivered by smoking. [ 58 ]  Because of those studies and other studies, vaporizers are considered medically sound devices for delivering THC. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9231", "text": "The proposed factors affecting output include: [ 9 ] [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9232", "text": "Not all those have been scientifically tested. Research using vaporizers found the delivery efficiency highest at around 226\u00a0\u00b0C (439\u00a0\u00b0F), falling to about half efficiency at 150 to 180\u00a0\u00b0C (302 to 356\u00a0\u00b0F) depending on material. [ 58 ]  The purest preparations produced the highest efficiencies, about 56% for pure THC versus 29% for plant material (female flower tops) with 12%  THCA  content. Besides THC, several other cannabinoids as well as a range of other plant components including terpenoids were detected in the plant material. Using pure THC in the vaporizer, no degradation products (delta-8-THC (D8-THC), cannabinol (CBN), or unknown compounds) were detected by  HPLC  analysis. [ 58 ]  The longer vapor is stored, the more THC is lost as it condenses on the surface of the vaporizer or the balloon. This loss may be negligible over a few minutes but may exceed 50% after 90 minutes. [ 58 ]  The Leiden University study found that as much as 30\u201340% of inhaled THC was not absorbed by the lungs but simply exhaled. However, they did not find large individual differences in the amounts exhaled. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9233", "text": "Vaporizers are sometimes used by chefs as a method of applying controlled heat to herbs and spices to release flavors that are otherwise difficult to titrate or apply, or that might be spoiled by overheating during cooking. [ 61 ] [ 62 ] [ 63 ]  Grant Achatz, chef-proprietor of  Alinea  in Chicago, \"uses the aroma-filled bags as place-mats, punctured when plates are placed in front of the customer\". [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9234", "text": "A  vesosome  is a multi-compartmental structure of  lipidic  nature used to deliver  drugs . They can be considered  multivesicular vesicles  ( MVV ) [ 1 ] [ 2 ] [ 3 ] [ 4 ]  and are, therefore,  liposome -derived structures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9235", "text": "Vesosomes consist of one or more  bilayers  enclosing an aqueous core that contains  unilamellar   vesicles  that function as internal compartments which contain the drug and which can vary in composition from each other.\nThe external bilayer defines the  lumen , limits emission of the vesicle contents, and protects the vesicle contents from degradation due to  lipolytic   enzymes .\nIts unique properties enable localized  drug delivery  to specific parts of the body and extend the duration of drug effect. Vesosomes are relatively straightforward to produce and they offer the flexibility to deliver multiple drugs within a single carrier, which has been shown to confer important advantages in  chemotherapy .\nInternal vesicle  diameters  range from 20-500\u00a0nm and vesosome diameters range from about 0.1  micron  to more than 1.0 micron. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9236", "text": "Shortly after the first description of  liposomes , by British haematologist  Alec D Bangham  in 1961 (published 1964), at the  Babraham Institute , in Cambridge, scientists first started to contemplate the possibility of employing them as transportation systems in the  blood  stream. Since then, there have been many advances in this area, and as of 2008 there were 11 clinically approved liposomal drugs targeting a variety of pathological conditions and illnesses, including  fungal infections ,  hepatitis A ,  influenza  and certain  cancers . Now, scientists plan to take full advantage of the 40 years of progress in liposome development to enhance this transportation system by employing vesosomes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9237", "text": "Vesosome multicompartment structure encapsulates unilamellar liposomes within a second bilayer. For this purpose, it is necessary to form bilayers that can be opened and closed at will, without disrupting the inner content. This is achieved by adding  ethanol  to a variety of  saturated   phospholipids  in the gel phase, which drives interdigitation of phospholipids bilayers and subsequent fusion of small  vesicles  to form flat bilayer sheets. These are steady to removal of the residual ethanol until heated above the  lipid  chain  melting temperature  (T m ). The bilayers become flexible, and the sheets spontaneously close on themselves to form unilamellar vesicles. During the closure, the sheets can entrap whatever is around in suspension. By adding the vesicles aggregates including drug-loaded vesicles to the pelleted sheets before heating the mixture, encapsulation is carried out to form vesosomes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9238", "text": "Vesosome structure has taken advantage of the progress in liposome development as  steric stabilization ,  pH  loading of drugs (it is loaded by pH gradient), and intrinsic biocompatibility (it can be modified with a variety of agents, for example to specifically target a disease site, or promote adhesion or fusion)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9239", "text": "A wide of molecular structures can be encapsulated in vesosomal vesicles, such as proteins with complex three-dimensional structures or condensed  DNA . The most common use is to fill the vesosome\u2019s vesicles with certain  drugs  that are going to be delivered in a particular area.\nDue to the small size of the vesosome and its good protection of the inner vesicles, it can be used in various cases, doing different functions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9240", "text": "If suitable receptors are included in the outer lipid bilayer of vesosomes during their preparation, then they are able to locate to inflamed areas. Once in the inflamed area, such vesosomes will deliver an  anti-inflammatory  substance from its vesicles though a  pH  gradient. Vesosomes that localise to  tumours  have also been demonstrated.\nThey can be used to create, in a positioned area, a different nano- environment  (considering that vesosome size is about 50 - 200 nanometres) either by altering the pH or the concentration of a particular substance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9241", "text": "Zydis  is a technology used to manufacture  orally disintegrating tablets  developed by  R.P. Scherer Corporation . Zydis tablets dissolve in the mouth within 3  seconds . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9242", "text": "Zydis technology was developed by  R.P. Scherer Corporation  (currently owned by  Catalent Pharma Solutions ) in 1986. [ 2 ]  The technology's first commercial application was in August, 1993, when a new dosage form of Pepcidine ( famotidine ) from  Merck & Co.  was launched in  Sweden . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9243", "text": "In November 1993 Imodium Lingual ( loperamide ) from  Janssen Pharmaceutica  was released in  Germany  with Zydis technology. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9244", "text": "In December, 1996, the  Food and Drug Administration  approved Claritin ( loratadine ) RediTabs from  Schering-Plough , the first prescription drug with Zydis technology sold in the U.S. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9245", "text": "A Zydis tablet is produced by lyophilizing or  freeze-drying  the \ndrug in a matrix usually consisting of  gelatin . The resulting product is very lightweight and fragile, and must be dispensed in a special blister pack."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9246", "text": "Amipara et al., in their article \"Oral disintirating tablet of antihypertensive drug\" explain the technology's limitations:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9247", "text": "The Zydis formulations consist of a drug physically trapped in a water-soluble matrix (saccharine mixture and polymer), which is freeze dried to produce a product that dissolves rapidly when placed in mouth. The ideal candidate for Zydis technology should be chemically stable and insoluble and particle size preferably less than 50  micron ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9248", "text": "Water soluble drugs might form  eutectic mixtures  and not freeze adequately, so dose is limited to 60 mg and the maximum drug limit is 400 mg for water insoluble drug as large particle sizes might present sedimentation problems during manufacture. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9249", "text": "Zydis tablets:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9250", "text": "Disadvantages include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9251", "text": "Data from \"Fast Disintegrating Drug Delivery Systems: A Review with Special Emphasis on Fast Disintegrating Tablets\" (2013). [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9252", "text": "Meir Bialer  (born January 30, 1948) is an Israeli pharmacologist who is a David H. Eisenberg Emeritus (active) Professor of Pharmacy at the School of Pharmacy, Faculty of Medicine, of The  Hebrew University of Jerusalem  in Israel."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9253", "text": "Bialer was born in  Petach Tikva , Israel, to a Jewish family. He completed his service in the  Israeli Army  in 1971-73. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9254", "text": "He received his  B.Sc.  Pharm in Pharmacy in 1969, his  M.Sc.  in  Medicinal Chemistry  from  The Hebrew University of Jerusalem  in 1971, his  MBA  in 1976 and his  PhD  in Medicinal Chemistry from the same university in 1977, with a dissertation on \"Antiviral Structure-Activity Relationship of Distamycin and its Derivatives.\" [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9255", "text": "After post-doctoral studies at the  University of Florida  (1977\u201379) and  University of Kentucky  (1979\u201380), he became a Lecturer (1980\u201384) and then Senior Lecturer (1984\u201388) and then Associate Professor (1988\u201393) at the School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem. In 1993 he became a Full Professor at the School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem. Currently, he is serving as a David H. Eisenberg Emeritus (active) Professor at the School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9256", "text": "Bialer was president of the Israel League Against  Epilepsy , a branch of the  International League Against Epilepsy  (ILAE), from 1996 to 2001, and as the chair of ILAE-Europe from 2009 to 2017. [ 2 ]  He also served as president of Israel Society of Clinical Pharmacy and Biopharmaceutics (ISCPB), a member of the European Society of Pharmaceutical Sciences (EUFEPS) (1991\u20132001)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9257", "text": "Bialer\u2019s research interests include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9258", "text": "In these areas, he has 264 peer-reviewed publications, and is an author of 16 book chapters. Since 1981 he has supervised 22 MSc students and 31 PhD students."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9259", "text": "Meir married Shoshana Novak in 1970. They have two children Michal Bialer-Mor Yosef and Oded Bialer, as well as five grandchildren: Adi, Omri and Roni Bialer and Adam and Eitan Mor Yosef."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9260", "text": "G\u00ebzim Bo\u00e7ari  (born 25 March 1949) is an  Albanian  professor of pharmacology and a politician."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9261", "text": "G\u00ebzim Bo\u00e7ari is head of the pharmacology sector of the medicine faculty at the  University of Tirana . [ 1 ]  He is one of the writers of medicine and pharmacology textbooks of Albanian universities. [ 2 ]  In the 2009 parliamentary elections for Albania he was the head candidate of the coalition of the Pole of Freedom ( Albanian :  Poli i Liris\u00eb ) in the district of  Vlor\u00eb ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9262", "text": "Oana Caruana Pulpan  (born 17 April 1978) is a Maltese  chess  player. [ 1 ] [ 2 ] [ 3 ]  She was awarded the  Woman FIDE Master  title in 2009. [ 4 ]  She is a member of the  Maltese Women's National Team . Her father introduced her to chess when she was very young and has been playing it since. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9263", "text": "She is sponsored by the company she works with,  Actavis . [ 5 ]  She is also a  pharmacologist . [ 6 ]  She teaches chess classes at St. Catherine's High School in  Pembroke, Malta . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9264", "text": "This biographical article related to chess is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9265", "text": "This biographical article relating to sports in Malta is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9266", "text": "Karel Chodounsk\u00fd  (Latinized as  Carolus Josephus Petrus Chodounsky ; 18 May 1843 \u2013 12 May 1931) was a Czech physician, pharmacologist and promoter of mountaineering. He was the founding professor at the institute of pharmacology at  Masaryk University . He is known as the author of the first Czech pharmacology textbook called  Farmakologie , printed in 1905. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9267", "text": "Chodounsk\u00fd was born in Stud\u00e9nka (today part of  Bakov nad Jizerou ) to estate administrator Petr and Julia n\u00e9e Svobodov\u00e1. He studied medicine at the  University of Prague  in 1868, also spending time in the natural history museum. He worked as an assistant in physiology under  Jan Evangelista Purkyn\u011b . He worked as a physician, practising privately until 1895 and in 1884 he became an assistant professor of  balneotherapy . He habilitated in pharmacology and toxicology in 1888 and became an associate professor in 1895. He headed the institute of pharmacology at Prague and received a doctorate in 1900 and became a full professor of pharmacology in 1902. Chodounsk\u00fd demonstrated by experiments that he conducted on himself that infectious colds had nothing to do with low temperatures. He wrote about this in his 1907 book  Erk\u00e4ltung und Erk\u00e4ltungskrankheiten . In 1919 he was involved in establishing pharmacology at the Masaryk University, Brno, and served there until 1923. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9268", "text": "Chodounsk\u00fd was a champion skater and took a keen interest in mountaineering. He was involved in the establishment of the Slovenian Alpine Society in Prague in 1897, serving as its president until 1914. He promoted the training of alpine guides, the opening of trails, and the publication of books on mountaineering. In 1901 he founded a society to support Slovenian students in Prague. He edited the Czech medical periodical  \u010casopis l\u00e9ka\u0159\u016f \u010desk\u00fdch  (1878\u20131888) and for his contributions he received a Knight's Cross of Emperor Franz Joseph. He was also awarded an honorary doctorate in 1929 by Masaryk University. [ 2 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9269", "text": "He died on 12 May 1931 in  Prague , aged 87. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9270", "text": "His daughter Marie Chodounsk\u00e1 (d. 1922) became an artist. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9271", "text": "Ferdinand Giese  ( Johann Emanuel Ferdinand Giese ; 13 January 1781 \u2013 22 May 1821) was a  Baltic German  pharmacologist. 1817\u20131818 he was the  rector of Tartu University . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9272", "text": "He graduated from  Erfurt University . 1804\u20131814 he worked at  Kharkiv University . Since 1814 he taught at  Tartu University . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9273", "text": "This  Estonian  academic-related biographical article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9274", "text": "Sabine Hadida  is a pharmacologist and senior vice president at Vertex Pharmaceuticals. She works at Vertex's cystic fibrosis research center in San Diego. She was awarded the  Breakthrough Prize in Life Sciences  in 2024."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9275", "text": "Hadida has a bachelor's degree, master's degree, and Ph.D. in pharmacy from the  University of Barcelona , Spain. [ 1 ]  She worked as a postdoctoral fellow at the  University of Pittsburgh  studying fluorous chemistry. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9276", "text": "At Vertex Pharmaceuticals, Hadida led the chemistry team to work on drug treatments for  cystic fibrosis  and pain. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9277", "text": "Hadida has garnered over 30 peer reviewed scientific articles and over 60 U.S. patents. [ 1 ]  She is the recipient of the 2022 Drug Hunter Award, 2019 Distinguished Scientist Award by the American Chemistry Society, San Diego Chapter, and the 2013 American Chemistry Society Heroes of Chemistry award. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9278", "text": "In September 2023, she received the 2024 Breakthrough Prize in Life Sciences alongside Paul Negulescu and Frederick Van Goor, for developing treatment for cystic fibrosis. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9279", "text": "James Alan Shayman  is an American  physician scientist ,  nephrologist , and  pharmacologist . He is Professor of Internal Medicine and Pharmacology and the Agnes C. And Frank D. McKay Professor at the  Medical School of the University of Michigan . [ 1 ]  He also serves as a staff nephrologist at the Ann Arbor Veterans Administration Medical Center. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9280", "text": "Shayman's research interests span the study of  lysosomal  biology and related disorders. His group is most known for the development of  small-molecule  inhibitors of  glycosphingolipid  synthesis and their use in lysosomal glycosphingolipid storage disorders. His team also discovered and characterized a novel lysosomal  phospholipase A2 , PLA2G15 and is investigating its role in  phospholipidosis . He has published over 160 articles. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9281", "text": "Shayman is a Fellow of the  American Heart Association  and  American Society of Nephrology  as well as a Life Fellow of  Clare Hall at the University of Cambridge . He has served as an Associate Editor for the  Journal of Clinical Investigation  and  Translational Research  and is serving in the same role for the  Journal of the American Society of Nephrology . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9282", "text": "Shayman obtained a Bachelor of Arts degree from  Cornell University  in 1976, and received an M.D. in 1980 from  Washington University in St. Louis . From July 1980 to June 1983, he served as a house officer in Medicine at  Barnes Hospital  in  St. Louis , Missouri. Beginning in 1983, he pursued a Postdoctoral Fellowship with a specialization in Nephrology and Pharmacology under the mentorship of Aubrey Morrison and  Oliver H. Lowry  at Washington University School of Medicine in St. Louis. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9283", "text": "Following his post-doctoral fellowship training, in 1985, Shayman began his academic career as an instructor in the Renal department of Washington University School of Medicine. He was recruited to the  University of Michigan  where from 1986 to 1992 he was appointed as assistant professor in the Department of Internal Medicine, Division of Nephrology. He subsequently was promoted to the positions of associate professor in 1992 and professor in 1997, respectively with a secondary appointment in Pharmacology. He has been serving as the Agnes C. and Frank D. McKay Professor. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9284", "text": "Shayman was the Associate Chair for Research Programs at the Department of Internal Medicine and Associate Vice President for Research in Health Sciences of the University of Michigan. [ 6 ]  In addition, he has been serving as a staff nephrologist Veterans Administration Medical Center in Michigan. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9285", "text": "Shayman's research is focused on lysosomal biology, the  pathophysiology  of traditional  lysosomal storage disorders , and the role of the lysosome in more prevalent diseases including  diabetes  mellitus and  polycystic kidney disease . A particular emphasis has been on the development of  drug therapeutics  for disorders of glycosphingolipid metabolism. This work has resulted in several patents including \"Amino ceramide-like compounds and therapeutic methods of use\" [ 7 ]  and \"Pyridine inhibitors of glucosylceramide synthase and therapeutic methods using the same.\" [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9286", "text": "An early collaboration with Norman Radin focused on substrate reduction as an alternative to enzyme replacement therapy for the treatment of lysosomal disorders such as Gaucher disease. It was suggested that substrate reduction posits that inhibition of metabolites that accumulate in the lysosome due to the loss of activity of a specific hydrolase can be treated with reversible inhibitors of specific anabolic enzymes. Following an early collaboration with Radin, the Shayman group went on to develop inhibitors of glucosylceramide synthase followed by proof of concept studies in models of Gaucher and Fabry disease that experimentally established the viability substrate reduction therapy. [ 9 ] [ 10 ]  Although this concept was initially met with skepticism from the academic and pharmaceutical communities, these compounds were eventually licensed to the Genzyme Corporation for clinical development in 2000. In 2014 eliglustat tartrate was approved by the Food and Drug Administration and the European Medicines Association. Eliglustat tartrate was the first orally bioavailable agent approved as the first stand-alone substrate reduction therapy for Gaucher disease type 1. [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9287", "text": "Shayman's work on developing the \"first in class\" glycosphingolipid synthesis inhibitor led to the consideration of whether more common disorders might be amenable to targeting glucosylceramide synthase. [ 13 ]  Based on fundamental studies by his group and others demonstrating a role for glucosylceramide metabolism in conditions associated with aerobic glycolysis, [ 14 ]  including diabetes [ 15 ]  and polycystic kidney disease, glucosylceramide synthase inhibitors have been the focus of preclinical and clinical studies evaluating the potential for extended use applications of eliglustat and related compounds. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9288", "text": "In collaboration with Scott D. Larsen, Shayman's work has also been directed toward the identification of brain-penetrant glycolipid synthesis inhibitors for the treatment of Gaucher disease types 2 and 3, [ 17 ]  GM2 gangliosidoses including Tay-Sachs and Sandhoff disease, and GM1 gangliosidosis. [ 18 ]  Using computational analysis comparing eliglustat to known CNS penetrant compounds, novel glucosylceramide synthase inhibitors were designed around the eliglustat pharmacophore, demonstrating the lower glucosylceramide and ganglioside levels within the brain. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9289", "text": "The Shayman group has worked on the elucidation of the mechanisms underlying the vasculopathy of Fabry disease. His initial work led to the identification of three inducible models of vascular disease in the alpha-galactosidase A knockout mouse. [ 20 ]  These models included oxidant-induced arterial thrombosis, accelerated atherogenesis, and impaired arterial relaxation. Both decreased nitric oxide bioavailability [ 21 ]  and endothelial nitric oxide synthase uncoupling have been demonstrated to underlie these abnormalities. The insights led to identifying 3-nitrotyrosine as a biomarker for endothelial dysfunction in both experimental models and patients affected by classic forms of Fabry disease. [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9290", "text": "Attempts to delineate potential off-target effects of eliglustat led to the discovery of a novel lysosomal hydrolase, phospholipase A2 group XV (PLA2GXV). This enzyme was initially identified as a transacylase and named 1-O-acylceramide synthase. [ 24 ]  PLA2GXV is 50 percent identical to LCAT. In collaboration with John Tesmer and colleagues, the structure of PLA2GXV and, by extension, of lecithin cholesterol acyltransferase (LCAT) were solved. Mice engineered to be deficient in PLA2GXV developed a pulmonary phenotype associated with the conversion of alveolar macrophages to foam cells, a phenotype that resembles amiodarone toxicity. [ 25 ]  A 2021 work has also identified PLA2GXV as the site of action for many drugs that cause a form of toxicity termed phospholipidosis. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9291", "text": "Hedwig Langecker  (29 January 1894 \u2013 31 January 1989) was a Bohemian, Czech, and German pharmacologist known for her discovery of the pharmacological properties of  Polygonatum officinale  and  Polygonatum multiflorum . She was also known for her studies of steroid hormone biochemistry and her prolific output, which included over 200 scientific articles and several textbooks. Her career began at the  German University in Prague , where she earned her M.D. in 1920 and a Ph.D. in 1923, and was  habilitated  in 1926; Langecker then became a professor and served in that role until 1945. That year, she moved to the  Free University of Berlin , where she was a professor until 1959 and an emerita professor until her death in 1989. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9292", "text": "This article about a German person in the field of medicine is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9293", "text": "Dr. Henry Isaac Clore Lowe   OJ   OD  (born April 9, 1939) is a Jamaican scientist, philanthropist and businessperson. His career began in academia where he worked at  College of Art, Science, and Technology  (CAST) for 16 years, before entering public life by joining the Ministry of Energy. He now owns and manages a variety of businesses in the health industry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9294", "text": "Henry Lowe was born on April 9, 1939, in St. Andrew, Jamaica. His family was \"far from being wealthy\" and were devout Catholics. His father David was a Cabinet Member and his mother Josephine was a part-time tailor and a homemaker. [ 1 ]  Lowe was the fourth of ten children. [ 2 ]  At four years old Lowe was enrolled at the Woods' infant school. Though it was located on Metcalfe Road, a neighborhood which was considered affluent at the time, his school hosted its classes in sheds behind a house.  Lowe attended primary school in  Port Maria  and later attended  Excelsior High School . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9295", "text": "Lowe was accepted into the  University of the West Indies  in 1959 with scholarship, [ 4 ]  where he graduated with a bachelor of Science and Honours degrees in natural science. Lowe obtained a Master's in Pharmaceutical and Medicinal chemistry from the  University of Sydney [ 5 ]  and his Ph.D. at  Manchester University . [ 6 ]  To both universities Lowe was awarded a  British commonwealth scholarship  becoming \"the first Jamaican, and maybe the only one ever, to be awarded two commonwealth Scholarships\". [ 7 ]  He pursued post-doctoral studies at the  Bolton Institute of Technology , the  Massachusetts Institute of Technology  and  Harvard University . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9296", "text": "The year after graduating from Excelsior high school Lowe was himself hired as a science teacher at Holmwood high school. [ 9 ]  After graduating from the University of the West Indies, he taught chemistry at Excelsior high school and was appointed the head of the Science Department for one year, after which he began lecturing at CAST on September 10, 1964. [ 10 ]  His time at this institution was interrupted intermittently by educational pursuits. Lowe returned to the College of Art Science and technology in 1970 and was made the head of the science department in 1973 \u2013 the first native Jamaican to have held this position. [ 11 ]  Lowe returned again where he was made vice principal of academic affairs. [ 12 ]  Being persuaded by Jamaica's then Ambassador to the U.S., Douglas Fletcher, Lowe left his position at CAST to join the Ministry of Energy to help manage the severe energy crisis Jamaica was experiencing. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9297", "text": "Lowe's research is focused on ascertaining medicinal and pharmacological qualities of  Jamaican plants; in particular  Cannabis  and  Tillandsia recurvata . Lowe has been involved in Cannabis research \"since 1972\". [ 14 ]  His Ph.D. focused on examining \"the structure activity relationships of some of the cannabinoids in ganja\". [ 15 ]  Lowe, in collaboration with various colleagues has produced experimental findings which demonstrate the efficacy of cannabis flavonoids in combating illnesses such as  hepatitis c . [ 16 ] [ 17 ] [ 18 ]  Lowe's interest in  Tillandsia recurvata  began during his doctoral studies. [ 6 ]  Lowe and his research team have since shown that it can be potent medicine for prostate cancer through its  cytotoxic  properties towards cancer cell lines (P-3C and P-45). [ 19 ]  Lowe produces a variety of health products based on his discoveries in these areas. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9298", "text": "Lowe developed the first National Energy Policy and Management plan for Jamaica as the director of its Ministry of Energy. It included  an agreement with  Venezuela  that 25% of the revenue generated from Jamaica's purchase of Venezuelan oil would be re-directed towards various Jamaican development projects. Lowe also achieved  the reduction of Jamaica's use of oil by 20 percent. [ 21 ]  After this, Lowe helped establish the Ministry of Science, Technology and the Environment, before joining the Ministry of Agriculture, [ 22 ]  and then the Ministry of Public Utilities and Transport. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9299", "text": "Lowe had been a consultant for Blue Cross of Jamaica since the 1970s, and was appointed to the board of trustees in 1988. Following the resignation of then CEO Hylton McIntosh, Lowe was appointed as CEO in 1990. [ 24 ]  Lowe would later acquire the majority of the Blue Cross of Jamaica from its previous holder, the  Blue Cross Blue Shield Association . Lowe sold his shares in 2008 to  Sagicor . [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9300", "text": "In 2000 Lowe purchased a two-acre property on 39 Lady Musgrave road. Lowe used this land to create the \"Eden gardens wellness center and spa\" \u2013 a business venture which also aligns with his ideals of promoting wellness and health in Jamaica. [ 26 ]  More property was purchased across from 44 lady Musgrave road which was being used for an expansion as of 2012. Novlet green took over management of the facility in 2006. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9301", "text": "In 2007 at a conference of the Caribbean poison information network (CARPIN), Lowe spoke of the commercial benefits possible from research into medicinal  cannabis . [ 28 ]   In 2013 Lowe established Medicanja; a company to produce  and commercialize  products based on cannabis. [ 29 ] [ 30 ] [ 31 ]  He is the firm's  Executive Chairman and chief scientist. [ 32 ] [ 33 ]  Medicanja has a research facility at the University of the West Indies. [ 34 ]  On July 26, 2018, Medicanja released twelve nutraceutical products. Six of these products; CanjaRub, CanjaCol, Relevium Cream, Relevium Spray, Somnican (One Drop) Orals, and Tivasat, are designed to inhibit pain. Six others are intended for specific usage: CBD Oil Sublingual Drops designed to reduce nausea, I-Cann designed for those with glaucoma and intra-ocular pressure, Epilec Pro for epilepsy, Sclorican for pain and discomfort caused by  multiple sclerosis , Cannrepel a mosquito repellent; and the \"Oromuccosol Spray\". All of these products have been approved by the  FDA . [ 35 ] [ 36 ]  On December 3, 2018, the Development Bank of Jamaica   agreed to provide Medicanja with $7 million to facilitate the clinical trials of its experimental drug, \"Drug X Version 2\". [ 37 ]  The firm developed drug, Chrysoeriol, which could be used to treat  acute myeloid leukaemia.  On July 12, 2017, Lowe announced Chrysoeriol had been given orphan drug status by the FDA [ 38 ] [ 39 ] [ 40 ]  Lowe,  working with various academics, has filed for sixteen patents in the  United States , six of which have been granted. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9302", "text": "In 1992 Lowe founded the \"Environmental Health Foundation\", a non-governmental charitable organization which identifies, implements and gives grants to pro-social projects. in \"health, education, environment, science & technology and the development of knowledge\". [ 42 ]  In 2015, the EHF won an  Energy Globe award  for its three-year program (2011-2014) designed to increase the resilience of Jamaican farmers to climate change, in partnership with the  United States Agency for International Development  from which it received funding. As of 2018, Lowe was the charity's executive chairman. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9303", "text": "[ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9304", "text": "Collen Masimirembwa  (born 1967) is a biomedical pharmacologist from  Zimbabwe . He is a  Distinguished Professor  of  Clinical Pharmacology  at the  University of Witswatersrand , [ 1 ]  and serves as the president and chief scientific officer at the African Institute of Biomedical Science and Technology (AiBST). His research in Africa has contributed to the field of pharmacogenetics, particularly in understanding the genetic diversity and drug response of African populations. In 2018, he was awarded the HUGO Africa Award. [ 2 ]  He is a fellow of the Calestous Juma Leadership Fellowship, [ 3 ]  African Academy of Sciences (AAS) and the Zimbabwe Academy of Sciences (ZAS)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9305", "text": "He has authored over 100 papers in peer-reviewed journals and book chapters and has guided numerous postgraduate students and postdoctoral fellows. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9306", "text": "Masimirembwa was born in 1967 in Zimbabwe [ 5 ]  and received his BSc (Hons) and DPhil degrees in biochemistry from the University of Zimbabwe in 1993. [ 6 ]  Fascinated by the then-emerging field of pharmacogenetics, he conducted studies at the Karolinska Institute in Sweden in 1995, [ 5 ]  where he earned his PhD in Medical Biochemistry and Biophysics. His doctoral research was centered on the molecular mechanisms of drug metabolism and toxicity. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9307", "text": "After obtaining his PhD, Masimirembwa returned to the University of Zimbabwe and served as a senior lecturer and head of the Department of Biochemistry from 1992 to 1997. [ 6 ]  He later joined AstraZeneca R&D in Sweden as a principal scientist and project leader, focusing on drug discovery and development in various areas such as cardiovascular, gastrointestinal, and infectious diseases. He played a key role in establishing the AstraZeneca Africa Pharmacogenetics Research Network, which aimed to study the genetic diversity and drug response of African populations. [ 7 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9308", "text": "Later in 2008, Masimirembwa founded and assumed the position of president and chief scientific officer at the African Institute of Biomedical Science and Technology (AiBST), a non-profit research institute in Zimbabwe that focuses on biomedical science and technology, with an emphasis on pharmacogenetics and clinical pharmacology. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9309", "text": "At the institute, he manages collaborations with various academic, industry, and government partners. He also leads the African Pharmacogenomics Consortium (APC), a network that aims to advance pharmacogenomics research and applications in Africa. [ 6 ]  He is also a distinguished professor of health sciences research at the University of the Witwatersrand (South Africa).  [ 7 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9310", "text": "Masimirembwa is a fellow of the Zimbabwe Academy of Sciences (ZAS) [ 5 ]  and the African Academy of Sciences (AAS) among many other honors .  In November 2021, Masimirembwa was selected as a Calestous Juma Science Leadership Fellow by the Bill and Melinda Gates Foundation, to develop a research and innovation ecosystem, train scientists, and create centres of excellence in genomic medicine research to enhance Africa\u2019s sustainable development in genomic and pharmaceutical capabilities. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9311", "text": "Collen Masimirembwa was named a Fellow of the  Zimbabwe Academy of Sciences  in 2017 and the  African Academy of Sciences  in 2018. In 2018, he was awarded the  HUGO Africa  Award. [ 12 ]  The Grand Challenges Africa Award was presented to him in 2016. He was the recipient of the  EDCTP Senior Fellowship  Award in 2014 [ 13 ]  and the  Wellcome Trust  Senior Fellowship Award in 2012.  AstraZeneca R&D  acknowledged his work with the Global Scientific Award in 2006 and the Global Innovation Award in 2005. [ 7 ] [ 11 ]  Additionally, he received the Calestous Juma Leadership Fellowship in 2021 [ 14 ]  and the PMCW 2025 Pioneer Award. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9312", "text": "Viness Pillay  FAAS  (1970\u20132020) was a South African professor of  pharmacy  at the  University of the Witwatersrand  in  Johannesburg . [ 1 ] [ 2 ]  He was the Director of the Wits Advanced Drug Delivery Platform (WADDP), a member of  African Academy of Sciences , Academy of Translational Medicine Professionals (ATMP) and a beneficiary of the 2013  Olusegun Obasanjo  Innovative Award for developing the RapiDiss Wafer Technology as an innovative way to provide effective  anti-retroviral  (ARV) drug therapy to children afflicted with  HIV/AIDS . [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9313", "text": "He obtained his master's degree in pharmacy from the  University of Durban-Westville  (South Africa) in 1996 and bagged his PhD at  Temple University  in 2000 as a Fulbright Scholar. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9314", "text": "He developed RapiDiss Wafer Technology as an innovative way to provide effective anti-retroviral (ARV) drug therapy to children afflicted with HIV/AIDS. He developed the world's fastest dissolving matrix for the onset of rapid drug action in the human body, a neural device for therapeutic intervention in spinal cord injury and novel wound healing technologies. He also came up with his own molecular modelling paradigms called PEiGOR Theory - Pillay's Electro-influenced Geometrical Organization-Reorganization. This theory was published in the International Journal of Pharmaceutics. [ 6 ] [ 7 ] [ 5 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9315", "text": "He was elected a Fellow of the  Academy of Science of South Africa  in 2012. He was also a member of the  American Chemical Society , the American Association of Pharmaceutical Scientists, the  New York Academy of Sciences , the Academy of Pharmaceutical Sciences of South Africa, and The Biomaterials Network. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9316", "text": "He was a beneficiary of National Research Foundation (NRF) Awards. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9317", "text": "Pillay died on 24 July 2020 after a lengthy illness. He left behind a wife and a daughter. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9318", "text": "J\u0101nis Polis  (25 June 1938 \u2013 12 April 2011) was a  Soviet  and  Latvian   pharmacologist  and the developer of one of the first methods of synthesis of  rimantadine , which was discovered in 1963 by William W. Prichard of Du Pont & Co. [ 1 ]  He was born in  Eleja parish , Latvia. On 6 February 2009, Polis was awarded the  WIPO  Award for Outstanding Inventors. [ 2 ]  Polis died in  Riga ,  Latvia  on 12 April 2011 at the age of 72."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9319", "text": "This Latvian biographical article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9320", "text": "Kenneth D. Tew  is a  Scottish-American   pharmacologist , academic and author. He is a professor in the Department of Cell &  Molecular Pharmacology  and the  John C. West  Endowed Chair in  Cancer Research  at the  Medical University of South Carolina . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9321", "text": "Tew's research primarily focuses on identifying cancer strategies with strong translational potential, particularly in the context of  redox  pathways, and resistance to various drugs to understand redox mechanisms and their connections to essential signaling pathways. [ 2 ]  He has authored, co-authored and edited research articles and books such as  Preclinical and Clinical Modulation of Anticancer Drugs  and  Basic Science of Cancer . He is the recipient of the Outstanding Investigator Grant from the  National Cancer Institute  in 1993, the 2003  American Cancer Society  Scientific Research Award and the 2010 Astellas USA Foundation Award from the  American Society for Pharmacology and Experimental Therapeutics . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9322", "text": "Tew is an Elected Fellow of the  American Association for the Advancement of Science [ 4 ]  and the American Society for Pharmacology and Experimental Therapeutics. [ 5 ]  He is an Executive Editor of  Biomedicine & Pharmacotherapy . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9323", "text": "Tew earned a Bachelor of Science in  Microbiology / Genetics  from the  University of Wales, Swansea  in 1973 and a PhD in Biochemical  Pharmacology  from the  University of London , where he also received postdoctoral training in 1976. He served as the Head of the Basic Pharmacology Program at the  Lombardi Cancer Center  from 1982 to 1985, when he became a member and later Chairman of Pharmacology at the  Fox Chase Cancer Center . Concurrently, he worked as an Adjunct Associate Professor of Pharmacology at the  University of Pennsylvania  until 1990 and was awarded his DSc from the University of London in 1995. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9324", "text": "Tew was appointed the G. Willing Chair in Cancer Research at the  Medical University of South Carolina  from 1999 to 2004. He was the Director of the Developmental Cancer Therapeutics Program at Hollings Cancer Center from 2004 to 2019, and serves as a professor in the Department of Cell & Molecular Pharmacology at the Medical University of South Carolina. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9325", "text": "Tew has been the John C. West Chair in Cancer Research at the Medical University of South Carolina since 2004. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9326", "text": "Tew held the position of Associate Editor from 1993 to 2007 and later assumed the role of Senior Editor in the Experimental Therapeutics, Molecular Targets, and  Chemical Biology  Section from 2007 to 2018 for the journal  Cancer Research . Concurrently, he held editorial positions including, Editor for  Cellular Pharmacology , and Editor-in-Chief of  Journal of Pharmacology and Experimental Therapeutics . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9327", "text": "Tew has been the Editor (USA) of  Biomedicine & Pharmacotherapy  since 2002 [ 6 ]  and Serial Editor for  Advances in Cancer Research  since 2011. [ 9 ]  Additionally, he has held appointments at InVaMet Therapeutics and the  Greehey Children's Cancer Research Institute  Scientific External Advisory Board since 2019. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9328", "text": "Through his research laboratory, the Tew laboratory, he has conducted research in redox pathways, with an emphasis on  drug development ,  biomarker  identification, and comprehending the effects of  reactive oxygen  and  nitrogen species  on  cancer cells . [ 2 ] [ 11 ]  He has focused on distinct  post-translationally modified   S-glutathionylated  proteins affecting  cell-signaling  pathways, potentially acting as  surrogate plasma biomarkers  for drug response induced by  oxidative  and nitrosative stress. He holds patents for his work, contributing to the development of a  glutathione S-transferase -activated  prodrug  and two small molecules in clinical development as potential  myeloproliferative  agents. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9329", "text": "Tew has co-authored 2 books focusing on carcinogenesis and cancer treatment strategies. He co-wrote  Preclinical and Clinical Modulation of Anticancer Drugs  with Peter J. Houghton and Janet A. Houghton, providing an analysis of theoretical and practical approaches to the design and implementation of modulation principles. His collaborative work with Gary D. Kruh,  Basic Science of Cancer , explored the advancements in cancer research, covering interrelated topics such as  tumor suppressor genes ,  apoptosis ,  transcriptional regulation , pharmacology of anticancer drugs,  cytogenetic techniques ,  oncogenes , and  signal transductions . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9330", "text": "Tew co-edited books from the series  Advances in Cancer Research  alongside Paul B. Fisher, where they provided reviews on diverse cancer research topics. In a review published in the  Journal of Medicinal Chemistry , Thomas J. Bardos wrote about the series, \"This rapidly growing series of volumes containing many excellent, highly informative, in-depth reviews on a variety of timely topics relating to cancer research has always been most representative in the areas of tumor biology and immunology.\" [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9331", "text": "Tew's work on redox and pharmacogenetics focused on the discovery and development of drugs. Alongside colleagues, he introduced a novel zebrafish model with a glutathione S-transferase \u03c01 (gstp1) knockout, revealing insights into redox homeostasis, reductive stress, and responses to drugs inducing endoplasmic reticulum stress and the unfolded protein response. [ 15 ] [ 16 ]  His research has looked into the role of GTSP in cellular redox homeostasis and its over-expression in cancer drug resistance, particularly in the context of preclinical and clinical testing of the GSTP inhibitor TLK199 (Telintra) for treating myelodysplastic syndrome. [ 17 ]  He further revealed that the absence of microsomal glutathione transferase 1 (MGST1) impacts melanin biosynthesis and melanoma growth in mice and that, in numerous species, members of the GST family are involved in early hematopoiesis, [ 18 ]  and that the lack of GSTP in dendritic cells leads to increased proliferation, ROS levels and ER\u03b1 levels, suggesting a role for GSTP in controlling ER\u03b1 activity and dendritic cell function. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9332", "text": "Additionally, Tew and colleagues investigated how S-glutathionylation of the protein BiP, mediated by GSTP, contributes to acquired resistance to the multiple myeloma treatment bortezomib (Btz) by impacting BiP's foldase and ATPase activities. [ 20 ]  In another collaborative study published in  Scientific Reports , he found that S-glutathionylated serpins, specifically A1 and A3, are elevated in the blood of prostate cancer patients after radiation therapy, suggesting their potential as biomarkers for radiation exposure. [ 21 ]  He also explored melanoma cell lines resistant to reductive stress agents, showcasing changes in cell and mitochondrial morphology, metabolic preferences, and adaptive mechanisms in lethal reductive stress conditions. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9333", "text": "Tew has studied cancer strategies to devise new treatments. In a joint research, he highlighted the significance of microsomal glutathione transferase 1 (MGST1) in melanin biosynthetic pathways, revealing its role as a determinant of tumor progression, with MGST1 knockdown leading to depigmentation, increased oxidative stress, and hindered tumor growth. [ 23 ]  He also determined that inhibiting microsomal glutathione S-transferase 1 (MGST1) in melanoma enhances oxidative stress, increases sensitivity to anticancer drugs, and reduces metastasis, improving the effectiveness of therapies. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9334", "text": "Tew examined ME-344, a second-generation isoflavone with anticancer properties in 2019, demonstrating its impact on redox homeostasis, mitochondrial function, and specific targeting of heme oxygenase 1 (HO-1) in lung cancer cells. [ 25 ]  In 2020, he determined that ME-344 targets VDAC1 and VDAC2 in lung cancer cells, leading to ROS generation, Bax translocation, cytochrome c release, and apoptosis, highlighting their potential as therapeutic targets. [ 26 ]  He also assessed how reactive oxygen species (ROS) play a dual role in cancer evolution, influencing both tumorigenesis and cell death, and highlighted tumor cell adaptations in metabolism and antioxidant defenses to manage ROS levels during different stages of cancer development. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9335", "text": "Ferdinand Bernhard Vietz  (18 November 1772 in  Vienna  \u2013 15 December 1815 in Vienna), was an Austrian pharmacologist, a Doctor of the Healing Arts and Professor of Forensic Medicine at the  University of Vienna , and is best known for  Icones Plantarum Medico-Oeconomico-Technologicarum cum Earum Fructus ususque Descriptione  (1800\u20131822), an 11-volume compilation of medicinal, culinary and decorative plant species consulted by pharmacologists during the early 1800s.  The noted cartographic engraver,  Ignaz Alberti , worked on the 1100 hand-coloured copperplate engravings on laid-watermarked paper and completed the work after the early death of Vietz. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9336", "text": "Volumes 1 and 2 were printed in  Latin  and  German  in adjacent columns. Volumes 3-10 have the title in German only. Volume 11 is a supplementary volume by Joseph Lorenz Kendl. In the introduction to Volume 1, Vietz lists a lengthy bibliography of consulted works, an enormous number of sponsors and a dedication to Maria Theresa,  Empress of Austria ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9337", "text": "Vietz's monumental work is extremely rare, and the  British Natural History Museum  writes:\nThe work is \u201cnot being held in any other of the United Kingdom's national or public library collections. Only three copies have been found in North American libraries, of which two are certainly fragile and in need of conservation. One copy is in the Austrian National Library.\u201d  [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9338", "text": "On his death, Vietz was succeeded by  Joseph Bernt  (1770\u20131842), as professor of state medicine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9339", "text": "John Mitchell Watt  (1 December 1892 \u2013 23 April 1980) was a 20th-century South African physician and pharmacologist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9340", "text": "He served in both World Wars. He made extensive catalogues of traditional African medicines. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9341", "text": "He was born in  Port Elizabeth  in  Cape Colony  on 1 December 1892. He was educated at the Grey Institute High School in Port Elizabeth. His family moved to  Scotland  and he completed his education at  Stirling High School ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9342", "text": "He studied medicine at the  University of Edinburgh  graduating with an  MB ChB  in 1916. He then joined the  Royal Army Medical Corps ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9343", "text": "In 1921 he became Professor of  Pharmacology  at  University College, Johannesburg ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9344", "text": "In 1933 he was elected a Fellow of the  Royal Society of Edinburgh . His proposers were  John Phillips ,  Robert Burns Young ,  James Harvey Pirie  and Sir  William Wright Smith . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9345", "text": "In the  Second World War  he was in charge of medical supplies for the South African Defence Headquarters for the entire war."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9346", "text": "In 1957 he joined the South African Institute for Medical Research. In 1965 he moved back to Britain to teach at the  Plymouth  College of Technology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9347", "text": "He went into semi-retirement in 1965, also moving to  Australia . He was a part-time Demonstrator in  Physiology  at the  University of Queensland .  Rand Afrikaans University  awarded him an honorary doctorate (LLD) for his academic writing in 1972."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9348", "text": "He died in  Brisbane  on 23 April 1980."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9349", "text": "He was married twice: firstly in 1920 to Yelena Nikonova, secondly in 1942 to Betty Gwendoline Lory."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9350", "text": "Pharmacokinetics  (from  Ancient Greek   pharmakon  \"drug\" and  kinetikos  \"moving, putting in motion\"; see  chemical kinetics ), sometimes abbreviated as  PK ,  is a branch of  pharmacology  dedicated to describing how the body affects a specific substance after administration. [ 1 ]  The substances of interest include any chemical  xenobiotic  such as  pharmaceutical drugs ,  pesticides ,  food additives ,  cosmetics , etc. It attempts to analyze chemical  metabolism  and to discover the fate of a chemical from the moment that it is administered up to the point at which it is completely  eliminated from the body . Pharmacokinetics is based on mathematical modeling that places great emphasis on the relationship between drug plasma concentration and the time elapsed since the drug's administration. Pharmacokinetics is the study of how an organism affects the drug, whereas  pharmacodynamics  (PD) is the study of how the drug affects the organism. Both together influence  dosing , benefit, and  adverse effects , as seen in  PK/PD models ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9351", "text": "Pharmacokinetics :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9352", "text": "A number of phases occur once the drug enters into contact with the organism, these are described using the acronym ADME (or LADME if liberation is included as a separate step from absorption):"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9353", "text": "Some textbooks combine the first two phases as the drug is often administered in an active form, which means that there is no liberation phase. Others include a phase that combines distribution, metabolism and excretion into a disposition phase. Other authors include the drug's toxicological aspect in what is known as  ADME-Tox  or  ADMET . The two phases of metabolism and excretion can be grouped together under the title  elimination ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9354", "text": "The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason, in order to fully comprehend the  kinetics  of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as  excipients , the characteristics of the appropriate  biological membranes  and the way that substances can cross them, or the characteristics of the  enzyme reactions  that inactivate the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9355", "text": "The following are the most commonly measured pharmacokinetic metrics: [ 5 ]  The units of the dose in the table are expressed in  moles  (mol) and  molar  (M). To express the metrics of the table in units of mass, instead of  Amount of substance , simply replace 'mol' with 'g' and 'M' with 'g/L'. Similarly, other units in the table may be expressed in units of an equivalent  dimension  by scaling. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9356", "text": "where\n \n \n \n \n \n C \n \n \n av \n \n , \n \n ss \n \n \n \n = \n \n \n \n A \n U \n \n C \n \n \u03c4 \n , \n \n ss \n \n \n \n \n \u03c4 \n \n \n \n \n {\\displaystyle C_{{\\text{av}},{\\text{ss}}}={\\frac {AUC_{\\tau ,{\\text{ss}}}}{\\tau }}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9357", "text": "In pharmacokinetics,  steady state  refers to the situation where the overall intake of a drug is fairly in  dynamic equilibrium  with its elimination. In practice, it is generally considered that once regular dosing of a drug is started, steady state is reached after 3 to 5 times its half-life. In steady state and in linear pharmacokinetics, AUC \u03c4 =AUC \u221e . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9358", "text": "Models have been developed to simplify conceptualization of the many processes that take place in the interaction between an organism and a chemical substance. Pharmacokinetic modelling may be performed either by noncompartmental or  compartmental  methods.  Multi-compartment models  provide the best approximations to reality; however, the complexity involved in adding parameters with that modelling approach means that  monocompartmental models  and above all  two compartmental models  are the most-frequently used. The model outputs for a drug can be used in industry (for example, in calculating  bioequivalence  when designing generic drugs) or in the clinical application of pharmacokinetic concepts. Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals and in  veterinary medicine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9359", "text": "Models generally take the form of  mathematical formulas  that have a corresponding  graphical representation . The use of these models allows an understanding of the characteristics of a  molecule , as well as how a particular drug will behave given information regarding some of its basic characteristics such as its  acid dissociation constant  (pKa),  bioavailability  and  solubility , absorption capacity and distribution in the organism. A variety of analysis techniques may be used to develop models, such as  nonlinear regression  or curve stripping."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9360", "text": "Noncompartmental methods estimate PK parameters directly from a table of concentration-time measurements. Noncompartmental methods are versatile in that they do not assume any specific model and generally produce accurate results acceptable for bioequivalence studies. Total drug exposure is most often estimated by area under the curve (AUC) methods, with the  trapezoidal rule  ( numerical integration ) the most common method. Due to the dependence on the length of  x  in the trapezoidal rule, the area estimation is highly dependent on the blood/plasma sampling schedule. That is, the closer time points are, the closer the trapezoids reflect the actual shape of the concentration-time curve. The number of time points available in order to perform a successful NCA analysis should be enough to cover the absorption, distribution and elimination phase to accurately characterize the drug. Beyond AUC exposure measures, parameters such as Cmax (maximum concentration), Tmax (time to maximum concentration), CL and Vd can also be reported using NCA methods."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9361", "text": "Compartment models methods estimate the concentration-time graph by modeling it as a system of differential equations. These models are based on a consideration of an organism as a number of related  compartments . Both single compartment and  multi-compartment models  are in use. PK compartmental models are often similar to kinetic models used in other scientific disciplines such as  chemical kinetics  and  thermodynamics . The advantage of compartmental over noncompartmental analysis is the ability to modify parameters and to extrapolate to novel situations. The disadvantage is the difficulty in developing and validating the proper model. Although compartment models have the potential to realistically model the situation within an organism, models inevitably make simplifying assumptions and will not be applicable in all situations. However complicated and precise a model may be, it still does not truly represent reality despite the effort involved in obtaining various distribution values for a drug. This is because the concept of distribution volume is a relative concept that is not a true reflection of reality. The choice of model therefore comes down to deciding which one offers the lowest margin of error for the drug involved."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9362", "text": "The simplest PK compartmental model is the one-compartmental PK model. This models an organism as one homogenous compartment. This  monocompartmental model  presupposes that  blood plasma  concentrations of the drug are the only information needed to determine the drug's concentration in other fluids and tissues. For example, the concentration in other areas may be approximately related by known, constant factors to the blood plasma concentration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9363", "text": "In this one-compartment model, the most common model of elimination is  first order kinetics , where the elimination of the drug is directly proportional to the drug's concentration in the organism. This is often called   linear pharmacokinetics , as the change in concentration over time can be expressed as a linear differential equation  \n \n \n \n \n \n \n d \n C \n \n \n d \n t \n \n \n \n = \n \u2212 \n \n k \n \n el \n \n \n C \n \n \n {\\textstyle {\\frac {dC}{dt}}=-k_{\\text{el}}C} \n \n . Assuming a single IV bolus  dose  resulting in a concentration  \n \n \n \n \n C \n \n initial \n \n \n \n \n {\\displaystyle C_{\\text{initial}}} \n \n  at time  \n \n \n \n t \n = \n 0 \n \n \n {\\displaystyle t=0} \n \n , the equation can be solved to give  \n \n \n \n C \n = \n \n C \n \n initial \n \n \n \u00d7 \n \n e \n \n \u2212 \n \n k \n \n el \n \n \n \u00d7 \n t \n \n \n \n \n {\\displaystyle C=C_{\\text{initial}}\\times e^{-k_{\\text{el}}\\times t}} \n \n ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9364", "text": "Not all body tissues have the same   blood supply , so the distribution of the drug will be slower in these tissues than in others with a better blood supply. In addition, there are some tissues (such as the  brain  tissue) that present a real barrier to the distribution of drugs, that can be breached with greater or lesser ease depending on the drug's characteristics. If these relative conditions for the different tissue types are considered along with the rate of elimination, the organism can be considered to be acting like two compartments: one that we can call the  central compartment  that has a more rapid distribution, comprising organs and systems with a well-developed blood supply; and a  peripheral compartment  made up of organs with a lower blood flow. Other tissues, such as the brain, can occupy a variable position depending on a drug's ability to cross the  barrier  that separates the organ from the blood supply."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9365", "text": "Two-compartment models vary depending on which compartment elimination occurs in. The most common situation is that elimination occurs in the central compartment as the  liver  and  kidneys  are organs with a good blood supply. However, in some situations it may be that elimination occurs in the peripheral compartment or even in both. This can mean that there are three possible variations in the two compartment model, which still do not cover all possibilities. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9366", "text": "In the real world, each tissue will have its own distribution characteristics and none of them will be strictly linear. The two-compartment model may not be applicable in situations where some of the enzymes responsible for metabolizing the drug become saturated, or where an active elimination mechanism is present that is independent of the drug's plasma concentration. If we label the drug's  volume of distribution  within the organism  Vd F  and its volume of distribution in a tissue  Vd T  the former will be described by an equation that takes into account all the tissues that act in different ways, that is:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9367", "text": "This represents the  multi-compartment model  with a number of curves that express complicated equations in order to obtain an overall curve. A number of  computer programs  have been developed to plot these equations. [ 9 ]  The most complex PK models (called  PBPK  models) rely on the use of physiological information to ease development and validation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9368", "text": "The graph for the non-linear relationship between the various factors is represented by a  curve ; the relationships between the factors can then be found by calculating the dimensions of different areas under the curve. The models used in  non-linear pharmacokinetics  are largely based on  Michaelis\u2013Menten kinetics . A reaction's factors of non-linearity include the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9369", "text": "It can therefore be seen that non-linearity can occur because of reasons that affect the entire pharmacokinetic sequence: absorption, distribution, metabolism and elimination."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9370", "text": "At a practical level, a drug's bioavailability can be defined as the proportion of the drug that reaches the systemic circulation. From this perspective the  intravenous  administration of a drug provides the greatest possible bioavailability, and this method is considered to yield a bioavailability of 1 (or 100%). Bioavailability of other delivery methods is compared with that of intravenous injection (absolute bioavailability) or to a standard value related to other delivery methods in a particular study (relative bioavailability)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9371", "text": "Once a drug's bioavailability has been established it is possible to calculate the changes that need to be made to its dosage in order to reach the required blood plasma levels. Bioavailability is, therefore, a mathematical factor for each individual drug that influences the administered dose. It is possible to calculate the amount of a drug in the blood plasma that has a real potential to bring about its effect using the formula:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9372", "text": "where  De  is the  effective dose ,  B  bioavailability and  Da  the administered dose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9373", "text": "Therefore, if a drug has a bioavailability of 0.8 (or 80%) and it is administered in a dose of 100\u00a0mg, the equation will demonstrate the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9374", "text": "That is the 100\u00a0mg administered represents a blood plasma concentration of 80\u00a0mg that has the capacity to have a pharmaceutical effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9375", "text": "This concept depends on a series of factors inherent to each drug, such as: [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9376", "text": "These concepts, which are discussed in detail in their respective titled articles, can be mathematically quantified and integrated to obtain an overall mathematical equation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9377", "text": "where  Q  is the drug's purity. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9378", "text": "where  \n \n \n \n V \n a \n \n \n {\\displaystyle Va} \n \n  is the drug's rate of administration and  \n \n \n \n \u03c4 \n \n \n {\\displaystyle \\tau } \n \n  is the rate at which the absorbed drug reaches the circulatory system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9379", "text": "Finally, using the  Henderson-Hasselbalch equation , and knowing the drug's  \n \n \n \n p \n K \n a \n \n \n \n {\\displaystyle pKa\\,} \n \n  ( pH  at which there is an equilibrium between its ionized and non-ionized molecules), it is possible to calculate the non-ionized concentration of the drug and therefore the concentration that will be subject to absorption:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9380", "text": "When two drugs have the same bioavailability, they are said to be biological equivalents or bioequivalents. This concept of  bioequivalence  is important because it is currently used as a yardstick in the authorization of  generic drugs  in many countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9381", "text": "Bioanalytical methods  are necessary to construct a concentration-time profile. Chemical techniques are employed to measure the concentration of drugs in  biological matrix , most often plasma. Proper bioanalytical methods should be selective and sensitive. For example,  microscale thermophoresis  can be used to quantify how the biological matrix/liquid affects the affinity of a drug to its target. [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9382", "text": "Pharmacokinetics is often studied using  mass spectrometry  because of the complex nature of the matrix (often plasma or urine) and the need for high sensitivity to observe concentrations after a low dose and a long time period. The most common instrumentation used in this application is  LC-MS  with a  triple quadrupole mass spectrometer .  Tandem mass spectrometry  is usually employed for added specificity. Standard curves and internal standards are used for quantitation of usually a single pharmaceutical in the samples. The samples represent different time points as a pharmaceutical is administered and then metabolized or cleared from the body. Blank samples taken before administration are important in determining background and ensuring data integrity with such complex sample matrices. Much attention is paid to the linearity of the standard curve; however it is common to use  curve fitting  with more complex functions such as  quadratics  since the response of most mass spectrometers is not linear across large concentration ranges. [ 15 ] [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9383", "text": "There is currently considerable interest in the use of very high sensitivity mass spectrometry for  microdosing  studies, which are seen as a promising alternative to  animal experimentation . [ 18 ]  Recent studies show that  Secondary electrospray ionization  (SESI-MS) can be used in drug monitoring, presenting the advantage of avoiding animal sacrifice. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9384", "text": "Population pharmacokinetics  is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest. [ 20 ] [ 21 ] [ 22 ]  Certain patient demographic, pathophysiological, and therapeutical features, such as body weight, excretory and metabolic functions, and the presence of other therapies, can regularly alter dose-concentration relationships and can explain variability in exposures. For example, steady-state concentrations of drugs eliminated mostly by the kidney are usually greater in patients with  kidney failure  than they are in patients with normal kidney function receiving the same drug dosage. Population pharmacokinetics seeks to identify the measurable pathophysiologic factors and explain sources of variability that cause changes in the dose-concentration relationship and the extent of these changes so that, if such changes are associated with clinically relevant and significant shifts in exposures that impact the therapeutic index, dosage can be appropriately modified.\nAn advantage of population pharmacokinetic modelling is its ability to analyse sparse data sets (sometimes only one concentration measurement per patient is available)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9385", "text": "medication"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9386", "text": "(HIV) medication"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9387", "text": "Clinical pharmacokinetics (arising from the clinical use of population pharmacokinetics) is the direct application to a therapeutic situation of knowledge regarding a drug's pharmacokinetics and the characteristics of a population that a patient belongs to (or can be ascribed to)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9388", "text": "An example is the relaunch of the use of  ciclosporin  as an  immunosuppressor  to facilitate organ transplant. The drug's therapeutic properties were initially demonstrated, but it was almost never used after it was found to cause  nephrotoxicity  in a number of patients. [ 23 ]  However, it was then realized that it was possible to individualize a patient's dose of ciclosporin by analysing the patients plasmatic concentrations (pharmacokinetic monitoring). This practice has allowed this drug to be used again and has facilitated a great number of organ transplants."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9389", "text": "Clinical monitoring is usually carried out by determination of plasma concentrations as this data is usually the easiest to obtain and the most reliable. The main reasons for determining a drug's plasma concentration include: [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9390", "text": "Ecotoxicology  is the branch of science that deals with the nature, effects, and interactions of substances that are harmful to the environment such as  microplastics  and other  biosphere  harmful substances. [ 25 ] [ 26 ]  Ecotoxicology is studied in pharmacokinetics due to the substances responsible for harming the environment such as  pesticides  can get into the bodies of living organisms. The health effects of these chemicals is thus subject to research and  safety trials  by government or international agencies such as the  EPA  or  WHO . [ 27 ] [ 28 ]   How long these chemicals stay in the body , the  lethal dose  and other factors are the main focus of Ecotoxicology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9391", "text": "All model based software above."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9392", "text": "Global centres with the highest profiles for providing in-depth training include the Universities of  Buffalo ,\n Florida ,  Gothenburg ,  Leiden ,  Otago ,  San Francisco ,  Beijing , Tokyo,  Uppsala ,  Washington ,  Manchester , Monash University, and University of  Sheffield . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9393", "text": "Absorption  is the journey of a drug travelling from the site of administration to the site of action. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9394", "text": "The drug travels by some  route of administration  ( oral ,  topical-dermal , etc.) in a chosen  dosage form  (e.g.,  tablets ,  capsules , or in  solution ). [ 3 ]  Absorption by some other routes, such as  intravenous therapy ,  intramuscular injection ,  enteral nutrition , is even more straightforward and there is less variability in absorption and  bioavailability  is often near 100%.  Intravascular  administration does not involve absorption, and there is no loss of drug. [ 4 ]  The fastest route of absorption is  inhalation . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9395", "text": "Absorption is a primary focus in  drug development  and  medicinal chemistry , since a drug must be absorbed before any medicinal effects can take place.  Moreover, the drug's pharmacokinetic profile can be easily and significantly changed by adjusting factors that affect absorption."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9396", "text": "Oral ingestion is the most common route of administration of pharmaceuticals. [ 6 ]  Passing through the  esophagus  to the  stomach , the contents of the capsule or tablet are absorbed by the  GI tract . The absorbed pharmaceutical is then passed through the  liver  and  kidneys . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9397", "text": "The rate of dissolution is a key target for controlling the duration of a drug's effect, and as such, several dosage forms that contain the same active ingredient may be available, differing only in the rate of dissolution. If a drug is supplied in a form that is not readily dissolved, it may be released gradually and act for longer. Having a longer duration of action may improve  compliance  since the medication will not have to be taken as often.  Additionally, slow-release dosage forms may maintain concentrations within an acceptable therapeutic range over a longer period, whereas quick-release dosage forms may have sharper peaks and troughs in serum concentration. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9398", "text": "The rate of dissolution is described by the  Noyes\u2013Whitney equation  as shown below:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9399", "text": "As can be inferred from the Noyes\u2013Whitney equation, the rate of dissolution may be modified primarily by altering the surface area of the solid by altering the particle size (e.g., with  micronization ). For many drugs, reducing the particle size reduces the dose needed to achieve the same therapeutic effect. The particle size reduction increases the  specific surface area  and the dissolution rate and does not affect solubility."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9400", "text": "The rate of dissolution may also be altered by choosing a suitable  polymorph  of a compound. Different polymorphs have different solubility and dissolution rate characteristics.  Specifically, crystalline forms dissolve slower than amorphous forms since they require more energy to leave the lattice during dissolution. The stablest crystalline polymorph has the lowest dissolution rate. Dissolution also differs between anhydrous and hydrous forms of a drug. Anhydrous forms often dissolve faster but sometimes are less soluble."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9401", "text": "Esterification  is also used to control solubility. For example,  stearate  and estolate  esters  of drugs have decreased solubility in  gastric fluid . Later,  esterases  in the  gastrointestinal tract  (GIT) wall and blood  hydrolyze  these esters to release the parent drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9402", "text": "Coatings on a tablet or pellet may act as barriers to reducing the dissolution rate. Coatings may also be used to control where dissolution takes place. For example,  enteric coatings  only dissolve in the  basic  environment of the  intestines ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9403", "text": "Drugs held in solution do not need to be dissolved before being absorbed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9404", "text": "Lipid-soluble drugs are absorbed more rapidly than water-soluble drugs. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9405", "text": "The  gastrointestinal tract  is lined with  epithelial cells .  Drugs must pass through or permeate these cells to be absorbed into the  bloodstream .   Cell membranes  may act as barriers to some drugs.  They are essentially  lipid bilayers  which form  semipermeable membranes .  Pure lipid bilayers are generally permeable only to small, uncharged solutes.  Hence, whether or not a molecule is  ionized  will affect its absorption, since ionic molecules are charged.  Solubility favors charged species, and permeability favors neutral species.  Some molecules have special exchange proteins and channels to facilitate movement from the lumen into the circulation. [ vague ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9406", "text": "Ions cannot passively diffuse through the gastrointestinal tract because the epithelial cell membrane is made up of a  phospholipid bilayer , comprising two layers of phospholipids in which the charged hydrophilic heads face outwards and the uncharged hydrophobic fatty acid chains are in the middle of the layer. The fatty acid chains repel ionized, charged molecules. This means that the ionized molecules cannot pass through the intestinal membrane and be absorbed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9407", "text": "The  Henderson-Hasselbalch equation  offers a way to determine the proportion of a substance that is ionized at a given pH.  In the stomach, drugs that are  weak acids  (such as  aspirin ) will be present mainly in their non-ionic form, and  weak bases  will be in their ionic form.  Since non-ionic species diffuse more readily through  cell membranes , weak acids will have a higher absorption in the highly acidic  stomach ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9408", "text": "However, the reverse is true in the  basic  environment of the intestines\u2014weak bases (such as  caffeine ) will diffuse more readily since they will be non-ionic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9409", "text": "This aspect of absorption has been targeted by medicinal chemists.  For example, they may choose an  analog  that is more likely to be in a non-ionic form.  Also, the chemists may develop  prodrugs  of a compound\u2014these chemical variants may be more readily absorbed and then metabolized by the body into the active compound.  However, changing the structure of a molecule is less predictable than altering dissolution properties, since changes in chemical structure may affect the  pharmacodynamic  properties of a drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9410", "text": "The solubility and permeability of a drug candidate are important physicochemical properties the scientist wants to know as early as possible. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9411", "text": "Absorption also varies depending on bioactivity, resonance, the inductive effect, isosterism, bio-isosterism, and consideration, amongst others."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9412", "text": "Types of absorption in pharmacokinetics include the following: [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9413", "text": "An  active metabolite , or  pharmacologically active metabolite  is  a biologically active  metabolite  of a  xenobiotic  substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9414", "text": "An active metabolite results when a drug is metabolized by the body into a modified form which produces effects in the body. Usually these effects are similar to those of the  parent drug  but weaker, [ citation needed ]  although they can still be significant (see e.g.  11-hydroxy-THC ,  morphine-6-glucuronide ). Certain drugs such as  codeine  and  tramadol  have metabolites ( morphine  and  O -desmethyltramadol  respectively) that are stronger than the parent drug [ 2 ] [ 3 ] [ 4 ]  and in these cases the metabolite may be responsible for much of the therapeutic action of the parent drug. Sometimes, however, metabolites may produce toxic effects and patients must be monitored carefully to ensure they do not build up in the body. This is an issue with some well-known drugs, such as  pethidine  (meperidine) and  dextropropoxyphene . [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9415", "text": "Sometimes drugs are formulated in an inactive form that is designed to break down inside the body to form the active drug. These are called  prodrugs . The reasons for this type of formulation may be because the drug is more stable during manufacture and storage as the prodrug form, or because the prodrug is better absorbed by the body or has superior  pharmacokinetics  (e.g.,  lisdexamphetamine ). [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9416", "text": "ADME  is the four-letter abbreviation (acronym) for  absorption ,  distribution ,  metabolism , and  excretion , and is mainly used in fields such as  pharmacokinetics  and  pharmacology . The four letter stands for descriptors quantifying how a given drug interacts within body over time. The term ADME was first introduced in the 1960s, and has become a standard term widely used in scientific literature, teaching, drug regulations, and clinical practice. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9417", "text": "ADME, describes the  disposition  of a  pharmaceutical   compound  within an  organism . The four criteria all influence the  drug levels and kinetics  of drug exposure to the tissues and hence influence the performance and  pharmacological activity  of the compound as a  drug . Sometimes,  liberation  and/or  toxicity  are also considered, yielding LADME, ADMET, or LADMET."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9418", "text": "For a compound to reach a tissue, it usually must be taken into the  bloodstream  \u2013 often via  mucous  surfaces like the  digestive tract  ( intestinal  absorption) \u2013 before being taken up by the target cells.  Factors such as poor compound solubility, gastric emptying time, intestinal transit time, chemical instability in the stomach, and inability to permeate the intestinal wall can all reduce the extent to which a drug is absorbed after oral administration. Absorption critically determines the compound's  bioavailability . Drugs that absorb poorly when taken orally must  be administered  in some less desirable way, like  intravenously  or by  inhalation  (e.g.  zanamivir ).  Routes of administration  are an important consideration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9419", "text": "The compound needs to be carried to its effector site, most often via the bloodstream. From there, the compound may distribute into muscle and organs, usually to differing extents. After entry into the systemic circulation, either by  intravascular  injection or by absorption from any of the various extracellular sites, the drug is subjected to numerous distribution processes that tend to lower its plasma concentration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9420", "text": "Distribution is defined as the reversible transfer of a drug between one  compartment  to another.  Some factors affecting drug distribution include regional blood flow rates, molecular size, polarity and binding to serum proteins, forming a complex.  Distribution can be a serious problem at some natural barriers like the  blood\u2013brain barrier ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9421", "text": "Compounds begin to break down as soon as they enter the body.  The majority of small-molecule drug metabolism is carried out in the liver by  redox  enzymes, termed  cytochrome P450  enzymes.  As metabolism occurs, the initial (parent) compound is converted to new compounds called  metabolites .  When metabolites are pharmacologically inert, metabolism deactivates the administered dose of parent drug and this usually reduces the effects on the body.  Metabolites may also be pharmacologically active, sometimes more so than the parent drug (see  prodrug )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9422", "text": "Compounds and their  metabolites  need to be removed from the body via  excretion , usually through the  kidneys  (urine) or in the feces. Unless excretion is complete, accumulation of foreign substances can adversely affect normal metabolism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9423", "text": "There are three main sites where drug excretion occurs. The kidney is the most important site and it is where products are excreted through urine. Biliary excretion or fecal excretion is the process that initiates in the liver and passes through to the gut until the products are finally excreted along with waste products or feces. The last main method of excretion is through the lungs (e.g. anesthetic gases)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9424", "text": "Excretion of drugs by the kidney involves 3 main mechanisms:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9425", "text": "Sometimes, the potential or real  toxicity  of the compound is taken into account ( ADME-Tox  or  ADMET ).  Parameters used to characterize toxicity include the median lethal dose ( LD 50 ) and  therapeutic index ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9426", "text": "Computational chemists  try to predict the ADME-Tox qualities of compounds through methods like  QSPR  or  QSAR ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9427", "text": "The  route of administration  critically influences ADME."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9428", "text": "In the field of  pharmacokinetics , the  area under the curve  ( AUC ) is the  definite integral  of the  concentration  of a  drug  in  blood plasma  as a function of time (this can be done using  liquid chromatography\u2013mass spectrometry [ 1 ] ). In practice, the drug concentration is measured at certain discrete points in time and the  trapezoidal rule  is used to estimate AUC. In pharmacology, the area under the plot of plasma concentration of a drug  versus  time after dosage (called \u201carea under the curve\u201d or AUC) gives insight into the extent of exposure to a drug and its  clearance rate  from the body. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9429", "text": "The AUC (from zero to infinity) represents the  total drug exposure across time . AUC is a useful metric when trying to determine whether two  formulations  of the same dose (for example a  capsule  and a  tablet ) result in equal amounts of  tissue  or plasma exposure. Another use is in the  therapeutic drug monitoring  of drugs with a narrow  therapeutic index . For example,  gentamicin  is an  antibiotic  that can be  nephrotoxic  ( kidney  damaging) and  ototoxic  (hearing damaging); measurement of  gentamicin  through concentrations in a patient's plasma and calculation of the AUC is used to guide the dosage of this drug. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9430", "text": "AUC becomes useful for knowing the average concentration over a time interval, AUC/t. Also, AUC is referenced when talking about  elimination . The amount eliminated by the body (mass) = clearance (volume/time) * AUC (mass*time/volume). [ citation needed ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9431", "text": "In  pharmacokinetics ,  bioavailability  generally refers to the fraction of a drug that is absorbed systemically and is thus available to produce a  biological  effect. This is often measured by quantifying the \"AUC\". In order to determine the respective AUCs, the  serum  concentration vs. time plots are typically gathered using C-14 labelled drugs and AMS ( accelerated mass spectrometry ). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9432", "text": "Bioavailability  can be measured in terms of \"absolute bioavailability\" or \"relative bioavailability\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9433", "text": "Absolute bioavailability  refers to the  bioavailability  of a drug when administered via an  extravascular  dosage form (i.e. oral tablet,  suppository ,  subcutaneous , etc.) compared with the bioavailability of the same drug administered  intravenously  (IV). This is done by comparing the AUC of the non-intravenous dosage form with the AUC for the drug administered intravenously. This fraction is normalized by multiplying by each dosage form's respective dose. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9434", "text": "Relative bioavailability  compares the bioavailability between two different dosage forms. Again, the relative AUCs are used to make this comparison and relative doses are used to normalize the calculation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9435", "text": "AUC of  glucose  concentration change following food intake is used to calculate the  glycemic index . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9436", "text": "The use of  trapezoidal rule  in AUC calculation was known in literature by no later than 1975, in J.G. Wagner's  Fundamentals of Clinical Pharmacokinetics . A 1977 article compares the \"classical\" trapezoidal method to a number of methods that take into account the typical shape of the concentration plot, caused by  first-order kinetics . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9437", "text": "Notwithstanding the above knowledge, a 1994  Diabetes Care  article by Mary M. Tai purports to have independently discovered the trapezoidal rule. [ 9 ]  In Tai's response to the later  letters to the editors , she explained that the rule was new to her colleagues, who relied on grid-counting. [ 10 ]  Tai's paper has been discussed as a case of  scholarly peer review  failure. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9438", "text": "Despite the number of mathematically superior  numerical integration  schemes (such as those outlined in  Wagner & Ayres 1977 ), the trapezoidal rule remains the convention for AUC calculation. Later focus on improving the accuracy of AUC calculation shifted from improving the method to improving the sampling scheme. An example is a 2019  algorithm  known as OTTER: it performs a fit onto  sum of exponentials  curve for the input data but only uses it to suggest better sample times by finding more highly sloped periods. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9439", "text": "The  area under the effect curve  (AUEC) is an integral of the  effect  of a drug over time, estimated as a previously-established function of concentration. It was proposed to be used instead of AUC in animal-to-human dose translation, as  computer simulation  shows that it could cope better with  half-life  and dosing schedule variations than AUC. This is an example of a  PK/PD model , which combines  pharmacokinetics  and  pharmacodynamics . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9440", "text": "In  pharmacokinetics  and  receptor-ligand kinetics  the  binding potential  (BP) is a combined measure of the density of \"available\"  neuroreceptors  and the  affinity  of a drug to that neuroreceptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9441", "text": "Consider a  ligand  receptor binding system. Ligand with a concentration  L  associates with a receptor of concentration or availability  R  to form a ligand-receptor complex with concentration  RL . The binding potential is then the ratio ligand-receptor complex to free ligand at equilibrium and in the limit of L tending to 0, and is given symbol BP:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9442", "text": "B \n P \n = \n \n \n \n R \n L \n \n L \n \n \n \n \n \n | \n \n \n \n L \n \u2248 \n 0 \n \n \n \n \n {\\displaystyle BP={\\frac {RL}{L}}{\\bigg |}_{L\\approx 0}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9443", "text": "This quantity, originally defined by Mintun, [ 1 ]  describes the capacity of a receptor to bind ligand. It is a limit (L << Ki) of the general receptor association equation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9444", "text": "R \n L \n = \n \n \n \n R \n \u2217 \n L \n \n \n L \n + \n K \n i \n \n \n \n \n \n {\\displaystyle RL={\\frac {R*L}{L+Ki}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9445", "text": "and is thus also equivalent to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9446", "text": "B \n P \n = \n \n \n R \n \n K \n \n i \n \n \n \n \n \n \n {\\displaystyle BP={\\frac {R}{K_{i}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9447", "text": "These equations apply equally when measuring the total receptor density or the residual receptor density available after binding to second ligand - availability."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9448", "text": "BP is a pivotal measure in the use of  positron emission tomography  (PET) to measure the density of \"available\" receptors, e.g. to assess the occupancy by drugs or to characterize neuropsychiatric diseases (yet, one should keep in mind that binding potential is a combined measure that depends on receptor density as well as on affinity). An overview of the related methodology is e.g. given in Laruelle et al. (2002). [ 2 ] \nEstimating BP with PET usually requires that a reference tissue is available. A reference tissue has negligible receptor density and its distribution volume should be the same as the distribution volume in the target region if all receptors were blocked. Although the BP can be measured in a relatively unbiased way by measuring the whole time course of labelled ligand association and blood radioactivity, this is practically not always necessary. Two other common measures have been derived, which involve assumptions, but result in measures that should correlate with BP:  \n \n \n \n B \n \n P \n \n 1 \n \n \n \n \n {\\displaystyle BP_{1}} \n \n  and  \n \n \n \n B \n \n P \n \n 2 \n \n \n \n \n {\\displaystyle BP_{2}} \n \n ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9449", "text": "While  \n \n \n \n B \n \n P \n \n 1 \n \n \n \n \n {\\displaystyle BP_{1}} \n \n  and  \n \n \n \n B \n \n P \n \n 2 \n \n \n \n \n {\\displaystyle BP_{2}} \n \n  are nonambiguous symbols, BP is not. There are many publications in which BP denotes  \n \n \n \n B \n \n P \n \n 2 \n \n \n \n \n {\\displaystyle BP_{2}} \n \n . Generally, if there were no arterial samples (\"noninvasive imaging\"), BP denotes  \n \n \n \n B \n \n P \n \n 2 \n \n \n \n \n {\\displaystyle BP_{2}} \n \n ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9450", "text": "B \n \n m \n a \n x \n \n \n \n \n {\\displaystyle B_{max}} \n \n : Total density of receptors =  \n \n \n \n R \n + \n R \n L \n \n \n {\\displaystyle R+RL} \n \n . In PET imaging, the amount of radioligand is usually very small (L << Ki, see above), thus  \n \n \n \n \n B \n \n m \n a \n x \n \n \n \u2248 \n R \n \n \n {\\displaystyle B_{max}\\approx R}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9451", "text": "k \n \n 3 \n \n \n \n \n {\\displaystyle k_{3}} \n \n  and  \n \n \n \n \n k \n \n 4 \n \n \n \n \n {\\displaystyle k_{4}} \n \n : Transfer rate constants from the  two tissue compartment model ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9452", "text": "NEW NOTATIONAL CONVENTIONS:\nIn Innis et al., [ 3 ]  a large group of researchers who are active in this field agreed to a consensus nomenclature for these terms, with the intent of making the literature in this field more transparent to non-specialists.  The convention involves use of the subscripts p for quantities referred to plasma and ND for quantities referred to the free plus nonspecifically bound concentration in brain (NonDisplaceable).  Under the consensus nomenclature, the parameters referred to above as f 1  and BP 1  are now called f p  and BP p , while f 2  and BP 2  are called f ND  and BP ND ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9453", "text": "Bioanalysis  is a sub-discipline of  analytical chemistry  covering the  quantitative  measurement of  xenobiotics  (drugs and their  metabolites , and  biological molecules  in unnatural locations or concentrations) and biotics ( macromolecules ,  proteins ,  DNA , large molecule drugs, metabolites) in  biological systems ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9454", "text": "Many scientific endeavors are dependent upon accurate quantification of drugs and endogenous substances in biological samples; the focus of bioanalysis in the  pharmaceutical  industry is to provide a quantitative measure of the active drug and/or its metabolite(s) for the purpose of  pharmacokinetics ,  toxicokinetics ,  bioequivalence  and exposure\u2013response (pharmacokinetics/pharmacodynamics studies). Bioanalysis also applies to drugs used for illicit purposes,  forensic  investigations, anti- doping  testing in sports, and environmental concerns."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9455", "text": "Bioanalysis was traditionally thought of in terms of measuring small molecule drugs. However, the past twenty years has seen an increase in  biopharmaceuticals  (e.g.  proteins  and  peptides ), which have been developed to address many of the same diseases as small molecules. These larger biomolecules have presented their own unique challenges to quantification. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9456", "text": "The first studies measuring drugs in biological fluids were carried out to determine possible overdosing as part of the new science of forensic medicine/ toxicology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9457", "text": "Initially, nonspecific assays were applied to measuring drugs in biological fluids. These were unable to discriminate between the drug and its metabolites; for example,  aspirin  ( c. \u20091900 ) and  sulfonamides  (developed in the 1930s) were quantified by the use of  colorimetric  assays.  Antibiotics  were quantified by their ability to inhibit bacterial growth. The 1930s also saw the rise of pharmacokinetics, and as such the desire for more specific assays. [ 2 ]  Modern drugs are more potent, which has required more sensitive bioanalytical assays to accurately and reliably determine these drugs at lower concentrations. This has driven improvements in technology and analytical methods."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9458", "text": "Some techniques commonly used in bioanalytical studies include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9459", "text": "The most frequently used techniques are: liquid chromatography coupled with tandem mass spectrometry ( LC\u2013MS/MS ) for 'small' molecules and enzyme-linked immunosorbent assay ( ELISA ) for macromolecules. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9460", "text": "The bioanalyst deals with complex biological samples containing the analyte alongside a diverse range of chemicals that can have an adverse impact on the accurate and precise quantification of the analyte. As such, a wide range of techniques are applied to extract the analyte from its matrix. These include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9461", "text": "Bioanalytical laboratories often deal with large numbers of samples, for example resulting from clinical trials. As such, automated sample preparation methods and liquid-handling robots are commonly employed to increase efficiency and reduce costs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9462", "text": "There are several national and international bioanalytical organisations active throughout the world. Often they are part of a bigger organisation, e.g. Bioanalytical Focus Group and Ligand Binding Assay Bioanalytical Focus Group, which are both within the American Association of Pharmaceutical Scientists (AAPS) and FABIAN, a working group of the Analytical Chemistry Section of the  Royal Netherlands Chemical Society . The  European Bioanalysis Forum  (EBF), on the other hand, is independent of any larger society or association."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9463", "text": "Bioequivalence  is a term in  pharmacokinetics  used to assess the expected  in vivo  biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9464", "text": "One article defined bioequivalence by stating that, \"two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their  bioavailabilities  (rate and extent of availability) after administration in the same  molar dose  are similar to such a degree that their effects, with respect to both  efficacy  and safety, can be expected to be essentially the same. Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards.\" [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9465", "text": "For  The World Health Organization  (WHO) \"two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives, and their bioavailabilities, in terms of rate (Cmax and tmax) and extent of absorption (area under the curve), after administration of the same molar dose under the same conditions, are similar to such a degree that their effects can be expected to be essentially the same\". [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9466", "text": "The  United States   Food and Drug Administration  (FDA) has defined bioequivalence as, \"the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.\" [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9467", "text": "In determining bioequivalence between two products such as a commercially available Branded product and a potential to-be-marketed  Generic product ,  pharmacokinetic  studies are conducted whereby each of the preparations are administered in a  cross-over study  (sometimes parallel study, when a cross-over study is not feasible) to volunteer subjects, generally healthy individuals but occasionally in patients.  Serum/plasma  samples are obtained at prescribed times and assayed for parent drug (or occasionally  metabolite ) concentration. Occasionally, blood concentration levels are neither feasible or possible to compare the two products (e.g. inhaled  corticosteroids ), then  pharmacodynamic  endpoints rather than pharmacokinetic endpoints (see below) are used for comparison. For a pharmacokinetic comparison, the plasma concentration data are used to assess key pharmacokinetic parameters such as area under the curve (AUC), peak concentration ( C max ), time to peak concentration ( t max ), and absorption lag time ( t lag ). Testing should be conducted at several different doses, especially when the drug displays non-linear pharmacokinetics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9468", "text": "In addition to data from bioequivalence studies, other data may need to be submitted to meet  regulatory requirements  for bioequivalence. Such evidence may include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9469", "text": "The World Health Organization considers two formulation bioequivalent if the 90% confidence interval for the ratio multisource (generic) product/comparator lie within 80.00\u2013125.00% acceptance range for AUC 0\u2013t  and C max . For high variable finished pharmaceutical products, the applicable acceptance range for C max  can be expanded (up to 69.84\u2013143.19%). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9470", "text": "In  Australia , the  Therapeutics Goods Administration  (TGA) considers preparations to be bioequivalent if the 90%  confidence intervals  (90% CI) of the rate ratios, between the two preparations, of  C max  and AUC lie in the range 0.80\u20131.25.  T max  should also be similar between the products. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9471", "text": "There are tighter requirements for drugs with a narrow  therapeutic index  and/or saturable metabolism \u2013 thus no generic products exist on the Australian market for  digoxin  or  phenytoin  for instance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9472", "text": "According to regulations applicable in the  European Economic Area [ 5 ]  two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and if their bioavailabilities after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same. This is considered demonstrated if the 90%  confidence intervals  (90% CI) of the ratios for AUC 0\u2013t  and  C max  between the two preparations lie in the range 80\u2013125%."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9473", "text": "The FDA considers two products bioequivalent if the 90% CI of the relative mean C max , AUC (0\u2013t)  and AUC (0\u2013\u221e)  of the test (e.g. generic formulation) to reference (e.g. innovator brand formulation) should be within 80% to 125% in the fasting state. Although there are a few exceptions, generally a bioequivalent comparison of Test to Reference formulations also requires administration after an appropriate meal at a specified time before taking the drug, a so-called \"fed\" or \"food-effect\" study. A food-effect study requires the same statistical evaluation as the fasting study, described above. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9474", "text": "There were no requirements for bioequivalence in generic medications in China until the 2016  Opinion on Conducting Consistent Evaluation of the Quality and Efficacy of Generic Drugs  ( \u5173\u4e8e\u5f00\u5c55\u4eff\u5236\u836f\u8d28\u91cf\u548c\u7597\u6548\u4e00\u81f4\u6027\u8bc4\u4ef7\u7684\u610f\u89c1 ), which established basic rules for future bioequivalence work. Since July 2020, all newly-approved generics must pass bioequivalence checks; previous drugs may apply to be checked. Since 2019, National Centralized Volume-Based Procurement uses \"passes generic-consistency evalulation\" as one of the bidding criteria. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9475", "text": "The Chinese definition of \"bioequivalence\" entails having the test drug's geometric mean C max , AUC (0\u2013t) , and AUC (0\u2013\u221e)  fall into 80%\u2013125% of the reference drug in both fasting and fed states. The reference drug should be preferably the original brand-name drug, then (if not available) an internationally-recognized generic approved by a developed country, then (if still not available) an internationally-recognized generic approved domestically \u2013 this is to avoid deviation from the original drug by serial use of generics as reference. If pharmacokinetic values such as C max  do not apply to the type of drug (e.g. if the drug is not absorbed orally), comparisons can be made using other means such as  dose-response curves . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9476", "text": "According to Wei et al. (2022), the Consistency Evaluation Policy increased R&D spending for Chinese pharmaceutical companies, especially among private and high-yielding ones. [ 8 ]  Liu et al. (2023) argues that the Policy increased the innovation quality of the Chinese pharmaceutical industry. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9477", "text": "While the FDA maintains that approved generic drugs are equivalent to their branded counterparts, bioequivalence problems have been reported by physicians and patients for many drugs. [ 10 ]  Certain classes of drugs are suspected to be particularly problematic because of their chemistry. Some of these include  chiral drugs , poorly absorbed drugs, and cytotoxic drugs. In addition, complex delivery mechanisms can cause bioequivalence variances. [ 10 ]  Physicians are cautioned to avoid switching patients from branded to generic, or between different generic manufacturers, when prescribing anti-epileptic drugs,  warfarin , and  levothyroxine . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9478", "text": "Major issues were raised in the verification of bioequivalence when multiple generic versions of FDA-approved generic drug were found not to be equivalent in efficacy and side effect profiles. [ 12 ]  In 2007, two providers of consumer information on nutritional products and supplements,  ConsumerLab.com  and The People's Pharmacy, released the results of comparative tests of different brands of bupropion. [ 13 ]  The People's Pharmacy received multiple reports of increased side effects and decreased efficacy of generic bupropion, which prompted it to ask ConsumerLab.com to test the products in question. The tests showed that some generic versions of Wellbutrin XL 300\u00a0mg didn't perform the same as the brand-name pill in laboratory tests. [ 14 ]  The FDA investigated these complaints and concluded that the generic version is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL. [ 15 ]  After several years of denying patient reports, in 2012 the FDA reversed this opinion, announcing that \"Budeprion XL 300\u00a0mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300\u00a0mg.\" [ 16 ]  The FDA did not test the bioequivalence of any of the other generic versions of Wellbutrin XL 300\u00a0mg, but requested that the four manufacturers submit data on this question to the FDA by March 2013. As of October 2013, the FDA has made determinations on the formulations from some manufacturers not being bioequivalent. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9479", "text": "In 2004,  Ranbaxy  was revealed to have been falsifying data regarding the generic drugs they were manufacturing. As a result, 30 products were removed from US markets and Ranbaxy paid $500\u00a0million in fines. The FDA investigated many Indian drug manufacturers after this was discovered, and as a result at least 12 companies have been banned from shipping drugs to the US. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9480", "text": "In 2017, The  European Medicines Agency  recommended suspension of a number of nationally approved medicines for which bioequivalence studies were conducted by Micro Therapeutic Research Labs in India, due to inspections identifying misrepresentation of study data and deficiencies in documentation and data handling. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9481", "text": "Biological half-life  ( elimination half-life ,  pharmacological half-life ) is the time taken for concentration of a  biological substance  (such as a  medication ) to decrease from its maximum  concentration  ( C max ) to half of C max  in the  blood plasma . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  It is denoted by the abbreviation  \n \n \n \n \n t \n \n \n 1 \n 2 \n \n \n \n \n \n {\\displaystyle t_{\\frac {1}{2}}} \n \n . [ 2 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9482", "text": "This is used to measure the removal of things such as  metabolites ,  drugs , and  signalling molecules  from the body. Typically, the biological half-life refers to the body's natural  detoxification  (cleansing) through  liver metabolism  and through the  excretion  of the measured substance through the kidneys and intestines. This concept is used when the rate of removal is roughly  exponential . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9483", "text": "In a medical context, half-life explicitly describes the time it takes for the  blood plasma  concentration of a substance to halve ( plasma half-life ) its steady-state when circulating in the full blood of an  organism . This measurement is useful in medicine,  pharmacology  and  pharmacokinetics  because it helps determine how much of a drug needs to be taken and how frequently it needs to be taken if a certain average amount is needed constantly. By contrast, the stability of a substance in plasma is described as  plasma stability.  This is essential to ensure accurate analysis of drugs in plasma and for  drug discovery ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9484", "text": "The relationship between the biological and plasma half-lives of a substance can be complex depending on the substance in question, due to factors including accumulation in tissues,  protein binding , active metabolites, and receptor interactions. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9485", "text": "The biological half-life of water in a human is about 7 to 14 days. It can be altered by behavior. Drinking large amounts of  alcohol  will reduce the biological half-life of water in the body. [ 8 ] [ 9 ]  This has been used to decontaminate patients who are internally contaminated with  tritiated water . The basis of this decontamination method is to increase the rate at which the water in the body is replaced with new water."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9486", "text": "The removal of  ethanol  (drinking alcohol) through oxidation by  alcohol dehydrogenase  in the  liver  from the human body is limited. Hence the removal of a large concentration of alcohol from  blood  may follow  zero-order kinetics . Also the rate-limiting steps for one substance may be in common with other substances. For instance, the blood alcohol concentration can be used to modify the biochemistry of  methanol  and  ethylene glycol . In this way the oxidation of methanol to the  toxic   formaldehyde  and  formic acid  in the human body can be prevented by giving an appropriate amount of  ethanol  to a person who has  ingested  methanol. Methanol is very toxic and causes  blindness  and death. A person who has ingested  ethylene glycol  can be treated in the same way. Half life is also relative to the subjective metabolic rate of the individual in question."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9487", "text": "Active metabolite ( N-desalkylflurazepam ): 47\u2013100 hours [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9488", "text": "8\u201315 hours (higher doses) [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9489", "text": "in rare cases up to 8 days [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9490", "text": "Active metabolite ( nordazepam ): 30\u2013200 hours [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9491", "text": "Active lipophilic metabolite ( norfluoxetine ): 4\u201316 days [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9492", "text": "The biological half-life of  caesium  in humans is between one and four months. This can be shortened by feeding the person  prussian blue . The prussian blue in the digestive system acts as a solid  ion exchanger  which absorbs the caesium while releasing  potassium  ions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9493", "text": "For some substances, it is important to think of the human or animal body as being made up of several parts, each with its own affinity for the substance, and each part with a different biological half-life ( physiologically-based pharmacokinetic modelling ). Attempts to remove a substance from the whole organism may have the effect of increasing the burden present in one part of the organism. For instance, if a person who is contaminated with lead is given  EDTA  in a  chelation therapy , then while the rate at which lead is lost from the body will be increased, the lead within the body tends to relocate into the  brain  where it can do the most harm. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9494", "text": "Some substances may have different half-lives in different parts of the body. For example,  oxytocin  has a  half-life  of typically about three minutes in the blood when given  intravenously . Peripherally administered (e.g. intravenous) peptides like oxytocin cross the  blood-brain-barrier  very poorly, although very small amounts (< 1%) do appear to enter the  central nervous system  in humans when given via this route. [ 31 ]  In contrast to peripheral administration, when administered  intranasally  via a nasal spray, oxytocin reliably crosses the  blood\u2013brain barrier  and exhibits  psychoactive  effects in humans. [ 32 ] [ 33 ]  In addition, unlike the case of peripheral administration, intranasal oxytocin has a central duration of at least 2.25 hours and as long as 4 hours. [ 34 ] [ 35 ]  In likely relation to this fact, endogenous oxytocin concentrations in the brain have been found to be as much as 1000-fold higher than peripheral levels. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9495", "text": "Half-times apply to processes where the elimination rate is exponential. If  \n \n \n \n C \n ( \n t \n ) \n \n \n {\\displaystyle C(t)} \n \n  is the concentration of a substance at time  \n \n \n \n t \n \n \n {\\displaystyle t} \n \n , its time dependence is given by"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9496", "text": "where  k  is the  reaction rate constant . Such a decay rate arises from a  first-order reaction  where the rate of elimination is proportional to the amount of the substance: [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9497", "text": "The half-life for this process is [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9498", "text": "Alternatively, half-life is given by"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9499", "text": "where  \u03bb z  is the slope of the terminal phase of the time\u2013concentration curve for the substance on a semilogarithmic scale. [ 40 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9500", "text": "Half-life is determined by  clearance  (CL) and  volume of distribution  (V D ) and the relationship is described by the following equation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9501", "text": "In clinical practice, this means that it takes 4 to 5 times the half-life for a drug's serum concentration to reach steady state after regular dosing is started, stopped, or the dose changed.  So, for example, digoxin has a half-life (or t \u2060 1 / 2 \u2060 ) of 24\u201336 h; this means that a change in the dose will take the best part of a week to take full effect. For this reason, drugs with a long half-life (e.g.,  amiodarone , elimination t \u2060 1 / 2 \u2060  of about 58 days) are usually started with a  loading dose  to achieve their desired clinical effect more quickly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9502", "text": "Many drugs follow a biphasic elimination curve \u2014 first a steep slope then a shallow slope:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9503", "text": "The longer half-life is called the  terminal half-life  and the half-life of the largest component is called the  dominant half-life. [ 39 ]  For a more detailed description see  Pharmacokinetics \u00a7 Multi-compartmental models ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9504", "text": "Blood\u2013gas partition coefficient , also known as  Ostwald coefficient for blood\u2013gas , [ 1 ]  is a term used in  pharmacology  to describe the solubility of inhaled  general anesthetics  in blood. [ 2 ]  According to  Henry's law , the ratio of the concentration in blood to the concentration in gas that is in contact with that blood, when the  partial pressure  in both compartments is equal, is nearly constant at sufficiently low concentrations.  The partition coefficient is defined as this ratio and, therefore, has no units. The concentration of the anesthetic in blood includes the portion that is undissolved in plasma and the portion that is dissolved (bound to  plasma proteins ). The more  soluble  the inhaled anesthetic is in blood compared to in air, the more it binds to plasma proteins in the blood and the higher the blood\u2013gas  partition coefficient ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9505", "text": "It is inversely related to  induction rate . Induction rate is defined as the speed at which an agent produces anesthesia. The higher the  blood:gas partition coefficient , the slower the rate of induction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9506", "text": "Newer anesthetics (such as  desflurane ) typically have smaller blood\u2013gas partition coefficients than older ones (such as  ether ); this leads to faster onset of anesthesia and faster emergence from anesthesia once application of the anesthetic is stopped, which may be preferable in certain clinical scenarios. [ 3 ] [ 4 ]  If an anesthetic has a high coefficient, then a large amount of it will have to be taken up in the body's blood before being passed on to the fatty (lipid) tissues of the brain where it can exert its effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9507", "text": "The potency of an anesthetic is associated with its lipid solubility, which is measured by its oil/gas partition coefficient. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9508", "text": "Minimum alveolar concentration (MAC) is defined as the alveolar concentration of anesthetic gas that prevents a movement response in half of subjects undergoing a painful (surgical) stimulus; simplified, it is the exhaled gas concentration required to produce anaesthetic effects\u00a0\u2013  an inverse indicator of anesthetic gas potency."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9509", "text": "The  blood\u2013brain barrier  ( BBB ) is a highly selective  semipermeable  border of  endothelial cells  that regulates the transfer of solutes and chemicals between the  circulatory system  and the  central nervous system , thus protecting the  brain  from harmful or unwanted substances in the  blood . [ 1 ]  The blood\u2013brain barrier is formed by endothelial cells of the  capillary wall ,  astrocyte  end-feet ensheathing the capillary, and  pericytes  embedded in the capillary  basement membrane . [ 2 ]  This system allows the passage of some small molecules by  passive diffusion , as well as the selective and active transport of various nutrients, ions, organic anions, and macromolecules such as glucose and  amino acids  that are crucial to neural function. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9510", "text": "The blood\u2013brain barrier restricts the passage of  pathogens , the diffusion of  solutes  in the blood, and  large  or  hydrophilic  molecules into the  cerebrospinal fluid , while allowing the diffusion of  hydrophobic  molecules (O 2 , CO 2 , hormones) and small non-polar molecules. [ 4 ] [ 5 ]  Cells of the barrier actively transport  metabolic  products such as glucose across the barrier using specific  transport proteins . [ 6 ]  The barrier also restricts the passage of peripheral immune factors, like signaling molecules, antibodies, and immune cells, into the central nervous system, thus insulating the brain from damage due to peripheral immune events. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9511", "text": "Specialized brain structures participating in sensory and secretory integration within brain  neural circuits \u2014the  circumventricular organs  and  choroid plexus \u2014have in contrast highly permeable capillaries. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9512", "text": "The BBB results from the selectivity of the  tight junctions  between the endothelial cells of brain capillaries, restricting the passage of solutes. [ 1 ]   At the interface between blood and the brain, endothelial cells are adjoined continuously by these tight junctions, which are composed of smaller subunits of  transmembrane proteins , such as  occludin ,  claudins  (such as  Claudin-5 ),  junctional adhesion molecule  (such as JAM-A). [ 6 ]  Each of these tight junction proteins is stabilized to the endothelial cell membrane by another protein complex that includes scaffolding proteins such as  tight junction protein 1  (ZO1) and associated proteins. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9513", "text": "The BBB is composed of endothelial cells restricting passage of substances from the blood more selectively than endothelial cells of capillaries elsewhere in the body. [ 9 ]   Astrocyte  cell projections called astrocytic feet (also known as \" glia limitans \") surround the endothelial cells of the BBB, providing biochemical support to those cells. [ 10 ]  The BBB is distinct from the quite similar  blood-cerebrospinal fluid barrier , which is a function of the choroidal cells of the  choroid plexus , and from the  blood-retinal barrier , which can be considered a part of the whole realm of such barriers. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9514", "text": "Not all vessels in the human brain exhibit BBB properties. Some examples of this include the  circumventricular organs , the roof of the third and fourth  ventricles , capillaries in the pineal gland on the roof of the  diencephalon  and the  pineal gland . The pineal gland secretes the hormone  melatonin  \"directly into the systemic circulation\", [ 12 ]  thus melatonin is not affected by the blood\u2013brain barrier. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9515", "text": "The BBB appears to be functional by the time of birth.  P-glycoprotein , a  transporter , exists already in the embryonal endothelium. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9516", "text": "Measurement of brain uptake of various blood-borne solutes showed that newborn endothelial cells were functionally similar to those in adults, [ 15 ]  indicating that a selective BBB is operative at birth."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9517", "text": "In mice, Claudin-5 loss during development is lethal and results in size-selective (up to 742Da) loosening of the BBB. [ 16 ]  Mosaic deletion of claudin-5 in adult endothelial cells (in mice) reveals BBB leakage up to 10kDa molecule 6 days after deletion of claudin-5 and lethality after 10 days after deletion demonstrating a critical role of Claudin-5 in adult BBB. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9518", "text": "The blood\u2013brain barrier acts effectively to protect brain tissue from circulating  pathogens  and other potentially toxic substances. [ 18 ]  Accordingly,  blood-borne infections  of the brain are rare. [ 1 ]   Infections  of the brain that do occur are often difficult to treat.  Antibodies  are too large to cross the blood\u2013brain barrier, and only certain  antibiotics  are able to pass. [ 19 ]  In some cases, a drug has to be administered directly into the cerebrospinal fluid where it can enter the brain by crossing the  blood-cerebrospinal fluid barrier . [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9519", "text": "Circumventricular organs  (CVOs) are individual structures located adjacent to the  fourth ventricle  or  third ventricle  in the brain, and are characterized by dense capillary beds with  permeable  endothelial cells unlike those of the blood\u2013brain barrier. [ 22 ] [ 23 ]  Included among CVOs having highly permeable capillaries are the  area postrema ,  subfornical organ ,  vascular organ of the lamina terminalis ,  median eminence ,  pineal gland , and three lobes of the   pituitary gland . [ 22 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9520", "text": "Permeable capillaries of the sensory CVOs (area postrema, subfornical organ, vascular organ of the lamina terminalis) enable rapid detection of circulating signals in systemic blood, while those of the secretory CVOs (median eminence, pineal gland, pituitary lobes) facilitate transport of brain-derived signals into the circulating blood. [ 22 ] [ 23 ]  Consequently, the CVO permeable capillaries are the point of bidirectional blood\u2013brain communication for  neuroendocrine  function. [ 22 ] [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9521", "text": "The border zones between brain tissue \"behind\" the blood\u2013brain barrier and zones \"open\" to blood signals in certain CVOs contain specialized hybrid capillaries that are leakier than typical brain capillaries, but not as permeable as CVO capillaries. Such zones exist at the border of the area postrema\u2014 nucleus tractus solitarii  (NTS), [ 26 ]  and median eminence\u2014 hypothalamic   arcuate nucleus . [ 25 ] [ 27 ]  These zones appear to function as rapid transit regions for brain structures involved in diverse neural circuits\u2014like the NTS and arcuate nucleus\u2014to receive blood signals which are then transmitted into neural output. [ 25 ] [ 26 ]  The permeable capillary zone shared between the median eminence and hypothalamic arcuate nucleus is augmented by wide pericapillary spaces, facilitating bidirectional flow of solutes between the two structures, and indicating that the median eminence is not only a secretory organ, but may also be a sensory organ. [ 25 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9522", "text": "The blood\u2013brain barrier is formed by the brain capillary endothelium and excludes from the brain 100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. [ 28 ]  Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders. [ 29 ] [ 30 ]  In its neuroprotective role, the blood\u2013brain barrier functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and antibodies that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts to be clinically effective. [ 29 ]  To overcome this problem some peptides able to naturally cross the BBB have been widely investigated as a drug delivery system. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9523", "text": "Mechanisms for drug targeting in the brain involve going either \"through\" or \"behind\" the BBB. Modalities for  drug delivery to the brain  in  unit doses  through the BBB entail its disruption by  osmotic  means, or biochemically by the use of vasoactive substances, such as  bradykinin , [ 32 ]  or even by localized exposure to  high-intensity focused ultrasound (HIFU) . [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9524", "text": "Other methods used to get through the BBB may entail the use of endogenous transport systems, including carrier-mediated transporters, such as glucose and amino acid carriers, receptor-mediated  transcytosis  for  insulin  or  transferrin , and the blocking of  active efflux transporters  such as  p-glycoprotein . [ 29 ]  Some studies have shown that  vectors  targeting BBB transporters, such as the  transferrin receptor , have been found to remain entrapped in brain endothelial cells of capillaries, instead of being ferried across the BBB into the targeted area. [ 29 ] [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9525", "text": "The brain can be targeted non-invasively via the nasal passage. The drugs that remain in the passage after mucociliary clearance, enter the brain via three pathways: (1) Olfactory nerve-olfactory bulb-brain; (2) Trigeminal nerve-brain; and (3) Lungs/ Gastrointestinal tract-blood\u2013brain  [ 35 ]  The first and second methods involve the nerves, so they use the neuronal pathway and the third is via systemic circulation. However, these methods are less efficient to deliver drugs as they are indirect methods."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9526", "text": "Nanotechnology  is under preliminary research for its potential to facilitate the transfer of drugs across the BBB. [ 29 ] [ 36 ] [ 37 ]  Capillary endothelial cells and associated  pericytes  may be abnormal in tumors and the blood\u2013brain barrier may not always be intact in brain tumors. [ 37 ]  Other factors, such as  astrocytes , may contribute to the resistance of brain tumors to therapy using nanoparticles. [ 38 ]  Fat soluble molecules less than 400  daltons  in mass can freely diffuse past the BBB through  lipid  mediated passive diffusion. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9527", "text": "The blood\u2013brain barrier may become damaged in certain  neurological diseases , as indicated by  neuroimaging  studies of  Alzheimer's disease ,  amyotrophic lateral sclerosis ,  epilepsy , ischemic stroke, [ 18 ] [ 40 ] [ 41 ] [ 42 ]  and  brain trauma , [ 29 ]  and in  systemic diseases , such as  liver failure . [ 1 ]  Effects such as impaired glucose transport and endothelial degeneration may lead to metabolic dysfunction within the brain, and an increased permeability of the BBB to  proinflammatory  factors, potentially allowing antibiotics and  phagocytes  to move across the BBB. [ 1 ] [ 29 ]  However, in many neurodegenerative diseases, the exact cause and pathology remains unknown. It is still unclear whether the BBB dysfunction in the disease is a causative agent, a result of the disease, or somewhere in the middle."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9528", "text": "A 1898 study observed that low-concentration \" bile salts \" failed to affect behavior when injected into the blood of animals. Thus, in theory, the salts failed to enter the brain. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9529", "text": "Two years later,  Max Lewandowsky  may have been the first to coin the term \"blood\u2013brain barrier\" in 1900, referring to the hypothesized semipermeable membrane. [ 44 ]  There is some debate over the creation of the term  blood\u2013brain barrier  as it is often attributed to Lewandowsky, but it does not appear in his papers. The creator of the term may have been  Lina Stern . [ 45 ]  Stern was a Russian scientist who published her work in Russian and French. Due to the language barrier between her publications and English-speaking scientists, this could have made her work a lesser-known origin of the term."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9530", "text": "All the while,  bacteriologist   Paul Ehrlich  was studying  staining , a procedure that is used in many  microscopy studies  to make fine biological structures visible using chemical dyes. [ 46 ]  As Ehrlich injected some of these dyes (notably the  aniline dyes  that were then widely used), the dye stained all of the  organs  of some kinds of animals except for their brains. [ 46 ]  At that time, Ehrlich attributed this lack of staining to the brain simply not picking up as much of the dye. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9531", "text": "However, in a later experiment in 1913,  Edwin Goldmann  (one of Ehrlich's students) injected the dye directly into the  cerebrospinal fluid  of animal brains. He found then the brains did become dyed, but the rest of the body did not, demonstrating the existence of a compartmentalization between the two. At that time, it was thought that the blood vessels themselves were responsible for the barrier, since no obvious membrane could be found."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9532", "text": "A  caffeinated alcoholic drink  is a  drink  that contains both  alcohol  (also known formally as  ethanol ) and a significant amount of  caffeine . Caffeine, a  stimulant , masks some of the  depressant  effects of alcohol. [ 1 ]  However, in 2010 and 2011, this type of drink faced criticism for posing health risks to its drinkers. In some places there is a ban on caffeinated alcoholic drinks."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9533", "text": "Sometimes, caffeinated alcoholic drinks are made by mixing existing caffeinated drinks ( coffee ,  energy drinks ,  cola ) with alcoholic drinks."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9534", "text": "The main ingredients in caffeinated alcoholic drinks are  alcohol  and  caffeine . The caffeine is often added by ingredients like  energy drinks ,  coffee ,  tea , or  dark chocolate . A well-known and popular such drink is  Irish coffee ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9535", "text": "In 2010, the FDA advised that caffeinated alcoholic beverages should not be consumed because of the counteracting effects of caffeine and alcohol. The FDA posited that caffeine often causes consumers to drink more than they normally would because caffeine can mask some of the sensory cues individuals might normally rely on to determine their level of intoxication. This masking of intoxication then leads individuals to engage in behaviors that they would otherwise avoid if they understood their true level of intoxication. [ 3 ]  However, research has not fully supported this tenet. For example, one study found that Australian students thought they were more intoxicated when mixing caffeine with alcohol than when consuming alcohol on its own for every level of blood alcohol content. [ citation needed ]  Consuming high levels of caffeine was associated with more alcohol-related consequences than when consuming alcohol on its own, even when consuming relatively little alcohol. It may be that caffeine causes individuals to focus on the stimulant effects of the intoxication, which have been associated with greater perceived intoxication than the depressant effects of alcohol. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9536", "text": "It is inferred that caffeinated alcoholic drinks cause one to act in ways that would be less likely if one were drinking non-caffeinated alcoholic drinks."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9537", "text": "Universities have conducted studies to compare the outcomes of the consumption of regular alcoholic drinks and of caffeinated alcoholic drinks:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9538", "text": "In  Australia , the Ministerial Council on Drug Strategy is considering regulation to address the growing concerns over the drinks.  [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9539", "text": "In  Canada , regulations restrict the manufacture and sale of caffeinated alcoholic drinks unless the caffeine comes from a natural ingredient such as guarana; caffeine as an ingredient cannot be directly added to an alcoholic drink. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9540", "text": "In  Mexico , caffeinated alcoholic drinks cannot be sold in bars or nightclubs. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9541", "text": "Several  Scottish  politicians and social activists have singled out the a caffeinated alcoholic drink  Buckfast Tonic Wine  as being particularly responsible for crime, disorder, and general social deprivation in certain communities. There have been numerous calls for the drink to be banned (either throughout the country or in certain areas or shops), made more expensive to dissuade people from buying the product, or sold in plastic bottles to reduce  glassing  incidents.  Helen Liddell , former  Secretary of State for Scotland , called for the wine to be banned. [ 10 ]  In 2005, Scottish Justice Minister  Cathy Jamieson  suggested that retailers should stop selling the wine. [ 11 ]  All of these initiatives have been countered by lawyers acting for Buckfast distributors, J. Chandler & Company, in  Andover . [ 10 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9542", "text": "In January 2010, a  BBC  investigation revealed that  Buckfast Tonic Wine  had been mentioned in 5,638 crime reports in the  Strathclyde  area of Scotland from 2006 to 2009, equating to an average of three per day.  In 2017, Scottish Police reported there had been 6,500 crimes related to the drink in the previous two years. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9543", "text": "The adverse effects of caffeinated alcoholic drinks have led to increased regulation.  Under the  Federal Food, Drug, and Cosmetic Act , a substance intentionally added to food (such as caffeine in alcoholic drinks) is deemed \"unsafe\" and is unlawful unless its particular use has been approved by FDA (Food and Drug Administration) regulation. The substance is subject to a prior sanction until the substance is Generally Regarded As Safe ( GRAS ). [ 14 ]   In order for a substance to be characterized as GRAS, there must be sufficient evidence to prove its safety; this evidence should be generally known and accepted by qualified professionals. [ 9 ]   The FDA did not approve the use of caffeine in alcoholic drinks, and thus the drinks cannot be legally marketed.  As a result, the FDA sent letters to four manufacturers of caffeinated alcoholic drinks (Phusion Projects, Charge Beverages Corporation, New Century Brewing Company, and United Brands Company, Inc.) to alert them that the agency would be considering whether caffeine can lawfully be added to alcoholic drinks. [ 9 ]  These letters also gave the manufacturers fifteen days to stop the addition of caffeine to the alcoholic drinks or to stop selling the drinks altogether."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9544", "text": "The  Federal Trade Commission  (FTC) also took action against the four companies, warning that their marketing tactics might violate federal law and urging them to take swift and appropriate steps to protect consumers. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9545", "text": "CDC  recommends against the combination of alcohol and caffeine. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9546", "text": "The  Dietary Guidelines for Americans  recommend avoidance of concomitant consumption of alcohol and caffeine, as this may lead to increased alcohol consumption, with a higher risk of alcohol-associated injury."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9547", "text": "In 2009, the FDA required several manufacturers to remove caffeine from their  alcopops  including City Brewing of La Crosse, Wisc. which makes Hard Wired and 24/7; Gaamm Imports Inc., of Deerfield Beach, Fla. which makes Booya Espresso Silver Tequila and Caffeine, and United Brands Co., maker of  Joose , Max Vibe, Max Fury, Max Live and 3Sum. Anheuser-Busch and Miller have stopped making their caffeinated alcoholic drinks,  Tilt ,  Bud Extra  and  Sparks . [ 17 ]   Rhythm  was also banned 2009."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9548", "text": "The day before the FDA sent out the warning letters, Phusion Projects (now  Four Loko ), a five-year-old Chicago company, said it would stop putting caffeine in the drinks and put a non-caffeinated version of the drink on the market in December 2010.  In a statement, the company's founders said that they still believed it was safe to blend caffeine and alcohol but wanted to cooperate with regulators. [ 15 ]  The FDA continues work with Phusion Projects and other manufacturers to assure their products meet safety standards. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9549", "text": "Targeted drug delivery  is one of many ways researchers seek to improve drug delivery systems' overall efficacy, safety, and delivery. Within this medical field is a special reversal form of  drug delivery  called chemotactic drug targeting. [ 1 ] [ 2 ]  By using chemical agents to help guide a drug carrier to a specific location within the body, this innovative approach seeks to improve precision and control during the drug delivery process, decrease the risk of toxicity, and potentially lower the required medical dosage needed. [ 2 ] [ 3 ] [ 4 ] [ 5 ]  The general components of the conjugates are designed as follows: (i) carrier \u2013 regularly possessing promoter effect also on internalization into the cell; (ii) chemotactically active ligands acting on the target cells; (iii) drug to be delivered in a selective way and (iv) spacer sequence which joins drug molecule to the carrier and due to it enzyme labile moiety makes possible the intracellular compartment specific release of the drug. Careful selection of chemotactic component of the ligand not only the  chemoattractant  character could be expended, however,  chemorepellent  ligands are also valuable as they are useful to keep away cell populations degrading the conjugate containing the drug. In a larger sense, chemotactic drug-targeting has the potential to improve cancer, inflammation, and arthritis treatment by taking advantage of the difference in environment between the target site and its surroundings. [ 6 ] [ 7 ] [ 8 ]  Therefore, this Wikipedia article aims to provide a brief overview of chemotactic drug targeting, the principles behind the approach, possible limitations and advantages, and its application to cancer and inflammation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9550", "text": "In general terms,  chemotaxis  is a biological process where living entities, such as cells or organisms, detect, maneuver, and react in response to a chemical signal in their environment. [ 1 ]  Such a phenomenon is critical for many biological processes, including but not limited to wound healing, detection of food, and avoidance of many toxins. [ 2 ]   Chemotaxis  also plays an essential role in several diseases, such as tumor metastasis, the recruitment of T-lymphocytes during inflammation, and HIV-1 entry into T cells. [ 6 ] [ 9 ] [ 10 ]  At the core of  chemotaxis  are specialized sensory cells called chemoreceptors. These cells allow an organism to detect chemical molecules within its environment and respond accordingly. Such chemical molecules are either known as chemoattractants or chemorepellents, which play a crucial role in attracting or repelling the organism towards or away from the source of the chemical signal, respectively. Thus, with this natural process of chemotaxis in mind, researchers have sought to apply the same phenomenon to  targeted drug delivery , a medical technique aimed at delivering drugs to a specific cell, tissue, or organ within the body while minimizing its disruptive effects on healthy tissue. [ 4 ]  By using both chemotaxes to help guide the drug delivery process, researchers aim to reduce toxicity by avoiding healthy tissues, improve drug efficacy by focusing only on the intended site, and decrease drug dosage by delivering the directly rather than throughout the whole body. [ 3 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9551", "text": "Chemotactic drug delivery systems are an emerging field of drug delivery that aims to apply the natural phenomenon of chemotaxis in guiding and delivering a drug to a specific tissue or cell within the body. Thus, similar to how organisms use chemotaxis, researchers have designed drug delivery systems to detect, maneuver, and react to chemical molecules released by a desired cell or its surrounding area."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9552", "text": "Recent progress in the field of  microfluidics  has led to the development of microdroplets, a new drug-delivery system that uses uniform droplets to deliver drugs to specific locations within the body. [ 2 ] [ 12 ]  These microdroplets allow researchers to load drugs during the polymerization step of their formation and provide variations in porosity, which can control the time it takes to release a therapeutic payload. [ 13 ]  Thus, by using the natural process of chemotaxis, researchers aim to guide these tiny droplets by using chemical gradients released by a specific cell, tissue, or organ within the body. [ 2 ] [ 4 ] [ 12 ]  In fact, a few examples of microdroplet systems that use chemotaxis are self-propelling, ionic liquid-based, and synthetic base. [ 2 ] [ 12 ]  These microdroplet-based drug delivery systems offer several advantages over traditional drug delivery methods, which are talked about later in the advantage and limitations subsection of this article. Overall, the development of microdroplet-based drug delivery systems using the phenomenon of chemotaxis is just one of may avenues to potentially revolutionize the field of medicine and targeted drug delivery. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9553", "text": "Another drug delivery system that has shown potential for chemotactic applicability is protocells. [ 15 ]  In general, protocells are artificial cells that mimic living cells but cannot reproduce and have genetic mutations like living cells do. [ 15 ]  Moreover, protocells combine the advantages of liposomes with that of mesoporous silica nanoparticles. [ 16 ]  These advantages include but are not limited to stability, large capacity for various cargos, low toxicity, immunogenicity, and the ability to circulate the blood for long periods. [ 16 ]  Thus, researchers aim to create a tunable chemotactic protocell that can move towards or away from a chemical signal. [ 17 ] [ 18 ]  In fact, researchers have devised a way to use the enzymes catalase, urease, and ATPase to move the protocell closer or further away from the reactant, giving them direction and movement control of these protocells. [ 17 ] [ 18 ]  Overall, the development of chemotactic controlled protocols holds great promise for the targeted delivery of drugs to specific areas of the body, potentially increasing treatment efficacy while minimizing side effects. However, more research is needed to fully understand the capabilities and limitations of protocells as drug delivery systems and optimize their design and functionality for specific applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9554", "text": "Finally, biological and bio-hybrid drug carriers have shown potential for chemotactic applications. In general, these systems are inspired by  microorganisms  or cells to help design drug delivery systems that mimic their surface, shape, texture, and movement. [ 4 ] [ 19 ]  One phenomenon that has become increasingly popular in improving the movement and release of  bio-hybrid  drug carriers is that of  chemotaxis . Indeed, thanks to their natural chemotactic sensing property, bacteria can be used to locate a tumor, carry a therapeutic payload to the site, and release that drug in a controlled manner. [ 4 ]  Researchers can also genetically modify these bacteria to produce a specific protein like anti-tumor cytotoxins for cancer treatment. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9555", "text": "Yet, this is not to say that they don't come with their own set of challenges and limitations. For one, the genetic modifications of the bacteria used can be manipulated by recent or unforeseen mutations, leading to a decrease in the efficacy of the drug and drug carrier. [ 4 ]  Moreover, the therapeutic proteins produced may have incomplete protein folding, decreasing the drug's effectiveness or causing unforeseen side effects. [ 4 ]  Generally speaking, using bacteria may provide some advantages, but further research and development are still needed to address their limitations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9556", "text": "Another example of bio-hybrid drug carriers is human cells, like macrophages, which offer compatibility with the human immune system and a simple way to load drugs as a bio-hybrid drug carrier. [ 4 ]  Leukocytes demonstrate great promise because Tumor cells secrete large amounts of chemoattractants when the cell undergoes inflammation. [ 4 ]  This secretion of chemoattractants naturally attracts leukocytes, such as macrophages, to the T cell location. [ 4 ]  Thus, with their well-known chemotactic homing behavior to inflammation or pathogens' sites in mind, researchers can manipulate leukocytes to carry and deliver a therapeutic payload to the tumor site. However, this is not to say that Biological and bio-hybrid drug carriers do not have challenges and limitations of their own. For example, Leukocytes cannot penetrate deeply into the tumors, have a low capacity for carrying drugs, and slow down when the tumor size reduces. Thus, similar to bacteria drug carriers, further research and development are still needed to address their limitations and improve the overall drug delivery system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9557", "text": "The applications of chemotactic drug delivery systems include but are not limited to  cancer  therapy, wound healing, and inflammation. The ability to target specific cells and locations within the body through chemical cues has opened up new avenues for the field of drug delivery, allowing for increased drug efficacy and reducing harmful side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9558", "text": "Cancer is not just one disease but a group of diseases involving abnormal cell growth and metastasis of such cells to other body parts. [ 20 ] [ 21 ]  There are also several types of cancers, each with its own distinctive characteristics and stages that may require different treatment or targeted drug delivery approaches. [ 21 ] [ 22 ]  Yet, even these treatments have their own advantages and disadvantages. Thus, since the discovery of cancer, researchers have constantly been developing new and innovative cancer treatments, including chemotactic drug delivery. For example, and as mentioned earlier in this article, researchers have sought to use microdroplets, protocells, and biological and bio-hybrid drug carriers to deliver drugs to cancer cells in a more effective manner, while reducing unwanted side effects. [ 2 ] [ 4 ] [ 12 ] [ 15 ] [ 19 ]  In fact, the justification for using such systems, guided by chemotaxis, is that the environment inside a tumor has a higher resting temperature, higher peroxide concentration, lower pH, and a lower oxygen concentration than its surrounding tissue. [ 4 ]  With these unique conditions, researchers can exploit chemotactic drug delivery to target tumor cells directly, avoiding healthy tissues, reducing toxicity, improving drug efficacy, and decreasing drug dosage. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9559", "text": "Inflammation  is the body's response to foreign objects, irritants, germs, and even pathogens. Although such a response is standard in some cases, if left untreated, chronic inflammation can lead to muscle degeneration, gastrointestinal disorders, and some types of cancers. [ 23 ] [ 24 ]  While most treatments, such as anti-inflammatory drugs and steroid injections, can help relieve symptoms, they often fail to address the condition's underlying cause. Therefore, researchers have sought to explore new and innovative ways of inflammation treatment, such as chemotactic drug delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9560", "text": "One promising drug delivery system was based on engineered neutrophils that targeted inflammation sites through chemotaxis's unique properties. [ 4 ] [ 7 ]  This approach took advantage of the concentration difference between iNOS and ROS for inflammatory disease sites and normal tissues. [ 7 ]  By doing so, this drug delivery system provides the possibility to target areas of inflammation, increase drug efficacy, and minimize damage to the surrounding tissue. [ 3 ] [ 11 ]  Moreover, because this concentration gradient is ubiquitous in the microenvironment of inflammatory diseases, common drug-targeting limitations such as individual differences can be avoided. [ 7 ]  Another example of an innovative drug delivery system that uses the property of chemotaxis is leukocytes. [ 4 ]  Indeed, during inflammation, the molecules on a cell that allows for adhesion are overly produced. [ 4 ]  With this unique condition, researchers can modify leukocytes to quickly detect the cell, attach itself to the surface, and deliver a therapeutic payload. [ 4 ]  Overall, many promising therapies and drug delivery systems are being developed to target inflammation more effectively. Chemotactic drug delivery systems are just one of many promising avenues that seek to increase target sites specifically, decreasing the needed drug dosage, reducing toxicity, and increasing drug efficacy. [ 3 ] [ 4 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9561", "text": "While this emerging field of drug delivery shows excellent promise in targeting specific cells and locations within the body, understanding current challenges and drawbacks can allow researchers to optimize design, development, and delivery to improve the overall outcome of their medical treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9562", "text": "Generally speaking, chemotactic drug-targeting is a drug delivery strategy with promising avenues for treating diseases such as cancer and inflammation. This approach mimics the biological process of chemotaxis, which biological organisms use to detect, maneuver, and react to chemical signals in their environment. By applying this technique to targeted drug delivery, researchers aim to create drugs that can precisely reach their intended targets, minimizing the potential for side effects, improving drug efficacy, and decreasing drug dosage. Some examples include but are not limited to microdroplets, protocells, biological and bio-hybrid drug carriers, leukocytes, and neutrophils."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9563", "text": "While chemotactic drug targeting holds great promise for drug delivery, there are key advantages and limitations that must be considered. One main advantage is that these systems can precisely target specific cells, tissues, or organs within the body while minimizing their disruptive effects on healthy tissue. Moreover, by delivering the drug directly to the desired target, researchers can effectively reduce the required drug dosage needed. However, some limitations to chemotactic drug targeting include issues with biocompatibility, drug-carrying capacity, and the life span of specific carriers. Another major challenge with this approach is motility, when either the chemical stimuli diminish, or the attached enzymes become oversaturated. This can limit the effectiveness of the drug delivery system and may require additional modifications to improve its performance. Thus, although these approaches have shown great promise, more research is still needed to fully understand chemotaxis mechanisms and optimize this property for targeted drug delivery strategies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9564", "text": "In  pharmacokinetics , a  compartment  is a defined volume of  body fluids , typically of the  human body , but also those of other animals with multiple  organ systems . The meaning in this area of study is different from the concept of  anatomic compartments , which are bounded by  fasciae , the sheath of  fibrous tissue  that enclose  mammalian  organs. Instead, the concept focuses on broad types of fluidic systems. This analysis is used in attempts to mathematically describe distribution of small molecules throughout organisms with multiple compartments. Various  multi-compartment models  can be used in the areas of pharmacokinetics and  pharmacology , in the support of  efforts in  drug discovery , and in  environmental science ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9565", "text": "In humans and related organisms, there are five major body compartments: the  blood plasma ,  interstitial fluids ,  fat tissues ,  intracellular fluids , and  transcellular fluids , the latter of which includes fluids in the  pleural  ( peritoneal ) cavity. [ 1 ] [ verification needed ]  The relative percents of body mass of these are included in the following table."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9566", "text": "Context-sensitive half-life  or  context sensitive half-time  is defined as the time taken for  blood plasma  concentration of a drug to decline by one half after an infusion designed to maintain a  steady state  (i.e. a constant plasma concentration) has been stopped.  The \"context\" is the duration of infusion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9567", "text": "When a drug which has a multicompartmental  pharmacokinetic  model is given by  intravenous   infusion  it initially will distribute to the central compartment and then move out of this compartment into one or two peripheral compartments.  Once this infusion is discontinued, drug continues to move into the peripheral compartments until an  equilibrium  is reached.  At this  time, the only way drug may leave plasma is by  metabolism  or  excretion .  As the plasma concentration falls, the  concentration gradient  of drug reverses and drug moves from peripheral compartments back into plasma, maintaining the plasma concentration of the drug, often prolonging the pharmacological effect.  If an infusion has reached steady state then the context-sensitive half-life is equal to the  terminal plasma half-life  of the drug.  Otherwise  it will be shorter than the terminal elimination half-life."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9568", "text": "Remifentanil  is relatively context insensitive whilst  fentanyl  and  thiopentone  are examples of drugs which have significant context-sensitive changes in their half-life. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9569", "text": "The Context-Sensitive Half-Time describes the time required for the plasma drug concentration to decline by 50% after terminating an infusion of a particular duration. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9570", "text": "It is the time required for drug plasma concentration to decrease by 50% after stopping administration. The drug is administered continuously."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9571", "text": "Remifentanil is relatively context insensitive. Fentanyl and thiopental are examples of drugs which have significant context-sensitive changes in their half-life."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9572", "text": "The  Cooperstown cocktail [ 1 ]  refers to a panel of four drug probes used in human  pharmacokinetic  studies to determine the activity of  drug metabolising  enzymes. The terminology 'cocktail' refers to the fact that the drug probes are given together."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9573", "text": "The Cooperstown cocktail consists of four drugs that are considered specific substrates for four  cytochrome P450  (CYP) isoforms. One of the drugs ( caffeine ) provides, through its  metabolites , substrates for two additional enzymes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9574", "text": "The drugs and the enzymes they probe are as follows - caffeine (probes  CYP1A2 ,  N-acetyltransferase 2 ,  xanthine oxidase ),  midazolam  (probes  CYP3A ),  omeprazole  (probes  CYP2C19 ) and  dextromethorphan  (probes  CYP2D6 ). After giving the cocktail, the concentrations of the drugs and their metabolites in plasma (for midazolam and omeprazole) and urine (for caffeine and dextromethorphan) are determined at various times. By analysing these concentrations, it is possible to determine the activity (i.e. the  phenotype ) of the relevant enzyme. Caffeine can be used as a probe for three different enzymes by measuring several of its urinary metabolites and comparing their relative concentrations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9575", "text": "The 'Cooperstown 5 + 1 cocktail', [ 2 ]  in addition to the four drug probes mentioned above, incorporates  warfarin  as well. Warfarin (actually the S-warfarin  enantiomer ) is a specific probe for CYP2C9. The '+ 1' refers to the vitamin K that is given together with the warfarin to prevent any anticoagulant effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9576", "text": "The Cooperstown cocktail and the Cooperstown 5 + 1 cocktail are powerful tools for investigating the activity of important drug metabolising enzymes. They are used in human  drug interaction  studies in which the ability of a study drug to inhibit or induce cytochrome p450 enzymes is studied."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9577", "text": "Cytochromes P450  ( P450s  or  CYPs ) are a  superfamily  of  enzymes  containing  heme  as a  cofactor  that mostly, but not exclusively, function as  monooxygenases . [ 1 ]  However, they are not omnipresent; for example, they have not been found in  Escherichia coli . [ 2 ]  In mammals, these enzymes oxidize  steroids ,  fatty acids ,   xenobiotics , and participate in many biosyntheses. [ 1 ]  By hydroxylation, CYP450 enzymes  convert xenobiotics into hydrophilic derivatives, which are more readily excreted."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9578", "text": "P450s are, in general, the terminal oxidase enzymes in  electron transfer  chains, broadly categorized as  P450-containing systems . The term \"P450\" is derived from the  spectrophotometric  peak at the  wavelength  of the  absorption maximum  of the enzyme (450\u00a0 nm ) when it is in the  reduced  state and complexed with  carbon monoxide . Most P450s require a protein partner to deliver one or more  electrons  to reduce the  iron  (and eventually molecular  oxygen )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9579", "text": "Genes  encoding P450 enzymes, and the enzymes themselves, are designated with the  root symbol   CYP  for the  superfamily , followed by a number indicating the  gene family , a capital letter indicating the subfamily, and another numeral for the individual gene. The convention is to  italicize  the name when referring to the gene. For example,  CYP2E1  is the gene that encodes the enzyme  CYP2E1 \u2014one of the enzymes involved in  paracetamol  (acetaminophen) metabolism. The  CYP  nomenclature is the official naming convention, although occasionally  CYP450  or  CYP 450  is used synonymously. These names should never be used as according to the nomenclature convention (as they denote a P450 in family number 450). However, some gene or enzyme names for P450s are also referred to by historical names (e.g. P450 BM3  for CYP102A1) or functional names, denoting the catalytic activity and the name of the compound used as substrate. Examples include  CYP5A1 ,  thromboxane  A 2  synthase, abbreviated to  TBXAS1  ( T hrom B o X ane  A 2   S ynthase  1 ), and  CYP51A1 , lanosterol 14-\u03b1-demethylase, sometimes unofficially abbreviated to LDM according to its substrate ( L anosterol) and activity ( D e M ethylation). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9580", "text": "The current nomenclature guidelines suggest that members of new CYP families share at least 40%  amino-acid  identity, while members of subfamilies must share at least 55% amino-acid identity. Nomenclature committees assign and track both base gene names ( Cytochrome P450 Homepage   Archived  2010-06-27 at the  Wayback Machine ) and  allele  names ( CYP Allele Nomenclature Committee ). [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9581", "text": "Based on the nature of the electron transfer proteins, P450s can be classified into several groups: [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9582", "text": "The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH), while the other oxygen atom is  reduced  to water:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9583", "text": "Many  hydroxylation  reactions (insertion of  hydroxyl  groups) use CYP enzymes, but many other hydroxylases exist.   Alpha-ketoglutarate-dependent hydroxylases  also rely on an Fe=O intermediate but lack hemes.  Methane monooxygenase, which converts methane to methanol, are non-heme iron-and iron-copper-based enzymes. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9584", "text": "The active site of cytochrome P450 contains a heme-iron center. The iron is tethered to the protein via a  cysteine   thiolate   ligand . This cysteine and several flanking residues are highly conserved in known P450s, and have the formal  PROSITE  signature consensus pattern [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} -  C  - [LIVMFAP] - [GAD]. [ 8 ]   In general, the P450 catalytic cycle proceeds as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9585", "text": "Mechanistic details, including the  oxygen rebound mechanism , have been investigated with synthetic analogues, consisting of iron oxo heme complexes. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9586", "text": "Binding of substrate is reflected in the spectral properties of the enzyme, with an increase in absorbance at 390\u00a0nm and a decrease at 420\u00a0nm. This can be measured by difference spectroscopies and is referred to as the \"type\u00a0I\" difference spectrum (see inset graph in figure).  Some substrates cause an opposite change in spectral properties, a \"reverse type\u00a0I\" spectrum, by processes that are as yet unclear.  Inhibitors and certain substrates that bind directly to the heme iron give rise to the type\u00a0II difference spectrum, with a maximum at 430\u00a0nm and a minimum at 390\u00a0nm (see inset graph in figure).  If no reducing equivalents are available, this complex may remain stable, allowing the degree of binding to be determined from absorbance measurements  in vitro [ 13 ] \nC: If carbon monoxide (CO) binds to reduced P450, the catalytic cycle is interrupted. This reaction yields the classic CO difference spectrum with a maximum at 450\u00a0nm. However, the interruptive and inhibitory effects of CO varies upon different CYPs such that the CYP3A family is relatively less affected. [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9587", "text": "In  biochemistry ,  cytochrome P450 enzymes  have been identified in all  kingdoms  of life:  animals ,  plants ,  fungi ,  protists ,  bacteria , and  archaea , as well as in  viruses . [ 1 ]  As of 2018 [update] , more than 300,000 distinct CYP proteins are known. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9588", "text": "Human P450s are primarily membrane-associated proteins [ 4 ]  located either in the inner membrane of  mitochondria  or in the  endoplasmic reticulum  of cells. P450s metabolize thousands of  endogenous  and  exogenous  chemicals. Some P450s metabolize only one (or a very few) substrates, such as  CYP19  ( aromatase ), while others may metabolize multiple  substrates . Both of these characteristics account for  medicinal interest . Cytochrome P450 enzymes play roles in  hormone  synthesis and breakdown (including  estrogen  and  testosterone  synthesis and metabolism),  cholesterol  synthesis, and  vitamin D  metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including  drugs  and products of endogenous metabolism such as  bilirubin , principally in the  liver ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9589", "text": "The  Human Genome Project  has identified 57 human genes coding for the various cytochrome P450 enzymes. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9590", "text": "P450s are the major enzymes involved in  drug metabolism , accounting for about 75% of the total metabolism. [ 7 ]  Most drugs undergo deactivation by P450s, either directly or by facilitated  excretion  from the body. However, many substances are  bioactivated  by P450s to form their active compounds like the  antiplatelet drug   clopidogrel  and the opiate  codeine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9591", "text": "The CYP450 enzyme superfamily comprises 57 active subsets, with seven playing roles in the metabolism of most pharmaceuticals. [ 8 ]  The fluctuation in the amount of CYP450 enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) in phase 1 (detoxification) can have varying effects on individuals, as genetic expression varies from person to person. This variation is due to the enzyme's genetic polymorphism, which leads to variability in its function and expression. To optimize drug metabolism in individuals, genetic testing should be conducted to determine functional foods and specific phytonutrients that cater to the individual's CYP450 polymorphism. Understanding these genetic variations can help personalize drug therapies for improved effectiveness and reduced adverse reactions. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9592", "text": "Many drugs may increase or decrease the activity of various P450  isozymes  either by inducing the biosynthesis of an isozyme ( enzyme induction ) or by directly inhibiting the activity of the P450 ( enzyme inhibition ). A classical example includes  anti-epileptic drugs , such as  phenytoin , which induces  CYP1A2 ,  CYP2C9 ,  CYP2C19 , and  CYP3A4 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9593", "text": "Effects on P450 isozyme activity are a major source of adverse  drug interactions , since changes in P450 enzyme activity may affect the  metabolism  and  clearance  of various drugs. For example, if one drug inhibits the P450-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels. Hence, these drug interactions may necessitate dosage adjustments or choosing drugs that do not interact with the P450 system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9594", "text": "Many substrates for CYP3A4 are drugs with a narrow  therapeutic index , such as  amiodarone [ 10 ]  or  carbamazepine . [ 11 ]  Because these drugs are metabolized by CYP3A4, the  mean plasma levels  of these drugs may increase because of enzyme inhibition or decrease because of enzyme induction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9595", "text": "Naturally occurring compounds may also induce or inhibit P450 activity. For example,  bioactive  compounds found in  grapefruit juice  and some other fruit juices, including  bergamottin ,  dihydroxybergamottin , and  paradicin-A , have been found to inhibit CYP3A4-mediated metabolism of  certain medications , leading to increased  bioavailability  and, thus, the strong possibility of  overdosing . [ 12 ]  Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9596", "text": "Other examples:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9597", "text": "A subset of cytochrome P450 enzymes play roles in the synthesis of  steroid hormones  ( steroidogenesis ) by the  adrenals ,  gonads , and peripheral tissue:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9598", "text": "Certain cytochrome P450 enzymes are critical in metabolizing  polyunsaturated fatty acids  (PUFAs) to biologically active, intercellular  cell signaling  molecules ( eicosanoids ) and/or metabolize biologically active metabolites of the PUFA to less active or inactive products.  These CYPs possess  cytochrome P450 omega hydroxylase  and/or  epoxygenase  enzyme activity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9599", "text": "Humans have 57 genes and more than 59  pseudogenes  divided among 18 families of cytochrome P450 genes and 43 subfamilies. [ 23 ]  This is a summary of the genes and of the proteins they encode. See the homepage of the cytochrome P450 Nomenclature Committee for detailed information. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9600", "text": "Other animals often have more P450 genes than humans do. Reported numbers range from 35 genes in the sponge  Amphimedon queenslandica  to 235 genes in the cephalochordate  Branchiostoma floridae . [ 24 ]   Mice  have genes for 101 P450s, and  sea urchins  have even more (perhaps as many as 120 genes). [ 25 ] \nMost CYP enzymes are presumed to have monooxygenase activity, as is the case for most mammalian CYPs that have been investigated (except for, e.g.,  CYP19  and  CYP5 ).  Gene  and  genome sequencing  is far outpacing  biochemical  characterization of enzymatic function, though many genes with close  homology  to CYPs with known function have been found, giving clues to their functionality."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9601", "text": "The classes of P450s most often investigated in non-human animals are those either involved in  development  (e.g.,  retinoic acid  or  hormone  metabolism) or involved in the metabolism of toxic compounds (such as  heterocyclic amines  or  polyaromatic hydrocarbons ). Often there are differences in  gene regulation  or  enzyme function  of P450s in related animals that explain observed differences in susceptibility to toxic compounds (ex. canines' inability to metabolize xanthines such as caffeine). Some drugs undergo metabolism in both species via different enzymes, resulting in different metabolites, while other drugs are metabolized in one species but excreted unchanged in another species. For this reason, one species's reaction to a substance is not a reliable indication of the substance's effects in humans. A species of Sonoran Desert Drosophila that uses an upregulated expression of the  CYP28A1  gene for detoxification of cacti rot is  Drosophila mettleri . Flies of this species have adapted an upregulation of this gene due to exposure of high levels of alkaloids in host plants."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9602", "text": "P450s have been extensively examined in  mice ,  rats ,  dogs ,  zebrafish , and turkeys. [ 26 ]   CYP1A5  and  CYP3A37  in turkeys were found to be very similar to the human  CYP1A2  and  CYP3A4  respectively, in terms of their kinetic properties as well as in the metabolism of aflatoxin B1. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9603", "text": "CYPs have also been extensively studied in  insects , often to understand  pesticide resistance .  For example,  CYP6G1  is linked to insecticide resistance in  DDT -resistant  Drosophila melanogaster [ 28 ]  and  CYP6M2  in the mosquito  malaria  vector  Anopheles gambiae  is capable of directly metabolizing  pyrethroids . [ 29 ]  Other cytochromes, such as those in  Anopheles gambiae , are under preliminary research for their potential role in  pesticide resistance ,  infectious diseases , and  malaria . [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9604", "text": "Microbial cytochromes P450 are often soluble enzymes and are involved in diverse metabolic processes. In bacteria the distribution of P450s is very variable with many bacteria having no identified P450s (e.g.  E.coli ). Some bacteria, predominantly actinomycetes, have numerous P450s (e.g., [ 31 ] [ 32 ] ). Those so far identified are generally involved in either biotransformation of xenobiotic compounds (e.g.  CYP105A1  from  Streptomyces griseolus  metabolizes  sulfonylurea herbicides  to less toxic derivatives, [ 33 ] ) or are part of specialised metabolite biosynthetic pathways (e.g.  CYP170B1  catalyses production of the  sesquiterpenoid  albaflavenone in  Streptomyces albus [ 34 ] ). Although no P450 has yet been shown to be essential in a microbe, the  CYP105 family  is highly conserved with a representative in every  streptomycete  genome sequenced so far. [ 35 ]  Due to the solubility of bacterial P450 enzymes, they are generally regarded as easier to work with than the predominantly membrane bound eukaryotic P450s. This, combined with the remarkable chemistry they catalyse, has led to many studies using the  heterologously expressed proteins  in vitro. Few studies have investigated what P450s do in vivo, what the natural substrate(s) are and how P450s contribute to survival of the bacteria in the natural environment.Three examples that have contributed significantly to structural and mechanistic studies are listed here, but many different families exist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9605", "text": "The commonly used  azole  class of antifungal drugs works by inhibition of the fungal  cytochrome P450 14\u03b1-demethylase . [ 40 ] [ better\u00a0source\u00a0needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9606", "text": "Cytochromes P450 are involved in a variety of processes of plant growth, development, and defense. It is estimated that P450 genes make up approximately 1% of the plant genome. [ 41 ] [ 42 ]  These enzymes lead to various  fatty acid  conjugates,  plant hormones ,  secondary metabolites ,  lignins , and a variety of defensive compounds. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9607", "text": "Cytochromes P450 play roles in plant defense\u2013 involvement in phytoalexin biosynthesis, hormone metabolism, and biosynthesis of diverse secondary metabolites. [ 44 ]  The expression of cytochrome p450 genes is regulated in response to environmental stresses indicative of a critical role in plant defense mechanisms. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9608", "text": "The biosynthesis of phytoalexins, antimicrobial compounds produced by some plants, involves the P450 enzymes CYP79B2, CYP79B3, CYP71A12, CYP71A13, and CYP71B15. The first step of camalexin biosynthesis produces indole-3-acetaldoxime (IAOx) from tryptophan and is catalyzed by either CYP79B2 or CYP79B3. IAOx is then immediately converted to indole-3-acetonitrile (IAN) and is controlled by either CYP71A13 or its homolog CYP71A12. The last two steps of the biosynthesis pathway of camalexin are catalyzed by CYP71B15. In these steps, indole-3-carboxylic acid (DHCA) is formed from cysteine-indole-3-acetonitrile (Cys(IAN)) followed by the biosynthesis of camalexin. There are some intermediate steps within the pathway that remain unclear, but it is well understood that cytochrome P450 is pivotal in camalexin biosynthesis and that this phytoalexin plays a major role in plant defense mechanisms. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9609", "text": "Cytochromes P450 are largely responsible for the synthesis of the jasmonic acid (JA), a common hormonal defenses against abiotic and biotic stresses for plant cells. For example, a P450, CYP74A is involved in the dehydration reaction to produce an insatiable allene oxide from hydroperoxide. [ 47 ]  JA chemical reactions are critical in the presence of biotic stresses that can be caused by plant wounding, specifically shown in the plant, Arabidopsis. As a prohormone, jasmonic acid must be converted to the JA-isoleucine (JA-Ile) conjugate by JAR1 catalysation in order to be considered activated. Then, JA-Ile synthesis leads to the assembly of the co-receptor complex compo`sed of COI1 and several JAZ proteins. Under low JA-Ile conditions, the JAZ protein components act as transcriptional repressors to suppress downstream JA genes. However, under adequate JA-Ile conditions, the JAZ proteins are ubiquitinated and undergo degradation through the 26S proteasome, resulting in functional downstream effects. Furthermore, several CYP94s (CYP94C1 and CYP94B3) are related to JA-Ile turnover and show that JA-Ile oxidation status impacts plant signaling in a catabolic manner. [ 41 ]  Cytochrome P450 hormonal regulation in response to extracellular and intracellular stresses is critical for proper plant defense response. This has been proven through thorough analysis of various CYP P450s in jasmonic acid and phytoalexin pathways."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9610", "text": "Cytochrome P450 aromatic O-demethylase , which is made of two distinct promiscuous parts: a cytochrome P450 protein (GcoA) and three domain reductase, is significant for its ability to convert Lignin, the aromatic biopolymer common in plant cell walls, into renewable carbon chains in a catabolic set of reactions. In short, it is a facilitator of a critical step in Lignin conversion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9611", "text": "InterPro  subfamilies:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9612", "text": "Clozapine, imipramine, paracetamol, phenacetin Heterocyclic aryl amines\nInducible and CYP1A2 5-10% deficient\noxidize uroporphyrinogen to uroporphyrin (CYP1A2) in heme metabolism, but they may have additional undiscovered endogenous substrates.\nare inducible by some polycyclic hydrocarbons, some of which are found in cigarette smoke and charred food."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9613", "text": "These enzymes are of interest, because in assays, they can activate compounds to carcinogens.\nHigh levels of CYP1A2 have been linked to an increased risk of colon cancer. Since the 1A2 enzyme can be induced by cigarette smoking, this links smoking with colon cancer. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9614", "text": "In the pharmaceutical industry, drug  dissolution testing  is routinely used to provide critical  in vitro  drug release information for both  quality control  purposes, i.e., to assess batch-to-batch consistency of solid oral dosage forms such as tablets, and  drug development , i.e., to predict  in vivo  drug release profiles. [ 1 ]  There are three typical situations where dissolution testing plays a vital role: (i) formulation and optimization decisions: during product development, for products where dissolution performance is a critical quality attribute, both the product formulation and the manufacturing process are optimized based on achieving specific dissolution targets. (ii) Equivalence decisions: during generic product development, and also when implementing post-approval process or formulation changes, similarity of in vitro dissolution profiles between the reference product and its generic or modified version are one of the key requirements for regulatory approval decisions. (iii) Product compliance and release decisions: during routine manufacturing, dissolution outcomes are very often one of the criteria used to make product release decisions. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9615", "text": "The main objective of developing and evaluating an  IVIVC  is to establish the dissolution test as a surrogate for human studies, as stated by the  Food and Drug Administration  (FDA). [ 5 ]  Analytical data from drug dissolution testing are sufficient in many cases to establish  safety  and  efficacy  of a drug product without  in vivo  tests, following minor formulation and manufacturing changes (Qureshi and Shabnam, 2001). Thus, the dissolution testing which is conducted in dissolution apparatus must be able to provide  accurate  and  reproducible  results."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9616", "text": "Several dissolution apparatuses exist.  In  United States Pharmacopeia  (USP) General Chapter <711> Dissolution, there are four dissolution apparatuses standardized and specified. [ 6 ]  They are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9617", "text": "The vessels of the dissolution method are usually either partially immersed in a water bath solution or heated by a jacket. An apparatus is used on solution within the vessels for a predetermined amount of time which depends on the method for the particular drug. The dissolution medium within the vessels are heated to 37\u00a0\u00b0C with an acceptable difference of \u00b1 0.5\u00a0\u00b0C  [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9618", "text": "The performances of dissolution apparatuses are highly dependent on hydrodynamics due to the nature of dissolution testing.   The designs of the dissolution apparatuses and the ways of operating dissolution apparatuses have huge impacts on the hydrodynamics, thus the performances.  Hydrodynamic studies in dissolution apparatuses were carried out by researchers over the past few years with both experimental methods and numerical modeling such as  Computational Fluid Dynamics  (CFD). The main target was USP Dissolution Apparatus 2. [ 1 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ]  The reason is that many researchers suspect that USP Dissolution Apparatus 2 provides inconsistent and sometimes faulty data. [ 15 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ] [ 20 ] [ 21 ]  The hydrodynamic studies of USP Dissolution Apparatus 2 mentioned above clearly showed that it does have intrinsic hydrodynamic issues which could result in problems. In 2005, Professor Piero Armenante from  New Jersey Institute of Technology  (NJIT) and Professor Fernando Muzzio from  Rutgers University  submitted a technical report to the FDA. [ 22 ]  In this technical report, the intrinsic hydrodynamic issues with USP Dissolution Apparatus 2 based on the research findings of Armenante's group and Muzzio's group were discussed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9619", "text": "More recently, hydrodynamic studies were conducted in USP Dissolution Apparatus 4. [ 23 ] [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9620", "text": "The general procedure for a dissolution involves a liquid known as Dissolution Medium which is placed in the vessels of a dissolution unit. The medium can range from degassed or sonicated deionized water to pH adjusted chemically-prepared solutions and mediums that are prepared with surfactants. [ 26 ]  Degassing the dissolution medium through sonication or other means is important since the presence of dissolved gases may affect results.  The drug is placed within the medium in the vessels after it has reached sufficient temperature and then the dissolution apparatus is operated. Sample solutions collected from dissolution testing are commonly analyzed by  HPLC  or  Ultraviolet\u2013visible spectroscopy . [ 27 ]  There are criteria known as 'release specifications' that samples tested must meet statistically, both as individual values and as average of the whole. [ 28 ] [ 29 ]  One such criteria is the parameter \"Q\", which is a percentage value denoting the quantity of dissolved active ingredient within the monograph of a sample solution. If the initial sample analysis, known as S1 or stage 1 testing fails to meet the acceptable value for Q, then additional testing known as stage 2 and 3 testing is required. S3 testing is performed only if S2 testing still fails the Q parameter. If there is a deviation from the acceptable Q values at S3, then an OOS (Out of Specification) investigation is generally initiated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9621", "text": "Distribution  in  pharmacology  is a branch of  pharmacokinetics  which describes the reversible transfer of a drug from one location to another within the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9622", "text": "Once a drug enters into systemic circulation by absorption or direct administration, it must be distributed into interstitial and intracellular fluids. Each organ or tissue can receive different doses of the drug and the drug can remain in the different organs or tissues for a varying amount of time. [ 1 ]  The distribution of a drug between tissues is dependent on  vascular permeability , regional blood flow, cardiac output and  perfusion  rate of the tissue and the ability of the drug to bind tissue and  plasma proteins  and its lipid solubility.  pH partition  plays a major role as well. The drug is easily distributed in highly perfused organs such as the liver, heart and kidney. It is distributed in small quantities through less perfused tissues like muscle, fat and peripheral organs. The drug can be moved from the plasma to the tissue until the equilibrium is established (for unbound drug present in plasma)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9623", "text": "The concept of compartmentalization of an organism must be considered when discussing a drug's distribution. This concept is used in pharmacokinetic modelling."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9624", "text": "There are many factors that affect a drug's distribution throughout an organism, but Pascuzzo [ 1 ]  considers that the most important ones are the following: an organism's physical volume, the removal rate and the degree to which a drug binds with plasma proteins and / or tissues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9625", "text": "This concept is related to multi-compartmentalization. Any drugs within an organism will act as a  solute  and the organism's tissues will act as  solvents . The differing specificities of different tissues will give rise to different concentrations of the drug within each group. Therefore, the chemical characteristics of a drug will determine its distribution within an organism. For example, a liposoluble drug will tend to accumulate in body fat and water-soluble drugs will tend to accumulate in extracellular fluids.  The  volume of distribution  (V D ) of a drug is a property that quantifies the extent of its distribution. It can be defined as the theoretical volume that a drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. It can be determined from the following formula:\n \n \n \n \n V \n d \n = \n \n \n \n A \n b \n \n \n C \n p \n \n \n \n \n \n \n {\\displaystyle Vd={\\frac {Ab}{Cp}}\\,} \n \n \nWhere:  \n \n \n \n A \n b \n \n \n {\\displaystyle Ab} \n \n  is total amount of the drug in the body and  \n \n \n \n C \n p \n \n \n {\\displaystyle Cp} \n \n  is the drug's plasma concentration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9626", "text": "As the value for  \n \n \n \n A \n b \n \n \n {\\displaystyle Ab} \n \n  is equivalent to the dose of the drug that has been administered the formula shows us that there is an inversely proportional relationship between  \n \n \n \n V \n d \n \n \n {\\displaystyle Vd} \n \n  and  \n \n \n \n C \n p \n \n \n {\\displaystyle Cp} \n \n . That is, that the greater  \n \n \n \n C \n p \n \n \n {\\displaystyle Cp} \n \n  is the lower  \n \n \n \n V \n d \n \n \n {\\displaystyle Vd} \n \n  will be and vice versa. It therefore follows that the factors that increase  \n \n \n \n C \n p \n \n \n {\\displaystyle Cp} \n \n  will decrease  \n \n \n \n V \n d \n \n \n {\\displaystyle Vd} \n \n . This gives an indication of the importance of knowledge relating to the drug's plasma concentration and the factors that modify it."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9627", "text": "If this formula is applied to the concepts relating to bioavailability, we can calculate the amount of drug to administer in order to obtain a required concentration of the drug in the organism (' loading dose ):"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9628", "text": "D \n c \n = \n \n \n \n V \n d \n . \n C \n p \n \n \n D \n a \n . \n B \n \n \n \n \n \n {\\displaystyle Dc={\\frac {Vd.Cp}{Da.B}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9629", "text": "This concept is of clinical interest as it is sometimes necessary to reach a certain concentration of a drug that is known to be optimal in order for it to have the required effects on the organism (as occurs if a patient is to be scanned)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9630", "text": "A drug's removal rate will be determined by the proportion of the drug that is removed from circulation by each organ once the drug has been delivered to the organ by the circulating blood supply. [ 1 ]  \nThis new concept builds on earlier ideas and it depends on a number of distinct factors:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9631", "text": "Some drugs have the capacity to bind with certain types of proteins that are carried in blood plasma. This is important as only drugs that are present in the plasma in their free form can be transported to the tissues. Drugs that are bound to plasma proteins therefore act as a reservoir of the drug within the organism and this binding reduces the drug's final concentration in the tissues. The binding between a drug and plasma protein is rarely specific and is usually  labile  and reversible. The binding generally involves  ionic bonds ,  hydrogen bonds ,  Van der Waals forces  and, less often,  covalent bonds . This means that the bond between a drug and a protein can be broken and the drug can be replaced by another substance (or another drug) and that, regardless of this, the protein binding is subject to  saturation . An equilibrium also exists between the free drug in the blood plasma and that bound to proteins, meaning that the proportion of the drug bound to plasma proteins will be stable, independent of its total concentration in the plasma."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9632", "text": "In vitro studies carried out under optimum conditions have shown that the equilibrium between a drug's plasmatic concentration and its tissue concentration is only significantly altered at binding rates to plasma proteins of greater than 90%. Above these levels the drug is \"sequestered\", which decreases its presence in tissues by up to 50%. This is important when considering pharmacological interactions: the tissue concentration of a drug with a plasma protein binding rate of less than 90% is not going to significantly increase if that drug is displaced from its union with a protein by another substance.  On the other hand, at binding rates of greater than 95% small changes can cause important modifications in a drug's tissue concentration. This will, in turn, increase the risk of the drug having a toxic effect on tissues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9633", "text": "Perhaps the most important plasma proteins are the  albumins  as they are present in relatively high concentrations and they readily bind to other substances. Other important proteins include the  glycoproteins , the  lipoproteins  and to a lesser degree the  globulins ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9634", "text": "It is therefore easy to see that clinical conditions that modify the levels of plasma proteins (for example,  hypoalbuminemias  brought on by renal dysfunction) may affect the effect and toxicity of a drug that has a binding rate with plasma proteins of above 90%."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9635", "text": "Highly lipid-soluble drugs given by intravenous or inhalation methods are initially distributed to organs with high blood flow. Later, less vascular but more bulky tissues (such as muscle and fat) take up the drug\u2014plasma concentration falls and the drug is withdrawn from these sites. If the site of action of the drug was in one of the highly perfused organs, redistribution results in termination of the drug action. The greater the lipid solubility of the drug, the faster its redistribution will be. For example, the anaesthetic action of thiopentone is terminated in a few minutes due to redistribution. However, when the same drug is given repeatedly or continuously over long periods, the low-perfusion and high-capacity sites are progressively filled up and the drug becomes longer-acting."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9636", "text": "Dosage forms  (also called  unit doses ) are  pharmaceutical drug  products presented in a specific form for use. They contain a mixture of  active ingredients  and inactive components ( excipients ), configured in a particular way (such as a  capsule  shell) and apportioned into a specific  dose . For example, two products may both be  amoxicillin , but one may come in 500\u00a0mg capsules, while another may be in 250\u00a0mg chewable tablets."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9637", "text": "The term  unit dose  can also refer to non-reusable packaging, particularly when each drug product is individually packaged. [ 1 ]  However, the FDA differentiates this by referring to it as  unit-dose \"packaging\" or \"dispensing\" . [ 2 ]  Depending on the context,  multi(ple) unit dose  may refer to multiple distinct drug products  packaged  together or a  single  product containing multiple drugs and/or doses."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9638", "text": "The term  dosage form  may also sometimes refer only to the  pharmaceutical formulation  of a drug product's constituent substances, without considering its final configuration as a consumable product (e.g., capsule, patch, etc.). Due to the somewhat ambiguous nature and overlap of these terms within the pharmaceutical industry, caution is advisable when discussing them with others who may interpret the terminology differently."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9639", "text": "Dosage forms vary depending on the method/route of administration, which can include many types of liquid, solid, and semisolid forms. Common dosage forms include  pills ,  tablets , capsules,  drinks , and  syrups , among others."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9640", "text": "A  combination drug  (or fixed-dose combination; FDC) is a product that contains more than one  active ingredient  (e.g., one tablet, one capsule, or one syrup with multiple drugs)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9641", "text": "In  naturopathy , dosages can take the form of  decoctions  and  herbal teas , in addition to the more conventional methods mentioned above."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9642", "text": "The  route of administration  (ROA) for  drug delivery  depends on the dosage form of the  substance . Different dosage forms may be available for a particular drug, especially if certain conditions restrict the ROA. For example, if a patient is unconscious or experiencing persistent  nausea  and  vomiting , oral administration may not be feasible, necessitating the use of alternative routes, such as  inhalational ,  buccal ,  sublingual ,  nasal ,  suppository , or  parenteral ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9643", "text": "A specific dosage form may also be required due to issues such as  chemical stability  or  pharmacokinetic  properties. For instance,  insulin  cannot be given orally because it is extensively  metabolized  in the  gastrointestinal tract  (GIT) before it reaches the  bloodstream , preventing it from reaching therapeutic target destinations. Similarly, the oral and intravenous doses of a drug like  paracetamol  differ for the same reason. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9644", "text": "Talc is an  excipient  often used in pharmaceutical tablets that may end up being crushed to a powder against medical advice or for recreational use. Also,  illicit drugs  that occur as white powder in their pure form are often  cut  with cheap  talc . Natural talc is cheap but contains  asbestos  while asbestos-free talc is more expensive. Inhaled talc that has asbestos is generally accepted as being able to cause lung cancer if it is inhaled. The evidence about asbestos-free talc is less clear, according to the  American Cancer Society . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9645", "text": "These are usually solutions and suspensions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9646", "text": "Eye drops  (normal saline in disposable packages) are distributed to syringe users by  needle exchange programs . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9647", "text": "The injection of talc from crushed pills has been associated with  pulmonary talcosis  in intravenous drug users. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9648", "text": "The  action of drugs  on the human body (or any other organism's body) is called  pharmacodynamics , and the  body's response to drugs  is called  pharmacokinetics . The drugs that enter an individual tend to stimulate certain  receptors ,  ion channels , act on  enzymes  or  transport proteins . As a result, they cause the human body to react in a specific way."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9649", "text": "Based on drug action on receptors, there are 2 different types of drugs:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9650", "text": "Once the receptors are activated, they either trigger a particular response directly on the body, or they trigger the release of  hormones  and/or other endogenous drugs in the body to stimulate a particular response."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9651", "text": "Drugs interact with receptors by bonding at specific binding sites. Most receptors are made up of proteins, and the drugs can therefore interact with the amino acids to change the conformation of the receptor proteins."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9652", "text": "These interactions are very basic, just like that of other chemical bondings:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9653", "text": "Mainly occur through attractions between opposite charges; for example, between protonated amino (on  salbutamol ) or quaternary ammonium (e.g.  acetylcholine ), and the dissociated  carboxylic acid  group. Similarly, the dissociated carboxylic acid group on the drug can bind with  amino  groups on the receptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9654", "text": "This type of bond is very strong, and varies with the inverse of the distance between the atoms so that it can act over large distances."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9655", "text": "Cation-\u03c0 interactions  can also be classified as ionic bonding. This type of interaction occurs when a cation, e.g. acetylcholine, interacts with the negative  \u03c0 bonds  on an aromatic group of the receptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9656", "text": "Ion-dipole  and  dipole-dipole  bonds have similar interactions, but are more complicated and are weaker than ionic bonds."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9657", "text": "There is a small but significant attraction between  hydrogen atoms  and polar functional groups (e.g. the  hydroxyl  [-OH] group). These so-called hydrogen bonds only act over short distances, and are dependent on the correct alignment between functional groups."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9658", "text": "Receptors are located on all cells in the body. The same receptor can be located on different organs, and even on different types of tissues. There are also different subtypes of receptor which elicit different effects in response to the same agonist. For example, there are two types of  histamine receptor :  H1  and  H2 . Activation of the H1 subtype receptor causes contraction of smooth muscle, whereas activation of the H2 receptor stimulates gastric secretion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9659", "text": "It is this phenomenon that gives rise to drug specificity. Of course, drugs do not only act on receptors: they also act on  ion channels ,  enzymes , and cell transporter proteins. These hydrogen bonds are so powerful than the  ionic bonds ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9660", "text": "When talking about the  shape of molecules ,  biochemists  are mainly concerned with the three-dimensional conformation of drug molecules. There are many  isomers  of a particular drug, and each one will have its own effects. Differences in isomer affect not only what the drug activates, but also changes the  potency  of each drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9661", "text": "Potency  is a measure of how much a drug is required in order to produce a particular effect. Therefore, only a small dosage of a high potency drug is required to induce a large response. The other terms used to measure the ability of a drug to trigger a response are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9662", "text": "Drug companies invest significant effort in designing drugs that interact specifically with particular receptors, [ 1 ]  since non-specific drugs can cause more side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9663", "text": "An example is the  endogenous  drug acetylcholine (ACh).  ACh is used by the  parasympathetic nervous system  to activate muscarinic receptors and by the neuromuscular system to activate nicotinic receptors.  However, the compounds muscarine and nicotine can each preferentially interact one of the two receptor types, allowing them to activate only one of the two systems where ACh itself would activate both."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9664", "text": "The specificity of drugs cannot be talked about without mentioning the  affinity  of the drugs. The affinity is a measure of how tightly a drug binds to the receptor. If the drug does not bind well, then the action of the drug will be shorter and the chance of binding will also be less. This can be measured numerically by using the dissociation constant K D . The value of K D  is the same as the concentration of drug when 50% of receptors are occupied."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9665", "text": "The equation can be expressed as K D  =  \n \n \n \n \n \n \n [ \n d \n r \n u \n g \n ] \n [ \n r \n e \n c \n e \n p \n t \n o \n r \n ] \n \n \n [ \n c \n o \n m \n p \n l \n e \n x \n ] \n \n \n \n \n \n {\\displaystyle {\\frac {[drug][receptor]}{[complex]}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9666", "text": "But the value of K D  is also affected by the conformation, bonding and size of the drug and the receptor. The higher the K D  the lower the affinity of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9667", "text": "Drug metabolism  is the  metabolic breakdown  of  drugs  by living  organisms , usually through specialized  enzymatic  systems. More generally,  xenobiotic metabolism  (from the Greek  xenos  \"stranger\"  and biotic \"related to living beings\") is the set of  metabolic pathways  that modify the chemical structure of  xenobiotics , which are compounds foreign to an organism's normal biochemistry, such as any  drug  or  poison . These pathways are a form of  biotransformation  present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to  detoxify  poisonous compounds (although in some cases the  intermediates  in xenobiotic metabolism can themselves cause toxic effects). The study of drug metabolism is the object of  pharmacokinetics . Metabolism is one of the stages (see  ADME ) of the drug's transit through the body that involves the breakdown of the drug so that it can be excreted by the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9668", "text": "The metabolism of  pharmaceutical drugs  is an important aspect of  pharmacology  and  medicine . For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects  multidrug resistance  in  infectious diseases  and in  chemotherapy  for  cancer , and the actions of some drugs as  substrates  or  inhibitors  of enzymes involved in xenobiotic metabolism are a common reason for hazardous  drug interactions . These pathways are also important in  environmental science , with the xenobiotic metabolism of  microorganisms  determining whether a pollutant will be broken down during  bioremediation , or  persist  in the environment. The enzymes of xenobiotic metabolism, particularly the  glutathione S-transferases  are also important in agriculture, since they may produce resistance to  pesticides  and  herbicides ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9669", "text": "Drug metabolism is divided into three phases. In phase I, enzymes such as  cytochrome P450 oxidases  introduce reactive or polar groups into xenobiotics. These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalysed by  transferase  enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognised by  efflux transporters  and pumped out of cells. Drug metabolism often converts  lipophilic  compounds into  hydrophilic  products that are more readily  excreted . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9670", "text": "The exact compounds an organism is exposed to will be largely unpredictable, and may differ widely over time; these are major characteristics of xenobiotic toxic stress. [ 1 ]  The major challenge faced by xenobiotic detoxification systems is that they must be able to remove the almost-limitless number of xenobiotic compounds from the complex mixture of chemicals involved in normal  metabolism . The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificity  enzymatic  systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9671", "text": "All organisms use  cell membranes  as hydrophobic permeability barriers to control access to their internal environment. Polar compounds cannot diffuse across these cell membranes, and the uptake of useful molecules is mediated through  transport proteins  that specifically select substrates from the extracellular mixture. This selective uptake means that most  hydrophilic  molecules cannot enter cells, since they are not recognised by any specific transporters. [ 2 ]  In contrast, the diffusion of  hydrophobic  compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude  lipid -soluble xenobiotics using membrane barriers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9672", "text": "However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics. These systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound. [ 1 ]  Useful metabolites are excluded since they are polar, and in general contain one or more charged groups."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9673", "text": "The detoxification of the reactive by-products of normal metabolism cannot be achieved by the systems outlined above, because these species are derived from normal cellular constituents and usually share their polar characteristics. However, since these compounds are few in number, specific enzymes can recognize and remove them. Examples of these specific detoxification systems are the  glyoxalase system , which removes the reactive  aldehyde  methylglyoxal, [ 3 ]  and the various antioxidant systems that eliminate  reactive oxygen species . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9674", "text": "The metabolism of xenobiotics is often divided into three phases: modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9675", "text": "In phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the  cytochrome P-450-dependent mixed-function oxidase system . These enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates. [ 5 ]  The reaction mechanism of the P-450 oxidases proceeds through the reduction of cytochrome-bound oxygen and the generation of a highly-reactive oxyferryl species, according to the following scheme: [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9676", "text": "Phase I reactions (also termed nonsynthetic reactions) may occur by  oxidation ,  reduction ,  hydrolysis ,  cyclization , decyclization, and addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve a  cytochrome P450  monooxygenase (often abbreviated CYP), NADPH and oxygen. The classes of pharmaceutical drugs that utilize this method for their metabolism include  phenothiazines ,  paracetamol , and steroids. If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an  endogenous   substrate  combines with the newly incorporated functional group to form a highly polar conjugate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9677", "text": "A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts a pharmacologically inactive compound (a  prodrug ) to a pharmacologically active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one ( toxification ). Simple hydrolysis in the stomach is normally an innocuous reaction, however there are exceptions. For example, phase I metabolism converts  acetonitrile  to HOCH 2 CN, which rapidly dissociates into  formaldehyde  and  hydrogen cyanide . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9678", "text": "Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts. [ 8 ]  This example of a  biomimetic  reaction tends to give products that often contains the Phase I metabolites. As an example, the major metabolite of the pharmaceutical  trimebutine , desmethyltrimebutine (nor-trimebutine), can be efficiently produced by in vitro oxidation of the commercially available drug.  Hydroxylation of an N-methyl group leads to expulsion of a molecule of  formaldehyde , while oxidation of the O-methyl groups takes place to a lesser extent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9679", "text": "Cytochrome P450 reductase, also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR, is a membrane-bound enzyme required for electron transfer to cytochrome P450 in the microsome of the eukaryotic cell from a FAD- and FMN-containing enzyme NADPH:cytochrome P450 reductase\nThe general scheme of electron flow in the POR/P450 system is:\nNADPH\n\u2192\nFAD\n\u2192\nFMN\n\u2192\nP450\n\u2192\nO 2"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9680", "text": "During reduction reactions, a chemical can enter  futile cycling , in which it gains a free-radical electron, then promptly loses it to  oxygen  (to form a  superoxide anion )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9681", "text": "In subsequent phase II reactions, these activated xenobiotic metabolites are  conjugated  with charged species such as  glutathione  (GSH),  sulfate ,  glycine , or  glucuronic acid . Sites on drugs where conjugation reactions occur include  carboxy  (-COOH),  hydroxy  (-OH),  amino  (NH 2 ), and  thiol  (-SH) groups. Products of conjugation reactions have increased  molecular weight and tend to be less active than their substrates, unlike Phase I reactions which often produce  active metabolites . The addition of large anionic groups (such as GSH) detoxifies reactive  electrophiles  and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9682", "text": "These reactions are catalysed by a large group of broad-specificity transferases, which in combination can metabolise almost any hydrophobic compound that contains nucleophilic or electrophilic groups. [ 1 ]  One of the most important classes of this group is that of the  glutathione S-transferases  (GSTs)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9683", "text": "After phase II reactions, the xenobiotic conjugates may be further metabolized. A common example is the processing of glutathione conjugates to  acetylcysteine  (mercapturic acid) conjugates. [ 11 ]  Here, the  \u03b3-glutamate  and  glycine  residues in the glutathione molecule are removed by  gamma-glutamyl transpeptidase  and  dipeptidases . In the final step, the  cysteine  residue in the conjugate is  acetylated ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9684", "text": "Conjugates and their metabolites can be excreted from cells in phase III of their metabolism, with the anionic groups acting as affinity tags for a variety of membrane transporters of the  multidrug resistance protein  (MRP) family. [ 12 ]  These proteins are members of the family of  ATP-binding cassette transporters  and can catalyse the ATP-dependent transport of a huge variety of hydrophobic anions, [ 13 ]  and thus act to remove phase II products to the extracellular medium, where they may be further metabolized or excreted. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9685", "text": "The detoxification of endogenous reactive metabolites such as  peroxides  and reactive  aldehydes  often cannot be achieved by the system described above. This is the result of these species' being derived from normal cellular constituents and usually sharing their polar characteristics. However, since these compounds are few in number, it is possible for enzymatic systems to utilize specific molecular recognition to recognize and remove them. The similarity of these molecules to useful metabolites therefore means that different detoxification enzymes are usually required for the metabolism of each group of endogenous toxins. Examples of these specific detoxification systems are the  glyoxalase system , which acts to dispose of the reactive aldehyde  methylglyoxal , and the various  antioxidant  systems that remove  reactive oxygen species ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9686", "text": "Quantitatively, the  smooth endoplasmic reticulum  of the  liver  cell is the principal organ of drug metabolism, although every  biological tissue  has some ability to metabolize drugs.\nFactors responsible for the liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in the  gut , and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs.\nIf a drug is taken into the GI tract, where it enters hepatic circulation through the  portal vein , it becomes well-metabolized and is said to show the  first pass effect ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9687", "text": "Other sites of drug metabolism include  epithelial cells  of the  gastrointestinal tract ,  lungs ,  kidneys , and the  skin .\nThese sites are usually responsible for localized toxicity reactions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9688", "text": "The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The  Cytochrome P450 monooxygenase system  is a crucial pathway in this regard. In general, anything that  increases  the rate of metabolism (e.g.,  enzyme induction ) of a pharmacologically active metabolite will  decrease  the duration and intensity of the drug action. The opposite is also true, as in  enzyme inhibition . However, in cases where an enzyme is responsible for metabolizing a pro-drug into a drug, enzyme induction can accelerate this conversion and increase drug levels, potentially causing toxicity. [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9689", "text": "Various  physiological  and  pathological  factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (e.g.,  pharmacogenetics ),  enterohepatic circulation ,  nutrition ,  sex differences  or  gut microbiota . [ medical citation needed ]  This last factor has significance because gut microorganisms are able to chemically modify the structure of drugs through degradation and biotransformation processes, thus altering the activity and toxicity of drugs. These processes can decrease the efficacy of drugs, as is the case of  digoxin  in the presence of  Eggerthella lenta  in the microbiota. [ 15 ]  Genetic variation ( polymorphism ) accounts for some of the variability in the effect of drugs. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9690", "text": "In general, drugs are metabolized more slowly in  fetal ,  neonatal  and  elderly   humans  and  animals  than in  adults . Inherited genetic variations in drug metabolising enzymes result in their different catalytic activity levels. For example, N-acetyltransferases (involved in  Phase II  reactions), individual variation creates a group of people who acetylate slowly ( slow acetylators ) and those who acetylate quickly ( rapid acetylators ), split roughly 50:50 in the population of Canada. However, variability in  NAT2  alleles distribution across different populations is high and some ethnicities have higher proportion of slow acetylators. [ 16 ]  This variation in metabolising capacity may have dramatic consequences, as the  slow acetylators  are more prone to dose-dependent toxicity.  NAT2  enzyme is a primary metaboliser of antituberculosis ( isoniazid ), some antihypertensive ( hydralazine ), anti-arrythmic drugs ( procainamide ), antidepressants ( phenelzine ) and many more  [ 17 ]  and increased toxicity as well as drug adverse reactions in slow acetylators have been widely reported. Similar phenomenons of altered metabolism due to inherited variations have been described for other drug-metabolising enzymes, like  CYP2D6 ,  CYP3A4 ,  DPYD ,  UGT1A1 .  DPYD  and  UGT1A1  genotyping is now required before administration of the corresponding substrate compounds ( 5-FU  and  capecitabine  for DPYD and  irinotecan  for UGT1A1) to determine the activity of DPYD and UGT1A1 enzyme and reduce the dose of the drug in order to avoid severe adverse reactions. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9691", "text": "Dose, frequency, route of administration, tissue distribution and protein binding of the drug affect its metabolism. [ medical citation needed ]   Pathological factors  can also influence drug metabolism, including  liver ,  kidney , or  heart  diseases. [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9692", "text": "In silico  modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects. [ 19 ]  This can be used to identify individuals most at risk from adverse reaction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9693", "text": "Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as  benzaldehyde  could be oxidized and conjugated to amino acids in the human body. [ 20 ]  During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as  methylation ,  acetylation , and  sulfonation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9694", "text": "In the early twentieth century, work moved on to the investigation of the enzymes and pathways that were responsible for the production of these metabolites. This field became defined as a separate area of study with the publication by  Richard Williams  of the book  Detoxication mechanisms  in 1947. [ 21 ]  This modern biochemical research resulted in the identification of glutathione  S -transferases in 1961, [ 22 ]  followed by the discovery of cytochrome P450s in 1962, [ 23 ]  and the realization of their central role in xenobiotic metabolism in 1963. [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9695", "text": "This is a table of  drugs  that are  secreted  in the  kidney ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9696", "text": "Acid medication are, because of  pH partition , secreted to a higher extent when urine is basic. In the same way, basic medications are secreted to a higher extent when urine is acidic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9697", "text": "In  pharmacology , the  elimination  or  excretion  of a drug is understood to be any one of a number of processes by which a drug is eliminated (that is,  cleared  and  excreted ) from an organism either in an unaltered form (unbound molecules) or modified as a metabolite. The  kidney  is the main excretory organ although others exist such as the  liver , the  skin , the  lungs  or  glandular  structures, such as the  salivary glands  and the  lacrimal glands . These organs or structures use specific routes to expel a drug from the body, these are termed  elimination pathways :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9698", "text": "Drugs are excreted from the kidney by  glomerular filtration  and by active  tubular secretion  following the same steps and mechanisms as the products of intermediate metabolism. Therefore, drugs that are filtered by the  glomerulus  are also subject to the process of passive  tubular reabsorption .  Glomerular filtration will only remove those drugs or metabolites that are not bound to proteins present in blood plasma (free fraction) and many other types of drugs (such as the organic acids) are actively secreted.  In the  proximal  and   distal convoluted tubules , non-ionised acids and weak bases are reabsorbed both actively and passively. Weak acids are excreted when the tubular fluid becomes too alkaline and this reduces passive reabsorption. The opposite occurs with weak bases. Poisoning treatments use this effect to increase elimination, by alkalizing the urine causing  forced diuresis  which promotes excretion of a weak acid, rather than it getting reabsorbed. As the acid is  ionised , it cannot pass through the  plasma membrane  back into the blood stream and instead gets excreted with the urine. Acidifying the urine has the same effect for weakly basic drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9699", "text": "On other occasions drugs combine with bile juices and enter the intestines. In the intestines the drug will join with the unabsorbed fraction of the administered dose and be eliminated with the faeces or it may undergo a new process of absorption to eventually be eliminated by the kidney."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9700", "text": "The other elimination pathways are less important in the elimination of drugs, except in very specific cases, such as the respiratory tract for alcohol or anaesthetic gases. The case of mother's milk is of special importance. The liver and kidneys of newly born  infants  are relatively undeveloped and they are highly sensitive to a drug's  toxic effects . For this reason it is important to know if a drug is likely to be eliminated from a woman's body if she is breast feeding in order to avoid this situation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9701", "text": "Pharmacokinetics studies the manner and speed with which drugs and their metabolites are eliminated by the various excretory organs. This elimination will be proportional to the drug's plasmatic concentrations. In order to model these processes a working definition is required for some of the concepts related to excretion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9702", "text": "The plasma half-life or  half life of elimination  is the time required to eliminate 50% of the absorbed dose of a drug from an organism. Or put another way, the time that it takes for the plasma concentration to fall by half from its maximum levels."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9703", "text": "The difference in a drug's concentration in arterial blood (before it has circulated around the body) and venous blood (after it has passed through the body's organs) represents the amount of the drug that the body has eliminated or  cleared . Although clearance may also involve other organs than the kidney, it is almost synonymous with  renal clearance  or  renal plasma clearance .  Clearance is therefore expressed as the plasma volume totally free of the drug per unit of time, and it is measured in units of volume per units of time.\nClearance can be determined on an overall, organism level (\u00absystemic clearance\u00bb) or at an organ level (hepatic clearance, renal clearance etc.). The equation that describes this concept is:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9704", "text": "Where:  \n \n \n \n C \n \n L \n \n o \n \n \n \n \n {\\displaystyle CL_{o}} \n \n  is the organ's clearance rate,  \n \n \n \n \n C \n \n A \n \n \n \n \n {\\displaystyle C_{A}} \n \n  is the drug's plasma concentration in arterial blood,  \n \n \n \n \n C \n \n V \n \n \n \n \n {\\displaystyle C_{V}} \n \n  is the drug's plasma concentration in venous blood and  \n \n \n \n Q \n \n \n {\\displaystyle Q} \n \n  an organ's blood flow."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9705", "text": "Each organ will have its own specific clearance conditions, which will relate to its mode of action. The \u00abrenal clearance\u00bb rate will be determined by factors such as the degree of  plasma protein binding  as the drug will only be filtered out if it is in the unbound free form, the degree of  saturation  of the transporters (active secretion depends on transporter proteins that can become saturated) or the number of functioning  nephrons  (hence the importance of factors such as  kidney failure )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9706", "text": "As \u00abhepatic clearance\u00bb is an active process it is therefore determined by factors that alter an organism's metabolism such as the number of functioning  hepatocytes , this is the reason that  liver failure  has such clinical importance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9707", "text": "The steady state or  stable concentration  is reached when the drug's supply to the blood plasma is the same as the rate of elimination from the plasma. It is necessary to calculate this concentration in order to decide the period between doses and the amount of drug supplied with each dose in prolonged treatments."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9708", "text": "Other parameters of interest include a drug's  bioavailability  and the  apparent volume of distribution ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9709", "text": "For elimination via bile please see: Estimation of Biliary Excretion of Foreign Compounds Using Properties of Molecular Structure. 2014. Sharifi M., Ghafourian T. AAPS J. 16(1) 65\u201378."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9710", "text": "An  enteric coating  is a  polymer  barrier applied to oral  medication  that prevents its dissolution or disintegration in the gastric environment. [ 1 ]  This helps by either protecting drugs from the acidity of the stomach, the stomach from the detrimental effects of the drug, or to release the drug after the stomach (usually in the upper tract of the intestine). [ 2 ]  Some drugs are unstable at the  pH  of gastric acid and need to be protected from degradation. Enteric coating is also an effective method to obtain  drug targeting  (such as gastro-resistant drugs). Other drugs such as some  anthelmintics  may need to reach a high concentration in a specific part of the intestine. [ 1 ]  Enteric coating may also be used during studies as a research tool to determine drug absorption. [ 3 ]  Enteric-coated medications pertain to the \"delayed action\" dosage form category.  Tablets , mini-tablets, pellets and granules (usually filled into  capsule  shells) are the most common enteric-coated  dosage forms . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9711", "text": "Most enteric coatings work by presenting a surface that is stable at the intensely acidic  pH  found in the stomach, but breaks down rapidly at a higher pH (alkaline pH). For example, they will not dissolve in the gastric acids of the  stomach  (pH ~3), but they will in the alkaline (pH 7\u20139) environment present in the  small intestine . [ 4 ] [ 5 ]  The time required for an enteric-coated dosage form to reach the intestine mostly depends on the presence and type of food in the stomach. It varies from 30 minutes up to 7 hours, with an average time of 6 hours. [ 6 ]  Although some studies indicated that larger sized dosage forms may require additional time for gastric emptying, others suggested that the size, shape, or volume of the tablet possess no significant effects instead. [ 7 ] [ 8 ] [ 9 ]  Enteric coated granules emptying rate is, however, less affected by the presence of food and present the more uniform release and reproducible transit time typical of the multiparticulates  dispersion . [ clarification needed ] [ 3 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9712", "text": "By preventing the drug from dissolving into the stomach, enteric coating may protect  gastric mucosa  from the irritating effects of the medication itself. When the drug reaches the neutral or alkaline environment of the intestine, its active ingredients can then dissolve and become available for absorption into the bloodstream. Drugs that have an irritant effect on the stomach, such as  aspirin  or  potassium chloride , can be coated with a substance that will dissolve only in the small intestine. However, it has been shown that enteric coated aspirin may lead to incomplete inhibition of  platelets , [ 10 ]   potentially negating the intended effect for those being treated for vascular disease. Likewise, certain groups of  proton pump inhibitors  ( esomeprazole ,  omeprazole ,  pantoprazole  and all grouped azoles) are acid-activated. For such drugs, enteric coating added to the formulation tends to avoid  activation  in the  mouth  and  esophagus ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9713", "text": "Materials used for enteric coatings include  fatty acids ,  waxes ,  shellac ,  plastics , and plant fibers. Conventional materials used are solutions of film resins. However, as the solvents for such solutions are organic solvents, there is a concern about the toxicity potential of the traces of the residual solvents in the tablet coating. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9714", "text": "The first form of gastro-resistant coating was introduced by Unna in 1884 in the form of  keratin -coated pills, although it was later discovered that they were not able to withstand gastric  digestion . [ 12 ]   Salol  was also used by Ceppi as one of the first forms of enteric coating. [ 13 ]  However, the first material that was extensively used as enteric coating agent was  shellac , since its introduction in 1930. Properly treated or hydrolyzed shellac showed different enteric release properties. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9715", "text": "Recently, some companies have begun to apply enteric coatings to  fish oil  ( omega-3 fatty acids ) supplements. The coating prevents the fish oil capsules from being digested in the stomach, which has been known to cause  gastroesophageal reflux ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9716", "text": "Sometimes the abbreviation \"EC\" is added beside the name of the drug to indicate that it has an enteric coating."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9717", "text": "Enzyme induction  is a process in which a  molecule  ( e.g.  a drug) induces ( i.e.  initiates or enhances) the  expression  of an  enzyme ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9718", "text": "Enzyme inhibition  can refer to"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9719", "text": "If the molecule induces enzymes that are responsible for its own  metabolism , this is called  auto-induction  (or  auto-inhibition  if there is inhibition). These processes are particular forms of  gene expression regulation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9720", "text": "These terms are of particular interest to  pharmacology , and more specifically to  drug metabolism  and  drug interactions . They also apply to  molecular biology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9721", "text": "In the late 1950s and early 1960s, the French molecular biologists  Fran\u00e7ois Jacob  and  Jacques Monod  became the first to explain enzyme induction, in the context of the  lac operon  of  Escherichia coli . In the absence of lactose, the constitutively expressed  lac repressor  protein binds to the operator region of the DNA and prevents the transcription of the operon genes. When present, lactose binds to the lac repressor, causing it to separate from the DNA and thereby enabling transcription to occur. Monod and Jacob generated this theory following 15 years of work by them and others (including  Joshua Lederberg ), partially as an explanation for Monod's observation of  diauxie . Previously, Monod had hypothesized that enzymes could physically adapt themselves to new substrates; a series of experiments by him, Jacob, and  Arthur Pardee  eventually demonstrated this to be incorrect and led them to the modern theory, for which he and Jacob shared the 1965  Nobel Prize in Physiology or Medicine  (together with  Andr\u00e9 Lwoff ). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9722", "text": "Index inducer  or just  inducer  predictably induce metabolism via a given  pathway  and are commonly used in prospective clinical  drug-drug interaction  studies. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9723", "text": "Strong, moderate, and weak inducers are drugs that decreases the AUC of  sensitive index substrates  of a given metabolic pathway by \u226580%, \u226550% to <80%, and \u226520% to <50%, respectively. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9724", "text": "A growing body of research has begun to highlight differences in the way racial and ethnic groups respond to psychiatric medication. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9725", "text": "Understanding the relevance between mental health and cultural associations is key to attempting to understand more about how the brain works for people of different ethnic and cultural groups. Mental health can be attributed to both the brain function but it can also be associated with environmental factors which can have a physiological effect. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9726", "text": "It has been noted that there are \"dramatic cross-ethnic and cross-national variations in the dosing practices and side-effect profiles in response to practically all classes of psychotropics.\" [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9727", "text": "It is important to understand epidemiology briefly since it can be connected with ethnopsychopharmacology. Studying how culture impacts the way disease is spread is important to in order to fully understand the racial disparities that impact how Western medication is used and perceived. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9728", "text": "Drug metabolism is controlled by a number of specific enzymes, and the action of these enzymes varies among individuals. For example, most individuals show normal activity of the IID6 isoenzyme that is responsible for the metabolism of many tricyclic antidepressant medications and most antipsychotic drugs. However, studies have found that one-third of Asian Americans and African Americans have a genetic alteration that decreases the metabolic rate of the IID6 isoenzyme, leading to a greater risk of side effects and toxicity. [ 5 ]  The CYP2D6 enzyme, important for the way in which the liver clears many drugs from the body, varies greatly between individuals in ways that can be ethnically specific. [ 2 ]   \nThough enzyme activity is genetically influenced, it can also be altered by cultural and environmental factors such as diet, the use of other medications, alcohol and disease states."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9729", "text": "If two individuals have the same blood level of a medication there may still be differences in the way that the body responds due to  pharmacodynamic  differences; pharmacodynamic responses may also be influenced by racial and cultural factors. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9730", "text": "In addition to biology and environment,  culturally determined  attitudes toward illness may affect how an individual responds to psychiatric medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9731", "text": "In addition to biology and environment,  culturally determined  attitudes toward illness and its treatment may affect how an individual responds to psychiatric medication. Some cultures see suffering and illness as unavoidable and not amenable to medication, [ 7 ]  while others treat symptoms with polypharmacy, often mixing medications with herbal drugs. [ 8 ]  Cultural differences may have an effect on adherence to medication regimes as well as influence the  placebo effect . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9732", "text": "Further, the way an individual expresses and reacts to the symptoms of psychiatric illness, and the cultural expectations of the physician, may affect the diagnosis a patient receives. For example, bipolar disorder often is misdiagnosed as schizophrenia in people of color."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9733", "text": "The differential response of many ethnic minorities to certain psychiatric medications raises important concerns for both research and practice."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9734", "text": "Include Ethnic Groups . Most studies of psychiatric medications have white male subjects. [ 6 ]  Because there is often a greater difference  within  racial and ethnic groups than between them, researchers must be certain they choose prototypical representatives of these groups, or use a larger random sample. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9735", "text": "Further, because broad racial and ethnic groups have many different subgroups. For example, in North American research it may not be enough to characterize individuals as Asian, Hispanic, Native American, or African American. [ 10 ]  Even within the same ethnic group, there are no reliable measures to determine important cultural differences. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9736", "text": "\" Start Low and Go Slow .\" Individuals who receive a higher dose of psychiatric medication than needed may discontinue treatment because of side effects, or they may develop toxic levels that lead to serious complications. A reasonable approach to prescribing medication to any psychiatric patient, regardless of race or culture, is to \"start low and go slow\". [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9737", "text": "Someday there may be a simple blood test to predict how an individual will respond to a specific class of drugs; research in these fields fall in the domain of  pharmacogenomics  and  pharmacometabolomics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9738", "text": "The  first pass effect  (also known as  first-pass metabolism  or  presystemic metabolism ) is a phenomenon of  drug metabolism  at a specific location in the body which leads to a reduction in the  concentration  of the active  drug  before it reaches the site of action or systemic circulation. [ 1 ] [ 2 ]  The effect is most associated with orally administered medications, but some drugs still undergo first-pass metabolism even when delivered via an alternate route (e.g., IV, IM, etc.). [ 3 ]  During this metabolism, drug is lost during the process of absorption which is generally related to the  liver  and gut wall. The liver is the major site of first pass effect; however, it can also occur in the lungs, vasculature or other metabolically active tissues in the body. Notable drugs that experience a significant first pass effect are  buprenorphine ,  chlorpromazine ,  cimetidine ,  diazepam ,  ethanol  (drinking alcohol),  imipramine ,  insulin ,  lidocaine ,  midazolam ,  morphine ,  pethidine ,  propranolol , and  tetrahydrocannabinol  (THC). First-pass metabolism is not to be confused with Phase I metabolism, which is a separate process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9739", "text": "First-pass metabolism may occur in the liver (for propranolol, lidocaine,  clomethiazole , and nitroglycerin) or in the gut (for  benzylpenicillin  and  insulin ). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9740", "text": "After a drug is swallowed, it is absorbed by the  digestive system  and enters the  hepatic portal system . It is carried through the  portal vein  into the  liver  before it reaches the rest of the body. The liver  metabolizes  many drugs, sometimes to such an extent that only a small amount of  active drug  emerges from the liver to the rest of the  circulatory system . This  first pass  through the liver thus may greatly reduce the  bioavailability  of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9741", "text": "An example of a drug where first-pass metabolism is a complication and disadvantage is in the antiviral drug  remdesivir . Remdesivir cannot be administered orally because the entire dose would be trapped in the liver with little achieving systemic circulation or reaching target organs and cells (for example, cells infected with  SARS-CoV-2 ). [ 5 ] [ 6 ]  For this reason, remdesivir is administered by IV infusion, bypassing the portal vein. However, significant hepatic extraction still occurs because of second pass metabolism, whereby a fraction of venous blood travels through the hepatic portal vein and hepatocytes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9742", "text": "The four primary systems that affect the first pass effect of a drug are the  enzymes  of the  gastrointestinal   lumen , gut wall enzymes, bacterial enzymes, and hepatic enzymes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9743", "text": "In  drug design , drug candidates may have good  druglikeness  but fail on first-pass metabolism because it is biochemically selective. [ ambiguous ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9744", "text": "Alternative  routes of administration , such as  insufflation ,  rectal administration , [ 7 ] [ 8 ]   intravenous ,  intramuscular ,  inhalational aerosol ,  transdermal , or  sublingual , avoid or partially avoid the first pass effect because they allow drugs to be absorbed directly into the  systemic circulation . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9745", "text": "Drugs with high first pass effect typically have a considerably higher oral dose than sublingual or  parenteral  dose. There is marked individual variation in the oral dose due to differences in the extent of first-pass metabolism, frequently among several other factors. Oral bioavailability of many vulnerable drugs appears to be increased in patients with compromised liver function. Bioavailability is also increased if another drug competing for first-pass metabolism enzymes is given concurrently (e.g., propranolol and  chlorpromazine )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9746", "text": "The  free fraction  is a parameter in  pharmacokinetics  and  receptor-ligand kinetics .\nOne speaks of two different free fractions:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9747", "text": "The  plasma free fraction  is the fraction of the  ligand  at equilibrium in  blood plasma  that is not bound to  plasma proteins ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9748", "text": "Glycopegylation  \"is a site-selective  PEGylation  method developed for modifying complex  glycoproteins \". [ 1 ]  It can be useful to improve bioavailability and extend the half-life of various  therapeutic proteins . [ 2 ] [ 1 ] [ 3 ]  Examples of glycopegylated molecules include  pegozafermin [ 4 ]  and  recombinant factor IX . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9749", "text": "Some fruit juices and fruits can  interact  with numerous drugs, in many cases causing  adverse effects . [ 1 ]  The effect is most studied with  grapefruit  and  grapefruit juice , [ 1 ]  but similar effects have been observed with certain other  citrus fruits . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9750", "text": "One whole grapefruit, or a small glass (200\u00a0mL, 6.8\u00a0US\u00a0fl\u00a0oz) of grapefruit juice, can cause drug overdose toxicity. [ 1 ]  Fruit consumed three days before the medicine can still have an effect. [ 5 ]  The relative risks of different types of citrus fruit have not been systematically studied. [ 1 ]  Affected drugs typically have an  auxiliary label  saying \"Do not take with grapefruit\" on the container, and the interaction is elaborated upon in the package insert. [ 6 ]  People are advised to ask their  physician  or  pharmacist  about drug interactions. [ 6 ]  However, some experts believe that for the majority of patients, complete avoidance of grapefruit is unwarranted. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9751", "text": "Although a  prospective cohort study  of middle-aged women indicated that some  flavonoid -rich foods are associated with a reduction in  all-cause mortality , frequent grapefruit consumption was associated with a small increase in all-cause mortality, possibly because of the clinically significant drug interactions of the non-flavonoid components. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9752", "text": "The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989 by a group led by  pharmacologist David Bailey . Their first published clinical report on grapefruit drug interactions was in 1991. [ 9 ]  The effect was first discovered accidentally in 1989, when a test of drug interactions with alcohol used grapefruit juice to  hide the taste  of the ethanol. [ 9 ] [ 10 ]  A 2005 medical review advised patients to avoid all citrus juices until further research clarifies the risks. [ 11 ]  It was reported in 2008 that similar effects had been observed with apple juice. [ 2 ] [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9753", "text": "Citrus fruits contain various  polyphenols , which may include  furanocoumarins  and  naringin , such as  bergamottin ,  dihydroxybergamottin , and  bergapten . [ 14 ]  Grapefruit,  Seville oranges , [ 15 ]  and  bergamot [ 16 ]  contain  naringin . Furanocoumarins may have a stronger effect than naringin. [ 15 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9754", "text": "The effects are caused by  furanocoumarins  (and, to a lesser extent,  flavonoids ) which are compounds produced by many plants including but not limited to grapefruit. [ 18 ]  These chemicals inhibit key  drug metabolizing   enzymes , such as  cytochrome P450 3A4  (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells. [ 19 ]  Organic derivatives of furanocoumarin interfere with  liver  and  intestinal  enzyme  CYP3A4  and may be responsible for the effects of grapefruit on the enzyme. [ 20 ]   Cytochrome isoforms  affected by grapefruit components include  CYP1A2 ,  CYP2C9 , and  CYP2D6 , [ 21 ] [ 22 ] [ 23 ] [ 24 ] [ 25 ]  but CYP3A4 is the major CYP enzyme in the intestine. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9755", "text": "Inhibition of enzymes can have two different effects:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9756", "text": "Grapefruit or grapefruit juice can reduce the absorption of many drugs by inhibiting transport across cell membranes by the transporters  P-glycoprotein  (a member of the superfamily of  ATP-binding cassette (ABC) transporters ) and members of the  organo anion transporter family . [ 26 ] [ 7 ]  These transporters appear to have a minimal effect on systemic exposure of the drugs they affect, however. [ 7 ]  Many drugs are affected by consumption of citrus juice. When the metabolizing enzyme is inhibited, less of the drug will be metabolized by it in the epithelial cells. [ 19 ]  This interaction is particularly dangerous when the drug in question has a low  therapeutic index , so that a small increase in blood concentration can be the difference between therapeutic effect and toxicity. Citrus juice inhibits the enzyme only within the  intestines  if consumed in small amounts. When larger amounts are consumed they may in addition inhibit the enzyme in the liver. The hepatic enzyme inhibition may cause an additional increase in potency and a prolonged metabolic half-life (prolonged metabolic half-life for all ways of drug administration). [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9757", "text": "Grapefruit\u2013drug interactions that affect the pre-systemic metabolism (i.e., the metabolism that occurs before the drug enters the blood) of drugs have a different duration of action than interactions that work by other mechanisms, such as on absorption, discussed below. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9758", "text": "The interaction is greatest when the juice is ingested with the drug or up to 4 hours before the drug. [ 1 ] [ 5 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9759", "text": "The location of the inhibition occurs in the lining of the intestines, not within the liver. [ 30 ]  The effects last because grapefruit-mediated inhibition of drug metabolizing enzymes, like  CYP3A4 , is  irreversible ; [ 30 ]  that is, once the grapefruit has \"broken\" the enzyme, the intestinal cells must produce more of the enzyme to restore their capacity to metabolize drugs that the enzyme is used to metabolize. [ 19 ]  It takes around 24 hours to regain 50% of the cell's baseline enzyme activity and it can take 72 hours for the enzyme activity to completely return to baseline. For this reason, simply separating citrus consumption and medications taken daily does not avoid the drug interaction. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9760", "text": "For medications that interact due to inhibition of  OATP (organic anion-transporting polypeptides) , a relative short period of time is needed to avoid this interaction, and a four-hour interval between grapefruit consumption and the medication should suffice. [ 19 ] [ 31 ]  For drugs recently sold on the market, drugs have information pages (monographs) that provide information on any potential interaction between a medication and grapefruit juice. [ 19 ]  Because there is a growing number of medications that are known to interact with citrus, [ 1 ]  patients should consult a pharmacist or physician before consuming citrus while taking their medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9761", "text": "Grapefruit is not the only  citrus fruit  that can interact with medications. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  One medical review advised patients to avoid all citrus. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9762", "text": "There are three ways to test if a fruit interacts with drugs:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9763", "text": "The first approach involves risk to trial volunteers. The first and second approaches have another problem: the same fruit  cultivar  could be tested twice with different results. Depending on growing and processing conditions, concentrations of the interacting polyphenol compounds can vary dramatically. The third approach is hampered by a paucity of knowledge of the genes in question. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9764", "text": "A descendant of citrus cultivars that cannot produce the problematic polyphenol compounds would presumably also lack the genes to produce them. Many citrus cultivars are hybrids of a small number of ancestral species, which have now been fully genetically sequenced. [ 33 ] [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9765", "text": "Many traditional citrus groups, such as true sweet oranges and lemons, seem to be  bud sports , mutant descendants of a single hybrid ancestor. [ 35 ]  In theory, cultivars in a bud sport group would be either all safe or all problematic. Nonetheless, new citrus varieties arriving on the market are increasingly likely to be sexually created hybrids, not asexually created sports."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9766", "text": "The ancestry of a hybrid cultivar may not be known. Even if it is known, it is not possible to be certain that a cultivar will not interact with drugs on the basis of taxonomy, as it is not known which ancestors lack the capacity to make the problematic polyphenol compounds. Nonetheless, many of the citrus cultivars known to be problematic seem to be closely related."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9767", "text": "Pomelo  (the Asian fruit that was crossed with an orange to produce grapefruit) contains high amounts of  furanocoumarin  derivatives.  Grapefruit relatives  and other varieties of pomelo have variable amounts of furanocoumarin. [ 11 ] [ 2 ] [ 36 ] [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9768", "text": "The  Dancy  cultivar has a small amount of pomelo ancestry, [ 34 ]  but is genetically close to a non-hybrid  true mandarin  (unlike most commercial mandarins, which may have much more extensive hybridization). Eight Dancy fruits, all picked at one time from one tree, have been blended and tested for furanocoumarins; none were detectable. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9769", "text": "No  citron  or  papeda  seems to have been tested. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9770", "text": "Both  sweet oranges  and  bitter oranges  are  mandarin - pomelo  hybrids. [ 34 ] [ 35 ]  Bitter oranges (such as the  Seville oranges  often used in  marmalade ) can interfere with drugs [ 38 ]  including  etoposide , a chemotherapy drug, some  beta blocker  drugs used to treat high blood pressure, and  cyclosporine , taken by transplant patients to prevent rejection of their new organs. [ 12 ]  Evidence on sweet oranges is more mixed. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9771", "text": "Tests on some tangelos (hybrids of mandarins/tangerines and pomelo or grapefruit) have not shown significant amounts of furanocoumarin; these studies were also conducted on eight fruit all picked at one time from one tree. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9772", "text": "Common lemons are the product of orange/citron hybridization, and hence have pomelo ancestry, and although  Key limes  are papeda/citron hybrids, the more commercially prevalent  Persian limes  and similar varieties are crosses of the Key lime with lemons, and hence likewise have pomelo ancestry. [ 33 ] [ 34 ]  These limes can also inhibit drug metabolism. [ 38 ]  Other less-common citrus species also referred to as lemons or limes are genetically distinct from the more common varieties, with different proportions of pomelo ancestry. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9773", "text": "Marketing classifications often do not correspond to taxonomic ones. The \"Ambersweet\" cultivar is marketed and sold as an orange, but does not descend from the same common ancestor as sweet oranges; it has grapefruit, orange, and mandarin ancestry. Fruits are often sold as mandarin,  tangerine , or  satsuma  (which may be synonyms [ 39 ] ). Fruit sold under these names include many that are, like Sunbursts and  Murcotts , hybrids with grapefruit ancestry. [ 36 ] [ 40 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9774", "text": "The discovery that flavonoids are responsible for some interactions make it plausible that other fruit and vegetables are affected. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9775", "text": "Apple juice, especially commercially produced products, interferes with the action of  OATPs . [ 42 ]  This interference can decrease the absorption of a variety of commonly used medications, including  beta blockers  like  atenolol ,  antibiotics  like  ciprofloxacin , and  antihistamines  like  montelukast . [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9776", "text": "Pomegranate juice inhibits the action of the drug metabolizing enzymes  CYP2C9  and  CYP3A4 . [ 44 ]  As of 2014 [update] , the currently available literature does not appear to indicate a clinically relevant impact of pomegranate juice on drugs that are metabolized by CYP2C9 and CYP3A4. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9777", "text": "Researchers have identified over 85 drugs with which grapefruit reacts adversely. [ 45 ] [ 1 ]  According to a review done by the  Canadian Medical Association , [ 1 ]  there is an increase in the number of potential drugs that can interact with grapefruit juice, and of the number of fruit types that can interact with those drugs. From 2008 to 2012, the number of drugs known to potentially interact with grapefruit, with risk of harmful or even dangerous effects ( gastrointestinal bleeding ,  nephrotoxicity ), increased from 17 to 43. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9778", "text": "The interaction between citrus and medication depends on the individual drug, and not the class of the drug. Drugs that interact usually share three common features: they are taken orally, normally only a small amount enters systemic blood circulation, and they are metabolized by CYP3A4. [ 1 ]  The effects on the CYP3A4 in the liver could, in principle, cause interactions with non-oral drugs (e.g.  parenteral ,  inhaled substances ,  transdermal ), [ citation needed ]  and non-CYP3A4-mediated effects also exist. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9779", "text": "Cytochrome isoforms affected by grapefruit components include  CYP3A4 ,  CYP1A2 ,  CYP2C9 , and  CYP2D6 . [ 21 ]  Drugs that are metabolized by these enzymes may have interactions with components of grapefruit."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9780", "text": "An easy way to tell if a medication may be affected by grapefruit juice is by researching whether another known CYP3A4 inhibitor drug is already  contraindicated  with the active drug of the medication in question. Examples of such known CYP3A4  inhibitors  include  cisapride  (Propulsid), [ 46 ]   erythromycin ,  itraconazole  (Sporanox),  ketoconazole  (Nizoral), and  mibefradil  (Posicor). [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9781", "text": "Drugs that interact with grapefruit compounds at  CYP3A4  include"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9782", "text": "Drugs that interact with grapefruit compounds at  CYP1A2  include"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9783", "text": "Drugs that interact with grapefruit compounds at  CYP2D6  include"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9784", "text": "Research has been done on the interaction between  amphetamines  and CYP2D6 enzyme, and researchers concluded that some parts of substrate molecules contribute to the binding of the enzyme. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9785", "text": "Additional drugs affected by grapefruit juice include, but are not limited to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9786", "text": "clonazepam  (Klonopin)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9787", "text": "ketamine"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9788", "text": "In  toxicology ,  Haber's rule  or  Haber's law  is a  mathematical  statement of the relationship between the  concentration  of a  poisonous   gas  and how long the gas must be breathed to produce death, or other  toxic  effect. The rule was formulated by  German   chemist   Fritz Haber  in the early 1900s."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9789", "text": "Haber's rule states that, for a given poisonous gas,  \n \n \n \n t \n C \n = \n k \n \n \n {\\displaystyle tC=k} \n \n , where  \n \n \n \n C \n \n \n {\\displaystyle C} \n \n  is the concentration of the gas (mass per unit volume),  \n \n \n \n t \n \n \n {\\displaystyle t} \n \n  is the amount of time necessary to breathe the gas to produce a given toxic effect, and  \n \n \n \n k \n \n \n {\\displaystyle k} \n \n  is a constant, depending on both the gas and the effect. Thus, the rule states that doubling the concentration will halve the time, for example."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9790", "text": "It makes  equivalent  any two groupings of  dose concentration  and  exposure time  that have equivalent  mathematical products .  For instance, if we assign  dose   concentration  the  symbol  C, and  time  the classic t, then for any two dose  schema , if C 1 t 1 =C 2 t 2 , then under Haber's rule the two dose schema are equivalent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9791", "text": "Haber's rule is an approximation, useful with certain inhaled poisons under certain conditions, and Haber himself acknowledged that it was not always applicable. If a substance is efficiently eliminated in the host, for example, then Haber's Law breaks down in the limit of t approaching the  order  of the  half-life  of the  drug , rewriting the equation as the integral \u222bCdt = constant for arbitrary varying C and elapsed time T.  It is very convenient, however, because its relationship between  \n \n \n \n C \n \n \n {\\displaystyle C} \n \n  and  \n \n \n \n t \n \n \n {\\displaystyle t} \n \n  appears as a straight line in a  log-log plot ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9792", "text": "In 1940,  statistician  C. I. Bliss published a study of  toxicity  in  insecticides  in which he proposed more complex  models , for example, expressing the relationship between  \n \n \n \n C \n \n \n {\\displaystyle C} \n \n  and  \n \n \n \n t \n \n \n {\\displaystyle t} \n \n  as two straight line segments in a  log-log plot . [ 1 ]  However, because of its simplicity, Haber's rule continued to be widely used. Recently, some researchers have argued that it is time to move beyond the simple relationship expressed by Haber's rule and to make regular use of more sophisticated models. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9793", "text": "Integrated discrete Multiple Organ Culture (IdMOC)  is an  in vitro , cell culture based experimental model for the study of  intercellular communication .  In conventional  in vitro  systems, each cell type is studied in isolation ignoring critical interactions between organs or cell types. IdMOC technology is based on the concept that multiple organs signal or communicate via the systemic circulation (i.e., blood)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9794", "text": "The IdMOC plate consists of multiple inner wells within a large interconnecting chamber. Multiple cell types are first individually seeded in the inner wells and, when required, are flooded with an overlying medium to facilitate well-to-well communication. Test material can be added to the overlying medium and both media and cells can be analyzed individually. Plating of  hepatocytes  with other organ-specific cells allows evaluation of  drug metabolism  and organotoxicity. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9795", "text": "The IdMOC system has numerous applications in  drug development , such as the evaluation of  drug metabolism  and  toxicity . It can simultaneously evaluate the toxic potential of a drug on cells from multiple organs and evaluate drug stability, distribution, metabolite formation, and efficacy. By modeling multiple-organ interactions, IdMOC can examine the  pharmacological  effects of a drug and its metabolites on target and off-target organs as well as evaluate  drug-drug interactions  by measuring  cytochrome P450  (CYP) induction or inhibition in hepatocytes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9796", "text": "IdMOC can also be used for routine and  high throughput screening  of drugs with desirable  ADME  or  ADME-Tox  properties.  In vitro toxicity  screening using hepatocytes in conjunction with other primary cells such as cardiomyocytes ( cardiotoxicity  model), kidney proximal tubule epithelial cells ( nephrotoxicity  model), astrocytes ( neurotoxicity  model), endothelial cells (vascular toxicity model), and airway epithelial cells ( pulmonary toxicity  model) is invaluable to the  drug design  and  discovery  process. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9797", "text": "The IdMOC was patented by Dr.  Albert P. Li  in 2004. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9798", "text": "In cell biology,  ion trapping  is the build-up of a higher concentration of a chemical across a  cell membrane  due to the  pKa  value of the chemical and difference of  pH  across the cell membrane. [ 1 ] [ 2 ]  This results in basic chemicals accumulating in acidic bodily fluids such as the  cytosol , and acidic chemicals accumulating in basic fluids."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9799", "text": "Many  cells  have other mechanisms to pump a  molecule  inside or outside the cell against the  concentration gradient , but these processes are active ones, meaning that they require  enzymes  and consume cellular  energy . In contrast, ion trapping does not require any enzyme or energy. It is similar to  osmosis  in that they both involve the  semipermeable  nature of the cell membrane."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9800", "text": "Cells have a more acidic  pH  inside the cell than outside ( gastric mucosal  cells being an exception). Therefore, basic drugs (like  bupivacaine ,  pyrimethamine ) are more charged inside the cell than outside. The  cell membrane  is permeable to non-ionized (fat-soluble) molecules; ionized (water-soluble) molecules cannot cross it easily. Once a non-charged molecule of a basic chemical crosses the cell membrane to enter the cell, it becomes charged due to gaining a hydrogen ion because of the lower pH inside the cell, and thus becomes unable to cross back. Because transmembrane equilibrium must be maintained, another unionized molecule must diffuse into the cell to repeat the process. Thus its concentration inside the cell increases many times that of the outside. The non-charged molecules of the drug remain in equal concentration on either side of the cell membrane."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9801", "text": "The charge of a molecule depends upon the pH of its solution. In an acidic medium, basic drugs are more charged and acidic drugs are less charged. The converse is true in a basic medium. For example,  Naproxen  is a  non-steroidal anti-inflammatory drug  that is a weak acid (its  pKa  value is 5.0). The  gastric juice  has a pH of 2.0. It is a three-fold difference (due to log scale) between its pH and its pKa; therefore there is a 1000\u00d7 difference between the charged and uncharged concentrations. So, in this case, for every one molecule of charged  Naproxen , there are 1000 molecules of uncharged Naproxen at a pH of 2. [ 3 ]  This is why weak acids are better absorbed from the stomach and weak bases from intestine where the pH is alkaline. When pH of a solution is equal to pKa of dissolved drug, then 50% of the drug is ionized, another 50% is unionized. This is described by the  Henderson-Hasselbalch equation . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9802", "text": "Ion trapping is the reason why basic (alkaline) drugs are secreted into the stomach (for example  morphine ), where pH is acidic, and acidic drugs are excreted in urine where the conditions are alkaline. Similarly, ingesting  sodium bicarbonate  with  amphetamine , a weak base, causes better absorption of amphetamine (in stomach) and its lesser excretion (in urine), thus prolonging its actions. Ion trapping can cause partial failure of certain anti-cancer chemotherapies. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9803", "text": "Ion trapping is also important outside of  pharmacology . For example, it causes weakly acidic  hormones  to accumulate in the cytosol of cells. This is important in keeping the external concentration of the hormone low in the extracellular environment where many hormones are sensed. Examples of plant hormones that are subjected to ion trapping are  abscisic acid ,  gibberellic acid  and  retinoic acid . Examples of animal hormones subjected to ion trapping include  Prostacyclin  and  Leukotrienes ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9804", "text": "Release  ( Liberation ) is the first step in the process by which medication enters the body and liberates the   active ingredient  that has been administered. The  pharmaceutical drug  must separate from the   vehicle  or the  excipient  that it was mixed with during   manufacture . Some authors split the process of liberation into three steps: disintegration, disaggregation and dissolution. A limiting factor in the adsorption of pharmaceutical drugs is the degree to which they are ionized, as cell membranes are relatively impermeable to ionized molecules."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9805", "text": "The characteristics of a medication's excipient play a fundamental role in creating a suitable environment for the correct absorption of a drug. This can mean that the same dose of a drug in different forms can have different  bioequivalence , as they yield different plasma concentrations and therefore have different therapeutic effects.  Dosage forms  with  modified release  (such as delayed or extended release) allow this difference to be usefully applied."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9806", "text": "In a typical situation, a pill taken orally will pass through the  oesophagus  and into the  stomach . As the stomach has an aqueous environment, it is the first place where the pill can dissolve. The rate of dissolution is a key element in controlling the duration of a drug's effect. For this reason, different forms of the same medication can have the same active ingredients but different dissolution rates. If a drug is administered in a form that is not rapidly dissolved, the drug will be absorbed more gradually over time and its action will have a longer duration. A consequence of this is that patients will comply more closely to a prescribed course of treatment, if the medication does not have to be taken as frequently. In addition, a slow release system will maintain drug concentrations within a therapeutically acceptable range for longer than quicker releasing delivery systems as these result in more pronounced peaks in plasma concentration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9807", "text": "The dissolution rate is described by the  Noyes\u2013Whitney equation :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9808", "text": "As the solution is already in a dissolved state, it does not have to go through a dissolution stage before absorption begins."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9809", "text": "Cell membranes present a greater barrier to the movement of ionized molecules than non-ionized liposoluble substances. This is particularly important for substances that are weakly   amphoteric . The stomach's acidic  pH  and the subsequent alkalization in the  intestine  modifies the degree of ionization of acids and weak bases depending on a substance's  pKa . [ 1 ]  The pKa is the pH at which a substance is present at an equilibrium between ionized and non-ionized molecules. The  Henderson\u2013Hasselbalch equation  is used to calculate pKa."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9810", "text": "Lipophilic efficiency [ 1 ]  ( LiPE ), sometimes referred to as  ligand-lipophilicity efficiency  ( LLE ) is a parameter used in  drug design  and  drug discovery   to evaluate the quality of research compounds, linking potency and  lipophilicity  in an attempt to estimate  druglikeness . [ 2 ] [ 3 ]  For a given compound LiPE is defined as the  pIC 50  (or  pEC 50 ) of interest minus the  LogP  of the compound."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9811", "text": "In practice, calculated values such as cLogP or calculated LogD are often used instead of the measured LogP or LogD. LiPE is used to compare compounds of different potencies (pIC 50 s) and lipophilicities (LogP). High potency (high value of pIC 50 ) is a desirable attribute in drug candidates, as it reduces the risk of non-specific, off-target pharmacology at a given concentration. When associated with low clearance, high potency also allows for low total dose, which lowers the risk of  idiosyncratic drug reaction . [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9812", "text": "On the other hand, LogP is an estimate of a compound's overall lipophilicity, a value that influence its behavior in a range of biological processes relevant to a drug discovery, such as solubility, permeability through biological membranes, hepatic  clearance , lack of selectivity and non-specific toxicity. [ 6 ]  For oral drugs, a LogP value comprised between 2 and 3 is often considered optimal to achieve a compromise between permeability and first-pass clearance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9813", "text": "LiPE allows capturing both values in a single parameter, and empirical evidence suggest that quality drug candidates have a high LiPE (>6); this value corresponds to a compound with a pIC 50  of 8 and a LogP of 2. Plotting LogP against pIC 50  for a range of compounds allows ranking series and individual compounds."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9814", "text": "An alternative equation uses the logarithm of the ratio of potency (measured as binding energy) and the partition coefficient to compute a lipophilic  ligand efficiency  index (LE) with a different scale. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9815", "text": "The following review discusses LipE in the context of other compound efficiency metrics. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9816", "text": "In  pharmacokinetics , a  loading dose  is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower  maintenance dose . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9817", "text": "A loading dose is most useful for drugs that are eliminated from the body relatively slowly, i.e. have a long  systemic   half-life .  Such drugs need only a low maintenance dose in order to keep the amount of the drug in the body at the appropriate  therapeutic level , but this also means that, without an initial higher dose, it would take a long time for the amount of the drug in the body to reach that level."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9818", "text": "Drugs which may be started with an initial loading dose include  digoxin ,  teicoplanin ,  voriconazole ,  procainamide  and  fulvestrant ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9819", "text": "One or series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9820", "text": "For an example, one might consider the \nhypothetical drug  foosporin .  Suppose it has a long  lifetime in the body , and only ten percent of it is cleared from the blood each day by the liver and kidneys.  Suppose also that the drug works best when the total amount in the body is exactly one gram.  So, the maintenance dose of  foosporin  is 100 milligrams (100\u00a0mg) per day\u2014just enough to offset the amount cleared."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9821", "text": "Suppose a patient just started taking 100\u00a0mg of  foosporin  every day."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9822", "text": "As one can see, it would take many days for the total amount of drug within the body to come close to 1 gram (1000\u00a0mg) and achieve its full therapeutic effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9823", "text": "For a drug such as this, a doctor might prescribe a loading dose of  one gram  to be taken on the first day.  That immediately gets the drug's concentration in the body up to the therapeutically-useful level."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9824", "text": "Four variables are used to calculate the loading dose:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9825", "text": "The required loading dose may then be calculated as"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9826", "text": "For an intravenously administered drug, the bioavailability  F  will equal 1, since the drug is directly introduced to the bloodstream. If the patient requires an oral dose, bioavailability will be less than 1 (depending upon absorption, first pass metabolism etc.), requiring a larger loading dose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9827", "text": "In  pharmacokinetics , a  maintenance dose  is the maintenance rate [mg/h] of drug administration equal to the rate of elimination at steady state.  This is not to be confused with  dose regimen , which is a type of drug therapy in which the  dose  [mg] of a  drug  is given at a regular dosing interval on a repetitive basis. Continuing the maintenance dose for about 4 to 5  half-lives  (t 1/2 ) of the drug will approximate the  steady state  level. [ 1 ]  One or more doses higher than the maintenance dose can be given together at the beginning of therapy with a  loading dose . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9828", "text": "A loading dose is most useful for drugs that are  eliminated from the body  relatively slowly.  Such drugs need only a low maintenance dose in order to keep the amount of the drug in the body at the appropriate level, but this also means that, without an initial higher dose, it would take a long time for the amount of the drug in the body to reach that level."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9829", "text": "The required maintenance dose may be calculated as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9830", "text": "Microdosing , or  micro-dosing , involves the administration of sub-therapeutic doses of  drugs  to study their effects in humans, aiming to gather preliminary data on safety,  pharmacokinetics , and potential therapeutic benefits without producing significant physiological effects.  This is called a \" Phase 0  study\" and is usually conducted before clinical  Phase I  to predict whether a drug is viable for the next phase of testing. Human microdosing aims to reduce the resources spent on non-viable drugs and the amount of testing done on animals.  [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9831", "text": "Less commonly, the term \"microdosing\" is also sometimes used to refer to precise dispensing of small amounts of a drug substance (e.g., a powder API) for a drug product (e.g., a capsule) [ 2 ]  and, when the drug substance also happens to be liquid, this can potentially overlap what is termed  microdispensing . For example,  psychedelic microdosing . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9832", "text": "The basic approach is to  label  a candidate drug using the radio  isotope   carbon-14 , [ 4 ]  then administer the compound to human volunteers at levels typically about 100 times lower than the proposed therapeutic dosage (from around 1 to 100  micrograms  but not above). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9833", "text": "As only microdose levels of the drug are used, analytical methods are limited. Extreme sensitivity is needed.  Accelerator mass spectrometry  (AMS) is the most common method for microdose analysis. AMS was developed in the late 1970s from two distinct research threads with a common goal: [ 5 ]  an improvement in radiocarbon dating that would make efficient use of datable material and that would extend the routine and maximum reach of radiocarbon dating. AMS is routinely used in geochronology and archaeology, [ 6 ]  but biological applications began appearing in 1990 mainly due to the work of scientists at Lawrence Livermore National Laboratory. AMS service is now more accessible for biochemical quantitation from several private companies and non-commercial access to AMS is available at the National Institutes of Health (NIH) Research Resource at Lawrence Livermore National Laboratory, [ 7 ]  or through the development of smaller affordable spectrometers. AMS does not measure the radioactivity of carbon-14 in microdose samples. AMS, like other mass spectrometry methods, measures ionic species according to mass-to-charge ratio."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9834", "text": "Psychedelic microdosing is the practice of using sub-threshold doses (microdoses) of  serotonergic   psychedelic drugs  in an attempt to improve creativity, boost physical energy level, emotional balance, increase performance on problems-solving tasks and to treat anxiety, depression and addiction, [ citation needed ]  though there is very little evidence supporting these purported effects as of 2019. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9835", "text": "In 2021 it was reported in a study done that an increased conscientiousness was seen due to microdosing.  [ 9 ]  Microdosing was seen to have improved mental health after microdosing with psychedelics after 30 days. [ 10 ]  More research is needed to ultimately decide whether or not microdosing helps those who suffer from depression and anxiety.  [ 10 ]  Microdosing has not seen to improve participants motor responses, attention, and cognitive problem-solving abilities. [ 10 ]  Microdosing is still under investigation as to whether it works or not. Researchers are investigating into microdosing more and more, the placebo effect causes difficulties in research on this topic. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9836", "text": "In January 2006, the European Union Microdose AMS Partnership Programme (EUMAPP) was launched. [ 12 ]  Ten organizations from five different countries (United Kingdom, Sweden, Netherlands, France, and Poland) will study various approaches to the basic AMS technique. The study is set to be published in 2009. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9837", "text": "One of the most meaningful potential outcomes of Phase-0/Microdosing studies is the early termination of development. In 2017, Okour et al published the first example in literature of a termination of an oral drug based on IV microdose data. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9838", "text": "Oculomucocutaneous syndrome  is characterized by  keratoconjunctivitis sicca  ( dry eyes ) and the resulting  scarring ,  fibrosis ,  metaplasia , and shrinkage of the  conjunctiva . [ 1 ]  It is a drug  side effect  observed in  practolol  and  eperisone . It is speculated that  antibodies  against drug  metabolites  cause the syndrome. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9839", "text": "This cutaneous condition article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9840", "text": "Open flow microperfusion  ( OFM ) is a sampling method for clinical and preclinical drug development studies and  biomarker  research. OFM is designed for continuous sampling of analytes from the  interstitial fluid  (ISF) of various tissues. It provides direct access to the ISF by insertion of a small, minimally invasive, membrane-free probe with macroscopic openings. [ 1 ]  Thus, the entire biochemical information of the ISF becomes accessible regardless of the analyte's molecular size, protein-binding property or  lipophilicity . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9841", "text": "OFM is capable of sampling lipophilic and hydrophilic compounds, [ 2 ]  protein bound and unbound drugs, [ 3 ] [ 4 ]   neurotransmitters ,  peptides  and  proteins ,  antibodies , [ 5 ] [ 6 ] [ 7 ]   nanoparticles  and  nanocarriers ,  enzymes  and  vesicles ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9842", "text": "The OFM probes are perfused with a physiological solution (the perfusate) which equilibrates with the ISF of the surrounding tissue. Operating flow rates range from 0.1 to 10 \u03bcL/min. OFM allows unrestricted exchange of compounds via an open structure across the open exchange area of the probe. This exchange of compounds between the probe\u2019s perfusate and the surrounding ISF is driven by convection and diffusion, and occurs non-selectively in either direction (Figure 1)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9843", "text": "The direct liquid pathway between the probe\u2019s perfusate and the surrounding fluid results in collection of ISF samples. These samples can be collected frequently and are then subjected to bioanalytical analysis to enable monitoring of substance concentrations with temporal resolution during the whole sampling period. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9844", "text": "The concentric OFM probe (Figure 2) works according to the same principle. The perfusate is pumped to the tip of the OFM probe through the inner, thin lumen and exits beyond the Open Exchange Area, where it then mixes with exogenous substances present in the ISF before being withdrawn through the outer, thick lumen. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9845", "text": "The first OFM sampling probe to be used as an alternative to  microdialysis  was described in an Austrian patent application filed by Falko Skrabal in 1987, where OFM was described as a device, which can be implanted into the tissue of living organisms. [ 10 ]  In 1992, a US patent was filed claiming a device for determining at least one medical variable in the tissue of living organisms. [ 11 ]  In a later patent by Helmut Masoner, Falko Skrabal and  Helmut List  a linear type of the sampling probe with macroscopic circular holes was also disclosed. [ 12 ]  Alternative and current OFM versions for  dermal  and  adipose tissue  application were developed by  Joanneum Research , and were patented by Manfred Bodenlenz et al. [ 13 ] [ 14 ]  Alternative materials featuring low absorption were used to enable manufacturing of probes with diameters of 0.55\u00a0mm and exchange areas of 15\u00a0mm in length. For cerebral application, special OFM probes were patented by Birngruber et al. [ 15 ]  Additionally, a patent was filed to manage the fluid handling of the ISF by using a portable peristaltic pump with a flow range of 0.1 to 10 \u03bcL/min that enables operation of up to three probes per pump. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9846", "text": "Two types of OFM probes are currently available: Linear OFM probes for implantation into superficial tissues such as skin (dermal OFM, dOFM) and subcutaneous adipose tissue (adipose OFM, aOFM) as well as concentric probes for implantation into various regions of the  brain  (cerebral OFM, cOFM). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9847", "text": "OFM is routinely applied in pharmaceutical research in preclinical (e.g. mice, rats, pigs, primates) and in clinical studies in humans (Figure 3). OFM-related procedures such as probe insertions or prolonged sampling with numerous probes are well tolerated by the subjects. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9848", "text": "dOFM (Figure 4) allows the investigation of transport of drugs in the dermis and their penetration into the dermis after local, topical or systemic application, and dOFM is mentioned by the  U.S. Food and Drug Administration  as a new method for assessment of bioequivalence of topical drugs. [ 17 ] [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9849", "text": "dOFM is used for:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9850", "text": "Head-to-head settings with OFM have proven particularly useful for the evaluation of topical generic products, which need to demonstrate  bioequivalence [ 9 ]  to the reference listed drug product to obtain market approval."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9851", "text": "Applications of dOFM include  ex vivo  studies with tissue explants and preclinical and clinical  in vivo  studies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9852", "text": "aOFM (Figure 4) allows continuous on-line monitoring of metabolic processes in the subcutaneous adipose tissue, e.g.  glucose  and  lactate , [ 21 ] [ 22 ] [ 23 ]  as well as larger analytes such as  insulin  (5.9 kDa). [ 24 ] [ 23 ]  The role of polypeptides for metabolic signaling ( leptin ,  cytokine  IL-6, TNF\u03b1) has also been studied with aOFM. [ 25 ]  aOFM allows the quantification of proteins (e.g. albumin size: 68 kDa) in adipose tissue [ 4 ]  and thus opens up the possibility to investigate protein-bound drugs directly in peripheral target tissues, such as highly protein-bound insulin analogues designed for a prolonged, retarded insulin action. [ 26 ]  Most recently, aOFM has been used to sample agonists to study  obesity ,  lipid metabolism  and immune-inflammation. Applications of aOFM include  ex vivo  studies with tissue explants and preclinical and clinical  in vivo  studies. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9853", "text": "cOFM (Figure 5) is used to conduct PK/PD preclinical studies in the animal brain. Access to the brain includes monitoring of the  blood-brain barrier  function and drug transport across the intact blood-brain barrier. [ 27 ]  cOFM allows taking a look behind the blood-brain barrier and assesses concentrations and effects of  neuroactive  substances directly in the targeted brain tissue. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9854", "text": "The blood-brain barrier is a natural shield that protects the brain and limits the exchange of  nutrients ,  metabolites  and  chemical messengers  between blood and brain. The blood-brain barrier also prevents potential harmful substances from entering and damaging the brain. However, this highly effective barrier also prevents neuroactive substances from reaching appropriate targets. For researchers that develop neuroactive drugs, it is therefore of major interest to know whether and to what extent an active pharmaceutical component can pass the blood-brain barrier. Experiments have shown that the blood-brain barrier has fully reestablished 15 days after implantation of the cOFM probe in the brain of rats. [ 29 ]  The cOFM probe has been specially designed to avoid a reopening of the blood-brain barrier or causing additional  trauma  to the brain after implantation. cOFM enables continuous sampling of cerebral ISF with intact blood-brain barrier cOFM and thus allows continuous PK monitoring in brain tissue. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9855", "text": "ISF compounds can be quantified either indirectly from merely diluted ISF samples by using OFM and additional calibration techniques, or directly from undiluted ISF samples which can be collected with additional OFM methods. Quantification of compounds from diluted ISF samples requires additional application of calibration methods, such as Zero Flow Rate, [ 30 ]  No Net Flux [ 31 ]  or Ionic Reference. [ 32 ]  Zero Flow Rate has been used in combination with dOFM by Schaupp et al. [ 3 ]  to quantify  potassium ,  sodium  and glucose in adipose ISF samples. No Net Flux has been applied to quantify several analytes in OFM studies in subcutaneous adipose,  muscle  and dermal ISF: the absolute lactate concentrations [ 33 ]  and the absolute glucose concentrations in adipose ISF, [ 3 ]  the absolute  albumin  concentration in muscle ISF [ 4 ]  and the absolute insulin concentration in adipose and muscle ISF have been successfully determined. [ 34 ]  Dragatin et al. [ 5 ]  used No Net Flux in combination with dOFM to assess the absolute ISF concentration of a fully human therapeutic antibody. Ionic Reference has been used in combination with OFM to assess the absolute glucose concentration [ 3 ]  and the absolute lactate concentration in adipose ISF. [ 33 ]  Dermal OFM has also been used to quantify the concentrations of human insulin and an insulin analogue in the ISF with inulin as exogenous marker. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9856", "text": "Additional OFM methods, such as OFM recirculation and OFM suction can collect undiluted ISF samples from which direct and absolute quantification of compounds is feasible. [ 35 ]  OFM recirculation to collect undiluted ISF samples recirculates the perfusate in a closed loop until equilibrium concentrations between perfusate and ISF are established. Using albumin as analyte, 20 recirculation cycles have been enough to reach equilibrium ISF concentrations. OFM suction is performed by applying a mild vacuum, which pulls ISF from the tissue into the OFM probe. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9857", "text": "In  medicinal chemistry ,  parallel artificial membrane permeability assay  ( PAMPA ) is a method which determines the permeability of substances from a donor compartment, through a  lipid -infused artificial membrane into an acceptor compartment. [ 1 ]   A multi-well microtitre plate is used for the donor and a membrane/acceptor compartment is placed on top; the whole assembly is commonly referred to as a \u201csandwich\u201d.  At the beginning of the test, the drug is added to the donor compartment, and the acceptor compartment is drug-free. After an incubation period which may include stirring, the sandwich is separated and the amount of drug is measured in each compartment.   Mass balance allows calculation of drug that remains in the membrane."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9858", "text": "To date, PAMPA models have been developed that exhibit a high degree of correlation with permeation across a variety of barriers, including  Caco-2  cultures, [ 2 ] [ 3 ]  the  gastrointestinal tract , [ 4 ]   blood\u2013brain barrier [ 5 ]  and skin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9859", "text": "The donor and/or acceptor compartments may contain solubilizing agents, or additives that bind the drugs as they permeate.  To improve the  in vitro  -  in vivo  correlation and performance of the PAMPA method, the lipid, pH and chemical composition of the system is often designed with biomimetic considerations in mind."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9860", "text": "Although  active transport  is not modeled by the artificial PAMPA membrane, up to 95% of known drugs are absorbed by  passive transport . [ 6 ]  Some experts support a lower figure, so the amount is open to some interpretation.  Microtiter plates with 96 wells can be used for the assay which increases the speed and lowers the per sample cost."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9861", "text": "Since the first publication by Kansy and coworkers, [ 7 ]  several companies developed their own versions of the assay.  Early models incorporated iso-pH conditions in the compartments separated by a simple lipid membrane; subsequently, commercial products were introduced which incorporated more sophisticated lipid membranes. [ 8 ]   The commercial products helped ensure that medicinal chemists across different corporate labs within a worldwide organization used the same standardized methodology, reagents and obtained equivalent system performance as demonstrated with a set of test compounds.  This has proved very useful as various operational activities have been outsourced to other countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9862", "text": "A  Patlak plot  (sometimes called  Gjedde\u2013Patlak plot ,  Patlak\u2013Rutland plot , or  Patlak analysis ) [ 1 ] [ 2 ]  is a  graphical  analysis technique based on the  compartment  model that uses  linear regression  to identify and analyze  pharmacokinetics  of tracers involving irreversible uptake, such as in the case of  deoxyglucose . [ 3 ] [ 4 ]  It is used for the evaluation of  nuclear medicine   imaging  data after the injection of a  radioopaque  or  radioactive tracer ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9863", "text": "The method is model-independent because it does not depend on any specific compartmental model configuration for the tracer, and the minimal assumption is that the behavior of the tracer can be approximated by two compartments \u2013 a \"central\" (or reversible) compartment that is in rapid equilibrium with  plasma , and a \"peripheral\" (or irreversible) compartment, where tracer enters without ever leaving during the time of the measurements. [ 1 ] [ 2 ]   The amount of tracer in the  region of interest  is accumulating according to the equation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9864", "text": "where  \n \n \n \n t \n \n \n {\\displaystyle t} \n \n  represents time after tracer injection,  \n \n \n \n R \n ( \n t \n ) \n \n \n {\\displaystyle R(t)} \n \n  is the amount of tracer in  region of interest ,  \n \n \n \n \n C \n \n p \n \n \n ( \n t \n ) \n \n \n {\\displaystyle C_{p}(t)} \n \n  is the concentration of tracer in plasma or blood,  \n \n \n \n K \n \n \n {\\displaystyle K} \n \n  is the  clearance  determining the rate of entry into the peripheral (irreversible) compartment, and  \n \n \n \n \n V \n \n 0 \n \n \n \n \n {\\displaystyle V_{0}} \n \n  is the  distribution volume  of the tracer in the central compartment. The first term of the right-hand side represents tracer in the peripheral compartment, and the second term tracer in the central compartment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9865", "text": "By  dividing  both sides by  \n \n \n \n \n C \n \n p \n \n \n ( \n t \n ) \n \n \n {\\displaystyle C_{p}(t)} \n \n , one obtains:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9866", "text": "The unknown constants  \n \n \n \n K \n \n \n {\\displaystyle K} \n \n  and  \n \n \n \n \n V \n \n 0 \n \n \n \n \n {\\displaystyle V_{0}} \n \n  can be obtained by  linear regression  from a  graph  of  \n \n \n \n \n \n \n R \n ( \n t \n ) \n \n \n \n C \n \n p \n \n \n ( \n t \n ) \n \n \n \n \n \n {\\displaystyle {R(t) \\over C_{p}(t)}} \n \n  against  \n \n \n \n \n \u222b \n \n 0 \n \n \n t \n \n \n \n C \n \n p \n \n \n ( \n \u03c4 \n ) \n \n d \n \u03c4 \n \n / \n \n \n C \n \n p \n \n \n ( \n t \n ) \n \n \n {\\displaystyle \\int _{0}^{t}C_{p}(\\tau )\\,d\\tau /C_{p}(t)} \n \n ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9867", "text": "PEGylation  (or  pegylation ) is the process of both covalent and non-covalent attachment or amalgamation of  polyethylene glycol  (PEG, in pharmacy called  macrogol ) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein or vesicle, which is then described as  PEGylated . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  PEGylation affects the resulting derivatives or aggregates interactions, which typically slows down their coalescence and degradation as well as elimination in vivo. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9868", "text": "PEGylation is routinely achieved by the incubation of a reactive derivative of PEG with the target molecule. The covalent attachment of PEG to a drug or therapeutic protein can \"mask\" the agent from the host's immune system (reducing  immunogenicity  and  antigenicity ), and increase its hydrodynamic size (size in solution), which prolongs its circulatory time by reducing  renal  clearance. PEGylation can also provide water solubility to  hydrophobic  drugs and proteins. Having proven its  pharmacological  advantages and acceptability, PEGylation technology is the foundation of a growing multibillion-dollar industry. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9869", "text": "PEGylation is the process of attaching the strands of the polymer PEG to molecules, most typically  peptides ,  proteins , and  antibody  fragments, that can improve the safety and efficiency of many  therapeutics . [ 9 ] [ 10 ]  It produces alterations in the physiochemical properties including changes in  conformation ,  electrostatic   binding ,  hydrophobicity  etc. These physical and chemical changes increase systemic retention of the therapeutic agent. Also, it can influence the binding affinity of the therapeutic moiety to the cell receptors and can alter the absorption and distribution patterns."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9870", "text": "PEGylation, by increasing the molecular weight of a  molecule , can impart several significant pharmacological advantages over the unmodified form, such as improved  drug  solubility, reduced dosage frequency with potentially reduced  toxicity  and without diminished efficacy, extended circulating life, increased  drug  stability, and enhanced protection from proteolytic degradation; PEGylated forms may also be eligible for patent protection. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9871", "text": "The attachment of an inert and  hydrophilic  polymer was first reported around 1970 to extend blood life and control  immunogenicity  of  proteins . [ 12 ]   Polyethylene glycol was chosen as the polymer. [ 13 ] [ 14 ]  In 1981 Davis and Abuchowski founded Enzon, Inc., which brought three PEGylated drugs to market. Abuchowski later founded and is CEO of Prolong Pharmaceuticals. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9872", "text": "The clinical value of PEGylation is now well established. ADAGEN (pegademase bovine) manufactured by Enzon Pharmaceuticals, Inc., US was the first PEGylated protein approved by the  U.S. Food and Drug Administration  (FDA) in March 1990, to enter the market.  It is used to treat a form of   severe combined immunodeficiency syndrome  (ADA-SCID), as an alternative to  bone marrow transplantation  and enzyme replacement by  gene therapy . Since the introduction of ADAGEN, a large number of PEGylated protein and peptide  pharmaceuticals  have followed and many others are under clinical trial or under development stages. Sales of the two most successful products, Pegasys and Neulasta, exceeded $5 billion in 2011. [ 16 ] [ 17 ]  All commercially available PEGylated pharmaceuticals contain methoxypoly(ethylene glycol) or mPEG. PEGylated pharmaceuticals on the market (in reverse chronology by FDA approval year) have included: [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9873", "text": "The PEGylated  lipid   nanoparticle drug delivery  (LNP) system of the  mRNA vaccine  known as  mRNA-1273  has been the subject of ongoing patent litigation with  Arbutus Biopharma , from whom  Moderna  had previously licensed LNP technology. [ 25 ] [ 26 ]   On 4 September 2020,  Nature Biotechnology  reported that Moderna had lost a key challenge in the ongoing case. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9874", "text": "PEGylation has practical uses in biotechnology for protein delivery, [ 28 ]  cell  transfection , and  gene editing  in non-human cells. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9875", "text": "The first step of the PEGylation is the suitable functionalization of the PEG polymer at one or both ends. PEGs that are activated at each end with the same reactive moiety are known as \" homobifunctional \", whereas if the functional groups present are different, then the PEG derivative is referred as \" heterobifunctional \" or \" heterofunctional \". The chemically active or activated derivatives of the PEG polymer are prepared to attach the PEG to the desired molecule. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9876", "text": "The overall PEGylation processes used to date for  protein conjugation  can be broadly classified into two types, namely a solution phase batch process and an on-column fed-batch process. [ 31 ]  The simple and commonly adopted batch process involves the mixing of  reagents  together in a suitable  buffer solution , preferably at a temperature between 4 and 6\u00a0\u00b0C, followed by the separation and purification of the desired product using a suitable technique based on its  physicochemical properties , including  size exclusion chromatography  (SEC),  ion exchange chromatography  (IEX),  hydrophobic interaction chromatography  (HIC) and  membranes  or  aqueous   two-phase systems  ( ATPS ). [ 32 ] [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9877", "text": "The choice of the suitable functional group for the PEG derivative is based on the type of available reactive group on the molecule that will be coupled to the PEG. For proteins, typical reactive amino acids include  lysine ,  cysteine ,  histidine ,  arginine ,  aspartic acid ,  glutamic acid ,  serine ,  threonine  and  tyrosine . The N-terminal amino group and the C-terminal  carboxylic acid  can also be used as a site specific site by conjugation with  aldehyde  functional  polymers . [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9878", "text": "The techniques used to form first generation PEG derivatives are generally reacting the PEG polymer with a group that is reactive with  hydroxyl  groups, typically  anhydrides ,  acid chlorides ,  chloroformates  and  carbonates . In the second generation PEGylation chemistry more efficient functional groups such as aldehyde,  esters ,  amides  etc. are made available for conjugation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9879", "text": "As applications of PEGylation have become more and more advanced and sophisticated, there has been an increase in need for heterobifunctional PEGs for conjugation. These heterobifunctional PEGs are very useful in linking two entities, where a  hydrophilic , flexible and  biocompatible  spacer is needed. Preferred end groups for heterobifunctional PEGs are  maleimide ,  vinyl sulfones ,  pyridyl disulfide ,  amine ,  carboxylic acids  and  NHS  esters. [ 35 ] [ 36 ] [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9880", "text": "Third-generation pegylation agents, where the polymer has been branched, Y-shaped or comb-shaped are available and show reduced viscosity and lack of  organ accumulation . [ 38 ]  Recently also  enzymatic  approaches of PEGylation have been developed, thus further expanding the conjugation tools. [ 39 ] [ 40 ]  PEG-protein conjugates obtained by enzymatic methods are already in clinical use, for example:  Lipegfilgrastim ,  Rebinyn ,  Esperoct ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9881", "text": "Unpredictability in clearance times for PEGylated compounds may lead to the accumulation of large-molecular-weight compounds in the liver leading to  inclusion bodies  with no known toxicologic consequences. [ 41 ]  Furthermore, alteration in the chain length may lead to unexpected clearance times  in vivo . [ 42 ] \nMoreover, the experimental conditions of PEGylation reaction (i.e. pH, temperature, reaction time, overall cost of the process and molar ratio between PEG derivative and peptide) also have an impact on the stability of the final PEGylated products. [ 43 ] \nTo overcome the above-mentioned limitations different strategies such as changing the size (Mw), the number, the location and the type of linkage of PEG molecule were offered by several researchers. [ 44 ] [ 45 ]  Conjugation to biodegradable  polysaccharides , which is a promising alternative to PEGylation, is another way to solve the  biodegradability  issue of PEG. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9882", "text": "Physical pharmacy  is the branch of  pharmacy  that concentrates on the applications of  physics  and  chemistry  to the study of pharmacy. In other words, it is the study of the effects that  dosage forms  have on their environment by addressing issues at the molecular level. [ 1 ]  It emphasis on the physical characteristics and actions of the  drug delivery system  before the same is given to the patient. [ 1 ]  It forms the basis for  design , manufacture, and distribution of drug products and serves as the foundation for the stable and proper use of  medical drugs . [ 2 ]  It covers areas such as  solubility ,  pharmacokinetics  and drug delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9883", "text": "Physical pharmacy serves as principles that guide the pharmaceutical developments. [ 2 ]  It also serves as a basis for the understanding of drug  absorptions ,  distributions ,  metabolism , and  eliminations  that happen during the course of drug treatment. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9884", "text": "Physical pharmacy deals with the science that works on the following aspects which are related to the development of a  drug product . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9885", "text": "Physiologically based pharmacokinetic (PBPK) modeling  is a  mathematical modeling  technique for predicting the absorption, distribution, metabolism and excretion (ADME) of synthetic or natural chemical substances in humans and other animal species. PBPK modeling is used in pharmaceutical research and drug development, and in health  risk assessment  for cosmetics or general chemicals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9886", "text": "PBPK models strive to be mechanistic by mathematically transcribing anatomical, physiological, physical, and chemical descriptions of the phenomena involved in the complex ADME processes. A large degree of residual simplification and empiricism is still present in those models, but they have an extended domain of applicability compared to that of classical, empirical function based,  pharmacokinetic  models. PBPK models may have purely predictive uses, but other uses, such as statistical inference, have been made possible by the development of  Bayesian  statistical tools able to deal with complex models. [ 1 ]  That is true for both toxicity risk assessment and therapeutic drug development."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9887", "text": "PBPK models try to rely  a priori  on the anatomical and physiological structure of the body, and to a certain extent, on biochemistry. They are usually  multi-compartment models , with compartments corresponding to predefined organs or tissues, with interconnections corresponding to blood or lymph flows (more rarely to diffusions). A system of  differential equations  for concentration or quantity of substance on each compartment can be written, and its parameters represent blood flows, pulmonary ventilation rate, organ volumes etc., for which information is available in scientific publications. Indeed, the description they make of the body is simplified and a balance needs to be struck between complexity and simplicity. Besides the advantage of allowing the recruitment of  a priori  information about parameter values, these models also facilitate inter-species transpositions or extrapolation from one mode of administration to another ( e.g. , inhalation to oral). An example of a 7-compartment PBPK model, suitable to describe the fate of many solvents in the mammalian body, is given in the Figure on the right."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9888", "text": "The first pharmacokinetic model described in the scientific literature [ 2 ] \nwas in fact a PBPK model. It led, however, to computations intractable at that time. The focus shifted then to simpler models, [ 3 ] \nfor which analytical solutions could be obtained (such solutions were sums of exponential terms, which led to further simplifications.) The availability of computers and numerical integration algorithms marked a renewed interest in  physiological models  in the early 1970s. [ 4 ] [ 5 ] \nFor substances with complex kinetics, or when inter-species extrapolations were required, simple models were insufficient and research continued on physiological models. [ 6 ] [ 7 ] [ 8 ] \nBy 2010, hundreds of scientific publications had described and used PBPK models, and at least two private companies have based their business on their expertise in this area."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9889", "text": "The model equations follow the principles of mass transport, fluid dynamics, and biochemistry in order to simulate the fate of a substance in the body. [ 9 ] \nCompartments are usually defined by grouping organs or tissues with similar blood perfusion rate and lipid content ( i.e.  organs for which chemicals' concentration  vs.  time profiles will be similar). Ports of entry (lung, skin, intestinal tract...), ports of exit (kidney, liver...) and target organs for therapeutic effect or toxicity are often left separate. Bone can be excluded from the model if the substance of interest does not distribute to it. Connections between compartment follow physiology ( e.g. , blood flow in exit of the gut goes to liver,  etc. )"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9890", "text": "Drug distribution into a tissue can be rate-limited by either perfusion or permeability. [ 10 ] [ 11 ]  Perfusion-rate-limited kinetics apply when the tissue membranes present no barrier to diffusion. Blood flow, assuming that the drug is transported mainly by blood, as is often the case, is then the limiting factor to distribution in the various cells of the body. That is usually true for small lipophilic drugs. Under perfusion limitation, the instantaneous rate of entry for the quantity of drug in a compartment is simply equal to (blood) volumetric flow rate through the organ times the incoming blood concentration. In that case; for a generic compartment  i , the differential equation for the quantity  Q i  of substance, which defines the rate of change in this quantity, is:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9891", "text": "d \n \n Q \n \n i \n \n \n \n \n d \n t \n \n \n \n = \n \n F \n \n i \n \n \n ( \n \n C \n \n a \n r \n t \n \n \n \u2212 \n \n \n \n \n Q \n \n i \n \n \n \n \n \n P \n \n i \n \n \n \n V \n \n i \n \n \n \n \n \n ) \n \n \n {\\displaystyle {dQ_{i} \\over dt}=F_{i}(C_{art}-{{Q_{i}} \\over {P_{i}V_{i}}})}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9892", "text": "where  F i  is blood flow (noted  Q  in the Figure above),  C art  incoming arterial blood concentration,  P i  the tissue over blood partition coefficient and  V i  the volume of compartment  i ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9893", "text": "A complete set of differential equations for the 7-compartment model shown above could therefore be given by the following table:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9894", "text": "The above equations include only transport terms and do not account for inputs or outputs. \nThose can be modeled with specific terms, as in the following."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9895", "text": "Modeling inputs is necessary to come up with a meaningful description of a chemical's pharmacokinetics. The following examples show how to write the corresponding equations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9896", "text": "When dealing with an oral  bolus  dose ( e.g.  ingestion of a tablet), first order absorption is a very common assumption. In that case the gut equation is augmented with an input term, with an absorption rate constant  K a :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9897", "text": "d \n \n Q \n \n g \n \n \n \n \n d \n t \n \n \n \n = \n \n F \n \n g \n \n \n ( \n \n C \n \n a \n r \n t \n \n \n \u2212 \n \n \n \n \n Q \n \n g \n \n \n \n \n \n P \n \n g \n \n \n \n V \n \n g \n \n \n \n \n \n ) \n + \n \n K \n \n a \n \n \n \n Q \n \n i \n n \n g \n \n \n \n \n {\\displaystyle {dQ_{g} \\over dt}=F_{g}(C_{art}-{{Q_{g}} \\over {P_{g}V_{g}}})+K_{a}Q_{ing}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9898", "text": "That requires defining an equation for the quantity ingested and present in the gut lumen:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9899", "text": "d \n \n Q \n \n i \n n \n g \n \n \n \n \n d \n t \n \n \n \n = \n \u2212 \n \n K \n \n a \n \n \n \n Q \n \n i \n n \n g \n \n \n \n \n {\\displaystyle {dQ_{ing} \\over dt}=-K_{a}Q_{ing}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9900", "text": "In the absence of a gut compartment, input can be made directly in the liver. However, in that case local metabolism in the gut may not be correctly described. The case of approximately continuous absorption ( e.g. via  drinking water) can be modeled by a zero-order absorption rate (here  R ing  in units of mass over time):"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9901", "text": "d \n \n Q \n \n g \n \n \n \n \n d \n t \n \n \n \n = \n \n F \n \n g \n \n \n ( \n \n C \n \n a \n r \n t \n \n \n \u2212 \n \n \n \n \n Q \n \n g \n \n \n \n \n \n P \n \n g \n \n \n \n V \n \n g \n \n \n \n \n \n ) \n + \n \n R \n \n i \n n \n g \n \n \n \n \n {\\displaystyle {dQ_{g} \\over dt}=F_{g}(C_{art}-{{Q_{g}} \\over {P_{g}V_{g}}})+R_{ing}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9902", "text": "More sophisticated gut absorption model can be used. In those models, additional compartments describe the various sections of the gut lumen and tissue. Intestinal pH, transit times and presence of active transporters can be taken into account\n. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9903", "text": "The absorption of a chemical deposited on skin can also be modeled using first order terms. It is best in that case to separate the skin from the other tissues, to further differentiate exposed skin and non-exposed skin, and differentiate viable skin (dermis and epidermis) from the  stratum corneum  (the actual skin upper layer exposed). This is the approach taken in [Bois F., Diaz Ochoa J.G. Gajewska M., Kovarich S., Mauch K., Paini A., P\u00e9ry A., Sala Benito J.V., Teng S., Worth A., in press, Multiscale modelling approaches for assessing cosmetic ingredients safety, Toxicology. doi: 10.1016/j.tox.2016.05.026]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9904", "text": "Unexposed  stratum corneum  simply exchanges with the underlying viable skin by diffusion:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9905", "text": "d \n \n Q \n \n \n \n s \n c \n \n \n u \n \n \n \n \n \n \n d \n t \n \n \n \n = \n \n K \n \n p \n \n \n \u00d7 \n \n S \n \n s \n \n \n \u00d7 \n ( \n 1 \n \u2212 \n \n f \n \n \n S \n \n e \n \n \n \n \n ) \n \u00d7 \n ( \n \n \n \n Q \n \n \n s \n \n u \n \n \n \n \n \n \n P \n \n s \n c \n \n \n \n V \n \n \n \n s \n c \n \n \n u \n \n \n \n \n \n \n \n \u2212 \n \n C \n \n \n \n s \n c \n \n \n u \n \n \n \n \n ) \n \n \n {\\displaystyle {dQ_{{sc}_{u}} \\over dt}=K_{p}\\times S_{s}\\times (1-f_{S_{e}})\\times ({Q_{s_{u}} \\over {P_{sc}V_{{sc}_{u}}}}-C_{{sc}_{u}})}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9906", "text": "where  \n \n \n \n \n K \n \n p \n \n \n \n \n {\\displaystyle K_{p}} \n \n  is the partition coefficient,  \n \n \n \n \n S \n \n s \n \n \n \n \n {\\displaystyle S_{s}} \n \n  is the total skin surface area,  \n \n \n \n \n f \n \n \n S \n \n e \n \n \n \n \n \n \n {\\displaystyle f_{S_{e}}} \n \n  the fraction of skin surface area exposed, ..."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9907", "text": "For the viable skin unexposed:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9908", "text": "d \n \n Q \n \n \n s \n \n u \n \n \n \n \n \n \n d \n t \n \n \n \n = \n \n F \n \n s \n \n \n ( \n 1 \n \u2212 \n \n f \n \n \n S \n \n e \n \n \n \n \n ) \n ( \n \n C \n \n a \n r \n t \n \n \n \u2212 \n \n \n \n \n Q \n \n \n s \n \n u \n \n \n \n \n \n \n \n P \n \n s \n \n \n \n V \n \n \n s \n \n u \n \n \n \n \n \n \n \n ) \n \u2212 \n \n \n \n d \n \n Q \n \n \n \n s \n c \n \n \n u \n \n \n \n \n \n \n d \n t \n \n \n \n \n \n {\\displaystyle {dQ_{s_{u}} \\over dt}=F_{s}(1-f_{S_{e}})(C_{art}-{{Q_{s_{u}}} \\over {P_{s}V_{s_{u}}}})-{dQ_{{sc}_{u}} \\over dt}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9909", "text": "For the skin  stratum corneum  exposed:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9910", "text": "d \n \n Q \n \n \n \n s \n c \n \n \n e \n \n \n \n \n \n \n d \n t \n \n \n \n = \n \n K \n \n p \n \n \n \u00d7 \n \n S \n \n s \n \n \n \u00d7 \n \n f \n \n \n S \n \n e \n \n \n \n \n \u00d7 \n ( \n \n \n \n Q \n \n \n s \n \n e \n \n \n \n \n \n \n P \n \n s \n c \n \n \n \n V \n \n \n \n s \n c \n \n \n e \n \n \n \n \n \n \n \n \u2212 \n \n C \n \n \n \n s \n c \n \n \n e \n \n \n \n \n ) \n \n \n {\\displaystyle {dQ_{{sc}_{e}} \\over dt}=K_{p}\\times S_{s}\\times f_{S_{e}}\\times ({Q_{s_{e}} \\over {P_{sc}V_{{sc}_{e}}}}-C_{{sc}_{e}})}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9911", "text": "for the viable skin exposed:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9912", "text": "d \n \n Q \n \n \n s \n \n e \n \n \n \n \n \n \n d \n t \n \n \n \n = \n \n F \n \n s \n \n \n \n f \n \n \n S \n \n e \n \n \n \n \n ( \n \n C \n \n a \n r \n t \n \n \n \u2212 \n \n \n \n \n Q \n \n \n s \n \n e \n \n \n \n \n \n \n \n P \n \n s \n \n \n \n V \n \n \n s \n \n e \n \n \n \n \n \n \n \n ) \n \u2212 \n \n \n \n d \n \n Q \n \n \n \n s \n c \n \n \n e \n \n \n \n \n \n \n d \n t \n \n \n \n \n \n {\\displaystyle {dQ_{s_{e}} \\over dt}=F_{s}f_{S_{e}}(C_{art}-{{Q_{s_{e}}} \\over {P_{s}V_{s_{e}}}})-{dQ_{{sc}_{e}} \\over dt}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9913", "text": "dt(QSkin_u) and dt(QSkin_e) feed from arterial blood and back to venous blood."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9914", "text": "More complex diffusion models have been published [reference to add]."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9915", "text": "Intravenous injection is a common clinical route of administration. (to be completed)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9916", "text": "Inhalation occurs through the lung and is hardly dissociable from exhalation (to be completed)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9917", "text": "There are several ways metabolism can be modeled. For some models, a linear excretion rate is preferred. This can be accomplished with a simple differential equation. Otherwise a  Michaelis-Menten  equation, as follows, is generally appropriate for a more accurate result."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9918", "text": "PBPK models are compartmental models like many others, but they have a few advantages over so-called \"classical\" pharmacokinetic models, which are less grounded in physiology. PBPK models can first be used to abstract and eventually reconcile disparate data (from physicochemical or biochemical experiments,  in vitro  or  in vivo  pharmacological or toxicological experiments,  etc. ) They give also access to internal body concentrations of chemicals or their metabolites, and in particular at the site of their effects, be it therapeutic or toxic. Finally they also help interpolation and extrapolation of knowledge between:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9919", "text": "Some of these extrapolations are \"parametric\"\u00a0: only changes in input or parameter values are needed to achieve the extrapolation (this is usually the case for dose and time extrapolations). Others are \"nonparametric\" in the sense that a change in the model structure itself is needed ( e.g. , when extrapolating to a pregnant female, equations for the foetus should be added)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9920", "text": "Owing to the mechanistic basis of PBPK models, another potential use of PBPK modeling is hypothesis testing.  For example, if a drug compound showed lower-than-expected oral bioavailability, various model structures (i.e., hypotheses) and parameter values can be evaluated to determine which models and/or parameters provide the best fit to the observed data.  If the hypothesis that metabolism in the intestines was responsibility for the low bioavailability yielded the best fit, then the PBPK modeling results support this hypothesis over the other hypotheses evaluated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9921", "text": "As such, PBPK modeling can be used,  inter alia , to evaluate the involvement of carrier-mediated transport, clearance saturation, enterohepatic recirculation of the parent compound, extra-hepatic/extra-gut elimination; higher  in vivo  solubility than predicted  in vitro ; drug-induced gastric emptying delays; gut loss and regional variation in gut absorption. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9922", "text": "Each type of modeling technique has its strengths and limitations.  PBPK modeling is no exception.  One limitation is the potential for a large number of parameters, some of which may be correlated.  This can lead to the issues of parameter identifiability and redundancy. However, it is possible (and commonly done) to model explicitly the correlations between parameters (for example, the non-linear relationships between age, body-mass, organ volumes and blood flows)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9923", "text": "After numerical values are assigned to each PBPK model parameter, specialized or general computer software is typically used to numerically integrate a set of ordinary differential  equations like those described above, in order to calculate the numerical value of each compartment at specified values of time (see Software).  However, if such equations involve only linear functions of each compartmental value, or under limiting conditions (e.g., when input values remain very small) that guarantee such linearity is closely approximated, such equations may be solved analytically to yield explicit equations (or, under those limiting conditions, very accurate approximations) for the time-weighted average (TWA) value of each compartment as a function of the TWA value of each specified input (see, e.g., [ 16 ] [ 17 ] )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9924", "text": "PBPK models can rely on chemical property prediction models ( QSAR  models or predictive chemistry models) on one hand. For example, QSAR models can be used to estimate partition coefficients.  They also extend into, but are not destined to supplant,  systems biology  models of metabolic pathways. They are also parallel to  physiome  models, but do not aim at modelling physiological functions beyond fluid circulation in detail. In fact the above four types of models can reinforce each other when integrated. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9925", "text": "Further references:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9926", "text": "Dedicated software:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9927", "text": "General software:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9928", "text": "Plasma protein binding  refers to the degree to which  medications  attach to  blood proteins  within the  blood plasma . A  drug 's  efficacy  may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse through  cell membranes . Common  blood proteins  that drugs bind to are  human serum albumin ,  lipoprotein ,  glycoprotein , and \u03b1, \u03b2\u201a and \u03b3  globulins ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9929", "text": "A drug in blood exists in two forms: bound and unbound. Depending on a specific drug's affinity for  plasma proteins , a proportion of the drug may become bound to the proteins, with the remainder being unbound. If the protein binding is reversible, then a  chemical equilibrium  will exist between the bound and unbound states, such that:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9930", "text": "Notably, it is the unbound fraction which exhibits pharmacologic effects. It is also the fraction that may be  metabolized  and/or excreted. For example, the \"fraction bound\" of the  anticoagulant   warfarin  is 97%. This means that out of the amount of warfarin in the blood, 97% is bound to plasma proteins. The remaining 3% (the fraction unbound) is the fraction that is actually active and may be excreted."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9931", "text": "Protein binding can influence the drug's  biological half-life . The bound portion may act as a reservoir or depot from which the drug is slowly released as the unbound form. Since the unbound form is being metabolized and/or excreted from the body, the bound fraction will be released in order to maintain equilibrium."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9932", "text": "Since albumin is alkalotic, acidic and neutral drugs will primarily bind to  albumin .  If albumin becomes saturated, then these drugs will bind to  lipoprotein . Basic drugs will bind to the acidic  alpha-1 acid glycoprotein .  This is significant because various medical conditions may affect the levels of albumin, alpha-1 acid glycoprotein, and lipoproteins."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9933", "text": "Only the unbound fraction of the drug undergoes metabolism in the liver and other tissues. As the drug dissociates from the protein, more and more drug undergoes metabolism. Changes in the levels of free drug change the volume of distribution because free drug may distribute into the tissues leading to a decrease in plasma concentration profile. For the drugs which rapidly undergo metabolism,  clearance  is dependent on the hepatic blood flow.  For drugs which slowly undergo metabolism, changes in the unbound fraction of the drug directly change the clearance of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9934", "text": "The most commonly used methods for measuring drug concentration levels in the plasma measure bound as well as unbound fractions of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9935", "text": "The fraction unbound can be altered by a number of variables, such as the concentration of drug in the body, the amount and quality of plasma protein, and other drugs that bind to plasma proteins.  Higher drug concentrations would lead to a higher fraction unbound, because the plasma protein would be saturated with drug and any excess drug would be unbound.  If the amount of plasma protein is decreased (such as in  catabolism ,  malnutrition ,  liver disease ,  renal disease ), there would also be a higher fraction unbound.  Additionally, the quality of the plasma protein may affect how many drug-binding sites there are on the protein."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9936", "text": "Using 2 drugs at the same time can sometimes affect each other's fraction unbound.  For example, assume that Drug A and Drug B are both protein-bound drugs.  If Drug A is given, it will bind to the plasma proteins in the blood.  If Drug B is also given, it can displace Drug A from the protein, thereby increasing Drug A's fraction unbound.  This may increase the effects of Drug A, since only the unbound fraction may exhibit activity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9937", "text": "Note that for Drug A, the\u00a0% increase in unbound fraction is 100% \u2013 hence, Drug A's pharmacological effect can potentially double (depending on whether the free molecules get to their target before they are eliminated by metabolism or excretion).  This change in pharmacologic effect could have adverse consequences."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9938", "text": "However, this effect is really only noticeable in closed systems where the pool of available proteins could potentially be exceeded by the number of drug molecules. Biological systems, such as humans and animals, are open systems where molecules can be gained, lost or redistributed and where the protein pool capacity is almost never exceeded by the number of drug molecules. A drug that is 99% bound means that 99% of the drug molecules are bound to blood proteins not that 99% of the blood proteins are bound with drug. When two, highly protein-bound drugs (A and B) are added into the same biological system it will lead to an initial small increase in the concentration of free drug A (as drug B ejects some of the drug A from its proteins). However, this free drug A is now more available for redistribution into the body tissues and/or for excretion. This means the total amount of drug in the system will decrease quite rapidly, keeping the free drug fraction (the concentration of free drug divided by the total drug concentration) constant and yielding almost no change in clinical effect. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9939", "text": "The effects of drugs displacing each other and changing the clinical effect (though important in some examples) is vastly overestimated usually and a common example incorrectly used to display the importance of this effect is the anticoagulant  warfarin . Warfarin is highly protein-bound (>95%) and has a low  therapeutic index . Since a low therapeutic index indicates that there is a high risk of toxicity when using the drug, any potential increases in warfarin concentration could be very dangerous and lead to hemorrhage. In horses, it is very true that if warfarin and  phenylbutazone  are administered concurrently, the horse can develop bleeding issues which can be fatal. This is often explained as being due to the effect of phenylbutazone ejecting warfarin from its plasma protein, thus increasing the concentration of free warfarin and increasing its anticoagulant effect. However, the real problem is that phenylbutazone interferes with the liver's ability to metabolize warfarin so free warfarin cannot be metabolized properly or excreted. This leads to an increase in free warfarin and the resulting bleeding problems. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9940", "text": "The  plateau principle  is a  mathematical model  or  scientific law  originally developed to explain the time course of drug action ( pharmacokinetics ). [ 1 ]  The principle has wide applicability in pharmacology, physiology, nutrition, biochemistry, and system dynamics. It applies whenever a drug or nutrient is infused or ingested at a relatively constant rate and when a constant fraction is eliminated during each time interval. Under these conditions, any change in the rate of infusion leads to an exponential increase or decrease until a new level is achieved. This behavior is also called an  approach to  steady state  because rather than causing an indefinite increase or decrease, a natural balance is achieved when the rate of infusion or production is balanced by the rate of loss."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9941", "text": "An especially important use of the plateau principle is to study the renewal of tissue constituents in the human and animal body. In adults, daily synthesis of tissue constituents is nearly constant, and most constituents are removed with a first- order   reaction rate . Applicability of the plateau principle was recognized during  radioactive tracer  studies of protein turnover in the 1940s by  Rudolph Schoenheimer [ 2 ]  and  David Rittenberg . [ 3 ]  Unlike the case with drugs, the initial amount of tissue or tissue protein is not zero because daily synthesis offsets daily elimination. In this case, the model is also said to approach a  steady state  with  exponential  or  logarithmic   kinetics . Constituents that change in this manner are said to have a  biological half-life ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9942", "text": "A practical application of the plateau principle is that most people have experienced \"plateauing\" during regimens for weight management or training for sports. After a few weeks of progress, one seems unable to continue gaining in ability or losing weight. This outcome results from the same underlying quantitative model. This entry will describe the popular concepts as well as development of the plateau principle as a scientific, mathematical model."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9943", "text": "In the sciences, the broadest application of the plateau principle is creating realistic time signatures for change in kinetic models (see  Mathematical model ). One example of this principle is the long time required to effectively change human body composition. Theoretical studies have shown that many months of consistent physical training and food restriction are needed to bring about permanent weight stability in people who were previously  overweight . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9944", "text": "Most drugs are eliminated from the  blood plasma  with first- order   kinetics . For this reason, when a drug is introduced into the body at a constant rate by  intravenous therapy , it approaches a new steady concentration in the blood at a rate defined by its  half-life . Similarly, when the intravenous infusion is ended, the drug concentration decreases exponentially and reaches an undetectable level after 5\u20136 half-lives have passed. [ 5 ] [ 6 ]  If the same drug is administered as a  bolus (medicine)  with a single injection, peak concentration is achieved almost immediately and then the concentration declines exponentially."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9945", "text": "Most drugs are taken by mouth. In this case, the assumption of constant infusion is only approximated as doses are repeated over the course of several days. The plateau principle still applies but more complex models are required to account for the  route of administration ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9946", "text": "Derivation of equations that describe the time course of change for a system with zero- order  input and first-order elimination are presented in the articles  Exponential decay  and  Biological half-life , and in scientific literature. [ 1 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9947", "text": "The relationship between the elimination rate constant and half-life is given by the following equation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9948", "text": "Because ln 2 equals 0.693, the half-life is readily calculated from the elimination rate constant. Half-life has units of time, and the elimination rate constant has units of 1/time, e.g., per hour or per day."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9949", "text": "An equation can be used to forecast the concentration of a compound at any future time when the fractional degration rate and steady state concentration are known:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9950", "text": "The exponential function in parentheses corresponds to the fraction of total change that has been achieved as time passes and the difference between  C ss  and  C 0  equals the total amount of change. Finally, at steady state, the concentration is expected to equal the rate of synthesis, production or infusion divided by the first-order elimination constant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9951", "text": "Although these equations were derived to assist with predicting the time course of drug action, [ 1 ]  the same equation can be used for any substance or quantity that is being produced at a measurable rate and degraded with first-order kinetics. Because the equation applies in many instances of  mass balance , it has very broad applicability in addition to  pharmacokinetics . The most important inference derived from the steady state equation and the equation for fractional change over time is that the elimination rate constant ( k e ) or the sum of rate constants that apply in a model determine the time course for change in mass when a system is perturbed (either by changing the rate of inflow or production, or by changing the elimination rate(s))."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9952", "text": "When experimental data are available, the normal procedure for estimating rate parameters such as  k e  and  C ss  is to minimize the  sum of squares  of differences between observed data and values predicted based on initial estimates of the rate constant and steady state value. This can be done using any software package that contains a  curve fitting  routine. An example of this methodology implemented with spreadsheet software has been reported. [ 8 ]  The same article reports a method that requires only 3 equally spaced data points to obtain estimates for kinetic parameters. Spreadsheets that compare these methods are available. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9953", "text": "Dr.  Wilbur O. Atwater , who developed the first database of food composition in the United States, recognized that the response to excessive or insufficient nutrient intake included an adjustment in efficiency that would result in a plateau. He observed: \"It has been found by numerous experiments that when the nutrients are fed in large excess, the body may continue for a time to store away part of the extra material, but after it has accumulated a certain amount, it refuses to take on more, and the daily consumption equals the supply even when this involves great waste.\" [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9954", "text": "In general, no  essential nutrient  is produced in the body. Nutrient kinetics therefore follow the plateau principle with the distinction that most are ingested by mouth and the body must contain an amount adequate for health. The plateau principle is important in determining how much time is needed to produce a deficiency when intake is insufficient. Because of this, pharmacokinetic considerations should be part of the information needed to set a  dietary reference intake  for essential nutrients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9955", "text": "The blood plasma concentration of  vitamin C  or  ascorbic acid  as a function of dose attains a plateau with a half-life of about 2 weeks. [ 10 ]   Bioavailability  of vitamin C is highest at dosages below 200\u00a0mg per day. Above 500\u00a0mg, nearly all of excess vitamin C is excreted through urine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9956", "text": "Vitamin D metabolism is complex because the  provitamin  can be formed in the skin by ultraviolet irradiation or obtained from the diet. Once hydroxylated, the vitamin has a half-life of about 2 months. [ 11 ] \nVarious studies have suggested that current intakes are inadequate for optimum bone health and much current research is aimed at determining recommendations for obtaining adequate circulating vitamin D 3  and calcium while also minimizing potential toxicity. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9957", "text": "Many healthful qualities of foods and beverages may be related to the content of phytochemicals (see  List of phytochemicals in food ). Prime examples are  flavonoids  found in green tea, berries,  cocoa , and  spices  as well as in the skins and seeds of apples, onions, and grapes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9958", "text": "Investigations into healthful benefits of phytochemicals follow exactly the same principles of pharmacokinetics that are required to study drug therapy. The initial concentration of any non-nutritive phytochemical in the blood plasma is zero unless a person has recently ingested a food or beverage. For example, as increasing amounts of green tea extract are consumed, a graded increase in plasma  catechin  can be measured, and the major compound is eliminated with a half-life of about 5 hours. [ 13 ]  Other considerations that must be evaluated include whether the ingested compound interacts favorably or unfavorably with other nutrients or drugs, and whether there is evidence for a threshold or  toxicity  at higher levels of intake."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9959", "text": "It is especially common for people who are trying to lose weight to experience plateaus after several weeks of successful weight reduction. The plateau principle suggests that this leveling off is a sign of success. Basically, as one loses weight, less  food energy  is required to maintain the resting metabolic rate, which makes the initial regimen less effective. [ 14 ]  The idea of weight plateaus has been discussed for subjects who are participating in a  calorie restriction experiment   [ 15 ]  Food energy is expended largely through work done against gravity (see  Joule ), so weight reduction lessens the effectiveness of a given workout. In addition, a trained person has greater skill and therefore greater efficiency during a workout. Remedies include increasing the workout intensity or length and reducing portion sizes of meals more than may have been done initially."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9960", "text": "The fact that weight loss and dieting reduce the metabolic rate is supported by research. In one study, heat production was reduced 30% in obese men after a weight loss program, and this led to resistance to further lose body weight. [ 16 ]  Whether body mass increases or decreases, adjustments in the  thermic effect of food , resting energy expenditure, and non-resting energy expenditure all oppose further change. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9961", "text": "Any athlete who has trained for a sport has probably experienced plateaus, and this has given rise to various strategies to continue improving. [ 18 ]  Voluntary  skeletal muscle  is in balance between the amount of muscle synthesized or renewed each day and the amount that is degraded. Muscle fibers respond to repetition and load, and increased training causes the quantity of exercised muscle fiber to increase exponentially (simply meaning that the greatest gains are seen during the first weeks of training). Successful training produces  hypertrophy  of muscle fibers as an adaptation to the training regimen. In order to make further gains, greater workout intensity is required with heavier loads and more repetitions, although improvement in skill can contribute to gains in ability."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9962", "text": "When a bodily constituent adjusts exponentially over time, it usually attains a new stable level as a result of the plateau principle. The new level may be higher than the initial level ( hypertrophy ) in the case of strength training or lower in the case of dieting or disuse  atrophy . This adjustment contributes to  homeostasis  but does not require  feedback  regulation. Gradual, asymptotic approach to a new balance between synthesis and degradation produces a stable level. Because of this, the plateau principle is sometimes called the  stability principle.  Mathematically, the result is  linear  dynamics despite the fact that most biological processes are non-linear (see  Nonlinear system ) if considered over a very broad range of inputs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9963", "text": "Data from the  Minnesota Starvation Experiment  by  Ancel Keys  and others [ 19 ]  demonstrate that during food restriction, total body mass, fat mass and lean body mass follow an exponential approach to a new steady state. [ 20 ]  The observation that body mass changes exponentially during partial or complete starvation seems to be a general feature of adaptation to energy restriction. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9964", "text": "Each cell produces thousands of different kinds of  protein  and  enzymes . One of the key methods of cellular regulation is to change the rate of  transcription  of  messenger RNA , which gives rise to a change in the rate of synthesis for the protein that the messenger RNA encodes. The plateau principle explains why the concentration of different enzymes increases at unique rates in response to a single  hormone . Because each enzyme is degraded with at a unique rate (each has a different  half-life ), the rate of change differs even when the same stimulus is applied. This principle has been demonstrated for the response of liver enzymes that degrade amino acids to  cortisone , which is a  catabolic  hormone. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9965", "text": "The method of approach to steady state has also been used to analyze the change in messenger RNA levels when synthesis or degradation changes, and a model has also been reported in which the plateau principle is used to connect the change in messenger RNA synthesis to the expected change in protein synthesis and concentration as a function of time. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9966", "text": "Excessive gain in body weight contributes to the  metabolic syndrome , which may include elevated fasting  blood sugar  (or  glucose ), resistance to the action of  insulin , elevated  low-density lipoprotein  (LDL cholesterol) or decreased  high-density lipoprotein  (HDL cholesterol), and elevated  blood pressure .  Obesity  was designated as a disease in 2013 by the American Medical Association. It is defined as a chronic, relapsing, multi-factorial, neurobehavioral disease, wherein an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial health consequences. [ 23 ]  Because body mass, fat mass and fat free mass all change exponentially during weight reduction, it is a reasonable hypothesis to expect that symptoms of metabolic syndrome will also adjust exponentially towards normal values."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9967", "text": "Scientists have evaluated turnover of bodily constituents using  radioactive tracers  and  stable isotope  tracers. [ 24 ]  If given orally, the tracers are absorbed and move into the  blood plasma , and are then distributed throughout the bodily tissues. In such studies, a  multi-compartment model  is required to analyze turnover by  isotopic labeling . The isotopic marker is called a  tracer  and the material being analyzed is the  tracee ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9968", "text": "In studies with humans, blood plasma is the only tissue that can be easily sampled. A common procedure is to analyze the dynamics by assuming that changes can be attributed to a sum of exponentials. A single mathematical  compartment  is usually assumed to follow first-order kinetics in accord with the plateau principle. There are many examples of this kind of analysis in nutrition, for example, in the study of metabolism of zinc, [ 25 ]  and carotenoids. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9969", "text": "The commonest assumption in compartmental modeling is that material in a homogeneous compartment behaves exponentially. However, this assumption is sometimes modified to include a saturable response that follows  Michaelis\u2013Menten kinetics  or a related model called a  Hill equation . When the material in question is present at a concentration near the  K M , it often behaves with pseudo first-order kinetics (see  Rate equation ) and the plateau principle applies despite the fact that the model is non-linear."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9970", "text": "Compartmental modeling in biomedical sciences primarily originated from the need to study metabolism by using tracers. In contrast,  System dynamics  originated as a simple method of developing mathematical models by  Jay Wright Forrester  and colleagues. System dynamics represents a compartment or pool as a  stock  and movement among compartments as  flows . In general, the rate of flow depends on the amount of material in the stock to which it is connected. It is common to represent this dependence as a constant proportion (or first-order) using a  connector  element in the model."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9971", "text": "System dynamics is one application of the field of  control theory . In the biomedical field, one of the strongest advocates for computer-based analysis of physiological problems was Dr.  Arthur Guyton . For example, system dynamics has been used to analyze the problem of body weight regulation. [ 27 ]  Similar methods have been used to study the spread of epidemics (see  Compartmental models in epidemiology )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9972", "text": "Software that solves systems of equations required for compartmental modeling and system dynamics makes use of  finite difference  methods to represent a set of  ordinary differential equations . An expert appraisal of the different types of dynamic behavior that can be developed by application of the plateau principle to the field of system dynamics has been published. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9973", "text": "In  biotechnology ,  polymersomes [ 1 ]  are a class of artificial  vesicles , tiny hollow spheres that enclose a solution. Polymersomes are made using  amphiphilic  synthetic block  copolymers  to form the vesicle membrane, and have radii ranging from 50\u00a0nm to 5\u00a0\u03bcm or more. [ 2 ]  Most reported polymersomes contain an  aqueous solution  in their core and are useful for encapsulating and protecting sensitive molecules, such as drugs, enzymes, other proteins and peptides, and  DNA  and  RNA  fragments. The polymersome membrane provides a physical barrier that isolates the encapsulated material from external materials, such as those found in biological systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9974", "text": "Synthosomes  are polymersomes engineered to contain channels ( transmembrane proteins ) that allow certain chemicals to pass through the membrane, into or out of the vesicle. This allows for the collection or enzymatic modification of these substances. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9975", "text": "The term \"polymersome\" for vesicles made from block copolymers was coined in 1999. [ 1 ]  Polymersomes are similar to  liposomes , which are vesicles formed from naturally occurring  lipids . While having many of the properties of natural liposomes, polymersomes exhibit increased stability and reduced permeability. Furthermore, the use of synthetic polymers enables designers to manipulate the characteristics of the membrane and thus control permeability, release rates, stability and other properties of the polymersome."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9976", "text": "Several different morphologies of the block copolymer used to create the polymersome have been used. The most frequently used are the linear diblock or triblock copolymers. In these cases, the block copolymer has one block that is  hydrophobic ; the other block or blocks are  hydrophilic . Other morphologies used include comb copolymers, [ 4 ] [ 5 ]  where the backbone block is hydrophilic and the comb branches are hydrophobic, and  dendronized block copolymers , [ 6 ]  where the  dendrimer  portion is hydrophilic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9977", "text": "In the case of diblock, comb and dendronized copolymers the polymersome membrane has the same  bilayer  morphology of a liposome, with the hydrophobic blocks of the two layers facing each other in the interior of the membrane. In the case of triblock copolymers the membrane is a  monolayer  that mimics a bilayer, the central block filling the role of the two facing hydrophobic blocks of a bilayer. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9978", "text": "In general they can be prepared by the methods used in the preparation of liposomes. Film rehydration, direct injection method or dissolution method."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9979", "text": "Polymersomes that contain active enzymes and that provide a way to selectively transport substrates for conversion by those enzymes have been described as nanoreactors. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9980", "text": "Polymersomes have been used to create controlled release  drug delivery  systems. [ 9 ]   Similar to coating liposomes with  polyethylene glycol , polymersomes can be made invisible to  the immune system  if the hydrophilic block consists of polyethylene glycol. [ 10 ]  Thus, polymersomes are useful carriers for targeted medication."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9981", "text": "For  in vivo  applications, polymersomes are  de facto  limited to the use of  FDA -approved polymers, as most pharmaceutical firms are unlikely to develop novel  polymers  due to cost issues. Fortunately, there are a number of such polymers available, with varying properties, including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9982", "text": "Hydrophilic blocks"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9983", "text": "Hydrophobic blocks"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9984", "text": "If enough of the block copolymer molecules that make up a polymersome are  cross-linked , the polymersome can be made into a transportable powder. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9985", "text": "Polymersomes can be used to make an  artificial cell  if  hemoglobin  and other components are added. [ 13 ] [ 14 ]  The first artificial cell was made by  Thomas Chang . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9986", "text": "Polypharmacy  (polypragmasia) is an  umbrella term  to describe the simultaneous use of multiple medicines by a patient for their conditions. [ 1 ] [ 2 ]  The term polypharmacy is often defined as regularly taking five or more medicines but there is no standard definition and the term has also been used in the context of when a person is prescribed 2 or more medications at the same time. [ 1 ] [ 3 ] [ 4 ]  Polypharmacy may be the consequence of having multiple long-term conditions, also known as  multimorbidity  and is more common in people who are older. [ 5 ] [ 6 ]  In some cases, an excessive number of medications at the same time is worrisome, especially for people who are older with many chronic health conditions, because this increases the risk of an adverse event in that population. [ 7 ] [ 8 ]  In many cases, polypharmacy cannot be avoided, but 'appropriate polypharmacy' practices are encouraged to decrease the risk of adverse effects. [ 9 ]  Appropriate polypharmacy is defined as the practice of prescribing for a person who has multiple conditions or complex health needs by ensuring that medications prescribed are optimized and follow 'best evidence' practices. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9987", "text": "The prevalence of polypharmacy is estimated to be between 10% and 90% depending on the definition used, the age group studied, and the geographic location. [ 10 ]  Polypharmacy continues to grow in importance because of  aging populations . Many countries are experiencing a fast growth of the older population, 65 years and older. [ 11 ] [ 12 ] [ 13 ]  This growth is a result of the  baby-boomer  generation getting older and an increased  life expectancy  as a result of ongoing improvement in health care services worldwide. [ 14 ] [ 15 ]  About 21% of adults with  intellectual disability  are also exposed to polypharmacy. [ 16 ]  The level of polypharmacy has been increasing in the past decades. Research in the USA shows that the percentage of patients greater than 65 years-old using more than 5 medications increased from 24% to 39% between 1999 and 2012. [ 17 ]  Similarly, research in the UK found that the number of older people taking 5 plus medication had quadrupled from 12% to nearly 50% between 1994 and 2011. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9988", "text": "Polypharmacy is not necessarily ill-advised, but in many instances can lead to negative outcomes or poor treatment effectiveness, often being  more harmful than helpful  or presenting  too much risk for too little benefit . Therefore,  health professionals  consider it a situation that requires monitoring and review to validate whether all of the medications are still necessary. Concerns about polypharmacy include increased  adverse drug reactions ,  drug interactions ,  prescribing cascade , and higher costs. [ 19 ]  A prescribing cascade occurs when a person is prescribed a drug and experiences an adverse drug effect that is misinterpreted as a new medical condition, so the patient is prescribed another drug. [ 20 ]  Polypharmacy also increases the burden of medication taking particularly in older people and is associated with  medication non-adherence . [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9989", "text": "Polypharmacy is often  associated with  a decreased  quality of life , including decreased  mobility  and  cognition . [ 22 ]  Patient factors that influence the number of medications a patient is prescribed include a high number of chronic conditions requiring a complex drug regimen. Other systemic factors that impact the number of medications a patient is prescribed include a patient having multiple prescribers and multiple pharmacies that may not communicate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9990", "text": "Whether or not the advantages of polypharmacy (over taking single medications or  monotherapy ) outweigh the disadvantages or risks depends upon the particular combination and diagnosis involved in any given case. [ 23 ]  The use of multiple drugs, even in fairly straightforward illnesses, is not an indicator of poor treatment and is not necessarily  overmedication . Moreover, it is well accepted in  pharmacology  that it is impossible to accurately predict the side effects or clinical effects of a combination of drugs without studying that particular combination of drugs in test subjects. Knowledge of the pharmacologic profiles of the individual drugs in question does not assure accurate prediction of the side effects of combinations of those drugs; and effects also vary among individuals because of  genome -specific  pharmacokinetics . Therefore, deciding whether and how to reduce a list of medications ( deprescribe ) is often not simple and requires the experience and judgment of a practicing clinician, as the clinician must weigh the pros and cons of keeping the patient on the medication. However, such thoughtful and wise review is an ideal that too often does not happen, owing to problems such as poorly handled  care transitions  (poor continuity of care, usually because of  siloed information ), overworked physicians and other clinical staff, and  interventionism ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9991", "text": "While polypharmacy is typically regarded as undesirable, prescription of multiple medications can be appropriate and therapeutically beneficial in some circumstances. [ 24 ]  \u201cAppropriate polypharmacy\u201d is described as prescribing for complex or multiple conditions in such a way that necessary medicines are used based on the best available evidence at the time to preserve safety and well-being. [ 24 ]  Polypharmacy is clinically indicated in some chronic conditions, for example in  diabetes mellitus , but should be discontinued when evidence of benefit from the prescribed drugs no longer outweighs potential for harm (described below in Contraindications). [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9992", "text": "Often certain medications can interact with others in a positive way specifically intended when prescribed together, to achieve a greater effect than any of the single agents alone. This is particularly prominent in the field of anesthesia and pain management \u2013 where atypical agents such as  antiepileptics ,  antidepressants ,  muscle relaxants ,  NMDA antagonists , and other medications are combined with more typical analgesics such as  opioids ,  prostaglandin  inhibitors,  NSAIDS  and others. This practice of pain management  drug synergy [ 25 ]  is known as an  analgesia sparing  effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9993", "text": "People who are at greatest risk for negative polypharmacy consequences include  elderly  people, people with  psychiatric  conditions, patients with intellectual or developmental disabilities, [ 28 ]  people taking five or more drugs at the same time, those with multiple  physicians  and  pharmacies , people who have been recently hospitalized, people who have concurrent  comorbidities , [ 29 ]  people who live in rural communities, people with inadequate access to education, [ 30 ]  and those with impaired vision or dexterity. Marginalized populations may have a greater degrees of polypharmacy, which can occur more frequently in younger age groups. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9994", "text": "It is not uncommon for people who are dependent or addicted to substances to enter or remain in a state of polypharmacy misuse. [ 32 ]  About 84% of prescription drug misusers reported using multiple drugs. [ 32 ]  Note, however, that the term  polypharmacy  and its variants generally refer to legal drug use as-prescribed, even when used in a negative or critical context."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9995", "text": "Measures can be taken to limit polypharmacy to its truly legitimate and appropriate needs. This is an emerging area of research, frequently called  deprescribing . [ 33 ]  Reducing the number of medications, as part of a clinical review, can be an effective healthcare intervention. [ 34 ]  Clinical pharmacists can perform drug therapy reviews and teach physicians and their patients about drug safety and polypharmacy, as well as collaborating with physicians and patients to correct polypharmacy problems. Similar programs are likely to reduce the potentially deleterious consequences of polypharmacy such as adverse drug events, non-adherence, hospital admissions, drug-drug interactions, geriatric syndromes, and mortality. [ 35 ]  Such programs hinge upon patients and doctors informing pharmacists of other medications being prescribed, as well as herbal, over-the-counter substances and supplements that occasionally interfere with prescription-only medication. Staff at residential aged care facilities have a range of views and attitudes towards polypharmacy that, in some cases, may contribute to an increase in medication use. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9996", "text": "The risk of polypharmacy increases with age, although there is some evidence that it may decrease slightly after age 90 years. [ 2 ]  Poorer health is a strong predictor of polypharmacy at any age, although it is unclear whether the polypharmacy causes the poorer health or if polypharmacy is used because of the poorer health. [ 2 ]  It appears possible that the risk factors for polypharmacy may be different for younger and middle-aged people compared to older people. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9997", "text": "The use of polypharmacy is correlated to the use of potentially inappropriate medications. Potentially inappropriate medications are generally taken to mean those that have been agreed upon by expert consensus, such as by the  Beers Criteria . These medications are generally inappropriate for older adults because the risks outweigh the benefits. [ 37 ]  Examples of these include urinary  anticholinergics  used to treat  incontinence ; the associated risks, with anticholinergics, include constipation, blurred vision, dry mouth, impaired cognition, and falls. [ 38 ]  Many older people living in long term care facilities experience polypharmacy, and under-prescribing of potentially indicated medicines and use of high risk medicines can also occur. [ 37 ]  Medicine use rises from 6.0 \u00b1 3.8 regular medicines on average when people enter long term care to 8.9 \u00b1 4.1 regular medicines after two years. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_9998", "text": "Polypharmacy is associated with an increased risk of falls in elderly people. [ 40 ] [ 41 ]  Certain medications are well known to be associated with the risk of falls, including cardiovascular and  psychoactive medications . [ 42 ] [ 43 ]  There is some evidence that the risk of falls increases cumulatively with the number of medications. [ 44 ] [ 45 ]  Although often not practical to achieve, withdrawing all medicines associated with falls risk can halve an individual's risk of future falls."}
{"_id": "WikiPedia_Pharmacology$$$corpus_9999", "text": "Every medication has potential adverse side-effects. With every drug added, there is an additive risk of side-effects. Also, some medications have  interactions  with other substances, including foods, other medications, and herbal supplements. [ 46 ]  15% of older adults are potentially at risk for a major drug-drug interaction. [ 47 ]  Older adults are at a higher risk for a drug-drug interaction due to the increased number of medications prescribed and  metabolic  changes that occur with aging. [ 48 ]  When a new drug is prescribed, the risk of interactions increases exponentially. Doctors and  pharmacists  aim to avoid prescribing medications that interact; often, adjustments in the dose of medications need to be made to avoid interactions. For example,  warfarin  interacts with many medications and supplements that can cause it to lose its effect. [ 48 ] [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10000", "text": "Pill burden is the number of pills (tablets or capsules, the most common dosage forms) that a person takes on a regular basis, along with all associated efforts that increase with that number - like storing, organizing, consuming, and understanding the various medications in one's regimen. The use of individual medications is growing faster than pill burden. [ 50 ]  A recent study found that older adults in long term care are taking an average of 14 to 15 tablets every day. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10001", "text": "Poor medical adherence is a common challenge among individuals who have increased pill burden and are subject to polypharmacy. [ 52 ]  It also increases the possibility of adverse medication reactions ( side effects ) and  drug-drug interactions . High pill burden has also been associated with an increased risk of hospitalization, medication errors, and increased costs for both the pharmaceuticals themselves and for the treatment of adverse events. Finally, pill burden is a source of dissatisfaction for many patients and family carers. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10002", "text": "High pill burden was commonly associated with  antiretroviral drug  regimens to control  HIV , [ 53 ]  and is also seen in other patient populations. [ 52 ]  For instance, adults with multiple common chronic conditions such as  diabetes ,  hypertension ,  lymphedema ,  hypercholesterolemia ,  osteoporosis ,  constipation ,  inflammatory bowel disease , and  clinical depression  may be prescribed more than a dozen different medications daily. [ 54 ]  The combination of multiple drugs has been associated with an increased risk of adverse drug events. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10003", "text": "Reducing pill burden is recognized as a way to improve medication  compliance , also referred to as adherence. This is done through \" deprescribing \", where the risks and benefits are weighed when considering whether to continue a medication. [ 56 ]  This includes drugs such as  bisphosphonates  (for  osteoporosis ), which are often taken indefinitely although there is only evidence to use it for five to ten years. [ 56 ]  Patient educational programs, reminder messages, medication packaging, and the use of memory tricks has also been seen to improve adherence and reduce pill burden in several countries. [ 48 ]  These include associating medications with mealtimes, recording the dosage on the box, storing the medication in a special place, leaving it in plain sight in the living room, or putting the prescription sheet on the refrigerator. [ 48 ]  The development of applications has also shown some benefit in this regard. [ 48 ]  The use of a  polypill  regimen, such as combination pill for HIV treatment, as opposed to a multi-pill regimen, also alleviates pill burden and increases adherence. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10004", "text": "The selection of long-acting active ingredients over short-acting ones may also reduce pill burden. For instance,  ACE inhibitors  are used in the management of  hypertension . [ medical citation needed ]  Both  captopril  and  lisinopril  are examples of ACE inhibitors. However, lisinopril is dosed once a day, whereas captopril may be dosed 2-3 times a day. Assuming that there are no contraindications or potential for drug interactions, using lisinopril instead of captopril may be an appropriate way to limit pill burden. [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10005", "text": "The most common intervention to help people who are struggling with polypharmacy is  deprescribing . [ 57 ]  Deprescribing can be confused with medication simplification, which does not attempt to reduce the number of medicines but rather reduce the number of dose forms and administration times. [ 58 ]  Deprescribing refers to reducing the number of medications that a person is prescribed and includes the identification and discontinuance of medications when the benefit no longer outweighs the harm. [ 59 ]  In elderly patients, this can commonly be done as a patient becomes more frail and treatment focus needs to shift from  preventative  to  palliative . [ 59 ]  Deprescribing is feasible and effective in many settings including residential care, communities and hospitals. [ 57 ]  This preventative measure should be considered for anyone who exhibits one of the following: (1) a new symptom or adverse event arises, (2) when the person develops an end-stage disease, (3) if the combination of drugs is risky, or (4) if stopping the drug does not alter the disease trajectory. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10006", "text": "Several tools exist to help physicians decide when to deprescribe and what medications can be added to a  pharmaceutical  regimen. The  Beers Criteria  and the STOPP/START criteria help identify medications that have the highest risk of  adverse drug events  (ADE) and  drug-drug interactions . [ 60 ] [ 61 ] [ 62 ]  The  Medication appropriateness tool for comorbid health conditions during dementia  (MATCH-D) is the only tool available specifically for people with dementia, and also cautions against polypharmacy and complex medication regimens. [ 63 ] [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10007", "text": "Barriers faced by both physicians and people taking the medications have made it challenging to apply deprescribing strategies in practice. [ 65 ]  For physicians, these include fear of consequences of deprescribing, the prescriber's own confidence in their skills and knowledge to deprescribe, reluctance to alter medications that are prescribed by specialists, the feasibility of deprescribing, lack of access to all of patients' clinical notes, and the complexity of having multiple providers. [ 65 ] [ 66 ] [ 67 ]  For patients who are prescribed or require the medication, barriers include attitudes or beliefs about the medications, inability to communicate with physicians, fears and uncertainties surrounding deprescribing, and influence of physicians, family, and the media. [ 65 ]  Barriers can include other health professionals or carers, such as in residential care, believing that the medicines are required. [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10008", "text": "In people with multiple long-term conditions (multimorbidity) and polypharmacy deprescribing represents a complex challenge as clinical guidelines are usually developed for single conditions. In these cases tools and guidelines like the Beers Criteria and STOPP/START could be used safely by clinicians but not all patients might benefit from stopping their medication. There is a need for clarity about how much clinicians can do beyond the guidelines and the responsibility they need to take could help them prescribing and deprescribing for complex cases. Further factors that can help clinicians tailor their decisions to the individual are: access to detailed data on the people in their care (including their backgrounds and personal medical goals), discussing plans to stop a medicine already when it is first prescribed, and a good relationship that involves mutual trust and regular discussions on progress. Furthermore, longer appointments for prescribing and deprescribing would allow time explain the process of deprescribing, explore related concerns, and support making the right decisions. [ 69 ] [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10009", "text": "The effectiveness of specific interventions to improve the appropriate use of polypharmacy such as  pharmaceutical care  and computerised decision support is unclear. [ 9 ]  This is due to low quality of current evidence surrounding these interventions. [ 9 ]  High quality evidence is needed to make any conclusions about the effects of such interventions in any environment, including in care homes. [ 71 ]  Deprescribing is not influenced by whether medicines are prescribed through a paper-based or an electronic system. [ 72 ]  Deprescribing rounds has been proposed as a potentially successful methodology in reducing polypharmacy. [ 73 ]  Sharing of positive outcomes from physicians who have implemented deprescribing, increased communication between all practitioners involved in patient care, higher compensation for time spent deprescribing, and clear deprescribing guidelines can help enable the practice of deprescribing. [ 67 ]  Despite the difficulties, a recent blinded study of deprescribing reported that participants used an average of two fewer medicines each after 12 months showing again that deprescribing is feasible. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10010", "text": "PottersWheel  is a  MATLAB  toolbox for mathematical modeling of time-dependent  dynamical systems  that can be expressed as  chemical reaction networks  or  ordinary differential equations  (ODEs). [ 1 ]  It allows the automatic calibration of model parameters by fitting the model to experimental measurements. CPU-intensive functions are written or \u2013 in case of model dependent functions \u2013 dynamically generated in C. Modeling can be done interactively using graphical user interfaces or based on MATLAB scripts using the PottersWheel function library. The software is intended to support the work of a mathematical modeler as a real  potter's wheel  eases the modeling of pottery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10011", "text": "The basic use of PottersWheel covers seven phases from model creation to the prediction of new\nexperiments."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10012", "text": "The dynamical system is formalized into a set of reactions or differential equations using a visual model designer or a text editor. The model is stored as a MATLAB *.m ASCII file. Modifications can therefore be tracked using a version control system like  subversion  or  git . Model import and export is supported for  SBML . Custom import-templates may be used to import custom model structures.  Rule-based modeling  is also supported, where a pattern represents a set of automatically generated reactions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10013", "text": "Example for a simple model definition file for a reaction network A \u2192 B \u2192 C \u2192 A with observed species A and C:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10014", "text": "External data saved in *.xls or *.txt files can be added to a model creating a  model-data-couple . A mapping dialog allows to connect data column names to observed species names. Meta information in the data files comprise information about the experimental setting. Measurement errors are either stored in the data files, will be calculated using an error model, or are estimated automatically."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10015", "text": "To fit a model to one or more data sets, the corresponding model-data-couples are combined into a  fitting-assembly . Parameters like initial values, rate constants, and scaling factors can be fitted in an experiment-wise or global fashion. The user may select from several numerical integrators, optimization algorithms, and calibration strategies like fitting in normal or logarithmic parameter space."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10016", "text": "The quality of a fit is characterized by its  chi-squared  value.  As a rule of thumb, for\n N  fitted data points and  p  calibrated parameters, the chi-squared value should have a similar value\nas  N \u00a0\u2212\u00a0 p  or at least\u00a0 N . Statistically, this is expressed using a  chi-squared test  resulting in a  p-value  above a significance threshold of e.g.\u00a00.05. For lower p-values, the model is"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10017", "text": "Apart from further chi-squared based characteristics like  AIC  and  BIC , data-model-residual analyses exist, e.g. to investigate whether the  residuals  follow a  Gaussian distribution . Finally, parameter  confidence intervals  may be estimated using either the  Fisher information matrix  approximation or based on the  profile-likelihood function , if parameters are not unambiguously identifiable."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10018", "text": "If the fit is not acceptable, the model has to be refined and the procedure continues with step 2. Else, the dynamic model properties can be examined and predictions calculated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10019", "text": "If the model structure is not able to explain the experimental measurements, a set of physiologically reasonable alternative models should be created. In order to avoid redundant model paragraphs and copy-and-paste errors, this can be done using a common core-model which is the same for all variants.  Then,  daughter -models are created and fitted to the data, preferably using batch processing strategies based on MATLAB scripts. As a starting point to envision suitable model variants, the PottersWheel  equalizer  may be used to understand the dynamic behavior of the original system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10020", "text": "A mathematical model may serve to display the concentration time-profile of unobserved species, to determine sensitive parameters representing potential targets within a clinical setting, or to calculate model characteristics like the half-life of a species."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10021", "text": "Each analysis step may be stored into a modeling report, which may be exported as a Latex-based PDF."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10022", "text": "An experimental setting corresponds to specific characteristics of  driving input functions  and\ninitial concentrations. In a signal transduction pathway model the concentration of a ligand\nlike EGF may be controlled experimentally.  The driving input designer allows investigating the effect of a continuous, ramp, or pulse stimulation in combination with varying initial concentrations using the equalizer.  In order to discriminate competing model hypotheses, the designed experiment should have as different observable time-profiles as possible."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10023", "text": "Many dynamical systems can only be observed partially, i.e. not all system species are accessible experimentally. For biological applications the amount and quality of experimental data is often limited. In this setting parameters can be structurally or practically non-identifiable. Then, parameters may compensate each other and fitted parameter values strongly depend on initial guesses. In PottersWheel non-identifiability can be detected using the  Profile Likelihood Approach . [ 2 ]  For characterizing functional relationships between the non-identifiable parameters PottersWheel applies random and systematic fit sequences. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10024", "text": "A  prodrug  is a pharmacologically inactive  medication  or compound that, after  intake , is  metabolized  (i.e., converted within the body) into a  pharmacologically active  drug. [ 1 ] [ 2 ]  Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug is absorbed, distributed, metabolized, and excreted ( ADME ). [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10025", "text": "Prodrugs are often designed to improve  bioavailability  when a drug itself is poorly absorbed from the  gastrointestinal tract . [ 2 ]  A prodrug may be used to improve how selectively the drug interacts with cells or processes that are not its intended target.  This reduces adverse or unintended effects of a drug, especially important in treatments like  chemotherapy , which can have severe unintended and undesirable side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10026", "text": "Compound that undergoes biotransformation before exhibiting  pharmacological  effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10027", "text": "Note 1 : Modified from ref. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10028", "text": "Note 2 : Prodrugs can thus be viewed as  drugs  containing specialized nontoxic protective groups used in a transient manner to alter or to eliminate undesirable properties in the parent molecule. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10029", "text": "Many herbal extracts historically used in medicine contain  glycosides  (sugar derivatives) of the active agent, which are hydrolyzed in the intestines to release the active and more bioavailable  aglycone .  For example,  salicin  is a  \u03b2-D-glucopyranoside  that is cleaved by esterases to release  salicylic acid .   Aspirin , acetylsalicylic acid, first made by  Felix Hoffmann  at  Bayer  in 1897, is a synthetic prodrug of salicylic acid. [ 7 ] [ 8 ]   However, in other cases, such as  codeine  and  morphine , the administered drug is  enzymatically   activated  to form sugar derivatives (morphine- glucuronides ) that are more active than the parent compound. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10030", "text": "The first synthetic antimicrobial drug,  arsphenamine , discovered in 1909 by  Sahachiro Hata  in the laboratory of  Paul Ehrlich , is not toxic to bacteria until it has been converted to an active form by the body.  Likewise,  prontosil , the first  sulfa drug  (discovered by  Gerhard Domagk  in 1932), must be cleaved in the body to release the active molecule,  sulfanilamide .  Since that time, many other examples have been identified."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10031", "text": "Terfenadine , the first non-sedating  antihistamine , had to be withdrawn from the market because of the small risk of a serious side effect.  However, terfenadine was discovered to be the prodrug of the active molecule,  fexofenadine , which does not carry the same risks as the parent compound.  Therefore, fexofenadine could be placed on the market as a safe replacement for the original drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10032", "text": "Loratadine , another non-sedating antihistamine, is the prodrug of  desloratadine , which is largely responsible for the antihistaminergic effects of the parent compound.  However, in this case the parent compound does not have the side effects associated with terfenadine, and so both loratadine and its  active metabolite , desloratadine, are currently marketed. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10033", "text": "Approximately 10% of all marketed drugs worldwide can be considered prodrugs. Since 2008, at least 30 prodrugs have been approved by the  FDA . [ 1 ]  Seven prodrugs were  approved in 2015 and six in 2017. Examples of recently approved prodrugs are such as  dabigatran etexilate  (approved in 2010),  gabapentin enacarbil  (2011),  sofosbuvir  (2013),  tedizolid phosphate  (2014),  isavuconazonium  (2015),  aripiprazole lauroxil  (2015),  selexipag  (2015),  latanoprostene bunod  (2017),  benzhydrocodone  (2018),  tozinameran  (2020) and  serdexmethylphenidate  (2021)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10034", "text": "Prodrugs can be classified into two major types, [ 10 ]  based on how the body converts the prodrug into the final active drug form:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10035", "text": "Both major types can be further categorized into subtypes, based on factors such as (Type I) whether the intracellular bioactivation location is also the site of therapeutic action, or (Type 2) whether or not bioactivation occurs in the gastrointestinal fluids or in the circulation system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10036", "text": "Type IA prodrugs include many antimicrobial and chemotherapy agents (e.g., 5-flurouracil). Type IB agents rely on metabolic enzymes, especially in hepatic cells, to bioactivate the prodrugs intracellularly to active drugs. Type II prodrugs are bioactivated extracellularly, either in the milieu of GI fluids (Type IIA), within the systemic circulation and/or other extracellular fluid compartments (Type IIB), or near therapeutic target tissues/cells (Type IIC), relying on common enzymes such as esterases and phosphatases or target directed enzymes. Importantly, prodrugs can belong to multiple subtypes (i.e., Mixed-Type). A Mixed-Type prodrug is one that is bioactivated at multiple sites, either in parallel or sequential steps. For example, a prodrug, which is bioactivated concurrently in both target cells and metabolic tissues, could be designated as a \"Type IA/IB\" prodrug (e.g., HMG Co-A reductase inhibitors and some chemotherapy agents; note the symbol \" / \" applied here). When a prodrug is bioactivated sequentially, for example initially in GI fluids then systemically within the target cells, it is designated as a \"Type IIA-IA\" prodrug (e.g.,  tenofovir disoproxil ; note the symbol \" - \" applied here). Many antibody- virus- and gene-directed enzyme prodrug therapies ( ADEPTs ,  VDEPTs ,  GDEPTs ) and proposed  nanoparticle - or nanocarrier-linked drugs can understandably be Sequential Mixed-Type prodrugs. To differentiate these two Subtypes, the symbol dash \" - \" is used to designate and to indicate sequential steps of bioactivation, and is meant to distinguish from the symbol slash \" / \" used for the Parallel Mixed-Type prodrugs. [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10037", "text": "The  residence time  of a  fluid parcel  is the total time that the parcel has spent inside a  control volume  (e.g.: a  chemical reactor , a  lake , a  human body ). The residence time of a  set  of parcels is quantified in terms of the  frequency distribution  of the residence time in the set, which is known as  residence time distribution (RTD) , or in terms of its average, known as  mean residence time ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10038", "text": "Residence time plays an important role in  chemistry  and especially in  environmental science  and  pharmacology . Under the name  lead time  or  waiting time  it plays a central role respectively in  supply chain management  and  queueing theory , where the material that flows is usually discrete instead of continuous."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10039", "text": "The concept of residence time originated in models of chemical reactors. The first such model was an  axial dispersion model  by  Irving Langmuir  in 1908. This received little attention for 45 years; other models were developed such as the  plug flow reactor model  and the  continuous stirred-tank reactor , and the concept of a  washout function  (representing the response to a sudden change in the input) was introduced. Then, in 1953,  Peter Danckwerts  resurrected the axial dispersion model and formulated the modern concept of residence time. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10040", "text": "The time that a particle of fluid has been in a  control volume  (e.g. a reservoir) is known as its  age . In general, each particle has a different age. The frequency of occurrence of the age  \n \n \n \n \u03c4 \n \n \n {\\displaystyle \\tau } \n \n  in the set of all the particles that are located inside the control volume at time  \n \n \n \n t \n \n \n {\\displaystyle t} \n \n  is quantified by means of the (internal)  age distribution   \n \n \n \n I \n \n \n {\\displaystyle I} \n \n . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10041", "text": "At the moment a particle leaves the control volume, its age is the total time that the particle has spent inside the control volume, which is known as its  residence time . The frequency of occurrence of the age  \n \n \n \n \u03c4 \n \n \n {\\displaystyle \\tau } \n \n  in the set of all the particles that are leaving the control volume at time  \n \n \n \n t \n \n \n {\\displaystyle t} \n \n  is quantified by means of the  residence time distribution , also known as  exit age distribution   \n \n \n \n E \n \n \n {\\displaystyle E} \n \n . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10042", "text": "Both distributions are positive and have by definition unitary integrals along the age: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10043", "text": "In the case of  steady flow , the distributions are assumed to be independent of time, that is  \n \n \n \n \n \u2202 \n \n t \n \n \n E \n = \n \n \u2202 \n \n t \n \n \n I \n = \n 0 \n \n \u2200 \n t \n \n \n {\\displaystyle \\partial _{t}E=\\partial _{t}I=0\\;\\forall t} \n \n , which may allow to redefine the distributions as simple functions of the age only."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10044", "text": "If the flow is steady (but a generalization to non-steady flow is possible [ 3 ] ) and is  conservative , then the exit age distribution and the internal age distribution can be related one to the other: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10045", "text": "Distributions other than  \n \n \n \n E \n \n \n {\\displaystyle E} \n \n  and  \n \n \n \n I \n \n \n {\\displaystyle I} \n \n  can be usually traced back to them. For example, the fraction of particles leaving the control volume at time  \n \n \n \n t \n \n \n {\\displaystyle t} \n \n  with an age greater or equal than  \n \n \n \n \u03c4 \n \n \n {\\displaystyle \\tau } \n \n  is quantified by means of the  washout function   \n \n \n \n W \n \n \n {\\displaystyle W} \n \n , that is the complementary to one of the cumulative exit age distribution:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10046", "text": "The  mean age  of all the particles inside the control volume at time  t  is the first  moment  of the age distribution: [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10047", "text": "The  mean residence time  or  mean transit time , that is the mean age of all the particles leaving the control volume at time  t , is the first moment of the residence time distribution: [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10048", "text": "The mean age and the mean transit time generally have different values, even in stationary conditions: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10049", "text": "If the flow is  steady  and  conservative , the mean residence time equals the ratio between the amount of fluid contained in the control volume and the flow rate through it: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10050", "text": "This ratio is commonly known as the  turnover time  or  flushing time . [ 4 ]  When applied to liquids, it is also known as the  hydraulic retention time  ( HRT ),  hydraulic residence time  or  hydraulic detention time . [ 5 ]  In the field of chemical engineering this is also known as  space time . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10051", "text": "The residence time of a specific compound in a mixture equals the turnover time (that of the compound, as well as that of the mixture) only if the compound does not take part in any chemical reaction (otherwise its flow is not conservative) and its concentration is  uniform . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10052", "text": "Although the equivalence between the residence time and the ratio  \n \n \n \n m \n \n / \n \n f \n \n \n {\\displaystyle m/f} \n \n  does not hold if the flow is not stationary or it is not conservative, it does hold  on average  if the flow is steady and conservative  on average , and not necessarily at any instant. Under such conditions, which are common in  queueing theory  and  supply chain management , the relation is known as  Little's Law ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10053", "text": "Design equations are equations relating the space time to the fractional conversion and other properties of the reactor. Different design equations have been derived for different types of the reactor and depending on the reactor the equation more or less resemble that describing the average residence time. Often design equations are used to minimize the reactor volume or volumetric flow rate required to operate a reactor. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10054", "text": "In an ideal  plug flow reactor  (PFR) the fluid particles leave in the same order they arrived, not mixing with those in front and behind. Therefore, the particles entering at time  t  will exit at time  t  +  T , all spending a time  T  inside the reactor. The residence time distribution will be then a  Dirac delta function  delayed by  T :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10055", "text": "The mean is  T  and the variance is zero. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10056", "text": "The RTD of a real reactor deviates from that of an ideal reactor, depending on the hydrodynamics within the vessel. A non-zero variance indicates that there is some dispersion along the path of the fluid, which may be attributed to turbulence, a non-uniform velocity profile, or diffusion. If the mean of the distribution is earlier than the expected time  T  it indicates that there is  stagnant fluid  within the vessel. If the RTD curve shows more than one main peak it may indicate channeling, parallel paths to the exit, or strong internal circulation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10057", "text": "In PFRs, reactants enter the reactor at one end and react as they move down the reactor. Consequently, the reaction rate is dependent on the concentrations which vary along the reactor requiring the inverse of the reaction rate to be integrated over the fractional conversion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10058", "text": "Batch reactors are reactors in which the reactants are put in the reactor at time 0 and react until the reaction is stopped. Consequently, the space time is the same as the average residence time in a batch reactor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10059", "text": "In an ideal  continuous stirred-tank reactor  (CSTR), the flow at the inlet is completely and instantly mixed into the bulk of the reactor. The reactor and the outlet fluid have identical, homogeneous compositions at all times. The residence time distribution is exponential:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10060", "text": "Where; the mean is  T  and the variance is 1. [ 1 ]  A notable difference from the plug flow reactor is that material introduced into the system will never completely leave it. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10061", "text": "In reality, it is impossible to obtain such rapid mixing, as there is necessarily a delay between any molecule passing through the inlet and making its way to the outlet, and hence the RTD of a real reactor will deviate from the ideal exponential decay, especially in the case of large reactors. For example, there will be some finite delay before  E  reaches its maximum value and the length of the delay will reflect the rate of mass transfer within the reactor. Just as was noted for a plug-flow reactor, an early mean will indicate some stagnant fluid within the vessel, while the presence of multiple peaks could indicate channeling, parallel paths to the exit, or strong internal circulation. Short-circuiting fluid within the reactor would appear in an RTD curve as a small pulse of concentrated tracer that reaches the outlet shortly after injection.\nReactants continuously enter and leave a tank where they are mixed. Consequently, the reaction proceeds at a rate dependent on the outlet concentration:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10062", "text": "In a  laminar flow reactor , the fluid flows through a long tube or parallel plate reactor and the flow is in layers parallel to the walls of the tube. The velocity of the flow is a parabolic function of radius. In the absence of  molecular diffusion , the RTD is [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10063", "text": "The variance is infinite. In a real reactor, diffusion will eventually mix the layers so that the tail of the RTD becomes exponential and the variance finite; but laminar flow reactors can have variance greater than 1, the maximum for CTSD reactors. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10064", "text": "Recycle reactors are PFRs with a recycle loop. Consequently, they behave like a hybrid between PFRs and CSTRs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10065", "text": "In all of these equations\u00a0: \n \n \n \n \u2212 \n \n r \n \n A \n \n \n \n \n {\\displaystyle -r_{A}} \n \n  is the consumption rate of  A , a reactant. This is equal to the rate expression  A  is involved in. The rate expression is often related to the fractional conversion both through the consumption of  A  and through any  k  changes through temperature changes that are dependent on conversion. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10066", "text": "In some reactions the reactants and the products have significantly different densities. Consequently, as the reaction proceeds the volume of the reaction changes. This variable volume adds terms to the design equations. Taking this volume change into consideration the volume of the reaction becomes:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10067", "text": "Plugging this into the design equations results in the following equations:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10068", "text": "Generally, when reactions take place in the liquid and solid phases the change in volume due to reaction is not significant enough that it needs to be taken into account. Reactions in the gas phase often have significant changes in volume and in these cases one should use these modified equations. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10069", "text": "Residence time distributions are measured by introducing a non-reactive  tracer  into the system at the inlet. Its input concentration is changed according to a known function and the output concentration measured. The tracer should not modify the physical characteristics of the fluid (equal density, equal viscosity) or the  hydrodynamic  conditions and it should be easily detectable. [ 9 ] \nIn general, the change in tracer concentration will either be a  pulse  or a  step . Other functions are possible, but they require more calculations to  deconvolute  the RTD curve."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10070", "text": "This method required the introduction of a very small volume of concentrated tracer at the inlet of the reactor, such that it approaches the  Dirac delta function . [ 10 ] [ 8 ]  Although an infinitely short injection cannot be produced, it can be made much smaller than the mean residence time of the vessel. If a mass of tracer,  \n \n \n \n M \n \n \n {\\displaystyle M} \n \n , is introduced into a vessel of volume  \n \n \n \n V \n \n \n {\\displaystyle V} \n \n  and an expected residence \ntime of  \n \n \n \n \u03c4 \n \n \n {\\displaystyle \\tau } \n \n , the resulting curve of  \n \n \n \n C \n ( \n t \n ) \n \n \n {\\displaystyle C(t)} \n \n  can be transformed into a dimensionless residence time distribution curve by the following relation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10071", "text": "The concentration of tracer in a step experiment at the reactor inlet changes abruptly from 0 to  \n \n \n \n \n C \n \n 0 \n \n \n \n \n {\\displaystyle C_{0}} \n \n . The concentration of tracer at the outlet is measured and normalized to the concentration  \n \n \n \n \n C \n \n 0 \n \n \n \n \n {\\displaystyle C_{0}} \n \n  to obtain the non-dimensional curve  \n \n \n \n F \n ( \n t \n ) \n \n \n {\\displaystyle F(t)} \n \n  which goes from 0 to 1:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10072", "text": "The step- and pulse-responses of a reactor are related by the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10073", "text": "A step experiment is often easier to perform than a pulse experiment, but it tends to smooth over some of the details that a pulse response could show. It is easy to numerically integrate an experimental pulse response to obtain a very high-quality estimate of the step response, but the reverse is not the case because any noise in the concentration measurement will be amplified by numeric differentiation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10074", "text": "In  chemical reactors , the goal is to make components react with a high  yield . In a homogeneous,  first-order reaction , the probability that an atom or molecule will react depends only on its residence time:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10075", "text": "for a  rate constant   \n \n \n \n k \n \n \n {\\displaystyle k} \n \n . Given a RTD, the average probability is equal to the ratio of the concentration  \n \n \n \n a \n \n \n {\\displaystyle a} \n \n  of the component before and after: [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10076", "text": "If the reaction is more complicated, then the output is not uniquely determined by the RTD. It also depends on the degree of  micromixing , the mixing between molecules that entered at different times. If there is no mixing, the system is said to be  completely segregated , and the output can be given in the form"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10077", "text": "For given RTD, there is an upper limit on the amount of mixing that can occur, called the  maximum mixedness , and this determines the achievable yield. A continuous stirred-tank reactor can be anywhere in the spectrum between completely segregated and  perfect mixing . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10078", "text": "The RTD of chemical reactors can be obtained by  CFD  simulations. The very same procedure that is performed in experiments can be followed. A pulse of inert tracer particles (during a very short time) is injected into the reactor. The linear motion of tracer particles is governed by Newton's second law of motion and a one-way coupling is stablished between fluid and tracers. In one-way coupling, fluid affects tracer motion by drag force while tracer does not affect fluid. The size and density of tracers are chosen so small that the  time constant  of tracers becomes very small. In this way, tracer particles exactly follow the same path as the fluid does. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10079", "text": "Hydraulic residence time (HRT) is an important factor in the transport of environmental toxins or other chemicals through  groundwater . The amount of time that a pollutant spends traveling through a delineated subsurface space is related to the saturation and the  hydraulic conductivity  of the soil or rock. [ 12 ]   Porosity  is another significant contributing factor to the mobility of water through the ground (e.g. toward the  water table ). The intersection between pore density and size determines the degree or magnitude of the flow rate through the media. This idea can be illustrated by a comparison of the ways water moves through  clay  versus  gravel . The retention time through a specified vertical distance in clay will be longer than through the same distance in gravel, even though they are both characterized as high porosity materials. This is because the pore sizes are much larger in gravel media than in clay, and so there is less  hydrostatic tension  working against the subsurface  pressure gradient  and gravity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10080", "text": "Groundwater flow is important parameter for consideration in the design of waste rock basins for  mining  operations. Waste rock is heterogeneous material with particles varying from boulders to clay-sized particles, and it contains  sulfidic pollutants  which must be controlled such that they do not compromise the quality of the water table and also so the runoff does not create environmental problems in the surrounding areas. [ 12 ]   Aquitards  are clay zones that can have such a degree of impermeability that they partially or completely retard water flow. [ 5 ] [ 13 ]  These clay lenses can slow or stop seepage into the water table, although if an aquitard is fractured and contaminated then it can become a long-term source of groundwater contamination due to its low permeability and high HRT. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10081", "text": "Primary treatment  for wastewater or drinking water includes settling in a  sedimentation  chamber to remove as much of the solid matter as possible before applying additional treatments. [ 5 ]  The amount removed is controlled by the hydraulic residence time (HRT). [ 5 ]  When water flows through a volume at a slower rate, less energy is available to keep solid particles entrained in the stream and there is more time for them to settle to the bottom. Typical HRTs for sedimentation basins are around two hours, [ 5 ]  although some groups recommend longer times to remove  micropollutants  such as pharmaceuticals and hormones. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10082", "text": "Disinfection  is the last step in the  tertiary treatment  of wastewater or drinking water. The types of pathogens that occur in untreated water include those that are easily killed like  bacteria  and  viruses , and those that are more robust such as  protozoa  and  cysts . [ 5 ]  The disinfection chamber must have a long enough HRT to kill or deactivate all of them."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10083", "text": "Atoms and molecules of gas or liquid can be trapped on a solid surface in a process called  adsorption . This is an  exothermic process  involving a release of  heat , and heating the surface increases the probability that an atom will escape within a given time. At a given temperature  \n \n \n \n T \n \n \n {\\displaystyle T} \n \n , the residence time of an adsorbed atom is given by"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10084", "text": "where  \n \n \n \n R \n \n \n {\\displaystyle R} \n \n  is the  gas constant ,  \n \n \n \n \n E \n \n \n a \n \n \n \n \n \n {\\displaystyle E_{\\mathrm {a} }} \n \n  is an  activation energy , and  \n \n \n \n \n \u03c4 \n \n 0 \n \n \n \n \n {\\displaystyle \\tau _{0}} \n \n  is a prefactor that is correlated with the vibration times of the surface atoms (generally of the order of  \n \n \n \n \n 10 \n \n \u2212 \n 12 \n \n \n \n \n {\\displaystyle 10^{-12}} \n \n  seconds). [ 15 ] :\u200a27\u200a [ 16 ] :\u200a196"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10085", "text": "In  vacuum technology , the residence time of gases on the surfaces of a vacuum chamber can determine the pressure due to  outgassing . If the chamber can be heated, the above equation shows that the gases can be \"baked out\"; but if not, then surfaces with a low residence time are needed to achieve  ultra-high vacuums . [ 16 ] :\u200a195"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10086", "text": "In environmental terms, the residence time definition is adapted to fit with ground water, the atmosphere,  glaciers , lakes, streams, and oceans. More specifically it is the time during which water remains within an aquifer, lake, river, or other water body before continuing around the  hydrological cycle . The time involved may vary from days for shallow gravel  aquifers  to millions of years for deep aquifers with very low values for  hydraulic conductivity . Residence times of water in rivers are a few days, while in large lakes residence time ranges up to several decades. Residence times of continental ice sheets is hundreds of thousands of years, of small glaciers a few decades."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10087", "text": "Ground water residence time applications are useful for determining the amount of time it will take for a pollutant to reach and  contaminate  a ground water drinking water source and at what concentration it will arrive. This can also work to the opposite effect to determine how long until a ground water source becomes uncontaminated via inflow, outflow, and volume. The residence time of lakes and streams is important as well to determine the concentration of pollutants in a lake and how this may affect the local population and marine life."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10088", "text": "Hydrology, the study of water, discusses the water budget in terms of residence time. The amount of time that water spends in each different stage of life (glacier, atmosphere, ocean, lake, stream, river), is used to show the relation of all of the water on the earth and how it relates in its different forms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10089", "text": "A large class of  drugs  are  enzyme inhibitors  that bind to  enzymes  in the body and inhibit their activity. In this case it is the drug-target residence time (the length of time the drug stays bound to the target) that is of interest. The residence time is defined as the reciprocal value of the koff rate constant (residence time = 1/koff). Drugs with long residence times are desirable because they remain effective for longer and therefore can be used in lower doses. [ 17 ] :\u200a88\u200a  This residence time is determined by the  kinetics  of the interaction, [ 18 ]  such as how complementary the shape and charges of the target and drug are and whether outside solvent molecules are kept out of the  binding site  (thereby preventing them from breaking any bonds formed), [ 19 ]  and is proportional to the  half-life  of the  chemical dissociation . [ 18 ]  One way to measure the residence time is in a  preincubation-dilution  experiment where a target enzyme is incubated with the inhibitor, allowed to approach equilibrium, then rapidly diluted. The amount of product is measured and compared to a control in which no inhibitor is added. [ 17 ] :\u200a87\u201388"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10090", "text": "Residence time can also refer to the amount of time that a drug spends in the part of the body where it needs to be absorbed. The longer the residence time, the more of it can be absorbed. If the drug is delivered in an oral form and destined for the  upper intestines , it usually moves with food and its residence time is roughly that of the food. This generally allows 3 to 8 hours for absorption. [ 20 ] :\u200a196\u200a  If the drug is delivered through a  mucous membrane  in the mouth, the residence time is short because  saliva  washes it away. Strategies to increase this residence time include  bioadhesive   polymers , gums,  lozenges  and dry powders. [ 20 ] :\u200a274"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10091", "text": "In  size-exclusion chromatography , the residence time of a molecule is related to its volume, which is roughly proportional to its molecular weight. Residence times also affect the performance of  continuous fermentors . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10092", "text": "Biofuel cells  utilize the metabolic processes of anodophiles ( electronegative  bacteria) to convert chemical energy from organic matter into electricity. [ 21 ] [ 22 ] [ 23 ]  A biofuel cell mechanism consists of an  anode  and a  cathode  that are separated by an internal  proton exchange membrane  (PEM) and connected in an external circuit with an external load. Anodophiles grow on the anode and consume biodegradable organic molecules to produce electrons, protons, and  carbon dioxide  gas, and as the electrons travel through the circuit they feed the external load. [ 22 ] [ 23 ]  The HRT for this application is the rate at which the feed molecules are passed through the anodic chamber. [ 23 ]  This can be quantified by dividing the volume of the anodic chamber by the rate at which the feed solution is passed into the chamber. [ 22 ]  The hydraulic residence time (HRT) affects the substrate loading rate of the microorganisms that the anodophiles consume, which affects the electrical output. [ 23 ] [ 24 ]  Longer HRTs reduce substrate loading in the anodic chamber which can lead to reduced anodophile population and performance when there is a deficiency of nutrients. [ 23 ]  Shorter HRTs support the development of non- exoelectrogenous  bacteria which can reduce the  Coulombic efficiency  electrochemical performance of the fuel cell if the anodophiles must compete for resources or if they do not have ample time to effectively degrade nutrients. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10093", "text": "This is a table of  volume of distribution  (V d ) for various  medication . For comparison, those with a V d  L/kg body weight of less than 0.2 are mainly distributed in  blood plasma , 0.2-0.7 mostly in the  extracellular fluid  and those with more than 0.7 are distributed throughout total body water."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10094", "text": "Targeted drug delivery , sometimes called  smart drug delivery , [ 1 ]  is a method of delivering  medication  to a patient in a manner that increases the  concentration  of the medication in some parts of the body relative to others. This means of delivery is largely founded on nanomedicine, which plans to employ  nanoparticle -mediated drug delivery in order to combat the downfalls of conventional drug delivery. These nanoparticles would be loaded with drugs and targeted to specific parts of the body where there is solely diseased tissue, thereby avoiding interaction with healthy tissue. The goal of a targeted  drug delivery  system is to prolong, localize, target and have a protected drug interaction with the diseased tissue.  The conventional  drug delivery system  is the absorption of the drug across a  biological membrane , whereas the  targeted release system  releases the drug in a dosage form.  The advantages to the targeted release system is the reduction in the frequency of the dosages taken by the patient, having a more uniform effect of the drug, reduction of drug  side-effects , and reduced fluctuation in circulating drug levels. The disadvantage of the system is high cost, which makes productivity more difficult, and the reduced ability to adjust the dosages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10095", "text": "Targeted drug delivery systems have been developed to optimize regenerative techniques. The system is based on a method that delivers a certain amount of a therapeutic agent for a prolonged period of time to a targeted diseased area within the body. This helps maintain the required plasma and tissue drug levels in the body, thereby preventing any damage to the healthy tissue via the drug.  The drug delivery system is highly integrated and requires various disciplines, such as chemists, biologists, and engineers, to join forces to optimize this system. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10096", "text": "In traditional  drug delivery  systems such as oral ingestion or intravascular injection, the medication is distributed throughout the body through the systemic  blood circulation . For most therapeutic agents, only a small portion of the medication reaches the organ to be affected, such as in chemotherapy where roughly 99% of the drugs administered do not reach the tumor site. [ 3 ]  Targeted drug delivery seeks to concentrate the medication in the tissues of interest while reducing the relative concentration of the medication in the remaining tissues. For example, by avoiding the host's defense mechanisms and inhibiting non-specific distribution in the liver and spleen, [ 4 ]  a system can reach the intended site of action in higher concentrations. Targeted delivery is believed to improve  efficacy  while reducing  side-effects ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10097", "text": "When implementing a targeted release system, the following design criteria for the system must be taken into account: the drug properties, side-effects of the drugs, the route taken for the delivery of the drug, the targeted site, and the disease."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10098", "text": "Increasing developments to novel treatments requires a controlled microenvironment that is accomplished only through the implementation of therapeutic agents whose side-effects can be avoided with targeted drug delivery.  Advances in the field of targeted drug delivery to cardiac tissue will be an integral component to regenerate cardiac tissue. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10099", "text": "There are two kinds of targeted drug delivery: active targeted drug delivery, such as some  antibody  medications, and passive targeted drug delivery, such as the  enhanced permeability and retention effect  (EPR-effect)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10100", "text": "This ability for nanoparticles to concentrate in areas of solely diseased tissue is accomplished through either one or both means of targeting: passive or active."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10101", "text": "Passive targeting is achieved by incorporating the therapeutic agent into a macromolecule or nanoparticle that passively reaches the target organ. In passive targeting, the drug's success is directly related to circulation time. [ 6 ]  This is achieved by cloaking the nanoparticle with some sort of coating. Several substances can achieve this, with one of them being polyethylene glycol (PEG). By adding PEG to the surface of the nanoparticle, it is rendered hydrophilic, thus allowing water molecules to bind to the oxygen molecules on PEG via hydrogen bonding. The result of this bond is a film of hydration around the nanoparticle which makes the substance antiphagocytic. The particles obtain this property due to the hydrophobic interactions that are natural to the  reticuloendothelial system (RES) , thus the drug-loaded nanoparticle is able to stay in circulation for a longer period of time. [ 7 ]  To work in conjunction with this mechanism of passive targeting, nanoparticles that are between 10 and 100 nanometers in size have been found to circulate systemically for longer periods of time. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10102", "text": "Active targeting of drug-loaded nanoparticles enhances the effects of passive targeting to make the nanoparticle more specific to a target site. There are several ways that active targeting can be accomplished. One way to actively target solely diseased tissue in the body is to know the nature of a receptor on the cell for which the drug will be targeted to. [ 9 ]  Researchers can then utilize cell-specific ligands that will allow the nanoparticle to bind specifically to the cell that has the complementary receptor. This form of active targeting was found to be successful when utilizing transferrin as the cell-specific ligand. [ 9 ]  The transferrin was conjugated to the nanoparticle to target tumor cells that possess transferrin-receptor mediated endocytosis mechanisms on their membrane. This means of targeting was found to increase uptake, as opposed to non-conjugated nanoparticles. Another cell-specific ligand is the  RGD motif  which binds to the integrin  \u03b1v\u03b23 . [ 10 ]  This integrin is upregulated in tumor and activated endothelial cells. [ 11 ]  Conjugation of RGD to chemotherapeutic-loaded nanoparticles has been shown to increase cancer cell uptake  in vitro  and therapeutic efficacy  in vivo . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10103", "text": "Active targeting can also be achieved by utilizing magnetoliposomes, which usually serves as a contrast agent in magnetic resonance imaging. [ 9 ]  Thus, by grafting these liposomes with a desired drug to deliver to a region of the body, magnetic positioning could aid with this process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10104", "text": "Furthermore, a nanoparticle could possess the capability to be activated by a trigger that is specific to the target site, such as utilizing materials that are pH responsive. [ 9 ]  Most of the body has a consistent, neutral pH. However, some areas of the body are naturally more acidic than others, and, thus, nanoparticles can take advantage of this ability by releasing the drug when it encounters a specific pH. [ 9 ]  Another specific triggering mechanism is based on the redox potential. One of the side effects of tumors is  hypoxia , which alters the redox potential in the vicinity of the tumor. By modifying the redox potential that triggers the payload release the vesicles can be selective to different types of tumors. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10105", "text": "By utilizing both passive and active targeting, a drug-loaded nanoparticle has a heightened advantage over a conventional drug. It is able to circulate throughout the body for an extended period of time until it is successfully attracted to its target through the use of cell-specific ligands, magnetic positioning, or pH responsive materials. Because of these advantages, side effects from conventional drugs will be largely reduced as a result of the drug-loaded nanoparticles affecting only diseased tissue. [ 13 ]  However, an emerging field known as nanotoxicology has concerns that the nanoparticles themselves could pose a threat to both the environment and human health with side effects of their own. [ 14 ]  Active targeting can also be achieved through peptide based drug targeting system. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10106", "text": "There are different types of drug delivery vehicles, such as polymeric micelles, liposomes, lipoprotein-based drug carriers, nano-particle drug carriers, dendrimers, etc. An ideal drug delivery vehicle must be non-toxic, biocompatible, non-immunogenic, biodegradable, [ 5 ]  and must avoid recognition by the host's defense mechanisms [3] ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10107", "text": "Cell Surface Peptides provide one way to introduce drug delivery into a target cell. [ 16 ]  This method is accomplished by the peptide binding to a target cells surface receptors, in a way that bypasses immune defenses that would otherwise compromise a slower delivery, without causing harm to the host. In particular, peptides, such as intercellular adhesion molecule-1, have shown a great deal of binding ability in a target cell. This method has shown a degree of efficacy in treating both autoimmune diseases as well as forms of cancer as a result of this binding affinity. [ 17 ]  Peptide mediated delivery is also of promise due to the low cost of creating the peptides as well as the simplicity of their structure."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10108", "text": "The most common vehicle currently used for targeted drug delivery is the  liposome . [ 19 ]  Liposomes are non-toxic, non- hemolytic , and non- immunogenic  even upon repeated injections; they are  biocompatible  and biodegradable and can be designed to avoid  clearance  mechanisms (reticuloendothelial system (RES), renal clearance, chemical or enzymatic inactivation, etc.) [ 20 ] [ 21 ]  Lipid-based, ligand-coated  nanocarriers  can store their payload in the hydrophobic shell or the hydrophilic interior depending on the nature of the drug/ contrast agent  being carried. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10109", "text": "The only problem to using liposomes  in vivo  is their immediate uptake and clearance by the RES system and their relatively low  stability  in vitro. To combat this,  polyethylene glycol  (PEG) can be added to the surface of the liposomes. Increasing the mole percent of PEG on the surface of the liposomes by 4-10% significantly increased circulation time  in vivo  from 200 to 1000 minutes. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10110", "text": "PEGylation of the liposomal nanocarrier elongates the half-life of the construct while maintaining the passive targeting mechanism that is commonly conferred to lipid-based nanocarriers. [ 22 ]  When used as a delivery system, the ability to induce instability in the construct is commonly exploited allowing the selective release of the encapsulated therapeutic agent in close proximity to the target tissue/cell  in vivo . This nanocarrier system is commonly used in anti-cancer treatments as the acidity of the tumour mass caused by an over-reliance on glycolysis triggers drug release. [ 22 ] [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10111", "text": "Additional endogenous trigger pathways have been explored through the exploitation of inner and outer tumor environments, such as reactive oxygen species, glutathione, enzymes, hypoxia, and adenosine-5\u2019- triphosphate (ATP), all of which are generally highly present in and around tumors. [ 25 ]  External triggers are also used, such as light, low frequency ultrasound (LFUS), electrical fields, and magnetic fields. [ 26 ]  In specific, LFUS has demonstrated high efficacy in the controlled trigger of various drugs in mice, such as cisplatin and calcein. [ 27 ] [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10112", "text": "Another type of drug delivery vehicle used is polymeric  micelles . They are prepared from certain  amphiphilic   co-polymers  consisting of both hydrophilic and hydrophobic monomer units. [ 2 ]  They can be used to carry drugs that have poor solubility.  This method offers little in the terms of size control or function malleability. Techniques that utilize reactive polymers along with a hydrophobic additive to produce a larger  micelle  that create a range of sizes have been developed. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10113", "text": "Dendrimers  are also polymer-based delivery vehicles.  They have a core that branches out in regular intervals to form a small, spherical, and very dense nanocarrier. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10114", "text": "Biodegradable particles have the ability to target diseased tissue as well as deliver their payload as a  controlled-release therapy . [ 31 ]  Biodegradable particles bearing ligands to  P-selectin , endothelial selectin ( E-selectin ) and  ICAM-1  have been found to adhere to inflamed  endothelium . [ 32 ]  Therefore, the use of biodegradable particles can also be used for cardiac tissue."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10115", "text": "There are biocompatible  microalgae   hybrid microrobots  for active drug-delivery in the lungs and the gastrointestinal tract. The  microrobots  proved effective in tests with mice. In the two studies, \"Fluorescent dye or cell membrane\u2013coated nanoparticle functionalized algae motors were further embedded inside a pH-sensitive capsule\" and \"antibiotic-loaded neutrophil membrane-coated polymeric nanoparticles [were attached] to natural microalgae\". [ 33 ] [ 34 ] [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10116", "text": "The success of  DNA nanotechnology  in constructing  artificially designed  nanostructures out of  nucleic acids  such as  DNA , combined with the demonstration of systems for  DNA computing , has led to speculation that artificial nucleic acid nanodevices can be used to target drug delivery based upon directly sensing its environment.  These methods make use of DNA solely as a structural material and a chemical, and do not make use of its biological role as the carrier of genetic information.  Nucleic acid logic circuits that could potentially be used as the core of a system that releases a drug only in response to a stimulus such as a specific  mRNA  have been demonstrated. [ 36 ]  In addition, a DNA \"box\" with a controllable lid has been synthesized using the  DNA origami  method.  This structure could encapsulate a drug in its closed state, and open to release it only in response to a desired stimulus. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10117", "text": "Targeted drug delivery can be used to treat many diseases, such as the  cardiovascular diseases  and  diabetes . However, the most important application of targeted  drug delivery  is to treat  cancerous tumors . In doing so, the passive method of targeting tumors takes advantage of the  enhanced permeability and retention (EPR) effect . This is a situation specific to tumors that results from rapidly forming blood vessels and poor lymphatic drainage. When the blood vessels form so rapidly, large fenestrae result that are 100 to 600 nanometers in size, which allows enhanced nanoparticle entry. Further, the poor lymphatic drainage means that the large influx of nanoparticles are rarely leaving, thus, the tumor retains more nanoparticles for successful treatment to take place. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10118", "text": "The American Heart Association rates cardiovascular disease as the number one cause of death in the United States. Each year 1.5 million myocardial infarctions (MI), also known as heart attacks, occur in the United States, with 500,000 leading to deaths. The costs related to heart attacks exceed $60 billion per year. Therefore, there is a need to come up with an optimum recovery system.  The key to solving this problem lies in the effective use of pharmaceutical drugs that can be targeted directly to the diseased tissue. This technique can help develop many more  regenerative techniques  to cure various diseases. The development of a number of regenerative strategies in recent years for  curing  heart disease represents a paradigm shift away from conventional approaches that aim to  manage  heart disease. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10119", "text": "Stem cell therapy  can be used to help regenerate myocardium tissue and return the contractile function of the heart by creating/supporting a microenvironment before the MI. Developments in targeted drug delivery to tumors have provided the groundwork for the burgeoning field of targeted drug delivery to cardiac tissue. [ 5 ]  Recent developments have shown that there are different endothelial surfaces in tumors, which has led to the concept of endothelial  cell adhesion  molecule-mediated targeted drug delivery to tumors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10120", "text": "Liposomes  can be used as drug delivery for the treatment of  tuberculosis . The traditional treatment for TB is skin to chemotherapy which is not overly effective, which may be due to the failure of chemotherapy to make a high enough concentration at the infection site. The liposome delivery system allows for better microphage penetration and better builds a concentration at the infection site. [ 38 ]  The delivery of the drugs works intravenously and by inhalation. Oral intake is not advised because the liposomes break down in the Gastrointestinal System."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10121", "text": "3D printing  is also used by doctors to investigate how to target  cancerous tumors  in a more efficient way. By printing a plastic 3D shape of the tumor and filling it with the drugs used in the treatment the flow of the liquid can be observed allowing the modification of the doses and targeting location of the drugs. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10122", "text": "Therapeutic drug monitoring (TDM)  is a branch of  clinical chemistry  and  clinical pharmacology  that specializes in the measurement of  medication  levels in  blood . Its main focus is on drugs with a narrow  therapeutic range , i.e. drugs that can easily be under- or overdosed. [ 1 ]  TDM aimed at improving patient care by individually adjusting the dose of drugs for which clinical experience or clinical trials have shown it improved outcome in the general or special populations.  It can be based on a  a priori  pharmacogenetic, demographic and clinical information, and/or on the  a posteriori  measurement of blood concentrations of drugs (pharmacokinetic monitoring) or biological surrogate or end-point markers of effect (pharmacodynamic monitoring). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10123", "text": "There are numerous variables that influence the interpretation of drug concentration data: time, route and dose of drug given, time of blood sampling, handling and storage conditions, precision and accuracy of the analytical method, validity of pharmacokinetic models and assumptions, co-medications and, last but not least, clinical status of the patient (i.e. disease, renal/hepatic status, biologic tolerance to drug therapy, etc.). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10124", "text": "Many different professionals ( physicians ,  clinical pharmacists ,  nurses ,  medical laboratory scientists , etc.) are involved with the various elements of drug concentration monitoring, which is a truly multidisciplinary process. Because failure to properly carry out any one of the components can severely affect the usefulness of using drug concentrations to optimize therapy, an organized approach to the overall process is critical. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10125", "text": "A priori  TDM consists of determining the initial dose regimen to be given to a patient, based on clinical endpoint and on established population  pharmacokinetic - pharmacodynamic  ( PK/PD ) relationships.  These relationships help to identify sub-populations of patients with different dosage requirements, by utilizing demographic data, clinical findings, clinical chemistry results, and/or, when appropriate, pharmacogenetic characteristics. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10126", "text": "The concept of  a posteriori  TDM corresponds to the usual meaning of TDM in medical practice, which refers to the readjustment of the dosage of a given treatment in response to the measurement of an appropriate marker of drug exposure or effect. TDM encompasses all aspects of this  feedback control , namely: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10127", "text": "In  pharmacotherapy , many medications are used without monitoring of blood levels, as their dosage can generally be varied according to the clinical response that a patient gets to that substance. For certain drugs, this is impracticable, while insufficient levels will lead to undertreatment or resistance, and excessive levels can lead to toxicity and tissue damage."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10128", "text": "Indications in favor of therapeutic drug monitoring include: [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10129", "text": "TDM determinations are also used to detect and diagnose poisoning with drugs, should the suspicion arise."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10130", "text": "Examples of drugs widely analysed for therapeutic drug monitoring: [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10131", "text": "TDM increasingly proposed for a number of therapeutic drugs, e.g. many  antibiotics , small molecule  tyrosine kinase inhibitors  and other  targeted anticancer agents ,  TNF inhibitors  and other biological agents,   antifungal agents ,  antiretroviral agents  used in HIV infection,  psychiatric drugs [ 7 ]  etc."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10132", "text": "Automated analytical methods such as  enzyme multiplied immunoassay technique  or  fluorescence polarization immunoassay  are widely available in  medical laboratories  for drugs frequently measured in practice. Nowadays, most other drugs can be readily measured in blood or plasma using versatile methods such as  liquid chromatography\u2013mass spectrometry  or  gas chromatography\u2013mass spectrometry , which progressively replaced  high-performance liquid chromatography . Yet, TDM is not limited to the provision of precise and accurate concentration measurement results, it also involves appropriate medical interpretation, based on robust scientific knowledge."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10133", "text": "In order to guarantee the quality of this clinical interpretation, it is essential that the sample be taken under good conditions: i.e., preferably under a stable dosage, at a standardized sampling time (often at the end of a dosing interval), excluding any source of bias (sample contamination or dilution, analytical interferences) and having carefully recorded the sampling time, the last dose intake time, the current dosage and the influential patient's characteristics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10134", "text": "The interpretation of a drug concentration result goes through the following stages: [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10135", "text": "Ideally, the usefulness of a TDM strategy should be confirmed through an  evidence-based  approach involving the performance of well-designed  controlled clinical trials . In practice however, TDM has undergone formal clinical evaluation only for a limited number of drugs to date, and much of its development rests on empirical foundations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10136", "text": "Point-of-care tests  for an easy performance of TDM at the medical practice are under elaboration. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10137", "text": "The evolution of  information technology  holds great promise for using the methods and knowledge of  pharmacometrics  to bring patient treatment closer to the ideal of  precision medicine  (which is not just about adjusting treatments to genetic factors, but encompasses all aspects of therapeutic individualization).  Model-informed precision dosing  (MIPD) should enable significant progress to be made in taking into account the many factors influencing drug response, in order to optimize therapies ( a priori  TDM ). It should also make it possible to take optimal account of TDM results to individualize drug dosage  ( a posteriori   TDM ). Ideally, these computational approaches will be integrated into the electronic patient record in the form of  clinical decision support systems  (CDSS), automatically and seamlessly linking laboratory resources and pharmacological expertise with clinicians and caregivers at the patient's bedside. Software tools already exist and continue to be developed for this purpose. They are set to play an increasingly important role in patient treatment, in the same way that instrument piloting has become the norm in aviation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10138", "text": "The  therapeutic index  ( TI ; also referred to as  therapeutic ratio ) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the  therapeutic effect . [ 1 ]  The related terms  therapeutic window  or  safety window  refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10139", "text": "Classically, for clinical  indications  of an approved drug, TI refers to the ratio of the  dose  of the drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects,  TD 50 ) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED 50 ). In contrast, in a  drug development  setting TI is calculated based on plasma  exposure  levels. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10140", "text": "In the early days of pharmaceutical toxicology, TI was frequently determined in animals as lethal dose of a drug for 50% of the population ( LD 50 ) divided by the minimum  effective dose  for 50% of the population (ED 50 ). In modern settings, more sophisticated toxicity endpoints are used."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10141", "text": "For many drugs, severe toxicities in humans occur at sublethal doses, which limit their maximum dose. A higher safety-based therapeutic index is preferable instead of a lower one; an individual would have to take a much higher dose of a drug to reach the lethal threshold than the dose taken to induce the therapeutic effect of the drug. However, a lower efficacy-based therapeutic index is preferable instead of a higher one; an individual would have to take a higher dose of a drug to reach the toxic threshold than the dose taken to induce the therapeutic effect of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10142", "text": "Generally, a drug or other therapeutic agent with a narrow therapeutic range (i.e. having little difference between toxic and therapeutic doses) may have its dosage adjusted according to measurements of its blood levels in the person taking it. This may be achieved through  therapeutic drug monitoring  (TDM) protocols. TDM is recommended for use in the treatment of psychiatric disorders with  lithium  due to its narrow therapeutic range. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10143", "text": "Based on  efficacy  and  safety  of drugs, there are two types of therapeutic index:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10144", "text": "T \n \n I \n \n safety \n \n \n = \n \n \n \n L \n \n D \n \n 50 \n \n \n \n \n E \n \n D \n \n 50 \n \n \n \n \n \n \n \n {\\displaystyle TI_{\\text{safety}}={\\frac {LD_{50}}{ED_{50}}}} \n \n \nIt is desirous for the value of LD 50  to be as large as possible, to decrease risk of lethal effects and increase the therapeutic window. In the above formula, TI safety  increases as the difference between LD 50  and ED 50  increases\u2014hence, a higher safety-based therapeutic index indicates a larger therapeutic window, and vice versa."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10145", "text": "T \n \n I \n \n efficacy \n \n \n = \n \n \n \n E \n \n D \n \n 50 \n \n \n \n \n T \n \n D \n \n 50 \n \n \n \n \n \n \n \n {\\displaystyle TI_{\\text{efficacy}}={\\frac {ED_{50}}{TD_{50}}}} \n \n \nIdeally the ED 50  is as low as possible for faster drug response and larger therapeutic window, whereas a drugs TD 50  is ideally as large as possible to decrease risk of toxic effects. In the above equation, the greater the difference between ED 50  and TD 50 , the greater the value of TI efficacy . Hence, a lower efficacy-based therapeutic index indicates a larger therapeutic window."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10146", "text": "Similar to safety-based therapeutic index, the  protective index  uses TD 50  (median  toxic  dose) in place of LD 50 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10147", "text": "Protective index \n \n = \n \n \n \n T \n \n D \n \n 50 \n \n \n \n \n E \n \n D \n \n 50 \n \n \n \n \n \n = \n \n \n 1 \n \n T \n \n I \n \n efficacy \n \n \n \n \n \n \n \n {\\displaystyle {\\text{Protective index}}={\\frac {TD_{50}}{ED_{50}}}={\\frac {1}{TI_{\\text{efficacy}}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10148", "text": "For many substances, toxicity can occur at levels far below lethal effects (that cause death), and thus, if toxicity is properly specified, the protective index is often more informative about a substance's relative safety. Nevertheless, the safety-based therapeutic index ( \n \n \n \n \n T \n \n I \n \n safety \n \n \n \n \n \n {\\displaystyle {TI_{\\text{safety}}}} \n \n ) is still useful as it can be considered an  upper bound  of the protective index, and the former also has the advantages of objectivity and easier comprehension."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10149", "text": "Since the protective index (PI) is calculated as TD 50  divided by ED 50 , it can be mathematically expressed that:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10150", "text": "which means that  \n \n \n \n T \n \n I \n \n efficacy \n \n \n \n \n {\\displaystyle TI_{\\text{efficacy}}} \n \n  is a  reciprocal  of protective index."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10151", "text": "All the above types of therapeutic index can be used in both  pre-clinical trials  and  clinical trials ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10152", "text": "A low efficacy-based therapeutic index ( \n \n \n \n T \n \n I \n \n efficacy \n \n \n \n \n {\\displaystyle TI_{\\text{efficacy}}} \n \n ) and a high safety-based therapeutic index ( \n \n \n \n T \n \n I \n \n safety \n \n \n \n \n {\\displaystyle TI_{\\text{safety}}} \n \n ) are preferable for a drug to have a favorable efficacy vs safety profile. At the early discovery/development stage, the clinical TI of a drug candidate is unknown. However, understanding the preliminary TI of a drug candidate is of utmost importance as early as possible since TI is an important indicator of the probability of successful development. Recognizing drug candidates with potentially suboptimal TI at the earliest possible stage helps to initiate mitigation or potentially re-deploy resources."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10153", "text": "TI is the quantitative relationship between pharmacological efficacy and toxicological safety of a drug, without considering the nature of pharmacological or toxicological endpoints themselves. However, to convert a calculated TI into something useful, the nature and limitations of pharmacological and/or toxicological endpoints must be considered. Depending on the intended clinical indication, the associated unmet medical need and/or the competitive situation, more or less weight can be given to either the safety or efficacy of a drug candidate in order to create a well balanced indication-specific efficacy vs safety profile."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10154", "text": "In general, it is the exposure of a given tissue to drug (i.e. drug concentration over time), rather than dose, that drives the pharmacological and toxicological effects. For example, at the same dose there may be marked inter-individual variability in exposure due to polymorphisms in metabolism, DDIs or differences in body weight or environmental factors. These considerations emphasize the importance of using exposure instead of dose to calculate TI. To account for delays between exposure and toxicity, the TI for toxicities that occur after multiple dose administrations should be calculated using the exposure to drug at steady state rather than after administration of a single dose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10155", "text": "A review published by Muller and Milton in  Nature Reviews Drug Discovery  critically discusses TI determination and interpretation in a translational drug development setting for both small molecules and biotherapeutics. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10156", "text": "The therapeutic index varies widely among substances, even within a related group."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10157", "text": "For instance, the  opioid   painkiller   remifentanil  is very forgiving, offering a therapeutic index of 33,000:1, while  Diazepam , a  benzodiazepine   sedative-hypnotic  and skeletal  muscle relaxant , has a less forgiving therapeutic index of 100:1. [ 9 ]  Morphine is even less so with a therapeutic index of 70."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10158", "text": "Less safe are  cocaine  (a  stimulant  and  local anaesthetic ) and  ethanol  (colloquially, the \"alcohol\" in  alcoholic beverages , a widely available  sedative  consumed worldwide): the therapeutic indices for these substances are 15:1 and 10:1, respectively. [ 10 ]   Paracetamol , alternatively known by its trade names  Tylenol  or Panadol, also has a therapeutic index of 10. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10159", "text": "Even less safe are drugs such as  digoxin , a  cardiac glycoside ; its therapeutic index is approximately 2:1. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10160", "text": "Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include  dimercaprol ,  theophylline ,  warfarin  and  lithium carbonate ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10161", "text": "Some antibiotics and antifungals require monitoring to balance efficacy with minimizing  adverse effects , including:  gentamicin ,  vancomycin ,  amphotericin B  (nicknamed 'amphoterrible' for this very reason), and  polymyxin B ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10162", "text": "Radiotherapy aims to shrink tumors and kill cancer cells using high energy. The energy arises from  x-rays ,  gamma rays , or  charged  or heavy particles. The therapeutic ratio in radiotherapy for cancer treatment is determined by the maximum radiation dose for killing cancer cells and the minimum radiation dose causing acute or late morbidity in cells of normal tissues. [ 13 ]  Both of these parameters have  sigmoidal   dose\u2013response curves . Thus, a favorable outcome in dose\u2013response for tumor tissue is greater than that of normal tissue for the same dose, meaning that the treatment is effective on tumors and does not cause serious morbidity to normal tissue. Conversely, overlapping response for two tissues is highly likely to cause serious morbidity to normal tissue and ineffective treatment of tumors. The mechanism of radiation therapy is categorized as direct or indirect radiation. Both direct and indirect radiation induce  DNA mutation  or  chromosomal rearrangement  during its repair process. Direct radiation creates a DNA  free radical  from radiation energy deposition that damages DNA. Indirect radiation occurs from  radiolysis  of water, creating a free  hydroxyl radical ,  hydronium  and electron. The hydroxyl radical transfers its radical to DNA. Or together with hydronium and electron, a free hydroxyl radical can damage the base region of DNA. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10163", "text": "Cancer cells cause an imbalance of signals in the  cell cycle . G1 and G2/M arrest were found to be major checkpoints by irradiating human cells. G1 arrest delays the repair mechanism before synthesis of DNA in  S phase  and  mitosis  in M phase, suggesting it is a key checkpoint for survival of cells. G2/M arrest occurs when cells need to repair after S phase but before mitotic entry. It is known that S phase is the most resistant to radiation and M phase is the most sensitive to radiation.  p53 , a tumor suppressor protein that plays a role in G1 and G2/M arrest, enabled the understanding of the cell cycle through radiation. For example, irradiation of  myeloid leukemia  cells leads to an increase in p53 and a decrease in the level of DNA synthesis. Patients with  Ataxia telangiectasia  delays have hypersensitivity to radiation due to the delay of accumulation of p53. [ 15 ]  In this case, cells are able to replicate without repair of their DNA, becoming prone to incidence of cancer. Most cells are in G1 and S phase. Irradiation at G2 phase showed increased radiosensitivity and thus G1 arrest has been a focus for therapeutic treatment.\nIrradiation of a tissue induces a response in both irradiated and non-irridiated cells. It was found that even cells up to 50\u201375 cell diameters distant from irradiated cells exhibit a  phenotype  of enhanced genetic instability such as micronucleation. [ 16 ]  This suggests an effect on cell-to-cell communication such as  paracrine  and  juxtacrine signaling . Normal cells do not lose their  DNA repair  mechanism whereas cancer cells often lose it during radiotherapy. However, the high energy radiation can override the ability of damaged normal cells to repair, leading to additional risk of  carcinogenesis . This suggests a significant risk associated with radiation therapy. Thus, it is desirable to improve the therapeutic ratio during radiotherapy. Employing IG-IMRT, protons and heavy ions are likely to minimize the dose to normal tissues by altered fractionation. Molecular targeting of the DNA repair pathway can lead to radiosensitization or radioprotection. Examples are direct and indirect inhibitors on DNA  double-strand breaks . Direct inhibitors target proteins ( PARP family ) and  kinases  (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target protein tumor cell signaling proteins such as  EGFR  and  insulin growth factor . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10164", "text": "The effective therapeutic index can be affected by  targeting , in which the therapeutic agent is concentrated in its desirable area of effect. For example, in  radiation therapy  for cancerous tumors, shaping the radiation beam precisely to the profile of a tumor in the \"beam's eye view\" can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching the agent to an oncophilic substance, as in  peptide receptor radionuclide therapy  for  neuroendocrine tumors  and in  chemoembolization  or radioactive microspheres therapy for liver tumors and metastases. This concentrates the agent in the targeted tissues and lowers its concentration in others, increasing efficacy and lowering toxicity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10165", "text": "Sometimes the term  safety ratio  is used, particularly when referring to  psychoactive drugs  used for non-therapeutic purposes, e.g. recreational use. [ 10 ]  In such cases, the  effective  dose is the amount and frequency that produces the  desired  effect, which can vary, and can be greater or less than the therapeutically effective dose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10166", "text": "The  Certain Safety Factor , also referred to as the  Margin of Safety (MOS) , is the ratio of the  lethal dose  to 1% of population to the  effective dose  to 99% of the population (LD 1 /ED 99 ). [ 17 ]  This is a better safety index than the  LD 50  for materials that have both desirable and undesirable effects, because it factors in the ends of the spectrum where doses may be necessary to produce a response in one person but can, at the same dose, be lethal in another."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10167", "text": "A therapeutic index does not consider drug interactions or  synergistic  effects. For example, the risk associated with  benzodiazepines  increases significantly when taken with alcohol, opiates, or stimulants when compared with being taken alone. [ medical citation needed ]  Therapeutic index also does not take into account the ease or difficulty of reaching a toxic or lethal dose. This is more of a consideration for recreational drug users, as the purity can be highly variable."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10168", "text": "The  therapeutic window  (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects. [ 18 ]  Medication with a small therapeutic window must be administered with care and control, frequently measuring blood concentration of the drug, to avoid harm. Medications with narrow therapeutic windows include  theophylline ,  digoxin ,  lithium , and  warfarin ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10169", "text": "Optimal biological dose (OBD) is the quantity of a drug that will most effectively produce the desired effect while remaining in the range of acceptable toxicity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10170", "text": "The  maximum tolerated dose  (MTD) refers to the highest dose of a radiological or  pharmacological  treatment that will produce the desired effect without unacceptable  toxicity . [ 19 ] [ 20 ]  The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptable  adverse health effects  in a population, when the level of exposure is not sufficient to cause premature  mortality  due to short-term  toxic effects . The maximum dose is used, rather than a lower dose, to reduce the number of  test subjects  (and, among other things, the cost of testing), to detect an effect that might occur only rarely. This type of analysis is also used in establishing  chemical residue  tolerances in foods. Maximum tolerated dose studies are also done in  clinical trials ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10171", "text": "MTD is an essential aspect of a drug's profile. All modern healthcare systems dictate a maximum safe dose for each drug, and generally have numerous safeguards (e.g. insurance quantity limits and government-enforced maximum quantity/time-frame limits) to prevent the prescription and dispensing of quantities exceeding the highest dosage which has been demonstrated to be safe for members of the general patient population."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10172", "text": "Patients are often unable to tolerate the theoretical MTD of a drug due to the occurrence of side-effects which are not innately a manifestation of toxicity (not considered to severely threaten a patient's health) but cause the patient sufficient distress and/or discomfort to result in non-compliance with treatment. Such examples include emotional \"blunting\" with antidepressants,  pruritus  with  opiates , and blurred vision with  anticholinergics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10173", "text": "Toxication ,  toxification  or  toxicity exaltation  is the conversion of a  chemical compound  into a more toxic form in living organisms or in substrates such as  soil  or  water . The conversion can be caused by  enzymatic   metabolism  in the organisms, as well as by  abiotic   chemical reactions . While the parent drug is usually less active, both the parent drug and its metabolite can be chemically active and cause  toxicity , leading to mutagenesis, teratogenesis, and carcinogenesis. [ 1 ] [ 2 ]  Different classes of enzymes, such as  P450 monooxygenases ,  epoxide hydrolase , or  acetyltransferases  can catalyze the process in the cell, mostly in the liver. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10174", "text": "Parent non-toxic chemicals are generally referred to as  protoxins . While toxication is generally undesirable, in certain cases it is required for the  in vivo  conversion of a  prodrug  to a metabolite with desired pharmacological or toxicological activity.   Codeine  is an example of a prodrug, metabolized in the body to the active compounds  morphine  and  codeine-6-glucuronide ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10175", "text": "Phase I of  drug metabolism  are bioactivation pathways, which are catalyzed by  CYP450  enzymes, produce toxic metabolites and thus have the potential to damage cells. The unusual level of activity CYP450 enzymes might lead to the changes in drug metabolism and convert drugs into their more toxic forms. Among Phase I CYP450 enzymes, the subfamilies  CYP2D6  and  CYP3A  are responsible for  hepatotoxicity  during drug metabolism with a number of different drugs, including  flucloxacillin ,  troleandomycin , and  troglitazone . [ 3 ]   Hepatotoxicity indicates the drug's toxicity to liver."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10176", "text": "Paracetamol  (acetaminophen, APAP) is converted into the hepatotoxic metabolite  NAPQI  via the  cytochrome P450 oxidase  system, mainly by the subfamily CYP2E1. Hepatic reduced glutathione (GSH) will detoxify this formed NAPQI quickly if APAP is taken at a proper level. In the case of overdoses, the storage of GSH will not be enough for NAPQI detoxication, thereby resulting in acute liver injury. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10177", "text": "Oxidoreductases  are enzymes that catalyze the reactions that involve the transfer of electrons.  Methanol  in itself is toxic due to its  central nervous system depression  properties, but it can be converted to formaldehyde by alcohol dehydrogenase and then converted to formic acid by aldehyde dehydrogenase, which are significantly more toxic.  Formic acid  and  formaldehyde  can cause severe  acidosis , damage to the  optic nerve , and other life-threatening complications. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10178", "text": "Ethylene glycol  (common antifreeze) can be converted into toxic  glycolic acid ,  glyoxylic acid  and  oxalic acid  by aldehyde dehydrogenase, lactate dehydrogenase (LDH) and glycolate oxidase in mammalian organisms. [ 5 ] [ 6 ]  The accumulation of the end product of the ethylene glycol mechanism,  calcium oxalate , may cause malfunction in the kidney and lead to more severe consequences. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10179", "text": "Other examples of toxication by enzymatic metabolism include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10180", "text": "Increases in toxicity can also be caused by  abiotic   chemical reactions.  Non-living elements affect the abiotic chemical reactions. Anthropogenic trace compounds (ATCs) have potential toxicity to the organisms in aquatic system. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10181", "text": "Arsenic  contamination in drinking water can be chemically toxic. The uptake and metabolism of arsenic may result in damage to the body. When organic arsenic is converted into more toxic inorganic arsenic, it causes carcinogenesis, cytotoxicity (toxic to cells) and genotoxicity (causing mutations in genes). [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10182", "text": "Toxicokinetics  (often abbreviated as 'TK') is the description of both what rate a chemical will enter the body and what occurs to excrete and metabolize the compound once it is in the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10183", "text": "It is an application of  pharmacokinetics  to determine the relationship between the systemic exposure of a compound and its  toxicity .  It is used primarily for establishing relationships between exposures in  toxicology  experiments in animals and the corresponding exposures in humans. However, it can also be used in environmental risk assessments in order to determine the potential effects of releasing chemicals into the environment. In order to quantify toxic effects, toxicokinetics can be combined with toxicodynamics. Such toxicokinetic-toxicodynamic (TKTD) models are used in  ecotoxicology  (see  ecotoxmodels  a website on mathematical models in ecotoxicology)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10184", "text": "Similarly, physiological toxicokinetic models are  physiological pharmacokinetic models  developed to describe and predict the behavior of a toxicant in an animal body; for example, what parts (compartments) of the body a chemical may tend to enter (e.g. fat, liver, spleen, etc.), and whether or not the chemical is expected to be metabolized or excreted and at what rate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10185", "text": "Four potential processes exist for a chemical interacting with an animal:  absorption , distribution, metabolism and excretion (ADME). Absorption describes the entrance of the chemical into the body, and can occur through the air, water, food, or soil. Once a chemical is inside a body, it can be distributed to other areas of the body through diffusion or other biological processes. At this point, the chemical may undergo metabolism and be biotransformed into other chemicals ( metabolites ). These metabolites can be less or more toxic than the parent compound. After this potential  biotransformation  occurs, the metabolites may leave the body, be transformed into other compounds, or continue to be stored in the body compartments."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10186", "text": "A well designed toxicokinetic study may involve several different strategies and depends on the scientific question to be answered.  Controlled  acute  and repeated toxicokinetic animal studies are useful to identify a chemical's biological persistence, tissue and whole body  half-life , and its potential to bioaccumulate. Toxicokinetic profiles can change with increasing exposure duration or dose. Real world environmental exposures generally occur as low level mixtures, such as from air, water, food, or tobacco products. Mixture effects may differ from individual chemical toxicokinetic profiles because of chemical interactions, synergistic, or competitive processes. For other reasons, it is equally important to characterize the toxicokinetics of individual chemicals constituents found in mixtures as information on behavior or fate of the individual chemical can help explain environmental, human, and wildlife biomonitoring studies. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10187", "text": "In  pharmacology , the  volume of distribution  (V D , also known as  apparent volume of distribution , literally,  volume of dilution [ 1 ] ) is the theoretical  volume  that would be necessary to contain the total amount of an administered  drug  at the same concentration that it is observed in the  blood plasma . [ 2 ]  In other words, it is the ratio of  amount of drug in a body (dose)  to  concentration of the drug that is measured in blood, plasma, and un-bound in interstitial fluid . [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10188", "text": "The V D  of a drug represents the degree to which a drug is distributed in body tissue rather than the plasma. V D  is directly proportional with the amount of drug distributed into tissue; a higher V D  indicates a greater amount of tissue distribution. A V D  greater than the total volume of body water (approximately 42 liters in humans [ 5 ] ) is possible, and would indicate that the drug is highly distributed into tissue. In other words, the volume of distribution is smaller in the drug staying in the plasma than that of a drug that is widely distributed in tissues. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10189", "text": "In rough terms, drugs with a high lipid solubility (non-polar drugs), low rates of ionization, or low plasma protein binding capabilities have higher volumes of distribution than drugs which are more polar, more highly ionized or exhibit high plasma protein binding in the body's environment. Volume of distribution may be increased by  kidney failure  (due to fluid retention) and  liver failure  (due to altered body fluid and  plasma protein binding ). Conversely it may be decreased in dehydration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10190", "text": "The  initial volume of distribution  describes blood concentrations prior to attaining the apparent volume of distribution and uses the same formula."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10191", "text": "The volume of distribution is given by the following equation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10192", "text": "Therefore, the dose required to give a certain plasma concentration can be determined if the V D  for that drug is known. The V D  is  not  a physiological value; it is more a reflection of how a drug will distribute throughout the body depending on several physicochemical properties, e.g. solubility, charge, size, etc."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10193", "text": "The unit for Volume of Distribution is typically reported in  litres.  As body composition changes with age, V D  decreases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10194", "text": "The V D  may also be used to determine how readily a drug will displace into the body tissue compartments relative to the blood:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10195", "text": "If you administer a dose D of a drug intravenously in one go (IV-bolus), you would naturally expect it to have an immediate blood concentration  \n \n \n \n \n C \n \n 0 \n \n \n \n \n {\\displaystyle C_{0}} \n \n  which directly corresponds to the amount of blood contained in the body  \n \n \n \n \n V \n \n b \n l \n o \n o \n d \n \n \n \n \n {\\displaystyle V_{blood}} \n \n . Mathematically this would be:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10196", "text": "C \n \n 0 \n \n \n = \n D \n \n / \n \n \n V \n \n b \n l \n o \n o \n d \n \n \n \n \n {\\displaystyle C_{0}=D/V_{blood}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10197", "text": "But this is generally not what happens. Instead you observe that the drug has distributed out into some other volume (read organs/tissue). So probably the first question you want to ask is: how much of the drug is no longer in the blood stream?\nThe volume of distribution  \n \n \n \n \n V \n \n D \n \n \n \n \n {\\displaystyle V_{D}} \n \n  quantifies just that by specifying how big a volume you would need in order to observe the blood concentration actually measured."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10198", "text": "An example for a simple case (mono-compartmental) would be to administer D=8\u00a0mg/kg to a human. A human has a blood volume of around  \n \n \n \n \n V \n \n b \n l \n o \n o \n d \n \n \n = \n \n \n {\\displaystyle V_{blood}=} \n \n 0.08 L/kg \n. [ 7 ] \nThis gives a  \n \n \n \n \n C \n \n 0 \n \n \n = \n \n \n {\\displaystyle C_{0}=} \n \n 100\u00a0\u03bcg/mL if the drug stays in the blood stream only, and thus its volume of distribution is the same as  \n \n \n \n \n V \n \n b \n l \n o \n o \n d \n \n \n \n \n {\\displaystyle V_{blood}} \n \n  that is  \n \n \n \n \n V \n \n D \n \n \n = \n \n \n {\\displaystyle V_{D}=} \n \n  0.08 L/kg. If the drug distributes into all body water the volume of distribution would increase to approximately  \n \n \n \n \n V \n \n D \n \n \n = \n \n \n {\\displaystyle V_{D}=} \n \n 0.57 L/kg\n [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10199", "text": "If the drug readily diffuses into the body fat the volume of distribution may increase dramatically, an example is  chloroquine  which has a  \n \n \n \n \n V \n \n D \n \n \n = \n \n \n {\\displaystyle V_{D}=} \n \n 250-302 L/kg\n [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10200", "text": "In the simple mono-compartmental case the volume of distribution is defined as:  \n \n \n \n \n V \n \n D \n \n \n = \n D \n \n / \n \n \n C \n \n 0 \n \n \n \n \n {\\displaystyle V_{D}=D/C_{0}} \n \n , where the  \n \n \n \n \n C \n \n 0 \n \n \n \n \n {\\displaystyle C_{0}} \n \n  in practice is an extrapolated concentration at time = 0 from the first early plasma concentrations after an IV-bolus administration (generally taken around 5 min - 30 min after giving the drug)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10201", "text": "Pharmacodynamics  ( PD ) is the study of the  biochemical  and  physiologic  effects of  drugs  (especially  pharmaceutical drugs ). The effects can include those manifested within  animals  (including humans),  microorganisms , or combinations of  organisms  (for example,  infection )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10202", "text": "Pharmacodynamics and  pharmacokinetics  are the main branches of  pharmacology ,  being itself a topic of  biology  interested in the study of the interactions of both endogenous and exogenous chemical substances with living organisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10203", "text": "In particular, pharmacodynamics is the study of how a drug affects an organism, whereas pharmacokinetics is the study of how the organism affects the drug. Both together influence  dosing , benefit, and  adverse effects . Pharmacodynamics is sometimes abbreviated as PD and  pharmacokinetics  as PK, especially in combined reference (for example, when speaking of  PK/PD models )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10204", "text": "Pharmacodynamics places particular emphasis on  dose\u2013response relationships , that is, the relationships between drug  concentration  and effect. [ 1 ]   One dominant example is drug-receptor interactions as modeled by"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10205", "text": "where  L ,  R , and  LR  represent ligand (drug), receptor, and ligand-receptor complex concentrations, respectively. This equation represents a simplified model of  reaction dynamics  that can be studied mathematically through tools such as  free energy  maps."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10206", "text": "Pharmacodynamics : Study of pharmacological actions on living systems, including the reactions with and binding to cell constituents, and the biochemical and physiological consequences of these actions. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10207", "text": "There are four principal protein targets with which drugs can interact:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10208", "text": "NMBD = neuromuscular blocking drugs; NMDA = N-methyl-d-aspartate; EGF = epidermal growth factor. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10209", "text": "The majority of drugs either"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10210", "text": "There are 7 main drug actions: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10211", "text": "The desired activity of a drug is mainly due to successful targeting of one of the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10212", "text": "General anesthetics  were once thought to work by disordering the neural membranes, thereby altering the Na +  influx.  Antacids  and  chelating agents  combine chemically in the body. Enzyme-substrate binding is a way to alter the production or metabolism of key  endogenous  chemicals, for example  aspirin  irreversibly inhibits the enzyme  prostaglandin synthetase (cyclooxygenase)  thereby preventing  inflammatory  response.  Colchicine , a drug for gout, interferes with the function of the structural protein  tubulin , while  digitalis , a drug still used in heart failure, inhibits the activity of the carrier molecule,  Na-K-ATPase pump . The widest class of drugs act as ligands that bind to receptors that determine cellular effects. Upon drug binding, receptors can elicit their normal action (agonist), blocked action (antagonist), or even action opposite to normal (inverse agonist)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10213", "text": "In principle, a pharmacologist would aim for a target  plasma  concentration of the drug for a desired level of response. In reality, there are many factors affecting this goal. Pharmacokinetic factors determine peak concentrations, and concentrations cannot be maintained with absolute consistency because of metabolic breakdown and excretory clearance.  Genetic  factors may exist which would alter metabolism or drug action itself, and a patient's immediate status may also affect indicated dosage."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10214", "text": "Undesirable effects of a drug include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10215", "text": "The therapeutic window is the amount of a  medication  between the amount that gives an effect ( effective dose ) and the amount that gives more  adverse effects  than desired effects. For instance, medication with a small pharmaceutical window must be administered with care and control, e.g. by frequently measuring blood concentration of the drug, since it easily loses effects or gives adverse effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10216", "text": "The  duration of action  of a drug is the length of time that particular drug is effective. [ 5 ]   Duration of action is a function of several parameters including  plasma half-life , the time to equilibrate between plasma and target compartments, and the off rate of the drug from its  biological target . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10217", "text": "In recreational psychoactive drug spaces, duration refers to the length of time over which the  subjective effects  of a  psychoactive substance  manifest themselves. \nDuration can be broken down into 6 parts: (1) total duration (2) onset (3) come up (4) peak (5) offset and (6) after effects. Depending upon the substance consumed, each of these occurs in a separate and continuous fashion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10218", "text": "The total duration of a substance can be defined as the amount of time it takes for the effects of a substance to completely wear off into  sobriety , starting from the moment the substance is first  administered ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10219", "text": "The onset phase can be defined as the period until the very first changes in perception (i.e. \"first alerts\") are able to be detected."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10220", "text": "The \"come up\" phase can be defined as the period between the first noticeable changes in perception and the point of highest subjective intensity. This is colloquially known as \"coming up.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_10221", "text": "The peak phase can be defined as period of time in which the intensity of the substance's effects are at its height."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10222", "text": "The offset phase can be defined as the amount of time in between the conclusion of the peak and shifting into a sober state. This is colloquially referred to as \"coming down.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_10223", "text": "The after effects can be defined as any residual effects which may remain after the experience has reached its conclusion. After effects depend on the substance and usage. This is colloquially known as a \"hangover\" for negative after effects of substances, such as  alcohol ,  cocaine , and  MDMA  or an \"afterglow\" for describing a typically positive, pleasant effect, typically found in substances such as  cannabis ,  LSD  in low to high doses, and  ketamine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10224", "text": "The binding of ligands (drug) to receptors is governed by the  law of mass action  which relates the large-scale status to the rate of numerous molecular processes. The rates of formation and un-formation can be used to determine the equilibrium concentration of bound receptors. The  equilibrium dissociation constant  is defined by:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10225", "text": "where  L =ligand,  R =receptor, square brackets [] denote concentration. The fraction of bound receptors is"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10226", "text": "Where  \n \n \n \n \n \n p \n \n \n L \n R \n \n \n \n \n {\\displaystyle {p}_{LR}} \n \n  is the fraction of receptor bound by the ligand."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10227", "text": "This expression is one way to consider the effect of a drug, in which the response is related to the fraction of bound receptors (see:  Hill equation ). The fraction of bound receptors is known as occupancy. The relationship between occupancy and pharmacological response is usually non-linear. This explains the so-called  receptor reserve  phenomenon i.e. the concentration producing 50% occupancy is typically higher than the concentration producing 50% of maximum response. More precisely, receptor reserve refers to a phenomenon whereby stimulation of only a fraction of the whole receptor population apparently elicits the maximal effect achievable in a particular tissue."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10228", "text": "The simplest interpretation of receptor reserve is that it is a model that states there are excess receptors on the cell surface than what is necessary for full effect. Taking a more sophisticated approach, receptor reserve is an integrative measure of the response-inducing capacity of an  agonist  (in some receptor models it is termed intrinsic efficacy or  intrinsic activity ) and of the signal amplification capacity of the corresponding receptor (and its downstream signaling pathways). Thus, the existence (and magnitude) of receptor reserve depends on the agonist ( efficacy ), tissue (signal amplification ability) and measured effect (pathways activated to cause signal amplification). As receptor reserve is very sensitive to agonist's intrinsic efficacy, it is usually defined only for full (high-efficacy) agonists. [ 7 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10229", "text": "Often the response is determined as a function of log[ L ] to consider many orders of magnitude of concentration. However, there is no biological or physical theory that relates effects to the log of concentration. It is just convenient for graphing purposes. It is useful to note that 50% of the receptors are bound when [ L ]= K d  ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10230", "text": "The graph shown represents the conc-response for two hypothetical receptor agonists, plotted in a semi-log fashion. The curve toward the left represents a higher potency (potency arrow does not indicate direction of increase) since lower concentrations are needed for a given response. The effect increases as a function of concentration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10231", "text": "The concept of pharmacodynamics has been expanded to include  Multicellular Pharmacodynamics  (MCPD). MCPD is the study of the static and dynamic properties and relationships between a set of drugs and a dynamic and diverse multicellular four-dimensional organization. It is the study of the workings of a drug on a minimal multicellular system (mMCS), both  in vivo  and  in silico .  Networked Multicellular Pharmacodynamics  (Net-MCPD) further extends the concept of MCPD to model regulatory genomic networks together with signal transduction pathways, as part of a complex of interacting components in the cell. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10232", "text": "Toxicodynamics (TD) and pharmacodynamics (PD) link a therapeutic agent or toxicant, or toxin (xenobiotic)'s dosage to the features, amount, and time course of its biological action. [ 11 ]  The mechanism of action is a crucial factor in determining effect and toxicity of the drug, taking in consideration the pharmacokinetic (PK) factors. [ 12 ]  The sort and extent of altered cellular physiology will depend on the combination of the drug's presence (as established by pharmacokinetic (PK) studies) and/or its mechanism and duration of action (PD). Types of xenobiotic-target interaction can be described either by reversible, irreversible, noncompetitive, and allosteric interaction or agonist, partial agonist, antagonist, and inverse interactions.  In vitro, ex vivo,  or  in vivo  studies can be used to assess PD and TD from the molecule to the level of the entire organism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10233", "text": "The mechanism of drug action and adverse drug reaction is either physiochemical property based and biochemical based. Adverse drugs reactions can be classified as either idiosyncratic (type B) or intrinsic (type A). Idiosyncratic toxicity is not dosage dependent and defy the mass-action relationship. Immune-mediated processes are frequently cited as the source of type B reactions. [ 13 ]  These cannot be accurately described in preclinical research or clinical trials due to their low incidence frequency. Type A reactions are dosage (concentration) dependent. Usually, this kind of side effect is an extension of an ongoing treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10234", "text": "Pharmacokinetics and pharmacodynamics are termed  toxicokinetics  and  toxicodynamics  in the field of  ecotoxicology . Here, the focus is on toxic effects on a wide range of organisms. The corresponding models are called toxicokinetic-toxicodynamic models. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10235", "text": "An  agonist  is a chemical that activates a  receptor  to produce a biological response. Receptors are  cellular   proteins  whose activation causes the cell to modify what it is currently doing. In contrast, an  antagonist  blocks the action of the agonist, while an  inverse agonist  causes an action opposite to that of the agonist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10236", "text": "The word originates from the  Greek  word  \u03b1\u03b3\u03c9\u03bd\u03b9\u03c3\u03c4\u03ae\u03c2  (ag\u014dnist\u0113s), contestant; champion; rival <  \u03b1\u03b3\u03c9\u03bd  (ag\u014dn), contest, combat; exertion, struggle <  \u03b1\u03b3\u03c9  (ag\u014d), I lead, lead towards, conduct; drive."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10237", "text": "Receptors  can be activated by either  endogenous  agonists (such as  hormones  and  neurotransmitters ) or  exogenous  agonists (such as  drugs ), resulting in a biological response. A  physiological agonist  is a substance that creates the same bodily responses but does not bind to the same receptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10238", "text": "New findings that broaden the conventional definition of pharmacology demonstrate that  ligands  can concurrently behave as agonist  and  antagonists at the same receptor, depending on effector pathways or tissue type. Terms that describe this phenomenon are \" functional selectivity \", \"protean agonism\", [ 5 ] [ 6 ] [ 7 ]  or  selective receptor modulators . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10239", "text": "As mentioned above, agonists have the potential to bind in different locations and in different ways depending on the type of agonist and the type of receptor. [ 9 ]  The process of binding is unique to the receptor-agonist relationship, but binding induces a conformational change and activates the receptor. [ 9 ] [ 10 ]  This conformational change is often the result of small changes in  charge  or changes in  protein folding  when the agonist is bound. [ 10 ] [ 11 ]  Two examples that demonstrate this process are the  muscarinic acetylcholine receptor  and  NMDA receptor  and their respective agonists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10240", "text": "For the  muscarinic acetylcholine receptor , which is a  G protein-coupled receptor [ 10 ] (GPCR), the  endogenous agonist  is  acetylcholine . The binding of this  neurotransmitter  causes the conformational changes that propagate a signal into the cell. [ 10 ]  The conformational changes are the primary effect of the agonist, and are related to the agonist's binding affinity and agonist  efficacy . [ 9 ] [ 12 ]  Other agonists that bind to this receptor will fall under one of the different categories of agonist mentioned above based on their specific binding affinity and efficacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10241", "text": "The  NMDA receptor  is an example of an alternate mechanism of action, as the NMDA receptor requires co-agonists for activation. Rather than simply requiring a single specific agonist, the NMDA receptor requires both the  endogenous agonists ,  N-methyl-D-aspartate  (NMDA) and  glycine . [ 11 ]  These co-agonists are both required to induce the conformational change needed for the NMDA receptor to allow flow through the  ion channel , in this case calcium. [ 11 ]  An aspect demonstrated by the NMDA receptor is that the mechanism or response of agonists can be blocked by a variety of chemical and biological factors. [ 11 ]  NMDA receptors specifically are blocked by a  magnesium  ion unless the cell is also experiencing  depolarization . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10242", "text": "These differences show that agonists have unique mechanisms of action depending on the receptor activated and the response needed. [ 9 ] [ 10 ]  The goal and process remains generally consistent however, with the primary mechanism of action requiring the binding of the agonist and the subsequent changes in conformation to cause the desired response at the receptor. [ 9 ] [ 12 ]  This response as discussed above can vary from allowing flow of  ions  to activating a  GPCR  and transmitting a signal into the  cell . [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10243", "text": "Potency is the amount of agonist needed to elicit a desired response. The  potency  of an agonist is inversely related to its  half maximal effective concentration  (EC 50 ) value. The EC 50  can be measured for a given agonist by determining the concentration of agonist needed to elicit half of the maximum biological response of the agonist. The EC 50  value is useful for comparing the potency of drugs with similar  efficacies  producing physiologically similar effects.  The smaller the EC 50  value, the greater the potency of the agonist, the lower the concentration of drug that is required to elicit the maximum biological response."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10244", "text": "When a drug is used therapeutically, it is important to understand the margin of safety that exists between the dose needed for the desired effect and the dose that produces unwanted and possibly dangerous side-effects (measured by the TD 50 , the dose that produces toxicity in 50% of individuals). This relationship, termed the  therapeutic index , is defined as the ratio  TD 50 : ED 50 . In general, the narrower this margin, the more likely it is that the drug will produce unwanted effects. The therapeutic index emphasizes the importance of the margin of safety, as distinct from the potency, in determining the usefulness of a drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10245", "text": "In pharmacology the term  agonist-antagonist  or  mixed agonist/antagonist  is used to refer to a drug which under some conditions behaves as an  agonist  (a substance that fully activates the receptor that it binds to) while under other conditions, behaves as an  antagonist  (a substance that binds to a receptor but does not activate and can block the activity of other agonists)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10246", "text": "Types of mixed agonist/antagonist include  receptor ligands  that act as agonist for some receptor types and antagonist for others [ 1 ]  or agonist in some tissues while antagonist in others (also known as  selective receptor modulators )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10247", "text": "For synaptic receptors, an agonist is a compound that increases the activation of the receptor by binding directly to it or by increasing the amount of time  neurotransmitters  are in the synaptic cleft. An antagonist is a compound that has the opposite effect of an agonist. It decreases the activation of a synaptic receptor by binding and blocking neurotransmitters from binding or by decreasing the amount of time neurotransmitters are in the synaptic cleft. These actions can be achieved via multiple mechanisms. A common mechanism for agonists is  reuptake inhibition , where the agonist blocks neurotransmitters from reentering the pre-synaptic axon terminal. This gives the neurotransmitter more time in the synaptic cleft to act on the synaptic receptors. Conversely, antagonists often bind directly to receptors in the synaptic cleft, effectively blocking neurotransmitters from binding."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10248", "text": "At the  alpha adrenoceptors ,  ( R )-3-nitrobiphenyline  is an \u03b1 2C  selective agonist as well as being a weak  antagonist  at the \u03b1 2A  and \u03b1 2B  subtypes. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10249", "text": "The best known agonist-antagonists are  opioids . Examples of such opioids are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10250", "text": "Agonist\u2013antagonist opioids usually have a  ceiling effect  \u2013 over particular dose they don't increase their potency. [ 7 ]   Hence agonist\u2013antagonist opioids have a lower addiction potential but also lower analgesic efficacy and are more likely to produce  psychotomimetic  effects. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10251", "text": "Agonist\u2013antagonist opioids that block  delta  while activating  mu opioid receptors  produce analgesia without the development of  tolerance . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10252", "text": "Antidepressant treatment tachyphylaxis  ( ADT  tachyphylaxis ), also known as  Prozac poop-out , is a medical condition in which progressive or acute tolerance effects are seen following chronic administration of a drug. [ 1 ]  It occurs more often with  Selective serotonin reuptake inhibitors  (SSRIs), which are the most commonly prescribed antidepressants. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10253", "text": "Patients affected by ADT tachyphylaxis experience a noticeably sudden progressive decrease in response to SSRIs. The reported rates of this condition vary from 9% to 33% of SSRI users, and the majority of those affected are  responsive to subsequent treatments. [ 4 ]  In most observational studies, these individuals suffer a recurrence or relapse of depression without changing the previously effective dose. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10254", "text": "ADT tachyphylaxis incorporates  drug sensitivity  as a potential causal factor for the decreased response. However,  tolerance  provides a more accurate explanation. While the exact cause of ADT tachyphylaxis in individual cases is unknown, drug tolerance is a more comprehensive model, as it includes mechanisms of  pharmacodynamic tolerance ,  metabolic tolerance , and others. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10255", "text": "ADT tachyphylaxis specifically occurs in patients experiencing depression who are using SSRIs and  Monoamine Oxidase Inhibitors  (MAOIs). Currently, SSRIs are the preferred treatment for depression among clinicians, as MAOIs, despite being very effective, require a few dietary restrictions and some caution when taking with other medications due to the potential for interactions capable of inducing dangerous side effects. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10256", "text": "Following a declination or total extinction in response to a previously therapeutic dose of an antidepressant, the issue is clinically addressed as stemming from tolerance development. Several strategies are available, such as exploring drug options from a different drug class used to treat depression. The patient can also choose to switch to another SSRI (or MAOI, if applicable) while maintaining proportionate dose. If tolerance develops in a drug from the same class, the clinician may recommend a regular cycle consisting of all effective treatments within the SSRI or MAOI classes, in order to minimize transitional side effects while maximizing  therapeutic efficacy . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10257", "text": "Other options include increasing dose of the same medication, or supplementation with another antidepressant. Dual reuptake inhibitors, such as  serotonin\u2013norepinephrine reuptake inhibitors  and some  tricyclic antidepressants , have been preliminarily found to have lower rates of tachyphylaxis. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10258", "text": "Antimicrobial pharmacodynamics  is the relationship between the concentration of an  antibiotic  and its ability to inhibit vital processes of  endo- or ectoparasites  and  microbial  organisms. [ 1 ]  This branch of  pharmacodynamics  relates the concentration of an anti-infective agent to its effect, specifically to its antimicrobial effect. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10259", "text": "The  minimum inhibitory concentration  (MIC) and  minimum bactericidal concentration  are used to measure  in vitro  activity of  antimicrobial  agents. They are good indicators of antimicrobial potency, but don't give any information relating to time-dependent antimicrobial killing (the so-called post antibiotic effect). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10260", "text": "The post-antibiotic effect (PAE) is defined as persistent suppression of  bacterial  growth after a brief exposure (1 or 2 hours) of bacteria to an  antibiotic  even in the absence of  host defense mechanisms . [ 3 ]  Factors that affect the duration of the post-antibiotic effect include duration of antibiotic exposure, bacterial species, culture medium and class of antibiotic. It has been suggested that an alteration of DNA function is possibly responsible for the post-antibiotic effect following the observation that most inhibitors of protein and nucleic acid synthesis ( aminoglycosides ,  fluoroquinolones ,  tetracyclines ,  clindamycin , certain newer  macrolides / ketolides , and  rifampicin  and  rifabutin ) induce long-term PAE against susceptible bacteria. [ 3 ] [ 4 ]  Theoretically, the ability of an antibiotic to induce a PAE is an attractive property since antibiotic concentrations could fall below the MIC for the bacterium yet retain their effectiveness in their ability to suppress the growth. Therefore, an antibiotic with PAE would require less frequent administration and it could improve patient adherence with regard to pharmacotherapy. [ 3 ] [ 5 ]  Proposed mechanisms include (1) slow recovery after reversible nonlethal damage to cell structures; (2) persistence of the drug at a binding site or within the  periplasmic space ; and (3) the need to synthesize new enzymes before growth can resume. Most antimicrobials possess significant in vitro PAEs (\u2265 1.5 hours) against susceptible gram-positive  cocci . Antimicrobials with significant PAEs against susceptible gram-negative bacilli are limited to  carbapenems  and agents that inhibit protein or DNA synthesis. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10261", "text": "In  chemistry ,  binding selectivity  is defined with respect to the binding of  ligands  to a  substrate  forming a  complex . Binding selectivity describes how a ligand may bind more preferentially to one  receptor  than another. A selectivity coefficient is the  equilibrium constant  for the reaction of displacement by one ligand of another ligand in a complex with the substrate. Binding selectivity is of major importance in  biochemistry [ 1 ]  and in  chemical separation processes ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10262", "text": "The concept of selectivity is used to quantify the extent to which one chemical substance, A, binds each of two other chemical substances, B and C. The simplest case is where the complexes formed have 1:1  stoichiometry . Then, the two interactions may be characterized by  equilibrium constants   K AB  and  K AC . [ note 1 ] \n \n \n \n \n \n \n \n \n \n A \n + \n B \n \n \n \n \n \n \n \u21bd \n \n \n \n \n \u2212 \n \n \n \n \n \n \n \n \n \u2212 \n \n \n \n \n \u21c0 \n \n \n \n \n \n \n AB \n \n ; \n \n \n \n \n K \n \n \n A \n B \n \n \n \n = \n \n \n \n [ \n \n AB \n \n ] \n \n \n \n [ \n A \n ] \n \n \n [ \n B \n ] \n \n \n \n \n \n \n \n \n \n A \n + \n C \n \n \n \n \n \n \n \u21bd \n \n \n \n \n \u2212 \n \n \n \n \n \n \n \n \n \u2212 \n \n \n \n \n \u21c0 \n \n \n \n \n \n \n AC \n \n ; \n \n \n \n \n K \n \n \n A \n C \n \n \n \n = \n \n \n \n \n [ \n AC \n ] \n \n \n \n \n [ \n A \n ] \n \n \n [ \n C \n ] \n \n \n \n \n \n \n \n \n \n \n {\\displaystyle {\\begin{aligned}{\\ce {A + B <=> AB}};&\\quad K_{\\rm {AB}}={\\frac {[{\\ce {AB}}]}{{\\ce {[A][B]}}}}\\\\{\\ce {A + C <=> AC}};&\\quad K_{\\rm {AC}}={\\frac {{\\ce {[AC]}}}{{\\ce {[A][C]}}}}\\end{aligned}}} \n \n \nwhere [X] represents the  concentration  of substance X (A, B, C, \u2026)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10263", "text": "A  selectivity coefficient  is defined as the ratio of the two equilibrium constants.\n \n \n \n \n \n K \n \n \n B \n , \n C \n \n \n \n = \n \n \n \n K \n \n \n A \n C \n \n \n \n \n K \n \n \n A \n B \n \n \n \n \n \n \n \n {\\displaystyle K_{\\rm {B,C}}={\\frac {K_{\\rm {AC}}}{K_{\\rm {AB}}}}} \n \n \nThis selectivity coefficient is in fact the equilibrium constant for the displacement reaction"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10264", "text": "AB \n + \n C \n \n \n \n \n \n \n \u21bd \n \n \n \n \n \u2212 \n \n \n \n \n \n \n \n \n \u2212 \n \n \n \n \n \u21c0 \n \n \n \n \n \n \n AC \n + \n B \n \n ; \n \n \n K \n \n \n B \n , \n C \n \n \n \n = \n \n \n \n \n [ \n AC \n ] \n \n \n [ \n B \n ] \n \n \n \n \n [ \n AB \n ] \n \n \n [ \n C \n ] \n \n \n \n \n = \n \n \n \n \n K \n \n \n A \n C \n \n \n \n \n \n [ \n A \n ] \n \n \n [ \n B \n ] \n \n \n [ \n C \n ] \n \n \n \n \n \n K \n \n \n A \n B \n \n \n \n \n \n [ \n A \n ] \n \n \n [ \n B \n ] \n \n \n [ \n C \n ] \n \n \n \n \n \n = \n \n \n \n K \n \n \n A \n C \n \n \n \n \n K \n \n \n A \n B \n \n \n \n \n \n \n \n {\\displaystyle {\\ce {AB + C <=> AC + B}};\\quad K_{\\rm {B,C}}={\\frac {{\\ce {[AC][B]}}}{{\\ce {[AB][C]}}}}={\\frac {K_{\\rm {AC}}{\\ce {[A][B][C]}}}{K_{\\rm {AB}}{\\ce {[A][B][C]}}}}={\\frac {K_{\\rm {AC}}}{K_{\\rm {AB}}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10265", "text": "It is easy to show that the same definition applies to complexes of a different stoichiometry, A p B q  and A p C q . The greater the selectivity coefficient, the more the ligand C will displace the ligand B from the complex formed with the substrate A. An alternative interpretation is that the greater the selectivity coefficient, the lower the concentration of C that is needed to displace B from AB. Selectivity coefficients are determined experimentally by measuring the two equilibrium constants,  K AB  and  K AC ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10266", "text": "In biochemistry the substrate is known as a receptor. A receptor is a  protein  molecule, embedded in either the  plasma membrane  or the  cytoplasm  of a cell, to which one or more specific kinds of signalling molecules may bind. A  ligand  may be a  peptide  or another small molecule, such as a  neurotransmitter , a  hormone , a pharmaceutical drug, or a toxin. The specificity of a receptor is determined by its spatial geometry and the way it  binds  to the ligand through  non-covalent interactions , such as  hydrogen bonding  or  Van der Waals forces . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10267", "text": "If a receptor can be isolated a synthetic drug can be developed either to stimulate the receptor, an  agonist  or to block it, an  antagonist . The  stomach ulcer  drug  cimetidine  was developed as an  H 2  antagonist  by chemically engineering the molecule for maximum specificity to an isolated tissue containing the receptor. The further use of  quantitative structure-activity relationships  (QSAR) led to the development of other agents such as  ranitidine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10268", "text": "\"Selectivity\" when referring to a drug is relative. For example, in a higher dose, a specific drug molecule may also bind to other receptors than those said to be \"selective\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10269", "text": "Chelation therapy is a form of medical treatment in which a  chelating ligand [ note 2 ]  is used to selectively remove a metal from the body. When the metal exists as a divalent ion, such as with  lead , Pb 2+  or  mercury , Hg 2+  selectivity against  calcium , Ca 2+  and  magnesium , Mg 2+ , is essential in order that the treatment does not remove essential metals. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10270", "text": "Selectivity is determined by various factors. In the case of  iron overload , which may occur in individuals with \u03b2- thalessemia  who have received  blood transfusions , the target metal ion is in the +3  oxidation state  and so forms stronger complexes than the divalent ions. It also forms stronger complexes with oxygen-donor ligands than with nitrogen-donor ligands.  deferoxamine , a naturally occurring  siderophore  produced by the actinobacter  Streptomyces pilosus  and was used initially as a chelation therapy agent. Synthetic siderophores such as  deferiprone  and  deferasirox  have been developed, using the known structure of deferoxamine as a starting point. [ 4 ] [ 5 ]  Chelation occurs with the two oxygen atoms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10271", "text": "Wilson's disease  is caused by a defect in  copper  metabolism which results in accumulation of copper metal in various organs of the body. The target ion in this case is divalent, Cu 2+ . This ion is classified as borderline in the scheme of Ahrland, Chatt and Davies. [ 6 ]  This means that it forms roughly equally strong complexes with ligands whose donor atoms are N, O or F as with ligands whose donor atoms are P, S or Cl.  Penicillamine , which contains nitrogen and sulphur donor atoms, is used as this type of ligand binds more strongly to copper ions than to calcium and magnesium ions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10272", "text": "Treatment of poisoning by heavy metals such as lead and mercury is more problematical, because the ligands used do not have high specificity relative to calcium. For example,  EDTA  may be administered as a calcium salt to reduce the removal of calcium from bone together with the heavy metal. Factors determining selectivity for lead against zinc, cadmium and calcium have been reviewed, [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10273", "text": "In column chromatography a mixture of substances is dissolved in a mobile phase and passed over a stationary phase in a column. A selectivity factor is defined as the ratio of  distribution coefficients , which describe the equilibrium distribution of an  analyte  between the stationary phase and the mobile phase. The selectivity factor is equal to the selectivity coefficient with the added assumption that the  activity  of the stationary phase, the substrate in this case, is equal to 1, the standard assumption for a pure phase. [ 8 ]  The resolution of a chromatographic column,  R S  is related to the selectivity factor by:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10274", "text": "where \u03b1 is selectivity factor,  N  is the number of  theoretical plates   k A  and  k B  are the  retention factors  of the two analytes. Retention factors are proportional to distribution coefficients. In practice substances with a selectivity factor very close to 1 can be separated. This is particularly true in  gas-liquid chromatography  where column lengths up to 60 m are possible, providing a very large number of theoretical plates."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10275", "text": "In ion-exchange chromatography the selectivity coefficient is defined in a slightly different way [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10276", "text": "Solvent extraction [ 10 ]  is used to extract individual  lanthanoid  elements from the mixtures found in nature in ores such as  monazite . In one process, the metal ions in aqueous solution are made to form complexes with  tributylphosphate  (TBP), which are extracted into an organic solvent such as  kerosene . Complete separation is effected by using a  countercurrent exchange  method. A number of cells are arranged as a  cascade . After equilibration, the aqueous component of each cell is transferred to the previous cell and the organic component is transferred to the next cell, which initially contains only water. In this way the metal ion with the most stable complex passes down the cascade in the organic phase and the metal with the least stable complex passes up the cascade in the aqueous phase. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10277", "text": "If solubility in the organic phase is not an issue, a selectivity coefficient is equal to the ratio of the  stability constants  of the TBP complexes of two metal ions. For lanthanoid elements which are adjacent in the  periodic table  this ratio is not much greater than 1, so many cells are needed in the cascade."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10278", "text": "A potentiometric selectivity coefficient defines the ability of an  ion-selective electrode  to\ndistinguish one particular ion from others. The selectivity coefficient, K B,C  is evaluated by means of the emf response of the ion-selective electrode in mixed solutions of the primary ion, B, and interfering ion, C (fixed interference method) or less desirably, in separate solutions of B and C (separate\nsolution method). [ 12 ]   For example, a  potassium  ion-selective  membrane electrode  utilizes the naturally occurring macrocyclic  antibiotic   valinomycin . In this case the cavity in the macrocyclic ring is just the right size to encapsulate the potassium ion, but too large to bind the sodium ion, the most likely interference, strongly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10279", "text": "Chemical sensors , [ 13 ] [ 14 ]  are being developed for specific target molecules and ions in which the target (guest) form a complex with a sensor (host). The sensor is designed to be an excellent match in terms of the size and shape of the target in order to provide for the maximum binding selectivity. An indicator is associated with the sensor which undergoes a change when the target forms a complex with the sensor . The indicator change is usually a colour change (gray to yellow in the illustration) seen in  absorbance  or, with greater sensitivity,   luminescence . The indicator may be attached to the sensor via a spacer, in the ISR arrangement, or it may be displaced from the sensor, IDA arrangement."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10280", "text": "In  pharmacology , the term  ceiling effect  refers to the property of increasing doses of a given medication to have progressively smaller incremental effect (an example of  diminishing returns ).  Mixed  agonist-antagonist opioids , such as  nalbuphine , serve as a classic example of the ceiling effect; increasing the dose of a narcotic frequently leads to smaller and smaller gains in relief of  pain .  In many cases, the severity of  side effects  from a medication increases as the dose increases, long after its therapeutic ceiling has been reached."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10281", "text": "The term is defined as \"the phenomenon in which a drug reaches a maximum effect, so that increasing the drug dosage does not increase its effectiveness.\" [ 1 ]  Sometimes drugs cannot be compared across a wide range of treatment situations because one drug has a ceiling effect. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10282", "text": "Sometimes the desired effect increases with dose, but  side-effects  worsen or start being dangerous, and  risk to benefit ratio  increases. This is because of occupation of all the receptors in a given specimen."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10283", "text": "In  medicine  the term  course  generally takes one of two meanings, both reflecting the sense of \" path that something or someone moves along...process or sequence or steps \":"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10284", "text": "A patient may be said to be at the beginning, the middle or the end, or at a particular stage of the course of a disease or a treatment. A precursor is a sign or event that precedes the course or a particular stage in the course of a disease, for example chills often are precursors to fevers. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10285", "text": "Cross-tolerance  is a phenomenon that occurs when  tolerance  to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects\u2014for example, acting on the same  cell receptor  or affecting the transmission of certain  neurotransmitters . Cross-tolerance has been observed with pharmaceutical drugs such as  anti-anxiety agents  and  illicit substances , and sometimes the two of them together. Often, a person who uses one drug can be tolerant to a drug that has a completely different function. [ 1 ]  This phenomenon allows one to become tolerant to a drug that they have never used before. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10286", "text": "Excitation of the GABA receptor produces an influx of negatively charged chloride ions, which hyperpolarizes the neuron and makes it less likely to give rise to an action potential. In addition to  gamma-Aminobutyric acid  (GABA) itself, the GABA A  receptor can also bind barbiturates and benzodiazepines.  Benzodiazepine binding increases the binding of GABA and barbiturates maximize the time the pore is open.  Both of these mechanisms allow for influx of chloride ions.  When these drugs are taken together, especially with  ethanol  (drinking alcohol), there is a disproportionate increase in toxicity because the effects of both occur simultaneously and add up since they act on the same receptor at different sites.  Convergence upon the GABA A  receptor is why tolerance for one drug in the group will most likely cause cross-tolerance for the other drugs in the group. [ 1 ]   However, the barbiturates are also  AMPA receptor  blockers, and in addition interact with the  nAChR  and  voltage-gated calcium channels .  As a result, somebody who is tolerant to benzodiazepines is more sensitive to barbiturates than vice versa."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10287", "text": "These drugs block dopamine receptors and some also block serotonin receptors (such as  chlorpromazine , the first antipsychotic used clinically). Having been on one or more antipsychotics for any appreciable amount of time results in dramatically reduced sensitivity to others with similar mechanisms of action. However, an antipsychotic with a substantial disparity in  pharmacology  (e.g.  haloperidol  and  quetiapine ) may retain significant efficacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10288", "text": "MAO inhibitor drugs block an enzyme system resulting in increased stores of monoamine neurotransmitters. More common antidepressants such as tricyclic antidepressants and SSRIs block reuptake transporters causing increased levels of norepinephrine or serotonin in synapses. [ 1 ]  Mood stabilizers include lithium and many  anticonvulsants , such as  carbamazepine  and  lamotrigine  are also used for mood disorders. This would demonstrate little to zero cross-tolerance with serotonergic or  lithium  treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10289", "text": "These drugs mimic three classes of endorphins, such as endomorphins, enkephalins, and dynorphins. All three of these classes each have their own receptor-mu, kappa, and delta. Opioids will bind to the receptor for the endorphin they are most chemically similar to. Tolerance to some effects occurs with regular use, a result of the downregulation of the stimulated opioid receptors. Cross tolerance to analgesia may develop incompletely and less rapidly, allowing rotation between opioid medications be used to compensate somewhat for tolerance. This phenomenon is called  incomplete cross-tolerance . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10290", "text": "Cocaine, amphetamines, methylphenidate and ephedrine block the reuptake of dopamine and  norepinephrine . With increasing doses, amphetamines also cause the direct release of these neurotransmitters."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10291", "text": "Serotonergic psychedelics  act through modulation of serotonin receptors. Most of these drugs share a high affinity for the  5-HT 2A  receptor subtype, known to result in their common perceptual and psychological effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10292", "text": "Sometimes cross-tolerance occurs between two drugs that do not share mechanisms of action or classification. For example, in rats some amphetamine-like stimulants have been shown to exhibit cross-tolerance with  caffeine , though this effect was not observed with amphetamine itself.  It is likely that this mechanism of cross-tolerance involves the  dopamine receptor D 1 . [ 4 ]  Amphetamines also have cross-tolerance with  pseudoephedrine , as pseudoephedrine can block dopamine uptake in the same manner that amphetamines do, but less potently. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10293", "text": "Alcohol is another substance that often cross-tolerates with other drugs. Findings of cross-tolerance with nicotine in animal models suggest that it is also possible in humans, and may explain why the two drugs are often used together. [ 6 ]  Numerous studies have also suggested the possibility of cross-tolerance between alcohol and cannabis. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10294", "text": "Cigarette smoking  produces increased metabolic tolerance to caffeine due to upregulation of the CYP1A enzyme family (see  aryl hydrocarbon receptor )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10295", "text": "In  pharmacology , a  dirty drug  is an informal term for  drugs  that may bind to many different molecular targets or receptors in the body, and so tend to have a wide range of effects and possibly  adverse drug reactions . Today, pharmaceutical companies try to make new drugs as selective as possible to minimise binding to  antitargets  and hence reduce the occurrence of side effects and risk of adverse reactions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10296", "text": "Examples of  compounds  often cited as \"dirty drugs\" include  tramadol ,  chlorpromazine ,  olanzapine ,  dextromethorphan ,  ibogaine , and  ethanol , all of which bind to multiple receptors or influence multiple receptor systems.  There may be instances of advantages to drugs that exhibit multi-receptor activity such as the anti-addictive drug ibogaine that acts within a broad range of neurohormonal systems where activity is also exhibited by drugs commonly associated with addiction including  opioids ,  nicotine , and  alcohol . [ 1 ] [ 2 ]  Similarly chlorpromazine is primarily used as an  antipsychotic , but its strong serotonin receptor blocking effects make it useful for treating serotonergic crisis such as  serotonin syndrome . Dextromethorphan for its part is widely used as a  cough medication , but its other actions have led to trials for several conditions such as its use as an adjunct to analgesia, and a potential anti-addictive drug, as well as its occasional recreational use as a  dissociative . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10297", "text": "Kanamycin  is an aminoglycoside  antibiotic  which induces  deafness  through blockage of the  outer hair cells  of the  cochlea ; yet it has many other effects, weakening for instance the  collagen  and  DNA   biosynthesis . It acts by inhibiting the synthesis of  proteins  in susceptible organisms. Kanamycin requires close clinical supervision because of its potential toxicity and adverse side effects to the auditory and vestibular branches of the eighth cranial nerve and to the renal tubules. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10298", "text": "Clozapine  and  latrepirdine  are examples of drugs used in the treatment of CNS disorders that have a superior efficacy precisely  because  of their \"multifarious\" broadspectrum mode of activity. Likewise, in cancer chemotherapeutics, it has been recognized that drugs active at more than one target have a higher probability of being efficacious. [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10299", "text": "The anti-histamine and anti-cholinergic effects of atypical and low potency typical antipsychotics, such as the aforementioned clozapine and chlorpromazine, can also mediate against potentially distressing movement disorders such as extrapyramidal symptoms and akathisia associated with dopamine antagonism. In fact, clozapine may even help treat movement problems associated with Parkinson's disease. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10300", "text": "Examples of \"promiscuous\" cancer drugs include:  Sutent ,  Sorafenib ,  Zactima , and  AG-013736 . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10301", "text": "In the field of drugs used to treat depression, the nonselective  MAOIs  and the  TCAs  are sometimes believed to have an efficacy that is superior to the  SSRIs . [ 13 ]  SSRIs are usually nevertheless picked as the first-line choice of agent and not the (less-selective) MAOIs and TCAs for several reasons. Firstly, SSRIs are safer in overdose than TCAs. Secondly, MAOIs can cause serious side effects when mixed with certain foods, including life-threatening  hypertensive crisis . MAOIs and TCAs generally have more side effects than SSRIs. TCAs in particular have  anticholinergic  side effects such as constipation and blurred vision, whereas SSRIs have fewer anticholinergic side effects. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10302", "text": "The  dose\u2013response relationship , or  exposure\u2013response relationship , describes the magnitude of the  response  of an  organism , as a  function  of exposure (or  doses ) to a  stimulus  or  stressor  (usually a  chemical ) after a certain exposure time. [ 1 ]  Dose\u2013response relationships can be described by  dose\u2013response curves . This is explained further in the following sections. A  stimulus response function  or  stimulus response curve  is defined more broadly as the response from any type of stimulus, not limited to chemicals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10303", "text": "Studying dose response, and developing dose\u2013response models, is central to determining \"safe\", \"hazardous\" and (where relevant) beneficial levels and dosages for drugs, pollutants, foods, and other substances to which humans or other  organisms  are exposed. These conclusions are often the basis for public policy. The  U.S. Environmental Protection Agency  has developed extensive guidance and reports on dose\u2013response modeling and assessment, as well as software. [ 2 ]  The  U.S. Food and Drug Administration  also has guidance to elucidate dose\u2013response relationships [ 3 ]  during  drug development . Dose response relationships may be used in individuals or in populations. The adage  The dose makes the poison  reflects how a small amount of a toxin has no significant effect, while a large amount may be fatal. This reflects how dose\u2013response relationships can be used in individuals. In populations, dose\u2013response relationships can describe the way groups of people or organisms are affected at different levels of exposure. Dose response relationships modelled by dose response curves are used extensively in pharmacology and drug development. In particular, the shape of a drug's dose\u2013response curve (quantified by EC50, nH and ymax parameters) reflects the biological activity and strength of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10304", "text": "Some example measures for dose\u2013response relationships are shown in the tables below. Each sensory stimulus corresponds with a particular  sensory receptor , for instance the nicotinic acetylcholine receptor for nicotine, or the  mechanoreceptor  for mechanical pressure. However, stimuli (such as temperatures or radiation) may also affect physiological processes beyond sensation (and even give the measurable response of death). Responses can be recorded as continuous data (e.g. force of muscle contraction) or discrete data (e.g. number of deaths)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10305", "text": "A  dose\u2013response curve  is a  coordinate graph  relating the magnitude of a dose (stimulus) to the response of a biological system. A number of effects (or  endpoints ) can be studied. The applied dose is generally plotted on the X axis and the response is plotted on the Y axis. In some cases, it is the  logarithm  of the dose that is plotted on the X axis. The curve is typically  sigmoidal , with the steepest portion in the middle. Biologically based models using dose are preferred over the use of log(dose) because the latter can visually imply a  threshold dose  when in fact there is none. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10306", "text": "Statistical analysis of dose\u2013response curves may be performed by regression methods such as the  probit model  or  logit model , or other methods such as the Spearman\u2013K\u00e4rber method. [ 5 ]  Empirical models based on nonlinear regression are usually preferred over the use of some transformation of the data that linearizes the dose-response relationship. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10307", "text": "Typical experimental design for measuring dose-response relationships are  organ bath  preparations,  ligand binding assays ,  functional assays , and  clinical drug trials ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10308", "text": "Specific to response to doses of radiation the Health Physics Society (in the United States) has published a  documentary series  on the origins of the linear no-threshold (LNT) model though the society has not adopted a policy on LNT.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_10309", "text": "Logarithmic dose\u2013response curves are generally  sigmoidal-shape  and monotonic and can be fit to a classical  Hill equation . The Hill equation is a  logistic function  with respect to the logarithm of the dose and is similar to a  logit model . A generalized model for multiphasic cases has also been suggested. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10310", "text": "The  Hill equation  is the following formula, where  \n \n \n \n E \n \n \n {\\displaystyle E} \n \n  is the magnitude of the response,  \n \n \n \n \n \n [ \n A \n ] \n \n \n \n \n {\\displaystyle {\\ce {[A]}}} \n \n  is the drug concentration (or equivalently, stimulus intensity) and  \n \n \n \n \n \n E \n C \n \n \n 50 \n \n \n \n \n {\\displaystyle \\mathrm {EC} _{50}} \n \n  is the drug concentration that produces a 50% maximal response and  \n \n \n \n n \n \n \n {\\displaystyle n} \n \n  is the  Hill coefficient ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10311", "text": "The parameters of the dose response curve reflect measures of  potency  (such as EC50, IC50, ED50, etc.) and measures of efficacy (such as tissue, cell or population response)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10312", "text": "A commonly used dose\u2013response curve is the  EC 50  curve, the half maximal effective concentration, where the EC 50  point is defined as the inflection point of the curve."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10313", "text": "Dose response curves are typically fitted to the  Hill equation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10314", "text": "The first point along the graph where a response above zero (or above the control response) is reached is usually referred to as a threshold dose. For most beneficial or recreational drugs, the desired effects are found at doses slightly greater than the threshold dose. At higher doses, undesired  side effects  appear and grow stronger as the dose increases. The more potent a particular substance is, the steeper this curve will be. In quantitative situations, the Y-axis often is designated by percentages, which refer to the percentage of exposed individuals registering a standard response (which may be death, as in  LD 50 ). Such a curve is referred to as a quantal dose\u2013response curve, distinguishing it from a graded dose\u2013response curve, where response is continuous (either measured, or by judgment)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10315", "text": "The Hill equation can be used to describe dose\u2013response relationships, for example ion channel-open-probability vs.  ligand  concentration. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10316", "text": "Dose is usually in milligrams,  micrograms , or grams per kilogram of body-weight for oral exposures or milligrams per cubic meter of ambient air for inhalation exposures. Other dose units include moles per body-weight, moles per animal, and for dermal exposure, moles per square centimeter."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10317", "text": "The E max  model is a generalization of the Hill equation where an effect can be set for zero dose. Using the same notation as above, we can express the model as: [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10318", "text": "Compare with a rearrangement of Hill:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10319", "text": "The E max  model is the single most common model for describing dose-response relationship in drug development. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10320", "text": "The shape of dose-response curve typically depends on the topology of the targeted reaction network. While the shape of the curve is often  monotonic , in some cases non-monotonic dose response curves can be seen. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10321", "text": "The concept of linear dose\u2013response relationship, thresholds, and all-or-nothing responses may not apply to non-linear situations. A  threshold model  or  linear no-threshold model  may be more appropriate, depending on the circumstances.\nA recent critique of these models as they apply to endocrine disruptors argues for a substantial revision of testing and toxicological models at low doses because of observed non- monotonicity , i.e. U-shaped dose/response curves. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10322", "text": "Dose\u2013response relationships generally depend on the exposure time and exposure route (e.g., inhalation, dietary intake); quantifying the response after a different exposure time or for a different route leads to a different relationship and possibly different conclusions on the effects of the stressor under consideration. This limitation is caused by the complexity of biological systems and the often unknown biological processes operating between the external exposure and the adverse cellular or tissue response. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10323", "text": "Schild analysis  may also provide insights into the effect of drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10324", "text": "Dosing  generally applies to feeding  chemicals  or  medicines  when used in small quantities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10325", "text": "For medicines the term  dose  is generally used. In the case of inanimate objects the word dosing is typical. The term  dose titration , referring to stepwise  adjustment  of doses until a desired level of effect is reached, is common in  medicine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10326", "text": "The word  dosing  is very commonly used by  engineers  in thermal  power stations , in water treatment, in any industry where  steam  is being generated, and in  building services  for heating and cooling water treatment. Dosing procedures are also in vogue in  textile  and similar industries where chemical treatment is involved."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10327", "text": "Commercial  swimming pools  also require chemical dosing in order to control  pH  balance,  chlorine  level, and other such water quality criteria. Modern swimming pool plant will have bulk storage of chemicals held in separate  dosing tanks , and will have automated controls and  dosing pumps  to top up the various chemicals as required to control the water quality."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10328", "text": "In a power station treatment chemicals are injected or fed to  boiler  and also to feed and make up water under  pressure , but in small dosages or rate of  injection . The feeding at all places is done by means of small capacity dosing  pumps  specially designed for the duty demanded."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10329", "text": "In building services the water quality of various pumped fluid systems, including for heating, cooling, and condensate water, will be regularly checked and topped up with chemicals manually as required to suit the required water quality. Most commonly  inhibitors  will be added to protect the pipework and components against corrosion, or a  biocide  will be added to stop the growth of bacteria in lower temperature systems. The required chemicals will be added to the fluid system by use of a  dosing pot ; a multi-valved chamber in which the chemical can be added, and then introduced to the fluid system in a controlled manner."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10330", "text": "In food industries, the dosing of ingredients is particularly important in order to ensure the quality of the recipe as well as its food safety where the consumers' health may be directly implicated. Dosing is done in wet processes with dosing pumps but even more importantly in dry processes, just prior to the packaging of the product. Dosing of dry materials is commonly done through Gain-in-Weight dosing or Loss-in-Weight dosing using equipment on load cells. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10331", "text": "See pesticide application"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10332", "text": "The feeding of chemicals in  agriculture  has also become common due to technology developments. However  agricultural dosing  is done by means of hand held pressure spray pumps."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10333", "text": "Sometimes aerial spraying of chemicals by fixed quantities at intervals or dosing is also adopted for agricultural spraying or for atmospheric spraying for eliminating certain types of harmful  insects ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10334", "text": "A  drug class  is a group of  medications  and other compounds that share similar  chemical structures , act through the same  mechanism of action  (i.e., binding to the same  biological target ), have similar  modes of action , and/or are used to treat similar diseases. [ 1 ] [ 2 ]  The  FDA  has long worked to classify and license new medications. Its Drug Evaluation and Research Center categorizes these medications based on both their  chemical  and  therapeutic  classes. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10335", "text": "In several major drug classification systems, these four types of classifications are organized into a hierarchy. [ 4 ]  For example,  fibrates  are a chemical class of drugs (amphipathic carboxylic acids) that share the same mechanism of action ( PPAR agonist ), the same mode of action (reducing blood  triglyceride  levels), and are used to prevent and treat the same disease ( atherosclerosis ). However, not all PPAR agonists are fibrates, not all triglyceride-lowering agents are PPAR agonists, and not all drugs used to treat atherosclerosis lower triglycerides.\nA drug class is typically defined by a  prototype drug , the most important, and typically the first developed drug within the class, used as a reference for comparison."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10336", "text": "This type of categorisation of drugs is from a  chemical  perspective and categorises them by their chemical structure. Examples of drug classes that are based on chemical structures include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10337", "text": "This type of categorisation is from a  pharmacological  perspective and categorises them by their biological target. Drug classes that share a common molecular  mechanism of action  modulate the activity of a specific  biological target . [ 6 ]  The definition of a mechanism of action also includes the type of activity at that biological target. For receptors, these activities include  agonist ,  antagonist ,  inverse agonist , or  modulator .  Enzyme target mechanisms include  activator  or  inhibitor . Ion channel modulators include  opener  or  blocker .  The following are specific examples of drug classes whose definition is based on a specific mechanism of action:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10338", "text": "This type of categorisation of drugs is from a  biological  perspective and categorises them by the anatomical or functional change they induce. Drug classes that are defined by common  modes of action  (i.e. the functional or anatomical change they induce) include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10339", "text": "This type of categorisation of drugs is from a  medical  perspective and categorises them by the pathology they are used to treat. Drug classes that are defined by their  therapeutic use  (the pathology they are intended to treat) include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10340", "text": "Some drug classes have been amalgamated from these three principles to meet practical needs. The class of  nonsteroidal anti-inflammatory drugs  (NSAIDs) is one such example. Strictly speaking, and also historically, the wider class of anti-inflammatory drugs also comprises  steroidal  anti-inflammatory drugs . These drugs were in fact the predominant anti-inflammatories during the decade leading up to the introduction of the term \"nonsteroidal anti-inflammatory drugs.\" Because of the disastrous reputation that the corticosteroids had got in the 1950s, the new term, which offered to signal that an anti-inflammatory drug was not a steroid, rapidly gained currency. [ 7 ]  The drug class of \"nonsteroidal anti-inflammatory drugs\" (NSAIDs) is thus composed by one element (\"anti-inflammatory\") that designates the mechanism of action, and one element (\"nonsteroidal\") that separates it from other drugs with that same mechanism of action. Similarly, one might argue that the class of disease-modifying anti-rheumatic drugs (DMARD) is composed by one element (\"disease-modifying\") that albeit vaguely designates a mechanism of action, and one element (\"anti-rheumatic drug\") that indicates its therapeutic use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10341", "text": "Other systems of drug classification exist, for example the  Biopharmaceutics Classification System  which determines a drugs' attributes by solubility and intestinal permeability."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10342", "text": "Drug intolerance  or  drug sensitivity  refers to an inability to tolerate the  adverse effects  of a medication, generally at therapeutic or subtherapeutic doses. Conversely, a patient is said to be \"tolerating\" a drug when they can tolerate its adverse effects.  Some instances of drug intolerance are known to result from genetic variations in  drug metabolism ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10343", "text": "Drugs in systemic circulation have a certain concentration in the blood, which serves as a surrogate marker for how much drug will be delivered throughout the body (how much drug the rest of the body will \"see\"). There exists a minimum concentration of drug within the blood that will give rise to the intended therapeutic effect ( minimum effective concentration , MEC), as well as a minimum concentration of drug that will give rise to an unintended  adverse drug event  (minimum toxic concentration, MTC). The difference between these two values is generally referred to as the  therapeutic window . Different drugs have different therapeutic windows, and different people will have different MECs and MTCs for a given drug. If someone has a very low MTC for a drug, they are likely to experience adverse effects at drug concentrations lower than what it would take to produce the same adverse effects in the general populace; thus, the individual will experience significant toxicity at a dose that is otherwise considered \"normal\" for the average person. This individual will be considered \"intolerant\" to that drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10344", "text": "There are a variety of factors that can affect the MTC, which is often the subject of clinical  pharmacokinetics . Variations in MTC can occur at any point in the  ADME  ( absorption ,  distribution ,  metabolism , and  excretion ) process. For example, a patient could possess a genetic defect in a drug metabolizing enzyme in the  cytochrome P450  superfamily. While most individuals will possess the effective metabolizing machinery, a person with a defect will have a difficult time trying to  clear  the drug from their system. Thus, the drug will accumulate within the blood to higher-than-expected concentrations, reaching a MTC at a dose that would otherwise be considered normal for the average person. In other words, in a person that is intolerant to a medication, it is possible for a dose of 10\u00a0mg to \"feel\" like a dose of 100\u00a0mg, resulting in an overdose\u2014a \"normal\" dose can be a \"toxic\" dose in these individuals, leading to clinically significant effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10345", "text": "There is also an aspect of drug intolerance that is subjective. Just as different people have different pain tolerances, so too do people have different tolerances for dealing with the adverse effects from their medications. For example, while  opioid-induced constipation  may be tolerable to some individuals, other people may stop taking an  opioid  due to the unpleasantness of the constipation even if it brings them significant pain relief."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10346", "text": "Intolerance to  analgesics , particularly  NSAIDs , is relatively common. It is thought that a variation in the metabolism of  arachidonic acid  is responsible for the intolerance.  Symptoms include chronic  rhinosinusitis  with  nasal polyps ,  asthma ,  gastrointestinal ulcers ,  angioedema , and  urticaria . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10347", "text": "Drug tolerance  or  drug insensitivity  is a  pharmacological  concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, further reducing the drug's effects. Drug tolerance is indicative of drug use but is not necessarily associated with  drug dependence  or  addiction . [ 4 ]  The process of tolerance development is reversible (e.g., through a  drug holiday [ 5 ] ) and can involve both  physiological  factors and  psychological  factors. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10348", "text": "One may also develop drug tolerance to  side effects , [ 7 ]  in which case tolerance is a desirable characteristic. A medical intervention that has an objective to increase tolerance (e.g.,  allergen immunotherapy , in which one is exposed to larger and larger amounts of  allergen  to decrease one's  allergic reactions ) is called  drug desensitization . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10349", "text": "The opposite concept to drug tolerance is  reverse tolerance , in which case the subject's reaction or effect will increase following its repeated use. The two notions are not incompatible and tolerance may sometimes lead to reverse tolerance. For example, heavy drinkers initially develop tolerance to alcohol (requiring them to drink larger amounts to achieve a similar effect) but excessive drinking can cause  liver damage , which then puts them at risk of intoxication when drinking even very small amounts of alcohol. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10350", "text": "Drug tolerance should not be confused with  drug tolerability , which refers to the degree to which overt  adverse effects  of a drug can be tolerated by a patient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10351", "text": "Tachyphylaxis  is a subcategory of drug tolerance referring to cases of sudden, short-term onset of tolerance following the administration of a drug. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10352", "text": "Pharmacodynamic tolerance begins when the cellular response to a substance is reduced with repeated use. A common cause of pharmacodynamic tolerance is high concentrations of a substance constantly binding with the  receptor , desensitizing it through constant interaction. [ 11 ]  Other possibilities include a reduction in receptor density (usually associated with receptor agonists), other mechanisms leading to changes in action potential firing rate, or alterations in protein transcription among others adaptations. [ 12 ] [ 13 ]  Pharmacodynamic tolerance to a  receptor antagonist  involves the reverse, i.e., increased receptor firing rate, an increase in receptor density, or other mechanisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10353", "text": "While most occurrences of pharmacodynamic tolerance occur after sustained exposure to a drug, instances of acute or instant tolerance (tachyphylaxis) can occur. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10354", "text": "Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of drugs (ADME). All psychoactive drugs are first absorbed into the bloodstream, carried in the blood to various parts of the body including the site of action (distribution), broken down in some fashion (metabolism), and ultimately removed from the body (excretion). All of these factors are very important determinants of crucial pharmacological properties of a drug, including its potency, side effects, and duration of action."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10355", "text": "Pharmacokinetic tolerance (dispositional tolerance) occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in  induction  of the enzymes required for degradation of the drug e.g. CYP450 enzymes. This is most commonly seen with substances such as  ethanol ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10356", "text": "This type of tolerance is most evident with oral ingestion, because other routes of drug administration bypass  first-pass metabolism . Enzyme induction is partly responsible for the phenomenon of tolerance, in which repeated use of a drug leads to a reduction of the drug's effect. However, it is only one of several mechanisms leading to tolerance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10357", "text": "Behavioral tolerance occurs with the use of certain psychoactive drugs, where tolerance to a behavioral effect of a drug, such as increased motor activity by methamphetamine, occurs with repeated use. It may occur through drug-independent learning or as a form of pharmacodynamic tolerance in the brain; the former mechanism of behavioral tolerance occurs when one learns how to actively overcome drug-induced impairment through practice. Behavioral tolerance is often context-dependent, meaning tolerance depends on the environment in which the drug is administered, and not on the drug itself. [ 15 ]   Behavioral sensitization  describes the opposite phenomenon."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10358", "text": "Half maximal effective concentration  ( EC 50 ) is a measure of the concentration of a drug, antibody or toxicant which induces a  biological response  halfway between the baseline and maximum after a specified exposure time. [ 1 ]  More simply, EC 50  can be defined as the  concentration required to obtain a 50% [...] effect [ 2 ]  and may be also written as [A] 50 . [ 3 ]  It is commonly used as a measure of a drug's  potency , although the use of EC 50  is preferred over that of 'potency', which has been criticised for its vagueness. [ 3 ]  EC 50  is a measure of concentration, expressed in  molar units  (M), where 1\u00a0M is equivalent to 1\u00a0 mol / L ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10359", "text": "The EC 50  of a  graded   dose response curve  therefore represents the concentration of a compound where 50% of its maximal effect is observed. [ 4 ]  \nThe EC 50  of a  quantal  dose response curve represents the concentration of a compound where 50% of the population exhibit a response, [ 5 ]  after a specified exposure duration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10360", "text": "For clarification, a graded dose response curve shows the graded effect of the drug (y axis) over the dose of the drug (x axis) in one or an average of subjects. A quantal dose response curve shows the percentage of subjects where a response is noted in an all-or-none manner (y axis) over the dose of the drug (x axis)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10361", "text": "For competition binding assays and functional antagonist assays  IC 50  is the most common summary measure of the dose-response curve.  For agonist/stimulator assays the most common summary measure is the EC 50 . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10362", "text": "The EC 50  is also related to  IC 50  which is a measure of a compound's inhibition (50% inhibition)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10363", "text": "Biological responses to  ligand  concentrations typically follow a  sigmoidal  function. The  inflection point  at which the increase in response with increasing ligand concentration begins to slow is the EC 50 , which can be mathematically determined by derivation of the best-fit line. While relying on a graph for estimation is more convenient, this typical method yields less accurate and precise results. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10364", "text": "The response or effect, E, is dependent on both the binding of the drug and the drug-bound receptor. The  agonist  that binds to the receptor and initiates the response is usually abbreviated A or D. At low agonist concentrations, [A], the response, E is immeasurably low but at higher [A], E becomes measurable. E increases with [A] until at sufficiently high [A], when E plateaus towards an asymptotic maximum attainable response, E max . The [A] at which E is 50% of E max  is termed the  half maximal effective concentration  and is abbreviated EC 50 , or rarely [A] 50 . The term \"potency\" refers to the EC 50  value. The lower the EC 50 , the less the concentration of a drug is required to produce 50% of maximum effect and the higher the potency. The EC 10  and EC 90  concentrations to induce 10% and 90% maximal responses are defined similarly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10365", "text": "There is a wide range of EC 50  values of drugs; they are typically anywhere from nM to mM. Hence, it is often more practical to refer to the logarithmically transformed  p EC 50  values instead of EC 50 , where"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10366", "text": "pEC \n \n 50 \n \n \n \n \n \n \n = \n \u2212 \n \n log \n \n 10 \n \n \n \u2061 \n ( \n \n \n EC \n \n 50 \n \n \n \n \n \n \n ) \n \n \n {\\displaystyle {\\ce {pEC50}}=-\\log _{10}({\\ce {EC50}})} \n \n ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10367", "text": "A drug's potency is dependent on the drug's  affinity  and  efficacy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10368", "text": "Affinity  describes how well a drug can bind to a receptor. Faster or stronger binding is represented by a higher affinity, or equivalently a lower dissociation constant. The EC 50  should not be confused with the affinity constant, K d . While the former reflects the drug concentration needed for a level of tissue response, the latter reflects the drug concentration needed for an amount of receptor binding."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10369", "text": "Efficacy  is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10370", "text": "The EC 50  relates to the  Hill equation , which is a function of the agonist concentration, [A]:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10371", "text": "where E is the observed response or effect above baseline, and n, the  Hill coefficient  reflects the slope of the curve. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10372", "text": "The EC 50  represents the  point of inflection  of the Hill equation, beyond which increases of [A] have less impact on E. In  dose response curves , the logarithm of [A] is often taken, turning the Hill equation into a sigmoidal  logistic function . In this case, the EC 50  represents the rising section of the sigmoid curve."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10373", "text": "The effects of a stressor or drug generally depend on the exposure time. Therefore, the EC 50  (and similar statistics) will be a function of exposure time. The exact shape of this time function will depend upon the stressor (e.g., the specific toxicant), its mechanism of action, the organism exposed, etc. This time dependency hampers the comparison of  potency  or  toxicity  between compounds and between different organisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10374", "text": "A drug will not have a single value of EC 50  due to different tissues having different sensitivities to the drug (in part due to tissue specific receptor expression). [ citation needed ]  Furthermore, EC 50  is dependent on many factors including species, tissue and cell type and genetics. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10375", "text": "Efficacy  is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as  effectiveness , and it has often been used synonymously, although in  pharmacology  a  distinction is now often made between efficacy and effectiveness . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10376", "text": "The word  efficacy  is used in  pharmacology  and  medicine  to refer both to the maximum response achievable from a  pharmaceutical drug  in research settings, [ 2 ]  and to the capacity for sufficient therapeutic effect or beneficial change in clinical settings."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10377", "text": "In pharmacology, efficacy ( E max ) is the maximum response achievable from an applied or dosed agent, for instance, a small molecule drug. [ 2 ]   Intrinsic activity  is a relative term for a drug's efficacy relative to a drug with the highest observed efficacy. [ 3 ]  It is a purely descriptive term that has little or no mechanistic interpretation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10378", "text": "In order for a drug to have an effect, it needs to bind to its target, and then to affect the function of this target. The target of a drug is commonly referred to as a  receptor , but can in general be any chemically sensitive site on any molecule found in the body. The nature of such binding can be quantified by characterising how tightly these molecules, the drug and its receptor, interact: this is known as the  affinity . Efficacy, on the other hand, is a measure of the action of a drug once binding has occurred. The maximum response,  E max , will be reduced if efficacy is sufficiently low."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10379", "text": "The definition of efficacy has been object for discussion. [ 4 ]  The only way in which absolute measures of efficacy have been obtained is by single ion channel analysis of ligand gated ion channels. It is still not possible to do this for G protein-linked receptors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10380", "text": "In the case of the glycine receptor and the nicotinic acetylcholine receptor (muscle type), it has been proposed by Sivilotti  et al . that opening of the ion channel involves two steps after agonist is bound. Firstly a conformation change to a higher affinity (but still shut) form, followed by the conformation change from shut to open. [ 5 ] [ 6 ]  It was found that partial agonism results from deficiency in the first step, and that the opening and shutting steps are essentially the same for both full and partial agonists. This has been confirmed and extended by Sine and colleagues (2009). [ 7 ]  The implication of this work [ 6 ]  is that efficacy has to be defined by at least two equilibrium constants (or, more generally, by four rate constants)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10381", "text": "The combined influences of affinity and efficacy determine how effectively a drug will produce a biological effect, a property known as  potency ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10382", "text": "In medicine, efficacy is the capacity for beneficial change (or  therapeutic effect ) of a given intervention (for example a drug,  medical device ,  surgical procedure , or a  public health  intervention). [ 8 ]  Establishment of the efficacy of an intervention is often done relative to other available interventions, with which it will be compared. [ 9 ]  Specifically, efficacy refers to \"whether a drug demonstrates a health benefit over a placebo or other intervention when tested in an ideal situation, such as a tightly controlled clinical trial.\" [ 10 ]  These studies focus on a primary parameter to be shown statistically different between placebo and intervention groups. Comparisons of this type are called 'explanatory'  randomized controlled trials , whereas 'pragmatic' trials are used to establish the  effectiveness  of an intervention regarding also non-specific parameters. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10383", "text": "Effectiveness refers to \"how the drug works in a real-world situation\", [ 11 ]  and is \"often lower than efficacy because of interactions with other medications or health conditions of the patient, sufficient dose or duration of use not prescribed by the physician or followed by the patient, or use for an off-label condition that had not been tested.\" [ 10 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10384", "text": "In agriculture and forestry, efficacy is used to describe whether a  pesticide  is effective in controlling a pest or disease. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10385", "text": "In  Protestant Theology  (esp. in  Lutheran  but also in  Calvinist  doctrine)  efficacy  is an attribute of  Scripture . The efficacy of Scripture means that it is united with the power of the Holy Spirit and with it, not only demands, but also creates the acceptance of its  teaching [ 14 ] [ 15 ] [ 16 ]  and that this teaching produces faith and  obedience . Efficacy further means that Holy Scripture is not a dead letter, but rather, the power of the Holy Spirit is inherent in it [ 17 ] [ 18 ] [ 19 ]  and that Scripture does not compel a mere  intellectual assent  to its doctrine, resting on logical argumentation, but rather it creates the  living agreement of faith . [ 20 ] [ 21 ]  The  Smalcald Articles  affirm, \"in those things which concern the  spoken, outward Word , we must firmly hold that God  grants His Spirit  or grace to no one, except through or with the preceding outward Word.\" [ 22 ]  The  Formula of Concord  teaches that when humans  reject the calling  of the Holy Spirit, it is not a result of the Word being less efficacious. Instead, contempt for the  means of grace  is the result of \"the  perverse will  of man, which rejects or perverts the means and instrument of the Holy Ghost, which God offers him through the  call , and resists the Holy Ghost, who wishes to be efficacious, and works through the  Word ...\" [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10386", "text": "In  pharmacology , an  endogenous agonist  for a particular  receptor  is a compound naturally produced by the body which binds to and  activates  that receptor. For example, the primary endogenous agonist for  serotonin receptors  is  serotonin , and the primary endogenous agonist for  dopamine receptors  is  dopamine . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10387", "text": "In general, receptors for  small molecule   neurotransmitters  such as serotonin will have only one endogenous agonist, but often have many different receptor subtypes (e.g. 13 different  receptors for serotonin ). On the other hand,  neuropeptide  receptors tend to have fewer subtypes, but may have several different endogenous agonists. This allows for a high degree of complexity in the body's signalling system, with different tissues often showing quite distinct responses to a particular  ligand . Some endogenous  antagonists  and  inverse agonists  are also known (e.g.,  kynurenic acid  at the  NMDA receptor ), but these are much less common."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10388", "text": "The  eudysmic ratio  (also spelled  eudismic ratio ) represents the difference in  pharmacologic activity  between the two  enantiomers  of a drug. In most cases where a  chiral compound  is biologically active, one enantiomer is more active than the other. The eudysmic ratio is the ratio of activity between the two. A eudysmic ratio  significantly differing  from 1 means that they are statistically different in activity. Eudisimic ratio (ER) reflects the degree of enantioselectivity of the biological systems. [ 1 ] [ 2 ]  For example,  (S)-propranolol (ER = 130) meaning that (S)-propranolol is 130 times more active than its (R)-enantiomer. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10389", "text": "The  eutomer  is the enantiomer having the desired pharmacological activity, [ 4 ]  e.g.,  as an active ingredient in a drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10390", "text": "The  distomer , on the other hand, is the enantiomer of the eutomer which may have undesired bioactivity or may be bio-inert. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10391", "text": "A  racemic mixture  is an equal mixture of both enantiomers, which may be easier to manufacture than a single enantiomeric form."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10392", "text": "It is often the case that only a single one of the enantiomers contains all of the wanted bioactivity, the distomer is often less active, has no desired activity or may even be toxic. [ 6 ]  In some cases, the eudysmic ratio is so high, that it is desired to separate out the two enantiomers instead of leaving it as a racemic product. It is also possible that the distomer is not simply completely inactive but actually  antagonizes  the effects of the eutomer. There are a few examples of chiral drugs where both the enantiomers contribute, in different ways, to the overall desired effect. An interesting situation is that in which the distomer antagonizes a side-effect of the eutomer for the desired action, mutually beneficial action form therapeutic standpoint.\u00a0 This is convincingly demonstrated by the diuretic  indacrinone . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10393", "text": "The (R)-(+)-isomer, the eutomer, is responsible for the diuretic action and undesired uric acid retention, a side-effect common to many diuretics.\u00a0 The (S)-(-)-isomer, the distomer, acts as a uricosuric agent and thus antagonizes the side-effect caused by the (R)-isomer.\u00a0 A superficial examination of these facts might suggest the marketing of this product as a racemate (1:1 mixture of both enantiomers) to be desirable, since both enantiomers are complementing each other, but for optimal action, the ideal eutomer to distomer ratio for indacrinone has been determined to be 9:1. [ 8 ]   [ 9 ] [ 10 ] [ 11 ]  This is a classical case of a non-racemic drug. Alternatively, it is possible that in the body the distomer converts, at least in part, into the eutomer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10394", "text": "One way the eudysmic ratio is computed is by dividing the  EC 50  or the  IC 50  of the eutomer by the same measurement of the distomer. [ 12 ] [ 13 ]   Whether one chooses to use the  EC 50  or  IC 50  depends on the drug in question."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10395", "text": "Functional selectivity  (or \u201cagonist trafficking\u201d, \u201cbiased agonism\u201d, \u201cbiased signaling\u201d, \"ligand bias\" and \u201cdifferential engagement\u201d) is the  ligand -dependent selectivity for certain  signal transduction  pathways relative to a reference ligand (often the endogenous hormone or peptide) at the same  receptor . [ 1 ]  Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor. [ 2 ]  Functional selectivity, or biased signaling, is most extensively characterized at  G protein coupled receptors  (GPCRs). [ 3 ]  A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics [ 4 ]  or antiproliferative drugs, [ 5 ]  or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with  G protein  biased agonists at the  \u03bc-opioid receptor  show equivalent efficacy for treating pain with reduced risk for addictive potential and  respiratory depression . [ 1 ] [ 6 ]  Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor  CXCR3  induced greater  chemotaxis  of T cells relative to a G protein biased agonist. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10396", "text": "Functional selectivity has been proposed to broaden conventional definitions of  pharmacology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10397", "text": "Traditional pharmacology   posits  that a  ligand  can be either classified as an  agonist  (full or partial),  antagonist  or more recently an  inverse agonist  through a specific receptor subtype, and that this characteristic will be consistent with all  effector  ( second messenger ) systems coupled to that receptor.  While this dogma has been the backbone of ligand-receptor interactions for decades now, more recent data indicates that this classic definition of ligand-protein associations does not hold true for a number of compounds; such compounds may be termed as  mixed agonist-antagonists ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10398", "text": "Functional selectivity  posits that a ligand may inherently produce a mix of the classic characteristics through a single receptor isoform depending on the effector pathway coupled to that receptor. For instance, a ligand can not easily be classified as an agonist or antagonist, because it can be a little of both, depending on its preferred signal transduction pathways. Thus, such ligands must instead be classified on the basis of their individual effects in the cell, instead of being either an agonist or antagonist to a receptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10399", "text": "These observations were made in a number of different  expression systems , and therefore functional selectivity is not just an  epiphenomenon  of one particular expression system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10400", "text": "One notable example of functional selectivity occurs with the  5-HT 2A  receptor , as well as the  5-HT 2C  receptor .  Serotonin , the main endogenous ligand of  5-HT receptors , is a functionally selective agonist at this receptor, activating  phospholipase C  (which leads to  inositol triphosphate  accumulation), but does not activate  phospholipase A2 , which would result in  arachidonic acid  signaling. However, the other endogenous compound  dimethyltryptamine  activates arachidonic acid signaling at the 5-HT 2A  receptor, as do many exogenous hallucinogens such as  DOB  and  lysergic acid diethylamide  (LSD). Notably, LSD does not activate IP 3  signaling through this receptor to any significant extent. (Conversely, LSD, unlike serotonin, has negligible affinity for the 5-HT 2C-VGV  isoform, is unable to promote calcium release, and is, thus, functionally selective at 5-HT 2C . [ 8 ] ) Oligomers, specifically 5-HT 2A \u2013 mGluR2 Tooltip metabotropic glutamate receptor 2   heteromers , mediate this effect. This may explain why some direct 5-HT 2  receptor agonists have  psychedelic  effects, whereas compounds that indirectly increase serotonin signaling at the 5-HT 2  receptors generally do not, for example:  selective serotonin reuptake inhibitors  (SSRIs),  monoamine oxidase inhibitors  (MAOIs), and medications using 5HT 2A  receptor agonists that do not have constitutive activity at the mGluR2  dimer , such as  lisuride . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10401", "text": "Tianeptine , an  atypical antidepressant , is thought to exhibit functional selectivity at the  \u03bc-opioid receptor  to mediate its antidepressant effects. [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10402", "text": "Oliceridine  is a \u03bc-opioid receptor agonist that has been described to be functionally selective towards G protein and away from \u03b2-arrestin2 pathways. [ 12 ]  However, recent reports highlight that, rather than functional selectivity or 'G protein bias', this agonist has low intrinsic efficacy. [ 13 ]   In vivo , it has been reported to mediate pain relief without tolerance nor gastrointestinal side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10403", "text": "The  delta opioid receptor  agonists  SNC80  and  ARM390  demonstrate functional selectivity that is thought to be due to their differing capacity to cause  receptor internalization . [ 14 ]  While SNC80 causes delta opioid receptors to internalize, ARM390 causes very little receptor internalization. [ 14 ]  Functionally, that means that the effects of SNC80 (e.g.  analgesia ) do not occur when a subsequent dose follows the first, whereas the effects of ARM390 persist. [ 14 ]  However, tolerance to ARM390's analgesia still occurs eventually after multiple doses, though through a mechanism that does not involve receptor internalization. [ 14 ]  Interestingly, the other effects of ARM390 (e.g. decreased anxiety) persist after tolerance to its analgesic effects has occurred. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10404", "text": "An example of functional selectivity to bias metabolism was demonstrated for an electron transfer protein  cytochrome P450 reductase  (POR) with binding of small molecule ligands shown to alter the protein conformation and interaction with various redox partner proteins of POR. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10405", "text": "Half maximal inhibitory concentration  ( IC 50 ) is a measure of the  potency  of a substance in inhibiting a specific biological or biochemical function. IC 50  is a quantitative measure that indicates how much of a particular  inhibitory  substance (e.g. drug) is needed to inhibit,  in vitro , a given biological process or biological component by 50%. [ 1 ]  The biological component could be an  enzyme ,  cell ,  cell receptor  or  microbe . IC 50  values are typically expressed as  molar concentration ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10406", "text": "IC 50  is commonly used as a measure of  antagonist drug   potency  in  pharmacological  research. IC 50  is comparable to other measures of potency, such as  EC 50  for  excitatory drugs . EC 50  represents the dose or plasma concentration required for obtaining 50% of a maximum effect  in vivo . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10407", "text": "IC 50  can be determined with functional assays or with competition binding assays."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10408", "text": "Sometimes, IC 50  values are converted to the  pIC 50  scale."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10409", "text": "Due to the minus sign, higher values of pIC 50  indicate exponentially more potent inhibitors. pIC 50  is usually given in terms of  molar concentration  (mol/L, or M), thus requiring IC 50  in units of M. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10410", "text": "The IC 50  terminology is also used for some behavioral measures in vivo, such as the  two bottle fluid consumption test . When animals decrease consumption from the drug-laced water bottle, the concentration of the drug that results in a 50% decrease in consumption is considered the IC 50  for fluid consumption of that drug. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10411", "text": "The IC 50  of a drug can be determined by constructing a  dose-response curve  and examining the effect of different concentrations of antagonist on reversing agonist activity. IC 50  values can be calculated for a given antagonist by determining the concentration needed to inhibit half of the maximum biological response of the agonist. [ 4 ]  IC 50  values can be used to compare the potency of two antagonists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10412", "text": "IC 50  values are very dependent on conditions under which they are measured. In general,  a higher concentration of inhibitor leads to lowered agonist activity.  IC 50  value increases as agonist concentration increases. Furthermore, depending on the type of inhibition, other factors may influence IC 50  value; for  ATP  dependent enzymes, IC 50  value has an interdependency with concentration of ATP, especially if inhibition is  competitive . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10413", "text": "In this type of assay, a single concentration of radioligand (usually an agonist) is used in every assay tube. The ligand is used at a low concentration, usually at or below its  K d  value. The level of specific binding of the radioligand is then determined in the presence of a range of concentrations of other competing non-radioactive compounds (usually antagonists), in order to measure the potency with which they compete for the binding of the radioligand. Competition curves may also be computer-fitted to a logistic function as described under direct fit."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10414", "text": "In this situation the IC 50  is the concentration of competing ligand which displaces 50% of the specific binding of the radioligand. The IC 50  value is converted to an absolute  inhibition constant  K i  using the  Cheng-Prusoff equation  formulated by   Yung-Chi Cheng  and  William Prusoff  (see K i ). [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10415", "text": "IC 50  is not a direct indicator of  affinity , although the two can be related at least for competitive agonists and antagonists by the Cheng-Prusoff equation. [ 6 ]  For enzymatic reactions, this equation is:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10416", "text": "where K i  is the binding affinity of the inhibitor, IC 50  is the functional strength of the inhibitor, [S] is fixed substrate concentration and K m  is the  Michaelis constant  i.e. concentration of substrate at which enzyme activity is at half maximal (but is frequently confused with substrate affinity for the enzyme, which it is not)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10417", "text": "Alternatively, for inhibition constants at cellular receptors: [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10418", "text": "where [A] is the fixed concentration of agonist and EC 50  is the concentration of agonist that results in half maximal activation of the receptor. Whereas the IC 50  value for a compound may vary between experiments depending on experimental conditions, (e.g. substrate and enzyme concentrations) the K i  is an absolute value. K i  is the inhibition constant for a drug; the concentration of competing ligand in a competition assay which would occupy 50% of the receptors if no ligand were present. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10419", "text": "The Cheng-Prusoff equation produces good estimates at high agonist concentrations, but over- or under-estimates K i  at low agonist concentrations. In these conditions, other analyses have been recommended. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10420", "text": "In  pharmacology , an  indirect agonist  or  indirect-acting agonist  is a substance that enhances the release or action of an  endogenous   neurotransmitter  but has no specific  agonist  activity at the neurotransmitter  receptor  itself. Indirect agonists work through varying mechanisms to achieve their effects, including transporter blockade, induction of transmitter release, and inhibition of transmitter breakdown."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10421", "text": "Cocaine  is a  monoamine transporter  blocker and, thus, an indirect agonist of  dopamine receptors . [ 1 ]   Cocaine  binds the  dopamine transporter  (DAT), blocking the protein's ability to uptake  dopamine  from the  synaptic cleft  and also blocking DAT from terminating  dopamine  signaling. Blockage of DAT increases the  extracellular  concentration of  dopamine , therefore increasing the amount of  dopamine  receptor binding and signaling."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10422", "text": "Dipyridamole  inhibits reuptake of  adenosine , resulting in greater extracellular concentrations of  adenosine .  Dipyridamole  also inhibits the  enzyme   adenosine deaminase , the  enzyme  that catalyzes the breakdown of  adenosine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10423", "text": "Fenfluramine  is an indirect agonist of  serotonin receptors . [ 2 ]   Fenfluramine  binds to the  serotonin transporter , blocking  serotonin  reuptake. However,  fenfluramine  also acts to induce non- exocytotic   serotonin  release; in a mechanism similar to that of  methamphetamine  in  dopamine  neurons,  fenfluramine  binds to  VMAT2 , disrupting the compartmentalization of  serotonin  into  vesicles  and increasing the concentration of  cytoplasmic   serotonin  available for drug-induced release. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10424", "text": "Intrinsic activity  ( IA ) and  efficacy  ( E max ) refer to the relative ability of a  drug - receptor  complex to produce a maximum functional response. This must be distinguished from the  affinity , which is a measure of the ability of the drug to bind to its molecular target, and the  EC 50 , which is a measure of the  potency  of the drug and which is proportional to both efficacy and affinity. This use of the word \"efficacy\" was introduced by Stephenson (1956) [ 1 ]  to describe the way in which  agonists  vary in the response they produce, even when they occupy the same number of receptors. High efficacy agonists can produce the maximal response of the receptor system while occupying a relatively low proportion of the receptors in that system. There is a distinction between efficacy and intrinsic activity. [ clarification needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10425", "text": "Agonists of lower efficacy are not as efficient at producing a response from the drug-bound receptor, by stabilizing the active form of the drug-bound receptor. Therefore, they may not be able to produce the same maximal response, even when they occupy the entire receptor population, as the efficiency of transformation of the inactive form of the drug-receptor complex to the active drug-receptor complex may not be high enough to evoke a maximal response. Since the observed response may be less than maximal in systems with no spare receptor reserve, some low efficacy agonists are referred to as partial agonists. [ 2 ]  However, it is worth bearing in mind that these terms are relative - even partial agonists may appear as full agonists in a different system/experimental setup, as when the number of receptors increases, there may be enough drug-receptor complexes for a maximum response to be produced, even with individually low efficacy of transducing the response. There are actually relatively few  true  full agonists or silent antagonists; many compounds usually considered to be full agonists (such as  DOI ) are more accurately described as high efficacy partial agonists, as a partial agonist with efficacy over \u224880-90% is indistinguishable from a full agonist in most assays. Similarly many antagonists (such as  naloxone ) are in fact partial agonists or inverse agonists, but with very low efficacy (less than 10%). Compounds considered partial agonists tend to have efficacy in between this range. Another case is represented by silent agonists, [ 3 ]  which are ligands that can place a receptor, typically an ion channel, into a desensitized state with little or no apparent activation of it, forming a complex that can subsequently generate currents when treated with an allosteric modulator. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10426", "text": "Intrinsic activity of a test agonist is defined as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10427", "text": "R. P. Stephenson (1925\u20132004) was a British pharmacologist. [ 6 ]  Efficacy has historically been treated as a proportionality constant between the binding of the drug and the generation of the biological response. [ 7 ]  Stephenson defined efficacy as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10428", "text": "where  \n \n \n \n p \n \n \n {\\displaystyle p} \n \n  is the proportion of agonist-bound receptors (given by the  Hill equation ) and  \n \n \n \n S \n \n \n {\\displaystyle S} \n \n  is the stimulus to the biological system. [ 8 ]  The response is generated by an unknown function  \n \n \n \n f \n ( \n S \n ) \n \n \n {\\displaystyle f(S)} \n \n , which is assumed to be  hyperbolic . [ 8 ]  This model was arguably flawed in that it did not incorporate the equilibrium between the  inactivated  agonist-bound-receptor and the  activated  agonist-bound-receptor that is shown in the del Castillo Katz model."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10429", "text": "Robert F. Furchgott  later improved on Stephenson's model with the definition of efficacy, e, as"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10430", "text": "where  \n \n \n \n \u03b5 \n \n \n {\\displaystyle \\varepsilon } \n \n  is the  intrinsic efficacy  and  \n \n \n \n [ \n \n R \n \n \n ] \n \n \n T \n o \n t \n \n \n \n \n \n {\\displaystyle [{\\ce {R}}]_{\\mathrm {Tot} }} \n \n  is the total concentration of receptors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10431", "text": "Stevenson and Furchgott's models of efficacy have been criticised and many more have been developed. The models of efficacy are shown in Bindslev (2008). [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10432", "text": "In  pharmacology , an  inverse agonist  is a  drug  that binds to the same  receptor  as an  agonist  but induces a pharmacological response opposite to that of the agonist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10433", "text": "A  neutral antagonist  has no activity in the absence of an agonist or inverse agonist but can block the activity of either; [ 1 ]  they are in fact sometimes called  blockers  (examples include  alpha blockers ,  beta blockers , and  calcium channel blockers ). Inverse agonists have opposite actions to those of agonists but the effects of both of these can be blocked by antagonists. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10434", "text": "A prerequisite for an inverse agonist response is that the receptor must have a  constitutive  (also known as  intrinsic  or basal) level of activity in the absence of any  ligand . [ 3 ]  An agonist increases the activity of a receptor above its basal level, whereas an inverse agonist decreases the activity below the basal level."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10435", "text": "The  efficacy  of a full agonist is by definition 100%, a neutral antagonist has 0% efficacy, and an inverse agonist has < 0% (i.e., negative) efficacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10436", "text": "Receptors for which inverse agonists have been identified include the  GABA A ,  melanocortin ,  mu opioid ,  histamine  and  beta adrenergic receptors . Both  endogenous  and  exogenous  inverse agonists have been identified, as have drugs at ligand gated ion channels and at G protein-coupled receptors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10437", "text": "An example of a receptor site that possesses basal activity and for which inverse agonists have been identified is the  GABA A  receptors . Agonists for GABA A  receptors (such as  muscimol ) create a  relaxant  effect, whereas inverse agonists have  agitation  effects (for example,  Ro15-4513 ) or even  convulsive  and  anxiogenic  effects (certain  beta-carbolines ). [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10438", "text": "Two known endogenous inverse agonists are the  Agouti-related peptide  (AgRP) and its associated peptide  Agouti signalling peptide  (ASIP). AgRP and ASIP appear naturally in humans and bind  melanocortin receptors  4 and 1 ( Mc4R  and  Mc1R ), respectively, with nanomolar affinities. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10439", "text": "The  opioid antagonists   naloxone  and  naltrexone  act as  neutral antagonists  of the  mu opioid receptors  under basal conditions, but as inverse agonists when an opioid such as  morphine  is bound to the same channel. 6\u03b1-naltrexo,  6\u03b2-naltrexol , 6\u03b2-naloxol, and 6\u03b2-naltrexamine acted  neutral antagonists  regardless of opioid binding and caused significantly reduced withdrawal jumping when compared to  naloxone  and  naltrexone . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10440", "text": "Nearly all antihistamines acting at  H1 receptors  and  H2 receptors  have been shown to be inverse agonists. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10441", "text": "The  beta blockers   carvedilol  and  bucindolol  have been shown to be low level inverse agonists at  beta adrenoceptors . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10442", "text": "Like  agonists , inverse agonists have their own unique ways of inducing pharmacological and physiological responses depending on many factors, such as the type of inverse agonist, the type of  receptor , mutants of receptors, binding affinities and whether the effects are exerted acutely or chronically based on receptor population density. [ 9 ]  Because of this, they exhibit a spectrum of activity below the  Intrinsic activity  level. [ 9 ] [ 10 ]  Changes in constitutive activity of receptors affect response levels from ligands like inverse agonists. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10443", "text": "To illustrate, mechanistic models have been made for how inverse agonists induce their responses on  G protein-coupled receptors  (GPCRs). Many types of Inverse agonists for  GPCRs  have been shown to exhibit the following conventionally accepted mechanism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10444", "text": "Based on the Extended  Ternary complex  model, the mechanism contends that inverse agonists switch the receptor from an active state to an inactive state by undergoing conformational changes. [ 12 ]  Under this model, current thinking is that the  GPCRs  can exist in a continuum of active and inactive states when no ligand is present. [ 12 ]  Inverse agonists stabilize the inactive states, thereby suppressing agonist-independent activity. [ 12 ]  However, the implementation of 'constitutively active mutants' [ 12 ]  of  GPCRs  change their intrinsic activity. [ 9 ] [ 10 ]  Thus, the effect an inverse agonist has on a receptor depends on the basal activity of the receptor, assuming the inverse agonist has the same binding affinity (as shown in the figure 2)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10445", "text": "In  pharmacology , the term  mechanism of action  ( MOA ) refers to the specific biochemical  interaction  through which a  drug  substance produces its  pharmacological effect . [ 2 ]   A mechanism of action usually includes mention of the specific molecular targets to which the drug binds, such as an  enzyme  or  receptor . [ 3 ]  Receptor sites have specific affinities for drugs based on the chemical structure of the drug, as well as the specific action that occurs there."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10446", "text": "Drugs that do not bind to receptors produce their corresponding therapeutic effect by simply interacting with chemical or physical properties in the body. Common examples of drugs that work in this way are  antacids  and  laxatives . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10447", "text": "In contrast, a  mode of action (MoA)  describes functional or anatomical changes, at the cellular level, resulting from the exposure of a living organism to a substance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10448", "text": "Elucidating the mechanism of action of novel drugs and medications is important for several reasons:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10449", "text": "Bioactive compounds induce  phenotypic  changes in target cells, changes that are observable by  microscopy  and that can give insight into the mechanism of action of the compound. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10450", "text": "With  antibacterial agents , the conversion of target cells to  spheroplasts  can be an indication that  peptidoglycan  synthesis is being inhibited, and  filamentation  of target cells can be an indication that  PBP 3,  FtsZ , or  DNA synthesis  is being inhibited. Other antibacterial agent-induced changes include ovoid cell formation, pseudomulticellular forms, localized swelling, bulge formation, blebbing, and peptidoglycan thickening. [ 4 ]   In the case of  anticancer agents ,  bleb  formation can be an indication that the compound is disrupting the  plasma membrane . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10451", "text": "A current limitation of this approach is the time required to manually generate and interpret data, but advances in automated microscopy and  image analysis  software may help resolve this. [ 4 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10452", "text": "Direct biochemical methods include methods in which a protein or a small molecule, such as a drug candidate, is labeled and is traced throughout the body. [ 15 ]  This proves to be the most direct approach to find target protein that will bind to small targets of interest, such as a basic representation of a drug outline, in order to identify the  pharmacophore  of the drug. Due to the physical interactions between the labeled molecule and a protein, biochemical methods can be used to determine the toxicity, efficacy, and mechanism of action of the drug. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10453", "text": "Typically, computation inference methods are primarily used to predict protein targets for small molecule drugs based on computer based pattern recognition. [ 15 ]  However, this method could also be used for finding new targets for existing or newly developed drugs. By identifying the  pharmacophore  of the drug molecule, the profiling method of pattern recognition can be carried out where a new target is identified. [ 15 ]  This provides an insight at a possible mechanism of action since it is known what certain functional components of the drug are responsible for when interacting with a certain area on a protein, thus leading to a therapeutic effect. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10454", "text": "Omics based methods use omics technologies, such as  chemoproteomics ,  reverse genetics  and  genomics ,  transcriptomics , and  proteomics , to identify the potential targets of the compound of interest. [ 16 ]  Reverse genetics and genomics approaches, for instance, uses genetic perturbation (e.g.  CRISPR - Cas9  or  siRNA ) in combination with the compound to identify genes whose knockdown or  knockout  abolishes the pharmacological effect of the compound. On the other hand, transcriptomics and proteomics profiles of the compound can be used to compare with profiles of compounds with known targets. Thanks to computation inference, it is then possible to make hypotheses about the mechanism of action of the compound, which can subsequently be tested. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10455", "text": "There are many drugs in which the mechanism of action is known. One example is aspirin. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10456", "text": "The  mechanism of action of aspirin  involves irreversible inhibition of the enzyme  cyclooxygenase ; [ 17 ]  therefore suppressing the production of  prostaglandins  and  thromboxanes , thus reducing pain and inflammation. This mechanism of action is specific to aspirin and is not constant for all  nonsteroidal anti-inflammatory drugs  (NSAIDs). Rather, aspirin is the only NSAID that irreversibly inhibits COX-1. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10457", "text": "Some drug mechanisms of action are still unknown.  However, even though the mechanism of action of a certain drug is unknown, the drug still functions; it is just unknown or unclear how the drug interacts with receptors and produces its therapeutic effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10458", "text": "In some literature articles, the terms \"mechanism of action\" and \" mode of action \" are used interchangeably, typically referring to the way in which the drug interacts and produces a medical effect. However, in actuality, a mode of action describes functional or anatomical changes, at the cellular level, resulting from the exposure of a living organism to a substance. [ 19 ]  This differs from a mechanism of action since it is a more specific term that focuses on the interaction between the drug itself and an  enzyme  or  receptor  and its particular form of interaction, whether through  inhibition ,  activation ,  agonism , or  antagonism . Furthermore, the term \"mechanism of action\" is the main term that is primarily used in pharmacology, whereas \"mode of action\" will more often appear in the field of microbiology or certain aspects of biology. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10459", "text": "In statistics, in particular in the  design of experiments , a  multi-valued treatment  is a treatment that can take on more than two values. It is related to the  dose-response model  in the medical literature."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10460", "text": "Generally speaking, treatment levels may be finite or infinite as well as ordinal or cardinal, which leads to a large collection of possible treatment effects to be studied in applications. [ 1 ]  One example is the effect of different levels of program participation (e.g. full-time and part-time) in a job training program. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10461", "text": "Assume there exists a finite collection of multi-valued treatment status  \n \n \n \n T \n = \n { \n 0 \n , \n 1 \n , \n 2 \n , \n \u2026 \n , \n J \n , \n } \n \n \n {\\displaystyle T=\\{0,1,2,\\ldots ,J,\\}} \n \n  with J some fixed integer. As in the potential outcomes framework, denote   \n \n \n \n Y \n ( \n j \n ) \n \u2282 \n R \n \n \n {\\displaystyle Y(j)\\subset R} \n \n  the collection of potential outcomes under the treatment  J , and  \n \n \n \n Y \n = \n \n \n \u2211 \n \n j \n = \n 0 \n \n \n J \n \n \n \n \n D \n \n j \n \n \n Y \n ( \n j \n ) \n \n \n \n \n {\\displaystyle Y=\\textstyle \\sum _{j=0}^{J}\\displaystyle D_{j}Y(j)} \n \n  denotes the observed outcome and  \n \n \n \n \n D \n \n j \n \n \n \n \n {\\displaystyle D_{j}} \n \n  is an indicator that equals  1  when the treatment equals  j  and  0  when it does not equal  j , leading to a fundamental problem of  causal inference . [ 3 ]   A general framework that analyzes ordered choice models in terms of marginal treatment effects and average treatment effects has been extensively discussed by Heckman and Vytlacil. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10462", "text": "Recent work in the econometrics and statistics literature has focused on estimation and inference for multivalued treatments and ignorability conditions for identifying the treatment effects. In the context of program evaluation, the propensity score has been generalized to allow for multi-valued treatments, [ 5 ]  while other work has also focused on the role of the conditional mean independence assumption. [ 6 ]   Other recent work has focused more on the large sample properties of an estimator of the marginal mean treatment effect conditional on a treatment level in the context of a difference-in-differences model, [ 7 ]  and on the efficient estimation of multi-valued treatment effects in a semiparametric framework. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10463", "text": "Non-competitive inhibition  is a type of  enzyme inhibition  where the inhibitor reduces the activity of the enzyme and binds equally well to the enzyme whether or not it has already bound the substrate. [ 1 ]  This is unlike  competitive inhibition , where binding affinity for the substrate in the enzyme is decreased in the presence of an inhibitor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10464", "text": "The inhibitor may bind to the enzyme whether or not the substrate has already been bound, but if it has a higher affinity for binding the enzyme in one state or the other, it is called a  mixed inhibitor . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10465", "text": "During his years working as a physician  Leonor Michaelis   and a friend Peter Rona built a compact lab, in the hospital, and over the course of five years \u2013 Michaelis successfully became published over 100 times. During his research in the hospital, he was the first to view the different types of inhibition; specifically using fructose and glucose as inhibitors of  maltase  activity. Maltase breaks maltose into two units of  glucose . Findings from that experiment allowed for the divergence of non-competitive and  competitive inhibition . Non-competitive inhibition affects the  k cat  value (but not the K m ) on any given graph; this inhibitor binds to a site that has specificity for the certain molecule. Michaelis determined that when the inhibitor is bound, the enzyme would become inactivated. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10466", "text": "Like many other scientists of their time, Leonor Michaelis and  Maud Menten  worked on a reaction that was used to change the composition of  sucrose  and make it  lyse  into two products \u2013 fructose and glucose. [ 2 ]  The enzyme involved in this reaction is called  invertase , and it is the enzyme the kinetics of which have been supported by Michaelis and Menten to be revolutionary for the kinetics of other enzymes. While expressing the rate of the reaction studied, they derived an equation that described the rate in a way which suggested that it is mostly dependent on the enzyme concentration, as well as on presence of the substrate, but only to a certain extent. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10467", "text": "Adrian John Brown  and  Victor Henri  laid the groundwork for the discoveries in enzyme kinetics that Michaelis and Menten are known for. [ 4 ]  Brown theoretically envisioned the mechanism now accepted for enzyme kinetics, but did not have the quantitative data to make a claim. [ 4 ]  Victor Henri made significant contributions to enzyme kinetics during his doctoral thesis, however he lacked noting the importance of hydrogen ion concentration and mutarotation of glucose. The goal of Henri's thesis was to compare his knowledge of enzyme-catalysed reactions to the recognized laws of physical chemistry. [ 2 ]  Henri is credited with being the first to write the equation that is now known as the Michaelis-Menten equation. Using glucose and fructose in the catalytic reactions controlled by maltase and invertase, Leonor Michaelis was the first scientist to distinguish the different types of inhibition by using the pH scale which did not exist in Henri's time. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10468", "text": "Particularly during their work on describing the rate of this reaction they also tested and extrapolated on the idea of another scientist,  Victor Henri , that enzyme they were using had some affinity for both products of this reaction \u2013 fructose and glucose. [ 2 ] [ 3 ]  Using Henri's methods, Michaelis and Menten nearly perfected this concept of initial-rate method for steady-state experiments. They were studying inhibition when they found that non-competitive (mixed) inhibition is characterized by its effect on  k cat  (catalyst rate) while competitive is characterized by its effect on velocity (V). [ 2 ]  In the Michaelis and Menten experiments they heavily focused on pH effects of invertase using hydrogen ions. [ 2 ]  Invertase is an enzyme found in extracellular yeast and catalyzed reactions by hydrolysis or inverting a sucrose (mixture of sucrose and fructose) to \u201c invert sugar .\u201d The main reason for using invertase was that it could be easily assayed and experiments could be done in quicker manner.  Sucrose rotates in  polarimeter  as  dextroratatory-D  whereas invert sugar is  levorotatory-L . This made tracking the inversion of sugar relatively simple. They also found that  \u03b1-D-glucose  is released in reactions catalyzed by invertase which is very unstable and spontaneously changes to  \u03b2-D-glucose . [ 4 ]  Although, these are both in the dextrorotatory form, this is where they noted that glucose can change spontaneously, also known as mutarotation. Failing to take this into consideration was one of the main reasons Henri's experiments fell short. Using invertase to catalyze sucrose inversion, they could see how fast the enzyme was reacting by polarimetry; therefore, non-competitive inhibition was found to occur in the reaction where sucrose was inverted with invertase. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10469", "text": "It is important to note that while all non-competitive inhibitors bind the enzyme at allosteric sites (i.e. locations other than its  active site )\u2014not all inhibitors that bind at allosteric sites are non-competitive inhibitors. [ 1 ]   In fact, allosteric inhibitors may act as  competitive , non-competitive, or  uncompetitive  inhibitors. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10470", "text": "Many sources continue to conflate these two terms, [ 5 ]  or state the definition of allosteric inhibition as the definition for non-competitive inhibition."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10471", "text": "Non-competitive inhibition models a system where the inhibitor and the substrate may both be bound to the enzyme at any given time. When both the substrate and the inhibitor are bound, the enzyme-substrate-inhibitor complex cannot form product and can only be converted back to the enzyme-substrate complex or the enzyme-inhibitor complex. Non-competitive inhibition is distinguished from general mixed inhibition in that the inhibitor has an equal affinity for the enzyme and the enzyme-substrate complex."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10472", "text": "For example, in the enzyme-catalyzed reactions of  glycolysis , accumulation phosphoenol is catalyzed by  pyruvate kinase  into  pyruvate .  Alanine  is an amino acid which is synthesized from pyruvate also inhibits the enzyme pyruvate kinase during glycolysis. Alanine is a non-competitive inhibitor, therefore it binds away from the active site to the substrate in order for it to still be the final product. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10473", "text": "Another example of non-competitive inhibition is given by  glucose-6-phosphate  inhibiting hexokinase in the brain. Carbons 2 and 4 on glucose-6-phosphate contain hydroxyl groups that attach along with the phosphate at carbon 6 to the enzyme-inhibitor complex. The substrate and enzyme are different in their group combinations that an inhibitor attaches to. The ability of glucose-6-phosphate to bind at different places at the same time makes it a non-competitive inhibitor. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10474", "text": "The most common mechanism of non-competitive inhibition involves reversible binding of the inhibitor to an  allosteric site , but it is possible for the inhibitor to operate via other means including direct binding to the active site. It differs from competitive inhibition in that the binding of the inhibitor does not prevent binding of substrate, and vice versa, but simply prevents product formation for a limited time."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10475", "text": "This type of inhibition reduces the  maximum rate  of a  chemical reaction  without changing the apparent binding  affinity  of the  catalyst  for the  substrate  (K m app  \u2013 see  Michaelis-Menten kinetics ). When a non-competitive inhibitor is added the Vmax is changed, while the Km remains unchanged. According to the  Lineweaver-Burk plot  the Vmax is reduced during the addition of a non-competitive inhibitor, which is shown in the plot by a change in both the slope and y-intercept when a non-competitive inhibitor is added. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10476", "text": "The primary difference between competitive and non-competitive is that competitive inhibition affects the substrate's ability to bind by binding an inhibitor in place of a substrate, which lowers the affinity of the enzyme for the substrate. In non-competitive inhibition, the inhibitor binds to an allosteric site and prevents the enzyme-substrate complex from performing a chemical reaction. This does not affect the Km (affinity) of the enzyme (for the substrate). Non-competitive inhibition differs from uncompetitive inhibition in that it still allows the substrate to bind to the enzyme-inhibitor complex and form an enzyme-substrate-inhibitor complex, this is not true in uncompetitive inhibition, it prevents the substrate from binding to the enzyme inhibitor through conformational change upon allosteric binding."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10477", "text": "In the presence of a non-competitive inhibitor, the apparent enzyme affinity is equivalent to the actual affinity. In terms of  Michaelis-Menten kinetics ,  K m app  = K m . This can be seen as a consequence of  Le Chatelier's principle  because the inhibitor binds to both the enzyme and the enzyme-substrate complex equally so that the equilibrium is maintained. However, since some enzyme is always inhibited from converting the substrate to product, the effective enzyme concentration is lowered."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10478", "text": "Mathematically,"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10479", "text": "Noncompetitive inhibitors of  CYP2C9   enzyme  include  nifedipine ,  tranylcypromine ,  phenethyl isothiocyanate , and 6-hydroxyflavone. Computer docking simulation and constructed mutants substituted indicate that the noncompetitive binding site of 6-hydroxyflavone is the reported allosteric binding site of  CYP2C9   enzyme . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10480", "text": "Off-target activity  is  biological activity  of a  drug  that is different from and not at that of its intended  biological target . It most commonly contributes to  side effects . However, in some cases, off-target activity can be taken advantage of for therapeutic purposes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10481", "text": "An example of this is the repurposing of the  antimineralocorticoid  and  diuretic   spironolactone , which was found to produce  feminization  and  gynecomastia  as side effects, for use as an  antiandrogen  in the treatment of  androgen-dependent conditions  like  acne  and  hirsutism  in women. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10482", "text": "Metformin  also causes off-target activity. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10483", "text": "An  organ chamber ,  organ bath , or  isolated tissue bath , is a chamber in which isolated organs or tissues can be administered with  drugs , or stimulated electrically, in order to measure their function. The tissue in the organ bath is typically oxygenated with  carbogen  and kept in a solution such as  Tyrode's solution  or  lactated Ringer's solution . [ citation needed ]  Historically, they have also been called  gut baths . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10484", "text": "It is used in  pharmacology  research, particularly when studying the contraction of  smooth muscle  in tissues such as  ileum , [ 2 ]   colon , [ 3 ]   vas deferens , [ 4 ]   trachea , [ 5 ]   bladder , [ 6 ]   corpus cavernosum , [ 7 ]  and blood vessels such as  aortic  rings. The contraction of smooth muscle tissues can be readily measured with a  myograph ; this type of physiological response is more readily quantifiable than that of other tissues. Organ baths were originally developed to study the effects of  agonists  and  antagonists  on excitable tissues, such as  nervous tissue  and  muscle  though they have been adapted to study tissues such as  epithelium . [ 8 ]  Typical tissues and receptors studied with organ bath preparations include  nicotinic ,  muscarinic , and  histamine receptors  in the  ileum  or  beta adrenoceptors  in the  bladder . [ 8 ]  Tissues are typically taken from  rodents , such as  guinea pigs ,  mice , and  rats ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10485", "text": "For studying the effects of  drugs  on receptors in  drug discovery  and  combinatorial chemistry , novel techniques such as  high throughput screening , ultrahigh throughput screening and high content screening,  pharmacogenomics ,\n proteomics , and array technology have largely superseded the use of organ baths. [ 9 ]  These techniques can allow more receptor specificity than organ bath preparations, as a single tissue sample can express many different receptor types. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10486", "text": "The use of organ bath preparations for the measurement of physiological tissue responses to drug concentrations allows the generation of  dose response curves . This in turn allows the quantification of a drug's pharmacological profile in the tissue in question, such as the calculation of the drug's  EC50 ,  IC50 , and  Hill coefficient . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10487", "text": "Examples of important contributions made using this technique include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10488", "text": "Physiological agonism  describes the action of a substance which ultimately produces the same effects in the body as another substance\u2014as if they were both  agonists  at the same  receptor \u2014without actually binding to the same receptor.  Physiological antagonism  describes the behavior of a substance that produces effects counteracting those of another substance (a result similar to that produced by an  antagonist  blocking the action of an agonist at the same receptor) using a mechanism that does not involve binding to the same receptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10489", "text": "Porous silicon  (abbreviated as \"PS\" or \"pSi\") is a form of the chemical element  silicon  that has introduced  nanopores  in its  microstructure , rendering a large surface to volume ratio in the order of 500 m 2 /cm 3 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10490", "text": "Porous silicon was discovered by accident in 1956 by Arthur Uhlir Jr. and Ingeborg Uhlir at the  Bell Labs  in the U.S. At the time, the Uhlirs were in the process of developing a technique for polishing and shaping the surfaces of silicon and  germanium . However, it was found that under several conditions a crude product in the form of thick black, red or brown film were formed on the surface of the material. At the time, the findings were not taken further and were only mentioned in Bell Lab's technical notes. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10491", "text": "Despite the discovery of porous silicon in the 1950s, the scientific community was not interested in porous silicon until the late 1980s. At the time,  Leigh Canham  \u2013 while working at the  Defence Research Agency  in England \u2013 reasoned that the porous silicon may display quantum confinement effects. [ 2 ]  The intuition was followed by successful experimental results published in 1990. In the published experiment, it was revealed that silicon wafers can emit light if subjected to  electrochemical  and  chemical  dissolution."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10492", "text": "The published result stimulated the interest of the scientific community in its  non-linear optical  and  electrical  properties. The growing interest was evidenced in the number of published work concerning the properties and potential applications of porous silicon. In an article published in 2000, it was found that the number of published work grew exponentially in between 1991 and 1995. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10493", "text": "In 2001, a team of scientists at the  Technical University of Munich  inadvertently discovered that  hydrogenated  porous silicon reacts explosively with  oxygen  at  cryogenic  temperatures, releasing several times as much energy as an equivalent amount of  TNT , at a much greater speed. (An abstract of the study can be found below.) Explosion occurs because the oxygen, which is in a liquid state at the necessary temperatures, is able to  oxidize  through the porous molecular structure of the silicon extremely rapidly, causing a very quick and efficient  detonation . Although hydrogenated porous silicon would probably not be effective as a weapon, due to its functioning only at low temperatures, other uses are being explored for its explosive properties, such as providing thrust for  satellites ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10494", "text": "Anodization  and  stain-etching  are the two most common methods used for fabrication of porous silicon; however, there are almost twenty other methods to fabricate this material. [ citation needed ]   Drying and surface modification might be needed afterwards.  If anodization in an aqueous solution is used to form microporous silicon, the material is commonly treated in ethanol immediately after fabrication, to avoid damage to the structure that results due to the stresses of the capillary effect of the aqueous solution. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10495", "text": "One method of introducing pores in silicon is through the use of an anodization cell. A possible anodization cell is made of Teflon and employs a platinum cathode and a crystalline Si wafer anode immersed in  hydrogen fluoride  (HF) electrolyte. Recently, inert diamond cathodes were used to avoid metallic impurities in the electrolyte and inert diamond anodes form an improved electrical back plate contact to the silicon wafers.  Corrosion  of the  anode  is produced by running electric current through the cell. It is noted that etching with constant  DC  is usually implemented to ensure steady tip-concentration of HF resulting in a more  homogeneous  porous layer, while pulsed current is more appropriate for the formation of thick PS layers with thickness greater than 50\u00a0\u03bcm. [ 5 ]  Pore direction is governed by crystal orientation. In (100)-cut Si the pores are oriented perpendicular to the wafer's surface."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10496", "text": "It was noted by Halimaoui that  hydrogen  evolution occurs during the formation of porous silicon."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10497", "text": "When purely aqueous HF solutions are used for the PS formation, the hydrogen bubbles stick to the surface and induce lateral and in-depth inhomogeneity"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10498", "text": "The hydrogen evolution is normally treated with absolute  ethanol  in concentration exceeding 15%. It was found that the introduction of ethanol eliminates hydrogen and ensures complete infiltration of HF solution within the pores. Subsequently, uniform distribution of porosity and thickness is improved."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10499", "text": "It is possible to obtain porous silicon through stain-etching with  hydrofluoric acid ,  nitric acid  and  water . A publication in 1957 revealed that stain films can be grown in dilute solutions of nitric acid in concentrated hydrofluoric acid. Porous silicon formation by stain-etching is particularly attractive because of its simplicity and the presence of readily available corrosive reagents; namely nitric acid (HNO 3 ) and hydrogen fluoride (HF). Furthermore, stain-etching is useful if one needs to produce a very thin porous Si films. [ 6 ]  A publication in 1960 by R. J. Archer revealed that it is possible to create stain films as thin as 25\u00a0\u00c5 through stain-etching with HF-HNO 3  solution. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10500", "text": "Porous silicon can be synthesized chemically from  silicon tetrachloride , using self-forming salt byproducts as templates for pore formation. The salt templates are later removed with water. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10501", "text": "Porous silicon is systematically prone to presence of cracks when the water is evaporated. The cracks are particularly evident in thick or highly porous silicon layers. [ 9 ]  The origin of the cracks has been attributed to the large  capillary  stress due to the minute size of the pores. In particular, it has been known that cracks will appear for porous silicon samples with thickness larger than a certain critical value. Bellet concluded that it was impossible to avoid cracking in thick porous silicon layers under normal evaporating conditions. Hence, several appropriate techniques have been developed to minimize the risk of cracks formed during drying."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10502", "text": "Supercritical drying  is reputed to be the most efficient drying technique but is rather expensive and difficult to implement. It was first implemented by Canham in 1994 and involves  superheating  the liquid pore above the critical point to avoid interfacial tension. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10503", "text": "Freeze drying  procedure was first documented around 1996. [ 11 ]  After the formation of porous silicon, the sample is frozen at a temperature of about 200 K and sublimed under vacuum. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10504", "text": "The technique uses  pentane  as the drying liquid instead of water. In doing so the capillary stress is reduced because pentane has a lower surface tension than water. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10505", "text": "Slow evaporating  technique can be implemented following the water or ethanol rinsing. It was found that slow evaporation decreased the trap density."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10506", "text": "Physical parameters describing PS are pore diameter, pore density and thickness of the porous layer. During formation of porous silicon layer by means of anodization of a Si wafer, these parameter can be controlled by the Si resistivity, HF concentration, current density and etching time. It is possible to create several porous layers with different pore densities and diameters of the pores on the same substrate by etching with different current densities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10507", "text": "Porosity is defined as volume fraction of voids within the PS layer and can be determined easily by weight measurement. [ 5 ]  The porosity of PS may range from 4% for macroporous layers to 95% for mesoporous layers. A study by Canham in 1995 found that \"a 1\u00a0\u03bcm thick layer of high porosity silicon completely dissolved within a day of in-vitro exposure to a  simulated body fluid \". [ 14 ]  It was also found that a silicon wafer with medium to low porosity displayed more stability. Hence, the porosity of PS is chosen according to its potential application areas. The porosity of PS is a macroscopic parameter and doesn\u2019t yield any information regarding the microstructure of the layer. It is proposed that the properties of a sample are more accurately predicted if the pore size and pore distribution within the sample can be obtained."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10508", "text": "PS demonstrates  optical properties  based on porosity and complex  refractive indices  of Si and the medium inside the pores. Effective refractive index of PS can be modelled by means of  effective medium approximations  (EMA). Usually generalised Bruggeman model is used. If the refractive index of the medium inside pores is high, the effective refractive index of PS will be high as well. This phenomenon causes the  spectrum  to shift towards longer  wavelength . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10509", "text": "Porous silicon is classified into three categories according to the size of its pores:  macroporous ,  mesoporous , and  microporous ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10510", "text": "The surface of porous silicon may be modified to exhibit different properties. Often, freshly etched porous silicon may be unstable due to the rate of its  oxidation  by the atmosphere or unsuitable for cell attachment purposes. Therefore, it can be surface modified to improve stability and cell attachment"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10511", "text": "Following the formation of porous silicon, its surface is covered with  covalently  bonded hydrogen. Although the hydrogen coated surface is sufficiently stable when exposed to inert atmosphere for a short period of time, prolonged exposure render the surface prone to oxidation by atmospheric oxygen. The oxidation promotes instability in the surface and is undesirable for many applications. Thus, several methods were developed to promote the surface stability of porous silicon."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10512", "text": "An approach that can be taken is through  thermal oxidation . The process involves heating the silicon to a temperature above 1000 C to promote full oxidation of silicon. The method reportedly produced samples with good stability to aging and electronic surface  passivation . [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10513", "text": "Porous silicon exhibits a high degree of  biocompatibility . The large surface area enables  organic  molecules to adhere well. It degrades to  Orthosillicic acid (H 4 SiO 4 ) , [ 17 ]  which causes no harm to the body. This has opened potential applications in medicine such as a framework of the growth of  bone ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10514", "text": "Surface modification can also affect properties that promote  cell adhesion . One particular research in 2005 studied the mammalian cell adhesion on the modified surfaces of porous silicon. The research used rat  PC12 cells  and  Human Lens Epithelial (HLE)  cells cultured for four hours on the surface modified porous silicon. Cells were then stained with vital dye FDA and observed under  fluorescence microscopy . The research concluded that \"amino  silanisation  and coating the pSi surface with collagen enhanced cell attachment and spreading\". [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10515", "text": "Porous silicon studies conducted in 1995 showed that the behaviour of porous silicon can be altered in between \"bio-inert\", \"bioactive\" and \"resorbable\" by varying the porosity of the silicon sample. [ 14 ]  The in-vitro study used simulated body fluid containing ion concentration similar to the human blood and tested the activities of porous silicon sample when exposed to the fluids for prolonged period of time. It was found that high porosity mesoporous layers were completely removed by the simulated body fluids within a day. In contrast, low to medium porosity microporous layers displayed more stable configurations and induced hydroxyapatite growth."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10516", "text": "The first sign of porous silicon as a  bioactive  material was found in 1995. In the conducted study, it was found that  hydroxyapatite  growth was occurring on porous silicon areas. It was then suggested that \"hydrated microporous Si could be a bioactive form of the  semiconductor  and suggest that Si itself should be seriously considered for development as a material for widespread  in vivo  applications.\" [ 14 ]  Another paper published the finding that porous silicon may be used a substrate for hydroxyapatite growth either by simple soaking process or laser-liquid-solid interaction process. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10517", "text": "Since then,  in-vitro  studies have been conducted to evaluate the interaction of cells with porous silicon. A 1995 study of the interaction of  B50 rat hippocampal cells  with porous silicon found that B50 cells have clear preference for adhesion to porous silicon over untreated surface. The study indicated that porous silicon can be suitable for  cell culturing  purposes and can be used to control cell growth pattern. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10518", "text": "Another positive attribute of porous silicon is the degradation of porous silicon into  monomeric  silicic acid (SiOH4). Silicic acid is reputed to be the most natural form of element in the environment and is readily removed by  kidneys ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10519", "text": "The human  blood plasma  contains monomeric silicic acid at levels of less than 1\u00a0mg Si/L, corresponding to the average dietary intake of 20\u201350\u00a0mg/day. It was proposed that the small thickness of silicon coatings presents minimal risk to a toxic concentration being reached. The proposal was supported by an experiment involving volunteers and silicic-acid drinks. It was found that concentration of the acid rose only briefly above the normal 1\u00a0mg Si/L level and was efficiently expelled by urine excretion. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10520", "text": "The simple adjustment of pore morphology and geometry of porous silicon also offers a convenient way to control its wetting behavior. Stable ultra- and  superhydrophobic  states on porous silicon can be fabricated and used in  lab-on-a-chip ,  microfluidic  devices for the improved surface-based bioanalysis. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10521", "text": "In  pharmacology ,  potency  or  biological potency [ 1 ]  is a measure of a drug's  biological activity  expressed in terms of the dose required to produce a pharmacological effect of given intensity. [ 2 ]  A highly potent drug (e.g.,  fentanyl ,  clonazepam ,  risperidone ,  benperidol ,  bumetanide ) evokes a given response at low concentrations, while a drug of lower potency (e.g.  morphine ,  alprazolam ,  ziprasidone ,  haloperidol ,  furosemide ) evokes the same response only at higher concentrations. Higher potency does not necessarily mean greater  effectiveness  nor more  side effects  nor less side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10522", "text": "The  International Union of Basic and Clinical Pharmacology  (IUPHAR) has stated that \"potency is an imprecise term that should always be further defined\", [ 2 ]  and lists of types of potency as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10523", "text": "https://www.addictioncenter.com/news/2019/08/15-most-dangerous-drugs/ \n https://nida.nih.gov/research-topics/commonly-used-drugs-charts#top"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10524", "text": "In  pharmacology  and  pharmaceutics , a  prototype drug  is an individual  drug  that represents a  drug class  \u2013 group of medications having similar  chemical structures ,  mechanism of action  and  mode of action . Prototypes are the most important, and typically the first developed drugs within the class, and are used as a reference to which all other drugs are compared. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10525", "text": "A  receptor antagonist  is a type of   receptor   ligand  or  drug  that blocks or dampens a biological response by binding to and blocking a  receptor  rather than activating it like an  agonist . Antagonist drugs interfere in the natural operation of receptor proteins. [ 1 ]  They are sometimes called  blockers ; examples include  alpha blockers ,  beta blockers , and  calcium channel blockers . In  pharmacology ,  antagonists  have  affinity  but no  efficacy  for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an  agonist  or  inverse agonist  at receptors. Antagonists mediate their effects by binding to the  active site  or to the  allosteric site  on a receptor, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist\u2013receptor complex, which, in turn, depends on the nature of antagonist\u2013receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10526", "text": "The English word antagonist in pharmaceutical terms comes from the  Greek  \u1f00\u03bd\u03c4\u03b1\u03b3\u03c9\u03bd\u03b9\u03c3\u03c4\u03ae\u03c2 \u2013  antagonist\u0113s , \"opponent, competitor, villain,  enemy, rival\", which is derived from  anti-  (\"against\") and  agonizesthai  (\"to contend for a prize\"). Antagonists were discovered in the 20th century by American biologist Bailey Edgren. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10527", "text": "Biochemical  receptors  are large  protein  molecules that can be activated by the binding of a  ligand  such as a  hormone  or a  drug . [ 5 ]  Receptors can be membrane-bound, as  cell surface receptors , or inside the cell as  intracellular receptors , such as  nuclear receptors  including those of the  mitochondrion . Binding occurs as a result of  non-covalent interactions  between the receptor and its ligand, at locations called the  binding site  on the receptor.  A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly. [ 5 ]  The activity of receptors can also be  regulated  by the binding of a ligand to other sites on the receptor, as in  allosteric binding sites . [ 6 ]  Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses. This may be accomplished by binding to the active site or the allosteric site. [ 7 ]  In addition, antagonists may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity to exert their effects. [ 7 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10528", "text": "The term  antagonist  was originally coined to describe different profiles of drug effects. [ 10 ]  The biochemical definition of a receptor antagonist was introduced by Ariens [ 11 ]  and Stephenson [ 12 ]  in the 1950s. The current accepted definition of receptor antagonist is based on the  receptor occupancy model . It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn \"on\" a  single  cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell. Antagonists were thought to turn \"off\" that response by 'blocking' the receptor from the agonist. This definition also remains in use for  physiological antagonists , substances that have opposing physiological actions, but act at different receptors. For example,  histamine  lowers arterial pressure through  vasodilation  at the  histamine H 1  receptor , while  adrenaline  raises arterial pressure through vasoconstriction mediated by alpha -adrenergic receptor  activation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10529", "text": "Our understanding of the mechanism of drug-induced receptor activation and  receptor theory  and the biochemical definition of a receptor antagonist continues to evolve. The two-state model of receptor activation has given way to multistate models with intermediate conformational states. [ 13 ]  The discovery of  functional selectivity  and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others. [ 14 ]   This means efficacy may actually depend on where that receptor is expressed, altering the view that  efficacy  at a receptor is receptor-independent property of a drug. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10530", "text": "By definition, antagonists display no  efficacy [ 12 ]  to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, however, antagonists inhibit the function of  agonists ,  inverse agonists , and  partial agonists . In functional antagonist assays, a  dose-response curve  measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist. [ 5 ]  The  potency  of an antagonist is usually defined by its  half maximal inhibitory concentration  (i.e.,  IC 50  value). This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the maximum biological response of an agonist. Elucidating an IC 50  value is useful for comparing the potency of drugs with similar efficacies, however the dose-response curves produced by both drug antagonists must be similar. [ 16 ]  The lower the IC 50  the greater the potency of the antagonist, and the lower the concentration of drug that is required to inhibit the maximum biological response. Lower concentrations of drugs may be associated with fewer side-effects. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10531", "text": "The affinity of an antagonist for its  binding site  (K i ), i.e. its ability to bind to a receptor, will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using  Schild regression  or for competitive antagonists in radioligand binding studies using the  Cheng-Prusoff equation . Schild regression can be used to determine the nature of antagonism as beginning either competitive or non-competitive and K i  determination is independent of the affinity, efficacy or concentration of the agonist used. However, it is important that equilibrium has been reached. The effects of receptor desensitization on reaching equilibrium must also be taken into account. The affinity constant of antagonists exhibiting two or more effects, such as in competitive neuromuscular-blocking agents that also block ion channels as well as antagonising agonist binding, cannot be analyzed using Schild regression. [ 18 ] [ 19 ]  Schild regression involves comparing the change in the dose ratio, the ratio of the EC 50  of an agonist alone compared to the EC 50  in the presence of a competitive antagonist as determined on a dose response curve. Altering the amount of antagonist used in the assay can alter the dose ratio. In Schild regression, a plot is made of the log (dose ratio-1) versus the log concentration of antagonist for a range of antagonist concentrations. [ 20 ]  The affinity or K i  is where the line cuts the x-axis on the regression plot. Whereas, with Schild regression, antagonist concentration is varied in experiments used to derive K i  values from the Cheng-Prusoff equation, agonist concentrations are varied. Affinity for competitive agonists and antagonists is related by the Cheng-Prusoff factor used to calculate the K i  (affinity constant for an antagonist) from the shift in IC 50  that occurs during  competitive inhibition . [ 21 ]  The Cheng-Prusoff factor takes into account the effect of altering agonist concentration and agonist affinity for the receptor on inhibition produced by competitive antagonists. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10532", "text": "Competitive antagonists bind to receptors at the same  binding site  (active site) as the endogenous ligand or agonist, but without activating the receptor. Agonists and antagonists \"compete\" for the same binding site on the receptor. Once bound, an antagonist will block agonist binding. Sufficient concentrations of an antagonist will displace the agonist from the binding sites, resulting in a lower frequency of receptor activation.  The level of activity of the receptor will be determined by the relative  affinity  of each molecule for the site and their relative concentrations. High concentrations of a competitive agonist will increase the proportion of receptors that the agonist occupies, higher concentrations of the antagonist will be required to obtain the same degree of binding site occupancy. [ 17 ]  In functional assays using competitive antagonists, a parallel rightward shift of agonist dose\u2013response curves with no alteration of the maximal response is observed. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10533", "text": "Competitive antagonists are used to prevent the activity of drugs, and to reverse the effects of drugs that have already been consumed.  Naloxone  (also known as Narcan) is used to reverse  opioid overdose  caused by drugs such as  heroin  or  morphine . Similarly,  Ro15-4513  is an antidote to  alcohol  and  flumazenil  is an antidote to  benzodiazepines ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10534", "text": "Competitive antagonists are sub-classified as  reversible  ( surmountable ) or  irreversible  ( insurmountable ) competitive antagonists, depending on how they interact with their  receptor protein  targets. [ 22 ]  Reversible antagonists, which bind via noncovalent intermolecular forces, will eventually dissociate from the receptor, freeing the receptor to be bound again. [ 24 ]  Irreversible antagonists bind via covalent intermolecular forces. Because there is not enough  free energy  to break covalent bonds in the local environment, the bond is essentially \"permanent\", meaning the receptor-antagonist complex will never dissociate. The receptor will thereby remain permanently antagonized until it is  ubiquitinated  and thus destroyed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10535", "text": "A non-competitive antagonist is a type of insurmountable antagonist that may act in one of two ways: by binding to an  allosteric  site of the receptor, [ 25 ] [ 22 ]  or by irreversibly binding to the active site of the receptor. The former meaning has been standardised by the  IUPHAR , [ 22 ]  and is equivalent to the antagonist being called an  allosteric antagonist . [ 22 ]   While the mechanism of antagonism is different in both of these phenomena, they are both called \"non-competitive\" because the end-results of each are functionally very similar. Unlike competitive antagonists, which affect the amount of agonist necessary to achieve a maximal response but do not affect the magnitude of that maximal response, non-competitive antagonists reduce the magnitude of the maximum response that can be attained by any amount of agonist. This property earns them the name \"non-competitive\" because their effects cannot be negated, no matter how much agonist is present.  In functional assays of non-competitive antagonists,  depression  of the maximal response of agonist dose-response curves, and in some cases, rightward shifts, is produced. [ 23 ]  The rightward shift will occur as a result of a  receptor reserve  (also known as spare receptors) [ 12 ]  and inhibition of the agonist response will only occur when this reserve is depleted."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10536", "text": "An antagonist that binds to the active site of a receptor is said to be \"non-competitive\" if the bond between the active site and the antagonist is irreversible or nearly so. [ 25 ]  This usage of the term \"non-competitive\" may not be ideal, however, since the term \"irreversible competitive antagonism\" may also be used to describe the same phenomenon without the potential for confusion with the second meaning of \"non-competitive antagonism\" discussed below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10537", "text": "The second form of \"non-competitive antagonists\" act at an  allosteric  site. [ 25 ]  These antagonists bind to a distinctly separate binding site from the agonist, exerting their action to that receptor via the other binding site. They  do not compete with agonists for binding at the active site. The bound antagonists may prevent conformational changes in the receptor required for receptor activation after the agonist binds. [ 26 ]   Cyclothiazide  has been shown to act as a reversible non-competitive antagonist of  mGluR1 receptor . [ 27 ]  Another example of a non-competitive is  phenoxybenzamine  which binds irreversibly (with  covalent bonds ) to alpha- adrenergic receptors , which in turn reduces the fraction of available receptors and reduces the maximal effect that can be produced by the  agonist . [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10538", "text": "Uncompetitive antagonists differ from non-competitive antagonists in that they require receptor activation by an agonist before they can bind to a separate allosteric binding site. This type of antagonism produces a kinetic profile in which \"the same amount of antagonist blocks higher concentrations of agonist better than lower concentrations of agonist\". [ 29 ]   Memantine , used in the treatment of  Alzheimer's disease , is an uncompetitive antagonist of the  NMDA receptor . [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10539", "text": "Silent antagonists are competitive receptor antagonists that have zero intrinsic activity for activating a receptor. They are true antagonists, so to speak. The term was created to distinguish fully inactive antagonists from weak partial agonists or inverse agonists. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10540", "text": "Partial agonists are defined as drugs that, at a given receptor, might differ in the amplitude of the functional response that they elicit after maximal receptor occupancy. Although they are agonists, partial agonists can act as a  competitive antagonist  in the presence of a  full agonist , as it competes with the full agonist for receptor occupancy, thereby producing a net decrease in the receptor activation as compared to that observed with the full agonist alone. [ 32 ] [ 33 ]  Clinically, their usefulness is derived from their ability to enhance deficient systems while simultaneously blocking excessive activity. Exposing a receptor to a high level of a partial agonist will ensure that it has a constant, weak level of activity, whether its normal agonist is present at high or low levels. In addition, it has been suggested that partial agonism prevents the adaptive regulatory mechanisms that frequently develop after repeated exposure to potent full agonists or antagonists. [ 34 ] [ 35 ]  E.g.  Buprenorphine , a partial agonist of the  \u03bc-opioid receptor , binds with weak morphine-like activity and is used clinically as an  analgesic  in pain management and as an alternative to  methadone  in the treatment of opioid dependence. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10541", "text": "An  inverse agonist  can have effects similar to those of an antagonist, but causes a distinct set of downstream biological responses.  Constitutively active receptors  that exhibit intrinsic or basal activity can have inverse agonists, which not only block the effects of binding agonists like a classical antagonist but also inhibit the basal activity of the receptor. Many drugs previously classified as antagonists are now beginning to be reclassified as inverse agonists because of the discovery of constitutive active receptors. [ 37 ] [ 38 ]   Antihistamines , originally classified as antagonists of  histamine   H 1  receptors  have been reclassified as inverse agonists. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10542", "text": "Many antagonists are reversible antagonists that, like most agonists, will bind and unbind a receptor at rates determined by  receptor-ligand kinetics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10543", "text": "Irreversible antagonists  covalently  bind to the receptor target and, in general, cannot be removed; inactivating the receptor for the duration of the antagonist effects is determined by the rate of receptor turnover, the rate of synthesis of new receptors.  Phenoxybenzamine  is an example of an irreversible  alpha blocker \u2014it permanently binds to  \u03b1   adrenergic receptors , preventing  adrenaline  and  noradrenaline  from binding. [ 40 ]  Inactivation of receptors normally results in a depression of the maximal response of agonist dose-response curves and a right shift in the curve occurs where there is a receptor reserve similar to non-competitive antagonists. A washout step in the assay will usually distinguish between non-competitive and irreversible antagonist drugs, as effects of non-competitive antagonists are reversible and activity of agonist will be restored. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10544", "text": "Irreversible competitive antagonists also involve competition between the agonist and antagonist of the receptor, but the rate of covalent bonding differs and depends on affinity and reactivity of the antagonist. [ 16 ]  For some antagonists, there may be a distinct period during which they behave competitively (regardless of basal efficacy), and freely associate to and dissociate from the receptor, determined by  receptor-ligand kinetics . But, once irreversible bonding has taken place, the receptor is deactivated and degraded. As for non-competitive antagonists and irreversible antagonists in functional assays with irreversible competitive antagonist drugs, there may be a shift in the log concentration\u2013effect curve to the right, but, in general, both a decrease in slope and a reduced maximum are obtained. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10545", "text": "A  receptor modulator , or  receptor ligand , is a general term for a substance, endogenous or exogenous, that binds to and regulates the activity of chemical  receptors . They are  ligands  that can act on different parts of receptors and regulate activity in a positive, negative, or neutral direction with varying degrees of efficacy. Categories of these modulators include  receptor agonists  and  receptor antagonists , as well as receptor  partial agonists ,  inverse agonists , orthosteric modulators, and  allosteric modulators , [ 1 ]  Examples of receptor modulators in modern medicine include CFTR modulators, [ 2 ]  selective androgen receptor modulators (SARMs), and muscarinic ACh receptor modulators."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10546", "text": "Currently, receptor modulators are categorized in the Agonist, Partial Agonist, Selective Tissue Modulators, Antagonist, and Inverse Agonist categories in terms of the effect they cause. They are further divided into Orthosteric or Allosteric Modulators according to how they effect said result. Typically, a chemical acts in an agonist fashion whenever it instigates or else facilitates a particular reaction by binding to a particular receptor. In contract, a chemical acts as an antagonist whenever binding to a particular receptor blocks or inhibits a particular response. Between these endpoints exists a gradient defined by a number of variables. One example is Selective Tissue Modulators, which mean a given ligand can behave differently according to the tissue type it is in. As for orthosteric and allosteric modulation, this describes the manner in which the ligand binds to the receptor in question: if it binds directly to the prescribed binding site of a receptor, the ligand is orthosteric in this instance; if the ligand alters the receptor by interacting with it at any place other than a binding site, allosteric interaction occurred. Note that a drug's categorization does not dictate how another drug of the same family could be categorized or whether the same drug may also function in another category. An example is found in medications used to treat opioid addiction, with  methadone ,  buprenorphine ,  naloxone , and  naltrexone  all in separate categories or in more than one simultaneously. In addition, depending on the cell type, the specific effect, whether agonist, antagonist, inverse agonist, etc., could have a unique specific effect. An example is seen in  insulin , under \"Receptor Agonists,\" as it interacts with multiple different cell types as an agonist, but incites multiple and different responses in both."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10547", "text": "A  receptor agonist  is a chemical that binds to a receptor with the end result of directly inducing a  conformational change  in the bound receptor and activating a downstream effect. Some common examples are opium derivates, such as  heroin  and Toll-like receptor agonists. [ 3 ]  Heroin functions in this manner, along with other opioids, when bound to  \u03bc-opioid receptors . [ 4 ]  Opioids' manner of action are both concentration- and receptor-dependent, which provides a key difference between agonists and partial agonists. Another example is  insulin , which activates cell receptors to instigate  blood glucose  uptake. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10548", "text": "Partial agonists  are any chemical that can bind to a receptor without eliciting the maximum downstream response as compared to the response from a full agonist. A given partial agonist's affinity for a given receptor is also irrelevant to the consequent effect. An example is  buprenorphine , a partial opioid receptor agonist used to treat opioid addictions by directly substituting for them without the same strength of effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10549", "text": "A  receptor antagonist  is any given ligand that binds to a receptor in some way without causing any immediate or downstream response, essentially neutralizing the receptor until something with a stronger affinity removes the antagonist or the antagonist itself unbinds. Generally, antagonists can act one of two ways: 1) they can either block the receptors directly, preventing the usual ligand from binding, such as in the case of atropine when it blocks specific  acetylcholine  receptors to provide important medical benefits. This is competitive antagonism, as they are competing for the same binding sites on the receptor. [ 6 ]  The other is by binding to a receptor in a site other than the designated receptor site, inducing a conformational change to prevent the usual ligand(s) from binding and activating a downstream cascade. A commonly-seen and used receptor antagonist is  naloxone , another opioid competitive antagonist typically used to treat opioid overdoses by blocking receptors outright. [ 7 ]  Further elaboration can be found in \"Orthosteric v. Allosteric Modulators.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_10550", "text": "Inverse agonists  differ from regular agonists in that they effect receptors to which a regular agonist binds such that the bound receptors demonstrate reduced activity compared to when they are normally inactive. [ 8 ]  In other words, inverse antagonists limit the efficacy of the bound receptor in some way. This is noted to be beneficial in instances wherein expression of receptors or up-regulated receptor sensitivity could be detrimental, thus making suppression of response the best recourse. A handful of examples of inverse agonist use in therapy include  \u03b2-blockers ,  antihistamines ,  ACP-103  to treat  Parkinson's disease ,  hemopressin , drugs to treat  obesity , and more besides. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10551", "text": "Reuptake inhibitors  ( RIs ) are a type of  reuptake modulators . It is a drug that inhibits the  plasmalemmal   transporter -mediated  reuptake  of a  neurotransmitter  from the  synapse  into the  pre-synaptic neuron . This leads to an increase in  extracellular   concentrations  of the neurotransmitter and  an increase in  neurotransmission . Various  drugs  exert their  psychological  and  physiological  effects through reuptake inhibition, including many  antidepressants  and  psychostimulants . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10552", "text": "Most known reuptake inhibitors affect the  monoamine neurotransmitters   serotonin ,  norepinephrine  (and  epinephrine ), and  dopamine . [ 1 ]  However, there are also a number of  pharmaceuticals  and  research chemicals  that act as reuptake inhibitors for other  neurotransmitters  such as  glutamate , [ 2 ]   \u03b3-aminobutyric acid  (GABA), [ 3 ]   glycine , [ 4 ]   adenosine , [ 5 ]   choline  (the  precursor  of  acetylcholine ), [ 6 ]  and the  endocannabinoids , [ 7 ]  among others. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10553", "text": "Standard reuptake inhibitors are believed to act simply as  competitive   substrates  that work by  binding  directly to the  plasmalemma   transporter  of the  neurotransmitter  in question. [ 8 ] [ 9 ] [ 10 ] [ 11 ]  They  occupy  the  transporter  in place of the respective  neurotransmitter  and  competitively   block  it from being  transported  from the  nerve terminal  or  synapse  into the  pre-synaptic   neuron . With high enough doses,  occupation  becomes as much as 80\u201390%. At this level of inhibition, the  transporter  will be considerably less efficient at removing excess  neurotransmitter  from the  synapse  and this causes a substantial increase in the  extracellular   concentrations  of the  neurotransmitter  and therefore an increase in overall  neurotransmission ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10554", "text": "Alternatively, some reuptake inhibitors  bind  to  allosteric sites  and inhibit  reuptake  indirectly and  noncompetitively ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10555", "text": "Phencyclidine  and related  drugs  such as  benocyclidine ,  tenocyclidine ,  ketamine , and  dizocilpine  (MK-801), have been shown to inhibit the reuptake of the  monoamine neurotransmitters . [ 12 ] [ 13 ] [ 14 ]  They appear to exert their reuptake inhibition by binding to vaguely characterized allosteric sites on each of the respective  monoamine transporters . [ 15 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ]   Benztropine ,  mazindol , and  vanoxerine  also bind to these sites and have similar properties. [ 15 ] [ 19 ] [ 20 ]  In addition to their high  affinity  for the  main site  of the monoamine transporters, several  competitive   transporter   substrates  such as  cocaine  and  indatraline  have lower affinity for these allosteric sites as well. [ 17 ] [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10556", "text": "A few of the  selective serotonin reuptake inhibitors  (SSRIs) such as the dextro- enantiomer  of  citalopram  appear to be allosteric reuptake inhibitors of serotonin. [ 21 ] [ 22 ]  Instead of binding to the active site on the  serotonin transporter , they bind to an allosteric site, which exerts its effects by causing  conformational changes  in the  transporter protein  and thereby modulating the affinity of substrates for the active site. [ 21 ]  As a result,  escitalopram  has been  marketed  as an  allosteric serotonin reuptake inhibitor . Notably, this allosteric site may be directly related to the above-mentioned  PCP   binding sites . [ 15 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10557", "text": "A second type of reuptake inhibition affects  vesicular   transport , and  blocks  the  intracellular   repackaging  of  neurotransmitters  into  cytoplasmic  vesicles. In contrast to  plasmalemmal  reuptake inhibitors, vesicular reuptake inhibitors do not increase the  synaptic   concentrations  of a  neurotransmitter , only the  cytoplasmic   concentrations ; unless, that is, they also act as  plasmalemmal   transporter   reversers  via  phosphorylation  of the  transporter protein , also known as a  releasing agent . Pure vesicular reuptake inhibitors tend to actually lower  synaptic   neurotransmitter   concentrations , as  blocking  the  repackaging  of, and  storage  of the  neurotransmitter  in question leaves them vulnerable to  degradation  via  enzymes  such as  monoamine oxidase  (MAO) that exist in the  cytoplasm . With vesicular  transport   blocked ,  neurotransmitter  stores quickly become depleted."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10558", "text": "Reserpine  (Serpasil) is an  irreversible  inhibitor of the  vesicular monoamine transporter 2  (VMAT2), and is a prototypical example of a vesicular reuptake inhibitor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10559", "text": "Two of the primary  active constituents  of the  medicinal herb   Hypericum perforatum  (St. John's Wort) are  hyperforin  and  adhyperforin . [ 23 ] [ 24 ]  Hyperforin and adhyperforin are wide-spectrum inhibitors of the reuptake of serotonin, norepinephrine, dopamine, glutamate, GABA, glycine, [ 25 ]  and choline, [ 26 ]  and they exert these effects by binding to and  activating  the  transient receptor potential   cation channel   TRPC6 . [ 24 ] [ 27 ]  Activation of TRPC6 induces the entry of  calcium  (Ca 2+ ) and  sodium  (Na + ) into the  cell , which causes the effect through unknown mechanism. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10560", "text": "In  pharmacology ,  Schild regression analysis , based upon the  Schild equation , both named for  Heinz Otto Schild , are tools for studying the effects of  agonists  and  antagonists  on the  response  caused by the  receptor  or on ligand-receptor binding."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10561", "text": "Dose-response curves  can be constructed to describe response or ligand-receptor complex formation as a function of the ligand concentration. Antagonists make it harder to form these complexes by inhibiting interactions of the ligand with its receptor. This is seen as a change in the dose response curve: typically a rightward shift or a lowered maximum. A reversible competitive antagonist should cause a rightward shift in the dose response curve, such that the new curve is parallel to the old one and the maximum is unchanged. This is because reversible competitive antagonists are surmountable antagonists. The magnitude of the rightward shift can be quantified with the dose ratio, r. The dose ratio r is the ratio of the dose of agonist required for half maximal response with the antagonist  \n \n \n \n \n B \n \n \n \n {\\displaystyle {\\ce {B}}} \n \n  present divided by the agonist required for half maximal response without antagonist (\"control\"). In other words, the ratio of the  EC50s  of the inhibited and un-inhibited curves. Thus, r represents both the strength of an antagonist and the concentration of the antagonist that was applied. An equation derived from the  Gaddum equation  can be used to relate r to  \n \n \n \n [ \n \n B \n \n ] \n \n \n {\\displaystyle [{\\ce {B}}]} \n \n , as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10562", "text": "A  Schild plot  is a double logarithmic plot, typically  \n \n \n \n \n log \n \n 10 \n \n \n \u2061 \n ( \n r \n \u2212 \n 1 \n ) \n \n \n {\\displaystyle \\log _{10}(r-1)} \n \n  as the  ordinate  and  \n \n \n \n \n log \n \n 10 \n \n \n \u2061 \n [ \n \n B \n \n ] \n \n \n {\\displaystyle \\log _{10}[{\\ce {B}}]} \n \n  as the  abscissa . This is done by taking the base-10 logarithm of both sides of the previous equation after subtracting 1:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10563", "text": "This equation is linear with respect to  \n \n \n \n \n log \n \n 10 \n \n \n \u2061 \n [ \n \n B \n \n ] \n \n \n {\\displaystyle \\log _{10}[{\\ce {B}}]} \n \n , allowing for easy construction of graphs without computations. This was particular valuable before the use of computers in pharmacology became widespread. The y-intercept of the equation represents the negative logarithm of  \n \n \n \n \n K \n \n B \n \n \n \n \n {\\displaystyle K_{B}} \n \n  and can be used to quantify the strength of the antagonist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10564", "text": "These experiments must be carried out on a very wide range (therefore the logarithmic scale) as the mechanisms differ over a large scale, such as at high concentration of drug. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10565", "text": "The fitting of the Schild plot to observed data points can be done with  regression analysis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10566", "text": "Although most experiments use cellular response as a measure of the effect, the effect is, in essence, a result of the binding kinetics; so, in order to illustrate the mechanism,  ligand  binding is used. A ligand A will bind to a  receptor  R according to an equilibrium constant\u00a0:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10567", "text": "Although the equilibrium constant is more meaningful, texts often mention its inverse, the affinity constant (K aff  = k 1 /k \u22121 ): A better binding means an increase of binding affinity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10568", "text": "The equation for simple ligand binding to a single homogeneous receptor is"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10569", "text": "This is the Hill-Langmuir equation, which is practically the  Hill equation  described for the agonist binding. In chemistry, this relationship is called the  Langmuir equation , which describes the adsorption of molecules onto sites of a surface (see  adsorption )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10570", "text": "[ \n R \n \n ] \n \n t \n \n \n \n \n {\\displaystyle [R]_{t}} \n \n  is the total number of binding sites, and when the equation is plotted it is the horizontal asymptote to which the plot tends; more binding sites will be occupied as the ligand concentration increases, but there will never be 100% occupancy.  The binding affinity is the concentration needed to occupy 50% of the sites; the lower this value is the easier it is for the ligand to occupy the binding site."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10571", "text": "The binding of the ligand to the receptor at equilibrium follows the same kinetics as an enzyme at steady-state ( Michaelis\u2013Menten equation ) without the conversion of the bound substrate to product."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10572", "text": "Agonists and antagonists can have various effects on ligand binding.  They can change the maximum number of binding sites, the affinity of the ligand to the receptor, both effects together or even more bizarre effects when the system being studied is more intact, such as in tissue samples. (Tissue absorption, desensitization, and other non equilibrium steady-state can be a problem.)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10573", "text": "A surmountable drug changes the binding affinity:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10574", "text": "A nonsurmountable drug changes the maximum binding:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10575", "text": "The Schild regression also can reveal if there are more than one type of receptor and it can show if the experiment was done wrong as the system has not reached equilibrium."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10576", "text": "The first radio-receptor assay (RRA) was done in 1970 by Lefkowitz et al., [ dubious  \u2013  discuss ]  using a radiolabeled hormone to determine the binding affinity for its receptor. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10577", "text": "A radio-receptor assay requires the separation of the bound from the free ligand.  This is done by  filtration ,  centrifugation  or  dialysis . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10578", "text": "A method that does not require separation is the  scintillation proximity assay  that relies on the fact that \u03b2-rays from  3 H travel extremely short distances.  The receptors are bound to beads coated with a polyhydroxy scintillator.  Only the bound ligands to be detected."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10579", "text": "Today, the fluorescence method is preferred to radioactive materials due to a much lower cost, lower hazard, and the possibility of multiplexing the reactions in a high-throughput manner.  One problem is that fluorescent-labeled ligands have to bear a bulky fluorophore that may cause it to hinder the ligand binding.  Therefore, the fluorophore used, the length of the linker, and its position must be carefully selected."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10580", "text": "An example is by using  FRET , where the ligand's fluorophore transfers its energy to the fluorophore of an antibody raised against the receptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10581", "text": "Other detection methods such as  surface plasmon resonance  do not even require fluorophores."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10582", "text": "Tachyphylaxis  ( Greek  \u03c4\u03b1\u03c7\u03cd\u03c2,  tachys , \"rapid\", and \u03c6\u03cd\u03bb\u03b1\u03be\u03b9\u03c2,  phylaxis , \"protection\") is a medical term describing an  acute , sudden decrease in response to a drug after its administration (i.e., a rapid and short-term onset of  drug tolerance ). [ 1 ]  It can occur after an initial dose or after a series of small doses. Increasing the dose of the drug may be able to restore the original response. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10583", "text": "Tachyphylaxis is characterized by the rate sensitivity: the response of the system depends on the rate with which a stimulus is presented. To be specific, a high-intensity prolonged stimulus or often-repeated stimulus may bring about a diminished response also known as desensitization."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10584", "text": "In biological sciences, molecular interactions are the physical bases of the operation of the system. The control of the operation, in general, involves interaction of a stimulus molecule with a receptor/enzyme subsystem by, typically, binding to the macromolecule A and causing an activation or an inhibition of the subsystem by forming an activated form of the macromolecule B. The following schematic represents the activity:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10585", "text": "A \n \n \n \u2192 \n \n \u00a0 \n \u00a0 \n p \n \u00a0 \n \u00a0 \n \n \n \n B \n \n \n {\\displaystyle A{\\xrightarrow {\\ \\ p\\ \\ }}B}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10586", "text": "where p is the activation rate coefficient. It is customary that p is called a rate constant, but, since the p stands for measure of the intensity of the stimulus causing the activation, p may be variable (non-constant)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10587", "text": "More complete is an open system, namely, in its simplest form,"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10588", "text": "R \n \n \n \u2192 \n \n \n \n A \n \n \n \u2192 \n \n \u00a0 \n \u00a0 \n p \n ( \n S \n ) \n \u00a0 \n \u00a0 \n \n \n \n B \n \n \n \u2192 \n \n \u00a0 \n \u00a0 \n q \n \u00a0 \n \u00a0 \n \n \n \n , \n \n \n {\\displaystyle R{\\xrightarrow {}}A{\\xrightarrow {\\ \\ p(S)\\ \\ }}B{\\xrightarrow {\\ \\ q\\ \\ }},}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10589", "text": "where  R  stands for the  rate of production  of  A ,  p(S)  is the  activation  rate coefficient explicitly expressing its dependence on the stimulus intensity  S  and  q  represents the rate coefficient of  removal  from the state  B . In this elementally open system the steady state of  B  always equal to  R/q ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10590", "text": "The above scheme is only the necessary condition for the rate sensitivity phenomenon, and other pathways of deactivation of B may be considered, with the subsequent return to the inactive form of the receptor/enzyme A. Examples [ 3 ] [ 4 ] [ 5 ]  offer particular use of such (mathematical) models in endocrinology, physiology and pharmacology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10591", "text": "Psychedelics  such as  LSD , [ 6 ]  and  psilocybin -containing  mushrooms  demonstrate very rapid tachyphylaxis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10592", "text": "In a patient fully withdrawn from  opioids , going back to an intermittent schedule or maintenance dosing protocol, a fraction of the old tolerance level will rapidly develop, usually starting two days after therapy is resumed and, in general, leveling off after day 7. Whether this is caused directly by  opioid receptors  modified in the past or affecting a change in some metabolic set-point is unclear. Increasing the dose will usually restore efficacy; relatively rapid opioid rotation may also be of use if the increase in tolerance continues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10593", "text": "Inhalation of an agonist for the  beta-2 adrenergic receptor , such as  salbutamol  (albuterol \u2014  USAN ), is the most common treatment for  asthma . Polymorphisms of the beta-2 receptor play a role in tachyphylaxis. Expression of the Gly-16 allele (glycine at position 16) results in greater receptor downregulation by endogenous catecholamines at baseline compared to Arg-16. This results in a greater single-use bronchodilator response in individuals homozygous for Arg-16 compared to Gly-16 homozygotes. [ 7 ]  However, with regular beta-2 agonist use, asthmatic Arg-16 individuals experience a significant decline in bronchodilator response. This decline does not occur in Gly-16 individuals. It has been proposed that the tachyphylactic effect of regular exposure to exogenous beta-2 agonists is more apparent in Arg-16 individuals because their receptors have not been downregulated prior to agonist administration. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10594", "text": "Nicotine  may also show tachyphylaxis over the course of a day, although the mechanism of this action is unclear. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10595", "text": "Acute tachyphylaxis which does not carry into the next day has been observed in children taking  methylphenidate , and inspired the development of  OROS  methylphenidate. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10596", "text": "Use of nasal decongestants (e.g.,  oxymetazoline ) for more than three days leads to tachyphylaxis of response and rebound  congestion , caused by  alpha-adrenergic receptor  downregulation and desensitization. The mechanism may specifically include receptor internalisation and resistance to endogenous vasoconstrictors causing worsening in symptoms post use of medication.  Oxymetazoline-induced tachyphylaxis and rebound congestion are reversed by intranasal  fluticasone . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10597", "text": "Toxicodynamics , termed  pharmacodynamics  in  pharmacology , describes the dynamic interactions of a toxicant with a biological target and its biological effects. [ 1 ]  A  biological target , also known as the site of action, can be binding proteins,  ion channels ,  DNA , or a variety of other receptors. When a  toxicant  enters an organism, it can interact with these receptors and produce structural or functional alterations. The  mechanism of action  of the toxicant, as determined by a toxicant\u2019s chemical properties, will determine what receptors are targeted and the overall toxic effect at the cellular level and organismal level."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10598", "text": "Toxicants have been grouped together according to their chemical properties by way of  quantitative structure-activity relationships  (QSARs), which allows prediction of toxic action based on these properties.   endocrine disrupting chemicals  (EDCs) and  carcinogens  are examples of classes of toxicants that can act as QSARs. EDCs mimic or block transcriptional activation normally caused by natural  steroid hormones .  These types of chemicals can act on  androgen receptors ,  estrogen receptors  and  thyroid hormone receptors .  This mechanism can include such toxicants as  dichlorodiphenyltrichloroethane  (DDE) and  polychlorinated biphenyls  (PCBs). Another class of chemicals, carcinogens, are substances that cause  cancer  and can be classified as  genotoxic  or nongenotoxic carcinogens.  These categories include toxicants such as  polycyclic aromatic hydrocarbon  (PAHs) and  carbon tetrachloride  (CCl 4 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10599", "text": "The process of toxicodynamics can be useful for application in environmental  risk assessment  by implementing toxicokinetic-toxicodynamic (TKTD) models.  TKTD models include phenomenas such as time-varying exposure, carry-over  toxicity , organism recovery time, effects of mixtures, and extrapolation to untested  chemicals  and  species .  Due to their advantages, these types of models may be more applicable for risk assessment than traditional modeling approaches."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10600", "text": "While  toxicokinetics  describes the changes in the concentrations of a toxicant over time due to the uptake,  biotransformation , distribution and elimination of toxicants, toxicodynamics involves the interactions of a toxicant with a  biological target  and the functional or structural alterations in a cell that can eventually lead to a toxic effect. Depending on the toxicant\u2019s chemical reactivity and vicinity, the toxicant may be able to interact with the biological target. Interactions between a toxicant and the biological target may also be more specific, where high-affinity  binding sites  increase the selectivity of interactions. For this reason, toxicity may be expressed primarily in certain  tissues  or  organs . The targets are often receptors on the cell surface or in the  cytoplasm  and  nucleus . Toxicants can either induce an unnecessary response or inhibit a natural response, which can cause damage. If the biological target is critical and the damage is severe enough, irreversible injury can occur first at the molecular level, which will translate into effects at higher levels of organization. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10601", "text": "EDCs are generally considered to be toxicants that either mimic or block the transcriptional activation normally caused by natural steroid hormones. [ 2 ]  These chemicals include those acting on androgen receptors, estrogen receptors and thyroid hormone receptors. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10602", "text": "Endocrine disrupting chemicals can interfere with the  endocrine system  in a number of ways including hormone synthesis, storage/release, transport and clearance, receptor recognition and binding, and postreceptor activation. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10603", "text": "In wildlife, exposure to EDCs can result in altered fertility, reduced viability of offspring, impaired hormone secretion or activity and modified reproductive anatomy. [ 4 ]  The reproductive anatomy of offspring can particularly be affected if maternal exposure occurs. [ 5 ]  In females, this includes  mammary glands ,  fallopian tubes ,  uterus ,  cervix , and  vagina . In males, this includes the  prostate ,  seminal vesicles ,  epididymitis  and  testes . [ 5 ]  Exposure of fish to EDCs has also been associated with abnormal thyroid function, decreased fertility, decreased hatching success, de-feminization and masculinization of female fish and alteration of  immune function . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10604", "text": "Endocrine disruption as a  mode of action  for  xenobiotics  was brought into awareness by  Our Stolen Future  by Theo Colborn. [ 2 ]  Endocrine disrupting chemicals are known to accumulate in body tissue and are highly persistent in the environment. [ 6 ]  Many toxicants are known EDCs including  pesticides ,  phthalates ,  phytoestrogens , some industrial/commercial products, and  pharmaceuticals . [ 3 ]  These chemicals are known to cause endocrine disruption via a few different mechanisms. While the mechanism associated with the thyroid hormone receptor is not well understood, two more established mechanisms involve the inhibition of the androgen receptor and activation of the estrogen receptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10605", "text": "Certain toxicants act as endocrine disruptors by interacting with the androgen receptor. DDE is one example of a chemical that acts via this mechanism. DDE is a  metabolite  of  DDT  that is widespread in the environment. [ 1 ]  Although production of DDT has been banned in the Western world, this chemical is extremely persistent and is still commonly found in the environment along with its metabolite DDE. [ 1 ]  DDE is an  antiandrogen , which means it alters the expression of specific androgen-regulated genes, and is an androgen receptor (AR)-mediated mechanism. [ 1 ]  DDE is a  lipophilic  compound which diffuses into the cell and binds to the AR. [ 1 ]  Through binding, the receptor is inactivated and cannot bind to the androgen response element on DNA. [ 1 ]  This inhibits the transcription of androgen-responsive genes [ 1 ]  which can have serious consequences for exposed wildlife. In 1980, there was a spill in  Lake Apopka , Florida which released the pesticide dicofol and DDT along with its metabolites. [ 4 ]  The neonatal and juvenile alligators present in this lake have been extensively studied and observed to have altered  plasma  hormone concentrations, decreased clutch viability, increased juvenile mortality, and morphological abnormalities in the testis and ovary. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10606", "text": "Toxicants may also cause endocrine disruption through interacting with the estrogen receptor. This mechanism has been well-studied with PCBs. These chemicals have been used as coolants and lubricants in transformers and other electrical equipment due to their insulating properties. [ 7 ]  A purely  anthropogenic  substance, PCBs are no longer in production in the United States due to the adverse health effects associated with exposure, but they are highly persistent and are still widespread in the environment. [ 7 ]  PCBs are a  xenoestrogen , which elicit an enhancing (rather than inhibiting) response, and are mediated by the estrogen receptor. [ 1 ]  These are often referred to as estrogen mimics because they mimic the effects of estrogen. PCBs often build up in sediments and  bioaccumulate  in organisms. [ 1 ]  These chemicals diffuse into the nucleus and bind to the estrogen receptor. [ 1 ]  The estrogen receptor is kept in an inactive conformation through interactions with proteins such as  heat shock proteins  59, 70, and 90. [ 8 ]  After the toxicant binding occurs, the estrogen receptor is activated and forms a  homodimer  complex which seeks out estrogen response elements in the DNA. [ 8 ]  The binding of the complex to these elements causes a rearrangement of the  chromatin  and transcription of the gene, resulting in production of a specific protein. [ 8 ]  In doing this, PCBs elicit an estrogenic response which can affect numerous functions within the organism. [ 1 ]  These effects are observed in various aquatic species. The levels of PCBs in marine mammals are often very high as a result of bioaccumulation. [ 9 ]  Studies have demonstrated that PCBs are responsible for reproductive impairment in the  harbor seal  ( Phoca vitulina ). [ 9 ]  Similar effects have been found in the  grey seal  ( Halichoerus grypus ), the  ringed seal  ( Pusa hispida ) and the  California sea lion  ( Zalophys californianus ). [ 9 ]  In the grey seals and ringed seals, uterine occlusions and  stenosis  were found which led to  sterility . [ 9 ]  If exposed to a xenoestrogen such as PCBs, male fish have also been seen to produce  vitellogenin . [ 8 ]  Vitellogenin is an egg protein female fish normally produce but is not usually present in males except at very low concentrations. [ 8 ]  This is often used as a  biomarker  for EDCs. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10607", "text": "Carcinogens  are defined as any substance that causes  cancer . The toxicodynamics of carcinogens can be complex due to the varying mechanisms of action for different carcinogenic toxicants. Because of their complex nature, carcinogens are classified as either genotoxic or nongenotoxic carcinogens."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10608", "text": "The effects of carcinogens are most often related to human exposures but mammals are not the only species that can be affected by cancer-causing toxicants. [ 10 ]   Many studies have shown that cancer can develop in fish species as well. [ 10 ]   Neoplasms  occurring in  epithelial tissue  such as the  liver , gastrointestinal tract, and the  pancreas  have been linked to various environmental toxicants. [ 10 ]  Carcinogens preferentially target the liver in fish and develop hepatocellular and biliary lesions. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10609", "text": "Genotoxic carcinogens interact directly with DNA and genetic material or indirectly by their reactive metabolites. [ 11 ]  Toxicants such as  PAHs  can be genotoxic carcinogens to aquatic organisms. [ 10 ] [ 12 ]   PAHs are widely spread throughout the environment through the incomplete burning of coal, wood, or petroleum products. [ 12 ]  Although PAHs do not bioaccumulate in vertebrate tissue, many studies have confirmed that certain PAH compounds such as  benzo(a)pyrene ,  benz(a)anthracene , and Benzofluoranthene, are  bioavailable  and responsible for liver  diseases  like cancer in wild fish populations. [ 12 ]  One mechanism of action for genotoxic carcinogens includes the formation of  DNA adducts . Once the PAH compound enters an organism, it becomes  metabolized  and available for biotransformation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10610", "text": "The  biotransformation  process can activate the PAH compound and transform it into a diol epoxide, [ citation needed ]  which is a very  reactive intermediate . These diol-epoxides  covalently bind  with DNA  base pairs , most often with  guanine  and  adenine  to form stable adducts within the DNA structure. [ citation needed ]   The binding of diol epoxides and DNA base pairs blocks  polymerase  replication activity. This blockage ultimately contributes to an increase in DNA damage by reducing repair activity. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10611", "text": "Due to these processes, PAH compounds are thought to play a role in the initiation and early promotion stage of  carcinogenesis . Fish exposed to PAHs develop a range of liver  lesions , some of which are characteristic of  hepatocarcinogenicity . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10612", "text": "Nongenotoxic, or  epigenetic  carcinogens are different and slightly more ambiguous than genotoxic carcinogens since they are not directly carcinogenic. Nongenotoxic carcinogens act by secondary mechanisms that do not directly damage genes. This type of carcinogenesis does not change the sequence of DNA; instead it alters the expression or repression of certain genes by a wide variety of cellular processes. [ 11 ]  Since these toxicants do not directly act on DNA, little is known about the mechanistic pathway. [ 10 ]  It has been proposed that modification of gene expression from nongenotoxic carcinogens can occur by  oxidative stress , peroxisome proliferation, suppression of  apoptosis , alteration of intercellular communication, and modulation of metabolizing enzymes. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10613", "text": "Carbon tetrachloride   is an example of a probable nongenotoxic carcinogen to aquatic vertebrates. Historically, carbon tetrachloride has been used in pharmaceutical production, petroleum refining, and as an industrial solvent. [ 13 ]  Due to its widespread industrial use and release into the environment, carbon tetrachloride has been found in drinking water and therefore, has become a concern for aquatic organisms. [ 14 ]  Because of its high  hepatotoxic  properties, carbon tetrachloride could potentially be linked to liver cancer. Experimental cancer studies have shown that carbon tetrachloride may cause  benign  and  malignant  liver  tumors  to  rainbow trout . [ 13 ] [ 14 ]  carbon tetrachloride works as a nongenotoxic carcinogen by formulating  free radicals  which induce oxidative stress. [ 12 ]  It has been proposed that once carbon tetrachloride enters the organism, it is metabolized to trichloromethyl and trichloromethyl peroxy radicals by the  CYP2E1   enzyme . [ 12 ] [ 15 ]  The more reactive radical, trichloromethyl peroxy, can attack  polyunsaturated fatty acids  in the  cellular membrane  to form  fatty acid  free radicals and initiate  lipid peroxidation . [ 15 ]  The attack on the cellular membrane increases its permeability, causing a leakage of enzymes and disrupts cellular calcium  homeostasis . [ 15 ]  This loss of calcium homeostasis activates calcium dependent  degradative enzymes  and  cytotoxicity , causing hepatic damage. [ 15 ]  The regenerative and proliferative changes that occur in the liver during this time could increase the frequency of genetic damage, resulting in a possible increase of cancer. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10614", "text": "Toxicodynamics can be used in combination with  toxicokinetics  in  environmental risk assessment  to determine the potential effects of releasing a toxicant into the environment.  The most widely used method of incorporating this are TKTD models."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10615", "text": "Both toxicokinetics and toxicodynamics have now been described, and using these definitions models were formed, where the internal concentration (TK) and damage (TD) are  simulated  in response to exposure.  TK and TD are separated in the model to allow for the identification of properties of toxicants that determine TK and those that determine TD.  To use this type of model,  parameter  values for TK processes need to be obtained first.  Second, the TD parameters need to be estimated.  Both of these steps require a large database of toxicity information for  parameterization .  After establishing all the parameter values for the TKTD model, and using basic scientific precautions, the model can be used to predict toxic effects, calculate recovery times for organisms, or establish extrapolations from the model to toxicity of untested toxicants and species. [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10616", "text": "It has been argued that the current challenges facing risk assessments can be addressed with TKTD modeling. [ 16 ]   TKTD models were derived in response to a couple of factors.  One is the lack of time being considered as a factor in toxicity and risk assessment.  Some of the earliest developed TKTD models, such as the  Critical Body Residue  (CBR) model and Critical Target Occupation (CTO) model, have considered time as a factor but a criticism has been that they are for very specific circumstances such as reversibly acting toxicants or irreversibly acting toxicants.  Further extrapolation of the CTO and CBR models are  DEBtox , which can model sublethal endpoints, and hazard versions of the CTO, which takes into account  stochastic  death as opposed to individual  tolerance . [ 18 ]   Another significant step to developing TKTD models was the incorporation of a  state variable  for damage.  By using damage as a toxicodynamic state-variable, modeling intermediate recovery rates can be accomplished for toxicants that act reversibly with their targets, without the assumptions of instant recovery (CBR model) or irreversible interactions (CTO model). TKTD models that incorporate damage are the Damage Assessment Model (DAM) and the Threshold Damage Model (TDM). [ 16 ] [ 18 ]  For what may seem like straightforward  endpoints , a variety of different TKTD approaches exist.  A review of the assumptions and  hypotheses  of each was previously published in the creation of a general unified threshold model of survival (GUTS). [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10617", "text": "As referenced above, TKTD models have several advantages to traditional models for risk assessments.  The principal advantages to using TKTD models are: [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10618", "text": "Due to its advantages, TKTD models may be more powerful than the traditional  dose-response  models because of their incorporation of chemical  concentrations  as well as temporal dimensions. [ 16 ]   Toxicodynamic modeling (such as TKTD models) has been shown to be a useful tool for toxicological research, with increasing opportunities to use these results in risk assessment to permit a more scientifically based risk assessment that is less reliable on  animal testing . [ 21 ]   Overall, these types of models can formalize knowledge about the toxicity of toxicants and organism  sensitivity , create new hypotheses, and simulate temporal aspects of toxicity, making them useful tools for risk assessment. [ 16 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10619", "text": "Neuropharmacology  is the study of how drugs affect function in the nervous system, and the neural mechanisms through which they influence behavior. [ 1 ]  There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior ( neuropsychopharmacology ), including the study of how drug dependence and  addiction  affect the  human brain . [ 2 ]  Molecular neuropharmacology involves the study of neurons and their  neurochemical  interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of  neurotransmitters ,  neuropeptides ,  neurohormones ,  neuromodulators ,  enzymes ,  second messengers ,  co-transporters ,  ion channels , and  receptor proteins  in the  central  and  peripheral nervous systems . Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including  pain , neurodegenerative diseases such as  Parkinson's disease  and  Alzheimer's disease , psychological disorders, addiction, and many others."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10620", "text": "Neuropharmacology did not appear in the scientific field until, in the early part of the 20th century, scientists were able to figure out a basic understanding of the nervous system and how nerves communicate between one another. Before this discovery, there were drugs that had been found that demonstrated some type of influence on the nervous system. In the 1930s, French scientists began working with a compound called phenothiazine in the hope of synthesizing a drug that would be able to combat malaria. Though this drug showed very little hope in the use against malaria-infected individuals, it was found to have sedative effects along with what appeared to be beneficial effects toward patients with Parkinson's disease. This black box method, wherein an investigator would administer a drug and examine the response without knowing how to relate drug action to patient response, was the main approach to this field, until, in the late 1940s and early 1950s, scientists were able to identify specific neurotransmitters, such as  norepinephrine  (involved in the constriction of blood vessels and the increase in heart rate and blood pressure),  dopamine  (the chemical whose shortage is involved in Parkinson's disease), and  serotonin  (soon to be recognized as deeply connected to depression [ citation needed ] ). In the 1950s, scientists also became better able to measure levels of specific neurochemicals in the body and thus correlate these levels with behavior. [ 3 ]  The invention of the  voltage clamp  in 1949 allowed for the study of ion channels and the nerve  action potential . These two major historical events in neuropharmacology allowed scientists not only to study how information is transferred from one neuron to another but also to study how a neuron processes this information within itself. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10621", "text": "Neuropharmacology is a very broad region of science that encompasses many aspects of the nervous system from single neuron manipulation to entire areas of the brain, spinal cord, and peripheral nerves. To better understand the basis behind  drug development , one must first understand how neurons communicate with one another. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10622", "text": "To understand the potential advances in medicine that neuropharmacology can bring, it is important to understand how human behavior and thought processes are transferred from neuron to neuron and how medications can alter the chemical foundations of these processes. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10623", "text": "Neurons are known as excitable cells because on its surface membrane there are an abundance of proteins known as ion-channels that allow small charged particles to pass in and out of the cell. The structure of the neuron allows chemical information to be received by its  dendrites , propagated through the  perikaryon  (cell body) and down its  axon , and eventually passing on to other neurons through its  axon terminal . These  voltage-gated ion channels  allow for rapid  depolarization  throughout the cell. This depolarization, if it reaches a certain threshold, will cause an  action potential . Once the action potential reaches the axon terminal, it will cause an influx of calcium ions into the cell. The calcium ions will then cause vesicles, small packets filled with  neurotransmitters , to bind to the cell membrane and release its contents into the synapse. This cell is known as the pre-synaptic neuron, and the cell that interacts with the neurotransmitters released is known as the post-synaptic neuron. Once the neurotransmitter is released into the synapse, it can either bind to receptors on the post-synaptic cell, the pre-synaptic cell can re-uptake it and save it for later transmission, or it can be broken down by enzymes in the synapse specific to that certain neurotransmitter. These three different actions are major areas where drug action can affect communication between neurons. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10624", "text": "There are two types of receptors that neurotransmitters interact with on a post-synaptic neuron. The first types of receptors are ligand-gated ion channels or LGICs. LGIC receptors are the fastest types of transduction from chemical signal to electrical signal. Once the neurotransmitter binds to the receptor, it will cause a conformational change that will allow ions to directly flow into the cell. The second types are known as G-protein-coupled receptors or GPCRs. These are much slower than LGICs due to an increase in the amount of biochemical reactions that must take place intracellularly. Once the neurotransmitter binds to the GPCR protein, it causes a cascade of intracellular interactions that can lead to many different types of changes in cellular biochemistry, physiology, and gene expression. Neurotransmitter/receptor interactions in the field of neuropharmacology are extremely important because many drugs that are developed today have to do with disrupting this binding process. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10625", "text": "Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, and receptors on neurons, with the goal of developing new drugs that will treat neurological disorders such as pain, neurodegenerative diseases, and psychological disorders (also known in this case as  neuropsychopharmacology ). There are a few technical words that must be defined when relating neurotransmission to receptor action: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10626", "text": "The following neurotransmitter/receptor interactions can be affected by synthetic compounds that act as one of the three above. Sodium/potassium ion channels can also be manipulated throughout a neuron to induce inhibitory effects of action potentials. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10627", "text": "The GABA neurotransmitter mediates the fast synaptic inhibition in the central nervous system. When GABA is released from its pre-synaptic cell, it will bind to a receptor (most likely the GABA A  receptor) that causes the post-synaptic cell to hyperpolarize (stay below its action potential threshold). This will counteract the effect of any excitatory manipulation from other neurotransmitter/receptor interactions. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10628", "text": "This GABA A  receptor contains many binding sites that allow conformational changes and are the primary target for drug development. The most common of these binding sites, benzodiazepine, allows for both agonist and antagonist effects on the receptor. A common drug,  diazepam , acts as an allosteric enhancer at this binding site. [ 5 ]  Another receptor for GABA, known as GABA B , can be enhanced by a molecule called baclofen. This molecule acts as an agonist, therefore activating the receptor, and is known to help control and decrease spastic movement. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10629", "text": "The  dopamine  neurotransmitter mediates synaptic transmission by binding to five specific GPCRs. These five receptor proteins are separated into two classes due to whether the response elicits an excitatory or inhibitory response on the post-synaptic cell. There are many types of drugs, legal and illegal, that affect dopamine and its interactions in the brain. With Parkinson's disease, a disease that decreases the amount of dopamine in the brain, the dopamine precursor Levodopa is given to the patient due to the fact that dopamine cannot cross the  blood\u2013brain barrier  and L-dopa can. Some dopamine agonists are also given to Parkinson's patients that have a disorder known as restless leg syndrome or RLS. Some examples of these are  ropinirole  and  pramipexole . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10630", "text": "Psychological disorders like that of  attention deficit hyperactivity disorder  (ADHD) can be treated with drugs like  methylphenidate  (also known as Ritalin), which block the re-uptake of dopamine by the pre-synaptic cell, thereby providing an increase of dopamine left in the synaptic gap. This increase in synaptic dopamine will increase binding to receptors of the post-synaptic cell. This same mechanism is also used by other illegal and more potent stimulant drugs such as  cocaine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10631", "text": "The neurotransmitter  serotonin  has the ability to mediate synaptic transmission through either GPCR's or LGIC receptors. The excitatory or inhibitory post-synaptic effects of serotonin are determined by the type of receptor expressed in a given brain region. The most popular and widely used drugs for the regulation of serotonin during depression are known as  selective serotonin reuptake inhibitors  (SSRIs). These drugs inhibit the transport of serotonin back into the pre-synaptic neuron, leaving more serotonin in the synaptic gap. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10632", "text": "Before the discovery of SSRIs, there were also drugs that inhibited the enzyme that breaks down serotonin.  Monoamine oxidase inhibitors  (MAOIs) increased the amount of serotonin in the synapse, but had many side-effects including intense migraines and high blood pressure. This was eventually linked to the drugs interacting with a common chemical known as  tyramine  found in many types of food. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10633", "text": "Ion channels located on the surface membrane of the neuron allows for an influx of sodium ions and outward movement of potassium ions during an action potential. Selectively blocking these ion channels will decrease the likelihood of an action potential to occur. The drug  riluzole  is a neuroprotective drug that blocks sodium ion channels. Since these channels cannot activate, there is no action potential, and the neuron does not perform any transduction of chemical signals into electrical signals and the signal does not move on. This drug is used as an anesthetic as well as a sedative. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10634", "text": "One form of behavioral neuropharmacology focuses on the study of drug dependence and how drug addiction affects the human mind. Most research has shown that the major part of the brain that reinforces addiction through neurochemical reward is the  nucleus accumbens . The image to the right shows how dopamine is projected into this area. Long-term excessive alcohol use can cause  dependence  and  addiction . How this addiction occurs is described below. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10635", "text": "Alcohol's rewarding and reinforcing (i.e.,  addictive ) properties are mediated through its effects on  dopamine  neurons in the  mesolimbic reward pathway , which connects the  ventral tegmental area  to the  nucleus accumbens  (NAcc). [ 9 ] [ 10 ]  One of alcohol's primary effects is the allosteric inhibition of  NMDA receptors  and facilitation of  GABA A  receptors  (e.g., enhanced GABA A  receptor-mediated  chloride  flux through  allosteric regulation  of the receptor). [ 11 ]  At high doses,  ethanol  inhibits most  ligand gated ion channels  and  voltage gated ion channels  in neurons as well. [ 11 ]  Alcohol inhibits  sodium\u2013potassium pumps  in the  cerebellum  and this is likely how it impairs cerebellar computation and body co-ordination. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10636", "text": "With acute alcohol consumption,  dopamine  is released in the  synapses  of the mesolimbic pathway, in turn heightening activation of postsynaptic  D1 receptors . [ 9 ] [ 10 ]  The activation of these receptors triggers postsynaptic internal signaling events through  protein kinase A  which ultimately  phosphorylate   cAMP response element binding protein  (CREB), inducing CREB-mediated changes in  gene expression . [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10637", "text": "With chronic alcohol intake, consumption of ethanol similarly induces CREB phosphorylation through the D1 receptor pathway, but it also alters  NMDA receptor  function through phosphorylation mechanisms; [ 9 ] [ 10 ]  an adaptive  downregulation  of the D1 receptor pathway and CREB function occurs as well. [ 9 ] [ 10 ]   Chronic consumption is also associated with an effect on CREB phosphorylation and function via postsynaptic NMDA receptor signaling cascades through a  MAPK/ERK pathway  and  CAMK -mediated pathway. [ 10 ]   These modifications to CREB function in the mesolimbic pathway  induce expression  (i.e., increase gene expression) of  \u0394FosB  in the  NAcc , [ 10 ]  where \u0394FosB is the \"master control protein\" that, when overexpressed in the NAcc, is  necessary and sufficient  for the development and maintenance of an addictive state (i.e., its overexpression in the nucleus accumbens produces and then directly modulates compulsive alcohol consumption). [ 10 ] [ 14 ] [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10638", "text": "Parkinson's disease  is a  neurodegenerative disease  described by the selective loss of  dopaminergic  neurons located in the  substantia nigra . Today, the most commonly used drug to combat this disease is levodopa or  L-DOPA . This precursor to dopamine can penetrate through the  blood\u2013brain barrier , whereas the neurotransmitter dopamine cannot. There has been extensive research to determine whether L-dopa is a better treatment for Parkinson's disease rather than other dopamine agonists. Some believe that the long-term use of L-dopa will compromise neuroprotection and, thus, eventually lead to dopaminergic cell death. Though there has been no proof,  in-vivo  or  in-vitro , some still believe that the long-term use of dopamine agonists is better for the patient. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10639", "text": "While there are a variety of hypotheses that have been proposed for the cause of  Alzheimer's disease , the knowledge of this disease is far from complete to explain, making it difficult to develop methods for treatment. In the brain of Alzheimer's patients, both neuronal nicotinic acetylcholine (nACh) receptors and NMDA receptors are known to be down-regulated. Thus, four anticholinesterases, such as  Donepezil  and  Rivastigmine , have been developed and approved by the  U.S. Food and Drug Administration  (FDA) for the treatment in the U.S.A. However, these are not ideal drugs, considering their side-effects and limited effectiveness. The excessive stimulation of muscarinic and nicotinic receptors by acetylcholine may contribute to the side effects that anticholinesterases have. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10640", "text": "One promising drug,  nefiracetam , is being developed for the treatment of Alzheimer's and other patients with dementia, and has unique actions in potentiating the activity of both nACh receptors and NMDA receptors. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10641", "text": "With advances in technology and our understanding of the nervous system, the development of drugs will continue with increasing drug  sensitivity and specificity .  Structure\u2013activity relationships  are a major area of research within neuropharmacology; an attempt to modify the effect or the potency (i.e., activity) of bioactive chemical compounds by modifying their chemical structures. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10642", "text": "In  pharmacology  and  biochemistry ,  allosteric modulators  are a group of substances that bind to a  receptor  to change that receptor's response to stimuli. Some of them, like  benzodiazepines  or  alcohol , function as  psychoactive  drugs. [ 1 ]  The site that an allosteric modulator binds to (i.e., an  allosteric site ) is not the same one to which an endogenous  agonist  of the receptor would bind (i.e., an  orthosteric site ). Modulators and agonists can both be called receptor  ligands . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10643", "text": "Allosteric modulators can be 1 of 3 types either: positive, negative or neutral. Positive types increase the response of the receptor by increasing the probability that an agonist will bind to a receptor (i.e.  affinity ), increasing its ability to activate the receptor (i.e.  efficacy ), or both. Negative types decrease the agonist affinity and/or efficacy. Neutral types don't affect agonist activity but can stop other modulators from binding to an allosteric site. Some modulators also work as allosteric agonists and yield an agonistic effect by themselves. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10644", "text": "The term \"allosteric\" derives from the Greek language.  Allos  means \"other\", and  stereos , \"solid\" or \"shape\". This can be translated to \"other shape\", which indicates the  conformational  changes within receptors caused by the modulators through which the modulators affect the receptor function. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10645", "text": "Allosteric modulators can alter the affinity and efficacy of other substances acting on a receptor. A modulator may also increase affinity and lower efficacy or vice versa. [ 4 ]   Affinity  is the ability of a substance to bind to a  receptor .  Efficacy  is the ability of a substance to activate a receptor, given as a percentage of the ability of the substance to activate the receptor as compared to the receptor's endogenous  agonist . If efficacy is zero, the substance is considered an  antagonist . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10646", "text": "The site to which endogenous agonists bind to is named the  orthosteric site . Modulators don't bind to this site. They bind to any other suitable sites, which are named  allosteric sites . [ 2 ]  Upon binding, modulators generally change the three-dimensional structure (i.e.  conformation ) of the receptor. This will often cause the orthosteric site to also change, which can alter the effect of an agonist binding. [ 4 ]  Allosteric modulators can also stabilize one of the normal configurations of a receptor. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10647", "text": "In practice, modulation can be complicated. A modulator may function as a  partial agonist , meaning it doesn't need the agonist it modulates to yield agonistic effects. [ 6 ]  Also, modulation may not affect the affinities or efficacies of different agonists equally. If a group of different agonists that should have the same action bind to the same receptor, the agonists might not be modulated the same by some modulators. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10648", "text": "A modulator can have 3 effects within a receptor. One is its capability or incapability to activate a receptor (2 possibilities). The other two are agonist affinity and efficacy. They may be increased, lowered or left unaffected (3 and 3 possibilities). This yields 17 possible modulator combinations. [ 4 ]  There are 18 (=2*3*3) if neutral modulator type is also included."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10649", "text": "For all practical considerations, these combinations can be generalized only to 5 classes [ 4 ]  and 1 neutral:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10650", "text": "Due to the variety of locations on receptors that can serve as sites for allosteric modulation, as well as the lack of regulatory sites surrounding them, allosteric modulators can act in a wide variety of mechanisms. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10651", "text": "Some allosteric modulators induce a  conformational  change in their target receptor which increases the binding affinity and/or efficacy of the receptor agonist. [ 2 ]  Examples of such modulators include  benzodiazepines  and  barbiturates , which are  GABA A  receptor positive allosteric modulators . Benzodiazepines like  diazepam  bind between \u03b1 and \u03b3 subunits of the GABA A  receptor  ion channels  and increase the channel opening frequency, but not the duration of each opening. Barbiturates like  phenobarbital  bind \u03b2 domains and increase the duration of each opening, but not the frequency. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10652", "text": "Some modulators act to stabilize conformational changes associated with the agonist-bound state. This increases the probability that the receptor will be in the active conformation, but does not prevent the receptor from switching back to the inactive state. With a higher probability of remaining in the active state, the receptor will bind agonist for longer.  AMPA receptors  modulated by  aniracetam  and  CX614  will deactivate slower, and facilitate more overall cation transport. This is likely accomplished by aniracetam or CX614 binding to the back of the \"clam shell\" that contains the binding site for  glutamate , stabilizing the closed conformation associated with activation of the AMPA receptor. [ 5 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10653", "text": "Overall signal can be increased by preventing the  desensitization  of a receptor. Desensitization prevents a receptor from activating, despite the presence of an agonist. This is often caused by repeated or intense exposures to an agonist. Eliminating or reducing this phenomenon increases the receptor's overall activation. AMPA receptors are susceptible to desensitization via a disruption of a ligand-binding domain dimer interface.  Cyclothiazide  has been shown to stabilize this interface and slow desensitization, and is therefore considered a positive allosteric modulator. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10654", "text": "Modulators can directly regulate receptors rather than affecting the binding of the agonist. Similar to stabilizing the bound conformation of the receptor, a modulator that acts in this mechanism stabilizes a conformation associated with the active or inactive state. This increases the probability that the receptor will conform to the stabilized state, and modulate the receptor's activity accordingly.  Calcium-sensing receptors  can be modulated in this way by adjusting the  pH . Lower pH increases the stability of the inactive state, and thereby decreases the sensitivity of the receptor. It is speculated that the changes in charges associated with adjustments to pH cause a conformational change in the receptor favoring inactivation. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10655", "text": "Modulators that increase only the affinity of partial and full agonists allow their efficacy maximum to be reached sooner at lower agonist concentrations \u2013 i.e. the slope and plateau of a  dose-response curve  shift to lower concentrations. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10656", "text": "Efficacy increasing modulators increase maximum efficacy of partial agonists. Full agonists already activate receptors fully so modulators don't affect their maximum efficacy, but somewhat shift their response curves to lower agonist concentrations. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10657", "text": "Related receptors have orthosteric sites that are very similar in structure, as  mutations  within this site may especially lower receptor function. This can be harmful to organisms, so  evolution  doesn't often favor such changes. Allosteric sites are less important for receptor function, which is why they often have great variation between related receptors. This is why, in comparison to orthosteric drugs, allosteric drugs can be very  specific , i.e. target their effects only on a very limited set of receptor types. However, such allosteric site variability occurs also between species so the effects of allosteric drugs vary greatly between species. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10658", "text": "Modulators can't turn receptors fully on or off as modulator action depends on endogenous ligands like  neurotransmitters , which have limited and controlled production within body. This can lower  overdose  risk relative to similarly acting orthosteric drugs. It may also allow a strategy where doses large enough to saturate receptors can be taken safely to prolong the drug effects. [ 4 ]  This also allows receptors to activate at prescribed times (i.e. in response to a stimulus) instead of being activated constantly by an agonist, irrespective of timing or purpose. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10659", "text": "Modulators affect the existing responses within tissues and can allow tissue specific drug targeting. This is unlike orthosteric drugs, which tend to produce a less targeted effect within body on all of the receptors they can bind to. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10660", "text": "Some modulators have also been shown to lack the desensitizing effect that some agonists have.  Nicotinic acetylcholine receptors , for example, quickly desensitize in the presence of agonist drugs, but maintain normal function in the presence of PAMs. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10661", "text": "Allosteric modulation has demonstrated as beneficial to many conditions that have been previously difficult to control with other pharmaceuticals. These include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10662", "text": "L -\u03b1-Glycerophosphorylcholine  ( alpha-GPC ,  choline alfoscerate ,  sn -glycero-3-phosphocholine ) is a natural  choline  compound found in the brain. It is also a  parasympathomimetic   acetylcholine  precursor [ 1 ]  which has been investigated for its potential for the treatment of  Alzheimer's disease [ 2 ]  and other  dementias . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10663", "text": "Alpha-GPC rapidly delivers  choline  to the brain across the  blood\u2013brain barrier  and is a biosynthetic precursor of  acetylcholine . [ 2 ]  It is a non-prescription drug in most countries. The  FDA  determined that intake of no more than 196.2\u00a0mg/person/day is considered  generally recognized as safe  (GRAS). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10664", "text": "Industrially, alpha-GPC is produced by the chemical or enzymatic deacylation of  phosphatidylcholine  enriched soya  phospholipids  followed by  chromatographic purification . Alpha-GPC may also be derived in small amounts from highly purified soy  lecithin  as well as from purified sunflower lecithin. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10665", "text": "Alpha-GPC metabolizes to  trimethylamine n-oxide  in the gastrointestinal tract, which has implications for cardiovascular health. In one study, risk of stroke over a ten-year period was increased by about 40% in users of alpha-GPC. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10666", "text": "Founded in 1961, the  American College of Neuropsychopharmacology (ACNP)  is a professional organization of leading  brain  and  behavior  scientists. [ 1 ]  The principal functions of the College are research and education.\u00a0Their goals in research are to offer investigators an opportunity for cross-disciplinary communication and to promote the application of various scientific disciplines to the study of the brain's effect on behavior, with a focus on  mental illness  of all forms.\u00a0 Their educational goals are to encourage young scientists to enter research careers in  neuropsychopharmacology  and to develop and provide accurate information about  behavioral disorders  and their pharmacological treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10667", "text": "The College is an  honorific  society.\u00a0 Members are selected primarily on the basis of their original research contributions to the broad field of  neuroscience . [ 2 ] \u00a0 The membership of the College is drawn from scientists in multiple fields including behavioral  pharmacology ,  neuroimaging ,  chronobiology , clinical  psychopharmacology ,  epidemiology ,  genetics ,  molecular biology ,  neurochemistry ,  neuroendocrinology ,  neuroimmunology ,  neurology ,  neurophysiology ,  psychiatry , and  psychology . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10668", "text": "The annual meeting of the College is a closed meeting; only the ACNP members and their invited guests may attend. [ 4 ]  Because of the College's intense concern with, and involvement in, the education and training of tomorrow's brain scientists, the College selects a number of young scientists to be invited to the annual meeting through a competitive process open to all early career researchers. This meeting, a mix of foremost brain and behavior research world-wide, is designed to encourage dialogue, discussion, and synergy by those attending."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10669", "text": "The ACNP offers the following awards. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10670", "text": "The Springer-Nature Publishing Group journals  Neuropsychopharmacology  and  NPP-Digital Psychiatry and Neuroscience  are their official publications.  Neuropsychopharmacology   [ 6 ]  was first published in 1987 and  NPP-Digital Psychiatry and Neuroscience  is an Open Access journal that started in 2023."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10671", "text": "Anabaseine  (3,4,5,6-tetrahydro-2,3\u2032-bipyridine) is an  alkaloid   toxin  produced by  Nemertines  worms and  Aphaenogaster  ants. [ 1 ]  It is structurally similar to  nicotine  and  anabasine . [ 2 ]  Similarly, it has been shown to act as an  agonist  on most  nicotinic acetylcholine receptors  in the  central nervous system  and  peripheral nervous system . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10672", "text": "The  iminium  form of anabaseine binds to most  nicotinic acetylcholine receptors  in both the  peripheral nervous system  and  central nervous system . But, there is a higher binding affinity for receptors in the brain with a \u03b17 subunit, as well as skeletal muscle receptors. [ 3 ]  Binding causes the  depolarization  of neurons, and induces the release of both  dopamine  and  norepinephrine . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10673", "text": "Anabaseine causes paralysis in  crustaceans  and  insects , but not in  vertebrates , presumably by acting as an agonist on peripheral neuromuscular nicotinic acetylcholine receptors. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10674", "text": "The anabaseine molecule consists of a non- aromatic  tetrahydropyridine ring connected to the 3rd carbon of a 3- pyridyl  ring. It can exist in three forms at physiological pH:  a  ketone ,  imine , or  iminium  structure. [ 2 ]  Due to conjugation between the imine and 3-pyridyl ring, anabaseine exists as a nearly coplanar molecule."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10675", "text": "Spath and Mamoli first synthesized anabaseine in 1936. [ 4 ]  The researchers reacted  benzoic anhydride  with \u03b4- valerolactam  to yield  N -benzoylpiperidone. Then,  N -benzoylpiperidone is reacted with nicotinic acid ethyl ester to produce \u03b1-nicotinoyl- N -benzoyl-2-piperidone. This product then is  decarboxylated , undergoes a  ring closure , and  amide hydrolysis  to form anabaseine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10676", "text": "Additional synthetic strategies have since been developed by Bloom, [ 5 ]  Zoltewicz, [ 6 ]  Smith, [ 7 ]  and Villemin. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10677", "text": "Due to anabaseine\u2019s fairly non-specific binding to nicotinic acetylcholine receptors, the molecule was largely discarded as a useful tool in research or medicine. However, anabaseine derivatives have been identified with a more selective \u03b17 binding profile. One such derivative ( GTS-21 , 3-(2,4-dimethoxybenzylidene)-anabaseine) has been studied as a drug candidate for cognitive and memory deficits, particularly associated with  schizophrenia ; it has been studied in  phase II clinical trials  without progression to phase III. [ 9 ]  Moreover, the modification of the anabaseine pyridine nucleus led to the obtainment of new derivatives endowed with binding and functional selectivity for the \u03b13\u03b24 nicotinic acetylcholine receptor subtype. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10678", "text": "Chemical"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10679", "text": "Neurological"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10680", "text": "Biohappiness , or  bio-happiness , is the elevation of well-being in humans and other animals through biological methods, including  germline engineering  through screening embryos with genes associated with a high level of happiness, or the use of drugs intended to raise baseline levels of happiness. The object is to facilitate the achievement of a state of \"better than well\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10681", "text": "Proponents of biohappiness include the  transhumanist  philosopher  David Pearce , whose goal is to  end the suffering  of all  sentient  beings [ 2 ]  and the Canadian ethicist  Mark Alan Walker . Walker coined the term \"bio-happiness\" to describe the idea of directly manipulating the biological roots of happiness in order to increase it. [ 3 ]  He sought to defend it on the grounds that happiness ought to be of interest to a wide range of moral theorists; and that  hyperthymia , a state of high baseline happiness, is associated with better outcomes in health and human achievement. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10682", "text": "A significant danger of bio happiness is the ethical problems of altering the natural human emotional state through technological methods. Molding organic brain chemistry or genetic structures to achieve happiness would raise concerns about the authenticity of the human body/experience. [ 3 ] [ 6 ]  It is argued that tampering with the state of the human mind and creating an eternal happiness would disrupt the natural range of emotions that a human will experience. Sadness, grief and anger are all crucial for emotional growth, empathy and understanding. Additionally, the long term effects of bio happiness are not yet understood, meaning later down the line, issues could arise. Loss of individuality, emotional depth and the risk of being dependent on an external source for happiness are all concerns regarding this. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10683", "text": "A  counterirritant  is a substance which creates irritation or mild inflammation in one location with the goal of lessening discomfort and/or inflammation in another location. [ 1 ]  This strategy falls into the more general category of  counterstimulation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10684", "text": "Topical counter-irritants are non-analgesic, non-anesthetic substances or treatments used to treat pain.  Capsaicin ,  menthol  (mint oil),  methyl salicylate , and  camphor  are examples of counterirritants. Heat and cold therapy and massage relieve pain by counterstimulation. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10685", "text": "The US  Food and Drug Administration  defines a counterirritant as \"An externally applied substance that causes irritation or mild inflammation of the skin for the purpose of relieving pain in muscles, joints and viscera distal to the site of application. They differ from the  anesthetics ,  analgesics , and  antipruritic  agents, however, in that the pain relief they produce results from stimulation\u2014rather than depression\u2014of the cutaneous sensory receptors and occurs in structures of the body other than the skin areas to which they are applied as for example, in joints, muscles,  tendons  and certain viscera. The use of these products dates from antiquity.\" [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10686", "text": "This  dermatologic   drug  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10687", "text": "A  ganglionic blocker  (or  ganglioplegic ) is a type of medication that inhibits transmission between  preganglionic  and  postganglionic  neurons in the  autonomic nervous system , often by acting as a  nicotinic receptor antagonist . [ 1 ]  Nicotinic acetylcholine receptors are found on skeletal muscle, but also within the route of transmission for the parasympathetic and sympathetic nervous system (which together comprise the autonomic nervous system). More specifically, nicotinic receptors are found within the ganglia of the autonomic nervous system, allowing outgoing signals to be transmitted from the presynaptic to the postsynaptic cells. Thus, for example, blocking nicotinic acetylcholine receptors blocks both sympathetic (excitatory) and parasympathetic (calming) stimulation of the heart. The nicotinic antagonist hexamethonium, for example, does this by blocking the transmission of outgoing signals across the autonomic ganglia at the postsynaptic nicotinic acetylcholine receptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10688", "text": "Because ganglionic blockers block both the  parasympathetic nervous system  and  sympathetic nervous system , the effect of these drugs depends upon the dominant tone in the organ system. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10689", "text": "The opposite of a ganglionic blocker is referred to as a  ganglionic stimulant . Some substances can exhibit both stimulating and blocking effects on autonomic ganglia, depending on dosage and/or duration of action. An example for such a \"dual\" action is nicotine, which does this via depolarization block (see classification below)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10690", "text": "The first ganglion-blocker to be used clinically was  tetraethylammonium , although it was soon superseded by better drugs. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10691", "text": "Nicotinic receptor antagonists:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10692", "text": "Nicotinic receptor agonists (acting through  depolarization block ):"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10693", "text": "Blocking ACh release in autonomic ganglia (although these have many other actions elsewhere):"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10694", "text": "Ganglionic blockers are used less frequently now than they were in the past, because  antihypertensives  with fewer side effects are now available.  Hexamethonium  has been described as the \"first effective antihypertensive drug\". [ 4 ]  However, they are still used in some emergency situations, such as  aortic dissection  or  autonomic dysreflexia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10695", "text": "The  effects of long-term benzodiazepine use  include  drug dependence  as well as the possibility of adverse effects on cognitive function, physical health, and mental health. [ 1 ]  Long-term use is sometimes described as use not shorter than three months. [ 2 ]  Benzodiazepines are generally effective when used therapeutically in the short term, [ 3 ]  but even then the risk of dependency can be significantly high. There are significant physical, mental and social risks associated with the long-term use of  benzodiazepines . [ 3 ]  Although anxiety can temporarily increase as a withdrawal symptom, there is evidence that a reduction or  withdrawal from benzodiazepines  can lead to a reduction of anxiety symptoms in the long run. [ 4 ] [ 5 ]  Due to these increasing physical and mental symptoms from long-term use of benzodiazepines, slow withdrawal is recommended for long-term users. [ 6 ] [ 7 ] [ 8 ] [ 9 ]  Not everyone, however, experiences problems with long-term use. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10696", "text": "Some of the symptoms that could possibly occur as a result of a withdrawal from benzodiazepines after long-term use include emotional clouding, [ 1 ]  flu-like symptoms, [ 5 ]   suicide , [ 11 ]   nausea ,  headaches ,  dizziness ,  irritability ,  lethargy , sleep problems,  memory impairment , personality changes,  aggression ,  depression , social deterioration as well as employment difficulties, while others never have any side effects from long-term benzodiazepine use. Abruptly or rapidly stopping benzodiazepines can be dangerous; when withdrawing, a gradual reduction in dosage is recommended, under professional supervision. [ 7 ] [ 12 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10697", "text": "While benzodiazepines are highly effective in the short term, adverse effects associated with long-term use, including impaired cognitive abilities, memory problems, mood swings, and overdoses when combined with other drugs, may make the risk-benefit ratio unfavourable. In addition, benzodiazepines have reinforcing properties in some individuals and thus are considered to be addictive drugs, especially in individuals that have a \"drug-seeking\" behavior; further, a  physical dependence  can develop after a few weeks or months of use. [ 13 ]  Many of these adverse effects associated with long-term use of benzodiazepines begin to show improvements three to six months after withdrawal. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10698", "text": "Other concerns about the effects associated with long-term benzodiazepine use, in some, include dose escalation,  benzodiazepine use disorder ,  tolerance  and  benzodiazepine dependence  and benzodiazepine withdrawal problems. Both physiological tolerance and dependence can be associated with worsening the adverse effects associated with benzodiazepines. Increased risk of death has been associated with long-term use of benzodiazepines in several studies; however, other studies have not found increased  mortality . Due to conflicting findings in studies regarding benzodiazepines and increased risks of death including from cancer, further research in long-term use of benzodiazepines and mortality risk has been recommended; most of the available research has been conducted in prescribed users, even less is known about illicit misusers. [ 16 ] [ 17 ]  The long-term use of benzodiazepines is controversial and has generated significant debate within the medical profession. Views on the nature and severity of problems with long-term use of benzodiazepines differ from expert to expert and even from country to country; some experts even question whether there is any problem with the long-term use of benzodiazepines. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10699", "text": "Effects of long-term benzodiazepine use may include  disinhibition , impaired concentration and memory,  depression , [ 19 ] [ 20 ]  as well as  sexual dysfunction . [ 6 ] [ 21 ]  The long-term effects of benzodiazepines may differ from the adverse effects seen after acute administration of benzodiazepines. [ 22 ]  An analysis of cancer patients found that those who took  tranquillisers  or  sleeping tablets  had a substantially poorer quality of life on all measurements conducted, as well as a worse clinical picture of symptomatology. Worsening of symptoms such as  fatigue ,  insomnia ,  pain ,  dyspnea  and  constipation  was found when compared against those who did not take tranquillisers or sleeping tablets. [ 23 ]  Most individuals who successfully discontinue  hypnotic  therapy after a gradual taper and do not take benzodiazepines for 6 months have less severe sleep and anxiety problems, are less distressed and have a general feeling of improved health at 6-month follow-up. [ 15 ]  The use of benzodiazepines for the treatment of anxiety has been found to lead to a significant increase in healthcare costs due to accidents and other adverse effects associated with the long-term use of benzodiazepines. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10700", "text": "Long-term benzodiazepine use can lead to a generalised impairment of  cognition , including sustained attention, verbal learning and  memory  and  psychomotor ,  visuo-motor  and  visuo-conceptual  abilities. [ 25 ] [ 26 ]  Transient changes in the brain have been found using  neuroimaging  studies, but no brain abnormalities have been found in patients treated long term with benzodiazepines. [ 27 ]  When benzodiazepine users cease long-term benzodiazepine therapy, their cognitive function improves in the first six months, although deficits may be permanent or take longer than six months to return to baseline. [ 28 ]  In the elderly, long-term benzodiazepine therapy is a risk factor for amplifying cognitive decline, [ 29 ]  although gradual  withdrawal  is associated with improved cognitive status. [ 30 ]  A study of  alprazolam  found that 8 weeks administration of alprazolam resulted in deficits that were detectable after several weeks but not after 3.5 years. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10701", "text": "Sleep can be adversely affected by benzodiazepine dependence. Possible adverse effects on sleep include induction or worsening of sleep disordered breathing. Like  alcohol ,  benzodiazepines  are commonly used to treat insomnia in the short term (both prescribed and self-medicated), but worsen sleep in the long term. Although benzodiazepines can put people to sleep, while asleep, the drugs disrupt sleep architecture, decreasing sleep time, delayed and decreased REM sleep, increased alpha and beta activity, decreased  K complexes  and delta activity, and decreased deep  slow-wave sleep  (i.e., NREM stages 3 and 4, the most restorative part of sleep for both energy and mood). [ 32 ] [ 33 ] [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10702", "text": "The long-term use of benzodiazepines may have a similar effect on the brain as  alcohol , and is also implicated in  depression ,  anxiety , post-traumatic stress disorder (PTSD), mania, psychosis,  sleep disorders , sexual dysfunction, delirium, and neurocognitive disorders. [ 35 ] [ 36 ]  However a 2016 study found no association between long-term usage and dementia. [ 37 ]  As with alcohol, the effects of benzodiazepine on neurochemistry, such as decreased levels of  serotonin  and  norepinephrine , are believed to be responsible for their effects on mood and anxiety. [ 38 ] [ 39 ] [ 40 ] [ 41 ] [ 42 ] [ 43 ]  Additionally, benzodiazepines can indirectly cause or worsen other psychiatric symptoms (e.g., mood, anxiety, psychosis, irritability) by worsening sleep (i.e., benzodiazepine-induced sleep disorder). These effects are  paradoxical  to the use of benzodiazepines, both clinically and  non-medically , in management of mental health conditions. [ 44 ] [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10703", "text": "Long-term benzodiazepine use may lead to the creation or exacerbation of physical and mental health conditions, which improve after six or more months of abstinence. After a period of about 3 to 6 months of abstinence after completion of a gradual-reduction regimen, marked improvements in mental and physical wellbeing become apparent. For example, one study of hypnotic users gradually withdrawn from their hypnotic medication reported after six months of abstinence that they had less severe sleep and anxiety problems, were less distressed, and had a general feeling of improved health. Those who remained on  hypnotic  medication had no improvements in their insomnia, anxiety, or general health ratings. [ 15 ]  A study found that individuals having withdrawn from benzodiazepines showed a marked reduction in use of medical and mental health services. [ 46 ] [ non-primary source needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10704", "text": "Approximately half of patients attending mental health services for conditions including  anxiety disorders  such as  panic disorder  or  social phobia  may be the result of alcohol or benzodiazepine dependence. [ 47 ]  Sometimes anxiety disorders precede  alcohol  or benzodiazepine dependence but the alcohol or  benzodiazepine dependence  often acts to keep the anxiety disorders going and often progressively makes them worse. [ 47 ] [ non-primary source needed ]  Many people who are addicted to alcohol or prescribed benzodiazepines decide to quit when it is explained to them they have a choice between ongoing ill mental health or quitting and recovering from their symptoms. It was noted that because every individual has an individual sensitivity level to alcohol or sedative hypnotic drugs, what one person can tolerate without ill health will cause another to develop very ill health, and that even moderate drinking in sensitive individuals can cause rebound anxiety syndromes and sleep disorders. A person who experiences the toxic effects of alcohol or benzodiazepines will not benefit from other therapies or medications as they do not address the root cause of the symptoms. [ 47 ]  Recovery from benzodiazepine dependence tends to take a lot longer than recovery from alcohol, [ 47 ] [ 48 ]  but people can regain their previous good health. [ 47 ] [ medical citation needed ]  A review of the literature regarding benzodiazepine  hypnotic  drugs concluded that these drugs cause an unjustifiable risk to the individual and to public health. The risks include  dependence , accidents and other adverse effects. Gradual discontinuation of hypnotics leads to improved health without worsening of sleep. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10705", "text": "Daily users of benzodiazepines are also at a higher risk of experiencing  psychotic  symptomatology such as  delusions  and  hallucinations . [ 50 ]  A study found that of 42 patients treated with alprazolam, up to a third of long-term users of the benzodiazepine drug alprazolam ( Xanax ) develop  depression . [ 40 ]  Studies have shown that long-term use of benzodiazepines and the benzodiazepine receptor agonist  nonbenzodiazepine   Z drugs  are associated with causing depression as well as a markedly raised suicide risk and an overall increased  mortality  risk. [ 41 ] [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10706", "text": "A study of 50 patients who attended a benzodiazepine withdrawal clinic found that, after several years of chronic benzodiazepine use, a large portion of patients developed health problems including  agoraphobia ,  irritable bowel syndrome ,  paraesthesiae , increasing anxiety, and  panic attacks , which were not preexisting. The mental health and physical health symptoms induced by long-term benzodiazepine use gradually improved significantly over a period of a year following completion of a slow withdrawal. Three of the 50 patients had wrongly been given a preliminary diagnosis of  multiple sclerosis  when the symptoms were actually due to chronic benzodiazepine use. Ten of the patients had taken  drug overdoses  whilst on benzodiazepines, despite the fact that only two of the patients had any prior history of depressive symptomatology. After withdrawal, no patients took any further overdoses after one year post-withdrawal. The cause of the deteriorating mental and physical health in a significant proportion of patients was hypothesised to be caused by increasing tolerance where withdrawal-type symptoms emerged, despite the administration of stable prescribed doses. [ 52 ]  Another theory is that chronic benzodiazepine use causes subtle increasing toxicity, which in turn leads to increasing psychopathology in long-term users of benzodiazepines. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10707", "text": "Long-term use of benzodiazepines can induce  perceptual  disturbances and  depersonalization  in some people, even in those taking a stable daily dosage, and it can also become a  protracted withdrawal  feature of the  benzodiazepine withdrawal syndrome . [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10708", "text": "In addition, chronic use of benzodiazepines is a risk factor for  blepharospasm . [ 55 ]  Drug-induced symptoms that resemble withdrawal-like effects can occur on a set dosage as a result of prolonged use, also documented with  barbiturate -like substances, as well as alcohol and  benzodiazepines . This demonstrates that the effects from chronic use of benzodiazepine drugs are not unique but occur with other GABAergic  sedative  hypnotic drugs, i.e., alcohol and barbiturates. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10709", "text": "Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department. [ 57 ]   Diazepam  and  clonazepam  have been found to have long-lasting, but not permanent, immunotoxic effects in fetuses of rats. However, single very high doses of diazepam have been found to cause lifelong immunosuppression in neonatal rats. No studies have been done to assess the immunotoxic effects of diazepam in humans; however, high prescribed doses of diazepam, in humans, have been found to be a major risk of pneumonia, based on a study of people with tetanus. It has been proposed that diazepam may cause long-lasting changes to the GABA A  receptors with resultant long-lasting disturbances to behaviour,  endocrine  function and immune function. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10710", "text": "Use of prescribed benzodiazepines is associated with an increased rate of suicide or attempted  suicide . The prosuicidal effects of benzodiazepines are suspected to be due to a psychiatric disturbance caused by side effects or withdrawal symptoms. [ 11 ]  Because benzodiazepines in general may be associated with increased suicide risk, care should be taken when prescribing, especially to at-risk patients. [ 59 ] [ 60 ]  Depressed adolescents who were taking benzodiazepines were found to have a greatly increased risk of  self-harm  or  suicide , although the sample size was small. The effects of benzodiazepines in individuals under the age of 18 requires further research. Additional caution is required in using benzodiazepines in depressed adolescents. [ 61 ]   Benzodiazepine dependence  often results in an increasingly deteriorating clinical picture, which includes social deterioration leading to comorbid  alcohol use disorder  and  substance use disorder .  Benzodiazepine misuse  or misuse of other  CNS depressants  increases the risk of suicide in drug misusers. [ 62 ] [ 63 ]  Benzodiazepine has several risks based on its biochemical function and symptoms associated with this medication like exacerbation of sleep apnea, sedation, suppression of self-care functions, amnesia and disinhibition are suggested as a possible explanation to the increase in mortality. Studies also demonstrate that an increased mortality associated with benzodiazepine use has been clearly documented among 'drug misusers'. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10711", "text": "There has been some controversy around the possible link between benzodiazepine use and development of cancer; early cohort studies in the 1980s suggested a possible link, but follow-up case-control studies have found no link between benzodiazepines and cancer. In the second U.S. national cancer study in 1982, the  American Cancer Society  conducted a survey of over 1.1 million participants. A markedly increased risk of cancer was found in users of sleeping pills, mainly benzodiazepines. [ 64 ]  Fifteen  epidemiologic  studies have suggested that  benzodiazepine  or  nonbenzodiazepine   hypnotic  drug use is associated with increased  mortality , mainly due to increased  cancer  death. The cancers included cancer of the  brain ,  lung ,  bowel ,  breast , and  bladder , and other  neoplasms . It has been hypothesised [ by whom? ]  that benzodiazepines depress immune function and increase viral infections and could be the cause or trigger of the increased rate of cancer. While initially  U.S. Food and Drug Administration  reviewers expressed concerns about approving the  nonbenzodiazepine   Z drugs  due to concerns of cancer, ultimately they changed their minds and approved the drugs. [ 65 ]  A 2017 meta-analysis of multiple observational studies found that benzodiazepine use is associated with increased cancer risk. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10712", "text": "In a study in 1980 in a group of 55 consecutively admitted patients having engaged in non-medical use of exclusively sedatives or hypnotics, neuropsychological performance was significantly lower and signs of intellectual impairment significantly more often diagnosed than in a matched control group taken from the general population. These results suggested a relationship between non-medical use of sedatives or hypnotics and cerebral disorder. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10713", "text": "A publication asked in 1981 if  lorazepam  is more toxic than  diazepam . [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10714", "text": "In a study in 1984, 20 patients having taken long-term benzodiazepines were submitted to brain CT scan examinations. Some scans appeared abnormal. The mean  ventricular-brain ratio  measured by planimetry was increased over mean values in an age- and sex-matched group of control subjects but was less than that in a group of alcoholics. There was no significant relationship between CT scan appearances and the duration of benzodiazepine therapy. The clinical significance of the findings was unclear. [ 69 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10715", "text": "In 1986, it was presumed that permanent brain damage may result from chronic use of benzodiazepines similar to  alcohol-related brain damage . [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10716", "text": "In 1987, 17 inpatient people who used high doses of benzodiazepines non-medically have anecdotally shown enlarged  cerebrospinal fluid  spaces with associated  cerebral atrophy .\nCerebral atrophy reportedly appeared to be dose dependent with low-dose users having less atrophy than higher-dose users. [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10717", "text": "However, a CT study in 1987 found no evidence of cerebral atrophy in prescribed benzodiazepine users. [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10718", "text": "In 1989, in a 4- to 6-year follow-up study of 30 inpatient people who used benzodiazepines non-medically,  Neuropsychological  function was found to be permanently affected in some people with long-term high dose non-medical use of benzodiazepines.  Brain damage  similar to  alcoholic  brain damage was observed. The  CT scan  abnormalities showed dilatation of the  ventricular system . However, unlike people who consume excessive alcohol, people who use sedative hypnotic agents non-medically showed no evidence of widened  cortical   sulci . The study concluded that, when  cerebral  disorder is diagnosed in people who use high doses of sedative hypnotic benzodiazepines, it is often permanent. [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10719", "text": "A CT study in 1993 investigated brain damage in benzodiazepine users and found no overall differences to a healthy control group. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10720", "text": "A study in 2000 found that long-term benzodiazepine therapy does not result in brain abnormalities. [ 75 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10721", "text": "Withdrawal from high-dose use of  nitrazepam  anecdotally was alleged in 2001 to have caused severe  shock  of the whole brain with diffuse slow activity on  EEG  in one patient after 25 years of use. After withdrawal, abnormalities in hypofrontal brain wave patterns persisted beyond the withdrawal syndrome, which suggested to the authors that organic brain damage occurred from chronic high-dose use of nitrazepam. [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10722", "text": "Professor Heather Ashton , a leading expert on benzodiazepines from  Newcastle University  Institute of Neuroscience, has stated that there is no structural damage from benzodiazepines, and advocates for further research into long-lasting or possibly permanent symptoms of long-term use of benzodiazepines as of 1996. [ 77 ]  She has stated that she believes that the most likely explanation for lasting symptoms is persisting but slowly resolving functional changes at the  GABA A   benzodiazepine receptor  level. Newer and more detailed brain scanning technologies such as PET scans and MRI scans had as of 2002 to her knowledge never been used to investigate the question of whether benzodiazepines cause functional or structural brain damage. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10723", "text": "A 2018 review of the research found a likely causative role between the use of benzodiazepines and an increased risk of dementia, [ 79 ]  but the exact nature of the relationship is still a matter of debate. [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10724", "text": "Benzodiazepines, when introduced in 1961, were widely believed to be safe drugs but as the decades went by increased awareness of  adverse effects  connected to their long-term use became known. Recommendations for more restrictive medical guidelines followed. [ 81 ] [ 82 ]  Concerns regarding the long-term effects of benzodiazepines have been raised since 1980. [ 83 ]  These concerns are still not fully answered. A review in 2006 of the literature on use of benzodiazepine and nonbenzodiazepine hypnotics concluded that more research is needed to evaluate the long-term effects of hypnotic drugs. [ 84 ]  The majority of the problems of benzodiazepines are related to their long-term use rather than their short-term use. [ 85 ]  There is growing evidence of the harm of long-term use of benzodiazepines, especially at higher doses. In 2007, the  Department of Health  recommended that individuals on long-term benzodiazepines be monitored at least every 3 months and also recommended against long-term substitution therapy in benzodiazepine drug misusers due to a lack of  evidence base  for effectiveness and due to the risks of long-term use. [ 86 ]  The long-term effects of benzodiazepines are very similar to the  long-term effects of alcohol consumption  (apart from organ toxicity) and other sedative-hypnotics. Withdrawal effects and dependence are not identical. Dependence can be managed, with a medical professional of course, but withdrawal can be fatal. Physical dependence and withdrawal are very much related but not the same thing. A report in 1987 by the Royal College of Psychiatrists in Great Britain reported that any benefits of long-term use of benzodiazepines are likely to be far outweighed by the risks of long-term use. [ 87 ]  Despite this benzodiazepines are still widely prescribed. The  socioeconomic  costs of the continued widespread prescribing of benzodiazepines is high. [ 88 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10725", "text": "In 1980, the  Medical Research Council (United Kingdom)  recommended that research be conducted into the effects of long-term use of benzodiazepines [ 89 ]  A 2009  British Government   parliamentary inquiry  recommended that research into the long-term effects of benzodiazepines must be carried out. [ 90 ]  The view of the Department of Health is that they have made every effort to make doctors aware of the problems associated with the long-term use of benzodiazepines, [ 91 ]  as well as the dangers of benzodiazepine drug addiction. [ 92 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10726", "text": "In 1980, the  Medicines and Healthcare products Regulatory Agency 's  Committee on the Safety of Medicines  issued guidance restricting the use of benzodiazepines to short-term use and updated and strengthened these warnings in 1988. When asked by  Phil Woolas  in 1999 whether the Department of Health had any plans to conduct research into the long-term effects of benzodiazepines, the Department replied, saying they have no plans to do so, as benzodiazepines are already restricted to short-term use and monitored by regulatory bodies. [ 93 ]  In a  House of Commons  debate, Phil Woolas claimed that there had been a cover-up of problems associated with benzodiazepines because they are of too large of a scale for governments, regulatory bodies, and the pharmaceutical industry to deal with.  John Hutton  stated in response that the Department of Health took the problems of benzodiazepines extremely seriously and was not sweeping the issue under the carpet. [ 94 ]  In 2010, the All-Party Parliamentary Group on Involuntary Tranquilliser Addiction filed a complaint with the  Equality and Human Rights Commission  under the  Disability Discrimination Act 1995  against the Department of Health and the  Department for Work and Pensions  alleging discrimination against people with a benzodiazepine prescription drug dependence as a result of denial of specialised treatment services, exclusion from medical treatment, non-recognition of the protracted  benzodiazepine withdrawal syndrome , as well as denial of rehabilitation and back-to-work schemes. Additionally the APPGITA complaint alleged that there is a \"virtual prohibition\" on the collection of statistical information on benzodiazepines across government departments, whereas with other controlled drugs there are enormous volumes of statistical data. The complaint alleged that the discrimination is deliberate, large scale and that government departments are aware of what they are doing. [ 95 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10727", "text": "The  Medical Research Council (UK)  held a closed meeting among top UK medical doctors and representatives from the pharmaceutical industry between 30 October 1980 and 3 April 1981. The meeting was classified under the  Public Records Act 1958  until 2014 but became available in 2005 as a result of the  Freedom of Information Act . The meeting was called due to concerns that 10\u2013100,000 people could be dependent; meeting chairman Professor Malcolm Lader later revised this estimate to include approximately half a million members of the British public suspected of being dependent on therapeutic dose levels of benzodiazepines, with about half of those on long-term benzodiazepines. It was reported that benzodiazepines may be the third- or fourth-largest drug problem in the UK (the largest being alcohol and tobacco). The chairman of the meeting followed up after the meeting with additional information, which was forwarded to the Medical Research Council neuroscience board, raising concerns regarding tests that showed definite cortical atrophy in 2 of 14 individuals tested and borderline abnormality in five others. He felt that, due to the methodology used in assessing the scans, the abnormalities were likely an underestimate, and more refined techniques would be more accurate. Also discussed were findings that tolerance to benzodiazepines can be demonstrated by injecting diazepam into long-term users; in normal subjects, increases in  growth hormone  occurs, whereas in benzodiazepine-tolerant individuals this effect is blunted. Also raised were findings in animal studies that showed the development of tolerance in the form of a 15 percent reduction in binding capacity of benzodiazepines after seven days administration of high doses of the partial agonist benzodiazepine drug  flurazepam  and a 50 percent reduction in binding capacity after 30 days of a low dose of diazepam. The chairman was concerned that papers soon to be published would \"stir the whole matter up\" and wanted to be able to say that the Medical Research Council \"had matters under consideration if questions were asked in parliament\". The chairman felt that it \"was very important, politically that the MRC should be 'one step ahead'\" and recommended epidemiological studies be funded and carried out by Roche Pharmaceuticals and MRC sponsored research conducted into the biochemical effects of long-term use of benzodiazepines. The meeting aimed to identify issues that were likely to arise, alert the Department of Health to the scale of the problem and identify the pharmacology and nature of benzodiazepine dependence and the volume of benzodiazepines being prescribed. The  World Health Organization  was also interested in the problem and it was felt the meeting would demonstrate to the WHO that the MRC was taking the issue seriously. Among the psychological effects of long-term use of benzodiazepines discussed was a reduced ability to cope with stress. The chairman stated that the \"withdrawal symptoms from valium were much worse than many other drugs including, e.g., heroin\". It was stated that the likelihood of withdrawing from benzodiazepines was \"reduced enormously\" if benzodiazepines were prescribed for longer than four months. It was concluded that benzodiazepines are often prescribed inappropriately, for a wide range of conditions and situations. Dr Mason ( DHSS ) and Dr Moir ( SHHD ) felt that, due to the large numbers of people using benzodiazepines for long periods of time, it was important to determine the effectiveness and toxicity of benzodiazepines before deciding what regulatory action to take. [ 89 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10728", "text": "Controversy resulted in 2010 when the previously secret files came to light over the fact that the Medical Research Council was warned that benzodiazepines prescribed to millions of patients appeared to cause  cerebral atrophy  similar to hazardous alcohol use in some patients and failed to carry out larger and more rigorous studies.  The Independent on Sunday  reported allegations that \"scores\" of the 1.5 million members of the UK public who use benzodiazepines long-term have symptoms that are consistent with brain damage. It has been described as a \"huge scandal\" by  Jim Dobbin , and legal experts and MPs have predicted a class action lawsuit. A solicitor said she was aware of the past failed litigation against the drug companies and the relevance the documents had to that court case and said it was strange that the documents were kept 'hidden' by the MRC. [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10729", "text": "Professor Lader, who chaired the MRC meeting, declined to speculate as to why the MRC declined to support his request to set up a unit to further research benzodiazepines and why they did not set up a special safety committee to look into these concerns. Professor Lader stated that he regrets not being more proactive on pursuing the issue, stating that he did not want to be labeled as the guy who pushed only issues with benzos. Professor Ashton also submitted proposals for grant-funded research using MRI, EEG, and cognitive testing in a randomized controlled trial to assess whether benzodiazepines cause permanent damage to the brain, but similarly to Professor Lader was turned down by the MRC. [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10730", "text": "The MRC spokesperson said they accept the conclusions of Professor Lader's research and said that they fund only research that meets required quality standards of scientific research, and stated that they were and continue to remain receptive to applications for research in this area. No explanation was reported for why the documents were sealed by the Public Records Act. [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10731", "text": "Jim Dobbin , who chaired the All-Party Parliamentary Group for Involuntary Tranquilliser Addiction, stated that:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10732", "text": "Many victims have lasting physical, cognitive and psychological problems even after they have withdrawn. We are seeking legal advice because we believe these documents are the bombshell they have been waiting for. The MRC must justify why there was no proper follow-up to Professor Lader's research, no safety committee, no study, nothing to further explore the results. We are talking about a huge scandal here. [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10733", "text": "The legal director of  Action Against Medical Accidents  said urgent research must be carried out and said that, if the results of larger studies confirm Professor Lader's research, the government and MRC could be faced with one of the biggest group actions for damages the courts have ever seen, given the large number of people potentially affected. People who report enduring symptoms post-withdrawal such as neurological pain, headaches, cognitive impairment, and memory loss have been left in the dark as to whether these symptoms are drug-induced damage or not due to the MRC's inaction, it was reported. Professor Lader reported that the results of his research did not surprise his research group given that it was already known that alcohol could cause permanent brain changes. [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10734", "text": "Benzodiazepines spurred the largest-ever  class-action lawsuit  against  drug manufacturers  in the United Kingdom, in the 1980s and early 1990s, involving 14,000 patients and 1,800  law firms  that alleged the manufacturers knew of the potential for dependence but intentionally withheld this information from doctors. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of  dependence  and  withdrawal . This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines. [ 97 ]  The court case against the drug manufacturers never reached a verdict;  legal aid  had been withdrawn, leading to the collapse of the trial, and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest. This litigation led to changes in  British law , making class-action lawsuits more difficult. [ 98 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10735", "text": "Benzodiazepines have been found to cause teratogenic malformations. [ 99 ]  The literature concerning the safety of benzodiazepines in pregnancy is unclear and controversial. Initial concerns regarding benzodiazepines in pregnancy began with alarming findings in animals but these do not necessarily cross over to humans. Conflicting findings have been found in babies exposed to benzodiazepines. [ 100 ]  A recent analysis of the Swedish Medical Birth Register found an association with preterm births, low birth weight and a moderate increased risk for congenital malformations. An increase in pylorostenosis or  alimentary tract   atresia  was seen. An increase in orofacial clefts was not demonstrated, however, and it was concluded that benzodiazepines are not major teratogens. [ 101 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10736", "text": "Neurodevelopmental disorders  and clinical symptoms are commonly found in babies exposed to benzodiazepines  in utero . Benzodiazepine-exposed babies have a  low birth weight  but catch up to normal babies at an early age, but smaller head circumferences found in exposed infants persists. Other adverse effects of benzodiazepines taken during pregnancy are deviating  neurodevelopmental  and clinical symptoms including  craniofacial  anomalies, delayed development of pincer grasp, deviations in  muscle tone  and pattern of movements. Motor impairments in the babies are impeded for up to 1 year after birth. Gross  motor development  impairments take 18 months to return to normal but fine motor function impairments persist. [ 102 ]  In addition to the smaller head circumference found in benzodiazepine-exposed babies  mental retardation , functional deficits, long-lasting behavioural anomalies, and  lower intelligence  occurs. [ 103 ] [ 104 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10737", "text": "Benzodiazepines, like many other sedative hypnotic drugs, cause  apoptotic   neuronal  cell death. However, benzodiazepines do not cause as severe  apoptosis  to the developing brain as alcohol does. [ 105 ] [ 106 ] [ 107 ]  The  prenatal  toxicity of benzodiazepines is most likely due to their effects on  neurotransmitter systems ,  cell membranes  and  protein synthesis . [ 104 ]  This, however, is complicated in that  neuropsychological  or  neuropsychiatric  effects of benzodiazepines, if they occur, may not become apparent until later  childhood  or even  adolescence . [ 108 ]  A review of the literature found data on long-term follow-up regarding neurobehavioural outcomes is very limited. [ 109 ]  However, a study was conducted that followed up 550 benzodiazepine-exposed children, which found that, overall, most children developed normally. There was a smaller subset of benzodiazepine-exposed children who were slower to develop, but by four years of age most of this subgroup of children had normalised. There was a small number of benzodiazepine-exposed children who had continuing developmental abnormalities at 4-year follow-up, but it was not possible to conclude whether these deficits were the result of benzodiazepines or whether social and environmental factors explained the continuing deficits. [ 110 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10738", "text": "Concerns regarding whether benzodiazepines during pregnancy cause major malformations, in particular cleft palate, have been hotly debated in the literature. A  meta analysis  of the data from  cohort studies  found no link but  meta analysis  of  case\u2013control studies  did find a significant increase in major malformations. (However, the cohort studies were homogenous and the case\u2013control studies were heterogeneous, thus reducing the strength of the case\u2013control results). There have also been several reports that suggest that benzodiazepines have the potential to cause a syndrome similar to  fetal alcohol syndrome , but this has been disputed by a number of studies. As a result of conflicting findings, use of benzodiazepines during pregnancy is controversial. The best available evidence suggests that benzodiazepines are not a major cause of  birth defects , i.e. major malformations or  cleft lip  or  cleft palate . [ 111 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10739", "text": "Significant toxicity from benzodiazepines can occur in the elderly as a result of long-term use. [ 112 ]   Benzodiazepines , along with  antihypertensives  and drugs affecting the cholinergic system, are the most common cause of drug-induced  dementia  affecting over 10 percent of patients attending memory clinics. [ 113 ] [ 114 ]  Long-term use of benzodiazepines in the elderly can lead to a pharmacological syndrome with symptoms including  drowsiness ,  ataxia , fatigue,  confusion ,  weakness ,  dizziness ,  vertigo ,  syncope , reversible  dementia ,  depression , impairment of intellect,  psychomotor  and  sexual dysfunction ,  agitation ,  auditory  and  visual hallucinations ,  paranoid ideation ,  panic ,  delirium ,  depersonalization ,  sleepwalking ,  aggressivity ,  orthostatic hypotension  and  insomnia . Depletion of certain neurotransmitters and  cortisol  levels and alterations in immune function and biological markers can also occur. [ 115 ]  Elderly individuals who have been long-term users of benzodiazepines have been found to have a higher incidence of post-operative confusion. [ 116 ]  Benzodiazepines have been associated with increased body sway in the elderly, which can potentially lead to fatal accidents including falls. Discontinuation of benzodiazepines leads to improvement in the balance of the body and also leads to improvements in cognitive functions in the elderly benzodiazepine  hypnotic  users without worsening of insomnia. [ 117 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10740", "text": "A review of the evidence has found that whilst long-term use of benzodiazepines impairs memory, its association with causing dementia is not clear and requires further research. [ 118 ]  A more recent study found that benzodiazepines are associated with an increased risk of dementia and it is recommended that benzodiazepines be avoided in the elderly. [ 119 ]  A later study, however, found no increase in dementia associated with long-term usage of benzodiazepine. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10741", "text": "Mar\u00eda Teresa Miras Portugal  (19 February 1948 \u2013 27 May 2021) [ 1 ]  was a Spanish  scientist , pharmacist, biochemist, molecular biologist and  Emeritus   professor  at the  Complutense University of Madrid . She was a member of the Spanish \" Real Academia Nacional de Farmacia \" and served as President of this Institution from 2007 to 2013, becoming the first woman to be elected for this position in a Spanish \" Real Academia \". [ 2 ] [ 3 ]  She was Honorary President. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10742", "text": "She was also a member of several scientific institutions such as the Spanish Biophysical Society, the Spanish Society of Biochemistry and Molecular Biology, the Spanish Society of Neuroscience, the  European Society for Neurochemistry , the  International Society for Neurochemistry , the Advisory Board of Chromaffin Cells, the Purinergic Club, the editorial board of the  Journal of Neurochemistry , the  IUPHAR  sub-committee for the nomenclature of  P2Y nucleotide receptors  and the Scientific Panel of the  NATO . [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10743", "text": "Mar\u00eda Teresa Miras Portugal was born in 1948 in  O Carballi\u00f1o  ( Orense ), where she completed her primary and secondary studies. She started her university studies in Pharmacy in the  University of Santiago de Compostela  and continued them at the  Complutense University of Madrid . Her marks at the  Licenciate  university degree led her to get a Special Mention at National Level. [ 10 ]  She completed a PhD in Sciences at the  University of Strasbourg  and Pharmacy at the Complutense University of Madrid. [ 11 ]  She later became a professor of Biochemistry and Molecular Biology at the  University of Oviedo , the  University of Murcia  and the Complutense University of Madrid. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10744", "text": "In her more than 40 years engaged in research, she focused in the study of nucleotide receptors and their impact on neurodegenerative diseases [ 13 ] [ 14 ]  and published more than 350 research articles in specialized journals, [ 2 ]  combining this research with teaching and institutional work. In 2012, she was appointed president of the Committee of Experts for the study of the need for reforms in the Spanish university system. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10745", "text": "In 2005 she received the Alberto Sols Medal to Research in Biochemistry, [ 4 ]  in 2008 the Mar\u00eda Josefa Wonenburger Planells Prize by the Xunta de Galicia, [ 15 ]  in 2011 the Community of Madrid honoured her with the Miguel Catal\u00e1n Research Award for her entire professional career [ 13 ]  and in 2016 in Galicia received the Castelao Medal. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10746", "text": "She was given  honorary doctorates  from the  University of Murcia  and the  King Juan Carlos University  and was an honorific member of the Academia Nacional de Farmacia y Bioqu\u00edmica de Argentina, Acad\u00e9mie Nationale de Pharmacie de France, Acad\u00e9mie Europ\u00e9enne des Sciences des Arts et des Lettres and the  European Academy  (physiology and medicine). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10747", "text": "Neuropharmacology  is a  peer-reviewed   scientific journal  in the field of  neuroscience . It was established in 1962 as the  International Journal of Neuropharmacology  and obtained its current name in 1970."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10748", "text": "This article about a  neuroscience   journal  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10749", "text": "Neuropsychopharmacology , an interdisciplinary science related to  psychopharmacology  (study of effects of drugs on the mind) and fundamental  neuroscience , is the study of the neural mechanisms that drugs act upon to influence behavior. It entails research of mechanisms of  neuropathology ,  pharmacodynamics (drug action) ,  psychiatric illness , and states of  consciousness . These studies are instigated at the detailed level involving  neurotransmission / receptor  activity,  bio-chemical  processes, and  neural  circuitry. Neuropsychopharmacology supersedes psychopharmacology in the areas of \"how\" and \"why\", and additionally addresses other issues of brain function. Accordingly, the clinical aspect of the field includes  psychiatric  (psychoactive) as well as  neurologic  (non-psychoactive) pharmacology-based treatments. Developments in neuropsychopharmacology may directly impact the studies of  anxiety disorders ,  affective disorders ,  psychotic disorders ,  degenerative disorders ,  eating behavior , and  sleep behavior ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10750", "text": "Drugs such as  opium ,  alcohol , and certain plants have been used for millennia by humans to ease suffering or change awareness, but until the modern scientific era knowledge of how the substances actually  worked  was quite limited, most pharmacological knowledge being more a series of observation than a coherent model. The first half of the 20th century saw  psychology  and  psychiatry  as largely  phenomenological , in that behaviors or themes which were observed in patients could often be correlated to a limited variety of factors such as childhood experience, inherited tendencies, or injury to specific brain areas. Models of mental function and dysfunction were based on such observations. Indeed, the  behavioral  branch of psychology dispensed altogether with what actually happened inside the brain, regarding most mental dysfunction as what could be dubbed as \"software\" errors. In the same era, the nervous system was progressively being studied at the microscopic and chemical level, but there was virtually no mutual benefit with clinical fields\u2014until several developments after  World War II  began to bring them together. Neuropsychopharmacology may be regarded to have begun in the earlier 1950s with the discovery of drugs such as  MAO inhibitors ,  tricyclic antidepressants ,  thorazine  and  lithium  which showed some clinical specificity for mental illnesses such as depression and schizophrenia. [ 1 ]  Until that time, treatments that actually targeted these complex illnesses were practically non-existent. The prominent methods which  could  directly affect brain circuitry and neurotransmitter levels were the  prefrontal lobotomy , and  electroconvulsive therapy , the latter of which was conducted without muscle relaxants and both of which often caused the patient great physical and psychological injury."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10751", "text": "The field now known as neuropsychopharmacology has resulted from the growth and extension of many previously isolated fields which have met at the core of psychiatric medicine, and engages a broad range of professionals from psychiatrists to researchers in genetics and chemistry. The use of the term has gained popularity since 1990 with the founding of several journals and institutions such as the  Hungarian College of Neuropsychopharmacology . [1]  This rapidly maturing field shows some degree of flux, as research hypotheses are often restructured based on new information."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10752", "text": "An implicit premise in neuropsychopharmacology with regard to the psychological aspects is that all states of  mind , including both normal and drug-induced altered states, and diseases involving mental or  cognitive   dysfunction , have a  neurochemical  basis at the fundamental level, and certain circuit pathways in the  central nervous system  at a higher level. (See also:  Neuron doctrine ) Thus the understanding of nerve cells or  neurons  in the brain is central to understanding the mind. It is reasoned that the mechanisms involved can be elucidated through modern  clinical  and research methods such as  genetic manipulation  in animal subjects, imaging techniques such as  functional magnetic resonance imaging  ( fMRI ), and  in vitro  studies using selective binding agents on live tissue cultures. These allow neural activity to be monitored and measured in response to a variety of test conditions. Other important observational tools include  radiological imaging [2]  such as  positron emission tomography  ( PET ) and  single-photon emission computed tomography  ( SPECT ). These imaging techniques are extremely sensitive and can image tiny molecular concentrations on the order of 10 \u221210  M such as found with extrastriatal D 1  receptor for dopamine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10753", "text": "One of the ultimate goals is to devise and develop prescriptions of treatment for a variety of  neuropathological  conditions and  psychiatric disorders . More profoundly, though, the knowledge gained may provide insight into the very nature of human thought, mental abilities like learning and memory, and perhaps consciousness itself. A direct product of neuropsychopharmacological research is the knowledge base required to develop  drugs  which act on very specific receptors within a neurotransmitter system. These \"hyperselective-action\" drugs would allow the direct targeting of specific sites of relevant neural activity, thereby maximizing the  efficacy  (or technically the  potency ) of the drug within the clinical target and minimizing  adverse effects . However, there are some cases when some degree of pharmacological promiscuity is tolerable and even desirable, producing more desirable results than a more selective agent would. An example of this is  Vortioxetine , a drug which is not particularly selective as a serotonin reuptake inhibitor, having a significant degree of serotonin modulatory activity, but which has demonstrated reduced discontinuation symptoms (and reduced likelihood of  relapse ) and greatly reduced incidence of  sexual dysfunction , without loss in antidepressant efficacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10754", "text": "The groundwork is currently being paved for the next generation of  pharmacological  treatments, which will improve quality of life with increasing efficiency. For example, contrary to previous thought, it is now known that the adult brain does to some extent grow new  neurons \u2014the study of which, in addition to  neurotrophic factors , may hold hope for neurodegenerative diseases like  Alzheimer's ,  Parkinson's ,  ALS , and types of  chorea . All of the  proteins  involved in neurotransmission are a small fraction of the more than 100,000 proteins in the brain. Thus there are many proteins which are not even in the direct path of  signal transduction , any of which may still be a target for specific therapy. At present, novel pharmacological approaches to diseases or conditions are reported at a rate of almost one per week. [3]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10755", "text": "So far as we know, everything we perceive, feel, think, know, and do are a result of neurons firing and resetting. When a cell in the brain fires, small chemical and electrical swings called the  action potential  may affect the firing of as many as a thousand other neurons in a process called  neurotransmission . In this way signals are generated and carried through networks of neurons, the bulk electrical effect of which can be measured directly on the scalp by an  EEG  device."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10756", "text": "By the last decade of the 20th century, the essential knowledge of all the central features of neurotransmission had been gained. [4]  These features are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10757", "text": "The more recent advances involve understanding at the  organic  molecular level; biochemical action of the  endogenous   ligands ,  enzymes ,  receptor proteins , etc. The critical changes affecting cell firing occur when the signalling neurotransmitters from one neuron, acting as ligands, bind to receptors of another neuron. Many neurotransmitter systems and receptors are well known, and research continues toward the identification and characterization of a large number of very specific subtypes of receptors. For the six more important neurotransmitters  Glu ,  GABA ,  Ach ,  NE ,  DA , and  5HT  (listed at  neurotransmitter ) there are at least 29 major subtypes of receptor. Further \"sub-subtypes\" exist together with variants, totalling in the hundreds for just these 6 transmitters.  - (see  serotonin receptor  for example.)  It is often found that receptor subtypes have differentiated function, which in principle opens up the possibility of refined intentional control over brain function."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10758", "text": "It has previously been known that ultimate control over the membrane voltage or potential of a nerve cell, and thus the firing of the cell, resides with the transmembrane  ion channels  which control the membrane currents via the  ions   K + ,  Na + , and  Ca ++ , and of lesser importance  Mg ++  and  Cl \u2212 . The concentration differences between the inside and outside of the cell determine the membrane voltage."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10759", "text": "Precisely how these currents are controlled has become much clearer with the advances in receptor structure and  G-protein coupled  processes. Many receptors are found to be pentameric clusters of five transmembrane proteins (not necessarily the same) or  receptor subunits , each a chain of many amino acids. Transmitters typically bind at the junction between two of these proteins, on the parts that protrude from the cell membrane. If the receptor is of the  ionotropic  type, a central pore or channel in the middle of the proteins will be mechanically moved to allow certain ions to flow through, thus altering the ion concentration difference. If the receptor is of the  metabotropic  type, G-proteins will cause metabolism inside the cell that may eventually change other ion channels. Researchers are better understanding precisely how these changes occur based on the protein structure shapes and chemical properties."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10760", "text": "The scope of this activity has been stretched even further to the very blueprint of life since the clarification of the mechanism underlying  gene transcription . The  synthesis  of cellular proteins from nuclear  DNA  has the same fundamental machinery [5]  for all cells; the exploration of which now has a firm basis thanks to the  Human Genome Project  which has enumerated the entire human DNA sequence, although many of the estimated 35,000 genes remain to be identified. The complete neurotransmission process extends to the genetic level.  Gene expression  determines protein structures through type II  RNA polymerase . So enzymes which synthesize or breakdown neurotransmitters, receptors, and ion channels are each made from  mRNA  via the DNA transcription of their respective gene or genes. But neurotransmission, in addition to controlling ion channels either directly or otherwise through  metabotropic  processes, also actually modulates gene expression. This is most prominently achieved through modification of the  transcription initiation process  by a variety of transcription factors produced from receptor activity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10761", "text": "Aside from the important pharmacological possibilities of gene expression pathways, the correspondence of a gene with its protein allows the important analytical tool of  gene knockout . Living specimens can be created using  homolog recombination  in which a specific gene cannot be expressed. The organism will then be deficient in the associated protein which may be a specific receptor. This method avoids chemical blockade which can produce confusing or ambiguous secondary effects so that the effects of a lack of receptor can be studied in a purer sense."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10762", "text": "The inception of many classes of drugs is in principle straightforward: any chemical that can enhance or diminish the action of a target protein could be investigated further for such use. The trick is to find such a chemical that is receptor-specific (cf. \" dirty drug \") and safe to consume. The 2005  Physicians' Desk Reference  lists twice the number of  prescription drugs  as the 1990 version. [6]  Many people by now are familiar with \" selective serotonin reuptake inhibitors \", or SSRIs which exemplify modern  pharmaceuticals . These SSRI  antidepressant  drugs, such as Paxil and Prozac, selectively and therefore primarily inhibit the transport of serotonin which prolongs the activity in the synapse. There are numerous categories of selective drugs, and transport blockage is only one mode of action. The  FDA  has approved drugs which selectively act on each of the major neurotransmitters such as  NE  reuptake inhibitor antidepressants,  DA  blocker  anti-psychotics , and  GABA   agonist   tranquilizers  ( benzodiazepines )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10763", "text": "New endogenous chemicals are continually identified. Specific receptors have been found for the drugs  THC  (cannabis) and  GHB , [7]  with endogenous transmitters anandamide and GHB.  Another recent major discovery occurred in 1999 when  orexin , or hypocretin, was found to have a role in arousal, since the lack of orexin receptors mirrors the condition of  narcolepsy . Orexin agonism may explain the antinarcoleptic action of the drug  modafinil  which was already being used only a year prior."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10764", "text": "The next step, which major  pharmaceutical companies  are currently working hard to develop, are receptor subtype-specific drugs and other specific agents. An example is the push for better anti-anxiety agents ( anxiolytics ) based on GABA A (\u03b12) agonists,  CRF 1  antagonists, and 5HT 2c  antagonists. [8]  Another is the proposal of new routes of exploration for antipsychotics such as  glycine reuptake inhibitors . [9]  Although the capabilities exist for receptor-specific drugs, a shortcoming of drug therapy is the lack of ability to provide  anatomical  specificity. By altering receptor function in one part of the brain, abnormal activity can be induced in other parts of the brain due to the same type of receptor changes. A common example is the effect of D 2  altering drugs (neuroleptics) which can help schizophrenia, but cause a variety of  dyskinesias  by their action on motor cortex."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10765", "text": "Modern studies are revealing details of mechanisms of damage to the nervous system such as  apoptosis  (programmed cell death) and  free-radical  disruption.  Phencyclidine  has been found to cause cell death in striatopallidal cells and abnormal  vacuolization  in  hippocampal  and other neurons. The  hallucinogen persisting perception disorder  (HPPD), also known as  post-psychedelic perception disorder , has been observed in patients as long as 26 years after LSD use. The plausible cause of HPPD is damage to the inhibitory GABA circuit in the visual pathway (GABA agonists such as midazolam can decrease some effects of LSD intoxication). The damage may be the result of an  excitotoxic  response of 5HT 2   interneurons . [Note: the vast majority of LSD users do not experience HPPD. Its manifestation may be equally dependent on individual brain chemistry as on the drug use itself.] As for  MDMA , aside from persistent losses of 5HT and  SERT , long-lasting reduction of serotonergic  axons  and terminals is found from short-term use, and regrowth may be of compromised function."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10766", "text": "Many functions of the brain are somewhat localized to associated areas like motor and speech ability. Functional associations of brain anatomy are now being complemented with clinical, behavioral, and genetic correlates of receptor action, completing the knowledge of neural signalling  (see also:  Human Cognome Project ) . The signal paths of neurons are hyperorganized beyond the cellular scale into often complex neural circuit pathways. Knowledge of these pathways is perhaps the easiest to interpret, being most recognizable from a systems analysis point of view, as may be seen in the following abstracts."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10767", "text": "Almost all drugs with a known potential for abuse have been found to modulate activity (directly or indirectly) in the mesolimbic dopamine system, which includes and connects the ventral tegmental area in the midbrain to the hippocampus, medial prefrontal cortex, and amygdala in the forebrain; as well as the nucleus accumbens in the ventral striatum of the basal ganglia. [ 2 ]  In particular, the nucleus accumbens (NAc) plays an important role in integrating experiential memory from the hippocampus, emotion from the amygdala, and contextual information from the PFC to help associate particular stimuli or behaviors with feelings of pleasure and reward; continuous activation of this reward indicator system by an addictive drug can also cause previously neutral stimuli to be encoded as cues that the brain is about to receive a reward. This happens via the selective release of dopamine, a neurotransmitter responsible for feelings of euphoria and pleasure. The use of dopaminergic drugs alters the amount of dopamine released throughout the mesolimbic system, and regular or excessive use of the drug can result in a long-term downregulation of dopamine signaling, [ 3 ]  even after an individual stops ingesting the drug. This can lead the individual to engage in mild to extreme drug-seeking behaviors as the brain begins to regularly expect the increased presence of dopamine and the accompanying feelings of euphoria, but how problematic this is depends highly on the drug and the situation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10768", "text": "Significant progress has been made on central mechanisms of certain  hallucinogenic drugs . It is at this point known with relative certainty that the primary shared effects of a broad pharmacological group of hallucinogens, sometimes called the \"classical psychedelics\", can be attributed largely to agonism of serotonin receptors. The 5HT 2A  receptor, which seems to be the most critical receptor for psychedelic activity, and the 5HT 2C  receptor, which is a significant target of most psychedelics but which has no clear role in hallucinogenesis, are involved by releasing  glutamate  in the  frontal cortex , while simultaneously in the  locus coeruleus  sensory information is promoted and spontaneous activity decreases. 5HT 2A  activity has a net pro-dopaminergic effect, whereas 5HT 2C  receptor agonism has an inhibitory effect on dopaminergic activity, particularly in the prefrontal cortex. One hypothesis suggests that in the frontal cortex, 5HT 2A  promotes late asynchronous  excitatory postsynaptic potentials , a process antagonized by serotonin itself through 5HT 1  receptors, which may explain why SSRIs and other serotonin-affecting drugs do not normally cause a patient to hallucinate. However, the fact that many classical psychedelics do in fact have significant affinity for 5HT 1  receptors throws this claim into question. The head twitch response, a test used for assessing classical psychedelic activity in rodents, is produced by serotonin itself only in the presence of beta-Arrestins, but is triggered by classical psychedelics independent of beta-Arrestin recruitment. [ 4 ]  This may better explain the difference between the pharmacology of serotonergic neurotransmission (even if promoted by drugs such as SSRIs) and that of classical psychedelics. Newer findings, however, indicate that binding to the 5HT 2A - mGlu2   heterodimer  is also necessary for classical psychedelic activity. [ 5 ] [ 6 ] [ 7 ]  This, too, may be relevant to the pharmacological differences between the two. While early in the history of psychedelic drug research it was assumed that these hallucinations were comparable to those produced by psychosis and thus that classical psychedelics could serve as a model of psychosis, it is important to note that modern neuropsychopharmacological knowledge of psychosis has progressed significantly since then, and we now know that psychosis shows little similarity to the effects of classical psychedelics in mechanism, reported experience or most other respects aside from the surface similarity of \"hallucination\".."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10769", "text": "Circadian rhythm , or sleep/wake cycling, is centered in the  suprachiasmatic nucleus  (SCN) within the hypothalamus, and is marked by  melatonin  levels 2000\u20134,000% higher during sleep than in the day. A circuit is known to start with  melanopsin  cells in the eye which stimulate the SCN through glutamate neurons of the  hypothalamic tract . GABAergic neurons from the SCN inhibit the  paraventricular nucleus , which signals the  superior cervical ganglion  (SCG) through  sympathetic  fibers. The output of the SCG, stimulates NE receptors ( \u03b2 ) in the  pineal gland  which produces N-acetyltransferase, causing production of melatonin from serotonin. Inhibitory melatonin receptors in the SCN then provide a positive feedback  pathway . Therefore, light  inhibits  the production of melatonin which \" entrains \" the 24-hour cycle of SCN activity. [10] [11]  The SCN also receives signals from other parts of the brain, and its (approximately) 24-hour cycle does not only depend on light patterns. In fact, sectioned tissue from the SCN will exhibit daily cycle  in vitro  for many days. Additionally, (not shown in diagram), the  basal nucleus  provides GABA-ergic inhibitory input to the  pre-optic anterior hypothalamus  (PAH). When  adenosine  builds up from the metabolism of ATP throughout the day, it binds to adenosine receptors, inhibiting the basal nucleus. The PAH is then activated, generating slow-wave sleep activity.  Caffeine  is known to block adenosine receptors, thereby inhibiting sleep among other things."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10770", "text": "Research in the field of neuropsychopharmacology encompasses a wide range of objectives. These might include the study of a new chemical compound for potentially beneficial cognitive or behavioral effects, or the study of an old chemical compound in order to better understand its mechanism of action at the cell and neural circuit levels. For example, the addictive stimulant drug cocaine has long been known to act upon the reward system in the brain, increasing dopamine and norepinephrine levels and inducing euphoria for a short time. More recently published studies however have gone deeper than the circuit level and found that a particular G-protein coupled receptor complex called A2AR-D2R-Sigma1R is formed in the NAc following cocaine usage; this complex reduces D2R signaling in the mesolimbic pathway and may be a contributing factor to cocaine addiction. [ 8 ]  Other cutting-edge studies have focused on genetics to identify specific biomarkers that may predict an individual's specific reactions or degree of response to a drug or their tendency to develop addictions in the future. [ 9 ]  These findings are important because they provide detailed insight into the neural circuitry involved in drug use and help refine old as well as develop new treatment methods for disorders or addictions. Different treatment-related studies are investigating the potential role of peptide nucleic acids in treating Parkinson's disease and schizophrenia [ 10 ]  while still others are attempting to establish previously unknown neural correlates underlying certain phenomena. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10771", "text": "Research in neuropsychopharmacology comes from a wide range of activities in neuroscience and clinical research. This has motivated organizations such as the  American College of Neuropsychopharmacology  (ACNP) , the  European College of Neuropsychopharmacology  (ECNP) , and the  Collegium Internationale Neuro-psychopharmacologicum  (CINP)  to be established as a measure of focus.\nThe  ECNP  publishes  European Neuropsychopharmacology , and as part of the  Reed Elsevier Group , the ACNP publishes the journal  Neuropsychopharmacology , and the CINP publishes the journal  International Journal of Neuropsychopharmacology [ permanent dead link \u200d ]  with  Cambridge University Press .\nIn 2002, a recent comprehensive collected work of the ACNP, \"Neuropsychopharmacology: The Fifth Generation of Progress\" was compiled. It is one measure of the state of knowledge in 2002, and might be said to represent a landmark in the century-long goal to establish the basic neurobiological principles which govern the actions of the brain."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10772", "text": "Many other journals exist which contain relevant information such as  Neuroscience .\nSome of them are listed at  Brown University Library ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10773", "text": "Neurotrophin mimetics  are small molecules or peptide like molecules that can modulate the action of the neurotrophin receptor.\nOne of the main causes of  neurodegeneration  involves changes in the expression of  neurotrophins  (NTs) and/or their receptors ( TrkA ,  TrkB ,  TrkC  and  p75NTR ). Indeed, these imbalances or changes in their activity, lead to neuronal damage resulting in neurological and neurodegenerative conditions. The therapeutic properties of neurotrophins attracted the focus of many researchers during the years, but the poor  pharmacokinetic  properties, such as reduced  bioavailability  and low metabolic stability, the  hyperalgesia , the inability to penetrate the  blood\u2013brain barrier  and the short  half-lives  render the large neurotrophin proteins not suitable to be implemented as drugs. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10774", "text": "For this reason, several efforts have been made to develop neurotrophin mimetics (small molecules and  peptidomimetics ) that can modulate the action of the neurotrophin receptors ( Trks  and p75NTR) and possess drug-like pharmacokinetic and  pharmacodynamic  profiles. Specifically, these mimetics can be classified as TrkA and TrkB receptor agonists and p75NTR modulators/antagonists. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10775", "text": "Among the TrkA agonists, the small molecule gambogic amide exerts a potent neurotrophic activity decreasing  apoptosis  in primary  hippocampal  neurons. [ 3 ]  The non-peptidic TrkA agonist MT2 protects neurons from  A\u03b2 amyloid -mediated death in  NGF -deficient neurons [ 4 ]  and talaumidin and its derivatives show  neuroprotective  effects, promoting  neurite outgrowth  in  PC12 cells . [ 5 ]  Furthermore, the  peptidomimetic   cerebrolysin  is known for its  protective  role in  Alzheimer's disease  (AD). [ 6 ]  It was shown to improve the activities of daily living and the psychiatric symptoms in patients with mild to severe form of AD, after intravenous administration in a  double-blind trial . [ 7 ]  In addition, the cyclic peptide  tavilermide  (MIM-D3), acting as a partial  TrkA  receptor agonist, showed a relevant improvement of  cognitive capacities  of treated aged rats, leading to a selective survival of the  cholinergic neurons . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10776", "text": "A  phase 3 clinical trial  of 5% and 1% tavilermide ophthalmic solutions for the treatment of dry eye was completed in 2020 (NCT03925727), with positive results concerning safety and efficacy. Recent studies demonstrated the neurotrophic activity of  carvacrol  by inducing neurite outgrowth and  phosphorylation  of TrkA in cells deprived of NGF. [ 9 ]  The same research group investigated the neurotrophic effect of the well-known antibiotic  doxycycline  and they found that it prevents amyloid toxicity in a  Drosophila  model of AD both  in vitro  and  in vivo  and induces neuritogenesis by activation of TrkA. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10777", "text": "Additionally, some novel  DHEA  derivatives were shown to be TrkA agonists. In particular, the C17-spiroepoxy derivative,  BNN-27 , [ 11 ]  induces phosphorylation of TrkA in neuronal and  glial cells  in culture and it exerts  antiapoptotic  effect without inducing  hyperalgesia . [ 12 ]  Moreover, it improved memorizing abilities in rats after i.p. administration [ 13 ]  and restored the  myelin  loss in cuprizone-induced  demyelination   in vivo . [ 14 ]  Moreover, the C17-spirocyclopryl DHEA derivatives, ENT-A010 and ENT-A013, were shown to be potent TrkA agonists. [ 15 ] [ 16 ]  In particular, ENT-A010 acts as dual TrkA and TrkB agonist while, ENT-A013 acts as a selective TrkA agonist. Both induce phosphorylation of TrkA and its  downstream signaling pathways , and promote  cell survival  of PC12 cells from serum deprivation. In addition, they exhibit potent neuroprotective effects in  dorsal root ganglia  and anti-amyloid activity in hippocampal neurons. [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10778", "text": "TrkB agonists have received extensive interest from the scientific community resulting in the synthesis and biological evaluation of a large number of mimetics.  Deoxygedunin , with a selective TrkB activity, is able to promote  axon regeneration  in topical treatments. [ 17 ]  Furthermore, it shows efficacy in two  Parkinson's disease  (PD) animal models, leading to the protection of  locomotor function  and the reduction of  neuronal death  in  dopaminergic neurons . [ 18 ]  A number of studies corroborated that the  flavonoid  7,8-Dihydroxyflavone (7,8-DHF) shows neuroprotection in PD and  Huntington's disease  (HD) models [ 19 ] [ 20 ]  together with  antioxidant activity [ 21 ]  and enhancement of motor neuronal survival, motor function and spine density in  amyotrophic lateral sclerosis  (ALS) model. [ 22 ]  The benzothiazole  riluzole  exerts neuroprotective effects by increasing  BDNF  and  GDNF  levels with improvement of motor neuron survival. It has been approved for the treatment of ALS and delays the onset of  ventilator-dependence  or  tracheostomy  in some people and may increase survival by two to three months. [ 23 ]  Furthermore, several combinations of riluzole with other drugs are in clinical trials (NCT02588677, NCT03127267)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10779", "text": "Brimonidine  exerts neuroprotective effects in  retinal ganglion cells  (RGCs) through up-regulation of the expression of BDNF in these cells. [ 24 ]  It is used in the treatment of  glaucoma  as eye drops to reduce  intraocular pressure  (IOP) under the brand name Lumify\u00ae. Different drugs, used against PD also behave as neurotrophin mimetics such as  rotigotine ,  selegiline ,  rasagiline ,  memantine  and  levodopa  interacting with TrkB and increasing BDNF expression. [ 25 ]  Furthermore, of particular note, the groups of F. Longo and S. Massa discovered small molecule neurotrophic mimetics exhibiting  specificity  for TrkB at  nanomolar concentrations . [ 26 ]  In particular,  LM22A-4 , prevents neuronal death in  in vitro  models of AD, HD and PD. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10780", "text": "Among the peptidomimetic TrkB agonists, the dimeric dipeptide GSB-106 showed neurotrophic and neuroprotective effects by specific activation of TrkB and its  signaling pathways . [ 28 ] [ 29 ]  Furthermore, the tricyclic dimeric peptide TDP6 acts as a TrkB agonist mimicking BDNF and induces  autophosphorylation  of TrkB in primary  oligodendrocyte  cultures, leading to oligodendrocyte myelination. [ 30 ]  Regarding DHEA derivatives, the C17-spiroepoxy analogue,  BNN-20 , binds with high affinity to TrkB, showing antiapoptotic activity  in vitro . Its neuroprotective activity was analyzed in the  Weaver mouse  genetic model of PD in which long term administration of BNN-20 protects the dopaminergic neurons by mimicking BDNF and induces antiapoptotic, antioxidant and anti-inflammatory effects. [ 11 ] [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10781", "text": "In this class it is worthwhile to highlight the small non-peptide molecules LM22A-24 and  LM11A-31  developed by Longo and Massa. Through the modulation of  p75NTR  activity, these compounds downregulate degenerative and upregulate trophic signaling. [ 32 ]  In particular, LM11A-31 was found to inhibit several pathophysiological mechanisms involved in AD and related to p75NTR. [ 33 ] [ 34 ]  Oral administration in AD mice models reduces degeneration of cholinergic neurites. [ 34 ]  Furthermore, by a direct activation of p75NTR signaling and inhibition of apoptotic pathway, it improves motor function in a  spinal cord injury  (SCI) mice model and leads to an antiapoptotic effect in mice after  traumatic brain injury  (TBI). [ 35 ] [ 36 ]  In February 2017, a  phase 2 clinical trial  started focusing on the evaluation of the safety of LM11A-31 in mild to moderate AD (NCT03069014). This study was completed in June 2020, but the results have not been published yet."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10782", "text": "Another drug belonging to the class of p75NTR antagonists is THX-B, which inhibits NGF-p75NTR binding and prevents the death of RGCs in  axotomy  and glaucoma. In addition, in combination with LM22A-24, THX-B delays the loss of retinal structure, prevents RGC degeneration and preserves  ganglion cell layer - inner plexiform layer  thickness with a better efficacy compared to LM22A-24. [ 37 ]  Finally, a p75NTR antagonist, EVT901, was able to improve functional outcomes in two models of traumatic brain injury. [ 38 ]  Furthermore it was found to reduce inflammation  in vivo  in the TGFAD344 rat model of AD. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10783", "text": "There are a number of natural products with neurotrophic activity, which results from several mechanisms including enhancing BDNF  gene transcription , upregulating the expression of BDNF and TrkB, and  extracellular signal-regulated kinase  (ERK) and  CREB  signalling. [ 40 ] [ 41 ] [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10784", "text": "The first discovered non-protein neurotrophic natural product was  lactacystin , isolated from a culture broth of  Streptomyces sp . [ 40 ]   Magnolol  and  honokiol , the main constituents of  Magnolia officinalis  and  Magnolia obovata  stem bark, have been reported to have neurotrophic activity in primary cultured rat cortical by enhancing the BDNF expression. [ 41 ] [ 42 ]   Merrilactone A , jiadifenin,  jiadifenolide , (1R,10S)-2-oxo-3,4-dehydroxyneomajucin, jiadifenoxolane A, (2R)-hydroxynorneomajucin, 11- O -debenzoyltashironin,tricycloillicinone, and bicycloillicinone, natural products of the  Illicium  family have been shown to promote neurite outgrowth in primary cultures of cortical neurons of fetal rats. [ 40 ] [ 41 ]  Neurotrophic properties are also possessed by several members of the  Lycopodium   alkaloids  ( huperzine A , lyconadins, complanadine A and B, and nankakurine A and B). Studies have shown that huperazine A can elevate the levels of NGF and BDNF. Synthesis of NGF can be upregulated by administration of cyathanediterpenoids specifically  erinacines ,  scabronines  and cyrneines. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10785", "text": "Some  flavonoids ,  Isoflavonoids  and  neoflavonoids  were found to have neuroprotective activity. Among the effective flavonoids,  luteolin  from  Lonicera japonica sp. ,  isorhamnetin  from  Opuntia ficus-indica ,  genistein  from  Genista tinctoria , and  calycosin  from  Astragalus membranaceus  showed the most promising effects by increasing the  mRNA expression  and  protein secretion  of NGF, GDNF, and BDNF. [ 42 ]  Paecilomycine A and spirotenuipesines A and B, members of the  trichothecenes , isolated from the  fruiting bodies  of  Paecilomycestenuipes,  have significant neurotrophic profiles especially paecilomycine A which can stimulate the synthesis of neurotrophic factors. [ 40 ]  Polyprenylatedacylphloroglucinols (PPAPs) represented by  hyperforin ,  hypericin  and garsubellin A, have neurotrophic like properties. Hyperforin, isolated from the herb  St. John's wort  ( Hypericum perforatum ), can stimulate the upregulation of the TrkB receptor. [ 40 ] [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10786", "text": "Beside natural products, there are some small molecules of natural origin that exert neurotrophic activities such as:  Panaxytriol  (promotes NGF-induced neurite outgrowth in PC-12 cells); 7,8- dihydroxyflavone  (TrkB activator);  Deoxygedunin  (BDNF mimetic); Kansuinin E (promotes neurotrophic activity, most likely through TrkA activation);  Tripchlorolide  (stimulates expression of BDNF mRNA);  Fucoxanthin  (increases BDNF production and activates PKA/CREB pathway);  Silibinin  (Activate hippocampal ROS-BDNF-TrkB patway). [ 40 ] [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10787", "text": "OSU-6162  ( PNU-96391 ) is a compound which acts as a  partial agonist  at both  dopamine D 2  receptors  and  5-HT 2A  receptors . It acts as a dopamine stabilizer in a similar manner to the closely related drug  pridopidine , and has  antipsychotic , anti- addictive  and anti- Parkinsonian  effects in animal studies. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ]  Both  enantiomers  show similar activity but with different ratios of effects, with the (S) enantiomer (\u2013)-OSU-6162 that is more commonly used in research, having higher  binding affinity  to D 2  but is a weaker partial agonist at 5-HT 2A , while the (R) enantiomer (+)-OSU-6162 has higher efficacy at 5-HT 2A  but lower D 2  affinity. [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10788", "text": "A  psychiatric  or  psychotropic medication  is a  psychoactive drug  taken to exert an effect on the chemical makeup of the  brain  and nervous system. Thus, these medications are used to treat  mental illnesses . These medications are typically made of  synthetic   chemical compounds  and are usually prescribed in  psychiatric  settings, potentially  involuntarily  during  commitment . Since the mid-20th century, such medications have been leading treatments for a broad range of mental disorders and have decreased the need for long-term hospitalization, thereby lowering the cost of mental health care. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The  recidivism  or rehospitalization of the mentally ill is at a high rate in many countries, and the reasons for the  relapses  are under research. [ 5 ] [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10789", "text": "Several significant psychiatric drugs were developed in the mid-20th century. In 1948,  lithium  was first used as a psychiatric medicine. One of the most important discoveries was  chlorpromazine , an  antipsychotic  that was first given to a patient in 1952. In the same decade,  Julius Axelrod  carried out research into the interaction of neurotransmitters, which provided a foundation for the development of further drugs. [ 9 ]   The popularity of these drugs have increased significantly since then, with millions prescribed annually. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10790", "text": "The introduction of these drugs brought profound changes to the treatment of mental illness. It meant that more patients could be treated without the need for confinement in a  psychiatric hospital . It was one of the key reasons why many countries moved towards  deinstitutionalization , closing many of these hospitals so that patients could be treated at home, in general hospitals and smaller facilities. [ 11 ] [ 12 ]  Use of physical restraints such as  straitjackets  also declined."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10791", "text": "As of 2013, the 10 most prescribed psychiatric drugs by number of prescriptions were  alprazolam ,  sertraline ,  citalopram ,  fluoxetine ,  lorazepam ,  trazodone ,  escitalopram ,  duloxetine ,  bupropion XL , and  venlafaxine XR . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10792", "text": "Psychiatric medications are  prescription medications , requiring a prescription from a  physician , such as a  psychiatrist , or a psychiatric  nurse practitioner , PMHNP, before they can be obtained. Some  U.S. states  and  territories , following the creation of the  prescriptive authority for psychologists movement , have granted prescriptive privileges to  clinical psychologists  who have undergone additional specialised education and training in  medical psychology . [ 14 ]  In addition to the familiar dosage in pill form, psychiatric medications are evolving into more novel methods of drug delivery. New technologies include  transdermal ,  transmucosal ,  inhalation ,  suppository  or  depot injection  supplements. [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10793", "text": "Psychopharmacology studies a wide range of substances with various types of psychoactive properties. The professional and commercial fields of  pharmacology  and psychopharmacology do not typically focus on  psychedelic  or  recreational drugs , and so the majority of studies are conducted on psychiatric medication. While studies are conducted on all psychoactive drugs by both fields, psychopharmacology focuses on psychoactive and chemical interactions within the brain. Physicians who research psychiatric medications are  psychopharmacologists , specialists in the field of psychopharmacology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10794", "text": "Psychiatric disorders, including depression, psychosis, and bipolar disorder, are common and gaining more acceptance in the United States. The most commonly used classes of medications for these disorders are antidepressants, antipsychotics, and lithium. Unfortunately, these medications are associated with significant neurotoxicities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10795", "text": "Psychiatric medications carry risk for neurotoxic  adverse effects . The occurrence of neurotoxic effects can potentially reduce  drug compliance . Some adverse effects can be  treated symptomatically   by using adjunct medications such as  anticholinergics  (antimuscarinics). Some  rebound  or  withdrawal  adverse effects, such as the possibility of a sudden or severe emergence or re-emergence of  psychosis  in antipsychotic withdrawal, may appear when the drugs are discontinued, or discontinued too rapidly. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10796", "text": "While  clinical trials  of psychiatric medications, like other medications, typically test medicines separately, there is a practice in psychiatry (more so than in somatic medicine) to use  polypharmacy  in combinations of medicines that have never been tested together in clinical trials (though all medicines involved have passed clinical trials separately). It is argued that this presents a risk of adverse effects, especially  brain damage , in real-life mixed medication psychiatry that are not visible in the clinical trials of one medicine at a time (similar to mixed drug abuse causing significantly more damage than the additive effects of brain damages caused by using only one illegal drug). Outside clinical trials, there is evidence for an increase in mortality when psychiatric patients are transferred to polypharmacy with an increased number of medications being mixed. [ 18 ] [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10797", "text": "There are five main groups of psychiatric medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10798", "text": "Antidepressants are drugs used to treat  clinical depression , and they are also often used for anxiety and other disorders. Most antidepressants will hinder the breakdown of  serotonin ,  norepinephrine , and/or  dopamine . A commonly used class of antidepressants are called  selective serotonin reuptake inhibitors  (SSRIs), which act on serotonin transporters in the brain to increase levels of serotonin in the  synaptic cleft . [ 22 ]  Another is the  serotonin-norepinephrine reuptake inhibitors  (SNRIs), which increase both serotonin and norepinephrine. Antidepressants will often take 3\u20135 weeks to have a noticeable effect as the regulation of receptors in the brain adapts. There are multiple classes of antidepressants which have different mechanisms of action. Another type of antidepressant is a  monoamine oxidase inhibitor  (MAOI), which is thought to block the action of  monoamine oxidase , an enzyme that breaks down serotonin and  norepinephrine . MAOIs are not used as first-line treatment due to the risk of  hypertensive crisis  related to the consumption of foods containing the amino acid  tyramine . [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10799", "text": "Common antidepressants:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10800", "text": "Antipsychotics are drugs used to treat various symptoms of psychosis, such as those caused by psychotic disorders or  schizophrenia .  Atypical antipsychotics  are also used as  mood stabilizers  in the treatment of  bipolar disorder , and they can augment the action of antidepressants in  major depressive disorder . [ 22 ] \nAntipsychotics are sometimes referred to as neuroleptic drugs and some antipsychotics are branded \"major tranquilizers\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10801", "text": "There are two categories of antipsychotics:  typical antipsychotics  and  atypical antipsychotics . Most antipsychotics are available only by prescription."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10802", "text": "Common antipsychotics:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10803", "text": "Benzodiazepines  are effective as hypnotics, anxiolytics, anticonvulsants, myorelaxants and amnesics. [ 24 ]   Having less proclivity for overdose and toxicity, they have widely supplanted  barbiturates , although barbiturates (such as  pentobarbital ) are still used for  euthanasia . [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10804", "text": "Developed in the 1950s onward, benzodiazepines were originally thought to be non-addictive at therapeutic doses, but are now known to cause  withdrawal  symptoms similar to barbiturates and  alcohol . [ 27 ]  Benzodiazepines are generally recommended for short-term use. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10805", "text": "Z-drugs  are a group of drugs with effects generally similar to benzodiazepines, which are used in the treatment of insomnia."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10806", "text": "Common benzodiazepines and z-drugs include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10807", "text": "In 1949, the Australian  John Cade  discovered that  lithium salts  could control  mania , reducing the frequency and severity of manic episodes. This introduced the now popular drug  lithium carbonate  to the mainstream public, as well as being the first mood stabilizer to be approved by the U.S.  Food & Drug Administration . \nBesides lithium, several  anticonvulsants  and  atypical antipsychotics  have mood stabilizing activity. The mechanism of action of mood stabilizers is not well understood."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10808", "text": "Common non-antipsychotic mood stabilizers include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10809", "text": "A stimulant is a drug that stimulates the central nervous system, increasing arousal, attention and endurance. Stimulants are used in psychiatry to treat  attention deficit-hyperactivity disorder . Because the medications can be addictive, patients with a history of drug abuse are typically monitored closely or treated with a non-stimulant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10810", "text": "Common stimulants:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10811", "text": "Professionals, such as  David Rosenhan ,  Peter Breggin ,  Paula Caplan ,  Thomas Szasz  and  Stuart A. Kirk  sustain that psychiatry engages \"in the systematic medicalization of normality\". [ 28 ]  More recently these concerns have come from insiders who have worked for and promoted the APA (e.g.,  Robert Spitzer ,  Allen Frances ). [ 29 ] :\u200a185"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10812", "text": "Scholars such as  Cooper ,  Foucalt ,  Goffman ,  Deleuze  and  Szasz  believe that pharmacological \"treatment\" is only a  placebo  effect, [ 30 ]  and that administration of drugs is just a  religion  in disguise and ritualistic chemistry. [ 31 ]  Other scholars [ who? ]  have argued against psychiatric medication in that significant aspects of mental illness are related to the psyche or environmental factors, but medication works exclusively on a pharmacological basis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10813", "text": "Antipsychotics have been associated with decreases in brain volume over time, which may indicate a neurotoxic effect. However, untreated psychosis has also been associated with decreases in brain volume and treatments have been shown improve cognitive functioning. [ 32 ] [ 33 ] [ 34 ] [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10814", "text": "This is an alphabetical  list of  psychiatric medications  used by  psychiatrists  and other  physicians  to treat  mental illness  or distress."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10815", "text": "Acamprosate ,  Alprazolam ,  Alpidem ,  Amisulpride ,  Amitriptyline ,  Amoxapine ,  Amphetamine ,  Mixed Amphetamine Salts ,  Aripiprazole ,  Atomoxetine"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10816", "text": "Benperidol ,  Bromazepam ,  Bupropion ,  Buspirone"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10817", "text": "Calcium carbimide ,  Carbamazepine ,  Chloralhydrate ,  Chlordiazepoxide ,  Clorgiline ,  Chlorpromazine ,  Citalopram ,  Clomipramine ,  Clonazepam ,  Clonidine , Clorazepate ,  Clozapine"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10818", "text": "Desvenlafaxine ,  Dextroamphetamine ,  Diazepam ,  Disulfiram ,  Divaplon ,  Duloxetine"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10819", "text": "Escitalopram ,  Eszopiclone"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10820", "text": "Fasiplon ,  Fluoxetine ,  Fluphenazine ,  Flurazepam ,  Fluvoxamine"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10821", "text": "Gabapentin ,  Guanfacine"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10822", "text": "Haloperidol"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10823", "text": "Imipramine ,  Indalpine , Indiplon ,   Itopride"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10824", "text": "Lamotrigine ,  Lemborexant ,  Levoamphetamine ,  Levomepromazine ,  Lisdexamfetamine ,  Lithium ,  Lorazepam ,  Lorediplon ,  Loxapine ,  Lumateperone ,  Lurasidone"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10825", "text": "Maprotiline ,  Melperone ,  Meprobamate ,  Mesoridazine ,  Methamphetamine ,  Methaqualone ,  Methylphenidate ,  Mianserin ,  Mirtazapine ,  Mixed Amphetamine Salts ,  Moclobemide ,  Modafinil"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10826", "text": "Naltrexone ,  Necopidem ,  Nitrazepam ,  Nortriptyline"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10827", "text": "Ocinaplon ,  Olanzapine ,  Oxazepam ,  Oxcarbazepine"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10828", "text": "Pagoclone ,  Paliperidone ,  Panadiplon ,  Pargyline ,  Paroxetine ,  Pazinaclone ,  Perphenazine ,  Phenelzine ,  Phenytoin ,  Pipamperone ,  Pimavanserin ,  Pimozide ,  Pipotiazine ,  Pramipexole ,  Pregabalin ,  Primidone ,  Prochlorperazine ,  Promethazine ,  Prothipendyl ,  Protriptyline"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10829", "text": "Quetiapine"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10830", "text": "Reboxetine ,  Risperidone ,  Rozerem ,  Rubidium chloride"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10831", "text": "Saripidem ,  Scopolamine ,  Selegiline ,  Sertraline ,  Sodium Thiopental ,  Sulfonmethane ,  Sulpiride ,  Suriclone"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10832", "text": "Taniplon ,  Temazepam ,  Thioridazine ,  Thiothixene ,  Topiramate ,  Tranylcypromine ,  Trazodone ,  Triazolam ,  Trifluoperazine ,  Trimipramine"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10833", "text": "Valbenazine ,  Valproate ,  Venlafaxine"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10834", "text": "Zaleplon ,  Zimelidine ,  Ziprasidone ,  Zolpidem ,  Zopiclone ,  Zotepine ,  Zuclopenthixol"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10835", "text": "Psychopharmacology  (from  Greek   \u03c8\u1fe1\u03c7\u03ae ,  ps\u0233kh\u0113 , 'breath, life, soul';  \u03c6\u03ac\u03c1\u03bc\u03b1\u03ba\u03bf\u03bd ,  pharmakon , 'drug'; and  -\u03bb\u03bf\u03b3\u03af\u03b1 ,  -logia ) is the scientific study of the effects  drugs  have on  mood ,  sensation ,  thinking ,  behavior ,  judgment  and  evaluation , and  memory . It is distinguished from  neuropsychopharmacology , which emphasizes the correlation between drug-induced changes in the functioning of  cells  in the  nervous system  and changes in  consciousness  and behavior. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10836", "text": "The field of psychopharmacology studies a wide range of substances with various types of  psychoactive  properties, focusing primarily on the chemical interactions with the brain. The term \"psychopharmacology\" was likely first coined by  David Macht  in 1920. Psychoactive drugs interact with particular target sites or receptors found in the  nervous system  to induce widespread changes in physiological or psychological functions. The specific interaction between drugs and their receptors is referred to as \" drug action \", and the widespread changes in physiological or psychological function is referred to as \" drug effect \". [ 2 ]  These drugs may originate from natural sources such as plants and animals, or from artificial sources such as  chemical synthesis  in the laboratory."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10837", "text": "Not often mentioned or included in the field of psychopharmacology today are  psychoactive  substances not identified as useful in modern  mental health  settings or references. These substances are naturally occurring, but nonetheless psychoactive, and are compounds identified through the work of  ethnobotanists  and  ethnomycologists  (and others who study the native use of naturally occurring psychoactive drugs). However, although these substances have been used throughout history by various cultures, and have a profound effect on mentality and brain function, they have not always attained the degree of scrutinous evaluation that lab-made compounds have. Nevertheless, some, such as  psilocybin  and  mescaline , have provided a basis of study for the compounds that are used and examined in the field today.  Hunter-gatherer  societies tended to favor  hallucinogens , and today their use can still be observed in many surviving  tribal  cultures. The exact drug used depends on what the particular  ecosystem  a given tribe lives in can support, and are typically found growing wild. Such drugs include various  psychoactive mushrooms  containing psilocybin or  muscimol  and  cacti  containing mescaline and other chemicals, along with myriad other  plants containing psychoactive chemicals . These societies generally attach spiritual significance to such drug use, and often incorporate it into their religious practices.\nWith the dawn of the  Neolithic  and the proliferation of agriculture, new psychoactives came into use as a natural by-product of farming. Among them were  opium ,  cannabis , and  alcohol  derived from the fermentation of cereals and fruits. Most societies began developing  herblores , lists of herbs which were good for treating various physical and mental ailments. For example,  St. John's wort  was traditionally prescribed in parts of Europe for depression (in addition to use as a general-purpose tea), and  Chinese medicine  developed elaborate lists of  herbs  and preparations. These and various other substances that have an effect on the brain are still used as remedies in many cultures. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10838", "text": "The dawn of contemporary psychopharmacology marked the beginning of the use of psychiatric drugs to treat psychological illnesses. It brought with it the use of opiates and barbiturates for the management of acute behavioral issues in patients. In the early stages, psychopharmacology was primarily used for sedation. With the 1950s came the establishment of  lithium  for  mania ,  chlorpromazine  for  psychoses , and then in rapid succession, the development of tricyclic antidepressants, monoamine oxidase inhibitors, and benzodiazepines, among other antipsychotics and antidepressants. A defining feature of this era includes an evolution of research methods, with the establishment of  placebo-controlled ,  double-blind  studies, and the development of methods for analyzing blood levels with respect to clinical outcome and increased sophistication in clinical trials. The early 1960s revealed a revolutionary model by  Julius Axelrod  describing nerve signals and  synaptic transmission , which was followed by a drastic increase of biochemical brain research into the effects of psychotropic agents on brain chemistry. [ 4 ]  After the 1960s, the field of psychiatry shifted to incorporate the indications for and efficacy of pharmacological treatments, and began to focus on the use and toxicities of these medications. [ 5 ] [ 6 ]  The 1970s and 1980s were further marked by a better understanding of the synaptic aspects of the action mechanisms of drugs. However, the model has its critics, too \u2013 notably  Joanna Moncrieff  and the  Critical Psychiatry Network . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10839", "text": "Psychoactive drugs exert their sensory and behavioral effects almost entirely by acting on  neurotransmitters  and by modifying one or more aspects of synaptic transmission. Neurotransmitters can be viewed as chemicals through which  neurons  primarily communicate; psychoactive drugs affect the mind by altering this communication. Drugs may act by 1) serving as a  precursor  to a neurotransmitter; 2) inhibiting neurotransmitter synthesis; 3) preventing storage of neurotransmitters in the pre synaptic vesicle ; 4) stimulating or inhibiting neurotransmitter release; 5) stimulating or blocking post-synaptic receptors; 6) stimulating  autoreceptors , inhibiting neurotransmitter release; 7) blocking autoreceptors, increasing neurotransmitter release; 8) inhibiting neurotransmission breakdown; or 9) blocking neurotransmitter  reuptake  by the presynaptic neuron. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10840", "text": "The other central method through which drugs act is by affecting communications between cells through  hormones . Neurotransmitters can usually only travel a microscopic distance before reaching their target at the other side of the  synaptic cleft , while hormones can travel long distances before reaching target cells anywhere in the body. Thus, the  endocrine system  is a critical focus of psychopharmacology because 1) drugs can alter the secretion of many hormones; 2) hormones may alter the behavioral responses to drugs; 3) hormones themselves sometimes have psychoactive properties; and 4) the secretion of some hormones, especially those dependent on the  pituitary gland , is controlled by neurotransmitter systems in the brain. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10841", "text": "Alcohol  is a  depressant , the effects of which may vary according to dosage amount, frequency, and chronicity. As a member of the sedative-hypnotic class, at the lowest doses, the individual feels relaxed and less anxious. In quiet settings, the user may feel drowsy, but in settings with increased sensory stimulation, individuals may feel uninhibited and more confident. High doses of alcohol rapidly consumed may produce  amnesia  for the events that occur during intoxication. Other effects include reduced coordination, which leads to slurred speech, impaired fine-motor skills, and delayed reaction time. The effects of alcohol on the body's neurochemistry are more difficult to examine than some other drugs. This is because the chemical nature of the substance makes it easy to penetrate into the brain, and it also influences the  phospholipid bilayer  of neurons. This allows alcohol to have a widespread impact on many normal cell functions and modifies the actions of several neurotransmitter systems. Alcohol inhibits  glutamate  (a major excitatory neurotransmitter in the nervous system) neurotransmission by reducing the effectiveness at the  NMDA  receptor, which is related to memory loss associated with intoxication. It also modulates the function of  GABA , a major inhibitory amino acid neurotransmitter. Abuse of alcohol has also been correlated with thiamine deficiencies within the brain, leading to lasting neurological conditions that affect primarily the ability of the brain to effectively store memories. [ 7 ]  One such neurological condition is called  Korsakoff's syndrome , for which very few effective treatment modalities have been found. [ 7 ] [ 8 ]  The reinforcing qualities of alcohol leading to repeated use \u2013 and thus also the mechanisms of withdrawal from chronic alcohol use \u2013 are partially due to the substance's action on the  dopamine  system. This is also due to alcohol's effect on the  opioid  systems, or  endorphins , that have opiate-like effects, such as modulating pain, mood, feeding, reinforcement, and response to stress. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10842", "text": "Antidepressants  reduce symptoms of mood disorders primarily through the regulation of  norepinephrine  and  serotonin  (particularly the  5-HT receptors ). After chronic use, neurons adapt to the change in biochemistry, resulting in a change in pre- and postsynaptic receptor density and second messenger function. [ 1 ]  The Monoamine Theory of Depression and Anxiety, which states that the disruption of the activity of nitrogen containing neurotransmitters (i.e. serotonin, norepinephrine, and dopamine) is strongly correlated with the presence of depressive symptoms. [ 9 ]  Despite its longstanding prominence in pharmaceutical advertising, the myth that low serotonin levels cause depression is not supported by scientific evidence. [ 10 ] [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10843", "text": "Monoamine oxidase inhibitors  (MAOIs) are the oldest class of antidepressants. They inhibit  monoamine oxidase , the enzyme that metabolizes the monoamine neurotransmitters in the presynaptic terminals that are not contained in protective synaptic vesicles. The inhibition of the enzyme increases the amount of neurotransmitter available for release. It increases norepinephrine, dopamine, and 5-HT, thus increasing the action of the transmitters at their receptors. MAOIs have been somewhat disfavored because of their reputation for more serious side effects. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10844", "text": "Tricyclic antidepressants  (TCAs) work through binding to the presynaptic transporter proteins and blocking the reuptake of norepinephrine or 5-HT into the presynaptic terminal, prolonging the duration of transmitter action at the synapse."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10845", "text": "Selective serotonin reuptake inhibitors  (SSRIs) selectively block the reuptake of serotonin (5-HT) through their inhibiting effects on the sodium/potassium  ATP -dependent serotonin transporter in presynaptic neurons. This increases the availability of 5-HT in the synaptic cleft. [ 13 ]  The main parameters to consider in choosing an antidepressant are side effects and safety. Most SSRIs are available generically and are relatively inexpensive. Older antidepressants such as TCAs and MAOIs usually require more visits and monitoring, which may offset the low expense of the drugs. SSRIs are relatively safe in overdoses and better tolerated than TCAs and MAOIs for most patients. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10846", "text": "All proven antipsychotics are postsynaptic dopamine receptor blockers (dopamine  antagonists ). For an antipsychotic to be effective, it generally requires a dopamine antagonism of 60%\u201380% of dopamine D 2  receptors. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10847", "text": "First generation (typical) antipsychotics : Traditional  neuroleptics  modify several neurotransmitter systems, but their clinical effectiveness is most likely due to their ability to antagonize dopamine transmission by competitively blocking the receptors or by inhibiting dopamine release. The most serious and troublesome side effects of these classical antipsychotics are movement disorders that resemble the symptoms of  Parkinson's disease , because the neuroleptics antagonize dopamine receptors broadly, also reducing the normal dopamine-mediated inhibition of  cholinergic  cells in the  striatum . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10848", "text": "Second-generation (atypical) antipsychotics : The concept of \"atypicality\" is from the finding that second generation antipsychotics (SGAs) have a greater serotonin/dopamine ratio than earlier drugs, and might be associated with improved efficacy (particularly for the  negative symptoms  of psychosis) and reduced  extrapyramidal side effects . Some of the efficacy of atypical antipsychotics may be due to 5-HT 2  antagonism or the blockade of other dopamine receptors. Agents that purely block 5-HT 2  or dopamine receptors other than D 2  have often failed as effective antipsychotics. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10849", "text": "Benzodiazepines  are often used to reduce anxiety symptoms, muscle tension, seizure disorders, insomnia, symptoms of alcohol withdrawal, and panic attack symptoms. Their action is primarily on specific benzodiazepine sites on the GABA A  receptor. This receptor complex is thought to mediate the  anxiolytic , sedative, and  anticonvulsant  actions of the benzodiazepines. [ 13 ]  Use of benzodiazepines carries the risk of tolerance (necessitating increased dosage), dependence, and abuse. Taking these drugs for a long period of time can lead to  severe withdrawal symptoms  upon abrupt discontinuation. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10850", "text": "Psychedelics  cause perceptual and cognitive distortions without delirium. The state of intoxication is often called a \"trip\". Onset is the first stage after an individual ingests ( LSD ,  psilocybin ,  ayahuasca , and  mescaline ) or smokes ( dimethyltryptamine ) the substance. This stage may consist of visual effects, with an intensification of colors and the appearance of geometric patterns that can be seen with one's eyes closed. This is followed by a plateau phase, where the subjective sense of time begins to slow and the visual effects increase in intensity. The user may experience  synesthesia , a crossing-over of sensations (for example, one may \"see\" sounds and \"hear\" colors). These outward sensory effects have been referred to as the \"mystical experience\", and current research suggests that this state could be beneficial to the treatment of some mental illnesses, such as depression and possibly addiction. [ 15 ]  In instances where some patients have seen a lack of improvement from the use of antidepressants, serotonergic hallucinogens have been observed to be rather effective in treatment. [ 16 ]  In addition to the sensory-perceptual effects, hallucinogenic substances may induce feelings of depersonalization, emotional shifts to a euphoric or anxious/fearful state, and a disruption of logical thought. Hallucinogens are classified chemically as either  indolamines  (specifically  tryptamines ), sharing a common structure with serotonin, or as  phenethylamines , which share a common structure with norepinephrine. Both classes of these drugs are  agonists  at the 5-HT 2  receptors; this is thought to be the central component of their hallucinogenic properties. Activation of 5-HT 2A  may be particularly important for hallucinogenic activity. However, repeated exposure to hallucinogens leads to rapid tolerance, likely through down-regulation of these receptors in specific target cells. [ 1 ]  Research suggests that hallucinogens affect many of these receptor sites around the brain and that through these interactions, hallucinogenic substances may be capable of inducing positive introspective experiences. [ 16 ]  The current research implies that many of the effects that can be observed occur in the occipital lobe and the frontomedial cortex; however, they also present many secondary global effects in the brain that have not yet been connected to the substance's biochemical mechanism of action. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10851", "text": "Another class of hallucinogens, known as  dissociatives , includes drugs such as  ketamine ,  phencyclidine  (PCP), and  Salvia divinorum . Drugs such as these are thought to interact predominantly with glutamate receptors within the brain. Specifically, ketamine is thought to block NMDA receptors that are responsible for signalling in the glutamate pathways. [ 17 ]  Ketamine's more tranquilizing effects can be seen in the central nervous system through interactions with parts of the thalamus by inhibition of certain functions. [ 17 ]  Ketamine has become a major drug of research for the treatment of depression. [ 18 ]  These antidepressant effects are thought to be related to the drug's action on the glutamate receptor system and the relative spike in glutamate levels, as well as its interaction with mTOR, which is an enzymatic protein involved in catabolic processes in the human body. [ 19 ] [ 18 ]  Phencyclidine's biochemical properties are still mostly unknown; however, its use has been associated with dissociation, hallucinations, and in some cases seizures and death. [ 20 ]   Salvia divinorum , a plant native to Mexico, has strong dissociative and hallucinogenic properties when the dry leaves are smoked or chewed. [ 21 ]  The qualitative value of these effects, whether negative or positive, has been observed to vary between individuals with many other factors to consider. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10852", "text": "Hypnotics  are often used to treat the symptoms of insomnia or other sleep disorders. Benzodiazepines are still among the most widely prescribed sedative-hypnotics in the United States today. Certain non-benzodiazepine drugs are used as hypnotics as well. Although they lack the chemical structure of the benzodiazepines, their sedative effect is similarly through action on the GABA A  receptor. They also have a reputation of being less addictive than benzodiazepines.  Melatonin , a naturally-occurring hormone, is often used over the counter (OTC) to treat insomnia and jet lag. This hormone appears to be excreted by the pineal gland early during the sleep cycle and may contribute to human  circadian rhythms . Because OTC melatonin supplements are not subject to careful and consistent manufacturing, more specific melatonin agonists are sometimes preferred. They are used for their action on melatonin receptors in the  suprachiasmatic nucleus , responsible for sleep-wake cycles. Many barbiturates have or had an FDA-approved indication for use as sedative-hypnotics, but have become less widely used because of their limited safety margin in overdose, their potential for dependence, and the degree of  central nervous system depression  they induce. The amino-acid  L-tryptophan  is also available OTC, and seems to be free of dependence or abuse liability. However, it is not as powerful as the traditional hypnotics. Because of the possible role of serotonin in sleep patterns, a new generation of 5-HT 2  antagonists are in current development as hypnotics. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10853", "text": "Cannabis  consumption produces a dose-dependent state of intoxication in humans. There is commonly increased blood flow to the skin, which leads to an increased heart rate and sensations of warmth or flushing. It also frequently induces increased hunger. [ 1 ]  Iversen (2000) categorized the subjective and behavioral effects often associated with cannabis into three stages. The first is the \"buzz\", a brief period of initial responding where the main effects are lightheadedness or slight dizziness, in addition to possible tingling sensations in the extremities or other parts of the body. The \"high\" is characterized by feelings of euphoria and exhilaration characterized by mild psychedelia as well as a sense of disinhibition. If the individual has taken a sufficiently large dose of cannabis, the level of intoxication progresses to the stage of being \"stoned\", and the user may feel calm, relaxed, and possibly in a dreamlike state. Sensory reactions may include the feeling of floating, enhanced visual and auditory perception, visual illusions, or the perception of the slowing of time passage, which are somewhat psychedelic in nature. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10854", "text": "There exist two primary CNS cannabinoid receptors, on which marijuana and the cannabinoids act. Both the  CB 1  and  CB 2  receptor  are found in the brain. The CB 2  receptor is also found in the immune system. CB 1  is expressed at high densities in the  basal ganglia ,  cerebellum ,  hippocampus , and  cerebral cortex . Receptor activation can inhibit  cAMP  formation, inhibit voltage-sensitive calcium ion channels, and activate potassium ion channels. Many CB 1  receptors are located on axon terminals, where they act to inhibit the release of various neurotransmitters. In combination, these chemical actions work to alter various functions of the central nervous system, including the motor system, memory, and various cognitive processes. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10855", "text": "The  opioid  category of drugs \u2013 including drugs such as  heroin ,  morphine , and  oxycodone  \u2013 belong to the class of  narcotic   analgesics , which reduce pain without producing unconsciousness but do produce a sense of relaxation and sleep, and at high doses may result in coma and death. The ability of opioids (both  endogenous  and  exogenous ) to relieve pain depends on a complex set of neuronal pathways at the spinal cord level, as well as various locations above the spinal cord. Small  endorphin  neurons in the spinal cord act on receptors to decrease the conduction of pain signals from the spinal cord to higher brain centers. Descending neurons originating in the  periaqueductal gray  give rise to two pathways that further block pain signals in the spinal cord. The pathways begin in the locus coeruleus (noradrenaline) and the nucleus of raphe (serotonin). Similar to other abused substances, opioid drugs increase dopamine release in the  nucleus accumbens . [ 1 ]  Opioids are more likely to produce  physical dependence  worse than that of other classes of psychoactive drugs, and can lead to painful withdrawal symptoms if discontinued abruptly after regular use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10856", "text": "Cocaine  is one of the more common stimulants and is a complex drug that interacts with various neurotransmitter systems. It commonly causes heightened alertness, increased confidence, feelings of exhilaration, reduced fatigue, and a generalized sense of well-being. The effects of cocaine are similar to those of amphetamines, though cocaine tends to have a shorter duration of effect. In high doses or with prolonged use, cocaine can result in a number of negative effects, including irritability, anxiety, exhaustion, total insomnia, and even psychotic symptomatology. Most of the behavioral and physiological actions of cocaine can be explained by its ability to block the reuptake of the two  catecholamines , dopamine and norepinephrine, as well as serotonin. Cocaine binds to transporters that normally clear these transmitters from the synaptic cleft, inhibiting their function. This leads to increased levels of neurotransmitter in the cleft and transmission at the synapses. [ 1 ]  Based on in-vitro studies using rat brain tissue, cocaine binds most strongly to the serotonin transporter, followed by the dopamine transporter, and then the norepinephrine transporter. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10857", "text": "Amphetamines  tend to cause the same behavioral and subjective effects of cocaine. Various forms of amphetamine are commonly used to treat the symptoms of  attention deficit hyperactivity disorder  (ADHD) and  narcolepsy , or are used recreationally. Amphetamine and  methamphetamine  are indirect agonists of the catecholaminergic systems. They block catecholamine reuptake, in addition to releasing catecholamines from nerve terminals. There is evidence that dopamine receptors play a central role in the behavioral responses of animals to cocaine, amphetamines, and other psychostimulant drugs. One action causes the dopamine molecules to be released from inside the vesicles into the cytoplasm of the nerve terminal, which are then transported outside by the  mesolimbic  dopamine pathway to the nucleus accumbens. This plays a key role in the rewarding and reinforcing effects of cocaine and amphetamine in animals, and is the primary mechanism for amphetamine dependence. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10858", "text": "In psychopharmacology, researchers are interested in any substance that crosses the  blood\u2013brain barrier  and thus has an effect on behavior, mood, or cognition. Drugs are researched for their physiochemical properties, physical  side effects , and psychological side effects. Researchers in psychopharmacology study a variety of different psychoactive substances, including alcohol, cannabinoids,  club drugs , psychedelics, opiates,  nicotine ,  caffeine ,  psychomotor stimulants ,  inhalants , and  anabolic\u2013androgenic steroids . They also study drugs used in the treatment of affective and anxiety disorders, as well as  schizophrenia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10859", "text": "Clinical studies are often very specific, typically beginning with animal testing and ending with human testing. In the human testing phase, there is often a group of subjects: one group is given a placebo, and the other is administered a carefully measured  therapeutic dose  of the drug in question. After all of the testing is completed, the drug is proposed to the concerned regulatory authority (e.g. the U.S.  FDA ), and is either commercially introduced to the public via  prescription , or deemed safe enough for  over-the-counter  sale."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10860", "text": "Though particular drugs are prescribed for specific symptoms or syndromes, they are usually not specific to the treatment of any single mental disorder."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10861", "text": "A somewhat controversial application of psychopharmacology is \"cosmetic psychiatry\": persons who do not meet criteria for any psychiatric disorder are nevertheless prescribed psychotropic medication. The antidepressant  bupropion  is then prescribed to increase perceived energy levels and assertiveness while diminishing the need for sleep. The antihypertensive compound  propranolol  is sometimes chosen to eliminate the discomfort of day-to-day anxiety.  Fluoxetine  in nondepressed people can produce a feeling of generalized well-being.  Pramipexole , a treatment for restless leg syndrome, can dramatically increase libido in women. These and other off-label lifestyle applications of medications are not uncommon. Although occasionally reported in the medical literature, no guidelines for such usage have been developed. [ 24 ]  There is also a potential for the misuse of prescription psychoactive drugs by elderly persons, who may have multiple drug prescriptions. [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10862", "text": "Psychoplastogens  are a group of  small molecule drugs  that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single administration. [ 1 ] [ 2 ]  Several existing psychoplastogens have been identified and their therapeutic effects demonstrated; several are presently at various stages of development as medications including  ketamine ,  MDMA ,  scopolamine , and the  serotonergic psychedelics , including  LSD ,  psilocin  (the active metabolite of  psilocybin ),  DMT , and  5-MeO-DMT . Compounds of this sort are being explored as therapeutics for a variety of  brain disorders  including  depression ,  addiction , and  PTSD . The ability to rapidly promote neuronal changes via mechanisms of  neuroplasticity  was recently discovered as the common therapeutic activity and mechanism of action. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10863", "text": "The term psychoplastogen comes from the Greek roots  psych - (mind), - plast  (molded), and - gen  (producing) and covers a variety of chemotypes and receptor targets. It was coined by  David E. Olson  in collaboration with Valentina Popescu, both at the University of California, Davis. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10864", "text": "The term neuroplastogen is sometimes used as a synonym for psychoplastogen, especially when speaking to the biological substrate rather than the therapeutic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10865", "text": "Psychoplastogens come in a variety of  chemotypes  and chemical families, but, by definition, are small-molecule drugs. [ 1 ]  Ketamine has been described as, \"the prototypical psychoplastogen\". [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10866", "text": "Psychoplastogens exert their effects by promoting structural and functional  neural plasticity  through diverse targets including, but not limited to,  5-HT2A ,  NMDA , and  muscarinic receptors . Some are  biased agonists . While each compound may have a different receptor binding profile, signaling appears to converge at the  tyrosine kinase B  (TrkB) and  mammalian target of rapamycin  (mTOR) pathways. [ 3 ] [ 4 ]  Convergence at TrkB and mTOR parallels that of traditional antidepressants with known efficacies, but with more rapid onset. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10867", "text": "Due to their rapid and sustained effects, psychoplastogens could potentially be dosed intermittently. In addition to the  neuroplasticity  effects, these compounds can have other epiphenomena including sedation, dissociation, and hallucinations. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10868", "text": "Psychedelics  show complex effects on neuroplasticity and can both promote and inhibit neuroplasticity depending on the circumstances. [ 7 ]  Single doses of  DMT ,  5-MeO-DMT ,  psilocybin , and  DOI  have been found to produce robust and long-lasting increases in neuroplasticity in animals. [ 7 ]  Likewise, repeated doses of  LSD  for 7 \u00a0 days increased neuroplasticity. [ 7 ]  However, chronic intermittent administration of DMT for several weeks resulted in dendritic spine retraction, suggesting physiological homeostatic compensation in response to overstimulation. [ 7 ]  In addition, DOI has been found to decrease  brain-derived neurotrophic factor  (BDNF) levels in the  hippocampus . [ 7 ]  The effects of psychedelics on neuroplasticity appear to be dependent on  serotonin   5-HT 2A  receptor  activation, as they are abolished in 5-HT 2A  receptor  knockout mice . [ 7 ]  Non-hallucinogenic serotonin 5-HT 2A  receptor agonists, like  tabernanthalog  and  lisuride , have also been found to increase neuroplasticity, and to a magnitude comparable to psychedelics. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10869", "text": "In terms of  neurogenesis , DOI and LSD showed no impact on hippocampal neurogenesis, while psilocybin and  25I-NBOMe  decreased hippocampal neurogenesis. [ 7 ]  5-MeO-DMT however has been found to increase hippocampal neurogenesis, and this could be blocked by  sigma   \u03c3 1  receptor   antagonists . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10870", "text": "Several psychoplastogens have either been approved or are in development for the treatment of a variety of brain disorders associated with neuronal atrophy where neuroplasticity can elicit beneficial effects. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10871", "text": "Esketamine , sold under the brand name Spravato and produced by  Janssen Pharmaceuticals , was approved by the  FDA  in March 2019 for the treatment of  Treatment-Resistant Depression  (TRD) and  suicidal ideation . [ 8 ]  As of 2022, it is the only psychoplastogen approved in the US for the treatment of a neuropsychiatric disorder. [ 6 ]  Esketamine is the S(+)  enantiomer  of ketamine and functions as an  NMDA receptor  antagonist. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10872", "text": "Other psychoplastogens that are being investigated in the clinic include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10873", "text": "Miodrag (Misha) Radulovacki  ( Serbian Cyrillic : \u041c\u0438\u043e\u0434\u0440\u0430\u0433 \u0420\u0430\u0434\u0443\u043b\u043e\u0432\u0430\u0447\u043a\u0438;  Serbian Latin : Miodrag Radulova\u010dki), was a  Serbian American  scientist and inventor.  He was Professor of  Pharmacology  in the  College of Medicine at the University of Illinois at Chicago  (UIC), [ 1 ]  Radulovacki's research accomplishments include: (1) the  Adenosine  Sleep Theory, [ 2 ]  and (2) pioneering pharmacological studies for the treatment of  sleep apnea , [ 3 ]  together with research collaborator, David W. Carley, [ 4 ]  (Professor of Medicine at the UIC). Radulovacki and Carley invented several  drug therapies  for the treatment of sleep apnea which have been patented by the UIC. The UIC recognized them as the 2010 \"Inventors of the Year.\" [ 5 ] [ 6 ]  Radulovacki published more than 170 scientific papers. [ 7 ]  Radulovacki was also a Foreign Member of the  Serbian Academy of Sciences and Arts . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10874", "text": "Miodrag Radulovacki was born on April 28, 1933, in  Parage , a village in northwestern  Serbia . Both of his parents were  elementary school   teachers . At the beginning of  World War II , Radulovacki's father was drafted into the  Yugoslav Army  and was later taken prisoner by the invading  Germans . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10875", "text": "In 1943, Radulovacki moved to  Sremski Karlovci  after his mother accepted a teaching position in the town.  Sremski Karlovci (also known as Karlovci), a  baroque  Serbian town on the banks of the  Danube River , had been home to the Radulovacki family for over 200 years. [ citation needed ]  Radulovacki attended  Karlovci High School  or \"Gymnasium,\" which is the oldest high school in Serbia. [ 9 ] [ 10 ]  Radulovacki called Karlovci Gymnasium the \"Serbian  Cambridge  and  Oxford \". [ 9 ] [ 10 ]  Radulovacki graduated as  valedictorian  of the Karlovci High School Class of 1951. [ 9 ] [ 10 ]  Radulovacki gained admission to the  University of Belgrade   School of Medicine . [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10876", "text": "Radulovacki graduated from the University of Belgrade School of Medicine in 1959. [ 11 ] [ 12 ] [ 13 ]  He went on to obtain a  PhD  in  Neurophysiology . [ 12 ] [ 13 ]  The topic of his PhD thesis was: \"Sleep in Split-Brain Cats,\" partly done at the Brain Research Institute at UCLA. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10877", "text": "Radulovacki spent 18 months at the  University of California, Los Angeles  (UCLA) Brain Research Institute [ 14 ] [ failed verification ]  where his mentor was Ross Adey. [ 15 ]  One of the findings of his research at UCLA was that the  electroencephalographic  (EEG) pattern of sleep in cats with split brain to the  pons  is synchronous in both  brain hemispheres , indicating the importance of the  brainstem  in sleep regulation. [ 11 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10878", "text": "In 1966, Radulovacki accepted a teaching position with the  Physiology  Department in the College of Medicine at the  University of Khartoum ,  Sudan . [ 11 ]  There he invented an approach for obtaining  cerebrospinal fluid  using a  cannula  to the  cisterna magna  in the brain of cats. The cannulation method enabled researchers to obtain cerebrospinal fluid during sleep and wakefulness for the analysis of  monoamine   metabolites . [ 17 ]  This approach was of interest since  Michel Jouvet 's  Monoamine  Theory of Sleep, [ 18 ]  with  serotonin  as the sleep inducing agent, was dominant at the time. From 1970 to 1984, at the University of Illinois, Radulovacki published a series of papers dealing with the role of monoamines in sleep. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10879", "text": "In 1970, Radulovacki was recruited by Klaus Unna [ 19 ]   to join the Department of Pharmacology in the College of Medicine at the University of Illinois at Chicago as an Assistant Professor. [ 11 ]  Radulovacki published more than 170 scientific papers during his career at the UIC. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10880", "text": "In 1984, Radulovacki postulated the Adenosine Sleep Theory, (JPET, 228: 268-274, 1984). [ 20 ]  The idea for adenosine's role in sleep occurred to him after reading a paper by  Sol Snyder 's group (Proc. Natl. Acad. Sci, 78: 3260-64, 1981) [ 21 ]  about the importance of adenosine receptors in the behavioral actions of  methylxanthines . In the article, the authors correlated the behavioral excitation produced by  theophylline  in  micromolar  concentrations with the blockade of adenosine  receptors ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10881", "text": "Radulovacki reasoned that if the blocking of adenosine receptors produces excitation, then perhaps stimulation of the same receptors could induce sleep. [ 22 ]  He knew that experiments by John Phillis and his group (Can. J. Physiol. Pharmacol. 57:1289-1312, 1979), [ 23 ]  which utilized an  iontophoretic  application of adenosine in the brain, had demonstrated adenosine's  depressant  effect on the responses of  neurons  in several brain regions and that the general  neurophysiological  effects of adenosine were shown to be inhibitory. In addition, the preliminary experiments in dogs by Haulica  et al.  (J. Neurochem. 21:,1019\u201320, 1973) [ 24 ]  and the administration of adenosine into the brains of rats, cats and fowl suggested that adenosine was able to produce  behavioral   sleep . The explanation of adenosine's  hypnotic  effect was through its interaction with  serotonin , widely believed to be a sleep inducing agent. However, since there was no suggestion how this adenosine-serotonin link was achieved, experiments highlighting the potential role of adenosine in sleep had largely been forgotten."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10882", "text": "In 1993, Radulovacki started a collaboration with David W. Carley, a Professor of  Medicine ,  Bioengineering  and Pharmacology at the UIC. Their research efforts focused on developing pharmacological approaches for the treatment of  sleep apnea . [ 25 ]  Since there were no medicines to alleviate this condition, Radulovacki and Carley set out to develop a  drug treatment . [ 26 ]  Their initial work focussed on an  experimental   model  of sleep apnea in rats, initially testing the effects of adenosine compounds. [ 27 ]  Eventually, they obtained positive results using serotonin and other compounds. As a result, the UIC  patented  their discoveries, obtaining numerous US and international patents. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10883", "text": "Patents for sleep and sleep-related disorders include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10884", "text": "Radulovacki was named the 2010 Inventor of the Year at the University of Illinois, alongside Carley. [ 5 ]  Radulovacki and Carley were honored by the University of Illinois for producing a dozen potential treatments for sleep apnea, many of which are now under consideration for commercial development. [ 38 ]  Their results have culminated in an IllinoisVentures-supported start-up company, Pier Pharmaceuticals, that focuses on the treatment of obstructive sleep apnea. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10885", "text": "In October 2003, the Serbian Academy of Sciences and Arts in Belgrade elected Radulovacki as one of its Foreign Members for his significant scientific research contributions in the fields of Neuropharmacology, sleep disorders and sleep-related breathing disorders. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10886", "text": "In 1990, Radulovacki initiated the Yugoslav Student Summer Program at the  University of Illinois  at Chicago (UIC) and the University of Illinois at  Champaign-Urbana  (UIUC) after the creation of International Linkage Agreements between the UIC and the Universities of Belgrade and  Novi Sad  in Yugoslavia. [ 40 ]  The Yugoslav Student Summer Program lasted for 12 years and had 304 participants. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10887", "text": "In 2005, Radulovacki established the Miodrag Radulovacki Family Prize for Excellence in Basic Sciences at the University of Illinois College of Medicine at Chicago. [ 11 ]  The purpose of the prize, given annually, is to honor a fourth year Medical student who displays a high degree of intellectual integrity and who has demonstrated strong academic achievement. The prize consists of a plaque and a check for $1,000."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10888", "text": "Radulovacki made numerous contributions to his home town of  Sremski Karlovci ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10889", "text": "Radulovacki lived in  Chicago . He was a  cross-country skier . [ 12 ]  He participated in several Birkebeiner-Kortelopet cross-country ski marathons in Cable-Hayward,  Wisconsin . [ citation needed ]  Radulovacki died on May 27, 2014, in Belgrade, Serbia, while on two-week trip to promote his philanthropic projects.  He is survived by two sons (Brad Radulovacki and Branko Radulovacki) and four grandchildren (Grant, Katie, Reid and Ryan). [ 46 ] [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10890", "text": "Reward dependence  ( RD ) is characterized as a tendency to respond markedly to signals of  reward , particularly to verbal signals of social approval, social support, and sentiment. [ 1 ]  When reward dependence levels deviate from normal we see the rise of several personality and addictive disorders."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10891", "text": "In  psychology , reward dependence is considered a moderately heritable  personality trait  which is stable throughout our lives. It is an inherited neurophysiological mechanism that drives our perception of our society and the environment. Even though we are born with these personality traits, their expression during our life span can be modulated throughout our development."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10892", "text": "Reward dependence is one of the  temperament  dimensions from the  \"tridimensional personality theory\" , which was proposed by  C. Robert Cloninger  as part of his \"unified bio-social theory of personality\". [ 2 ]  His personality theory suggested the hypothesis that specific  neurochemical transmitters  in our brain determine how we respond to a specific stimulus we may experience."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10893", "text": "These innate personality traits can play a significant role not only in an individual's predisposition to certain disorders, but also in their maintenance of those disorders."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10894", "text": "By understanding the specific temperamental traits that are common among individuals with specific disorders, clinicians can form a more targeted, informed approach to treatment and look to newer psychotherapies for guidance. The relationship between temperament and individual clusters of  DSM  personality disorders is often investigated. According to the DSM-IV, [ 3 ]  the tridimensional structure allows up to nine major  personality disorders  to be identified, the theory thereby making a great contribution to the understanding of psychiatric disorders."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10895", "text": "Cloninger's tridimensional personality theory offers three independent \"temperament\" dimensions which aid in measuring how different individuals feel or behave. Reward Dependence (RD) is one of the three temperament dimensions, the other two being  \"Harm Avoidance (HA)\"  and  \"Novelty Seeking (NS)\" . A temperament, according to Cloninger, is the automatic emotional response to experience. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10896", "text": "Cloninger suggested that RD is influenced by a single  monoamine neurotransmitter  system: the  noradrenergic  system  [ 2 ]  and RD is correlated with low basal noradrenergic activity. This suggestion has led to several research experiments that have investigated and supported his hypothesis, that RD traits are indeed in part determined by norepinephrine. [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10897", "text": "Measure of the RD dimension, as suggested by Cloninger, is used to assess the Altruistic-warm  versus  detached-tough mindedness components of our personalities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10898", "text": "According to Cloninger's theory, [ 8 ]  individuals  high  in reward dependence and  low  in norepinephrine levels are ambitious, warm, sentimental, pleasant, sociable, sensitive, sympathetic and socially dependent. Individuals with high RD personalities have a disposition to recognize salient social cues which in turn facilitates effective communication, warm social relations, and their genuine care for others, but these individuals are then disadvantaged in being excessively socially dependent. High reward dependent individuals also exhibit persistent behaviors and are easily influenced by emotional appeals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10899", "text": "Individuals  low  in reward dependence and  high  in norepinephrine levels are then hypothesized to be typically independent, non-conformist, practical, tough-minded, cynical, unwilling to share their intimate feelings with others, socially detached, irresolute, insensitive to social cues and pressures, and content to be alone. They are also minimally motivated to please others and act for immediate gratification. So being low in reward dependence is related to social withdrawal, with aggressive anti-social behavior, [ 9 ] [ 10 ]  detachment, and coldness in social attitudes. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10900", "text": "The RD temperament interacts with other temperaments and  characters  inherent in us enabling us to adapt to life experiences and influence susceptibility to emotional and behavioral disorders [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10901", "text": "Two questionnaires were devised by Cloninger to measure the temperaments and characters of individuals. RD can be measured using both the  Tridimensional Personality Questionnaire  (TPQ) personality test and by the newer and refined version of the personality test called  Temperament and Character Inventory  (TCI) and its revised version (TCI-R). Owing to the limitations encountered in the TPQ, in that the three dimensions' clinical utility was not readily apparent to many clinicians, [ 12 ]  Cloninger revamped the questionnaire and produced the TCI scale, which incorporates four dimensions of \"temperament\" and three dimensions of \"character\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10902", "text": "The so-called subscales of RD in TCI-R are"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10903", "text": "A study comparing the TCI to the  five factor model  of personality found that reward dependence was substantially positively associated with  extraversion  and to a lesser extent  openness to experience . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10904", "text": "Cloninger describes reward dependence as being a prime component of the  Behavior   maintenance  System (BMS). [ 6 ]   Norepinephrine  (NE), apart from producing alertness and arousal, is seen as influencing the brain reward system [ 14 ]  by aiding in the learning of new paired  associations . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10905", "text": "According to Cloninger, the norepinephrine neurotransmitter has its major ascending pathways arising in the locus coeruleus in the  pons , projecting onward to the  hypothalamic  and  limbic structures , and then branching upwards to the  neocortex . [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10906", "text": "Cloninger's theory suggests that over  expression  of the RD temperament could cause psychiatric illnesses, such as  addictive behaviors ,  sociopathies , and  personality disorders . [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10907", "text": "Low levels of norepinephrine cause an increase in reward dependence. When produced in normal levels, norepinephrine creates a sense of well-being, but low levels of norepinephrine cause symptoms of  depression , lack of  arousal  and lack of  motivation . In humans, this leads to then a  negative feedback  mechanism whereby we seek out pleasurable activities to remove the negative  affect  caused by the low levels of norepinephrine, therefore increasing our reward dependence."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10908", "text": "An increase in the RD temperament leads us to seek out those behaviors or substances that will allow us to remain in a pleasant physical and/or mental state, attributing to the fact that we humans are  hedonistic  individuals, seeking to avoid pain and embracing pleasurable stimuli. [ 23 ]  Our pleasure and reward systems in the brain are hyper-activated, which makes us display continuous approach behaviors to the reward in question. Our neuro-circuitry is as such that when we stop having access to such pleasurable objects of desire, we then experience negative consequences ( withdrawal  symptoms). Addictive behaviors then arise to alleviate such negative consequences and the cycle continues. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10909", "text": "People who have high reward dependent personalities but find themselves in situations where they are unable to find rewards and approval through family support or other types, will seek reward through other means e.g.  substance abuse  or over-eating. It is then suggested that individuals with such predispositions should adopt preventive strategies or avoid such situations, where they seek such rewards that could potentially have adverse consequences. [ 20 ]  Reward dependence drives behavior maintenance systems, and in addictive behaviors, maintenance of behaviors occurs despite adverse consequences."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10910", "text": "According to researchers the reward circuit is continuously involved in initiating behaviors that are essential for the sustenance of the individual (such as eating) or of the preservation of the species (such as sexual reproduction). Food intake or sexual stimuli then lead to endorphin regulated release of dopamine in core substrates of the reward processing system, which subsequently activate  craving  sensations. The development of addictions is then directly related to the acquired or genetic abuse of the reward circuit. This finding then suggests that individuals with increased reward dependence have a relative deficit of endorphins and are possibly at higher risk for developing addictive behaviors. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10911", "text": "Adolescents  low in reward dependence may find conventional sources of reward unfulfilling (e.g., academic achievement or activities involving social affiliation), and eventually turn to unconventional reward sources (e.g.,  smoking  and other forms of substance misuse) to derive satisfaction and pleasure. [ 25 ]  A study conducted using adolescents with Excessive Internet video Game Play (EIGP) showed that such addictive behaviors were correlated with higher RD scores on the TCI, [ 26 ]  whereas both low and high scores of RD were implicated in specific alcoholic and drug addictions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10912", "text": "Social reward dependence is hypothesized to be related to behaviors that represent the RD personality dimension sub-scales of  social sensitivity  and attachment. It is suggested that the brain substrates that are involved in the response to simple primary rewards stimuli are also implicated in the response to complex social rewards stimuli. The RD sub-scale from the TCI inventory measures how sensitive individuals are to social rewards. High RD scores on the test correlate to increased attachment and an increased need for social relationships. Low RD scores show a movement towards social detachment and insensitivity. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10913", "text": "At the 2010 Annual meeting of the  American Psychological Association  (APA), a study looking at treatment methods of personality disorders was presented in which it was found, that panic disorder patients with higher RD scores were more resistant to  Escitalopram  treatment. Since long-term  pharmacotherapy  is needed for treatment of panic disorder, the present results suggest that development of therapeutic strategy for panic patients with high reward dependence is needed. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10914", "text": "In response to  a lack of social reward , individuals with high reward dependence are more likely to have increased noradrenergic activity. These individuals experience feelings of depression,  agitation  and extreme discontent, leading them to indulge in habits that reinforce reward-seeking, such as increased sexual activity or overeating. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10915", "text": "Individuals with higher reward dependence also look for more social approval, and are more inclined to succumb to peer-pressure. They often become overly concerned with their  body image  and maybe prone to eating disorders, such as  Bulimia nervosa . [ 41 ]  Whereas restricting  anorexia , in particular, tends to reflect low reward dependence. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10916", "text": "Reward dependence is not consistently associated with diagnosis but can also significantly affect treatment issues, such as  Therapeutic alliance . Persistence in completing  weight-loss programs  were related to high RD scores during pre-treatment. This demonstrates that, having higher reward dependence enhances an individual's disposition to being more dedicated and sociable, making them increasingly respond to societal pressures, thereby reducing their risk of dropping out from weight-loss programs. [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10917", "text": "A study of norepinephrine levels in gamblers found high  cerebrospinal fluid  (CSF) levels of the norepinephrine (NE) metabolite 3-methoq-4-hydroxyphenylglycol (MI-IPG). [ 43 ]  This could suggest a relationship between the noradrenergic system and gambling, and gambling could be seen as a reward-dependent behavior, but according to Cloninger's theory these gamblers should exhibit low levels of NE, not high. Cloninger suggests that had these gamblers been retested after they had refrained from gambling for a determined period, their CSF MHPG levels might have been low. [ 12 ]  A study of norepinephrine levels in alcoholics with high reward dependence also showed a significant decrease of MHPG in their CSF. [ 44 ]  This finding demonstrates a significant relationship between reward dependence and norepinephrine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10918", "text": "Several genes have also been found to express the RD temperament dimension. Specifically, the gene  MAOA-uVNTR  has been highly implicated in evoking the RD personality trait. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10919", "text": "The Ritalin class-action lawsuits  were a series of federal lawsuits in 2000, filed in five separate US states. [ 1 ]  All five lawsuits were dismissed by the end of 2002. The lawsuits alleged that the makers of  methylphenidate  (brand name Ritalin) and the  American Psychiatric Association  had conspired to invent and promote the disorder  ADHD  to create a highly profitable market for the drug. The lawsuit also alleged that  CHADD  (children and adults with attention deficit/hyperactivity disorder) deliberately attempted to increase the supply of Ritalin and ease restrictions on the supply of Ritalin to help increase profits for  Novartis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10920", "text": "Beginning in the 1980s, a series of lawsuits were filed based on the perceived harmful side effects of Ritalin.  John Coale , who had participated in one of these lawsuits, joined what became an ever larger contingent of lawyers involved in what was then a growing series of Ritalin class action lawsuits. In the late 1990s, there was a significant increase in production of Ritalin. A minority but vocal group of critics perceived that a crisis was on hand. [ 2 ]  Coale also expressed alarm, \"They were giving this stuff away like candy\". The  Church of Scientology  advocacy organization,  Citizens Commission on Human Rights , and  anti-psychiatry  critics believed Ritalin to be highly dangerous and completely unnecessary. Coale seemed to share these beliefs as he stated the purpose of the lawsuit to be; \"...to put [Ritalin] off the market.\" [ 3 ]  The  St. Petersburg Times  wrote at that time that Coale, like his wife  Greta Van Susteren , was a practicing Scientologist. [ 4 ]   Richard Scruggs , like John Coale, and a few other lawyers who participated in the Ritalin class action lawsuits, had previously helped win a landmark settlement from the asbestos and tobacco industries, Ritalin was to be the next major battleground. Scruggs would lead and also become a spokesman for the plaintiffs. He asserted the Ritalin defendants, \"manufactured a disease\"...and \"it has been grossly over-prescribed. It is a huge risk.\" [ 5 ]   Peter Breggin  who is a noted psychiatrist and industry critic, was hired as a medical consultant by the firm and was also involved as a consultant in the other lawsuits. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10921", "text": "The first class action was filed in Texas by the law firm Waters & Kraus in 2000. They created a webpage called Ritalinfraud.com which had an online form to seek additional participants in class action lawsuits. According to Breggin, plaintiff Andy Waters had previously read his book  Talking back to Ritalin  before filing his lawsuit.  The firm believed that the improper conduct of Novartis rivaled the improper conduct of the tobacco and asbestos industries and that the drug company could be liable for billions of dollars. The firm claimed that Novartis specifically took the following steps to dramatically increase the sale of Ritalin. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10922", "text": "A spokesperson for Novartis responded to the Texas suit, \"Ritalin has been used safely and effectively in the treatment of millions of ADHD patients for over 40 years, and is the most studied drug prescribed for the disorder.\" [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10923", "text": "The American Psychiatric Association stated, \"the allegation that it had conspired with Novartis to create the ADHD diagnosis was \"ludicrous and totally false,\" and said there existed \"a mountain of scientific evidence to refute these meritless allegations.\" [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10924", "text": "The first suit to be dismissed occurred in California in 2001. U.S. District Judge Rudi Brewster dismissed the suit under California's anti- SLAPP  statute. A SLAPP (strategic lawsuit against public participation) is a form of litigation filed to intimidate and silence a less powerful critic by so severely burdening them with the cost of a legal defense that they abandon their criticism. The Anti-SLAPP statute is designed to eliminate potential lawsuits that are in reality political actions by stopping them early in court procedures. Judge Brewster dismissed the suit stating that the defendants' speech is \"protected under both the United States and California Constitutions\" and that plaintiffs \"failed to state a cause of action.\" In addition to dismissing the suit, the court also ordered that the plaintiffs pay the legal fees for Novartis, APA and CHADD."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10925", "text": "In the conclusion to one of the other lawsuits, Judge Tagla stated \"that the allegations were fully without merit. Plaintiffs failed to provide any concrete statements to document their claims.\" [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10926", "text": "By 2002 all five class action lawsuits had been dismissed or had been withdrawn. A Novartis spokesperson stated;\"...the fact that all five of the class action lawsuits have been dismissed, sends a strong message that the decision of how to treat ADHD is between the parent, patient and physician, and has no place in the courts.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_10927", "text": "Arsenic biochemistry  is the set of  biochemical  processes that can use  arsenic  or its compounds, such as  arsenate . Arsenic is a  moderately abundant element in Earth's crust , and although many arsenic compounds are often considered  highly toxic  to most life, a wide variety of  organoarsenic compounds  are produced biologically and various organic and inorganic arsenic compounds are metabolized by numerous  organisms . This pattern is general for other related elements, including  selenium , which can exhibit both beneficial and deleterious effects. Arsenic biochemistry has become topical since many toxic arsenic compounds are found in some  aquifers , [ 1 ]  potentially affecting many millions of people via biochemical processes. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10928", "text": "The evidence that arsenic may be a beneficial nutrient at trace levels below the background to which living organisms are normally exposed has been reviewed. [ 3 ]  Some organoarsenic compounds found in nature are  arsenobetaine  and arsenocholine, [ 4 ]  both being found in many marine organisms. [ 2 ]   Some As-containing  nucleosides  (sugar derivatives) are also known. [ 5 ]   Several of these organoarsenic compounds arise via  methylation  processes.  For example, the mold  Scopulariopsis brevicaulis  produces significant amounts of  trimethylarsine  if inorganic arsenic is present. [ 6 ]  The organic compound  arsenobetaine  is found in some marine foods such as fish and algae, and also in mushrooms in larger concentrations. In clean environments, the edible mushroom species  Cyanoboletus pulverulentus  hyperaccumulates arsenic in concentrations reaching even 1,300\u00a0mg/kg in dry weight;  cacodylic acid  is the major As compound. [ 7 ]  A very unusual composition of organoarsenic compounds was found in deer truffles ( Elaphomyces  spp.). [ 8 ]  The average person's intake is about 10\u201350\u00a0\u03bcg/day. Values about 1000\u00a0\u03bcg are not unusual following consumption of fish or mushrooms; however, there is little danger in eating fish since this arsenic compound is nearly non-toxic. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10929", "text": "A topical source of arsenic are the green pigments once popular in wallpapers, e.g.  Paris green . A variety of illness have been blamed on this compound, although its toxicity has been exaggerated. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10930", "text": "Trimethylarsine , once known as Gosio's gas, is an intensely malodorous organoarsenic compound that is commonly produced by microbial action on inorganic arsenic substrates. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10931", "text": "Arsenic (V) compounds are easily reduced to arsenic (III) and could have served as an electron acceptor on primordial Earth. [ 12 ]  Lakes that contain a substantial amount of dissolved inorganic arsenic, harbor arsenic-tolerant  biota ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10932", "text": "Although phosphate and arsenate are structurally similar, there is no evidence that arsenic replaces phosphorus in  DNA  or  RNA . [ 13 ]   A 2010 experiment involving the bacteria  GFAJ-1  that made this claim was refuted by 2012. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10933", "text": "Anthropogenic (man-made) sources of arsenic, like the natural sources, are mainly arsenic oxides and the associated anions. Man-made sources of arsenic, include wastes from mineral processing, swine and poultry farms. [ 16 ]  For example, many ores, especially  sulfide minerals , are contaminated with arsenic, which is released in  roasting  (burning in air). In such processing,  arsenide  is converted to  arsenic trioxide , which is volatile at high temperatures and is released into the atmosphere. Poultry and swine farms make heavy use of the organoarsenic compound  roxarsone  as an  antibiotic  in feed. [ 17 ] [ 18 ]  Some wood is treated with copper arsenates as a preservative. The mechanisms by which these sources affect \"downstream\" living organisms remains uncertain but are probably diverse. One commonly cited pathway involves  methylation . [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10934", "text": "The monomethylated acid, methanearsonic acid (CH 3 AsO(OH) 2 ), is a precursor to fungicides (tradename Neoasozin) in the cultivation of rice and cotton.  Derivatives of  phenylarsonic acid  (C 6 H 5 AsO(OH) 2 ) are used as feed additives for livestock, including  4-hydroxy-3-nitrobenzenearsonic acid  (3-NHPAA or Roxarsone), ureidophenylarsonic acid, and   p -arsanilic acid .  These applications are controversial as they introduce soluble forms of arsenic into the environment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10935", "text": "Despite, or possibly because of, its long-known toxicity, arsenic-containing potions and drugs have a history in  medicine  and  quackery  that continues into the 21st century. [ 20 ] [ 21 ]   Starting in the early 19th century and continuing into the 20th century,  Fowler's solution , a toxic concoction of  sodium arsenite , was sold. The organoarsenic compound  Salvarsan  was the first  synthetic   chemotherapeutic agent , discovered by  Paul Ehrlich . [ 21 ]  The treatment, however, led to many problems causing long lasting health complications. [ 22 ]   Around 1943 it was finally superseded by  penicillin .\nThe related drug  Melarsoprol  is still in use against late-state  African trypanosomiasis  (sleeping sickness), despite its high toxicity and possibly fatal side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10936", "text": "Arsenic trioxide  (As 2 O 3 ) inhibits cell growth and induces  apoptosis  (programmed cell death) in certain types of cancer cells, [ 23 ]  which are normally immortal and can multiply without limit. In combination with  all-trans retinoic acid , it is FDA-approved as first-line treatment for  promyelocytic leukemia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10937", "text": "Inorganic arsenic and its compounds, upon entering the  food chain , are progressively metabolised (detoxified) through a process of  methylation . [ 19 ]  The methylation occurs through alternating reductive and oxidative methylation reactions, that is, reduction of pentavalent to trivalent arsenic followed by addition of a  methyl group  (CH 3 ). [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10938", "text": "In mammals, methylation occurs in the liver by  methyltransferases , the products being the (CH 3 ) 2 AsOH ( dimethylarsinous acid ) and (CH 3 ) 2 As(O)OH ( dimethylarsinic acid ), which have the oxidation states As(III) and As(V), respectively. [ 2 ]   Although the mechanism of methylation of arsenic in humans has not been elucidated, the source of  methyl  is  methionine , which suggests a role of  S-adenosyl methionine . [ 25 ]   Exposure to toxic doses begin when the liver's methylation capacity is exceeded or inhibited."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10939", "text": "There are two major forms of arsenic that can enter the body, arsenic (III) and arsenic (V). [ 26 ]  Arsenic (III) enters the cells though  aquaporins  7 and 9, which is a type of aquaglyceroporin. [ 26 ]  Arsenic (V) compounds use phosphate transporters to enter cells. [ 26 ]  The arsenic (V) can be converted to arsenic (III) by the enzyme  purine nucleoside phosphorylase . [ 26 ]  This is classified as a bioactivation step, as although arsenic (III) is more toxic, it is more readily methylated. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10940", "text": "There are two routes by which inorganic arsenic compounds are methylated. [ 28 ]  The first route uses Cyt19 arsenic methyltransferase to methylate arsenic (III) to a mono-methylated arsenic (V) compound. [ 26 ]  This compound is then converted to a mono-methylated arsenic (III) compound using Glutathione S-Transferase Omega-1 ( GSTO1 ). [ 26 ]  The mono-methylated arsenic (V) compound can then be methylated again by Cyt19 arsenic methyltransferase, which forms a dimethyl arsenic (V) compound, which can be converted to a dimethyl arsenic (III) compound by Glutathione S-Transferase Omega-1 (GTSO1). [ 26 ]  The other route uses  glutathione  (GSH) to conjugate with arsenic (III) to form an arsenic (GS)  3  complex. [ 26 ]  This complex can form a monomethylated arsenic (III) GS complex, using Cyt19 arsenic methyltransferase, and this monomethylated GS complex is in equilibrium with the monomethylated arsenic (III). [ 26 ]  Cyt19 arsenic methyltransferase can methylate the complex one more time, and this forms a dimethylated arsenic GS complex, which is in equilibrium with a dimethyl arsenic (III) complex. [ 26 ]  Both of the mono-methylated and di-methylated arsenic compounds can readily be excreted in urine. [ 27 ]  However, the monomethylated compound was shown to  be more reactive and more toxic than the inorganic arsenic compounds to human  hepatocytes  (liver), keratinocytes in the skin, and bronchial epithelial cells (lungs). [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10941", "text": "Studies in experimental animals and humans show that both inorganic arsenic and methylated metabolites cross the  placenta  to the  fetus , however, there is evidence that methylation is increased during pregnancy and that it could be highly protective for the developing organism. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10942", "text": "Enzymatic methylation of arsenic is a detoxification process; it can be methylated to methylarsenite, dimethylarsenite or trimethylarsenite, all of which are trivalent. The methylation is catalyzed by arsenic  methyltransferase  (AS3MT) in mammals, which transfers a methyl group on the  cofactor  S-adenomethionine (SAM) to arsenic (III). An orthologue of AS3MT is found in bacteria and is called CmArsM. This enzyme was tested in three states (ligand free, arsenic (III) bound and SAM bound). Arsenic (III) binding sites usually use thiol groups of cysteine residues. The catalysis involves thiolates of Cys72, Cys174, and Cys224. In an SN2 reaction, the positive charge on the SAM sulfur atom pulls the bonding electron from the carbon of the methyl group, which interacts with the arsenic lone pair to form an As\u2212C bond, leaving SAH. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10943", "text": "In humans, the major route of excretion of most arsenic compounds is via the  urine . The biological  half-life  of inorganic arsenic is about 4 days, but is slightly shorter following exposure to arsenate than to arsenite.  The main metabolites excreted in the urine of humans exposed to inorganic arsenic are mono- and dimethylated  arsenic acids , together with some unmetabolized inorganic arsenic. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10944", "text": "The biotransformation of arsenic for excretion is primarily done through the nuclear factor erythroid 2 related factor 2 ( Nrf2 ) pathway. [ 32 ]  Under normal conditions the Nrf2 is bound to Kelch-like ECH associated protein 1 ( Keap1 ) in its inactive form. [ 33 ]  With the uptake of arsenic within cells and the subsequent reactions that result in the production of  reactive oxygen species  (ROS), the Nrf2 unbinds and becomes active. Keap1 has reactive thiol moieties that bind ROS or electrophilic arsenic species such as monomethylted arsenic (III) and induces the release of Nrf2 which then travels through the  cytoplasm  to the  nucleus . [ 34 ]  The Nrf2 then activates antioxidant responsive element (ARE) as well as electrophilic responsive element (EpRE) both of which contribute in the increase of antioxidant proteins. [ 35 ]  Of particular note in these antioxidant proteins is heme oxygenase 1 ([HO-1]), NAD(P)H-quinone oxidoreductase 1 (NQO1), and \u03b3-glutamylcysteine synthase (\u03b3GCS) which work in conjunction to reduce the oxidative species such as  hydrogen peroxide  to decrease the oxidative stress upon the cell. The increase in \u03b3GCS causes an increased production of arsenite triglutathionine (As(SG) 3 ) an important adduct that is taken up by either multidrug associated protein 1 or 2 ( MRP1  or  MRP2 ) which removes the arsenic out of the cell and into  bile  for excretion. [ 34 ]  This adduct can also decompose back into inorganic arsenic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10945", "text": "Of particular note in the excretion of arsenic is the multiple  methylation  steps that take place which may increase the toxicity of arsenic [ 36 ]  due to MMeAsIII being a potent inhibitor of glutathione peroxidase, [ 37 ]  glutathione reductase, pyruvate dehydrogenase, [ 38 ]  and thioredoxin reductase. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10946", "text": "Arsenic is a cause of mortality throughout the world; associated problems include heart, respiratory, gastrointestinal, liver, nervous and kidney diseases. [ 2 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10947", "text": "Arsenic interferes with cellular longevity by  allosteric inhibition  of an essential metabolic enzyme  pyruvate dehydrogenase  (PDH) complex, which catalyzes the oxidation of  pyruvate  to  acetyl-CoA  by  NAD + . With the enzyme inhibited, the energy system of the cell is disrupted resulting in a cellular  apoptosis  episode. Biochemically, arsenic prevents use of thiamine resulting in a clinical picture resembling  thiamine deficiency . Poisoning with arsenic can raise lactate levels and lead to  lactic acidosis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10948", "text": "Genotoxicity  involves inhibition of DNA repair and DNA methylation.  The  carcinogenic  effect of arsenic arises from the  oxidative stress  induced by arsenic.  Arsenic's high toxicity naturally led to the development of a variety of arsenic compounds as  chemical weapons , e.g. dimethylarsenic chloride. Some were employed as  chemical warfare agents , especially in  World War I .  This threat led to many studies on  antidotes  and an expanded knowledge of the interaction of arsenic compounds with living organisms.  One result was the development of antidotes such as  British anti-Lewisite .  Many such antidotes exploit the affinity of As(III) for  thiolate   ligands , which convert highly toxic organoarsenicals to less toxic derivatives. It is generally assumed that arsenates bind to  cysteine  residues in proteins."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10949", "text": "By contrast, arsenic oxide is an approved and effective chemotherapeutic drug for the treatment of  acute promyelocytic leukemia  (APL). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10950", "text": "Due to its similar structure and properties, pentavalent arsenic metabolites are capable of replacing the phosphate group of many metabolic pathways. [ 40 ]  The replacement of phosphate by arsenate is initiated when arsenate reacts with glucose and gluconate in vitro. [ 40 ]  This reaction generates glucose-6-arsenate and 6-arsenogluconate, which act as analogs for glucose-6-phosphate and 6-phosphogluconate. [ 40 ]  At the substrate level, during  glycolysis , glucose-6-arsenate binds as a substrate to glucose-6-phosphate dehydrogenase, and also inhibits hexokinase through negative feedback. [ 40 ]  Unlike the importance of phosphate in glycolysis, the presence of arsenate restricts the generation of  ATP  by forming an unstable anhydride product, through the reaction with D-glyceraldehyde-3-phosphate. [ 40 ]  The anhydride 1-arsenato-3-phospho-D-glycerate generated readily hydrolyzes due to the longer bond length of As-O compared to P-O. [ 40 ]  At the mitochondrial level, arsenate uncouples the synthesis of ATP by binding to ADP in the presence of  succinate , thus forming an unstable compound that ultimately results in a decrease of ATP net gain. [ 40 ]  Arsenite (III) metabolites, on the other hand, have limited effect on ATP production in red blood cells. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10951", "text": "Enzymes and receptors that contain thiol or  sulfhydryl  functional groups are actively targeted by arsenite (III) metabolites. [ 40 ]  These sulfur-containing compounds are normally glutathione and the  amino acid  cysteine. [ 40 ]  Arsenite derivatives generally have higher binding affinity compared to the arsenate metabolites. [ 40 ]  These bindings restrict activity of certain metabolic pathways. [ 40 ]  For example, pyruvate dehydrogenase (PDH) is inhibited when monomethylarsonous acid (MMA III ) targets the thiol group of the lipoic acid cofactor. [ 40 ]  PDH is a precursor of  acetyl-CoA , thus the inhibition of PDH eventually limits the production of ATP in  electron transport chain , as well as the production of  gluconeogenesis  intermediates. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10952", "text": "Arsenic can cause oxidative stress through the formation of  reactive oxygen species  (ROS), and  reactive nitrogen species  (RNS). [ 28 ]  Reactive oxygen species are produced by the enzyme  NADPH oxidase , which transfers electrons from  NADPH  to oxygen, synthesizing a  superoxide , which is a reactive free radical. This superoxide can react to form  hydrogen peroxide  and a reactive oxygen species. The enzyme  NADPH oxidase  is able to generate more reactive oxygen species in the presence of arsenic, due to the subunit p22phox, which is responsible for the electron transfer, being upregulated by arsenic. [ 28 ]  The reactive oxygen species are capable of stressing the  endoplasmic reticulum , which increases the amount of the unfolded protein response signals. [ 28 ]  This leads to inflammation, cell proliferation, and eventually to cell death. [ 28 ]  Another mechanism in which reactive oxygen species cause cell death would be through the  cytoskeleton  rearrangement, which affects the contractile proteins. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10953", "text": "The reactive nitrogen species arise once the reactive oxygen species destroy the  mitochondria . [ 28 ]  This leads to the formation of the reactive nitrogen species, which are responsible for damaging  DNA  in arsenic poisoning. [ 28 ]  Mitochondrial damage is known to cause the release of reactive nitrogen species, due to the reaction between superoxides and  nitric oxide  (NO). [ 28 ]  Nitric oxide (NO) is a part of cell regulation, including cellular  metabolism , growth, division and death. [ 28 ]  Nitric oxide (NO) reacts with reactive oxygen species to form  peroxynitrite . [ 28 ]  In cases of chronic arsenic exposure, the nitric oxide levels are depleted, due to the superoxide reactions. [ 28 ]  The enzyme NO synthase (NOS) uses L-arginine to form nitric oxide, but this enzyme is inhibited by monomethylated arsenic (III) compounds. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10954", "text": "Arsenic is reported to cause  DNA  modifications such as  aneuploidy ,  micronuclei  formation,  chromosome abnormality ,  deletion mutations ,  sister chromatid exchange  and  crosslinking of DNA  with proteins. [ 41 ]  It has been demonstrated that arsenic does not directly interact with DNA and it is considered a poor  mutagen , but instead, it helps mutagenicity of other  carcinogens . [ 42 ]  For instance, a synergistic increase in the mutagenic activity of arsenic with  UV light  has been observed in human and other mammalian cells after exposing the UV-treated cells to arsenic. [ 43 ] [ 44 ]  A series of experimental observations suggest that the arsenic  genotoxicity  is primarily linked to the generation of  reactive oxygen species  (ROS) during its biotransformation. [ 45 ] [ 46 ] [ 47 ]  The ROS production is able to generate  DNA adducts , DNA strand breaks, crosslinks and chromosomal aberrations. [ 48 ] [ 49 ] [ 50 ]  The oxidative damage is caused by modification of DNA  nucleobases , in particular  8-oxoguanine  (8-OHdG) which leads to G:C to T:A  mutations. [ 51 ]  Inorganic arsenic can also cause DNA strand break even at low concentrations. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10955", "text": "Inhibition of  DNA repair  processes is considered one of main mechanism of inorganic arsenic genotoxicity.  Nucleotide excision repair  (NER) and  base excision repair  (BER) are the processes implicated in the repair of DNA base damage induced by ROS after arsenic exposure. In particular, the NER mechanism is the major pathway for repairing bulky distortions in DNA double helix, while the BER mechanism is mainly implicated in the repair of single strand breaks induced by ROS, [ 53 ] [ 54 ] [ 55 ] [ 56 ]  but inorganic arsenic could also repress the BER mechanism. [ 57 ] [ 58 ] [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10956", "text": "Exposure of isolated  lymphocytes  to arsenic causes decreased expression of the  DNA repair  protein  ERCC1 . [ 60 ]   Consistent with an inhibitory effect on DNA repair, lymphocytes from arsenic exposed individuals have higher levels of  DNA damage . [ 60 ]   Arsenic can act as a co-carcinogen by inhibiting repair of DNA damage through its interaction with sensitive  zinc finger  DNA repair proteins. [ 61 ] [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10957", "text": "Arsenic is highly detrimental to the innate and the adaptive  immune system  of the body. [ 63 ]   When the amount of unfolded and misfolded proteins in  endoplasmic reticulum  stress is excessive, the  unfolded protein response  (UPR) is activated to increase the activity of several receptors that are responsible the restoration of homeostasis. [ 63 ]  The inositol-requiring enzyme-1 (IRE1) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) are two receptors that restrict the rate of translation. [ 63 ]  On the other hand, the unfolded proteins are corrected by the production of  chaperones , which are induced by the activating transcription factor 6 (ATF6). [ 63 ]  If the number of erroneous proteins elevates, further mechanism is active which triggers  apoptosis . [ 63 ]  Arsenic has evidentially shown to increase the activity of these protein sensors. [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10958", "text": "Arsenic exposure in small children distorts the ratio of  T helper cells  ( CD4 ) to  cytotoxic T cells  ( CD8 ), which are responsible for immunodepression. [ 64 ]  In addition, arsenic also increases the number of  inflammatory  molecules being secreted through  macrophages . [ 64 ]  The excess amount of  granulocytes  and  monocytes  lead to a chronic state of inflammation, which might result in  cancer  development. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10959", "text": "There are three molecules that serve as  chelator  agents that bond to arsenic. These three are  British Anti-Lewisite  (BAL, Dimercaprol), succimer ( DMSA ) and Unithiol ( DMPS ). [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10960", "text": "When these agents  chelate  inorganic arsenic, it is converted into an organic form of arsenic because it is bound to the organic chelating agent. The  sulfur  atoms of the  thiol  groups are the site of interaction with arsenic. This is because the thiol groups are  nucleophilic  while the arsenic atoms are  electrophilic . Once bound to the chelating agent the molecules can be excreted, and therefore free inorganic arsenic atoms are removed from the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10961", "text": "Other chelating agents can be used, but may cause more side effects than British Anti-Lewisite (BAL, Dimercaprol), succimer ( DMSA ) and ( DMPS ). DMPS and DMSA also have a higher  therapeutic index  than BAL. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10962", "text": "These drugs are efficient for acute poisoning of arsenic, which refers to the instantaneous effects caused by arsenic poisoning. For example, headaches, vomiting or sweating are some of the common examples of an instantaneous effect. In comparison, chronic poisonous effects arise later on, and unexpectedly such as organ damage. Usually it is too late to prevent them once they appear. Therefore, action should be taken as soon as acute poisonous effects arise. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10963", "text": "Arsenic poisoning  (or  arsenicosis ) is a medical condition that occurs due to elevated levels of  arsenic  in the body. [ 4 ]  If arsenic poisoning occurs over a brief period of time, symptoms may include  vomiting ,  abdominal pain ,  encephalopathy , and watery  diarrhea  that contains  blood . [ 1 ]  Long-term exposure can result in thickening of the skin,  darker skin , abdominal pain, diarrhea,  heart disease ,  numbness , and  cancer . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10964", "text": "The most common reason for long-term exposure is contaminated  drinking water . [ 3 ]   Groundwater  most often becomes contaminated naturally; however, contamination may also occur from  mining  or agriculture. [ 1 ]  It may also be found in the soil and air. [ 5 ]  Recommended levels in water are less than 10\u201350\u00a0\u03bcg/L (10\u201350  parts per billion ). [ 1 ]  Other routes of exposure include  toxic waste sites  and  pseudo-medicine . [ 1 ] [ 3 ]  Most cases of poisoning are accidental. [ 1 ]  Arsenic acts by changing the functioning of around 200  enzymes . [ 1 ]  Diagnosis is by testing the urine, blood, or hair. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10965", "text": "Prevention is by using water that does not contain high levels of arsenic. [ 1 ]  This may be achieved by the use of special filters or using  rainwater . [ 1 ]  There is not good evidence to support specific treatments for long-term poisoning. [ 1 ]  For acute poisonings treating  dehydration  is important. [ 4 ]   Dimercaptosuccinic acid  or  dimercaptopropane sulfonate  may be used while  dimercaprol  (BAL) is not recommended. [ 2 ]   Hemodialysis  may also be used. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10966", "text": "Through drinking water, more than 200 million people globally are exposed to higher-than-safe levels of arsenic. [ 3 ]  The areas most affected are  Bangladesh  and  West Bengal . [ 3 ]  Exposure is also more common in people of low income and minorities. [ 6 ]  Acute poisoning is uncommon. [ 3 ]  The toxicity of arsenic has been described as far back as 1500 BC in the  Ebers papyrus . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10967", "text": "Ingesting large amounts of arsenic can cause symptoms similar to  food poisoning , with  abdominal pain ,  nausea ,  vomiting , and  diarrhea  starting within hours. [ 8 ]  Bloody diarrhea can cause severe fluid loss, resulting in  hypovolemic shock . [ 8 ]  The heart and nervous system can also be affected, causing disruption to heart rhythms ( QT interval prolongation  or  tachycardia ), heart failure,  confusion ,  seizures , brain swelling,  coma , and death. [ 8 ] [ 9 ]  Inhaling  arsine  gas \u2013 the most toxic form of arsenic \u2013 causes a multisystem disease starting 2 to 24 hours after inhalation. Symptoms include gastrointestinal distress, headache, weakness, difficulty breathing, kidney and liver dysfunction, and the destruction of red blood cells. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10968", "text": "Chronic ingestion of lower levels of arsenic causes visible changes in the skin, typically  hyperpigmentation  (dark areas), but sometimes  hypopigmentation  (light areas) or an alternating areas of each. [ 10 ]  Some experience general  thickening of the skin  on the palms and soles of the feet, or  small thickened areas . [ 10 ]  Around 5% of those affected develop light-colored bands across the fingernail, called  Mees' lines . [ 8 ]  Chronic exposure eventually causes disease across multiple body systems, including  peripheral neuropathy  (numbness and tingling), enlargement of the  liver  and  spleen ,  diabetes ,  heart disease ,  cognitive impairment , and damage to the  portal vein  ( non-cirrhotic portal fibrosis  and  portal hypertension ). [ 8 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10969", "text": "Repeated arsenic exposure also increases the risk for developing several cancers, particularly of the  skin ,  lung ,  liver ,  bladder ,  prostate , and  blood vessels . [ 8 ] [ 11 ]  The most common arsenic-induced skin cancer is  squamous cell carcinoma in situ  which typically occurs 2 to 20 years after arsenic exposure. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10970", "text": "Arsenic poisoning is caused by incidental ingestion or inhalation of arsenic, typically from drinking contaminated  well  water, eating food cooked in contaminated water, or being exposed to arsenic-containing pesticides, folk medicines, or industrial chemicals. [ 8 ]  The  World Health Organization  considers arsenic levels above 10  parts per billion  (10  micrograms  per  liter ) to be unsafe. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10971", "text": "Arsenic is a ubiquitous naturally occurring  chemical element , and the 20th most common element on Earth. [ 13 ]  Arsenic levels in the groundwater vary from around 0.5 parts per billion to 5000 parts per billion, depending on an area's geologic features, and possible presence on industrial waste. [ 13 ] [ 11 ]  The highest groundwater arsenic levels have been recorded in Brazil, Cambodia, Afghanistan, Australia, and  Bangladesh . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10972", "text": "Arsenic is a ubiquitous element present in American drinking water. [ 14 ]   In the US, the  U.S. Geological Survey  estimates that the median groundwater concentration is 1\u00a0\u03bcg/L or less, although some groundwater  aquifers , particularly in the western United States, can contain much higher levels. For example, median levels in Nevada were about 8\u00a0\u03bcg/L [ 15 ]  but levels of naturally occurring arsenic as high as 1000\u00a0\u03bcg/L have been measured in the United States in drinking water. [ 16 ]  Groundwater associated with volcanics in California contain As at concentrations ranging up to 48,000 \u03bcg/L, with As-bearing sulfide minerals as the main source. [ 17 ]  Geothermal waters on Dominica in the Lesser Antilles also contain concentrations of As >50 \u03bcg/L. [ 18 ]  In Wisconsin, As concentrations of water in sandstone and dolomite aquifers were as high as 100\u00a0\u03bcg/L. Oxidation of pyrite hosted by these formations was the likely source of the As. [ 19 ]  In the Piedmont of Pennsylvania and New Jersey, groundwater in  Mesozoic  age aquifers contains elevated levels of As\u2014domestic well waters from Pennsylvania contained up to 65\u00a0\u03bcg/L, [ 20 ]  whereas in New Jersey the highest concentration measured recently was 215\u00a0\u03bcg/L. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10973", "text": "Organic arsenic is less harmful than inorganic arsenic. Seafood is a common source of the less toxic organic arsenic in the form of  arsenobetaine . [ 22 ]  Because of its high toxicity, arsenic is seldom used in the Western world, although in Asia it is still a popular pesticide. Arsenic is mainly encountered occupationally in the smelting of zinc and copper ores."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10974", "text": "In the United States, Schoof et al. estimated an average adult intake of 3.2\u00a0\u03bcg/day, with a range of 1\u201320\u00a0\u03bcg/day. [ 23 ]  Estimates for children were similar. [ 24 ]  Food also contains many organic arsenic compounds. The key organic arsenic compounds that can be routinely found in food (depending on food type) include monomethylarsonic acid (MMAsV), dimethylarsinic acid (DMAsV), arsenobetaine, arsenocholine, arsenosugars, and arsenolipids. DMAsV or MMAsV can be found in various types of fin fish, crabs, and mollusks, but often at very low levels. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10975", "text": "Arsenobetaine is the major form of arsenic in marine animals, and is considered nontoxic. Arsenocholine, which is mainly found in shrimp, is chemically similar to arsenobetaine, and is considered to be \"essentially nontoxic\". [ 26 ]  Although arsenobetaine is little studied, available information indicates it is not mutagenic, immunotoxic, or embryotoxic. [ 27 ]  Arsenosugars and arsenolipids have recently been identified. Exposure to these compounds and toxicological implications are currently being studied. Arsenosugars are detected mainly in seaweed but are also found to a lesser extent in marine mollusks. [ 28 ]  Studies addressing arsenosugar toxicity, however, have largely been limited to in vitro studies, which show that arsenosugars are significantly less toxic than both inorganic arsenic and trivalent methylated arsenic metabolites. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10976", "text": "It has been found that rice is particularly susceptible to accumulation of arsenic from soil. [ 30 ]   Rice grown in the United States has an average 260\u00a0 ppb  of arsenic, according to a study; but U.S. arsenic intake remains far below  World Health Organization -recommended limits. [ 31 ]   China has set a standard for arsenic limits in food (150\u00a0ppb), [ 32 ]  as levels in rice exceed those in water. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10977", "text": "The European Commission (2000) reports that levels of arsenic in air range 0\u20131\u00a0ng/m 3  in remote areas, 0.2\u20131.5\u00a0ng/m 3  in rural areas, 0.5\u20133\u00a0ng/m 3  in urban areas, and up to about 50\u00a0ng/m 3  in the vicinity of industrial sites. Based on these data, the European Commission (2000) estimated that in relation to food, cigarette smoking, water, and soil, air contributes less than 1% of total arsenic exposure. [ better\u00a0source\u00a0needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10978", "text": "The use of lead arsenate pesticides has been effectively eliminated for over 50 years. However, because of the pesticide's environmental persistence, it is estimated that millions of acres of land are still contaminated with lead arsenate residues. This presents a potentially significant public health concern in some areas of the United States (e.g., New Jersey, Washington, and Wisconsin), where large areas of land used historically as orchards have been converted into residential developments. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10979", "text": "Some modern uses of arsenic-based pesticides still exist. Chromated copper arsenate has been registered for use in the United States since the 1940s as a wood preservative, protecting wood from insects and microbial agents. In 2003, manufacturers of chromated copper arsenate instituted a voluntary recall of residential uses of wood treated with the chemical. The Environmental Protection Agency Act 2008 final report stated that chromated copper arsenate is still approved for use in nonresidential applications, such as in marine facilities (pilings and structures), utility poles, and sand highway structures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10980", "text": "Exposure studies in the copper  smelting  industry are much more extensive and have established definitive links between arsenic, a by-product of copper smelting, and lung cancer via inhalation. [ 35 ]  Dermal and neurological effects were also increased in some of these studies. [ 36 ]  Although as time went on, occupational controls became more stringent and workers were exposed to reduced arsenic concentrations, the arsenic exposures measured from these studies ranged from about 0.05 to 0.3\u00a0mg/m 3  and are significantly higher than airborne environmental exposures to arsenic (which range from 0 to 0.000003\u00a0mg/m 3 ). [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10981", "text": "Arsenic interferes with cellular longevity by  allosteric inhibition  of an essential metabolic enzyme  pyruvate dehydrogenase  complex, which catalyzes the oxidation of  pyruvate  to  acetyl-CoA  by  NAD + . With the enzyme inhibited, the energy system of the cell is disrupted resulting in cellular  apoptosis . Biochemically, arsenic prevents use of  thiamine  resulting in a clinical picture resembling  thiamine deficiency . Poisoning with arsenic can raise lactate levels and lead to  lactic acidosis . Low potassium levels in the cells increases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide. [ citation needed ] \nArsenic in cells clearly stimulates the production of  hydrogen peroxide  (H 2 O 2 ). When the H 2 O 2  reacts with certain metals such as  iron  or  manganese  it produces a highly reactive  hydroxyl radical . Inorganic  arsenic trioxide  found in ground water particularly affects  voltage-gated potassium channels , [ 38 ] \ndisrupting cellular electrolytic function resulting in neurological disturbances, cardiovascular episodes such as prolonged QT interval,  neutropenia ,  high blood pressure , [ 39 ] \ncentral nervous system dysfunction,  anemia , and death."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10982", "text": "Arsenic exposure plays a key role in the pathogenesis of vascular endothelial dysfunction as it inactivates endothelial nitric oxide synthase, leading to reduction in the generation and bioavailability of nitric oxide. In addition, the chronic arsenic exposure induces high oxidative stress, which may affect the structure and function of cardiovascular system. Further, the arsenic exposure has been noted to induce atherosclerosis by increasing the platelet aggregation and reducing  fibrinolysis . Moreover, arsenic exposure may cause arrhythmia by increasing the QT interval and accelerating the cellular calcium overload. The chronic exposure to arsenic upregulates the expression of tumor necrosis factor-\u03b1, interleukin-1, vascular cell adhesion molecule and vascular endothelial growth factor to induce cardiovascular pathogenesis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10983", "text": "Arsenic has also been shown to induce  cardiac hypertrophy  by activating certain  transcription factors  involved in pathologically remodeling the heart. [ 41 ]  Tissue culture studies have shown that arsenic compounds block both IKr and Iks channels and, at the same time, activate IK-ATP channels. Arsenic compounds also disrupt  ATP  production through several mechanisms. At the level of the  citric acid cycle , arsenic inhibits  pyruvate dehydrogenase  and by competing with phosphate it uncouples  oxidative phosphorylation , thus inhibiting energy-linked reduction of  NAD+ , mitochondrial respiration, and ATP synthesis. Hydrogen peroxide production is also increased, which might form reactive oxygen species and oxidative stress. These metabolic interferences lead to death from multi-system  organ failure , probably from  necrotic  cell death, not  apoptosis . A  post mortem  reveals brick red colored  mucosa , due to severe  hemorrhage .  Although arsenic causes toxicity, it can also play a protective role. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10984", "text": "Arsenite inhibits not only the formation of acetyl-CoA but also the enzyme succinic dehydrogenase. Arsenate can replace phosphate in many reactions. It is able to form Glc-6-arsenate in vitro; therefore it has been argued that hexokinase could be inhibited. [ 43 ]  (Eventually this may be a mechanism leading to muscle weakness in chronic arsenic poisoning.) In the  glyceraldehyde 3-phosphate dehydrogenase  reaction arsenate attacks the enzyme-bound thioester. The formed 1-arseno-3-phosphoglycerate is unstable and hydrolyzes spontaneously. Thus, ATP formation in glycolysis is inhibited while bypassing the phosphoglycerate kinase reaction. (Moreover, the formation of 2,3-bisphosphoglycerate in erythrocytes might be affected, followed by a higher oxygen affinity of hemoglobin and subsequently enhanced cyanosis.) As shown by Gresser (1981), submitochondrial particles synthesize adenosine-5'-diphosphate-arsenate from ADP and arsenate in presence of succinate. Thus, by a variety of mechanisms arsenate leads to an impairment of cell respiration and subsequently diminished ATP formation. [ 44 ]  This is consistent with observed ATP depletion of exposed cells and histopathological findings of mitochondrial and cell swelling, glycogen depletion in liver cells and fatty change in liver, heart and kidney."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10985", "text": "Experiments demonstrated enhanced arterial thrombosis in a rat animal model, elevations of serotonin levels, thromboxane A[2] and adhesion proteins in platelets, while human platelets showed similar responses. [ 45 ]  The effect on vascular endothelium may eventually be mediated by the arsenic-induced formation of nitric oxide.\nIt was demonstrated that +3 As concentrations substantially lower than concentrations required for inhibition of the lysosomal protease cathepsin L in B cell line TA3 were sufficient to trigger apoptosis in the same B cell line, while the latter could be a mechanism mediating immunosuppressive effects. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10986", "text": "Its comutagenic effects may be explained by interference with base and nucleotide excision repair, eventually through interaction with zinc finger structures. [ 47 ]  Dimethylarsinic acid, DMA(V), caused DNA single strand breaks resulting from inhibition of repair enzymes at levels of 5 to 100 mM in human epithelial  type II  cells. [ 48 ] [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10987", "text": "MMA(III) and DMA(III) were also shown to be directly genotoxic by effectuating scissions in supercoiled \u03a6X174 DNA. [ 50 ]  Increased arsenic exposure is associated with an increased frequency of chromosomal aberrations, [ 51 ]  micronuclei [ 52 ] [ 53 ]  and sister-chromatid exchanges. An explanation for chromosomal aberrations is the sensitivity of the protein tubulin and the mitotic spindle to arsenic. Histological observations confirm effects on cellular integrity, shape and locomotion. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10988", "text": "DMA(III) is able to form reactive oxygen species by reaction with molecular oxygen. Resulting metabolites are the dimethylarsenic radical and the dimethylarsenic peroxyl radical. [ 55 ] \nBoth DMA(III) and DMA(V) were shown to release iron from horse spleen as well as from human liver ferritin if ascorbic acid was administered simultaneously. Thus, formation of reactive oxygen species can be promoted. [ 56 ] \nMoreover, arsenic could cause oxidative stress by depleting the cell's antioxidants, especially the ones containing thiol groups. The accumulation of reactive oxygen species like that cited above and hydroxyl radicals, superoxide radicals and hydrogen peroxides causes aberrant gene expression at low concentrations and lesions of lipids, proteins and DNA in higher concentrations which eventually lead to cellular death.\nIn a rat animal model, urine levels of 8-hydroxy-2'-deoxyguanosine (as a biomarker of DNA damage byreactive oxygen species) were measured after treatment with DMA(V). In comparison to control levels, they turned out to be significantly increased. [ 57 ]  This theory is further supported by a cross-sectional study which found elevated mean serum lipid peroxides in the As exposed individuals which correlated with blood levels of inorganic arsenic and methylated metabolites and inversely correlated with nonprotein sulfhydryl (NPSH) levels in whole blood. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10989", "text": "Another study found an association of As levels in whole blood with the level of reactive oxidants in plasma and an inverse relationship with plasma antioxidants. [ 59 ]  A finding of the latter study indicates that methylation might in fact be a detoxification pathway with regard to oxidative stress: the results showed that the lower the As methylation capacity was, the lower the level of plasma antioxidant capacity. As reviewed by Kitchin (2001), the oxidative stress theory provides an explanation for the preferred tumor sites connected with arsenic exposure. [ 60 ]  Considering that a high partial pressure of oxygen is present in lungs and DMA(III) is excreted in gaseous state via the lungs, this seems to be a plausible mechanism for special vulnerability. The fact that DMA is produced by methylation in the liver, excreted via the kidneys and later on stored in the bladder accounts for the other tumor localizations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10990", "text": "Regarding DNA methylation, some studies suggest interaction of As with methyltransferases which leads to an inactivation of tumor suppressor genes through hypermethylation; others state that hypomethylation might occur due to a lack of SAM resulting in aberrant gene activation. [ 61 ]  An experiment by Zhong et al. (2001) with arsenite-exposed human lung A549, kidney UOK123, UOK109 and UOK121 cells isolated eight different DNA fragments by methylation-sensitive arbitrarily primed polymerase chain reactions. [ 62 ]  It turned out that six of the fragments were hyper- and two of them were hypomethylated. [ 62 ]  Higher levels of DNA methyltransferase mRNA and enzyme activity were found. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10991", "text": "Kitchin (2001) proposed a model of altered growth factors which lead to cell proliferation and thus to  carcinogenesis . [ 60 ]  From observations, it is known that chronic low-dose arsenic poisoning can lead to increased tolerance to its acute toxicity. [ 63 ] [ 64 ]  MRP1-overexpressing lung tumor GLC4/Sb30 cells poorly accumulate arsenite and arsenate. This is mediated through MRP-1 dependent efflux. [ 65 ]  The efflux requires glutathione, but no arsenic-glutathione complex formation. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10992", "text": "Although many mechanisms have been proposed, no definite model can be given for the mechanisms of chronic arsenic poisoning. The prevailing events of toxicity and carcinogenicity might be quite tissue-specific. Current consensus on the mode of carcinogenesis is that it acts primarily as a tumor promoter. Its co-carcinogenicity has been demonstrated in several models. However, the finding of several studies that chronically arsenic-exposed Andean populations (as most extremely exposed to UV-light) do not develop skin cancer with chronic arsenic exposure, is puzzling. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10993", "text": "The two forms of inorganic arsenic, reduced (trivalent As(III)) and oxidized (pentavalent As(V)), can be absorbed, and accumulated in tissues and body fluids. [ 68 ]  In the liver, the metabolism of arsenic involves enzymatic and non-enzymatic methylation; the most frequently excreted metabolite (\u2265 90%) in the urine of mammals is  dimethylarsinic acid  or cacodylic acid, DMA(V). [ 69 ]  Dimethylarsenic acid is also known as  Agent Blue  and was used as herbicide in the American war in  Vietnam ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10994", "text": "In humans inorganic arsenic is reduced nonenzymatically from pentoxide to trioxide, using glutathione or it is mediated by enzymes. Reduction of arsenic pentoxide to arsenic trioxide increases its toxicity and bio availability, Methylation occurs through methyltransferase enzymes. S-adenosylmethionine (SAM) may serve as methyl donor. Various pathways are used, the principal route being dependent on the current environment of the cell. [ 70 ]  Resulting metabolites are monomethylarsonous acid, MMA(III), and dimethylarsinous acid, DMA(III)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_10995", "text": "Methylation had been regarded as a detoxification process,  [ by whom? ]  but reduction from +5 As to +3 As may be considered as a bioactivation  [ clarification needed ]  instead. [ 71 ]  Another suggestion is that methylation might be a detoxification if \"As[III] intermediates are not permitted to accumulate\" because the pentavalent organoarsenics have a lower affinity to  thiol groups  than inorganic pentavalent arsenics. [ 70 ]  Gebel (2002) stated that methylation is a detoxification through accelerated excretion. [ 72 ]  With regard to carcinogenicity it has been suggested that methylation should be regarded as a toxification. [ 60 ] [ 73 ] [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10996", "text": "Arsenic, especially +3 As, binds to single, but with higher affinity to  vicinal   sulfhydryl groups , thus reacts with a variety of  proteins  and inhibits their activity. It was also proposed that binding of arsenite at nonessential sites might contribute to detoxification. [ 75 ]  Arsenite inhibits members of the disulfide oxidoreductase family like glutathione reductase [ 76 ]  and thioredoxin reductase. [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10997", "text": "The remaining unbound arsenic (\u2264 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers. [ 69 ]  Other forms of arsenic toxicity in humans have been observed in blood, bone marrow, cardiac, central nervous system, gastrointestinal, gonadal, kidney, liver, pancreatic, and skin tissues. [ 69 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10998", "text": "The acute minimal lethal dose of arsenic in adults is estimated to be 70 to 200\u00a0mg or 1\u00a0mg/kg/day. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_10999", "text": "Another aspect is the similarity of arsenic effects to the heat shock response. Short-term arsenic exposure has effects on signal transduction inducing heat shock proteins with masses of 27, 60, 70, 72, 90, and 110 kDa as well as  metallothionein ,  ubiquitin , mitogen-activated [MAP] kinases,  extracellular regulated kinase  [ERK], c-jun terminal kinases [JNK] and p38. [ 54 ] [ 79 ] \nVia JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines. [ 54 ] [ 80 ] [ 81 ]  The effects are largely dependent on the dosing regime and may be as well inversed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11000", "text": "As shown by some experiments reviewed by Del Razo (2001), reactive oxygen species induced by low levels of inorganic arsenic increase the transcription and the activity of the activator protein 1 (AP-1) and the nuclear factor-\u03baB ( NF-\u03baB ) (maybe enhanced by elevated MAPK levels), which results in c-fos/c-jun activation, over-secretion of pro-inflammatory and growth promoting cytokines stimulating cell proliferation. [ 79 ] [ 82 ]  Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water. [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11001", "text": "Increased AP-1 and NF-\u03baB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels. [ 84 ]  Thus, taking into account p53's function, a lack of it could cause a faster accumulation of mutations contributing to carcinogenesis. However, high levels of inorganic arsenic inhibit NF-\u03baB activation and cell proliferation. An experiment of Hu et al. (2002) demonstrated increased binding activity of AP-1 and NF-\u03baB after acute (24 h) exposure to +3 sodium arsenite, whereas long-term exposure (10\u201312 weeks) yielded the opposite result. [ 85 ]  The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis. [ 85 ]  As the contradicting findings and connected mechanistic hypotheses indicate, there is a difference in acute and chronic effects of arsenic on signal transduction which is not clearly understood yet. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11002", "text": "Studies have demonstrated that the oxidative stress generated by arsenic may disrupt the signal transduction pathways of the nuclear transcriptional factors PPARs, AP-1, and NF-\u03baB, [ 69 ] [ 85 ] [ 86 ]  as well as the pro-inflammatory cytokines IL-8 and TNF-\u03b1. [ 69 ] [ 85 ] [ 86 ] [ 87 ] [ 88 ] [ 89 ] [ 90 ] [ 91 ]   The interference of oxidative stress with signal transduction pathways may affect physiological processes associated with cell growth, metabolic syndrome X, glucose homeostasis, lipid metabolism, obesity,  insulin resistance , inflammation, and diabetes-2. [ 92 ] [ 93 ] [ 94 ]  Recent scientific evidence has elucidated the physiological roles of the PPARs in the \u03c9- hydroxylation of fatty acids and the inhibition of pro-inflammatory transcription factors (NF-\u03baB and AP-1), pro-inflammatory cytokines (IL-1, \u22126, \u22128, \u221212, and TNF-\u03b1), cell4 adhesion molecules (ICAM-1 and VCAM-1), inducible nitric oxide synthase, proinflammatory nitric oxide (NO), and anti-apoptotic factors. [ 69 ] [ 87 ] [ 92 ] [ 94 ] [ 95 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11003", "text": "Epidemiological studies have suggested a correlation between chronic consumption of drinking water contaminated with arsenic and the incidence of type 2 diabetes. [ 69 ]  The human liver after exposure to therapeutic drugs may exhibit hepatic non-cirrhotic portal hypertension, fibrosis, and cirrhosis. [ 69 ]  However, the literature provides insufficient scientific evidence to show cause and effect between arsenic and the onset of diabetes mellitus Type 2. [ 69 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11004", "text": "Arsenic may be measured in blood or urine to monitor excessive environmental or occupational exposure, confirm a diagnosis of poisoning in hospitalized victims or to assist in the forensic investigation in a case of fatal over dosage. Some analytical techniques are capable of distinguishing organic from inorganic forms of the element. Organic arsenic compounds tend to be eliminated in the urine in unchanged form, while inorganic forms are largely converted to organic arsenic compounds in the body prior to urinary excretion. The current biological exposure index for U.S. workers of 35\u00a0\u03bcg/L total urinary arsenic may easily be exceeded by a healthy person eating a seafood meal. [ 96 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11005", "text": "Tests are available to diagnose poisoning by measuring arsenic in blood, urine, hair, and fingernails. The urine test is the most reliable test for arsenic exposure within the last few days. Urine testing needs to be done within 24\u201348\u00a0hours for an accurate analysis of an acute exposure. Tests on hair and fingernails can measure exposure to high levels of arsenic over the past 6\u201312 months. These tests can determine if one has been exposed to above-average levels of arsenic. They cannot predict, however, whether the arsenic levels in the body will affect health. [ 97 ]  Chronic arsenic exposure can remain in the body systems for a longer period of time than a shorter term or more isolated exposure and can be detected in a longer time frame after the introduction of the arsenic, important in trying to determine the source of the exposure."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11006", "text": "Hair is a potential bioindicator for arsenic exposure due to its ability to store trace elements from blood. Incorporated elements maintain their position during growth of hair. Thus for a temporal estimation of exposure, an assay of hair composition needs to be carried out with a single hair which is not possible with older techniques requiring homogenization and dissolution of several strands of hair. This type of biomonitoring has been achieved with newer microanalytical techniques like synchrotron radiation based X-ray fluorescence spectroscopy and microparticle induced X-ray emission. The highly focused and intense beams study small spots on biological samples allowing analysis to micro level along with the chemical speciation. In a study, this method has been used to follow arsenic level before, during and after treatment with arsenious oxide in patients with acute promyelocytic leukemia. [ 98 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11007", "text": "Dimercaprol  and  dimercaptosuccinic acid  are  chelating agents  that sequester the arsenic away from blood proteins and are used in treating acute arsenic poisoning.  The most important side effect is  hypertension .  Dimercaprol is considerably more toxic than succimer. [ citation needed ] [ 99 ]  Dimercaptosuccinic acid monoesters, e.g. MiADMSA, are promising antidotes for arsenic poisoning. [ 100 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11008", "text": "Supplemental potassium decreases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide. [ 101 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11009", "text": "Beginning in about 3000 BC arsenic was mined and added to copper in the alloying of  bronze , but the adverse health effects of working with arsenic led to it being abandoned when a viable alternative, tin, was discovered. [ 104 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11010", "text": "In addition to its presence as a poison, for centuries arsenic was used medicinally. It has been used for over 2,400 years as a part of traditional Chinese medicine. [ 105 ]  In the western world, arsenic compounds, such as  salvarsan , were used extensively to treat  syphilis  before  penicillin  was introduced. It was eventually replaced as a therapeutic agent by  sulfa drugs  and then by other  antibiotics . Arsenic was also an ingredient in many tonics (or \" patent medicines \")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11011", "text": "In addition, during the  Elizabethan era , some  women  used a mixture of  vinegar ,  chalk , and arsenic applied topically to whiten their skin. This use of arsenic was intended to prevent aging and creasing of the skin, but some arsenic was inevitably absorbed into the blood stream. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11012", "text": "During the  Victorian era  (late 19th century) in the United States, U.S. newspapers advertised \"arsenic complexion wafers\" that promised to remove facial blemishes such as moles and pimples. [ 103 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11013", "text": "Some pigments, most notably the popular  Emerald Green  (known also under several other names), were based on arsenic compounds. Overexposure to these pigments was a frequent cause of accidental poisoning of artists and craftsmen."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11014", "text": "Arsenic became a favored method for murder of the  Middle Ages  and  Renaissance , particularly among ruling classes in Italy allegedly. Because the symptoms are similar to those of  cholera , which was common at the time, arsenic poisoning often went undetected. [ 106 ] :\u200a63\u200a   By the 19th century, it had acquired the nickname \"inheritance powder\", perhaps because impatient heirs were known or suspected to use it to ensure or accelerate their inheritances. [ 106 ] :\u200a21\u200a  It was also a common murder technique in the 19th century in domestic violence situations, such as the case of  Rebecca Copin , who attempted to poison her husband by \"putting arsenic in his coffee\". [ 107 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11015", "text": "In post-WW1  Hungary , arsenic extracted by boiling fly paper was used in an estimated 300 murders by the  Angel Makers of Nagyr\u00e9v ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11016", "text": "In imperial China, arsenic trioxide and sulfides were used in murder, as well as for capital punishment for members of the royal family or aristocracy.  Forensic studies have determined that the  Guangxu Emperor  (d. 1908) was murdered by arsenic, most likely ordered by the  Empress Dowager Cixi  or Generalissimo  Yuan Shikai .  Likewise, in ancient  Korea , and particularly in the  Joseon Dynasty , arsenic-sulfur compounds had been used as a major ingredient of  sayak  (\uc0ac\uc57d; \u8cdc\u85e5), which was a poison cocktail used in  capital punishment  of high-profile political figures and members of the royal family. [ 108 ]  Due to social and political prominence of the condemned, many of these events were well-documented, often in the  Annals of Joseon Dynasty ; they are sometimes portrayed in historical television  miniseries  because of their dramatic nature. [ 109 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11017", "text": "One of the worst incidents of  arsenic poisoning via well water occurred in Bangladesh , which the World Health Organization called the \"largest mass poisoning of a population in history\" [ 110 ]  and was recognized as a major public health concern. The contamination in the Ganga-Brahmaputra fluvial plains in India and Padma-Meghna fluvial plains in Bangladesh demonstrated adverse impacts on human health. [ 111 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11018", "text": "Arsenic poisoning from exposure to groundwater is believed to be responsible for the illness experienced by those that witnessed the  2007 Carancas impact event  in  Peru , as local residents inhaled steam which was contaminated with arsenic, produced from groundwater which boiled from the intense heat and pressure produced by a  chondrite  meteorite impacting the ground. [ 112 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11019", "text": "In the U.S. in 1975, under the authority of the Safe Drinking Water Act, the U.S. Environmental Protection Agency determined the National Interim Primary Drinking Water Regulation levels of arsenic (inorganic contaminant \u2013 IOCs) to be 0.05\u00a0mg/L (50 parts per billion \u2013 ppb). [ 113 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11020", "text": "Throughout the years, many studies reported dose-dependent effects of arsenic in drinking water and skin cancer. In order to prevent new cases and death from cancerous and non-cancerous diseases, the Safe Drinking Water Act directed the Environmental Protection Agency to revise arsenic's levels and specified the maximum contaminant level (MCL). MCLs are set as close to the health goals as possible, considering cost, benefits and the ability of public water systems to detect and remove contaminants using suitable treatment technologies. [ 113 ] [ 114 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11021", "text": "In 2001, Environmental Protection Agency adopted a lower standard of MCL 0.01\u00a0mg/L (10 ppb) for arsenic in drinking water that applies to both community water systems and non-transient non-community water systems. [ 113 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11022", "text": "In some other countries, when developing national drinking water standards based on the guideline values, it is necessary to take account of a variety of geographical, socio-economic, dietary and other conditions affecting potential exposure. These factors lead to national standards that differ appreciably from the guideline values. That is the case in countries such as India and Bangladesh, where the permissible limit of arsenic in absence of an alternative source of water is 0.05\u00a0mg/L. [ 115 ] [ 116 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11023", "text": "Arsenic removal technologies are traditional treatment processes which have been tailored to improve removal of arsenic from drinking water. Although some of the removal processes, such as precipitative processes, adsorption processes, ion exchange processes, and separation (membrane) processes, may be technically feasible, their cost may be prohibitive. [ 113 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11024", "text": "For underdeveloped countries, the challenge is finding the means to fund such technologies. The Environmental Protection Agency, for example, has estimated the total national annualized cost of treatment, monitoring, reporting, record keeping, and administration to enforce the MCL rule to be approximately $181 million. Most of the cost is due to the installation and operation of the treatment technologies needed to reduce arsenic in public water systems. [ 117 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11025", "text": "Arsenic exposure through groundwater is highly concerning throughout the perinatal period. Pregnant people are a high-risk population because not only are they at risk for adverse outcomes, but in-utero exposure also poses health risks to the foetus."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11026", "text": "There is a  dose-dependent relationship  between perinatal exposure to arsenic and infant mortality, meaning that infants born to people exposed to higher concentrations, or exposed for longer periods of time, have a higher mortality rate. [ 118 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11027", "text": "Studies have shown that ingesting arsenic through groundwater during pregnancy poses dangers to the pregnant person including, but not limited to abdominal pain, vomiting, diarrhea, skin pigmentation changes, and cancer. [ 119 ]  Research has also demonstrated that arsenic exposure also causes low birth weight, low birth size, infant mortality, and a variety of other outcomes in infants. [ 119 ] [ 120 ]  Some of these effects, like lower birth-rate and size may be due to the effects of arsenic on weight gain during pregnancy. [ 120 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11028", "text": "Berylliosis , or  chronic beryllium disease  ( CBD ), is a chronic allergic-type lung response and chronic lung  disease  caused by exposure to  beryllium  and its compounds, a form of  beryllium poisoning . It is distinct from  acute beryllium poisoning , which became rare following occupational exposure limits established around 1950. [ 1 ]  Berylliosis is an  occupational lung disease ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11029", "text": "While there is no cure, symptoms can be treated. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11030", "text": "With single or prolonged exposure by inhalation the lungs may become sensitized to beryllium. Berylliosis has a slow onset and progression. Some people who are sensitized to beryllium may not have symptoms. [ 1 ]  Continued exposure causes the development of small inflammatory nodules, called  granulomas . [ 3 ]  Of note, the authors of a 2006 study suggested that beryllium inhalation was not the only form of exposure and perhaps skin exposure was also a cause, as they found that a reduction in beryllium inhalation did not result in a reduction in chronic beryllium disease or beryllium sensitization. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11031", "text": "Granuloma formation is seen in other diseases such as  tuberculosis  and  sarcoidosis . Sarcoidosis, like berylliosis, also produces  granulomas without a necrotic core , and so distinction between the two processes can be difficult."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11032", "text": "Ultimately, this process leads to  restrictive lung disease  (a decrease in  diffusion capacity )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11033", "text": "The earliest symptoms are typically  cough  and  shortness of breath . [ 5 ]  Other symptoms include  chest pain ,  joint aches ,  weight loss , and  fever ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11034", "text": "Rarely, one can get granulomas in other organs including the  liver ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11035", "text": "The onset of symptoms can range from weeks up to tens of years from the initial exposure. In some individuals, a single exposure to beryllium can cause berylliosis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11036", "text": "In susceptible persons, beryllium exposure can lead to a cell-mediated immune response. The T-cells become sensitized to beryllium. Each subsequent exposure leads to an immune response involving  CD4+ helper T-lymphocytes  and  macrophages  accumulating in the lungs. As this response continues macrophages, CD4+ T-lymphocytes and plasma cells aggregate together to form the  noncaseating granulomas . [ 6 ] [ 7 ]  When beryllium is  phagocytized  by macrophages, the beryllium triggers macrophage apoptosis, thereby reducing beryllium clearance from the lungs and eventually resulting in secondary necrosis and lysis. [ 8 ]  Eventually, the outcome is  fibrosis  of the lung. [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11037", "text": "Several studies have shown that there is a genetic component to beryllium sensitivity. Specifically, those beryllium-exposed workers with a mutation at the  HLA-DPB1  Glu 69  position have increased prevalence of beryllium sensitization and chronic beryllium disease. [ 11 ]   The HLA-DPB1 gene is important for  MHC class II  molecule function on  antigen presenting cells . [ 11 ]  A study of the immune response to beryllium in individuals who express the  HLA-DP2  allele found that CD4 T-cells do not detect the  Be 2+  cation itself, but instead detect surface changes in the HLA-DP2/peptide complex in which  Be 2+  is embedded. Those researchers concluded that chronic beryllium disease is a predisposition that lies between \" allergic hypersensitivity  and  autoimmunity .\" [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11038", "text": "According to the  International Agency for Research on Cancer , beryllium and beryllium compounds are  Category 1 carcinogens ; they are carcinogenic to both animals and humans. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11039", "text": "The differential diagnosis for berylliosis includes: [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11040", "text": "Diagnosis of berylliosis is based on history of beryllium exposures, documented beryllium sensitivity, and granulomatous inflammation on  lung biopsy . Given the invasive nature of a lung biopsy, diagnosis can also be based on clinical history consistent with berylliosis, abnormal  chest x-ray  or  CT scan  findings, and abnormalities in  pulmonary function tests . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11041", "text": "The radiologic and pathologic features of berylliosis are very similar to sarcoidosis.  Due to the strong clinical and histopathological resemblance of sarcoidosis and berylliosis, patients are sometimes misdiagnosed with sarcoidosis until the history of exposure to beryllium is elicited and beryllium hypersensitivity demonstrated with specific testing. Some studies suggest that up to 6% of all cases of sarcoidosis are actually berylliosis. [ 16 ]   [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11042", "text": "The beryllium lymphocyte proliferation test (BeLPT) is the standard way of determining sensitivity to beryllium. [ 15 ]  The test is performed by acquiring either peripheral blood or fluid from a bronchial alveolar lavage, and lymphocytes are cultured with beryllium sulfate. Cells are then counted and those with elevated number of cells are considered abnormal. [ 18 ]  Those exposed persons with two abnormal BeLPT tested with peripheral blood, or one abnormal and one borderline result, are considered beryllium sensitized. Also, those with one abnormal BeLPT tested with fluid from a bronchial alveolar lavage are considered sensitized. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11043", "text": "Chest radiography findings of berylliosis are non-specific. Early in the disease radiography findings are usually normal. In later stages interstitial fibrosis,  pleural irregularities, hilar  lymphadenopathy  and  ground-glass opacities  have been reported. [ 19 ] [ 20 ]  Findings on CT are also not specific to berylliosis. Findings that are common in CT scans of people with berylliosis include parenchymal nodules in early stages. One study found that ground-glass opacities were more commonly seen on CT scan in berylliosis than in sarcoidosis. In later stages hilar lymphadenopathy, interstitial pulmonary fibrosis and pleural thickening. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11044", "text": "Berylliosis is an  occupational disease . [ 1 ]  Relevant occupations are those where beryllium is mined, processed or converted into metal alloys, or where machining of metals containing beryllium and recycling of scrap alloys occurs. [ 21 ]  It is associated with aerospace manufacturing, microwave semiconductor electronics, beryllium mining or manufacturing of fluorescent light bulbs (which once contained beryllium compounds in their internal phosphor coating). [ 22 ] [ 23 ] [ 24 ]   Beryllia  was used in lamp manufacture because of ceramic's obvious virtues for insulation and heat resistance, and also because beryllia could be made transparent. [ 25 ]  Certain welding anodes along with other electrical contacts and even non-sparking tools are made of  beryllium copper  alloy and the subsequent machining of such materials would cause the disease as well."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11045", "text": "Because it can be difficult to control industrial exposures to beryllium, it is advisable to use any methods possible to reduce airborne and surface contamination by beryllium, to minimize the use of beryllium and beryllium-containing alloys whenever possible, and to educate people about the potential hazards if they are likely to encounter beryllium dust or fumes. [ 26 ]  It is important to damp wipe  metallographic  preparation equipment to prevent accumulation of dry particles. Sectioning, grinding, and polishing must be performed under sufficiently vented hoods equipped with special filters. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11046", "text": "On 29 January 2009, the Los Alamos National Laboratory announced it was notifying nearly 2,000 current and former employees and visitors that they may have been exposed to beryllium in the lab and may be at risk of disease. Concern over possible exposure to the material was first raised in November 2008, when a box containing beryllium was received at the laboratory's short-term storage facility. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11047", "text": "There is no cure for berylliosis; the goals of treatment are to reduce symptoms and slow the progression of disease. [ 10 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11048", "text": "Although the evidence that stopping exposure to beryllium decreases progression of the disease is limited, [ 30 ]  it is still considered to be an accepted approach to treatment in any stage of disease. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11049", "text": "People with early stages of disease, without lung function abnormalities or clinical symptoms, are periodically monitored with physical exams, pulmonary function testing and radiography. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11050", "text": "Once clinical symptoms or significant abnormalities in pulmonary function testing appear, treatments include oxygen and oral  corticosteroids  and whatever  supportive therapy  is required. [ 1 ] [ 15 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11051", "text": "Overall mortality rates are 5\u201338%. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11052", "text": "The number of workers in the United States exposed to beryllium vary but has been estimated to be as high as 800,000 during the 1960s and 1970s. [ 33 ]  A more recent study from 2004 estimated the number of exposed workers in the United States to be around 134,000. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11053", "text": "The rate of workers becoming sensitized to beryllium varies based on genetics and exposure levels. In one study researchers found the prevalence of beryllium sensitization to range from 9\u201319% depending on the industry. [ 35 ]  Many workers who are found to be sensitive to beryllium also meet the diagnostic criteria for chronic beryllium disease. [ 35 ]  In one study of nuclear workers, among those who were sensitized to beryllium, 66% were found to have chronic beryllium disease as well. [ 36 ]  The rate of progression from beryllium sensitization to chronic beryllium disease has been estimated to be approximately 6\u20138% per year. [ 30 ] [ 37 ]  Stopping exposure to beryllium in those sensitized has not been definitively shown to stop the progression to chronic beryllium disease. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11054", "text": "The overall prevalence of chronic beryllium disease among workers exposed to beryllium has ranged from 1\u20135% depending on industry and time period of study. [ 35 ] [ 36 ] [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11055", "text": "The general population is unlikely to develop acute or chronic beryllium disease because ambient air levels of beryllium are normally very low (<0.03\u00a0ng/m 3 ). [ 39 ]   However, a study found 1% of people living within 3/4 of a mile of a beryllium plant in Lorain, Ohio, had berylliosis after exposure to concentrations estimated to be less than 1 milligram per cubic metre of air. In the United States the Beryllium Case Registry contained 900 records, early cases relating to extraction and fluorescent lamp manufacture, later ones coming from the aerospace, ceramics and metallurgical industries. [ 40 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11056", "text": "Since the 1920s, beryllium has been used in electronics, ceramics, research and development labs, aircraft, and the atomic energy and defense industry. [ 26 ]  Cases of bronchitis and pneumonia-like symptoms were reported in Germany and Russia in the 1930s among workers mining and refining beryllium. By 1946, a cluster of cases associated with fluorescent lamp manufacturers were apparent in the United States, and the lamp industry stopped using beryllium in 1949. [ 31 ]  At that time, most construction trades and industries were unaware of the potential risks associated with beryllium exposure. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11057", "text": "It occasionally killed early workers in nuclear weapons design, such as  Herbert L. Anderson . [ 43 ]  The physicist  W. W. Hansen  who was instrumental in the development of the  klystron  also died of the disease in 1949."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11058", "text": "Beryllium sensitivity testing was first performed as a cutaneous beryllium patch test in the early 1950s, but was discontinued due to the test stimulating sensitization or aggravating existing chronic beryllium disease. [ 44 ] :\u200a115"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11059", "text": "In the 1990s, the  DOE  began screening employees using the BeLPT test in facilities where beryllium was used, to take preventive measures against beryllium exposure. Somewhat alarmingly, clerical staff who were never involved in handling the material had developed asymptomatic sensitivities. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11060", "text": "Acute beryllium poisoning  is acute  chemical pneumonitis  resulting from the toxic effect of  beryllium  in its elemental form or in various chemical compounds, and is distinct from  berylliosis  (also called chronic beryllium disease). After  occupational safety  procedures were put into place following the realization that the metal caused berylliosis around 1950, acute beryllium poisoning became extremely rare. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11061", "text": "Generally associated with exposure to beryllium levels at or above 100 \u03bcg/m 3 , [ 1 ]  it produces severe cough, sore nose and throat, weight loss, labored breathing, anorexia, and increased fatigue. [ 2 ] :\u200a46"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11062", "text": "In addition to beryllium's toxicity when inhaled, when brought into contact with skin at relatively low doses, beryllium can cause local irritation and  contact dermatitis , and contact with skin that has been scraped or cut may cause rashes or ulcers. [ 3 ]  Beryllium dust or powder can irritate the eyes. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11063", "text": "Acute beryllium poisoning is an  occupational disease . [ 1 ]  Relevant occupations are those where beryllium is mined, processed or converted into metal alloys, or where machining of metals containing beryllium or recycling of scrap alloys occurs. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11064", "text": "Metallographic preparation equipment and laboratory work surfaces must be damp-wiped occasionally to inhibit buildup of particles. Cutting, grinding, and polishing procedures that generate dust or fumes must be handled within sufficiently vented coverings supplied with particulate filters. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11065", "text": "Therapy is supportive and includes removal from further beryllium exposure. [ 1 ]  For very severe cases mechanical ventilation may be required. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11066", "text": "The signs and symptoms of acute beryllium pneumonitis usually resolve over several weeks to months, but may be fatal in 10 percent of cases, [ 1 ]  and about 15\u201320% of cases may progress to  chronic beryllium disease . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11067", "text": "Acute beryllium poisoning approximately doubles the risk of lung cancer. [ 9 ]  The mechanism by which beryllium is carcinogenic is unclear, but may be due to ionic beryllium binding to nucleic acids; it is not mutagenic. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11068", "text": "Acute beryllium disease was first reported in Europe in 1933 and in the United States in 1943. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11069", "text": "This article incorporates  public domain material  from  Beryllium .  Occupational Safety and Health Administration . Retrieved  28 March  2016 . \n \u00a0This article incorporates  public domain material  from  ToxGuide for Beryllium   (PDF) .  United States Department of Health and Human Services ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11070", "text": "A  bioeffector   is a viable  microorganism  or active natural compound which directly or indirectly affects plant performance ( biofertilizer ), and thus has the potential to reduce  fertilizer  and  pesticide  use in crop production. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11071", "text": "Bioeffectors directly or indirectly affect plant performance by influencing the functional implementation or activation of biological mechanisms, particularly those interfering with soil-plant-microbe interactions. [ 2 ] \nIn contrast to conventional fertilizers and pesticides, the effectiveness of bioeffectors is not based on a substantial direct input of mineral plant nutrients, either in inorganic or organic forms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11072", "text": "Under the Acronym  Biofector  the European Union supports the Research of Bioeffectors under the leadership of the  University of Hohenheim . Coordinator  Guenter Neumann , Projectmembers:  Ji\u0159\u00ed Bal\u00edk ,  Borbala Biro ,  Karl Fritz Lauer ,  Uwe Ludewig ,  Torsten M\u00fcller ,  Alessandro Piccolo ,  Manfred G. Raupp ,  Kornelia Smalla ,  Pavel Tlusto\u0161 ,  Markus Weinmann ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11073", "text": "The results of the project will be evaluated by the members of the  Association Biostimulants in Agriculture  (ABISTA) and provided agriculture for use and EU institutions for the legislative and registration procedures. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11074", "text": "Other Biostimulants Organisations are  European Biostimulant Industry Council ,  International Biocontrol Manufacturers' Association  and  Annual Biocontrol Industry Meeting ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11075", "text": "Biogenic silica  (bSi), also referred to as  opal , biogenic opal, or  amorphous  opaline  silica , forms one of the most widespread biogenic  minerals . For example, microscopic particles of silica called  phytoliths  can be found in grasses and other plants."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11076", "text": "Silica is an amorphous metalloid  oxide  formed by complex  inorganic   polymerization  processes. This is opposed to the other major  biogenic  minerals, comprising  carbonate  and  phosphate , which occur in nature as crystalline iono-covalent solids (e.g.  salts ) whose  precipitation  is dictated by  solubility equilibria . [ 1 ]  Chemically, bSi is  hydrated silica  (SiO 2 \u00b7 n H 2 O), which is essential to many plants and animals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11077", "text": "Diatoms in both fresh and salt water extract  dissolved silica  from the water to use as a component of their cell walls. Likewise, some  holoplanktonic   protozoa  ( Radiolaria ), some  sponges , and some plants (leaf  phytoliths ) use silicon as a structural material. Silicon is known to be required by chicks and rats for growth and skeletal development. Silicon is in human  connective tissues ,  bones ,  teeth ,  skin ,  eyes ,  glands  and  organs ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11078", "text": "Silicate , or  silicic acid  (H 4 SiO 4 ), is an important  nutrient  in the ocean. Unlike the other major nutrients such as  phosphate ,  nitrate , or  ammonium , which are needed by almost all marine  plankton , silicate is an essential chemical requirement for very specific  biota , including  diatoms ,  radiolaria ,  silicoflagellates , and  siliceous sponges . These organisms extract dissolved silicate from open ocean surface waters for the buildup of their particulate silica (SiO 2 ), or opaline, skeletal structures (i.e. the biota's hard parts). [ 2 ] [ 3 ]  Some of the most common siliceous structures observed at the cell surface of silica-secreting organisms include: spicules, scales, solid plates, granules, frustules, and other elaborate geometric forms, depending on the species considered. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11079", "text": "Five major sources of  dissolved  silica to the marine environment can be distinguished: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11080", "text": "Once the organism has perished, part of the siliceous skeletal material  dissolves , as it settles through the  water column , enriching the deep waters with dissolved silica. [ 3 ]  Some of the siliceous scales can also be preserved over time as  microfossils  in  deep-sea   sediments , providing a window into modern and ancient  plankton / protists  communities. This biologic process has operated, since at least early  Paleozoic  time, to regulate the balance of silica in the ocean. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11081", "text": "Radiolarians ( Cambrian / Ordovician - Holocene ),  diatoms  ( Cretaceous - Holocene ), and silicoflagellates ( Cretaceous - Holocene ) form the ocean's main contributors to the global silica biogenic cycle throughout  geologic time . Diatoms account for 43% of the ocean primary production, and are responsible for the bulk of silica extraction from ocean waters in the modern ocean, and during much of the past fifty million years. In contrast, oceans of  Jurassic  and older ages, were characterized by  radiolarians  as major silica-utilizing phyla. [ 2 ]  Nowadays, radiolarians are the second (after diatoms) major producers of suspended amorphous silica in ocean waters. Their distribution ranges from the  Arctic  to the  Antarctic , being most abundant in the equatorial zone. In equatorial  Pacific  waters, for example, about 16,000 specimens per cubic meter can be observed. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11082", "text": "The silicon cycle has gained increasingly in scientific attention the past decade for several reasons:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11083", "text": "Firstly , the modern  marine  silica cycle is widely believed to be dominated by diatoms for the fixation and export of  particulate matter  (including  organic   carbon ), from the  euphotic zone  to the deep ocean, via a process known as the  biological pump .  As a result, diatoms, and other silica-secreting organisms, play a crucial role in the global  carbon cycle , and have the ability to affect  atmospheric  CO 2  concentrations on a variety of time scales, by  sequestering  CO 2  in the ocean. This connection between  biogenic silica  and organic carbon, together with the significantly higher  preservation potential  of biogenic siliceous compounds, compared to organic carbon, makes opal accumulation records very interesting for  paleoceanography  and  paleoclimatology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11084", "text": "Secondly , biogenic silica accumulation on the sea floor contains lot of information about where in the ocean  export production  has occurred on time scales ranging from hundreds to millions of years. For this reason, opal deposition records provide valuable information regarding large-scale oceanographic reorganizations in the geological past, as well as paleoproductivity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11085", "text": "Thirdly , the mean oceanic  residence time  for silicate is approximately 10,000\u201315,000 yr. This relative short residence time, makes oceanic silicate concentrations and fluxes sensitive to  glacial / interglacial  perturbations, and thus an excellent  proxy  for evaluating climate changes. [ 3 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11086", "text": "Increasingly,  isotope ratios  of oxygen (O 18 :O 16 ) and silicon (Si 30 :Si 28 ) are analysed from biogenic silica preserved in lake and marine sediments to derive records of past  climate change  and  nutrient cycling  (De La Rocha, 2006; Leng and Barker, 2006). This is a particularly valuable approach considering the role of  diatoms  in global carbon cycling. In addition, isotope analyses from BSi are useful for tracing past climate changes in regions such as in the  Southern Ocean , where few biogenic  carbonates  are preserved."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11087", "text": "The remains of diatoms and other silica-utilizing organisms are found, as opal sediments within pelagic deep-sea deposits.  Pelagic sediments , containing significant quantities of siliceous biogenic remains, are commonly referred to as  siliceous ooze . Siliceous ooze are particularly abundant in the modern ocean at high latitudes in the northern and southern hemispheres. A striking feature of siliceous ooze distribution is a ca. 200\u00a0km wide belt stretching across the  Southern Ocean . Some equatorial regions of  upwelling , where  nutrients  are abundant and  productivity  is high, are also characterized by local siliceous ooze. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11088", "text": "Siliceous oozes are composed primarily of the remains of diatoms and radiolarians, but may also include other siliceous organisms, such as silicoflagellates and  sponge   spicules . Diatom ooze occurs mainly in high-latitude areas and along some continental margins, whereas radiolarian ooze are more characteristic of equatorial areas. Siliceous ooze are modified and transformed during burial into bedded  cherts . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11089", "text": "Southern Ocean sediments are a major sink for biogenic silica (50-75% of the oceanic total of 4.5 \u00d7 10 14  g SiO 2  yr \u22121 ; DeMaster, 1981), but only a minor sink for organic  carbon  (<1% of the oceanic 2 \u00d7 10 14  g of organic C yr \u22121 ). These relatively high rates of biogenic silica accumulation in the Southern Ocean sediments (predominantly beneath the Polar Front) relative to organic carbon (60:1 on a weight basis) results from the preferential preservation of biogenic silica in the Antarctic water column."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11090", "text": "In contrast to what was previously thought, these high rates of biogenic silica accumulation are not the result from high rates of  primary production . Biological production in the Southern Ocean is strongly limited due to the low levels of  irradiance  coupled with deep mixed layers and/or by limited amounts of  micronutrients , such as  iron . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11091", "text": "This preferential preservation of biogenic silica relative to organic carbon is evident in the steadily increasing ratio of silica/organic C as function of depth in the water column. About thirty-five percent of the biogenic silica produced in the  euphotic  zone survives dissolution within the surface layer; whereas only 4% of the organic carbon escapes  microbial  degradation in these near-surface waters."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11092", "text": "Consequently, considerable decoupling of organic C and silica occurs during settling through the water column. The accumulation of biogenic silica in the seabed represents 12% of the surface production, whereas the seabed organic-carbon accumulation rate accounts for solely <0.5% of the surface production. As a result, polar sediments account for most of the ocean's biogenic silica accumulation, but only a small amount of the sedimentary organic-carbon flux. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11093", "text": "Large-scale oceanic circulation has a direct impact on  opal  deposition. The Pacific (characterized by nutrient poor surface waters, and deep nutrient rich waters) and Atlantic Ocean circulations favor the  production / preservation  of silica and carbonate respectively. For instance, Si/N and Si/P ratios increase from the Atlantic to the Pacific and Southern Ocean, favoring opal versus  carbonate  producers. Consequently, the modern configuration of large-scale oceanic circulation resulted in the localization of major opal burial zones in the Equatorial Pacific, in the eastern boundary current upwelling systems, and by far the most important, the Southern Ocean. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11094", "text": "Waters from the modern Pacific and Southern ocean, typically observe an increase in Si/N ratio at intermediate depth, which results in an increase in opal export (~ increase in opal production). In the Southern Ocean and North Pacific, this relationship between opal export and Si/N ratio switches from linear to exponential for Si/N ratios greater than 2. This gradual increase in the importance of silicate (Si) relative to nitrogen (N) has tremendous consequences for the ocean biological production. The change in nutrient ratios contributes to select  diatoms  as main producers, compared to other (e.g., calcifying) organisms. For example,  microcosm  experiments have demonstrated that diatoms are DSi supercompetitors and dominate other producers above 2 \u03bcM DSi. Consequently, opal vs. carbonate export will be favored, resulting in increasing opal production. The Southern Ocean and the North Pacific also display maximum biogenic silicate/C organic  flux ratios, and consist thus in an enrichment in biogenic silicate, compared to C organic  export flux. This combined increase in opal preservation and export makes the Southern Ocean the most important  sink  for DSi today. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11095", "text": "In the Atlantic Ocean, intermediate and deep waters are characterized by a lower content in DSi, compared to the modern Pacific and Southern Ocean. This lower interbasin difference in DSi has the effect of decreasing the  preservation potential  of opal in the Atlantic compared to its Pacific and Southern ocean counterparts. Atlantic DSi depleted waters tends to produce relatively less  silicified  organisms, which has a strong influence on the preservation of their  frustules . This mechanism in best illustrated when comparing the Peru and northwest Africa upwelling systems. The  dissolution /production ratio is much higher in the Atlantic upwelling than in the Pacific upwelling. This is due to the fact that coastal upwelling source waters are much richer in DSi off Peru, than off NW Africa. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11096", "text": "Rivers and submarine  hydrothermal  emanations supply 6.1 \u00d7 10 14  g SiO 2  yr \u22121  to the marine environment. Approximately two-thirds of this silica input is stored in  continental margin  and  deep-sea  deposits. Siliceous deep-sea sediments located beneath the  Antarctic Convergence  ( convergence zone ) host some 25% of the silica supplied to the oceans (i.e. 1.6 \u00d7 10 14  g SiO 2  yr \u22121 ) and consequently form one of Earth's major silica sinks. The highest biogenic silica accumulation rates in this area are observed in the South Atlantic, with values as large as 53\u00a0cm.kyr \u22121  during the last 18,000 yr. Further, extensive biogenic silica accumulation has been recorded in the deep-sea sediments of the  Bering Sea ,  Sea of Okhotsk , and  Subarctic   North Pacific . Total biogenic silica accumulation rates in these regions amounts nearly 0.6 \u00d7 10 14  g SiO 2  yr \u22121 , which is equivalent to 10% of the dissolved silica input to the oceans."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11097", "text": "Continental margin upwelling areas, such as the  Gulf of California , the Peru and Chile coast, are characteristic for some of the highest biogenic silica accumulation rates in the world. For example, biogenic silica accumulation rates of 69 g SiO 2 /cm 2 /kyr have been reported for the Gulf of California. Due to the laterally confined character of these rapid biogenic silica accumulation zones, upwelling areas solely account for approximately 5% of the dissolved silica supplied to the oceans. At last, extremely low biogenic silica accumulation rates have been observed in the extensive deep-sea deposits of the Atlantic, Indian and Pacific Oceans, rendering these oceans insignificant for the global marine silica budget. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11098", "text": "The mean daily BSi rate strongly depends on the region:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11099", "text": "Likewise, the integrated annual BSi production strongly depends on the region:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11100", "text": "BSi production is controlled by:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11101", "text": "BSi dissolution is controlled by:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11102", "text": "BSi preservation is measured by:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11103", "text": "BSi preservation is controlled by:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11104", "text": "In the  Gusev crater  of Mars, the  Mars Exploration Rover   Spirit  inadvertently discovered opaline silica.  One of its wheels had earlier become immobilized and thus was effectively trenching the Martian  regolith  as it dragged behind the traversing rover.  Later analysis showed that the silica was evidence for hydrothermal conditions. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11105", "text": "Fluorine  may interact with biological systems in the form of fluorine-containing compounds. Though elemental fluorine (F 2 ) is very rare in everyday life, fluorine-containing compounds such as  fluorite  occur naturally as minerals. Naturally occurring  organofluorine  compounds are extremely rare. Man-made fluoride compounds are common and are used in medicines, pesticides, and materials. Twenty percent of all commercialized pharmaceuticals contain fluorine, including  Lipitor  and  Prozac . [ 1 ] [ 2 ]  In many contexts, fluorine-containing compounds are harmless or even beneficial to living organisms; in others, they are  toxic ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11106", "text": "Aside from their use in medicine, man-made fluorinated compounds have also played a role in several noteworthy environmental concerns.  Chlorofluorocarbons  (CFCs), once major components of numerous commercial aerosol products, have proven damaging to Earth's  ozone layer  and resulted in the wide-reaching  Montreal Protocol ; though in truth the  chlorine  in CFCs is the destructive actor, fluorine is an important part of these molecules because it makes them very stable and long-lived. Similarly, the stability of many  organofluorine compounds  has raised the issue of  biopersistence . Long-lived molecules from waterproofing sprays, for example  PFOA  and  PFOS , are found worldwide in the tissues of wildlife and humans, including newborn children."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11107", "text": "Fluorine biology is also relevant to a number of cutting-edge technologies. PFCs ( perfluorocarbons ) are capable of holding enough oxygen to support human  liquid breathing . Organofluorine in the form of its radioisotope  18 F  is also at the heart of a modern medical imaging technique known as  positron emission tomography  (PET). A PET scan produces three-dimensional colored images of parts of the body that use a lot of sugar, particularly the brain or tumors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11108", "text": "Since the mid-20th century, it has been discerned from population studies (though incompletely understood) that fluoride reduces  tooth decay . Initially, researchers hypothesized that fluoride helped by converting  tooth enamel  from the more acid-soluble mineral  hydroxyapatite  to the less acid-soluble mineral fluorapatite. However, more recent studies showed no difference in the frequency of  caries  (cavities) between teeth that were pre-fluoridated to different degrees. Current thinking is that fluoride prevents cavities primarily by helping teeth that are in the very early stages of tooth decay. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11109", "text": "When teeth begin to decay from the acid produced by sugar-consuming bacteria,  calcium  is lost ( demineralization ). However, teeth have a limited ability to recover calcium if decay is not too far advanced ( remineralization ). Fluoride appears to reduce demineralization and increase remineralization. Also, there is some evidence that fluoride interferes with the bacteria that consume sugars in the mouth and make tooth-destroying acids. [ 3 ]  In any case, it is only the fluoride that is directly present in the mouth ( topical treatment ) that prevents cavities; fluoride ions that are swallowed do not benefit the teeth. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11110", "text": "Water fluoridation  is the controlled addition of fluoride to a  public water supply  in an effort to reduce tooth decay in people who drink the water. [ 4 ]  Its use began in the 1940s, following studies of children in a region where water is naturally fluoridated. It is now used widely in public water systems in the United States and some other parts of the world, such that about two-thirds of the U.S. population is exposed to fluoridated water supplies [ 5 ]  and about 5.7% of people worldwide. [ 6 ]  Although the best available evidence shows no association with adverse effects other than fluorosis ( dental  and, in worse cases,  skeletal ), most of which is mild, [ 7 ]  water fluoridation has been contentious for ethical, safety, and efficacy reasons, [ 6 ]  and  opposition to water fluoridation  exists despite its widespread support by  public health  organizations. [ 8 ]  The benefits of water fluoridation have lessened recently, presumably because of the availability of fluoride in other forms, but are still measurable, particularly for low-income groups. [ 9 ]   Systematic reviews  in 2000 and 2007 showed significant reduction of cavities in children exposed to water fluoridation. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11111", "text": "Sodium fluoride ,  tin difluoride , and, most commonly,  sodium monofluorophosphate , are used in  toothpaste . In 1955, the first fluoride toothpaste was introduced in the United States. Now, almost all toothpaste in developed countries is fluoridated. For example, 95% of European toothpaste contains fluoride. [ 9 ]  Gels and foams are often advised for special patient groups, particularly those undergoing radiation therapy to the head (cancer patients). The patient receives a four-minute application of a high amount of fluoride. Varnishes, which can be more quickly applied, exist and perform a similar function. Fluoride is also often present in prescription and non-prescription  mouthwashes  and is a trace component of foods manufactured using fluoridated water supplies. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11112", "text": "Of all commercialized pharmaceutical drugs, twenty percent contain fluorine, including important drugs in many different pharmaceutical classes. [ 12 ]  Fluorine is often added to drug molecules during  drug design , as even a single atom can greatly change the chemical properties of the molecule in desirable ways."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11113", "text": "Because of the considerable stability of the  carbon\u2013fluorine bond , many drugs are fluorinated to delay their  metabolism , which is the chemical process in which the drugs are turned into compounds that allows them to be eliminated. This prolongs their  half-lives  and allows for longer times between dosing and activation. For example, an  aromatic ring  may prevent the metabolism of a drug, but this presents a safety problem, because some aromatic compounds are metabolized in the body into poisonous  epoxides  by the organism's native  enzymes . Substituting a fluorine into a  para  position, however, protects the aromatic ring and prevents the epoxide from being produced. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11114", "text": "Adding fluorine to biologically active organic compounds increases their  lipophilicity  (ability to dissolve in fats), because the carbon\u2013fluorine bond is even more hydrophobic than the  carbon\u2013hydrogen bond . This effect often increases a drug's  bioavailability  because of increased cell membrane penetration. [ 14 ]  Although the potential of fluorine being released in a fluoride  leaving group  depends on its position in the molecule, [ 15 ]  organofluorides are generally very stable, since the carbon\u2013fluorine bond is strong."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11115", "text": "Fluorines also find their uses in common  mineralocorticoids , a class of drugs that increase the  blood pressure . Adding a fluorine increases both its medical power and anti-inflammatory effects. [ 16 ]  Fluorine-containing  fludrocortisone  is one of the most common of these drugs. [ 17 ]   Dexamethasone  and  triamcinolone , which are among the most potent of the related synthetic  corticosteroid  class of drugs, contain fluorine as well. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11116", "text": "Several inhaled general  anesthetic  agents, including the most commonly used inhaled agents, also contain fluorine. The first fluorinated anesthetic agent,  halothane , proved to be much safer (neither explosive nor flammable) and longer-lasting than those previously used. Modern fluorinated anesthetics are longer-lasting still and almost insoluble in blood, which accelerates the awakening. [ 18 ]  Examples include  sevoflurane ,  desflurane ,  enflurane , and  isoflurane , all  hydrofluorocarbon  derivatives. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11117", "text": "Prior to the 1980s,  antidepressants  altered not only  serotonin  uptake but also the uptake of altered  norepinephrine ; the latter caused most of the side effects of antidepressants. The first drug to alter only the serotonin uptake was  Prozac ; it gave birth to the extensive  selective serotonin reuptake inhibitor  (SSRI) antidepressant class and is the best-selling antidepressant. Many other SSRI antidepressants are fluorinated organics, including  Celexa ,  Luvox , and  Lexapro . [ 20 ]   Fluoroquinolones  are a commonly used family of  broad-spectrum antibiotics . [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11118", "text": "Compounds containing fluorine-18, a radioactive isotope that emits  positrons , are often used in  positron emission tomography  (PET) scanning, because the isotope's half-life of about 110 minutes is usefully long by positron-emitter standards. One such  radiopharmaceutical  is  2-deoxy-2-( 18 F)fluoro-D-glucose  (generically referred to as fludeoxyglucose), commonly abbreviated as  18 F-FDG, or simply FDG. [ 22 ]  In PET imaging, FDG can be used for assessing glucose metabolism in the brain and for imaging cancer tumors. After injection into the blood, FDG is taken up by \"FDG-avid\" tissues with a high need for glucose, such as the brain and most types of malignant tumors. [ 23 ]   Tomography , often  assisted by a computer  to form a PET/CT (CT stands for \"computer tomography\") machine, can then be used to diagnose or monitor treatment of cancers, especially  Hodgkin's lymphoma , lung cancer, and breast cancer. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11119", "text": "Natural fluorine is monoisotopic, consisting solely of  fluorine-19 . Fluorine compounds are highly amenable to  nuclear magnetic resonance  (NMR), because fluorine-19 has a  nuclear spin  of  1 \u2044 2 , a high  nuclear magnetic moment , and a high  magnetogyric ratio . Fluorine compounds typically have a fast NMR  relaxation , which enables the use of fast averaging to obtain a  signal-to-noise ratio  similar to  hydrogen-1  NMR spectra. [ 25 ]  Fluorine-19 is commonly used in NMR study of metabolism, protein structures and conformational changes. [ 26 ]  In addition, inert fluorinated gases have the potential to be a cheap and efficient tool for imaging lung ventilation. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11120", "text": "Liquid  fluorocarbons  have a very high capacity for holding gas in solution. They can hold more oxygen or carbon dioxide than blood does. For that reason, they have attracted ongoing interest related to the possibility of artificial blood or of liquid breathing. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11121", "text": "Blood substitutes are the subject of research because the demand for blood transfusions grows faster than donations. In some scenarios, artificial blood may be more convenient or safe. Because fluorocarbons do not normally mix with water, they must be mixed into emulsions (small droplets of perfluorocarbon suspended in water) in order to be used as blood. [ 29 ] [ 30 ]  One such product,  Oxycyte , has been through initial clinical trials. [ 31 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11122", "text": "Possible medical uses of liquid breathing (which uses pure perfluorocarbon liquid, not a water emulsion) involve assistance for premature babies or for burn patients (if normal lung function is compromised). Both partial and complete filling of the lungs have been considered, although only the former has undergone any significant tests in humans. Several animal tests have been performed and there have been some human partial liquid ventilation trials. [ 33 ]  One effort, by Alliance Pharmaceuticals, reached clinical trials but was abandoned because of insufficient advantage compared to other therapies. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11123", "text": "Nanocrystals represent a possible method of delivering water- or fat-soluble drugs within a perfluorochemical fluid. The use of these particles is being developed to help treat babies with damaged lungs. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11124", "text": "Perfluorocarbons are banned from sports, where they may be used to increase oxygen use for endurance athletes. One cyclist,  Mauro Gianetti , was investigated after a near-fatality where PFC use was suspected. [ 36 ] [ 37 ]  Other posited applications include deep-sea diving and space travel, applications that both require total, not partial, liquid ventilation. [ 38 ] [ 39 ]  The 1989 film  The Abyss  depicted a fictional use of perfluorocarbon for human diving but also filmed a real rat surviving while cooled and immersed in perfluorocarbon. [ 40 ]  (See also  list of fictional treatments  of perfluorocarbon breathing.)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11125", "text": "An estimated 30% of  agrichemical compounds  contain fluorine. [ 41 ]  Most of them are used as poisons, but a few stimulate growth instead."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11126", "text": "Sodium fluoroacetate  has been used as an insecticide, but it is especially effective against mammalian pests. [ 42 ]  The name \"1080\" refers to the catalogue number of the poison, which became its brand name. [ 43 ]  Fluoroacetate is similar to acetate, which has a pivotal role in the  Krebs cycle  (a key part of cell metabolism). Fluoroacetate halts the cycle and causes cells to be deprived of energy. [ 43 ]  Several other insecticides contain sodium fluoride, which is much less toxic than fluoroacetate. [ 44 ]  Insects fed 29-fluorostigmasterol use it to produce fluoroacetates. If a fluorine is transferred to a body cell, it blocks metabolism at the position occupied. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11127", "text": "Trifluralin  was widely used in the 20th century, for example, in over half of U.S. cotton field acreage in 1998. [ 46 ]  Because of its suspected carcinogenic properties some Northern European countries banned it in 1993. [ 47 ]  As of 2015, the European Union has banned it, although Dow made a case to cancel the decision in 2011. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11128", "text": "Biologically synthesized organofluorines are few in number, although some are widely produced. [ 49 ] [ 50 ]  The most common example is  fluoroacetate , with an active poison molecule identical to commercial \"1080\". It is used as a  defense against herbivores  by at least 40 green plants in Australia, Brazil, and Africa; [ 43 ]  other biologically synthesized organofluorines include \u03c9-fluoro  fatty acids ,  fluoroacetone , and 2-fluorocitrate. [ 50 ]  In bacteria, the enzyme  adenosyl-fluoride synthase , which makes the carbon\u2013fluorine bond, has been isolated. The discovery was touted as possibly leading to biological routes for organofluorine synthesis. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11129", "text": "Fluoride is considered a semi-essential element for humans: not necessary to sustain life, but contributing (within narrow limits of daily intake) to dental health and bone strength. Daily requirements for fluorine in humans vary with age and sex, ranging from 0.01\u00a0mg in infants below 6 months to 4\u00a0mg in adult males, with an upper tolerable limit of 0.7\u00a0mg in infants to 10\u00a0mg in adult males and females. [ 52 ] [ 53 ]  Small amounts of fluoride may be beneficial for bone strength, but this is an issue only in the formulation of artificial diets. [ 54 ]  (See also  fluoride deficiency .)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11130", "text": "Elemental fluorine is highly toxic. Above a concentration of 25\u00a0ppm, it causes significant irritation while attacking the eyes, airways and lungs and affecting the liver and kidneys. At a concentration of 100\u00a0ppm, human eyes and noses are seriously damaged. [ 57 ]  People can be exposed to fluorine in the workplace by breathing it in, skin contact, or eye contact. The  Occupational Safety and Health Administration  (OSHA) has set the legal limit ( Permissible exposure limit ) for fluorine exposure in the workplace as 0.1 ppm (0.2\u00a0mg/m 3 ) over an 8-hour workday. The  National Institute for Occupational Safety and Health  (NIOSH) has set a  recommended exposure limit  (REL) of 0.1 ppm (0.2\u00a0mg/m 3 ) over an 8-hour workday. At levels of 25 ppm, fluorine is  immediately dangerous to life and health . [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11131", "text": "Hydrofluoric acid , the water solution of hydrogen fluoride (HF), is a contact poison. Even though it is from a chemical perspective a relatively weak acid, it is far more dangerous than conventional strong  mineral acids , such as  nitric acid ,  sulfuric acid , or  hydrochloric acid . Owing to its lesser chemical dissociation in water (remaining a neutral molecule), hydrogen fluoride penetrates tissue more quickly than typical acids. Poisoning can occur readily through the skin or eyes or when inhaled or swallowed. From 1984 to 1994, at least nine workers died in the United States from accidents with HF. [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11132", "text": "Once in the blood, hydrogen fluoride reacts with calcium and magnesium, resulting in electrolyte imbalances, potentially including  hypocalcemia . The consequent effect on the heart ( cardiac arrhythmia ) may be fatal. [ 60 ]  Formation of insoluble  calcium fluoride  also causes severe pain. [ 61 ]  Burns with areas larger than 160\u00a0cm 2 , about the size of a man's hand, can cause serious systemic toxicity. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11133", "text": "Symptoms of exposure to hydrofluoric acid may not be immediately evident, with an eight-hour delay for 50% HF and up to 24 hours for lower concentrations. Hydrogen fluoride interferes with nerve function, meaning that burns may not initially be painful. If the burn has been initially noticed, then HF should be washed off with a forceful stream of water for ten to fifteen minutes to prevent its further penetration into the body. Clothing used by the person burned may also present a danger. [ 63 ]  Hydrofluoric acid exposure is often treated with  calcium gluconate , a source of Ca 2+  that binds with the fluoride ions. Skin burns can be treated with a water wash and 2.5 percent calcium gluconate gel [ 64 ] [ 65 ]  or special rinsing solutions. [ 66 ]  Because HF is absorbed, further medical treatment is necessary. Calcium gluconate may be injected or administered intravenously. Use of  calcium chloride  is contraindicated and may lead to severe complications. Sometimes surgical excision of tissue or amputation is required. [ 62 ] [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11134", "text": "Soluble fluorides are moderately toxic. For sodium fluoride, the lethal dose for adults is 5\u201310\u00a0g, which is equivalent to 32\u201364\u00a0mg of elemental fluoride per kilogram of body weight. [ 68 ]  The dose that may lead to adverse health effects is about one fifth of the lethal dose. [ 69 ]  Chronic excess fluoride consumption can lead to  skeletal fluorosis , a disease of the bones that affects millions in Asia and Africa. [ 69 ] [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11135", "text": "The fluoride ion is readily absorbed by the stomach and intestines. Ingested fluoride forms hydrofluoric acid in the stomach. In this form, fluoride crosses cell membranes and then binds with calcium and interferes with various enzymes. Fluoride is  excreted  through urine. Fluoride exposure limits are based on urine testing, which is used to determine the human body's capacity for ridding itself of fluoride. [ 69 ] [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11136", "text": "Historically, most cases of fluoride poisoning have been caused by accidental ingestion of insecticides containing inorganic fluoride. [ 72 ]  Most calls to poison control centers for possible fluoride poisoning come from the ingestion of fluoride-containing toothpaste. [ 69 ]  Malfunction of water fluoridation equipment has occurred several times, including an Alaskan incident that sickened nearly 300 people and killed one. [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11137", "text": "Because of the strength of the carbon\u2013fluorine bond, organofluorines endure in the environment.  Perfluorinated compounds  (PFCs) have attracted particular attention as  persistent global contaminants .  These compounds can enter the environment from their direct uses in waterproofing treatments and firefighting foams or indirectly from leaks from fluoropolymer production plants (where they are intermediates). Because of the acid group, PFCs are water-soluble in low concentrations. [ 74 ]   While there are other PFAAs, the lion's share of environmental research has been done on the two most well-known:  perfluorooctanesulfonic acid  (PFOS) and  perfluorooctanoic acid  (PFOA).  The U.S. Environmental Protection Agency classifies these materials as \"emerging contaminants\" based on the growing but still incomplete understanding of their environmental impact. [ 75 ] [ 76 ] [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11138", "text": "Trace quantities of PFCs have been detected worldwide, in organisms from polar bears in the Arctic to the global human population.  Both PFOS and PFOA have been detected in breast milk and the blood of newborns.  A 2013 review showed widely varying amounts of PFOS and PFOA in different soils and groundwater, with no clear pattern of one chemical dominating. PFC concentrations were generally higher in areas with more human population or industrial activity, and areas with more PFOS generally also had more PFOA. [ 78 ]   the two chemicals have been found at different concentrations in different populations; for example, one study showed more PFOS than PFOA in Germans, while another study showed the reverse for Americans. PFCs may be starting to decrease in the biosphere: one study indicated that PFOS levels in wildlife in Minnesota were decreasing, presumably because  3M  discontinued its production. [ 75 ] [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11139", "text": "In the body, PFCs bind to proteins such as  serum albumin . Their tissue distribution in humans is unknown, but studies in rats suggest it is present mostly in the liver, kidney, and blood. They are not metabolized by the body but are excreted by the kidneys. Dwell time in the body varies greatly by species.  Rodents have half-lives of days, while in humans they remain for years. Many animals show sex differences in the ability to rid the body of PFAAs, but without a clear pattern. Gender differences of half lives vary by animal species. [ 75 ] [ 76 ] [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11140", "text": "The potential health impact of PFCs is unclear. Unlike chlorinated hydrocarbons, PFCs are not  lipophilic  (stored in fat), nor  genotoxic  (damaging genes). Both PFOA and PFOS in high doses cause cancer and the death of newborns in rodents. Studies on humans have not been able to prove an impact at current exposures.  Bottlenose dolphins  have some of the highest PFOS concentrations of any wildlife studied; one study suggests an impact on their immune systems. [ 75 ] [ 76 ] [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11141", "text": "The biochemical causes of toxicity are also unclear and may differ by molecule, health effect, and even animal.  PPAR-alpha  is a protein that interacts with PFAAs and is commonly implicated in contaminant-caused rodent cancers. [ 75 ] [ 76 ] [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11142", "text": "Less fluorinated chemicals (i.e. not perfluorinated compounds) can also be detected in the environment. Because biological systems do not metabolize fluorinated molecules easily, fluorinated pharmaceuticals like antibiotics and antidepressants can be found in treated city sewage and wastewater. [ 80 ]  Fluorine-containing agrichemicals are measurable in farmland  runoff  and nearby rivers. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11143", "text": "Biometals  (also called  biocompatible metals ,  bioactive metals ,  metallic biomaterials ) are  metals  normally present, in small but important and measurable amounts, in  biology ,  biochemistry , and  medicine . The metals  copper ,  zinc ,  iron , and  manganese  are examples of metals that are essential for the normal functioning of most  plants  and the bodies of most  animals , such as the  human body . A few ( calcium ,  potassium ,  sodium ) are present in relatively larger amounts, whereas most others are  trace metals , present in smaller but important amounts (the image shows the percentages for humans). Approximately 2/3 of the existing periodic table is composed of metals with varying properties, [ 1 ]  accounting for the diverse ways in which metals (usually in  ionic  form) have been utilized in nature and medicine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11144", "text": "At first, the study of biometals was referred to as  bioinorganic chemistry . Each branch of bioinorganic chemistry studied separate, particular sub-fields of the subject. However, this led to an isolated view of each particular aspect in a biological system. This view was revised into a holistic approach of biometals in  metallomics . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11145", "text": "Metal ions in  biology  were studied in various specializations. In  nutrition , it was to define the essentials for life; in  toxicology , to define how the adverse effects of certain metal ions in biological systems and in  pharmacology  for their therapeutic effects. [ 2 ]  In each field, at first, they were studied and separated on a basis of concentration. In low amounts, metal ions in a biological system could perform at their optimal functionality whereas in higher concentrations, metal ions can prove fatal to biological systems. However, the concentration gradients were proved to be arbitrary as low concentrations of non-essential metals (like  lithium  or  helium ) in essential metals (like  sodium  or  potassium ) can cause an adverse effect in biological systems and vice versa. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11146", "text": "Investigations into biometals and their effects date back to the 19th century and even further back to the 18th century with the identification of iron in blood. [ 2 ]   Zinc  was identified to be essential in fungal growth of  yeast  as shown by  Jules Raulin  in 1869 yet no proof for the need of zinc in human cells was shown until the late 1930s where its presence was demonstrated in  carbonic anhydrase  and the 1960s where it was identified as a necessary element for humans. [ 2 ]  Since then, understanding of zinc in human biology has advanced to the point that it is considered as important as iron. Modern advancements in analytical technology have made it clear the importance of biometals in  signalling pathways  and the initial thoughts on the  chemical basis of life . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11147", "text": "Metal ions are essential to the function of many proteins present in living organisms, such as  metalloproteins  and enzymes that require metal ions as  cofactors . [ 3 ]  Processes including oxygen transport and DNA replication are carried out using enzymes such as  DNA polymerase , which in humans requires magnesium and zinc to function properly. [ 4 ]  Other biomolecules also contain metal ions in their structure, such as iodine in human thyroid hormones. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11148", "text": "The uses of some of them are listed below. The list is not exhaustive, because it covers only the principal class members; others that are  trace metals  of especially low bioconcentration are not explored herein. Some elements that are  nonmetals  or  metalloids  (such as  selenium ) are beyond the scope of this article."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11149", "text": "Calcium  is the most abundant metal in the eukaryotes and by extension humans. The body is made up of approximate 1.5% calcium and this abundance is reflected in its lack of redox toxicity and its participation in the structure stability of membranes and other biomolecules. [ 6 ]  Calcium plays a part in  fertilization  of an egg, controls several developmental process and may regulate cellular processes like  metabolism  or learning. Calcium also plays a part in  bone  structure as the rigidity of vertebrae bone matrices are akin to the nature of the  calcium hydroxyapatite . [ 6 ]  Calcium usually binds with other proteins and molecules in order to perform other functions in the body. The calcium bound proteins usually play an important role in  cell-cell adhesion ,  hydrolytic processes  (such as hydrolytic enzymes like  glycosidases  and  sulfatases ) and  protein folding  and sorting. [ 6 ]  These processes play into the larger part of  cell structure  and metabolism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11150", "text": "Magnesium  is the most abundant free cation in plant  cytosol , is the central atom in  chlorophyll  and offers itself as a bridging ion for the  aggregation  of  ribosomes  in plants. [ 7 ]  Even small changes in the concentration of magnesium in plant cytosol or  chloroplasts  can drastically affect the key enzymes present in the chloroplasts. It is most commonly used as a  co-factor  in  eukaryotes  and functions as an important functional key in enzymes like  RNA Polymerase  and  ATPase . [ 7 ]  In phosphorylating enzymes like ATPase or  kinases  and  phosphates , magnesium acts as a stabilizing ion in  polyphosphate  compounds due its  Lewis acidity . [ 6 ]  Magnesium has also been noted as a possible secondary messenger for neural transmissions. [ 6 ]  Magnesium acts as an  allosteric inhibitor  for the enzyme  vacuolar   pyrophosphatase  (V-PP i ase).  In vitro , the concentration of free magnesium acts as a strict regulator and stabilizer for the enzyme activity of V-PP i ase. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11151", "text": "Manganese  like magnesium plays a crucial role as a co-factor in various enzymes though its concentration is noticeably lower than the other. [ 6 ]  Enzymes that use manganese as a co-factor are known as \"manganoproteins.\" These proteins include enzymes, like  oxidoreductases ,  transferases  and  hydrolases , which are necessary for metabolic functions and antioxidant responses. [ 6 ]  Manganese plays a significant role in host defense, blood clotting, reproduction, digestion and various other functions in the body. In particular, when concerning host defense, manganese acts as a preventative measure for oxidative stress by destroying  free radicals  which are  ions  that have an unpaired electron in their outer shells."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11152", "text": "Zinc  is the second most abundant  transition metal  present in living organisms second only to iron. It is critical for the growth and survival of cells. In humans, zinc is primarily found in various organs and tissues such as the brain, intestines, pancreas and mammary glands. [ 8 ]  In  prokaryotes , zinc can function as an  antimicrobial , zinc oxide nano-particles can function as an  antibacterial  or antibiotic. Zinc  homeostasis  is highly controlled to allow for its benefits without risk of death via its high toxicity. [ 8 ]  Because of zinc's antibiotic nature, it is often used in many drugs against bacterial infections in humans. Inversely, due to the bacterial nature of mitochondria, zinc antibiotics are also lethal to mitochondria and results in cell death at high concentrations. [ 8 ]  Zinc is also used in a number of transcription factors, proteins and enzymes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11153", "text": "Sodium is a metal where humans have discovered a great deal of its total roles in the body as well as being one of the only two  alkali metals  that play a major role in the bodily functions. It plays an important role in maintenance of the cell membrane potential and the electrochemical gradient in the body via the  sodium-potassium pump  and  sodium-glucose transport proteins . Sodium also serves a purpose in the  nervous system  and cell communication as they flood into  axons  during an action potential to preserve the strength of the signal. [ 9 ]  It has also been shown that sodium affects immune response both in efficiency and speed. Macrophages have increased proliferation rates at high-salt concentrations and the body uses high-sodium concentrations in isolated regions to generate an heightened immune response which fades after the infection has been dealt with. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11154", "text": "In plants, potassium plays a key role in maintaining plant health. High concentrations of potassium in plants play a key role in synthesis of essential proteins in plants as well as development of plant organelles like cell walls to prevent damage from viruses and insects. [ 11 ]  It also lowers the concentration of low molecular weight molecules like sugars and amino acids and increases the concentration of high weight molecular weight molecules like protein which also prevent the development and propagation of viruses. [ 11 ]  Potassium absorption has a positive correlation with  aquaporins  and the uptake of water in plant cells via cell membrane proteins. [ 11 ]  Because of this correlation, it has been noted that potassium also plays a key part in stomatal movement and regulation as high concentrations of potassium are moved into the plant  stomata  to keep them open and promote  photosynthesis . [ 11 ]  In animals, potassium also plays a key part along with sodium in maintaining resting cell membrane potential and in cell-cell communication via repolarization of axon pathways after an action potential between neurons. [ 9 ]  Potassium may also play a key part in maintaining blood pressure in animals as shown in a study where increased severity of periodontal disease and hypertension were inversely correlated to urinary potassium excretion (a telltale sign of low potassium intake). [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11155", "text": "Iron is also the most abundant  transition metal  in the human body and it is used in various processes like oxygen transport and ATP production. It plays a key role in the function of enzymes like  cytochrome a ,  b  and  c  as well as  iron-sulfur complexes  which play an important role in ATP production. [ 13 ]  It is present in every type of cell in the brain as the brain itself has a very high energy requirement and by extension a very high iron requirement. [ 13 ]  In animals, iron plays a very important role in transporting oxygen from the lungs to tissues and CO 2  from tissues to the lungs. It does this via two important transport proteins called  hemoglobin  and  myoglobin . [ 14 ]  Hemoglobin in the blood transports oxygen from the lungs to myoglobin in tissues. Both proteins are  tetramer  complexes with iron protein complexes called  hemes  built into each  subunit  of the tetramer. The oxygen binds to the iron in the heme via  affinity-based binding  or liganding and dissociates from the protein once it has reached its destination. [ 14 ]  Iron can also be a potential  carcinogen  in three ways; first being the production of  hydroxyl radicals .  Ferric  ions can be  reduced  via  superoxide  and the product can be  reoxidized  via  peroxide  to form hydroxyl radicals. Hydroxyl radicals and other  reactive oxygen species  when generated near  DNA  can cause  point mutations ,  cross-linkage  and  breaks . [ 15 ]  The second being the bolstering of the growth of  neoplastic cells  by suppressing host defenses. Excessive iron inhibits the activity of  CD 4  lymphocytes  and suppresses the  tumoricidal  activity of  macrophages . [ 15 ]  The third way it can act as a carcinogen is by functioning as an essential nutrient for unrestricted proliferation of tumor cells. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11156", "text": "Lithium  is present in biological systems in  trace amounts ; its functions are uncertain. Lithium salts have proven to be useful as a  mood stabilizer  and  antidepressant  in the treatment of mental illness such as  bipolar disorder ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11157", "text": "The term biometal can be used as a synonym to a metallic element that is involved in the function of a  biomolecule , [ 16 ]  hence also artificial systems can be considered when talking about biometals. Systems such as  metalloproteins ,  metallopeptides  and  artificial metalloenzymes  are examples of  biomolecules  containing metallic elements. The  de novo design  of structures involving metals in the function of the  biomolecule  itself is done in a  biomimetic  fashion but also to enable non-natural activity in  biomolecules . [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11158", "text": "Metal ions and metallic compounds are often used in medical treatments and diagnoses. [ 18 ]  Compounds containing metal ions can be used as medicine, such as  lithium compounds  and  auranofin . [ 19 ] [ 20 ]  Metal compounds and ions can also produce harmful effects on the body due to the toxicity of several types of metals. [ 18 ]  For example,  arsenic  works as a potent poison due to its effects as an enzyme inhibitor, disrupting  ATP  production. [ 21 ]  On the other hand, Ni\u2013Ti\u2013Cu wires are\u00a0used for artificial heart muscles [ 22 ]  and iron and gold particles can guide magnetic drug delivery or destroy tumor cells. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11159", "text": "Bigger biometal structures (relying on  metallic elements  and  alloys ) in medicine can be classified into three types:  fibre , bulk scaffolds, and  nanotubes . [ 23 ]  And in some cases the term biometal is also used to refer to metal system with application in  biomedicine  not directly correlated to the  biochemical  function of  biomolecules  but to the  biocompatibility  of these metal systems. [ 24 ]  Examples are scaffolds of  stainless steel  or  titanium   alloy  to create  screws  or plates for  osteosynthesis , and  titanium  bulk for precise engineering of\u00a0 bone tissue . [ 24 ] [ 22 ]  For analytical purposes biometals can be employed in magnetic separation of different materials. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11160", "text": "Calcium (Ca) deficiency  is a plant disorder that can be caused by insufficient level of biologically available  calcium  in the growing medium, but is more frequently a product of low  transpiration  of the whole plant or more commonly the affected tissue.  Plants are susceptible to such localized calcium deficiencies in low or non-transpiring tissues because calcium is not transported in the  phloem . [ 1 ]  This may be due to water shortages, which slow the transportation of  calcium  to the plant, poor uptake of calcium through the stem, [ 2 ]  or too much  nitrogen  in the soil. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11161", "text": "Acidic, sandy, or coarse  soils  often contain less calcium. Uneven soil moisture and overuse of  fertilizers  can also cause calcium deficiency. At times, even with sufficient calcium in the soil, it can be in an insoluble form and is then unusable by the plant or it could be attributed to a \"transport protein\". [ 2 ]  Soils containing high phosphorus are particularly susceptible to creating insoluble forms of calcium. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11162", "text": "Calcium and  magnesium  are opposed within the plant cells, and have antagonistic interactions. As a result, a homeostatic balance between Ca and Mg within the plant is necessary for optimal growth and proper development. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11163", "text": "Calcium deficiency symptoms appear initially as localized tissue  necrosis  leading to stunted plant growth,  necrotic   leaf margins  on young leaves or curling of the leaves, and eventual death of  terminal buds  and  root tips . Generally, the new growth and rapidly growing tissues of the plant are affected first. The mature leaves are rarely if ever affected because calcium accumulates to high concentrations in older leaves. [ 5 ]  Calcium deficiencies in plants are associated with reduced height, fewer nodes, and less leaf area. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11164", "text": "Crop-specific symptoms include: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11165", "text": "Calcium deficiency can sometimes be rectified by adding  agricultural lime  to acid soils, aiming at a  pH  of 6.5, [ 10 ]  unless the subject plants specifically prefer acidic soil. Organic matter should be added to the soil to improve its moisture-retaining capacity. [ 10 ]   However, because of the nature of the disorder (i.e. poor transport of calcium to low transpiring tissues), the problem cannot generally be cured by the addition of calcium to the roots. [ 10 ]   In some species, the problem can be reduced by prophylactic spraying with  calcium chloride  of tissues at risk. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11166", "text": "Plant damage is difficult to reverse, so  corrective action should be taken immediately, supplemental applications of  calcium nitrate  at 200 ppm nitrogen, for example. Soil  pH  should be tested, and corrected if needed, because calcium deficiency is often associated with low pH. [ 14 ] [ 15 ] [ citation needed ] \n [ 16 ] \nEarly fruit will generally have the worst symptoms, with them typically lessening as the season progresses. Preventative measures, such as irrigating prior to especially high temperatures and stable irrigation will minimize the occurrence."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11167", "text": "Calcium  ions  (Ca 2+ ) contribute to the  physiology  and  biochemistry  of organisms'  cells . They play an important role in  signal transduction  pathways, [ 2 ] [ 3 ]  where they act as a  second messenger , in  neurotransmitter  release from  neurons , in contraction of all  muscle  cell types, and in  fertilization . Many  enzymes  require calcium ions as a  cofactor , including several of the  coagulation factors . Extracellular calcium is also important for maintaining the  potential difference  across  excitable cell   membranes , as well as proper bone formation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11168", "text": "Plasma calcium levels in mammals are tightly regulated, [ 2 ] [ 3 ]  with  bone  acting as the major  mineral storage  site. Calcium  ions , Ca 2+ , are released from bone into the bloodstream under controlled conditions. Calcium is transported through the bloodstream as dissolved ions or bound to proteins such as  serum albumin .   Parathyroid hormone  secreted by the  parathyroid gland  regulates the  resorption  of Ca 2+  from bone,  reabsorption  in the kidney back into circulation, and increases in the activation of  vitamin D 3  to  calcitriol . Calcitriol, the active form of vitamin D 3 , promotes  absorption  of calcium from the intestines and bones.  Calcitonin  secreted from the  parafollicular cells  of the  thyroid gland  also affects calcium levels by opposing parathyroid hormone; however, its physiological significance in humans is dubious."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11169", "text": "Intracellular  calcium is stored in  organelles  which repetitively release and then reaccumulate Ca 2+  ions in response to specific cellular events: storage sites include  mitochondria  and the  endoplasmic reticulum . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11170", "text": "Characteristic concentrations of calcium in model organisms are: in  E.\u00a0coli  3\u00a0 mM  (bound), 100\u00a0 nM  (free), in budding yeast 2\u00a0mM (bound), in mammalian cell 10\u2013100\u00a0nM (free) and in blood plasma 2\u00a0mM. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11171", "text": "In 2022, it was the 277th most commonly prescribed medication in the United States, with more than 700,000 prescriptions. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11172", "text": "The US Institute of Medicine (IOM) established  Recommended Dietary Allowances  (RDAs) for calcium in 1997 and updated those values in 2011. [ 6 ]  See table. The \n European Food Safety Authority  (EFSA) uses the term Population Reference Intake (PRIs) instead of RDAs and sets slightly different numbers: ages 4\u201310 800\u00a0mg, ages 11\u201317 1150\u00a0mg, ages 18\u201324 1000\u00a0mg, and >25 years 950\u00a0mg. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11173", "text": "Because of concerns of long-term adverse side effects such as calcification of arteries and kidney stones, the IOM and EFSA both set  Tolerable Upper Intake Levels  (ULs) for the combination of dietary and supplemental calcium. From the IOM, people ages 9\u201318 years are not supposed to exceed 3,000\u00a0mg/day; for ages 19\u201350 not to exceed 2,500\u00a0mg/day; for ages 51 and older, not to exceed 2,000\u00a0mg/day. [ 11 ]  The EFSA set UL at 2,500\u00a0mg/day for adults but decided the information for children and adolescents was not sufficient to determine ULs. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11174", "text": "For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For calcium labeling purposes, 100% of the Daily Value was 1000\u00a0mg, but as of 27 May 2016, it was revised to 1300\u00a0mg to bring it into agreement with the RDA. [ 13 ] [ 14 ]  A table of the old and new adult daily values is provided at  Reference Daily Intake ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11175", "text": "Although as a general rule, dietary supplement labeling and marketing are not allowed to make disease prevention or treatment claims, the FDA has for some foods and dietary supplements reviewed the science, concluded that there is significant scientific agreement, and published specifically worded allowed health claims. An initial ruling allowing a health claim for calcium dietary supplements and  osteoporosis  was later amended to include calcium and  vitamin D  supplements, effective 1 January 2010. Examples of allowed wording are shown below. In order to qualify for the calcium health claim, a dietary supplement must contain at least 20% of the Reference Dietary Intake, which for calcium means at least 260\u00a0mg/serving. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11176", "text": "In 2005, the FDA approved a Qualified Health Claim for calcium and hypertension, with suggested wording \"Some scientific evidence suggests that calcium supplements may reduce the risk of hypertension. However, FDA has determined that the evidence is inconsistent and not conclusive.\" Evidence for pregnancy-induced hypertension and preeclampsia was considered inconclusive. [ 16 ]  The same year, the FDA approved a QHC for calcium and colon cancer, with suggested wording \"Some evidence suggests that calcium supplements may reduce the risk of colon/rectal cancer, however, FDA has determined that this evidence is limited and not conclusive.\" Evidence for breast cancer and prostate cancer was considered inconclusive. [ 17 ]  Proposals for QHCs for calcium as protective against kidney stones or against menstrual disorders or pain were rejected. [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11177", "text": "The  European Food Safety Authority  (EFSA) concluded that \"Calcium contributes to the normal development of bones.\" [ 20 ]  The EFSA rejected a claim that a cause-and-effect relationship existed between the dietary intake of calcium and potassium and maintenance of normal acid-base balance. [ 21 ]  The EFSA also rejected claims for calcium and nails, hair, blood lipids, premenstrual syndrome and body weight maintenance. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11178", "text": "The  United States Department of Agriculture  (USDA) web site has a very complete searchable table of calcium content (in milligrams) in foods, per common measures such as per 100 grams or per a normal serving. [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11179", "text": "The amount of calcium in  blood  (more specifically, in  blood plasma ) can be measured as  total calcium , which includes both protein-bound and free calcium. In contrast,  ionized calcium  is a measure of free calcium. An abnormally high level of calcium in plasma is termed  hypercalcemia  and an abnormally low level is termed  hypocalcemia , with \"abnormal\" generally referring to levels outside the  reference range ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11180", "text": "The main methods to measure serum calcium are: [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11181", "text": "The total amount of Ca 2+  present in a tissue may be measured using  Atomic absorption spectroscopy , in which the tissue is vaporized and combusted.  To measure Ca 2+  concentration or spatial distribution within the cell  cytoplasm   in vivo  or  in vitro , a range of  fluorescent  reporters may be used. These include cell permeable, calcium-binding fluorescent  dyes  such as  Fura-2  or genetically engineered variant of  green fluorescent protein  (GFP) named  Cameleon ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11182", "text": "As access to an ionized calcium is not always available a corrected calcium may be used instead. To calculate a corrected calcium in mmol/L one takes the total calcium in mmol/L and adds it to ((40 minus the serum  albumin  in g/L) multiplied by 0.02). [ 33 ]  There is, however, controversy around the usefulness of corrected calcium as it may be no better than total calcium. [ 34 ]  It may be more useful to correct total calcium for both albumin and the  anion gap . [ 35 ] [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11183", "text": "In  vertebrates , calcium ions, like many other ions, are of such vital importance to many physiological processes that its concentration is maintained within specific limits to ensure adequate homeostasis. This is evidenced by human  plasma  calcium, which is one of the most closely regulated physiological variables in the human body. Normal plasma levels vary between 1 and 2% over any given time. Approximately half of all ionized calcium circulates in its unbound form, with the other half being complexed with plasma proteins such as  albumin , as well as  anions  including  bicarbonate ,  citrate ,  phosphate , and  sulfate . [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11184", "text": "Different  tissues  contain calcium in different concentrations. For instance, Ca 2+  (mostly  calcium phosphate  and some  calcium sulfate ) is the most important (and specific) element of  bone  and calcified  cartilage . In humans, the total body content of calcium is present mostly in the form of bone mineral (roughly 99%). In this state, it is largely unavailable for exchange/bioavailability. The way to overcome this is through the process of  bone resorption , in which calcium is liberated into the bloodstream through the action of bone  osteoclasts . The remainder of calcium is present within the extracellular and intracellular fluids."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11185", "text": "Within a typical cell, the intracellular concentration of ionized calcium is roughly 100 nM, but is subject to increases of 10- to 100-fold during various cellular functions. The intracellular calcium level is kept relatively low with respect to the extracellular fluid, by an approximate magnitude of 12,000-fold. This gradient is maintained through various plasma membrane  calcium pumps  that utilize  ATP  for energy, as well as a sizable storage within intracellular compartments. In  electrically excitable cells , such as skeletal and cardiac muscles and neurons, membrane depolarization leads to a Ca 2+  transient with cytosolic Ca 2+  concentration reaching around 1 \u03bcM. [ 39 ]  Mitochondria are capable of sequestering and storing some of that Ca 2+ . It has been estimated that mitochondrial matrix free calcium concentration rises to the tens of micromolar levels  in situ  during neuronal activity. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11186", "text": "The effects of calcium on human cells are specific, meaning that different types of cells respond in different ways. However, in certain circumstances, its action may be more general. Ca 2+  ions are one of the most widespread  second messengers  used in  signal transduction . They make their entrance into the  cytoplasm  either from outside the cell through the  cell membrane  via calcium channels (such as  calcium-binding proteins  or voltage-gated calcium channels), or from some internal  calcium storages  such as the  endoplasmic reticulum [ 4 ]  and  mitochondria . Levels of intracellular calcium are regulated by  transport proteins  that remove it from the cell. For example, the  sodium-calcium exchanger  uses energy from the  electrochemical gradient  of sodium by coupling the influx of sodium into cell (and down its concentration gradient) with the transport of calcium out of the cell. In addition, the  plasma membrane Ca 2+  ATPase  (PMCA) obtains energy to pump calcium out of the cell by  hydrolysing   adenosine triphosphate  (ATP). In  neurons ,  voltage-dependent, calcium-selective ion channels  are important for  synaptic  transmission through the release of  neurotransmitters  into the  synaptic cleft  by  vesicle fusion  of  synaptic vesicles ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11187", "text": "Calcium's function in  muscle contraction  was found as early as 1882 by Ringer. Subsequent investigations were to reveal its role as a messenger about a century later. Because its action is interconnected with  cAMP , they are called synarchic messengers. Calcium can bind to several different calcium-modulated proteins such as  troponin-C  (the first one to be identified) and  calmodulin , proteins that are necessary for promoting contraction in muscle."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11188", "text": "In the endothelial cells which line the inside of blood vessels, Ca 2+  ions can regulate several signaling pathways which cause the smooth muscle surrounding blood vessels to relax. [ citation needed ]   Some of these Ca 2+ -activated pathways include the stimulation of eNOS to produce nitric oxide, as well as the stimulation of K ca  channels to efflux K +  and cause hyperpolarization of the cell membrane.  Both nitric oxide and hyperpolarization cause the smooth muscle to relax in order to regulate the amount of tone in blood vessels. [ 41 ]   However, dysfunction within these Ca 2+ -activated pathways can lead to an increase in tone caused by unregulated smooth muscle contraction.  This type of dysfunction can be seen in cardiovascular diseases, hypertension, and diabetes. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11189", "text": "Calcium coordination plays an important role in defining the structure and function of proteins. An example a protein with calcium coordination is  von Willebrand factor  (vWF) which has an essential role in blood clot formation process. It was discovered using single molecule  optical tweezers  measurement that calcium-bound vWF acts as a shear force sensor in the blood. Shear force leads to unfolding of the A2 domain of vWF whose refolding rate is dramatically enhanced in the presence of calcium. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11190", "text": "Ca 2+  ion flow regulates several secondary messenger systems in  neural adaptation  for visual, auditory, and the olfactory system. It may often be bound to  calmodulin  such as in the olfactory system to either enhance or repress cation channels. [ 44 ]  Other times the calcium level change can actually release  guanylyl cyclase  from inhibition, like in the photoreception system. [ 45 ]  Ca 2+  ion can also determine the speed of adaptation in a neural system depending on the receptors and proteins that have varied affinity for detecting levels of calcium to open or close channels at high concentration and low concentration of calcium in the cell at that time. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11191", "text": "Substantial decreases in extracellular Ca 2+  ion concentrations may result in a condition known as  hypocalcemic   tetany , which is marked by spontaneous  motor neuron  discharge. In addition, severe  hypocalcaemia  will begin to affect aspects of  blood coagulation  and signal transduction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11192", "text": "Ca 2+  ions can damage cells if they enter in excessive numbers (for example, in the case of  excitotoxicity , or over-excitation of  neural circuits , which can occur in  neurodegenerative diseases , or after insults such as  brain trauma  or  stroke ). Excessive entry of  calcium  into a cell may damage it or even cause it to undergo  apoptosis , or death by  necrosis . Calcium also acts as one of the primary regulators of osmotic stress ( osmotic shock ). Chronically elevated plasma calcium ( hypercalcemia ) is associated with  cardiac arrhythmias  and decreased neuromuscular excitability. One cause of hypercalcemia is a condition known as  hyperparathyroidism ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11193", "text": "Some  invertebrates  use calcium compounds for building their  exoskeleton  ( shells  and  carapaces ) or  endoskeleton  ( echinoderm  plates and  poriferan  calcareous  spicules )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11194", "text": "When  abscisic acid  signals the guard cells, free Ca 2+  ions enter the cytosol from both outside the cell and internal stores, reversing the concentration gradient so the K+ ions begin exiting the cell. The loss of solutes makes the cell flaccid and closes the stomatal pores."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11195", "text": "Calcium is a necessary ion in the formation of the  mitotic spindle . Without the mitotic spindle,  cellular division  cannot occur. Although young leaves have a higher need for calcium, older leaves contain higher amounts of calcium because calcium is relatively immobile through the plant. It is not transported through the  phloem  because it can bind with other nutrient ions and  precipitate  out of liquid solutions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11196", "text": "Ca 2+  ions are an essential component of plant  cell walls  and  cell membranes , and are used as  cations  to balance  organic   anions  in the plant  vacuole . [ 49 ]   The Ca 2+  concentration of the vacuole may reach millimolar levels.  The most striking use of Ca 2+  ions as a structural element in algae occurs in the marine  coccolithophores , which use Ca 2+  to form the  calcium carbonate  plates, with which they are covered."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11197", "text": "Calcium is needed to form the  pectin  in the  middle lamella  of newly formed cells."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11198", "text": "Calcium is needed to stabilize the permeability of cell membranes. Without calcium, the cell walls are unable to stabilize and hold their contents. This is particularly important in developing fruits. Without calcium, the cell walls are weak and unable to hold the contents of the fruit."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11199", "text": "Some  plants  accumulate Ca in their tissues, thus making them more firm. Calcium is stored as Ca- oxalate  crystals in  plastids ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11200", "text": "Ca 2+  ions are usually kept at nanomolar levels in the  cytosol  of  plant cells , and act in a number of signal transduction pathways as  second messengers ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11201", "text": "Carbon  is a primary component of all known  life  on  Earth , and represents approximately 45\u201350% of all dry  biomass . [ 1 ]  Carbon compounds occur naturally in great abundance on Earth. Complex biological  molecules  consist of carbon atoms  bonded  with other  elements , especially  oxygen  and  hydrogen  and frequently also  nitrogen ,  phosphorus , and  sulfur  (collectively known as  CHNOPS ). [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11202", "text": "Because it is lightweight and relatively small in size, carbon molecules are easy for  enzymes  to manipulate.  Carbonic anhydrase  is part of this process. Carbon has an  atomic number  of 6 on the  periodic table .  The  carbon cycle  is a  biogeochemical cycle  that is important in maintaining life on Earth over a long time span. The cycle includes  carbon sequestration  and  carbon sinks . [ 4 ] [ 5 ]   Plate tectonics  are needed for life over a long time span, and carbon-based life is important in the plate tectonics process. [ 6 ]  Iron- and sulfur-based  Anoxygenic photosynthesis  life forms that lived from 3.80 to 3.85 billion years ago on Earth produced an abundance of  black shale  deposits. These shale deposits increase heat flow and crust buoyancy, especially on the sea floor, helping to increase plate tectonics.  Talc  is another organic mineral that helps drive plate tectonics. [ 7 ] [ 8 ]   Inorganic processes  also help drive plate tectonics. [ 9 ]  Carbon-based  photosynthesis  life caused a rise in  oxygen  on  Earth. This increase of oxygen helped plate tectonics form the first continents. [ 10 ]  It is frequently assumed in  astrobiology  that if life exists elsewhere in the  Universe , it will also be carbon-based. [ 11 ] [ 12 ]  Critics, like  Carl Sagan  in 1973, refer to this assumption as  carbon chauvinism . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11203", "text": "Carbon is capable of forming a vast number of  compounds , more than any other element, with almost ten million compounds described to date, [ 14 ]  and yet that is but a fraction of the number of compounds that are theoretically possible under standard conditions. The enormous diversity of carbon compounds, known as  organic compounds , has led to a distinction between them and the  inorganic compounds  that do not contain carbon. The branch of chemistry that studies organic compounds is known as  organic chemistry . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11204", "text": "Carbon is the 15th  most abundant element in the Earth's crust , and the  fourth most abundant element in the universe  by mass, after  hydrogen ,  helium , and  oxygen . Carbon's widespread abundance, its ability to form stable bonds with numerous other elements, and its unusual ability to form  polymers  at the temperatures commonly encountered on  Earth  enables it to serve as a common element of all known living organisms. In a 2018 study, carbon was found to compose approximately 550 billion tons of all life on Earth. [ 16 ] [ 17 ]  It is the second most abundant element in the  human body  by mass (about 18.5%) after oxygen. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11205", "text": "The most important characteristics of carbon as a basis for the  chemistry  of  cellular life  are that each carbon atom is capable of forming up to four  valence bonds  with other atoms simultaneously, and that the energy required to make or break a bond with a carbon atom is at an appropriate level for building large and complex molecules which may be both stable and reactive. [ 19 ]  Carbon atoms bond readily to other carbon atoms; this allows the building of arbitrarily long  macromolecules  and  polymers  in a process known as  catenation . [ 20 ] [ 21 ] [ 22 ]  \"What we normally think of as 'life' is based on chains of carbon atoms, with a few other atoms, such as nitrogen or phosphorus\", per  Stephen Hawking  in a 2008 lecture, \"carbon [...] has the richest chemistry.\" [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11206", "text": "Norman Horowitz  was the head of the  Jet Propulsion Laboratory 's bioscience section for the first U.S. mission,  Viking Lander of 1976 , to successfully land an unmanned probe on the surface of  Mars . He considered that the great versatility of the carbon atom makes it the element most likely to provide solutions, even exotic solutions, to the problems of survival on other planets. However, the  results of this mission  indicated that Mars was presently  extremely hostile  to carbon-based life. He also considered that, in general, there was only a remote possibility that non-carbon life forms would be able to evolve with genetic information systems capable of self-replication and adaptation. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11207", "text": "The most notable classes of biological  macromolecules  used in the fundamental processes of living organisms include: [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11208", "text": "Liquid water  is essential for carbon-based life. Chemical bonding of carbon molecules requires liquid water. [ 30 ]  Water has the  chemical property  to make compound-solvent pairing. [ 31 ]  Water provides the reversible  hydration  of  carbon dioxide . Hydration of carbon dioxide is needed in carbon-based life. All life on Earth uses the same  biochemistry  of carbon.  Water is important in life's  carbonic anhydrase  the interaction of between carbon dioxide and water. Carbonic anhydrase needs a family of carbon base enzymes for the hydration of carbon dioxide and  acid\u2013base homeostasis , that regulates  PH  levels in life.  [ 32 ] [ 33 ]  In  plant  life, liquid water  is needed for  photosynthesis , the  biological process  plants use to  convert   light energy  and carbon dioxide into  chemical energy . [ 34 ]  Water makes up 55% to 60% of the human body by weight. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11209", "text": "A few other elements have been proposed as candidates for supporting biological systems and processes as fundamentally as carbon does, for example, processes such as  metabolism . The most frequently suggested alternative is  silicon . [ 36 ]  Silicon, atomic number of 14, more than twice the size of carbon, shares a group in the  periodic table  with carbon, can also form four  valence bonds , and also bonds to itself readily, though generally in the form of  crystal lattices  rather than long chains. Despite these similarities, silicon is considerably more  electropositive  than carbon, and silicon compounds do not readily  recombine  into different permutations in a manner that would plausibly support lifelike processes. Silicon is abundant on Earth, but as it is more electropositive and in a water based environment it  forms Si\u2013O bonds rather than Si\u2013Si bonds. [ 37 ]   Boron  does not react with acids and does not form chains naturally. Thus boron is not a candidate for life. [ 38 ]   Arsenic  is  toxic  to life, and its possible candidacy has been rejected. [ 39 ] [ 40 ]  In the past (1960s-1970s) other candidates for life were plausible, but with time and more research, only carbon has the complexity and stability to make large molecules and polymers essential for life. [ 41 ] [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11210", "text": "Speculations about the chemical structure and properties of hypothetical non-carbon-based life have been a recurring theme in  science fiction . Silicon is often used as a substitute for carbon in fictional lifeforms because of its chemical similarities. In cinematic and literary science fiction, when man-made machines cross from non-living to living, this new form is often presented as an example of non-carbon-based life. Since the advent of the  microprocessor  in the late 1960s, such machines are often classed as \"silicon-based life\". Other examples of fictional \"silicon-based life\" can be seen in the 1967 episode \" The Devil in the Dark \" from  Star Trek: The Original Series , in which a living rock creature's biochemistry is based on silicon. [ 44 ]  In the 1994  The X-Files  episode \" Firewalker \", in which a silicon-based organism is discovered in a volcano. [ 45 ] [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11211", "text": "In the  1984 film adaptation  of  Arthur C. Clarke 's 1982 novel  2010: Odyssey Two , a character argues, \"Whether we are based on carbon or on silicon makes no fundamental difference; we should each be treated with appropriate respect.\" [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11212", "text": "In  JoJolion , the eighth part of the larger  JoJo's Bizarre Adventure  series, a mysterious race of silicon-based lifeforms \"Rock Humans\" serve as the primary antagonists. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11213", "text": "CHNOPS  and  CHON  are  mnemonic   acronyms  for the most common  elements  in living organisms. \"CHON\" stands for  c arbon ,  h ydrogen ,  o xygen , and  n itrogen , which together make up more than 95 percent of the mass of biological systems. [ 1 ]  \"CHNOPS\" adds  p hosphorus  and  s ulfur ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11214", "text": "Carbon, hydrogen, nitrogen, oxygen, phosphorus, and sulfur are the six most important  chemical elements  whose  covalent  combinations make up most  biological   molecules  on Earth. [ 2 ]  All of these elements are  nonmetals ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11215", "text": "In animals in general, the four elements\u2014C, H, N, and O\u2014compose about 96% of the weight, and major  minerals  (macrominerals) and minor minerals (also called  trace elements ) compose the remainder. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11216", "text": "Sulfur is contained in the  amino acids   cysteine  and  methionine . [ 3 ] \nPhosphorus is contained in  phospholipids , a class of  lipids  that are a major component of all  cell membranes , as they can form  lipid bilayers , which keep  ions ,  proteins , and other molecules where they are needed for  cell  function, and prevent them from diffusing into areas where they should not be. Phosphate groups are also an essential component of the backbone of  nucleic acids  (general name for  DNA  &  RNA ) and are required to form  ATP \u00a0\u2013 the main molecule used as energy powering the cell in all living creatures. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11217", "text": "Carbonaceous asteroids  are rich in CHON elements. [ 5 ] \nThese asteroids are the most common type and frequently collide with Earth as  meteorites . Such collisions were especially common early in  Earth's history , and these impactors may have been crucial in the formation of the planet's oceans. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11218", "text": "The simplest compounds to contain all of the CHON elements are isomers  fulminic acid  (HCNO),  isofulminic acid  (HONC),  cyanic acid  (HOCN) and  isocyanic acid  (HNCO), having one of each atom. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11219", "text": "Cobalt  is essential to the metabolism of all  animals . It is a key constituent of  cobalamin , also known as vitamin B 12 , the primary biological reservoir of cobalt as an  ultratrace element . [ 1 ] [ 2 ]   Bacteria  in the stomachs of  ruminant  animals convert cobalt salts into vitamin B 12 , a compound which can only be produced by bacteria or  archaea . A minimal presence of cobalt in soils therefore markedly improves the health of  grazing  animals, and an uptake of 0.20\u00a0mg/kg a day is recommended because they have no other source of vitamin B 12 . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11220", "text": "Proteins based on cobalamin use  corrin  to hold the cobalt. Coenzyme B 12  features a reactive C-Co bond that participates in the reactions. [ 4 ]  In humans, B 12  has two types of  alkyl   ligand :  methyl  and adenosyl.  MeB 12  promotes methyl (\u2212CH 3 ) group transfers. The adenosyl version of B 12  catalyzes rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcohol, or an amine.  Methylmalonyl coenzyme A mutase  (MUT) converts  MMl-CoA  to  Su-CoA , an important step in the extraction of energy from proteins and fats. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11221", "text": "Although far less common than other  metalloproteins  (e.g. those of zinc and iron), other cobaltoproteins are known besides B 12 . These proteins include  methionine aminopeptidase 2 , an enzyme that occurs in humans and other mammals that does not use the corrin ring of B 12 , but binds cobalt directly. Another non-corrin cobalt enzyme is  nitrile hydratase , an enzyme in bacteria that metabolizes  nitriles . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11222", "text": "In humans, consumption of cobalt-containing vitamin B 12  meets all needs for cobalt. For cattle and sheep, which meet vitamin B 12  needs via synthesis by resident bacteria in the rumen, there is a function for inorganic cobalt. In the early 20th century, during the development of farming on the  North Island Volcanic Plateau  of New Zealand, cattle suffered from what was termed \"bush sickness\". It was discovered that the volcanic soils lacked the cobalt salts essential for the cattle food chain. [ 7 ] [ 8 ]  The \"coast disease\" of sheep in the  Ninety Mile Desert  of the  Southeast  of  South Australia  in the 1930s was found to originate in nutritional deficiencies of trace elements cobalt and copper. The cobalt deficiency was overcome by the development of \"cobalt bullets\", dense pellets of cobalt oxide mixed with clay given orally for lodging in the animal's  rumen . [ clarification needed ] [ 9 ] [ 8 ] [ 10 ]"}
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{"_id": "WikiPedia_Pharmacology$$$corpus_11225", "text": "Fluoride  ( / \u02c8 f l \u028a\u0259r a\u026a d ,   \u02c8 f l \u0254\u02d0r -/ ) [ 3 ]  is an  inorganic ,  monatomic   anion  of  fluorine , with the  chemical formula   F \u2212  (also written  [F] \u2212 ), whose salts are typically white or colorless. Fluoride salts typically have distinctive bitter tastes, and are odorless. Its salts and minerals are important  chemical reagents  and industrial chemicals, mainly used in the production of  hydrogen fluoride  for  fluorocarbons . Fluoride is classified as a weak base since it only partially associates in solution, but concentrated fluoride is corrosive and can attack the skin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11226", "text": "Fluoride is the simplest fluorine  anion . In terms of charge and size, the fluoride  ion  resembles the  hydroxide  ion. Fluoride ions occur on  Earth  in several minerals, particularly  fluorite , but are present only in trace quantities in bodies of water in nature."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11227", "text": "Fluorides include compounds that contain ionic fluoride and those in which fluoride does not dissociate. The nomenclature does not distinguish these situations. For example,  sulfur hexafluoride  and  carbon tetrafluoride  are not sources of fluoride ions under ordinary conditions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11228", "text": "The systematic name  fluoride , the valid  IUPAC  name, is determined according to the additive nomenclature. However, the name  fluoride  is also used in compositional IUPAC nomenclature which does not take the nature of bonding involved into account.\n Fluoride  is also used non-systematically, to describe compounds which release fluoride upon dissolving. Hydrogen fluoride is itself an example of a non-systematic name of this nature. However, it is also a  trivial name , and the  preferred IUPAC name  for  fluorane . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11229", "text": "Fluorine  is estimated to be the 13th-most  abundant element  in Earth's crust and is widely dispersed in nature, entirely in the form of fluorides. The vast majority is held in  mineral deposits , the most commercially important of which is  fluorite  (CaF 2 ). [ 4 ]  Natural weathering of some kinds of rocks, [ 5 ] [ 6 ]  as well as human activities, releases fluorides into the  biosphere  through what is sometimes called the  fluorine cycle ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11230", "text": "Fluoride is naturally present in groundwater,  fresh  and  saltwater  sources, as well as in rainwater, particularly in urban areas. [ 7 ]  Seawater fluoride levels are usually in the range of 0.86 to 1.4\u00a0mg/L, and average 1.1\u00a0mg/L [ 8 ]  (milligrams per  litre ). For comparison,  chloride  concentration in seawater is about 19\u00a0g/L. The low concentration of fluoride reflects the insolubility of the  alkaline earth  fluorides, e.g., CaF 2 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11231", "text": "Concentrations in fresh water vary more significantly.  Surface water  such as rivers or lakes generally contains between 0.01 and 0.3\u00a0mg/L. [ 9 ]   Groundwater  (well water) concentrations vary even more, depending on the presence of local fluoride-containing minerals. For example, natural levels of under 0.05\u00a0mg/L have been detected in parts of Canada but up to 8\u00a0mg/L in parts of China; in general levels rarely exceed 10\u00a0mg/litre [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11232", "text": "Fluoride can be present in rain, with its concentration increasing significantly upon exposure to volcanic activity [ 14 ]  or atmospheric pollution derived from burning fossil fuels or other sorts of industry, [ 15 ] [ 16 ]  particularly  aluminium smelters . [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11233", "text": "All vegetation contains some fluoride, which is absorbed from soil and water. [ 10 ]  Some plants concentrate fluoride from their environment more than others. All tea leaves contain fluoride; however, mature leaves contain as much as 10 to 20 times the fluoride levels of young leaves from the same plant. [ 18 ] [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11234", "text": "Fluoride can act as a  base . It can combine with a  proton  ( \u200a H + ):"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11235", "text": "This neutralization reaction forms  hydrogen fluoride  (HF), the  conjugate acid  of fluoride."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11236", "text": "In aqueous solution, fluoride has a  p K b  value of 10.8. It is therefore a  weak base , and tends to remain as the fluoride ion rather than generating a substantial amount of hydrogen fluoride. That is, the following equilibrium favours the left-hand side in water:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11237", "text": "However, upon prolonged contact with moisture, soluble fluoride salts will decompose to their respective hydroxides or oxides, as the hydrogen fluoride escapes. Fluoride is distinct in this regard among the halides. The identity of the solvent can have a dramatic effect on the equilibrium shifting it to the right-hand side, greatly increasing the rate of decomposition."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11238", "text": "Salts containing fluoride are numerous and adopt myriad structures. Typically the fluoride anion is surrounded by four or six cations, as is typical for other halides.  Sodium fluoride  and  sodium chloride  adopt the same structure. For compounds containing more than one fluoride per cation, the structures often deviate from those of the chlorides, as illustrated by the main fluoride mineral  fluorite  (CaF 2 ) where the Ca 2+  ions are surrounded by eight F \u2212  centers. In CaCl 2 , each Ca 2+  ion is surrounded by six Cl \u2212  centers. The difluorides of the transition metals often adopt the  rutile  structure whereas the dichlorides have  cadmium chloride  structures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11239", "text": "Upon treatment with a standard acid, fluoride salts convert to  hydrogen fluoride  and metal  salts . With strong acids, it can be doubly protonated to give  H 2 F + . Oxidation of fluoride gives fluorine. Solutions of inorganic fluorides in water contain F \u2212  and  bifluoride   HF \u2212 2 . [ 21 ]  Few inorganic fluorides are soluble in water without undergoing significant hydrolysis. In terms of its reactivity, fluoride differs significantly from  chloride  and other halides, and is more strongly solvated in  protic solvents  due to its smaller radius/charge ratio. Its closest chemical relative is  hydroxide , since both have similar geometries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11240", "text": "Most fluoride salts dissolve to give the bifluoride ( HF \u2212 2 ) anion. Sources of true F \u2212  anions are rare because the highly basic fluoride anion abstracts protons from many, even adventitious, sources. Relative  unsolvated  fluoride, which does exist in aprotic solvents, is called \"naked\".  Naked fluoride  is a strong  Lewis base , [ 22 ]  and a powerful nucleophile. Some quaternary ammonium salts of naked fluoride include  tetramethylammonium fluoride   and  tetrabutylammonium fluoride . [ 23 ]   Cobaltocenium  fluoride is another example. [ 24 ]  However, they all lack structural characterization in aprotic solvents. Because of their high basicity, many so-called naked fluoride sources are in fact bifluoride salts. In late 2016  imidazolium  fluoride was synthesized that is the closest approximation of a thermodynamically stable and structurally characterized example of a \"naked\" fluoride source in an aprotic solvent (acetonitrile). [ 25 ]  The sterically demanding imidazolium cation stabilizes the discrete anions and protects them from polymerization. [ 26 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11241", "text": "At physiological pHs,  hydrogen fluoride  is usually fully ionised to fluoride. In  biochemistry , fluoride and hydrogen fluoride are equivalent. Fluorine, in the form of fluoride, is considered to be a  micronutrient  for human health, necessary to prevent dental cavities, and to promote healthy bone growth. [ 28 ]  The tea plant ( Camellia sinensis  L.) is a known accumulator of fluorine compounds, released upon forming infusions such as the common beverage. The fluorine compounds decompose into products including fluoride ions. Fluoride is the most bioavailable form of fluorine, and as such, tea is potentially a vehicle for fluoride dosing. [ 29 ]  Approximately, 50% of absorbed fluoride is excreted renally with a twenty-four-hour period. The remainder can be retained in the oral cavity, and lower digestive tract. Fasting dramatically increases the rate of fluoride absorption to near 100%, from a 60% to 80% when taken with food. [ 29 ]  Per a 2013 study, it was found that consumption of one litre of tea a day, can potentially supply the daily recommended intake of 4\u00a0mg per day. Some lower quality brands can supply up to a 120% of this amount. Fasting can increase this to 150%. The study indicates that tea drinking communities are at an increased risk of  dental  and  skeletal fluorosis , in the case where water fluoridation is in effect. [ 29 ]  Fluoride ion in low doses in the mouth reduces tooth decay. [ 30 ]  For this reason, it is used in toothpaste and water fluoridation. At much higher doses and frequent exposure, fluoride causes health complications and can be toxic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11242", "text": "Fluoride salts and hydrofluoric acid are the main fluorides of industrial value."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11243", "text": "Organofluorine compounds are pervasive. Many drugs, many polymers, refrigerants, and many inorganic compounds are made from fluoride-containing reagents. Often fluorides are converted to hydrogen fluoride, which is a major reagent and precursor to reagents. Hydrofluoric acid and its anhydrous form,  hydrogen fluoride , are particularly important. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11244", "text": "The main uses of fluoride, in terms of volume, are in the production of cryolite, Na 3 AlF 6 . It is used in  aluminium smelting . Formerly, it was mined, but now it is derived from hydrogen fluoride. Fluorite is used on a large scale to separate slag in steel-making. Mined  fluorite  (CaF 2 ) is a commodity chemical used in steel-making.   Uranium hexafluoride  is employed in the purification of uranium isotopes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11245", "text": "Fluoride-containing compounds, such as  sodium fluoride  or  sodium monofluorophosphate  are used in topical and systemic  fluoride therapy  for preventing  tooth decay . They are used for  water fluoridation  and in many products associated with  oral hygiene . [ 31 ]  Originally, sodium fluoride was used to fluoridate water;  hexafluorosilicic acid  (H 2 SiF 6 ) and its salt  sodium hexafluorosilicate  (Na 2 SiF 6 ) are more commonly used additives, especially in the United States. The fluoridation of water is known to prevent tooth decay [ 32 ] [ 33 ]  and is considered by the U.S.  Centers for Disease Control and Prevention  to be \"one of 10 great public health achievements of the 20th century\". [ 34 ] [ 35 ]  In some countries where large, centralized water systems are uncommon, fluoride is delivered to the populace by fluoridating table salt. For the method of action for cavity prevention, see  Fluoride therapy . Fluoridation of water has its critics  (see  Water fluoridation controversy ) . [ 36 ]  Fluoridated  toothpaste  is in common use.  Meta-analysis  show the efficacy of 500 ppm fluoride in toothpastes. [ 37 ] [ 38 ]  However, no beneficial effect can be detected when more than one fluoride source is used for daily oral care. [ 39 ] [ need quotation to verify ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11246", "text": "Fluoride salts are commonly used in biological assay processing to  inhibit  the activity of  phosphatases , such as  serine / threonine  phosphatases. [ 40 ]  Fluoride mimics the  nucleophilic   hydroxide  ion in these enzymes' active sites. [ 41 ]   Beryllium fluoride  and  aluminium fluoride  are also used as phosphatase inhibitors, since these compounds are structural mimics of the  phosphate  group and can act as analogues of the  transition state  of the reaction. [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11247", "text": "The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for some minerals in 1997. Where there was not sufficient information to establish EARs and RDAs, an estimate designated Adequate Intake (AI) was used instead. AIs are typically matched to actual average consumption, with the assumption that there appears to be a need, and that need is met by what people consume. The current AI for women 19 years and older is 3.0\u00a0mg/day (includes pregnancy and lactation). The AI for men is 4.0\u00a0mg/day. The AI for children ages 1\u201318 increases from 0.7 to 3.0\u00a0mg/day. The major known risk of  fluoride deficiency  appears to be an increased risk of bacteria-caused tooth cavities. As for safety, the IOM sets tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of fluoride the UL is 10\u00a0mg/day. Collectively the EARs, RDAs, AIs and ULs are referred to as  Dietary Reference Intakes  (DRIs). [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11248", "text": "The  European Food Safety Authority  (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For women ages 18 and older the AI is set at 2.9\u00a0mg/day (including pregnancy and lactation). For men, the value is 3.4\u00a0mg/day. For children ages 1\u201317 years, the AIs increase with age from 0.6 to 3.2\u00a0mg/day. These AIs are comparable to the U.S. AIs. [ 45 ]  The EFSA reviewed safety evidence and set an adult UL at 7.0\u00a0mg/day (lower for children). [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11249", "text": "For U.S. food and dietary supplement labeling purposes, the amount of a vitamin or mineral in a serving is expressed as a percent of Daily Value (%DV). Although there is information to set Adequate Intake, fluoride does not have a Daily Value and is not required to be shown on food labels. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11250", "text": "Daily intakes of fluoride can vary significantly according to the various sources of exposure. Values ranging from 0.46 to 3.6\u20135.4\u00a0mg/day have been reported in several studies (IPCS, 1984). [ 28 ]  In areas where water is  fluoridated  this can be expected to be a significant source of fluoride, however fluoride is also naturally present in virtually all foods and beverages at a wide range of concentrations. [ 48 ]  The maximum safe daily consumption of fluoride is 10\u00a0mg/day for an adult (U.S.) or 7\u00a0mg/day (European Union). [ 44 ] [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11251", "text": "The upper limit of fluoride intake from all sources (fluoridated water, food, beverages, fluoride dental products and dietary fluoride supplements) is set at 0.10\u00a0mg/kg/day for infants, toddlers, and children through to 8 years old. For older children and adults, who are no longer at risk for dental fluorosis, the upper limit of fluoride is set at 10\u00a0mg/day regardless of weight. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11252", "text": "According to the U.S. Department of Agriculture, the Dietary Reference Intakes, which is the \"highest level of daily nutrient intake that is likely to pose no risk of adverse health effects\" specify 10\u00a0mg/day for most people, corresponding to 10 L of fluoridated water with no risk. For young children the values are smaller, ranging from 0.7\u00a0mg/d to 2.2\u00a0mg/d for infants. [ 51 ]  Water and food sources of fluoride include community water fluoridation, seafood, tea, and gelatin. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11253", "text": "Soluble fluoride salts, of which  sodium fluoride  is the most common, are toxic, and have resulted in both accidental and self-inflicted deaths from  acute poisoning . [ 4 ]  The lethal dose for most adult humans is estimated at 5 to 10\u00a0g (which is equivalent to 32 to 64\u00a0mg elemental fluoride per kg body weight). [ 53 ] [ 54 ] [ 55 ]  A case of a fatal poisoning of an adult with 4\u00a0grams of sodium fluoride is documented, [ 56 ]  and a dose of 120\u00a0g sodium fluoride has been survived. [ 57 ]  For  sodium fluorosilicate  (Na 2 SiF 6 ), the  median lethal dose  (LD 50 ) orally in rats is 125\u00a0mg/kg, corresponding to 12.5\u00a0g for a 100\u00a0kg adult. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11254", "text": "Treatment may involve oral administration of dilute  calcium hydroxide  or  calcium chloride  to prevent further absorption, and injection of  calcium gluconate  to increase the calcium levels in the blood. [ 56 ]   Hydrogen fluoride  is more dangerous than salts such as NaF because it is corrosive and volatile, and can result in fatal exposure through inhalation or upon contact with the skin; calcium gluconate gel is the usual antidote. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11255", "text": "In the higher doses used to treat  osteoporosis , sodium fluoride can cause pain in the legs and incomplete stress fractures when the doses are too high; it also irritates the stomach, sometimes so severely as to cause ulcers. Slow-release and  enteric -coated versions of sodium fluoride do not have gastric side effects in any significant way, and have milder and less frequent complications in the bones. [ 60 ]  In the lower doses used for  water fluoridation , the only clear adverse effect is  dental fluorosis , which can alter the appearance of children's teeth during  tooth development ; this is mostly mild and is unlikely to represent any real effect on aesthetic appearance or on public health. [ 61 ]  Fluoride was known to enhance bone mineral density at the lumbar spine, but it was not effective for vertebral fractures and provoked more nonvertebral fractures. [ 62 ]  In areas that have naturally occurring high levels of fluoride in  groundwater  which is used for  drinking water , both  dental  and  skeletal fluorosis  can be prevalent and severe. [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11256", "text": "Around one-third of the human population drinks water from groundwater resources. Of this, about 10%, approximately 300 million people, obtain water from groundwater resources that are heavily contaminated with arsenic or fluoride. [ 64 ]   These trace elements derive mainly from minerals. [ 65 ]  Maps locating potential problematic wells are available. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11257", "text": "Concentrated fluoride solutions are corrosive. [ 67 ]  Gloves made of  nitrile rubber  are worn when handling fluoride compounds. The hazards of solutions of fluoride salts depend on the concentration. In the presence of  strong acids , fluoride salts release  hydrogen fluoride , which is corrosive, especially toward glass. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11258", "text": "Organic and inorganic anions are produced from fluoride, including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11259", "text": "GFAJ-1  is a  strain  of  rod-shaped   bacteria  in the family  Halomonadaceae . It is an  extremophile  that was isolated from the  hypersaline  and  alkaline   Mono Lake  in eastern  California  by geobiologist  Felisa Wolfe-Simon , a NASA  research fellow  in residence at the  US Geological Survey . In a 2010  Science  journal publication, [ 1 ]  the authors claimed that the microbe, when starved of  phosphorus , is capable of substituting  arsenic  for a small percentage of its phosphorus to sustain its growth. [ 2 ] [ 3 ]  Immediately after publication, other microbiologists and biochemists expressed doubt about this claim, which was robustly criticized in the scientific community. Subsequent independent studies published in 2012 found no detectable arsenate in the DNA of GFAJ-1, refuted the claim, and demonstrated that GFAJ-1 is simply an arsenate-resistant, phosphate-dependent organism. [ 4 ] [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11260", "text": "The GFAJ-1 bacterium was discovered by  geomicrobiologist   Felisa Wolfe-Simon , a  NASA   astrobiology  fellow in residence at the  US Geological Survey  in  Menlo Park, California . [ 8 ]  GFAJ stands for \"Give Felisa a Job\". [ 9 ]  The organism was isolated and  cultured  beginning in 2009 from samples she and her colleagues collected from sediments at the bottom of  Mono Lake , California, U.S.A. [ 10 ]  Mono Lake is  hypersaline  (about 90\u00a0grams/liter) and highly  alkaline  ( pH  9.8). [ 11 ]  It also has one of the highest natural concentrations of  arsenic  in the world (200\u00a0\u03bc M ). [ 1 ]  The discovery was widely publicized on 2 December 2010. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11261", "text": "Escherichia coli  strain  O157:H7"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11262", "text": "Halomonas alkaliphila"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11263", "text": "Halomonas venusta  strain NBSL13"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11264", "text": "GFAJ-1"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11265", "text": "Halomonas  sp. GTW"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11266", "text": "Halomonas  sp. G27"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11267", "text": "Halomonas  sp. DH77"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11268", "text": "Halomonas  sp. mp3"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11269", "text": "Halomonas  sp. IB-O18"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11270", "text": "Halomonas  sp. ML-185"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11271", "text": "Molecular  analysis based on  16S rRNA  sequences shows GFAJ-1 to be closely related to other moderate  halophile  (\"salt-loving\") bacteria of the family  Halomonadaceae . Although the authors produced a  cladogram  in which the strain is nested among members of  Halomonas , including  H.\u00a0alkaliphila  and  H.\u00a0venusta , [ 12 ]  they did not explicitly assign the strain to that genus. [ 1 ] [ 10 ]  Many bacteria are known to be able to tolerate high levels of arsenic, and to have a proclivity to take it up into their cells. [ 1 ] [ 13 ]  However, GFAJ-1 was controversially proposed to go a step further; when starved of phosphorus, it was proposed to instead incorporate arsenic into its metabolites and macromolecules and continue growing. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11272", "text": "The sequence of the genome of the bacterium GFAJ-1 is now posted in  GenBank . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11273", "text": "In the  Science  journal article, GFAJ-1 is referred to as a  strain  of Halomonadaceae and not as a new  species . [ 1 ]  The  International Code of Nomenclature of Bacteria , the set of regulations which govern the  taxonomy  of bacteria, and certain articles in the  International Journal of Systematic and Evolutionary Microbiology  contain the guidelines and minimal standards to describe a new species, e.g. the minimal standards to describe a member of the  Halomonadaceae . [ 15 ]  Organisms are described as new species if they meet certain physiological and genetic conditions, such as generally less than 97%  16S rRNA  sequence identity to other known species [ 16 ]  and metabolic differences allowing them to be discerned apart. In addition to indicators to tell the novel species from other species, other analyses are required, such as  fatty acid composition , respiratory quinone used and tolerance ranges and deposition of the strain in at least two microbiological repositories. New proposed names are given in italics followed by  sp. nov.  (and  gen. nov.  if it is a novel genus according to the descriptions of that  clade ). [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11274", "text": "In the instance of the GFAJ-1 strain these criteria are not met, and the strain is not claimed to be a new species. [ 1 ]  When a strain is not assigned to a species (e.g. due to insufficient data or choice) it is often labeled as the genus name followed by \"sp.\" (i.e., undetermined species of that genus) and the strain name. In the case of GFAJ-1 the authors chose to refer to the strain by strain designation only. Strains closely related to GFAJ-1 include  Halomonas  sp. GTW and  Halomonas  sp. G27, neither of which were described as valid species. [ 19 ] [ 20 ]  If the authors had formally assigned strain GFAJ-1 to the genus  Halomonas , [ 10 ]  the name would be given as  Halomonas  sp. GFAJ-1."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11275", "text": "Until release R220, the  Genome Taxonomy Database  assigned GFAJ-1 its own tentative species,  Halomonas sp002966495 . This means that the strain falls into  Halomonas  phylogenetically, and its whole-genome similarity compared to other defined species of the genus is low enough. Neither strain GTW nor strain G27 has a genome available for the database to run its classification. In release R220, the databased moved the strain to  Vreelandella , a new genus published in 2023 (and validated in 2024). [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11276", "text": "A phosphorus-free  growth medium  (which actually contained 3.1 \u00b1 0.3\u00a0\u03bcM of residual phosphate, from impurities in reagents) was used to culture the bacteria in a regime of increasing exposure to  arsenate ; the initial level of 0.1\u00a0mM was eventually ramped up to 40\u00a0mM. Alternative media used for comparative experiments contained either high levels of  phosphate  (1.5\u00a0mM) with no arsenate, or had neither added phosphate nor added arsenate.  It was observed that GFAJ-1 could grow through many doublings in cell numbers when cultured in either phosphate or arsenate media, but could not grow when placed in a medium of a similar composition to which neither phosphate nor arsenate was added. [ 1 ]  The phosphorus content of the arsenic-fed, phosphorus-starved bacteria (as measured by  ICP-MS)  was only 0.019 (\u00b1 0.001)\u00a0% by dry weight, one thirtieth of that when grown in phosphate-rich medium. This phosphorus content was also only about one tenth of the cells' average arsenic content (0.19 \u00b1 0.25% by dry weight). [ 1 ]  The arsenic content of cells as measured by ICP-MS varies widely and can be lower than the phosphorus contents in some experiments, and up to fourteen times higher in others. [ 22 ]  Other data from the same study obtained with nano- SIMS  suggest a ~75-fold excess of phosphate (P) over arsenic (As) when expressed as P:C and As:C ratios, even in cells grown with arsenate and no added phosphate. [ 12 ]  When cultured in the arsenate solution, GFAJ-1 only grew 60% as fast as it did in phosphate solution. [ 2 ]  The phosphate-starved bacteria had an intracellular volume 1.5\u00a0times normal; the greater volume appeared to be associated with the appearance of large \" vacuole -like regions\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11277", "text": "When the researcher, Joseph Tolle added  isotope-labeled  arsenate to the solution to  track its distribution , they found that arsenic was present in the cellular fractions containing the bacteria's  proteins ,  lipids  and metabolites such as  ATP , as well as its  DNA  and  RNA . [ 2 ]  Nucleic acids from  stationary phase  cells starved of phosphorus were concentrated via five  extractions  (one with  phenol , three with  phenol-chloroform  and one with  chloroform  extraction solvent), followed by  ethanol precipitation . Although direct evidence of the incorporation of arsenic into biomolecules is still lacking,  radioactivity  measurements suggested that approximately one-tenth (11.0 \u00b1 0.1%) of the arsenic absorbed by these bacteria ended up in the fraction that contained the  nucleic acids  (DNA and RNA) and all other co-precipitated compounds not extracted by the previous treatments. [ 1 ]  A comparable control experiment with isotope-labeled phosphate was not performed.\nWith the distribution of the strain in mid-2011, other labs began to independently test the validity of the discovery.  Rosemary Redfield  from the  University of British Columbia , following issues with the growth conditions, investigated the growth requirements of GFAJ-1, and found that the strain grows better on solid  agar  medium than in liquid culture. Redfield attributed this to low potassium levels and hypothesized that the potassium levels in basal ML60 medium may be too low to support growth. [ 23 ]  Redfield after finding and addressing further issues (ionic strength, pH and the use of glass tubes instead of polypropylene) found that arsenate marginally stimulated growth, but didn't affect the final densities of the cultures, unlike what was claimed. [ 24 ]  Subsequent studies using mass spectrometry by the same group found no evidence of arsenate being incorporated into the DNA of GFAJ-1. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11278", "text": "Arsenate  esters , such as those that would be  present in DNA , are generally expected to be  orders of magnitude  less stable to  hydrolysis  than corresponding  phosphate esters . [ 26 ]  dAMAs, the structural arsenic analog of the DNA building block  dAMP , has a  half-life  of 40 minutes in water at neutral pH. [ 27 ]  Estimates of the half-life in water of arsenodiester bonds, which would link the nucleotides together, are as short as 0.06 seconds\u2014compared to 30 million years for the  phosphodiester bonds  in DNA. [ 28 ]  The authors speculate that the bacteria may stabilize arsenate esters to a degree by using  poly-\u03b2-hydroxybutyrate  (which has been found to be elevated in \"vacuole-like regions\" of related species of the genus  Halomonas [ 29 ] \n) or other means to lower the  effective concentration  of water. [ 1 ] [ 10 ]  Polyhydroxybutyrates are used by many bacteria for energy and carbon storage under conditions when growth is limited by elements other than carbon, and typically appear as large waxy granules closely resembling the \"vacuole-like regions\" seen in GFAJ-1 cells. [ 30 ]  The authors present no mechanism by which insoluble polyhydroxybutyrate may lower the effective concentration of water in the cytoplasm sufficiently to stabilize arsenate esters. Although all halophiles must reduce the  water activity  of their cytoplasm by some means to avoid desiccation, [ 31 ]  the cytoplasm always remains an aqueous environment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11279", "text": "NASA's announcement of a news conference \"that will impact the search for evidence of extraterrestrial life\" was criticized as sensationalistic and misleading; an editorial in  New Scientist  commented \"although the discovery of alien life, if it ever happens, would be one of the biggest stories imaginable, this was light-years from that\". [ 32 ] [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11280", "text": "In addition, many experts who have evaluated the paper have concluded that the reported studies do not provide enough evidence to support the claims made by the authors. [ 34 ]  In an online article on  Slate , science writer  Carl Zimmer  discussed the skepticism of several scientists: \"I reached out to a dozen experts ... Almost unanimously, they think the NASA scientists have failed to make their case\". [ 35 ] [ 36 ]  Chemist  Steven A. Benner  has expressed doubts that  arsenate  has replaced phosphate in the DNA of this organism. He suggested that the  trace contaminants  in the growth medium used by Wolfe-Simon in her laboratory cultures are sufficient to supply the phosphorus needed for the cells' DNA. He believes that it is more likely that arsenic is being sequestered elsewhere in the cells. [ 2 ] [ 10 ]   University of British Columbia   microbiologist  Rosemary Redfield said that the paper \"doesn't present any convincing evidence that arsenic has been incorporated into DNA or any other biological molecule\", and suggests that the experiments lacked the washing steps and  controls  necessary to properly validate their conclusions. [ 37 ] [ 38 ]  Harvard microbiologist Alex Bradley said that arsenic-containing DNA would be so unstable in water it could not have survived the analysis procedure. [ 35 ] [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11281", "text": "On 8 December 2010,  Science  published a response by Wolfe-Simon, in which she stated that criticism of the research was expected. In response, a \" Frequently Asked Questions \" page to improve understanding of the work was posted on 16 December 2010. [ 40 ]  The team plans to deposit the GFAJ-1 strain in the  ATCC  and  DSMZ  culture collections to allow widespread distribution. [ 41 ]  In late May 2011 the strain was made available upon request directly from the laboratory of the authors. [ 42 ]   Science  has made the article freely available. [ 43 ]  The article was published in print six months after acceptance in the 3 June 2011 issue of  Science .  The publication was accompanied by eight technical comments addressing various concerns regarding the article's experimental procedure and conclusion, [ 44 ] [ 45 ] [ 46 ] [ 47 ] [ 48 ] [ 49 ] [ 50 ] [ 51 ] [ 52 ]  as well as a response by the authors to these concerns. [ 42 ] [ 53 ]  The editor in chief  Bruce Alberts  has indicated that some issues remain and that their resolution is likely to be a long process. [ 54 ]  A review by Rosen  et al. , [ 55 ]  in the March 2011 issue of the journal  BioEssays  discusses the technical issues with the  Science  paper, provides alternative explanations, and highlights known biochemistry of other arsenic resistant and arsenic utilizing microbes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11282", "text": "On 27 May 2011, Wolfe-Simon and her team responded to the criticism in a follow-up  Science  journal publication. [ 42 ]  Then in January 2012 a group of researchers led by Rosie Redfield at the  University of British Columbia  analyzed the DNA of GFAJ-1 using  liquid chromatography\u2013mass spectrometry  and could not detect any arsenic, which Redfield calls a \"clear refutation\" of the original paper's findings. [ 56 ]  Following the publication of the analysis, Wolfe-Simon stated that she and her colleagues \"expect to publish new information in the next few months\", [ 57 ]  but as of 2024 has not submitted any new publications since 2011."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11283", "text": "A simple explanation for the GFAJ-1 growth in medium supplied with arsenate instead of phosphate was provided by a team of researchers at the  University of Miami  in Florida.  After labeling the  ribosomes  of a laboratory strain of  Escherichia coli  with radioactive isotopes (forming a  radioactive tracer ), they followed bacterial growth in medium containing arsenate but no phosphate.  They found that arsenate induces massive  degradation  of ribosomes, thus providing sufficient phosphate for the slow growth of arsenate tolerant bacteria.  Similarly, they suggest, GFAJ-1 cells grow by recycling phosphate from degraded ribosomes, rather than by replacing it with arsenate. [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11284", "text": "Following the publication of the articles challenging the conclusions of the original  Science  article first describing GFAJ-1, the website  Retraction Watch  argued that the original article should be retracted because of misrepresentation of critical data. [ 59 ] [ 60 ]  As of January\u00a02024 [update] , the paper had not been retracted. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11285", "text": "Human iron metabolism  is the set of chemical reactions that maintain  human homeostasis  of  iron  at the systemic and cellular level.  Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease.  Hematologists  have been especially interested in systemic iron  metabolism , because iron is essential for  red blood cells , where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of  iron overload , such as  hereditary hemochromatosis , and  iron deficiency , such as  iron-deficiency anemia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11286", "text": "Iron is an essential bioelement for most forms of life, from  bacteria  to  mammals . Its importance lies in its ability to mediate electron transfer. In the ferrous state (Fe 2+ ), iron acts as an  electron donor , while in the ferric state (Fe 3+ ) it acts as an  acceptor . Thus, iron plays a vital role in the  catalysis  of enzymatic reactions that involve electron transfer (reduction and oxidation,  redox ). Proteins can contain iron as part of different  cofactors , such as  iron\u2013sulfur clusters  (Fe-S) and  heme  groups, both of which are assembled in  mitochondria ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11287", "text": "Human cells require iron in order to obtain energy as  ATP  from a multi-step process known as cellular respiration, more specifically from  oxidative phosphorylation  at the mitochondrial  cristae . Iron is present in the iron\u2013sulfur cluster and heme groups of the  electron transport chain  proteins that generate a  proton gradient  that allows  ATP synthase  to synthesize ATP ( chemiosmosis )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11288", "text": "Heme groups are part of  hemoglobin , a protein found in red blood cells that serves to transport oxygen from the  lungs  to other tissues. Heme groups are also present in  myoglobin  to store and diffuse oxygen in muscle cells."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11289", "text": "The human body needs iron for oxygen transport. Oxygen (O 2 ) is required for the functioning and survival of nearly all cell types. Oxygen is transported from the lungs to the rest of the body bound to the  heme  group of  hemoglobin  in red blood cells. In muscles cells, iron binds oxygen to  myoglobin , which regulates its release."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11290", "text": "Iron is also potentially toxic. Its ability to donate and accept electrons means that it can catalyze the conversion of  hydrogen peroxide  into  free radicals . Free radicals can cause damage to a wide variety of cellular structures, and ultimately kill the cell. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11291", "text": "Iron bound to proteins or  cofactors  such as  heme  is safe. Also,  there are virtually no truly free iron ions in the cell, since they readily form complexes with organic molecules. However, some of the intracellular iron is bound to low-affinity complexes, and is termed labile iron or \"free\" iron. Iron in such complexes can cause damage as described above. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11292", "text": "To prevent that kind of damage, all life forms that use iron bind the iron atoms to  proteins . This binding allows cells to benefit from iron while also limiting its ability to do harm. [ 1 ] [ 3 ]  Typical intracellular labile iron concentrations in bacteria are 10-20 micromolar, [ 4 ]  though they can be 10-fold higher in anaerobic environment, [ 5 ]  where free radicals and  reactive oxygen species  are scarcer. In mammalian cells, intracellular labile iron concentrations are typically smaller than 1 micromolar, less than 5 percent of total cellular iron. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11293", "text": "In response to a systemic bacterial infection, the immune system initiates a process known as \" iron withholding \". If bacteria are to survive, then they must obtain iron from their environment. Disease-causing bacteria do this in many ways, including releasing iron-binding molecules called  siderophores  and then reabsorbing them to recover iron, or scavenging iron from hemoglobin and  transferrin . The harder the bacteria have to work to get iron, the greater a  metabolic price  they must pay. That means that iron-deprived bacteria reproduce more slowly. So, control of iron levels appears to be an important defense against many bacterial infections. Certain bacteria species have developed strategies to circumvent that defense,  TB  causing bacteria can reside within  macrophages , which present an iron rich environment and  Borrelia burgdorferi  uses  manganese  in place of iron. People with increased amounts of iron, as, for example, in hemochromatosis, are more susceptible to some bacterial infections. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11294", "text": "Although this mechanism is an elegant response to short-term bacterial infection, it can cause problems when it goes on so long that the body is deprived of needed iron for red cell production. Inflammatory  cytokines  stimulate the liver to produce the iron metabolism regulator protein  hepcidin , that reduces available iron. If hepcidin levels increase because of non-bacterial sources of inflammation, like viral infection, cancer, auto-immune diseases or other chronic diseases, then the  anemia of chronic disease  may result. In this case, iron withholding actually impairs health by preventing the manufacture of enough hemoglobin-containing red blood cells. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11295", "text": "Most well-nourished people in industrialized countries have 4 to 5\u00a0grams of iron in their bodies (~38\u00a0mg iron/kg body weight for women and ~50\u00a0mg iron/kg body for men). [ 7 ]  Of this, about  2.5\u00a0g  is contained in the hemoglobin needed to carry oxygen through the blood (around 0.5\u00a0mg of iron per mL of blood), [ 8 ]  and most of the rest (approximately 2\u00a0grams in adult men, and somewhat less in women of childbearing age) is contained in  ferritin  complexes that are present in all cells, but most common in bone marrow,  liver , and  spleen . The liver stores of ferritin are the primary physiologic source of reserve iron in the body. The reserves of iron in industrialized countries tend to be lower in children and women of child-bearing age than in men and in the elderly. Women who must use their stores to compensate for iron lost through  menstruation ,  pregnancy  or  lactation  have lower non-hemoglobin body stores, which may consist of  500\u00a0mg , or even less."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11296", "text": "Of the body's total iron content, about  400\u00a0mg  is devoted to cellular proteins that use iron for important cellular processes like storing oxygen (myoglobin) or performing energy-producing redox reactions ( cytochromes ). A relatively small amount (3\u20134\u00a0mg) circulates through the  plasma , bound to transferrin. [ 9 ]  Because of its toxicity, free soluble iron is kept in low concentration in the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11297", "text": "Iron deficiency  first affects the storage of iron in the body, and depletion of these stores is thought to be relatively asymptomatic, although some vague and  non-specific symptoms  have been associated with it. Since iron is primarily required for hemoglobin,  iron deficiency anemia  is the primary clinical manifestation of iron deficiency. Iron-deficient people will suffer or die from organ damage well before their cells run out of the iron needed for intracellular processes like electron transport."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11298", "text": "Macrophages  of the  reticuloendothelial system  store iron as part of the process of breaking down and processing hemoglobin from engulfed red blood cells. Iron is also stored as a pigment called  hemosiderin , which is an ill-defined deposit of protein and iron, created by macrophages where excess iron is present, either locally or systemically, e.g., among people with iron overload due to frequent blood cell destruction and the necessary transfusions their condition calls for. If systemic iron overload is corrected, over time the hemosiderin is slowly resorbed by the macrophages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11299", "text": "Human iron homeostasis is regulated at two different levels. Systemic iron levels are balanced by the controlled absorption of dietary iron by  enterocytes , the cells that line the interior of the  intestines , and the uncontrolled loss of iron from epithelial sloughing, sweat, injuries and blood loss. In addition, systemic iron is continuously recycled. Cellular iron levels are controlled differently by different cell types due to the expression of particular iron regulatory and transport proteins."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11300", "text": "The absorption of dietary iron is a variable and dynamic process. The amount of iron absorbed compared to the amount ingested is typically low, but may range from 5% to as much as 35% depending on circumstances and type of iron. The efficiency with which iron is absorbed varies depending on the source. Generally, the best-absorbed forms of iron come from animal products. Absorption of dietary iron in iron salt form (as in most supplements) varies somewhat according to the body's need for iron, and is usually between 10% and 20% of iron intake. Absorption of iron from animal products, and some plant products, is in the form of heme iron, and is more efficient, allowing absorption of from 15% to 35% of intake. Heme iron in animals is from blood and heme-containing proteins in meat and mitochondria, whereas in plants, heme iron is present in mitochondria in all cells that use oxygen for respiration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11301", "text": "Like most mineral nutrients, the majority of the iron absorbed from digested food or supplements is absorbed in the  duodenum  by  enterocytes  of the duodenal lining. These cells have special molecules that allow them to move iron into the body. To be absorbed, dietary iron can be absorbed as part of a protein such as heme protein or iron must be in its ferrous Fe 2+  form. A ferric reductase enzyme on the enterocytes'  brush border , duodenal cytochrome B ( Dcytb ), reduces ferric Fe 3+  to Fe 2+ . [ 10 ]  A protein called divalent metal transporter 1 ( DMT1 ), which can transport several  divalent  metals across the plasma membrane, then transports iron across the enterocyte's  cell membrane  into the cell. If the iron is bound to heme, it is instead transported across the apical membrane by  heme carrier protein 1  (HCP1). [ 11 ]  Heme is then  catabolized  by microsomal  heme oxygenase  into  biliverdin , releasing Fe 2+ . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11302", "text": "These intestinal lining cells can then either store the iron as  ferritin , which is accomplished by Fe 2+  binding to apoferritin (in which case the iron will leave the body when the cell dies and is sloughed off into  feces ), or the cell can release it into the body via the only known iron exporter in mammals,  ferroportin .  Hephaestin , a  ferroxidase  that can oxidize Fe 2+  to Fe 3+  and is found mainly in the small intestine, helps ferroportin transfer iron across the basolateral end of the intestine cells. Upon release into the bloodstream, Fe 3+  binds transferrin and circulates to tissues. In contrast, ferroportin is post-translationally repressed by  hepcidin , a 25-amino acid peptide hormone. The body regulates iron levels by regulating each of these steps. For instance, enterocytes synthesize more Dcytb, DMT1 and ferroportin in response to iron deficiency anemia. [ 13 ]  Iron absorption from diet is enhanced in the presence of vitamin C and diminished by excess calcium, zinc, or manganese. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11303", "text": "The human body's rate of iron absorption appears to respond to a variety of interdependent factors, including total iron stores, the extent to which the bone marrow is producing new red blood cells, the concentration of hemoglobin in the blood, and the oxygen content of the blood. The body also absorbs less iron during times of  inflammation , in order to deprive bacteria of iron. Recent discoveries demonstrate that hepcidin regulation of ferroportin is responsible for the syndrome of anemia of chronic disease."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11304", "text": "Most of the iron in the body is hoarded and recycled by the reticuloendothelial system, which breaks down aged red blood cells. In contrast to iron uptake and recycling, there is no physiologic regulatory mechanism for  excreting  iron. People lose a small but steady amount by gastrointestinal blood loss, sweating and by shedding cells of the skin and the  mucosal  lining of the  gastrointestinal tract . The total amount of loss for healthy people in the developed world amounts to an estimated average of  1\u00a0mg  a day for men, and 1.5\u20132\u00a0mg a day for women with regular menstrual periods. [ 15 ]  People with gastrointestinal parasitic infections, more commonly found in developing countries, often lose more. [ 1 ]  Those who cannot regulate absorption well enough get disorders of iron overload. In these diseases, the toxicity of iron starts overwhelming the body's ability to bind and store it. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11305", "text": "Most cell types take up iron primarily through  receptor-mediated endocytosis  via  transferrin receptor 1  (TFR1),  transferrin receptor 2  (TFR2) and  GAPDH . TFR1 has a 30-fold higher affinity for transferrin-bound iron than TFR2 and thus is the main player in this process. [ 17 ] [ 18 ]  The higher order multifunctional glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) also acts as a transferrin receptor. [ 19 ] [ 20 ]  Transferrin-bound ferric iron is recognized by these transferrin receptors, triggering a conformational change that causes endocytosis. Iron then enters the cytoplasm from the endosome via importer DMT1 after being reduced to its ferrous state by a STEAP family reductase. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11306", "text": "Alternatively, iron can enter the cell directly via plasma membrane divalent cation importers such as DMT1 and ZIP14 (Zrt-Irt-like protein 14). [ 22 ]  Again, iron enters the cytoplasm in the ferrous state after being reduced in the extracellular space by a reductase such as STEAP2, STEAP3 (in red blood cells), Dcytb (in enterocytes) and SDR2. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11307", "text": "Iron can also enter cells via  CD44  in complexes bound to  hyaluronic acid  during  epithelial\u2013mesenchymal transition  (EMT). In this process,  epithelial cells  transform into  mesenchymal cells  with detachment from the  basement membrane , to which they\u2019re normally anchored, paving the way for the newly differentiated motile mesenchymal cells to begin migration away from the epithelial layer. [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11308", "text": "While EMT plays a crucial role in physiological processes like  implantation , where it enables the  embryo  to invade the  endometrium  to facilitate  placental  attachment, its dysregulation can also fuel the  malignant  spread of  tumors  empowering them to invade surrounding tissues and establish distant colonies ( metastasis ). [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11309", "text": "Malignant cells often exhibit a heightened demand for iron, fueling their transition towards a more invasive mesenchymal state. This iron is necessary for the expression of mesenchymal genes, like those encoding  transforming growth factor beta  (TGF-\u03b2), crucial for EMT. Notably, iron\u2019s unique ability to catalyze  protein  and  DNA   demethylation  plays a vital role in this gene expression process. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11310", "text": "Conventional iron uptake pathways, such as those using the transferrin receptor 1 (TfR1), often prove insufficient to meet these elevated iron demands in cancer cells. As a result, various  cytokines  and  growth factors  trigger the upregulation of CD44, a surface molecule capable of internalizing iron bound to the hyaluronan complex. This alternative pathway, relying on CD44-mediated endocytosis, becomes the dominant iron uptake mechanism compared to the traditional TfR1-dependent route. [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11311", "text": "In the cytoplasm, ferrous iron is found in a soluble, chelatable state which constitutes the labile iron pool (~0.001 mM). [ 25 ]  In this pool, iron is thought to be bound to low-mass compounds such as peptides, carboxylates and phosphates, although some might be in a free, hydrated form ( aqua ions ). [ 25 ]  Alternatively, iron ions might be bound to specialized proteins known as  metallochaperones . [ 26 ]  Specifically, poly-r(C)-binding proteins  PCBP1  and  PCBP2  appear to mediate transfer of free iron to ferritin (for storage) and  non-heme iron enzymes  (for use in catalysis). [ 22 ] [ 27 ]  The labile iron pool is potentially toxic due to iron's ability to generate reactive oxygen species. Iron from this pool can be taken up by mitochondria via  mitoferrin  to synthesize Fe-S clusters and heme groups. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11312", "text": "Iron can be stored in ferritin as ferric iron due to the  ferroxidase  activity of the ferritin heavy chain. [ 28 ]  Dysfunctional ferritin may accumulate as  hemosiderin , which can be problematic in cases of iron overload. [ 29 ]  The ferritin storage iron pool is much larger than the labile iron pool, ranging in concentration from 0.7 mM to 3.6 mM. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11313", "text": "Iron export occurs in a variety of cell types, including  neurons , red blood cells, hepatocytes, macrophages and enterocytes. The latter two are especially important since systemic iron levels depend upon them. There is only one known iron exporter,  ferroportin . [ 30 ]  It transports ferrous iron out of the cell, generally aided by  ceruloplasmin  and/or  hephaestin  (mostly in enterocytes), which oxidize iron to its ferric state so it can bind ferritin in the extracellular medium. [ 21 ]   Hepcidin  causes the internalization of ferroportin, decreasing iron export. Besides, hepcidin seems to downregulate both TFR1 and DMT1 through an unknown mechanism. [ 31 ]  Another player assisting ferroportin in effecting cellular iron export is GAPDH. [ 32 ]  A specific post translationally modified isoform of GAPDH is recruited to the surface of iron loaded cells where it recruits apo-transferrin in close proximity to ferroportin so as to rapidly chelate the iron extruded. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11314", "text": "The expression of hepcidin, which only occurs in certain cell types such as  hepatocytes , is tightly controlled at the transcriptional level and it represents the link between cellular and systemic iron homeostasis due to hepcidin's role as \"gatekeeper\" of iron release from enterocytes into the rest of the body. [ 21 ]   Erythroblasts  produce  erythroferrone , a hormone which inhibits hepcidin and so increases the availability of iron needed for hemoglobin synthesis. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11315", "text": "Although some control exists at the transcriptional level, the regulation of cellular iron levels is ultimately controlled at the translational level by  iron-responsive element-binding proteins  IRP1 and especially IRP2. [ 36 ]  When iron levels are low, these proteins are able to bind to  iron-responsive elements  (IREs). IREs are stem loop structures in the untranslated regions (UTRs) of mRNA. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11316", "text": "Both ferritin and ferroportin contain an IRE in their 5' UTRs, so that under iron deficiency their translation is repressed by IRP2, preventing the unnecessary synthesis of storage protein and the detrimental export of iron. In contrast, TFR1 and some DMT1 variants contain 3' UTR IREs, which bind IRP2 under iron deficiency, stabilizing the mRNA, which guarantees the synthesis of iron importers. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11317", "text": "Functional or actual iron deficiency can result from a variety of causes. These causes can be grouped into several categories:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11318", "text": "The body is able to substantially reduce the amount of iron it absorbs across the mucosa. It does not seem to be able to entirely shut down the iron transport process. Also, in situations where excess iron damages the intestinal lining itself (for instance, when children eat a large quantity of iron tablets produced for adult consumption), even more iron can enter the bloodstream and cause a potentially deadly syndrome of iron overload. Large amounts of free iron in the circulation will cause damage to critical cells in the liver, the  heart  and other metabolically active organs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11319", "text": "Iron toxicity results when the amount of circulating iron exceeds the amount of transferrin available to bind it, but the body is able to vigorously regulate its iron uptake. Thus, iron toxicity from ingestion is usually the result of extraordinary circumstances like iron tablet over-consumption [1] [ 42 ]  rather than variations in  diet . The type of acute toxicity from iron ingestion causes severe mucosal damage in the gastrointestinal tract, among other problems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11320", "text": "Excess iron has been linked to higher rates of disease and mortality. For example, breast cancer patients with low  ferroportin  expression (leading to higher concentrations of intracellular iron) survive for a shorter period of time on average, while high ferroportin expression predicts 90% 10-year survival in breast cancer patients. [ 43 ]  Similarly, genetic variations in iron transporter genes known to increase serum iron levels also reduce  lifespan  and the average number of years spent in good health. [ 44 ]  It has been suggested that mutations that increase iron absorption, such as the ones responsible for hemochromatosis (see below), were selected for during  Neolithic  times as they provided a  selective advantage  against iron-deficiency anemia. [ 45 ]  The increase in systemic iron levels becomes pathological in old age, which supports the notion that  antagonistic pleiotropy  or \"hyperfunction\" drives human aging. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11321", "text": "Chronic iron toxicity is usually the result of more chronic iron overload syndromes associated with genetic diseases, repeated transfusions or other causes. In such cases the iron stores of an adult may reach 50\u00a0grams (10 times normal total body iron) or more. The most common diseases of iron overload are  hereditary hemochromatosis  (HH), caused by mutations in the  HFE  gene, and the more severe disease  juvenile hemochromatosis  (JH), caused by mutations in either  hemojuvelin  ( HJV ) [ 46 ]  or hepcidin ( HAMP ). The exact mechanisms of most of the various forms of adult hemochromatosis, which make up most of the genetic iron overload disorders, remain unsolved. So, while researchers have been able to identify genetic mutations causing several adult variants of hemochromatosis, they now must turn their attention to the normal function of these mutated genes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11322", "text": "Iodine  is an essential  trace element  in  biological  systems. It has the distinction of being the heaviest  element  commonly needed by living organisms as well as the second-heaviest known to be used by any form of life (only  tungsten , a component of a few bacterial enzymes, has a higher  atomic number  and  atomic weight ). It is a component of biochemical pathways in organisms from all biological kingdoms, suggesting its fundamental significance throughout the evolutionary history of life. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11323", "text": "Iodine is critical to the proper functioning of the vertebrate  endocrine  system, and plays smaller roles in numerous other organs, including those of the digestive and reproductive systems. An adequate intake of iodine-containing compounds is important at all stages of development, especially during the fetal and neonatal periods, and diets  deficient in iodine  can present serious consequences for growth and metabolism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11324", "text": "In  vertebrate  biology, iodine's primary function is as a constituent of the  thyroid   hormones ,  thyroxine  (T4) and  triiodothyronine  (T3). These  molecules  are made from addition-condensation products of the  amino acid   tyrosine , and are stored prior to release in an iodine-containing  protein  called  thyroglobulin . T4 and T3 contain four and three  atoms  of iodine per molecule, respectively; iodine accounts for 65% of the molecular weight of T4 and 59% of T3. The  thyroid gland  actively absorbs iodine from the  blood  to produce and release these hormones into the blood, actions which are regulated by a second hormone, called  thyroid-stimulating hormone  (TSH), which is produced by the  pituitary gland . Thyroid hormones are  phylogenetically  very old molecules which are synthesized by most  multicellular   organisms , and which even have some effect on  unicellular  organisms.\nThyroid hormones play a fundamental role in biology, acting upon gene  transcription  mechanisms to regulate the  basal metabolic rate . T3 acts on  small intestine  cells and  adipocytes  to increase  carbohydrate  absorption and  fatty acid  release, respectively. [ 2 ]  A deficiency of thyroid hormones can reduce basal metabolic rate up to 50%, while an excessive production of thyroid hormones can increase the basal metabolic rate by 100%. [ 3 ]  T4 acts largely as a  precursor  to T3, which is (with minor exceptions) the biologically active hormone.\nVia the thyroid hormones, iodine has a nutritional relationship with  selenium . A family of selenium-dependent  enzymes  called  deiodinases  converts T4 to T3 (the active hormone) by removing an iodine atom from the outer tyrosine ring. These enzymes also convert T4 to  reverse T3  (rT3) by removing an inner ring iodine atom, and also convert T3 to  3,3'-Diiodothyronine  (T2) by removing an inner ring atom. Both of the latter products are inactivated hormones which have essentially no biological effects and are quickly prepared for disposal. A family of non-selenium-dependent enzymes then further deiodinates the products of these reactions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11325", "text": "The total amount of iodine in the human body is still controversial, and in 2001,  M.T. Hays published in  Thyroid  that \"it is surprising that the total iodine content of the human body remains uncertain after many years of interest in iodine metabolism. Only the iodine content of the thyroid gland has been measured accurately by fluorescent scanning, and it is now well estimate of 5\u201315\u00a0mg in the normal human thyroid. But similar methods are not available for other tissues and for the extrathyroidal organs. Many researchers reported different numbers of 10\u201350\u00a0mg of the total iodine content in human body\". [ 4 ] [ 5 ]  \nSelenium also plays a very important role in the production of  glutathione , the body's most powerful  antioxidant . During the production of the thyroid hormones,  hydrogen peroxide  is produced in large quantities, and therefore high iodine in the absence of selenium can destroy the thyroid gland (often described as a  sore throat  feeling); the peroxides are neutralized through the production of glutathione from selenium. In turn, an excess of selenium increases demand for iodine, and deficiency will result when a diet is high in selenium and low in iodine. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11326", "text": "Extra-thyroidal iodine exists in several other organs, including the  mammary glands , eyes,  gastric mucosa ,  cervix ,  cerebrospinal fluid , arterial walls,  ovary  and  salivary glands . [ 6 ]  In the cells of these tissues the  iodide  ion (I \u2212 ) enters directly by the  sodium-iodide symporter  (NIS). Different tissue responses for iodine and iodide occur in the mammary glands and the thyroid gland of rats. [ 7 ]  The role of iodine in mammary tissue is related to fetal and neonatal development, but its role in the other tissues is not well known. [ 8 ]  It has been shown to act as an antioxidant [ 8 ]  and antiproliferant [ 9 ]  in various tissues that can uptake iodine. Molecular iodine (I 2 ) has been shown to have a suppressive effect on benign and cancerous  neoplasias . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11327", "text": "The U.S. Food and Nutrition Board and Institute of Medicine recommended daily allowance of iodine ranges from 150 micrograms per day for adult humans to 290 micrograms per day for lactating mothers. However, the thyroid gland needs no more than 70 micrograms per day to synthesize the requisite daily amounts of T4 and T3. The higher recommended daily allowance levels of iodine seem necessary for optimal function of a number of other body systems, including lactating breasts, gastric mucosa, salivary glands, oral mucosa, arterial walls,  thymus , epidermis,  choroid plexus  and  cerebrospinal fluid , among others. [ 10 ] [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11328", "text": "Iodine and thyroxine have also been shown to stimulate the spectacular  apoptosis  of the cells of the larval gills, tail and fins during  metamorphosis  in  amphibians , as well as the transformation of their nervous system from that of the aquatic, herbivorous  tadpole  into that of the terrestrial, carnivorous adult. The  frog  species  Xenopus laevis  has proven to be an ideal  model organism  for experimental study of the mechanisms of apoptosis and the role of iodine in developmental biology. [ 13 ] [ 1 ] [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11329", "text": "It is believed that  thyroid hormones  evolved in the  Urbilaterian  well before the development of the  thyroid  itself and molluscs, echinoderms, cephalochordates and ascidians all use such hormones. [ 16 ]  Cnidarians also respond to Thyroid hormone despite being  parahoxozoans  rather than  bilaterians . [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11330", "text": "Insects use hormones similar to thyroid hormone using iodine. [ 18 ] [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11331", "text": "Phosphorylated tyrosines  created with  tyrosine kinases  are fundamental signalling molecules in all animals and in  choanoflagellates . [ 21 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11332", "text": "Iodine is known to be crucial for life in many unicellular organisms [ 23 ]   Phosphorylated tyrosines  created with  tyrosine kinases  are fundamental signalling molecules in all animals and in  Choanoflagellates [ 21 ] [ 22 ]  and may be linked to the usage of tyrosine iodine compounds for similar roles. [ 23 ]   Crockford  proposes that iodine was originally used in protecting cell membranes from oxidative damage in  photosynthesis  and later moved into cytoplasm and became involved with balancing cytoplasmic composition of ions, and later the non enzymatic synthesis of tyrosine in early life. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11333", "text": "It is common across all domains of life and uses  tyrosine  bonded to iodine. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11334", "text": "Plants, insects, zooplankton and algae store iodine as mono-iodotyrosine (MIT), di-iodotyrosine (DIT), iodocarbons, or iodoproteins. [ 24 ] [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11335", "text": "Many plants use thyroid like hormones for regulating growth. [ 24 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11336", "text": "Gut-inhabiting bacteria use iodine from host thyroid hormone. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11337", "text": "Thyroid-like hormones may be linked to the development of multicellularity. [ 29 ] [ 30 ]  Iodotyrosines are highly reactive with other molecules [ 31 ]  which may have made them important cell signalling molecules early in evolutionary history. [ 23 ]  They form spontaneously without need for enzymatic catalysts which may have contributed to their early adoption by organisms, [ 32 ] [ 33 ]  although enzymes make the yields significantly higher. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11338", "text": "The ease of reaction with water may explain why iodine is so common across cell signalling in all domains of life. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11339", "text": "Many photosynthetic microbes are able to reduce inorganic  iodate  to  iodide  in their cell walls [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ]  but much of it gets released into the environment rather than cytoplasm in compounds such as  methyl iodide . [ 41 ] [ 36 ] [ 42 ]  Many  sulfate-reducing microorganisms  and  Iron-oxidizing bacteria  also reduce iodate to iodide [ 43 ] [ 40 ]  as well as many  facultative anaerobic organisms [ 44 ]  suggesting this may be ancestral among anaerobic organisms. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11340", "text": "Kelp  store large quantities of iodide primarily as iodotyrosines for unknown reasons. [ 45 ] [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11341", "text": "Molecular iodine (I 2 ) is toxic to most single-celled organisms by disrupting the cell membrane [ 47 ]  however  Alphaproteobacteria  and  Choanoflagellates  are resistant. [ 48 ]  Organisms such as  Escherichia coli  are killed by molecular iodine but require iodine from host thyroid hormone, [ 28 ]  indicating that not all organisms that need iodine are resistant to the toxic effects of pure iodine. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11342", "text": "The  U.S. Institute of Medicine  (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for iodine in 2000. For people age 14 and up, the iodine RDA is 150 \u03bcg/day; the RDA for pregnant women is 220 \u03bcg/day and the RDA during lactation is 290\u00a0\u03bcg/day. For children aged 1\u20138 years, the RDA is 90\u00a0\u03bcg/day; for children aged 8\u201313 years, it is 130\u00a0\u03bcg/day. [ 49 ]  As a safety consideration, the IOM sets  tolerable upper intake levels  (ULs) for vitamins and minerals when evidence is sufficient. The UL for iodine for adults is 1,100\u00a0\u03bcg/day. This UL was assessed by analyzing the effect of supplementation on  thyroid-stimulating hormone . [ 8 ]  Collectively, the EARs, RDAs, AIs and ULs are referred to as  Dietary Reference Intakes  (DRIs). [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11343", "text": "The  European Food Safety Authority  (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR; AI and UL are defined the same as in the United States. For women and men ages 18 and older, the PRI for iodine is set at 150\u00a0\u03bcg/day; the PRI during pregnancy or lactation is 200\u00a0\u03bcg/day. For children aged 1\u201317 years, the PRI increases with age from 90 to 130\u00a0\u03bcg/day. These PRIs are comparable to the U.S. RDAs with the exception of that for lactation. [ 50 ]  The EFSA reviewed the same safety question and set its adult UL at 600\u00a0\u03bcg/day, which is a bit more than half the U.S. value. [ 51 ]  Notably, Japan reduced its adult iodine UL from 3,000 to 2,200\u00a0\u03bcg/day in 2010, but then increased it back to 3,000\u00a0\u03bcg/day in 2015. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11344", "text": "As of 2000, the median observed intake of iodine from food in the United States was 240 to 300\u00a0\u03bcg/day for men and 190 to 210\u00a0\u03bcg/day for women. [ 49 ]  In Japan, consumption is much higher due to the frequent consumption of  seaweed  or  kombu  kelp. [ 8 ]  The average daily intake in Japan ranges from 1,000 to 3,000 \u03bcg/day; previous estimates suggested an average intake as high as 13,000 \u03bcg/day. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11345", "text": "For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of  Daily Value  (%DV). For iodine specifically, 100% of the Daily Value is considered 150 \u03bcg, and this figure remained at 150 \u03bcg in the May 27, 2016 revision. [ 54 ] [ 55 ]  \nA table of the old and new adult daily values is provided at  Reference Daily Intake ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11346", "text": "Natural sources of iodine include many marine organisms, such as  kelp  and certain seafood products, as well as plants grown on iodine-rich soil. [ 56 ] [ 57 ]   Iodized salt  is fortified with iodine. [ 57 ]  According to a Food Fortification Initiative 2016 report, 130 countries have mandatory iodine fortification of salt and an additional 10 have voluntary fortification. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11347", "text": "Worldwide,  iodine deficiency  affects two billion people and is the leading preventable cause of  intellectual disability . [ 58 ]  Mental disability is a result which occurs primarily when babies or small children are rendered  hypothyroidic  by a lack of dietary iodine (new hypothyroidism in adults may cause temporary mental slowing, but not permanent damage)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11348", "text": "In areas where there is little iodine in the diet, typically remote inland areas and semi-arid equatorial climates where no marine foods are eaten, iodine deficiency also gives rise to  hypothyroidism , the most serious symptoms of which are epidemic  goitre  (swelling of the thyroid gland), extreme fatigue, mental slowing, depression, weight gain, and low basal body temperatures. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11349", "text": "The addition of iodine to table salt (so-called  iodized salt ) has largely eliminated the most severe consequences of iodine deficiency in wealthier nations, but deficiency remains a serious public health problem in the developing world. [ 60 ]  Iodine deficiency is also a problem in certain areas of Europe; in Germany, an estimated one billion dollars in healthcare costs is spent each year in combating and treating iodine deficiency. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11350", "text": "Source: [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11351", "text": "Elemental iodine is an  oxidizing  irritant, and direct contact with skin can cause  lesions , so iodine crystals should be handled with care. Solutions with high elemental iodine concentration such as  tincture of iodine  are capable of causing tissue damage if use for cleaning and antisepsis is prolonged. Although elemental iodine is used in the formulation of  Lugol's solution , a common medical disinfectant, it becomes  triiodide  upon reacting with the  potassium iodide  used in the solution and is therefore non-toxic. [ citation needed ]  Only a small amount of elemental iodine will dissolve in water, but triiodides are highly soluble; potassium iodide thus serves as a  phase transfer catalyst  in the tincture.  This allows Lugol's iodine to be produced in strengths varying from 2% to 15% iodine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11352", "text": "Elemental iodine (I 2 ) is poisonous if taken orally in large amounts; 2\u20133 grams is a lethal dose for an adult human. [ 71 ] [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11353", "text": "Iodine vapor  is very irritating to the  eye , to mucous membranes, and in the respiratory tract. Concentration of iodine in the air should not exceed 1\u00a0mg/m 3  (eight-hour time-weighted average)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11354", "text": "When mixed with  ammonia  and water, elemental iodine forms  nitrogen triiodide , which is extremely shock-sensitive and can explode unexpectedly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11355", "text": "Compared to the elemental form, potassium iodide has a  median lethal dose  (LD 50 ) that is relatively high in several animals: in rabbits, it is 10\u00a0g/kg; in rats, 14\u00a0g/kg, and in mice, 22\u00a0g/kg. [ 73 ]  The tolerable upper intake level for iodine as established by the  Food and Nutrition Board  is 1,100\u00a0\u03bcg/day for adults. The safe upper limit of consumption set by the Ministry of Health, Labor and Welfare in Japan is 3,000\u00a0\u03bcg/day. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11356", "text": "The biological half-life of iodine differs between the various organs of the body, from 100 days in the thyroid, to 14 days in the kidneys and spleen, to 7 days in the reproductive organs. Typically the daily urinary elimination rate ranges from 100 to 200\u00a0\u03bcg/L in humans. [ 75 ]  However, the Japanese diet, high in iodine-rich  kelp , contains 1,000 to 3,000\u00a0\u03bcg of iodine per day, and research indicates the body can readily eliminate excess iodine that is not needed for thyroid hormone production. [ 74 ]  The literature reports as much as 30,000\u00a0\u03bcg/L (30\u00a0mg/L) of iodine being safely excreted in the urine in a single day, with levels returning to the standard range in a couple of days, depending on seaweed intake. [ 76 ]  One study concluded the range of total body iodine content in males was 12.1\u00a0mg to 25.3\u00a0mg, with a mean of 14.6\u00a0mg. [ 77 ]  It is presumed that once  thyroid-stimulating hormone  is suppressed, the body simply eliminates excess iodine, and as a result, long-term supplementation with high doses of iodine has no additional effect once the body is replete with enough iodine. It is unknown if the thyroid gland is the rate-limiting factor in generating thyroid hormone from iodine and tyrosine, but assuming it is not, a short-term loading dose of one or two weeks at the tolerable upper intake level may quickly restore thyroid function in iodine-deficient patients. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11357", "text": "Excessive iodine intake presents symptoms similar to those of iodine deficiency. Commonly encountered symptoms are abnormal growth of the  thyroid  gland and disorders in functioning, [ 78 ]  as well as in growth of the organism as a whole. Iodide toxicity is similar to (but not the same as) toxicity to ions of the other  halogens , such as  bromides  or  fluorides . Excess  bromine  and  fluorine  can prevent successful iodine uptake, storage and use in organisms, as both elements can selectively replace iodine biochemically."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11358", "text": "Excess iodine may also be more  cytotoxic  in combination with  selenium deficiency . [ 79 ]  Iodine supplementation in selenium-deficient populations is theoretically problematic, partly for this reason. [ 8 ]   Selenocysteine  (abbreviated as  Sec  or  U , in older publications also as  Se-Cys ) [ 80 ]  is the 21st  proteinogenic amino acid , and is the root of iodide ion toxicity when there is a simultaneous insufficiency of biologically available selenium. Selenocysteine exists naturally in all kingdoms of life as a building block of  selenoproteins . [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11359", "text": "Some people develop a  hypersensitivity  to compounds of iodine but there are no known cases of people being directly  allergic  to elemental iodine itself. [ 82 ]  Notable sensitivity reactions that have been observed in humans include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11360", "text": "Medical use of iodine compounds (i.e. as a  contrast agent ) can cause  anaphylactic shock  in highly sensitive patients, presumably due to sensitivity to the chemical carrier. Cases of sensitivity to iodine compounds should not be formally classified as iodine allergies, as this perpetuates the erroneous belief that it is the iodine to which patients react, rather than to the specific allergen. Sensitivity to iodine-containing compounds is rare but has a considerable effect given the extremely widespread use of  iodine-based contrast media ; however, the only adverse effect of contrast material that can convincingly be ascribed to free iodide is iodide mumps and other manifestations of iodism. [ 84 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11361", "text": "Iron  is an important biological element. [ 1 ] [ 2 ] [ 3 ]  It is used in both the ubiquitous  iron-sulfur proteins [ 1 ]  and in  vertebrates  it is used in  hemoglobin  which is essential for  blood  and oxygen transport. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11362", "text": "Iron is required for life. [ 1 ] [ 2 ] [ 3 ]  The  iron\u2013sulfur clusters  are pervasive and include  nitrogenase , the enzymes responsible for biological  nitrogen fixation . Iron-containing proteins participate in transport, storage and use of oxygen. [ 1 ]  Iron proteins are involved in  electron transfer . [ 5 ]  The ubiquity of Iron in life has led to the  Iron\u2013sulfur world hypothesis  that iron was a central component of the environment of early life. [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11363", "text": "Examples of iron-containing proteins in higher organisms include hemoglobin,  cytochrome  (see  high-valent iron ), and  catalase . [ 1 ] [ 11 ]  The average adult human contains about 0.005% body weight of iron, or about four grams, of which three quarters is in hemoglobin \u2013 a level that remains constant despite only about one milligram of iron being absorbed each day, [ 5 ]  because the human body recycles its hemoglobin for the iron content. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11364", "text": "Microbial growth may be assisted by oxidation of iron(II) or by reduction of iron (III). [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11365", "text": "Iron acquisition poses a problem for aerobic organisms because  ferric  iron is poorly soluble near neutral pH. Thus, these organisms have developed means to absorb iron as complexes, sometimes taking up ferrous iron before oxidising it back to ferric iron. [ 1 ]  In particular, bacteria have evolved very high-affinity  sequestering  agents called  siderophores . [ 14 ] [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11366", "text": "After uptake in human  cells , iron storage is precisely regulated. [ 1 ] [ 17 ]  A major component of this regulation is the protein  transferrin , which binds iron ions absorbed from the  duodenum  and carries it in the  blood  to cells. [ 1 ] [ 18 ]  Transferrin contains Fe 3+  in the middle of a distorted  octahedron , bonded to one nitrogen, three oxygens and a chelating  carbonate  anion that traps the Fe 3+  ion: it has such a high  stability constant  that it is very effective at taking up Fe 3+  ions even from the most stable complexes. At the bone marrow, transferrin is reduced from Fe 3+  and Fe 2+  and stored as  ferritin  to be incorporated into hemoglobin. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11367", "text": "The most commonly known and studied  bioinorganic  iron compounds (biological iron molecules) are the  heme proteins : examples are  hemoglobin ,  myoglobin , and  cytochrome P450 . [ 1 ]  These compounds participate in transporting gases, building  enzymes , and transferring  electrons . [ 5 ]   Metalloproteins  are a group of proteins with metal ion  cofactors . Some examples of iron metalloproteins are  ferritin  and  rubredoxin . [ 5 ]  Many enzymes vital to life contain iron, such as  catalase , [ 19 ]   lipoxygenases , [ 20 ]  and  IRE-BP . [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11368", "text": "Hemoglobin is an oxygen carrier that occurs in  red blood cells  and contributes their color, transporting oxygen in the arteries from the lungs to the muscles where it is transferred to  myoglobin , which stores it until it is needed for the metabolic oxidation of  glucose , generating energy. [ 1 ]  Here the hemoglobin binds to  carbon dioxide , produced when glucose is oxidized, which is transported through the veins by hemoglobin (predominantly as  bicarbonate  anions) back to the lungs where it is exhaled. [ 5 ]  In hemoglobin, the iron is in one of four  heme  groups and has six possible coordination sites; four are occupied by nitrogen atoms in a  porphyrin  ring, the fifth by an  imidazole  nitrogen in a  histidine  residue of one of the protein chains attached to the heme group, and the sixth is reserved for the oxygen molecule it can reversibly bind to. [ 5 ]  When hemoglobin is not attached to oxygen (and is then called deoxyhemoglobin), the Fe 2+  ion at the center of the  heme  group (in the hydrophobic protein interior) is in a  high-spin configuration . It is thus too large to fit inside the porphyrin ring, which bends instead into a dome with the Fe 2+  ion about 55\u00a0picometers above it. In this configuration, the sixth coordination site reserved for the oxygen is blocked by another histidine residue. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11369", "text": "When deoxyhemoglobin picks up an oxygen molecule, this histidine residue moves away and returns once the oxygen is securely attached to form a  hydrogen bond  with it. This results in the Fe 2+  ion switching to a low-spin configuration, resulting in a 20% decrease in ionic radius so that now it can fit into the porphyrin ring, which becomes planar. [ 5 ]  (Additionally, this hydrogen bonding results in the tilting of the oxygen molecule, resulting in a Fe\u2013O\u2013O bond angle of around 120\u00b0 that avoids the formation of Fe\u2013O\u2013Fe or Fe\u2013O 2 \u2013Fe bridges that would lead to electron transfer, the oxidation of Fe 2+  to Fe 3+ , and the destruction of hemoglobin.) This results in a movement of all the protein chains that leads to the other subunits of hemoglobin changing shape to a form with larger oxygen affinity. Thus, when deoxyhemoglobin takes up oxygen, its affinity for more oxygen increases, and vice versa. [ 5 ]  Myoglobin, on the other hand, contains only one heme group and hence this cooperative effect cannot occur. Thus, while hemoglobin is almost saturated with oxygen in the high partial pressures of oxygen found in the lungs, its affinity for oxygen is much lower than that of myoglobin, which oxygenates even at low partial pressures of oxygen found in muscle tissue. [ 5 ]  As described by the  Bohr effect  (named after  Christian Bohr , the father of  Niels Bohr ), the oxygen affinity of hemoglobin diminishes in the presence of carbon dioxide. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11370", "text": "Carbon monoxide  and [[phosphorus trifluoride\u00bf\u2020\u00bf \u27e8\u27e9 ]] are poisonous to humans because they bind to hemoglobin similarly to oxygen, but with much more strength, so that oxygen can no longer be transported throughout the body. Hemoglobin bound to carbon monoxide is known as  carboxyhemoglobin . This effect also plays a minor role in the toxicity of  cyanide , but there the major effect is by far its interference with the proper functioning of the electron transport protein cytochrome a. [ 5 ]  The cytochrome proteins also involve heme groups and are involved in the metabolic oxidation of glucose by oxygen. The sixth coordination site is then occupied by either another imidazole nitrogen or a  methionine  sulfur, so that these proteins are largely inert to oxygen \u2013 with the exception of cytochrome a, which bonds directly to oxygen and thus is very easily poisoned by cyanide. [ 5 ]  Here, the electron transfer takes place as the iron remains in low spin but changes between the +2 and +3 oxidation states. Since the reduction potential of each step is slightly greater than the previous one, the energy is released step-by-step and can thus be stored in  adenosine triphosphate . Cytochrome a is slightly distinct, as it occurs at the mitochondrial membrane, binds directly to oxygen, and transports protons as well as electrons, as follows: [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11371", "text": "Although the heme proteins are the most important class of iron-containing proteins, the  iron\u2013sulfur proteins  are also very important, being involved in electron transfer, which is possible since iron can exist stably in either the +2 or +3 oxidation states. These have one, two, four, or eight iron atoms that are each approximately tetrahedrally coordinated to four sulfur atoms; because of this tetrahedral coordination, ths in the surrounding peptide chains. Another important class of iron\u2013sulfur proteins is the  ferredoxins , which have multiple iron atoms. Transferrin does not belong to either of these classes. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11372", "text": "The ability of sea  mussels  to maintain their grip on rocks in the ocean is facilitated by their use of  organometallic  iron-based bonds in their protein-rich  cuticles . Based on synthetic replicas, the presence of iron in these structures increased  elastic modulus  770 times,  tensile strength  58 times, and  toughness  92 times. The amount of stress required to permanently damage them increased 76 times. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11373", "text": "In vertebrates, iron is an essential component of  hemoglobin , the oxygen transport protein. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11374", "text": "Most well-nourished people in industrialized countries have 4 to 5\u00a0grams of iron in their bodies (~38\u00a0mg iron/kg body weight for women and ~50\u00a0mg iron/kg body for men). [ 24 ]  Of this, about  2.5\u00a0g  is contained in the hemoglobin needed to carry oxygen through the blood (around 0.5\u00a0mg of iron per mL of blood), [ 25 ]  and most of the rest (approximately 2\u00a0grams in adult men, and somewhat less in women of childbearing age) is contained in  ferritin  complexes that are present in all cells, but most common in bone marrow,  liver , and  spleen . The liver stores of ferritin are the primary physiologic source of reserve iron in the body. The reserves of iron in industrialized countries tend to be lower in children and women of child-bearing age than in men and in the elderly. Women who must use their stores to compensate for iron lost through  menstruation ,  pregnancy  or  lactation  have lower non-hemoglobin body stores, which may consist of  500\u00a0mg , or even less."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11375", "text": "Of the body's total iron content, about  400\u00a0mg  is devoted to cellular proteins that use iron for important cellular processes like storing oxygen (myoglobin) or performing energy-producing redox reactions ( cytochromes ). A relatively small amount (3\u20134\u00a0mg) circulates through the  plasma , bound to transferrin. [ 26 ]  Because of its toxicity, free soluble iron is kept in low concentration in the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11376", "text": "Like most mineral nutrients, the majority of the iron absorbed from digested food or supplements is absorbed in the  duodenum  by  enterocytes  of the duodenal lining. These cells have special molecules that allow them to move iron into the body. To be absorbed, dietary iron can be absorbed as part of a protein such as heme protein or iron must be in its ferrous Fe 2+  form. A ferric reductase enzyme on the enterocytes'  brush border , duodenal cytochrome B ( Dcytb ), reduces ferric Fe 3+  to Fe 2+ . [ 27 ]  A protein called divalent metal transporter 1 ( DMT1 ), which can transport several  divalent  metals across the plasma membrane, then transports iron across the enterocyte's  cell membrane  into the cell. If the iron is bound to heme it is instead transported across the apical membrane by  heme carrier protein 1  (HCP1). [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11377", "text": "These intestinal lining cells can then either store the iron as  ferritin , which is accomplished by Fe 2+  binding to apoferritin (in which case the iron will leave the body when the cell dies and is sloughed off into  feces ), or the cell can release it into the body via the only known iron exporter in mammals,  ferroportin .  Hephaestin , a  ferroxidase  that can oxidize Fe 2+  to Fe 3+  and is found mainly in the small intestine, helps ferroportin transfer iron across the basolateral end of the intestine cells. In contrast, ferroportin is post-translationally repressed by  hepcidin , a 25-amino acid peptide hormone. The body regulates iron levels by regulating each of these steps. For instance, enterocytes synthesize more Dcytb, DMT1 and ferroportin in response to iron deficiency anemia. [ 29 ]  Iron absorption from diet is enhanced in the presence of vitamin C and diminished by excess calcium, zinc, or manganese. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11378", "text": "Most of the iron in the body is hoarded and recycled by the reticuloendothelial system, which breaks down aged red blood cells. In contrast to iron uptake and recycling, there is no physiologic regulatory mechanism for  excreting  iron. People lose a small but steady amount by gastrointestinal blood loss, sweating and by shedding cells of the skin and the  mucosal  lining of the  gastrointestinal tract . The total amount of loss for healthy people in the developed world amounts to an estimated average of  1\u00a0mg  a day for men, and 1.5\u20132\u00a0mg a day for women with regular menstrual periods. [ 31 ]  People with gastrointestinal parasitic infections, more commonly found in developing countries, often lose more. [ 32 ]  Those who cannot regulate absorption well enough get disorders of iron overload. In these diseases, the toxicity of iron starts overwhelming the body's ability to bind and store it. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11379", "text": "Most cell types take up iron primarily through  receptor-mediated endocytosis  via  transferrin receptor 1  (TFR1),  transferrin receptor 2  (TFR2) and  GAPDH . TFR1 has a 30-fold higher affinity for transferrin-bound iron than TFR2 and thus is the main player in this process. [ 34 ] [ 35 ]  The higher order multifunctional glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) also acts as a transferrin receptor. [ 36 ] [ 37 ]  Transferrin-bound ferric iron is recognized by these transferrin receptors, triggering a conformational change that causes endocytosis. Iron then enters the cytoplasm from the endosome via importer DMT1 after being reduced to its ferrous state by a STEAP family reductase. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11380", "text": "Alternatively, iron can enter the cell directly via plasma membrane divalent cation importers such as DMT1 and ZIP14 (Zrt-Irt-like protein 14). [ 39 ]  Again, iron enters the cytoplasm in the ferrous state after being reduced in the extracellular space by a reductase such as STEAP2, STEAP3 (in red blood cells), Dcytb (in enterocytes) and SDR2. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11381", "text": "In the cytoplasm, ferrous iron is found in a soluble, chelatable state which constitutes the labile iron pool (~0.001 mM). [ 40 ]  In this pool, iron is thought to be bound to low-mass compounds such as peptides, carboxylates and phosphates, although some might be in a free, hydrated form ( aqua ions ). [ 40 ]  Alternatively, iron ions might be bound to specialized proteins known as  metallochaperones . [ 41 ]  Specifically, poly-r(C)-binding proteins  PCBP1  and  PCBP2  appear to mediate transfer of free iron to ferritin (for storage) and  non-heme iron enzymes  (for use in catalysis). [ 39 ] [ 42 ]  The labile iron pool is potentially toxic due to iron's ability to generate reactive oxygen species. Iron from this pool can be taken up by mitochondria via  mitoferrin  to synthesize Fe-S clusters and heme groups. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11382", "text": "Iron can be stored in ferritin as ferric iron due to the  ferroxidase  activity of the ferritin heavy chain. [ 43 ]  Dysfunctional ferritin may accumulate as  hemosiderin , which can be problematic in cases of iron overload. [ 44 ]  The ferritin storage iron pool is much larger than the labile iron pool, ranging in concentration from 0.7 mM to 3.6 mM. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11383", "text": "Iron export occurs in a variety of cell types, including  neurons , red blood cells, macrophages and enterocytes. The latter two are especially important since systemic iron levels depend upon them. There is only one known iron exporter,  ferroportin . [ 45 ]  It transports ferrous iron out of the cell, generally aided by  ceruloplasmin  and/or  hephaestin  (mostly in enterocytes), which oxidize iron to its ferric state so it can bind ferritin in the extracellular medium. [ 38 ]   Hepcidin  causes the internalization of ferroportin, decreasing iron export. Besides, hepcidin seems to downregulate both TFR1 and DMT1 through an unknown mechanism. [ 46 ]  Another player assisting ferroportin in effecting cellular iron export is GAPDH. [ 47 ]  A specific post translationally modified isoform of GAPDH is recruited to the surface of iron loaded cells where it recruits apo-transferrin in close proximity to ferroportin so as to rapidly chelate the iron extruded. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11384", "text": "The expression of hepcidin, which only occurs in certain cell types such as  hepatocytes , is tightly controlled at the transcriptional level and it represents the link between cellular and systemic iron homeostasis due to hepcidin's role as \"gatekeeper\" of iron release from enterocytes into the rest of the body. [ 38 ]   Erythroblasts  produce  erythroferrone , a hormone which inhibits hepcidin and so increases the availability of iron needed for hemoglobin synthesis. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11385", "text": "Although some control exists at the transcriptional level, the regulation of cellular iron levels is ultimately controlled at the translational level by  iron-responsive element-binding proteins  IRP1 and especially IRP2. [ 50 ]  When iron levels are low, these proteins are able to bind to  iron-responsive elements  (IREs). IREs are stem loop structures in the untranslated regions (UTRs) of mRNA. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11386", "text": "Both ferritin and ferroportin contain an IRE in their 5' UTRs, so that under iron deficiency their translation is repressed by IRP2, preventing the unnecessary synthesis of storage protein and the detrimental export of iron. In contrast, TFR1 and some DMT1 variants contain 3' UTR IREs, which bind IRP2 under iron deficiency, stabilizing the mRNA, which guarantees the synthesis of iron importers. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11387", "text": "Iron plays an essential role in marine systems and can act as a limiting nutrient for planktonic activity. [ 51 ]  Because of this, too much of a decrease in iron may lead to a decrease in growth rates in phytoplanktonic organisms such as diatoms. [ 52 ]  Iron can also be oxidized by marine microbes under conditions that are high in iron and low in oxygen. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11388", "text": "Iron can enter marine systems through adjoining rivers and directly from the atmosphere. Once iron enters the ocean, it can be distributed throughout the water column through ocean mixing and through recycling on the cellular level. [ 54 ]  In the arctic, sea ice plays a major role in the store and distribution of iron in the ocean, depleting oceanic iron as it freezes in the winter and releasing it back into the water when thawing occurs in the summer. [ 55 ]  The iron cycle can fluctuate the forms of iron from aqueous to particle forms altering the availability of iron to primary producers. [ 56 ]  Increased light and warmth increases the amount of iron that is in forms that are usable by primary producers. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11389", "text": "Landsupport  (spelling: LANDSUPPORT) is a pilot consulting project funded by the  European Union  for land use for the near-natural modeling of different types and methods of land use while at the same time protecting the environment. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11390", "text": "In the long term, sustainable use of the soil must be guaranteed in order to meet the needs of the world's population. The project brings together numerous universities, research institutions, companies and stakeholders with the aim of creating a web-based, free system to support practical agriculture and land users in making decisions about sustainable land use, environmental protection and agricultural use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11391", "text": "With the active participation of various and numerous stakeholders in and outside Europe, the consortium also aims at legislation at European level, based on scientific data that is processed and modeled in the system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11392", "text": "In the research framework program Horizon 2020, the project is organized under the direction of  Fabio Terribile  at the  University of Naples Federico II ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11393", "text": "The Landsupport consortium consists of the following partners:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11394", "text": "The results of the investigations are internationally evaluated by the members in specialist committees and made available to practice and the responsible bodies at regional and state level, as well as to the European Uninion for  legislative and approval procedures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11395", "text": "Certain  lithium compounds , also known as  lithium salts , are used as  psychiatric medication , [ 5 ]  primarily for  bipolar disorder  and for  major depressive disorder . [ 5 ]  Lithium is taken orally (by mouth). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11396", "text": "Common side effects include  increased urination , shakiness of the hands, and increased thirst. [ 5 ]  Serious side effects include  hypothyroidism ,  diabetes insipidus , and  lithium toxicity . [ 5 ]  Blood level monitoring is recommended to decrease the risk of potential toxicity. [ 5 ]  If levels become too high, diarrhea, vomiting, poor coordination, sleepiness, and  ringing in the ears  may occur. [ 5 ]  Lithium is  teratogenic  and can cause birth defects at high doses, especially during the first trimester of pregnancy. The use of lithium while breastfeeding is controversial; however, many international health authorities advise against it, and the long-term outcomes of perinatal lithium exposure have not been studied. [ 6 ]  The  American Academy of Pediatrics  lists lithium as contraindicated for pregnancy and lactation. [ 7 ]  The United States  Food and Drug Administration  categorizes lithium as having positive evidence of risk for pregnancy and possible hazardous risk for lactation. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11397", "text": "Lithium salts are classified as  mood stabilizers . [ 5 ]  Lithium's mechanism of action is not known. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11398", "text": "In the nineteenth century, lithium was used in people who had  gout ,  epilepsy , and  cancer . [ 9 ]  Its use in the treatment of  mental disorders  began with  Carl Lange  in Denmark [ 10 ]  and  William Alexander Hammond  in New York City, [ 11 ]  who used lithium to treat  mania  from the 1870s onwards, based on now-discredited theories involving its effect on uric acid. Use of lithium for mental disorders was re-established (on a different theoretical basis) in 1948 by  John Cade  in Australia. [ 9 ]   Lithium carbonate  is on the  World Health Organization's List of Essential Medicines , [ 12 ]  and is available as a  generic medication . [ 5 ]  In 2022, it was the 212th most commonly prescribed medication in the United States, with more than 1 \u00a0 million prescriptions. [ 13 ] [ 14 ]  It appears to be underused in older people, [ 15 ]  and in certain countries, for reasons including patients\u2019 negative beliefs about lithium. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11399", "text": "In 1970, lithium was approved by the United States  Food and Drug Administration  (FDA) for the treatment of bipolar disorder, which remains its primary use in the US. [ 5 ] [ 17 ]  It is sometimes used when other treatments are not effective in a number of other conditions, including  major depression , [ 18 ]   schizophrenia , disorders of impulse control, and some psychiatric disorders in children. [ 5 ]  Because the FDA has not approved lithium for the treatment of other disorders, such use is  off-label . [ 19 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11400", "text": "Lithium is primarily used as a maintenance drug in the treatment of bipolar disorder to stabilize mood and prevent  manic episodes , but it may also be helpful in the acute treatment of manic episodes. [ 20 ]  Although recommended by treatment guidelines for the treatment of depression in bipolar disorder, the evidence that lithium is superior to placebo for acute depression is low-quality; [ 21 ] [ 22 ]   atypical antipsychotics  are considered more effective for treating acute depressive episodes. [ 23 ]   Lithium carbonate  treatment was previously considered to be unsuitable for children; however, more recent studies show its effectiveness for treatment of early-onset bipolar disorder in children as young as eight. The required dosage is slightly less than the toxic level (representing a low  therapeutic index ), requiring close monitoring of blood levels of lithium carbonate during treatment. [ 24 ]  Within the therapeutic range there is a dose-response relationship. [ 25 ]  A limited amount of evidence suggests lithium carbonate may contribute to the treatment of substance use disorders for some people with bipolar disorder. [ 26 ] [ 27 ] [ 28 ]  Although it is believed that lithium prevents suicide in people with bipolar disorder, a 2022 systematic review found that \"Evidence from randomised trials is inconclusive and does not support the idea that lithium prevents suicide or suicidal behaviour.\" [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11401", "text": "Lithium is recommended for the treatment of schizophrenic disorders only after other antipsychotics have failed; it has limited effectiveness when used alone. [ 5 ]  The results of different clinical studies of the efficacy of combining lithium with antipsychotic therapy for treating schizophrenic disorders have varied. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11402", "text": "Lithium is widely prescribed as an adjunct treatment for depression. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11403", "text": "If therapy with antidepressants (such as  selective serotonin reuptake inhibitors  [SSRIs]) does not fully treat and discontinue [ 30 ]  the symptoms of  major depressive disorder  (MDD) (also known as refractory depression or treatment resistant depression [TRD]) [ 31 ]  then a second  augmentation agent  is sometimes added to the therapy. [ 32 ]  Lithium is one of the few augmentation agents for antidepressants to demonstrate efficacy in treating MDD in multiple randomized controlled trials and it has been prescribed ( off-label ) for this purpose since the 1980s. [ 18 ]  A 2019 systematic review found some evidence of the clinical utility of adjunctive lithium, but the majority of supportive evidence is dated. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11404", "text": "While  SSRIs  have been mentioned above as a drug class in which lithium is used to augment, there are other classes in which lithium is added to increase effectiveness. Such classes are  antipsychotics  (used for bipolar disorder) as well as  antiepileptic  drugs (used for both psychiatric and epileptic cases).  Lamotrigine  and  topiramate  are two specific antiepileptic drugs in which lithium is used to augment. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11405", "text": "There are a few old studies indicating efficacy of lithium for acute depression with lithium having the same efficacy as  tricyclic antidepressants . [ 35 ]  A recent study concluded that lithium works best on chronic and recurrent depression when compared to modern antidepressant (i.e. citalopram) but not for patients with no history of depression. [ 36 ]  A 2019 systemic review found no evidence to support the use of lithium for monotherapy. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11406", "text": "Lithium is widely believed to prevent suicide and is often used in clinical practice towards that end. However, meta-analyses, faced with evidence base limitations, have yielded differing results, and it therefore remains unclear whether or not lithium is efficacious in the prevention of suicide. [ 37 ] [ 38 ] [ 39 ] [ 40 ] [ 41 ] [ 42 ]  However, some evidence suggets it is effective in significantly reducing the risk of  self-harm  and  unintentional injury  for bipolar disorder in comparison to no treatment and to  anti-psychotics  or  valporate . [ 43 ] [ 44 ]  According to meta-analyses, the increased presence of lithium in drinking water is correlated with lower overall suicide rates, especially among men. It is noted that further testing is needed to confirm this benefit. [ 45 ] [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11407", "text": "Alzheimer's disease affects forty-five million people and is the fifth leading cause of death in the 65-plus population. [ 47 ] [ failed verification ]  There is no complete cure for the disease, currently. However, lithium is being evaluated for its effectiveness as a potential therapeutic measure. One of the leading causes of Alzheimer's is the hyperphosphorylation of the tau protein by the enzyme GSK-3, which leads to the overproduction of amyloid peptides that cause cell death. [ 47 ]  To combat this toxic amyloid aggregation, lithium upregulates the production of neuroprotectors and neurotrophic factors, as well as inhibiting the GSK-3 enzyme. [ 48 ]  Lithium also stimulates neurogenesis within the hippocampus, making it thicker. [ 48 ]  Yet another cause of Alzheimer's disease is the dysregulation of calcium ions within the brain. [ 49 ]  Too much or too little calcium within the brain can lead to cell death. [ 49 ]  Lithium can restore intracellular calcium homeostasis by inhibiting the wrongful influx of calcium upstream. [ 49 ]  It also promotes the redirection of the influx of calcium ions into the lumen of the endoplasmic reticulum of the cells to reduce the oxidative stress within the mitochondria. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11408", "text": "In 2009, a study was performed by Hampel and colleagues [ 50 ]  that asked patients with Alzheimer's to take a low dose of lithium daily for three months; it resulted in a significant slowing of cognitive decline, benefitting patients being in the prodromal stage the most. [ 48 ]  Upon a secondary analysis, the brains of the Alzheimer's patients were studied and shown to have an increase in BDNF markers, meaning they had actually shown cognitive improvement. [ 48 ]  Another study, a population study this time by Kessing et al., [ 51 ]  showed a negative correlation between Alzheimer's disease deaths and the presence of lithium in drinking water. [ 48 ]  Areas with increased lithium in their drinking water showed less dementia overall in their population. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11409", "text": "Those who use lithium should receive regular serum level tests and should monitor thyroid and kidney function for abnormalities, as it interferes with the regulation of  sodium  and water levels in the body, and can cause  dehydration . Dehydration, which is compounded by heat, can result in increasing lithium levels. The dehydration is due to lithium inhibition of the action of  antidiuretic hormone , which normally enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine, leading to consequent loss of body water and thirst. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11410", "text": "Lithium concentrations in whole blood, plasma, serum, or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdosage. Serum lithium concentrations are usually in the range of 0.5\u20131.3\u00a0 mmol/L  (0.5\u20131.3\u00a0 mEq/L ) in well-controlled people, but may increase to 1.8\u20132.5\u00a0mmol/L in those who accumulate the drug over time and to 3\u201310\u00a0mmol/L in acute overdose. [ 53 ] [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11411", "text": "Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring  plasma  concentrations are available. Doses are adjusted to achieve plasma concentrations of 0.4 [ a ] [ b ]  to 1.2\u00a0mmol/L [ 55 ]  on samples taken 12 hours after the preceding dose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11412", "text": "Given the rates of thyroid dysfunction, thyroid parameters should be checked before lithium is instituted and monitored after 3\u20136 months and then every 6\u201312 months. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11413", "text": "Given the risks of kidney malfunction, serum creatinine, and eGFR should be checked before lithium is instituted and monitored after 3\u20136 months at regular intervals. Patients who have a rise in creatinine on three or more occasions, even if their eGFR is > 60 ml/min/\n1.73m2 require further evaluation, including a urinalysis for haematuria, and proteinuria, a review of their medical history with attention paid to cardiovascular, urological, and medication history, and blood pressure control and management. Overt proteinuria should be further quantified with a urine protein-to-creatinine ratio. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11414", "text": "For patients who have achieved long-term remission, it is recommended to discontinue lithium gradually and in a controlled fashion. [ 58 ] [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11415", "text": "Discontinuation symptoms may occur in patients stopping the medication including irritability, restlessness, and somatic symptoms like vertigo, dizziness, or lightheadedness. Symptoms occur within the first week and are generally mild and self-limiting within weeks. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11416", "text": "Studies testing  prophylactic  use of lithium in cluster headaches (when compared to  verapamil ),  migraine  attacks, and  hypnic headache  indicate good efficacy. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11417", "text": "The adverse effects of lithium include: [ 60 ] [ 61 ] [ 62 ] [ 63 ] [ 64 ] [ 65 ] [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11418", "text": "Lithium carbonate can induce a 1\u20132\u00a0kg of weight gain. [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11419", "text": "In addition to tremors, lithium treatment appears to be a risk factor for development of  parkinsonism -like symptoms, although the causal mechanism remains unknown. [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11420", "text": "In the average bipolar patient, chronic lithium use is not associated with cognitive decline. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11421", "text": "Most side effects of lithium are dose-dependent. The lowest effective dose is used to limit the risk of side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11422", "text": "The rate of  hypothyroidism  is around six times higher in people who take lithium. Low thyroid hormone levels in turn increase the likelihood of developing depression. People taking lithium thus should routinely be assessed for hypothyroidism and treated with synthetic thyroxine if necessary. [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11423", "text": "Because lithium competes with the  antidiuretic hormone  in the kidney, it increases water output into the urine, a condition called nephrogenic  diabetes insipidus . Clearance of lithium by the kidneys is usually successful with certain diuretic medications, including  amiloride  and  triamterene . [ 75 ]  It increases the appetite and thirst (\"polydypsia\") and reduces the activity of  thyroid hormone  ( hypothyroidism ). [ 76 ] [ 77 ]  The latter can be corrected by treatment with  thyroxine  and does not require the lithium dose to be adjusted. Lithium is also believed to cause renal dysfunction, although this does not appear to be common. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11424", "text": "Lambert et al. (2016), comparing the rate of hypothyroidism in patients with bipolar disorder treated with 9 different medications, found that lithium users do not have a particularly high rate of hypothyroidism (8.8%) among BD patients \u2013 only 1.39 times the rate in  oxcarbazepine  users (6.3%). Lithium and quetiapine are not statistically different in terms of hypothyroidism rates. However, lithium users are tested much more frequently for hypothyroidism than those using other drugs. The authors write that there may be an element of surveillance bias in understanding lithium's effects on the thyroid glands, as lithium users are tested 2.3\u20133.1 times as often. Furthermore, the authors argue that because hypothyroidism is common among BD patients regardless of lithium treatment, regular thyroid testing should be applied to all BD patients, not just those on lithium. [ 79 ] [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11425", "text": "Lithium is a  teratogen , which can cause birth defects in a small number of newborns.  Case reports  and several  retrospective studies  have demonstrated possible increases in the rate of a  congenital heart defects  including  Ebstein's anomaly  if taken during pregnancy. Teratogenicity is affected by trimester and dose of Lithium. Most significantly affecting first-trimester cardiac development with greater effects at higher doses.  [ 80 ] [ 81 ] [ 82 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11426", "text": "As the risks of stopping Lithium can be significant, patients are sometimes recommended to stay on this medicine while pregnant. Careful weighing of the risks and benefits should be made in consultation with a  psychiatric physician .  [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11427", "text": "For patients who are exposed to lithium, or plan to stay on the medication throughout their pregnancy, fetal  echocardiography  is routinely performed to monitor for cardiac anomalies. [ 84 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11428", "text": "While lithium is typically the most effective treatment, possible alternatives to Lithium include  Lamotrigine  and  Second generation Antipsychotics  for the treatment of acute  bipolar depression  or for the management of bipolar patients with  normal mood  during pregnancy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11429", "text": "While only small amounts of Lithium are transmitted to the infant in breastmilk, there is limited data on the safety of  Breastfeeding  while on Lithium. Medical evaluation and monitoring of infants consuming breastmilk during maternal prescription may be indicated. [ 85 ] [ 86 ] [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11430", "text": "Lithium has been associated with several forms of kidney injury. [ 88 ] [ 89 ]   It is estimated that impaired urinary concentrating ability is present in at least half of individuals on chronic lithium therapy, a condition called lithium-induced  nephrogenic diabetes insipidus . [ 89 ]  Continued use of lithium can lead to more serious  kidney damage  in an aggravated form of  diabetes insipidus . [ 90 ] [ 91 ]  In rare cases, some forms of lithium-caused kidney damage may be progressive and lead to end-stage kidney failure with a reported incidence of 0.2% to 0.7%. [ 92 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11431", "text": "Some reports of kidney damage may be wrongly attributed to lithium, increasing the apparent rate of this adverse effect. [ 68 ]  Nielsen et al. (2018), citing 6 large observational studies since 2010, argue that findings of decreased kidney function are partially inflated by surveillance bias. Furthermore, modern data does not show that lithium increases the risk of end-stage kidney disease. [ 70 ]  Davis et al. (2018), using literature from a wider timespan (1977\u20132018), also found that lithium's association with chronic kidney disease is unproven with various contradicting results. They also find contradicting results regarding end-stage kidney disease. [ 93 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11432", "text": "A 2015 nationwide study suggests that chronic kidney disease can be avoided by maintaining the serum lithium concentration at a level of 0.6\u20130.8\u00a0mmol/L and by monitoring  serum creatinine  every 3\u20136 months. [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11433", "text": "Lithium-associated  hyperparathyroidism  is the leading cause of  hypercalcemia  in lithium-treated patients. Lithium may lead to exacerbation of pre-existing  primary hyperparathyroidism  or cause an increased set-point of calcium for parathyroid hormone suppression, leading to  parathyroid hyperplasia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11434", "text": "Lithium  plasma   concentrations  are known to be increased with concurrent use of  diuretics \u2014especially  loop diuretics  (such as furosemide) and  thiazides \u2014and  non-steroidal anti-inflammatory drugs  (NSAIDs) such as  ibuprofen . [ 60 ]  Lithium concentrations can also be increased with concurrent use of  ACE inhibitors  such as  captopril ,  enalapril , and  lisinopril . [ 94 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11435", "text": "Lithium is primarily  cleared  from the body through  glomerular filtration , but some is then reabsorbed together with sodium through the  proximal tubule . Its levels are therefore sensitive to water and  electrolyte  balance. [ 95 ]  Diuretics act by lowering water and sodium levels; this causes more reabsorption of lithium in the proximal tubules so that the removal of lithium from the body is less, leading to increased blood levels of lithium. [ 95 ] [ 96 ]  ACE inhibitors have also been shown in a retrospective case-control study to increase lithium concentrations. This is likely due to constriction of the afferent arteriole of the glomerulus, resulting in decreased glomerular filtration rate and clearance. Another possible mechanism is that ACE inhibitors can lead to a decrease in sodium and water. This will increase lithium reabsorption and its concentrations in the body. [ 95 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11436", "text": "Some drugs can increase the clearance of lithium from the body, which can result in decreased lithium levels in the blood. These drugs include  theophylline ,  caffeine , and  acetazolamide . Additionally, increasing dietary  sodium  intake may also reduce lithium levels by prompting the kidneys to excrete more lithium. [ 97 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11437", "text": "Lithium is known to be a potential precipitant of  serotonin syndrome  in people concurrently on serotonergic medications such as  antidepressants ,  buspirone  and certain opioids such as  pethidine  (meperidine),  tramadol ,  oxycodone ,  fentanyl  and others. [ 60 ] [ 98 ]  Lithium co-treatment is also a risk factor for  neuroleptic malignant syndrome  in people on antipsychotics and other antidopaminergic medications. [ 99 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11438", "text": "High doses of  haloperidol ,  fluphenazine , or  flupenthixol  may be hazardous when used with lithium; irreversible  toxic encephalopathy  has been reported. [ 100 ] \nIndeed, these and other  antipsychotics  have been associated with an increased risk of lithium  neurotoxicity , even with low therapeutic lithium doses. [ 101 ] [ 102 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11439", "text": "Classical psychedelics such as  psilocybin  and  LSD  may cause seizures if taken while using lithium, although further research is needed. [ 103 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11440", "text": "Lithium toxicity, which is also called lithium overdose and lithium poisoning, is the condition of having too much lithium in the blood. This condition also happens in persons who are taking lithium in which the lithium levels are affected by  drug interactions  in the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11441", "text": "In acute toxicity, people have primarily gastrointestinal symptoms such as vomiting and  diarrhea , which may result in  volume depletion . During acute toxicity, lithium distributes later into the central nervous system resulting in mild neurological symptoms, such as dizziness. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11442", "text": "In chronic toxicity, people have primarily neurological symptoms which include  nystagmus ,  tremor ,  hyperreflexia ,  ataxia , and  change in mental status . During chronic toxicity, the gastrointestinal symptoms seen in acute toxicity are less prominent. The symptoms are often vague and nonspecific. [ 104 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11443", "text": "If the lithium toxicity is mild or moderate, lithium dosage is reduced or stopped entirely. If the toxicity is severe, lithium may need to be removed from the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11444", "text": "The specific biochemical mechanism of lithium action in stabilizing mood is unknown. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11445", "text": "Upon ingestion, lithium becomes widely distributed in the  central nervous system  and interacts with a number of  neurotransmitters  and  receptors , decreasing  norepinephrine  release and increasing  serotonin  synthesis. [ 105 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11446", "text": "Unlike many other  psychoactive drugs ,  Li +  typically produces no obvious psychotropic effects (such as  euphoria ) in normal individuals at therapeutic concentrations. [ 105 ] \nLithium may also increase the release of  serotonin  by neurons in the brain. [ 106 ]  In vitro studies performed on serotonergic neurons from rat  raphe nuclei  have shown that when these neurons are treated with lithium,  serotonin  release is enhanced during a  depolarization  compared to no lithium treatment and the same depolarization. [ 107 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11447", "text": "Lithium both directly and indirectly inhibits  GSK3\u03b2 (glycogen synthase kinase 3\u03b2)  which results in the activation of  mTOR . This leads to an increase in neuroprotective mechanisms by facilitating the  Akt signaling pathway . [ 108 ]  GSK-3\u03b2 is a downstream target of monoamine systems. As such, it is directly implicated in cognition and mood regulation. [ 109 ] [ 108 ]  During mania, GSK-3\u03b2 is activated via dopamine overactivity. [ 108 ]  GSK-3\u03b2 inhibits the transcription factors  \u03b2-catenin  and cyclic AMP (cAMP) response element binding protein (CREB), by phosphorylation. This results in a decrease in the transcription of important genes encoding for  neurotrophins . [ 110 ] [ 111 ] [ 112 ]  In addition, several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium. [ 113 ] [ 114 ]  This hypothesis was supported by the low Ki of lithium for human pAp-phosphatase compatible within the range of therapeutic concentrations of lithium in the plasma of people (0.8\u20131 mM). The Ki of human pAp-phosphatase is ten times lower than that of  GSK3\u03b2 (glycogen synthase kinase 3\u03b2) . Inhibition of pAp-phosphatase by lithium leads to increased levels of pAp (3\u2032-5\u2032 phosphoadenosine phosphate), which was shown to inhibit  PARP-1 . [ 115 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11448", "text": "Another mechanism proposed in 2007 is that lithium may interact with  nitric oxide  (NO) signaling pathway in the central nervous system, which plays a crucial role in neural plasticity. The NO system could be involved in the antidepressant effect of lithium in the Porsolt forced swimming test in mice. [ 116 ] [ 117 ]  It was also reported that  NMDA receptor  blockage augments antidepressant-like effects of lithium in the mouse forced swimming test, [ 118 ]  indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of  learned helplessness ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11449", "text": "Lithium possesses  neuroprotective  properties by preventing  apoptosis  and increasing cell longevity. [ 119 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11450", "text": "Although the search for a novel lithium-specific receptor is ongoing, the high concentration of lithium compounds required to elicit a significant pharmacological effect leads mainstream researchers to believe that the existence of such a receptor is unlikely. [ 120 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11451", "text": "Evidence suggests that  mitochondrial  dysfunction is present in patients with bipolar disorder. [ 119 ] \n Oxidative stress  and reduced levels of  anti-oxidants  (such as  glutathione ) lead to cell death. Lithium may protect against oxidative stress by up-regulating complexes I and II of the  mitochondrial electron transport chain . [ 119 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11452", "text": "During mania, there is an increase in  neurotransmission  of  dopamine  that causes a secondary  homeostatic  down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression. [ 119 ]   Additionally, the post-synaptic actions of dopamine are mediated through  G-protein coupled receptors . Once dopamine is coupled to the G-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmission. Studies found that in  autopsies  (which do not necessarily reflect living people), people with bipolar disorder had increased G-protein coupling compared to people without bipolar disorder. [ 119 ]  Lithium treatment alters the function of certain subunits of the dopamine-associated G-protein, which may be part of its mechanism of action. [ 119 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11453", "text": "Glutamate  levels are observed to be elevated during  mania . Lithium is thought to provide long-term mood stabilization and have anti- manic  properties by modulating glutamate levels. [ 119 ]  It is proposed that lithium competes with magnesium for binding to  NMDA glutamate receptor ,  increasing the availability of glutamate in  post-synaptic   neurons , leading to a homeostatic increase in glutamate re-uptake which reduces glutamatergic transmission. [ 119 ] \nThe NMDA receptor is also affected by other  neurotransmitters  such as  serotonin  and  dopamine . Effects observed appear exclusive to lithium and have not been observed by other  monovalent  ions such as  rubidium  and  cesium . [ 119 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11454", "text": "GABA  is an inhibitory  neurotransmitter  that plays an important role in regulating  dopamine  and  glutamate   neurotransmission . [ 119 ]  It was found that patients with bipolar disorder had lower GABA levels, which results in  excitotoxicity  and can cause  apoptosis  (cell loss). Lithium has been shown to increase the level of GABA in plasma and cerebral spinal fluid. [ 121 ]  Lithium counteracts these degrading processes by decreasing pro-apoptotic  proteins  and stimulating release of  neuroprotective  proteins. [ 119 ]  Lithium's regulation of both excitatory dopaminergic and glutamatergic systems through GABA may play a role in its mood-stabilizing effects. [ 122 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11455", "text": "Lithium's therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms. [ 123 ]  The  cyclic AMP  secondary messenger system is shown to be modulated by lithium. Lithium was found to increase the basal levels of cyclic AMP but impair receptor-coupled stimulation of cyclic AMP production. [ 119 ]  It is hypothesized that the dual effects of lithium are due to the inhibition of  G-proteins  that mediate cyclic AMP production. [ 119 ]  Over a long period of lithium treatment, cyclic AMP and  adenylate cyclase  levels are further changed by  gene transcription factors . [ 119 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11456", "text": "Lithium treatment has been found to inhibit the enzyme  inositol monophosphatase , involved in degrading inositol monophosphate to inositol required in  PIP 2  synthesis. This leads to lower levels of  inositol triphosphate , created by decomposition of PIP 2 . [ 124 ]  This effect has been suggested to be further enhanced with an inositol triphosphate  reuptake inhibitor .  Inositol  disruptions have been linked to memory impairment and depression. It is known with good certainty that signals from the receptors coupled to the  phosphoinositide   signal transduction  are affected by lithium. [ 125 ]   myo-inositol  is also regulated by the high affinity  sodium mI transport system  (SMIT). Lithium is hypothesized to inhibit mI entering the cells and mitigate the function of SMIT. [ 119 ]  Reductions of cellular levels of  myo-inositol  results in the inhibition of the  phosphoinositide cycle . [ 119 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11457", "text": "Lithium's actions on Gsk3 result in activation of CREB, leading to higher expression of BDNF.  (Valproate, another mood stabilizer, also increases the expression of BDNF.) As expected of increased BDNF expression, chronic lithium treatment leads to increased  grey matter  volume in brain areas implicated in emotional processing and cognitive control. [ 126 ]  Bipolar patients treated with lithium also have higher  white matter  integrity compared to those taking other drugs. [ 127 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11458", "text": "Lithium also increases the expression of  mesencephalic astrocyte-derived neurotrophic factor  (MANF), another  neurotrophic factor , via the  AP-1 transcription factor . MANF is able to regulate  proteostasis  by interacting with  GRP78 , a protein involved in the  unfolded protein response . [ 128 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11459", "text": "Lithium was first used in the 19th century as a treatment for  gout  after scientists discovered that, at least in the laboratory, lithium could dissolve  uric acid  crystals isolated from the kidneys. The levels of lithium needed to dissolve urate in the body, however, were toxic. [ 129 ]  Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders,  Carl Lange  in Denmark [ 10 ]  and  William Alexander Hammond  in New York City [ 11 ]  used lithium to treat mania from the 1870s onwards."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11460", "text": "By the turn of the 20th century, as theory regarding mood disorders evolved and so-called \"brain gout\" disappeared as a medical entity, the use of lithium in psychiatry was largely abandoned; however, several lithium preparations were still produced for the control of renal calculi and  uric acid diathesis . [ 19 ]  As accumulating knowledge indicated a role for excess sodium intake in  hypertension  and  heart disease , lithium salts were prescribed to patients for use as a replacement for dietary  table salt  ( sodium chloride ). This practice and the sale of lithium itself were both banned in the United States in February 1949, following the publication of reports detailing side effects and deaths. [ 130 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11461", "text": "Also in 1949, the Australian psychiatrist  John Cade  and Australian  biochemist   Shirley Andrews  rediscovered the usefulness of lithium salts in treating mania while working at the Royal Park Psychiatric Hospital in  Victoria. [ 131 ]  They were injecting rodents with urine extracts taken from manic patients in an attempt to isolate a metabolic compound which might be causing mental symptoms. Since uric acid in gout was known to be psychoactive, ( adenosine receptors  on neurons are stimulated by it;  caffeine  blocks them), they needed soluble urate for a control. They used lithium urate, already known to be the most soluble urate compound, and observed that it caused the rodents to become tranquil. Cade and Andrews traced the effect to the lithium-ion itself, and after Cade ingested lithium himself to ensure its safety in humans, he proposed lithium salts as  tranquilizers . He soon succeeded in controlling mania in chronically hospitalized patients with them. This was one of the first successful applications of a drug to treat mental illness, and it opened the door for the development of medicines for other mental problems in the next decades. [ 132 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11462", "text": "The rest of the world was slow to adopt this treatment, largely because of deaths that resulted from even relatively minor overdosing, including those reported from the use of  lithium chloride  as a substitute for table salt. Largely through the research and other efforts of Denmark's  Mogens Schou  and  Paul Baastrup  in Europe, [ 129 ]  and  Samuel Gershon  and  Baron Shopsin  in the U.S., this resistance was slowly overcome. Following the recommendation of the  APA  Lithium Task Force  (William Bunney ,  Irvin Cohen  (Chair),  Jonathan Cole ,  Ronald R. Fieve , Samuel Gershon, Robert Prien, and Joseph Tupin [ 133 ] ), the application of lithium in manic illness was approved by the United States  Food and Drug Administration  in 1970, [ 134 ]  becoming the 50th nation to do so. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11463", "text": "Lithium has now become a part of Western popular culture. Characters in  Pi ,   Premonition ,  Stardust Memories ,   American Psycho ,  Garden State , and  An Unmarried Woman  all take lithium. It's the chief constituent of the calming drug in  Ira Levin 's dystopian  This Perfect Day .  Sirius XM  Satellite Radio in North America has a 1990s alternative rock station called Lithium, and several songs refer to the use of lithium as a mood stabilizer. These include: \"Equilibrium met Lithium\" by  South African  artist  Koos Kombuis , \" Lithium \" by  Evanescence , \" Lithium \" by  Nirvana , \"Lithium and a Lover\" by  Sirenia , \"Lithium Sunset\", from the album  Mercury Falling  by  Sting , [ 135 ]  and \"Lithium\" by  Thin White Rope ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11464", "text": "As with  cocaine in Coca-Cola , lithium was widely marketed as one of several  patent medicine  products popular in the late 19th and early 20th centuries and was the medicinal ingredient of a refreshment beverage.  Charles Leiper Grigg , who launched his St. Louis-based company The Howdy Corporation, invented a formula for a  lemon-lime  soft drink in 1920. The product, originally named \"Bib-Label Lithiated Lemon-Lime Soda\", was launched two weeks before the  Wall Street Crash of 1929 . [ 136 ]  It contained the  mood stabilizer   lithium citrate , and was one of many patent medicine products popular in the late-19th and early-20th centuries. [ 137 ]  Its name was soon changed to  7 Up . All American beverage makers were forced to remove lithium from beverages in 1948. Despite the ban, in 1950, the  Painesville Telegraph  still carried an advertisement for a lithiated lemon beverage. [ 138 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11465", "text": "Lithium carbonate  ( Li 2 CO 3 ) is the most commonly used form of  lithium salts , a  carbonic acid  involving the  lithium element  and a  carbonate ion . Other lithium salts are also used as medication, such as  lithium citrate  ( Li 3 C 6 H 5 O 7 ),  lithium sulfate ,  lithium chloride , and  lithium orotate . [ 139 ] [ 140 ]   Nanoparticles  and  microemulsions  have also been invented as  drug delivery  mechanisms. As of 2020, there is a lack of evidence that alternate formulations or salts of lithium would reduce the need for monitoring serum lithium levels or lower systemic toxicity. [ 139 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11466", "text": "As of 2017 lithium was marketed under many brand names worldwide, including Cade, Calith, Camcolit, Carbolim, Carbolit, Carbolith, Carbolithium, Carbolitium, Carbonato de Litio, Carboron, Ceglution, Contemnol, Efadermin (Lithium and Zinc Sulfate), Efalith (Lithium and Zinc Sulfate), Elcab, Eskalit, Eskalith, Frimania, Hypnorex, Kalitium, Karlit, Lalithium, Li-Liquid, Licarb, Licarbium, Lidin, Ligilin, Lilipin, Lilitin, Limas, Limed, Liskonum, Litarex, Lithane, Litheum, Lithicarb, Lithii carbonas, Lithii citras, Lithioderm, Lithiofor, Lithionit, Lithium, Lithium aceticum, Lithium asparagicum, Lithium Carbonate, Lithium Carbonicum, Lithium Citrate, Lithium DL-asparaginat-1-Wasser, Lithium gluconicum, Lithium-D-gluconat, Lithiumcarbonaat, Lithiumcarbonat, Lithiumcitrat, Lithiun, Lithobid, Lithocent, Lithotabs, Lithuril, Litiam, Liticarb, Litijum, Litio, Litiomal, Lito, Litocarb, Litocip, Maniprex, Milithin, Neurolepsin, Plenur, Priadel, Prianil, Prolix, Psicolit, Quilonium, Quilonorm, Quilonum, T\u00e9ralithe, and Theralite. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11467", "text": "Tentative evidence in  Alzheimer's disease  showed that lithium may slow progression. [ 141 ] [ 142 ]  It has been studied for its potential use in the treatment of  amyotrophic lateral sclerosis  (ALS), but a study showed lithium had no effect on ALS outcomes. [ 143 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11468", "text": "Lithium toxicity , also known as  lithium overdose , is the condition of having too much  lithium . Symptoms may include a tremor, increased reflexes, trouble walking, kidney problems, and an  altered level of consciousness . Some symptoms may last for a year after levels return to normal. Complications may include  serotonin syndrome . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11469", "text": "Lithium toxicity can occur due to excessive intake or decreased excretion. [ 1 ]  Excessive intake may be either a  suicide attempt  or accidental. [ 1 ]  Decreased excretion may occur as a result of  dehydration  such as from  vomiting  or  diarrhea , a  low sodium diet , or from  kidney problems . [ 1 ]  The diagnosis is generally based on symptoms and supported by a lithium level in blood serum of greater than 1.2 mEq/L. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11470", "text": "Gastric lavage  and  whole bowel irrigation  may be useful if done early. [ 1 ]   Activated charcoal  is not effective. [ 1 ]  For severe toxicity  hemodialysis  is recommended. [ 1 ]  The risk of death is generally low. [ 3 ]  Acute toxicity generally has better outcomes than chronic toxicity. [ 4 ]  In the United States about 5,000 cases are reported to  poison control centers  a year. [ 2 ]  Lithium toxicity was first described in 1898. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11471", "text": "Symptoms of lithium toxicity can be mild, moderate, or severe. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11472", "text": "Mild symptoms include nausea, feeling tired, and tremor occur at a level of 1.5 to 2.5 mEq/L in blood serum. Moderate symptoms include confusion, an increased heart rate, and low muscle tone occur at a level of 2.5 to 3.5 mEq/L. [ 1 ]  Severe symptoms include coma, seizures, low blood pressure and increased body temperature which occur at a lithium concentration greater than 3.5 mEq/L. [ 1 ]  When lithium overdoses produce neurological deficits or cardiac toxicity, the symptoms are considered serious and can be fatal. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11473", "text": "In acute toxicity, people have primarily gastrointestinal symptoms such as  vomiting  and  diarrhea , which may result in  volume depletion . During acute toxicity, lithium distributes later into the central nervous system causing dizziness and other mild neurological symptoms. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11474", "text": "In chronic toxicity, people have primarily neurological symptoms which include  nystagmus ,  tremor ,  hyperreflexia ,  ataxia , and  change in mental status . During chronic toxicity, the gastrointestinal symptoms seen in acute toxicity are less prominent. The symptoms are often vague and nonspecific. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11475", "text": "In acute on chronic toxicity [ clarification needed ] , people have symptoms of both acute and chronic toxicity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11476", "text": "People who survive an intoxication episode may develop persistent health problems. [ 8 ]  This group of persistent health symptoms are called syndrome of irreversible lithium-effectuated  neurotoxicity  (SILENT). [ 9 ]  The syndrome presents with irreversible neurological and neuro-psychiatric effects. [ 10 ]  The neurological signs are  cerebellar  dysfunction,  extrapyramidal symptoms , and  brainstem  dysfunction. [ 11 ]  The neuro-psychiatric findings present with memory deficits,  cognitive deficits, and  sub-cortical dementia . For a diagnosis, the syndrome requires the absence of prior symptoms and persistence of symptoms for greater than 2 months after cessation of lithium. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11477", "text": "Lithium is readily absorbed from the  gastrointestinal tract . [ 5 ]  It is distributed to the body with higher levels in the kidney,  thyroid , and bone as compared to other tissues. Since lithium is almost exclusively excreted by the  kidneys , people with preexisting  chronic kidney disease  are at high risk of developing lithium intoxication. [ 13 ]  The drug itself is also known to be  nephrotoxic , opening up the possibility of spontaneous emergence of toxicity at doses that were previously well-tolerated. Lithium toxicity can be mistaken for other syndromes associated with antipsychotic use, such as  serotonin syndrome  because lithium increases  serotonin  metabolites in the  cerebrospinal fluid . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11478", "text": "There are several drug interactions with lithium. Interactions can occur from  typical antipsychotics  or  atypical antipsychotics . In particular, certain drugs enhance lithium levels by increasing renal re-absorption at the proximal tubule. These drugs are  angiotensin-converting enzyme inhibitors ,  non-steroidal anti-inflammatory drugs  and  thiazide diuretics . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11479", "text": "The diagnosis is generally based on symptoms and supported by a lithium level blood level. [ 1 ] [ 2 ]  Blood levels are most useful six to twelve hours after the last dose. [ 2 ]  The normal blood serum lithium level in those on treatment is between 0.6-1.2 mEq/L. [ 1 ]  Some blood tubes contain  lithium heparin  which may result in falsely elevated results. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11480", "text": "When lithium toxicity is suspected tests may include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11481", "text": "Imaging tests are not helpful."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11482", "text": "If the person's lithium toxicity is mild or moderate, lithium dosage is reduced or stopped entirely. [ 13 ]  If the toxicity is severe, lithium may need to be removed from the body. The removal of lithium is done in a  hospital   emergency department . It may involve:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11483", "text": "Magnesium  is an essential element in biological systems. Magnesium occurs typically as the Mg 2+  ion. It is an essential mineral  nutrient  (i.e., element) for life [ 1 ] [ 2 ] [ 3 ] [ 4 ]  and is present in every  cell  type in every organism. For example,  adenosine triphosphate  (ATP), the main source of energy in cells, must bind to a magnesium ion in order to be biologically active. What is called ATP is often actually Mg-ATP. [ 5 ]  As such, magnesium plays a role in the stability of all  polyphosphate  compounds in the cells, including those associated with the synthesis of  DNA  and  RNA . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11484", "text": "Over 300  enzymes  require the presence of magnesium ions for their catalytic action, including  all  enzymes utilizing or synthesizing ATP, or those that use other  nucleotides  to synthesize DNA and RNA. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11485", "text": "In plants, magnesium is necessary for synthesis of  chlorophyll  and  photosynthesis . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11486", "text": "A balance of magnesium is vital to the well-being of all organisms. Magnesium is a relatively abundant ion in Earth's crust and mantle and is highly bioavailable in the  hydrosphere . This availability, in combination with a useful and very unusual chemistry, may have led to its utilization in evolution as an ion for signaling, enzyme activation, and  catalysis . However, the unusual nature of ionic magnesium has also led to a major challenge in the use of the ion in biological systems. Biological membranes are impermeable to magnesium (and other ions), so  transport proteins  must facilitate the flow of magnesium, both into and out of cells and intracellular compartments. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11487", "text": "Inadequate magnesium intake frequently causes muscle  spasms , and has been associated with  cardiovascular disease ,  diabetes ,  high blood pressure ,  anxiety  disorders,  migraines ,  osteoporosis , and  cerebral infarction . [ 8 ] [ 9 ]  Acute deficiency (see  hypomagnesemia ) is rare, and is more common as a drug side-effect (such as chronic alcohol or diuretic use) than from low food intake per se, but it can occur in people fed intravenously for extended periods of time. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11488", "text": "The most common symptom of excess oral magnesium intake is  diarrhea . Supplements based on  amino acid   chelates  (such as  glycinate ,  lysinate  etc.) are much better-tolerated by the  digestive system  and do not have the  side-effects  of the older compounds used, while  sustained-release   dietary supplements  prevent the occurrence of diarrhea. [ citation needed ]  Since the kidneys of adult humans excrete excess magnesium efficiently, oral magnesium poisoning in adults with normal  renal function  is very rare. Infants, which have less ability to excrete excess magnesium even when healthy, should not be given magnesium supplements, except under a physician's care. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11489", "text": "Pharmaceutical preparations with magnesium  are used to treat conditions including  magnesium deficiency  and  hypomagnesemia , as well as  eclampsia . [ 10 ]  Such preparations are usually in the form of  magnesium sulfate  or chloride when given  parenterally . Magnesium is absorbed with reasonable efficiency (30% to 40%) by the body from any soluble magnesium salt, such as the chloride or citrate. Magnesium is similarly absorbed from  Epsom salts , although the sulfate in these salts adds to their laxative effect at higher doses. Magnesium absorption from the insoluble oxide and hydroxide salts ( milk of magnesia ) is erratic and of poorer efficiency, since it depends on the neutralization and solution of the salt by the acid of the stomach, which may not be (and usually is not) complete."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11490", "text": "Magnesium orotate  may be used as adjuvant therapy in patients on optimal treatment for severe  congestive heart failure , increasing survival rate and improving clinical symptoms and patient's  quality of life . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11491", "text": "In 2022, magnesium salts were the 207th most commonly prescribed medication in the United States, with more than 1 \u00a0 million prescriptions. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11492", "text": "Magnesium can affect muscle relaxation through direct action on cell membranes. Mg 2+  ions close certain types of  calcium channels , which conduct positively charged  calcium ions  into  neurons . With an excess of magnesium, more channels will be blocked and nerve cells activity will decrease. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11493", "text": "Intravenous magnesium sulphate is used in treating  pre-eclampsia . [ 16 ]  For other than pregnancy-related hypertension, a meta-analysis of 22 clinical trials with dose ranges of 120 to 973\u00a0mg/day and a mean dose of 410\u00a0mg, concluded that magnesium supplementation had a small but statistically significant effect, lowering systolic blood pressure by 3\u20134\u00a0mm Hg and diastolic blood pressure by 2\u20133\u00a0mm Hg. The effect was larger when the dose was more than 370\u00a0mg/day. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11494", "text": "Higher dietary intakes of magnesium correspond to lower diabetes incidence. [ 18 ]  For people with diabetes or at high risk of diabetes, magnesium supplementation lowers fasting glucose. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11495", "text": "Magnesium is essential as part of the process that generates  adenosine triphosphate . [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11496", "text": "Mitochondria  are often referred to as the \"powerhouses of the cell\" because their primary role is generating energy for cellular processes. They achieve this by breaking down  nutrients , primarily  glucose , through a series of chemical reactions known as  cellular respiration . This process ultimately produces adenosine triphosphate (ATP), the cell's main energy currency."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11497", "text": "Magnesium and  vitamin D  have a synergistic relationship in the body, meaning they work together to optimize each other's functions: [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11498", "text": "Overall, maintaining adequate levels of both magnesium and vitamin D is essential for optimal health and well-being."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11499", "text": "It is theorized that the process of making testosterone from cholesterol, needs magnesium to function properly. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11500", "text": "Studies have shown that significant gains in testosterone occur after taking 10 mg magnesium/kg body weight/day. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11501", "text": "The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and  Recommended Dietary Allowances  (RDAs) for magnesium in 1997. If there is not sufficient information to establish EARs and RDAs, an estimate designated Adequate Intake (AI) is used instead. The current EARs for magnesium for women and men ages 31 and up are 265\u00a0mg/day and 350\u00a0mg/day, respectively. The RDAs are 320 and 420\u00a0mg/day. RDAs are higher than EARs so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy is 350 to 400\u00a0mg/day depending on age of the woman. RDA for lactation ranges 310 to 360\u00a0mg/day for same reason. For children ages 1\u201313 years, the RDA increases with age from 65 to 200\u00a0mg/day. As for safety, the IOM also sets  Tolerable upper intake levels  (ULs) for vitamins and minerals when evidence is sufficient. In the case of magnesium the UL is set at 350\u00a0mg/day. The UL is specific to magnesium consumed as a dietary supplement, the reason being that too much magnesium consumed at one time can cause diarrhea. The UL does not apply to food-sourced magnesium. Collectively the EARs, RDAs and ULs are referred to as  Dietary Reference Intakes . [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11502", "text": "* = Adequate intake"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11503", "text": "The  European Food Safety Authority  (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For women and men ages 18 and older, the AIs are set at 300 and 350\u00a0mg/day, respectively. AIs for pregnancy and lactation are also 300\u00a0mg/day. For children ages 1\u201317 years, the AIs increase with age from 170 to 250\u00a0mg/day. These AIs are lower than the U.S. RDAs. [ 28 ]  The European Food Safety Authority reviewed the same safety question and set its UL at 250\u00a0mg/day\u00a0\u2013  lower than the U.S. value. [ 29 ]  The magnesium UL is unique in that it is lower than some of the RDAs. It applies to intake from a pharmacological agent or dietary supplement only and does not include intake from food and water."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11504", "text": "For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of daily value (%DV). For magnesium labeling purposes, 100% of the daily value was 400\u00a0mg, but as of May 27, 2016, it was revised to 420\u00a0mg to bring it into agreement with the RDA. [ 30 ] [ 31 ]  A table of the old and new adult Daily Values is provided at  Reference Daily Intake ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11505", "text": "Green vegetables  such as  spinach  provide magnesium because of the abundance of  chlorophyll  molecules, which contain the ion.  Nuts  (especially  Brazil nuts ,  cashews  and  almonds ),  seeds  (e.g.,  pumpkin seeds ),  dark chocolate , roasted  soybeans ,  bran , and some  whole grains  are also good sources of magnesium. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11506", "text": "Although many foods contain magnesium, it is usually found in low levels. As with most nutrients, daily needs for magnesium are unlikely to be met by one serving of any single food. Eating a wide variety of fruits, vegetables, and grains will help ensure adequate intake of magnesium."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11507", "text": "Because magnesium readily dissolves in water, refined foods, which are often processed or cooked in water and dried, in general, are poor sources of the nutrient. For example,  whole-wheat bread  has twice as much magnesium as white bread because the magnesium-rich germ and bran are removed when white flour is processed. The table of food sources of magnesium suggests many dietary sources of magnesium."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11508", "text": "\"Hard\" water  can also provide magnesium, but  \"soft\" water  contains less of the ion. Dietary surveys do not assess magnesium intake from water, which may lead to underestimating total magnesium intake and its variability."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11509", "text": "Too much magnesium may make it difficult for the body to absorb  calcium . Not enough magnesium can lead to  hypomagnesemia  as described above, with irregular heartbeats, high blood pressure (a sign in humans but not some experimental animals such as rodents), insomnia, and muscle spasms ( fasciculation ). However, as noted, symptoms of low magnesium from pure dietary deficiency are thought to be rarely encountered."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11510", "text": "Following are some foods and the amount of magnesium in them: [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11511", "text": "In  animals , it has been shown that different cell types maintain different concentrations of magnesium. [ 35 ] [ 36 ] [ 37 ] [ 38 ]  It seems likely that the same is true for  plants . [ 39 ] [ 40 ]  This suggests that different cell types may regulate influx and efflux of magnesium in different ways based on their unique metabolic needs. Interstitial and systemic concentrations of free magnesium must be delicately maintained by the combined processes of buffering (binding of ions to proteins and other molecules) and muffling (the transport of ions to storage or extracellular spaces [ 41 ] )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11512", "text": "In plants, and more recently in animals, magnesium has been recognized as an important signaling ion, both activating and mediating many biochemical reactions. The best example of this is perhaps the regulation of  carbon  fixation in  chloroplasts  in the  Calvin cycle . [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11513", "text": "Magnesium is very important in cellular function. Deficiency of the  nutrient  causes disease of the affected organism. In single-cell organisms such as  bacteria  and  yeast , low levels of magnesium manifests in greatly reduced growth rates. In magnesium transport  knockout  strains of bacteria, healthy rates are maintained only with exposure to very high external concentrations of the ion. [ 44 ] [ 45 ]  In yeast,  mitochondrial  magnesium deficiency also leads to disease. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11514", "text": "Plants deficient in magnesium show stress responses. The first observable signs of both magnesium starvation and overexposure in plants is a decrease in the rate of  photosynthesis . This is due to the central position of the Mg 2+  ion in the  chlorophyll  molecule. The later effects of magnesium deficiency on plants are a significant reduction in growth and reproductive viability. [ 4 ]  Magnesium can also be toxic to plants, although this is typically seen only in  drought  conditions. [ 47 ] [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11515", "text": "In animals, magnesium deficiency ( hypomagnesemia ) is seen when the environmental availability of magnesium is low. In ruminant animals, particularly vulnerable to magnesium availability in pasture grasses, the condition is known as 'grass tetany'. Hypomagnesemia is identified by a loss of balance due to muscle weakness. [ 49 ]  A number of genetically attributable hypomagnesemia disorders have also been identified in humans. [ 50 ] [ 51 ] [ 52 ] [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11516", "text": "Overexposure to magnesium may be toxic to individual cells, though these effects have been difficult to show experimentally. [ citation needed ]   Hypermagnesemia , an overabundance of magnesium in the blood, is usually caused by loss of  kidney  function. Healthy animals rapidly excrete excess magnesium in the urine and stool. [ 54 ]  Urinary magnesium is called  magnesuria . Characteristic concentrations of magnesium in model organisms are: in  E. coli  30-100mM (bound), 0.01-1mM (free), in budding yeast 50mM, in mammalian cell 10mM (bound), 0.5mM (free) and in blood plasma 1mM. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11517", "text": "Mg 2+  is the fourth-most-abundant  metal   ion  in cells (per  moles ) and the most abundant free divalent cation \u2014 as a result, it is deeply and intrinsically woven into cellular  metabolism . Indeed, Mg 2+ -dependent  enzymes  appear in virtually every metabolic pathway: Specific binding of Mg 2+  to biological membranes is frequently observed, Mg 2+  is also used as a signalling molecule, and much of nucleic acid biochemistry requires Mg 2+ , including all reactions that require release of energy from ATP. [ 56 ] [ 57 ] [ 43 ]  In nucleotides, the triple-phosphate moiety of the compound is invariably stabilized by association with Mg 2+  in all enzymatic processes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11518", "text": "In photosynthetic organisms, Mg 2+  has the additional vital role of being the  coordinating ion  in the  chlorophyll  molecule. This role was discovered by  Richard Willst\u00e4tter , who received the Nobel Prize in Chemistry 1915 for the purification and structure of chlorophyll binding with sixth number of carbon"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11519", "text": "The chemistry of the Mg 2+  ion, as applied to enzymes, uses the full range of this ion's unusual reaction chemistry to fulfill a range of functions. [ 56 ] [ 58 ] [ 59 ] [ 60 ]  Mg 2+  interacts with substrates, enzymes, and occasionally both (Mg 2+  may form part of the active site). In general, Mg 2+  interacts with substrates through inner sphere coordination, stabilising anions or reactive intermediates, also including binding to ATP and activating the molecule to nucleophilic attack. When interacting with enzymes and other proteins, Mg 2+  may bind using inner or outer sphere coordination, to either alter the conformation of the enzyme or take part in the chemistry of the catalytic reaction. In either case, because Mg 2+  is only rarely fully dehydrated during ligand binding, it may be a water molecule associated with the Mg 2+  that is important rather than the ion itself. The  Lewis acidity  of Mg 2+  ( p K a  11.4) is used to allow both hydrolysis and condensation reactions (most common ones being phosphate ester hydrolysis and phosphoryl transfer) that would otherwise require pH values greatly removed from physiological values."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11520", "text": "ATP  (adenosine triphosphate), the main source of energy in cells, must be bound to a magnesium ion in order to be biologically active. What is called ATP is often actually Mg-ATP. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11521", "text": "Nucleic acids  have an important range of interactions with Mg 2+ . The binding of Mg 2+  to  DNA  and  RNA  stabilises structure; this can be observed in the increased melting temperature ( T m ) of double-stranded DNA in the presence of Mg 2+ . [ 56 ]  In addition,  ribosomes  contain large amounts of Mg 2+  and the stabilisation provided is essential to the complexation of this ribo-protein. [ 61 ]  A large number of enzymes involved in the biochemistry of nucleic acids bind Mg 2+  for activity, using the ion for both activation and catalysis. Finally, the  autocatalysis  of many  ribozymes  (enzymes containing only RNA) is Mg 2+  dependent (e.g. the yeast mitochondrial group II self splicing introns [ 62 ] )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11522", "text": "Magnesium ions can be critical in maintaining the positional integrity of closely clustered phosphate groups. These clusters appear in numerous and distinct parts of the  cell nucleus  and  cytoplasm . For instance, hexahydrated Mg 2+  ions bind in the deep  major groove  and at the outer mouth of A-form nucleic acid  duplexes . [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11523", "text": "Biological  cell membranes  and  cell walls  are polyanionic surfaces. This has important implications for the transport of ions, in particular because it has been shown that different membranes preferentially bind different ions. [ 56 ]  Both Mg 2+  and Ca 2+  regularly stabilize membranes by the cross-linking of  carboxylated  and  phosphorylated  head groups of lipids. However, the envelope membrane of  E. coli  has also been shown to bind Na + , K + , Mn 2+  and Fe 3+ . The transport of ions is dependent on both the concentration gradient of the ion and the electric potential (\u0394\u03a8) across the membrane, which will be affected by the charge on the membrane surface. For example, the specific binding of Mg 2+  to the  chloroplast  envelope has been implicated in a loss of photosynthetic efficiency by the blockage of K +  uptake and the subsequent acidification of the chloroplast stroma. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11524", "text": "The Mg 2+  ion tends to bind only weakly to  proteins  ( K a  \u2264 10 5 [ 56 ] ) and this can be exploited by the cell to switch  enzymatic  activity on and off by changes in the local concentration of Mg 2+ . Although the concentration of free cytoplasmic Mg 2+  is on the order of 1\u00a0mmol/L, the total Mg 2+  content of animal cells is 30\u00a0mmol/L [ 64 ]  and in plants the content of leaf endodermal cells has been measured at values as high as 100\u00a0mmol/L (Stelzer  et al. , 1990), much of which buffered in storage compartments. The cytoplasmic concentration of free Mg 2+  is buffered by binding to  chelators  (e.g., ATP), but also, what is more important, it is buffered by storage of Mg 2+  in intracellular compartments. [ citation needed ]  The transport of Mg 2+  between intracellular compartments may be a major part of regulating enzyme activity. The interaction of Mg 2+  with proteins must also be considered for the transport of the ion across biological membranes. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11525", "text": "In biological systems, only  manganese  (Mn 2+ ) is readily capable of replacing Mg 2+ , but only in a limited set of circumstances. Mn 2+  is very similar to Mg 2+  in terms of its chemical properties, including inner and outer shell complexation. Mn 2+  effectively binds ATP and allows hydrolysis of the energy molecule by most ATPases. Mn 2+  can also replace Mg 2+  as the activating ion for a number of Mg 2+ -dependent enzymes, although some enzyme activity is usually lost. [ 56 ]  Sometimes such enzyme metal preferences vary among closely related species: For example, the  reverse transcriptase  enzyme of  lentiviruses  like  HIV ,  SIV  and  FIV  is typically dependent on Mg 2+ , whereas the analogous enzyme for other  retroviruses  prefers Mn 2+ ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11526", "text": "The use of radioactive tracer elements in ion uptake assays allows the calculation of km, Ki and Vmax and determines the initial change in the ion content of the cells.  28 Mg decays by the emission of a high-energy beta or gamma particle, which can be measured using a scintillation counter. However, the radioactive half-life of  28 Mg, the most stable of the radioactive magnesium isotopes, is only 21 hours. This severely restricts the experiments involving the nuclide. Also, since 1990, no facility has routinely produced  28 Mg, and the price per mCi is now predicted to be approximately US$30,000. [ 65 ]  The chemical nature of Mg 2+  is such that it is closely approximated by few other cations. [ 66 ]  However, Co 2+ , Mn 2+  and Ni 2+  have been used successfully to mimic the properties of Mg 2+  in some enzyme reactions, and radioactive forms of these elements have been employed successfully in cation transport studies. The difficulty of using metal ion replacement in the study of enzyme function is that the relationship between the enzyme activities with the replacement ion compared to the original is very difficult to ascertain. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11527", "text": "A number of chelators of divalent cations have different fluorescence spectra in the bound and unbound states. [ 67 ]  Chelators for Ca 2+  are well established, have high affinity for the cation, and low interference from other ions. Mg 2+  chelators lag behind and the major fluorescence dye for Mg 2+  (mag-fura 2 [ 68 ] ) actually has a higher affinity for Ca 2+ . [ 69 ]  This limits the application of this dye to cell types where the resting level of Ca 2+  is < 1 \u03bcM and does not vary with the experimental conditions under which Mg 2+  is to be measured. Recently, Otten  et al.  (2001) have described work into a new class of compounds that may prove more useful, having significantly better binding affinities for Mg 2+ . [ 70 ]  The use of the fluorescent dyes is limited to measuring the free Mg 2+ . If the ion concentration is buffered by the cell by chelation or removal to subcellular compartments, the measured rate of uptake will give only minimum values of km and Vmax. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11528", "text": "First, ion-specific microelectrodes can be used to measure the internal free ion concentration of cells and organelles. The major advantages are that readings can be made from cells over relatively long periods of time, and that unlike dyes very little extra ion buffering capacity is added to the cells. [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11529", "text": "Second, the technique of two-electrode voltage-clamp allows the direct measurement of the ion flux across the membrane of a cell. [ 72 ]  The membrane is held at an electric potential and the responding current is measured. All ions passing across the membrane contribute to the measured current. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11530", "text": "Third, the technique of patch-clamp uses isolated sections of natural or artificial membrane in much the same manner as voltage-clamp but without the secondary effects of a cellular system. Under ideal conditions the conductance of individual channels can be quantified. This methodology gives the most direct measurement of the action of ion channels. [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11531", "text": "Flame  atomic absorption spectroscopy  (AAS) determines the total magnesium content of a biological sample. [ 67 ]  This method is destructive; biological samples must be broken down in concentrated acids to avoid clogging the fine nebulising apparatus. [ citation needed ]  Beyond this, the only limitation is that samples must be in a volume of approximately 2 mL and at a concentration range of 0.1 \u2013 0.4 \u03bcmol/L for optimum accuracy. [ citation needed ]  As this technique cannot distinguish between Mg 2+  already present in the cell and that taken up during the experiment, only content not uptaken can be quantified. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11532", "text": "Inductively coupled plasma  (ICP) using either the  mass spectrometry  (MS) or  atomic emission spectroscopy  (AES) modifications also allows the determination of the total ion content of biological samples. [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11533", "text": "The chemical and biochemical properties of Mg 2+  present the cellular system with a significant challenge when transporting the ion across biological membranes. The dogma of ion transport states that the transporter recognises the ion then progressively removes the water of hydration, removing most or all of the water at a selective pore before releasing the ion on the far side of the membrane. [ 74 ]  Due to the properties of Mg 2+ , large volume change from hydrated to bare ion, high energy of hydration and very low rate of ligand exchange in the inner  coordination sphere , these steps are probably more difficult than for most other ions. To date, only the ZntA protein of  Paramecium  has been shown to be a Mg 2+  channel. [ 75 ]  The mechanisms of Mg 2+  transport by the remaining proteins are beginning to be uncovered with the first three-dimensional structure of a Mg 2+  transport complex being solved in 2004. [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11534", "text": "The  hydration shell  of the Mg 2+  ion has a very tightly bound inner shell of six water molecules and a relatively tightly bound second shell containing 12\u201314 water molecules (Markham  et al. , 2002). Thus, it is presumed that recognition of the Mg 2+  ion requires some mechanism to interact initially with the hydration shell of Mg 2+ , followed by a direct recognition/binding of the ion to the protein. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11535", "text": "In spite of the mechanistic difficulty, Mg 2+  must be transported across membranes, and a large number of Mg 2+  fluxes across membranes from a variety of systems have been described. [ 77 ]  However, only a small selection of Mg 2+  transporters have been characterised at the molecular level."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11536", "text": "Magnesium   ions  (Mg 2+ ) in  cellular biology  are usually in almost all senses opposite to  Ca 2+  ions, because they are  bivalent  too, but have greater  electronegativity  and thus exert greater pull on water molecules, preventing passage through the channel (even though the magnesium itself is smaller). Thus, Mg 2+  ions block Ca 2+  channels such as ( NMDA channels ) and have been shown to affect gap junction channels forming  electrical synapses ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11537", "text": "The previous sections have dealt in detail with the chemical and biochemical aspects of Mg 2+  and its transport across cellular membranes. This section will apply this knowledge to aspects of whole plant physiology, in an attempt to show how these processes interact with the larger and more complex environment of the multicellular organism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11538", "text": "Mg 2+  is essential for plant growth and is present in higher plants in amounts on the order of 80 \u03bcmol g \u22121  dry weight. [ 4 ]  The amounts of Mg 2+  vary in different parts of the plant and are dependent upon nutritional status. In times of plenty, excess Mg 2+  may be stored in vascular cells (Stelzer  et al. , 1990; [ 40 ]  and in times of starvation Mg 2+  is redistributed, in many plants, from older to newer leaves. [ 4 ] [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11539", "text": "Mg 2+  is taken up into plants via the roots. Interactions with other cations in the  rhizosphere  can have a significant effect on the uptake of the ion.(Kurvits and Kirkby, 1980; [ 79 ]  The structure of root cell walls is highly permeable to water and ions, and hence ion uptake into root cells can occur anywhere from the root hairs to cells located almost in the centre of the root (limited only by the  Casparian strip ). Plant cell walls and membranes carry a great number of negative charges, and the interactions of cations with these charges is key to the uptake of cations by root cells allowing a local concentrating effect. [ 80 ]  Mg 2+  binds relatively weakly to these charges, and can be displaced by other cations, impeding uptake and causing deficiency in the plant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11540", "text": "Within individual plant cells, the Mg 2+  requirements are largely the same as for all cellular life; Mg 2+  is used to stabilise membranes, is vital to the utilisation of ATP, is extensively involved in the nucleic acid biochemistry, and is a cofactor for many enzymes (including the ribosome). Also, Mg 2+  is the coordinating ion in the chlorophyll molecule. It is the intracellular compartmentalisation of Mg 2+  in plant cells that leads to additional complexity. Four compartments within the plant cell have reported interactions with Mg 2+ . Initially, Mg 2+  will enter the cell into the cytoplasm (by an as yet unidentified system), but free Mg 2+  concentrations in this compartment are tightly regulated at relatively low levels (\u22482\u00a0mmol/L) and so any excess Mg 2+  is either quickly exported or stored in the second intracellular compartment, the vacuole. [ 81 ]  The requirement for Mg 2+  in mitochondria has been demonstrated in yeast [ 82 ]  and it seems highly likely that the same will apply in plants. The chloroplasts also require significant amounts of internal Mg 2+ , and low concentrations of cytoplasmic Mg 2+ . [ 83 ] [ 84 ]  In addition, it seems likely that the other subcellular organelles (e.g., Golgi, endoplasmic reticulum, etc.) also require Mg 2+ ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11541", "text": "Once in the cytoplasmic space of root cells Mg 2+ , along with the other cations, is probably transported radially into the stele and the vascular tissue. [ 85 ]  From the cells surrounding the xylem the ions are released or pumped into the xylem and carried up through the plant. In the case of Mg 2+ , which is highly mobile in both the xylem and phloem, [ 86 ]  the ions will be transported to the top of the plant and back down again in a continuous cycle of replenishment. Hence, uptake and release from vascular cells is probably a key part of whole plant Mg 2+  homeostasis. Figure 1 shows how few processes have been connected to their molecular mechanisms (only vacuolar uptake has been associated with a transport protein, AtMHX)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11542", "text": "The diagram shows a schematic of a plant and the putative processes of Mg 2+  transport at the root and leaf where Mg 2+  is loaded and unloaded from the vascular tissues. [ 4 ]  Mg 2+  is taken up into the root cell wall space (1) and interacts with the negative charges associated with the cell walls and membranes. Mg 2+  may be taken up into cells immediately (symplastic pathway) or may travel as far as the Casparian band (4) before being absorbed into cells (apoplastic pathway; 2). The concentration of Mg 2+  in the root cells is probably buffered by storage in root cell vacuoles (3). Note that cells in the root tip do not contain vacuoles. Once in the root cell cytoplasm, Mg 2+  travels toward the centre of the root by  plasmodesmata , where it is loaded into the xylem (5) for transport to the upper parts of the plant. When the Mg 2+  reaches the leaves it is unloaded from the xylem into cells (6) and again is buffered in vacuoles (7). Whether cycling of Mg 2+  into the phloem occurs via general cells in the leaf (8) or directly from xylem to phloem via  transfer cells  (9) is unknown. Mg 2+  may return to the roots in the phloem sap."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11543", "text": "When a Mg 2+  ion has been absorbed by a cell requiring it for metabolic processes, it is generally assumed that the ion stays in that cell for as long as the cell is active. [ 4 ]  In vascular cells, this is not always the case; in times of plenty, Mg 2+  is stored in the vacuole, takes no part in the day-to-day metabolic processes of the cell (Stelzer  et al. , 1990), and is released at need. But for most cells it is death by senescence or injury that releases Mg 2+  and many of the other ionic constituents, recycling them into healthy parts of the plant. In addition, when Mg 2+  in the environment is limiting, some species are able to mobilise Mg 2+  from older tissues. [ 78 ]  These processes involve the release of Mg 2+  from its bound and stored states and its transport back into the vascular tissue, where it can be distributed to the rest of the plant. In times of growth and development, Mg 2+  is also remobilised within the plant as source and sink relationships change. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11544", "text": "The homeostasis of Mg 2+  within single plant cells is maintained by processes occurring at the plasma membrane and at the vacuole membrane (see Figure 2). The major driving force for the translocation of ions in plant cells is \u0394pH. [ 87 ]   H + -ATPases  pump H +  ions against their concentration gradient to maintain the pH differential that can be used for the transport of other ions and molecules. H +  ions are pumped out of the cytoplasm into the extracellular space or into the vacuole. The entry of Mg 2+  into cells may occur through one of two pathways, via channels using the \u0394\u03a8 (negative inside) across this membrane or by  symport  with H +  ions. To transport the Mg 2+  ion into the vacuole requires a Mg 2+ /H +   antiport  transporter (such as AtMHX). The H + -ATPases are dependent on Mg 2+  (bound to ATP) for activity, so that Mg 2+  is required to maintain its own homeostasis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11545", "text": "A schematic of a plant cell is shown including the four major compartments currently recognised as interacting with Mg 2+ .  H + -ATPases  maintain a constant \u0394pH across the plasma membrane and the vacuole membrane. Mg 2+  is transported into the vacuole using the energy of \u0394pH (in  A. thaliana  by AtMHX). Transport of Mg 2+  into cells may use either the negative \u0394\u03a8 or the \u0394pH. The transport of Mg 2+  into mitochondria probably uses \u0394\u03a8 as in the mitochondria of yeast, and it is likely that  chloroplasts  take Mg 2+  by a similar system. The mechanism and the molecular basis for the release of Mg 2+  from vacuoles and from the cell is not known. Likewise, the light-regulated Mg 2+  concentration changes in chloroplasts are not fully understood, but do require the transport of H +  ions across the  thylakoid  membrane."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11546", "text": "Mg 2+  is the coordinating metal ion in the chlorophyll molecule, and in plants where the ion is in high supply about 6% of the total Mg 2+  is bound to chlorophyll. [ 4 ] [ 88 ] [ 89 ]  Thylakoid stacking is stabilised by Mg 2+  and is important for the efficiency of photosynthesis, allowing phase transitions to occur. [ 90 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11547", "text": "Mg 2+  is probably taken up into chloroplasts to the greatest extent during the light-induced development from proplastid to chloroplast or etioplast to chloroplast. At these times, the synthesis of chlorophyll and the biogenesis of the thylakoid membrane stacks absolutely require the divalent cation. [ 91 ] [ 92 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11548", "text": "Whether Mg 2+  is able to move into and out of chloroplasts after this initial developmental phase has been the subject of several conflicting reports. Deshaies  et al.  (1984) found that Mg 2+  did move in and out of isolated chloroplasts from young pea plants, [ 93 ]  but Gupta and Berkowitz (1989) were unable to reproduce the result using older spinach chloroplasts. [ 94 ]  Deshaies  et al.  had stated in their paper that older pea chloroplasts showed less significant changes in Mg 2+  content than those used to form their conclusions. The relative proportion of immature chloroplasts present in the preparations may explain these observations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11549", "text": "The metabolic state of the chloroplast changes considerably between night and day. During the day, the chloroplast is actively harvesting the energy of light and converting it into chemical energy. The activation of the metabolic pathways involved comes from the changes in the chemical nature of the stroma on the addition of light. H +  is pumped out of the stroma (into both the cytoplasm and the lumen) leading to an alkaline pH. [ 95 ] [ 96 ]  Mg 2+  (along with K + ) is released from the lumen into the stroma, in an electroneutralisation process to balance the flow of H + . [ 97 ] [ 98 ] [ 99 ] [ 100 ]  Finally, thiol groups on enzymes are reduced by a change in the redox state of the stroma. [ 101 ]  Examples of enzymes activated in response to these changes are fructose 1,6-bisphosphatase, sedoheptulose bisphosphatase and  ribulose-1,5-bisphosphate carboxylase . [ 4 ] [ 59 ] [ 101 ]  During the dark period, if these enzymes were active a wasteful cycling of products and substrates would occur."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11550", "text": "Two major classes of the enzymes that interact with Mg 2+  in the stroma during the light phase can be identified. [ 59 ]  Firstly, enzymes in the glycolytic pathway most often interact with two atoms of Mg 2+ . The first atom is as an allosteric modulator of the enzymes' activity, while the second forms part of the active site and is directly involved in the catalytic reaction. The second class of enzymes includes those where the Mg 2+  is complexed to nucleotide di- and tri-phosphates (ADP and ATP), and the chemical change involves phosphoryl transfer. Mg 2+  may also serve in a structural maintenance role in these enzymes (e.g., enolase)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11551", "text": "Plant stress responses can be observed in plants that are under- or over-supplied with Mg 2+ . The first observable signs of Mg 2+  stress in plants for both starvation and toxicity is a depression of the rate of photosynthesis, it is presumed because of the strong relationships between Mg 2+  and chloroplasts/chlorophyll. In pine trees, even before the visible appearance of yellowing and necrotic spots, the photosynthetic efficiency of the needles drops markedly. [ 78 ]  In Mg 2+  deficiency, reported secondary effects include carbohydrate immobility, loss of RNA transcription and loss of protein synthesis. [ 102 ]  However, due to the mobility of Mg 2+  within the plant, the deficiency phenotype may be present only in the older parts of the plant. For example, in Pinus radiata starved of Mg 2+ , one of the earliest identifying signs is the  chlorosis  in the needles on the lower branches of the tree. This is because Mg 2+  has been recovered from these tissues and moved to growing (green) needles higher in the tree. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11552", "text": "A Mg 2+  deficit can be caused by the lack of the ion in the media (soil), but more commonly comes from inhibition of its uptake. [ 4 ]  Mg 2+  binds quite weakly to the negatively charged groups in the root cell walls, so that excesses of other cations such as K + , NH 4 + , Ca 2+ , and Mn 2+  can all impede uptake.(Kurvits and Kirkby, 1980; [ 79 ]  In acid soils Al 3+  is a particularly strong inhibitor of Mg 2+  uptake. [ 103 ] [ 104 ]  The inhibition by Al 3+  and Mn 2+  is more severe than can be explained by simple displacement, hence it is possible that these ions bind to the Mg 2+  uptake system directly. [ 4 ]  In bacteria and yeast, such binding by Mn 2+  has already been observed. Stress responses in the plant develop as cellular processes halt due to a lack of Mg 2+  (e.g. maintenance of \u0394pH across the plasma and vacuole membranes). In Mg 2+ -starved plants under low light conditions, the percentage of Mg 2+  bound to chlorophyll has been recorded at 50%. [ 105 ]  Presumably, this imbalance has detrimental effects on other cellular processes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11553", "text": "Mg 2+  toxicity stress is more difficult to develop. When Mg 2+  is plentiful, in general the plants take up the ion and store it (Stelzer  et al. , 1990). However, if this is followed by drought then ionic concentrations within the cell can increase dramatically. High cytoplasmic Mg 2+  concentrations block a K +  channel in the inner envelope membrane of the chloroplast, in turn inhibiting the removal of H +  ions from the chloroplast stroma. This leads to an acidification of the stroma that inactivates key enzymes in  carbon fixation , which all leads to the production of oxygen  free radicals  in the chloroplast that then cause oxidative damage. [ 106 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11554", "text": "Magnesium \"oil\"  (also referred to as  transdermal magnesium, magnesium hexahydrate ) is a colloquial misnomer for a concentrated solution of  magnesium chloride  in water. It is oily only in the sense that it feels oily to the touch, but unlike a true oil it mixes freely with water\u2014as it must, being an aqueous solution. Magnesium oil is supposed to be applied to the skin as an alternative to taking a magnesium supplement by mouth, [ 1 ]  although it is ineffective and scientifically unsupported due to lack of any convincing data that magnesium is absorbed in significant amounts through the skin. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11555", "text": "This  inorganic   compound \u2013related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11556", "text": "Magnesium transporters  are  proteins  that transport magnesium across the  cell membrane . All forms of life require  magnesium , yet the molecular mechanisms of Mg 2+  uptake from the environment and the distribution of this vital element within the organism are only slowly being elucidated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11557", "text": "The ATPase function of MgtA is highly  cardiolipin  dependent and has been shown to detect free magnesium in the \u03bcM range  [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11558", "text": "In bacteria, Mg 2+  is probably mainly supplied by  the CorA protein [ 2 ]  and, where the CorA protein is absent, by the  MgtE protein . [ 3 ] [ 4 ]  In yeast the initial uptake is via the Alr1p and Alr2p proteins, [ 5 ]  but at this stage the only internal Mg 2+  distributing protein identified is Mrs2p. [ 6 ]  Within the protozoa only one Mg 2+  transporter (XntAp) has been identified. [ 7 ]  In metazoa, Mrs2p [ 8 ]  and MgtE homologues [ 9 ]  have been identified, along with two novel Mg 2+  transport systems TRPM6/TRPM7 [ 10 ] [ 11 ]  and PCLN-1. [ 12 ]  Finally, in plants, a family of Mrs2p homologues has been identified [ 13 ] [ 14 ]  along with another novel protein, AtMHX. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11559", "text": "The evolution of Mg 2+  transport appears to have been rather complicated. Proteins apparently based on MgtE are present in bacteria and metazoa, but are missing in fungi and plants, whilst proteins apparently related to CorA are present in all of these groups. The two active transport transporters present in bacteria, MgtA and MgtB, do not appear to have any homologies in higher organisms. There are also Mg 2+  transport systems that are found only in the higher organisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11560", "text": "There are a large number of proteins yet to be identified that transport Mg 2+ . Even in the best studied eukaryote, yeast, Borrelly [ 16 ]  has reported a Mg 2+ /H +  exchanger without an associated protein, which is probably localised to the Golgi. At least one other major Mg 2+  transporter in yeast is still unaccounted for, the one affecting Mg 2+  transport in and out of the yeast vacuole. In higher, multicellular organisms, it seems that many Mg 2+  transporting proteins await discovery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11561", "text": "The CorA-domain-containing Mg 2+  transporters (CorA, Alr-like and Mrs2-like) have a similar but not identical array of affinities for divalent cations. In fact, this observation can be extended to all of the Mg 2+  transporters identified so far. This similarity suggests that the basic properties of Mg 2+  strongly influence the possible mechanisms of recognition and transport. However, this observation also suggests that using other metal ions as tracers for Mg 2+  uptake will not necessarily produce results comparable to the transporter's ability to transport Mg 2+ . Ideally, Mg 2+  should be measured directly. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11562", "text": "Since  28 Mg 2+  is practically unobtainable, much of the old data will need to be reinterpreted with new tools for measuring Mg 2+  transport, if different transporters are to be compared directly. The pioneering work of Kolisek [ 18 ]  and Froschauer [ 19 ]  using mag-fura 2 has shown that free Mg 2+  can be reliably measured  in vivo  in some systems. By returning to the analysis of CorA with this new tool, we have gained an important baseline for the analysis of new Mg 2+  transport systems as they are discovered. However, it is important that the amount of transporter present in the membrane is accurately determined if comparisons of transport capability are to be made. This bacterial system might also be able to provide some utility for the analysis of eukaryotic Mg 2+  transport proteins, but differences in biological systems of prokaryotes and eukaryotes will have to be considered in any experiment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11563", "text": "Comparing the functions of the characterised Mg 2+  transport proteins is currently almost impossible, even though the proteins have been investigated in different biological systems using different methodologies and technologies. Finding a system where all the proteins can be compared directly would be a major advance. If the proteins could be shown to be functional in bacteria ( S. typhimurium ), then a combination of the techniques of mag-fura 2, quantification of protein in the envelope membrane, and structure of the proteins (X-ray crystal or cryo-TEM) might allow the determination of the basic mechanisms involved in the recognition and transport of the Mg 2+  ion. However, perhaps the best advance would be the development of methods allowing the measurement of the protein's function in the patch-clamp system using artificial membranes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11564", "text": "In 1968, Lusk [ 20 ]  described the limitation of bacterial ( Escherichia coli ) growth on Mg 2+ -poor media, suggesting that bacteria required Mg 2+  and were likely to actively take this ion from the environment. The following year, the same group [ 21 ]  and another group, Silver, [ 22 ]  independently described the uptake and efflux of Mg 2+  in metabolically active  E. coli  cells using  28 Mg 2+ . By the end of 1971, two papers had been published describing the interference of Co 2+ , Ni 2+  and Mn 2+  on the transport of Mg 2+  in  E. coli [ 23 ]  and in Aerobacter aerogenes and Bacillus megaterium. [ 24 ]  In the last major development before the cloning of the genes encoding the transporters, it was discovered that there was a second Mg 2+  uptake system that showed similar affinity and transport kinetics to the first system, but had a different range of sensitivities to interfering cations. This system was also repressible by high extracellular concentrations of Mg 2+ \n. [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11565", "text": "The CorA gene and its corresponding protein are the most exhaustively studied Mg 2+  transport system in any organism. Most of the published literature on the CorA gene comes from the laboratory of M. E. Maguire. Recently the group of R. J. Schweyen made a significant impact on the understanding of Mg 2+  transport by CorA. The gene was originally named after the cobalt-resistant phenotype in  E. coli  that was caused by the gene's inactivation. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11566", "text": "The gene was genetically identified in  E. coli  by Park  et al. , [ 26 ]  but wasn't cloned until Hmiel  et al. [ 2 ]  isolated the  Salmonella enterica  serovar Typhimurium ( S. typhimurium ) homologue. Later it would be shown by Smith and Maguire [ 27 ]  that the CorA gene was present in 17\u00a0gram-negative bacteria. With the large number of complete genome sequences now available for prokaryotes, CorA has been shown to be virtually ubiquitous among the Eubacteria, as well as being widely distributed among the Archaea. [ 28 ]  The CorA locus in  E. coli  contains a single open reading frame of 948 nucleotides, producing a protein of 316 amino acids. This protein is well conserved amongst the Eubacteria and Archaea. Between  E. coli  and  S. typhimurium , the proteins are 98% identical, but in more distantly related species, the similarity falls to between 15 and 20%. [ 28 ]  In the more distantly related genes, the similarity is often restricted to the C-terminal part of the protein, and a short amino acid motif GMN within this region is very highly conserved. The CorA domain, also known as PF01544 in the pFAM conserved protein domain database ( http://webarchive.loc.gov/all/20110506030957/http%3A//pfam.sanger.ac.uk/ ), is additionally present in a wide range of higher organisms, and these transporters will be reviewed below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11567", "text": "The CorA gene is constitutively expressed in  S. typhimurium  under a wide range of external Mg 2+  concentrations. [ 29 ]  However, recent evidence suggests that the activity of the protein may be regulated by the PhoPQ  two-component regulatory system . [ 30 ]  This sensor responds to low external Mg 2+  concentrations during the infection process of  S. typhimurium  in humans. [ 31 ]  In low external Mg 2+  conditions, the PhoPQ system was reported to suppress the function of CorA and it has been previously shown that the transcription of the alternative Mg 2+  transporters MgtA and MgtB is activated in these conditions. [ 29 ]  Chamnongpol and Groisman suggest that this allows the bacteria to escape metal ion toxicity caused by the transport of other ions, particularly Fe(II), by CorA in the absence of Mg 2+ . [ 30 ]  Papp and Maguire offer a conflicting report on the source of the toxicity. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11568", "text": "The figure (not to scale) shows the originally published transmembrane (TM) domain topology of the  S. typhimurium  CorA protein, which was said to have three membrane-spanning regions in the C-terminal part of the protein (shown in blue), as determined by Smith  et al. . [ 33 ]  Evidence for CorA acting as a homotetramer was published by Warren  et al.  in 2004. [ 34 ]  In December 2005 the crystal structure of the CorA channel was posted to the RSCB protein structure database. The results showed that the protein has two TM domains and exists as a homopentamer, in direct conflict with the earlier reports.  Follow this link to see the structure in 3D . The soluble intracellular parts of the protein are highly charged, containing 31 positively charged and 53 negatively charged residues. Conversely, the TM domains contain only one charged amino acid, which has been shown to be unimportant in the activity of the transporter. [ 35 ]  From mutagenesis experiments, it appears that the chemistry of the Mg 2+  transport relies on the hydroxyl groups lining the inside of the transport pore; there is also an absolute requirement for the GMN motif (shown in red). [ 35 ] [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11569", "text": "Before the activity of CorA could be studied  in vivo , any other Mg 2+  transport systems in the bacterial host had to be identified and inactivated or deleted (see below). A strain of  S. typhimurium  containing a functional CorA gene but lacking MgtA and MgtB was constructed [ 37 ] (also see below), and the uptake kinetics of the transporter were analysed. [ 38 ]  This strain showed nearly normal growth rates on standard media (50 \u03bcM Mg 2+ ), but the removal of all three genes created a bacterial strain requiring 100 mM external Mg 2+  for normal growth. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11570", "text": "Mg 2+  is transported into cells containing only the CorA transport system with similar kinetics and cation sensitivities as the Mg 2+  uptake described in the earlier papers, and has additionally been quantified [ 38 ] (see table). The uptake of Mg 2+  was seen to plateau as in earlier studies, and although no actual mechanism for the decrease in transport has been determined, so it has been assumed that the protein is inactivated. [ 19 ]  Co 2+  and Ni 2+  are toxic to  S. typhimurium  cells containing a functional CorA protein and this toxicity stems from the blocking of Mg 2+  uptake (competitive inhibition) and the accumulation of these ions inside the cell. [ 2 ]  Co 2+  and Ni 2+  have been shown to be transported by CorA by using radioactive tracer analysis, [ 2 ] [ 39 ]  although with lower affinities (km) and velocities (Vmax) than for Mg 2+  (see table). The km values for Co 2+  and Ni 2+  are significantly above those expected to be encountered by the cells in their normal environment, so it is unlikely that the CorA transport system mediates the uptake of these ions under natural conditions. [ 2 ]  To date, the evidence for Mn 2+  transport by CorA is limited to  E. coli . [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11571", "text": "The table lists the transport kinetics of the CorA Mg 2+  transport system. This table has been compiled from the publications of Snavely  et al.  (1989b), [ 38 ]  Gibson  et al.  (1991) [ 39 ]  and Smith  et al.  (1998a) [ 35 ]  and summarises the kinetic data for the CorA transport protein expressed from the wild type promoter in bacteria lacking MgtA and MgtB. km and Vmax were determined at 20\u00a0\u00b0C as the uptake of Mg 2+  at 37\u00a0\u00b0C was too rapid to measure accurately."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11572", "text": "Recently the Mg 2+ -dependent fluorescence of mag-fura 2 was used to measure the free Mg 2+  content of  S. typhimurium  cells in response to external Mg 2+ , which showed that CorA is the major uptake system for Mg 2+  in bacteria. [ 19 ]  The authors also showed for the first time that the changes in the electric potential (\u0394\u03a8) across the plasma membrane of the cell affected both the rate of Mg 2+  uptake and the free Mg 2+  content of the cell; depolarisation suppressed transport, while hyperpolarisation increased transport. The kinetics of transport were defined only by the rate of change of free Mg 2+  inside the cells (250 \u03bcM s \u22121 ). Because no quantification of the amount of CorA protein in the membrane was made, this value cannot be compared with other experiments on Mg 2+  transporters. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11573", "text": "The efflux of Mg 2+  from bacterial cells was first observed by Lusk and Kennedy (1969) [ 21 ]  and is mediated by the CorA Mg 2+  transport system in the presence of high extracellular concentrations of Mg 2+ . [ 38 ]  The efflux can also be triggered by Co 2+ , Mn 2+  and Ni 2+ , although not to the same degree as Mg 2+ . [ 23 ]  No Co 2+  efflux through the CorA transport system was observed. The process of Mg 2+  efflux additionally requires one of the CorB, CorC or CorD genes. [ 39 ]  The mutation of any single one of these genes leads to a Co 2+  resistance a little less than half of that provided by a CorA mutant. This effect may be due to the inhibition of Mg 2+  loss that would otherwise occur in the presence of high levels of Co 2+ . It is currently unknown whether Mg 2+  is more toxic when the CorBCD genes are deleted."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11574", "text": "It has been speculated that the Mg 2+  ion will initially interact with any transport protein through its hydration shell. [ 40 ]  Cobalt (III) hexaammine, Co(III)Hex, is a covalently bound (non-labile) analog for the first shell of hydration for several divalent cations, including Mg 2+ . The radius of the Co(III)Hex molecule is 244 pm, very similar to the 250 pm radius of the first hydration shell of Mg 2+ . This analog is a potent inhibitor of the CorA transport system, more so than Mg 2+ , Co 2+  or Ni 2+ . [ 41 ]  The additional strength of the Co(III)Hex inhibition might come from the blocking of the transport pore due to the inability of the protein to \u2018dehydrate\u2019 the substrate. It was also shown that Co(III)Hex was not transported into the cells, [ 41 ]  suggesting that at least partial dehydration would be required for the transport of the normal substrate (Mg 2+ ). Nickel (II) hexaammine, with a radius of 255 pm, did not inhibit the CorA transport system, suggesting a maximum size limit exists for the binding of the CorA substrate ion. [ 41 ]  These results suggest that the important property involved in the recognition of Mg 2+  by CorA is the size of the ion with its first shell of hydration. Hence, the volume change generally quoted for the bare to hydrated Mg 2+  ion of greater than 500-fold, including the second sphere of hydration, may not be biologically relevant, and may be a reason for the first sphere volume change of 56-fold to be more commonly used."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11575", "text": "The presence of these two genes was first suspected when Nelson and Kennedy (1972) [ 25 ]  showed that there were Mg 2+ -repressible and non-repressible Mg 2+  uptake systems in  E. coli . The non-repressible uptake of Mg 2+  is mediated by the CorA protein. In  S. typhimurium  the repressible Mg 2+  uptake was eventually shown to be via the MgtA and MgtB proteins. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11576", "text": "Both MgtA and MgtB are regulated by the PhoPQ system and are actively transcribed during the process of infection of human patients by  S. typhimurium . [ 31 ] [ 42 ] [ 43 ]  Although neither gene is required for pathogenicity, the MgtB protein does enhance the long-term survival of the pathogen in the cell. [ 44 ]  The genes are also upregulated  in vitro  when the Mg 2+  concentration falls below 50 \u03bcM (Snavely  et al. , 1991a). Although the proteins have km values similar to CorA and transport rates approximately 10 times less, the genes may be part of a Mg 2+  scavenging system. Chamnongpol and Groisman (2002) presents evidence that the role of these proteins may be to compensate for the inactivation of the CorA protein by the PhoPQ regulon. [ 30 ]  The authors suggest that the CorA protein is inactivated to allow the avoidance of metal toxicity via the protein in the low Mg 2+  environments  S. typhimurium  is subjected to by cells after infection."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11577", "text": "The proteins are both P-type ATPases [ 38 ] \n [ 45 ]  and neither gene shows any similarity to CorA. The MgtA and MgtB proteins are 75% similar (50% identical), although it seems that MgtB may have been acquired by  horizontal gene transfer  as part of Salmonella Pathogenicity Island 3. [ 45 ] [ 46 ]  The TM topology of the MgtB protein has been experimentally determined, showing that the protein has ten TM-spanning helices with the termini of the protein in the cytoplasm (see figure\n). MgtA is present in widely divergent bacteria, but is not nearly as common as CorA, while MgtB appears to have a quite restricted distribution. [ 47 ]  No hypotheses for the unusual distribution have been suggested."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11578", "text": "The figure, adapted from Smith  et al.  (1993b), [ 48 ]  shows the experimentally determined membrane topology of the MgtB protein in  S. typhimurium . The TM domains are shown in light blue and the orientation in the membrane and the positions of the N- and C-termini are indicated. The figure is not drawn to scale."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11579", "text": "While the MgtA and MgtB proteins are very similar, they do show some minor differences in activity. MgtB is very sensitive to temperature, losing all activity (with regard to Mg 2+  transport) at a temperature of 20\u00a0\u00b0C. [ 38 ]  Additionally, MgtB and MgtA are inhibited by different ranges of cations (Table A10.1 [ 38 ] )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11580", "text": "The table lists cation transport characteristics of the MgtA and MgtB proteins in  S. typhimurium  as well as the kinetic data for the MgtA and MgtB transport proteins at 37\u00a0\u00b0C. [ 38 ]  The Vmax numbers listed in parentheses are those for uptake at 20\u00a0\u00b0C. The inhibition of Mg 2+  transport by Mn 2+  via MgtA showed unusual kinetics (see Figure 1 of Snavely  et al. , 1989b [ 38 ] )"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11581", "text": "The MgtA and MgtB proteins are ATPases, using one molecule of ATP per transport cycle, whereas the Mg 2+  uptake via CorA is simply electrochemically favourable. Chamnongpol and Groisman (2002) have suggested that the MgtA and MgtB proteins form part of a metal toxicity avoidance system. [ 30 ]  Alternatively, as most P-type ATPases function as efflux mediating transporters, it has been suggested that the MgtA and MgtB proteins act as efflux proteins for a currently unidentified cation, and Mg 2+  transport is either non-specific or exchanged to maintain the electro-neutrality of the transport process. [ 49 ]  Further experiments will be required to define the physiological function of these proteins."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11582", "text": "Two papers describe MgtE, a fourth Mg 2+  uptake protein in bacteria unrelated to MgtA/B or CorA. [ 3 ] [ 4 ]  This gene has been sequenced and the protein, 312 amino acids in size, is predicted to contain either four or five TM spanning domains that are closely arranged in the C-terminal part of the protein (see figure). This region of the protein has been identified in the  Pfam  database as a conserved protein domain (PF01769) and species containing proteins that have this protein domain are roughly equally distributed throughout the Eubacteria and Archaea, although it is quite rare in comparison with the distribution of CorA. However, the diversity of the proteins containing the domain is significantly larger than that of the CorA domain. The Pfam database lists seven distinct groups of MgtE domain containing proteins, of which six contain an archaic or eubacterial member. The expression of MgtE is frequently controlled by a conserved RNA structure,  YkoK leader  or M-box. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11583", "text": "The figure (right), adapted from Smith  et al.  (1995) [ 4 ]  and the PFAM database entry, shows the computer-predicted membrane topology of the MgtE protein in  Bacillus firmus  OF4. The TM domains are shown in light blue. The  CBS domains , named for the protein they were identified in,  cystathionine-beta synthase , shown in orange, are identified in the Pfam database as regulatory domains, but the mechanism of action has not yet been described. They are found in several voltage-gated chloride channels. [ 52 ]  The orientation in the membrane and the positions of the N- and C-termini are indicated. This figure is not drawn to scale. This transporter has recently had its structure solved by x-ray crystallography. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11584", "text": "The MgtE gene was first identified by Smith  et al.  (1995) during a screen for CorA-like proteins in bacteria and complements the Mg 2+ -uptake-deficient  S. typhimurium  strain MM281 (corA mgtA mgtB), restoring wild type growth on standard media. [ 4 ]  The kinetics of Mg 2+  transport for the protein were not determined, as  28 Mg 2+  was unavailable. As a substitute, the uptake of  57 Co 2+  was measured and was shown to have a km of 82 \u03bcM and a Vmax of 354 pmol min \u22121  10 8  cells \u22121 . Mg 2+  was a competitive inhibitor with a Ki of 50 \u03bcM\u2014the Ki of Mg 2+  inhibition of  60 Co 2+  uptake via CorA is 10 \u03bcM. [ 2 ]  A comparison of the available kinetic data for MgtA and CorA is shown in the table. Clearly, MgtE does not transport Co 2+  to the same degree as CorA, and the inhibition of transport by Mg 2+  is also less efficient, which suggests that the affinity of MgtE for Mg 2+  is lower than that of CorA. The strongest inhibitor of Co 2+  uptake was Zn 2+ , with a Ki of 20 \u03bcM. [ 4 ]  The transport of Zn 2+  by this protein may be as important as that of Mg 2+ ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11585", "text": "The table shows a comparison of the transport kinetics of MgtE and CorA, and key kinetic parameter values for them are listed. As shown, the data has been generated at differing incubation temperatures. km and Ki are not significantly altered by the differing incubation temperature. Conversely, Vmax shows a strong positive correlation with temperature, hence the value of Co 2+  Vmax for MgtE is not directly comparable with the values for CorA."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11586", "text": "The earliest research showing that yeast takes up Mg 2+  appears to be done by Schmidt  et al.  (1949). However, these authors only showed altered yeast Mg 2+  content in a table within the paper, and the report's conclusions dealt entirely with the metabolism of phosphate. A series of experiments by Rothstein [ 54 ] [ 55 ]  shifted the focus more towards the uptake of the metal cations, showing that yeast take up cations with the following affinity series; Mg 2+ , Co 2+ , Zn 2+  > Mn 2+  > Ni 2+  > Ca 2+  > Sr 2+ . Additionally, it was suggested that the transport of the different cations is mediated by the same transport system [ 55 ] [ 56 ] [ 57 ] [ 58 ]  \u2014 a situation very much like that in bacteria."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11587", "text": "In 1998, MacDiarmid and Gardner finally identified the proteins responsible for the observed cation transport phenotype in  Saccharomyces cerevisiae . [ 5 ]  The genes involved in this system and a second mitochondrial Mg 2+  transport system, functionally identified significantly after the gene was cloned, are described in the sections below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11588", "text": "Two genes, ALR1 and ALR2, were isolated in a screen for Al 3+  tolerance (resistance) in yeast. [ 5 ]  Over-expression constructs containing yeast genomic DNA were introduced into wild type yeast and the transformants were screened for growth on toxic levels of Al 3+ . ALR1 and ALR2 containing plasmids allowed the growth of yeast in these conditions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11589", "text": "The Alr1p and Alr2p proteins consist of 859 and 858 amino acids respectively and are 70% identical. In a region in the C-terminal, half of these proteins are weakly similar to the full CorA protein. The computer-predicted TM topology of Alr1p is shown in the figure. The presence of a third TM domain was suggested by MacDiarmid and Gardner (1998), [ 5 ]  on the strength on sequence homology, and more recently by Lee and Gardner (2006), [ 59 ]  on the strength of mutagenesis studies, making the TM topology of these proteins more like that of CorA (see figure). Also, Alr1p contains the conserved GMN motif at the outside end of TM 2 (TM 2') and the mutation of the methionine (M) in this motif to a leucine (L) led to the loss of transport capability. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11590", "text": "The figure shows the two possible TM topologies of Alr1p. Part A of the figure shows the computer-predicted membrane topology of the Alr1p protein in yeast and part B shows the topology of Alr1p based on the experimental results of Lee and Gardner (2006). [ 59 ]  The GMN motif location is indicated in red and the TM domains in light blue. The orientation in the membrane and the positions of the N- and C-termini are indicated, the various sizes of the soluble domains are given in amino acids (AA), and TM domains are numbered by their similarity to CorA. Where any TM domain is missing, the remaining domains are numbered with primes. The figure is not drawn to scale.\nA third ALR-like gene is present in  S. cerevisiae  and there are two homologous genes in both  Schizosaccharomyces pombe  and  Neurospora crassa . These proteins contain a GMN motif like that of CorA, with the exception of the second  N. crassa  gene. No ALR-like genes have been identified in species outside of the fungi."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11591", "text": "Membrane fractionation and green fluorescent protein (GFP) fusion studies established that Alr1p is localised to the plasma membrane. [ 60 ] [ 61 ]  The localisation of the Alr1p was observed to be internalised and degraded in the vacuole in response to extracellular cations. Mg 2+ , at very low extracellular concentrations (100 \u03bcM; < 10% of the standard media Mg 2+  content), and Co 2+  and Mn 2+  at relatively high concentrations (> 20\u00d7 standard media), induced the change in Alr1p protein localisation, and the effect was dependent on functional ubiquitination, endocytosis and vacuolar degradation. [ 60 ]  This mechanism was proposed to allow the regulation of Mg 2+  uptake by yeast. \nHowever, a recent report  [ 61 ]  indicates that several of the observations made by Stadler et al. [ 60 ]  were not reproducible. [ 61 ]  For example, regulation of ALR1 mRNA accumulation by Mg 2+  supply was not observed, and the stability of the Alr1 protein was not reduced by exposure to excess Mg 2+ . The original observation of Mg-dependent accumulation of the Alr1 protein under steady-state low-Mg conditions was replicated, but this effect was shown to be an artifact caused by the addition of a small peptide (epitope) to the protein to allow its detection. Despite these problems, Alr1 activity was demonstrated to respond to Mg supply, [ 61 ]  suggesting that the activity of the protein is regulated directly, as was observed for some bacterial CorA proteins. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11592", "text": "A functional Alr1p (wild type) or Alr2p (overexpressed) is required for  S. cerevisiae  growth in standard conditions (4 mM Mg 2+ [ 5 ] ), and Alr1p can support normal growth at Mg 2+  concentrations as low as 30 \u03bcM. [ 60 ]   57 Co 2+  is taken up into yeast via the Alr1p protein with a km of 77 \u2013 105 \u03bcM (; [ 56 ]  C. MacDiarmid and R. C. Gardner, unpublished data), but the Ki for Mg 2+  inhibition of this transport is currently unknown. The transport of other cations by the Alr1p protein was assayed by the inhibition of yeast growth. The overexpression of Alr1p led to increased sensitivity to Ca 2+ , Co 2+ , Cu 2+ , La 3+ , Mn 2+ , Ni 2+  and Zn 2+ , an array of cations similar to those shown to be transported into yeast by a CorA-like transport system. [ 5 ]  The increased toxicity of the cations in the presence of the transporter is assumed to be due to the increased accumulation of the cation inside the cell."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11593", "text": "The evidence that Alr1p is primarily a Mg 2+  transporter is that the loss of Alr1p leads to a decreased total cell content of Mg 2+ , but not of other cations. Additionally, two electrophysiological studies where Alr1p was produced in yeast or  Xenopus  oocytes showed a Mg 2+ -dependent current in the presence of the protein; [ 62 ]  Salih  et al. , in prep."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11594", "text": "The kinetics of Mg 2+  uptake by Alr1p have been investigated by electrophysiology techniques on whole yeast cells. [ 62 ]  The results suggested that Alr1p is very likely to act as an ion-selective channel. In the same paper, the authors reported that Mg 2+  transport by Alr1p varied from 200 pA to 1500 pA, with a mean current of 264 pA. No quantification of the amount of protein producing the current was presented, so the results lack comparability with the bacterial Mg 2+  transport proteins."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11595", "text": "The alternative techniques of  28 Mg 2+  radiotracer analysis and mag-fura 2 to measure Mg 2+  uptake have not yet been used with Alr1p.  28 Mg 2+  is currently not available and the mag-fura 2 system is unlikely to provide simple uptake data in yeast. The yeast cell maintains a heterogeneous distribution of Mg 2+ [ 63 ]  suggesting that multiple systems inside the yeast are transporting Mg 2+  into storage compartments. This internal transport will very likely mask the uptake process. The expression of ALR1 in  S. typhimurium  without Mg 2+  uptake genes may be an alternative, but, as stated earlier, the effects of a heterologous expression system would need to be taken into account."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11596", "text": "The MNR2 gene encodes a protein closely related to the Alr proteins, but includes conserved features that define a distinct subgroup of CorA proteins in fungal genomes, suggesting a distinct role in Mg 2+  homeostasis. Like an alr1 mutant, growth of an mnr2 mutant was sensitive to Mg 2+ -deficient conditions, but the mnr2 mutant was observed to accumulate more Mg 2+  than a wild-type strain under these conditions. [ 64 ]  These phenotypes suggested that Mnr2 may regulate Mg 2+  storage within an intracellular compartment. Consistent with this interpretation, the Mnr2 protein was localized to the membrane of the vacuole, an internal compartment implicated in the storage of excess mineral nutrients by yeast. A direct role of Mnr2 in Mg 2+  transport was suggested by the observation that increased Mnr2 expression, which redirected some Mnr2 protein to the cell surface, also suppressed the Mg 2+ -requirement of an alr1 alr2 double mutant strain. The mnr2 mutation also altered accumulation of other divalent cations, suggesting this mutation may increase Alr gene expression or protein activity. Recent work  [ 61 ]  supported this model, by showing that Alr1 activity was increased in an mnr2 mutant strain, and that the mutation was associated with induction of Alr1 activity at a higher external Mg concentration than was observed for an Mnr2 wild-type strain. These effects were observed without any change in Alr1 protein accumulation, again indicating that Alr1 activity may be regulated directly by the Mg concentration within the cell."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11597", "text": "Like the ALR genes, the MRS2 gene was cloned and sequenced before it was identified as a Mg 2+  transporter. The MRS2 gene was identified in the nuclear genome of yeast in a screen for suppressors of a mitochondrial gene RNA splicing mutation, [ 65 ]  and was cloned and sequenced by Wiesenberger  et al.  (1992). [ 66 ]  Mrs2p was not identified as a putative Mg 2+  transporter until Bui  et al.  (1999). [ 6 ]  Gregan  et al.  (2001a) identified LPE10 by homology to MRS2 and showed that both LPE10 and MRS2 mutants altered the Mg 2+  content of yeast mitochondria and affected RNA splicing activity in the organelle. [ 67 ] [ 68 ]  Mg 2+  transport has been shown to be directly mediated by Mrs2p, [ 18 ]  but not for Lpe10p."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11598", "text": "The Mrs2p and Lpe10p proteins are 470 and 413 amino acid residues in size, respectively, and a 250\u2013300 amino acid region in the middle of the proteins shows a weak similarity to the full CorA protein. The TM topologies of the Mrs2p and Lpe10p proteins have been assessed using a protease protection assay [ 6 ] [ 67 ]  and are shown in the figure. TM 1 and 2 correspond to TM 2 and 3 in the CorA protein. The conserved GMN motif is at the outside end of the first TM domain, and when the glycine (G) in this motif was mutated to a cysteine (C) in Mrs2p, Mg 2+  transport was strongly reduced. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11599", "text": "The figure shows the experimentally determined topology of Mrs2p and Lpe10p as adapted from Bui  et al.  (1999) [ 6 ]  and Gregan  et al.  (2001a). [ 67 ]  The GMN motif location is indicated in red and the TM domains in light blue. The orientation in the membrane and the positions of the N- and C-termini are indicated. The various sizes of the soluble domains are given in amino acids (AA), TM domains are numbered, and the figure is not drawn to scale."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11600", "text": "Mrs2p has been localised to the mitochondrial inner membrane by subcellular fractionation and immunodetection [ 6 ]  and Lpe10p to the mitochondria. [ 67 ]  Mitochondria lacking Mrs2p do not show a fast Mg 2+  uptake, only a slow \u2018leak\u2019, and overaccumulation of Mrs2p leads to an increase in the initial rate of uptake. [ 18 ]  Additionally, CorA, when fused to the mitochondrial leader sequence of Mrs2p, can partially complement the mitochondrial defect conferred by the loss of either Mrs2p or Lpe10p. Hence, Mrs2p and/or Lpe10p may be the major Mg 2+  uptake system for mitochondria. A possibility is that the proteins form heterodimers, as neither protein (when overexpressed) can fully complement the loss of the other. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11601", "text": "The characteristics of Mg 2+  uptake in isolated mitochondria by Mrs2p were quantified using mag-fura 2. [ 18 ]  The uptake of Mg 2+  by Mrs2p shared a number of attributes with CorA. First, Mg 2+  uptake was directly dependent on the electric potential (\u0394\u03a8) across the boundary membrane. Second, the uptake is saturated far below that which the \u0394\u03a8 theoretically permits, so the transport of Mg 2+  by Mrs2p is likely to be regulated in a similar manner to CorA, possibly by the inactivation of the protein. Third, Mg 2+  efflux was observed via Mrs2p upon the artificial depolarisation of the mitochondrial membrane by valinomycin. Finally, the Mg 2+  fluxes through Mrs2p are inhibited by cobalt (III) hexaammine. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11602", "text": "The kinetics of Mg 2+  uptake by Mrs2p were determined in the Froschauer  et al.  (2004) paper on CorA in bacteria. [ 19 ]  The initial change in free Mg 2+  concentration was 150 \u03bcM s-1 for wild type and 750 \u03bcM s-1 for mitochondria from yeast overexpressing MRS2. No attempt was made to scale the observed transport to the amount of transporter present."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11603", "text": "The transport of Mg 2+  into Paramecium has been characterised largely by R. R. Preston and his coworkers. Electrophysiological techniques on whole Paramecium were used to identify and characterise Mg 2+  currents in a series of papers [ 69 ] [ 70 ] [ 71 ] [ 72 ]  before the gene was cloned by Haynes  et al.  (2002). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11604", "text": "The open reading frame for the XNTA gene is 1707 bp in size, contains two introns and produces a predicted protein of 550 amino acids. [ 7 ]  The protein has been predicted to contain 11 TM domains and also contains the \u03b11 and \u03b12 motifs (see figure) of the SLC8 ( Na+/Ca 2+  exchanger [ 73 ] ) and SLC24 ( K+ dependent Na+/Ca 2+  exchanger [ 74 ] ) human solute transport proteins. The XntAp is equally similar to the SLC8 and SLC24 protein families by amino acid sequence, but the predicted TM topology is more like that of SLC24, but the similarity is at best weak and the relationship is very distant. [ 7 ]  The AtMHX protein from plants also shares a distant relationship with the SLC8 proteins."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11605", "text": "The figure shows the predicted TM topology of XntAp. Adapted from Haynes  et al.  (2002), [ 7 ]  this figure shows the computer predicted membrane topology of XntAp in Paramecium. The orientation in the membrane was determined using HMMTOP. [ 75 ] [ 76 ]  The TM domains are shown in light blue, the \u03b11 and \u03b12 domains are shown in green. The orientation in the membrane and the positions of the N- and C-termini are indicated and the figure is not drawn to scale."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11606", "text": "The Mg 2+ -dependent currents carried by XntAp are kinetically like that of a channel protein and have an ion selectivity order of Mg 2+  > Co 2+ , Mn 2+  > Ca 2+  \u2014 a series again very similar to that of CorA. [ 72 ]  Unlike the other transport proteins reported so far, XntAp is dependent on intracellular Ca 2+ . The transport is also dependent on \u0394\u03a8, but again Mg 2+  is not transported to equilibrium, being limited to approximately 0.4 mM free Mg 2+  in the cytoplasm. The existence of an intracellular compartment with a much higher free concentration of Mg 2+  (8 mM) was supported by the results."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11607", "text": "The investigation of Mg 2+  in animals, including humans, has lagged behind that in bacteria and yeast. This is largely because of the complexity of the systems involved, but also because of the impression within the field that Mg 2+  was maintained at high levels in all cells and was unchanged by external influences. Only in the last 25 years has a series of reports begun to challenge this view, with new methodologies finding that free Mg 2+  content is maintained at levels where changes might influence cellular metabolism. [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11608", "text": "A bioinformatic search of the sequence databases identified one homologue of the MRS2 gene of yeast in a range of metazoans. [ 8 ]  The protein has a very similar sequence and predicted TM topology to the yeast protein, and the GMN motif is intact at the end of the first TM domain. The human protein, hsaMrs2p, has been localised to the mitochondrial membrane in mouse cells using a GFP fusion protein."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11609", "text": "Very little is known about the Mg 2+  transport characteristics of the protein in mammals, but Zsurka  et al.  (2001) has shown that the human Mrs2p complements the mrs2 mutants in the yeast mitochondrial Mg 2+  uptake system. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11610", "text": "The identification of this gene family in the metazoa began with a signal sequence trap method for isolating secreted and membrane proteins. [ 9 ]  Much of the identification has come from bioinformatic analyses. Three genes were eventually identified in humans, another three in mouse and three in  Caenorhabditis elegans , with a single gene in  Anopheles gambiae . The pFAM database lists the MgtE domain as pFAM01769 and additionally identifies a MgtE domain-containing protein in  Drosophila melanogaster . The proteins containing the MgtE domain can be divided into seven classes, as defined by pFAM using the type and organisation of the identifiable domains in each protein. Metazoan proteins are present in three of the seven groups. All of the metazoa proteins contain two MgtE domains, but some of these have been predicted only by context recognition (Coin, Bateman and Durbin, unpublished. See the pFAM website for further details)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11611", "text": "The human SLC41A1 protein contains two MgtE domains with 52% and 46% respective similarity to the PF01769 consensus sequence and is predicted to contain ten TM domains, five in each MgtE domain (see figure), which suggests that the MgtE protein of bacteria may work as a dimer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11612", "text": "Adapted from Wabakken  et al.  (2003) [ 9 ]  and the pFAM database, the figure shows the computer predicted membrane topology of MgtE in  H. sapiens . The TM domains are shown in light blue, the orientation in the membrane and the positions of the N- and C-termini are indicated, and the figure is not drawn to scale."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11613", "text": "Wabakken  et al.  (2003) [ 9 ]  found that the transcript of the SLC41A1 gene was expressed in all human tissues tested, but at varying levels, with the heart and testis having the highest expression of the gene. No explanation of the expression pattern has been suggested with regard to Mg 2+ -related physiology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11614", "text": "It has not been shown whether the SLC41 proteins transport Mg 2+  or complement a Mg 2+  transport mutation in any experimental system. However, it has been suggested that as MgtE proteins have no other known function, they are likely to be Mg 2+  transporters in the metazoa as they are in the bacteria. [ 9 ]  This will need to be verified using one of the now standard experiment systems for examining Mg 2+  transport."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11615", "text": "The investigation of the TRPM genes and proteins in human cells is an area of intense recent study and, at times, debate. Montell  et al.  (2002) [ 78 ]  have reviewed the research into the TRP genes, and a second review by Montell (2003) [ 79 ]  has reviewed the research into the TRPM genes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11616", "text": "The TRPM family of ion channels has members throughout the metazoa. The TRPM6 and TRPM7 proteins are highly unusual, containing both an ion channel domain and a kinase domain (Figure 1.7), the role of which brings about the most heated debate. [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11617", "text": "The activity of these two proteins has been very difficult to quantify. TRPM7 by itself appears to be a Ca 2+  channel [ 80 ]  but in the presence of TRPM6 the affinity series of transported cations places Mg 2+  above Ca 2+ . [ 10 ] [ 81 ]  The differences in reported conductance were caused by the expression patterns of these genes. TRPM7 is expressed in all cell types tested so far, while TRPM6 shows a more restricted pattern of expression. [ 82 ]  An unfortunate choice of experimental system by Voets  et al. , (2004) [ 83 ]  led to the conclusion that TRPM6 is a functional Mg 2+  transporter. However, later work by Chubanov  et al.  (2004) [ 82 ]  clearly showed that TRPM7 is required for TRPM6 activity and that the results of Voets  et al.  are explained by the expression of TRPM7 in the experimental cell line used by Voets  et al.  in their experiments. Whether TRPM6 is functional by itself is yet to be determined."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11618", "text": "The predicted TM topology of the TPRM6 and TRPM7 proteins has been adapted from Nadler  et al.  (2001), [ 10 ]  Runnels  et al.  (2001) [ 84 ]  and Montell  et al.  (2002), [ 78 ]  this figure shows the computer predicted membrane topology of the TRPM6 and TRPM7 proteins in  Homo sapiens . At this time, the topology shown should be considered a tentative hypothesis. The TM domains are shown in light blue, the pore loop in purple, the TRP motif in red and the kinase domain in green. The orientation in the membrane and the positions of the N- and C-termini are indicated and the figure is not drawn to scale."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11619", "text": "The conclusions of the Voets  et al.  (2004) [ 83 ]  paper are probably incorrect in attributing the Mg 2+  dependent currents to TRPM7 alone, and their kinetic data are likely to reflect the combined TRPM7/ TRPM6 channel. The report presents a robust collection of data consistent with a channel-like activity passing Mg 2+ , based on both electrophysiological techniques and also mag-fura 2 to determine changes in cytoplasmic free Mg 2+ ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11620", "text": "Claudins  allow for Mg 2+  transport via the  paracellular  pathway; that is, it mediates the transport of the ion through the tight junctions between cells that form an epithelial cell layer. In particular, Claudin-16 allows the selective reuptake of Mg 2+  in the human kidney. Some patients with mutations in the  CLDN19  gene also have altered magnesium transport. [ 85 ] [ 86 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11621", "text": "The gene  Claudin-16  was cloned by Simon  et al.  (1999), [ 12 ]  but only after a series of reports described the Mg 2+  flux itself with no gene or protein. [ 87 ] [ 88 ] [ 89 ]  The expression pattern of the gene was determined by RT-PCR, and was shown to be very tightly confined to a continuous region of the kidney tubule running from the medullary thick descending limb to the distal convoluted tubule. [ 12 ]  This localisation was consistent with the earlier reports for the location of Mg 2+  re-uptake by the kidney. Following the cloning, mutations in the gene were identified in patients with familial hypomagnesaemia with hypercalciuria and nephrocalcinosis, [ 90 ] [ 91 ]  strengthening the links between the gene and the uptake of Mg 2+ ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11622", "text": "The current knowledge of the molecular mechanisms for Mg 2+  transport in plants is very limited, with only three publications reporting a molecular basis for Mg 2+  transport in plants. [ 13 ] [ 14 ] [ 15 ]  However, the importance of Mg 2+  to plants has been well described, and physiological and ecophysiological studies about the effects of Mg 2+  are numerous. This section will summarise the knowledge of a gene family identified in plants that is distantly related to CorA. Another gene, a Mg 2+ /H +  exchanger (AtMHX [ 15 ] ), unrelated to this gene family and to CorA has also been identified, is localised to the vacuolar membrane, and will be described last."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11623", "text": "Schock  et al.  (2000) identified and named the family AtMRS2 based on the similarity of the genes to the MRS2 gene of yeast. [ 13 ]  The authors also showed that the AtMRS2-1 gene could complement a \u0394mrs2 yeast mutant phenotype. Independently, Li  et al.  (2001) [ 14 ]  published a report identifying the family and showing that two additional members could complement Mg 2+  transport deficient mutants, one in  S. typhimurium  and the other in  S. cerevisiae ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11624", "text": "The three genes that have been shown to transport Mg 2+  are AtMRS2-1, AtMRS2-10 and AtMRS2-11, and these genes produce proteins 442, 443 and 459 amino acids in size, respectively. Each of the proteins shows significant similarity to Mrs2p of yeast and a weak similarity to CorA of bacteria, contains the conserved GMN amino acid motif at the outside end of the first TM domain, and is predicted to have two TM domains."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11625", "text": "The AtMRS2-1 gene, when expressed in yeast from the MRS2 promoter and being fused C-terminally to the first 95 amino acids of the Mrs2p protein, was directed to the mitochondria, where it complemented a \u0394mrs2 mutant both phenotypically (mitochondrial RNA splicing was restored) and with respect to the Mg 2+  content of the organelle. [ 13 ]  No data on the kinetics of the transport was presented. The AtMRS2-11 gene was analysed in yeast (in the alr1 alr2 strain), where it was shown that expression of the gene significantly increased the rate of Mg 2+  uptake into starved cells over the control, as measured using flame atomic absorption spectroscopy of total cellular Mg 2+  content. However, Alr1p was shown to be significantly more effective at transporting Mg 2+  at low extracellular concentrations, suggesting that the affinity of AtMRS2-11 for Mg 2+  is lower than that of Alr1p. [ 14 ]  An electrophysiological (voltage clamp) analysis of the AtMRS2-11 protein in Xenopus oocytes also showed a Mg 2+ -dependent current at membrane potentials (\u0394\u03a8) of \u2013100 \u2013 \u2013150 mV inside. [ 92 ]  These values are physiologically significant, as several membranes in plants maintain \u0394\u03a8 in this range. However, the author had difficulty reproducing these results due to an apparent \"death\" of oocytes containing the AtMRS2-11 protein, and therefore these results should be viewed with caution."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11626", "text": "The AtMRS2-10 transporter has been analysed using radioactive tracer uptake analysis. [ 14 ]  63Ni 2+  was used as the substitute ion and Mg 2+  was shown to inhibit the uptake of 63Ni 2+  with a Ki of 20 \u03bcM. Uptake was also inhibited by Co(III)Hex and by other divalent cations. Only Co 2+  and Cu 2+  inhibited transport with Ki values less than 1 mM."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11627", "text": "The AtMRS2-10 protein was fused to GFP, and was shown to be localised to the plasma membrane. [ 14 ]  A similar experiment was attempted in the Schock  et al.  (2000) paper, [ 13 ]  but the observed localisation was not significantly different from that seen with unfused GFP. The most likely reason for the lack of a definitive localisation of AtMRS2-1 in the Schock  et al.  paper is that the authors removed the TM domains from the protein, thereby precluding its insertion into a membrane."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11628", "text": "The exact physiological significance of the AtMRS2-1 and AtMRS2-10 proteins in plants has yet to be clarified. The AtMRS2-11 gene has been overexpressed (from the CaMV 35S promoter) in A. thaliana. [ 92 ]  The transgenic line has been shown to accumulate high levels of the AtMRS2-11 transcript. A strong Mg 2+  deficiency phenotype (necrotic spots on the leaves, see Chapter 1.5 below) was recorded during the screening process (in both the T1 and T2 generations) for a homozygote line, but this phenotype was lost in the T3 generation and could not be reproduced when the earlier generations were screened a second time. The author suggested that environmental effects were the most likely cause of the inconsistent phenotype."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11629", "text": "The first magnesium transporter isolated in any multicellular organism, AtMHX shows no similarity to any previously isolated Mg 2+  transport protein. [ 15 ]  The gene was initially identified in the A. thaliana genomic DNA sequence database, by its similarity to the SLC8 family of Na+/Ca 2+  exchanger genes in humans."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11630", "text": "The cDNA sequence of 1990 bp is predicted to produce a 539-amino acid protein. AtMHX is quite closely related to the SLC8 family at the amino acid level and shares a topology with eleven predicted TM domains (Figure A10.5). There is one major difference in the sequence, in that the long non-membranal loop (see Figure A10.5) is 148 amino acids in the AtMHX protein but 500 amino acids in the SLC8 proteins. However, this loop is not well conserved and is not required for transport function in the SLC8 family. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11631", "text": "The AtMHX gene is expressed throughout the plant but most strongly in the vascular tissue. [ 15 ]  The authors suggest that the physiological role of the protein is to store Mg 2+  in these tissues for later release when needed. The protein localisation to the vacuolar membrane supports this suggestion (see also Chapter 1.5)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11632", "text": "The protein transports Mg 2+  into the vacuolar space and H +  out, as demonstrated by electrophysiological techniques. [ 15 ]  The transport is driven by the \u0394pH maintained between the vacuolar space (pH 4.5 \u2013 5.9) and the cytoplasm (pH 7.3 \u2013 7.6) by an H + -ATPase. [ 93 ] [ 94 ]  How the transport of Mg 2+  by the protein is regulated was not determined. Currents were observed to pass through the protein in both directions, but the Mg 2+  out current required a \u2018cytoplasmic\u2019 pH of 5.5, a condition not found in plant cells under normal circumstances. In addition to the transport of Mg 2+ , Shaul  et al.  (1999) [ 15 ]  also showed that the protein could transport Zn 2+  and Fe 2+ , but did not report on the capacity of the protein to transport other divalent cations (e.g. Co 2+  and Ni 2+ ) or its susceptibility to inhibition by cobalt (III) hexaammine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11633", "text": "The detailed kinetics of Mg 2+  transport have not been determined for AtMHX. However, physiological effects have been demonstrated. When A. thaliana plants were transformed with overexpression constructs of the AtMHX gene driven by the CaMV 35S promoter, the plants over-accumulated the protein and showed a phenotype of necrotic lesions in the leaves, which the authors suggest is caused by a disruption in the normal function of the vacuole, given their observation that the total Mg 2+  (or Zn 2+ ) content of the plants was not altered in the transgenic plants."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11634", "text": "The image has been adapted from Shaul  et al.  (1999) [ 15 ]  and Quednau et al. (2004), [ 73 ]  and combined with an analysis using HMMTOP, this figure shows the computer predicted membrane topology of the AtMHX protein in  Arabidopsis thaliana . At this time the topology shown should be considered a tentative hypothesis. The TM domains are shown in light blue, the orientation in the membrane and the positions of the N- and C-termini are indicated, and the figure is not drawn to scale. The \u03b11 and \u03b12 domains, shown in green, are both quite hydrophobic and may both be inserted into the membrane."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11635", "text": "Manganese  is an essential biological element in all organisms. [ 1 ]  It is used in many  enzymes  and proteins. [ 2 ] [ 3 ]  It is essential in  plants . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11636", "text": "The classes of  enzymes  that have manganese  cofactors  include  oxidoreductases ,  transferases ,  hydrolases ,  lyases ,  isomerases  and  ligases . Other enzymes containing manganese are  arginase  and  Mn-containing  superoxide dismutase  ( Mn-SOD ).  Also the enzyme class of  reverse transcriptases  of many  retroviruses  (though not  lentiviruses  such as  HIV ) contains manganese. Manganese-containing  polypeptides  are the  diphtheria toxin ,   lectins  and  integrins . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11637", "text": "Manganese is an essential human dietary element. It is present as a  coenzyme  in several biological processes, which include macronutrient metabolism, bone formation, and  free radical  defense systems. It is a critical component in dozens of proteins and enzymes. [ 3 ]  The human body contains about 12\u00a0mg of manganese, mostly in the bones. The soft tissue remainder is concentrated in the liver and kidneys. [ 5 ]  In the human brain, the manganese is bound to manganese  metalloproteins , most notably  glutamine synthetase  in  astrocytes . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11638", "text": "The  U.S. Institute of Medicine  (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for minerals in 2001. For manganese, there was not sufficient information to set EARs and RDAs, so needs are described as estimates for  Adequate Intakes  (AIs). As for safety, the IOM sets  Tolerable upper intake levels  (ULs) for vitamins and minerals when evidence is sufficient. In the case of manganese, the adult UL is set at 11\u00a0mg/day. Collectively the EARs, RDAs, AIs and ULs are referred to as  Dietary Reference Intakes  (DRIs). [ 7 ]  Manganese deficiency is rare. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11639", "text": "The  European Food Safety Authority  (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For people ages 15 and older, the AI is set at 3.0\u00a0mg/day. AIs for pregnancy and lactation is 3.0\u00a0mg/day. For children ages 1\u201314 years, the AIs increase with age from 0.5 to 2.0\u00a0mg/day. The adult AIs are higher than the U.S. RDAs. [ 9 ]  The EFSA reviewed the same safety question and decided that there was insufficient information to set a UL. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11640", "text": "For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For manganese labeling purposes, 100% of the Daily Value was 2.0\u00a0mg, but as of 27 May 2016 it was revised to 2.3\u00a0mg to bring it into agreement with the RDA. [ 11 ] [ 12 ]  A table of the old and new adult daily values is provided at  Reference Daily Intake ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11641", "text": "Excessive exposure or intake may lead to a condition known as  manganism , a  neurodegenerative  disorder that causes  dopaminergic  neuronal death and symptoms similar to  Parkinson's disease . [ 5 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11642", "text": "Manganese deficiency in humans, which is rare, results in a number of medical problems. Many common vitamin and mineral supplement products fail to include manganese in their compositions. Relatively high dietary intake of other minerals such as iron, magnesium, and calcium may inhibit the proper intake of manganese. A deficiency of manganese causes skeletal deformation in animals and inhibits the production of collagen in wound healing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11643", "text": "Many enzymatic systems need Mn to function, but in high levels, Mn can become toxic. One environmental reason Mn levels can increase in seawater is when hypoxic periods occur. [ 14 ]  Since 1990 there have been reports of Mn accumulation in marine organisms including fish, crustaceans, mollusks, and echinoderms. Specific tissues are targets in different species, including the gills, brain, blood, kidney, and liver/hepatopancreas. Physiological effects have been reported in these species. Mn can affect the renewal of immunocytes and their functionality, such as phagocytosis and activation of pro-phenoloxidase, suppressing the organisms' immune systems. This causes the organisms to be more susceptible to infections. As climate change occurs, pathogen distributions increase, and in order for organisms to survive and defend themselves against these pathogens, they need a healthy, strong immune system. If their systems are compromised from high Mn levels, they will not be able to fight off these pathogens and die. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11644", "text": "Mn-SOD is the type of SOD present in  eukaryotic   mitochondria , and also in most bacteria (this fact is in keeping with the bacterial-origin theory of mitochondria). The Mn-SOD enzyme is probably one of the most ancient, for nearly all organisms living in the presence of oxygen use it to deal with the toxic effects of  superoxide  ( O \u2212 2 ), formed from the 1-electron reduction of dioxygen. The exceptions, which are all bacteria, include  Lactobacillus plantarum  and related  lactobacilli , which use a different nonenzymatic mechanism with manganese (Mn 2+ ) ions complexed with polyphosphate, suggesting a path of evolution for this function in aerobic life."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11645", "text": "Manganese is also important in photosynthetic  oxygen evolution  in  chloroplasts  in plants. The  oxygen-evolving complex  (OEC) is a part of  photosystem II  contained in the  thylakoid membranes  of chloroplasts; it is responsible for the terminal  photooxidation of water  during the  light reactions  of  photosynthesis , and has a metalloenzyme core containing four atoms of manganese. [ 16 ] [ 17 ]  To fulfill this requirement, most broad-spectrum plant fertilizers contain manganese."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11646", "text": "Molybdenum  is an essential element in most organisms. [ 1 ]  It is most notably present in  nitrogenase [ 2 ]  which is an essential part of  nitrogen fixation . [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11647", "text": "Molybdenum is an essential element in most organisms; a 2008 research paper speculated that a scarcity of molybdenum in the Earth's early oceans may have strongly influenced the evolution of  eukaryotic life  (which includes all plants and animals). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11648", "text": "At least 50 molybdenum-containing enzymes have been identified, mostly in bacteria. [ 5 ] [ 6 ]  Those enzymes include  aldehyde oxidase ,  sulfite oxidase  and  xanthine oxidase . [ 7 ]  With one exception, Mo in proteins is bound by  molybdopterin  to give the molybdenum cofactor. The only known exception is  nitrogenase , which uses the  FeMoco  cofactor, which has the formula Fe 7 MoS 9 C. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11649", "text": "In terms of function, molybdoenzymes catalyze the oxidation and sometimes reduction of certain small molecules in the process of regulating  nitrogen ,  sulfur , and  carbon . [ 9 ]  In some animals, and in humans, the oxidation of  xanthine  to  uric acid , a process of  purine   catabolism , is catalyzed by  xanthine oxidase , a molybdenum-containing enzyme. The activity of xanthine oxidase is directly proportional to the amount of molybdenum in the body. An extremely high concentration of molybdenum reverses the trend and can inhibit purine catabolism and other processes. Molybdenum concentration also affects  protein synthesis ,  metabolism , and growth. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11650", "text": "Mo is a component in most  nitrogenases . Among molybdoenzymes, nitrogenases are unique in lacking the molybdopterin. [ 11 ] [ 12 ]  Nitrogenases catalyze the production of ammonia from atmospheric nitrogen:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11651", "text": "The  biosynthesis  of the  FeMoco   active site  is highly complex. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11652", "text": "Molybdate is transported in the body as MoO 4 2\u2212 . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11653", "text": "Molybdenum is an essential trace  dietary element . [ 14 ]  Four mammalian Mo-dependent enzymes are known, all of them harboring a  pterin -based  molybdenum cofactor  (Moco) in their active site:  sulfite oxidase ,  xanthine oxidoreductase ,  aldehyde oxidase , and  mitochondrial amidoxime reductase . [ 15 ]  People severely deficient in molybdenum have poorly functioning sulfite oxidase and are prone to toxic reactions to sulfites in foods. [ 16 ] [ 17 ]  The human body contains about 0.07\u00a0mg of molybdenum per kilogram of body weight, [ 18 ]  with higher concentrations in the liver and kidneys and lower in the vertebrae. [ 19 ]  Molybdenum is also present within human  tooth enamel  and may help prevent its decay. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11654", "text": "Acute toxicity has not been seen in humans, and the toxicity depends strongly on the chemical state. Studies on rats show a  median lethal dose  (LD 50 ) as low as 180\u00a0mg/kg for some Mo compounds. [ 21 ]  Although human toxicity data is unavailable, animal studies have shown that chronic ingestion of more than 10\u00a0mg/day of molybdenum can cause diarrhea, growth retardation,  infertility , low birth weight, and  gout ; it can also affect the lungs, kidneys, and liver. [ 22 ] [ 23 ]   Sodium tungstate  is a  competitive inhibitor  of molybdenum. Dietary tungsten reduces the concentration of molybdenum in tissues. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11655", "text": "Low soil concentration of molybdenum in a geographical band from northern China to Iran results in a general dietary  molybdenum deficiency , and is associated with increased rates of  esophageal cancer . [ 24 ] [ 25 ] [ 26 ]  Compared to the United States, which has a greater supply of molybdenum in the soil, people living in those areas have about 16 times greater risk for  esophageal   squamous cell carcinoma . [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11656", "text": "Molybdenum deficiency has also been reported as a consequence of non-molybdenum supplemented  total parenteral nutrition  (complete intravenous feeding) for long periods of time. It results in high blood levels of  sulfite  and  urate , in much the same way as  molybdenum cofactor deficiency . Since pure molybdenum deficiency from this cause occurs primarily in adults, the neurological consequences are not as marked as in cases of congenital cofactor deficiency. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11657", "text": "A congenital  molybdenum cofactor deficiency  disease, seen in infants, is an inability to synthesize  molybdenum cofactor , the heterocyclic molecule discussed above that binds molybdenum at the active site in all known human enzymes that use molybdenum. The resulting deficiency results in high levels of  sulfite  and  urate , and neurological damage. [ 29 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11658", "text": "Most molybdenum is excreted from the human body as molybdate in the urine. Furthermore, urinary excretion of molybdenum increases as dietary molybdenum intake increases. Small amounts of molybdenum are excreted from the body in the feces by way of the bile; small amounts also can be lost in sweat and in hair. [ 31 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11659", "text": "High levels of molybdenum can interfere with the body's uptake of  copper , producing  copper deficiency . Molybdenum prevents plasma proteins from binding to copper, and it also increases the amount of copper that is excreted in  urine .  Ruminants  that consume high levels of molybdenum suffer from  diarrhea , stunted growth,  anemia , and  achromotrichia  (loss of fur pigment). These symptoms can be alleviated by copper supplements, either dietary or injection. [ 33 ]  The effective copper deficiency can be aggravated by excess  sulfur . [ 19 ] [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11660", "text": "Copper reduction or deficiency can also be deliberately induced for therapeutic purposes by the compound  ammonium tetrathiomolybdate , in which the bright red anion  tetrathiomolybdate  is the copper-chelating agent. Tetrathiomolybdate was first used therapeutically in the treatment of  copper toxicosis  in animals. It was then introduced as a treatment in  Wilson's disease , a hereditary copper metabolism disorder in humans; it acts both by competing with copper absorption in the bowel and by increasing excretion. It has also been found to have an inhibitory effect on  angiogenesis , potentially by inhibiting the membrane translocation process that is dependent on copper ions. [ 35 ]  This is a promising avenue for investigation of treatments for  cancer ,  age-related macular degeneration , and other diseases that involve a pathologic proliferation of blood vessels. [ 36 ] [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11661", "text": "In some grazing livestock, most strongly in cattle, molybdenum excess in the soil of pasturage can produce scours ( diarrhea ) if the pH of the soil is neutral to alkaline; see  teartness ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11662", "text": "Nickel allergy  is any of several  allergic  conditions provoked by exposure to the chemical element  nickel . Nickel allergy often takes the form of  nickel allergic contact dermatitis  ( Ni-ACD ), a form of  allergic contact dermatitis  (ACD). Ni-ACD typically causes a rash that is red and itchy and that may be bumpy or scaly.  The main treatment for it is avoiding contact with nickel-releasing metals, such as inexpensive jewelry. Another form of nickel allergy is a  systemic  form:  systemic nickel allergy syndrome  ( SNAS ) can mimic some of the symptoms of  irritable bowel syndrome  (IBS) and also has a dermatologic component. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11663", "text": "The most common sign of nickel allergy is inflammation of the skin at an area that comes into regular contact with nickel. [ 2 ]  This often takes the form of a  reddened  patch of skin with raised bumps ( papules ) or small blisters ( vesicles ), and  edema . [ 2 ]  People with chronic dermatitis tend to have dry, scaly, and cracked skin at the site of contact. [ 2 ]  These sites of inflammation (called \"primary eruptions\") can occur anywhere on the skin that contacts nickel, but are most common on the hands, face, or anywhere that contacts metal objects such as jewelry or metal clothes buttons. [ 2 ]  Particularly high levels of nickel exposure can cause irritated patches of skin to appear at other sites on the body (called \"secondary eruptions\"). These typically occur as blistering rashes on the hands, eyelids, and at the inside of flexing joints (inside the elbow, back of the knee, etc.). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11664", "text": "Ingestion of nickel may cause a systemic reaction, which can result in generalized inflammation of the skin across the body, small blisters in the hands, irritation inside the flexing joints (flexural eczema), and  redness and irritation of both buttocks . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11665", "text": "Systemic contact dermatitis  (SCD) is defined as a  dermatitis  occurring in an epi-cutaneously contact-sensitized person when exposed to  haptens  systemically such as  orally ,  per rectum ,  intravesically ,  transcutaneously ,  intrauterinely ,  intravenously , or by  inhalation . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11666", "text": "The  pathophysiology  of systemic nickel allergy syndrome (SNAS) is not well understood. The  clinical course  is determined by an immunological interplay between two types of  T cells  (Th1 and  Th2  responses). SCD is often considered a subset of SNAS, but with only skin manifestations. [ 4 ]  SNAS presents with an array of symptoms ranging from respiratory to generalized skin rash to gastrointestinal symptoms. [ 5 ]  The gastrointestinal symptoms may mimic those of  irritable bowel syndrome . [ 1 ]  A meta review evaluating SNAS found that 1% of patients sensitized to nickel reacted to the nickel content of a 'normal' diet, and with increasing doses of nickel more individuals reacted [ 6 ]  SNAS is a multilayered immunological response demonstrating variance between individuals and doses of nickel exposure."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11667", "text": "Nickel is both naturally abundant \u2013 it is the fifth most common element on earth \u2013 and widely used in industry and commercial goods. [ 2 ]  Workplace nickel exposure is common in many industries, and the performance of normal work tasks can result in nickel skin levels sufficient to elicit dermatitis. [ 2 ]  Within the workplace, individuals may be exposed to significant amounts of nickel, airborne from the combustion of  fossil fuels  or from contact with tools that are  nickel plated . [ 7 ]  Historically, workplaces where prolonged contact with soluble nickel has been high have shown high risks for allergic contact nickel dermatitis. For example, nickel dermatitis was common in the past among nickel platers. [ 8 ]  Outbreaks of nickel allergy from consumer goods have been documented throughout the 20th century, with jewelry, stocking suspenders, and metallic buttons on blue jeans each resulting in dermatitis at the point of contact. [ 2 ]  Nickel can also be present in food and drinking water; ingestion of increased nickel is not associated with systemic allergic disease, but is associated with flare-ups of dermatitis or aggravation of vesicular hand eczema. [ 2 ]  Similarly, aggravation of dermatitis has been reported in response to nickel-containing surgical implants or dental gear. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11668", "text": "The risk of an object eliciting nickel allergy is linked to the amount of nickel released by its surface (and not to its total nickel content). [ 2 ]  Suspected objects can be screened by wiping the surface with a 1%  dimethylglyoxime  solution that turns pink if more than 0.5 \u03bcg/cm 2  per week is released by the surface. [ 2 ]  Various methods exist to test the skin or nails for nickel exposure, typically relying on wiping the skin, then quantifying the nickel on the wipe via  mass spectrometry . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11669", "text": "Dietary nickel exposure may come from high-nickel foods, possibly canned food (via the packaging), possibly stainless steel cookware (whereas some grades of stainless steel contain more nickel than others), or plumbing (especially the first water run from the tap in the morning). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11670", "text": "Nickel allergy results in a skin response after the skin comes in contact with an item that releases a large amount of nickel from its surface. It is commonly associated with nickel-containing belt buckles coming into prolonged contact with the skin. [ 9 ] [ 10 ] [ 11 ]  The skin reaction can occur at the site of contact, or sometimes spread beyond to the rest of the body. Free (released) nickel that is able to penetrate the  skin  is taken up by scavenger ( dendritic ) cells and then presented to the  immune system  T-Cells. With each subsequent exposure to nickel these  T cells  become stimulated and  duplicate  themselves. With enough exposure to nickel, the amassing clones of T-cells reach \"threshold\" and the skin develops a  rash . The rash can appear as acute, subacute, or chronic  eczema-like  skin patches, primarily at the site of contact with the nickel (e.g., earlobe from nickel earrings). From the time of exposure, the rash usually appears within 12\u2013120 hours and can last for 3\u20134 weeks or for the continued duration of nickel contact/exposure. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11671", "text": "Three simultaneous conditions must occur to trigger Ni-ACD:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11672", "text": "The  pathophysiology  is divided into  induction elicitation phases . Induction is the critical phase (immunological event) when skin contact to nickel results in antigen presentation to the T cells, and T cell duplication (cloning) occurs. The metal cation Ni ++  is a low molecular weight  hapten  that easily penetrates the  stratum corneum  (top layer of skin). Nickel then binds to skin protein carriers creating an antigenic  epitope . [ 13 ]  The determining factor in  sensitization  is exposure of significant amounts of \"free nickel\". [ 14 ]  This is important because different metal  alloys  release different amounts of free nickel. The antigenic epitope is collected by dermal dendritic cells and  Langerhans cells , the  antigen-presenting cells  (APC) of the skin, and undergo maturation and migration to regional  lymph nodes . The complex is predominantly expressed on  major histocompatibility complex  ( MHC) II , which activates and clonally expands naive  CD4+ T cells . [ 15 ]  Upon re-exposure these now primed T cells will be activated and massively recruited to the skin, resulting in the elicitation phase and the clinical presentation of Ni-ACD."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11673", "text": "Although ACD has been considered a  Th1  predominate process, recent studies highlight a more complex picture. In Ni-ACD other cells are involved including:  Th17 , Th22, Th1/ IFN  and the  innate immune  responses consistent with  toll-like receptor 4 . [ 16 ] \n [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11674", "text": "Nickel has a wide utility of application in manufactured metals because it is both strong and malleable, leading to ubiquitous presence and the potential for consumers to be in contact with it daily. However, for those who have the rash of allergic contact dermatitis (ACD) due to a nickel allergy, it can be a challenge to avoid. Foods, common kitchen utensils, cell phones, jewelry, and many other items may contain nickel and be a source of irritation due to the allergic reaction caused by the absorption of free released nickel through direct and prolonged contact. The most appropriate measure for nickel-allergic persons is to prevent contact with the allergen."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11675", "text": "In 2011, researchers showed that applying a thin layer of  glycerine   emollient  containing  nanoparticles  of either  calcium carbonate  or  calcium phosphate  on an isolated piece of pig skin ( in vitro ) and on the skin of mice ( in vivo ) prevents the penetration of nickel ions into the skin. The  nanoparticles  capture nickel ions by cation exchange, and remain on the surface of the skin, allowing them to be removed by simple washing with water. Approximately 11-fold fewer nanoparticles by mass are required to achieve the same efficacy as the  chelating  agent  ethylenediamine tetraacetic acid . Using nanoparticles with diameters smaller than 500\u00a0nm in topical creams may be an effective way to limit the exposure to  metal ions  that can cause skin irritation'. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11676", "text": "Pre-emptive avoidance strategies (PEAS) might ultimately lower the sensitization rates of children who would develop ACD [ 19 ]  It is theorized that prevention of exposure to nickel early on could reduce the number of those that are sensitive to nickel by one-quarter to one-third. Identification of the many sources of nickel is vital to understanding the nickel sensitization story, food like chocolate and fish, zippers, buttons, cell phones and even orthodontic braces and eyeglass frames might contain nickel.  Items that contain sentimental value (heirlooms, wedding rings) could be treated with an  enamel  or  rhodium plating . [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11677", "text": "The Dermatitis Academy has created an educational website to provide more information about nickel, including information about prevention, exposure, sources, and general information about nickel allergy. These resources provide guidance in a prevention initiative for children worldwide."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11678", "text": "Prevention of SNAS includes modifying dietary choices to avoid certain foods that are higher in nickel than others. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11679", "text": "Nickel allergy is typically diagnosed by  patch testing  \u2013 applying a patch with 2.5% (in North America) or 5% (in Europe)  nickel sulfate  to the upper back and looking for irritation on the skin. [ 2 ]  As with other causes of allergic contact dermatitis, patches containing several common allergens are typically applied to the back for 48 hours, removed, then the spots examined for allergic reactions 2 to 5 days later. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11680", "text": "SNAS can often mimic IBS [ 1 ]  and may be more common than is widely appreciated. [ 1 ]  It therefore should be considered as a  differential diagnosis  item when a doctor is considering a diagnosis of IBS, [ 1 ]  and nickel allergy testing is advisable as a means to exclude or confirm SNAS. [ 1 ]  Even before such testing, some differentiating factors in the  medical history  are if certain foods prompt the symptoms (for example, peanuts or shellfish), [ 1 ]  whereas IBS is not specific to those foods. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11681", "text": "Once a nickel allergy is detected, the best treatment is avoidance of nickel-releasing items. The top 13 categories that contain nickel include beauty accessories, eyeglasses, money, cigarettes, clothes, kitchen and household, electronics and office equipment, metal utensils, aliment, jewelry, batteries, orthodontic and dental appliances, and medical equipment. [ 22 ]  Other than strict avoidance of items that release free nickel, there are other treatment options for reduction of exposure. The first step is to limit friction between skin and metallic items. Susceptible people may try to limit sweating while wearing nickel items, to reduce nickel release and thus decrease chances for developing sensitization or allergy. Another option is to shield electronics, metal devices, and tools with fabric, plastic, or acrylic coverings. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11682", "text": "There are  dimethylglyoxime  test kits that can be very helpful to check for nickel release from items prior to purchasing. [ 23 ]  The American Contact Dermatitis Society 'find a provider' resource can help identify clinicians with training in providing guidance lists of safe items. [ 24 ]   In addition to avoidance, healthcare providers may prescribe additional creams or medications to help relieve the skin reaction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11683", "text": "Nickel allergy is the most common  contact allergy  in industrialized countries, affecting around 8% to 19% of adults and 8% to 10% of children. [ 2 ]  Women are affected 4\u201310 times as frequently as men. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11684", "text": "As nickel can be harmful to skin, its use in daily products must be regulated. A safety directive has been in place in Europe since 2004.  Denmark  in 1980, and then shortly after the  European Union  (EU), enacted legislation that limited the amount of free nickel in consumer products that come in contact with the skin. This resulted in significantly decreased rates of sensitization among Danish children 0 to 18 years of age from 24.8% to 9.2% between 1985 and 1998, with similar reductions in sensitization throughout the EU. [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11685", "text": "No such directive exists in the United States, but efforts are under way to mandate safe use guidelines for nickel. In August 2015, the  American Academy of Dermatology  (AAD) adopted a nickel safety position paper. [ 27 ]  The exact prevalence of Ni-ACD in the general population in the US is largely unknown. However, current estimates gauge that roughly 2.5 million US adults and 250,000 children have a nickel allergy, which costs an estimated $5.7 billion per year for treatment of symptoms. [ 28 ]   Loma Linda University , Nickel Allergy Alliance, and Dermatitis Academy created the first open access self-reported patient registry to record nickel allergy prevalence data in the US.[ref 23] [ full citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11686", "text": "In the 17th century, copper miners in  Saxony , Germany, began to experience irritation caused by a \"dark red ore\". Since the substance, which would later be called nickel, led to many ailments, they believed it to be protected by \" goblins \", and called it \"Goblin's Copper\". [ 29 ]   Josef Jadassohn  described the first case of metal  contact dermatitis  in 1895, to a  mercury -based therapeutic cream, and confirmed the cause by  epi-cutaneous  patch testing. [ 30 ]  In the next century nickel began to be mass-produced for jewelry worldwide due to its cheap cost, resistance to corrosion and high supply."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11687", "text": "In 1979 a large comprehensive study of healthy US volunteers found that 9% had been unknowingly sensitized to nickel. [ 31 ]  As of 2008 [update] , that number has tripled. [ 32 ]  Most importantly, nickel allergy among children is increasing, with an estimated 250,000 children sensitized to nickel. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11688", "text": "Published literature shows an exponential increase in reported nickel allergy cases. [ 34 ]  The North American Contact Dermatitis Group (NACDG) patch tested 5,085 adults, presenting with eczema-like symptoms, showing 19.5% had a positive reaction to nickel. [ 35 ]  Nickel allergy is also more prevalent in women (17.1%) than men (3%), possibly due to cultural norms related to jewelry and ear piercings and therefore increased exposure to nickel. [ 36 ]  In order to investigate the current prevalence of nickel,  Loma Linda University , Nickel Allergy Alliance, and Dermatitis Academy, [ 37 ]  are conducting a self-reporting nickel allergy-dermatitis survey. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11689", "text": "A  nutrient  is a  substance  used by an organism to survive, grow and reproduce. The requirement for dietary nutrient intake applies to  animals ,  plants ,  fungi  and  protists . Nutrients can be incorporated into cells for  metabolic purposes  or  excreted  by cells to create non-cellular structures such as  hair ,  scales ,  feathers , or  exoskeletons . Some nutrients can be metabolically converted into smaller molecules in the process of releasing energy such as for  carbohydrates ,  lipids ,  proteins  and  fermentation  products ( ethanol  or  vinegar ) leading to end-products of water and  carbon dioxide . All organisms require water. Essential nutrients for animals are the energy sources, some of the  amino acids  that are combined to create  proteins , a subset of  fatty acids ,  vitamins  and certain  minerals . Plants require more diverse minerals absorbed through roots, plus carbon dioxide and oxygen absorbed through leaves.  Fungi  live on dead or living organic matter and meet nutrient needs from their host."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11690", "text": "Different types of organisms have different essential nutrients. Ascorbic acid ( vitamin C ) is essential to humans and some animal species but most other animals and many plants are able to synthesize it. Nutrients may be  organic  or inorganic: organic compounds include most compounds containing carbon, while all other chemicals are inorganic. Inorganic nutrients include nutrients such as  iron ,  selenium , and  zinc , while organic nutrients include, protein, fats, sugars and vitamins."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11691", "text": "A classification used primarily to describe nutrient needs of animals divides nutrients into  macronutrients  and  micronutrients . Consumed in relatively large amounts ( grams  or  ounces ), macronutrients (carbohydrates,  fats , proteins, water) are primarily used to generate energy or to incorporate into tissues for growth and repair. Micronutrients are needed in smaller amounts ( milligrams  or  micrograms ); they have subtle  biochemical  and  physiological  roles in cellular processes, like  vascular functions  or  nerve conduction . Inadequate amounts of essential nutrients or diseases that interfere with absorption, result in a deficiency state that compromises growth, survival and reproduction. Consumer advisories for dietary nutrient intakes such as the United States  Dietary Reference Intake , are based on the amount required to prevent deficiency and provide macronutrient and micronutrient guides for both lower and  upper limits  of intake. In many countries, regulations require that food product labels display information about the amount of any macronutrients and micronutrients present in the food in significant quantities. Nutrients in larger quantities than the body needs may have harmful effects. [ 1 ]  Edible plants also contain thousands of compounds generally called  phytochemicals  which have unknown effects on disease or health including a diverse class with non-nutrient status called  polyphenols  which remain poorly understood as of 2024."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11692", "text": "Macronutrients are defined in several ways. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11693", "text": "Macronutrients provide energy:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11694", "text": "Micronutrients  are essential dietary elements required in varying quantities throughout life to serve  metabolic  and  physiological functions . [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11695", "text": "An  essential nutrient  is a nutrient required for normal physiological function that cannot be synthesized in the body\u00a0\u2013 either at all or in sufficient quantities\u00a0\u2013 and thus must be obtained from a  dietary  source. [ 10 ] [ 11 ]  Apart from  water , which is universally required for the maintenance of  homeostasis  in mammals, [ 12 ]  essential nutrients are indispensable for various cellular  metabolic processes  and for the maintenance and function of tissues and organs. [ 13 ]  The nutrients considered essential for humans comprise nine amino acids, two fatty acids, thirteen  vitamins , fifteen  minerals  and  choline . [ 13 ]  In addition, there are several molecules that are considered conditionally essential nutrients since they are indispensable in certain developmental and pathological states. [ 13 ] [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11696", "text": "An essential amino acid is an amino acid that is required by an organism but cannot be synthesized  de novo  by it, and therefore must be supplied in its diet. Out of the twenty standard protein-producing amino acids, nine cannot be  endogenously  synthesized by humans:  phenylalanine ,  valine ,  threonine ,  tryptophan ,  methionine ,  leucine ,  isoleucine ,  lysine , and  histidine . [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11697", "text": "Essential fatty acids (EFAs) are  fatty acids  that humans and other animals must ingest because the body requires them for good health but cannot  synthesize  them. [ 18 ]  Only two fatty acids are known to be essential for humans:  alpha-linolenic acid  (an  omega-3 fatty acid ) and  linoleic acid  (an  omega-6 fatty acid ). [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11698", "text": "Vitamins occur in a variety of related forms known as  vitamers . The vitamers of a given vitamin perform the functions of that vitamin and prevent symptoms of deficiency of that vitamin. Vitamins are those essential organic molecules that are not classified as amino acids or fatty acids. They commonly function as  enzymatic cofactors , metabolic regulators or  antioxidants . Humans require thirteen vitamins in their diet, most of which are actually groups of related molecules (e.g.  vitamin E  includes  tocopherols  and  tocotrienols ): [ 20 ]  vitamins A, C, D, E, K,  thiamine  (B 1 ),  riboflavin  (B 2 ),  niacin  (B 3 ),  pantothenic acid  (B 5 ),  pyridoxine  (B 6 ),  biotin  (B 7 ),  folate  (B 9 ), and  cobalamin  (B 12 ). The requirement for vitamin D is conditional, as people who get sufficient exposure to ultraviolet light, either from the sun or an artificial source, synthesize vitamin D in the skin. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11699", "text": "Minerals are the  exogenous   chemical elements  indispensable for life. Although the four elements:  carbon ,  hydrogen ,  oxygen , and  nitrogen  ( CHON ) are essential for life, they are so plentiful in food and drink that these are not considered nutrients and there are no recommended intakes for these as minerals. The need for nitrogen is addressed by requirements set for protein, which is composed of nitrogen-containing amino acids.  Sulfur  is essential, but again does not have a recommended intake. Instead, recommended intakes are identified for the sulfur-containing amino acids  methionine  and  cysteine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11700", "text": "The essential nutrient  trace elements  for humans, listed in order of  Recommended Dietary Allowance  (expressed as a mass), are  potassium ,  chloride ,  sodium ,  calcium ,  phosphorus ,  magnesium ,  iron ,  zinc ,  manganese ,  copper ,  iodine ,  chromium ,  molybdenum , and  selenium . Additionally,  cobalt  is a component of Vitamin B 12  which is essential. There are other minerals which are essential for some plants and animals, but may or may not be essential for humans, such as  boron  and  silicon ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11701", "text": "Choline is an essential nutrient. [ 22 ] [ 23 ] [ 24 ]  The cholines are a family of water-soluble  quaternary ammonium compounds . [ 25 ] [ 26 ]  Choline is the parent compound of the cholines class, consisting of ethanolamine having three methyl substituents attached to the amino function. [ 27 ]  Healthy humans fed artificially composed diets that are deficient in choline develop fatty liver, liver damage, and muscle damage. Choline was not initially classified as essential because the human body can produce choline in small amounts through phosphatidylcholine metabolism. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11702", "text": "Conditionally essential nutrients are certain organic molecules that can normally be synthesized by an organism, but under certain conditions in insufficient quantities. In humans, such conditions include  premature birth , limited nutrient intake, rapid growth, and certain disease states. [ 14 ]   Inositol ,  taurine ,  arginine ,  glutamine  and  nucleotides  are classified as conditionally essential and are particularly important in neonatal diet and metabolism. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11703", "text": "Non-essential nutrients are substances within foods that can have a significant impact on health.  Dietary fiber  is not absorbed in the human digestive tract. [ 29 ]   Soluble fiber  is metabolized to butyrate and other short-chain fatty acids by bacteria residing in the large intestine. [ 30 ] [ 31 ] [ 32 ]  Soluble fiber is marketed as serving a  prebiotic  function with claims for promoting \"healthy\" intestinal bacteria. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11704", "text": "Ethanol  (C 2 H 5 OH) is not an essential nutrient, but it does supply approximately 29 kilojoules (7 kilocalories) of food energy per gram. [ 34 ]  For spirits (vodka, gin, rum, etc.) a standard serving in the United States is  44 millilitres ( 1 + 1 \u2044 2  US fluid ounces), which at 40% \u00a0 ethanol (80 \u00a0 proof) would be 14 grams and 410\u00a0kJ (98\u00a0kcal). At 50% \u00a0 alcohol, 17.5\u00a0g and 513\u00a0kJ (122.5\u00a0kcal). Wine and beer contain a similar amount of ethanol in servings of 150 and 350\u00a0mL (5 and 12\u00a0US\u00a0fl\u00a0oz), respectively, but these beverages also contribute to food energy intake from components other than ethanol. A 150\u00a0mL (5\u00a0US\u00a0fl\u00a0oz) serving of wine contains 420 to 540\u00a0kJ (100 to 130\u00a0kcal). A 350\u00a0mL (12\u00a0US\u00a0fl\u00a0oz) serving of beer contains 400 to 840\u00a0kJ (95 to 200\u00a0kcal). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11705", "text": "According to the U.S. Department of Agriculture, based on  NHANES  2013\u20132014 surveys, women ages 20 and up consume on average 6.8 \u00a0 grams of alcohol per day and men consume on average 15.5 grams per day. [ 35 ]  Ignoring the non-alcohol contribution of those beverages, the average ethanol contributions to daily food energy intake are 200 and 450\u00a0kJ (48 and 108\u00a0kcal), respectively. Alcoholic beverages are considered  empty calorie  foods because, while providing energy, they contribute no essential nutrients. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11706", "text": "By definition,  phytochemicals  include all nutritional and non-nutritional components of edible plants. [ 36 ]  Included as nutritional constituents are  provitamin  A  carotenoids , [ 37 ]  whereas those without nutrient status are diverse  polyphenols ,  flavonoids ,  resveratrol , and  lignans  that are present in numerous plant foods. [ 38 ]  Some phytochemical compounds are under preliminary research for their potential effects on human diseases and health. [ 36 ] [ 37 ] [ 38 ]  However, the qualification for nutrient status of compounds with poorly defined properties  in vivo  is that they must first be defined with a  Dietary Reference Intake  level to enable accurate food labeling, [ 39 ]  a condition not established for most phytochemicals that are claimed to provide antioxidant benefits. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11707", "text": "See  Vitamin ,  Mineral (nutrient) ,  Protein (nutrient)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11708", "text": "An inadequate amount of a nutrient is a deficiency. Deficiencies can be due to several causes, including an inadequacy in nutrient intake, called a dietary deficiency, or any of several conditions that interfere with the utilization of a nutrient within an organism. [ 1 ]  Some of the conditions that can interfere with nutrient utilization include problems with nutrient absorption, substances that cause a greater-than-normal need for a nutrient, conditions that cause nutrient destruction, and conditions that cause greater nutrient excretion. [ 1 ]  Nutrient toxicity occurs when excess consumption of a nutrient does harm to an organism. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11709", "text": "In the United States and Canada, recommended dietary intake levels of essential nutrients are based on the minimum level that \"will maintain a defined level of nutriture in an individual\", a definition somewhat different from that used by the  World Health Organization  and  Food and Agriculture Organization  of a \"basal requirement to indicate the level of intake needed to prevent pathologically relevant and clinically detectable signs of a dietary inadequacy\". [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11710", "text": "In setting human nutrient guidelines, government organizations do not necessarily agree on amounts needed to avoid deficiency or maximum amounts to avoid the risk of toxicity. [ 43 ] [ 44 ] [ 45 ]  For example, for  vitamin C , recommended intakes range from 40\u00a0mg/day in India [ 46 ]  to 155\u00a0mg/day for the European Union. [ 47 ]  The table below shows U.S. Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for vitamins and minerals, PRIs for the European Union (same concept as RDAs), followed by what three government organizations deem to be the safe upper intake. RDAs are set higher than EARs to cover people with higher-than-average needs. Adequate Intakes (AIs) are set when there is insufficient information to establish EARs and RDAs. Countries establish  tolerable upper intake levels , also referred to as upper limits (ULs), based on amounts that cause adverse effects. Governments are slow to revise information of this nature. For the U.S. values, except calcium and vitamin D, all data date from 1997 to 2004. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11711", "text": "* The daily recommended amounts of niacin and magnesium are higher than the tolerable upper limit because, for both nutrients, the ULs identify the amounts which will not increase risk of adverse effects when the nutrients are consumed as a serving of a dietary supplement. Magnesium supplementation above the UL may cause diarrhea. Supplementation with niacin above the UL may cause flushing of the face and a sensation of body warmth. Each country or regional regulatory agency decides on a safety margin below when symptoms may occur, so the ULs may differ based on source. [ 43 ] [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11712", "text": "EAR  U.S. Estimated Average Requirements."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11713", "text": "RDA  U.S. Recommended Dietary Allowances; higher for adults than for children, and may be even higher for women who are pregnant or lactating."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11714", "text": "AI   U.S. Adequate Intake; AIs established when there is not sufficient information to set EARs and RDAs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11715", "text": "PRI  Population Reference Intake is European Union equivalent of RDA; higher for adults than for children, and may be even higher for women who are pregnant or lactating. For Thiamin and Niacin, the PRIs are expressed as amounts per megajoule (239 kilocalories) of food energy consumed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11716", "text": "Upper Limit   Tolerable upper intake levels."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11717", "text": "ND   ULs have not been determined."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11718", "text": "NE   EARs, PRIs or AIs have not yet been established or will not be (EU does not consider chromium an essential nutrient)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11719", "text": "Plants absorb carbon, hydrogen, and oxygen from air and soil as  carbon dioxide  and water. [ 48 ]  Other nutrients are absorbed from soil (exceptions include some parasitic or carnivorous plants). Counting these, there are 17 important nutrients for plants: [ 49 ]  these are macronutrients; nitrogen (N), phosphorus (P), potassium (K), calcium (Ca), sulfur (S), magnesium (Mg), carbon (C), oxygen(O) and hydrogen (H), and the micronutrients; iron (Fe), boron (B), chlorine (Cl), manganese (Mn), zinc (Zn), copper (Cu), molybdenum (Mo) and nickel (Ni). In addition to carbon, hydrogen, and oxygen,  nitrogen ,  phosphorus , and  sulfur  are also needed in relatively large quantities. Together, these  six  are the elemental macronutrients for all  organisms . [ 50 ] \nThey are sourced from inorganic matter (for example, carbon dioxide, water,  nitrates ,  phosphates ,  sulfates , and  diatomic molecules  of nitrogen and, especially, oxygen) and organic compounds such as carbohydrates, lipids, proteins."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11720", "text": "Octasulfur  is an  inorganic   substance  with the chemical formula  S 8 . It is an odourless and tasteless yellow solid, and is a major industrial chemical. It is the most common  allotrope  of  sulfur  and occurs widely in nature. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11721", "text": "The name  octasulfur  is the most commonly used for this chemical. It is systematically named  cyclo -octasulfur  (which is the preferred IUPAC name) and  cyclooctasulfane . It is also the final member of the  thiocane heterocylic series , where every carbon atom is substituted with a sulfur atom, thus this sulfur allotrope is systematically named  octathiocane  as well."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11722", "text": "The chemical consists of rings of 8 sulfur atoms. It adopts a crown conformation with D 4d   point group symmetry . The S\u2013S bond lengths are equal, at about 2.05  \u00c5 . Octasulfur crystallizes in three distinct  polymorphs : rhombohedral, and two monoclinic forms, of which only two are stable at standard conditions. The rhombohedral crystal form is the accepted  standard state . The remaining polymorph is only stable between 96 and 115\u00a0\u00b0C at 100 kPa. Octasulfur forms several allotropes: \u03b1-sulfur, \u03b2-sulfur, \u03b3-sulfur, and \u03bb-sulfur."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11723", "text": "\u03bb-Sulfur is the liquid form of octasulfur, from which \u03b3-sulfur can be crystallised by quenching. If \u03bb-sulfur is crystallised slowly, it will revert to \u03b2-sulfur. Since it must have been heated over 115\u00a0\u00b0C, neither crystallised \u03b2-sulfur or \u03b3-sulfur will be pure. The only known method of obtaining pure \u03b3-sulfur is by crystallising from solution."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11724", "text": "Octasulfur easily forms large crystals, which are typically yellow and are somewhat translucent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11725", "text": "Octasulfur is not typically produced as  S 8  per se. It is the main (99%) component of elemental sulfur, which is recovered from volcanic sources and is a major product of the  Claus process , associated with petroleum refineries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11726", "text": "The  oligodynamic effect  (from  Greek   oligos , \"few\", and  dynamis , \"force\") is a  biocidal  effect of  metals , especially  heavy metals , that occurs even in low concentrations. This effect is attributed to the antibacterial behavior of metal ions, which are absorbed by bacteria upon contact and damage their  cell membranes . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11727", "text": "In modern times, the effect was observed by  Carl N\u00e4geli , although he did not identify the cause. [ 2 ]  Brass  doorknobs , brass  handrails , and  silverware  all exhibit this effect to an extent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11728", "text": "The metals react with  thiol  (-SH) or  amine  (-NH (1,2,3) ) groups of proteins, a mode of action to which  microorganisms  may develop  resistance . Such resistance may be transmitted by  plasmids . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11729", "text": "Aluminium has been found to compete with iron and magnesium and bind to DNA, membranes, or cell walls, leading to its toxic effect on microbes, such as cyanobacteria, soil bacteria and mycorrhizal fungi. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11730", "text": "Aluminium triacetate  ( Burow's solution ) is used as an  astringent  mild  antiseptic . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11731", "text": "Orthoesters  of  diarylstibinic acids  are  fungicides  and  bactericides , used in  paints ,  plastics , and  fibers . [ 6 ]   Trivalent  organic antimony was used in therapy for  schistosomiasis . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11732", "text": "For many decades,  arsenic  was used medicinally to treat  syphilis . It is still used in  sheep dips ,  rat poisons ,  wood preservatives ,  weed killers , and other  pesticides . Arsenic is  poisonous  if it enters the human body. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11733", "text": "Barium polysulfide  is a  fungicide  and  acaricide  used in fruit and grape growing. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11734", "text": "Bismuth compounds have been used because of their  astringent ,  antiphlogistic ,  bacteriostatic , and  disinfecting  actions. In dermatology  bismuth subgallate  is still used in vulnerary salves and powders as well as in antimycotics. [ 10 ]  In the past, bismuth has also been used to treat  syphilis  and  malaria . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11735", "text": "Boric acid  esters derived from  glycols  (example, organo-borate formulation,  Biobor JF ) are being used for the control of microorganisms in fuel systems containing water. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11736", "text": "Brass  vessels release a small amount of  copper  ions into stored water, thus killing  fecal  bacterial counts as high as 1 million bacteria per milliliter. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11737", "text": "Copper sulfate  mixed with  lime  ( Bordeaux mixture ) is used as a  fungicide  and  antihelminthic . [ 14 ]  Copper sulfate is used chiefly to destroy green algae ( algicide ) that grow in reservoirs, stock ponds, swimming pools, and fish tanks.  Copper 8-hydroxyquinoline  is sometimes included in paint to prevent  mildew . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11738", "text": "Paint containing copper is  used on boat bottoms  to prevent  barnacle  growth ( biofouling )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11739", "text": "Copper also has the ability to destroy viruses, such as influenza viruses, noroviruses or human immunodeficiency virus (HIV). [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11740", "text": "Gold is used in  dental inlays  and inhibits the growth of bacteria. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11741", "text": "Physicians prescribed various forms of lead to heal ailments ranging from  constipation  to infectious diseases such as the  plague . Lead was also used to preserve or sweeten wine. [ 18 ]   Lead arsenate  is used in insecticides and herbicides. [ 19 ]  Some organic lead compounds are used as industrial biocides:  thiomethyl triphenyllead  is used as an antifungal agent, cotton preservative, and lubricant additive;  thiopropyl triphenyllead  as a rodent repellant;  tributyllead acetate  as a wood and cotton preservative;  tributyllead imidazole  as a lubricant additive and cotton preservative. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11742", "text": "Phenylmercuric borate  and  acetate  were used for disinfecting mucous membranes at an effective concentration of 0.07% in aqueous solutions. Due to toxicological and ecotoxicological reasons phenylmercury salts are no longer in use. However, some surgeons use  mercurochrome  despite toxicological objections. [ 3 ]  Mercurochrome is still available to purchase in Australia to use on minor wounds.  Dental amalgam  used in fillings inhibits bacterial reproduction. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11743", "text": "Organic mercury compounds have been used as topical disinfectants ( thimerosal ,  nitromersol , and  merbromin ) and preservatives in medical preparations ( thimerosal ) and grain products (both  methyl  and  ethyl mercurials ). Mercury was used in the treatment of  syphilis .  Calomel  was commonly used in infant teething powders in the 1930s and 1940s. Mercurials are also used agriculturally as  insecticides  and  fungicides . [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11744", "text": "The toxicity of  nickel  to bacteria, yeasts, and fungi differs considerably. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11745", "text": "The metabolism of bacteria is adversely affected by silver ions at concentrations of 0.01\u20130.1\u00a0mg/L. Therefore, even less soluble silver compounds, such as  silver chloride , also act as bactericides or germicides, but not the much less soluble  silver sulfide . In the presence of atmospheric oxygen, metallic silver also has a bactericidal effect due to the formation of  silver oxide , which is soluble enough to cause it. Even objects with a solid silver surface (e.g., table silver, silver coins, or silver foil) have a bactericidal effect. Silver drinking vessels were carried by military commanders on expeditions for protection against disease. It was once common to place silver foil or even silver coins on wounds for the same reason. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11746", "text": "Silver sulfadiazine  is used as an antiseptic ointment for extensive burns. An equilibrium dispersion of colloidal silver with dissolved silver ions can be used to purify drinking water at sea. [ 3 ]  Silver is incorporated into medical implants and devices such as  catheters .  Surfacine  ( silver iodide ) is a relatively new antimicrobial for application to surfaces. Silver-impregnated wound dressings have proven especially useful against antibiotic-resistant bacteria.  Silver nitrate  is used as a hemostatic, antiseptic and astringent. At one time, many states [ clarification needed ]  required that the eyes of newborns be treated with a few drops of silver nitrate to guard against an infection of the eyes called  gonorrheal neonatal ophthalmia , which the infants might have contracted as they passed through the birth canal. Silver ions are increasingly incorporated into many hard surfaces, such as plastics and steel, as a way to control microbial growth on items such as toilet seats, stethoscopes, and even refrigerator doors. Among the newer products being sold are plastic food containers infused with silver  nanoparticles , which are intended to keep food fresher, and silver-infused athletic shirts and socks, which claim to minimize odors. [ 15 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11747", "text": "Thallium compounds such as  thallium sulfate  have been used for impregnating wood and leather to kill fungal spores and bacteria, and for the protection of textiles from attack by moths. [ 24 ]  Thallium sulfate has been used as a depilatory and in the treatment of venereal disease, skin fungal infections, and tuberculosis. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11748", "text": "Tetrabutyltin  is used as an antifouling paint for ships, for the prevention of slimes in industrial recirculating water systems, for combating freshwater snails that cause  bilharzia , as a wood and textile preservative, and as a disinfectant.  Tricyclohexyltin hydroxide  is used as an acaricide.  Triphenyltin hydroxide  and  triphenyltin acetate  are used as fungicides. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11749", "text": "Zinc oxide  is used as a weak antiseptic and in paints as a white pigment and mold-growth inhibitor. [ 27 ]   Zinc chloride  is a common ingredient in mouthwashes and deodorants, and  zinc pyrithione  is an ingredient in antidandruff shampoos. Galvanized (zinc-coated) fittings on roofs impede the growth of algae. Copper- and zinc-treated shingles are available. [ 15 ]   Zinc iodide  and  zinc sulfate  are used as topical antiseptics. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11750", "text": "Besides the individual toxic effects of each metal, a wide range of metals are  nephrotoxic  in humans and/or in animals. [ 29 ]  Some metals and their compounds are carcinogenic to humans. [ citation needed ]  A few metals, such as lead and mercury, can cross the  placental barrier  and adversely affect  fetal development . [ 30 ]  Several (cadmium, zinc, copper, and mercury) can induce special protein complexes called  metallothioneins . [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11751", "text": "In  chemistry , a  phosphodiester bond  occurs when exactly two of the  hydroxyl groups  ( \u2212OH ) in  phosphoric acid  react with hydroxyl groups on other molecules to form two  ester  bonds. The \"bond\" involves this linkage  C\u2212O\u2212PO \u2212 2 O\u2212C . [ 1 ]   Discussion of phosphodiesters is dominated by their prevalence in  DNA  and  RNA , but phosphodiesters occur in other biomolecules, e.g.  acyl carrier proteins ,  phospholipids  and the cyclic forms of GMP and AMP ( cGMP  and  cAMP ). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11752", "text": "Phosphodiester bonds make up the  backbones  of  DNA  and  RNA . In the phosphodiester bonds of nucleic acids, a phosphate is attached to the 5' carbon of one nucleoside and to the 3' carbon of the adjacent nucleoside. Specifically, it is the phosphodiester bonds that link the  3' carbon atom  of one sugar molecule and the 5' carbon atom of another (hence the name 3', 5' phosphodiester linkage used with reference to this kind of bond in DNA and RNA chains). [ 3 ]  The involved saccharide groups are  deoxyribose  in DNA and  ribose  in RNA. In order for the phosphodiester bond to form ,  joining the  nucleosides , the tri-phosphate or di-phosphate forms of the nucleotide building blocks are broken apart to give off energy required to drive the  enzyme -catalyzed reaction. [ 4 ]  In DNA replication, for example, formation of the phosphodiester bonds is catalyzed by a  DNA polymerase   enzyme , using a pair of  magnesium   cations  and other supporting structures. [ 3 ]  Formation of the bond occurs not only in DNA and RNA replication, but also in the repair and recombination of nucleic acids, and may require the involvement of various polymerases, primers, and/or ligases. During the replication of DNA, for example, the  DNA polymerase I  leaves behind a hole between the phosphates in the newly formed backbone.  DNA ligase  is able to form a phosphodiester bond between the nucleotides on each side of the gap. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11753", "text": "Phosphodiesters are negatively charged at  pH  7. [ 5 ]  The negative charge attracts  histones , metal cations such as  magnesium , and  polyamines  [needs citation]. Repulsion between these negative charges influences the conformation of the polynucleic acids."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11754", "text": "Hydrolysis  (breaking) of phosphodiester bonds can be promoted in several ways.  Phosphodiesterases  are enzymes that catalyze the hydrolysis of the phosphodiester bond. These enzymes are involved in repairing DNA and RNA sequences, nucleotide salvage, and in the conversion of cGMP and cAMP to GMP and AMP, respectively. [ 2 ]   Hydrolysis of the phosphodiester bond also occurs chemically and spontaneously, without the aid of enzymes. For example, simple  ribose  (in RNA) has one more  hydroxyl group  than  deoxyribose  (in DNA), making the former less stable and more susceptible to  alkaline hydrolysis , wherein relatively high pH conditions induce the breaking of the phosphodiester linkage between two  ribonucleotides . The relative instability of RNA under hydroxyl attack of its phosphodiester bonds makes it inadequate for the storage of genomic information, but contributes to its usefulness in  transcription  and  translation .  [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11755", "text": "Plant nutrition  is the study of the  chemical elements  and  compounds  necessary for plant growth and reproduction, plant metabolism and their external supply. In its absence the plant is unable to complete a normal life cycle, or that the element is part of some essential plant constituent or  metabolite . This is in accordance with  Justus von Liebig's   law of the minimum . [ 1 ]  The total essential plant nutrients include seventeen different elements:  carbon ,  oxygen  and  hydrogen  which are absorbed from the air, whereas other nutrients including  nitrogen  are typically obtained from the soil (exceptions include some  parasitic  or  carnivorous plants )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11756", "text": "Plants must obtain the following mineral nutrients from their growing medium: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11757", "text": "These elements stay beneath soil as  salts , so plants absorb these elements as  ions . The macronutrients are taken-up in larger quantities; hydrogen, oxygen, nitrogen and carbon contribute to over 95% of a plant's entire biomass on a dry matter weight basis. Micronutrients are present in plant tissue in quantities measured in parts per million, ranging from 0.1 [ 3 ]  to 200\u00a0ppm, or less than 0.02% dry weight. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11758", "text": "Most  soil  conditions across the world can provide plants adapted to that climate and soil with sufficient nutrition for a complete life cycle, without the addition of nutrients as  fertilizer . However, if the soil is cropped it is necessary to artificially modify  soil fertility  through the addition of  fertilizer  to promote vigorous growth and increase or sustain yield. This is done because, even with adequate water and light,  nutrient deficiency  can limit growth and crop yield."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11759", "text": "Carbon ,  hydrogen  and  oxygen  are the basic nutrients plants receive from air and water.  Justus von Liebig  proved in 1840 that plants needed  nitrogen ,  potassium  and  phosphorus .  Liebig's law of the minimum  states that a plant's growth is limited by nutrient deficiency. [ 5 ]  Plant cultivation in media other than soil was used by Arnon and Stout in 1939 to show that  molybdenum  was essential to  tomato  growth. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11760", "text": "Plants take up  essential elements  from the soil through their roots and from the air through their leaves. Nutrient uptake in the soil is achieved by  cation exchange , wherein  root hairs  pump hydrogen ions (H + ) into the soil through  proton pumps . These hydrogen ions displace cations attached to negatively charged soil particles so that the cations are available for uptake by the root. In the leaves,  stomata  open to take in carbon dioxide and expel oxygen. The carbon dioxide molecules are used as the carbon source in  photosynthesis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11761", "text": "The  root , especially the root hair, a unique cell, is the essential organ for the uptake of nutrients. The structure and architecture of the root can alter the rate of nutrient uptake. Nutrient ions are transported to the center of the root, the  stele , in order for the nutrients to reach the conducting tissues, xylem and phloem. [ 6 ]  The  Casparian strip , a cell wall outside the stele but in the root, prevents passive flow of water and nutrients, helping to regulate the uptake of nutrients and water.  Xylem  moves water and mineral ions in the plant and  phloem  accounts for organic molecule transportation.  Water potential  plays a key role in a plant's nutrient uptake. If the water potential is more negative in the plant than the surrounding soils, the nutrients will move from the region of higher solute concentration\u2014in the soil\u2014to the area of lower solute concentration - in the plant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11762", "text": "There are three fundamental ways plants uptake nutrients through the root:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11763", "text": "Nutrients can be moved in plants to where they are most needed. For example, a plant will try to supply more nutrients to its younger leaves than to its older ones. When nutrients are mobile in the plant, symptoms of any deficiency become apparent first on the older leaves. However, not all nutrients are equally mobile. Nitrogen, phosphorus, and potassium are mobile nutrients while the others have varying degrees of mobility. When a less-mobile nutrient is deficient, the younger leaves suffer because the nutrient does not move up to them but stays in the older leaves.  This phenomenon is helpful in determining which nutrients a plant may be lacking."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11764", "text": "Many plants engage in  symbiosis  with microorganisms.  Two important types of these relationship are"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11765", "text": "The Earth's atmosphere contains over 78 percent nitrogen. Plants called legumes, including the agricultural crops alfalfa and soybeans, widely grown by farmers, harbour nitrogen-fixing bacteria that can convert atmospheric nitrogen into nitrogen the plant can use. Plants not classified as legumes such as wheat, corn and rice rely on nitrogen compounds present in the soil to support their growth. These can be supplied by  mineralization  of  soil organic matter  or added plant residues, nitrogen fixing bacteria, animal waste, through the breaking of triple bonded N 2  molecules by lightning strikes or through the application of  fertilizers ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11766", "text": "At least 17 elements are known to be essential nutrients for plants. In relatively large amounts, the soil supplies nitrogen, phosphorus, potassium, calcium, magnesium, and sulfur; these are often called the  macronutrients . In relatively small amounts, the  soil  supplies iron, manganese, boron, molybdenum, copper, zinc, chlorine, and cobalt, the so-called  micronutrients . Nutrients must be available not only in sufficient amounts but also in appropriate ratios."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11767", "text": "Plant nutrition is a difficult subject to understand completely, partially because of the variation between different plants and even between different species or individuals of a given clone. Elements present at low levels may cause deficiency symptoms, and toxicity is possible at levels that are too high. Furthermore, deficiency of one element may present as symptoms of toxicity from another element, and vice versa. An abundance of one nutrient may cause a deficiency of another nutrient. For example, K +  uptake can be influenced by the amount of NH + 4  available. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11768", "text": "Nitrogen is plentiful in the Earth's atmosphere, and a number of commercially-important agricultural plants engage in  nitrogen fixation  (conversion of atmospheric nitrogen to a biologically useful form). However, plants mostly receive their nitrogen through the soil, where it is already converted in biological useful form. This is important because the nitrogen in the atmosphere is too large for the plant to consume, and takes a lot of energy to convert into smaller forms. These include soybeans, edible beans and peas as well as clovers and alfalfa used primarily for feeding livestock.  Plants such as the commercially-important corn, wheat, oats, barley and rice require nitrogen compounds to be present in the soil in which they grow."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11769", "text": "Carbon and oxygen are absorbed from the air while other nutrients are absorbed from the soil.  Green plants  ordinarily obtain their carbohydrate supply from the carbon dioxide in the air by the process of  photosynthesis . Each of these nutrients is used for a different essential function. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11770", "text": "The basic nutrients are derived from air and water. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11771", "text": "Carbon  forms the backbone of most plant  biomolecules , including proteins,  starches  and  cellulose .   Carbon is fixed  through  photosynthesis ; this converts  carbon dioxide  from the air into  carbohydrates  which are used to store and transport energy within the plant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11772", "text": "Hydrogen  is necessary for building sugars and building the plant. It is obtained almost entirely from water. Hydrogen ions are imperative for a proton gradient to help drive the electron transport chain in photosynthesis and for respiration. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11773", "text": "Oxygen  is a component of many organic and inorganic molecules within the plant, and is acquired in many forms. These include:  O 2  and  CO 2  (mainly from the air via leaves) and  H 2 O ,  NO \u2212 3 ,  H 2 PO \u2212 4  and  SO 2\u2212 4  (mainly from the soil water via roots). Plants produce oxygen gas (O 2 ) along with  glucose  during  photosynthesis  but then require O 2  to undergo aerobic  cellular respiration  and break down this glucose to produce  ATP ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11774", "text": "Nitrogen  is a major constituent of several of the most important plant substances. For example, nitrogen compounds comprise 40% to 50% of the dry matter of  protoplasm , and it is a constituent of  amino acids , the building blocks of  proteins . [ 9 ]  It is also an essential constituent of  chlorophyll . [ 10 ]  In many agricultural settings, nitrogen is the limiting nutrient for rapid growth."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11775", "text": "Like nitrogen,  phosphorus  is involved with many vital plant processes. Within a plant, it is present mainly as a structural component of the  nucleic acids :  deoxyribonucleic acid  (DNA) and  ribonucleic acid  (RNA), as well as a constituent of fatty  phospholipids , that are important in membrane development and function. It is present in both organic and inorganic forms, both of which are readily translocated within the plant. All energy transfers in the cell are critically dependent on phosphorus.  As with all living things, phosphorus is part of the  Adenosine triphosphate  (ATP), which is of immediate use in all processes that require energy with the cells. Phosphorus can also be used to modify the activity of various enzymes by  phosphorylation , and is used for  cell signaling . Phosphorus is concentrated at the most actively growing points of a plant and stored within seeds in anticipation of their germination."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11776", "text": "Unlike other major elements,  potassium  does not enter into the composition of any of the important plant constituents involved in metabolism, [ 9 ]  but it does occur in all parts of plants in substantial amounts. It is essential for enzyme activity including enzymes involved in primary metabolism. It plays a role in  turgor  regulation, effecting the functioning of the stomata and cell volume growth. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11777", "text": "It seems to be of particular importance in leaves and at growing points. Potassium is outstanding among the nutrient elements for its mobility and solubility within plant tissues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11778", "text": "Processes involving potassium include the formation of  carbohydrates  and  proteins , the regulation of internal plant moisture, as a catalyst and condensing agent of complex substances, as an accelerator of enzyme action, and as contributor to  photosynthesis , especially under low light intensity. Potassium regulates the opening and closing of the  stomata  by a potassium ion pump. Since stomata are important in water regulation, potassium regulates water loss from the leaves and increases  drought  tolerance. Potassium serves as an activator of enzymes used in photosynthesis and respiration. [ 6 ]  Potassium is used to build cellulose and aids in photosynthesis by the formation of a chlorophyll precursor. The potassium ion (K + ) is highly mobile and can aid in balancing the anion (negative) charges within the plant. A relationship between potassium nutrition and cold resistance has been found in several tree species, including two species of spruce. [ 12 ]  Potassium helps in fruit coloration, shape and also increases its  brix . Hence, quality fruits are produced in potassium-rich soils."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11779", "text": "Research has linked K +  transport with auxin homeostasis, cell signaling, cell expansion, membrane trafficking and phloem transport. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11780", "text": "Sulfur  is a structural component of some amino acids (including  cystein  and  methionine ) and vitamins, and is essential for  chloroplast  growth and function; it is found in the iron-sulfur complexes of the electron transport chains in photosynthesis. It is needed for N 2  fixation by legumes, and the conversion of nitrate into amino acids and then into protein. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11781", "text": "Calcium  in plants occurs chiefly in the  leaves , with lower concentrations in seeds, fruits, and roots. A major function is as a constituent of cell walls. When coupled with certain acidic compounds of the jelly-like pectins of the middle lamella, calcium forms an insoluble salt. It is also intimately involved in  meristems , and is particularly important in root development, with roles in cell division, cell elongation, and the detoxification of hydrogen ions. Other functions attributed to calcium are: the neutralization of organic acids; inhibition of some potassium-activated ions; and a role in nitrogen absorption. A notable feature of calcium-deficient plants is a defective root system. [ 14 ]  Roots are usually affected before above-ground parts. [ 15 ]   Blossom end rot  is also a result of inadequate calcium. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11782", "text": "Calcium  regulates transport of other nutrients into the plant and is also involved in the activation of certain plant enzymes.  Calcium deficiency  results in stunting. This nutrient is involved in photosynthesis and plant structure. [ 16 ] [ 17 ]  It is needed as a balancing  cation  for  anions  in the  vacuole  and as an  intracellular messenger  in the  cytosol . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11783", "text": "The outstanding role of  magnesium  in plant nutrition is as a constituent of the  chlorophyll  molecule. As a carrier, it is also involved in numerous enzyme reactions as an effective activator, in which it is closely associated with energy-supplying  phosphorus  compounds."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11784", "text": "Plants are able sufficiently to accumulate most trace elements. Some plants are sensitive indicators of the chemical environment in which they grow (Dunn 1991), [ 19 ]  and some plants have barrier mechanisms that exclude or limit the uptake of a particular element or ion species, e.g., alder twigs commonly accumulate molybdenum but not arsenic, whereas the reverse is true of spruce bark (Dunn 1991). [ 19 ]  Otherwise, a plant can integrate the geochemical signature of the soil mass permeated by its root system together with the contained groundwaters. Sampling is facilitated by the tendency of many elements to accumulate in tissues at the plant's extremities. Some micronutrients can be applied as seed coatings."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11785", "text": "Iron  is necessary for photosynthesis and is present as an enzyme cofactor in plants.  Iron deficiency  can result in interveinal  chlorosis  and  necrosis .\nIron is not a structural part of chlorophyll but very much essential for its synthesis. Copper deficiency can be responsible for promoting an iron deficiency. [ 20 ] \nIt helps in the electron transport of plant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11786", "text": "As with other biological processes, the main useful form of iron is that of iron(II) due to its higher solubility in neutral pH. However, plants are also capable of using iron(III) via citric acid, using the photo-reduction of  ferric citrate . [ 21 ]  In the field, as with many other transitional metal elements, iron fertilizer is supplied as a  chelate . [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11787", "text": "Molybdenum  is a cofactor to enzymes important in building amino acids and is involved in nitrogen metabolism. Molybdenum is part of the  nitrate reductase  enzyme (needed for the reduction of nitrate) and the  nitrogenase  enzyme (required for  biological nitrogen fixation ). [ 10 ]  Reduced productivity as a result of  molybdenum deficiency  is usually associated with the reduced activity of one or more of these enzymes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11788", "text": "Boron has many functions in a plant: [ 23 ]  it affects flowering and fruiting, pollen germination, cell division, and active salt absorption. The metabolism of amino acids and proteins, carbohydrates, calcium, and water are strongly affected by boron. Many of those listed functions may be embodied by its function in moving the highly polar sugars through cell membranes by reducing their polarity and hence the energy needed to pass the sugar. If sugar cannot pass to the fastest growing parts rapidly enough, those parts die."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11789", "text": "Copper  is important for photosynthesis. Symptoms for copper deficiency include chlorosis. It is involved in many enzyme processes; necessary for proper photosynthesis; involved in the manufacture of lignin (cell walls) and involved in grain production. It is difficult to find in some soil conditions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11790", "text": "Manganese  is necessary for photosynthesis, [ 17 ]  including the building of  chloroplasts .  Manganese deficiency  may result in coloration abnormalities, such as discolored spots on the  foliage ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11791", "text": "Sodium  is involved in the regeneration of  phosphoenolpyruvate  in  CAM  and  C4  plants. Sodium can potentially replace potassium's regulation of stomatal opening and closing. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11792", "text": "Essentiality of sodium:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11793", "text": "Zinc  is required in a large number of enzymes and plays an essential role in  DNA transcription . A typical symptom of  zinc deficiency  is the stunted growth of leaves, commonly known as \"little leaf\" and is caused by the oxidative degradation of the growth hormone  auxin ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11794", "text": "In  vascular plants ,  nickel  is absorbed by plants in the form of Ni 2+  ion. Nickel is essential for activation of  urease , an enzyme involved with  nitrogen metabolism  that is required to process urea. Without nickel, toxic levels of urea accumulate, leading to the formation of necrotic lesions. In  non-vascular plants , nickel activates several enzymes involved in a variety of processes, and can substitute for zinc and iron as a cofactor in some enzymes. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11795", "text": "Chlorine , as compounded chloride, is necessary for  osmosis  and  ionic balance ; it also plays a role in  photosynthesis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11796", "text": "Cobalt  has proven to be beneficial to at least some plants although it does not appear to be essential for most species. [ 25 ]  It has, however, been shown to be essential for  nitrogen fixation  by the nitrogen-fixing bacteria associated with  legumes  and other plants. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11797", "text": "Silicon  is not considered an essential element for plant growth and development. It is always found in abundance in the environment and hence if needed it is available. It is found in the structures of plants and improves the health of plants. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11798", "text": "In plants,  silicon  has been shown in experiments to strengthen  cell walls , improve plant strength, health, and productivity. [ 27 ]  There have been studies showing evidence of silicon improving  drought  and  frost resistance , decreasing  lodging  potential and boosting the plant's natural pest and disease fighting systems. [ 28 ]  Silicon has also been shown to improve plant vigor and physiology by improving root mass and density, and increasing above ground plant  biomass  and  crop yields . [ 27 ]   Silicon is currently under consideration by the Association of American Plant Food Control Officials (AAPFCO) for elevation to the status of a \"plant beneficial substance\". [ 29 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11799", "text": "Vanadium  may be required by some plants, but at very low concentrations. It may also be substituting for  molybdenum ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11800", "text": "Selenium  is probably not essential for flowering plants, but it can be beneficial; it can stimulate plant growth, improve tolerance of oxidative stress, and increase resistance to pathogens and herbivory. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11801", "text": "Nitrogen is transported via the xylem from the roots to the leaf canopy as nitrate ions, or in an organic form, such as amino acids or amides. Nitrogen can also be transported in the phloem sap as amides, amino acids and ureides; it is therefore mobile within the plant, and the older leaves exhibit chlorosis and necrosis earlier than the younger leaves. [ 6 ] [ 10 ]  Because phosphorus is a mobile nutrient, older leaves will show the first signs of deficiency. Magnesium is very mobile in plants, and, like potassium, when  deficient  is translocated from older to younger tissues, so that signs of deficiency appear first on the oldest tissues and then spread progressively to younger tissues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11802", "text": "Because calcium is  phloem  immobile, calcium deficiency can be seen in new growth. When developing tissues are forced to rely on the  xylem , calcium is supplied by  transpiration  only."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11803", "text": "Boron is not relocatable in the plant via the  phloem . It must be supplied to the growing parts via the  xylem . Foliar sprays affect only those parts sprayed, which may be insufficient for the fastest growing parts, and is very temporary. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11804", "text": "In plants, sulfur cannot be mobilized from older leaves for new growth, so deficiency symptoms are seen in the youngest tissues first. [ 32 ]  Symptoms of deficiency include yellowing of leaves and stunted growth. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11805", "text": "The effect of a nutrient deficiency can vary from a subtle depression of growth rate to obvious stunting, deformity, discoloration, distress, and even death. Visual symptoms distinctive enough to be useful in identifying a deficiency are rare. Most deficiencies are multiple and moderate. However, while a deficiency is seldom that of a single nutrient, nitrogen is commonly the nutrient in shortest supply."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11806", "text": "Chlorosis  of foliage is not always due to mineral nutrient deficiency. Solarization can produce superficially similar effects, though mineral deficiency tends to cause premature defoliation, whereas solarization does not, nor does solarization depress nitrogen concentration. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11807", "text": "Nitrogen deficiency  most often results in stunted growth, slow growth, and chlorosis. Nitrogen deficient plants will also exhibit a purple appearance on the stems, petioles and underside of leaves from an accumulation of anthocyanin pigments. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11808", "text": "Phosphorus deficiency  can produce symptoms similar to those of nitrogen deficiency, [ 35 ]  characterized by an intense green coloration or reddening in leaves due to lack of chlorophyll. If the plant is experiencing high phosphorus deficiencies the leaves may become denatured and show signs of death. Occasionally the leaves may appear purple from an accumulation of  anthocyanin . As noted by Russel: [ 14 ]  \"Phosphate deficiency differs from nitrogen deficiency in being extremely difficult to diagnose, and crops can be suffering from extreme starvation without there being any obvious signs that lack of phosphate is the cause\". Russell's observation applies to at least some  coniferous  seedlings, but Benzian [ 36 ]  found that although response to phosphorus in very acid forest tree nurseries in England was consistently high, no species (including Sitka spruce) showed any visible symptom of deficiency other than a slight lack of lustre. Phosphorus levels have to be exceedingly low before visible symptoms appear in such seedlings. In sand culture at 0 ppm phosphorus, white spruce seedlings were very small and tinted deep purple; at 0.62 ppm, only the smallest seedlings were deep purple; at 6.2 ppm, the seedlings were of good size and color. [ 37 ] [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11809", "text": "The root system is less effective without a continuous supply of calcium to newly developing cells. Even short term disruptions in calcium supply can disrupt biological functions and root function. [ 39 ]  A common symptom of calcium deficiency in leaves is the curling of the leaf towards the veins or center of the leaf. Many times this can also have a blackened appearance. [ 40 ]  The tips of the leaves may appear burned and cracking may occur in some calcium deficient crops if they experience a sudden increase in humidity. [ 18 ]  Calcium deficiency may arise in tissues that are fed by the  phloem , causing blossom end rot in watermelons, peppers and tomatoes, empty peanut pods and bitter pits in apples. In enclosed tissues, calcium deficiency can cause celery black heart and \"brown heart\" in greens like  escarole . [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11810", "text": "Researchers found that partial deficiencies of K or P did not change the  fatty acid  composition of  phosphatidyl choline  in  Brassica napus L.  plants. Calcium deficiency did, on the other hand, lead to a marked decline of  polyunsaturated  compounds that would be expected to have negative impacts for integrity of the plant  membrane , that could effect some properties like its permeability, and is needed for the  ion  uptake activity of the root membranes. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11811", "text": "Potassium deficiency  may cause necrosis or  interveinal chlorosis . Deficiency may result in higher risk of pathogens, wilting, chlorosis, brown spotting, and higher chances of damage from frost and heat. When potassium is moderately deficient, the effects first appear in the older tissues, and from there progress towards the growing points. Acute deficiency severely affects growing points, and die-back commonly occurs. Symptoms of potassium deficiency in white spruce include: browning and death of needles (chlorosis); reduced growth in height and diameter; impaired retention of needles; and reduced needle length. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11812", "text": "Mo deficiency is usually found on older growth. Fe, Mn and  Cu effect new growth, causing green or yellow veins, Zn ca effect old and new leaves, and B will be seem on terminal buds. A plant with  zinc deficiency  may have leaves on top of each other due to reduced internodal expansion. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11813", "text": "Zinc is the most widely deficient micronutrient for industrial crop cultivation, followed by boron. Acidifying N fertilizers create micro-sites around the  granule  that keep micronutrient cations soluble for longer in alkaline soils, but high concentrations of P or C may negate these effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11814", "text": "Boron deficiencies effecting seed yields and pollen fertility are common in  laterite soils . [ 45 ]  Boron is essential for the proper forming and strengthening of cell walls. Lack of boron results in short thick cells producing stunted fruiting bodies and roots. Deficiency results in the death of the terminal growing points and stunted growth. [ citation needed ]  Inadequate amounts of boron affect many agricultural crops, legume forage crops most strongly. [ citation needed ]  Boron deficiencies can be detected by analysis of plant material to apply a correction before the obvious symptoms appear, after which it is too late to prevent crop loss. Strawberries deficient in boron will produce lumpy fruit; apricots will not blossom or, if they do, will not fruit or will drop their fruit depending on the level of boron deficit. Broadcast of boron supplements is effective and long term; a foliar spray is immediate but must be repeated. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11815", "text": "Boron concentration in soil water solution higher than one ppm is toxic to most plants. Toxic concentrations within plants are 10 to 50 ppm for small grains and 200 ppm in boron-tolerant crops such as sugar beets, rutabaga, cucumbers, and conifers. Toxic soil conditions are generally limited to arid regions or can be caused by underground borax deposits in contact with water or volcanic gases dissolved in percolating water. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11816", "text": "There is an abundant supply of nitrogen in the earth's atmosphere\u2014N 2  gas comprises nearly 79% of air. However, N 2  is unavailable for use by most organisms because there is a triple bond between the two nitrogen atoms in the molecule,  making it almost inert. In order for nitrogen to be used for growth it must be  \"fixed\"  (combined) in the form of  ammonium  (NH + 4 ) or nitrate (NO \u2212 3 ) ions. The weathering of rocks releases these ions so slowly that it has a negligible effect on the availability of fixed nitrogen. Therefore, nitrogen is often the limiting factor for growth and  biomass  production in all environments where there is a suitable climate and availability of water to support life."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11817", "text": "Microorganisms  have a central role in almost all aspects of nitrogen availability, and therefore for life support on earth. Some bacteria can convert N 2  into ammonia by the process termed  nitrogen fixation ; these bacteria are either free-living or form  symbiotic  associations with plants or other organisms (e.g., termites, protozoa), while other bacteria bring about transformations of  ammonia  to  nitrate , and of nitrate to N 2  or other nitrogen gases. Many  bacteria  and  fungi  degrade organic matter, releasing fixed nitrogen for reuse by other organisms. All these processes contribute to the  nitrogen cycle ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11818", "text": "Nitrogen enters the plant largely through the  roots . A \"pool\" of soluble nitrogen accumulates. Its composition within a species varies widely depending on several factors, including day length, time of day, night temperatures, nutrient deficiencies, and nutrient imbalance. Short day length promotes  asparagine  formation, whereas glutamine is produced under long day regimes. Darkness favors protein breakdown accompanied by high asparagine accumulation. Night temperature modifies the effects due to night length, and soluble nitrogen tends to accumulate owing to retarded synthesis and breakdown of proteins. Low night temperature conserves  glutamine ; high night temperature increases accumulation of asparagine because of breakdown. Deficiency of K accentuates differences between long- and short-day plants. The pool of soluble nitrogen is much smaller than in well-nourished plants when N and P are deficient since uptake of nitrate and further reduction and conversion of N to organic forms is restricted more than is protein synthesis. Deficiencies of Ca, K, and S affect the conversion of organic N to protein more than uptake and reduction. The size of the pool of soluble N is no guide  per se  to growth rate, but the size of the pool in relation to total N might be a useful ratio in this regard. Nitrogen availability in the rooting medium also affects the size and structure of tracheids formed in the long lateral roots of white spruce (Krasowski and Owens 1999). [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11819", "text": "Phosphorus is most commonly found in the soil in the form of polyprotic phosphoric acid (H 3 PO 4 ), but is taken up most readily in the form of H 2 PO \u2212 4 . Phosphorus is available to plants in limited quantities in most soils because it is released very slowly from insoluble phosphates and is rapidly fixed once again. Under most environmental conditions it is the element that limits growth because of this constriction and due to its high demand by plants and microorganisms. Plants can increase phosphorus uptake by a mutualism with mycorrhiza. [ 6 ]  On some  soils , the phosphorus nutrition of some  conifers , including the spruces, depends on the ability of  mycorrhizae  to take up, and make soil phosphorus available to the tree, hitherto unobtainable to the non-mycorrhizal root. Seedling white spruce, greenhouse-grown in sand testing negative for phosphorus, were very small and purple for many months until spontaneous mycorrhizal inoculation, the effect of which was manifested by a greening of foliage and the development of vigorous shoot growth."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11820", "text": "When  soil -potassium levels are high, plants take up more potassium than needed for healthy growth. The term  luxury consumption  has been applied to this. Potassium intake increases with root temperature and depresses calcium uptake. [ 47 ]  Calcium to boron ratio must be maintained in a narrow range for normal plant growth. Lack of boron causes failure of calcium metabolism which produces hollow heart in beets and peanuts. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11821", "text": "Calcium and magnesium inhibit the uptake of trace metals. Copper and zinc mutually reduce uptake of each other. Zinc also effects iron levels of plants. These interactions are dependent on species and growing conditions. For example, for clover, lettuce and red beet plants nearing toxic levels of zinc, copper and nickel, these three elements increased the toxicity of the others in a positive relationship. In barley positive interaction was observed between copper and zinc, while in French beans the positive interaction occurred between nickel and zinc. Other researchers have studied the synergistic and antagonistic effects of soil conditions on lead, zinc, cadmium and copper in radish plants to develop predictive indicators for uptake like  soil pH . [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11822", "text": "Calcium absorption is increased by water-soluble phosphate fertilizers, and is used when potassium and  potash  fertilizers decrease the uptake of phosphorus, magnesium and calcium. For these reasons, imbalanced application of potassium fertilizers can markedly decrease crop yields. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11823", "text": "Boron  is available to plants over a range of pH, from 5.0 to 7.5. Boron is absorbed by plants in the form of the anion BO 3\u2212 3 . It is available to plants in moderately soluble mineral forms of Ca, Mg and Na borates and the highly soluble form of organic compounds. It is mobile in the soil, hence, it is prone to leaching. Leaching removes substantial amounts of boron in sandy soil, but little in fine silt or clay soil. Boron's fixation to those minerals at high pH can render boron unavailable, while low pH frees the fixed boron, leaving it prone to leaching in wet climates. It precipitates with other minerals in the form of borax in which form it was first used over 400 years ago as a soil supplement. Decomposition of organic material causes boron to be deposited in the topmost soil layer. When soil dries it can cause a precipitous drop in the availability of boron to plants as the plants cannot draw nutrients from that desiccated layer. Hence, boron deficiency diseases appear in dry weather. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11824", "text": "Most of the nitrogen taken up by plants is from the soil in the forms of NO \u2212 3 , although in acid environments such as boreal forests where nitrification is less likely to occur, ammonium NH + 4  is more likely to be the dominating source of nitrogen. [ 49 ]  Amino acids and proteins can only be built from NH + 4 , so NO \u2212 3  must be reduced."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11825", "text": "Fe and Mn become oxidized and are highly unavailable in acidic soils. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11826", "text": "Nutrient status (mineral nutrient and trace element composition, also called ionome and nutrient profile) of plants are commonly portrayed by tissue elementary analysis. Interpretation of the results of such studies, however, has been controversial. [ 50 ]  During recent decades the nearly two-century-old \"law of minimum\" or \"Liebig's law\" (that states that plant growth is controlled not by the total amount of resources available, but by the scarcest resource) has been replaced by several mathematical approaches that use different models in order to take the interactions between the individual nutrients into account. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11827", "text": "Later developments in this field were based on the fact that the nutrient elements (and compounds) do not act independently from each other; [ 50 ]  Baxter, 2015, [ 51 ]  because there may be direct chemical interactions between them or they may influence each other's uptake, translocation, and biological action via a number of mechanisms [ 50 ]  as exemplified [ how? ]  for the case of ammonia. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11828", "text": "Boron is highly soluble in the form of borax or boric acid and is too easily leached from soil making these forms unsuitable for use as a fertilizer. Calcium borate is less soluble and can be made from  sodium tetraborate . Boron is often applied to fields as a contaminant in other soil amendments but is not generally adequate to make up the rate of loss by cropping. The rates of application of borate to produce an adequate alfalfa crop range from 15 pounds per acre for a sandy-silt, acidic soil of low organic matter, to 60 pounds per acre for a soil with high organic matter, high cation exchange capacity and high pH. Application rates should be limited to a few pounds per acre in a test plot to determine if boron is needed generally. Otherwise, testing for boron levels in plant material is required to determine remedies. Excess boron can be removed by irrigation and assisted by application of elemental sulfur to lower the pH and increase boron solubility. Foliar sprays are used on fruit crop trees in soils of high alkalinity. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11829", "text": "Selenium is, however, an essential mineral element for animal (including human) nutrition and  selenium deficiencies  are known to occur when food or animal feed is grown on selenium-deficient soils. The use of inorganic selenium fertilizers can increase selenium concentrations in edible crops and animal diets thereby improving animal health. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11830", "text": "It is useful to apply a high phosphorus content fertilizer, such as bone meal, to perennials to help with successful root formation. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11831", "text": "Hydroponics  is a method for growing plants in a water-nutrient solution without using nutrient-rich soil or substrates. Researchers and home gardeners can grow their plants in a controlled environment. The most common artificial nutrient solution is the  Hoagland solution , developed by D. R. Hoagland and W. C. Snyder in 1933. The solution (known as  A-Z solution ) consists of all the essential macro- and micronutrients in the correct proportions necessary for most plant growth. [ 6 ]  An aerator is used to prevent an  anoxic  event or hypoxia.  Hypoxia  can affect the nutrient uptake of a plant because, without oxygen present, respiration becomes inhibited within the root cells. The  nutrient film technique  is a hydroponic technique in which the roots are not fully submerged. Incomplete submergence allows for adequate aeration of the roots, while a \"film\" thin layer of nutrient-rich water is pumped through the system to provide nutrients and water to the plant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11832", "text": "Potassium  is the main  intracellular   ion  for all types of  cells , while having a major role in maintenance of  fluid  and  electrolyte  balance. [ 1 ] [ 2 ]  Potassium is necessary for the function of all living cells and is thus present in all plant and animal tissues. It is found in especially high concentrations within plant cells, and in a mixed diet, it is most highly concentrated in fruits. The high concentration of potassium in plants, associated with comparatively very low amounts of sodium there, historically resulted in potassium first being isolated from the ashes of plants ( potash ), which in turn gave the element its modern name. The high concentration of potassium in plants means that heavy crop production rapidly depletes soils of potassium, and agricultural fertilizers consume 93% of the potassium chemical production of the modern world economy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11833", "text": "The functions of potassium and sodium in living organisms are quite different. Animals, in particular, employ sodium and potassium differentially to generate electrical potentials in animal cells, especially in  nervous tissue . Potassium depletion in animals, including humans, results in various neurological dysfunctions. Characteristic concentrations of potassium in model organisms are: 30\u2013300\u00a0mM in  E. coli , 300\u00a0mM in budding yeast, 100\u00a0mM in mammalian cell and 4\u00a0mM in blood plasma. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11834", "text": "The main role of potassium in plants is to provide the ionic environment for metabolic processes in the  cytosol , and as such functions as a regulator of various processes including growth regulation. [ 4 ]  Plants require potassium  ions  (K + ) for  protein synthesis  and for the opening and closing of  stomata , which is regulated by  proton pumps  to make surrounding guard cells either  turgid  or  flaccid .  A deficiency of potassium ions can impair a plant's ability to maintain these processes. Potassium also functions in other physiological processes such as  photosynthesis ,  protein synthesis , activation of some  enzymes , phloem solute transport of photoassimilates into  source organs , and maintenance of cation:anion balance in the cytosol and  vacuole . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11835", "text": "Potassium is the major  cation  (K + , a positive ion) inside  animal cells , while  sodium  (Na + ) is the major cation outside animal cells. The difference between the  concentrations  of these charged particles causes a difference in  electric potential  between the inside and outside of cells, known as the  membrane potential .  The balance between potassium and sodium is maintained by  ion transporters  in the  cell membrane . All  potassium ion channels  are tetramers with several conserved secondary structural elements. A number of potassium channel structures have been  solved  including  voltage gated , [ 6 ] [ 7 ] [ 8 ]   ligand gated , [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ]   tandem-pore , [ 14 ] [ 15 ] [ 16 ]  and  inwardly rectifying  channels, [ 17 ] [ 18 ] [ 19 ] [ 20 ] [ 21 ]  from  prokaryotes  and  eukaryotes . The cell membrane potential created by potassium and sodium  ions allows the cell to generate an  action potential \u2014a \"spike\" of electrical discharge. The ability of cells to produce electrical discharge is critical for body functions such as  neurotransmission , muscle contraction, and heart function. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11836", "text": "The U.S.  National Academy of Medicine  (NAM), on behalf of both the U.S. and Canada, sets  Dietary Reference Intakes , including Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs), or  Adequate Intakes  (AIs) for when there is not sufficient information to set EARs and RDAs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11837", "text": "For both males and females under 9 years of age, the AIs for potassium are: 400 \u00a0 mg of potassium for 0 to 6-month-old infants, 860 \u00a0 mg of potassium for 7 to 12-month-old infants, 2,000 \u00a0 mg of potassium for 1 to 3-year-old children, and 2,300 \u00a0 mg of potassium for 4 to 8-year-old children."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11838", "text": "For males 9 years of age and older, the AIs for potassium are: 2,500 \u00a0 mg of potassium for 9 to 13-year-old males, 3,000 \u00a0 mg of potassium for 14 to 18-year-old males, and 3,400 \u00a0 mg for males that are 19 years of age and older."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11839", "text": "For females 9 years of age and older, the AIs for potassium are: 2,300 \u00a0 mg of potassium for 9 to 18-year-old females, and 2,600 \u00a0 mg of potassium for females that are 19 years of age and older."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11840", "text": "For pregnant and lactating females, the AIs for potassium are: 2,600 \u00a0 mg of potassium for 14 to 18-year-old pregnant females, 2,900 \u00a0 mg for pregnant females that are 19 years of age and older; furthermore, 2,500 \u00a0 mg of potassium for 14 to 18-year-old lactating females, and 2,800 \u00a0 mg for lactating females that are 19 years of age and older. As for safety, the NAM also sets  tolerable upper intake levels  (ULs) for vitamins and minerals, but for potassium the evidence was insufficient, so no UL was established. [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11841", "text": "In 2019, the  National Academies of Sciences, Engineering, and Medicine  revised the Adequate Intake for potassium to 2,600\u00a0mg/day for females 19 years of age and older who are not pregnant or lactating, and 3,400\u00a0mg/day for males 19 years of age and older. [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11842", "text": "The  European Food Safety Authority  (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For people ages 15 and older, the AI is set at 3,500\u00a0mg/day. AIs for pregnancy is 3,500\u00a0mg/day, for lactation 4,000\u00a0mg/day. For children ages 1\u201314 years, the AIs increase with age from 800 to 2,700\u00a0mg/day. These AIs are lower than the U.S. RDAs. [ 27 ]  The EFSA reviewed the same safety question and decided that there was insufficient data to establish a UL for potassium. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11843", "text": "For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For potassium labeling purposes, 100% of the Daily Value was 3500\u00a0mg, but as of May 2016, it has been revised to 4700\u00a0mg. [ 29 ] [ 30 ]  A table of the old and new adult Daily Values is provided at  Reference Daily Intake ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11844", "text": "20 mEq (781\u00a0mg) potassium from  potassium gluconate  (4680\u00a0mg), or  potassium citrate  (2040\u00a0mg), mixed with a half-cup (1.12 dL) water, taken two to four times a day, may be used on a daily basis. [ 31 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11845", "text": "Because of the risk of small-bowel lesions, the US  FDA  requires some potassium  salts  (for example  potassium chloride ) containing more than 99\u00a0mg (about 1.3 mEq) to be labeled with a warning. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11846", "text": "Eating a variety of foods that contain potassium is the best way to get an adequate amount. \nFoods with high sources of potassium include  kiwifruit ,  orange juice ,  potatoes ,  coconut ,  avocados ,  apricots ,  parsnips  and  turnips , although many other  fruits ,  vegetables , legumes, and meats contain potassium."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11847", "text": "Common foods very high in potassium: [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11848", "text": "Foods containing the highest concentration: [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11849", "text": "Diets low in potassium increase risk of hypertension, stroke and cardiovascular disease. [ 36 ] [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11850", "text": "A severe shortage of potassium in body fluids may cause a potentially fatal condition known as  hypokalemia .  Hypokalemia typically results from loss of potassium through   diarrhea ,  diuresis , or vomiting. Symptoms are related to alterations in  membrane potential and cellular metabolism.  Symptoms include muscle weakness and cramps, paralytic  ileus , ECG abnormalities, intestinal paralysis, decreased reflex response and (in severe cases) respiratory paralysis,  alkalosis  and  arrhythmia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11851", "text": "In rare cases, habitual consumption of large amounts of black licorice has resulted in hypokalemia. Licorice contains a compound ( Glycyrrhizin ) that increases urinary excretion of potassium. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11852", "text": "Adult women in the United States consume on average half the AI, for men two-thirds. For all adults, fewer than 5% exceed the AI. [ 39 ]  Similarly, in the  European Union , insufficient potassium intake is widespread. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11853", "text": "Gastrointestinal  symptoms are the most common side effects of potassium supplements, including nausea, vomiting, abdominal discomfort, and diarrhea.  Taking potassium with meals or taking a  microencapsulated form of potassium may reduce gastrointestinal side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11854", "text": "Hyperkalemia  is the most serious adverse reaction to potassium.  Hyperkalemia occurs when potassium builds up faster than the kidneys can remove it. It is most common in individuals with  renal failure .  Symptoms of hyperkalemia may include tingling of the hands and feet, muscular weakness, and temporary paralysis. The most serious complication of hyperkalemia is the development of an abnormal heart rhythm ( arrhythmia ), which can lead to cardiac arrest."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11855", "text": "Although hyperkalemia is rare in healthy individuals, oral doses greater than 18\u00a0grams taken at one time in individuals not accustomed to high intakes can lead to hyperkalemia."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11856", "text": "Selenium  is an essential  micronutrient  for animals, though it is toxic in large doses. In plants, it sometimes occurs in toxic amounts as  forage , e.g.  locoweed . Selenium is a component of the  amino acids   selenocysteine  and  selenomethionine . In humans, selenium is a  trace element  nutrient that functions as  cofactor  for  glutathione peroxidases  and certain forms of  thioredoxin reductase . [ 1 ]  Selenium-containing proteins are produced from inorganic selenium via the intermediacy of  selenophosphate  (PSeO 3 3\u2212 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11857", "text": "Selenium is an essential  micronutrient  in mammals, but is also recognized as toxic in excess. Selenium exerts its biological functions through  selenoproteins , which contain the  amino acid   selenocysteine . Twenty-five selenoproteins are encoded in the  human genome . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11858", "text": "The  glutathione peroxidase  family of enzymes (abbreviated GSH-Px) catalyze reduction of  hydrogen peroxide  and organic  hydroperoxides :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11859", "text": "The two H atoms are donated by thiols in a process that begins with oxidation of a  selenol  side chain in GSH-Px.  The  organoselenium compound   ebselen  is a drug used to supplement the action of GSH-Px.  It functions as a catalyst for the destruction of hydrogen peroxide. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11860", "text": "A related selenium-containing enzyme in some plants and in animals ( thioredoxin reductase ) generates reduced thioredoxin, a dithiol that serves as an electron source for peroxidases and also the important reducing enzyme  ribonucleotide reductase  that makes DNA precursors from RNA precursors. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11861", "text": "Selenium also plays a role in the functioning of the  thyroid  gland.  It participates as a  cofactor  for the three  thyroid hormone   deiodinases .  These enzymes activate and then deactivate various thyroid hormones and their metabolites. [ 5 ]  It may inhibit  Hashimoto's disease , an auto-immune disease in which the body's own thyroid cells are attacked by the immune system. A reduction of 21% on TPO antibodies was reported with the dietary intake of 0.2\u00a0mg of selenium. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11862", "text": "Some microorganisms utilize selenium in  formate dehydrogenase . Formate is produced in large amounts in the hepatic (liver cells) mitochondria of embryonic cells and in cancer cells by the folate cycle. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11863", "text": "Formate is reversibly oxidized by the enzyme  formate dehydrogenase : [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11864", "text": "Thioredoxin reductase  uses a cysteine-selenocysteine pair to reduce the  disulfide  in  thioredoxin . The selenocysteine  is arranged in an unusual Sec-His-Glu  catalytic triad , which tunes its pKa. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11865", "text": "Certain species of plants are considered indicators of high selenium content of the soil, since they require high levels of selenium to thrive. The main selenium indicator plants are  Astragalus  species (including some  locoweeds ), prince's plume ( Stanleya  sp.), woody asters ( Xylorhiza  sp.), and false goldenweed ( Oonopsis  sp.) [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11866", "text": "The substance loosely called  selenium sulfide  (with the approximate formula SeS 2 ) is the active ingredient in some anti-dandruff shampoos. [ 11 ]  The selenium compound kills the scalp fungus  Malassezia , which causes shedding of dry skin fragments. The ingredient is also used in body lotions to treat  Tinea versicolor  due to infection by a different species of  Malassezia  fungus. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11867", "text": "Several clinical trials have assessed the use of selenium supplements in critically ill adults; however, the effectiveness and potential benefits of selenium supplementation in this context is not well understood. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11868", "text": "Selenium may be measured in blood, plasma, serum or urine to monitor excessive environmental or occupational exposure, confirm a diagnosis of poisoning in hospitalized victims or to assist in a forensic investigation in a case of fatal overdosage. Some analytical techniques are capable of distinguishing organic from inorganic forms of the element. Both organic and inorganic forms of selenium are largely converted to monosaccharide conjugates (selenosugars) in the body prior to being eliminated in the urine. Cancer patients receiving daily oral doses of selenothionine may achieve very high plasma and urine selenium concentrations. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11869", "text": "Although selenium is an essential  trace element , it is toxic if taken in excess. Exceeding the  Tolerable Upper Intake Level  of 400 micrograms per day can lead to selenosis. [ 15 ]  This 400 microgram ( \u03bcg ) Tolerable Upper Intake Level is based primarily on a 1986 study of five Chinese patients who exhibited overt signs of selenosis and a follow-up study on the same five people in 1992. [ 16 ]  The 1992 study actually found the maximum safe dietary Se intake to be approximately 800 micrograms per day (15 micrograms per kilogram body weight), but suggested 400 micrograms per day to not only avoid  toxicity , but also to avoid creating an imbalance of nutrients in the diet and to account for data from other countries. [ 17 ]  In China, people who  ingested corn grown in extremely selenium-rich stony coal (carbonaceous  shale ) have suffered from selenium toxicity. This coal was shown to have selenium content as high as 9.1%, the highest concentration in coal ever recorded in literature. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11870", "text": "Symptoms of selenosis include a garlic odor on the breath, gastrointestinal disorders, hair loss, sloughing of nails, fatigue, irritability, and neurological damage. Extreme cases of selenosis can result in  cirrhosis  of the liver,  pulmonary edema , and death. [ 19 ]  Elemental selenium and most metallic  selenides  have relatively low toxicities because of their low  bioavailability . By contrast,  selenates  and  selenites  are very toxic, having an oxidant mode of action similar to that of arsenic trioxide. The chronic toxic dose of selenite for humans is about 2400 to 3000 micrograms of selenium per day for a long time. [ 20 ]   Hydrogen selenide  is an extremely toxic, corrosive gas. [ 21 ]  Selenium also occurs in organic compounds, such as dimethyl selenide,  selenomethionine ,  selenocysteine  and  methylselenocysteine , all of which have high  bioavailability  and are toxic in large doses."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11871", "text": "Selenium poisoning  of water systems may result whenever new agricultural runoff courses through normally dry, undeveloped lands. This process leaches natural soluble selenium compounds (such as selenates) into the water, which may then be concentrated in new \"wetlands\" as the water evaporates. High selenium levels produced in this fashion have been found to have caused certain congenital disorders in wetland birds. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11872", "text": "In fish and other wildlife, low levels of selenium cause deficiency while high levels cause toxicity.  For example, in salmon, the optimal concentration of selenium in the fish tissue (whole body) is about 1 microgram selenium per gram of tissue (dry weight).  At levels much below that concentration, young salmon die from selenium deficiency; [ 23 ]  much above that level they die from toxic excess. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11873", "text": "Selenium deficiency can occur in patients with severely compromised  intestinal  function, those undergoing  total parenteral nutrition , and [ 25 ]  in those of advanced age (over 90). Also, people dependent on food grown from selenium-deficient soil are at risk. Although  New Zealand  has low levels of selenium in its soil, adverse health effects have not been detected. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11874", "text": "Selenium deficiency as defined by low (<60% of normal) selenoenzyme activity levels in brain and endocrine tissues only occurs when a low selenium status is linked with an additional stress, such as high exposures to mercury [ 27 ]  or as a result of increased oxidant stress due to vitamin E deficiency. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11875", "text": "Selenium interacts with other nutrients, such as  iodide  and  vitamin E . The interaction is observed in the  etiology  of many deficiency diseases in animals, and pure selenium deficiency is rare. The effect of selenium deficiency on health remains uncertain, particularly in relation to  Kashin-Beck disease . [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11876", "text": "The US Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for selenium in 2000. If there is not sufficient information to establish EARs and RDAs, an estimate designated  Adequate Intake  (AI) is used instead. The current EAR for selenium for people ages 14 and up is 45 \u03bcg/day. The RDA is 55 \u03bcg/day. RDAs are higher than EARs so as to identify amounts that will cover people with higher-than-average requirements. RDA for pregnancy is 60 \u03bcg/day. RDA for lactation is 70 \u03bcg/day. For children ages 1\u201313 years, the RDA increases with age from 20 to 40 \u03bcg/day. As for safety, the IOM sets  Tolerable upper intake levels  (ULs) for vitamins and minerals when evidence is sufficient. In the case of selenium, the UL is 400 \u03bcg/day. Collectively the EARs, RDAs, AIs and ULs are referred to as  Dietary Reference Intakes  (DRIs). [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11877", "text": "The  European Food Safety Authority  (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For women and men ages 15 and older, the AI is set at 70 \u03bcg/day. AI for pregnancy is 70 \u03bcg/day; for lactation, 85 \u03bcg/day. For children ages 1\u201314 years, the AIs increase with age from 15 to 55 \u03bcg/day. These AIs are higher than the U.S. RDAs. [ 31 ]  The European Food Safety Authority reviewed the same safety question and set its UL at 300 \u03bcg/day, which is lower than the U.S. value. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11878", "text": "In the United States, selenium deficiency is not common. A federal survey of food consumption determined that for women and men over the age of 19, average consumption from foods and beverages was 89 and 125 \u03bcg/day, respectively. For women and men of all ages fewer than 3% consumed less than the EAR. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11879", "text": "For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For selenium labeling purposes, 100% of the Daily Value was 70 \u03bcg, but as of 27 May 2016 it was revised to 55 \u03bcg. [ 34 ] [ 35 ]  A table of the old and new adult daily values is provided at  Reference Daily Intake ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11880", "text": "Dietary selenium comes from nuts,  cereals ,  meat ,  mushrooms ,  fish , and  eggs .  Brazil nuts  are the richest ordinary dietary source and could cause selenium toxicity if consumed regularly \u2013 though the actual concentration of selenium (as with any plant-based food sources, such as another selenium-accumulating \"paradise nut\"  Lecythis , belonging to the same family  Lecythidaceae ) is soil-dependent and may vary significantly by geographic location. In descending order of concentration, high levels are also found in  kidney ,  tuna ,  crab , and  lobster . [ 36 ] [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11881", "text": "The human body's content of selenium is believed to be in the 13\u201320 milligram range. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11882", "text": "Selenium  has bimodal biological action depending on the concentration. At low nutritional doses, selenium acts as an  antioxidant  through  selenoproteins , scavenging  ROS , supporting cell survival and growth; while, at supra-nutritional higher pharmacological doses, selenium acts as a  pro-oxidant  generating  ROS  and inducing  cell death . In cancer, studies have been conducted mostly on the benefits of selenium intake in reducing the risk of cancer incidence at the nutritional level; however, fewer studies have explored the effects of supra-nutritional or pharmacological doses of selenium on cancer. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11883", "text": "\"Although an inverse association between selenium exposure and the risk of some types of cancer was found in some observational studies, this cannot be taken as evidence of a causal relation, and these results should be interpreted with caution... Conflicting results including inverse, null and direct associations have been reported for some cancer types... RCTs assessing the effects of selenium supplementation on cancer risk have yielded inconsistent results... To date, no convincing evidence suggests that selenium supplements can prevent cancer in humans.\" [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11884", "text": "To date, many studies have been conducted on the benefits of selenium intake in reducing the risk of  cancer incidence  at the nutritional level, indicating that likely selenium functions as an  immunostimulator , i.e. reversing the  immunosuppression  in  tumour microenvironment  towards antitumour  immunity  by activating  immune cells  (e.g.  M1 macrophages  and  CD8+ T-lymphocytes , the elevated number of  neutrophils  and activated cytotoxic  NK cells ) and releasing  pro-inflammatory   cytokines  such as  IFN\u03b3  and  TNF\u03b1 . [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11885", "text": "AIDS appears to involve a slow and progressive decline in levels of selenium in the body. Whether this decline in selenium levels is a direct result of the replication of HIV or related more generally to the overall malabsorption of nutrients by AIDS patients remains debated. Observational studies have found an association between decreased selenium levels and poorer outcomes in patients with HIV, though these studies were mostly done prior to the currently effective treatments with highly active antiretroviral therapy ( HAART ).  Currently there is inadequate evidence to recommend routine selenium supplementation for HIV patients, and further research is recommended. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11886", "text": "Selenium supplementation has no effect on overall mortality. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11887", "text": "As with other types of supplementation, there is no good evidence selenium supplementation helps in the treatment of tuberculosis. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11888", "text": "A meta-analysis of four RCTs concluded that there is no support for selenium supplementation for prevention of type 2 diabetes mellitus in Caucasians. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11889", "text": "Abnormally high or low levels of dietary selenium can have an adverse effect on sperm quality, with a consequent lowering of fertility. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11890", "text": "During the COVID-19 pandemic, some studies attempted to establish a correlation between selenium plasma level and severity of COVID-19 cases. One study done on 33 patients concluded that low plasma selenium levels were correlated with a high mortality rate among COVID-19 patients. However, the median age of deaths in this study was 89 years old; in contrast, survivors' median age was 69 years old, and the study stated that the causality remains unknown. [ 46 ]   \nOn the other hand, another study revealed that the mean selenium plasma level was within the normal range among all included COVID-19 patients; however, the mean selenium plasma level was elevated among severe cases of COVID-19. This study concluded that there was a significant elevation of selenium serum level among severe cases compared to non-severe cases of COVID-19, and could be correlated with the disease severity. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11891", "text": "Selenium has a protective effect towards mercury toxicity. Mercury binds to selenium with high affinity, so this metal can inhibit selenium-dependent enzymes. However, increased selenium intake can preserve the enzyme activities, reducing the adverse effects caused by mercury exposure. [ 48 ]   [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11892", "text": "Selenium is incorporated into several prokaryotic selenoprotein families in bacteria, archaea, and eukaryotes as selenocysteine, [ 50 ]  where selenoprotein peroxiredoxins protect bacterial and eukaryotic cells against oxidative damage. Selenoprotein families of GSH-Px and the deiodinases of eukaryotic cells seem to have a bacterial  phylogenetic  origin. The selenocysteine-containing form occurs in species as diverse as green algae, diatoms, sea urchin, fish and chicken. Selenium enzymes are involved in utilization of the small reducing molecules  glutathione  and  thioredoxin ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11893", "text": "Trace elements involved in GSH-Px and superoxide dismutase enzymes activities, i.e. selenium,  vanadium ,  magnesium ,  copper , and  zinc , may have been lacking in some terrestrial mineral-deficient areas. [ 50 ]  Marine organisms retained and sometimes expanded their seleno-proteomes, whereas the seleno-proteomes of some terrestrial organisms were reduced or completely lost. These findings suggest that aquatic life supports selenium utilization, whereas terrestrial habitats lead to reduced use of this trace element. [ 51 ] [ 52 ]  Marine fishes and vertebrate thyroid glands have the highest concentration of selenium and iodine. From about 500 Mya, freshwater and terrestrial plants slowly optimized the production of \"new\" endogenous antioxidants such as  ascorbic acid  (Vitamin C),  polyphenols  (including flavonoids),  tocopherols , etc. A few of these appeared more recently, in the last 50\u2013200 million years, in fruits and flowers of angiosperm plants. In fact, the angiosperms (the dominant type of plant today) and most of their antioxidant pigments evolved during the late  Jurassic  period."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11894", "text": "About 200 Mya, new selenoproteins were developed as mammalian GSH-Px enzymes. [ 53 ] [ 54 ] [ 55 ] [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11895", "text": "Selenium yeast  is a  feed additive  for livestock, used to increase the  selenium  content in their  fodder . It is a form of selenium currently approved for human consumption in the EU and Britain. [ 1 ]  Inorganic forms of selenium are used in feeds (namely  sodium selenate  and  sodium selenite , which appear to work in roughly the same manner). Since these products can be patented, producers can demand premium prices. [ 2 ]  It is produced by fermenting  Saccharomyces cerevisiae  (baker's yeast) in a selenium-rich media. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11896", "text": "There is considerable variability in products described as Se-yeast and the selenium compounds found within. Many manufacturers and products on the market are simply mixtures of largely inorganic selenium and some yeast. [ 4 ]  Selenium is found in different forms based upon the food in which it is found. For instance, the form found in mustard and garlic is different from the form found in wheat or corn. In some products, the added selenium is structurally substituted for sulfur in the amino acid  methionine , thus forming an  organic chemical  called  selenomethionine  via the same pathways and enzymes. Owing to its similarity to sulfur-containing methionine, selenomethionine is mistaken for an  amino acid  by the yeast anabolism and incorporated in its proteins. It has been claimed that selenomethionine makes a better source of dietary selenium in animal nutrition, since it is an organic chemical compound sometimes found in some common crops such as wheat. [ 3 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11897", "text": "Large amounts of  selenium are toxic ; however, it is physiologically necessary for animals in extremely small amounts. Many other uncharacterized selenium-containing organic chemicals are also produced by a method similar to that of selenomethionine; some have recently been characterized but remain relatively unknown, such as  S -seleno-methyl-glutathione and glutathione- S -selenoglutathione. [ 3 ] [ 4 ]  Due to this, the European Union has questioned the safety and potential toxicity of this food supplement for humans, and it may not be used as an additive after 2002."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11898", "text": "G.N Schrauzer , who has written two papers about selenomethionine, claims it should be an  essential amino acid , and that the product is completely safe. [ 3 ]  The  European Food Safety Authority  does allow the use of selenomethionine as a feed additive for animals. [ 6 ]  Because organic forms of selenium appear to be excreted from the body slower than inorganic forms, products enriched with organic selenium might detrimentally  bioaccumulate  in the body. Because selenium-enriched foods contain much more selenium than natural foods, selenium toxicity is a potential problem, and such foods must be treated with caution. [ 4 ]  The EU allows up to 300 micrograms of selenium per day, but one long-term study of selenium supplementation showed no evidence of toxicity at a dose as high as 800 micrograms per day. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11899", "text": "An organic selenium-containing chemical found in selenium yeast has been shown to differ in bioavailability and metabolism compared with common inorganic forms of dietary selenium. [ 8 ]  Dietary supplementation using selenium yeast is ineffective in the production of antioxidants in bovine milk compared to inorganic selenium (sodium selenate). [ 9 ]  One study examined if increased selenium in the diet of mutant mice (via a selenium yeast product) caused a higher production of selenium-containing enzymes which have an antioxidant effect. The effect was modest. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11900", "text": "Selenium supplementation in yeast form has been shown to increase pig selenium-containing antioxidant enzymes, [ 11 ]  broiler growth and meat quality, [ 12 ] [ 13 ]  the shelf life of turkey and rooster semen, [ 14 ] [ 15 ] [ 16 ]  and possibly cattle fertility. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11901", "text": "Selenium supplementation in animal feeds may be profitable for agribusinesses. It may be possible to market selenium-fortified foods to consumers as  functional foods , such as selenium-enriched eggs, meat, [ 18 ] [ 19 ] [ 20 ] [ 21 ]  or milk. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11902", "text": "A patented cultivar of yeast ( Saccharomyces cerevisiae  'CNCM I-3060') marketed as Sel-Plex\u00ae has been approved for use in animal  fodder :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11903", "text": "Total selenium in selenium yeast can be reliably determined using open acid digestion to extract selenium from the yeast matrix followed by flame atomic absorption spectrometry. [ 24 ]  Determination of the selenium species selenomethionine can be achieved via proteolytic digestion of selenium yeast followed by high-performance liquid chromatography with inductively coupled plasma mass spectrometry. [ 25 ] [ 26 ] [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11904", "text": "Nutritional muscular dystrophy"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11905", "text": "Sodium ions ( Na + ) are necessary in small amounts for some types of  plants , [ 1 ]  but  sodium  as a nutrient is more generally needed in larger amounts [ 1 ]  by  animals , due to their use of it for generation of  nerve impulses  and for maintenance of  electrolyte  balance and  fluid balance . In animals, sodium ions are necessary for the aforementioned functions and for  heart  activity and certain  metabolic  functions. [ 2 ]  The  health effects of salt  reflect what happens when the body has too much or too little sodium.\nCharacteristic concentrations of  sodium  in model organisms are: 10\u00a0 mM  in  E. coli , 30\u00a0mM in budding yeast, 10\u00a0mM in mammalian cell and 100\u00a0mM in blood plasma. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11906", "text": "Additionally, sodium ions are essential to several cellular processes. They are responsible for the co-transport of glucose in the sodium glucose symport, are used to help maintain membrane polarity with the help of the sodium potassium pump, and are paired with water to thin the mucus of the airway lumen when the active Cystic Fibrosis Transport Receptor moves chloride ions into the airway. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11907", "text": "The minimum physiological requirement for sodium is between 115 and 500\u00a0mg per day depending on sweating due to physical activity, and whether the person is adapted to the climate. [ 5 ]   Sodium chloride  is the principal source of sodium in the diet, and is used as seasoning and preservative, such as for  pickling  and  jerky ; most of it comes from processed foods. [ 6 ]  The  Adequate Intake  for sodium is 1.2 to 1.5\u00a0g per day, [ 7 ]  but on average people in the United States consume  3.4\u00a0g per day, [ 8 ] [ 9 ]  the minimum amount that promotes hypertension. [ 10 ]  Note that salt contains about 39.3% sodium by mass [ 11 ] \u2014the rest being chlorine and other trace chemicals; thus the  Tolerable Upper Intake Level  of 2.3\u00a0g sodium would be about 5.9\u00a0g of salt\u2014about 1  teaspoon . [ 12 ]  The average daily excretion of sodium is between 40 and 220 mEq. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11908", "text": "Normal serum sodium levels are between approximately 135 and 145  mEq /L (135 to 145\u00a0mmol/L). A serum sodium level of less than 135 mEq/L qualifies as  hyponatremia , which is considered severe when the serum sodium level is below 125 mEq/L. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11909", "text": "The  renin\u2013angiotensin system  and the  atrial natriuretic peptide  indirectly regulate the amount of  signal transduction  in the human  central nervous system , which depends on sodium ion motion across the nerve cell membrane, in all nerves. Sodium is thus important in  neuron  function and osmoregulation between cells and the  extracellular fluid ; the distribution of sodium ions are mediated in all animals by  sodium\u2013potassium pumps , which are active transporter  solute pumps , pumping ions against the gradient, and sodium-potassium channels. [ 16 ]  Sodium channels are known to be less selective in comparison to potassium channels. Sodium is the most prominent cation in extracellular fluid: in the 15 L of  extracellular fluid  in a 70\u00a0kg human there is around 50\u00a0grams of sodium, 90% of the body's total sodium content."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11910", "text": "Some potent  neurotoxins , such as  batrachotoxin , increase the sodium ion permeability of the  cell membranes  in nerves and muscles, causing a massive and irreversible  depolarization  of the membranes with potentially fatal consequences. However, drugs with smaller effects on sodium ion motion in nerves may have diverse pharmacological effects that range from anti-depressant to anti-seizure actions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11911", "text": "Since only some plants need sodium and those in small quantities, a completely  plant-based diet  will generally be very low in sodium. [ citation needed ]  This requires some herbivores to obtain their sodium from  salt licks  and other mineral sources. The animal need for sodium is probably the reason for the highly conserved ability to  taste  the sodium ion as \"salty.\" Receptors for the pure salty taste respond best to sodium; otherwise, the receptors respond only to a few other small monovalent cations ( Li + ,  NH + 4  and somewhat to  K + ). The  calcium  ion (Ca 2+ ) also tastes salty and sometimes bitter to some people but, like potassium, can trigger other tastes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11912", "text": "Sodium ions play a diverse and important role in many physiological processes, acting to regulate  blood volume ,  blood pressure ,  osmotic equilibrium  and  pH . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11913", "text": "In  C4 plants , sodium is a  micronutrient  that aids in metabolism, specifically in regeneration of  phosphoenolpyruvate  (involved in the biosynthesis of various aromatic compounds, and in  carbon fixation ) and synthesis of chlorophyll. [ 17 ]  In others, it substitutes for  potassium  in several roles, such as maintaining  turgor pressure  and aiding in the opening and closing of stomata. [ 18 ]  Excess sodium in the soil limits the uptake of water due to decreased  water potential , which may result in wilting; similar concentrations in the  cytoplasm  can lead to enzyme inhibition, which in turn causes necrosis and chlorosis. [ 19 ]  To avoid these problems, plants developed mechanisms that limit sodium uptake by roots, store them in cell  vacuoles , and control them over long distances; [ 20 ]  excess sodium may also be stored in old plant tissue, limiting the damage to new growth. Though much how excess sodium loading in the xylem is yet to be determined. However, anti porter CHX21 can be attributed to active loading of sodium into the xylem. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11914", "text": "Sodium is the primary  cation  (positively charged ion) in extracellular fluids in animals and humans. These fluids, such as blood plasma and extracellular fluids in other tissues, bathe cells and carry out transport functions for nutrients and wastes. Sodium is also the principal cation in seawater, although the concentration there is about 3.8 times what it is normally in extracellular body fluids."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11915", "text": "Although the system for maintaining optimal salt and water balance in the body is a complex one, [ 22 ]  one of the primary ways in which the human body keeps track of loss of body water is that  osmoreceptors  in the  hypothalamus  sense a balance of sodium and water concentration in extracellular fluids. Relative loss of body water will cause sodium concentration to rise higher than normal, a condition known as  hypernatremia . This ordinarily results in thirst. Conversely, an excess of body water caused by drinking will result in too little sodium in the blood ( hyponatremia ), a condition which is again sensed by the  hypothalamus , causing a decrease in  vasopressin  hormone secretion from the  posterior pituitary , and a consequent loss of water in the urine, which acts to restore blood sodium concentrations to normal."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11916", "text": "Severely dehydrated persons, such as people rescued from ocean or desert survival situations, usually have very high blood sodium concentrations. These must be very carefully and slowly returned to normal, since too-rapid correction of hypernatremia may result in brain damage from cellular swelling, as water moves suddenly into cells with high  osmolar  content."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11917", "text": "In humans, a high-salt intake was demonstrated to attenuate  nitric oxide  production. Nitric oxide (NO) contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11918", "text": "Because the  hypothalamus / osmoreceptor  system ordinarily works well to cause drinking or urination to restore the body's sodium concentrations to normal, this system can be used in medical treatment to regulate the body's total fluid content, by first controlling the body's sodium content. Thus, when a powerful  diuretic  drug is given which causes the kidneys to excrete sodium, the effect is accompanied by an excretion of body water (water loss accompanies sodium loss). This happens because the kidney is unable to efficiently retain water while excreting large amounts of sodium. In addition, after sodium excretion, the  osmoreceptor  system may sense lowered sodium concentration in the blood and then direct compensatory urinary water loss in order to correct the  hyponatremic  (low blood sodium) state."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11919", "text": "The  sodium-potassium pump  works with the sodium and potassium leak channels to maintain the membrane potential between the cell and the extracellular space. Sodium moves down the concentration gradient from the cytosol into the extracellular matrix. Potassium moves down its concentration gradient from the extracellular matrix into the cytosol. In order to maintain the membrane potential, the sodium-potassium pump acts as a form of direct active transport where the hydrolysis of ATP to ADP and an inorganic phosphate at the P-type ATPase moves 3 potassium ions back out of the cell and 2 sodium ions into the cell. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11920", "text": "The sodium-potassium pump plays a large role in neural signaling due to the maintenance of cell membrane potential. This creates an action potential that causes the neurons to polarize and depolarize their membranes by opening and closing the voltage gated channels: this alters voltage potential and leads to neurotransmitter secretion and ultimately signal transmission. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11921", "text": "When the pump fails to function, patients are susceptible to illnesses like heart failure and chronic obstructive lung disease (COLD). Those who experienced an event of heart failure had on average, a 40% lower concentration of the sodium-potassium ATPase. This lack of polarization of the membrane leads to an inability of action potentials to propagate at their usual rate, leading to a lowered hear rate and potentially heart failure. [ 25 ]  In COLD diagnoses, a majority of patients found to have a lowered amount of magnesium and potassium also had a decreased concentration of the sodium-potassium pump in skeletal and smooth muscle during respiratory failure. COLD is treatable in the short term by glucocorticoid which up-regulates the sodium-potassium pump, helping to support muscle endurance and increase muscle activity during these episodes of respiratory failure. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11922", "text": "In the  sodium-glucose symporter , sodium moves down its concentration gradient to move glucose up its concentration gradient. Sodium has a greater concentration outside of the cell, and binds to the symporter, which is in its outward facing conformation. Once sodium is bound, glucose can bind from the extracellular space, causing the symporter to switch into the occluded formation (closed) before opening to the inside of the cell and releasing the two sodium ions and the one glucose molecule. Once both are released, the symporter re-orients itself to the outward facing conformation and the process starts all over again. [ 4 ]  A major example of up-regulation of the sodium-glucose symporter is seen in patients with  type 2 diabetes , where there is roughly a 3-4 fold up-regulation of the sodium-glucose symporter (SGLT1). This leads to an influx of glucose into the cell and results in hyperglycemia. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11923", "text": "The  Cystic Fibrosis Transport Regulator (CFTR)  works by binding two ATP to the A1 and A2, ATP-binding domain. This opens the CFTR channel and allows chloride ions to flow into the lungs and airway lumen. This influx of negatively charged chloride ions into the airway lumen causes sodium to move into the airway lumen to balance the negative charge. Water then moves in with the sodium to balance the osmotic pressure and ultimately leads to the thinning of mucus. In cases of Cystic Fibrosis, the CFTR is defective and only binds a single ATP, leading to the channel failing to open and preventing chloride ions from diffusing into the airway lumen. Since chloride ions cannot diffuse in, there is no movement of sodium into the airway lumen, and no need for water to move into the lumen, leading to thick mucus that clogs and infects the airway lumen. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11924", "text": "Sulfur assimilation  is the process by which living organisms incorporate  sulfur  into their biological molecules. [ 1 ]  In plants, sulfate is absorbed by the roots and then transported to the chloroplasts by the transipration stream where the sulfur are reduced to  sulfide  with the help of a series of  enzymatic reactions . Furthermore, the reduced sulfur is incorporated into  cysteine , [ 2 ]  an amino acid that is a precursor to many other sulfur-containing compounds. In animals, sulfur assimilation occurs primarily through the diet, as animals cannot produce sulfur-containing compounds directly. Sulfur is incorporated into amino acids such as  cysteine  and  methionine , which are used to build  proteins  and other important molecules. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11925", "text": "Sulfate  uptake first occurs in roots that have a high affinity for sulfur.  [ 3 ]  The maximal sulfate uptake rate is generally already reached at sulfate levels of 0.1 mM and lower. The uptake of sulfate by the roots and its transport to the shoot is strictly controlled and it appears to be one of the primary regulatory sites of sulfur assimilation. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11926", "text": "Sulfate is actively taken up across the  plasma membrane  of the  root  cells, subsequently loaded into the  xylem  vessels and transported to the shoot by the  transpiration  stream.  [ 4 ]  The uptake and transport of sulfate is energy dependent (driven by a  proton gradient  generated by  ATPases ) through a proton/sulfate  co-transport . [ 5 ]  In the shoot the sulfate is unloaded and transported to the chloroplasts where it is reduced. The remaining sulfate in plant tissue is predominantly present in the  vacuole , since the concentration of sulfate in the  cytoplasm  is kept rather constant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11927", "text": "Distinct sulfate transporter proteins mediate the uptake, transport and subcellular distribution of sulfate. [ 6 ]  The sulfate  transporters   gene family  has been classified in up to 5 different groups according to their cellular and sub-cellular  gene expression , and possible functioning. [ 7 ]  Each group of transporter proteins may be expressed exclusively in the roots or shoots of the plant, or both."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11928", "text": "Regulation and expression of the majority of sulfate transporters are controlled by the sulfur  nutritional  status of the plants. [ 8 ]  Upon sulfate deprivation, the rapid decrease in root sulfate is regularly accompanied by a strongly enhanced expression of most sulfate transporter genes (up to 100-fold), accompanied by a substantially enhanced sulfate uptake capacity. It is not yet fully understood whether sulfate and other metabolic products of sulfur assimilation ( O-acetylserine ,  cysteine ,  glutathione ) act as signals in the regulation of sulfate uptake and transport, or in the expression of the sulfate transporters involved."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11929", "text": "Sulfate reduction predominantly takes place in the leaf  chloroplasts . Here, the reduction of  sulfate  to  sulfide  occurs in three steps. Sulfate needs to be activated to  adenosine 5'-phosphosulfate  (APS) prior to its reduction to  sulfite ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11930", "text": "The activation of sulfate is catalyzed by  ATP  sulfurylase, which affinity for sulfate is rather low (Km approximately 1 mM) and the in situ sulfate concentration in the chloroplast is most likely one of the limiting/regulatory steps in sulfur reduction. Subsequently, APS is reduced to sulfite, catalyzed by APS reductase with likely  glutathione  as  reductant ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11931", "text": "The latter reaction is assumed to be one of the primary regulation points in the sulfate reduction, since the activity of APS reductase is the lowest of the enzymes of the sulfate reduction pathway and it has a fast turnover rate.  Sulfite  is with high affinity reduced by  sulfite reductase  to  sulfide  with  ferredoxin  as a reductant. The remaining sulfate in plant tissue is transferred into the  vacuole . The remobilization and redistribution of the vacuolar sulfate reserves appear to be rather slow and sulfur-deficient plants may still contain detectable levels of sulfate."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11932", "text": "Sulfide  is incorporated into  cysteine , catalyzed by O-acetylserine (thiol)lyase, with O-acetylserine as substrate. The synthesis of O-acetylserine is catalyzed by  serine  acetyltransferase and together with O-acetylserine (thiol)lyase it is associated as enzyme complex named  cysteine synthase ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11933", "text": "The formation of cysteine is the direct coupling step between sulfur ( sulfur metabolism ) and  nitrogen assimilation  in plants. This differs from the process in yeast, where sulfide must be incorporated first in  homocysteine  then converted in two steps to cysteine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11934", "text": "Cysteine is sulfur donor for the synthesis of  methionine , the major other sulfur-containing amino acid present in plants. This happens through the  transsulfuration pathway  and the methylation of  homocysteine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11935", "text": "Both cysteine and methionine are sulfur-containing  amino acids  and are of great significance in the structure, conformation and function of  proteins  and  enzymes , but high levels of these amino acids may also be present in seed storage proteins. The thiol groups of the cysteine residues in proteins can be oxidized resulting in  disulfide  bridges with other cysteine  side chains  (and form  cystine ) and/or linkage of  polypeptides ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11936", "text": "Disulfide bridges ( disulfide bonds ) make an important contribution to the structure of proteins. The  thiol  groups are also of great importance in substrate binding of enzymes, in metal-sulfur clusters in proteins (e.g.  ferredoxins ) and in regulatory proteins (e.g.  thioredoxins )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11937", "text": "Glutathione  or its homologues, e.g. homoglutathione in  Fabaceae ; hydroxymethylglutathione in  Poaceae  are the major water-soluble non- protein   thiol  compounds present in plant tissue and account for 1-2% of the total sulfur. The content of glutathione in plant tissue ranges from 0.1 \u2013 3 mM. Cysteine is the direct precursor for the synthesis of glutathione (and its homologues). First, \u03b3-glutamylcysteine is synthesized from cysteine and glutamate catalyzed by  gamma-glutamylcysteine synthetase . Second, glutathione is synthesized from \u03b3-glutamylcysteine and  glycine  (in glutathione homologues,  \u03b2-alanine  or  serine ) catalyzed by glutathione synthetase. Both steps of the synthesis of glutathione are ATP dependent reactions. Glutathione is maintained in the reduced form by an  NADPH -dependent  glutathione reductase  and the ratio of reduced glutathione (GSH) to  oxidized  glutathione (GSSG) generally exceeds a value of 7.\nGlutathione fulfils various roles in plant functioning. In sulfur metabolism it functions as reductant in the reduction of APS to sulfite. It is also the major transport form of reduced sulfur in plants. Roots likely largely depend for their reduced sulfur supply on shoot/root transfer of glutathione via the  phloem , since the reduction of sulfur occurs predominantly in the chloroplast. Glutathione is directly involved in the reduction and assimilation of  selenite  into  selenocysteine . Furthermore, glutathione is of great significance in the protection of plants against oxidative and environmental stress and it depresses/scavenges the formation of toxic  reactive oxygen species , e.g.  superoxide ,  hydrogen peroxide  and lipid  hydroperoxides . Glutathione functions as reductant in the enzymatic detoxification of reactive oxygen species in the glutathione- ascorbate  cycle and as thiol buffer in the protection of proteins via direct reaction with reactive oxygen species or by the formation of mixed disulfides. The potential of glutathione as protectant is related to the pool size of glutathione, its redox state (GSH/GSSG ratio) and the activity of  glutathione reductase . Glutathione is the precursor for the synthesis of phytochelatins, which are synthesized enzymatically by a constitutive phytochelatin synthase. The number of \u03b3-glutamyl-cysteine residues in the phytochelatins may range from 2 \u2013 5, sometimes up to 11. Despite the fact that the  phytochelatins  form complexes which a few heavy metals, viz.  cadmium , it is assumed that these compounds play a role in heavy metal  homeostasis  and detoxification by buffering of the cytoplasmatic concentration of essential heavy metals. Glutathione is also involved in the detoxification of  xenobiotics , compounds without direct nutritional value or significance in metabolism, which at too high levels may negatively affect plant functioning. Xenobiotics may be detoxified in conjugation reactions with glutathione catalyzed by  glutathione S-transferase , which activity is constitutive; different xenobiotics may induce distinct  isoforms  of the enzyme. Glutathione S-transferases have great significance in  herbicide  detoxification and tolerance in agriculture and their induction by herbicide  antidotes  (' safeners ') is the decisive step for the induction of herbicide tolerance in many crop plants. Under natural conditions glutathione S-transferases are assumed to have significance in the detoxification of lipid  hydroperoxides , in the conjugation of endogenous metabolites,  hormones  and  DNA  degradation products, and in the transport of  flavonoids ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11938", "text": "Sulfolipids  are sulfur containing lipids.  Sulfoquinovosyl diacylglycerols  are the predominant sulfolipids present in plants. In leaves its content comprises up to 3 - 6% of the total sulfur present. This sulfolipid is present in  plastid   membranes  and likely is involved in  chloroplast  functioning. The route of  biosynthesis  and physiological function of sulfoquinovosyl  diacylglycerol  is still under investigation. From recent studies it is evident that  sulfite  it the likely sulfur  precursor  for the formation of the  sulfoquinovose  group of this lipid."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11939", "text": "Brassica  species contain  glucosinolates , which are sulfur-containing  secondary compounds . Glucosinolates are composed of a \u03b2-thioglucose moiety, a sulfonated oxime and a side chain. The synthesis of glucosinolates starts with the oxidation of the parent amino acid to an  aldoxime , followed by the addition of a thiol group (through conjugation with glutathione) to produce  thiohydroximate . The transfer of a  glucose  and a sulfate moiety completes the formation of the glucosinolates."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11940", "text": "The physiological significance of glucosinolates is still ambiguous, though they are considered to function as sink compounds in situations of sulfur excess. Upon tissue disruption glucosinolates are enzymatically degraded by  myrosinase  and may yield a variety of biologically active products such as  isothiocyanates ,  thiocyanates ,  nitriles  and oxazolidine-2-thiones. The glucosinolate-myrosinase system is assumed to play a role in plant- herbivore  and plant- pathogen  interactions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11941", "text": "Furthermore, glucosinolates are responsible for the flavor properties of  Brassicaceae  and recently \nhave received attention in view of their potential anti- carcinogenic  properties.\n Allium  species contain \u03b3- glutamylpeptides  and  alliins  (S-alk(en)yl cysteine sulfoxides). The content of these sulfur-containing  secondary compounds  strongly depends on stage of development of the plant, temperature, water availability and the level of nitrogen and sulfur nutrition. In onion  bulbs  their content may account for up to 80% of the organic sulfur fraction. Less is known about the content of secondary sulfur compounds in the seedling stage of the plant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11942", "text": "It is assumed that alliins are predominantly synthesized in the leaves, from where they are subsequently transferred to the attached bulb scale. The biosynthetic pathways of synthesis of \u03b3-glutamylpeptides and alliins are still ambiguous. \u03b3-Glutamylpeptides can be formed from cysteine (via \u03b3-glutamylcysteine or glutathione) and can be metabolized into the corresponding alliins via oxidation and subsequent hydrolyzation by \u03b3-glutamyl  transpeptidases ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11943", "text": "However, other possible routes of the synthesis of \u03b3-glutamylpeptides and alliins may not be excluded. Alliins and \u03b3-glutamylpeptides are known to have therapeutic utility and might have potential value as phytopharmaceutics. The alliins and their breakdown products (e.g.  allicin ) are the flavor precursors for the odor and taste of species. Flavor is only released when plant cells are disrupted and the enzyme alliinase from the vacuole is able to degrade the alliins, yielding a wide variety of volatile and non- volatile  sulfur-containing compounds. The physiological function of \u03b3-glutamylpeptides and alliins is rather unclear."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11944", "text": "Unlike in plants, animals do not have a pathway for the direct assimilation of inorganic sulfate into organic compounds. In animals, the primary source of sulfur is dietary  methionine , an essential amino acid that contains a sulfur atom. Methionine is first converted to  S-adenosylmethionine  (SAM), a compound that is involved in many important biological processes, including DNA  methylation  and  neurotransmitter  synthesis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11945", "text": "SAM can then be used to synthesize other important sulfur-containing compounds such as  cysteine ,  taurine , and  glutathione . Cysteine is a precursor for the synthesis of several important proteins and peptides, as well as glutathione, a powerful antioxidant that protects cells from oxidative stress.  Taurine  is involved in a variety of physiological processes, including  osmoregulation ,  modulation  of  calcium signaling , and regulation of mitochondrial function."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11946", "text": "In  bacteria  and  fungi , the sulfur assimilation pathway is similar to that in plants, where inorganic sulfate is reduced to sulfide, and then incorporated into cysteine and other sulfur-containing compounds."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11947", "text": "Bacteria and fungi can absorb inorganic sulfate from the environment through a sulfate transporter, which is regulated by the presence of sulfate in the medium. Once inside the cell, sulfate is activated by  ATP sulfurylase  to form  adenosine 5'-phosphosulfate  (APS), which is then reduced to sulfite by APS reductase. Sulfite is further reduced to sulfide by sulfite reductase, which is then incorporated into cysteine by enzyme."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11948", "text": "Cysteine, once synthesized, can be used for the biosynthesis of  methionine  and other important biomolecules. In addition, microorganisms also use sulfur-containing compounds for various other purposes, such as the synthesis of  antibiotics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11949", "text": "Sulfur assimilation in microorganisms is regulated by a variety of environmental factors, including the availability of sulfur in the medium and the presence of other nutrients. The activity of key enzymes in the sulfur assimilation pathway is also regulated by feedback inhibition from downstream products, similar to the regulation seen in plants."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11950", "text": "The rapid economic growth, industrialization and urbanization are associated with a strong increase in energy demand and emissions of  air pollutants  including  sulfur dioxide  (see also  acid rain ) and  hydrogen sulfide , which may affect plant  metabolism . Sulfur gases are potentially  phytotoxic , however, they may also be metabolized and used as sulfur source and even be beneficial if the sulfur  fertilization  of the roots is not sufficient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11951", "text": "Plant shoots form a sink for atmospheric  sulfur  gases, which can directly be taken up by the foliage (dry deposition). The foliar uptake of sulfur dioxide is generally directly dependent on the degree of opening of the  stomates , since the internal resistance to this gas is low. Sulfite is highly soluble in the  apoplastic  water of the  mesophyll , where it  dissociates  under formation of  bisulfite  and  sulfite ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11952", "text": "Sulfite may directly enter the sulfur reduction pathway and be reduced to  sulfide , incorporated into cysteine, and subsequently into other sulfur compounds. Sulfite may also be oxidized to  sulfate , extra- and intracellularly by  peroxidases  or non-enzymatically catalyzed by metal ions or  superoxide   radicals  and subsequently reduced and assimilated again. Excessive sulfate is transferred into the vacuole; enhanced foliar sulfate levels are characteristic for exposed plants.\nThe foliar uptake of hydrogen sulfide appears to be directly dependent on the rate of its metabolism into cysteine and subsequently into other sulfur compounds. There is strong evidence that O-acetyl-serine (thiol)lyase is directly responsible for the active fixation of atmospheric hydrogen sulfide by plants."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11953", "text": "Plants are able to transfer from sulfate to foliar absorbed atmospheric sulfur as sulfur source and levels of 60  ppb  or higher appear to be sufficient to cover the sulfur requirement of plants. There is an interaction between atmospheric and pedospheric sulfur utilization. For instance, hydrogen sulfide exposure may result in a decreased activity of APS reductase and a depressed sulfate uptake."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11954", "text": "Zinc  is an essential  trace element  for humans [ 1 ] [ 2 ] [ 3 ]  and other animals, [ 4 ]  for plants [ 5 ]  and for  microorganisms . [ 6 ]  Zinc is required for the function of over 300  enzymes  and 1000  transcription factors , [ 3 ]  and is stored and transferred in  metallothioneins . [ 7 ] [ 8 ]  It is the second most abundant trace metal in humans after iron and it is the only metal which appears in all  enzyme classes . [ 5 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11955", "text": "In proteins, zinc ions are often coordinated to the amino acid side chains of  aspartic acid ,  glutamic acid ,  cysteine  and  histidine . The theoretical and computational description of this zinc binding in proteins (as well as that of other  transition metals ) is difficult. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11956", "text": "Roughly  2\u20134 \u00a0grams of zinc [ 10 ]  are distributed throughout the human body. Most zinc is in the brain, muscle, bones, kidney, and liver, with the highest concentrations in the prostate and parts of the eye. [ 11 ]   Semen  is particularly rich in zinc, a key factor in  prostate gland  function and  reproductive organ  growth. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11957", "text": "Zinc homeostasis of the body is mainly controlled by the intestine. Here,  ZIP4  and especially  TRPM7  were linked to intestinal zinc uptake essential for postnatal survival. [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11958", "text": "In humans, the biological roles of zinc are ubiquitous. [ 15 ] [ 2 ]  It interacts with \"a wide range of organic  ligands \", [ 15 ]  and has roles in the metabolism of RNA and DNA,  signal transduction , and  gene expression . It also regulates  apoptosis . A review from 2015 indicated that about 10% of human proteins (~3000) bind zinc, [ 16 ]  in addition to hundreds more that transport and traffic zinc; a similar  in silico  study in the plant  Arabidopsis thaliana  found 2367 zinc-related proteins. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11959", "text": "In the  brain , zinc is stored in specific  synaptic vesicles  by  glutamatergic   neurons  and can modulate neuronal excitability. [ 2 ] [ 3 ] [ 17 ]  It plays a key role in  synaptic plasticity  and so in learning. [ 2 ] [ 18 ]  Zinc  homeostasis  also plays a critical role in the functional regulation of the  central nervous system . [ 2 ] [ 17 ] [ 3 ]  Dysregulation of zinc homeostasis in the central nervous system that results in excessive synaptic zinc concentrations is believed to induce  neurotoxicity  through mitochondrial oxidative stress (e.g., by disrupting certain enzymes involved in the  electron transport chain , including  complex I ,  complex III , and  \u03b1-ketoglutarate dehydrogenase ), the dysregulation of calcium homeostasis, glutamatergic neuronal  excitotoxicity , and interference with intraneuronal  signal transduction . [ 2 ] [ 19 ]  L- and D-histidine facilitate brain zinc uptake. [ 20 ]   SLC30A3  is the primary  zinc transporter  involved in cerebral zinc homeostasis. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11960", "text": "Zinc is an efficient  Lewis acid , making it a useful catalytic agent in  hydroxylation  and other enzymatic reactions. [ 21 ]  The metal also has a flexible  coordination geometry , which allows proteins using it to rapidly shift  conformations  to perform biological reactions. [ 22 ]  Two examples of zinc-containing enzymes are  carbonic anhydrase  and  carboxypeptidase , which are vital to the processes of  carbon dioxide  ( CO 2 ) regulation and digestion of proteins, respectively. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11961", "text": "In vertebrate blood, carbonic anhydrase converts  CO 2  into bicarbonate and the same enzyme transforms the bicarbonate back into  CO 2  for exhalation through the lungs. [ 24 ]  Without this enzyme, this conversion would occur about one million times slower [ 25 ]  at the normal blood  pH  of 7 or would require a pH of 10 or more. [ 26 ]  The non-related \u03b2-carbonic anhydrase is required in plants for leaf formation, the synthesis of  indole acetic acid  (auxin) and  alcoholic fermentation . [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11962", "text": "Carboxypeptidase cleaves peptide linkages during digestion of proteins. A  coordinate covalent bond  is formed between the terminal peptide and a C=O group attached to zinc, which gives the carbon a positive charge. This helps to create a  hydrophobic  pocket on the enzyme near the zinc, which attracts the non-polar part of the protein being digested. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11963", "text": "Zinc has been recognized as a messenger, able to activate signalling pathways. Many of these pathways provide the driving force in aberrant cancer growth. They can be targeted through  ZIP transporters . [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11964", "text": "Zinc serves a purely structural role in  zinc fingers , twists and clusters. [ 29 ]  Zinc fingers form parts of some  transcription factors , which are proteins that recognize  DNA base sequences  during the replication and transcription of  DNA . Each of the nine or ten  Zn 2+  ions in a zinc finger helps maintain the finger's structure by coordinately binding to four  amino acids  in the transcription factor. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11965", "text": "In  blood plasma , zinc is bound to and transported by  albumin  (60%, low-affinity) and  transferrin  (10%). [ 10 ]  Because transferrin also transports iron, excessive iron reduces zinc absorption, and vice versa. A similar antagonism exists with copper. [ 30 ]  The concentration of zinc in blood plasma stays relatively constant regardless of zinc intake. [ 21 ]  Cells in the salivary gland, prostate, immune system, and intestine use  zinc signaling  to communicate with other cells. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11966", "text": "Zinc may be held in  metallothionein  reserves within microorganisms or in the intestines or liver of animals. [ 32 ]  Metallothionein in intestinal cells is capable of adjusting absorption of zinc by 15\u201340%. [ 33 ]  However, inadequate or excessive zinc intake can be harmful; excess zinc particularly impairs copper absorption because metallothionein absorbs both metals. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11967", "text": "The human  dopamine transporter  contains a  high affinity  extracellular zinc  binding site  which, upon zinc binding, inhibits dopamine  reuptake  and amplifies  amphetamine -induced  dopamine efflux   in vitro . [ 35 ] [ 36 ] [ 37 ]  The human  serotonin transporter  and  norepinephrine transporter  do not contain zinc binding sites. [ 37 ]  Some  EF-hand   calcium binding proteins  such as  S100  or  NCS-1  are also able to bind zinc ions. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11968", "text": "The  U.S. Institute of Medicine  (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for zinc in 2001. The current EARs for zinc for women and men ages 14 and up is 6.8 and 9.4\u00a0mg/day, respectively. The RDAs are 8 and 11\u00a0mg/day. RDAs are higher than EARs so as to identify amounts that will cover people with higher-than-average requirements. RDA for pregnancy is 11\u00a0mg/day. RDA for lactation is 12\u00a0mg/day. For infants up to 12 months, the RDA is 3\u00a0mg/day. For children ages 1\u201313 years, the RDA increases with age from 3 to 8\u00a0mg/day. As for safety, the IOM sets  Tolerable upper intake levels  (ULs) for vitamins and minerals when evidence is sufficient. In the case of zinc the adult UL is 40\u00a0mg/day (lower for children). Collectively the EARs, RDAs, AIs and ULs are referred to as  Dietary Reference Intakes  (DRIs). [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11969", "text": "The  European Food Safety Authority  (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For people ages 18 and older, the PRI calculations are complex, as the EFSA has set higher and higher values as the  phytate  content of the diet increases. For women, PRIs increase from 7.5 to 12.7\u00a0mg/day as phytate intake increases from 300 to 1200\u00a0mg/day; for men, the range is 9.4 to 16.3\u00a0mg/day. These PRIs are higher than the U.S. RDAs. [ 39 ]  The EFSA reviewed the same safety question and set its UL at 25\u00a0mg/day, which is much lower than the U.S. value. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11970", "text": "For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For zinc labeling purposes, 100% of the Daily Value was 15\u00a0mg, but on May 27, 2016, it was revised to 11\u00a0mg. [ 41 ] [ 42 ]  A table of the old and new adult daily values is provided at  Reference Daily Intake ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11971", "text": "Animal products such as meat, fish, shellfish, fowl, eggs, and dairy contain zinc. The concentration of zinc in plants varies with the level in the soil. With adequate zinc in the soil, the food plants that contain the most zinc are wheat (germ and bran) and various seeds, including  sesame ,  poppy ,  alfalfa ,  celery , and  mustard . [ 43 ]  Zinc is also found in  beans ,  nuts ,  almonds ,  whole grains ,  pumpkin seeds ,  sunflower seeds , and  blackcurrant . [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11972", "text": "Other sources include  fortified food  and  dietary supplements  in various forms. A 1998 review concluded that  zinc oxide , one of the most common supplements in the United States, and  zinc carbonate  are nearly insoluble and poorly absorbed in the body. [ 45 ]  This review cited studies that found lower plasma zinc concentrations in the subjects who consumed zinc oxide and zinc carbonate than in those who took  zinc acetate  and sulfate salts. [ 45 ]  For fortification, however, a 2003 review recommended cereals (containing zinc oxide) as a cheap, stable source that is as easily absorbed as the more expensive forms. [ 46 ]  A 2005 study found that various compounds of zinc, including oxide and sulfate, did not show statistically significant differences in absorption when added as fortificants to maize tortillas. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11973", "text": "Nearly two billion people in the developing world are deficient in zinc. Groups at risk include children in developing countries and the elderly with chronic illnesses. [ 48 ]  In children, it causes an increase in infection and diarrhea and contributes to the death of about 800,000 children worldwide per year. [ 15 ]  The World Health Organization advocates zinc supplementation for severe malnutrition and diarrhea. [ 49 ]  Zinc supplements help prevent disease and reduce mortality, especially among children with low birth weight or stunted growth. [ 49 ]  However, zinc supplements should not be administered alone, because many in the developing world have several deficiencies, and zinc interacts with other micronutrients. [ 50 ]  While zinc deficiency is usually due to insufficient dietary intake, it can be associated with  malabsorption ,  acrodermatitis enteropathica , chronic liver disease, chronic renal disease, sickle cell disease, diabetes, malignancy, and other chronic illnesses. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11974", "text": "In the United States, a federal survey of food consumption determined that for women and men over the age of 19, average consumption was 9.7 and 14.2\u00a0mg/day, respectively. For women, 17% consumed less than the EAR, for men 11%. The percentages below EAR increased with age. [ 51 ]  The most recent published update of the survey (NHANES 2013\u20132014) reported lower averages \u2013 9.3 and 13.2\u00a0mg/day \u2013 again with intake decreasing with age. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11975", "text": "Symptoms of mild zinc deficiency are diverse. [ 21 ]  Clinical outcomes include depressed growth, diarrhea, impotence and delayed sexual maturation,  alopecia , eye and skin lesions, impaired appetite, altered cognition, impaired immune functions, defects in carbohydrate utilization, and reproductive  teratogenesis . [ 21 ]  Zinc deficiency depresses immunity, [ 53 ]  but excessive zinc does also. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11976", "text": "Despite some concerns, [ 54 ]  western vegetarians and vegans do not suffer any more from overt zinc deficiency than meat-eaters. [ 55 ]  Major plant sources of zinc include cooked dried beans, sea vegetables, fortified cereals, soy foods, nuts, peas, and seeds. [ 54 ]  However,  phytates  in many whole-grains and fibers may interfere with zinc absorption and marginal zinc intake has poorly understood effects. The zinc  chelator   phytate , found in seeds and  cereal   bran , can contribute to zinc malabsorption. [ 48 ]  Some evidence suggests that more than the US RDA (8\u00a0mg/day for adult women; 11\u00a0mg/day for adult men) may be needed in those whose diet is high in phytates, such as some vegetarians. [ 54 ]  The  European Food Safety Authority  (EFSA) guidelines attempt to compensate for this by recommending higher zinc intake when dietary phytate intake is greater. [ 39 ]  These considerations must be balanced against the paucity of adequate zinc  biomarkers , and the most widely used indicator, plasma zinc, has poor  sensitivity and specificity . [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11977", "text": "Zinc can be present in six different forms in soil namely; water soluble zinc, exchangeable zinc, organically bound zinc, carbonate bound zinc, aluminium and manganese oxide bound zinc and residual fractions of zinc. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11978", "text": "In toxic conditions, species of  Calluna ,  Erica  and  Vaccinium  can grow in zinc-metalliferous soils, because translocation of toxic ions is prevented by the action of  ericoid mycorrhizal fungi . [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11979", "text": "Zinc deficiency appears to be the most common micronutrient deficiency in crop plants; it is particularly common in high-pH soils. [ 59 ]  Zinc-deficient  soil  is  cultivated  in the cropland of about half of Turkey and India, a third of China, and most of Western Australia. Substantial responses to zinc fertilization have been reported in these areas. [ 5 ]  Plants that grow in soils that are zinc-deficient are more susceptible to disease. Zinc is added to the soil primarily through the weathering of rocks, but humans have added zinc through fossil fuel combustion, mine waste, phosphate fertilizers, pesticide ( zinc phosphide ), limestone, manure, sewage sludge, and particles from  galvanized  surfaces. Excess zinc is toxic to plants, although zinc toxicity is far less widespread. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11980", "text": "Zinc (Zn), alongside Magnesium (Mg) and Iron (Fe), constitutes one of the three families of biodegradable metals. [ 60 ]  Zinc, as an abundant trace element, ranks sixth among all the essential metallic elements crucial for sustaining life within the human body. [ 61 ]  Zinc exhibits an intermediate biodegradation rate, falling between that of Fe (relatively slow) and Mg (relatively high) which positions it as a promising material for use in biodegradable implants. [ 62 ] [ 63 ] [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11981", "text": "The  Australian Pharmaceutical Formulary  (APF) is the national  formulary  used by pharmacists in  Australia , compiled by the  Pharmaceutical Society of Australia . New editions of the APF are released every few years, with the latest edition being the 25th. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11982", "text": "The APF was originally a pocket-sized booklet first published in 1902, used by physicians as a drugs reference in Australia. In later editions, rather than simply being a listing of pharmaceuticals, medical and clinical information became incorporated within the publication as well, and eventually the title of the APF was extended to the  Australian Pharmaceutical Formulary and Handbook . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11983", "text": "The APF is divided in a number of sections, with each pertaining to a specific topic. Information includes"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11984", "text": "The  British National Formulary  ( BNF ) is a United Kingdom (UK)  pharmaceutical  reference book that contains a wide spectrum of information and advice on  prescribing  and  pharmacology , along with specific facts and details about many  medicines  available on the UK  National Health Service  (NHS).  Information within the BNF includes  indication(s) ,  contraindications ,  side effects ,  doses ,  legal classification , names and prices of available proprietary and  generic  formulations, and any other notable points. [ 1 ]   Though it is a national  formulary , it nevertheless also includes entries for some medicines which are not available under the NHS, and must be prescribed and/or purchased privately.  A symbol clearly denotes such drugs in their entry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11985", "text": "It is used by  pharmacists  and  doctors  (both  general practitioners  (GPs) and generalist hospital practitioners, and by other prescribing  healthcare professionals  (such as  nurses ,  pharmacy technicians ,  paramedics , and  dentists )); as a reference for correct dosage, indication, interactions and side effects of drugs.  It is also used as a reassurance by those administering drugs, for example a nurse on a hospital ward, and even for patients and others seeking an authoritative source of advice on any aspect of  pharmacotherapy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11986", "text": "Many individuals and organisations contribute towards the preparation of the BNF.  It is authored by  Pharmaceutical Press , the  Royal Pharmaceutical Society 's (RPS) knowledge business; and is jointly published by the  BMJ  (owned by the  BMA ), and Pharmaceutical Press (owned by the  RPS ). It is published under the authority of a Joint Formulary Committee (JFC), [ 2 ]  which comprises pharmacy, medical, nursing, and lay representatives; there are also representatives from the  Medicines and Healthcare products Regulatory Agency  (MHRA), the UK Health Departments, and a national guideline producer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11987", "text": "Information on drugs is drawn from the manufacturers' product literature, medical and pharmaceutical literature, regulatory authorities and professional bodies.  Advice is constructed from clinical literature, and reflects, as far as possible, an evaluation of the evidence from diverse sources.  The BNF also takes account of authoritative national guidelines and emerging safety concerns.  In addition, the Joint Formulary Committee takes advice on all therapeutic areas from advisers from expert groups; this ensures that the BNF's recommendations are relevant to practice.  In September 2016, the  National Institute for Health and Care Excellence  (NICE) in the UK gave NICE accreditation to the processes to produce BNF publications; a further review in 2021 resulted in the successful renewal of accreditation. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11988", "text": "It was first published in 1949, [ 2 ]  as the  National Formulary , with updated versions appearing every three years until 1976.  The fifth version in 1957 saw its name change to  The British National Formulary . [ 4 ] [ 5 ]   A new-look version, under the auspices of  Owen Wade , was released in 1981. [ 2 ] [ 6 ]   A study in Northern Ireland, looking at prescribing in 1965, reported that the BNF was likely able to serve the requirements of prescribers in general practice, while also achieving a cost saving. [ 7 ]   By 2003, issue 46 of the BNF contained 3000 interactions or groups of interactions, with about 900 of these marked by a bullet. [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11989", "text": "A new edition of the BNF book is published twice-yearly, in March and September. [ 1 ]   The current edition is 87, which was published in March 2024.  It is a tradition that the colour of each new edition is radically different from the previous. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11990", "text": "The BNF is presently available as a book, a website, and mobile applications - the latter for use on  smartphones  and tablets. [ 2 ]   The book is available for purchase, and the September edition is distributed to healthcare professionals in the UK at no direct cost to them. [ 1 ] [ 13 ]   NHS workers and healthcare professionals in the  HINARI  group of developing nations are entitled to free access via MedicinesComplete following registration (requires provision of a name, an address, an email address, and a phone number).  Other visitors can subscribe to the BNF on MedicinesComplete. [ 14 ]   Healthcare organisations can also subscribe to a customisable BNF via their corporate online intranet. [ 15 ]   In 2017, BNF Publications released applications for offline access to the BNF on  iOS  and  Android  devices.  Monthly content updates are available, over an internet connection. [ 16 ]  NICE provides a website providing the content of the BNF to the public, including non-NHS users. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11991", "text": "The BNF also includes the Nurse Prescribers' Formulary (NPF) and other NPF content for use by  District Nurses  and Specialist Community Public Health Nurses (including  Health Visitors ), who have received training to become nurse prescribers. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11992", "text": "The  British National Formulary for Children  (BNFC) [ 1 ] [ 19 ] [ 20 ]  book, first published September 2005, [ 2 ]  is published yearly, [ 2 ]  and details the doses and uses of medicines in children from  neonates  to  adolescents . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11993", "text": "The  British National Formulary  is divided into various sections; with the main sections on drugs and preparations being organised by body system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11994", "text": "BNF for Children  ( BNFC ) is the standard UK  paediatric  reference for prescribing and  pharmacology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11995", "text": "It contains a wide range of information and advice on prescribing for children - from newborn to adolescence.  \nThe entries are classified by group of drug, giving cautions for use,  side effects ,  indications  and dose for most of the drugs available for children in the UK  National Health Service . It also includes information on the unlicensed uses of certain drugs. Though published in and for the United Kingdom, the vast bulk of the clinical information will apply in any country."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11996", "text": "The  BNFC  is jointly published annually by  BMJ  (owned by the  BMA ),  Pharmaceutical Press  (owned by the  RPS ),  Royal College of Paediatrics and Child Health , and the Neonatal and Paediatric Pharmacists Group. [ 1 ]  The principal contributors are acknowledged in the front pages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11997", "text": "It is overseen by the BNFC Paediatric Formulary Committee\n [ 2 ]  \nand edited by a team of  pharmacists . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_11998", "text": "The BNF for Children developed from the  British National Formulary (BNF) , which prior to 2005 had provided information on the treatment of children, with the doses largely determined by calculations based on the body weight of the child. \nThe guidance was provided by pharmacists and doctors whose expertise was in the care of adults."}
{"_id": "WikiPedia_Pharmacology$$$corpus_11999", "text": "This was an anomaly, [ 4 ]  as in relation to responses to medicines, the difference between a newborn and a sixteen-year-old is greater than the difference between a sixteen-year-old and a sixty-year-old. Starting in 2002, Prof Martin Kendall, [ 5 ] [ 6 ]  then chairman of the BNF Joint Formulary Committee worked to get things changed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12000", "text": "The UK  Department of Health (now the DHSC)  agreed to fund the BNFC, as it does the BNF, to ensure that NHS clinicians can have up-to-date information in their pockets."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12001", "text": "The first edition was published in 2005, with George Rylance\n [ 7 ] \nchairing the Paediatric Formulary Committee and Dinesh Mehta as the first executive editor.   Anne, the Princess Royal  attended the launch on 14 July."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12002", "text": "The BNFC is published annually, but electronic updates\n [ 8 ] \nare produced monthly. The current 2022-2023 edition was published in September 2022."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12003", "text": "Though not aimed at the general public, the BNFC, like the BNF, is available for purchase.  [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12004", "text": "It is provided to NHS staff - usually through their employer, but may be accessed online through MedicinesComplete. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12005", "text": "The app is available through the usual app stores. [ 11 ]   [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12006", "text": "[ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12007", "text": "The  British Pharmaceutical Codex  (BPC) was first published in 1907, to supplement the  British Pharmacopoeia  which although extensive, did not cover all the medicinal items that a  pharmacist  might require in daily work. Other books existed, such as  Squire's , but the BPC was intended to be official, published by the  Pharmaceutical Society of Great Britain  (PSGB). It laid down standards for the composition of medicines and surgical dressings. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12008", "text": "Subsequent editions were published in 1911, 1923,  1934 , 1949, 1954, 1959,  1963 , 1968, and finally 1973."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12009", "text": "The 1934 edition was described by the  British Medical Journal  as \"one of the most useful reference books available to the medical profession\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12010", "text": "In 1963 Edward G Feldmann, director of revision for the US National Formulary, described it as \"a compilation of highly authoritative and useful therapeutic (actions and doses) information as well as a valuable compendium of recognised standards and specifications\". [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12011", "text": "In 1979 a new edition was published with a new title,  The Pharmaceutical Codex . The  Medicines Commission  had recommended in 1972 that the British Pharmacopoeia should henceforth be the only compendium of official standards for medicines in the UK, and the BPC lost its status as an official book. The PSGB remained as the publishers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12012", "text": "The current edition is the 12th, published in 1994."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12013", "text": "De materia medica  ( Latin  name for the  Greek  work  \u03a0\u03b5\u03c1\u1f76 \u1f55\u03bb\u03b7\u03c2 \u1f30\u03b1\u03c4\u03c1\u03b9\u03ba\u1fc6\u03c2 ,  Peri hul\u0113s iatrik\u0113s , both meaning \"On  Medical Material \") is a  pharmacopoeia  of  medicinal plants  and the  medicines  that can be obtained from them. The five-volume work was written between 50 and 70 CE by  Pedanius Dioscorides , a Greek physician in the Roman army. It was widely read for more than 1,500 years until supplanted by revised  herbals  in the  Renaissance , making it one of the longest-lasting of all  natural history  and  pharmacology  books."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12014", "text": "The work describes many drugs known to be effective, including  aconite ,  aloes ,  colocynth ,  colchicum ,  henbane ,  opium  and  squill . In total, about 600 plants are covered, along with some animals and mineral substances, and around 1000 medicines made from them."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12015", "text": "De materia medica  was circulated as illustrated manuscripts, copied by hand, in Greek, Latin, and  Arabic  throughout the  medieval  period. From the 16th century onwards, Dioscorides' text was translated into  Italian ,  German ,  Spanish ,  French , and into  English  in 1655. It served as the foundation for  herbals  in these languages by figures such as  Leonhart Fuchs ,  Valerius Cordus ,  Lobelius ,  Rembert Dodoens ,  Carolus Clusius ,  John Gerard , and  William Turner . Over time, these herbals incorporated increasing numbers of direct observations, gradually supplementing and eventually supplanting the classical text."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12016", "text": "Several manuscripts and early printed versions of  De materia medica  survive, including the illustrated  Vienna Dioscurides  manuscript written in the original Greek in 6th-century  Constantinople ; it was used there by the  Byzantines  as a hospital text for just over a thousand years.  Sir Arthur Hill  saw a monk on  Mount Athos  still using a copy of Dioscorides to identify plants in 1934."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12017", "text": "Between 50 and 70 AD, a Greek physician in the Roman army,  Dioscorides , wrote a five-volume book in his native  Greek ,  \u03a0\u03b5\u03c1\u1f76 \u1f55\u03bb\u03b7\u03c2 \u1f30\u03b1\u03c4\u03c1\u03b9\u03ba\u1fc6\u03c2  ( Peri hules iatrik\u0113s , \"On Medical Material\"), known more widely in Western Europe by its  Latin  title  De materia medica . He had studied pharmacology at  Tarsus  in  Roman Anatolia  (now Turkey). [ 1 ]  The book became the principal reference work on  pharmacology  across Europe and the Middle East for over 1,500 years, [ 2 ]  and was thus the precursor of all modern  pharmacopoeias . [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12018", "text": "In contrast to many classical authors,  De materia medica  was not \"rediscovered\" in the Renaissance, because it never left circulation; indeed, Dioscorides' text eclipsed the  Hippocratic Corpus . [ 5 ]  In the medieval period,  De materia medica  was circulated in Latin, Greek, and Arabic. [ 6 ]  In the  Renaissance  from 1478 onwards, it was printed in Italian, German, Spanish, and French as well. [ 7 ]  In 1655,  John Goodyer  made an English translation from a printed version, probably not corrected from the Greek. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12019", "text": "While being reproduced in manuscript form through the centuries, the text was often supplemented with commentary and minor additions from Arabic and Indian sources. Several illustrated manuscripts of  De materia medica  survive. The most famous is the lavishly illustrated  Vienna Dioscurides  (the  Juliana Anicia Codex ), written in the original Greek in  Byzantine  Constantinople in 512/513 AD; its illustrations are sufficiently accurate to permit identification, something not possible with later medieval drawings of plants; some of them may be copied from a lost volume owned by Juliana Anicia's great-grandfather,  Theodosius II , in the early 5th century. [ 9 ]  The  Naples Dioscurides  and  Morgan Dioscurides  are somewhat later Byzantine manuscripts in Greek, while other Greek manuscripts survive today in the monasteries of  Mount Athos . Densely-illustrated Arabic copies survive from the 12th and 13th centuries. [ 10 ]  The result is a complex set of relationships between  manuscripts , involving translation, copying errors, additions of text and illustrations, deletions, reworkings, and a combination of copying from one manuscript and correction from another. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12020", "text": "De materia medica  is the prime historical source of information about the  medicines  used by the  Greeks ,  Romans , and other cultures of antiquity. The work also records the  Dacian names  for some plants, [ 12 ]  which otherwise would have been lost. The work presents about 600  medicinal plants  in all, along with some animals and mineral substances, and around 1,000 medicines made from these sources. [ 13 ] [ 14 ]  Botanists have not always found Dioscorides' plants easy to identify from his short descriptions, partly because he had naturally described plants and animals from southeastern Europe, whereas by the 16th century his book was in use all over Europe and across the Islamic world. This meant that people attempted to force a match between the plants they knew and those described by Dioscorides, leading to what could be catastrophic results. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12021", "text": "Each entry gives a substantial amount of detail on the plant or substance in question, concentrating on medicinal uses but giving such mention of other uses (such as culinary) and help with recognition as considered necessary. For example, on the \"Mekon Agrios and Mekon Emeros\", [ 16 ]  the  opium poppy  and related species, Dioscorides states that the seed of one is made into bread: it has \"a somewhat long little head and white seed\", while another \"has a head bending down\" [ 16 ]  and a third is \"more wild, more medicinal and longer than these, with a head somewhat long\u2014and they are all cooling.\" [ 16 ]  After this brief description, he moves at once into pharmacology, saying that they cause sleep; other uses are to treat inflammation and  erysipela , and if boiled with honey to make a cough mixture. The account thus combines recognition, pharmacological effect, and guidance on drug preparation. Its effects are summarized, accompanied by a caution: [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12022", "text": "A little of it (taken with as much as a grain of ervum) is a pain-easer, a sleep-causer, and a digester, helping coughs and abdominal cavity afflictions. Taken as a drink too often it hurts (making men lethargic) and it kills. It is helpful for aches, sprinkled on with rosaceum; and for pain in the ears dropped in them with oil of almonds, saffron, and myrrh. For inflammation of the eyes it is used with a roasted egg yolk and saffron, and for erysipela and wounds with vinegar; but for gout with women's milk and saffron. Put up with the finger as a suppository it causes sleep."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12023", "text": "Dioscorides then describes how to tell a good from a counterfeit preparation. He mentions the recommendations of other physicians, Diagoras (according to Eristratus), Andreas, and Mnesidemus, only to dismiss them as false and not borne out by experience. He ends with a description of how the liquid is gathered from  poppy  plants, and lists names used for it:  chamaesyce ,  mecon   rhoeas ,  oxytonon ;  papaver  to the Romans, and  wanti  to the Egyptians. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12024", "text": "As late as in the  Tudor  and  Stuart periods  in Britain, herbals often still classified plants in the same way as Dioscorides and other classical authors, not by their structure or apparent relatedness but by how they smelt and tasted, whether they were edible, and what medicinal uses they had. [ 17 ]  Only when European botanists like  Matthias de l'Obel ,  Andrea Cesalpino  and  Augustus Quirinus Rivinus  (Bachmann) had done their best to match plants they knew to those listed in Dioscorides did they go further and create new  classification systems  based on similarity of parts, whether leaves, fruits, or flowers. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12025", "text": "The book is divided into five volumes. Dioscorides organized the substances by certain similarities, such as their being aromatic, or vines; these divisions do not correspond to any modern classification. In David Sutton's view the grouping is by the type of effect on the human body. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12026", "text": "Volume I covers aromatic oils, the plants that provide them, and ointments made from them. They include what are probably  cardamom ,  nard ,  valerian ,  cassia  or  senna ,  cinnamon ,  balm of Gilead ,  hops ,  mastic ,  turpentine ,   pine  resin,  bitumen ,  heather ,  quince ,  apple ,  peach ,  apricot ,  lemon ,  pear ,  medlar ,  plum  and many others. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12027", "text": "Volume II covers an assortment of topics: animals including sea creatures such as  sea urchin ,  seahorse ,  whelk ,  mussel ,  crab ,  scorpion ,  electric ray ,  viper ,  cuttlefish  and many others; dairy produce;  cereals ; vegetables such as  sea kale ,  beetroot ,  asparagus ; and sharp herbs such as  garlic ,  leek ,  onion ,  caper  and  mustard . [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12028", "text": "Volume III covers roots, seeds and herbs. These include plants that may be  rhubarb ,  gentian ,  liquorice ,  caraway ,  cumin ,  parsley ,  lovage ,  fennel  and many others. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12029", "text": "Volume IV describes further roots and herbs not covered in Volume III. These include herbs that may be  betony ,  Solomon's seal ,  clematis ,  horsetail ,  daffodil  and many others. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12030", "text": "Volume V covers the grapevine, wine made from it, grapes and raisins; but also strong medicinal potions made by boiling many other plants including  mandrake ,  hellebore , and various metal compounds, such as what may be  zinc oxide ,  verdigris  and  iron oxide . [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12031", "text": "Writing in  The Great Naturalists , the  historian of science  David Sutton describes  De materia medica  as \"one of the most enduring works of natural history ever written\" [ 25 ]  and that \"it formed the basis for Western knowledge of medicines for the next 1,500 years.\" [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12032", "text": "The historian of science  Marie Boas  writes that herbalists depended entirely on Dioscorides and  Theophrastus  until the 16th century, when they finally realized they could work on their own. [ 7 ]  She notes also that  herbals  by different authors, such as  Leonhart Fuchs ,  Valerius Cordus ,  Lobelius ,  Rembert Dodoens ,  Carolus Clusius ,  John Gerard  and  William Turner , were dominated by Dioscorides, his influence only gradually weakening as the 16th-century herbalists \"learned to add and substitute their own observations\". [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12033", "text": "Early science and medicine historian Paula Findlen, writing in the  Cambridge History of Science: Early Modern Science , calls  De materia medica  \"one of the most successful and enduring herbals of antiquity, [which] emphasized the importance of understanding the natural world in light of its medicinal efficiency\", in contrast to  Pliny 's  Natural History  (which emphasized the wonders of nature) or the  natural history  studies of  Aristotle  and  Theophrastus  (which emphasized the causes of natural phenomena). [ 27 ]  Medicine historian  Vivian Nutton , in  Ancient Medicine , writes that Dioscorides's \"five books in Greek On Materia medica attained canonical status in Late Antiquity.\" [ 28 ]  Science historian Brian Ogilvie calls Dioscorides \"the greatest ancient herbalist\", and  De materia medica  \"the  summa  of ancient descriptive botany\", observing that its success was such that few other books in his domain have survived from classical times. [ 29 ]  Further, his approach matched the Renaissance liking for detailed description, unlike the philosophical search for essential nature (as in Theophrastus's  Historia Plantarum ). A critical moment was the decision by  Niccol\u00f2 Leoniceno  and others to use Dioscorides \"as the model of the careful naturalist\u2014and his book  De materia medica  as the model for natural history.\" [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12034", "text": "The Dioscorides translator and editor Tess Anne Osbaldeston notes that \"For almost two millennia Dioscorides was regarded as the ultimate authority on plants and medicine\", [ 31 ]  and that he \"achieved overwhelming commendation and approval because his writings addressed the many ills of mankind most usefully.\" [ 31 ]  To illustrate this, she states that \"Dioscorides describes many valuable drugs including  aconite ,  aloes ,  bitter apple ,  colchicum ,  henbane , and  squill \". [ 32 ]  The work mentions the painkillers willow (leading ultimately to  aspirin , she writes),  autumn crocus  and  opium , which however is also narcotic. Many other substances that Dioscorides describes remain in modern pharmacopoeias as \"minor drugs, diluents, flavouring agents, and  emollients \u00a0... [such as]  ammoniacum ,  anise ,  cardamoms ,  catechu ,  cinnamon ,  colocynth ,  coriander ,  crocus ,  dill ,  fennel ,  galbanum ,  gentian ,  hemlock ,  hyoscyamus ,  lavender ,  linseed , mastic,  male fern ,  marjoram ,  marshmallow ,  mezereon ,  mustard ,  myrrh ,  orris  (iris),  oak galls ,  olive oil ,  pennyroyal ,  pepper ,  peppermint , poppy,  psyllium ,  rhubarb ,  rosemary ,  rue ,  saffron ,  sesame , squirting cucumber ( elaterium ),  starch , stavesacre ( delphinium ),  storax ,  stramonium ,  sugar ,  terebinth ,  thyme ,  white hellebore ,  white horehound , and  couch grass \u2014the last still used as a  demulcent   diuretic .\" [ 32 ]  She notes that medicines such as  wormwood ,  juniper ,  ginger , and  calamine  also remain in use, while \" Chinese  and  Indian physicians  continue to use  liquorice \". [ 32 ]  She observes that the many drugs listed to reduce the  spleen  may be explained by the frequency of  malaria  in his time. Dioscorides lists drugs for women to cause  abortion  and to treat  urinary tract infection ;  palliatives  for  toothache , such as  colocynth , and others for intestinal pains; and treatments for skin and eye diseases. [ 32 ]  As well as these useful substances, she observes that \"A few  superstitious practices  are recorded in  De materia medica ,\" [ 32 ]  such as using  Echium  as an  amulet  to ward off snakes, or  Polemonia  ( Jacob's ladder ) for  scorpion  stings. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12035", "text": "In the view of the historian Paula De Vos,  De materia medica  formed the core of the European pharmacopoeia until the end of the 19th century, suggesting that \"the timelessness of Dioscorides' work resulted from an  empirical tradition  based on trial and error; that it worked for generation after generation despite social and cultural changes and changes in medical theory\". [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12036", "text": "At  Mount Athos  in northern Greece Dioscorides's text was still in use in its original Greek into the 20th century, as observed in 1934 by  Sir Arthur Hill , Director of the  Royal Botanic Gardens, Kew :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12037", "text": "At  Karyes  there is an official Botanist Monk ... he was a remarkable old Monk with an extensive knowledge of plants and their properties. Though fully gowned in a long black cassock he traveled very quickly, usually on foot, and sometimes on a mule, carrying his 'Flora' with him in a large, black, bulky bag. Such a bag was necessary since his 'Flora' was nothing less than four manuscript folio volumes of Dioscorides, which apparently he himself had copied out. This Flora he invariably used for determining any plant which he could not name at sight, and he could find his way in his books and identify his plants\u2014to his own satisfaction\u2014with remarkable rapidity. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12038", "text": "Along with his fellow physicians of Ancient Rome,  Aulus Cornelius Celsus ,  Galen ,  Hippocrates  and  Soranus of Ephesus , Dioscorides had a major and long-lasting effect on  Arabic medicine  as well as medical practice across Europe. [ 34 ] [ 35 ]   De materia medica  was one of the first scientific works to be translated from Greek into Arabic (Arabic: Hay\u016bl\u0101 \u02bfil\u0101j al-\u1e6dibb ). It was translated first into  Syriac  and then into Arabic in 9th century Baghdad. [ 36 ] [ 37 ]  The translators were most often  Syriac Christians , such as  Hunayn ibn Ishaq , and their work is known to have been sponsored by local rulers, such as the  Artuqids . [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12039", "text": "Manuscript (Or. 289), dated 1083, an illustrated Arabic translation of Dioscurides'  De Materia medica . The work was originally translated from Greek into Arabic via Syriac by  Hunayn ibn Ishaq  (810\u2013873) with the collaboration of  Stephanus b. B\u0101s\u012bl  between 847\u2013861. This translation was slightly revised by  \u1e24usayn b. Ibr\u0101h\u012bm al-N\u0101til\u012b  in 990\u2013991. The current copy is based on an exemplar in the hand of al-N\u0101til\u012b. The work was offered to the am\u012br of  Samarqand ,  Ab\u016b \u02bfAl\u012b al-Sim\u01e7\u016br\u012b . Acquired by  Levinus Warner  (1619\u20131665) and bequeathed to  Leiden University Library  on his death. [ 39 ]  \nA digitized version is available via Leiden's Digital Collections. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12040", "text": "One  De materia medica  manuscript is dated to 1224, but its provenance is uncertain. It is generally cautiously attributed to \"Iraq or Northern Jazira, possibly Baghdad\". [ 41 ]  Its folios have been dispersed among multiple institutions and collectors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12041", "text": "This copy was created by Abd Al-Jabbar ibn Ali in 1229. [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12042", "text": "Note: Editions may vary by both text and numbering of chapters"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12043", "text": "Arabic"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12044", "text": "English"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12045", "text": "French"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12046", "text": "German"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12047", "text": "Greek"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12048", "text": "Greek and Latin"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12049", "text": "Latin"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12050", "text": "Spanish"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12051", "text": "Embase  (often styled  EMBASE  for  Excerpta Medica dataBASE ) is a  biomedical  and  pharmacological   bibliographic database  of published literature designed to support information managers and  pharmacovigilance  in complying with the regulatory requirements of a licensed  drug . Embase, produced by  Elsevier , contains over 32 million records from over 8,500 currently published journals from 1947 [ 1 ]  to the present. Through its international coverage, daily updates, and drug indexing with  EMTREE , Embase enables tracking and retrieval of drug information in the published literature. Each record is fully indexed and Articles in Press are available for some records and In Process are available for all records, ahead of full indexing. Embase's international coverage expands across biomedical journals from 95 countries and is available through a number of database vendors. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12052", "text": "In 1946, the beginnings of Embase was created as Excerpta Medica (EM) Abstract Journals by a group of Dutch physicians who promoted the flow of medical knowledge and reports post  World War II . Included in EM were 13 journal sections which categorized the medical school curriculum by  anatomy ,  pathology ,  physiology ,  internal medicine , and other basic clinical specialties. This database lasted until 1972 when it merged with  Elsevier ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12053", "text": "In 1972, EM had joined with  Elsevier  and later, in 1975, formed EMBASE (Excerpta Medica database) which had released electronic access to abstract journals. Following feedback from the EMBASE user community, EMBASE Classic was created as a separate database to supplement EMBASE as a backfile of medical journals from 1947-1973 which provides valuable documentation of drugs, adverse effects, endogenous compounds, etc. found at the time. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12054", "text": "In 2010, Excerpta Medica, excluding EMBASE, was sold by Elsevier to the  Omnicom Group . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12055", "text": "In addition to the 28 million reports, Embase's database steadily rises each year at a rate of over 900,000 records. [ 5 ]  This wide expanse of information is used in both professional and educational environments for retrieving any published biomedical or drug related information. Currently, Embase allows further customization for a personal experience such as implementing a  RSS feed  and email alert system. With new drug and disease-related information constantly released, Embase is updated daily to provide a comprehensive and reliable source of information."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12056", "text": "EMDEX  ( E ssential  M edicines Index) is the most commonly used reference source of drug and therapeutic information by healthcare professionals in  Nigeria . [ 1 ] [ 2 ]  It was first published in 1991 as Nigeria's Essential Drugs (NED) Guide. \nEMDEX drug information contents, arrangements, and therapeutic recommendations are supported by several references and clinical guidelines notably  WHO Model Formulary ,  WHO ATC (Anatomical Therapeutic Chemical) Classification System ,  Nigeria's Essential Medicines List , and  Standard Treatment Guidelines , etc. The information is regularly reviewed and updated by a select team of healthcare practitioners and academics. \nThe central objective of EMDEX has been to promote the rational use of medicines through the provision of independent drug information, and the use of  clinical guidelines  and  essential medicines list . [ 3 ]  It is the largest and most up-to-date source of information on drug products approved for use in Nigeria by  NAFDAC (National Agency for Food & Drug Administration & Control) . \nThe use of EMDEX as a reference drug manual is endorsed by  the Pharmacists Council of Nigeria ,  the Nursing & Midwifery Council of Nigeria , and major health institutions. It is used both within and outside Nigeria by  physicians ,  dentists ,  pharmacists ,  nurse practitioners , and auxiliary health workers at all levels of healthcare delivery. These healthcare providers rely on EMDEX for accuracy and completeness of drug information namely indications, contra-indications, precautions or warnings, adverse effects, dosages, and drug use in special populations like children, elderly, pregnancy & lactation. [ 4 ] [ 5 ] \nEMDEX publications are also in the syllabus of various colleges & schools of  medicine ,  pharmacy  &  nursing . [ 6 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12057", "text": "A national  formulary  is essentially a listing of available and affordable  medicines  that are relevant to the treatment of  diseases  in a particular country. It is usually a source of unbiased drug information and helps promote the rational use of safe, effective and good-quality medicines. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12058", "text": "EMDEX vol. 1 (Drug Information for Healthcare Professionals) is published annually. \nOther EMDEX print publications include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12059", "text": "Formularium Slovenicum  is  Slovenian  addendum to the  European Pharmacopoeia . [ 1 ]  It promotes Slovenian pharmaceutical  terminology  and the regulations affecting the field of  pharmacy  in Slovenia. [ 2 ]  It has been regularly published by the  Agency for Medicinal Products and Medical Devices of the Republic of Slovenia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12060", "text": "Slovenia does not have its own  pharmacopoeia , i.e. a collection of monographs and other provisions containing legally binding regulations regarding the development, manufacture, and quality assessment of medicinal products and their ingredients as well as other information on medicinal products and their use. Since 1997,  European Pharmacopoeia  has been in force in the Republic of Slovenia. [ 2 ]  The alignment of provisions of the national law in the field of medicinal products and regulations at the level of the  European Pharmacopoeia  brought forward the need for Slovenian addendum to the  European Pharmacopoeia . The committee for drafting the national addendum at the Office for Medicinal Products of the Slovenian Ministry of Health issued in June 1998 the first edition of  Formularium Slovenicum . [ 3 ]  Several amendments and updated editions have followed, though the work of the committee preparing  Formularium Slovenicum  was interrupted between 2013 and 2018. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12061", "text": "Formularium Slovenicum  supplements  European Pharmacopoeia  standards and provides translations of titles, complete translations of the main monographs or their individual parts, and translations of general chapters. The chapter  National monographs  comprises interesting and useful monographs for Slovenian pharmacy practice that the  European Pharmacopoeia  does not include. It also includes the chapter  Standard Terms for Pharrmaceutical Forms, Methods of Administration, and Containers .  Formularium Slovenicum  has an important role in the drafting, development, and promotion of Slovenian pharmaceutical terms. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12062", "text": "The first edition has been followed by numerous amendments and updated editions: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12063", "text": "Goodman & Gilman's The Pharmacological Basis of Therapeutics , commonly referred to as the  Blue Bible  or  Goodman & Gilman , is a  textbook  of  pharmacology  originally authored by  Louis S. Goodman  and  Alfred Gilman . First published in 1941, the book is in its 14th edition (as of 2022), and has the reputation of being the \"bible of pharmacology\". The readership of this book include physicians of all therapeutic and surgical specialties, clinical pharmacologists, clinical research professionals and pharmacists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12064", "text": "While teaching jointly in the  Yale School of Medicine 's Department of Pharmacology, Goodman and Gilman began developing a course textbook that emphasized relationships between  pharmacodynamics  and  pharmacotherapy , introduced recent pharmacological advances like  sulfa drugs , and discussed the history of drug development. [ 1 ] [ 2 ]   Yale physiologist  John Farquhar Fulton  encouraged them to publish the work for a broader audience and introduced them to a publisher at the  Macmillan Publishing Company . [ 1 ]  Their new text was first published in 1941 under the title  The Pharmacological Basis of Therapeutics: A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Student . [ 1 ]  Because the volume was twice as long as a typical textbook, Macmillan printed few copies, but demand for a readable, up-to-date pharmacological text proved high, and several printings followed. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12065", "text": "Although rapid pharmacological innovations were made in the years immediately following\u2014including the introduction of  chemotherapy ,  steroids ,  antibiotics , and  antihistamines \u2014a second edition could not be completed until 1955 because of the authors' service in World War II. [ 2 ] [ 1 ]  Thereafter, the text was revised every five years in collaboration with a large number of specialist coauthors. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12066", "text": "Gilman and Goodman remained the book's lead editors for the first five editions; Gilman remained an editor through the sixth edition, and Goodman through the seventh, which was published shortly after Gilman's death in 1984.  Alfred Goodman Gilman , the son of Alfred Gilman and winner of the 1994  Nobel Prize in Medicine and Physiology , joined as senior editor for the book's sixth, seventh, and eighth editions, and a contributing editor to the ninth and tenth. [ 3 ]  Goodman died in 2000, and Goodman Gilman in December 2015."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12067", "text": "The first five editions were published under the title  The Pharmacological Basis of Therapeutics: A Textbook of Pharmacology, Toxicology, and Therapeutics for Physicians and Medical Students ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12068", "text": "Editions 6 onwards were published under the title  Goodman & Gilman's The Pharmacological Basis of Therapeutics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12069", "text": "There have been many published book reviews of this widely used textbook. The first edition reviewer was highly enthusiastic and said that he was \u201cdelirious in his appraisal of the book\u201d, that it was an \u201camazing work\u201d, and \u201cthe product of enormous industry and keen insight\u201d. [ 4 ]  A reviewer of the eighteen-hundred page second-edition described it as encyclopedic, indispensable, and as an excellent resource for students. [ 5 ]  The fourth edition reviewer noted that \u201call other related books seem to pale by comparison\u201d. [ 6 ]  The 6th edition published in 1980 was praised for the extensive bibliography, but also noted that, although \u201cthis book is recommended to all those who prescribe drugs\u201d,  it had become \u201ctoo large to be used by medical students as a routine textbook\u201d. [ 7 ]  The ninth edition was designated as the \"blue bible of pharmacology\" and as the gold standard. [ 8 ]  The 12th edition was criticized for only one-ninth of authors being female. [ 9 ]  However, this had increased to one-fifth of the authors being female in the thirteen-edition. A policy of the editors has been to not disclose the potential conflicts of interest by the authors. The 12th edition authors were the recipients of over one-hundred and thirty patents. [ 10 ]  The thirteenth edition authors received three-million dollars from pharmaceutical companies which was undisclosed. Unlike earlier editions which were praised for being up to date, [ 4 ]  an analysis of the 13th edition found that the citations were older than those of other pharmacology textbooks. [ 9 ]  A team of the reviewers for the 2018 edition were more measured than those of earlier editions. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12070", "text": "King's American Dispensatory  is a book first published in 1854 that covers the uses of herbs used in American medical practice, especially by those involved in  eclectic medicine , which was the botanical school of medicine in the 19th to 20th centuries.  In 1880  John Uri Lloyd , an eclectic pharmacist of the late 19th and early 20th centuries, promised his friend, professor John King, to revise the pharmaceutical and chemical sections of the  American Dispensatory . Eighteen years later an entirely rewritten eighteenth edition (third revision) was published in 1898. It was co-authored by eclectic physician  Harvey Wickes Felter"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12071", "text": "This article about  alternative medicine  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12072", "text": "Martindale: The Complete Drug Reference  is a reference book published by  Pharmaceutical Press  listing some 6,000  drugs  and  medicines  used throughout the world, including details of over 125,000 proprietary preparations. It also includes almost 700 disease treatment reviews."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12073", "text": "It was first published in 1883 under the title  Martindale: The Extra Pharmacopoeia .  Martindale  contains information on drugs in clinical use worldwide, as well as selected investigational and veterinary drugs,  herbal  and complementary medicines, pharmaceutical excipients,  vitamins  and nutritional agents,  vaccines , radiopharmaceuticals,  contrast media  and  diagnostic agents , medicinal gases,  drugs of abuse  and  recreational drugs , toxic substances,  disinfectants , and  pesticides ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12074", "text": "Martindale  aims to cover drugs and related substances reported to be of clinical interest anywhere in the world. It provides health professionals with a useful source of information to identify medicines, such as confirming the drug and brand name of a medication being taken by a patient arriving from abroad. Alternatively, if the drug is not available, the class of agent can be determined allowing a  pharmacist  or doctor to determine which other equivalent drugs might be substituted. Monographs include  Chemical Abstracts Service  (CAS) numbers,  Anatomical Therapeutic Chemical Classification System  (ATC) codes and FDA  Unique Ingredient Identifier  (UNII) codes to help readers refer to other information systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12075", "text": "Martindale  is arranged into two main parts followed by three extensive indexes:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12076", "text": "Digital versions include an additional 1,000 drug monographs, 100,000 preparation names, and 5,000 manufacturers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12077", "text": "To date there have been 40 editions of  Martindale: The Complete Drug Reference .  The 40th edition was published in May 2020."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12078", "text": "Materia medica  ( lit. : 'medical material/substance') is a  Latin  term from the  history of pharmacy  for the body of collected knowledge about the therapeutic properties of any substance used for healing (i.e.,  medications ). The term derives from the title of a work by the Ancient Greek physician  Pedanius Dioscorides  in the 1st century AD,  De materia medica , 'On medical material' (\u03a0\u03b5\u03c1\u1f76 \u1f55\u03bb\u03b7\u03c2 \u1f30\u03b1\u03c4\u03c1\u03b9\u03ba\u1fc6\u03c2,  Peri hyl\u0113s iatrik\u0113s , in Greek)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12079", "text": "The term  materia medica  was used from the period of the  Roman Empire  until the 20th century, [ 1 ]  but has now been generally replaced in medical education contexts by the term  pharmacology . The term survives in the title of the  British Medical Journal ' s \"Materia Non Medica\" column."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12080", "text": "The earliest known writing about medicine was a 110-page Egyptian  papyrus . It was supposedly written by the god  Thoth  in about 16 BC. The  Ebers papyrus  is an ancient recipe book dated to approximately 1552 BC. It contains a mixture of magic and medicine with invocations to banish disease and a catalogue of useful plants, minerals, magic  amulets  and spells. [ 2 ]  The most famous Egyptian physician was  Imhotep , who lived in  Memphis  around 2500 B.C. Imhotep's materia medica consisted of procedures for treating head and torso injuries, tending of wounds, and prevention and curing of infections, as well as advanced principles of hygiene."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12081", "text": "In India, the  Ayurveda  is traditional medicine that emphasizes plant-based treatments, hygiene, and balance in the body's state of being. Indian materia medica included knowledge of plants, where they grow in all season, methods for storage and shelf life of harvested materials. It also included directions for making juice from vegetables, dried powders from herb, cold infusions and extracts. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12082", "text": "The earliest  Chinese manual of materia medica , the  Shennong Bencao Jing  ( Shennong Emperor's Classic of Materia Medica ), was compiled in the 1st century AD during the  Han dynasty , attributed to the mythical  Shennong . It lists some 365 medicines, of which 252 are herbs. Earlier literature included lists of prescriptions for specific ailments, exemplified by the  Recipes for Fifty-Two Ailments  found in the Mawangdui tomb, which was sealed in 168 BC. Succeeding generations augmented the  Shennong Bencao Jing , as in the  Yaoxing Lun  ( Treatise on the Nature of Medicinal Herbs ), a 7th-century  Tang dynasty  treatise on herbal medicine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12083", "text": "In Greece,  Hippocrates  (born 460 BC) was a philosopher later known as the Father of Medicine. He founded a school of medicine that focused on treating the causes of disease rather than its symptoms. Disease was dictated by natural laws and therefore could be treated through close observation of symptoms. His treatises,  Aphorisms  and  Prognostics , discuss 265 drugs, the importance of diet and external treatments for diseases. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12084", "text": "Theophrastus  (390\u2013280 BC) was a disciple of  Aristotle  and a philosopher of  natural history , considered by historians as the Father of Botany. He wrote a treatise entitled  Historia Plantarium  about 300 BC. It was the first attempt to organize and classify plants, plant lore, and botanical morphology in Greece. It provided physicians with a rough taxonomy of plants and details of medicinal herbs and herbal concoctions. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12085", "text": "Galen  was a philosopher, physician, pharmacist and prolific medical writer. He compiled an extensive record of the medical knowledge of his day and added his own observations. He wrote on the structure of organs, but not their uses; the pulse and its association with respiration; the arteries and the movement of blood; and the uses of  theriacs . \"In treatises such as  On Theriac to Piso ,  On Theriac to Pamphilius , and  On Antidotes , Galen identified theriac as a sixty-four-ingredient compound, able to cure any ill known\". [ 5 ]  His work was rediscovered in the 15th century and became the authority on medicine and healing for the next two centuries. His medicine was based on the regulation of the four humors (blood, phlegm, black bile, and yellow bile) and their properties (wet, dry, hot, and cold). [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12086", "text": "The Greek physician  Pedanius Dioscorides , of  Anazarbus  in Asia Minor, wrote a five-volume treatise concerning medical matters, entitled \u03a0\u03b5\u03c1\u1f76 \u1f55\u03bb\u03b7\u03c2 \u1f30\u03b1\u03c4\u03c1\u03b9\u03ba\u1fc6\u03c2 in Greek or  De materia medica  in Latin. This famous commentary covered about 600 plants along with therapeutically useful animal and mineral products. It documented  the effects of drugs made from these substances on patients.  De materia medica  was the first extensive  pharmacopeia , including about a thousand natural product drugs (mostly plant-based), 4,740 medicinal usages for drugs, and 360 medical properties (such as  antiseptic ,  anti-inflammatory ,  stimulant ). The book was heavily translated, and portrayed some of the emblematic actions of physicians and herbalists. One such page is  Physician Preparing an Elixir ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12087", "text": "Dioscorides' plant descriptions use an elementary classification, though he cannot be said to have used  botanical taxonomy . Book one describes the uses for aromatic oils,  salves  and  ointments , trees and  shrubs , and fleshy fruits, even if not aromatic. Book two included uses for animals, parts of animals, animal products, cereals,  leguminous , malvaceous,  cruciferous , and other garden  herbs . Book three detailed the properties of roots, juices, herbs and seeds used for food or medicine. Book four continued to describe the uses for roots and herbs, specifically  narcotic  and poisonous medicinal plants. Book five dealt with the medicinal uses for wine and metallic  ores . [ 7 ] [ 8 ]  It is a precursor to all modern pharmacopeias, and is considered one of the most influential herbal books in history. It remained in use until about 1600 AD. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12088", "text": "Avicenna  (980\u20131037 AD) was a Persian philosopher, physician, and Islamic scholar. He wrote about 40 books on medicine. His two most famous books are  The Canon of Medicine  and  The Book of Healing , used in medieval universities as medical textbooks. He did much to popularize the connection between Greek and Arabic medicine, translating works by Hippocrates, Aristotle and Galen into Arabic. Avicenna stressed the importance of diet, exercise, and hygiene. He also was the first to describe parasitic infection, to use urine for diagnostic purposes and discouraged physicians from the practice of surgery because it was too base and manual. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12089", "text": "In medieval Europe, medicinal herbs and plants were cultivated in monastery and nunnery gardens beginning about the 8th century.  Charlemagne  gave orders for the collection of medicinal plants to be grown systematically in his royal garden. This royal garden was an important precedent for  botanical gardens  and  physic gardens  that were established in the 16th century. It was also the beginning of the study of  botany  as a separate discipline. In about the 12th century, medicine and pharmacy began to be taught in universities. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12090", "text": "Shabbethai Ben Abraham, better known as  Shabbethai Donnolo , (913\u2013 c .982) was a 10th-century Italian Jew and the author of an early Hebrew text,  Antidotarium . It consisted of detailed drug descriptions, medicinal remedies, practical methods for preparing medicine from roots. It was a veritable glossary of herbs and drugs used during the medieval period. Donnollo was widely travelled and collected information from Arabic, Greek and Roman sources. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12091", "text": "In the Early and High Middle Ages  Nestorian  Christians were banished for their heretical views that they carried to  Asia Minor . The Greek text was translated into Syriac when pagan Greek scholars fled east after  Constantine \u2019s conquest of  Byzantium ,\n Stephanos  (son of Basilios, a Christian living in  Baghdad  under the Khalif Motawakki) made an Arabic translation of  De Materia Medica  from the Greek in 854. In 948 the Byzantine Emperor  Romanus II , son and co-regent of Constantine  Porphyrogenitos , sent a beautifully illustrated Greek manuscript of  De materia medica  to the Spanish Khalif,  Abd-Arrahman III .  In 1250, Syriac scholar  Bar Hebraeus  prepared an illustrated Syriac version, which was translated into Arabic. [ 7 ] [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12092", "text": "Matthaeus Silvaticus ,  Avicenna ,  Galen ,  Dioscorides , Platearius and Serapio inspired the appearance of three main works printed in  Mainz : In 1484 the  Herbarius , the following year the  Gart der Gesundheit , and in 1491 the  Ortus Sanitatis . The works contain 16, 242 and 570 references to Dioscorides, respectively. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12093", "text": "The first appearance of Dioscorides as a printed book was a Latin translation printed at  Colle , Italy by  Johanemm Allemanun de Mdemblik  in 1478. The Greek version appeared in 1499 by  Manutius  at  Venice ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12094", "text": "The most useful books of botany, pharmacy and medicine used by students and scholars were supplemented commentaries on Dioscorides, including the works of  Fuchs ,  Anguillara ,  Mattioli ,  Maranta ,  Cesalpino ,  Dodoens , Fabius Columna,  Gaspard  and  Johann Bauhin , and  De Villanueva/Servetus . In several of these versions, the annotations and comments exceed the Dioscoridean text and have much new botany. Printers were not merely printing the authentic materia medica, but hiring experts on the medical and botanical field for criticism, commentaries, that would raise the stature of the printers and the work. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12095", "text": "Most of these authors copied each other, from previous works. It was normal to add previous commentaries and marginalia, to make the text look more enriched or thorough."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12096", "text": "There were several De Materia Medica works noted as  Anonymous A, B, C and D  by the expert on Dioscorides-De Materia Medica professor  John M. Riddle . The  Anonymous A  has to do with authors on translations of handwriting. Riddle proved  Anonymous C  to be Bruyerinus Champier. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12097", "text": "During the 16th century, the most representative among them were  Ermolao Barbaro , Jean Ruel, Broyeurinus, Michel de Villeneuva,  Pietro Andrea Mattioli ,  Andres Laguna , Marcello Virgilio, Martin Mathee and  Valerius Cordus . [ 4 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12098", "text": "In 1789,  William Cullen  published his two volume  A Treatise of the Materia Medica , which was highly valued by other medical practitioners throughout Europe. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12099", "text": "The work of the Italian physician and humanist  Ermolao Barbaro  was published in 1516, 23 years after his death.  Poliziano  wrote to Ermalao Barbaro, forwarding a manuscript of the 1st-century pharmacologist  Pedanius Dioscorides , asking him to send it back \"annotated by that very learned hand of yours, thus lending the volume additional value and authority.\" [ 12 ]  Barbaro was professor of the  University of Padua  in 1477 and translated many texts from Greek to Latin. [ 13 ] \nHe sought to avoid mistakes by gathering as many manuscripts as he could for checking the texts. He claimed to have corrected 5000 mistakes between two editions of  Pliny the Elder 's  Naturalis historia , [ 14 ]  a work he found very similar to  Materia Medica , for which he used at least two editions as well."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12100", "text": "The result of Barbaro's effort occupied no fewer than 58 pages printed in three columns of about 50 entries each. The work provides a key to over 9,000 items; all references were to pages. This was the first annotated Latin translation of Dioscorides'  Materia Medica , and so Barbaro became the earliest of the  Renaissance  translators of Dioscorides, [ 13 ] [ 15 ]  a practice that saw its golden age in the 16th century. Barbaro's work was later corrected by Giovanni-Battista."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12101", "text": "Jean Ruel was the dean of the Faculty of Medicine and physician to King  Francis I of France . He perfected the Latin translation of the  Materia Medica  directly from the \" princeps \" edition. He tried to develop a translation joining  philology ,  botany  and  medicine . This work, printed in 1516 by  Henri Estienne/Stephano , became very popular, having 20 editions during the 16th century. He published editions until 1537, printed by  Simon de Colines . [ 4 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12102", "text": "From this point, Latin was the preferred language for presenting De Materia Medica, and Ruel's editions became the basis from which many other important authors would start to create their own Materia Medica. Ruel was also teacher of two great De Materia Medica authors: Michel de Villeneuve and Andres Laguna. [ 7 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12103", "text": "Bruyerinus Champier was the nephew of  Symphorien Champier , and physician of  Henry II of France . He was an Arabist, and translated works of  Avicena . [ 17 ]  In 1550 he published his first Materia Medica, printed by Balthazar Arnoullet in  Lyons . This work had a second edition in 1552 printed by Arnoullet in Lyon and  Vienne . Both works were illustrated with figures by  Fuchs , but in this last edition there were also 30 woodcuts by the botanist and physician Jacob Dalechamp. [ 4 ] [ 18 ]  It seems that the reason that he used his initials, H.B.P., and not his full name in the work; it could be that he practically transcribed commentaries of  Mattioli . [ 4 ] [ 19 ] [ clarification needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12104", "text": "According to Spanish scholar Gonz\u00e1lez Echeverr\u00eda [ 20 ]  in several communications in the  ISHM , [ 21 ] [ 22 ] [ 23 ]  the  John M. Riddle   Anonymous B  (De Materia Medica of 1543) would be  Michael Servetus , and that the  Anonymous D  (De Materia Medica of 1554 of  Mattioli  plus non-signed commentaries) is two commentarians, Servetus and  Mattioi , being the last one hired for editing the \" Lyons  printers' Tribute to Michel de Villeneuve \" [ 24 ]  edition.\nMichael Servetus, using the name \"Michel de Villeneuve\", who already had his first death sentence from the  University of Paris , anonymously published a Dioscorides-De Materia Medica in 1543, printed by Jean & Francois Frellon in Lyon. [ 25 ]   It has 277 marginalia and 20 commentaries on a De Materia Medica of Jean Ruel. [ 25 ]   According to Gonzalez Echeverr\u00eda, to be associated to an anonymous  Pharmacopeia  that \"Michel de Villeneuve\" published the same year, meant to be a single unit, [ 23 ]  which is typical when it comes to De Materia Medica-Pharmacopeia. This work had six later editions, in 1546 and 1547 by Jean Frellon, who considered Michael de Villeneuve \"his friend and brother\", another in 1547 by Thibaut Payen, etc. [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12105", "text": "There is another Materia Medica with commentaries [ 21 ]  on a Ruel edition of 1537, printed by  Simon de Colines . This work contains hundreds of manuscript marginaia, all along 420 out of 480 pages. The scholar Gonzalez Echeverria demonstrated in the  ISHM [ 21 ]  with a graphological, historical and linguistic study that this task was carried out by Michel de Villeneuve. It also demonstrated that this document was written by the same hand that wrote the famous [ 26 ]  \"Manuscript of Paris\", a work also by Michel de Villeneuve, consisting of a draft for his Christianismo Restitutio. \"The manuscript of the  Complutense \" is not just a union of the ideas of the previous works by Michel de Villeneuve, Syropum Ratio, etc., but also of the later works, Enquiridion, [ 23 ]  De Materia Medica of 1543, [ 25 ]  sharing with this last many of its 20 big commentaries, for instance. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12106", "text": "According to this theory, in 1554, [ 21 ]  after the immolation of Michael de Villeneuve/Servetus, the editors and printers that had worked with him would have decided to make a new De Materia Medica as a tribute to their colleague and friend. [ 21 ]  All the commentaries that could identify Michel de Villeneuve as the author disappeared, [ 26 ]  but the rest are copied from his work of 1543. It is a very strange edition because there exist four different kinds of copies with different covers, one per editor: Jean Frellon,  Guillaume Rouill\u00e9 , Antoine Vicent and Balthazar Arnoullet, who was also the printer of this unique edition, in  Lyons . [ 21 ]  For developing a bigger work and to blur the mark of Michel de Villeneuve, they hired the expert on De Materia Medica,  Pietro Andrea Mattioli . [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12107", "text": "Pietro Andrea Mattioli  was a renowned botanist and physician. He published a translation of De Materia Medica [ 27 ]  into Italian in 1544 and ten years later published a work in Latin with all the plants of  Dioscorides  and 562 woodcut illustrations. [ 7 ]  It appeared in 1554, printed by Vicenzo Valgrisi, in  Venice . Mattioli made a massive contribution to the original text of Pedani's Dioscorides. [ 27 ]  In some sections Mattioli added information that exceeded 15 times the length of the original text.  It resulted in a very big extension of the work, in beauty and information. It was later translated into German, French and  Bohemian . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12108", "text": "Mattioli held a post in the Imperial Court as physician to  Ferdinand II, Archduke of Austria , [ 27 ]  and the Emperor  Maximilian II, Holy Roman Emperor . [ 7 ]  This position granted him an immense influence. He frequently tested the effects of poisonous plants on prisoners in order to popularize his works. [ 4 ]  He also affirmed that Jean Ruel had declared some information in the lycopsis chapter of his Materia Medica. This is false, but still Mattioli used it as a reason for attacking Ruel. [ 7 ]  He did not tolerate either rivals nor corrections. The naturalists and physicians daring to disagree with him, or who had corrected him, were attacked. The list of important characters that were admonished, rebuked, or pursued by the  Inquisition  contains Wieland,  Anguillara ,  Gesner ,  Lusitanus  and others. This made editions of Matioli's De Materia Medica omnipresent throughout the continent, especially in northern Europe. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12109", "text": "In 1554 the physician  Andres Laguna  published his Annotations on  Dioscorides  of  Anazarbus [ 28 ]  printed by  Guillaume Rouill\u00e9  in Lyons. Laguna was the first to translate De Materia Medica into  Castilian . [ 28 ]  His translation was made from one of the Latin editions of Jean Ruel. It was also based on classes Laguna took from Ruel as his pupil in Paris. Laguna points out some of his teacher's erroneous translations, and adds many commentaries, which make up more than half of the total work."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12110", "text": "Laguna explored [ 28 ]  many  Mediterranean  areas and obtained results concerning many new herbs; he also added these prescriptions and commentaries to the recipes and teachings of Pedanius' Dioscorides. He also includes some animal and mineral products but only those related to simple medicines, that is, animal and  mineral  products that are medicine or are parts of a medical compound. [ 29 ]  This was not an illustrated work. In 1555 he re-edited this work with  woodcuts . [ 28 ] \nIt was reprinted twenty-two times by the end of the 18th century; Laguna wrote very well, with explanations and practical commentaries. [ 29 ]  He refers to anecdotes, adds commentaries on the plants, provides their synonyms in different languages, and explains their uses in the 16th century. These qualities and the number of woodcuts made this work very popular and appreciated in medicine far beyond the 16th century. He had problems with Mattioli for using some of his commentaries without mentioning him. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12111", "text": "Laguna had problems with the  Inquisition , just like  Michel de Villeneuve , for both were  jewish - converso , [ 30 ]  a fact that could have made them limit their commentaries to avoid risks. Nevertheless, he was the physician of  Charles V  and the  Pope Julius III , [ 28 ]  and that helped to establish his work as the last word in Materia Medica, and as the basis of Spanish botany. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12112", "text": "The physician  Valerius Cordus , son of the famous botanist Euricius Cordus, went through many woods and mountains discovering hundreds of new herbs. [ 32 ]  He gave lectures on Dioscorides at the  University of Wittenberg , which experts from the university attended. Cordus had no intention of publishing his work. Five years after his death, a Materia Medica with commentaries was published. [ 33 ]  It contained the index of the  Botanologicon , the outstanding work of his father Euricius, who developed a scientific classification of the plants. The following pages are on  Gesner 's Nomenclature, [ 34 ]   relating the different synonyms used for referring to the same plants of the Dioscorides work."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12113", "text": "The abstracts of the lectures of Valerius Cordus go from page 449 to 553 as commentaries. This section consisted of a very refined explanation of Dioscorides' teachings with more specifics on the variety of plants [ 35 ]  and habitats, and corrections of errors. Cordus refers to both his and his father's observations.  Eucharius R\u00f6sslin 's herbal [ 36 ]  illustrations are prominent in this work, followed by 200 of  Fuchs . This work and the model of botanical description and, many consider it the boldest innovation that was made by any botanist of the 16th century. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12114", "text": "The French physician Martin Mathee published in 1553 the French translation of De Materia Medica, printed by Balthazar Arnoullet, in Lyons. This granted much more access for the students of medicine to the teachings. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12115", "text": "The Greek version was reprinted in 1518, 1523 and 1529, and reprinted in 1518, 1523 and 1529. Between 1555 and 1752 there were at least 12 Spanish editions; and as many in Italian from 1542. French editions appeared from 1553; and German editions from 1546. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12116", "text": "The ancient phrase survives in modified form in the  British Medical Journal ' s long-established \"Materia Non Medica\" column, the title indicating non-medical material that doctors wished to report from their travels and other experiences. For example, in June 1977, the journal contained \"Materia Non Medica\" reports on an exhibition at the  Whitechapel Art Gallery  by a London physician, the making of matches by hand in an Indian village by a  missionary  general practitioner, and a cruise to Jamaica by a  University of the West Indies  lecturer in medicine. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12117", "text": "A subscription-based product of the  International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use  (ICH), MedDRA or Medical Dictionary for Regulatory Activities is a clinically validated international  medical terminology  dictionary- thesaurus  used by regulatory authorities and the biopharmaceutical industry during the regulatory process, from pre-marketing (clinical research phase 0 to phase 3) to post-marketing activities (pharmacovigilance or clinical research phase 4), and for safety information data entry, retrieval, evaluation, and presentation. [ 1 ]  Also, it is the  adverse event  classification dictionary. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12118", "text": "The first version of MedDRA was released in 1999 in English and Japanese."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12119", "text": "MedDRA is now translated into Chinese, Czech, Dutch, French, German, Hungarian, Italian, Korean, Portuguese, Brazilian Portuguese, Russian, and Spanish. [ 3 ]   In MedDRA version 25.0, Swedish and Latvian translations were also added. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12120", "text": "In many countries/regions the use of MedDRA by  biopharmaceutical  companies is mandated for safety reporting. \nMany other industries, including  tobacco  and  cosmetics , are also beginning to use MedDRA for capturing adverse health events."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12121", "text": "All Regulatory Members of ICH are expected to implement MedDRA within 5 years."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12122", "text": "As of 2020, the following ICH Regulatory Members have implemented MedDRA:  EC , Europe;  FDA , United States;  HSA , Singapore; [ 5 ]   Health Canada , Canada; [ 6 ]   MHLW / PMDA , Japan;  Swissmedic , Switzerland; and  TFDA , Taiwan. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12123", "text": "Information about the implementation status of MedDRA by ICH Regulatory Members is updated by ICH on its website. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12124", "text": "MedDRA is widely used internationally, with close to 7,500 subscribing organizations in almost 130 countries. [ 4 ] \nEach organization, regardless of its number of users, requires only one subscription to MedDRA."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12125", "text": "In developing and continuously maintaining MedDRA, ICH endeavours to facilitate the exchange of clinical information through a single standardized international medical terminology that can be used for regulatory communication and evaluation of data pertaining to medicinal products for human use. [ 8 ] \nAs a result, MedDRA is designed for use in the registration, documentation, and safety monitoring of medicinal products through all phases of the development life cycle. [ 8 ] \nThe single standardized terminology offers several clear advantages for regulators, industry, and other stakeholders:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12126", "text": "The MedDRA dictionary is organized with a five-level hierarchy. The highest or broadest level is System Organ Class (SOC), further divided into High-Level Group Terms (HLGT), High-Level Terms (HLT), Preferred Terms (PT), and finally into the most granular Lowest Level Terms (LLT). [ 9 ]  In addition, the MedDRA dictionary includes Standardized MedDRA Queries (SMQs). SMQs are groupings of terms that relate to a defined medical condition or area of interest. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12127", "text": "SMQs are developed to facilitate retrieval of MedDRA-coded data as a first step in investigating  drug safety  issues in  pharmacovigilance  and  clinical development ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12128", "text": "As of MedDRA 25.1, 110 SMQs have been created comprising 120 lower-level SMQs. Additional SMQs are created as the need arises. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12129", "text": "Individual cases are usually coded for data entry at the most specific (LLT) level, and outputs of counts or cases are usually provided at the PT level. The higher levels (HLT, HLGT, and SOC), as well as SMQs, are used for searching and for organizing and subtotalling outputs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12130", "text": "The five-level hierarchy provides degrees or levels of super-ordination and subordination. The superordinate term is a broad grouping term applicable to each subordinate descriptor linked to it. Hierarchical levels thus represent vertical links in the terminology. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12131", "text": "Hierarchies are an important mechanism for flexible data retrieval and for the clear presentation of data. The five-level structure of this terminology provides options for retrieving data by specific or broad groupings, according to the level of specificity required. The Lowest Level Term (LLT) level provides maximum specificity. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12132", "text": "The terminology was not developed as a formal classification or taxonomy; each level in the hierarchy may reflect a variable degree of specificity or \u201cgranularity\u201d from one System Organ Class to another. High-Level Terms (HLTs) and High-Level Group Terms (HLGTs) facilitate data retrieval and presentation by providing clinically relevant grouping of terms. Collectively, the HLT and HLGT levels are sometimes referred to as the \u201cgrouping terms\u201d in MedDRA. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12133", "text": "The 27 System Organ Classes (SOCs) represent parallel axes that are not mutually exclusive. This characteristic, called \u201cmulti-axiality,\u201d allows a term to be represented in more than one SOC and to be grouped by different classifications (e.g., by etiology or manifestation site), allowing retrieval and presentation via different data sets. Grouping terms are pre-defined in the terminology and not selected on an ad hoc basis by data entry staff. Rather, the terminology is structured so that selection of a data entry term leads to the automatic assignment of grouping terms higher in the hierarchy. Multi-axial links of terms are pre-assigned in MedDRA, ensuring comprehensive and consistent data retrieval, irrespective of which SOC is selected at data retrieval."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12134", "text": "As of MedDRA 25.1 (September 2022):"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12135", "text": "MedDRA is hierarchical, multiaxial, multilingual, [ 13 ]  regularly-updated, and strictly maintained by the Maintenance and Support Services Organization (MSSO). ICH holds the  intellectual property  rights (ownership) of MedDRA."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12136", "text": "MedDRA is available free for all regulators worldwide, academics, health care providers, and non-profit organizations. The subscription price is based according to company revenue for the industry. [ 14 ]  The Japanese counterpart for the MSSO is called the Japanese Maintenance Organization (JMO). [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12137", "text": "Four types of subscriptions are available from the MSSO:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12138", "text": "The MSSO updates MedDRA according to subscriber change requests, for example, to add a new medical concept that is not yet in MedDRA or to change/modify an existing concept. The decisions on submitted change requests are made by a team of international medical officers on how to map the terminology within the grouping categories according to a general team consensus. The final decisions are based on multiple factors including the Points to Consider documentation, implications on legacy data, and language considerations internationally."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12139", "text": "The MSSO and JMO release updated MedDRA versions twice a year - in March and September. The English and Japanese translation are released on 1 March and September and all other translations are released on the 15th. The March release is the main annual release and contains changes at the HLT level and above along with LLT and PT changes. The September release contains changes only at the LLT and PT level. As of September\u00a02024 [update] , Version 27.1 is the most recent version. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12140", "text": "The MSSO frequently incorporates feedback from the user community to stay abreast of its unique perspectives and nuanced needs.  Input from these constituencies helps MSSO adapt MedDRA accordingly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12141", "text": "As global regulators expand the scope of product types they regulate, there is a corresponding increase in the adaptation of and interest in the proactive use of MedDRA before regulatory mandates. Such expansion has increased in MedDRA terms applicable to many product types.  The addition of the 27th SOC Product issues in Version 19.0 has even further expanded use of MedDRA for product quality, supply, distribution, manufacturing and quality system issue as well as device issues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12142", "text": "https://www.meddra.org/how-to-use/support-documentation?current"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12143", "text": "The Pharma Letter  (or TPL), is an English pharmaceutical,  generics  and  biotechnology  news and analysis service. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12144", "text": "Coverage includes: [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12145", "text": "Barbara Obstoj is the Managing Editor, which in 2009 acquired the archives of The Pharma Marketletter, a publication Barbara owned since 1991 and prior to that edited when it was part of IMS Health. [ 1 ]   She was also the founding editor of  Scrip World Pharmaceutical News  from 1972 to 1976. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12146", "text": "Pharmaceutical Press  is the publishing arm of the  Royal Pharmaceutical Society  (formerly the  Royal Pharmaceutical Society of Great Britain ).  It is a provider of independent pharmaceutical information."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12147", "text": "Its principal publishing focus is the design, manufacture and therapeutic use of medicines, as well as the professional concerns of those working to ensure their safe administration and use. Its international catalogue contains more than 150 print and digital works, with a range of products consisting of reference works, textbooks, professional titles and subscription products."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12148", "text": "The most renowned resources include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12149", "text": "The  Physicians' Desk Reference  ( PDR ), renamed  Prescriber's Digital Reference  after its physical publication was discontinued, is a compilation of manufacturers' prescribing information ( package insert ) on  prescription drugs , updated regularly and published by  ConnectiveRx . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12150", "text": "The original PDR was titled  Physicians' Desk Reference  but was renamed because not all prescribers are  physicians  and the reference is no longer a hardback book used on a desk. While marketed as a means of providing physicians with the full legally mandated information relevant to writing prescriptions, it was widely available in  libraries  and  bookstores , was widely used by other medical specialists, and was sometimes valuable to the  layman . The book was distributed for free to all licensed medical doctors in America;  only drugs which drug manufacturers paid to appear, appeared in the PDR, and no generic drugs were listed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12151", "text": "The 71st Edition, published in 2017, was the final hardcover edition, weighed in at 4.6 pounds (2.1\u00a0kg) and contained information on over 1,000 drugs. [ 1 ]  Since then, the PDR has been available online for free."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12152", "text": "The  Physicians' Desk Reference  was first published in 1947 by Medical Economics Inc., a magazine publisher founded by Lansing Chapman. [ 2 ]  Medical Economics Inc. merged with Reinhold Publishing in 1966 to form Chapman-Reinhold. [ 3 ]   Litton Industries , which owned the  American Book Company , acquired Chapman-Reinhold in 1968. [ 4 ]  Litton sold its publishing business to the  International Thomson Organization  (ITO) in 1981. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12153", "text": "ITO successor  Thomson Reuters  sold the  Physicians' Desk Reference  to  Lee Equity Partners  in 2009; Lee formed the new parent company PDR Network. Lee sold PDR Network to  Genstar Capital  in 2015. [ 6 ]  Genstar merged PDR Network into the new company ConnectiveRx. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12154", "text": "The  PDR  material contained includes:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12155", "text": "The PDR has several versions and related volumes:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12156", "text": "Therapeutic Target Database  ( TTD ) is a pharmaceutical and medical repository [ 1 ]  constructed by the Innovative Drug Research and Bioinformatics Group (IDRB) at  Zhejiang University, China  and the Bioinformatics and Drug Design Group at the  National University of Singapore . It provides information about known and explored therapeutic  protein  and  nucleic acid  targets, [ 2 ]  the targeted disease, [ 3 ]  pathway information [ 4 ]  and the corresponding drugs directed at each of these targets. [ 1 ]  Detailed knowledge about target function, sequence, 3D structure, ligand binding properties,  enzyme  nomenclature and drug structure, therapeutic class, and clinical development status. [ 1 ]  TTD is freely accessible without any login requirement at  https://idrblab.org/ttd/ ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12157", "text": "This database contains 3,730 therapeutic targets (532 successful, 1,442 clinical trial, 239 preclincial/patented and 1,517 research targets) and 39,862 drugs (2,895 approved, 11,796 clinical trial, 5,041 preclincial/patented and 20,130 experimental drugs). The targets and drugs in TTD cover 583 protein biochemical classes and 958 drug therapeutic classes, respectively. [ 1 ]  The latest version of the International Classification of Diseases (ICD-11) codes released by WHO are incorporated in TTD to facilitate the clear definition of disease/disease class. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12158", "text": "Target validation normally requires the determination that the target is expressed in the disease-relevant cells/tissues, [ 6 ]  it can be directly modulated by a drug or drug-like molecule with adequate potency in biochemical assay, [ 7 ]  and that target modulation in cell and/or animal models ameliorates the relevant disease phenotype. [ 8 ]  Therefore, TTD collects three types of target validation data: [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12159", "text": "The therapeutic targets in TTD are categorized into successful target, clinical trial target, preclinical target, patented target, and literature-reported target, which are defined by the highest status of their corresponding drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12160", "text": "The molecular types of therapeutic targets in TTD include protein, nucleic acid, and other molecule."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12161", "text": "The main drug types in TTD include small molecule, antibody, nucleic acid drug, cell therapy, gene therapy and vaccine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12162", "text": "\u25a0  Target druggability illustrated by molecular interactions or regulations;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12163", "text": "\u25a0  Target druggability characterized by different human system features;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12164", "text": "\u25a0  Target druggability reflected by diverse cell-based expression variations;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12165", "text": "\u25a0  Structure-based activity landscape and drug-like property profile of targets;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12166", "text": "\u25a0  Prodrugs together with their parent drug and target;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12167", "text": "\u25a0  Co-targets modulated by approved/clinical trial drugs;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12168", "text": "\u25a0  Poor binders and non-binders of targets;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12169", "text": "\u25a0  Target regulators (microRNAs & transcription factors) and target-interacting proteins;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12170", "text": "\u25a0  Patented agents and their targets (structures and experimental activity values if available);"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12171", "text": "\u25a0  Differential expression profiles and downloadable data of targets in patients and healthy individuals;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12172", "text": "\u25a0  Target combination of multitarget drugs and combination therapies;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12173", "text": "\u25a0  Cross-links of most TTD target and drug entries to the corresponding pathway entries;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12174", "text": "\u25a0  Access of the multiple targets and drugs cross-linked to each of these pathway entries;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12175", "text": "\u25a0  Biomarkers for disease conditions;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12176", "text": "\u25a0  Drug scaffolds for drugs/leads;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12177", "text": "\u25a0  Target validation information (drug-target-disease);"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12178", "text": "\u25a0  Quantitative structure activity relationship models (QSAR) for compounds;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12179", "text": "\u25a0  Clinical trial drugs and their targets;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12180", "text": "\u25a0  Similarity target and drug search."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12181", "text": "The Top 100 Drugs: Clinical Pharmacology and Practical Prescribing  is a pocket-size  medical manual  focusing on the most commonly prescribed medicines by the British  National Health Service  (NHS). It was first published by  Churchill Livingstone ,  Elsevier , in 2014, revised in a second edition in 2018, and again in 2022 in a third edition. It is authored by four  clinical pharmacologists  from  St George's Hospital , London; Andrew Hitchings, Dagan Lonsdale, Daniel Burrage and  Emma Baker ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12182", "text": "The drugs are described in alphabetical order, with each drug or  drug class  on a double page. Each is subsequently explained in terms of clinical pharmacology and practical prescribing.  Intravenous fluids  are dealt with later in the book, followed by a self-assessment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12183", "text": "The book received a review in  Pulse , and in 2018 was listed as an essential reference book for junior doctors by the  Pharmaceutical Journal ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12184", "text": "The Top 100 Drugs  is a  medical manual  which aims to reduce risks in prescribing. It includes a list of commonly prescribed medicines by the British  NHS , for undergraduate and postgraduate medical education in the UK. [ 1 ] [ 2 ]  It was first published as an  e-book  by  Churchill Livingstone ,  Elsevier , in 2014. [ 2 ]  A second edition was published in 2018. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12185", "text": "The first edition was based on the 100 most frequently prescribed drugs by the NHS in 2006\u20132009, first described in the  British Journal of Clinical Pharmacology  in 2011 by  Emma Baker , who identified the drugs with how they appear in the  British National Formulary  ( BNF ). [ 5 ] [ 6 ]  The book is authored by Baker and three other  clinical pharmacologists  from  St George's Hospital ; Andrew Hitchings, Dagan Lonsdale and Daniel Burrage, [ 4 ]  and takes into account suggestions from junior doctors. [ 4 ] [ 7 ]  The list was revised in 2015, using data collected from a larger dataset to check that no significant changes had occurred, and formed the basis of the second edition, in which 11 drugs were replaced and the number of self-assessment questions doubled. [ 4 ] [ 5 ] [ 6 ]  A third edition was released in 2022. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12186", "text": "The book has 325 pages and being 180\u00a0mm (7.1\u00a0in) in height and 100\u00a0mm (3.9\u00a0in) width, it can fit in a pocket. [ 7 ] [ 9 ]  There is a contents page, followed by a list of abbreviations and an introduction. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12187", "text": "The introduction states how the most frequently prescribed drugs in primary and secondary care were identified. [ 6 ]  Each drug or  class of drugs  is listed in alphabetical order, displayed on a double page and explained in two sections; clinical pharmacology and practical prescribing. [ 6 ] [ 7 ]  These are then divided into; [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12188", "text": "The pharmacology of a drug or drug class is presented with guidance on prescribing. A drug can also be located by organ system or by clinical indication. [ 10 ]   Intravenous fluids  are dealt with towards the end of the book, followed by a self assessment and an index. [ 10 ]  Unlike the original list, the second includes the newer  diabetic drugs ,  blood thinners  and anti-epileptics such as  levetiracetam . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12189", "text": "In 2014, the book received a review from a  general practitioner  in  Pulse , in which they felt it to be aimed towards those unfamiliar with prescribing, but useful as an aid to revising drugs. [ 7 ]  It was mentioned in the  International Journal of Clinical Skills , [ 11 ]  and in 2018, the  Pharmaceutical Journal  listed the book in their \"nine essential resources for preregistration trainees\". [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12190", "text": "Pharmacy  is the  science  and practice of discovering, producing, preparing, dispensing, reviewing and monitoring  medications , aiming to ensure the safe, effective, and affordable use of  medicines . It is a miscellaneous science as it links  health sciences  with  pharmaceutical sciences  and  natural sciences . The professional practice is becoming more clinically oriented as most of the drugs are now manufactured by pharmaceutical industries. Based on the setting, pharmacy practice is either classified as community or institutional pharmacy. Providing direct patient care in the community of institutional pharmacies is considered  clinical pharmacy . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12191", "text": "The scope of pharmacy practice includes more traditional roles such as  compounding  and dispensing of medications. It also includes more modern services related to  health care  including clinical services, reviewing medications for safety and efficacy, and providing drug information with patient counselling.  Pharmacists , therefore, are experts on drug therapy and are the primary health professionals who optimize the use of medication for the benefit of the patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12192", "text": "An establishment in which pharmacy (in the first sense) is practiced is called a  pharmacy  (this term is more common in the United States) or  chemists  (which is more common in Great Britain, though  pharmacy  is also used). [ citation needed ]  In the United States and Canada,  drugstores  commonly sell medicines, as well as miscellaneous items such as  confectionery ,  cosmetics ,  office supplies ,  toys ,  hair care  products and  magazines , and occasionally refreshments and groceries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12193", "text": "In its investigation of herbal and chemical ingredients, the work of the  apothecary  may be regarded as a precursor of the modern sciences of chemistry and  pharmacology , prior to the formulation of the  scientific method . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12194", "text": "The field of pharmacy can generally be divided into various disciplines:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12195", "text": "The boundaries between these disciplines and with other sciences, such as biochemistry, are not always clear-cut.\nOften, collaborative teams from various disciplines (pharmacists and other scientists) work together toward the introduction of new therapeutics and methods for patient care. However, pharmacy is not a basic or biomedical science in its typical form. Medicinal chemistry is also a distinct branch of synthetic chemistry combining pharmacology, organic chemistry, and chemical biology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12196", "text": "Pharmacology  is sometimes considered the fourth discipline of pharmacy. Although pharmacology is essential to the study of pharmacy, it is not specific to pharmacy. Both disciplines are distinct. Those who wish to practice both pharmacy (patient-oriented) and pharmacology (a biomedical science requiring the scientific method) receive separate training and degrees unique to either discipline."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12197", "text": "Pharmacoinformatics  is considered another new discipline, for systematic drug discovery and development with efficiency and safety."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12198", "text": "Pharmacogenomics is the study of genetic-linked variants that effect patient clinical responses, allergies, and metabolism of drugs. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12199", "text": "The  World Health Organization  estimates that there are at least 2.6 million pharmacists and other pharmaceutical personnel worldwide. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12200", "text": "Pharmacists are  healthcare professionals  with specialized education and training who perform various roles to ensure optimal  health  outcomes for their patients through the quality use of medicines.  Pharmacists  may also be  small business  proprietors, owning the pharmacy in which they practice. Since pharmacists know about the mode of action of a particular drug, and its metabolism and physiological effects on the human body in great detail, they play an important role in optimization of drug treatment for an individual."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12201", "text": "Pharmacists are represented internationally by the  International Pharmaceutical Federation  (FIP), an  NGO  linked with  World Health Organization  (WHO). They are represented at the national level by  professional organisations  such as the  Royal Pharmaceutical Society  in the UK,  Pharmaceutical Society of Australia  (PSA),  Canadian Pharmacists Association  (CPhA),  Indian Pharmacist Association  (IPA),  Pakistan Pharmacists Association  (PPA),  American Pharmacists Association  (APhA), and the  Malaysian Pharmaceutical Society  (MPS). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12202", "text": "In some cases, the representative body is also the registering body, which is responsible for the regulation and  ethics  of the profession."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12203", "text": "In the United States, specializations in pharmacy practice recognized by the  Board of Pharmacy Specialties  include: cardiovascular,  infectious disease ,  oncology , pharmacotherapy, nuclear,  nutrition , and  psychiatry . [ 5 ]  The  Commission for Certification in Geriatric Pharmacy  certifies pharmacists in geriatric pharmacy practice. The  American Board of Applied Toxicology  certifies pharmacists and other medical professionals in applied  toxicology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12204", "text": "Pharmacy technicians support the work of pharmacists and other health professionals by performing a variety of pharmacy-related functions, including dispensing prescription drugs and other medical devices to patients and instructing on their use. They may also perform administrative duties in pharmaceutical practice, such as reviewing prescription requests with medic's offices and insurance companies to ensure correct medications are provided and payment is received."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12205", "text": "Legislation requires the supervision of certain pharmacy technician's activities by a pharmacist. The majority of pharmacy technicians work in  community pharmacies . In hospital pharmacies, pharmacy technicians may be managed by other senior pharmacy technicians. In the UK the role of a PhT in hospital pharmacy has grown and responsibility has been passed on to them to manage the pharmacy department and specialized areas in pharmacy practice allowing pharmacists the time to specialize in their expert field as medication consultants spending more time working with patients and in research. Pharmacy technicians are registered with the General Pharmaceutical Council (GPhC). The GPhC is the regulator of pharmacists, pharmacy technicians, and pharmacy premises."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12206", "text": "In the US, pharmacy technicians perform their duties under the supervision of pharmacists. Although they may perform, under supervision, most dispensing, compounding and other tasks, they are not generally allowed to perform the role of counseling patients on the proper use of their medications. Some states have a legally mandated  pharmacist-to-pharmacy technician ratio ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12207", "text": "Dispensing assistants are commonly referred to as \"dispensers\" and in community pharmacies perform largely the same tasks as a pharmacy technician. They work under the supervision of pharmacists and are involved in preparing (dispensing and labelling) medicines for provision to patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12208", "text": "In the UK, this group of staff can sell certain medicines (including pharmacy only and general sales list medicines) over the counter. They cannot prepare prescription-only medicines for supply to patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12209", "text": "The earliest known compilation of medicinal substances was the  Sushruta Samhita , an Indian  Ayurvedic treatise  attributed to  Sushruta  in the 6th century BC. However, the earliest text as preserved dates to the 3rd or 4th century AD."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12210", "text": "Many  Sumerian  (4th millennium BC \u2013 early 2nd millennium BC) cuneiform  clay tablets  record prescriptions for medicine. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12211", "text": "Ancient Egyptian pharmacological knowledge was recorded in various papyri such as the  Ebers Papyrus  of 1550 BC, and the  Edwin Smith Papyrus  of the 16th century BC."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12212", "text": "In  Ancient Greece ,  Diocles of Carystus  (4th century BC) was one of several men studying the medicinal properties of plants. He wrote several treatises on the topic. [ 7 ]  The Greek physician  Pedanius Dioscorides  is famous for writing a five-volume book in his native Greek \u03a0\u03b5\u03c1\u03af \u03cd\u03bb\u03b7\u03c2 \u03b9\u03b1\u03c4\u03c1\u03b9\u03ba\u03ae\u03c2 in the 1st century AD. The Latin translation  De Materia Medica  ( Concerning medical substances ) was used as a basis for many medieval texts and was built upon by many middle eastern scientists during the  Islamic Golden Age , themselves deriving their knowledge from earlier Greek  Byzantine medicine . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12213", "text": "Pharmacy in China  dates at least to the earliest known Chinese manual, the  Shennong Bencao Jing  ( The Divine Farmer's Herb-Root Classic ), dating back to the 1st century AD. It was compiled during the  Han dynasty  and was attributed to the mythical  Shennong . Earlier literature included lists of prescriptions for specific ailments, exemplified by a manuscript \"Recipes for 52 Ailments\", found in the  Mawangdui , sealed in 168 BC."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12214", "text": "In Japan, at the end of the  Asuka period  (538\u2013710) and the early  Nara period  (710\u2013794), the men who fulfilled roles similar to those of modern pharmacists were highly respected.  The place of pharmacists in society was expressly defined in the  Taih\u014d Code  (701) and re-stated in the  Y\u014dr\u014d Code  (718).  Ranked positions in the pre- Heian  Imperial court were established; and this organizational structure remained largely intact until the  Meiji Restoration  (1868).  In this highly stable hierarchy, the pharmacists\u2014and even pharmacist assistants\u2014were assigned status superior to all others in health-related fields such as physicians and acupuncturists. In the Imperial household, the pharmacist was even ranked above the two personal physicians of the Emperor. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12215", "text": "There is a stone sign for a pharmacy shop with a tripod, a mortar, and a pestle opposite one for a doctor in the Arcadian Way in Ephesus near Kusadasi in Turkey. [ 10 ]  The current Ephesus dates back to 400 BC and was the site of the Temple of Artemis, one of the seven wonders of the world."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12216", "text": "In  Baghdad  the first pharmacies, or drug stores, were established in 754, [ 11 ]  under the  Abbasid Caliphate  during the  Islamic Golden Age . By the 9th century, these pharmacies were state-regulated. [ 12 ] [ unreliable source? ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12217", "text": "The advances made in the Middle East in  botany  and  chemistry  led  medicine in medieval Islam  substantially to develop  pharmacology .  Muhammad ibn Zakar\u012bya R\u0101zi  (Rhazes) (865\u2013915), for instance, acted to promote the medical uses of chemical compounds.  Abu al-Qasim al-Zahrawi  (Abulcasis) (936\u20131013) pioneered the preparation of medicines by  sublimation  and  distillation . His  Liber servitoris  is of particular interest, as it provides the reader with recipes and explains how to prepare the \"simples\" from which were  compounded  the complex drugs then generally used. Sabur Ibn Sahl (d 869), was, however, the first physician to record his findings in a  pharmacopoeia , describing a large variety of drugs and remedies for ailments.  Al-Biruni  (973\u20131050) wrote one of the most valuable Islamic works on pharmacology, entitled  Kitab al-Saydalah  ( The Book of Drugs ), in which he detailed the properties of drugs and outlined the role of pharmacy and the functions and duties of the pharmacist.  Avicenna , too, described no less than 700 preparations, their properties, modes of action, and their indications. He devoted in fact a whole volume to simple drugs in  The Canon of Medicine . Of great impact were also the works by  al-Maridini of Baghdad  and  Cairo , and  Ibn al-Wafid  (1008\u20131074), both of which were printed in  Latin  more than fifty times, appearing as  De Medicinis universalibus et particularibus  by ' Mesue ' the younger, and the  Medicamentis simplicibus  by ' Abenguefit '.  Peter of Abano  (1250\u20131316) translated and added a supplement to the work of al-Maridini under the title  De Veneris . Al-Muwaffaq's contributions in the field are also pioneering. Living in the 10th century, he wrote  The foundations of the true properties of Remedies , amongst others describing  arsenious oxide , and being acquainted with  silicic acid . He made clear distinction between  sodium carbonate  and  potassium carbonate , and drew attention to the poisonous nature of  copper  compounds, especially copper  vitriol , and also  lead  compounds. He also describes the  distillation of sea-water  for drinking. [ 13 ] [ verification needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12218", "text": "In  Europe , pharmacy-like shops began to appear during the 12th century. In 1240, emperor  Frederic II  issued a decree by which the physician's and the apothecary's professions were separated. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12219", "text": "There are pharmacies in Europe that have been in operation since medieval times. In  Florence , Italy, the director of the museum in the  former  Santa Maria Novella pharmacy  says that the pharmacy there dates back to 1221. [ 15 ]  In  Trier  (Germany), the  L\u00f6wen-Apotheke  is in operation since 1241, the oldest pharmacy in Europe in continuous operation. [ 16 ]  In  Dubrovnik  (Croatia), a pharmacy that first opened in 1317 is located inside the Franciscan monastery: it is the 2nd oldest pharmacy in Europe that is still operating. [ 17 ] [ 18 ]  In  the Town Hall Square of  Tallinn  (Estonia), there is a pharmacy dating from at least 1422. [ citation needed ]   The medieval  Esteve Pharmacy , located in  Ll\u00edvia , a  Catalan   enclave  close to  Puigcerd\u00e0 , is a museum: the building dates back to the 15th century and the museum keeps  albarellos  from the 16th and 17th centuries, old prescription books and antique drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12220", "text": "Pharmacists practice in a variety of areas including community pharmacies, infusion pharmacies, hospitals, clinics, insurance companies, medical communication companies, research facilities, pharmaceutical companies, extended care facilities, psychiatric hospitals, and regulatory agencies. Pharmacists themselves may have expertise in a  medical specialty ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12221", "text": "A  pharmacy  (also known as a  chemist  in  Australia ,  New Zealand  and the  British Isles ; or  drugstore  in  North America ;  retail pharmacy  in industry terminology; or  apothecary , historically) is where most pharmacists practice the profession of pharmacy. It is the community pharmacy in which the dichotomy of the profession exists; health professionals who are also retailers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12222", "text": "Community pharmacies usually consist of a retail storefront with a dispensary, where medications are stored and dispensed. According to Sharif Kaf al-Ghazal, the opening of the first drugstores are recorded by  Muslim  pharmacists in  Baghdad  in 754 AD. [ 11 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12223", "text": "Pharmacies within  hospitals  differ considerably from community pharmacies. Some pharmacists in hospital pharmacies may have more complex clinical medication management issues, and pharmacists in community pharmacies often have more complex business and customer relations issues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12224", "text": "Because of the complexity of medications including specific indications, effectiveness of treatment regimens, safety of medications (i.e., drug interactions) and  patient compliance  issues (in the hospital and at home), many pharmacists practicing in hospitals gain more education and training after pharmacy school through a pharmacy practice residency, sometimes followed by another residency in a specific area. Those pharmacists are often referred to as clinical pharmacists and they often specialize in various disciplines of pharmacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12225", "text": "For example, there are pharmacists who specialize in hematology/oncology, HIV/AIDS, infectious disease, critical care,  emergency medicine , toxicology, nuclear pharmacy, pain management, psychiatry, anti-coagulation clinics,  herbal medicine , neurology/epilepsy management, pediatrics, neonatal pharmacists and more."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12226", "text": "Hospital pharmacies can often be found within the premises of the hospital. Hospital pharmacies usually stock a larger range of medications, including more specialized medications, than would be feasible in the community setting. Most hospital medications are unit-dose, or a single dose of medicine.  Hospital pharmacists and trained pharmacy technicians compound sterile products for patients including  total parenteral nutrition  (TPN), and other medications are given intravenously. That is a complex process that requires adequate training of personnel,  quality assurance  of products, and adequate facilities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12227", "text": "Several hospital pharmacies have decided to  outsource  high-risk preparations and some other compounding functions to companies who specialize in compounding. The high cost of medications and drug-related technology and the potential impact of medications and pharmacy services on patient-care outcomes and patient safety require hospital pharmacies to perform at the highest level possible."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12228", "text": "Pharmacists  provide direct patient care services that optimize the use of medication and promotes health, wellness, and disease prevention. [ 20 ]   Clinical pharmacists  care for patients in all  health care  settings, but the clinical pharmacy movement initially began inside  hospitals  and  clinics . Clinical pharmacists often collaborate with  physicians  and other healthcare professionals to improve pharmaceutical care. Clinical pharmacists are now an integral part of the interdisciplinary approach to patient care. They often participate in patient care rounds for drug product selection. In the UK clinical pharmacists can also prescribe some medications for patients on the NHS or privately, after completing a non-medical prescribers course to become an Independent Prescriber. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12229", "text": "The clinical pharmacist's role involves creating a comprehensive drug therapy plan for patient-specific problems, identifying goals of therapy, and reviewing all prescribed medications prior to dispensing and administration to the patient. The review process often involves an evaluation of the appropriateness of drug therapy (e.g., drug choice, dose, route, frequency, and duration of therapy) and its efficacy. Research shows that pharmacist led strategies reduce errors related to medication use. [ 22 ]   The pharmacist must also consider potential drug interactions, adverse drug reactions, and patient drug allergies while they design and initiate a drug therapy plan. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12230", "text": "Since the emergence of modern clinical pharmacy, ambulatory care pharmacy practice has emerged as a unique pharmacy practice setting. Ambulatory care pharmacy is based primarily on pharmacotherapy services that a pharmacist provides in a clinic. Pharmacists in this setting often do not dispense drugs, but rather see patients in-office visits to manage chronic disease states."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12231", "text": "In the U.S. federal health care system (including the VA, the Indian Health Service, and NIH) ambulatory care pharmacists are given full independent prescribing authority. In some states, such as  North Carolina  and  New Mexico , these pharmacist clinicians are given collaborative prescriptive and diagnostic authority. [ 24 ]  In 2011 the board of Pharmaceutical Specialties approved ambulatory care pharmacy practice as a separate board certification. The official designation for pharmacists who pass the ambulatory care pharmacy specialty certification exam will be Board Certified Ambulatory Care Pharmacist and these pharmacists will carry the initials BCACP. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12232", "text": "Compounding involves preparing drugs in forms that are different from the generic prescription standard. This may include altering the strength, ingredients, or dosage form. [ 26 ]  Compounding is a way to create custom drugs for patients who may not be able to take the medication in its standard form, such as due to an allergy or difficulty swallowing. Compounding is necessary for these patients to still be able to properly get the prescriptions they need."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12233", "text": "One area of compounding is preparing drugs in new dosage forms. For example, if a drug manufacturer only provides a drug as a tablet, a compounding pharmacist might make a medicated  lollipop  that contains the drug. Patients who have difficulty swallowing the tablet may prefer to suck the medicated lollipop instead."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12234", "text": "Another form of compounding is by mixing different strengths (g, mg, mcg) of capsules or tablets to yield the desired amount of medication indicated by the  physician ,  physician assistant ,  nurse practitioner , or  clinical pharmacist practitioner . This form of compounding is found at community or hospital pharmacies or in-home administration therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12235", "text": "Compounding pharmacies specialize in compounding, although many also dispense the same non-compounded drugs that patients can obtain from community pharmacies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12236", "text": "Consultant pharmacy practice focuses more on medication regimen review (i.e. \"cognitive services\") than on actual dispensing of drugs. Consultant pharmacists most typically work in  nursing homes , but are increasingly branching into other institutions and non-institutional settings. [ 27 ]  Traditionally [ where? ]  consultant pharmacists were usually independent business owners, though in the United States many now work for a large pharmacy management company such as  Omnicare ,  Kindred Healthcare  or  PharMerica . This trend may be gradually reversing [ citation needed ]  as consultant pharmacists begin to work directly with patients, primarily because many elderly people are now taking numerous medications but continue to live outside of institutional settings. Some community pharmacies employ consultant pharmacists and/or provide consulting services."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12237", "text": "The main principle of consultant pharmacy is developed by Hepler and Strand in 1990. [ 28 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12238", "text": "Veterinary pharmacies, sometimes called  animal pharmacies , may fall in the category of hospital pharmacy, retail pharmacy or mail-order pharmacy. Veterinary pharmacies stock different varieties and different strengths of medications to fulfill the pharmaceutical needs of animals.  Because the needs of animals, as well as the regulations on  veterinary medicine , are often very different from those related to people, in some jurisdictions veterinary pharmacy may be  kept separate from regular pharmacies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12239", "text": "Nuclear pharmacy focuses on preparing radioactive materials for diagnostic tests and for treating certain diseases. Nuclear pharmacists undergo additional training specific to handling radioactive materials, and unlike in community and hospital pharmacies, nuclear pharmacists typically do not interact directly with patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12240", "text": "Military pharmacy is a different working environment to civilian practise because military pharmacy technicians perform duties such as evaluating medication orders, preparing medication orders, and dispensing medications. This would be illegal in civilian pharmacies because these duties are required to be performed by a licensed registered pharmacist. [ 30 ]  In the US military, state laws that prevent technicians from counseling patients or doing the final medication check prior to dispensing to patients (rather than a pharmacist solely responsible for these duties) do not apply."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12241", "text": "Pharmacy informatics is the combination of pharmacy practice science and applied information science. [ 31 ]  Pharmacy informaticists work in many practice areas of pharmacy, however, they may also work in information technology departments or for  healthcare information technology  vendor companies.  As a practice area and specialist domain, pharmacy informatics is growing quickly to meet the needs of major national and international patient information projects and health system interoperability goals. Pharmacists in this area are trained to participate in medication management system development, deployment, and optimization."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12242", "text": "Specialty pharmacies supply high-cost injectable, oral, infused, or inhaled medications that are used for chronic and complex disease states such as cancer, hepatitis, and rheumatoid arthritis. [ 32 ]  Unlike a traditional community pharmacy where prescriptions for any common medication can be brought in and filled, specialty pharmacies carry novel medications that need to be properly stored, administered, carefully monitored, and clinically managed. [ 33 ]  In addition to supplying these drugs, specialty pharmacies also provide lab monitoring, adherence counseling, and assist patients with cost-containment strategies needed to obtain their expensive specialty drugs. [ 34 ]  In the US, it is currently the fastest-growing sector of the pharmaceutical industry with 19 of 28 newly FDA approved medications in 2013 being specialty drugs. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12243", "text": "Due to the demand for clinicians who can properly manage these specific patient populations, the Specialty Pharmacy Certification Board has developed a new certification exam to certify specialty pharmacists. Along with the 100 questions computerized multiple-choice exam, pharmacists must also complete 3,000 hours of specialty pharmacy practice within the past three years as well as 30 hours of specialty pharmacist continuing education within the past two years. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12244", "text": "The pharmaceutical sciences are a group of  interdisciplinary  areas of study concerned with the  design ,  manufacturing ,  action ,  delivery , and  classification  of  drugs . They apply knowledge from  chemistry  ( inorganic ,  physical ,  biochemical  and  analytical ),  biology  ( anatomy ,  physiology ,  biochemistry ,  cell biology , and  molecular biology ),  epidemiology ,  statistics ,  chemometrics ,  mathematics ,  physics , and  chemical engineering . [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12245", "text": "The pharmaceutical sciences are further subdivided into several specific  specialties , with four main branches:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12246", "text": "As new discoveries advance and extend the pharmaceutical sciences, subspecialties continue to be added to this list. Importantly, as  knowledge  advances, boundaries between these specialty areas of pharmaceutical sciences are beginning to blur. Many fundamental concepts are common to all pharmaceutical sciences. These shared fundamental concepts further the understanding of their applicability to all aspects of  pharmaceutical research  and  drug therapy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12247", "text": "Pharmacocybernetics  (also known as pharma-cybernetics, cybernetic pharmacy, and cyber pharmacy) is an emerging field that describes the science of supporting drugs and medications use through the application and evaluation of informatics and internet technologies, so as to improve the  pharmaceutical care  of patients. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12248", "text": "The word  pharmacy  is derived from  Old French   farmacie  \"substance, such as a food or in the form of a medicine which has a laxative effect\" from  Medieval Latin   pharmacia  from  Greek   pharmakeia  ( Ancient Greek :  \u03c6\u03b1\u03c1\u03bc\u03b1\u03ba\u03b5\u03af\u03b1 ) \"a medicine\", which itself derives from  pharmakon  ( \u03c6\u03ac\u03c1\u03bc\u03b1\u03ba\u03bf\u03bd ), meaning \"drug,  poison ,  spell \" [ 44 ] [ 45 ] [ a ]  (which is etymologically related to  pharmakos )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12249", "text": "Separation of prescribing and dispensing, also called dispensing separation, is a practice in  medicine  and pharmacy in which the  physician  who provides a  medical prescription  is independent from the  pharmacist  who provides the  prescription drug ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12250", "text": "In the  Western world  there are centuries of tradition for separating pharmacists from physicians. In Asian countries, it is traditional for physicians to also provide drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12251", "text": "In contemporary time researchers and health policy analysts have more deeply considered these traditions and their effects. Advocates for separation and advocates for combining make similar claims for each of their conflicting perspectives, saying that separating or combining reduces  conflict of interest in the healthcare industry ,  unnecessary health care , and lowers costs, while the opposite causes those things. Research in various places reports mixed outcomes in different circumstances."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12252", "text": "In 2022 the  Organisation for Economic Co-operation and Development  proposed that pharmaceutical companies should be required to collect and destroy unused or expired medicines that they have put on the market in order to reduce public health risks around the misuse of medicines obtained from waste bins, the development of antimicrobial resistant bacteria from the discharge of antibiotics into environmental systems and \"economic losses\" from wasted healthcare resources.  Potentially harmful concentrations of pharmaceutical waste has been detected  in more than a quarter of water samples taken from 258 rivers around the world.  OECD recommend that medicines should be collected separately from household waste and that  \"marketplaces and redistribution platforms for unused close-to-expiry-date medicines\" should be set up.  Such extended producer responsibility schemes are already running in France, Spain and Portugal. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12253", "text": "In the coming decades, pharmacists are expected to become more integral within the  health care system . Rather than simply dispensing medication, pharmacists are increasingly expected to be compensated for their patient care skills. [ 48 ]  In particular,  Medication Therapy Management  (MTM) includes the clinical services that pharmacists can provide for their patients.  Such services include a thorough analysis of all medication ( prescription , non-prescription, and herbals) currently being taken by an individual.  The result is a reconciliation of medication and patient education resulting in increased patient health outcomes and decreased costs to the health care system. [ 49 ] [ unreliable source? ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12254", "text": "This shift has already commenced in some countries; for instance, pharmacists in  Australia  receive remuneration from the  Australian Government  for conducting comprehensive Home Medicines Reviews. In Canada, pharmacists in certain provinces have limited prescribing rights (as in Alberta and British Columbia) or are remunerated by their provincial government for expanded services such as medications reviews (Medschecks in Ontario). In the United Kingdom, pharmacists who undertake additional training are obtaining prescribing rights and this is because of  pharmacy education . They are also being paid for by the government for  medicine use reviews . In Scotland, the pharmacist can write prescriptions for Scottish registered patients of their regular medications, for the majority of drugs, except for controlled drugs, when the patient is unable to see their doctor, as could happen if they are away from home or the doctor is unavailable. In the United States, pharmaceutical care or  clinical pharmacy  has had an evolving influence on the practice of pharmacy. [ 50 ]  Moreover, the  Doctor of Pharmacy  (Pharm. D.) degree is now required before entering practice and some pharmacists now complete one or two years of residency or fellowship training following graduation.  In addition,  consultant pharmacists , who traditionally operated primarily in  nursing homes , are now expanding into direct consultation with patients, under the banner of \"senior care pharmacy\". [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12255", "text": "In addition to patient care, pharmacies will be a focal point for medical adherence initiatives. There is enough evidence to show that integrated pharmacy based initiatives significantly impact adherence for chronic patients. For example, a study published in NIH shows \"pharmacy based interventions improved patients' medication adherence rates by 2.1 percent and increased physicians' initiation rates by 38 percent, compared to the control group\". [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12256", "text": "The  symbols  most commonly associated with pharmacy are the  mortar and pestle  (North America) and the \u211e ( medical prescription ) character, which is often written as \"Rx\" in typed text; the green  Greek cross  in  France ,  Argentina , the  United Kingdom ,  Belgium ,  Ireland ,  Italy ,  Spain , and  India ; the  Bowl of Hygieia  (only) often used in the  Netherlands  but may be seen combined with other symbols elsewhere. Other common symbols include  conical measures , and (in the US)  caduceuses , in their  logos .  A red stylized letter A in used  Germany  and  Austria  (from  Apotheke , the  German  word for pharmacy, from the same  Greek  root as the  English  word \" apothecary \"). The  show globe  was used in the US until the early 20th century; the  Gaper  in the Netherlands is increasingly rare."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12257", "text": "A  pharmacist , also known as a  chemist  in  Commonwealth English , is a  healthcare professional  who is knowledgeable about preparation, mechanism of action, clinical usage and legislation of  medications  in order to dispense them safely to the public and to provide consultancy services. [ 1 ] [ 2 ]  A pharmacist also often serves as a  primary care  provider in the community and offers services, such as health screenings and immunizations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12258", "text": "Pharmacists undergo university or graduate-level education to understand the biochemical mechanisms and actions of drugs, drug uses, therapeutic roles, side effects, potential  drug interactions , and monitoring parameters. This is mated to  anatomy ,  physiology , and  pathophysiology . Pharmacists interpret and communicate this specialized knowledge to patients,  physicians , and other health care providers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12259", "text": "Among other licensing requirements, different countries require pharmacists to hold either a  Bachelor of Pharmacy ,  Master of Pharmacy , or a  Doctor of Pharmacy  degree."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12260", "text": "The most common pharmacist positions are that of a  community pharmacist  (also referred to as a  retail pharmacist ,  first-line pharmacist  or  dispensing chemist ), or a  hospital pharmacist , where they instruct and counsel on the proper use and adverse effects of medically prescribed drugs and medicines. [ 3 ] [ 4 ]  In most countries, the profession is subject to professional regulation. Depending on the legal  scope of practice , pharmacists may contribute to prescribing (also referred to as \" pharmacist prescribers \") and administering certain medications (e.g., immunizations) in some jurisdictions. Pharmacists may also practice in a variety of other settings, including industry, wholesaling, research, academia, formulary management, military, and government."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12261", "text": "Historically, the fundamental role of pharmacists as a healthcare practitioner was to check and distribute drugs to doctors for medication that had been prescribed to patients. In more modern times, pharmacists advise patients and health care providers on the selection, dosages, interactions, and side effects of medications, and act as a  learned intermediary  between a prescriber and a patient. Pharmacists monitor the health and progress of patients to ensure the safe and effective use of medication. Pharmacists may practice  compounding ; however, many medicines are now produced by pharmaceutical companies in a standard dosage and drug delivery form. In some jurisdictions, pharmacists have  prescriptive authority  to either independently prescribe under their own authority or in collaboration with a  primary care physician  through an agreed upon protocol called a  collaborative practice agreement . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12262", "text": "Increased numbers of  drug therapies , aging but more knowledgeable and demanding populations, and deficiencies in other areas of the health care system seem to be driving increased demand for the clinical counseling skills of the pharmacist. [ 1 ]  One of the most important roles that pharmacists are currently taking on is one of pharmaceutical care. [ 6 ]  Pharmaceutical care involves taking direct responsibility for patients and their disease states, medications, and management of each to improve outcomes. Pharmaceutical care has many benefits that may include but are not limited to: decreased  medication errors ; increased  patient compliance  in medication regimen; better  chronic disease  state management, including hypertension and other cardiovascular disease risk factors; [ 7 ]  strong pharmacist\u2013patient relationship; and decreased long-term costs of medical care."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12263", "text": "Pharmacists are often the first point-of-contact for patients with health inquiries. Thus pharmacists have a significant role in assessing medication management in patients, and in  referring  patients to physicians. These roles may include, but are not limited to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12264", "text": "The role of pharmacy education, pharmacist licensing, and  continuing education  vary from country to country and between regions/localities within countries. In most countries, pharmacists must obtain a university degree at a  pharmacy school  or related institution, and/or satisfy other national/local credentialing requirements. In many contexts, students must first complete pre-professional (undergraduate) coursework, followed by about four years of professional academic studies to obtain a degree in pharmacy (such as  Doctorate of Pharmacy ). In the European Union, pharmacists are required to hold a Masters of Pharmacy, which allows them to practice in any other E.U. country, pending professional examinations and language tests in the country in which they want to practice. Pharmacists are educated in  pharmacology ,  pharmacognosy ,  chemistry ,  organic chemistry ,  biochemistry ,  pharmaceutical chemistry ,  microbiology ,  pharmacy practice  (including  drug interactions , medicine monitoring, medication management),  pharmaceutics , pharmacy law, pathophysiology,  physiology ,  anatomy , drug delivery, pharmaceutical care,  nephrology ,  hepatology , and compounding of medications. Additional curriculum may cover diagnosis with emphasis on laboratory tests, disease state management, therapeutics and prescribing (selecting the most appropriate medication for a given patient)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12265", "text": "Upon graduation, pharmacists are licensed, either nationally or regionally, to dispense medication of various types in the areas they have trained for."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12266", "text": "Some may undergo further specialized training, such as in cardiology or oncology or long-term care. Specialties include: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12267", "text": "The Ministry of Education and Ministry of Health oversee pharmacy school accreditation in  Armenia . Pharmacists are expected to have competency in the  WHO Model List of Essential Medicines  (EML), the use of Standard Treatment Guidelines, drug information, clinical pharmacy, and medicine supply management. There are currently no laws requiring pharmacists to be registered, but all pharmacies must have a license to conduct business. According to a  World Health Organization  (WHO) report from 2010, there are 0.53 licensed pharmacists and 7.82 licensed pharmacies per 10,000 people in Armenia. Pharmacists are able to substitute for generic equivalents at point of dispensing. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12268", "text": "The Australian Pharmacy Council is the independent accreditation agency for Australian pharmacists. [ 12 ]  The accreditation standards for Australian pharmacy degrees include compulsory clinical placements. [ 13 ]  with an emphasis on encouraging rural experiences to develop a rural workforce. [ 14 ] [ 15 ]  It conducts a written examination on behalf of the Pharmacy Board of Australia towards eligibility for registration. The Pharmacy Board of Australia conducts an oral examination at the end of the intern year as the last hurdle prior to registration.  The Pharmaceutical Society of Australia provides continuing education programs for pharmacists. The number of full-time equivalent pharmacists working in Australia over the past decade has remained stable. [ 16 ]  Pharmacy practice is described by the practice standards  [ 17 ]  and guidelines including those from the Pharmaceutical Society of Australia. [ 18 ] [ 19 ] [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12269", "text": "The Australian Pharmacy Council is developing accreditation standards for pharmacists to prescribe and for pharmacists to work in aged care.  The aged care accreditation standards are being developed in preparation for pharmacists working in residential aged care settings to ensure that they are adequately prepared. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12270", "text": "There is a shortage of pharmacists at present leaving many jobs unfilled. Despite many pharmacists leaving the profession, pharmacists remain optimistic about their profession. [ 23 ]  Contract and casual work is becoming more common. A contract pharmacist is self-employed and often called a locum; these pharmacists may be hired for one shift or for a longer period of time. The number of pharmacists has stayed stable over a number of years. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12271", "text": "The  Canadian Pharmacists Association  (CPhA) is the national professional organization for pharmacists in  Canada . Specific requirements for practice vary across provinces, but generally include a bachelor's (BSc Pharm) or  Doctor of Pharmacy (PharmD)  degree from one of  10 Canadian universities  offering a pharmacy program, successful completion of a national board examination through the  Pharmacy Examining Board of Canada  (PEBC) (Quebec being the exception), practical experience through an apprenticeship/internship program, and fluency in French or English. [ 24 ]  International pharmacy graduates can begin their journey of becoming licensed to practice in Canada by enrolling with the National Association of Pharmacy Regulatory Authorities (NAPRA) Pharmacists' Gateway Canada. [ 24 ] [ 25 ]  The vast majority (~70%) of Canada's licensed pharmacists work in community pharmacies, another 15% work in hospital, and the remainder work in other settings such as industry, government, or universities. [ 26 ] [ 27 ] [ 28 ]  Pharmacists' scope of practice varies widely among the 13 provinces and territories and continues to evolve with time. [ 29 ] [ 30 ]   As a result of pharmacists' expanding scope and knowledge application, there has been a purposeful effort to transition the professional programs in Canadian pharmacy schools to offer doctors of pharmacy over baccalaureate curriculums to ensure graduates have the most up to date level of training to match the increasing practice requirements. [ 31 ] [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12272", "text": "The pharmacist qualification in the  European Union  is regulated by the  Directive 2005/36/EC , [ 33 ]  where Section 7 Article 44(2) mandates at least five years of training including \"four years of full-time theoretical and practical training\" and \"six-month  traineeship  in a pharmacy which is open to the public or in a hospital, under the supervision of that hospital's pharmaceutical department\". The training of pharmacist must include at least: \"Plant and animal  biology ,  Physics , General and  inorganic chemistry ,  Organic chemistry ,  Analytical chemistry ,  Pharmaceutical chemistry , including analysis of medicinal products, General and applied  biochemistry  (medical),  Anatomy  and  physiology ;  medical terminology ,  Microbiology ,  Pharmacology  and  pharmacotherapy ,  Pharmaceutical technology ,  Toxicology ,  Pharmacognosy ,  Legislation  and, where appropriate,  professional ethics \", which can be adapted to \"scientific and technical  progress \" according to procedure in Directive 2005/36/EC. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12273", "text": "In Germany, the education and training is divided into three sections, each ending with a state examination:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12274", "text": "After the third state examination a person must become licensed as an RPh (\"registered pharmacist\") for a licence to practice pharmacy. \nToday, many pharmacists work as employees in public pharmacies. They will be paid according to the labour agreement of  Adexa  and employer associations. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12275", "text": "Polish pharmacists have to complete a  5 + 1 \u2044 2 -year Master of Pharmacy Programme at medical university and obtain the right to practice as a pharmacist in Poland from District Pharmaceutical Council. The Programme includes 6 months of pharmacy training. The Polish name for the Master of Pharmacy Degree (M.Pharm.) is  magister farmacji  (mgr farm). Not only pharmacists, but also pharmaceutical technicians are allowed to dispense prescription medicines, except for narcotics, psychotropics and very potent medicines. Pharmacists approve prescriptions fulfilled by pharmaceutical technicians subsequently. Pharmaceutical technicians have to complete 2 years of post-secondary occupational school and 2 years of pharmacy training afterwards. Pharmacists are eligible to prescribe medicines in exceptional circumstances. All Polish pharmacies are obliged to produce compound medicines. Most pharmacists in Poland are pharmacy managers and are responsible for pharmacy marketing in addition to traditional activities. To become a pharmacy manager in Poland, a pharmacist is expected to have at least 5 years of professional experience. All pharmacists in Poland have to maintain an adequate knowledge level by participating in various university- and industry-based courses and arrangements or by undergoing postgraduate specialization. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12276", "text": "In  Sweden , the national board of health and welfare regulates the practice of all legislated health care professionals, and is also responsible for registration of pharmacists in the country. The education to become a licensed pharmacist is regulated by the  European Union , and states that minimum educational requirements are five years of university studies in a pharmacy program, of which six months must be a pharmacy internship. To be admitted to pharmacy studies, students must complete a minimum of three years of gymnasium, similar to high school (school for about 15\u201320-year-old students) program in natural science after elementary school (6\u201316-year-olds). Only three universities in the whole of Sweden offer a pharmacy education,  Uppsala University , where the Faculty of Pharmacy is located, the  University of Gothenburg , and  Ume\u00e5 University . In Sweden, pharmacists are called  Apotekare . At pharmacies in Sweden, pharmacists work together with another class of legislated health care professionals called  Receptarier , in English so-called  prescriptionists , who have completed studies equal to a Bachelor of Science in pharmacy, i.e., three years of university. Prescriptionists also have dispensing rights in Sweden, Norway, Finland and Iceland. The majority of the staff in a pharmacy are  Apotekstekniker  or \"pharmacy technicians\" with a three -semester education at a vocational college. [ citation needed ]  Pharmacy technicians do not have dispensing rights in Sweden but are allowed to advise on and sell over-the-counter medicines."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12277", "text": "In ancient Japan, the men who fulfilled roles similar to pharmacists were respected. The place of pharmacists in society was settled in the  Taih\u014d Code  (701) and re-stated in the  Y\u014dr\u014d Code  (718). Ranked positions in the pre- Heian  Imperial court were established; and this organizational structure remained largely intact until the  Meiji Restoration  (1868). In this highly stable hierarchy, the pharmacists \u2014 and even  pharmacist assistants  \u2014 were assigned status superior to all others in health-related fields such as physicians and acupuncturists. In the Imperial household, the pharmacist was even ranked above the two personal physicians of the Emperor. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12278", "text": "As of 1997, 46 universities of pharmacy in Japan graduated about 8000 students annually. [ 36 ]  Contemporary practice of clinical pharmacists in Japan (as evaluated in September 2000) focuses on dispensing of drugs, consultation with patients, supplying drug information, advising on prescription changes and amending prescriptions. These practices have been linked to decreases in the average number of drugs in prescriptions, drug costs and incidence of  adverse drug events . [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12279", "text": "Training to become a registered pharmacist in Nigeria involves a five-year course after six years of secondary/high school or four years after eight years of secondary/high school (i.e. after 2 years of Advanced-level studies in  accredited Universities). The degree awarded by most pharmacy schools is a  Bachelor of Pharmacy Degree (B.Pharm.) However, in the near future, [ when? ]  all schools will offer a 6-year first Degree course leading to the award of a Pharm.D (Doctor of Pharmacy Degree). The  University of Benin  has started the Pharm.D programme with other pharmacy schools planning to start soon. The Pharmacy Degree in Nigeria is unclassified i.e. awarded without first class, second class upper, etc., however graduates could be awarded Pass with Distinctions in specific fields such as Pharmaceutics, Pharmacology, medicinal chemistry etc. Pharmacy Graduates are required to undergo 1 year of Tutelage under the supervision of an already Registered Pharmacist(a preceptor) in a recognized and designated Institution before they can become Registered Pharmacists. The Profession is Regulated by a Government Statutory body called the  Pharmacists Council of Nigeria . The West African Post Graduate College of Pharmacy runs post-registration courses on advanced-level practice in various fields of pharmacy. It is a college jointly  funded by a number of Countries in the West Africa sub-region. There are thousands of Nigerian-trained pharmacists registered and practicing in countries such as the US, the UK, Canada etc., due to the relatively poor public sector salaries in Nigeria. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12280", "text": "In  Pakistan , the Pharm.D. (Doctor of Pharmacy) degree is a graduate-level professional doctorate degree. Twenty-one universities are registered with the  Pharmacy Council of Pakistan  for imparting Pharmacy courses. In 2004 the  Higher Education Commission  of Pakistan and the Pharmacy Council of Pakistan revised the syllabus and changed the 4-year B.Pharmacy (Bachelor of Pharmacy) Program to a 5-year Pharm.D. (Doctor of Pharmacy) program. All 21 universities have started the 5-year Pharm.D Program. In 2011 the Pharmacy Council of Pakistan approved the awarding of a Doctor of Pharmacy degree, a five-year programme at the Department of Pharmacy,  University of Peshawar . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12281", "text": "In Switzerland, the federal office of public health regulates pharmacy practice. Four Swiss universities offer a major in pharmaceutical studies, the  University of Basel , the  University of Geneva , the  University of Lausanne  and the  ETH Zurich . To major in pharmaceutical studies takes at least five years. Students spend their last year as interns in a pharmacy combined with courses at the university, with focus on the validation of prescriptions and the manufacturing of pharmaceutical formulations. Since all public health professions are regulated by the government it is also necessary to acquire a federal diploma in order to work in a pharmacy. It is not unusual for pharmaceutical studies majors to work in other fields such as the pharmaceutical industry or in hospitals. Pharmacists work alongside  pharma assistants , an apprenticeship that takes three years to complete. Pharmacists can further specialize in various fields; this is organized by  PharmaSuisse , the pharmacists' association of Switzerland. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12282", "text": "In  Tanzania , pharmacy practice is regulated by the national Pharmacy Board, which is also responsible for registration of pharmacists in the country. By international standards, the density of pharmacists is very low, with a mean of 0.18 per 10,000 population. The majority of pharmacists are found in urban areas, with some underserved regions having only 2 pharmacists per region. According to 2007\u20132009 data, the largest group of pharmacists was employed in the public sector (44%). Those working in private retail pharmacies were 23%, and the rest were mostly working for private wholesalers, pharmaceutical manufacturers, in academia/teaching, or with faith-based or non-governmental facilities. The salaries of pharmacists varied significantly depending on the place of work. Those who worked in the academia were the highest paid followed by those who worked in the multilateral non-governmental organizations. The public sector including public retail pharmacies and faith based organizations paid much less. The  Ministry of Health  salary scale for medical doctors was considerably higher than that of pharmacists despite having a difference of only one year of training. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12283", "text": "In  Trinidad and Tobago , pharmacy practice is regulated by the Pharmacy Board of Trinidad and Tobago, which is responsible for the registration of pharmacists in the twin islands.  The  University of the West Indies  in St. Augustine offers a 4-year Bachelor of Science in Pharmacy as the sole practicing degree of pharmacy.  Graduates undertake a 6-month internship, known as pre-registration, under the supervision of a registered pharmacist, at a pharmacy of their choosing, whether community or institutional.  After completion of the required pre-registration period, the graduate can then apply to the Pharmacy Board to become a registered pharmacist.  After working 1 calendar year as a registered pharmacist, the individual can become a registered, responsible pharmacist.  Being a registered, responsible pharmacist allows the individual to license a pharmacy and be a pharmacist-in-charge."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12284", "text": "In  British English  (and to some extent  Australian English ), the professional title known as \"pharmacist\" is also known as  \"dispensing chemist\"  or, more commonly,  \"chemist\" . A dispensing chemist usually operates from a pharmacy or chemist's shop, and is allowed to fulfil  medical prescriptions  and sell  over-the-counter drugs  and other health-related goods. Pharmacists can undertake additional training to allow them to prescribe medicines for specific conditions. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12285", "text": "In the United Kingdom, most pharmacists working in the  National Health Service  practice in  hospital pharmacy  or  community pharmacy . The  Royal Commission on the National Health Service  in 1979 reported that there were nearly 3,000 pharmacists employed in the hospital and community health service in the UK at that time.  They were enthusiastic about the idea that pharmacists might develop their role of giving advice to the public. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12286", "text": "The new professional role for pharmacist as prescriber has been recognized in the UK since May 2006, called the \" Pharmacist Independent Prescriber \". Once qualified, a pharmacist independent prescriber can prescribe any licensed medicine for any medical condition within their competence. This includes controlled drugs except schedule 1 and prescribing certain drugs for the treatment of addiction ( cocaine ,  diamorphine  and  dipipanone ). [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12287", "text": "Pharmacists,  pharmacy technicians  and pharmacy premises in the  United Kingdom  are regulated by the  General Pharmaceutical Council (GPhC)  for  England ,  Scotland  and  Wales  and by the  Pharmaceutical Society of Northern Ireland  for  Northern Ireland . The role of regulatory and professional body on the  mainland  was previously carried out by the  Royal Pharmaceutical Society of Great Britain , which remained as a professional body after handing over the regulatory role to the GPhC in 2010. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12288", "text": "The following criteria must be met for qualification as a pharmacist in the United Kingdom (the Northern Irish body and the GPhC operate separately but have broadly similar registration requirements): [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12289", "text": "In 2014 the United States Bureau of Labor Statistics revealed that there were 297,100 American pharmacist jobs. By 2024 that number is projected to grow by 3%. [ 44 ]  The majority (65%) of those pharmacists work in retail settings, mostly as salaried employees but some as self-employed owners. About 22% work in hospitals, and the rest mainly in mail-order or  Internet pharmacies , pharmaceutical wholesalers, practices of physicians, and the Federal Government. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12290", "text": "All graduating pharmacists must now obtain the  Doctor of Pharmacy  (Pharm.D.) degree before they are eligible to sit for the North American Pharmacist Licensure Examination ( NAPLEX ) to enter into pharmacy practice. [ 45 ]  In addition, pharmacists are subject to state-level jurisprudence exams in order to practice from state to state. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12291", "text": "The  Accreditation Council for Pharmacy Education  (ACPE) has operated since 1932 as the accrediting body for schools of pharmacy in the United States. [ 47 ]  The mission of ACPE is \"To assure and advance excellence in education for the profession of pharmacy\". [ 47 ]   ACPE is recognized for the accreditation of professional degree programs by the  United States Department of Education  (USDE) and the  Council for Higher Education Accreditation  (CHEA). [ 48 ]  Since 1975, ACPE has also been the accrediting body for continuing pharmacy education. The ACPE board of directors are appointed by the  American Association of Colleges of Pharmacy  (AACP), the  American Pharmacists Association  (APhA), the  National Association of Boards of Pharmacy  (NABP) (three appointments each), and the  American Council on Education  (one appointment). To obtain licensure in the United States, applicants for the North American Pharmacist Licensure Examination (NAPLEX) must graduate from an ACPE accredited school of pharmacy. ACPE publishes standards that schools of pharmacy must comply with to gain accreditation. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12292", "text": "A  Pharmacy school  pursuing accreditation must first apply and be granted Pre-candidate status. [ 48 ]  These schools have met all the requirements for accreditation, but have not yet enrolled any students. This status indicates that the school of pharmacy has developed its program in accordance with the ACPE standards and guidelines. Once a school has enrolled students, but has not yet had a graduating class, they may be granted Candidate status. The expectations of a Candidate program are that they continue to mature in accordance with stated plans. The graduates of a Candidate program are the same as those of fully accredited programs. Full accreditation is granted to a program once they have demonstrated they comply with the standards set forth by ACPE."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12293", "text": "The customary review cycle for established accredited programs is six years, whereas for programs achieving their initial accreditation this cycle is two years. These are comprehensive on-site evaluations of the programs. Additional evaluations may be conducted at the discretion of ACPE in the interim between comprehensive evaluations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12294", "text": "Acceptance into a doctorate of pharmacy program depends upon completing specific prerequisites or obtaining a transferable bachelor's degree.  Pharmacy school  is four years of graduate school (accelerated Pharmacy Schools go January to January and are only 3 years), which include at least one year of practical experience. Graduates receive a Doctorate of Pharmacy ( PharmD ) upon graduation. Most schools require students to take a Pharmacy College Admissions Test  PCAT  and complete 90 credit hours of university coursework in the sciences, mathematics, composition, and humanities before entry into the  PharmD  program. Due to the large admittance requirements and highly competitive nature of the field, most pharmacy students complete a bachelor's degree before entry to pharmacy school."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12295", "text": "Possible prerequisites:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12296", "text": "Besides taking classes, additional requirements before graduating may include a certain number of hours for community service, e.g., working in hospitals, clinics, and retail."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12297", "text": "Estimated timeline: 4 years undergraduate + 4 years doctorate + 1\u20132 years residency + 1\u20133 years fellowship = 8\u201313 years"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12298", "text": "A doctorate of pharmacy (except non-traditional, i.e. transferring a license from another country) is the only degree accepted by the National Associate of Boards of Pharmacy  NABP  to be eligible to \"sit\" for the North American Pharmacist Licensure Examination ( NAPLEX ). Previously the United States had a 5-year bachelor's degree in pharmacy. For BS Pharmacy graduates currently licensed in US, there are 10 Universities offering non-traditional doctorate degree programs via part-time, weekend or on-line programs. These are programs fully accredited by Accreditation Council for Pharmacy Education ( ACPE ) but only available to current BS Pharmacy graduates with a license to practice pharmacy. Some institutions still offer 6 year accelerated  PharmD  programs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12299", "text": "The current Pharm.D. degree curriculum is considerably different from that of the prior BS in pharmacy. It now includes extensive didactic clinical preparation, a full year of hands-on practice experience in a wider array of healthcare settings, and a greater emphasis on clinical pharmacy practice pertaining to pharmacotherapy optimization. Legal requirements in the US to becoming a pharmacist include: graduating from an accredited  PharmD  program, conducting a specified number of internship hours under a licensed pharmacist (i.e. 1800 hours in some states), passing the  NAPLEX , and passing a Multi-state Pharmacy Jurisprudence Exam  MPJE .  Arkansas, California, and Virginia have their own exams instead of the MPJE;  in those states, pharmacists must pass the Arkansas Jurisprudence Exam, the California Jurisprudence Exam, or the Virginia Pharmacy Law Exam. [ 50 ] [ 51 ] [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12300", "text": "Residency is an option for post-graduates that is typically 1\u20132 years in length. A residency gives licensed pharmacists decades of clinical experience in an extremely condensed timeframe of only a few short years. In order for new graduates to remain competitive, employers generally favor residency trained applicants for clinical positions. The profession is moving toward resident-trained pharmacists who wish to provide direct patient care clinical services. In 1990, the American Association of Colleges of Pharmacy ( AACP ) required the new professional degree. Graduates from a  PharmD  program may also elect to do a fellowship that is geared toward research. Fellowships can varying in length but last 1\u20133 years depending on the program and usually require 1 year of residency at minimum."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12301", "text": "American pharmacists can become certified in recognized specialty practice areas by passing an examination administered by one of several credentialing boards."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12302", "text": "As of 2016, all 50 states and the District of Columbia permit pharmacists to provide vaccination services, but specific protocols vary between states. [ 56 ] [ 57 ] [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12303", "text": "All licensed California pharmacists can perform the following:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12304", "text": "The passage of Assembly Bill 1535 (2014) authorizes pharmacists in California to furnish naloxone without a physician's prescription. [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12305", "text": "With the passage of Senate Bill 159 in 2019, pharmacists in California are authorized to furnish  pre-exposure prophylaxis  (PrEP) and  post-exposure prophylaxis  (PEP) to patients without a physician's prescription. [ 62 ]  In order to be eligible to dispense, a pharmacists must first \"complete a training program approved by the\" California State Board of Pharmacy. [ 62 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12306", "text": "California pharmacists can apply for Advanced Practice Pharmacist (APh) licenses from the California State Board of Pharmacy. Senate Bill 493, written by Senator Ed Hernandez, established a section on the Advanced Practice Pharmacist and outlines the definition, scope of practice, qualifications, and regulations of those holding this license. [ 63 ]  An APh can:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12307", "text": "To qualify for an advanced practice pharmacist license in California, the applicant must be in good standing with the State Board of pharmacy, have an active pharmacist license, and fulfill two of three requirements, including certification in their area clinical practice. [ 64 ]  The license must be renewed every 2 years, and the APh applying for renewal must complete 10 hours of continuing education in at least one area relevant to their clinical practice. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12308", "text": "According to a 2010  PharmacyWeek  survey, pharmacists were paid the following average annual salaries, depending on their positions: [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12309", "text": "The  American Pharmacy Journal of Education  in 2014 reported the average salary around $112,160. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12310", "text": "According to the US Bureau of Labor Statistics'  Occupational Outlook Handbook, 2016\u201317 Edition , Median annual wages of wage and salary pharmacists in May 2015 were $121,500. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12311", "text": "In 2020  US News and World Report  noted that the median pharmacist salary was $128,710. The top 25 percent of pharmacist earners made $147,690 that year, while the lowest 25 percent made $112,690. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12312", "text": "School students must take a national exam to enter a university of pharmacy or the pharmacy department of a university of medicine and pharmacy. About 5\u20137% of students can pass the exam. There are 3 aspects to the exam. These are on math, chemistry, and physics or biology. After being trained at the university for 5 years, successful students receive a bachelor's degree in pharmacy. Or they are university pharmacists (university pharmacist to discriminate between college pharmacist or vocational pharmacist in some countries of the world these trainee pharmacists are called pharmacist assistants). An alternative method of obtaining a bachelor's degree is as follows. School pupils study at a college of pharmacy or a vocational school of pharmacy. After attending the school or college they go to work in a pharmacy, and with two years of practice they could take an exam to enter university of pharmacy or the pharmacy department of a university of medicine and pharmacy. This exam is easier than the national one. Passing the exam they continue studying to gain 3-year bachelor's degrees or 4-year bachelor's degrees. This degree is considered equivalent to a 5-year bachelor's degree. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12313", "text": "This article incorporates  public domain material  from websites or documents of the  United States Government ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12314", "text": "An  albarello  (a name of Italian descent meaning \"cell\", plural:  albarelli ) also known as a \"majolica drug jar\" because of the type of tin glaze used is known as  Majolica  (also known as maiolica). [ 1 ] [ 2 ]  This cylindrical storage unit or  maiolica  earthenware jar, is used for a plethora of purposes, most commonly for drug storage as a  medicinal jar . [ 1 ] [ 2 ]  The jar was also used for other purposes such as storing dried fruit, herbs, balms, and  apothecaries'  ointments and dry drugs. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12315", "text": "People usually stored their  albarelli  in buildings with medical purposes, like pharmacies, hospitals, and doctors' offices. [ 4 ] [ 5 ]  Such jars served both functional and decorative purposes in traditional apothecaries and  pharmacies , and represented status and wealth. The jars were generally sealed with a piece of  parchment  or  leather  tied with a piece of cord. Hospitals often used  albarelli  to hold products such as ointments, balms, and different remedies for patients.  [ 3 ]   Albarelli  were also utilized in ways other than its originally intended purpose: they were used to hold perfume, they could function as a form of  d\u00e9cor , and as vases to display flowers. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12316", "text": "According to the Oxford English Dictionary, the Italian word  albarello  means \"a decorated ceramic pharmacy jar of a cylindrical shape with a slight constriction halfway up (first used in 1344 as  alberello ; and then later, in the late 15th century as  albarello ), but the term's exact origin and etymology remains a topic for a debate. [ 6 ]  Some scholars argue that its etymology suggests that it derives either from the post-classical Latin word  albarus  meaning \"white poplar\" or the Classical Latin word  albus  meaning white. [ 6 ]  However, its important to note here that the poplar tree itself is not being compared to the jar, as the Italian usage of the word  albarello  for a white poplar tree came long after the naming of the  albarello  jar. [ 6 ]  The issue has further been muddled because some have claimed that these jars were originally manufactured in wood, even though there is no physical evidence of this in recovered materials and surviving jars. [ 7 ] [ 8 ]  Another possible origin of the term lies in another related Classical Latin word  albaris  (\"whitish\") and another Classical Latin term  albarius  referencing its relation to a whitewashing vessel. [ 6 ] [ 9 ]  Its important to note that both  albaris  and  albarius  are only recorded as adjectives \"of or relating to  stucco \" and therefore, do not have usage in relation to pottery or pottery glazes. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12317", "text": "The origin of this type of pharmacy jar has its roots in the  Middle East  during the time of the Islamic conquests. [ 10 ]  The term  majolica  specifically refers to a type of tin glaze that originated in the Near East along Islamic trade routes, showcasing the strong influence of Islamic material culture. [ 1 ]  The characteristic shape of the  arbarello  also has its roots in the East. [ 11 ]  Additionally, Chinese porcelain and its manufacturing played a significant role in influencing the development and spread of  arbarelli  across Europe. [ 10 ]  The influence from the Islamic empire coupled with the manufacturing of Chinese porcelain made for mass manufacture and subsequent exportation of  albarelli  for several cultures including those in Italy,  China , and Spain, and in turn were re-purposed for differing needs. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12318", "text": "Spanning out of the East from the Islamic empires and China, the  albarelli  were first introduced to Europe in  Syria  and  Spain  and then brought to Italy by Muslim Arab traders, during the height of the Italian Renaissance where its shape and purpose was adopted. [ 11 ] [ 10 ]  By importing majolica from Spain and Syria, Italian artists began producing versions of their own that differed from the traditional Islamic  arbarelli  with the addition of handles to heighten the functionality of the jar and the introduction of new designs including \"a trofei\" (with trophies), \"a foglie\" (leafy designs), and \"a frutti\" (decorated with fruits). [ 1 ] [ 2 ] [ 12 ]  While the styles in both Spain and Italy kept on developing, clear influence could still be linked backed to traditional Chinese and Islamic ceramic designs despite the changes in style and designs. [ 10 ]  Eventually Syrian manufacture of the jars lead to them being described in Italian as \" porcellana domaschina\"  (damascene porcelain), to distinguish that the blue-and-white lusterware were made in  Damascus  and were not authentic Chinese porcelain that had been imported into Europe previously. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12319", "text": "Albarelli  are known for having a cylindrical shape without handles and a thin neck to make them easy to handle and move. [ 1 ] [ 2 ] [ 11 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ]  Albarelli are usually made out of majolica, which has helped historians decipher the history between the  albarelli , due to it being such a resistant and strong material. [ 15 ]  In later forms after it spread throughout Europe, their design included the addition of handles that were adopted by the Italians after the 15th century. [ 17 ]  On average,  albarelli  were recorded to be 7-8 inches in height. [ 11 ]  Instead of having a fitted lid to cover the opening at the top, people would use a fitted paper to lay on top to seal it. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12320", "text": "Spain was introduced to Albarelli by the East, it was adopted quickly. [ 13 ]  They are known to have the same cylindrical shape, with a more narrow opening, and an indented base where artists usually sign their name. Albarelli were also labelled through the symbols on the outside and through parchment paper in the vase. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12321", "text": "The earliest Italian examples were produced in Florence in the 15th century.  Albarelli  were made in  Italy  from the first half of the 15th century through to the late 18th century and beyond. Italian-based  albarelli  are commonly measured to be 7-8 inches in height. [ 11 ] [ 11 ]  Italian  albarelli  adopted its shape from lustreware from Islamic Spain. [ 18 ]  Unlike English  albarelli , Italian-based pots had flat edges on the rims to account for the placement of a paper cover that functioned as a lid. [ 18 ]  There was a lot of Oriental inspiration when making these jars, noticed through the blue and white colors on majority of the pots, also referred to as  alla porcellana,  which means in the form of imported Chinese porcelain, \"a trofei\" meaning with trophies, \"a foglie\" meaning leafy designs, and \"a frutti\" meaning decorated with fruits. [ 2 ] [ 12 ]  Further designs include floral motifs against a white background, to more elaborate designs such as portraits of a  cherub  or  priest , and can include a label describing the contents of the jar. Specific styles of decoration are now associated with various Italian locations, including  Florence ,  Venice ,  Gerace  and  Palermo  in  Sicily ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12322", "text": "Middle Eastern and Islamic Styles"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12323", "text": "Spanish Styles"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12324", "text": "Italian Styles"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12325", "text": "An  auxiliary label  (also called  cautionary and advisory label  or  prescription drug warning label ) is a  label  added on to a dispensed medication package by a  pharmacist  in addition to the usual  prescription  label. These labels are intended to provide supplementary information regarding the safe administration, use, and storage of the medication. [ 1 ]  Auxiliary labels provide information which can augment but not replace verbal counselling from a pharmacist. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12326", "text": "Auxiliary labels became popular during the second half of the nineteenth century. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12327", "text": "In 2013, the first recommendations for auxiliary label usage in the  United States  were published as  USP  Chapter <17>. [ 4 ]  This included a recommendation to limit the use of auxiliary labels to evidence-based labels with critical information, and without pictures unless evidence shows increased efficacy when a picture is used. It is further recommended that labels are placed in a manner obvious to the patient without having to turn or rotate the package. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12328", "text": "Auxiliary labels are small stickers consisting of one or more lines of text intended to enhance patient knowledge, with or without a  pictogram . The directions for use included on the standard prescription label are typically limited to direct administration information, such as how often, when, and how to take the medication. As such, auxiliary labels are used for additional information that is not included in those directions for use printed on the label, or information which cannot fit on the prescription label itself due to limited space. Overall, auxiliary labels contain information intended to promote proper medication adherence through reminders about important information that will be seen anytime the bottle is picked up. [ 5 ]  They should be designed to be as simple as possible, written in plain language, and understandable for people with low health literacy. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12329", "text": "Sometimes auxiliary labels are used not to add additional information to the packaging, but instead to reinforce information with a pictorial representation of the instructions for use. This may consist of a pictoral representation of the frequency of use, time of day to take, the administration route, or other information. [ 7 ]  Picture representations of directions can be useful for patients with low literacy, or who have trouble reading and comprehending text instructions due to age, eyesight, or language barriers. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12330", "text": "As some medications must be stored under specific conditions (such as in original container with dessicant, or refrigerated), auxiliary labels may be used to reinforce these storage requirements to ensure it does not degrade through improper storage. Because some people may have difficulty swallowing medications whole, auxiliary labels may be used to provide advice on solutions, such as whether the medication can be chewed, crushed, or cut. Another use of auxiliary labels is important information on side effects or drug/food interactions. [ 8 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12331", "text": "A 2016 study found that many patients consider side effects to be important information to be included on a prescription package and that auxiliary labels are a good tool to provide this information on the packaging itself (as opposed to a separate information sheet/handout). [ 9 ]  The same study found that patients associated the use of red as a highlight color with information regarding warnings, allergies, or side effects. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12332", "text": "Deciding what auxiliary labels are suitable for a particular prescription requires knowledge of the drug's classification, interactions, and side effects. [ 10 ]  One study of auxiliary label usage found that about 80% of dispensed prescriptions would benefit from at least one auxiliary label to reinforce information, or provide  additional important information aside from the directions for use. [ 6 ]  The most common auxiliary labels on prescriptions include \"May cause drowsiness\" and \"alcohol may intensify the effect of this medication\". [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12333", "text": "There is no standard for how to place auxiliary labels on a prescription, but they should be placed in a manner that they will be visible and intelligible in the normal course of medication usage. [ 6 ]  Auxiliary labels placed on a prescription vial may be placed vertically, horizontally, or on the vial cap, which is called \"interactive placement\". Placement of the label in an interactive manner where the patient must interact with it to open the vial increases the chance the label is noticed and considered by the patient. [ 4 ]  Both horizontal and interactive placement are superior to vertical placement, which is due to the need to rotate the vial to read the information on a vertically placed label. [ 4 ]  One study in 2007 found that 82% of prescriptions had auxiliary labels placed vertically, requiring the bottle to be tilted to read the text. The same study found a wide variation in coloring used on auxiliary labels from different pharmacies, and that between 8-25% of prescriptions filled had no warning labels at all. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12334", "text": "The use of auxiliary labels does not substitute for pharmacist consultation about medications, nor for any supplemental medication guides or handouts recommended or required to be distributed with a drug. Auxiliary labels should only be used to remind or enhance instructions for use or warnings that have already been given by the pharmacist or doctor to the patient verbally. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12335", "text": "Auxiliary labels can commonly be misinterpreted, especially when multi-step or multi-part instructions are present on one label. [ 5 ]  Misinterpretation of auxiliary labels can occur when patients are unable to understand the wording of the label, and thus assume an instruction based on the pictogram or color of the label. [ 5 ]  In addition to misinterpretation, some studies have found that most patients ignore auxiliary labels on prescriptions completely, especially those with low  health literacy . [ 8 ]  This may be due in part to the belief that information presented on the bottle is not important, or due to the manner in which the labels are affixed to the vial. [ 8 ]  When auxiliary labels are used as a reminder to the patient of important information, failure to understand and follow the instructions from auxiliary labels can result in treatment failure or adverse effects. [ 8 ]  The effectiveness of auxiliary labels can vary greatly between different label formats and specific text, with a 2006 survey finding that one common multi-step, complex label (\"Do not take dairy products, antacids, or iron preparations within 1 hour of this medication\") was interpreted correctly only 7.6% of the time. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12336", "text": "The overall effectiveness of auxiliary labels depends on the number of labels affixed, the design of the label, and their positioning on the medication package or vial. [ 13 ]  Simplifying the content and number of auxiliary labels can improve patient comprehension. [ 14 ]  In the United States, many labels are commonly only stocked in English, which can decrease the chance of understanding in areas with significant non-English speaking populations. Only one third of auxiliary labels in the United States are available in languages other than English. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12337", "text": "Common elements considered to increase the chance of effectiveness of an auxiliary label include a single-step instruction, using easy-to-read text (for example, low  Lexile score ), use of clear, simple icons (if present), use of color to represent severity, and clarity of the instruction being represented. [ 15 ]  Font size and style, including boldface or capitalization patterns, can also impact the effectiveness of an auxiliary label. [ 15 ]  The effectiveness of auxiliary labels is also increased when pharmacists explicitly instruct patients on their presence on the package, and explain the importance of each of the warnings being presented using the auxiliary labels. [ 12 ]  It has also been recommended that people with low  health literacy  and low  literacy  in general be consulted during the design process for auxiliary labels to improve the chance for comprehension and effectiveness. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12338", "text": "Barrier isolator  is a general term that includes two types of devices: isolators and  restricted access barriers  (RABS).   Both are devices that provide a physical and aerodynamic (air overpressure) barrier between the external clean room environment and a work process. The isolator design is the more dependable of the two barrier design choices, as it prevents contamination hazards by achieving a more comprehensive separation of the processing environment from the surrounding facility.  Nonetheless, both Isolator and RABS designs are contemporary approaches developed over the last 35 years and a great advancement over designs of the 1950s-70s that were far more prone to microbial contamination problems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12339", "text": "Barrier and Isolator designs are used throughout the industries, from sterile injectable drug filling to  cytotoxic  sterile drug compounding to electronics manufacturing to orange juice filling.  Pharmaceutical industry and pharmacy compounding isolators are used for maintaining sterility of a drug, and that is the focus of this article.  This type of strict design and control is important when producing sterile medicines because consumers receiving injections, surgical irrigation fluid, or other \"parenterally\"-administered drugs are often highly vulnerable to infection.  As a result, contaminated drugs have caused grave (e.g., permanent injury, death) consequences for the consumer.   The sterility of other dosage forms, such as ophthalmic, is similarly important, as blindness or partial loss of vision has occurred due to intrinsically contaminated eye medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12340", "text": "Isolators  are routinely found within the  pharmaceutical industry  and are widely used in Europe (and increasingly in the US) for  pharmacy  aseptic compounding applications. See also  Asepsis .  They are designed to provide continuous and complete isolation of the inside of the isolator from the external room environment (including its operators).  Only installed gloves or robotic arms are used to manipulate the product.  This ensures that the environment is maintained as contamination-free to safeguard patients who will later be administered the drug.  Isolators operate as positive-pressure devices, and use full wall separation and substantial overpressure to both physically and aerodynamically separate the interior from the external room environment.  The more complete technical definition is as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12341", "text": "An isolator is a decontaminated unit, supplied with Class 100 (ISO 5) or higher air quality, that provides uncompromised, continuous isolation of its interior from the external environment (e.g., surrounding cleanroom air and personnel). There are two major types of isolators:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12342", "text": "While the positive pressure isolator is most common, \"negative\" pressure devices also exist for very large industrial operations that handle toxic products.  The \"negative pressure isolator,\" and has become less common and desirable, but is superior to the traditional biosafety cabinet which is vulnerable to contamination and can expose the worker to toxicological hazards if not operated properly."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12343", "text": "A simpler and more effective option for nearly all toxicological containment applications is the use of \"closed isolator\" design, which is maintained under positive pressure (this is the most appropriate containment option unless a company processes thousands of units per minute)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12344", "text": "If a negative isolator is used, its intricate design must fulfill two objectives: protect workers outside of the isolator, and assure sterility of sterile drugs inside the isolator.  As such, the term \"negative pressure\" isolator is somewhat of a misnomer, as contaminated (\"polluted\") room air must not be pulled into the main workstation isolator in a sterile operation.  Thus, the actual workstation isolator is always maintained under substantial positive pressure.   The \"negative\" pressure isolator does however include a separate buffer zone (an extra isolator compartment) that is designed to exhaust both incoming room air and outgoing positive pressure air from the main workstation.  The main workstation isolator, in which the sterile product is exposed, is therefore protected from contaminated air as the toxic product should be exhausted via the buffer zone before it reaches operators working outside of the isolation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12345", "text": "In addition to Isolators, there are also extensive barriers that provide sub-isolation protection, but have a very good track record of reducing hazards to sterile drugs during processing when they are designed and operated properly.  This extensive barrier is known as a  restricted access barrier system , or  RABS .  A barrier cabinet using RABS design and control, is below the isolator in its ability to assure sterility assurance and containment, but far better than the traditional laminar air flow hood or \"open process\" designs that are progressively being phased-out by the industries.  In particular, a RABS that operates only in closed-door mode after the equipment setup and sporadic disinfection is performed, is commonly used now and provides substantial risk mitigation.  These \"closed RABS\" require all processing interventions to be done using gauntlet gloves attached to the RABS walls.  RABS doors are only opened at the start of an operation to perform equipment setup, and must be locked thereafter until the conclusion of operations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12346", "text": "In contrast, other RABS designs allow for rare door openings in specified circumstances. Because this \"open RABS\" allows for a door to be opened to the surrounding cleanroom (albeit into a fully HEPA-filtered perimeter around the RABS structure) during aseptic operations, the design allows for higher contamination hazard than a RABS that is kept closed. If doors are opened to the \"open RABS\" on anything other than an exceptional basis, it may not represents an improvement over traditional aseptic processes.  Therefore, \"open RABS\" must be operated properly to realize sterility assurance gains."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12347", "text": "Some historical background regarding isolators and RABS is also important to understand how sterile product proaction has evolved. In the mid-1980s, after the industry had already begun to employ isolators,  RABS units became an alternative to separating people from the process.  While isolator usage continued to expand, RABS also became popular in the 1990s.  The acronym RABS was coined by Stewart Davenport of Upjohn (now  Pfizer ).  (See ISPE publications for a definition of RABS.)  Since that time, the technology and applications of these systems has developed and broadened significantly.  It is now very unusual for a sterile drug operation to be run without either an Isolator or RABS protective design."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12348", "text": "There are also other devices, which can offer some helpful separation.  These devices are known as  Gloveboxes .  Gloveboxes do not offer the separative control provisions of an isolator or RABS.  Gloveboxes were originally designed for non-sterile product applications, such as weighing or manipulating a toxic drug and have a long track record for such non-sterile applications.  Such gloveboxes can be very effective in preventing exposure of an operator to a toxic drug.  In limited cases, they can also be used to protect a sterile product, when supplied with ISO 5 unidirectional air.  However, in some notable cases, gloveboxes used for aseptic processing have provided no more sterile product protection than the traditional  laminar air flow hood  (LAF) design of the 1960s. In these cases, the glove boxes were problematic due to inappropriate design or controls (e.g., insufficient disinfection, transfer of contaminated materials, ingress of lower quality air into glovebox, poor design/integrity, poor transfers).  However, if gloveboxes are very meticulously designed, thoroughly disinfected (e.g., using sporocides) and carefully operated by well-trained aseptic processing personnel to prevent introduction of microbial contamination, it is possible to obtain some degree of increased sterile product protection versus the simple traditional LAF hood."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12349", "text": "Bioburden  is normally defined as the number of bacteria living on a surface that has not been sterilized. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12350", "text": "The term is most often used in the context of bioburden testing, also known as microbial limit testing, which is performed on  pharmaceutical products  and medical products for  quality control  purposes.  Products or components used in the pharmaceutical or medical field require control of  microbial  levels during processing and handling. Bioburden or microbial limit testing on these products proves that these requirements have been met.  Bioburden testing for medical devices made or used in the USA is governed by  Title 21 of the Code of Federal Regulations  and worldwide by  ISO  11737."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12351", "text": "The aim of bioburden testing is to measure the total number of viable micro-organisms (total microbial count) on a medical device prior to its final sterilization before implantation or use. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12352", "text": "21 C.F.R. 211.110 (a)(6) states that bioburden in-process testing must be conducted pursuant to written procedures during the manufacturing process of drug products. [ 3 ]  The United States Pharmacopeia (USP) outlines several tests that can be done to quantitatively determine the bioburden of non-sterile drug products. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12353", "text": "It is important when conducting these tests to ensure that the testing method does not either introduce bacteria into the test sample or kill bacteria in the test sample. [ 4 ]  To prepare drug products for testing, they must be dissolved in certain substances based on their \"physical characteristics.\" [ 4 ]  For example, a water-soluble drug product should be dissolved in \"Buffered Sodium Chloride-Peptone Solution pH 7.0, Phosphate Buffer Solution pH 7.2, or Soybean-Casein Digest Broth.\" [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12354", "text": "The Membrane-Filtration Method and Plate Count Method can be used to measure the number of microbes in a sample. [ 4 ]  In the  Membrane-Filtration Method , the sample is passed through a membrane filter with a pore size of 0.45 micrometers or less. [ 4 ]  The membrane filter is then placed onto Soybean-Casein Digest Agar and incubated in order to be able to determine the total aerobic microbial count (TAMC). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12355", "text": "In the  Plate Count Method , the sample of drug product to be tested and Soybean-Casein Digest Broth is poured into a Petri dish. [ 4 ]  The Petri dish is then incubated. The  most probable number  method (MPN) can also be performed for products considered to have a low bioburden [ clarification needed ] . The MPN is considered to be one of the least accurate tests. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12356", "text": "The bioburden quantification is expressed in  colony forming unit  (CFU). There are generally established guidelines for the maximum CFU that a drug product can contain. [ 4 ]  Contact plates or sterile swabs can also be used to test for microbes on a surface when compounding sterile products to ensure compliance with USP 797. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12357", "text": "As an alternative to traditional methods (membrane-filtration and plate count method) there are rapid microbiological methods (RMM) that correlate to plate counting and give results in less time (minutes or hours instead of days).  Soleil by Sievers is an example of a RMM that gives results in 45 minutes and detects biotics/ml thanks to flow cytometry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12358", "text": "Bioburden is also associated with  biofouling , where microbes collect on the surface of a device or inside of fan cooled equipment.  In healthcare settings, this increases the risk of  Healthcare-associated infections  (HAIs) or  Hospital-acquired infection  as pathogens can be spread through contact or through the air to new patients and hospital staff.  Fan cooled system are generally avoided in critical care and operating rooms, thus relying on natural convection or liquid cooling to cool devices and equipment. Clean rooms (surgical operating rooms, for example) are also required to maintain positive air pressure so that air may leave those rooms, but contaminated air cannot enter from adjacent spaces. [ 6 ]   HEPA  filters are also used to collect airborne pathogens larger than 0.3 microns."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12359", "text": "https://www.watertechnologies.com/products/analyzers-instruments/sievers-soleil"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12360", "text": "Bioenhancers  or biopotentiators [ 1 ]  or  bioavailability enhancers  is a new chapter in medical science first scientifically established in 1979 after the discovery of world's first bioenhancer piperine. [ 2 ]  It is a pocket friendly drug technology which reduces the destruction, wastage and elimination of several orally administered drugs inside the body."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12361", "text": "Definition  Bioenhancers are defined as substances that increase the  bioavailability  leading to increased bioefficacy of active substances with which they are combined without having any pharmacological activity of their own at the dose used. [ 1 ]  They may enhance bioavailability of allopathic drugs, vitamins, nutrients and toxins depending on its mechanism of action. For example, piperine increases bioavailability of several nutrients such as beta-carotene, [ 3 ]  vitamin A, vitamin B6, coenzyme Q10, [ 4 ] [ 5 ]  drugs such as phenytoin, [ 6 ]   theophylline , [ 7 ]  propanolol [ 7 ]  and a toxin called aflatoxin B1. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12362", "text": "Increased Bioavailabiity means increased levels of drug in the blood stream available for drug action. Increased Bioefficacy means the increased effectiveness of the drug due to increased bioavailability or due to other mechanisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12363", "text": "An observation made in 1929 by Bose describes an increased antiasthmatic activity of vasaka leaves when pepper was added to it.  No explanation for this observation was given nor any studies were done to explain the observation. The breakthrough in bioenhancers was finally provided about 50 years later in 1979 by Dr. C. K. Atal, director of RRL Jammu, who was researching on medicinal plants.   [ 1 ]  Bioenhancers or bioavailability enhancers as a term and chapter did not exist in any modern scientific literature prior to 1979. The term bioavailability enhancers was first coined in 1979 at Indian Institute of Integrative medicine, Jammu, formerly RRL, Jammu, by Indian scientists Dr. C. K. Atal, the Director of institute RRL Jammu proposed the hypothesis of increased bioavailability of drugs from a clue during research on traditional medicinal drugs. Subsequently, the concept of bioavailability enhancers was scientifically researched and scientifically established by him and his research team at RRL Jammu. The institute then discovered and scientifically validated Piperine as the world's first bioenhancer using Sparteine and Vasicine which became the world's first experimentally bioenhanced drugs. Dr. Atal also initiated the bioenhanced anti tubercular drug research project using Rifampicin [ 9 ]  which later resulted in development of world's first bioenhanced anti tubercular drug formulation. This DCGI approved formulation was officially released by Indian government at Anusandhan Bhawan Delhi on world tuberculosis day 2011, and also presented to Mr. Bill Gates, chairman of Microsoft same day at a function at Le Meridian in Delhi."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12364", "text": "After the discovery of bioenhancer Piperine in 1979, a new chapter was added in medical science. Since then it has generated global interest and research in the field and has led to discovery of many other new bioenhancers. Piperine remains the most potent and extensively researched bioenhancer till date. It is safe, effective, extremely economical and  easily manufactured for commercial use. It is also a broad spectrum bioenhancer acting on several classes of modern drugs as noted elsewhere. [ 10 ] [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12365", "text": "Bioenhancers can be classified according to their source of origin, either plant based or animal based or else according to their site of action. Bioenhancers so far almost exclusively discovered in plants, increase the bioavailability of other substances in different ways:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12366", "text": "Bioenhancers prevent this wastage of ingested drugs inside the body and increase quantity of drug reaching the blood, therefore a reduced dosage of oral drug is sufficient to achieve the desired blood levels."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12367", "text": "This reduced dose needed for desired drug action means beneficial effect on raw materials consumption required to develop drugs which is a great savings for any country."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12368", "text": "This also translates into ecological advantage in case of rare and expensive plant based drugs as less trees or plant have to be consumed to produce drugs, an example being the costly anti cancer drug taxol derived from very slow growing yew trees."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12369", "text": "This reduced dose in turn also reduces the cost of drugs. Billions of dollars are wasted globally in various countries due to poor bioavailability of drugs, which is a huge financial burden on any nation, particularly poor developing countries. This is particularly relevant in serious and dreaded diseases on mankind like tuberculosis for which treatment is expensive, toxic and prolonged and for which an emergency situation has been declared by UN due to emergence of AIDS and development of serious drug resistance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12370", "text": "This reduced dose in turn also reduces the side effects of drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12371", "text": "Lesser side effects also improve drug tolerability, drug compliance and promote completion of treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12372", "text": "This improved tolerability and compliance in turn reduces risk of developing dangerous drug resistance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12373", "text": "Even though bioenhancers are not pharmacologically active, [ 1 ]  they can have added benefits such as reduction of gastrointestinal side effects and hepatotoxicity of primary active drug which further makes formulation safer, better tolerated and again reduces drug toxicity and drug resistance."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12374", "text": "For example, by reducing the required dose of expensive toxic Rifampicin by 60 percent, it correspondingly reduces the cost and side effects of Rifampicin while treating the dreaded disease Tuberculosis. [ 13 ]  This is a great advantage to poor patients, poor countries and for dreaded diseases of man."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12375", "text": "The following examples of bioenhancers give an insight into the current pharmacological research and show how with pepper, curry, ginger and other herbal ingredients in food a lack of nutrients or insufficient effects of active agents can be prevented:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12376", "text": "Piperine , an ingredient of pepper, promotes intestinal absorption by activation of the \u03b3-glutamyltranspeptidase and inhibits the degradation of many compounds, by inhibiting different enzymes: aryl hydrocarbon hydroxylase (AHH), [ 14 ]  ethylmorphine N-demethylase, [ 14 ]  Uridine diphosphate glucuronic_acid, [ 15 ]  Uridine diphosphate glucuronyltransferase (UGT), [ 14 ]  P-glycoprotein, [ 16 ] [ 17 ]  CYP2EI [ 18 ]  and CYP3A4. [ 16 ] [ 19 ]  Especially the latter two enzymes contribute significantly to the first-pass effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12377", "text": "Piperine acts as bioenhancer to vitamins (A, B1, B2, B6, C, D, E, K), beta-carotene, [ 3 ]  amino acids (lysine, isoleucine, leucine, threonine, valine, tryptophan, phenylalanine, and methionine), minerals (iodine, calcium, iron, zinc, copper, selenium, magnesium, potassium, manganese), herbal compounds (including ginsenosides, Pycnogenol, resveratrol, epigallocatechin, curcumin [ 20 ] ), and drugs (such as ampicillin, [ citation needed ]  carbamazepine, [ 19 ]  chlorzoxazone, [ 18 ]  diclofenac, [ 21 ]  fexofenadine, [ 17 ]  ibuprofen, [ 22 ]  rifampicin, [ 23 ]  tetracycline, pyrazinamide)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12378", "text": "Allicin  from garlic enhances the effect of the fungicide amphotericin B on yeast cells by affecting the transport of the fungicide into the yeast vacuole."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12379", "text": "Curcumin  which inter alia is found in curry inhibits like piperine the enzyme CYP3A4 and affects the transport function of P-glycoprotein. In combination with curcumin an increased bioavailability of the active compounds celiprolol and midazolam was detected."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12380", "text": "Ginger  promotes due to the gingerols the intestinal absorption of many compounds (including drugs) and elements. In most cases, ginger acts synergistically with piperine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12381", "text": "Glycyrrhizin , a saponin of the liquorice plant, promotes the action of numerous antibiotics and the antifungal agent clotrimazole."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12382", "text": "Quercetin , a flavonoid from fruits and leaves, acts like curcumin and piperine. It increases the bioavailability of the active agent paclitaxel used to treat cancer."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12383", "text": "Carum carvi , a herb from Apiaceae enhances the bioavailability of anti tuberculosis drugs such as rifampicin, isoniazid, and pyrazinamide. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12384", "text": "The bioenhancer technology is primarily targeted for toxic drugs, expensive drugs, scarce drugs, poorly bioavailable drugs or drugs which need to be given for prolonged periods. However it can also be used in any drugs influenced by bioenhancers. The discovery and characterization of bioenhancers has led to several patent applications. [ 25 ] [ 26 ]  Piperine is marketed as bioenhancer in mono preparations and as a component of  dietary supplements  that contain different vitamins,  curcumin ,  resveratrol  or  Coenzyme Q 10 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12385", "text": "Since  bioenhancers can reduce the dosage and cost of expensive medication while making treatment safer, its application has for the first time been done in humans in treating tuberculosis for which the existing drugs are toxic and expensive and need to be administered over prolonged periods. In India where low treatment costs for medical care are essential, the drug Risorine is approved against tuberculosis. Besides the  antibiotics  rifampicin and isoniazid it contains piperine. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12386", "text": "The  Bloomsbury Dispensary for the Relief of the Sick Poor  was an institution founded in 1801 to provide medical aid and suitable nourishment to the poor people of  that part of London ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12387", "text": "George Pinckard  founded the  dispensary  on 26 October 1801 and became its first physician, remaining there for thirty years. [ 1 ]  It was established at  62  Great Russell Street . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12388", "text": "The  Bowl of Hygieia ,  \u27e8\ud83d\udd4f\u27e9 , is one of the  symbols  of  pharmacology , and along with the  Rod of Asclepius , it is one of the most ancient and important symbols related to medicine in western countries.  Hygieia  was the Greek goddess of health,  hygiene , cleanliness, and  sanitation , and the daughter of  Asclepius , who she is often closely associated with e.g. in prayers and hymns. Asclepius' symbol is his  rod , with a  snake  twined around it; correspondingly, Hygieia's symbol is a  cup  or  chalice  with a snake twined around its stem. Hygieia was also invoked, along with her father Asclepius, and  Panacea  in the original  Hippocratic Oath ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12389", "text": "The bowl of Hygieia has been used as a symbol of the pharmacy profession at least as far back as 1796, when it was used on a coin minted for the Parisian Society of Pharmacy. [ 1 ]  It has since been adopted by many more pharmaceutical associations worldwide, such as the  American Pharmacists Association , [ 2 ]  the  Canadian Pharmacists Association , [ 3 ]  the  Pharmaceutical Society of Australia , [ 4 ]  and the Doctor of pharmacy Association, [ 5 ]   Conseil de l'Ordre des Pharmaciens  in France [ 6 ]  (where is written in law with another symbol, the green Greek cross). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12390", "text": "The bowl of Hygieia is a common symbol on signs outside of pharmacies in Europe.  A  mortar and pestle  is a more common symbol in the United States."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12391", "text": "Breakthrough therapy  is a United States  Food and Drug Administration  designation that expedites  drug development  that was created by Congress under Section 902 of the 9 July 2012  Food and Drug Administration Safety and Innovation Act . [ 1 ] [ 2 ]  The FDA's \"breakthrough therapy\" designation is not intended to imply that a drug is actually a \"breakthrough\" or that there is high-quality evidence of treatment efficacy for a particular condition; [ 3 ] [ 4 ]  rather, it allows the FDA to grant  priority review  to drug candidates if preliminary  clinical trials  indicate that the therapy may offer substantial treatment advantages over existing options for patients with serious or life-threatening diseases. [ 4 ] [ 5 ]  The FDA has other mechanisms for expediting the review and approval process for promising drugs, including  fast track  designation,  accelerated approval , and  priority review . [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12392", "text": "A breakthrough therapy designation can be assigned to a drug if \"it is a drug which is intended alone or in  combination  with one or more other drugs to treat a serious or life threatening disease or condition\" and if the  preliminary clinical evidence  indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.\" [ 5 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12393", "text": "Requests are reviewed by the  Center for Drug Evaluation and Research  (CDER) and the  Center for Biologics Evaluation and Research  (CBER). CDER receives approximately 100 requests per year for breakthrough designation. Historically, about one third were approved. CBER receives 15\u201330 requests per year. [ 8 ]  Sponsors must apply for breakthrough status separately for each indication they intend to label the drug for."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12394", "text": "Breakthrough designation applications are submitted as an amendment to the  IND  applications, usually prior to end of Phase II meeting. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12395", "text": "Drugs that have been granted breakthrough status are given priority review. The FDA works with the sponsor of the drug application to expedite the approval process. This expedited process can include rolling reviews, smaller clinical trials, and alternative trial designs. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12396", "text": "Critics have said that the name is misleading and provides companies that obtain a breakthrough designation for a drug candidate with a marketing advantage that may be undeserved. [ 10 ] [ 11 ]  The FDA acknowledges that the name \"breakthrough therapy\" may be misleading. It was never meant to imply that these drugs are actually \"breakthroughs,\" and it does not ensure that they will provide clinical benefit, but still critics complain that they are based on preliminary evidence, including changes in surrogate markers such as laboratory measurements, that often don't reflect \"meaningful clinical benefit.\" [ 3 ] \nThe FDA guidance states: \"Not all products designated as breakthrough therapies ultimately will be shown to have the substantial improvement over available therapies suggested by the preliminary clinical evidence at the time of designation.  If the designation is no longer supported by subsequent data, FDA may rescind the designation.\" [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12397", "text": "As of August 2020, the FDA had granted breakthrough device designations to 298  medical devices  in total since its inception, including 50 for the year 2020. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12398", "text": "Clinical pharmacy  is the branch of  pharmacy  in which  clinical pharmacists  provide direct  patient   care  that optimizes the use of  medication  and promotes  health ,  wellness , and  disease   prevention . [ 1 ] [ 2 ]  Clinical  pharmacists  care for patients in all health care settings but the clinical pharmacy movement initially began inside  hospitals  and clinics. Clinical pharmacists often work in collaboration with  physicians , physician assistants,  nurse practitioners , and other  healthcare professionals . [ 3 ]  Clinical pharmacists can enter into a formal  collaborative practice agreement  with another healthcare provider, generally one or more physicians, that allows pharmacists to prescribe medications and order laboratory tests."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12399", "text": "Clinical pharmacists have extensive  education  in the biomedical,  pharmaceutical , socio-behavioural and clinical sciences.  Most clinical pharmacists have a  Doctor of Pharmacy  (Pharm.D.)  degree  and many have completed one or more years of  post-graduate  training (for example, a general and/or specialty  pharmacy residency ). In the  United States , clinical pharmacists can choose to become Board-certified through the  Board of Pharmacy Specialties  (BPS), which was organized in 1976 as an independent certification agency of the  American Pharmacists Association . The BPS certifies pharmacists in the following specialties: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12400", "text": "There are several types of clinical pharmacists in the United States. In California they are called advanced practice pharmacists (APh). [ 5 ]  In New Mexico, they are known as Pharmacist Clinicians (PhC) [ 6 ]  and lastly in Montana and North Carolina they are known as Clinical Pharmacist Practitioners (CPP). [ 7 ]  Clinical pharmacists in the Veteran Administration are known as Clinical Pharmacy Specialists (CPS). [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12401", "text": "Role in the health care system"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12402", "text": "Within the system of  health care , clinical pharmacists are  experts  in the therapeutic use of medications. They routinely provide medication  therapy  evaluations and recommendations to patients and other health care professionals. Clinical pharmacists are a primary source of scientifically valid  information  and advice regarding the safe, appropriate, and cost-effective use of medications. [ 9 ]  Clinical pharmacists are also making themselves more readily available to the public. In the past, access to a clinical pharmacist was limited to hospitals, clinics, or educational institutions. However, clinical pharmacists are making themselves available through a medication information hotline, and reviewing medication lists, all in an effort to prevent medication errors in the foreseeable future. In the United Kingdom, clinical pharmacists are routinely involved in the direct care of patients within hospitals, and increasingly, in doctors surgeries. They also develop  post registration professional education , professional curricula for workforce development, provide expertise on the use of medicines to national organizations such as  NICE , the  Department of Health , and the  MHRA , and develop medicines guidelines for use in therapeutic areas. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12403", "text": "Clinical pharmacists interact directly with patients in several different ways. They use their knowledge of medication (including dosage, drug interactions, side effects, expense, effectiveness, etc.) to determine if a medication plan is appropriate for their patient. If it is not, the pharmacist will consult the primary physician to ensure that the patient is on the proper medication plan. [ 10 ]  The pharmacist also works to educate their patients on the importance of taking and finishing their medications. Studies conducted into Pharmacist-led Chronic Disease Management show that it was associated with effects similar to usual care and might improve physiological goal attainment. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12404", "text": "In some states in the USA, clinical pharmacists are given prescriptive authority under protocol with a medical provider, and their scope of practice is constantly evolving. [ 12 ] [ 13 ]  In the United Kingdom clinical pharmacists are given independent prescriptive authority. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12405", "text": "Basic components of clinical pharmacy practice include prescribing drugs, [ 15 ]  administering drugs, monitoring prescriptions, managing drug use, and counselling patients. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12406", "text": "The  Committee for Veterinary Medicinal Products  ( CVMP ) is the  European Medicines Agency 's  committee  responsible for elaborating the agency's opinions on all issues regarding veterinary medicines. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12407", "text": "This article about the  European Union  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12408", "text": "In the field of  pharmacy ,  compounding  (performed in  compounding pharmacies ) is preparation of custom medications to fit unique needs of patients that cannot be met with mass-produced products. This may be done, for example, to provide medication in a form easier for a given patient to ingest (e.g., liquid vs. tablet), or to avoid a  non-active ingredient  a patient is allergic to, or to provide an exact dose that isn't otherwise available. This kind of patient-specific compounding, according to a prescriber's specifications, is referred to as \"traditional\" compounding. [ 1 ]  The nature of patient need for such customization can range from absolute necessity (e.g. avoiding allergy) to individual optimality (e.g. ideal dose level) to even preference (e.g. flavor or texture)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12409", "text": "Hospital pharmacies typically engage in compounding medications for  intravenous  administration, whereas outpatient or community pharmacies typically engage in compounding medications for  oral  or  topical  administration. Due to the rising cost of compounding and drug shortages, some hospitals  outsource  their compounding needs to large-scale compounding pharmacies, particularly of sterile-injectable medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12410", "text": "Compounding preparations of a given formulation in advance batches, as opposed to preparation for a specific patient on demand, is known as \"non-traditional\" compounding and is akin to small-scale manufacturing. Jurisdictions have varying regulations that apply to  drug manufacturers  and pharmacies that do advance bulk compounding."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12411", "text": "The earliest  chemists  were familiar with various natural substances and their uses. They compounded a variety of preparations such as medications, dyes, incense, perfumes, ceremonial compounds, preservatives and cosmetics. In the  medieval Islamic world  in particular,  Muslim pharmacists  and  chemists  developed advanced methods of compounding drugs. The first  drugstores  were opened by Muslim pharmacists in  Baghdad  in 754. [ 2 ] [ 3 ]  The modern age of pharmacy compounding began in the 19th century with the isolation of various compounds from  coal tar  for the purpose of producing  synthetic dyes . From this came the earliest  antibacterial   sulfa drugs ,  phenolic  compounds made famous by  Joseph Lister , and  plastics ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12412", "text": "During the 1800s, pharmacists specialized in the raising, preparation and compounding of  crude drugs .  Crude drugs, like  opium , are from natural sources and usually contain several  chemical compounds .  The pharmacist extracted these drugs using solvents such as  water  or  alcohol  to form  extracts ,  concoctions  and  decoctions . They eventually began isolating and identifying the  active ingredients  in these drug concoctions. Using  fractionation  or  recrystallization , they separated an active ingredient from the crude preparation, and compounded a medication using this active ingredient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12413", "text": "With the isolation of medications from the  raw materials  or crude drugs came the birth of the modern pharmaceutical company. Pharmacists were trained to compound the preparations made by the drug companies, but they could not do it efficiently on a small scale. So  economies of scale , not lack of skill or knowledge, produced the modern  pharmaceutical industry . With the turn of the 20th century came greater government  regulation  of the practice of medicine.  These new regulations forced the drug companies to prove that any new medication they brought to market was safe. With the discovery of  penicillin , modern marketing techniques and  brand  promotion, the drug manufacturing industry came of age.  Pharmacists continued to compound most  prescriptions  until the early 1950s when the majority of dispensed drugs came directly from the large pharmaceutical companies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12414", "text": "A physician may choose to prescribe a compounded medication for a patient with an unusual health need that cannot be met with commercially manufactured products. The physician may choose to prescribe a compounded medication for reasons such as"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12415", "text": "In hospitals, pharmacists and pharmacy technicians often make compounded sterile preparations (CSPs) using manual methods. The error rate for manually compounded sterile IV products is high. [ 13 ]  The  Institute for Safe Medication Practices  (ISMP) has expressed concern with manual methods, particularly the error-prone nature of the syringe pull-back method of verifying sterile preparations. [ 14 ]  To increase accuracy, some U.S. hospitals have adopted IV workflow management systems and robotic compounding systems. These technologies use barcode scanning to identify each ingredient and  gravimetric  weight measurement to confirm the proper dose amount. The workflow management systems incorporate software to guide pharmacy technicians through the process of preparing IV medications. The robotic systems prepare IV syringes and bags in an ISO Class 5 environment, and support sterility and dose accuracy by removing human error and contamination from the process. [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12416", "text": "In Australia the Pharmacy Board of Australia is responsible for registration of pharmacists and professional practice including compounding. Although almost all pharmacies are able to prepare at least simple compounded medicines, some pharmacy staff undertake further training and education to be able to prepare more complex products. Although pharmacists who have undertaken further training to do complex compounding are not yet easily identified, the Board has been working to put a credentialing system in place. In 2011 the Pharmacy Board convened a Compounding Working Party to advise on revised compounding standards. [ 17 ]  Draft compounding guidelines for comment were released in April 2014. Pharmacists must comply with current guidelines or may be sanctioned by the Board. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12417", "text": "Both sterile and non-sterile compounding are legal provided the compounding is done for therapeutic use in a particular patient, and the compounded product is supplied on or from the compounding pharmacy. [ 19 ]  There are additional requirements for sterile compounding. Not only must a laminar flow cabinet [laminar flow hood] be used, but the environment in which the hood is located must be strictly controlled for microbial and particulate contamination and all procedures, equipment and personnel must be validated to ensure the safe preparation of sterile products. In non-sterile compounding, a powder containment hood is required when any hazardous material (e.g. hormones) are prepared or when there is a risk of cross-contamination of the compounded product. Pharmacists preparing compounded products must comply with these requirements and others published in the Australian Pharmaceutical Formulary & Handbook. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12418", "text": "In the  United States , compounding pharmacies are licensed and regulated by states. National standards have been created by Pharmacy Compounding Accreditation Board (PCAB), [ 20 ]  however, obtaining accreditation is not mandatory and inspections for compliance occur only every three years. [ 21 ]  The  Food and Drug Administration  (FDA) has authority to regulate \"manufacturing\" of pharmaceutical products\u2014which applies when drug products are not made or modified as to be  tailored in some way to the individual patient \u2014regardless of whether this is done at a factory or at a pharmacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12419", "text": "In the Drug Quality and Security Act (DQSA) of 2013 (H.R. 3204), [ 22 ]  Congress amended the Federal Food, Drug, and Cosmetic Act (FFDCA) to clarify limits of FDA jurisdiction over patient-specific compounding, and to provide an optional pathway for \"non-traditional\" or bulk compounders to operate. The law established that pharmacies compounding only \"patient-specific\" preparations made in response to a prescription (503A pharmacies) cannot be required to obtain FDA approval for such products, as they will remain exclusively under state-level pharmacy regulation. At the same time, section 503B of the law regulates \"outsourcing facilities\" which conduct bulk compounding or are used as outsourcing for compounding by other pharmacies. These outsourcing facilities can be explicitly authorized by the Food and Drug Administration under specified circumstances, while being exempted from certain requirements otherwise imposed on mass-producers. In any pharmacy, compounding is not permitted for a drug product that is \"essentially a copy\" of a mass-produced drug product, however outsourcing pharmacies are subject to a broader definition of \"essentially a copy\". For traditional/patient-specific compounding, 503A's definition of \"copy\" retains its original focus on drug  products  or ultimate dosage forms rather than drug substances or active ingredients, [ 23 ]  and in any event it explicitly excludes from its definition any compounded drug product that a given patient's prescribing practitioner determines makes a \"significant difference\" for the patient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12420", "text": "The FDA weighs the following factors in deciding whether it has authority to \"exercise its discretion\" to require approval for a custom-compounded drug product: [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12421", "text": "The DQSA amended the FFDCA to create a new class of FDA-regulated entities known as \"outsourcing facilities\" whose compounding activities \"may  or  may not\" be patient-specific based on individualized prescriptions. [ 25 ]   Registered outsourcing facilities, unlike traditional compounding facilities, are subject to the FDA's oversight. In addition to being subjected to Food and Drug Administration inspections, registration, fees, and specified reporting requirements, other requirements of outsourcing facilities include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12422", "text": "Poor practices on the part of drug compounders can result in contamination of products, or products that do not meet their stated strength, purity, or quality. Unless a complaint is filed or a patient is harmed, drugs made by compounders are seldom tested. In Texas, one of only two states that does random testing, significant problems have been found. Random tests by the state's pharmacy board over the last several years have found that as many as one in four compounded drugs was either too weak or too strong. In Missouri, the only other state that does testing, potency varied by as much as 300 percent. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12423", "text": "In 2002, the  Food and Drug Administration , concerned about the rising number of accidents related to compounded medications, identified \"red flag\" factors and issued a guide devoted to human pharmacy compounding,  These factors include instances where pharmacists are: [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12424", "text": "In October 2012 news reports surfaced of an  outbreak of fungal meningitis  tied to the New England Compounding Center, a pharmacy which engaged in bulk compounding.\n [ 28 ]  At that time it was also disclosed that the United States and Massachusetts state health regulators were aware in 2002 that steroid treatments from the New England Compounding Center could cause adverse patient reactions. [ 29 ]  It was further disclosed that in 2001\u201302, four people died, more than a dozen were injured and hundreds exposed after they received back-pain injections tainted with a common fungus dispensed by two compounding pharmacies in California and South Carolina. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12425", "text": "In August 2013 further reports tied to the  New England  compounding center said that about 750 people were sickened, including 63 deaths, and that  infections were linked to more than 17,600 doses of  methylprednisolone acetate   steroid  injections used to treat back and  joint  pain that were shipped to 23 states. At that time, another incident was reported  after at least 15 people at two  Texas  hospitals developed bacterial infections. All lots of  medications dispensed since May 9, 2013,  made by Specialty Compounding, LLC of  Cedar Park, Texas  were recalled. The hospitals reported affected  were Corpus Christi Medical Center Bay Area and Corpus Christi Medical Center Doctors Regional. The patients had received intravenous infusions of  calcium gluconate , a drug used to treat  calcium  deficiencies and too much  potassium  in the blood. Implicated in these cases is the  Rhodococcus  bacteria, which can cause symptoms such as fever and pain. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12426", "text": "The FDA, among others, claims that larger compounding pharmacies act like drug manufacturers and yet circumvent FDA regulations under the banner of compounding. Drugs from compounding pharmacies can be cheaper or alleviate shortages, but can pose greater risk of contamination due in part to the lack of oversight. \"Non-traditional\" compounders behave like drug manufacturers in some cases by having sales teams that market non-personalized drug products or production capability to doctors, by making drugs that are essentially the same as commercially available mass-produced drug products, or by preparing large batches of a given drug product in anticipation of additional prescriptions before actually receiving them. [ 32 ] [ 33 ]  An FDA spokesperson stated, \"The methods of these companies seem far more consistent with those of drug manufacturers than with those of retail pharmacies.  Some firms make large amounts of compounded drugs that are copies or near copies of FDA-approved, commercially available drugs. Other firms sell to physicians and patients with whom they have only a remote professional relationship.\" [ 27 ]  The head of the FDA has recently requested the following authority from Congress: [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12427", "text": "Various ideas have been proposed to expand federal US regulation in this area, including laws making it easier to identify misuse or misnomered-use [ 35 ]  and/or stricter enforcement of the longstanding distinction between  compounding  versus  manufacturing . [ 36 ] [ 37 ]  Some US states have also taken initiatives to strengthen oversight of compounding pharmacies. [ 38 ]  A major source of opposition to new Food and Drug Administration regulation on compounding is makers of  dietary supplements . [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12428", "text": "Concomitant drugs  are two or more  drugs  used or given at or almost at the same time (one after the other, on the same day, etc.). The term has two contextual uses: as used in  medicine  or as used in  drug abuse ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12429", "text": "This designation is used when medicinal drugs are given either at the same time or almost at the same time. This is often the case in medicine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12430", "text": "Chemotherapy for cancer applies is an example. The standard of care (sometimes also called the \"gold standard\") for the adjuvant treatment of stage III colon cancer is the FOLFOX chemotherapy protocol (used in Europe, Japan, Canada, and Australia) and respectively the FLOX chemotherapy protocol (used in the USA). These 2 chemotherapy protocols are very similar in principle. Both consist of 3 medicinal drugs: a) Leucovorin (=  folinic acid  = calcium folinate), b) 5-Fluorouracil (= 5-FU), and c)  Oxaliplatin . Since these 3 medicinal drugs are \"concomitant\" to each other, such a constellation is called \"concomitant drugs\". [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12431", "text": "Contrast imaging in medicine is another example. These are imaging procedures in medicine that are performed after giving the patient an  iodinated contrast  medium (e.g. different types of contrast X-rays, CTs, MRIs). It is well known that such iodinated contrast media can lead to acute allergies in some patients. They may also lead to kidney damage. If the patient is receiving a \"concomitant\" medicinal drug (prescribed to the patient by another physician), and the radiologist performing the imaging procedure is unaware of this, potentially harmful side-effects can occur and increase the risk of contrast medium-induced nephropathy (i.e. increase the risk of damage to the kidneys). In general, radiologists carefully ask their patients about other medicinal drugs they are \"concomitantly\" taking before the imaging procedure. Often, they monitor the kidney function and the hydration status of their patients during the imaging procedure, especially whenever a concomitant drug (that is harmful to the kidney) is being used. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12432", "text": "If a drug abuser ingests or misuses two or more drugs, either at the same time or almost at the same time, this is also called \"concomitant drugs\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12433", "text": "Whether concomitant drug abuse leads to an increased number of deaths was scientifically analysed in Sheffield, UK. [ 3 ]  The researchers wanted to find out whether concomitant drug abuse (i.e. an opiate plus another drug of misuse) leads to an increased number of acute accidental opiate-related deaths. The authors showed that at least in the Sheffield area, intravenous (IV) administration of an opiate is the most consistent factor associated with drug abuse deaths. The co-administration of a concomitant drug of misuse appeared to be a feature rather than a risk factor per se in such deaths. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12434", "text": "A  consultant pharmacist  is a  pharmacist  who works as a  consultant  providing expert advice on clinical pharmacy, academic pharmacy or practice, public health pharmacy, industrial pharmacy, community pharmacy or practice, pharmaceutical analysis etc., regarding the safe use and production of  medications  or on the provision of  pharmaceutical services  to medical institutions, hospitals, universities, research institutions, medical practices and individual patients. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12435", "text": "In Australia, a consultant pharmacist has historically referred to a pharmacist accredited to access funding to be remunerated for providing Residential Medication Management Reviews and  Home Medication Reviews ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12436", "text": "These pharmacists undergo a credentialing process, that was historically referred to as accreditation, and were then able to access the funding to perform these roles.  The major accreditation organisation, known as the Australian Association of Consultant Pharmacy, was disbanded in 2022.  The Pharmaceutical Society of Australia, Society of Hospital Pharmacists Australia and the Australian College of Pharmacy (owned by the Queensland branch of the Pharmacy Guild of Australia) are now the three organisations that provide credentialing for pharmacists to be able to undertake domiciliary medication management reviews."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12437", "text": "The Australian Pharmacy Council will develop Aged Care Accreditation Standards in 2023 for pharmacists working in residential aged care settings and undertaking medication management reviews. These standards are being developed in response to a series of research papers published by the Consultant Pharmacists' Services Research Network (COHERENT) that has found inconsistencies in the delivery of these services and the preparedness of pharmacists generally to move into these settings. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12438", "text": "In the US, a consultant pharmacist focuses on reviewing and managing the medication regimens of  patients , particularly those in institutional settings such as  nursing homes . Consultant pharmacists ensure their patients\u2019 medications are appropriate, effective, as safe as possible and used correctly; and identify, resolve, and prevent  medication-related problems  that may interfere with the goals of therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12439", "text": "The demand for consultant pharmacists is on the rise. Licensing and accrediting agencies such as Centers for Medicare and Medicaid (CMS), [ 5 ]  Accreditation Association for Ambulatory Health Care (AAAHC), The Joint Commission (JC) and individual states licensing bodies encourage healthcare facilities to use consultant pharmacists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12440", "text": "Consultants may specialize in one of the following areas: Regulatory, Quality, Technical, or Clinical."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12441", "text": "In the UK's  NHS , the term consultant pharmacist refers to a pharmacist who has advanced roles in patient care, research and education in a specific medical speciality or expert area of practice."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12442", "text": "The Department of Health for England produced guidance in 2005 which described the role of the Consultant Pharmacist which is distinct from other roles in England and internationally. The posts are intended to be innovative new posts that will help improve patient care by retaining clinical excellence within the NHS and strengthening professional leadership. The consultant pharmacist posts have been created to provide a dynamic link between clinical practice and service development to support new models for delivering patient care. The title consultant pharmacist should only apply to approved posts that meet the principles, set out in the guidance, around four main functions:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12443", "text": "The guidance recommends that the title consultant pharmacist is not conferred on individuals purely in recognition of innovative or excellent practice, but for those practitioners who meet the required competencies for the post. In the NHS, the posts created within or across NHS organisations, are approved by Strategic Health Authorities (or clusters of SHA\u2019s). The SHA's provide approval panels for ratification of consultants posts to ensure that business plans match the spirit of this guidance and that posts are sustainable, equitable and transferable across the NHS."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12444", "text": "The competency requirements for consultant pharmacists are drawn from the Advanced and Consultant Level Competency Framework designed by the Competency Development and Evaluation Group (CoDEG, see www.codeg.org) which is divided into six capability (competency) clusters. Postholders are required to demonstrate:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12445", "text": "There is work is underway to make explicit links between the Competency Framework and the NHS Knowledge and Skills Framework. The role of consultant pharmacists in the NHS is evolving and although many posts are currently based in hospital practice, the role is developing in primary care."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12446", "text": "The  defined daily dose  ( DDD ) is a statistical measure of  drug  consumption, defined by the  World Health Organization  (WHO)  Collaborating Centre for Drug Statistics Methodology. It is defined in combination with the  ATC Code  drug classification system for grouping related drugs. The DDD enables comparison of drug usage between different drugs in the same group or between different health care environments, or to look at trends in drug utilisation over time. The DDD is not to be confused with the  therapeutic dose  or  prescribed daily dose  (PDD), or recorded daily dose (RDD), and will often be different to the dose actually prescribed by a physician for an individual person. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12447", "text": "The WHO's definition is: \"The DDD is the assumed average  maintenance dose  per day for a drug used for its main indication in adults.\" [ 1 ]  The Defined Daily Dose was first developed in the late 1970s. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12448", "text": "Before a DDD is assigned by the WHO Collaborating Centre for Drug Statistics Methodology, it must have an  ATC Code  and be approved for sale in at least one country. The DDD is calculated for a 70kg adult, except if this drug is only ever used in children. The dose is based on recommendations for treatment rather than prevention, except if prevention is the main indication. Generally there is only one DDD for all formulations of a drug, however exceptions are made if some formulations are typically used in significantly different strengths (e.g., antibiotic injection in a hospital vs tablets in the community). The DDD of combination tablets (containing more than one drug) is more complex, most taking into account a \"unit dose\", though combination tablets used for  high blood pressure  take the number of doses per day into account. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12449", "text": "The formula for determining the dose is: [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12450", "text": "The DDD of a drug is reviewed after three years. Ad hoc requests for change may be made but are discouraged and generally not permitted unless the main indication for the drug has changed or the average dose used has changed by more than 50%. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12451", "text": "The DDD is generally the same for all formulations of a drug, even if some (e.g., flavoured syrup) are designed with children in mind. Some types of drug are not assigned a DDD, for example: medicines applied to the skin, anaesthetics and vaccines. Because the DDD is a calculated value, it is sometimes a \"dose\" not actually ever prescribed (e.g., a midpoint of two prescribed tablet strengths may not be equal to or be a multiple of any available tablet). [ 1 ]  Different people may in practice be prescribed higher or lower doses than the DDD, for instance in children, people with liver or kidney impairment, patients with a  combination therapy , or due to differences in  drug metabolism  between individuals or  ethnicities  ( genetic polymorphism ). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12452", "text": "Although designed primarily for drug utilisation research, data using the DDD can only give a \"rough estimate\" compared with actually collecting statistics on drug use in practice. [ 1 ]  The DDD is often use for long term research and analysis of drug utilisation trends over time, so changes to the DDD are avoided if possible, [ 3 ]  whereas changes in the actual daily dose prescribed for a population may often occur. [ 4 ]  For example, the Recorded Daily Dose (RDD) of  simvastatin  in Canada in 1997 was only 8% different to the DDD, but by 2006 it was 67% different. In 2009, the DDD of several  statins  were updated, with simvastatin changing from 15mg to 30mg. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12453", "text": "The DDD is based on the maintenance dose, but in practice patients in a population will be on a mix of initial and maintenance doses. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12454", "text": "The DDD can be used as the basis for calculating various indicators of drug utilisation. The indicator  DDD per 1000 inhabitants per day  can suggest what portion of a population are regularly using a drug or class of drugs. The indicator  DDD per 100 bed days  estimates on average how many inpatients are given a drug every day in hospital. The indicator  DDDs per inhabitant per year  can be used for drugs normally prescribed for short treatment duration (e.g., antibiotics) to indicate the average number of days in a year a person may take that treatment. The extent to which estimates using DDD reflect actual clinical practice depends on how close the DDD is to the typical prescribed dose in that country or setting and at that point in history. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12455", "text": "Because the primary purpose of the ATC/DDD system is drug consumption measurement, the WHO recommend caution when considering its use for cost analysis: \"DDDs, if used with caution can be used to compare, for example, the costs of two formulations of the same drug.\" [ 5 ]  So, the  cost per DDD  of an extended-release tablet taken once a day compared with a standard tablet taken twice a day, may indicate the extended-release tablet costs much more to treat the same condition."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12456", "text": "In contrast, using DDD to compare the cost of different drugs or drug groups is \"usually not valid\" according to the WHO. They recommend that \"DDDs are not suitable for comparing drugs for specific, detailed pricing, reimbursement and cost-containment decisions\". The DDD may not necessarily compare well with the actual prescribed daily dose, and two drugs in the same ATC group may not be equally effective at their Daily Defined Dose. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12457", "text": "For example, an analysis of statin use in the Ontario Drug Benefit Program, 2006-07. The average  cost per DDD  of  rosuvastatin  was 21% more expensive than  atorvastatin  ($1.14 compared to $0.94), which would suggest the shift at the time from prescribing atorvastatin to prescribing rosuvastatin would result in increased costs to the healthcare budget. Both had a DDD at that time of 10mg, but 10mg was not the only dose prescribed. For example, atorvastatin once daily at 10mg, 20mg, 40mg and 80mg was prescribed 45%, 36%, 16% and 3% of the time respectively. If one compared  cost per unit  (daily tablet) then rosuvastatin was instead 24% cheaper than atorvastatin ($1.44 vs $1.90), and if one compares  cost per RDD  (recorded daily dose) then rosuvastatin was 26% cheaper than atorvastatin ($1.43 vs $1.93). An erroneous conclusion of a healthcare budget cost increase arises in this case from using  cost per DDD . At the time, the RDD of rosuvastatin was similar to its DDD (12.6 mg vs 10mg), but the RDD of atorvastatin was twice its DDD (20.6 mg vs 10mg). The DDD of atorvastatin was revised in 2009 to 20mg. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12458", "text": "The Canadian  Patented Medicine Prices Review Board  analysed the use of DDD for drug utilisation and cost analysis and offered recommendations. They particularly concentrated on the problems that occur when the Recorded Daily Dose (RDD) observed in the population deviates more than minimally from the Defined Daily Dose. They conclude that the DDD methodology \"should generally not be used to interpret Canadian drug utilization; should generally not be applied in cost analyses; and should generally not be applied in policy decisions\". [ 4 ]  The Board recommend that provided the agreement between DDD and RDD is known and minimal, then a cost per DDD \"can provide a rough idea of the treatment cost\" but \"caution should still be used, as misinterpretation of the results based on the DDD methodology may still occur\". If the agreement between DDD and RDD is unknown or a significant disagreement is known, then the DDD methodology \"should not be used in cost analyses\". In all cases, the Board state \"The DDD methodology should not be used in guiding policy decisions regarding reimbursement, therapeutic substitution and other pricing decisions\". [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12459", "text": "If the DDD for a certain drug is given, the number of DDDs used by an individual patient or (more commonly) by a collective of patients is as follows."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12460", "text": "D \n r \n u \n g \n \u00a0 \n u \n s \n a \n g \n e \n \u00a0 \n ( \n i \n n \n \u00a0 \n D \n D \n D \n s \n ) \n = \n \n \n \n I \n t \n e \n m \n s \n \u00a0 \n i \n s \n s \n u \n e \n d \n \u00d7 \n A \n m \n o \n u \n n \n t \n \u00a0 \n o \n f \n \u00a0 \n d \n r \n u \n g \n \u00a0 \n p \n e \n r \n \u00a0 \n i \n t \n e \n m \n \n \n D \n D \n D \n \n \n \n \n \n {\\displaystyle Drug\\ usage\\ (in\\ DDDs)={\\frac {Items\\ issued\\times Amount\\ of\\ drug\\ per\\ item}{DDD}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12461", "text": "For example, the  analgesic  (pain reliever)  paracetamol  has a DDD of 3\u00a0g, which means that an average patient who takes paracetamol for its main indication, which is pain relief, uses 3 grams per day. This is equivalent to six standard tablets of 500\u00a0mg each. If a patient consumes 24 such tablets (12\u00a0g of paracetamol in total) over a certain span of time, this equals a consumption of four DDDs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12462", "text": "D \n r \n u \n g \n \u00a0 \n u \n s \n a \n g \n e \n \u00a0 \n ( \n i \n n \n \u00a0 \n D \n D \n D \n s \n ) \n = \n \n \n \n 24 \n \u00a0 \n ( \n i \n t \n e \n m \n s \n ) \n \u00d7 \n 500 \n \u00a0 \n ( \n m \n g \n \n / \n \n i \n t \n e \n m \n ) \n \n \n 3000 \n \u00a0 \n m \n g \n \n \n \n = \n 4 \n \n \n {\\displaystyle Drug\\ usage\\ (in\\ DDDs)={\\frac {24\\ (items)\\times 500\\ (mg/item)}{3000\\ mg}}=4}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12463", "text": "A  dispensary  is an office in a school,  hospital , industrial plant, or other organization that dispenses  medications , medical supplies, and in some cases even medical and dental treatment. In a traditional dispensary set-up, a pharmacist dispenses medication per the prescription or order form. The English term originated from the  medieval Latin  noun  dispensaria  and is  cognate  with the  Latin  verb  dispensare , 'to distribute'. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12464", "text": "The term also refers to legal  cannabis dispensaries ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12465", "text": "The term also has  Victorian antiquity , in 1862 the term dispensary was used in the folk song the  Blaydon Races . [ 2 ]  The folk song differentiated the term dispensary from a Doctors surgery and an Infirmary. [ 2 ]   The advent of huge industrial plants in the late 19th and early 20th centuries, such as large  steel mills , created a demand for in-house  first responder  services, including  firefighting ,  emergency medical services , and even primary care that were closer to the point of need, under closer company control, and in many cases better  capitalized  than any services that the surrounding town could provide. In such contexts, company doctors and nurses were regularly on duty or  on call ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12466", "text": "Electronic dispensaries are designed to ensure efficient and consistent dispensing of  excipient  and  active ingredients  in a secure data environment with full audit traceability. A standard dispensary system consists of a range of modules such as manual dispensing, supervisory, bulk dispensing, recipe management and interfacing with external systems. Such a system might dispense much more than just medical related products, such as alcohol, tobacco or vitamins and minerals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12467", "text": "In  Kenya , a dispensary is a small outpatient health facility, usually managed by a registered nurse. It provides the most basic primary healthcare services to rural communities, e.g. childhood immunization, family planning, wound dressing and management of common ailments like colds, diarrhea and simple malaria. The nurses report to the nursing officer at the health center, where they refer patients with complicated diseases to be managed by  clinical officers ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12468", "text": "In India, a dispensary refers to a small setup with basic medical facilities where a doctor can provide a primary level of care.\nIt does not have a hospitalization facility and is generally owned by a single doctor.\nIn remote areas of India where hospital facilities are not available, dispensaries will be available."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12469", "text": "In  Turkey , the term dispensary is almost always used in reference to  tuberculosis  dispensaries ( Turkish :  verem sava\u015f dispanseri ) established across the country under a  programme to eliminate tuberculosis  initiated in 1923, [ 3 ]  the same year the country was founded. Although more than a hundred such dispensaries continue to operate as of 2023, they have been largely supplanted by hospitals by the end of 20th century with increased access to healthcare."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12470", "text": "The term  dispensary  in the  United States  was used to refer to government agencies that sell  alcoholic beverages , particularly in the state of  Idaho  and the  South Carolina ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12471", "text": "In  Arizona ,  British Columbia ,  California ,  Colorado ,  Connecticut ,  Illinois ,  Maine ,  Massachusetts ,  Oregon ,  Michigan ,  New Jersey ,  New Mexico ,  New York ,  Rhode Island ,  Ontario ,  Quebec , and  Washington ,  medical cannabis  is sold in specially designated stores called  cannabis dispensaries  or \"compassion clubs\". [ 4 ]  These clubs are for members or patients only, unless legal cannabis has already passed in the state or province in question. In Canada dispensaries are far less abundant than in the USA; most Canadian dispensaries are in British Columbia and Ontario. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12472", "text": "In 2013  Uruguay  became the first country to legalize marijuana cultivation, sale and consumption. The government is building a network of dispensaries that are meant to help to track marijuana sales and consumption. The move was meant to decrease the role of the criminal world in distribution and sales of it. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12473", "text": "Drug therapy problems  ( DTPs ) (or  drug related problems, DRPs ) represent the categorization and definition of clinical problems related to the use of  medications  or \"drugs\" in the field of  pharmaceutical care . [ 1 ]  In the course of clinical practice, DTPs are often identified, prevented, and/or resolved by  pharmacists  in the course of  medication therapy management , as experts on the safety and efficacy of medications, but other  healthcare professionals  may also manage DTPs. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12474", "text": "A drug-therapy (related) problem can be defined as an event or circumstance involving  drug   treatment  ( pharmacotherapy ) that interferes with the optimal provision of medical care. In 1990,  L.M. Strand and her colleagues (based on the previous work of R.L Mikeal [ 3 ]  and D.C Brodie, [ 4 ]  published respectively in 1975 and 1980) classified the DTPs into eight different categories. According to these categories, pharmacists generated a list of the DTPs for each patient. As a result, pharmacists had a cleaner picture of the patient's drug therapy and medical conditions. A second publication of R.J Cipolle with L.M Strand in 1998, change the eight categories into seven, grouped in four Pharmacotherapy needs: indication, effectiveness, safety and adherence. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12475", "text": "According to page 73 in  Introduction to Health Care Delivery: A Primer for Pharmacists , drug therapy problems (DTP) originated from Strand et al. (1990) who defined eight problems that could result in poorer health outcomes in an attempt to categorize DTP. [ 7 ]  Helper and Strand later in 1990 stated the mission statement or raison d'etre of  pharmacists  should be to correct these drug therapy problems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12476", "text": "The original eight problems have now been condensed into  seven categories of problems . As given by Shargel, they are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12477", "text": "DRPs can be broken down further into the following categories: [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12478", "text": "Requires Additional Drug Therapy"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12479", "text": "Unnecessary Drug Therapy"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12480", "text": "Requires Different Drug Product"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12481", "text": "Dosage Too Low"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12482", "text": "Adverse Drug Reaction"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12483", "text": "Dosage Too High"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12484", "text": "Non-adherence"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12485", "text": "Electronic prescription  ( e-prescribing  or  e-Rx ) is the computer-based electronic generation, transmission, and filling of a  medical prescription , taking the place of paper and faxed prescriptions. E-prescribing allows a  physician ,  physician assistant ,  pharmacist , or  nurse practitioner  to use digital prescription software to  electronically transmit  a new prescription or renewal authorization to a community or mail-order  pharmacy . It outlines the ability to send error-free, accurate, and understandable prescriptions electronically from the  healthcare provider  to the pharmacy. E-prescribing is meant to reduce the risks associated with traditional prescription script writing. It is also one of the major reasons for the push for  electronic medical records . By sharing medical prescription information, e-prescribing seeks to connect the patient's team of healthcare providers to facilitate knowledgeable decision making. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12486", "text": "An e-prescribing system used in the United States must be capable of performing all of the following functions: [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12487", "text": "The basic components of an electronic prescribing system are the: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12488", "text": "The PBM and transaction hub work closely together. The PBM works as an intermediate actor to ensure the accuracy of information, although other models may not include this to streamline the communication process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12489", "text": "In addition to pharmacies, medical tests can also be prescribed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12490", "text": "The prescriber, generally a clinician or healthcare staff, is defined as the electronic prescribing system user and sign into the system through a verification process to authenticate their identity. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12491", "text": "The prescriber searches through the database of patient records by using patient-specific information such as first and last name, date of birth, current address etc. Once the correct patient file has been accessed, the prescriber reviews the current medical information and uploads or updates new prescription information to the medical file. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12492", "text": "The transaction hub provides the common link between all actors (prescriber, pharmacy benefit manager, and pharmacy). It stores and maintains a master patient index for quick access to their medical information as well as a list of pharmacies. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12493", "text": "When the prescriber uploads new prescription information to the patient file, this is sent to the transaction hub. The transaction hub will verify against the patient index. This will automatically send information about this transaction to the PBM, who will respond to the hub with information on patient eligibility, formulary, and medication history back to the transaction hub. The transaction hub then sends this information to the prescriber to improve patient management and care by completing and authorizing the prescription. Upon which, the prescription information is sent to the pharmacy that the patient primarily goes to. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12494", "text": "When a pharmacy receives the prescription information from the transaction hub, it will send a confirmation message. The pharmacy also has the ability to communicate to the prescriber that the prescription order has been filled through the system. Further system development will soon allow different messages such as a patient not picking up their medication or is late to pick up medication to improve patient management. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12495", "text": "When an imaging center receives the prescription, the imaging center will then contact the patient and schedule the patient for his/her scan.  The advantage of ePrescribing radiology is that often when a patient is handed a paper script, the patient will lose the prescription or wait to call and schedule.  This can be disastrous for patients with severe underlying conditions.  The imaging center will call and schedule the patient as soon as the referral arrives.  There are mobile ePrescribing portals as well as web portals that handle this well, and there are advantages. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12496", "text": "Compared to paper-based prescribing, e-prescribing can improve health and reduce costs because it can: [ 2 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12497", "text": "Safety improvements are highly desirable; in 2000, the Institute of Medicine identified medication errors as the most common type of  medical error  in health care, estimating that this leads to several thousand deaths each year. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12498", "text": "Illegibility from handwritten prescriptions is eliminated, decreasing the risk of medication errors while simultaneously decreasing risks related to liability.  Oral miscommunications regarding prescriptions can be reduced, as e-prescribing should decrease the need for phone calls between prescribers and dispensers.  Causes of medication errors include mistakes by the pharmacist incorrectly interpreting illegible handwriting or ambiguous nomenclature, and lapses in the prescriber's knowledge of desired dosage of a drug or undesired interactions between multiple drugs. Electronic prescribing has the potential to eliminate most of these types of errors. Warning and alert systems are provided at the point of care. E-prescribing systems can enhance an overall medication management process through clinical decision support systems that can perform checks against the patient's current medications for drug-drug interactions, drug-allergy interactions, diagnoses, body weight, age, drug appropriateness, and correct dosing.  Based on these algorithms, the system can alert prescribers to contradictions, adverse reactions, and duplicate therapies.  The computer can also ensure that clear and unambiguous instructions are encoded in a structured message to the pharmacist, and  decision support systems  can flag lethal dosages and lethal combinations of drugs. [ 7 ]   E-prescribing allows for increased access to the patient's medical records and their medication history. Having access to this information from all health care providers at the time of prescribing can support alerts related to drug inappropriateness, in combination with other medications or with specific medical issues at hand.  Electronic prescribing has been shown to reduce prescribing errors by up to 30%. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12499", "text": "According to estimates, almost 30 percent of prescriptions require pharmacy callbacks. [ 10 ]  This translates into less time available to the pharmacist for other important functions, such as educating consumers about their medications.  In response, E-prescribing can significantly reduce the volume of pharmacy call-backs related to illegibility, mistaken prescription choices, formulary and pharmacy benefits, decreasing the amount of time wasted on the phone.  This ultimately impacts office workflow efficiency and overall productivity in a positive manner."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12500", "text": "Both prescribers and pharmacists can save time and resources spent on faxing prescriptions through a reduction in labor costs, handling costs, and paper expenses waste due to unreliability."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12501", "text": "With e-prescribing, renewal authorization can be an automated process that provides efficiencies for both the prescriber and pharmacist.  Pharmacy staff can generate a renewal request (authorization request) that is delivered through the electronic network to the prescriber's system.  The prescriber can then review the request and act accordingly by approving or denying the request through updating the system.  With limited resource utilization and just a few clicks on behalf of the prescriber, they can complete a medication renewal task while enhancing continuous patient documentation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12502", "text": "It is estimated that 20% of paper-based prescription orders go unfilled by the patient, partly due to the hassle of dropping off a paper prescription and waiting for it to be filled.  By elimination or reducing this waiting period, e-prescribing may help reduce the number of unfilled prescriptions and hence, increasing medication adherence.  Allowing the renewal of medications through this electronic system also helps improve the efficiency of this process, reducing obstacles that may result in less patient compliance.  Availability of information on when patient's prescriptions are filled can also help clinicians assess patient adherence."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12503", "text": "Improved prescriber convenience can be achieved when using mobile devices, that work on a wireless network, to write and renew prescriptions.  Such mobile devices may include laptops, PDAs, tablet computers, or mobile phones.  This freedom of mobility allows prescribers to write/renew prescriptions anywhere, even when not in the office."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12504", "text": "E-prescribing systems enable embedded, automated analytic tools to produce queries and reports, which would be close to impossible with a paper-based system.  Common examples of such reporting would be: finding all patients with a particular prescription during a drug recall, or the frequency and types of medication provided by certain health care providers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12505", "text": "Although e-prescribing has the ability to streamline workflow process and increase the system's efficiency, challenges and limitations that may hinder the widespread adoption of e-prescribing practices include: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12506", "text": "The vast majority of community medical prescriptions in Australia continue to be delivered on paper, either in printed or hand-written format. Electronic prescription in Australia is currently provided by two service providers, MediSecure and eRx. Both services can be integrated into many of the existing clinical and pharmacy prescribing software systems. Since December 1991, they have become interoperable allowing bilateral transfer of information. [ 17 ] [ 18 ] [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12507", "text": "Private companies started working with electronic prescriptions. On 2017 July easypres.com launched Bangladesh's [ 20 ]  first cloud-based electronic prescription and patient management software for Doctors in Bangladesh. [ 21 ]  Within a year, more than a thousand doctors registered for the software out of 83 thousand registered MBBS doctors in Bangladesh for this Digital prescription writing software. High court of Bangladesh issued a rule that doctors need to write the prescription in readable format meaning they need to use software of ALL caps later while writing prescription. This software also stores the medical history of patients and doctors can access these data easily from anywhere using the Internet."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12508", "text": "On March 22, 2016, the  Government of Canada  allocated funds to  Canada Health Infoway  to develop an e-prescribing service. [ 22 ]  Infoway is working with Health Canada, the provinces and territories and industry stakeholders to create PrescribeIT, a multi-jurisdiction e-prescribing service. Infoway will create, operate and maintain the service, along with its partners. The service will be financially self-sustaining and is designed to be scaled across the country and will enable prescribers to electronically transmit a prescription to a patient's pharmacy of choice. [ 23 ]  Physicians, physician assistants, nurse practitioners and other prescribers will be able to use the system either through their existing electronic medical record or through a standalone application. Health Canada included supporting better prescribing practices, including e-prescribing, as part of its Action on Opioid Misuse plan. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12509", "text": "Until recently in Canada, it was the position of Health Canada that, to allow for e-prescribing, amendments to Part C of the Food and Drugs Regulations made under the Food and Drugs Act, regulations made under the Controlled Drugs and Substances Act and possibly regulations made under Personal Information Protection and Electronic Documents Act would be required. After further review, Health Canada has concluded that there are currently no regulatory impediments to moving ahead with electronically generated and transmitted prescriptions and that these are permissible to the extent that they achieve the same objectives as written prescriptions. Provinces and territories wishing to proceed with e-prescribing are obligated to ensure that electronic prescriptions meet existing regulatory requirements and achieve the same objectives as written prescriptions. For example, there must be evidence of a genuine practitioner/patient relationship, and in the case of controlled substances, pharmacists filling prescriptions must verify prescriptions are signed by the practitioner before selling or providing drugs containing controlled substances to a patient. Health Canada has collaborated with Canada Health Infoway on the development of a technical document entitled Ensuring the Authenticity of Electronic Prescriptions, in order to provide advice about how to ensure the authenticity of electronic signatures.\n [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12510", "text": "The Czech healthcare system is moving towards a mandatory electronic prescribing system to take effect in 2020.  Patients and clinicians will have access to the prescribing records. Codes and names of medications are allocated by the  State Institute for Drug Control . [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12511", "text": "Electronic prescriptions were introduced in Estonia in January 2010 [ 27 ]  and by mid-2013, 95% of all prescriptions in the country were being issued electronically. [ 28 ] \ne-Prescription, is a centralized paperless system for issuing and handling medical prescriptions. When a doctor prescribes medicine using the system, he or she does so electronically, with the aid of an online form. At the pharmacy, all a patient needs to do is present an ID-card. The pharmacist then retrieves the patient's information from the system and issues the medicine. Because the e-Prescription system draws on data from the national health insurance fund, any state medical subsidies that the patient is entitled to, also appear, and the medicine is discounted accordingly. Another major advantage of the system is that doctor visits are no longer needed for repeat prescriptions. A patient can contact the doctor by e-mail, Skype or phone, and the doctors can issue repeats with just a few clicks, and the patient can collect the medicine from their closest pharmacy. 99% of all prescriptions in the country are issued electronically. This frees up time for patients and doctors, and reduces administrative strain on hospitals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12512", "text": "The use of electronic prescription has been designated as an important strategic policy to improve health care in Europe. The aim of the European Union is to have a cross-border electronic healthcare system in Europe which will enable EU citizens to obtain e-Prescriptions anywhere in Europe. The Scandinavian countries are leading Europe in deploying e-Prescription. Other countries which use the prescription process routinely are Norway, Denmark, Finland, Sweden, Belgium, [ 29 ]  the Netherlands, Italy, [ 30 ]  Iceland, Greece, England, Scotland, Wales and Northern Ireland.\nThe European Union is pushing for more cross border health data exchange. Multiple perceived barriers impede its incorporation in clinical practice. There are varying interpretations and implementations of data protection and confidentiality laws in the 27 member states. Infrastructures are not in place to support the system and stakeholders in some jurisdictions are reluctant to embrace e-health due to the high cost and the lack of security of the systems. Interoperability of different systems is only a partial solution. Security and enforcement of privacy must also be equally enforced. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12513", "text": "In India some private hospitals started using electronic prescription. But a major step was taken by government of West Bengal in August 2014 when they started the process of issuing e-prescriptions instead of hand-written instructions in top government hospitals.\nThe biggest advantage of the system is that a patient has all his medical data stored in the server of state health department which can be referred to in future.\nIn the private sector, a number of companies have started initiatives to build software to support e-prescriptions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12514", "text": "With the development and implementation of electronic technologies in Russian healthcare system, electronic prescription became part of the project called  EMIAS .  EMIAS  is the digital system designed to increase the quality and access of the medical aid in the public health facility. The project was designed and being implemented as part of \u00abDigital city\u00bb program in execution of the Moscow Government's order from April 7, 2014 (as Moscow government amended on 21.05.2013 No. 22-PP).  \nThe system offers special portal  Emias.Info , that provides appointment service to the patients and client area with different services including e-Prescription. Government social program allows getting pharmaceutical products for free or with the discount, depending on the category of the citizen."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12515", "text": "About 420 million repeat prescriptions are generated in the UK each year - about 200 for each general practitioner each week. They account for about 80% of the cost of medication in primary care. Paper based Repeat Dispensing Services were introduced by the  NHS  in 1991, and in 1992 it became possible to use the NHS Electronic Prescription Service for this purpose. In 2017 awareness of the scheme among patients was low. [ 32 ] \nIn October 2017 Keith McNeil,  NHS England 's chief clinical information officer demanded that NHS hospitals should be moved rapidly onto electronic prescribing in the light of research showing it would cut serious prescribing errors by more than half.  There was no information about the extent to which it is happening in hospitals. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12516", "text": "After successful pilots in London and the East Midlands it was agreed in April 2018 that electronic prescribing should be introduced in all urgent care settings in England, including  NHS 111  and other  Out-of-hours services  so that dispensed medication can be ready for collection at a pharmacy when patients arrive. [ 34 ]  \u00a378 million was allocated in December 2018 to encourage progress with implementing electronic prescribing in NHS organisations which were struggling. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12517", "text": "Electronic prescribing is to start in English hospitals in the summer of 2022, using the IC24 system which was piloted at  Midlands Partnership NHS Foundation Trust  from 2020. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12518", "text": "In the United States, the  HITECH Act  promotes adoption of this technology by defining e-prescribing as one meaningful use of an  electronic medical record . [ 37 ]  Standards for transmitting, recording, and describing prescriptions have been developed by the  National Council for Prescription Drug Programs , in particular the  SCRIPT  standard, which describes data formats.  Elsewhere in the world, health care systems have been slower to adopt e-prescribing standards. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12519", "text": "Adoption of e-prescribing technology has accelerated in the United States, in large part, due to the arrival of Stage 2 of meaningful use. One of the Stage 2 core measures is: \"Generate and transmit permissible prescriptions electronically (e-Rx.)\" In order to meet this measure, practices must prescribe and transmit at least 50 percent of permissible prescriptions electronically. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12520", "text": "According to data released in May 1991 by  Surescripts , a company which operates the nation's largest health information (e-prescribing) network, roughly 317,000 office-based physicians now e-prescribe in the United States. [ 40 ] \nA more recent report released by the Office of the National Coordinator for Health IT in June 2012 finds that 48 percent of U.S. physicians use e-prescribing systems. National growth in e-prescribing over the period September 2008 through June 2012 increased over 40 percent, with individual states increasing adoption anywhere from 28 percent to 70 percent. [ 41 ]   In 2019, the Federal Trade Commission sued Surescripts, alleging that the company employed unlawful restraints in order to maintain its monopolies over electronic prescribing. [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12521", "text": "Starting from April 2019, ePrescription is one of the key components of the reimbursement system in Ukraine. [ 44 ]  The e-prescription module integrates all primary care physicians (over 23,000 doctors) and almost 50% of pharmacies across the country. [ 45 ] [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12522", "text": "While the launch of e-prescription was done quickly, the quality was not compromised. The development of the tool was completed according to international standards as well as HL7 FHIR medical data requirements. Ukrainian eHealth system is a two layer system with central core component developed as storage of dictionaries and rules and private IT-companies who offers e-prescription's functionality through interfaces of the doctors and pharmacists. [ 47 ] [ 48 ]  The e-prescription code is open and available. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12523", "text": "As a next step of expansion of eRx functions in Ukraine, Ministry of Health of Ukraine develop the technical requirement for substitution of oldfashion, paper-based prescriptions with digital eRx for all applicable medicines. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12524", "text": "A study in the UK tested the Salford Medication Safety Dashboard (SMASH), a web application to help GPs and pharmacists find people in their electronic health records who might face safety hazards due to prescription errors. The dashboard was successfully used in identifying and helping patients with already registered unsafe prescriptions and later it helped monitoring new cases as they appeared. [ 51 ] [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12525", "text": "Essential medicines , as defined by the  World Health Organization  (WHO), are  medicines  that \" satisfy the priority  health care  needs of the population \". [ 1 ]  Essential medicines should be  accessible  to people at all times, in sufficient amounts, and be generally affordable. [ 2 ]  Since 1977, the WHO has published a model list of essential medicines, with the  2019 list for adult patients  containing over 400 medicines. [ 3 ]  Since 2007, a  separate list of medicines intended for child patients  has been published. [ 4 ]  A new list was published in 2021, for both adults and children. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12526", "text": "Several changes have been implemented since the 2021 edition, including that medication cost should not be grounds for exclusion criteria if it meets other selection criteria, and  cost-effectiveness  differences should be evaluated within therapeutic areas. The following year,  antiretroviral  agents, usually used in the treatment of  HIV/AIDS , were included on the list of essential medicines. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12527", "text": "The WHO distinguishes between \"core list\" and \"complementary list\" medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12528", "text": "This list forms the basis of the  national drugs policy  in more than 155 countries, both in the  developed  and  developing world . Many governments refer to WHO recommendations when making decisions on health spending. Countries are encouraged to prepare their own lists considering local priorities. Over 150 countries have published an official essential medicines list. [ 7 ]  Despite these efforts, an estimated 2 billion people still lack access to essential medicines, with some of the major obstacles being low supply, including shortages of inexpensive drugs. Following these shortages, the  US Food and Drug Administration  (FDA) released a report in fall of 2019 with strategies to overcome and  mitigate  supply issues. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12529", "text": "The original WHO definition in 1977 was that they were medicines \" of utmost importance, basic, indispensable, and necessary for the healthcare needs of the population \". [ 9 ]  The concept was mentioned in one of the ten points of the 1978  Alma Ata Declaration  on  primary health care ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12530", "text": "In 2002 the definition was changed to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12531", "text": "Essential medicines are those that satisfy the priority health care needs of the population. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12532", "text": "This remains the definition as of 2019 [update] . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12533", "text": "The use of essential medicines lists has resulted in better quality of care and improved management of health resources in the most cost-effective manner. The lists serve as a baseline for  health insurance  entities to include or exclude the medication, and modify the dose based on  clinical study  evidence. To improve the accessibility of essential medicines for both children and adults, it is necessary to ensure the rational use of medicine while also being cost-effective. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12534", "text": "In a 2023 study evaluating the availability, distribution, and progress of essential medicines in  China , results showed that access to essential medicines is lower in comparison to the WHO's goal, with little progress in expansion over the years. This systematic review and meta-analysis study pooled studies that reported the availability of essential medicines in various regions of China from 2009 to 2019.  [ 12 ]  The data supports the need to improve the access and distribution of medication across regions to ensure that the goal of  universal health coverage  is reached. [ 12 ]  Having essential medications be accessible to everyone is the foundation to a better health without financial hardships for the general public.  [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12535", "text": "The goal of  universal health coverage  was set in place in 2015, where multiple countries have taken steps towards ensuring treatment,  palliation ,  rehabilitation , and  preventative  health measures for everyone. [ 13 ]  Understanding that accessibility to appropriate and applicable essential medications within the region, is the first step towards reaching equitable and  universal healthcare .  [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12536", "text": "Items are chosen as essential medicines based on how common the disease that is being treated, evidence of benefit, the degree of  side effects  and the cost compared to other options. [ 14 ]  In order to explore the human rights law and WHO's essential medicines policies into national legislation regarding medicines, affordability and financing needs to be understood to enhance universal access to essential medicines. [ 15 ]  The intention of essential medicine lists is to provide appropriate use of treatment and not include medications that have been withdrawn from the market in other countries due to unfavorable benefit-to-harm balance. [ 16 ]  Despite many efforts from different countries, some individuals do not have their needs met and have to turn to an alternative plan called the judiciary in order to receive the medications required. The Judiciary also known as the \" Judicialization of access to medicines, \" this involves technical, scientific, legal, and social aspects. Further research is needed to explore these aspects comprehensively. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12537", "text": "Medications can be priced differently, due to the fact that each medication can have many qualities and uses. Because various medicines have different costs, individual uses, and distinct advantages, it prompts the theory of  cost effectiveness . [ 18 ]  Cost effectiveness is the subject of debate between producers ( pharmaceutical companies ) and purchasers of drugs (national health services). It is estimated that access to essential medicines could save 10 million people a year. [ 19 ]  Access to essential medicine is a cornerstone of effective healthcare systems and a fundamental component of  global health initiatives  aimed at improving  quality of life , reducing  health disparities , and fostering  sustainable development . [ 20 ]  Proper access to essential medicine can lower the amount for really expensive treatments and  hospitalizations  by managing early and effectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12538", "text": "The WHO made the  Model List of Essential Medicines  in 1977 based on the idea that certain medicines are required more often than others and are often inaccessible to many different populations. [ 21 ]  As of 2018, 146 countries are using the Essential Medicines concept, which is also used to guide the reimbursement of medicines depending on the importance to public health, the efficacy, the safety, and the cost of the medicines.  [ 22 ]  The goal of the Essential Medicine concept is that medicines that have the highest relevance in public health, meaning medicines that are used the most often, should be available equally to everyone in a population either for free or at a very affordable cost.  [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12539", "text": "The  WHO Model List of Essential Medicines  has been updated every two years since 1977. The 23rd version was published in July 2023. [ 23 ]  Over that period, the number of medications has more than doubled, from the original 208 in 1977, [ 7 ]  to more than 500 in 2023. [ 23 ]  Medicines are then categorized as essential or non-essential based on their inclusion in each country's EML. results are then analyzed by WHO regions, World Bank income groups, wealth inequality, and therapeutic groups. The group for essential medicines availability was higher (61.5%) than non-essential medicines (27.3%). But in the public sector, the median availability was 40% for essential medicines, compared to 6.6% for non-essential medicines. Thus, overall, the availability of essential medicines in the public sector is still suboptimal, indicating challenges in achieving equitable access. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12540", "text": "The first edition of the \" WHO Model List of Essential Medicines for Children \", was published in 2007, while the 9th edition was published in 2023. [ 7 ] [ 4 ] [ 23 ]  It was created to make sure that the needs of children were systematically considered such as availability of proper  formulations . [ 7 ]  While the EML (Essential Medicine List) is intended for the population as a whole, the EMLc (Essential Medicine List for Children) is intended for children up to 12 years old. [ 25 ]  The first edition contained 450 formulations of 200 different medications [ 7 ]  and the 2023 list contains 361 medications. [ 23 ]  The intention of creating an EML for children is to improve child survival and provide treatment options for mortality and  morbidity  causes. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12541", "text": "WHO launched a \"Make Medicines Child Size\" (MMCS) campaign in 2007 with the purpose of creating appropriate regimens and formulations for children based on their weight and age.  [ 27 ]  A 2021 study assessing the age-appropriateness of  enteral  formulations listed on the WHO Essential Medicine List for Children (EMLc) highlighted the dependence on factors such as dose adaptability, formulation flexibility, and the child's swallowing ability. Analysis of the EMLc between 2011 and 2019 revealed that most enteral medications were not age-appropriate for children under six years old, necessitating manipulation of the medicine prior to administration. This practice raises concerns regarding safety and efficacy. Consequently, the study emphasizes the urgent need for more comprehensive information and guidelines for selecting and developing age-appropriate essential enteral medicines for  pediatric  populations. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12542", "text": "While the practice of maintaining separate lists for the general population and children under 12 years of age is beneficial in tailoring healthcare interventions, it inadvertently excludes  adolescents  from the latter category. This age-based cutoff may lead to an oversight of the unique healthcare needs of this demographic.  [ 25 ]  It would be a good idea to create a list for adolescents as well. This is important as it allows healthcare providers to offer tailored care for each group. This differentiation ensures that treatments are appropriate for children's unique  physiological  needs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12543", "text": "The first EML was published in 1977 and was created as a tool to improve the accessibility and availability of medications for everyone. Multiple editions of EMLs and studies since then have been released, comparing the necessity, efficacy, safety, and of certain medications on the list. [ 29 ]  In addition, studies have been done comparing EMLs from multiple regions to ensure the appropriateness of dosing and safety of drug classes. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12544", "text": "Medication like  Codeine  has a potential of drug abuse and was established as an essential medication, yet raised some ethical questions. With the lack of literature highlighting its safety, it was highly discouraged to place Codeine as an essential medication. [ 29 ]  Not to mention, it was further discouraged in 2011 when Codeine was removed from WHO essential medicine list for children, causing greater discussion of its use in adults. [ 29 ]  Another article discusses the appropriateness of empirical dosing of different  antibiotics  on EMLs from multiple countries. [ 30 ]  Using the top 31 priority bacterial infections as a comparator, results showed how broadening the antibiotic list and dose, would not only increase adherence to treating the infections. It would also address the  antibiotic resistance  complication in most bacterial infections. [ 30 ]  This 2021  Cross-Sectional study , reviewed the antibiotics on the essential medicines list from 138 countries and assessed each countries national listing. The data showed that on average of the 44 essential antibiotic medications, 24 of them were accessible to the population, 5 of them considered on reserve, and 15 of them on WATCH using the AWaRe classification.  [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12545", "text": "Additionally, the use of therapeutic guidelines as a reference for the creation of the WHO Essential Medicine List has been used to provide consistency and alignment of treatment across the nation. [ 31 ]  In the 2022 quantitative analysis study of  cardiovascular  medications, the data suggests how adopting a common formulary of combination therapy and specific types of drug classes improved patient adherence and cardiovascular outcomes within the region. [ 31 ]  The study compared  South Africa  and 15 different South African Development Communities (SADC) essential medication lists of  2021 for cardiovascular medications. [ 31 ]  Having majority of SADC lists aligned with the WHO essential medicine lists of South Africa, supports how implementing this into the national EML would provide greater accessibility and availability of CVD medications consistently throughout the nation. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12546", "text": "While the WHO Essential Medicine Lists are a very valuable tool and integral to the country's medicine policy, there has not yet been enough effort to implement them. There are several factors that affect the adaptation and implementation of the WHO Essential Medicine Lists, as found by a 2022 qualitative evidence synthesis. [ 32 ]  This study identified areas that need support in order to implement EML at a country level.  [ 32 ]  The lack of effort to implement WHO Essential medicines lists undermines the potential health benefits, exacerbates inequities in access, increase health costs and infrastructure."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12547", "text": "Implementation of the WHO EML can be done with national medication selection committees that are able to operate with consultive mandates. [ 32 ]  These committees also need very clear leadership, monitoring, and evaluations. Implementation of EMLs can be done efficiently if there is a form of a reimbursement process in order to help keep costs low. [ 32 ]  Additionally, EMLs should have recommended clinical practices, such as listing necessary items, in order to make implementation of the list easy to do. For example, in the case of injectable medications, the EML should indicate that in addition to the medication a patient would also need an injection device and safety box. [ 33 ]  Finally, there needs to be clear legislation and monitoring to make sure there is compliance. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12548", "text": "Access to essential medicines are part of the  Sustainable Development Goals , specifically goal 3.8. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12549", "text": "A number of organizations, which are global in scope, use the list to determine which medications they will supply. [ 7 ]  Rather than strictly following the list, many nations refer to the essential medicines list as a guide for developing their own laws and regulations based on their own requirements. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12550", "text": "Ecuador ,  Ghana ,  The Philippines ,  South Africa , and  Ukraine  all include some mention of essential medicines or other health infrastructure that helps guide their economic policies on medicine pricing and benefit selection. [ 36 ]  Especially in middle income countries where  out-of-pocket spending  on medications is common, health equity measures and economic policy helps evaluate the affordability of medications as well as the effects of public health legislation.  [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12551", "text": "Brazil  had published their first EML called RENAME 13 years prior to the WHO's first essential medicines list. [ 37 ]  RENAME included medicines that focused on safety, efficacy, and availability of medications, as well as Brazil's health priority of their population. The WHO EML encouraged Brazil to separate medications based on therapeutic classes, leading to both lists having the same format, despite different medications listed. The addition of the WHO's 2009 children's EML inspired Brazil to consider their own RENAME pediatric list. But limitations have caused Brazil to wait for further pediatric drug evidence within the country before finalizing their own children-specific EML. Challenges such as high prices and poor availability have impacted how citizens are actually able to obtain their medications, despite healthcare being a constitutional right in the country.  [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12552", "text": "China first published their own EML in 1982, with the current EML containing over 2,000 herbal, chemical, and biological medicines.  [ 38 ]  The  Ministry of Health  (MOH) consists of medical and economic experts that are divided into a consult and review group to develop their national medicines list. Provinces in China are able to form their own EML, but are not allowed to remove medicines already listed in the national EML.  [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12553", "text": "India  first developed their National List of Essential Medicines (NLEM) back in 1996 with only a minimal amount of revisions. Evidence-based criteria is used to determine which medications to add or remove to the list. Clinicians,  pharmacologists ,  pharmacists , etc. discuss and review the list where an open-house discussion is used to modify and finalize the NLEM.  [ 40 ]  However, poor medical supplies and staff with low health investments in implementations have caused people to go to  private hospitals  and clinics for  treatment . And with a large variety on rural and urban populations throughout the country, healthcare services and general access are favored more towards the urban population.  [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12554", "text": "Many  developing nations  have developed national drug policies, a concept that has been actively promoted by the  WHO . For example, the  national drug policy  for  Indonesia [ 1 ]  drawn up in 1983 had the following objectives:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12555", "text": "To achieve these objectives in Indonesia, the following changes were implemented:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12556", "text": "One of the first challenges is to promote and develop rational prescribing, and a number of international initiatives exist in this area. WHO has actively promoted rational drug use as one of the major elements in its  Drug Action Programme . In its publication  A Guide to Good Prescribing [ 2 ]  the process is outlined as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12557", "text": "The emphasis is on developing a logical approach, and it allows for  clinicians  to develop personal choices in medicines (a personal formulary) which they may use regularly. The program seeks to promote appraisal of evidence in terms of proven efficacy and safety from controlled  clinical trial  data, and adequate consideration of quality, cost and choice of competitor drugs by choosing the item that has been most thoroughly investigated, has favorable  pharmacokinetic  properties and is reliably produced locally. The avoidance of combination drugs is also encouraged."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12558", "text": "The routine and irrational use of  injections  should also be challenged. One study undertaken in Indonesia found that nearly 50% of infants and children and 75% of the patients aged five years or over visiting government health centers received one or more injections. [ 3 ]  The highest use of injections was for  skin disorders ,  musculoskeletal  problems and  nutritional deficiencies . Injections, as well as being used inappropriately, are often administered by untrained personnel; these include drug sellers who have no understanding of clean or  aseptic  techniques."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12559", "text": "Another group active in this area is the  International Network for the Rational Use of Drugs  (INRUD). This organization, established in 1989, exists to promote rational drug use in developing countries. As well as producing training programs and publications, the group is undertaking research in a number of member countries, focused primarily on changing behavior to improve drug use. One of the most useful publications from this group is entitled  Managing Drug Supply . [ 4 ]  It covers most of the drug supply processes and is built up from research and experience in many developing countries. There a number of  case studies  described, many of which have general application for pharmacists working in developing countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12560", "text": "In all the talk of rational drug use, the impact of the  pharmaceutical industry  cannot be ignored, with its many incentive schemes for doctors and pharmacy staff who dispense, advise or encourage use of particular products. These issues have been highlighted in a study of  pharmaceutical sales representative  (medreps) in Mumbai. [ 5 ]  This was an observational study of medreps' interactions with  pharmacies , covering a range of neighborhoods containing a wide mix of  social classes . It is estimated that there are approximately 5000 medreps in Mumbai, roughly one for every four doctors in the city. Their salaries vary according to the employing organization, with the  multinationals  paying the highest salaries. The majority work to performance-related incentives. One medrep stated \"There are a lot of companies, a lot of competition, a lot of pressure to sell, sell! Medicine in India is all about incentives to doctors to buy your medicines, incentives for us to sell more medicines. Even the patient wants an incentive to buy from this shop or that shop. Everywhere there is a scheme, that's business, that's medicine in India.'"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12561", "text": "The whole system is geared to winning over confidence and getting results in terms of sales; this is often achieved by means of gifts or invitations to symposia to persuade doctors to prescribe. With the launch of new and expensive antibiotics worldwide, the pressure to sell with little regard to the national essential drug lists or  rational prescribing . One medrep noted that this was not a business for those overly concerned with morality. Such a statement is a sad reflection on parts of the pharmaceutical industry, which has an important role to play in the development of the health of a nation. It seems likely that short-term gains are made at the expense of increasing problems such as  antibiotic resistance . The only alternatives are to ensure practitioners have the skills to appraise medicine promotion activities or to more stringently control pharmaceutical promotional activities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12562", "text": "In situations where medicines are dispensed in small, twisted-up pieces of brown paper, the need for patient instruction takes on a whole new dimension. Medicines should be issued in appropriate containers and labelled. While the patient may be unable to read, the  healthcare  worker is probably  literate . There are many tried-and-tested methods in the literature for using pictures and diagrams to aid  patient compliance . Symbols such as a rising or setting sun to depict time of day have been used, particularly for treatments where regular medication is important, such as cases of  tuberculosis  or  leprosy . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12563", "text": "Poverty  may force patients to purchase one day's supply of medicines at a time, so it is important to ensure that  antibiotics  are used rationally and not just for one or two days' treatment. Often, poor patients need help from  pharmacists  to understand which are the most important medicines and to identify the items, typically  vitamins , that can be missed to reduce the cost of the  prescription  to a more manageable level."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12564", "text": "The essential drugs list concept was developed from a report to the 28th  World Health Assembly  in 1975 as a scheme to extend the range of necessary drugs to populations who had poor access because of the existing supply structure. The plan was to develop essential drugs lists based on the local health needs of each  country  and to periodically update these with the advice of experts in  public health ,  medicine ,  pharmacology ,  pharmacy  and drug management. Resolution number 28.66 at the Assembly [ 7 ]  requested the  WHO Director-General  to implement the proposal, which led subsequently to an initial model list of essential drugs (WHO Technical Series no 615, 1977). This model list has undergone regular review at approximately two-yearly intervals and the current 14th list was published in March 2005. [ 8 ]  The model list is perceived by the WHO to be an indication of a common core of medicines to cover most common needs. There is a strong emphasis on the need for national policy decisions and local ownership and implementation. In addition, a number of guiding principles for essential drug programs have emerged."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12565", "text": "The model list of essential drugs is divided into 27 main sections, which are listed in  English  in alphabetical order. Recommendations are for drugs and presentations. For example,  paracetamol  appears as  tablets  in strengths of 100\u00a0mg to 500\u00a0mg,  suppositories  100\u00a0mg and  syrup  125\u00a0mg/5ml. Certain drugs are marked with an asterisk (previously a \u17db), which denotes an example of a therapeutic group, and other drugs in the same group could serve as alternatives."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12566", "text": "The lists are drawn up by  consensus  and generally are sensible choices. There are ongoing initiatives to define the evidence that supports the list. This demonstrates the areas where RCTs ( randomized controlled trials ) or  systematic reviews  exist and serves to highlight areas either where further research is needed or where similar drugs may exist which have better supporting  evidence ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12567", "text": "In addition to work to strengthen the evidence base, there is a proposal to encourage the development of  Cochrane  reviews for drugs that do not have systematic review evidence."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12568", "text": "Application of NNTs ( numbers needed to treat ) to the underpinning evidence should further strengthen the lists. At present, there is an assumption among doctors in some parts of the world that the essential drugs list is really for the poor of society and is somehow inferior. The use of NNTs around  analgesics  in the list goes some way to disprove this and these developments may increase the importance of essential drugs lists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12569", "text": "The impact of pharmaceutical representatives and the power of this approach has led to the concept of  academic detailing  to provide clear messages. A study by Thaver and Harpham [ 9 ]  described the work of 25 private practitioners in area around  Karachi . The work was based on assessment of prescribing practices, and for each practitioner included 30 prescriptions for  acute respiratory infections  (ARIs) or  diarrhea  in children under 12 years of age. A total of 736 prescriptions were analysed and it was found that an average of four drugs were either prescribed or dispensed for each consultation. An  antibiotic  was prescribed in 66% of prescriptions, and 14% of prescriptions were for an  injection . Antibiotics were requested for 81% of diarrhea cases and 62% of ARI cases. Of the 177 prescriptions for diarrhea, only 29% were for oral  rehydration  solution. The researchers went on to convert this information into clear messages for academic dealing back to the doctors. The researchers went on to implement the program and assessed the benefits. This was a good piece of work based on developing messages that are supported by evidence."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12570", "text": "It is a natural human reaction to want to help in whatever way possible when face with human disaster, either as a result of some  catastrophe  or because of  extreme poverty . Sympathetic individuals want to take action to help in a situation in which they would otherwise be helpless, and workers in difficult circumstances, only too aware of waste and excess at home, want to make use of otherwise worthless materials. The problem is that these situations do not lend themselves to objectivity. There are numerous accounts of tons of useless drugs being air-freighted into disaster areas. It the requires huge resources to sort out these charitable acts and often the drugs cannot be identified because the labels are not in a familiar language. In many cases, huge quantities have to be destroyed simply because the drugs are out of date,  spoiled , unidentifiable, or totally irrelevant to local needs. Generally, had the cost of shipping been  donated  instead, then many more people would have benefited."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12571", "text": "In response to this, the WHO has generated guidelines for drug donations from a consensus of major international agencies involved in  emergency relief . If these are followed, a significant improvement in terms of patient benefit and use of  human resources  will result."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12572", "text": "While modern practices, including the development of  clinical pharmacy , are important, many basic issues await significant change in developing countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12573", "text": "Evidence is as important in the developing world as it is in the developed world.  Poverty  comes in many forms. While the most noticed are  famine  and poor  housing , both potent killers, medical and knowledge poverty are also significant.  Evidence-based  practice is one of the ways in which these problems can be minimized. Potentially, one of the greatest benefits of the  internet  is the possibility of ending  knowledge poverty  and in turn influencing the factors that undermine  wellbeing . Essential drugs programs have been a major step in ensuring that the maximum number benefit from effective  drug therapy  for disease."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12574", "text": "The following is a list of useful publications from the WHO  Department of Essential Drugs and Medicines Policy  about essential drugs programs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12575", "text": "An excipient is a substance formulated alongside the  active ingredient  of a  medication . They may be used to enhance the active ingredient\u2019s therapeutic properties; to facilitate drug absorption; to reduce viscosity; to enhance solubility; to improve long-term stabilization (preventing denaturation and aggregation during the expected shelf life); or to add bulk to solid formulations that have small amounts of potent active ingredients (in that context, they are often referred to as \"bulking agents\", \"fillers\", or \"diluents\"). [ 1 ] [ 2 ]  During the manufacturing process, excipients can improve the handling of active substances and facilitate powder flow. The choice of excipients depends on factors such as the intended route of administration, the dosage form, and compatibility with the active ingredient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12576", "text": "Virtually all marketed drugs contain excipients, and final drug formulations commonly contain more excipient than active ingredient.  Pharmaceutical regulations and standards mandate the identification and safety assessment of all ingredients in drugs, including their chemical decomposition products. Novel excipients can sometimes be patented, or the specific formulation can be kept as a  trade secret  to prevent competitors from duplicating it through  reverse engineering . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12577", "text": "Though excipients were at one time assumed to be \"inactive\" ingredients, it is now understood that they can sometimes be \"a key determinant of dosage form performance\"; [ 3 ]  in other words, their effects on  pharmacodynamics  and  pharmacokinetics , although usually negligible, cannot be  known  to be negligible without  empirical confirmation  and sometimes are important. For that reason, in  basic research  and  clinical trials  they are sometimes included in the  control substances  in order to minimize  confounding , reflecting that otherwise, the absence of the active ingredient would not be the only variable involved, because absence of excipient cannot always be assumed not to be a variable. [ 4 ]  Such studies are called excipient-controlled or  vehicle -controlled studies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12578", "text": "Adjuvants are added to vaccines to enhance or modify the immune system response to an immunization. An adjuvant may stimulate the immune system to respond more vigorously to a vaccine, which leads to more robust immunity in the recipient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12579", "text": "Antiadherents reduce the  adhesion  between the  powder  ( granules ) and the  punch  faces and thus prevent sticking to tablet punches by offering a  non-stick surface . They are also used to help protect tablets from sticking. The most commonly used is  magnesium stearate ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12580", "text": "Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to low active dose tablets. Binders are usually:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12581", "text": "Binders are classified according to their application:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12582", "text": "Tablet coatings protect tablet ingredients from deterioration by moisture in the air and make large or unpleasant-tasting tablets easier to swallow. For most coated tablets, a cellulose ether  hydroxypropyl methylcellulose  (HPMC) film coating is used which is free of sugar and potential  allergens . Occasionally, other coating materials are used, for example synthetic polymers,  shellac , corn protein  zein  or other polysaccharides.  Capsules  are coated with gelatin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12583", "text": "Enterics  control the rate of drug release and determine where the drug will be released in the digestive tract. Materials used for enteric coatings include fatty acids, waxes, shellac, plastics, and plant fibers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12584", "text": "Colours  are added to improve the appearance of a formulation. Colour consistency is important as it allows easy identification of a medication. Furthermore, colours often improve the aesthetic look and feel of medications. Small amounts of colouring agents are easily processed by the body, although rare reactions are known, notably to  tartrazine . [ 5 ]  Commonly, titanium oxide is used as a colouring agent to produce the popular opaque colours along with azo dyes for other colors. By increasing these  organoleptic  properties a patient is more likely to adhere to their schedule and therapeutic objectives will also have a better outcome for the patient especially children."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12585", "text": "Disintegrants expand and dissolve when wet causing the tablet to break apart in the  digestive tract , or in specific segments of the digestion process, releasing the active ingredients for  absorption . They ensure that when the tablet is in contact with  water , it rapidly breaks down into smaller fragments, facilitating  dissolution . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12586", "text": "Examples of disintegrants include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12587", "text": "Flavours  can be used to mask unpleasant tasting active ingredients and improve the acceptance that the patient will complete a course of medication. Flavourings may be natural (e.g. fruit extract) or artificial. [ 6 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12588", "text": "For example, to improve: [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12589", "text": "Glidants  are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce wall friction. Examples include  silica gel ,  fumed silica ,  talc , and  magnesium carbonate . However, some silica gel glidants such as Syloid(R) 244 FP and Syloid(R) XDP are multi-functional and offer several other performance benefits in addition to reducing interparticle friction including moisture resistance, taste, marketing, etc."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12590", "text": "Lubricants  prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low  friction  between the solid and die wall. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12591", "text": "Common minerals like  talc  or  silica , and  fats , e.g. vegetable  stearin ,  magnesium stearate  or  stearic acid  are the most frequently used lubricants in tablets or hard gelatin capsules. Lubricants are agents added in small quantities to tablet and capsule formulations to improve certain processing characteristics. While lubricants are often added to improve manufacturability of the drug products, it may also negatively impact the product quality. For example, extended mixing of lubricants during blending may results in delayed dissolution and softer tablets, which is often referred to as \"over-lubrication\". Therefore, optimizing lubrication time is critical during pharmaceutical development. [ 7 ] [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12592", "text": "There are three roles identified with lubricants as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12593", "text": "There are two major types of lubricants:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12594", "text": "Some typical  preservatives  used in pharmaceutical formulations are"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12595", "text": "Sorbents  are used for tablet/capsule moisture-proofing by limited fluid sorbing (taking up of a liquid or a gas either by  adsorption  or by  absorption ) in a dry state. For example,  desiccants  absorb water,  drying  out ( desiccating ) the surrounding materials."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12596", "text": "Sweeteners  are added to make the ingredients more palatable, especially in chewable tablets such as  antacid  or liquids like  cough syrup .  Sugar  can be used to mask unpleasant tastes or smells, but artificial sweeteners tend to be preferred, as natural ones tend to cause tooth decay. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12597", "text": "In liquid and gel formulations, the bulk excipient that serves as a medium for conveying the active ingredient is usually called the  vehicle .  Petrolatum ,  dimethyl sulfoxide  and  mineral oil  are common vehicles."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12598", "text": "A  film coating  is a thin  polymer -based coat that is typically sprayed onto solid  pharmaceutical   dosage forms , such as  tablets ,  capsules , pellets or granules. Film coating can impact both its appearance and its pharmacokinetics making it an essential process in making the final drug product."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12599", "text": "Film coatings are the most common form of drug coating and are generally applied in orally-administered pharmaceuticals. The motivation for applying film coatings to dosage forms range from cosmetic considerations (colour, gloss and branding), improving the  shelf life  by providing a protective barrier between the drug and the surrounding environment. These types of film coatings are known as non-functional film coatings. They may also be used to delay or augment the delivery and uptake of medications or delay release and uptake until the medication passes through the  stomach . These types of film coatings are known as functional film coatings."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12600", "text": "The conventional method of applying film coatings to oral dosage forms comprises a spraying phase and a drying phase. [ 1 ]  The spraying phase consists of applying a layer of a polymer,  plasticizer ,  colourant ,  opacifier ,  solvent , and a  vehicle  to the oral dosage form's core. [ 2 ]  Once applied, the oral dosage form is dried by passing hot air over the dosage form, which typically also removes the solvent as well. The final result is a thin film coating with the desired plasticizer, colour, opacifier, and vehicle. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12601", "text": "Non-functional film coating involves changes made to the aesthetic of the oral dosage form. Such changes affect an oral dosage form's appearance, organoleptic properties, swallowing properties, and provide protection against harsh environmental conditions that can damage the active pharmaceutical ingredient. [ 2 ]  These changes are conducted to improve the compliance and effects of the oral dosage form. For instance, changing appearance can be done by changing the colour of the drug, leading to a more appealing product. [ 2 ]  Changing the swallowing properties can make it easier for those suffering from dysphagia. [ 2 ]  Finally, adding a film that protects from harsh environments, such conditions include humidity, oxidation, or light, increases the shelf life of the final product. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12602", "text": "Functional film coating provides the same properties as non-functional film coating, but also has added properties that affect drug release. [ 2 ]  These changes alter the region in the gastrointestinal tract that the final drug product is released. [ 2 ]  See  modified-release dosage  and  enteric coatings ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12603", "text": "Organic solvent use in film coating is typically used to incorporate protective coatings to the oral dosage form, which aids in increasing the shelf life of the final drug product. [ 1 ]  This type of film coating can be dangerous  due to its potential for toxicity in the final product and flammability during the film coating process. [ 1 ]  As such, it is integral to have proper safety measures and ventilation in place when film coating."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12604", "text": "Aqueous film coating is the most common film coating method currently used. [ 1 ]  This type of film coating uses water to aid in the film coating process instead of organic solvents. [ 1 ]  The result is a safer means of film coating, as it avoids the toxic and flammable properties of organic solvents. Aqueous film coating requires the use of water insoluble polymer mixtures, with the addition of a plasticizer. [ 1 ]  Despite its widespread popularity, aqueous film coating is more time consuming than organic solvent-based coating, due to the increased time needed for complete evaporation of water. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12605", "text": "Solvent-free film coating is most commonly used in coating heat sensitive drugs due to the benefit of not requiring a drying phase. [ 1 ]  The end result of this type of film coating is an inert film coating that does not react with the  active pharmaceutical ingredients . [ 1 ]  Some methods to create a solvent-free film coating include injection molding coating, hot-melt coating, and spray congealing. [ 1 ]  Each method has its own advantages and disadvantages, but the common theme amongst them is the need for very precise conditions that can satisfactorily apply a film coating to the oral dosage form. [ 1 ]  As such, it is an inefficient type of film coating that has resulted in its lack of widespread use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12606", "text": "A  formulary  is a list of  pharmaceutical drugs , often decided upon by a group of people, for various reasons such as insurance coverage or use at a medical facility. [ 1 ]  Traditionally, a formulary contained a collection of formulas for the  compounding  and testing of medication (a resource closer to what would be referred to as a  pharmacopoeia  today). Today, the main function of a prescription formulary is to specify particular medications that are approved to be  prescribed  at a particular  hospital , in a particular  health system , or under a particular  health insurance  policy. The development of prescription formularies is based on evaluations of efficacy, safety, and  cost-effectiveness  of drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12607", "text": "Depending on the individual formulary, it may also contain additional clinical information, such as  side effects ,  contraindications , and  doses ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12608", "text": "By the turn of the millennium, 156 countries had national or provincial  essential medicines  lists and 135 countries had national treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12609", "text": "In Australia, where there is a public health care system, medications are subsidised under the  Pharmaceutical Benefits Scheme  (PBS) and medications that are available under the PBS and the indications for which they can be obtained under said scheme can be found in at least two places, the PBS webpage [ 2 ]  and the  Australian Medicines Handbook . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12610", "text": "The Prescription Drug List  is the national formulary that lists all medical ingredients for human and animal use available with a prescription with the exception of those under the  Controlled Drugs and Substances Act . [ 3 ] [ 4 ]  The  Canadian Agency for Drugs and Technologies in Health  (CADTH) is the advisory body that evaluates new medical technologies and prescription medication. Based on recommendations the provincial and territorial governments decide whether or not to implement changes to their healthcare system and public drug formularies. [ 5 ]  Provincial and territorial government provide partial prescription drug coverage and the overall drug payment is a mix of public taxation, private insurance and out-of-pocket expenses. [ 4 ] [ 6 ]  Insurance coverage differs regionally, although each public drug coverage plan must meet standards set by the federal government. [ 6 ]  Regional health authorities are in charge of regulating and providing its residents insurance while the federal government provides insurance for specifically eligible veterans,  First Nations ,  Inuit , Canadian Forces, federal inmates and some refugees. [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12611", "text": "In the US, where a system of quasi-private healthcare is in place, a formulary is a list of  prescription drugs  available to enrollees, and a tiered formulary provides financial incentives for patients to select lower-cost drugs. For example, under a 3-tier formulary, the first tier typically includes generic drugs with the lowest cost sharing (e.g., 10% coinsurance), the second includes preferred brand-name drugs with higher cost sharing (e.g., 25%), and the third includes non-preferred brand-name drugs with the highest cost-sharing (e.g., 40%). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12612", "text": "When used appropriately, formularies can help manage drug costs imposed on the insurance policy. [ 7 ]  However, for drugs that are not on formulary, patients must pay a larger percentage of the cost of the drug, sometimes 100%. Formularies vary between drug plans and differ in the breadth of drugs covered and costs of co-pay and  premiums . Most formularies cover at least one drug in each drug class, and encourage  generic  substitution (also known as a  preferred drug list ). [ 8 ]  Formularies have shown to cause issues in hospitals when patients are discharged when not aligned with outpatient drug insurance plans. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12613", "text": "In the UK, the  National Health Service  (NHS) provides  publicly funded   universal health care , financed by  national health insurance . Here, formularies exist to specify which drugs are available on the NHS. The two main reference sources providing this information are the  British National Formulary  ( BNF ) and the  Drug Tariff . There is a section in the Drug Tariff, known unofficially as the \" Blacklist \", detailing medicines which are not to be prescribed under the NHS and must be paid for privately by the patient. Recommendations for additions to the NHS formulary are provided by the  National Institute for Health and Care Excellence . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12614", "text": "In addition to this, local  NHS hospital trusts  and  Primary Care  ( General Practitioners )  Clinical Commissioning Groups  (CCGs), produce their own lists of medicines deemed preferable for prescribing within their locality or organisation; such lists are usually a subset of the more comprehensive BNF. These formularies are not absolutely binding, and  physicians  may prescribe a non-formulary medicine if they consider it necessary and justifiable. Often, these local formularies are shared between a Primary Care Organisation (PCO) and hospitals within that PCO's jurisdiction, in order to facilitate the procedure of transferring a patient from  primary care  to  secondary care , thus causing fewer \"interfacing\" issues in the process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12615", "text": "As in the United States, the NHS actively encourages prescribing of generic drugs, in order to save more of the budget allocated to them by the  Department of Health ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12616", "text": "A national formulary contains a list of medicines that are approved for  prescription  throughout the country, indicating which products are interchangeable. It includes key information on the composition, description, selection, prescribing, dispensing and administration of medicines. Those drugs considered less suitable for prescribing are clearly identified."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12617", "text": "Examples of national formularies are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12618", "text": "Hirudiculture  is the culture, or  farming , of  leeches  in both natural and artificial environments.  This practice drew the attention of  Parisian  savants and members of the French Soci\u00e9t\u00e9 Zoologique d'Acclimitation in the mid-to-late 19th century as a part of a larger interest in the culture of  fish  and  oysters . [ 1 ]   Leech culture was seen as a solution to growing demand for medicinal leeches throughout the world."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12619", "text": "The use of leeches for medicinal purposes, or  hirudotherapy , has been revived by contemporary medicine. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12620", "text": "This  annelid -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12621", "text": "This  agriculture  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12622", "text": "HOSPI  is a  hospital delivery robot  manufactured by  Panasonic . HOSPI service robots were originally developed to be used in healthcare amid Japan's rapidly aging society. [ 1 ]  It features  autonomous navigation  capabilities, which allows it navigate using onboard sensors instead of obtrusive rail systems or delineated routes. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12623", "text": "The HOSPI robot was launched in 2004. It was built to move autonomously through the pre-installed mapping information within them. It is installed with an on-board sensor and an advanced collision-avoidance system that helps it to move around avoiding obstacles, and stop if a person suddenly runs in front of it. [ 2 ]  At IREX in 2013, Panasonic introduced a new version of the robot and began to conduct  hospital  trials of it. Those trials were declared successful and Panasonic began to sell the robots. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12624", "text": "In January 2017, the Crowne Plaza ANA Narita hotel began using HOSPI robots primarily for serving drinks and clearing the tables. [ 4 ] [ 5 ] [ 6 ]   Panasonic also announced in the same year that there are four hospitals in Japan that use the HOSPI technology. [ 2 ]  In the same period,  Narita International Airport  also became the location of the first demonstration experiment of a HOSPI variant designed as an autonomous signage robot. [ 7 ]  This experiment is designed to evaluate the value of the signage robot in such a setting."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12625", "text": "Capabilities"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12626", "text": "Hospi has security features that prevent theft, its contents from being stolen."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12627", "text": "Hospi is able to deliver loads that are timely and loads that humans are incapable of carrying."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12628", "text": "Hospi is programmed and equipped with sensors to efficiently and flexibly navigate a hospital layout. Hospi is able to do this also do this all autonomously"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12629", "text": "Real Implementation"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12630", "text": "Changi general hospital uses hospi as part of the hospitals\u2019 porter management system"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12631", "text": "In 2017, Hospi was tested at a hotel call ANA Crowne Plaza Narita hotel and in Narita International Airport."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12632", "text": "This robotics-related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12633", "text": "The  Human Medicines Regulations 2012   in the United Kingdom were created, under statutory authority of the  European Communities Act 1972  and the  Medicines Act 1968  in 2012. The body responsible for their upkeep is the  Medicines and Healthcare products Regulatory Agency . The regulations partially repealed the  Medicines Act 1968  in line with  EU  legislation. [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12634", "text": "In October 2020, the regulations were amended to expand the workforce eligible to administer COVID-19 vaccines, so enabling additional healthcare professionals to vaccinate the public.  This was a temporary provision, but in January 2022 it was announced that this would be made permanent as would the provision for community pharmacy contractors to provide COVID-19 and flu vaccines \u201caway from their normal registered premises\u201d. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12635", "text": "Regulation 174 provides an exemption to the requirement for authorisation of Regulation 46, allowing for the sale or supply of any medicinal product to be temporarily authorised by the licensing authority (MHRA) in response to the suspected or confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12636", "text": "Pharmaceutical marketing  is a branch of  marketing  science and practice focused on the  communication , differential  positioning  and commercialization of  pharmaceutical products , like specialist drugs,  biotech drugs  and  over-the-counter drugs . By extension, this definition is sometimes also used for marketing practices applied to  nutraceuticals  and  medical devices ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12637", "text": "Whilst rule of law regulating  pharmaceutical industry  marketing activities is widely variable across the world, pharmaceutical marketing is usually strongly regulated by international and national agencies, like the  Food and Drug Administration  and the  European Medicines Agency . Local regulations from government or local pharmaceutical industry associations like  Pharmaceutical Research and Manufacturers of America  or  European Federation of Pharmaceutical Industries and Associations (EFPIA)  can further limit or specify allowed commercial practices."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12638", "text": "Marketing to health-care providers takes three main forms: activity by pharmaceutical sales representatives, provision of drug samples, and sponsoring  continuing medical education  (CME). [ 1 ]  The use of gifts, including pens and coffee mugs embossed with pharmaceutical product names, has been prohibited by PHRMA ethics guidelines since 2008. [ 2 ] [ 3 ] \nOf the 237,000 medical sites representing 680,000 physicians surveyed in SK&A's 2010 Physician Access survey, half said they prefer or require an appointment to see a rep (up from 38.5% preferring or requiring an appointment in 2008), while 23% won't see reps at all, according to the survey data.  Practices owned by hospitals or health systems are tougher to get into than private practices, since appointments have to go through headquarters, the survey found.\n13.3% of offices with just one or two doctors won't see representatives, compared with a no-see rate of 42% at offices with 10 or more doctors.\nThe most accessible physicians for promotional purposes are allergists/immunologists \u2013 only 4.2% won't see reps at all \u2013 followed by orthopedic specialists (5.1%) and diabetes specialists (7.6%). Diagnostic radiologists are the most rigid about allowing details \u2013 92.1% won't see reps \u2013 followed by pathologists and neuroradiologists, at 92.1% and 91.8%, respectively. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12639", "text": "E-detailing is widely used to reach \"no see physicians\"; approximately 23% of primary care physicians and 28% of specialists prefer computer-based e-detailing, according to survey findings reported in the 25 April 2011 edition of American Medical News (AMNews), published by the American Medical Association (AMA). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12640", "text": "The  Pharmaceutical Research and Manufacturers of America  (PhRMA) released updates to its voluntary Code on Interactions with Healthcare Professionals on 10 July 2008. The new guidelines took effect in January 2009. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12641", "text": "In addition to prohibiting small gifts and reminder items such as pens, notepads, staplers, clipboards, paperweights, pill boxes, etc., [ 6 ]  the revised Code:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12642", "text": "Free samples have been shown to affect physician prescribing behavior.  Physicians with access to free samples are more likely to prescribe brand name medication over equivalent generic medications. [ 2 ]   Other studies found that free samples decreased the likelihood that physicians would follow the standard of care practices. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12643", "text": "Receiving pharmaceutical samples does not reduce prescription costs. Even after receiving samples, sample recipients remain disproportionately burdened by prescription costs. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12644", "text": "It is argued that a benefit to free samples is the \"try it before you buy it\" approach. Free samples give immediate access to the medication and the patient can begin treatment right away.  It also saves time from going to a pharmacy to get it filled before treatment begins. Since not all medications work for everyone, and many do not work the same way for each person, free samples allow patients to find which dose and brand of medication works best before having to spend money on a filled prescription at a  pharmacy . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12645", "text": "Hours spent by physicians in industry-supported  continuing medical education  (CME) is greater than that from either  medical schools  or professional societies. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12646", "text": "Currently, there are approximately 81,000  pharmaceutical sales representatives  in the United States [ 8 ]  pursuing some 830,000 pharmaceutical prescribers. A pharmaceutical representative will often try to see a given physician every few weeks. Representatives often have a call list of about 200\u2013300 physicians with 120\u2013180 targets that should be visited in 1\u20132 or 3 week cycle."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12647", "text": "Because of the large size of the pharmaceutical sales force, the organization, management, and measurement of effectiveness of the sales force are significant business challenges. Management tasks are usually broken down into the areas of physician targeting, sales force size and structure, sales force optimization, call planning, and sales forces effectiveness. A few pharmaceutical companies have realized that training sales representatives on high science alone is not enough, especially when most products are similar in quality.  Thus, training sales representatives on relationship selling techniques in addition to medical science and product knowledge, can make a difference in sales force effectiveness.  Specialist physicians are relying more and more on specialty sales reps for product information, because they are more knowledgeable than primary care reps."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12648", "text": "The United States has 81,000 pharmaceutical representatives or 1 for every 7.9 physicians. [ 2 ]  The number and persistence of pharmaceutical representatives has placed a burden on the time of physicians. [ 9 ]  \"As the number of reps went up, the amount of time an average rep spent with doctors went down\u2014so far down, that tactical scaling has spawned a strategic crisis.  Physicians no longer spend much time with sales reps, nor do they see this as a serious problem.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_12649", "text": "Marketers must decide on the appropriate size of a sales force needed to sell a particular portfolio of drugs to the target market. Factors influencing this decision are the optimal reach (how many physicians to see) and frequency (how often to see them) for each individual physician, how many patients with that disease state, how many sales representatives to devote to office and group practice and how many to devote to hospital accounts if needed. To aid this decision, customers are broken down into different classes according to their prescription behavior, patient population, their business potential, and event their personality traits. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12650", "text": "Marketers attempt to identify the set of physicians most likely to prescribe a given drug. Historically, this was done by drug reps 'on the ground' using zip code sales and engaging in recon to figure out who the high prescribers were in a particular sales territory.  However, in the mid-1990s the industry, through third-party prescribing data (e.g., Quintiles/IMS) switched to \"script-tracking\"  [ 10 ]  technologies, measuring the number of total prescriptions (TRx) and new prescriptions (NRx) per week that each physician writes. This information is collected by commercial vendors. The physicians are then \"deciled\" into ten groups based on their writing patterns. Higher deciles are more aggressively targeted. Some pharmaceutical companies use additional information such as:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12651", "text": "Physicians are perhaps the most important component in sales. They write the prescriptions that determine which drugs will be used by people.  Influencing the physician is the key to pharmaceutical sales.  Historically, by a large pharmaceutical sales force. A medium-sized pharmaceutical company might have a sales force of 1000 representatives. [ citation needed ]   The largest companies have tens of thousands of representatives around the world. Sales representatives called upon physicians regularly, providing clinical information, approved journal articles, and free drug samples. This is still the approach today; however, economic pressures on the industry are causing pharmaceutical companies to rethink the traditional sales process to physicians. The industry has seen a large scale adoption of Pharma CRM systems that works on laptops and more recently  tablets . The new age pharmaceutical representative is armed with key data at his fingertips and tools to maximize the time spent with physicians."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12652", "text": "Pharmaceutical and medical device companies have also paid physicians to use their drugs, which could affect how often a drug is prescribed. For example, one study that looked at physician payments and pimavanserin found that \"extensive physician payments have been associated with increased pimavanserin prescription volume and Medicare expenditures.\" [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12653", "text": "More specifically, drug reps help to create a culture of gifting, or the \"pharmaceutical gift exchange,\" where actual monetary transactions are rare.  In reality, gifts, both large and small, ranging from cups of coffee to travel to medical conferences are exchanged on a routine basis with high prescribers in an effort to shift their obligations from patients to prescriptions and have proven effective. [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12654", "text": "Key opinion leaders (KOL), or \"thought leaders\", are respected individuals, such as prominent medical school faculty, who influence physicians through their professional status. Pharmaceutical companies generally engage key opinion leaders early in the drug development process to provide advocacy and key marketing feedback. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12655", "text": "Some pharmaceutical companies identify key opinion leaders through direct inquiry of physicians (primary research). Recently, pharmaceutical companies have begun to use  social network analysis  to uncover thought leaders; because it does not introduce respondent bias, which is commonly found in primary research; it can identify and map out the entire scientific community for a disease state; and it has greater compliance with state and federal regulations; because physician prescribing patterns are not used to create the social network. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12656", "text": "Physicians acquire information through informal contacts with their colleagues, including social events, professional affiliations, common hospital affiliations, and common medical school affiliations. Some pharmaceutical companies identify influential colleagues through commercially available prescription writing and patient level data. [ 17 ] \nDoctor dinner meetings are an effective way for physicians to acquire educational information from respected peers and to influence the so-called \"no-see\" physicians - those that are reluctant to engage directly with pharmaceutical reps through detailing but may come to a dinner program where a local or national expert is talking. [ 18 ]   These meetings are sponsored by some pharmaceutical companies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12657", "text": "Legal cases and US congressional hearings have provided access to  pharmaceutical industry documents  revealing new marketing strategies for drugs. [ 19 ]   Activities once considered independent of promotional intent, including  continuing medical education  and  medical research , are used, including paying to publish articles about promoted drugs for the medical literature, and alleged suppression of unfavorable study results. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12658", "text": "Public and private insurers affect the writing of prescriptions by physicians through  formularies  that restrict the number and types of drugs that the insurer will cover. Not only can the insurer affect drug sales by including or excluding a particular drug from a formulary, they can affect sales by tiering, or placing bureaucratic hurdles to prescribing certain drugs. In January 2006, the United States instituted a new public prescription drug plan through its  Medicare  program. Known as  Medicare Part\u00a0D , this program engages private insurers to negotiate with  pharmaceutical companies  for the placement of drugs on tiered formularies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12659", "text": "Only two countries as of 2008 allow  direct to consumer advertising  (DTCA): the United States and New Zealand. [ 21 ] [ 22 ] [ 2 ]  Since the late 1970s, DTCA of prescription drugs has become important in the United States. It takes two main forms: the promotion or creation of a disease out of a non-pathologic physical condition or the promotion of a medication. [ 2 ]  The rhetorical objective of direct-to-consumer advertising is to directly influence the patient-physician dialogue. [ 23 ]  Many patients will inquire about, or even demand a medication they have seen advertised on television. [ 21 ]  In the United States, recent years have seen an increase in mass media advertisements for pharmaceuticals.\nExpenditures on direct-to-users advertising almost quadrupled in the seven years between 1997 and 2005 since the FDA changed the guidelines, from $1.1 billion in 1997 to more than $4.2 billion in 2005, a 19.6% annual increase, according to the United States  Government Accountability Office , 2006). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12660", "text": "The mass marketing to users of pharmaceuticals is banned in over 30 industrialized nations, but not in the US and  New Zealand , [ 21 ]  which is considering a ban. [ 24 ]  Some feel it is better to leave the decision wholly in the hands of medical professionals; others feel that users education and participation in health is useful, but users need independent, comparative information about drugs (not promotional information). [ 21 ] [ 24 ]  For these reasons, most countries impose limits on pharmaceutical mass marketing that are not placed on the marketing of other products. In some areas it is required that ads for drugs include a list of possible side effects, so that users are informed of both facets of a medicine.  Canada 's limitations on pharmaceutical advertising ensure that commercials that mention the name of a product cannot in any way describe what it does. Commercials that mention a medical problem cannot also mention the name of the product for sale; at most, they can direct the viewer to a website or telephone number operated by the pharmaceutical company."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12661", "text": "Reynold Spector has provided examples of how positive and negative hype can affect perceptions of pharmaceuticals using examples of certain cancer drugs, such as  Avastin  and  Opdivo , in the former case and  statins  in the latter. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12662", "text": "In the United States, pharmaceutical companies often provide  drug coupons  to consumers to help offset the  copayments  charged by health insurers for prescription medication. These coupons are generally used to promote medications that compete with non-preferred products and cheaper, generic alternatives by reducing or eliminating the extra out-of-pocket costs that an insurers typically charge a patient for a non-preferred drug product. [ 26 ]  But sometimes coupons for brand-name drugs could potentially distort the market and leading to higher overall healthcare costs since they encourage the overuse of more expensive drugs over generic alternatives. Consumers often realize too late that the continued use of these drugs without coupons necessitates either switching to a cheaper generic or facing steep out-of-pocket expenses. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12663", "text": "Pharmaceutical company spending on marketing exceeds that spent on research. [ 28 ] [ 2 ]   In 2004 in Canada $1.7 billion a year was spent marketing drugs to physicians and in the United States $21 billion were spent in 2002. [ 29 ]   In 2005 money spent on pharmaceutical marketing in the United States was estimated at $29.9 billion with one estimate as high as $57 billion. [ 2 ]   When the US number are broken down 56% was free samples, 25% was detailing of physicians, 12.5% was direct to users advertising, 4% on hospital detailing, and 2% on journal ads. [ 29 ]  In the United States approximately $20 billion could be saved if generics were used instead of equivalent brand name products. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12664", "text": "Although pharmaceutical companies have made large investments in marketing their products, overall promotional spending has been decreasing over the last few years, and declined by 10 percent from 2009 to 2010. Pharmaceutical companies are cutting back mostly in detailing and sampling, while spending in mailings and print advertising grew since last year. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12665", "text": "In the European Union, marketing of pharmaceuticals is regulated by EU (formerly EEC)  Directive 92/28/EEC . [ 31 ]  Among other things, it requires member states to prohibit off-label marketing, and direct-to-consumer marketing of prescription-only medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12666", "text": "In the United States, marketing and distribution of pharmaceuticals is regulated by the  Federal Food, Drug, and Cosmetic Act  and the  Prescription Drug Marketing Act , respectively.  Food and Drug Administration  (FDA) regulations require all prescription drug promotion to be truthful and not misleading, based on \"substantial evidence or substantial clinical experience\", to provide a \"fair balance\" between the risks and benefits of the promoted drug, and to maintain consistency with labeling approved by the FDA. The FDA Office of Prescription Drug Promotion enforces these requirements."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12667", "text": "In the 1990s, antipsychotics were \"still seen as treatments for the most serious mental illnesses, like hallucinatory schizophrenia, and recast them for much broader uses\". Drugs such as  Abilify  and  Geodon  were given to a broad range of patients, from preschoolers to octogenarians. In 2010, more than a half-million youths took antipsychotic drugs, and one-quarter of nursing-home residents have used them. Yet the government warns that the drugs may be fatal to some older patients and have unknown effects on children. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12668", "text": "Every major company selling the drugs\u2014 Bristol-Myers Squibb ,  Eli Lilly ,  Pfizer ,  AstraZeneca , and  Johnson & Johnson \u2014has either settled recent government cases, under the False Claims Act, for hundreds of millions of dollars or is currently under investigation for possible health care fraud. Following charges of illegal marketing, two of the settlements in 2009 set records for the largest criminal fines ever imposed on corporations. One involved Eli Lilly's antipsychotic  Zyprexa , and the other involved  Bextra . In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic,  Geodon ; Pfizer settled that part of the claim for $301 million, without admitting any wrongdoing. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12669", "text": "The following is a list of the four largest settlements reached with  pharmaceutical companies  from 1991 to 2012, rank ordered by the size of the total settlement. Legal claims against the pharmaceutical industry have varied widely over the past two decades, including  Medicare and Medicaid fraud ,  off-label  promotion, and inadequate manufacturing practices. [ 33 ] [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12670", "text": "The emergence of new media and technologies in recent years is quickly changing the pharmaceutical marketing landscape in the United States. Both physicians and users are increasing their reliance on the Internet as a source of health and medical information, prompting pharmaceutical marketers to look at digital channels for opportunities to reach their target audiences. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12671", "text": "In 2008, 84% of U.S. physicians used the Internet and other technologies to access pharmaceutical, biotech or medical device information\u2014a 20% increase from 2004. [ citation needed ]  At the same time, sales reps are finding it more difficult to get time with doctors for in-person details.  Pharmaceutical companies are exploring online marketing as an alternative way to reach physicians. Emerging e-promotional activities include live video detailing, online events, electronic sampling, and physician customer service portals such as PV Updates, MDLinx, Aptus Health (former Physicians Interactive), and  Epocrates ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12672", "text": "Direct-to-users marketers are also recognizing the need to shift to digital channels as audiences become more fragmented and the number of access points for news, entertainment and information multiplies. Standard television, radio and print direct-to-users (DTC) advertisements are less relevant than in the past, and companies are beginning to focus more on  digital marketing  efforts like product websites,  online display advertising ,  search engine marketing ,  social media  campaigns, place-based media and  mobile advertising  to reach the over 145 million U.S. adults online for health information."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12673", "text": "In 2010, the  FDA 's Division of Drug Marketing, Advertising and Communications issued a warning letter concerning two unbranded consumer targeted Web sites sponsored by  Novartis  Pharmaceuticals Corporation as the websites promoted a drug for an unapproved use, the websites failed to disclose the risks associated with the use of the drug and made unsubstantiated dosing claims. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12674", "text": "The  Medication Appropriateness Tool for Comorbid Health conditions during Dementia  ( MATCH-D )  criteria  supports clinicians to manage medication use specifically for people with  dementia  without focusing only on the management of the  dementia  itself. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12675", "text": "The MATCH-D were developed by medical practitioners and pharmacists at Australian  Group of Eight Universities .  It was led by Dr Amy Theresa Page at the Western Australian Centre for Health and Ageing at the  University of Western Australia . The MATCH-D Criteria were developed through a consensus panel of experts using the  Delphi method . The criteria were originally published in the Internal Medicine Journal in 2016. [ 2 ]  The protocol explaining the rigorous methods used to develop the criteria were originally published in the  BMJ Open  in 2015. [ 3 ]  The systematic review that informed the criteria were published subsequently in 2018 and updated in 2022. [ 4 ]   [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12676", "text": "The MATCH-D is presented in categories of recommendations for all stages of dementia, as well as divided into specific recommendations for early, mid and late-stage dementia. [ 6 ]  The recommendations are groups as: medication side effects, principles for medication use, medication review, treatment goals, preventative medications, symptom management, psycho-active medications and medications to modify dementia progression."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12677", "text": "The MATCH-D attracted media attention as it was under development, and as it was released.  Page was interviewed on the ABC national radio's science show during its development. [ 7 ]  The health media picked up the story as soon as it was published. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12678", "text": "Respected organisations such as the British Geriatrics Society incorporated into their own medicines management guidelines. In New Zealand, the NZ Health Quality & Safety Commission have shared it in their communications. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12679", "text": "It is cited and promoted by influential professional bodies in many countries including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12680", "text": "- the British Geriatrics Society's End of Life Care in Frailty guidelines [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12681", "text": "- New Zealand's Health Quality & Safety Commission's medication management work [ 11 ]   [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12682", "text": "- Australia's Royal Australian College of General Practitioners (RACGP) aged care clinical guide known as the Silver Book [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12683", "text": "- Australia's Pharmaceutical Society of Australia (PSA) Choosing Wisely series"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12684", "text": "- Australian Commission on Safety and Quality in Health Care  [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12685", "text": "- Australian Deprescribing Network (ADeN)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12686", "text": "- Australia's NPS MedicinesWise recommended it in their Medication Management Review Reports: Best practice recommendations program and Changed Behaviour in Dementia. [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12687", "text": "- New South Wales' Therapeutic Advisory Group (TAG)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12688", "text": "Consumers considered the MATCH-D to be a useful tool for prompting and supporting conversations about their preferences for medication use. They would prefer that these conversations began as early as possible so that their treating health professionals knew their preferences. General practitioners, pharmacists and nurses stated they often felt less comfortable discussing these issues as they were concerned that it may cause distress to the consumer.  Health professionals and consumers alike thought that using the MATCH-D as a conversation starter could assist with these conversations. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12689", "text": "It is incorporated in to the TaperMD decision support tool and the PIMSPlus platform.  This incorporation has hastened the uptake of the criteria in both long term care facilities and community in Canada."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12690", "text": "More than one-quarter of Australian consultant pharmacists state that they use the MATCH-D during Home Medicine Reviews. [ 18 ]  This figure is suggestive of high uptake given that most Home Medicine Reviews are most likely undertaken for people who are not living with dementia."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12691", "text": "Translational research was undertaken with consumers, general practitioners, nurses and pharmacists to explore the enablers and barriers to using the MATCH-D in practice. [ 17 ]  This research showed the need for a website (since launched at  MATCH-D.com.au ), checklists (available at the website) and educational resources. These stakeholder roles have shown that there is a strong need for support and collaboration to improve medication use. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12692", "text": "Research at King's College London explored the hazards of suboptimal prescribing and polypharmacy in medicines use for people with dementia. They determined that each year there are globally up to 10 million people living with dementia require hospital treatment (emergency department or hospital admissions) related to medicines related harm for people with dementia. [ 20 ]   They concluded that, if the MATCH-D were successfully implemented that the relative hazards of medicines use for people with dementia would need to be re-evaluated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12693", "text": "The  National Health and Medical Research Council  (NHMRC) are currently funding a randomised controlled trial implementing the MATCH-D using pharmacists embedded in general practice. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12694", "text": "The Dementia Training Australia funding an interactive online education package for deprescribing in dementia centered around the MATCH-D. It was a joint collaboration between the University of Western Australia, University of Tasmania, La Trobe University, Monash University, Alfred Health and FireFilms. This education package launched in mid-2019. [ 22 ]  This online course is suitable for consumers and health professionals, with a target audience of nurses working in residential aged care facilities.  The training package was in the format of a documentary film, with its original developer, Dr Page featured as narrator and interviewer.  It includes simulated patient encounters and expert interviews, interspersed with interactive activities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12695", "text": "The MATCH-D and the training package by Dementia Training Australia have now been incorporated into undergraduate degrees for health professionals including the University of Tasmania's second year Bachelor of Nursing curriculum and Monash University's Bachelor of Pharmacy (Honours) curriculum."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12696", "text": "A  medicine chest  is a container or  cabinet  for storing  medicine .  All  ships  governed by the  regulations  of the  International Maritime Organization  must have medical supplies and suitable storage for them such as  refrigeration  and  locks . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12697", "text": "In Canada medicine chest has a related, symbolic meaning. Under the terms of  Treaty 6  between the Canadian government and several bands of First Nations people (\"Indians\"), the government was required to supply each  Indian reserve  with a medicine chest. That has been interpreted as an ongoing responsibility for the government to provide  healthcare  to First Nations people. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12698", "text": "In  pharmaceutics ,  micromixing  is a process in which ingredient particles rearrange to form a  blend .  Development of  pharmaceutical formulations  requires understanding how the ingredients blend with each other and how the blending progresses through different stages.  It is also important to establish in a scientific manner when the blending is considered complete, establishing the margins of blending performance, so that in production the blending is complete before the blending process stops."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12699", "text": "In order to achieve optimal  blending , the micromixing process must be studied to determine mixing parameters such as blending time, blending speed, type and size of blender.  When blending is performed too long, overblending may occur, with particles re-aggregating, resulting in segregation of the previously ideal blend. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12700", "text": "Formulation  scientists  and  technologists  need tools to select ingredients for new formulations.   Tablets  contain multiple ingredients beyond the active pharmaceutical ingredients (API) such as fillers, tableting agents,  disintegrants , and  absorption  enhancers or agents that slow down and control absorption.  Choice of materials is important to assure the flow characteristics, potency, and absorption of specific formulations.  In addition, proper particle size grades of the ingredients must be selected to produce an optimum blend for capsule filling."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12701", "text": "In order to study the rate and uniformity of blending, destructive analytical methods, such as  dissolution  followed by  chromatographic   separation  and detection are often used.  These methods require samples to be pulled from the blend, followed by time-consuming laboratory analysis.  In production, such analysis delays may lengthen time required for production formulation development."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12702", "text": "Near- infrared   hyperspectral imaging  can show the distribution of ingredients in pharmaceutical tablets.  In addition to  laboratory analysis , imaging of near line pull-samples has been used to indicate whether the mixing endpoint has been achieved.  However, such  measurements  were performed once blending was completed, and therefore, did not yield information about the progression of micromixing during the blending process. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12703", "text": "Nuclear pharmacy , also known as  radiopharmacy , involves preparation of  radioactive  materials for patient administration that will be used to diagnose and treat specific diseases in  nuclear medicine . It generally involves the practice of combining a  radionuclide tracer  with a pharmaceutical component that determines the biological localization in the patient. [ 1 ] [ 2 ]   Radiopharmaceuticals  are generally not designed to have a therapeutic effect themselves, but there is a risk to staff from  radiation exposure  and to patients from possible contamination in production. [ 3 ]  Due to these intersecting risks, nuclear pharmacy is a heavily regulated field. [ 4 ] [ 5 ]  The majority of diagnostic nuclear medicine investigations are performed using  technetium-99m . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12704", "text": "The concept of nuclear pharmacy was first described in 1960 by Captain William H. Briner while at the  National Institutes of Health  (NIH) in  Bethesda, Maryland . Along with Mr. Briner, John E. Christian, who was a professor in the School of Pharmacy at  Purdue University , had written articles and contributed in other ways to set the stage of nuclear pharmacy. William Briner started the NIH Radiopharmacy in 1958. [ 7 ] [ 8 ]  John Christian and William Briner were both active on key national committees responsible for the development, regulation and utilization of radiopharmaceuticals. A  technetium-99m generator  was commercially available, followed by the availability of a number of Tc-99m based radiopharmaceuticals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12705", "text": "In the  United States  nuclear pharmacy was the first  pharmacy  specialty established in 1978 by the  Board of Pharmacy Specialties . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12706", "text": "Various models of production exist internationally. Institutional nuclear pharmacy is typically operated through large  medical centers  or  hospitals  while commercial centralized nuclear pharmacies provide their services to subscriber hospitals. They prepare and dispense radiopharmaceuticals as unit  doses  that are then delivered to the subscriber hospital by nuclear pharmacy personnel."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12707", "text": "A few basic steps are typically involved in technetium based preparations. First the active technetium is obtained from a  radionuclide generator  on site, which is then added to a non-radioactive kit containing the pharmaceutical component. Further steps may be required depending on the materials in question to ensure full  binding  of the two components. These procedures are usually carried out in a  clean room  or isolator to provide radiation shielding and sterile conditions. [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12708", "text": "For  Positron Emission Tomography  (PET),  Fludeoxyglucose ( 18 F)  is the most common radiopharmaceutical, with the radioactive component usually obtained from a cyclotron. [ 11 ]  The short half life of  Fluorine-18  and many other PET  isotopes  necessitates rapid production. PET radiopharmaceuticals are now often produced by automated computer controlled systems to reduce complexity and radiation doses to staff. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12709", "text": "Radiopharmacy is a heavily regulated field, as it combines several practices and fields which may come under the purview of multiple  regulators  and legislation. These include occupational exposure of staff to  ionising radiation , preparation of medicines, patient exposure to ionising radiation, transport of radioactive materials, and environmental exposure to ionising radiation. [ 13 ]  Different regulations may cover the various stages involved in radiopharmacies, ranging from production of \"cold\" (non-radioactive) kits, to the marketing and distribution of final products. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12710", "text": "Staff working in nuclear pharmacies require extensive training on aspects of  good manufacturing practice ,  radiation safety  concerns and  aseptic dispensing . In the  United States  an authorised nuclear pharmacist must be a fully qualified pharmacist with evidence of additional training and qualification in nuclear pharmacy practice. [ 15 ]  Several  European Union   directives  cover radiopharmaceuticals as a special group of medicines, reflecting the wide range of types of producers and staff groups that may be involved. [ 16 ]  In the UK qualified pharmacists may be involved along with clinical scientists or technologists, with relevant training. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12711", "text": "Nutraceutical  is a marketing term used to imply a  pharmaceutical  effect from a compound or food product that has not been scientifically confirmed or approved to have  clinical benefits . [ 1 ] [ 2 ]  In the United States, nutraceuticals are  considered and regulated as a subset of foods (such as  dietary supplements ) by the  Food and Drug Administration  (FDA). [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12712", "text": "There are no internationally defined properties of nutraceuticals. [ 2 ]  Due to the vague, undiscriminating evidence for the biological effects of nutraceutical products, experts have proposed abandoning the term. [ 1 ]  The word \"nutraceutical\" is a  portmanteau , blending the words \"nutrition\" and \"pharmaceutical.\" [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12713", "text": "Nutraceuticals are treated differently in different jurisdictions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12714", "text": "Under Canadian law, a nutraceutical can be marketed as either a food or a drug; the terms \"nutraceutical\" and \"functional food\" have no legal distinction, [ 7 ]  as both refer to \"a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food [and] is demonstrated to have a physiological benefit or provide protection against chronic disease.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_12715", "text": "The term \"nutraceutical\" is not defined by the FDA. [ 8 ]  Depending on its ingredients and the claims with which it is marketed, a product is regulated as a drug,  dietary supplement , food ingredient, or food. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12716", "text": "In the global market, there are significant product quality issues. [ 1 ] [ 2 ]  Nutraceuticals from the international market may claim to use  organic  or  exotic  ingredients, yet the lack of regulation may compromise the safety and effectiveness of products. Companies looking to create a wide  profit margin  may create unregulated products overseas with low-quality or ineffective ingredients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12717", "text": "Nutraceuticals are products derived from food sources that are purported to provide extra health benefits, in addition to the basic nutritional value found in foods. Depending on the jurisdiction, products may claim to prevent  chronic diseases , improve health, delay the  aging  process, increase  life expectancy , or support the structure or function of the body. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12718", "text": "In the United States, the Dietary Supplement Health and Education Act (DSHEA) of 1994 defined the term \"dietary supplement\": \"A  dietary supplement  is a product taken by mouth that contains a 'dietary ingredient' intended to supplement the diet. The 'dietary ingredients' in these products may include: [ 8 ]   vitamins ,  minerals ,  herbs  or other botanicals,  amino acids , and substances such as  enzymes , organ tissues, glandulars, and  metabolites . Dietary supplements can also be extracts or concentrates, and may be found in many forms such as  tablets , capsules, softgels,  gelcaps , liquids, or powders.\" [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12719", "text": "Dietary supplements do not have to be approved by the FDA before marketing, but companies must register their manufacturing facilities with the FDA and follow current good manufacturing practices (cGMPs). [ 8 ]   With a few well-defined exceptions, dietary supplements may only be marketed to support the structure or function of the body, and may not claim to treat a disease or condition, and must include a label that says: \u201cThese statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.\u201d The exceptions are when the FDA has reviewed and approved a health claim. In those situations the FDA also stipulates the exact wording allowed. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12720", "text": "Functional foods  are  fortified  or enriched during  processing  and then marketed as providing some benefit to consumers. Sometimes, additional complementary nutrients are added, such as  vitamin D  to milk."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12721", "text": "Health Canada defines functional foods as \"ordinary food that has components or ingredients added to give it a specific medical or  physiological  benefit, other than a purely nutritional effect.\" [ 10 ]  In Japan, all functional foods must meet three established requirements: foods should be (1) present in their naturally occurring form, rather than a capsule, tablet, or powder; (2) consumed in the diet as often as daily; and (3) should regulate a biological process in hopes of preventing or controlling disease. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12722", "text": "Nutraceuticals have been considered as possible adjuncts to therapies for clinical disorders. [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12723", "text": "The modern nutraceutical market developed in Japan during the 1980s. In contrast to the natural  herbs  and  spices  used as  folk medicine  for centuries throughout Asia, the nutraceutical industry grew alongside the expansion of modern technology in the early 21st century. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12724", "text": "The market for nutraceuticals is projected to grow to about 614\u00a0billion  euros  (approx. US$675\u00a0billion; 2023) by the year 2027. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12725", "text": "The word \"nutraceutical\" is a portmanteau of the words \"nutrition\" and \" pharmaceutical \", coined in 1989 by Stephen L. DeFelice. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12726", "text": "Because nutraceuticals are unregulated, these supplements are sold by  marketing hype  rather than being based on actual  clinical evidence . [ 1 ] [ 8 ] [ 17 ]  There is no compelling evidence for efficacy in nutraceuticals. [ 1 ] [ 17 ]  After scientists disputed the benefits of nutraceuticals, such as  probiotics  in yogurt,  Danone  was forced to pay a large financial penalty for falsely claiming its products  Actimel  and Activia boosted the  immune system . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12727", "text": "Over-the-counter counseling  (or  OTC counseling ) refers to the counseling that a  pharmacist  may provide on the subject of initiating, modifying, or stopping an  over-the-counter  (OTC) drug product. [ 1 ]  OTC counseling requires an assessment of the patient's  self-care  concerns and drug-related needs. The types of drugs that are involved in OTC counseling are, for example, used to treat  self-diagnosable  conditions like heartburn, cough, and rashes, though  prescription drugs  and professional  diagnoses  are also relevant to the recommendation process. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12728", "text": "The aim of OTC counseling is to empower patients to take control of their healthcare-related needs for conditions that do not require an appointment with a  medical doctor . This benefits the healthcare system by reducing unnecessary physician visits. [ 2 ]  The pharmacist can also use OTC counseling to ensure the highest likelihood of success for the patient's self-care attempt and minimize the risk of any drug-related problems. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12729", "text": "Although OTC drugs are generally regarded as safe for use without a prescription (by definition), medication errors still occur. For example, patients sometimes misuse OTC products by taking larger than recommended doses, in order to bring about symptomatic relief more quickly, or even intentionally abuse them for unlabeled indications. [ 4 ]  Even when a patient is instructed not to use OTC products without speaking with their  primary care physician , patients can still fail to identify products as OTC medications worth avoiding. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12730", "text": "A pharmacist can use both  open-ended  questions (that start with the word  who ,  what ,  how ,  why  or  where ) as well as close-ended questions (that start with the word  will ,  can ,  do  or  did ) which are to be used only if the former do not get the appropriate response in order to obtain relevant information about a patient's potential needs for treatment or potential drug-therapy problems. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12731", "text": "Pharmacists ask patients about  comorbidities  to avoid any drug-disease state contraindications. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12732", "text": "Although OTC counseling does not necessarily involve the use of a formal framework, various frameworks have been proposed: [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12733", "text": "The QuEST approach has been described as both \"short\" and \"systematic.\" [ 2 ]  It takes the form of the following: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12734", "text": "As above, with the following addition: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12735", "text": "The WWHAM method is not strict; there is no requirement that the OTC counseling follow the exact order of the mnemonic. [ 9 ]  It takes the form of the following: [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12736", "text": "The ASMETHOD has been attributed to the London pharmacist, Derek Balon. [ 10 ]  It takes the form of the following: [ 10 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12737", "text": "The ENCORE method helps pharmacists focus intently on the patient's presenting symptoms while considering the appropriate OTC recommendation. It takes the form of the following: [ 11 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12738", "text": "For the selection of OTC proton-pump inhibitors (PPIs), pharmacists must first determine whether or not a patient is likely to benefit from self-care for the treatment of their  acid reflux  symptoms. Examples of exclusions to self-care treatment of acid-reflux symptoms include a positive family history of gastrointestinal cancers, since their symptoms may reflect a more serious, underlying condition, and patients that present with so-called \"alarm symptoms,\" which require a prompt evaluation by a  diagnostician . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12739", "text": "The available PPIs labeled for OTC use varies by country. As of October 2015, in the United States, available OTC proton-pump inhibitors include  omeprazole ,  lansoprazole , and  esomeprazole , whereas the UK approves the OTC use of omeprazole, esomeprazole,  pantoprazole , and  rabeprazole . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12740", "text": "Whether or not pharmacists should be involved with selling dietary supplements, which are not approved for the treatment or prevention of any disease or disorder, is the subject of much ethical debate. However, a 2009 review of the literature found that the common perception was that pharmacists should be involved in the OTC counseling process for dietary supplements where dietary supplements are sold. [ 13 ]  As experts in drug therapies that cause vitamin depletion, there are several recommendations that pharmacists commonly make. For example, pharmacists sometimes advise patients on long-term  metformin  therapy to supplement with  vitamin B12  to treat or prevent diabetic  peripheral neuropathy . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12741", "text": "While there are currently no OTC medications available for the treatment of  cancer  in the United States, there are specific OTC recommendations that apply to cancer patients that do not apply to the general population. Even a common OTC medication like  acetaminophen  may pose a risk to cancer patients by masking the presence of fever, which is an important sign of a serious side effect of some  chemotherapy  regimens called  febrile neutropenia . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12742", "text": "During OTC counseling, pharmacists differentiate between self-care appropriate upper respiratory tract infections, like the  common cold , and potentially devastating infections like the  flu . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12743", "text": "Pharmacists can offer non-pharmacological,  behavioral counseling  for patients with  urinary incontinence . This includes teaching patients about the important behavioral interventions that can reduce their symptoms and improve quality of life. This can include recommending daily  Kegel exercises , and instructing patients on the proper technique. In addition, pharmacists can provide resources for patients to learn more about how to control their symptoms. In terms of medications, pharmacists can help patients identify medications that may be worsening or causing their urinary incontinence, or offer recommendations for prescription medications for patients to take to their physicians. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12744", "text": "OTC counseling patients about self-care and non-prescription drugs does not follow the same format as counseling for  prescription drugs . [ 6 ]  A pharmacist who counsels for a prescription drug can view a patient's profile, which includes their current list of concurrent medications and allergies to medications. However, an OTC counseling session may occur in the aisle of the store, forcing pharmacists to elicit the necessary information from patients directly. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12745", "text": "Pharmaceutical care  is a pharmacy practice model developed in the 1990s [ 1 ]  that describes patient-centered medication management services performed by pharmacists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12746", "text": "There are many definitions for \"medication management service.\" The following definition was proposed in the 2012 textbook  Pharmaceutical Care Practice: The Patient-Centered Approach to Medication Management :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12747", "text": "\"Medication management services are the professional activities needed to meet the standard of care which ensures each patient's medications (whether they are prescription, nonprescription, alternative, traditional, vitamins, or nutritional supplements) are individually assessed to determine that each medication is appropriate for the medical condition being treated, that the medication is being effective and achieving the goals established, that the medication is safe for the patient in the presence of the co-morbidities and other medications the patient may be taking, and the patient is able and willing to take the medications as intended.\" [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12748", "text": "Pharmaceutical care as a pharmacy practice model developed out of the need to re-professionalize pharmacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12749", "text": "It is thought the first mention of pharmaceutical care came from Dr. Donald Brodie's 1973 lecture shared at The Ninth Annual  Rho Chi  Lecture in  Boston ,  MA ,  USA . [ 3 ]  Dr. Brodie defined pharmaceutical care as \"the care a given patient requires and receives which assures safe and rational drug usage.\" It was then popularized in 1990 after the  American Journal of Health-System Pharmacy  (AJHP) published an article by Drs. Charles Hepler and Linda Strand entitled \u2018 Opportunities and responsibilities in pharmaceutical care'. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12750", "text": "The concept was endorsed by  American Society of Health-System Pharmacists  (ASHP) and the  American Association of College of Pharmacy  (AACP) in 1991. [ 4 ] [ 5 ]  In 1992, the  American Pharmacists Association  (APhA) followed suit. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12751", "text": "In 1993, ASHP issued a statement in response to members seeking a standardized definition of pharmaceutical care. [ 7 ]  In this statement they defined pharmaceutical care as \"the direct, responsible provision of medication-related care for the purpose of achieving definite outcomes that improve a patient\u2019s quality of life.\" [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12752", "text": "In 1998, the textbook  Pharmaceutical Care Practice: The Patient-Centered Approach to Medication Management  was first published. [ 9 ]  This included a definition of pharmaceutical care informed by the research of Drs. Robert Cipolle, Linda Strand, and Peter Morley that spanned 5 years and involved 20 different community pharmacy practice sites and 54 practicing pharmacists. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12753", "text": "The  American Medical Association (AMA)  approved relevant reimbursement codes in 2004. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12754", "text": "In 2013, a European organization, the Pharmaceutical Care Network Europe (PCNE), created a new definition that could satisfy experts from a multitude of countries. After a review of existing definitions, a number of options were presented to the participants and in a one-day meeting consensus on a definition was reached: Pharmaceutical Care is the pharmacologist/pharmacist's contribution to the care of individuals in order to optimize medicines use and improve health outcomes. [ 10 ] [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12755", "text": "\"The philosophy of pharmaceutical care practice consists of:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12756", "text": "A philosophy of practice is expected when working with medicine and nursing and is practiced by all health care professionals.\" [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12757", "text": "The patient care process is a cognitive process in which the drug-related needs of patients are approached systematically and comprehensively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12758", "text": "\"The patient care process, which must be consistent with the patient care processes of the other health care providers, consists of:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12759", "text": "A principle of the patient care process is  patient-centeredness ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12760", "text": "The patient care process was initially called the \"Pharmacists Workup of Drug Therapy\" and served as a means to document drug therapy decisions. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12761", "text": "\"The practice management system includes all of the resources required to bring the service to the patient. Physical space, the appointment system, documentation, reporting, evaluation, payment for the service, and much more are included in the management of a service.\" [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12762", "text": "The ultimate goal of pharmaceutical care (optimize medicines use and improving health outcomes) exists in all practice settings and in all cultures where medicines are used. It involves two major functions: identifying potential and manifest problems in the pharmacotherapy (drug therapy problems, or DTPs), and then resolving the problems and preventing the potential problems from becoming real for the patient and his therapy outcomes. This should preferably be done together with other health care professionals and the patient through a review of the medication (and diseases) and subsequent counselling and discussions. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12763", "text": "Pharmaceutical ink  is an ingestible form of  water -based ink used on most medicine  pills  to indicate which drug it is, and/or how many  milligrams  the pill contains."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12764", "text": "The first U.S. patent for pharmaceutical inks was filed on 28 June 1966, and its method involved  ethyl alcohol ,  shellac ,  titanium dioxide  and  propylene glycol ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12765", "text": "Most pharmaceutical inks since the early 1990s eliminate ethyl alcohol in favour of faster ink drying times, and may include  methyl alcohol  and  isopropanol  in addition to the traditional ingredients titanium dioxide and propylene glycol."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12766", "text": "Pharmacocybernetics  (also known as  pharma-cybernetics ,  cybernetic pharmacy  and  cyberpharmacy ) is an upcoming field that describes the science of supporting drugs and medications use through the application and evaluation of informatics and internet technologies, so as to improve the  pharmaceutical care  of patients. [ 1 ]  It is an interdisciplinary field that integrates the domains of  medicine  and  pharmacy ,  computer sciences  (informatics, cybernetics, interactive digital media, human-computer-environment interactions) and  psychological sciences  to design, develop, apply and evaluate technological innovations which improve drugs and medications management, as well as prevent or solve drug-related problems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12767", "text": "\"Pharmaco\" originates from the Greek word \"pharmakon\", which means drugs or poisons; [ 2 ]  while \" cybernetics \" originates from the Greek word \"kubernetes\", which means \"the art of steering\". [ 3 ]   Norbert Wiener  first defined cybernetics as the science or study of \"control and communication in the animal and the machine\". [ 3 ] [ 4 ]  Since then, the  American Society for Cybernetics  has further described this field as \"the design or discovery and application of principles of regulation and communication\". [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12768", "text": "Cybernetics  has been applied to many fields, such as  anthropology ,  sociology ,  systems theory ,  psychology ,  biology ,  computer science  and  engineering . The defining characteristic of a cybernetic system is its relationship between endogenous goals and the external environment. [ 5 ]  In the 1970s, cybernetics was applied in healthcare as a means of setting positive outcome goals for patients who were not satisfied with their  plastic surgeries . [ 6 ]  The emergence of \" new cybernetics \" or \" second-order cybernetics \" further expanded this concept to include the interactions between cybernetic systems and the people interacting with them, as well as to society as a whole. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12769", "text": "Cybernetics also includes the concept of \" cyberspace \", which is described by the science fiction author  William Gibson  as a virtual representation of information in varying states of accessibility that is linked to various people and organizations in his book  Neuromancer . [ 8 ] [ 9 ] [ 10 ]  This concept is also reiterated in the movie \" The Matrix \" and its sequels, which revolves around  Neo  ( Keanu Reeves ), a computer programmer, who lives in a simulated matrix world created by sentient machines but perceived by humans as reality. The term \"cyberspace\" is now used ubiquitously to describe anything that is associated with computers, informatics and internet technologies, and also user experiences through interactions with these technologies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12770", "text": "The increased popularity of informatics and internet technologies in healthcare has led to the development of various software, tools and applications for healthcare professionals and patients to improve pharmaceutical care and health-related outcomes.  Pharmacoinformatics  (or  pharmacy informatics ) is a field within  e-health  that targets drug-related problems through the use of informatics and internet technologies. [ 11 ]  Pharmacocybernetics goes one step further by merging the science of technology with human-computer-environment interactions, so that technological innovations can be designed, developed, applied and evaluated in relation to supporting medicines and drugs use, as well as to reduce or prevent drug-related problems. Pharmacocybernetic approaches target patient care and safety, and they take into account the flow of information and knowledge between users and cybernetic systems or the environment, the actions taken by users to achieve their goals, user interactivity, as well as feedback. [ 1 ]  This field requires clinical knowledge and experience, as well as advanced skills and expertise to deal with technologies and human-computer-environment interactions in relation to the management of medicines and drug therapies. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12771", "text": "Pharmaceutical care  involves the identification, solving and prevention of medication/drug-related problems with regards to patients' drug therapies. [ 12 ]  These problems are classified into various categories, which differ slightly between the American and European systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12772", "text": "The  American Society of Health-System Pharmacists  classifies drug-related problems into eight major categories: [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12773", "text": "The Pharmaceutical Care Network Europe classifies them by problems and causes: [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12774", "text": "Classification by problems :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12775", "text": "Classification by causes :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12776", "text": "The rapid adoption of  cybermedicine  has led to several other associated medication/drug-related problems. [ 11 ]  These include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12777", "text": "Pharmacocybernetics approaches target the whole  digital healthcare  innovation cycle from identifying the healthcare problem, designing, developing, applying and evaluating the technological innovations that aim to address these drug-related problems. These technological innovations tend to be based on  user-centered ,  experience-centered  and  activity-centered  designs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12778", "text": "The types of environments that are relevant to pharmacocybernetics approaches follow  Urie Bronfenbrenner\u2019s   Ecological Systems Theory . [ 1 ] [ 14 ]  These environments, when applied to healthcare (for example, when a patient with a chronic disease searches the internet for information regarding his drug therapy), are as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12779", "text": "Four pharmacocybernetic maxims have been defined for designers and developers of pharmaco-informatics tools and applications that provide information on medications and drug therapies. [ 1 ] [ 15 ] [ 16 ]  These design principles are in relation to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12780", "text": "Pharmacognosy  is the study of  crude drugs  obtained from  medicinal plants ,  animals ,  fungi , and other natural sources. [ 1 ]  The  American Society of Pharmacognosy  defines pharmacognosy as \"the study of the physical, chemical,  biochemical , and biological properties of drugs, drug substances, or potential drugs or drug substances of natural origin as well as the  search for new drugs  from natural sources\". [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12781", "text": "The word \"pharmacognosy\" is derived from two  Greek  words:  \u03c6\u03ac\u03c1\u03bc\u03b1\u03ba\u03bf\u03bd ,  pharmakon  ( drug ), and  \u03b3\u03bd\u1ff6\u03c3\u03b9\u03c2   gnosis  ( knowledge ) or the  Latin  verb  cognosco  ( con , 'with', and  gn\u014dsc\u014d , 'know'; itself a  cognate  of the  Greek  verb  \u03b3\u03b9(\u03b3)\u03bd\u03ce\u03c3\u03ba\u03c9 ,  gi(g)n\u00f3sko , meaning 'I know, perceive'), [ 3 ]  meaning 'to conceptualize' or 'to recognize'. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12782", "text": "The term \"pharmacognosy\" was used for the first time by the German physician  Johann Adam Schmidt  (1759\u20131809) in his published book  Lehrbuch der Materia Medica  in 1811, and by  Anotheus Seydler  in 1815, in his  Analecta Pharmacognostica ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12783", "text": "Originally\u2014during the 19th century and the beginning of the 20th century\u2014\"pharmacognosy\" was used to define the branch of  medicine  or commodity sciences ( Warenkunde  in German) which deals with  drugs  in their crude, or unprepared form.  Crude drugs  are the dried, unprepared material of plant, animal or mineral origin, used for medicine. The study of these materials under the name  Pharmakognosie  was first developed in German-speaking areas of Europe, while other language areas often used the older term  materia medica  taken from the works of  Galen  and  Dioscorides . In German, the term  Drogenkunde  (\"science of crude drugs\") is also used synonymously."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12784", "text": "As late as the beginning of the 20th century, the subject had developed mainly on the botanical side, being particularly concerned with the description and identification of drugs both in their whole state and in powder form. Such branches of pharmacognosy are still of fundamental importance, particularly for botanical products (widely available as dietary supplements in the U.S. and Canada), quality control purposes, pharmacopoeial protocols and related health regulatory frameworks. At the same time, development in other areas of research has enormously expanded the subject. The advent of the 21st century brought a renaissance of pharmacognosy, and its conventional botanical approach has been broadened up to molecular and  metabolomic  levels. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12785", "text": "In addition to the previously mentioned definition, the  American Society of Pharmacognosy  defines pharmacognosy as \"the study of natural product molecules (typically secondary metabolites) that are useful for their medicinal, ecological, gustatory, or other functional properties.\" [ 6 ]  Similarly, the mission of the Pharmacognosy Institute at the University of Illinois at Chicago involves plant-based and plant-related health products for the benefit of human health. [ 7 ]  Other definitions are more encompassing, drawing on a broad spectrum of biological subjects, including  botany ,  ethnobotany ,  marine biology ,  microbiology ,  herbal medicine ,  chemistry ,  biotechnology ,  phytochemistry ,  pharmacology ,  pharmaceutics , clinical  pharmacy , and  pharmacy practice ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12786", "text": "All plants produce  chemical compounds  as part of their normal  metabolic  activities. These  phytochemicals  are divided into (1)  primary metabolites  such as  sugars  and  fats , which are found in all plants; and (2)  secondary metabolites \u2014compounds which are found in a smaller range of plants, serving more specific functions. [ 8 ]  For example, some secondary metabolites are  toxins  used by plants to  deter predation  and others are  pheromones  used to attract insects for  pollination . It is these secondary metabolites and pigments that can have therapeutic actions in humans and which can be refined to produce drugs\u2014examples are  inulin  from the roots of  dahlias ,  quinine  from the  cinchona ,  THC  and  CBD  from the flowers of  cannabis ,  morphine  and  codeine  from the  poppy , and  digoxin  from the  foxglove . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12787", "text": "Plants synthesize a variety of  phytochemicals , but most are derivatives: [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12788", "text": "A typical protocol to isolate a pure chemical agent from natural origin is  bioassay-guided fractionation , meaning step-by-step separation of extracted components based on differences in their physicochemical properties, and assessing the  biological activity , followed by next round of separation and assaying. Typically, such work is initiated after a given crude drug formulation (typically prepared by solvent extraction of the natural material) is deemed \"active\" in a particular  in vitro  assay. If the end-goal of the work at hand is to identify which one(s) of the scores or hundreds of compounds are responsible for the observed  in vitro  activity, the path to that end is fairly straightforward:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12789", "text": "In vitro  activity does not necessarily translate to biological activity in humans or other living systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12790", "text": "In the past, in some countries in  Asia  and Africa, up to 80% of the population may rely on  traditional medicine  (including  herbal medicine ) for primary health care. [ 10 ]  Native American cultures have also relied on traditional medicine such as ceremonial smoking of tobacco, potlatch ceremonies, and  herbalism , to name a few, prior to European colonization. [ 11 ]  Knowledge of traditional medicinal practices is disappearing in indigenous communities, particularly in the Amazon. [ 12 ] [ 13 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12791", "text": "With worldwide research into  pharmacology  as well as  medicine , traditional medicines or ancient herbal medicines are often translated into modern remedies, such as the anti-malarial group of drugs called  artemisinin  isolated from  Artemisia annua  herb, a herb that was known in Chinese medicine to treat fever. However, it was found that its plant extracts had  antimalarial  activity, leading to the Nobel Prize winning discovery of artemisinin. [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12792", "text": "Microscopic evaluation is essential for the initial identification of herbs, identifying small fragments of crude or powdered herbs, identifying  adulterants  (such as insects, animal feces, mold, fungi, etc.), and recognizing the plant by its characteristic tissue features. Techniques such as microscopic linear measurements, determination of leaf constants, and quantitative microscopy are also utilized in this evaluation. The determination of leaf constants includes stomatal number, stomatal index, vein islet number, vein termination number, and palisade ratio. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12793", "text": "The stomatal index is the percentage formed by the number of  stomata  divided by the total number of  epidermal cells , with each stoma being counted as one cell."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12794", "text": "S \n . \n I \n . \n = \n \n \n S \n \n E \n + \n S \n \n \n \n \u00d7 \n 100 \n \n \n {\\displaystyle S.I.={\\frac {S}{E+S}}\\times 100}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12795", "text": "S.I. is the stomatal index"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12796", "text": "S is the number of stomata per unit area"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12797", "text": "E is the number of epidermal cells in the same unit area. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12798", "text": "Pharmacotoxicology  entails the study of the consequences of  toxic  exposure to  pharmaceutical   drugs  and agents in the  health care  field.  The field of pharmacotoxicology also involves the treatment and prevention of pharmaceutically induced  side effects . Pharmacotoxicology can be separated into two different categories:  pharmacodynamics  (the effects of a drug on an organism), and  pharmacokinetics  (the effects of the organism on the drug)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12799", "text": "There are many mechanisms by which pharmaceutical drugs can have toxic implications. A very common mechanism is covalent binding of either the drug or its metabolites to specific enzymes or receptor in tissue-specific pathways that then will elicit toxic responses. Covalent binding can occur during both on-target and off-target situations and after  biotransformation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12800", "text": "On-target toxicity is also referred to as mechanism-based toxicity. This type of adverse effect that results from pharmaceutical drug exposure is commonly due to interactions of the drug with its intended target. In this case, both the therapeutic and toxic targets are the same. To avoid toxicity during treatment, many times the drug needs to be changed to target a different aspect of the illness or symptoms.  Statins  are an example of a drug class that can have toxic effects at the therapeutic target ( HMG CoA reductase ). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12801", "text": "Some pharmaceuticals can initiate allergic reactions, as in the case of  penicillins . In some people, administration of penicillin can induce production of specific antibodies and initiate an immune response. Activation of this response when unwarranted can cause severe health concerns and prevent proper immune system functioning. [ 1 ]  Immune responses to pharmaceutical exposure can be very common in accidental contamination events.  Tamoxifen , a  selective estrogen receptor modulator , has been shown to alter the humoral adaptive immune response in gilthead seabream. [ 2 ]  In this case, pharmaceuticals can produce adverse effects not only in humans, but also in organisms that are unintentionally exposed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12802", "text": "Adverse effects at targets other than those desired for pharmaceutical treatments often occur with drugs that are nonspecific. If a drug can bind to unexpected proteins, receptors, or enzymes that can alter different pathways other than those desired for treatment, severe downstream effects can develop. An example of this is the drug  eplerenone  (aldosterone receptor antagonist), which should increase aldosterone levels, but has shown to produce atrophy of the prostate. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12803", "text": "Bioactivation  is a crucial step in the activity of certain pharmaceuticals. Often, the parent form of the drug is not the active form and it needs to be metabolized in order to produce its therapeutic effects. In other cases, bioactivation is not necessarily needed for drugs to be active and can instead produce reactive intermediates that initiate stronger adverse effects than the original form of the drug. Bioactivation can occur through the action Phase I metabolic enzymes, such as  cytochrome P450  or  peroxidases . Reactive intermediates can cause a loss of function in some enzymatic pathways or can promote the production of  reactive oxygen species , both of which can increase stress levels and alter homeostasis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12804", "text": "Drug-drug interactions can occur when certain drugs are administered at the same time. Effects of this can be additive (outcome is greater than those of one individual drug), less than additive (therapeutic effects are less than those of one individual drug), or functional alterations (one drug changes how another is absorbed, distributed, and metabolized). [ 4 ]  Drug-drug interactions can be of serious concern for patients who are undergoing multi-drug therapies. [ 5 ]  Coadministration of  chloroquine , an anti-malaria drug, and statins for treatment of cardiovascular diseases has been shown to cause inhibition of  organic anion-transporting polypeptides  (OATPs) and lead to systemic statin exposure. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12805", "text": "There are many different pharmaceutical drugs that can produce adverse effects after biotransformation, interaction with alternate targets, or through drug-drug interactions. All pharmaceuticals can be toxic, depending on the dose. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12806", "text": "Acetaminophen  (APAP) is a very common drug used to treat pain. High doses of acetaminophen has been shown to produce severe  hepatotoxicity  after being biotransformed to produce reactive intermediates. Acetaminophen is metabolized by CYP2E1 to produce  NAPQI , which then causes significant oxidative stress due to increased  reactive oxygen species  (ROS). [ 7 ]  ROS can cause cellular damage in a multitude of ways, a few of which being DNA and mitochondrial damage and depletion of antioxidant enzymes such as  glutathione . In terms of drug-drug interactions, acetaminophen activates  CAR , a nuclear receptor involved in the production of metabolic enzymes, which increases the metabolism of other drugs. This could either cause reactive intermediates/drug activity to persist for longer than necessary, or the drug will be cleared quicker than normal and prevent any therapeutic actions from occurring. Ethanol induces CYP2E1 enzymes in the liver, which can lead to increased NAPQI formation in addition to that formed by acetaminophen. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12807", "text": "Aspirin is an  NSAID  used to treat inflammation and pain. Overdoses or treatments in conjunction with other NSAIDs can produce additive effects, which can lead to increased oxidative stress and ROS activity. Chronic exposure to aspirin can lead to CNS toxicity and eventually affect respiratory function. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12808", "text": "Anti-depressants have been prescribed since the 1950s, and their prevalence has significantly increased since then. There are many classes of anti-depressant pharmaceuticals, such as  selective serotonin reuptake inhibitors  (SSRIs),  monoamine oxidase inhibitors  (MAOIs), and  tricyclic anti-depressants . Many of these drugs, especially the SSRIs, function by blocking the metabolism or reuptake of neurotransmitters to treat depression and anxiety. Chronic exposure or overdose of these pharmaceuticals can lead to serotonin and CNS hyperexcitation, weight changes, and, in severe cases, suicide. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12809", "text": "Doxorubicin  is a very effective anti-cancer drug that causes congestive heart failure while treating tumors. [ 7 ]  Doxorubicin is an uncoupling agent in that it inhibits proper functioning of complex I of the electron transport chain in mitochondria. It then leads to the production of ROS and the inhibition of ATP production. Doxorubicin has been shown to be selectively toxic to cardiac tissue, although some toxicity has been seen in other tissues as well. [ 7 ]  Other anti-cancer drugs, such as  fluoropyrimidines  and  taxanes , are extremely effective at treating and reducing tumor proliferation, but have high incidences of cardiac arrhythmias and myocardial infarctions. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12810", "text": "The  Ghana Pharmacy Council  is a statutory regulatory body established by an Act of  Parliament of Ghana , the pharmacy Act, 1994(Act 489)Part IV of The Health Professions Regulatory Bodies Act, 2013 (Act 857). It is located in  Accra , the capital of  Ghana .Its core function is to secure public interest in the highest standards in the practice of  pharmacy [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12811", "text": "The Vision of the Council is \u201cTo guarantee the highest levels of pharmaceutical care\u201d. [ 2 ]  The Council\u2019s Mission is \u201cTo secure the highest level of pharmaceutical care by ensuring competent pharmaceutical care providers who practice within agreed standards and are accessible to the whole population. In addition we shall collaborate with related local agencies and international pharmaceutical organizations to enhance our effectiveness and our contribution to rational drug use in the nation. This mission shall be carried out with dedication, integrity, and professionalism.\u201d [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12812", "text": "This article about  government  in  Ghana  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12813", "text": "The  pharmacy management system , also known as the  pharmacy information system , is a system that stores data and enables functionality that organizes and maintains the medication use process within pharmacies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12814", "text": "These systems may be an independent technology for the pharmacy's use only, or in a hospital setting, pharmacies may be integrated within an inpatient hospital  computer physician order entry (CPOE)  system. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12815", "text": "Necessary actions for a basic, functioning pharmacy management system include a user interface, data entry and retention, and security limits to protect patient health information. [ 2 ] [ 3 ]  Pharmacy computer software is usually purchased ready-made or provided by a drug wholesaler as part of their service. Various pharmacy software  operating systems  are common place throughout the many practice settings. [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12816", "text": "The pharmacy management system serves many purposes, including the safe and effective dispensing of pharmaceutical drugs. During the dispensing process, the system will prompt the  pharmacist  to verify the medication they have is for the correct patient and has the correct quantity, dosage, and information on the prescription label. Advanced pharmacy management systems offer  clinical decision support  and may be configured to alert the pharmacist to perform clinical interventions, such as an opportunity to offer verbal counseling if the patient's prescription requires additional education in the pharmacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12817", "text": "Pharmacy management systems should also serve the pharmacist throughout the Pharmacists\u2019 Patient Care Process, a cycle developed by the  Joint Commission of Pharmacy Practitioners (JCPP) . The process details the steps pharmacists take to practice tangible, proven care to their patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12818", "text": "The JCPP's pharmacist patient care process consists of five steps:  collect ,  assess ,  plan ,  implement , and  follow-up. [ 7 ]  Ideally, the pharmacy management system assists with each of these practices. The pharmacy system should  Collect  data at intake and continue to store and organize information as the pharmacist learns more about the patient's medications, their history, goals, and other factors that may affect their health. The technology within the pharmacy information system should allow the pharmacists to  Assess  the collected information to form a  Plan  and  Implement  creative strategies that address the patient's issues. After implementing a plan, the pharmacist should routinely  Follow-Up  with the patient and make adjustments as needed to further progress."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12819", "text": "Outpatient  pharmacies typically are retail pharmacies that offer patient care services outside of hospitals and treatment facilities. Outpatient pharmacies, also known as community pharmacies or independent pharmacies, offer care in the form of  medication therapy management (MTM) , patient education, and clinical services."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12820", "text": "Developed in Florida in 1980, Rx30 is a multi-platform software that offers automated pharmacy processes, vendor integrations, and compounding functionality. [ 8 ]  The Core Services include Accounts Receivable, Point of Sale, and Virtual Pharmacist, a feature that automates the refill process. On October 6, 2016, Rx30 announced its merger with Computer-Rx. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12821", "text": "Inpatient  pharmacies operate within hospitals and dispense medications to admitted patients receiving treatment. Inpatient pharmacists manage patient health alongside doctors and nurses, and the pharmacy management system must integrate with the various systems operating throughout the hospital to maintain accurate Electronic Medical or Health Records (EMR, EHR)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12822", "text": "Epic , named for the long-form poems chronicling hero's lives, began in 1979 by founder  Judith R. Faulkner . Epic software currently manages over 200 million patient electronic records. The Willow Inpatient Pharmacy System, when combined with other Epic systems, allows pharmacies access to  medical administration records (MAR)  and links all aspects of the ordering and dispensing process to simplify collaboration amongst all parties involved in patient care management. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12823", "text": "Cerner Corporation  has provided  health information technology (HIT)  to hospitals and healthcare systems since 1979. Cerner PharmNet enables pharmacists to automate their workflow processes and center care around the patient, not the encounter. This software allows pharmacists and doctors to manage prescriptions and verification from the same order in order to streamline medication management. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12824", "text": "Datascan was started back in 1981 by Alex Minassian focused on providing pharmacy management software to independently owned community pharmacies.  Initially, Datascan modified the code it had purchased and began selling its DOS based version of the software.  In the early 2000's Winpharm was written and released as an updated Windows version of the software, which continued the ability to quickly fill prescriptions using only the keyboard as part of the fill screen. Back in 2009, Kevin Minassian stepped in to purchase Datascan.  Today, over 40 years later, Datascan continues to serve the needs of independent pharmacies nationwide with a focus on technology and support.   [ 12 ]   [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12825", "text": "Pharmacy practice research , also known as  pharmacy research , is a specialty field within the wider area of  health services research , which focuses on examining how and why people access  pharmacy  services, how much care costs, and what happens to patients as a result of this care. Its aim is to support  evidence-based policy  and practice decisions where  pharmacists  are employed or  medicines  are prescribed or used. [ 1 ] [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12826", "text": "The goals of pharmacy practice research are to support the clinical and effective use of  medicines , while ensuring that the risks of  adverse drug reactions  are minimised. It is generally concerned with the delivery of and equitable access to  pharmaceutical care  and other services delivered by pharmacists and related  health care providers . It is undertaken by researchers, often based in universities, from a wide range of health care disciplines. These may include  multidisciplinary  groups of pharmacists together with  statisticians , physicians, nurses, health psychologists,  social scientists ,  health economists  and  epidemiologists , among others. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12827", "text": "Areas of pharmacy research may include, for example: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12828", "text": "The approaches taken in pharmacy research can be summarised under the broad areas of understanding and describing the way care is accessed and delivered, identifying areas for improvement and evaluating new service models using rigorous research approaches. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12829", "text": "Pharmacy practice research often challenges traditional  professional boundaries , reflecting the shift in the balance of care currently observed in health care delivery. [ citation needed ]   For example, many conditions that were once primarily managed solely in a hospital setting are now managed in  primary care  settings, and many roles particularly delivered by doctors are now being delivered by other health care professionals including pharmacists. Pharmacy research aims to understand the clinical, humanistic and economic impact of these changes from the perspectives of pharmacists, patients and other health care professionals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12830", "text": "Findings from pharmacy practice research have supported  health policy  changes affecting pharmacy. In some instances they have been the driver for a new service to be delivered through pharmacy, such as smoking cessation or repeat dispensing. [ 5 ] [ 6 ]  In other instances they have provided evidence to underpin a policy change (e.g. pharmacist prescribing) or to evaluate a newly implemented initiative and make recommendations for continuation or change of the service (e.g. new Community Pharmacy Contractual Framework, [ 7 ]  Medicine Use Reviews, [ 8 ]  or New Medicines Service [ 9 ] )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12831", "text": "A  pharmacy technician (PhT)  performs  pharmacy -related functions including but not limited to filling out  prescription medications . Training, certification, licensing, and actual practice of pharmacy technicians varies not only worldwide but in some countries regionally as well as by employer. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12832", "text": "Pharmacy technicians are healthcare professionals trained in the technical aspects of supplying medicines and medical devices to patients since the 1950s. Pharmacy technicians work in a variety of locations (usually in community, retail, and hospital pharmacies), but can also work for long-term care facilities, pharmaceutical manufacturers, third-party  insurance  companies, computer software companies, in government, the military, or in teaching. Job responsibilities often include dispensing  prescription drugs  and other  medical devices  to patients and instructing them on their use. They may also perform administrative duties in a pharmaceutical practice, such as reviewing prescription requests with medical practices and insurance companies to ensure correct medications are provided and payment is received. Additionally, pharmacy technicians handle inventory related tasks such as  cycle counts  and returning expired and damaged medications back to the manufacturers. [ 2 ] [ 3 ] [ 4 ]  Pharmacy technicians may take on the role of compounding supervisor, overseeing day to day sterile and non-sterile medicines preparation while meeting standards required by regulatory bodies. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12833", "text": "In recent times, pharmacy technicians also speak directly with the patients on the phone to aid in the awareness of taking medications on time. In many countries, the relative importance of pharmacy technicians within the pharmacy workforce has been amplified in recent years, largely as a reaction to pharmacist shortages, resulting in an increase in their numbers and responsibilities. [ 5 ] [ 6 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12834", "text": "The  Pharmacy Examining Board of Canada  administers the Pharmacy Technician Qualifying Examination. Pharmacy technicians are required to be registered with a provincial or a national regulatory body or council. In provinces and jurisdictions where pharmacy technician is a regulated occupation,  liability insurance  is required to practice. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12835", "text": "According to a 2007 profile of the pharmacy technician workforce, 43% of technicians work in hospitals and other related facilities, 37% in chain or franchise community pharmacies, and 16% in independent community pharmacies. [ 9 ]  Most (62%) obtained pharmacy technician training from a career college or community college, some (16%) had only a high school education and no formal pharmacy training, while about 20% had some university education. A very small proportion (2%) had trained and worked abroad as either pharmacists or pharmacy technicians. [ 10 ]  The wide range of technical training and educational attainment likely reflects in part the variety of training programs for pharmacy technicians currently available in the different provinces and territories of the country. [ 9 ]  Accredited pharmacy technician diplomas, certificates and college programs are offered in the Ontario, Alberta, British Columbia, Nova Scotia, Manitoba, Saskatchewan and New Brunswick. [ 11 ]  The Canadian Association of Pharmacy Technicians is a professional organization of pharmacy technicians in Canada."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12836", "text": "According to the German Statistisches Bundesamt, 66,867 pharmacy technicians (\"Pharmazeutisch-technische Assistenten\") were working in 2011. About 90% were working as employees in community pharmacies. Their salary (approx. 1,837 \u2013 2,400 Euros) is part of agreements between employers associations and  Adexa ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12837", "text": "Pharmacy technicians are known as assistant pharmacists. Several universities offer programs of three and half years of education and training. This occupation appeared due to the lack of pharmacists in Saudi Arabia in 1990, a reason they are commonly confused with pharmacists. Pharmacy regency technicians are regulated and monitored by the  Saudi Commission for Health Specialties ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12838", "text": "According to the MOH Statistics, there were about 8,471 of pharmacy technicians working in MOH Saudi Arabia 2015."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12839", "text": "In 2010, the Minister of Health, Abdullah Al-Rabiah, issued a decision to stop the teaching of pharmacy technicians immediately."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12840", "text": "In Sri Lanka, the government agency National Apprentices and Industrial Training Authority (NAITA) has developed National Competency Standards (NCS) leading to the award of the NVQ Level 4 certification as pharmacy technician for pharmacy employees who have above four years of experience. The NCS is approved by the  Tertiary and Vocational Education Commission  in 2016 and is presently being implemented. \nThe one-year training consists of subject areas in compounding, dispensing, stock management, housekeeping practices and customer care development. The first batch of 154 certified pharmacy technicians are already employed in the community pharmacy sector. [ clarification needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12841", "text": "In 2009, a  World Health Organization  assessment identified a total of 918 practising pharmacy technicians or technologists (1 per 25,600 residents) and 1,642 medicine counter assistants (1 per 14,300 residents)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12842", "text": "In regards to training, the assessment identified only one pharmacy technologist training school in the country (enrolling 70 students in the Higher National Diploma program). [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12843", "text": "R.C.S.M. Govt Medical College and CPR Hospital, Kolhapur  provides training for pharmacy technicians in India. To be a pharmacy technician, completion of this program is 10+2 or diploma. [ clarification needed ]  There are two batches a year that intakes approximately 40 students per batch."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12844", "text": "Pharmacy technicians in Nigeria make up 75% of pharmaceutical work force.  Pharmacists Council of Nigeria  refused to allocate responsibilities that will give them right to practice at community level interdependently. The case was in court and the court ruled against PCN on December 3, 2008."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12845", "text": "Nigerian pharmacy technicians in collaboration with  National Board for Technical Education  (NBTE) are currently saving Nigerian Economy and Nigerians from the professional monopoly played by PCN which led to abundant fake drugs due lack of manpower. This exposed Nigerian to a lot of problems which lead reduction in productivity leading to sustainable poverty. \nNigerian pharmacy technicians in collaboration with NBTE are able to achieve these by introducing ND/HND in pharmaceutical technology. PCN is doing everything possible to stop this training to sustain its monopoly, demanding Federal ministry of education to direct NBTE to stop accrediting the polytechnics while these course are offered in Ghana, Sudan and other countries. The meeting called at the instance of NBTE on 25 May 2016 where the PCN, representative of the Honourable Minister of Health,  Federal Ministry of Education ,  Pharmaceutical Society of Nigeria  (PSN) and National Association of Pharmaceutical Technologists and Pharmacy Technicians of Nigeria were in attendance; certain issues bothering on the nomenclature Pharmaceutical Technologists, the curriculum and the accrediting body for polytechnic graduates of pharmaceutical Technology were raised. There it was made clear that the nomenclature (Pharmaceutical Technologist) is not new in Nigeria as the training of people bearing the name were trained at the former School of Pharmaceutical Technologists between 1981 and 1985. The premises of the school is being used as the liaison office of the PCN today. It was also established that NBTE is saddled with the accreditation of courses offered by Polytechnics and Monotechnics in the Federal Republic of Nigeria. As for the curriculum, findings revealed that NBTE is in line with the legal instrument that established the Board. Meanwhile, it was unanimously agreed that all relevant bodies should come together to review the complaints of the PCN."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12846", "text": "Tanzania has two pharmacy technician schools: one is a public sector institution under the  Ministry of Health and Social Welfare  and accredited by  Muhimbili University of Health and Allied Sciences , and the other is affiliated with a  faith-based organization  located in Kilimanjaro which offers diploma training. [ citation needed ]  The practice of pharmacy technician is regulated by Pharmacy Council Tanzania, which enrolls and enlists them. In 2010, the country had 0.11 registered pharmacy technicians per 10,000 population. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12847", "text": "The main job duties of Tanzanian pharmacy technicians include dispensing, stock management, compounding, quantification of pharmaceutical formulations, and laboratory work. In some areas of the country facing acute  shortage of physicians  and other clinicians, pharmacy technicians have also been found prescribing medicine. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12848", "text": "In the UK, the title  Pharmacy Technician  is a protected title. A prospective technician has two pathways that must be completed. One must complete both a  General Pharmaceutical Council -recognised course  and  a  SVQ  competence qualification  or  an accredited combined qualification and course. [ 14 ]  A period of time of working as a trainee or student pharmacy technician is needed before final qualification and compulsory registration with GPhC (formerly the Royal Pharmaceutical Society of Great Britain) is required before commencing work as a pharmacy technician. The period of on-the-job training is usually done concurrently whilst completing the course and typically over a two-year period. Pharmacy technicians may counsel patients on their medication (under the supervision or direction of a pharmacist, though counselling is not one of the learning outcomes for pharmacy technician training) [ 15 ]  as well as general dispensing of prescriptions. In community pharmacy, it has been recognised that the role is difficult to distinguish from that of a dispensing assistant with an NVQ2 qualification. Additional training is available to qualified pharmacy technicians and can include accuracy checking of dispensed prescriptions (though there is no legal requirement that a person be qualified as a pharmacy technician before undertaking an accuracy checking course), medicines management (hospital or PCT), participation in the running of hospital clinics such as  anticoagulant  clinics, dosing  warfarin  patients under dose banding guidance, [ citation needed ]  or other duties traditionally done by pharmacists."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12849", "text": "Training providers in the UK require a first degree subject, For example University of East Anglia requires \n2:1 or above undergraduate degree in a Life Science, Biomedical Science, Sport Science or Healthcare subject, 4 GCSEs or equivalent in English Language, Mathematics, Biology and Chemistry with one A Level or equivalent in a Science subject. Under exceptional circumstances, experience in healthcare practice may contribute/compensate absent the above requirements. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12850", "text": "In the  National Health Service  (NHS) pharmacy technicians work under the direct supervision of a senior or specialist pharmacy technician and is accountable to the chief pharmacy technician or lead pharmacist even if not in a dispensary. Technicians work mainly in one of two areas,  hospital pharmacy  or  community pharmacy . [ 17 ]  Some also work in doctors' general practices and in  primary care trusts ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12851", "text": "A pharmacy dispenser cannot call themselves or work as a pharmacy technician or register with the GPhC as one."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12852", "text": "Pharmacy technicians in hospitals are graded on the same  Agenda for Change  banding as audiovisual technicians, dental nurses and theatre support workers. [ 18 ]  They start on a set percentage of a Band 4 (usually 75% \u2013 an average annual wage of \u00a326,530  [ 19 ] ) as a trainee pharmacy technician completing 1,260 hours of clinical placement education moving on to Band 5 when newly qualified PhT and can work their way to a Band 8b in charge of a department/area. A Band 8b is the equivalent of a nurse lead/senior nurse manager in nursing or other head of department in the NHS. Although Band 8b is possible, a successful pharmacy technician can reasonably expect to reach Band 7a in the latter stage of his/her career, earning an average of \u00a354,320. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12853", "text": "Registered pharmacy technicians in the NHS may be responsible for the training and development of pharmacy support workers and pre-registration trainee pharmacy technicians. Further training and qualifications after initial registration enable them to perform this mentoring role. Pharmacy technicians in the UK (as with other countries e.g. Canada) are now referred to by some as professionals, although registered pharmacists are still considered experts in the pharmaceutical field and pharmacy technicians are subordinate to pharmacists. [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12854", "text": "A report was published by the  Pharmacists' Defence Association  in 2019 making proposals for the development of pharmacist and pharmacy technician roles and career frameworks symbiotically in community pharmacy. It also outlined various impediments and governance issues and called for these to be addressed. [ 21 ]  The Association of Pharmacy Technicians United Kingdom is a professional organisation for pharmacy technicians in the UK."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12855", "text": "There is no national regulatory agency governing pharmacy technicians and the duty falls to the individual state boards of pharmacies in the US. A  high school diploma  (or its  equivalent ) is typically required in all states but certification and licensing requirements vary by state. Some states require training from board-approved schools, national certification, on-the-job training or no requirements at all. A technician can become nationally certified by taking an NCAA-accredited examination administered by either the Pharmacy Technician Certification Board (PTCB) or the  National Healthcareer Association  (NHA). [ 22 ] [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12856", "text": "Beginning in January 2020, the PTCB enacted a requirement that prior to examination, an applicant for certification must complete an  American Society of Health-System Pharmacists -accredited pharmacy technician education program, a PTCB-recognized training program, or 500 hours of training [ 25 ]  however, the NHA had similar requirements prior to the PTCB enacting the 2020 requirements. Upon completion of the certification exam, a pharmacy technician earns the certified or CPhT credential.  Continuing education  after national certification is required for certification renewal every two years."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12857", "text": "According to the  Bureau of Labor Statistics , in 2011 about 75% of pharmacy technicians in the US work in a retail setting, [ 2 ]  such as an independently owned  drugstore , a mass retailer chain, or a mail-order or  online pharmacy . An additional 16% of pharmacy technician jobs were in hospitals, [ 2 ]  while others worked for nursing homes, pharmaceutical wholesalers, or the  federal government . As of 2016, the nationwide average hourly pay for pharmacy technicians working in retail or independent pharmacies is $12.26 [ 26 ] [ 27 ]  and for pharmacy technicians working in hospital setting is $14.57. [ 28 ]  American pharmacy technicians work under the supervision of a pharmacist, often following a  pharmacist-to-pharmacy technician ratio  if required by the state that the pharmacy is located in. The National Pharmacy Technician Association and American Association of Pharmacy Technicians are professional organizations of pharmacy technicians in the US."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12858", "text": "The states Delaware, Hawaii, Pennsylvania, and Wisconsin do not require licensing or certification but may require some form of training or registration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12859", "text": "Alabama, Alaska, Arizona, Arkansas, Colorado, Connecticut, Idaho, Illinois, Iowa, Kansas, Maryland, Massachusetts, Mississippi, Montana, New Mexico, North Dakota, Oregon, Utah, Virginia, Washington, West Virginia, Wyoming, and Washington, D.C. require both certification and licensing or registration, though some states may have a training period before these requirements."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12860", "text": "California, Florida, Georgia, Indiana, Kentucky, Louisiana, Maine, Michigan, Minnesota, Missouri, Nebraska, Nevada, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oklahoma, Rhode Island, South Carolina, South Dakota, Tennessee, Texas (with exceptions), and Vermont require only a license. [ 29 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12861", "text": "Pharmacy technicians are trained at  Harare Polytechnic . Students graduate with a diploma after three years of training. The program is run by the  Ministry of Health and Child Welfare of Zimbabwe . Yearly intake is about 35 students. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12862", "text": "Medication costs , also known as  drug costs  are a common  health care cost  for many people and health care systems.  Prescription costs  are the costs to the end consumer. Medication costs are influenced by multiple factors such as patents, stakeholder influence, and marketing expenses. A number of countries including Canada, parts of Europe, and Brazil use  external reference pricing  as a means to compare drug prices and to determine a base price for a particular medication. [ citation needed ]  Other countries use  pharmacoeconomics , which looks at the cost/benefit of a product in terms of  quality of life , alternative treatments (drug and non-drug), and cost reduction or avoidance in other parts of the health care system (for example, a drug may reduce the need for a surgical intervention, thereby saving money). Structures like the UK's  National Institute for Health and Clinical Excellence  and to a lesser extent Canada's Common Drug Review (a division of the  Canadian Agency for Drugs and Technologies in Health ) evaluate products in this way."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12863", "text": "Medication costs can be listed in a number of ways including cost per  defined daily dose , cost per specific period of time, cost per  prescribed daily dose , and cost proportional to  gross national product . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12864", "text": "A November 2020 study found that more than 1.1 million  senior citizens  in the U.S.  Medicare  program are expected to die prematurely over the next decade because they will be unable to afford their prescription medications, requiring an additional $17.7 billion to be spent annually on avoidable medical costs due to health complications. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12865", "text": "Medication costs can be the selling price from the manufacturer,  that price together with shipping , the wholesale price, the retail price, and the dispensed price. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12866", "text": "The dispensed price or prescription cost is defined as a cost which the patient has to pay to get medicines or treatments which are written as directions on prescription by a prescribers. [ 4 ]  The cost is generally influenced by a financial relationship between pharmaceutical manufacturers, wholesale distributors and pharmacies. [ 5 ]  In addition to the financial relationship, each nation has different systems to control the cost of prescriptions. In the United States, a pharmacy benefit manager, a third-party organization, such as private insurances or government-run health insurances will implement cost containment programs, such as establishing a formulary, to contain the cost. [ 5 ] [ 6 ] \u00a0 In the United Kingdom, the government negotiates an overall cap on drugs bill growth with the pharmaceutical industry. In addition a government agency, the National Institute of Health and Care Excellence (NICE) assesses cost effectiveness of individual prescription drugs pricing. [ 7 ]  The National Health Service also may negotiate direct with individual pharmaceutical companies for certain specialised medicines, as well as running competitive procurements for generic drugs and for patented medicines where there is more than one drug available for a condition. [ 8 ]  Prescription costs are a regular health care cost for the sick and may mean economic hardship for the underprivileged. [ 9 ] \nWith healthcare insurance, the patient in the U.S. pays a co-pay (the amount the patient must pay for each drug or medical visit), a deductible (the amount the patient has to pay before the insurance starts sharing the cost) and co-insurance (the amount the patient has to pay after deductible) for prescription costs. After reaching the out of pocket maximum, the insurance company will pay 100% of the prescription cost. The amount the patient has to pay depends on the healthcare insurance plan the patient has."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12867", "text": "As of 2017, prescription costs range from just more than 15% in high income countries to 25% in lower-middle income countries and low income countries. [ 10 ] :\u200a418"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12868", "text": "Pricing any pharmaceutical drug for sale to the general public is daunting. Per Forbes, setting a high ceiling price for a new drug could be problematic as physicians could shy away from prescribing the drug, because the cost could be too great for the benefit. [ 12 ]  Setting too low of a price could imply inferiority, that the drug is too \"weak\" for the market. [ 12 ]  There are many different pricing strategies and factors that go into the research and evaluation of a future drug's price with whole departments within US pharmaceutical companies like  Pfizer  devoted to cost analysis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12869", "text": "This chart shows discrepancies in drug pricing in different countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12870", "text": "A study has placed the amount spent on drug marketing at 2-19 times that on drug research. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12871", "text": "Much research, needed to create drugs is done by the  public sector . [ 14 ] [ 15 ]  In addition, pharmaceutical companies also do much research prior to producing medications. The table shows research and development statistics for pharmaceutical companies as of 2013 per Astra Zeneca. [ 16 ] [ page\u00a0needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12872", "text": "Severin Schwan , the CEO of the Swiss company Roche, reported in 2012 that Roche's research and development costs in 2014 amounted to $8.4 billion, a quarter of the entire  National Institutes of Health  budget. [ 12 ]  Given the profit-driven nature of pharmaceutical companies and their research and development expenses, companies use their research and development expenses as a starting point to determine appropriate yet profitable prices. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12873", "text": "Pharmaceutical companies spend a large amount on research and development before a drug is released to the market and costs can be further divided into three major fields: the discovery into the drug's specific medical field, clinical trials, and failed drugs. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12874", "text": "The process of drug discovery can involve scientists determining the germs, viruses, and bacteria that cause a specific disease or illness. [ 19 ]  The time frame can range from 3\u201320 years and costs can range between several million to tens of millions of dollars. Research teams attempt to break down disease components to find abnormal events/processes taking place in the body. [ 19 ]  Only then do scientists work on developing chemical compounds to treat these abnormalities with the aid of computer models. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12875", "text": "After \"discovery\" and a creation of a chemical compound, pharmaceutical companies move forward with the Investigational New Drug (IND) Application from the  FDA . [ 19 ]  After the investigation into the drug and given approval, pharmaceutical companies can move into pre-clinical trials and clinical trials. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12876", "text": "Drug development  and pre-clinical trials focus on non-human subjects and work on animals such as rats."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12877", "text": "The  Food and Drug Administration  requires at least 3 phases of clinical trials that assess the side effects and the effectiveness of the drug. An analysis of trial costs of approved drugs by the FDA from 2015 to 2016 found that out of 138 clinical trials, 59 new therapeutic agents were approved by the FDA. These trials have a median estimated cost of $19 million US dollars. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12878", "text": "Of these phases, the phase 3 is the most costly process of drug development. [ 22 ]  A single phase 3 trial can cost upwards of $100 million. [ 23 ]  It accounts for about 90 percent of the cost to pharmaceutical companies to develop a medication. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12879", "text": "The processes of \"discovery\" and clinical trials amounts to approximately 12 years from research lab to the patient, in which about 10% of all drugs that start pre-clinical trials ever make it to actual human testing. [ 19 ]  Each pharmaceutical company (who have hundreds of drugs moving in and out of these phases) will never recuperate the costs of \"failed drugs\". Thus, profits made from one drug need to cover the costs of previous \"failed drugs\". The cost of failure in R&D constitutes about 60% of all development costs. It emphasizes the importance of success rates as a key driver of R&D productivity. The average costs for studies are estimated at $30 million, $70 million, and $310 million for Phase I, II, and III, respectively. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12880", "text": "Overall, research and development expenses relating to a pharmaceutical drug amount to the billions. For example, it was reported that  AstraZeneca  spent upwards on average of $11 billion per drug for research and developmental purposes. [ 23 ]  The average of $11 billion only comprises the \"discovery\" costs, pre-clinical and clinical trial costs, and other expenses. [ citation needed ]  With the addition of \"failed drug\" costs, the $11 billion easily amounts to over $20 billion in expenses. [ citation needed ]  Therefore, an appropriate figure like $60 billion would be approximate sales figure that a pharmaceutical company like  AstraZeneca  would aim to generate to cover these costs and make a profit at the same time. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12881", "text": "Total research and development costs provide pharmaceutical companies a ballpark estimation of total expenses. This is important in setting projected profit goals for a particular drug and thus, is one of the most necessary steps pharmaceutical companies take in pricing a particular drug. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12882", "text": "A 2022 study invalidated the common  argument   as is  for high medication costs that research and development investments are reflected in and necessitate the treatment costs, finding no correlation for  investments in drugs  (for cases where transparency was sufficient) and their costs. [ 27 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12883", "text": "Patients and doctors can also have some input in pricing, though indirectly. Customers in the United States have been protesting the high prices for recent \"miracle\" drugs like  Daraprim  and  Harvoni , both of which attempt to cure or treat major diseases (HIV/AIDS and  hepatitis C ). [ 28 ]  Public outcry has worked in many cases to control and even decide the pricing for some drugs. For example, there was severe backlash over Daraprim, a drug that treats toxoplasmosis. [ 29 ]   Turing Pharmaceuticals  under the leadership of  Martin Shkreli  raised the price of the drug 5,500% from $13.50 to $750 per pill. [ 29 ]  After denouncement from 2016 presidential candidates  Hillary Clinton  and  Bernie Sanders , Martin Shkreli said he would reduce the price but later decided not to. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12884", "text": "With the recent trend of price gouging, legislators have introduced reform to curb these hikes, effectively controlling the pricing of drugs in the United States. Hillary Clinton announced a proposal to help patients with chronic and severe health conditions by placing a nationwide monthly cap of $250 on prescription out-of-pocket drugs. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12885", "text": "Research for a drug that is curing something no one has ever cured before will cost much more than research for the medicine of a very common disease that has known treatments. [ citation needed ]  Also, there would be more patients for a more common ailment so that prices would be lower. [ citation needed ]   Soliris  only treats two extremely rare diseases, so the number of consumers is low, making it an  orphan drug . Soliris still makes money because of its high price of over $400,000 per year per patient. [ 12 ]  The benefit of this drug is immense because it cures very rare diseases that would cost much more money to treat otherwise, which saves insurance companies and health agencies millions of dollars. Hence, insurance companies and health agencies are willing to pay these prices. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12886", "text": "Policy makers in some countries have placed controls on the amount pharmaceutical companies can raise the price of drugs. In 2017, Democratic party leaders proposed the creation of a new federal agency to investigate and perhaps fine drug manufacturers who make unjustified price increases. Pharmaceutical companies would be required to submit a justification for a drug with a \u201csignificant price increase\u201d within at least 30 days of implementation. Under the terms of the proposal, Mylan's well-publicized price increase for its EpiPen product would fall below the criteria for a significant price increase, while the 5000% overnight increase of Turing Pharmaceuticals Daraprim (pyrimethamine) would be subject to regulatory action. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12887", "text": "One of the most important factors that determine the cost of a drug is the availability of competing drugs and treatments.  Having two or more manufacturers producing drugs for the same disease tends to reduce costs. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12888", "text": "Patent  laws give pharmaceutical companies the exclusive right to market a drug for a period of time, allowing them to extract a high  monopoly price . [ 31 ]  For example,  U.S. patent law  grants a monopoly for 20 years after filing.  After that period, the same product from different manufacturers - known as  generic drugs  - can be sold, usually resulting in a substantial price reduction and possible shift in market share. Two patents that are commonly used are  process patents  and drug  product patents . [ 32 ]  Process patents only provide developers intellectual claim to the methods in which the product was manufactured, so a competitor can make the same drug by a different method without violating the patent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12889", "text": "In some cases, a new treatment is more effective than an older treatment, or a given drug may work better than competitors for only some patients.  The availability of an imperfect substitution erodes prices to a lesser degree than would a perfect substitute."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12890", "text": "Some countries grant additional protections from competition for a limited period, such as  test data exclusivity  or  supplementary protection certificates .  Additional incentives are available in some jurisdictions for manufacturers of  orphan drugs  for rare diseases, including extended monopoly protection, tax credits, waived fees, and relaxed approval processes due to the small number of affected patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12891", "text": "The process of creating drugs to testing them to selling them is a long process. [ 33 ]  Aside from the costs for research and trials, many consumers are unaware of the process of the  drug supply chain . There are many middlemen and companies that buy and sell the drugs. This includes \"drug manufacturers, drug wholesalers, pharmacies, and payers.\" [ 33 ]   Big Pharma 's influence in the policies and regulations regarding drug patents and prescription costs, protects pharmaceutical companies from having to be transparent about where the money goes and who those high prices benefit, including Pharmacy Benefit Managers. [ 34 ]  \u00a0Transparency between drug manufacturers and sellers increases accountability between producers and consumers and allows for patients to know more about what they are paying for. Prescription Drug Price Locators allow for patients to learn of more cost-effective sellers and find discounts that will benefit them."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12892", "text": "In an effort by the U.S. Department of Health and Human Services ( HHS ) to regulate drug price transparency in television advertising in 2019, the HHS saw a resistance to change against legislation. [ 35 ]  Although what the HHS sought to change was a step in the right direction for drug price transparency, Federal Judge Amit P. Mehta ruled in favor of the pharmaceutical industry. The ruling was based on the inability to give the HHS such power to enact such legislations. [ 35 ]  Policymakers have a lot to take into account when regarding the issue of transparency, as there are many middlemen involved in the selling and buying of prescription drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12893", "text": "When the price of medicine goes up the  quality of life  of consumers who need the medicine decreases. [ 36 ] [ 37 ]  Consumers who have increased costs for medicine are more likely to change their lifestyle to spend less money on groceries, entertainment, and routine family needs. [ 36 ]  They are more likely to go into debt or postpone paying their existing debts. [ 36 ]  High drug prices can prevent people from saving for retirement. [ 36 ]  It is not uncommon for typical people to have challenges paying medical bills. [ 36 ]  Some people fail to get the medical care they need due to lack of money to pay for it. [ 36 ]  In low and middle income countries up to 90% of people pay for medications out of pocket. [ 38 ]  A November 2020 study by the  West Health  Policy Center stated that more than 1.1 million  senior citizens  in the U.S.  Medicare  program are expected to die prematurely over the next decade because they will be unable to afford their prescription medications, requiring an additional $17.7 billion to be spent annually on avoidable medical costs due to health complications. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12894", "text": "The effects of high prescription costs on consumers also affects their long-term health and overall life expectancy. When properly used, a medication can benefit a patient and cure their disease. When a patient cannot afford to pay for their medication, they lose out on the optimal benefits of proper and adequate dosages. [ 39 ]  High prescription costs don't just affect patients in the short run, but also deteriorates their overall quality of life, as they are exposed to chronic illnesses that could have been prevented by that first prescription. [ 39 ]  Evidence from studies indicates that  insulin  therapy as a treatment for patients with high glucose levels that are not yet diabetic, leads to a decrease in  insulin resistance , which benefits patients. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12895", "text": "Consumers commonly respond to high or increasing drug prices by doing what they can to save drug costs. The most commonly recommended course of action for consumers who seek to lower their drug costs is for them to tell their own doctor and pharmacist that they need to save money and then ask for advice. [ 41 ]  Doctors and pharmacists are professionals who know their fields and are the most likely source of information about options for reducing cost. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12896", "text": "Depending on the country and health policies implemented, there are also options to search for the most convenient and affordable health insurance plans without having to consult a healthcare provider or obtain insurance through the employer. However, those who seek to purchase insurance individually through the individual market are most likely to be underinsured and therefore could potentially have a higher prescription cost. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12897", "text": "There can be significant variation of prices for drugs in different pharmacies, even within a single geographical area. [ 43 ]  Because of this, some people check prices at multiple pharmacies to seek lower prices. [ 43 ]   Online pharmacies  can offer low prices but many consumers using online services have experienced  Internet fraud  and other problems, [ 44 ]  such as long shipping times from overseas and a higher  insecurity  regarding  quality , genuineness and safety of the ordered products."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12898", "text": "Some consumers lower costs by asking their doctor for  generic drugs  when available. [ 45 ]  Because pharmaceutical companies often set prices by pills rather than by dose, consumers can sometimes buy double-dose pills,  split the pills  themselves with their doctor's permission, and save money in the process. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12899", "text": "In countries without universal healthcare, there can be unaffordable  out-of-pocket  costs for needed medications. Approximately 25% of Americans find it difficult to afford prescription drugs. [ 47 ]  In the case of expensive  anti-obesity medications  it has been noted that many people \"who could most benefit from weight loss may be unable to afford such expensive drugs\". [ 48 ]  This may be of higher concern for conditions that are more risky or detrimental to health and/or which, unlike obesity, don't have additional treatment options that are both widely known and effective \u2013 like further improvements in diet and physical activity in the case of obesity. A study found that among U.S. Medicare beneficiaries without subsidies, 30% of  prescriptions  written for anticancer drugs, 22% for hepatitis C, and more than 50% for disease-modifying therapies for either immune system disorders or hypercholesterolemia were not filled by patients. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12900", "text": "The  right to science and culture  is one of the rights in the  Universal Declaration of Human Rights  according to which \"Everyone has the right freely to participate in the cultural life of the community, to enjoy the arts and to share in scientific advancement and its benefits.\" [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12901", "text": "While some have concluded that \" drug development  is likely to remain an expensive and resource-intensive process\", [ 51 ]  a study found that wide range of medicines in the  WHO Model List of Essential Medicines  can be profitably  manufactured at very low cost  by  pharmaceutical industries  and that \"Most EML medicines are sold in the UK and South Africa at prices significantly higher than those estimated from  production  costs\". [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12902", "text": "Global spending on prescription drugs in 2020 may have been ~$1.3 trillion and \"The high cost of prescription drugs threatens healthcare budgets, and limits funding available for other areas in which  public investment  is needed\". [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12903", "text": "Prescription drug prices in the United States have been among the highest in the world. The high cost of prescription drugs became a major topic of discussion in the new millennium, leading up to the  U.S. health care reform  debate of 2009, and received renewed attention in 2015. High prices have been attributed to monopolies given to manufacturers by the government and a lack of ability for organizations to negotiate prices. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12904", "text": "Individuals are able to enroll in health insurance plans, which often include prescription medication coverage. However, insurance companies decide which drugs they will cover by creating a  formulary . If a medication is not on this list, the insurance company may require people to pay more money out-of-pocket compared to other medications that are on the formulary. There are also often tiers within this approved drug list, as the insurance company may be willing to cover a portion of one drug but prefer and completely cover a cheaper alternative. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12905", "text": "Medicare Part D  is a branch of Medicare that helps to cover costs of prescription medications for patients aged 65 and up. From 2010 to 2018, the Part D plan \"nearly quadrupled\" its spending on the catastrophic coverage phase. [ 56 ]  This increase in spending is attributed to the rising pricing of prescription medications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12906", "text": "It varies by region in the  United Kingdom . In Wales, Scotland and Northern Ireland prescription costs have been completely abolished, however in England the current prescription cost for adults as of 1 April 2024 is \u00a39.90 per item dispensed. [ 57 ]  There are subsidised costs for those claiming  Universal Credit ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12907", "text": "To provide context for the medication costs in Canada, the country is a member of the  OECD , an international organization that consists of 38 countries which includes countries like the United States, Australia, Germany, and more. Among these 38 countries, Canada ranks number three in medication costs in the OECD. [ 58 ]  The Government of Canada found that during the 2020-2021 year, the country had spent 12.3 billion dollars on medication costs. [ 59 ]  In Canada, each province and territory publicly funds their own insurance plan rather than a national insurance plan. [ 60 ]  With differing insurance plans, the medication costs the public varies from area to area. [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12908", "text": "In Canada, the medication pricing is overseen by the  Patented Medicine Prices Review Board  (PMPRB), which monitors the prices set for patented drugs. [ 62 ]  One way the PMPRB evaluates whether drug pricing by patentees is excessive by considering international drug pricing. [ 63 ]  The PMPRB also compares the price of the drug to a similar market. [ 64 ]  However, the patentees do not need approval of drug pricing with the PMPRB before listing drugs for sale. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12909", "text": "In  developing countries  medications make up between 25 and 70% of health care costs. [ 38 ]  Many medications are beyond the reach of the majority of the population. [ 66 ]  There have been attempts both by international agreements and by  pharmaceutical companies  to provide drugs at low cost, either supplied by manufacturers who own the drugs, [ 67 ]  or manufactured locally as  generic versions of drugs  which are elsewhere protected by  patent . [ 68 ]  Countries without manufacturing capability may import such generics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12910", "text": "The legal framework regarding generic versions of patented drugs is formalised in the  Doha Declaration  on  Trade-Related Aspects of Intellectual Property Rights  and later agreements. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12911", "text": "A  prescription drug  (also  prescription medication ,  prescription medicine  or  prescription-only medication ) is a  pharmaceutical drug  that is permitted to be dispensed only to those with a  medical prescription . In contrast,  over-the-counter drugs  can be obtained without a prescription. The reason for this difference in  substance control  is the potential scope of misuse, from  drug abuse  to  practicing medicine without a license  and without sufficient education. Different jurisdictions have different definitions of what constitutes a prescription drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12912", "text": "In North America,  \u211e , usually printed as \"Rx\", is used as an abbreviation of the word \"prescription\". It is a contraction of the Latin word \" recipe \" (an imperative form of \"recipere\") meaning \"take\". [ 1 ]  Prescription drugs are often dispensed together with a  monograph  (in Europe, a Patient Information Leaflet or PIL) that gives detailed information about the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12913", "text": "The use of prescription drugs has been increasing since the 1960s."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12914", "text": "In  Australia , the  Standard for the Uniform Scheduling of Medicines and Poisons  (SUSMP) governs the manufacture and supply of drugs with several categories: [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12915", "text": "As in other developed countries, the person requiring a prescription drug attends the clinic of a qualified  health practitioner , such as a  physician , who may write the prescription for the required drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12916", "text": "Many prescriptions issued by health practitioners in Australia are covered by the  Pharmaceutical Benefits Scheme , a scheme that provides subsidised prescription drugs to residents of Australia to ensure that all Australians have affordable and reliable access to a wide range of necessary medicines. When purchasing a drug under the PBS, the consumer pays no more than the patient co-payment contribution, which, as of January 1, 2022, is  A$ 42.50 for general patients. Those covered by government entitlements (low-income earners, welfare recipients, Health Care Card holders, etc.) and or under the  Repatriation Pharmaceutical Benefits Scheme  (RPBS) have a reduced co-payment, which is  A$ 6.80 in 2022. [ 3 ]  The co-payments are compulsory and can be discounted by pharmacies up to a maximum of  A$ 1.00 at cost to the pharmacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12917", "text": "In the  United Kingdom , the  Medicines Act 1968  and the  Prescription Only Medicines (Human Use) Order 1997  contain regulations that cover the supply of sale, use, prescribing and production of medicines. There are three categories of medicine: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12918", "text": "The simple possession of a prescription-only medicine without a prescription is legal unless it is covered by the  Misuse of Drugs Act 1971 . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12919", "text": "A patient visits a  medical practitioner  or  dentist , who may prescribe drugs and certain other medical items, such as blood glucose-testing equipment for  diabetics . Also, qualified and experienced nurses, paramedics and pharmacists may be independent prescribers. Both may prescribe all POMs (including controlled drugs), but may not prescribe Schedule 1 controlled drugs, and 3 listed controlled drugs for the treatment of addiction; which is similar to doctors, who require a special licence from the Home Office to prescribe schedule 1 drugs. Schedule 1 drugs have little or no medical benefit, hence their limitations on prescribing.  District nurses  and  health visitors  have had limited prescribing rights since the mid-1990s; until then, prescriptions for dressings and simple medicines had to be signed by a doctor. Once issued, a prescription is taken by the patient to a pharmacy, which dispenses the medicine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12920", "text": "Most prescriptions are  NHS prescriptions , subject to a standard charge that is unrelated to what is dispensed. The  NHS  prescription fee was increased to \u00a39.90 for each item in  England  in May 2024; [ 6 ]  prescriptions are free of charge if prescribed and dispensed in  Scotland , [ 7 ]   Wales  and  Northern Ireland , [ 8 ]  and for some patients in England, such as inpatients, children, those over 60s or with certain medical conditions, and claimants of certain benefits. [ 9 ]  The pharmacy charges the NHS the actual cost of the medicine, which may vary from a few pence to hundreds of pounds. [ 10 ] [ 11 ]  A patient can consolidate prescription charges by using a prescription payment certificate (informally a \"season ticket\"), effectively capping costs at \u00a331.25 a quarter or \u00a3111.60 for a year. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12921", "text": "Outside the NHS,  private prescriptions  are issued by private medical practitioner and sometimes under the NHS for medicines that are not covered by the NHS. [ 10 ] [ 11 ]  A patient pays the pharmacy the normal price for medicine prescribed outside the NHS."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12922", "text": "Survey results published by  Ipsos MORI  in 2008 found that around 800,000 people in England were not collecting prescriptions or getting them dispensed because of the cost, the same as in 2001. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12923", "text": "In the United States, the  Federal Food, Drug, and Cosmetic Act  defines what substances, known as legend drugs, require a prescription for them to be dispensed by a pharmacy. The federal government authorizes physicians (of any specialty),  physician assistants ,  nurse practitioners  and other  advanced practice nurses , veterinarians, dentists, and optometrists to prescribe any controlled substance. They are issued unique  DEA numbers . [ 13 ]  Many other mental and physical health technicians, including basic-level  registered nurses ,  medical assistants , emergency medical technicians, most psychologists, and social workers, are not authorized to prescribe legend drugs. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12924", "text": "The federal  Controlled Substances Act  (CSA) was enacted in 1970. It regulates manufacture, importation, possession, use, and distribution of  controlled  substances, which are drugs with potential for abuse or addiction. The legislation classifies these drugs into five schedules, with varying qualifications for each schedule. The schedules are designated  schedule I ,  schedule II ,  schedule III ,  schedule IV , and  schedule V . Many drugs other than controlled substances require a prescription."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12925", "text": "The safety and the effectiveness of prescription drugs in the US are regulated by the 1987  Prescription Drug Marketing Act  (PDMA). The  Food and Drug Administration  (FDA) is charged with implementing the law."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12926", "text": "As a general rule,  over-the-counter drugs  (OTC) are used to treat a condition that does not need care from a healthcare professional if have been proven to meet higher safety standards for self-medication by patients. Often, a lower strength of a drug will be approved for OTC use, but higher strengths require a prescription to be obtained; a notable case is  ibuprofen , which has been widely available as an OTC  pain killer  since the mid-1980s, but it is available by prescription in doses up to four times the OTC dose for severe pain that is not adequately controlled by the OTC strength."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12927", "text": "Herbal preparations ,  amino acids ,  vitamins ,  minerals , and other  food supplements  are regulated by the FDA as  dietary supplements . Because specific health claims cannot be made, the consumer must make informed decisions when purchasing such products. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12928", "text": "By law, American pharmacies operated by \"membership clubs\" such as  Costco  and  Sam's Club  must allow non-members to use their pharmacy services and may not charge more for these services than they charge as their members. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12929", "text": "Physicians may legally prescribe drugs for uses other than those specified in the FDA approval, known as  off-label use . [ citation needed ]  Drug companies, however, are prohibited from marketing their drugs for off-label uses. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12930", "text": "Some prescription drugs are commonly abused, particularly those marketed as  analgesics , including  fentanyl  (Duragesic),  hydrocodone  (Vicodin),  oxycodone  (OxyContin),  oxymorphone  (Opana),  propoxyphene  (Darvon),  hydromorphone  (Dilaudid),  meperidine  (Demerol), and  diphenoxylate  (Lomotil). [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12931", "text": "Some prescription painkillers have been found to be addictive, and unintentional poisoning deaths in the United States have skyrocketed since the 1990s according to the  National Safety Council . [ 17 ]  Prescriber education guidelines as well as patient education,  prescription drug monitoring programs  and regulation of pain clinics are regulatory tactics which have been used to curtail opioid use and misuse. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12932", "text": "The expiration date, required in several countries, specifies the date up to which the manufacturer guarantees the full potency and safety of a drug. In the United States, expiration dates are determined by regulations established by the FDA. [ 19 ]  The FDA advises consumers not to use products after their expiration dates. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12933", "text": "A study conducted by the U.S. Food and Drug Administration covered over 100 drugs, prescription and over-the-counter. The results showed that about 90% of them were safe and effective far past their original expiration date. At least one drug worked 15 years after its expiration date. [ 21 ]  Joel Davis, a former FDA expiration-date compliance chief, said that with a handful of exceptions\u2014notably  nitroglycerin ,  insulin , and some liquid antibiotics (outdated  tetracyclines  can cause  Fanconi syndrome )\u2014most expired drugs are probably effective. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12934", "text": "The  American Medical Association  issued a report and statement on Pharmaceutical Expiration Dates. [ 23 ]  The  Harvard Medical School  Family Health Guide notes that, with rare exceptions, \"it's true the effectiveness of a drug may decrease over time, but much of the original potency still remains even a decade after the expiration date\". [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12935", "text": "The expiration date is the final day that the manufacturer guarantees the full potency and safety of a medication. Drug expiration dates exist on most medication labels, including prescription, over-the-counter and dietary supplements. U.S. pharmaceutical manufacturers are required by law to place expiration dates on prescription products prior to marketing. For legal and liability reasons, manufacturers will not make recommendations about the stability of drugs past the original expiration date. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12936", "text": "Prices of prescription drugs  vary widely around the world.  Prescription costs  for  biosimilar  and  generic drugs  are usually less than brand names, but the cost is different from one pharmacy to another."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12937", "text": "To lower prescription drug costs, some  U.S.  states have sought federal approval to buy drugs in  Canada , as of 2022. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12938", "text": "Generics undergo strict scrutiny to meet the equal efficacy, safety, dosage, strength, stability, and quality of brand name drugs. [ 27 ]  Generics are developed after the brand name has already been established, and so generic drug approval in many aspects has a shortened approval process because it replicates the brand name drug. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12939", "text": "Brand name drugs cost more due to time, money, and resources that drug companies invest in them to conduct development, including clinical trials that the FDA requires for the drug to be marketed. [ 28 ]  Because drug companies have to invest more in research costs to do this, brand name drug prices are much higher when sold to consumers. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12940", "text": "When the patent expires for a brand name drug, generic versions of that drug are produced by other companies and are sold for lower price. By switching to generic prescription drugs, patients can save significant amounts of money: e.g. one study by the  FDA  showed an example with more than 52% savings of a consumer's overall costs of their prescription drugs. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12941", "text": "In the United States there are many resources available to patients to lower the costs of medication. These include copayments, coinsurance, and deductibles. [ neutrality  is  disputed ]  The  Medicaid Drug Rebate Program  is another example. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12942", "text": "Generic drug programs lower the amount of money patients have to pay when picking up their prescription at the pharmacy. As their name implies, they only cover generic drugs. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12943", "text": "Co-pay assistance programs are programs that help patients lower the costs of specialty medications; i.e., medications that are on restricted formularies, have limited distribution, and/or have no generic version available. These medications can include drugs for HIV, hepatitis C, and multiple sclerosis. Patient Assistance Program Center ( RxAssist ) has a list of foundations that provide co-pay assistance programs. Co-pay assistance programs are for under-insured patients. Patients without insurance are not eligible for this resource; however, they may be eligible for patient assistance programs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12944", "text": "Patient assistance programs are funded by the manufacturer of the medication. Patients can often apply to these programs through the manufacturer's website. This type of assistance program is one of the few options available to uninsured patients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12945", "text": "The out-of-pocket cost for patients enrolled in co-pay assistance or patient assistance programs is $0. It is a major resource to help lower costs of medications\u2014however, many providers and patients are not aware of these resources."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12946", "text": "Traces of prescription drugs\u2014including  antibiotics ,  anti-convulsants ,  mood stabilizers  and  sex hormones \u2014have been detected in drinking water. [ 32 ] [ 33 ]  Pharmaceutically active compounds (PhACs) discarded from human therapy and their metabolites may not be eliminated entirely by sewage treatment plants and have been detected at low concentrations in surface waters downstream from those plants. [ 34 ]  The continuous discarding of incompletely treated water may interact with other environmental chemicals and lead to uncertain ecological effects. [ 35 ]  Due to most pharmaceuticals being highly soluble, fish and other aquatic organisms are susceptible to their effects. [ 34 ]  The long-term effects of pharmaceuticals in the environment may affect survival and reproduction of such organisms. [ 34 ]  However, levels of medical drug waste in the water is at a low enough level that it is not a direct concern to human health. However, processes, such as  biomagnification , are potential human health concerns. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12947", "text": "On the other hand, there is clear evidence of harm to aquatic animals and fauna. Recent advancements in technology have allowed scientists to detect smaller, trace quantities of pharmaceuticals in the ng/ml range. [ 37 ]  Despite being found at low concentrations, female hormonal contraceptives may cause feminizing effects on male vertebrate species, such as fish, frogs and crocodiles. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12948", "text": "The FDA established guidelines in 2007 to inform consumers should dispose of prescription drugs. [ 38 ]  When medications do not include specific disposal instructions, patients should not flush medications in the toilet, but instead use medication take-back programs to reduce the amount of pharmaceutical waste in sewage and landfills. [ 39 ]  If no take-back programs are available, prescription drugs can be discarded in household trash after they are crushed or dissolved and then mixed in a separate container or sealable bag with undesirable substances like cat litter or other unappealing material (to discourage consumption). [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12949", "text": "Psychiatric pharmacy , also known as  mental health pharmacy , is the area of  clinical pharmacy  specializing in the treatment of people with  psychiatric illnesses  through the use of  psychotropic medications . It is a branch of  neuropsychiatric pharmacy , which includes  neurologic pharmacy . [ 1 ]  Areas where psychiatric pharmacists are found most abundantly are in chemical dependency, developmental disabilities, long-term care facilities, adherence clinics, mental health clinics, and within the prison system. [ 2 ]  However, psychiatry and neurology are not the only areas where psychiatric pharmacists require comprehensive knowledge. They must also be proficient in clinical problem solving, interprofessionalism, and communication with understanding and empathy for the patient population they serve, as they are a sensitive group. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12950", "text": "Psychiatric pharmacy was introduced in the late 1960s. The first time a psychiatric pharmacist was able to practice in a psychiatric unit was in 1971, as assigned by the US Public Health Service. This became the setting for the first published case where the role of a psychiatric pharmacist was elaborated upon. [ 4 ]  Psychiatric pharmacists were working not only in psychiatric inpatient and outpatient settings, but in methadone and disulfiram clinics, along with centers for mentally disabled people. During this time, the University of Tennessee created contracts which allowed for pharmacy dispensing and clinical services for local psychiatric facilities. This treatment paradigm involved some of the collaborative drug therapy management and medication therapy management (MTM) systems in which psychiatric pharmacists employ today. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12951", "text": "The  College of Psychiatric and Neurologic Pharmacists  (CPNP) is a  professional organization  that represents psychiatric pharmacists within the United States. CPNP credits two key  pharmacists  with developing clinical psychiatric pharmacy as a specialty: Dr. Glen Stimmel, PharmD, BCPP and Dr. R. Lee Evans, PharmD, FASHP, BCPP. [ 1 ] [ 6 ]  Dr. Stimmel would later become a founding member of CPNP, as well as serve as its president. [ 7 ]  Dr. Matthew Fuller PharmD, BCPP, FASHP, CPNP Foundation President 2006\u20132007, has recognized Dr. Stimmel as the \"Father of Psychiatric Pharmacy.\" [ 7 ] [ 8 ]  The specialty of psychiatric pharmacy was recognized by the  Board of Pharmacy Specialties  (BPS) in 1992. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12952", "text": "Psychiatric pharmacy is practiced by psychiatric (also called \"neuropsychiatric\")  pharmacists . Psychiatric pharmacists tend to have a board certification in the specialty of psychiatric pharmacy, granting the title of Board Certified Psychiatric Pharmacist (BCPP) by the  Board of Pharmacy Specialties  (BPS), and attach the post-nominals after their professional degrees. [ 9 ]  Because the BPS does not have a separate certification for neurologic pharmacists, neurologic pharmacists may be classified as BCPP's as well (indeed, there is a significant amount of overlap between the two subspecialties). It is not uncommon for psychiatric pharmacists to be residency trained through a specialized  residency  (post-graduate year 2, abbreviated \"PGY2\") program in psychiatric pharmacy. [ 10 ]  The BCPP program validates that the pharmacist being certified has the progressive knowledge and experience to improve outcomes and recovery for patients with mental or neurological disabilities by designing, implementing, monitoring, and modifying treatment plans for patients as needed. It also ensures that the pharmacist being certified will educate patients, health care professionals, and other stakeholders. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12953", "text": "Psychiatric pharmacists work in both the  inpatient  and  outpatient  settings."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12954", "text": "Psychiatric pharmacists working for the  Veterans Health Administration  can have salaries between $112,268-145,955. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12955", "text": "Psychiatric pharmacy is practiced by specialist mental health pharmacists. Specialist mental health pharmacists tend to work in the  inpatient  setting, within mental health hospitals. [ 13 ]  Credentialing is performed through the  College of Mental Health Pharmacy  (CMHP), which assesses the experience and aptitude of pharmacists working in the field of mental health (psychiatric) pharmacy. Credentialed members are granted the title of Member of the College of Mental Health Pharmacy (MCMHP), and attach the post-nominals after their professional degrees. [ 14 ]  Notable psychiatric pharmacists include  Professor David Taylor , foundation president of the college of mental health pharmacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12956", "text": "As experts in pharmacotherapy, psychiatric pharmacists are trained to assure that patients with mental illness are treated with the most appropriate medications for their conditions. They provide a variety of services aimed at making sure that patients are treated safely, that side effects are minimized (if not eliminated), and that pharmacologic treatments are efficacious at controlling or halting disease progression."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12957", "text": "Psychiatric pharmacists provide a service called comprehensive medication management (CMM), which involves a thorough assessment of a patient's present and past medication history, laboratory work-up and exam findings, and treatment goals. During CMM, psychiatric pharmacists look for drug related problems (DRPs) related to their patients' pharmacotherapy and correct them in collaboration with  psychiatrists ,  social workers , and other members of the interdisciplinary healthcare team, collaborating closely with the patient and their family. [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12958", "text": "Psychiatric pharmacists provide  therapeutic drug monitoring , which involves ordering laboratory tests that will measure the concentration of a medication in the blood. This is especially useful in the area of psychiatric pharmacy because a lot of drugs used to treat psychiatric illnesses (for example,  lithium citrate  and  clozapine ) have a narrow  therapeutic window . There is a lot of potential for severe adverse reactions when using certain psychiatric medications, making therapeutic drug monitoring a useful tool for preventing harmful outcomes. The National Council for Behavioral Health, a collaborative that represents the interests of psychiatric professional organizations, offers recommendations for targeted, interdisciplinary interventions by psychiatric pharmacists, including pharmacist-lead  clozapine  clinics and providing long-acting injectable  antipsychotic  administration services. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12959", "text": "Psychiatric pharmacists are sometimes involved in  collaborative practice agreements  which physicians, which allows pharmacists to add or remove medications from a patient's drug regimen, change the strengths/dose or frequencies of medications, the duration of treatment, and the route of administration. [ 18 ]  Combined with therapeutic drug monitoring, this allows psychiatric pharmacists to directly make changes to a patient's drug regimen based on the results from laboratory tests."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12960", "text": "Regenerative Medicine Advanced Therapy (RMAT)  is a designation given by the  Food and Drug Administration  to  drug candidates  intended to treat serious or life-threatening conditions under the  21st Century Cures Act . [ 1 ]  A RMAT designation allows for accelerated approval based surrogate or intermediate  endpoints . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12961", "text": "RMAT goes beyond  breakthrough therapy  features by allowing for accelerated  approval  of drugs based on  surrogate endpoints . A surrogate endpoint is a  biomarker  that substitutes for a direct endpoint, such as clinical benefit. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12962", "text": "Section 3033 of the  21st Century Cures Act  introduces section 506(g) of the  Federal Food, Drug, and Cosmetic Act (FD&C Act)  that allows for the designation of certain therapies as a 'regenerative medicine advanced therapy' (RMAT) ( 21\u00a0U.S.C. \u00a0 \u00a7\u00a0356 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12963", "text": "In order to qualify for RMAT status, a treatment must"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12964", "text": "A regenerative medicine therapy is defined in section 506(g)(8) of the  FD&C Act  to include  cell therapies ,  therapeutic tissue engineering , human cell and tissue products. Under the FDA's interpretation,  gene therapies  and genetically modified cells that have a lasting effect, such as  CAR-T  antitumor therapies, may also qualify as regenerative medicine therapies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12965", "text": "A RMAT designation includes all benefits of the  Fast Track  and  breakthrough therapy  designations. In addition, it opens up early interactions between the  FDA  and sponsors to facilitate accelerated approval. In this context, accelerated approval means approval based on"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12966", "text": "The ability to use 'Real World Evidence' (RWE), i.e. post-market evidence of safety and effectiveness, is particularly useful in the context of  orphan diseases , where recruiting a sufficiently large cohort for pre-marketing  clinical trials  may not be feasible. [ 5 ]  RWE may include data from patient registries, clinical records and case studies. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12967", "text": "Where a RMAT's sponsor fails to comply with the requirements for accelerated approval, the RMAT designation and the benefits conferred by it can be withdrawn ( 21\u00a0CFR   601.43 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12968", "text": "Viralym-M [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12969", "text": "(Roctavian,"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12970", "text": "Valrox)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12971", "text": "(Lentiglobin) [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12972", "text": "(Breyanzi)"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12973", "text": "(Ologo) [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12974", "text": "Vertex Pharmaceuticals"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12975", "text": "Transfusion-dependent  beta thalassemia"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12976", "text": "Castle Creek Biosciences"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12977", "text": "St. Jude Children's Research Hospital"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12978", "text": "In 2020, the FDA received 34 requests for RMAT status, of which 12 (35.3%) were granted. RMAT designated drugs include the novel  CAR-T  therapy  Kymriah  and  betibeglogene autotemcel  for  beta thalassemia . [ 34 ]  As of 31 March 2021, 62 requests for RMAT status have been granted. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12979", "text": "More than half of the RMAT applications received by March 2019 involved  autologous  or  allogeneic   cell therapy  products, including  CAR-T  therapies. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12980", "text": "Resinous glaze  is an  alcohol -based solution of various types of food-grade  shellac . The shellac is derived from the raw material  sticklac , which is a resin scraped from the branches of trees left from when the small insect,  Kerria lacca  (also known as  Laccifer lacca ), creates a hard, waterproof cocoon. [ 1 ]   When used in food and  confections , it is also known as  confectioner's glaze ,  pure food glaze ,  natural glaze , [ 2 ] [ 3 ]  or  confectioner's resin . [ 4 ]  When used on medicines, it is sometimes called  pharmaceutical glaze . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12981", "text": "Pharmaceutical glaze may contain 20\u201351% shellac in solution in  ethyl alcohol  (grain alcohol) that has not been denatured ( denatured alcohol  is poisonous), [ 5 ]  waxes, and titanium dioxide as an opacifying agent. Confectioner\u2019s glaze used for candy contains roughly 35% shellac, while the remaining components are  volatile organic compounds  that evaporate after the glaze is applied. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12982", "text": "Pharmaceutical glaze is used by the drug and  nutritional supplement  industry as a coating material for tablets and capsules. It serves to improve the product's appearance, extend  shelf life  and protect it from moisture, as well as provide a solid finishing film for pre-print coatings. It also serves to mask unpleasant odors and aid in the swallowing of the tablet. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12983", "text": "The shellac coating is insoluble in stomach acid and may make the tablet difficult for the body to break down or assimilate. For this reason, it can also be used as an ingredient in time-released, sustained or delayed-action pills. The product is listed on the U.S.  Food and Drug Administration 's (FDA) inactive ingredient list. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12984", "text": "Shellac is labeled as GRAS ( generally recognized as safe ) by the US FDA and is used as glaze for several types of foods, including some fruit, coffee beans, chewing gum, and candy. Examples of candies containing shellac include  candy corn ,  Hershey's   Whoppers  and  Milk Duds ,  Nestl\u00e9 's  Raisinets  and  Goobers ,  Tootsie Roll Industries 's  Junior Mints  and  Sugar Babies ,  Jelly Belly 's  jelly beans  and Mint Cremes,  Russell Stover 's jelly beans, and several candies by  Godiva Chocolatier  and  Gertrude Hawk .  M&M's  do not contain shellac. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12985", "text": "A competing non-animal-based product is  zein , a corn protein. [ 8 ]  It is preferred by some vegans [ 1 ]  because shellac production can kill many insects. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12986", "text": "Self-medication , sometime called  do-it-yourself  ( DIY )  medicine,  is a  human behavior  in which an individual uses a substance or any exogenous influence to self-administer treatment for physical or psychological conditions, for example  headaches  or  fatigue ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12987", "text": "The substances most widely used in self-medication are  over-the-counter  drugs and dietary supplements, which are used to treat common health issues at home. These do not require a  doctor's   prescription  to obtain and, in some countries, are available in supermarkets and convenience stores. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12988", "text": "The field of  psychology  surrounding the use of  psychoactive drugs  is often specifically in relation to the use of  recreational drugs ,  alcohol ,  comfort food , and other forms of behavior to alleviate symptoms of  mental distress ,  stress  and  anxiety , [ 2 ]  including  mental illnesses  or  psychological trauma . [ 3 ] [ 4 ]  Such treatment may cause serious detriment to  physical  and  mental health  if motivated by  addictive mechanisms . [ 5 ]  In postsecondary (university and college) students, self-medication with \" study drugs \" such as Adderall, Ritalin, and Concerta has been widely reported and discussed in literature. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12989", "text": "Products are marketed by manufacturers as useful for self-medication, sometimes on the basis of questionable evidence. Claims that  nicotine  has medicinal value have been used to  market cigarettes  as self-administered medicines. These claims have been criticized as inaccurate by independent researchers. [ 6 ] [ 7 ]  Unverified and unregulated third-party health claims are used to market dietary supplements. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12990", "text": "Self-medication is often seen as gaining personal independence from established medicine, [ 9 ]  and it can be seen as a  human right , implicit in, or closely related to the right to refuse professional medical treatment. [ 10 ]  Self-medication can cause unintentional self-harm. [ 11 ]  Self-medication with antibiotics has been identified as one of the primary reasons for the evolution of  antimicrobial resistance . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12991", "text": "Sometimes self-medication or DIY medicine occurs because patients disagree with a doctor's interpretation of their condition, [ 13 ]  to access experimental therapies that are not available to the public, [ 14 ] [ 15 ]  or because of legal bans on healthcare, as in the case of some transgender people [ 16 ]  or women seeking  self-induced abortion . [ 17 ]  Other reasons for relying on DIY medical care is to avoid  health care prices in the United States [ 18 ]  and  anarchist  beliefs. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12992", "text": "Generally speaking, self-medication is defined as \"the use of drugs to treat self-diagnosed disorders or symptoms, or the intermittent or continued use of a prescribed drug for chronic or recurrent disease or symptoms\". [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12993", "text": "Self-medication can be defined as the use of drugs to treat an illness or symptom when the user is not a medically qualified professional. The term is also used to include the use of drugs outside their license or off-label."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12994", "text": "As different drugs have different effects, they may be used for different reasons. According to the self-medication hypothesis (SMH), the individuals' choice of a particular drug is not accidental or coincidental, but instead, a result of the individuals' psychological condition, as the drug of choice provides relief to the user specific to his or her condition. Specifically,  addiction  is hypothesized to function as a compensatory means to modulate effects and treat distressful psychological states, whereby individuals choose the drug that will most appropriately manage their specific type of psychiatric distress and help them achieve emotional stability. [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12995", "text": "The self-medication hypothesis (SMH) originated in papers by  Edward Khantzian , Mack and Schatzberg, [ 24 ]   David F. Duncan , [ 25 ]  and a response to Khantzian by Duncan. [ 26 ]  The SMH initially focused on  heroin  use, but a follow-up paper added  cocaine . [ 27 ]  The SMH was later expanded to include alcohol, [ 28 ]  and finally all drugs of addiction. [ 22 ] [ 29 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12996", "text": "According to Khantzian's view of addiction, drug users compensate for deficient ego function [ 24 ]  by using a drug as an \"ego solvent\", which acts on parts of the self that are cut off from consciousness by  defense mechanisms . [ 22 ]  According to Khantzian, [ 27 ]  drug dependent individuals generally experience more psychiatric distress than non-drug dependent individuals, and the development of drug dependence involves the gradual incorporation of the drug effects and the need to sustain these effects into the defensive structure-building activity of the ego itself. The addict's choice of drug is a result of the interaction between the psychopharmacologic properties of the drug and the affective states from which the addict was seeking relief. The drug's effects substitute for defective or non-existent ego mechanisms of defense. The addict's drug of choice, therefore, is not random."}
{"_id": "WikiPedia_Pharmacology$$$corpus_12997", "text": "While Khantzian takes a psychodynamic approach to self-medication, Duncan's model focuses on behavioral factors. Duncan described the nature of  positive reinforcement  (e.g., the \"high feeling\", approval from peers), negative reinforcement (e.g. reduction of negative affect) and avoidance of withdrawal symptoms, all of which are seen in those who develop problematic drug use, but are not all found in all recreational drug users. [ 25 ]  While earlier behavioral formulations of drug dependence using operant conditioning maintained that positive and negative reinforcement were necessary for drug dependence, Duncan maintained that drug dependence was not maintained by positive reinforcement, but rather by negative reinforcement. Duncan applied a public health model to drug dependence, where the agent (the drug of choice) infects the host (the drug user) through a vector (e.g., peers), while the environment supports the disease process, through stressors and lack of support. [ 25 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12998", "text": "Khantzian revisited the SMH, suggesting there is more evidence that psychiatric symptoms, rather than personality styles, lie at the heart of drug use disorders. [ 22 ]  Khantzian specified that the two crucial aspects of the SMH were that (1) drugs of abuse produce a relief from psychological suffering and (2) the individual's preference for a particular drug is based on its psychopharmacological properties. [ 22 ]  The individual's drug of choice is determined through experimentation, whereby the interaction of the main effects of the drug, the individual's inner psychological turmoil, and underlying personality traits identify the drug that produces the desired effects. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_12999", "text": "Meanwhile, Duncan's work focuses on the difference between recreational and problematic drug use. [ 31 ]  Data obtained in the Epidemiologic Catchment Area Study demonstrated that only 20% of drug users ever experience an episode of drug abuse (Anthony & Helzer, 1991), while data obtained from the National Comorbidity Study demonstrated that only 15% of alcohol users and 15% of illicit drug users ever become dependent. [ 32 ]  A crucial determinant of whether a drug user develops drug abuse is the presence or absence of negative reinforcement, which is experienced by problematic users, but not by recreational users. [ 33 ]  According to Duncan, drug dependence is an avoidance behavior, where an individual finds a drug that produces a temporary escape from a problem, and taking the drug is reinforced as an operant behavior. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13000", "text": "Some people who have a  mental illness  attempt to correct their illnesses by using certain drugs.  Depression  is often self-medicated by the use of  alcohol ,  tobacco ,  cannabis , or other mind-altering drugs. [ 34 ]  While this may provide immediate relief of some symptoms such as  anxiety , it may evoke and/or exacerbate some symptoms of several kinds of mental illnesses that are already latently present, [ 35 ]  and may lead to addiction or physical dependency, among other side effects of long-term use of the drug. This does not differ significantly from the potential effects of drugs provided by physicians, which are equally capable of producing dependency and/or addiction and also have side effects arising from long-term use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13001", "text": "People with  post-traumatic stress disorder  have been known to self-medicate, as well as many individuals without this diagnosis who have experienced psychological trauma. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13002", "text": "Due to the different effects of the different classes of drugs, the SMH postulates that the appeal of a specific class of drugs differs from person to person. In fact, some drugs may be aversive for individuals for whom the effects could worsen affective deficits. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13003", "text": "Alcohol  and  sedative / hypnotic  drugs, such as  barbiturates  and  benzodiazepines , are  central nervous system  (CNS)  depressants  that lower inhibitions via  anxiolysis . Depressants produce feelings of relaxation and sedation, while relieving feelings of depression and anxiety. Though they are generally ineffective antidepressants, as most are short-acting, the rapid onset of alcohol and sedative/hypnotics softens rigid defenses and, in low to moderate doses, provides relief from depressive affect and anxiety. [ 22 ] [ 23 ]  As alcohol also lowers inhibitions, alcohol is also hypothesized to be used by those who normally constrain emotions by attenuating intense emotions in high or obliterating doses, which allows them to express feelings of affection, aggression and closeness. [ 23 ] [ 29 ]  Most patients that have been hospitalized for substance use or alcohol dependence reported using drugs in response to depressive symptoms. This type of misuse is more likely in men than in women. This makes diagnosing a psychiatric disorder very difficult in substance abusers, because of self medicating. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13004", "text": "People with  social anxiety disorder  commonly use alcohol to overcome their highly set inhibitions. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13005", "text": "Psychostimulants , such as  cocaine ,  amphetamines ,  methylphenidate ,  caffeine , and  nicotine , produce improvements in physical and mental functioning, including increased energy and alertness.  Stimulants tend to be most widely used by people with  attention deficit hyperactivity disorder  (ADHD), which can either be diagnosed or undiagnosed. Because a significant portion of people with ADHD have not been diagnosed they are more prone to using stimulants like  caffeine ,  nicotine  or  pseudoephedrine  to mitigate their symptoms.  Unawareness  concerning the effects of illicit substances such as  cocaine ,  methamphetamine  or  mephedrone   can result in self-medication with these drugs by individuals affected with ADHD symptoms. This self medication can effectively prevent them from  getting diagnosed  with ADHD and receiving treatment with stimulants like  methylphenidate  and  amphetamines ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13006", "text": "Stimulants also can be beneficial for individuals who experience  depression , to reduce  anhedonia [ 23 ]  and increase  self-esteem , [ 28 ]  however in some cases depression may occur as a  comorbid condition  originating from the prolonged presence of negative symptoms of undiagnosed ADHD, which can impair  executive functions , resulting in lack of  motivation ,  focus  and contentment with one's life, so stimulants may be useful for treating  treatment-resistant depression , especially in individuals thought to have ADHD. The SMH also hypothesizes that hyperactive and  hypomanic  individuals use stimulants to maintain their restlessness and heighten euphoria. [ 23 ] [ 27 ] [ 28 ]  Additionally, stimulants are useful to individuals with  social anxiety  by helping individuals break through their inhibitions. [ 23 ]  Some reviews suggest that students use psychostimulants to self medicate for underlying conditions, such as ADHD, depression or anxiety. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13007", "text": "Opiates , such as  heroin  and  morphine , function as an  analgesic  by binding to  opioid receptors  in the brain and  gastrointestinal tract . This binding reduces the perception of and reaction to  pain , while also increasing  pain tolerance . Opiates are hypothesized to be used as self-medication for  aggression  and  rage . [ 27 ] [ 29 ]  Opiates are effective  anxiolytics ,  mood stabilizers , and anti-depressants, however, people tend to self-medicate anxiety and depression with depressants and stimulants respectively, though this is by no means an absolute analysis. [ 23 ] [ 39 ] [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13008", "text": "Modern research into novel antidepressants targeting opioid receptors suggests that endogenous opioid dysregulation may play a role in medical conditions including  anxiety disorders ,  clinical depression , and  borderline personality disorder . [ 41 ] [ 42 ] [ 43 ]  BPD is typically characterized by sensitivity to rejection, isolation, and perceived failure, all of which are forms of  psychological pain . [ 44 ]  As research suggests that psychological pain and physiological pain both share the same underlying mechanism, it is likely that under the self-medication hypothesis some or most recreational opioid users are attempting to alleviate psychological pain with opioids in the same way opioids are used to treat physiological pain. [ 45 ] [ 46 ] [ 47 ] [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13009", "text": "Cannabis  is  paradoxical  in that it simultaneously produces stimulating, sedating and mildly psychedelic properties and both  anxiolytic  or  anxiogenic  properties, depending on the individual and  circumstances of use . Depressant properties are more obvious in occasional users, and stimulating properties are more common in chronic users. Khantzian noted that research had not sufficiently addressed a theoretical mechanism for cannabis, and therefore did not include it in the SMH. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13010", "text": "Self-medicating excessively for prolonged periods of time with  benzodiazepines  or  alcohol  often makes the symptoms of anxiety or depression worse. This is believed to occur as a result of the changes in brain chemistry from long-term use. [ 49 ] [ 50 ] [ 51 ] [ 52 ] [ 53 ]  Of those who seek help from mental health services for conditions including  anxiety disorders  such as  panic disorder  or  social phobia , approximately half have  alcohol  or  benzodiazepine dependence  issues. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13011", "text": "Sometimes anxiety precedes alcohol or benzodiazepine dependence but the alcohol or benzodiazepine dependence acts to keep the anxiety disorders going, often progressively making them worse. However, some people addicted to alcohol or benzodiazepines, when it is explained to them that they have a choice between ongoing poor mental health or quitting and recovering from their symptoms, decide on quitting alcohol or benzodiazepines or both. It has been noted that every individual has an individual sensitivity level to alcohol or sedative hypnotic drugs, and what one person can tolerate without ill health, may cause another to experience very ill health, and even moderate drinking can cause rebound anxiety syndrome and sleep disorders. A person experiencing the toxic effects of alcohol will not benefit from other therapies or medications, as these do not address the root cause of the symptoms. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13012", "text": "Nicotine addiction seems to worsen mental health problems. Nicotine withdrawal depresses mood, increases anxiety and stress, and disrupts sleep. Although nicotine products temporarily relieve their  nicotine withdrawal  symptoms, an addiction causes stress and mood to be worse on average, due to mild withdrawal symptoms between hits. Nicotine addicts need the nicotine to temporarily feel normal. [ 7 ] [ 55 ]   Nicotine industry marketing  has claimed that nicotine is both less harmful and therapeutic for people with mental illness, and is a form of self-medication. This claim has been criticised by independent researchers. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13013", "text": "Self medicating is a very common precursor to full addictions and the habitual use of any addictive drug has been demonstrated to greatly increase the risk of addiction to additional substances due to long-term neuronal changes. [ citation needed ]  Addiction to any/every  drug of abuse  tested so far has been correlated with an enduring reduction in the expression of GLT1 ( EAAT2 ) in the  nucleus accumbens  and is implicated in the drug-seeking behavior expressed nearly universally across all documented addiction syndromes. This long-term dysregulation of glutamate transmission is associated with an increase in vulnerability to both relapse-events after re-exposure to drug-use triggers as well as an overall increase in the likelihood of developing addiction to other reinforcing drugs. Drugs which help to re-stabilize the glutamate system such as  N-acetylcysteine  have been proposed for the treatment of addiction to  cocaine ,  nicotine , and alcohol. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13014", "text": "In 89% of countries, antibiotics can be prescribed only by a doctor and supplied only by a pharmacy. [ 57 ]  Self-medication with antibiotics is defined as \"the taking of medicines on one's own initiative or on another person's suggestion, who is not a certified medical professional\". It has been identified as one of the primary reasons for the evolution of  antimicrobial resistance . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13015", "text": "Self-medication with antibiotics is an unsuitable way of using them but a common practice in  developing countries . [ 58 ]  Many people resort to that out of necessity when access to a physician is unavailable because of lockdowns and GP surgery closures, or when the patients have a limited amount of time or money to see a prescribing doctor.  [ 59 ]  While being cited as an important alternative to a formal  healthcare system  where it may be lacking, self-medication can pose a risk to both the patient and community as a whole. The reasons behind self-medication are unique to each region and can relate to health system, societal, economic, health factors, gender, and age. Risks include allergies, lack of cure, and even death. [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13016", "text": "Besides developing countries, self-medication with  antibiotics  is also a problem for higher-income countries. In the European Union the average prevalence was 7% in 2016 with the highest rates in southern countries. There are high rates of self-medication with antibiotics in Russia (83%), Central America (19%) and Latin America (14-26%) too. [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13017", "text": "Two significant issues with self-medication are the lack of knowledge of the public on, firstly, the dangerous effects of certain antimicrobials (for example,  ciprofloxacin , which can cause  tendonitis ,  tendon rupture  and  aortic dissection ) [ 62 ] [ 63 ]  and, secondly, broad microbial resistance and when to seek medical care if the infection is not clearing. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13018", "text": "Also inappropriate use of over-the-counter  ibuprofen  or other  nonsteroidal anti-inflammatory drugs  during  winter   influenza   outbreaks  can lead to  death , e.g. due to  haemorrhagic   duodenitis  induced by ibuprofen, or the consequences of exceeding the recommended doses of paracetamol by combining doses of the generic product with proprietary flu-remedies and Tylex (paracetamol and  codeine ). [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13019", "text": "In a questionnaire designed to evaluate self-medication rates amongst the population of  Khartoum ,  Sudan , 48.1% of respondents reported self-medicating with antibiotics within the past 30 days, whereas 43.4% reported self-medicating with  antimalarials , and 17.5% reported self-medicating with both. Overall, the total prevalence of reported self-medication with one or both classes of anti-infective agents within the past month was 73.9%. [ 21 ]  Furthermore, according to the associated study, data indicated that self-medication \"varies significantly with a number of socio-economic characteristics\" and the \"main reason that was indicated for the self-medication was financial constraints\". [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13020", "text": "Similarly, in a survey of university students in  southern China , 47.8% of respondents reported self-medicating with antibiotics. [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13021", "text": "One area of DIY medicine is self-administered pharmaceutical drugs that are obtained without a prescription, as in the case of  DIY transgender hormone therapy  which is common among trans people. [ 67 ]  Prescription-only  lifestyle drugs  such as those to treat  erectile dysfunction ,  male pattern baldness , and obesity are often purchased online by people who have no diagnosis or prescription. [ 68 ] [ 69 ]  In 2017, the United Kingdom legalized the sale of  sildenafil  (Viagra) over the counter in part to cut down on the number of men buying it online from unlicensed pharmacies. [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13022", "text": "Self-managed abortion  with medication is safe and effective, but is illegal in some jurisdictions. [ 71 ] [ 72 ]  Before the current medication had been developed and in places where abortion is illegal, people may resort to unsafe methods of self-managed abortion. [ 73 ] [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13023", "text": "Another area is the creation of  medical devices , such as  PPE  for protection against  COVID-19 [ 75 ]  and  epinephrine  injectors. [ 76 ]  Some people with insulin-dependent diabetes have created their own  automated insulin delivery systems . [ 77 ] [ 78 ]  One review found that \"the quality of glucose control achieved with DIY AID systems is impressively good\". [ 79 ]  With DIY brain stimulation, individuals with depression create their own devices to access an  experimental treatment . [ 80 ] [ 81 ]  Other people self-administer  fecal transplant  as a treatment for various diseases. [ 82 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13024", "text": "In a survey of  West Bengal ,  India   undergraduate   medical school  students, 57% reported self-medicating. The type of drugs most frequently used for self-medication were antibiotics (31%),  analgesics  (23%),  antipyretics  (18%), antiulcerics (9%),  cough suppressants  (8%),  multivitamins  (6%), and  anthelmintics  (4%). [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13025", "text": "Another study indicated that 53% of physicians in  Karnataka ,  India  reported self-administration of antibiotics. [ 84 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13026", "text": "A study of  Luo  children in western Kenya found that 19% reported engaging in self-treatment with either  herbal  or  pharmaceutical  medicine. Proportionally, boys were much more likely to self-medicate using conventional medicine than herbal medicine as compared with girls, a phenomenon which was theorized to be influenced by their relative earning potential. [ 85 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13027", "text": "Self-medication is highly regulated in much of the world and many  classes of drugs  are available for administration only upon  prescription  by licensed medical personnel.  Safety ,  social order ,  commercialization , and  religion  have historically been among the prevailing factors that lead to such  prohibition ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13028", "text": "People trying to buy pharmaceutical drugs online without a prescription may be the victim of  fraud ,  phishing , or receive counterfeit medication. [ 86 ]  Selling prescription drugs to people without a valid prescription is illegal in many jurisdictions and can be considered an example of  transnational organized crime . [ 87 ]  In a 2021 article, Jack E. Fincham argues that unlicensed sales of prescription drugs online are a significant public health threat. It is also possible to obtain  controlled substances  such as  amphetamine ,  benzodiazepines , and  Z-drugs  online without a prescription. [ 88 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13029", "text": "Separation of prescribing and dispensing , also called  dispensing separation , is a practice in  medicine  and  pharmacy  in which the  physician  who provides a  medical prescription  is independent from the   pharmacist  who provides the  prescription drug ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13030", "text": "In the  Western world  there are centuries of tradition for separating pharmacists from physicians. In Asian countries it is traditional for physicians to also provide drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13031", "text": "Contemporary research indicates that separation of prescribing and dispensing lowers expenditure on drugs, [ 1 ] [ 2 ]  which is explained by the fact physician-prescribing gives doctors an incentive to over-prescribe. This is an example of a  conflict of interest in the healthcare industry  leading to  unnecessary health care ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13032", "text": "In many Western jurisdictions such as the  United States ,  pharmacists  are regulated separately from  physicians .  These jurisdictions also usually specify that  only  pharmacists may supply scheduled  pharmaceuticals  to the public, and that pharmacists cannot form business  partnerships  with physicians or give them \"kickback\" payments.  In other words, the diagnosing physicians' role is supposed to extend only as far as providing proper prescriptions to patients, who are then entitled to purchase the prescribed drugs at the pharmacies of their choice. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13033", "text": "However, the  American Medical Association  (AMA) Code of Ethics provides that physicians may dispense drugs within their office practices as long as there is no patient exploitation and patients have the right to a written prescription that can be filled elsewhere. [ 4 ]  7 to 10 percent of American physicians practices reportedly dispense drugs on their own. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13034", "text": "In some rural areas in the United Kingdom, there are dispensing physicians [ 6 ]  who are allowed to both prescribe and dispense prescription-only medicines to their patients from within their practices. The law requires that the GP practice be located in a designated rural area and that there is also a specified, minimum distance (currently 1 mile; 1.6 kilometres) between a patient's home and the nearest retail pharmacy. See  Dispensing Doctors' Association ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13035", "text": "This law also exists in  Austria  for general physicians if the nearest pharmacy is more than 4 kilometers ( 2 + 1 \u2044 2  miles) away, or where none is registered in the city.  Switzerland  also allows dispensing physicians in several Kantons. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13036", "text": "In other  jurisdictions  (particularly in  Asian  countries such as  China ,   Malaysia , and  Singapore ),  doctors  are allowed to dispense  drugs  themselves and the practice of pharmacy is sometimes integrated with that of the  physician , particularly in traditional  Chinese medicine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13037", "text": "In Canada it is common for a medical clinic and a pharmacy to be located together and for the ownership in both enterprises to be common, but licensed separately."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13038", "text": "The reason for the majority rule is the high risk of a conflict of interest and/or the avoidance of absolute powers. Otherwise, the physician has a financial self-interest in \"diagnosing\" as many conditions as possible, and in exaggerating their seriousness, because he or she can then sell more medications to the patient. Such self-interest directly conflicts with the patient's interest in obtaining cost-effective medication and avoiding the unnecessary use of medication that may have  side-effects .  This system reflects much similarity to the checks and balances system of the U.S. and many other governments. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13039", "text": "A campaign for separation has begun in many countries and has already been successful (as in  Korea ). As many of the remaining nations move towards separation, resistance and lobbying from dispensing doctors who have pecuniary interests may prove a major stumbling block (e.g. in  Malaysia ). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13040", "text": "In many Asian countries there is not a traditional separation between physician and pharmacist. [ 8 ]  In  Taiwan , a plan initiated in March 1997 experimented with separating doctors who prescribe from pharmacists who fulfill prescriptions on the theory that this would reduce  unnecessary health care . [ 8 ]  The plan had mixed results. [ 8 ]  The  South Korean  government passed a law in 2000 which separated drug prescribing from dispensing. [ 9 ]  The passing of the law achieved some of its intentions and also caused problems in unexpected ways. [ 9 ]   Japan  also is experimenting with separation of prescribing and dispensing. In  Malaysia , as of 2016 [update] , separation of prescribing and dispensing only occurs in government hospitals. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13041", "text": "Trap, B (1997).  \"Practices of dispensing doctors - drug use and health economics\" .  archives.who.int . World Health Organization . Retrieved  14 February  2017 . [ dead link \u200d ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13042", "text": "A  show globe  is a glass vessel of various shapes and sizes containing a colorful liquid. [ 1 ]  It has been a symbol of  pharmacy  from the 17th century  England  to the early 20th century in the  United States . It marked the drugstore or  apothecary  in much the same way as the  barber's pole  marked tonsorial establishments in some countries. People who were  illiterate  needed such symbols to locate these medical practitioners."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13043", "text": "Show globes were displayed almost exclusively in English-speaking countries, contrasting with the wider use of the  mortar and pestle  as a pharmaceutical symbol."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13044", "text": "The most dramatic story of their origin goes back to the time of  Julius Caesar  100\u201344\u00a0BC. When the  Romans  invaded  England , according to this report, Caesar's forces found an ideal landing site opposite a pharmacy window which displayed large containers of colored liquids.  Julius Caesar 's forces guaranteed the pharmacist that he would be safe from the invading forces as long as he kept lighted lanterns in his windows which would serve as a beacon for the landing forces. As a token of his appreciation, Caesar \"decreed that henceforth all apothecaries would be permitted to exhibit containers of colored liquids in their windows as a symbol of their calling.\" [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13045", "text": "The main problem with this theory is that this would have occurred at least twelve centuries before there was any recognizable profession of pharmacy. [ 2 ]   This story was reported in  The Pharmaceutical Journal  (the journal of the Royal Pharmaceutical Society of Great Britain) in 1931. As the columnist wrote, \"Surely further research is needed.\" [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13046", "text": "Another theory says that show globes had their origins in the  Middle East  during the period of  Islamic  domination. Shops were outdoors and pharmacists may have placed their material in elaborate jars or containers which could be the forerunners of show globes. Travelers from  Western Europe  admired these urns and took the idea back home.  There are two reasons why this is probably false; there is no evidence that show globes were popular as a symbol in the Middle East, and instead of show globes appearing throughout Europe they are almost exclusively  Anglo-American ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13047", "text": "Another hypothesis says that show globes may have been  maceration  vessels, which were used to steep organic material in sunlight. The trouble with this explanation is that \"England is not famous for its sunny days.\" [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13048", "text": "Another theory makes the show globe a kind of  first aid  beacon. Apothecary shops in coastal regions filled vessels with red and green liquids to show sailors where to obtain medical attention."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13049", "text": "Apothecaries in England had been competing with physicians since an act passed in 1542 permitted them to practice medicine along with anyone else. [ 5 ]  According to another theory which puts pharmacists in a good light, during the  Great Plague of London  (1665\u201366), while many physicians were fleeing the city, apothecaries placed containers of colored liquids in their windows \"to assure the threatened citizenry that they were still there ready to provide needed help.\" [ 2 ]   Apothecaries may have seen this as a chance to expand their medical activities, as well as acting altruistically."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13050", "text": "George Griffenhagen , pharmacist and acting curator of the  Smithsonian Institution , did extensive research into the evolution of the show globe and laid to rest many of the more unusual stories about its origin. [ 6 ]   He thought that the show globe appeared when the apothecaries and  alchemists  merged their professions during the mid 16th to mid 17th century. In England in the mid 1550s, just as  physicians  competed against apothecaries, the apothecaries, who delivered  surgical services  along with compounding and dispensing  herbal medicines , competed with chemists and druggists. Druggists bought drugs in bulk and sold them as merchants (not as medical practitioners like the apothecaries); while chemists, who were derived from alchemists, prepared and sold chemical preparations used for medicinal purposes, like  mercurials . [ 7 ] \nTo attract attention to themselves and to symbolize the mystery and art of their profession these chemists displayed show globes with solutions of colored chemicals. Apothecaries and physicians were usually considered more conservative in their practice before the 18th century and often restricted themselves to non-chemical drugs using material of largely botanical origins. Most historians today feel the show globe began as a symbol of the  chemist 's shop. Eventually the apothecaries began to use chemical remedies, and also adopted the globe as their symbol."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13051", "text": "For a largely illiterate public the show globe was a welcoming symbol.  Charles Dickens  once declared they were the only \"bright and cheery spot in a London street on a dark and wet night.\" [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13052", "text": "According to Charles Richardson, a collector of pharmaceutical artifacts, two apothecaries arrived in  Jamestown, Virginia  (1607) shortly after it was founded, and the colonists asked the  Virginia Company  to send more physicians and apothecaries to the colony. [ 5 ]   In the early American settlements there was a shortage of health professionals; public officials, religious leaders, educators and household heads served as health advisors. Herbs and Indian remedies were used and apothecary shops were set up in large population centers. During the Revolutionary War medicine and pharmacy emerged as separate professions, and the first American Pharmacopoeia was printed in 1778. [ 9 ]   By the 19th century, pharmacists had stopped practicing medicine and even the name apothecary faded away. Pharmacies developed the warmth and comfort of country stores and were displaying show globes, which by 1789 were being exported to America. [ 10 ]   According to one writer, the only way pharmacies distinguished themselves from other stores was this unique sign. \" Bakeries  and  hardware stores  did not differ greatly from pharmacies in their fa\u00e7ades.\" [ 11 ]   It was in the United States 19th century that the show globes started to develop their elaborate design and diverse forms. Although the show globe became a pharmacy symbol of mainly English-speaking countries, it did appear in a few other countries notably France. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13053", "text": "Next to their origins, the greatest debate about show globes is what, if anything, the colors of the liquids symbolized.  Red and blue may have indicated  arterial  and  venous blood . One belief was that if the globe was filled with red liquid there was a plague in town, but if it was filled with green all was well. Pharmacists could create vibrant colors with chemicals in their shops, often following a recipe book. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13054", "text": "Most globes were plain glass, but sometimes they were punty cut or etched glass. Some had multiple stoppers, each stopper smaller than the one below, tapering to a small finial at the top. They could be freestanding or wall-mounted. If they were freestanding, they hung from a brass chain; the most elaborate had multiple tiers, each chamber containing a different color of water. It was not so much the pharmacists who were responsible for the evolution of show globes to works of arts, but American glass manufacturers. Pharmaceutical catalogs during the 1870s advertised numerous styles of show globes with each glass manufacturer developing his own design. A U.S. patent was granted in 1869 to Henry Whitney of  Cambridge, Massachusetts , for a show globe with a colored glass body with a neck and base of transparent uncolored glass. The purpose of this design was to eliminate the need to use colored liquids, which could leave a residue inside the bottle. [ 13 ] \nThough oil could be used to illuminate the colored glass panes in windows, gas lighting in the early 19th century led to the general use of show globes. They could be lit from the interior or placed in front of a gas jet.  In the United States, globes were usually illuminated by a light placed behind them."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13055", "text": "Despite many attempts to revive show globes, they have disappeared from American pharmacies. By the early 20th century, new stores shunned them, and they were disappearing from many older pharmacies.  Renewed support for the globes in the 1930s moved the  Owens-Illinois Glass Company  to introduce a new style with an electric bulb inside to illuminate the globe. [ 4 ]   However, a 1935 American news article notes \"rarely is a show globe ever seen in a modern druggist's emporium\". [ 14 ]   Through the 1950s,  American Druggist  urged pharmacists to bring back the show globe, terming it \"the greatest trademark ever invented.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_13056", "text": "Tablet hardness testing  is a  laboratory technique  used by the  pharmaceutical  industry to determine the breaking point and structural integrity of a  tablet  and find out how it changes \"under conditions of storage, transportation, packaging and handling before usage\" [ 1 ] \nThe breaking point of a tablet is based on its shape. [ 2 ]  It is similar to  friability  testing, [ 1 ]  but they are not the same thing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13057", "text": "Tablet hardness testers first appeared in the 1930s. [ 3 ]  In the 1950s, the Strong-Cobb tester was introduced. It was patented by Robert Albrecht on July 21, 1953. [ 4 ]  and used an air pump. The tablet breaking force was based on arbitrary units referred to as Strong-Cobbs. [ 3 ]  The new one gave readings that were inconsistent to those given by the older testers. [ 3 ]  Later, electro-mechanical testing machines were introduced. They often include mechanisms like motor drives, and the ability to send measurements to a computer or printer. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13058", "text": "There are 2 main processes to test tablet hardness: compression testing and 3 point bend testing. For compression testing, the analyst generally aligns the tablet in a repeatable way, [ 2 ]  and the tablet is squeezed between a fixed and a moving jaw. The first machines continually applied force with a spring and screw thread until the tablet started to break. [ 3 ]  When the tablet fractured, the hardness was read with a sliding scale. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13059", "text": "There are several devices used to perform this task:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13060", "text": "According to the  International System of Units , the  units of measurement  of tablet hardness mostly follow standards used in materials testing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13061", "text": "Tall man lettering  ( tall-man lettering  or  tallman lettering ) is the practice of writing part of a  drug 's name in  upper case  letters to help distinguish sound-alike, look-alike drugs from one another in order to avoid medication errors. [ 1 ] [ 2 ]   For example, in tall man lettering, \" prednisone \" and \" prednisolone \" should be written \"predniSONE\" and \"predniSOLONE\", respectively. The Office of Generic Drugs of the US  Food and Drug Administration  (FDA) encourages  manufacturers  to use tall man lettering labels to visually differentiate their drugs' names, [ 1 ]  and a number of hospitals, clinics, and health care systems use tall man lettering in their computerized order entry, automated dispensing machines, medication admission records, prescription labels, and drug product labels. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13062", "text": "Wrong-drug errors have been found to occur at a rate of about one per thousand orders filled or dispensed. [ 4 ]   Evidence regarding the effect of Tall Man lettering on error rates is mixed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13063", "text": "A 2004  eye-tracking  study found that Tall Man lettering resulted in fewer errors when selecting a target drug from an array of choices. [ 5 ]   Other laboratory-based studies of Tall Man lettering show a mixture of positive and  null results , which may be further complicated due to  demand characteristics  of some of the studies. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13064", "text": "A 2016  time-series analysis  of data from 42 children's hospitals over a 9-year period found no significant difference before and after a 2007 recommendation for hospitals to adopt Tall Man lettering. [ 6 ]   However, this study has been criticized due to methodological limitations, such as not recording when and how Tall Man lettering was adopted, if at all, at each of the hospitals studied. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13065", "text": "The FDA published a list [ 7 ] :\u200aTable 1\u200a  of recommended Tall-Man Letters for look-alike drugs which includes, but is not limited to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13066", "text": "The  Institute for Safe Medication Practices  (ISMP) has a supplemental list covering pairs not recommended by the FDA, but considered necessary by the ISMP. [ 7 ] :\u200aTable 2\u200a  ISMP Canada also offers additional recommendations. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13067", "text": "Telepharmacy  is the delivery of  pharmaceutical care  via  telecommunications  to patients in locations where they may not have direct contact with a  pharmacist . It is an instance of the wider phenomenon of  telemedicine , as implemented in the field of  pharmacy . Telepharmacy services include  drug therapy  monitoring, patient counseling, prior authorization and refill authorization for  prescription drugs , and monitoring of  formulary  compliance with the aid of  teleconferencing  or  videoconferencing .  Remote dispensing  of medications by automated packaging and labeling systems can also be thought of as an instance of telepharmacy. Telepharmacy services can be delivered at retail pharmacy sites or through hospitals, nursing homes, or other medical care facilities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13068", "text": "The term can also refer to the use of videoconferencing in pharmacy for other purposes, such as providing education, training, and management services to pharmacists and pharmacy staff remotely. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13069", "text": "A primary appeal of telepharmacy is its potential to expand access to pharmacy care in smaller rural communities, some of which cannot support a full-time pharmacist or cannot easily recruit a pharmacist to reside in their region. Telepharmacy can potentially give patients in remote locations access to professional pharmacy care that could not be received locally, which can lower costs and improve patient safety through better patient counseling, drug administration monitoring, [ 2 ]  and compliance monitoring. Sharing of pharmacists between sites can also decrease costs in existing facilities, which might no longer need to employ a full-time pharmacist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13070", "text": "The potential costs of telepharmacy are broadly the same as those associated with all forms of  telemedicine : potentially decreased human interaction between medical professionals and patients, an increased risk of error when medical services are delivered in the absence of a registered professional, [ 3 ]  and an increased risk that  protected health information  may be compromised through electronic information storage and transmission. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13071", "text": "One concern is whether medication adherence is affected by the use of telepharmacy. One retrospective cohort study that examined the dispensing records of a low-income Chicago neighborhood showed that medication adherence was lower among users of telepharmacy than users of a traditional pharmacy in some but not all drug classes examined. [ 6 ]  More research is needed to see whether the usage of telepharmacies coupled with other interventions could improve medication adherence."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13072", "text": "The implementation of telepharmacy varies by region and jurisdiction. Factors including geography, laws and regulations, and economics influence its implementation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13073", "text": "A form of telepharmacy has been in use by  Australia 's  Royal Flying Doctor Service  since 1942. Medical chests containing medications and equipment are placed in remote communities where they can be administered to patients during a  telehealth  consultation. Some 3,500 chests were distributed around Australia as of 2006. In one year,  Queensland  recorded 21,470 telehealth consultations, of which 13.7% resulted in administration of a medication from a medical chest. The medication types administered most often are  antibiotics ,  analgesics  and  gastrointestinal medications . This system improves access to both emergency and routine medical care in remote parts of Australia and reduces the need for patients to travel to seek medical care. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13074", "text": "Another application of telepharmacy in Queensland has been the provision of pharmaceutical reviews in rural hospitals that lack on-staff pharmacists. [ 8 ]  Although broader use of telepharmacy could help alleviate a shortage of pharmacists, Australia has lagged the United States in its implementation of telepharmacy, partly because doctors, nurses, and other health care workers provide pharmacy services in rural and remote areas where there are no pharmacists. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13075", "text": "Implementation of telepharmacy in the United States began in the 2000s. A combination of factors, including  changes in Medicare reimbursement for medications [ 10 ]  and the  recession of 2007\u20138 , led to a decline in the number of independent pharmacies in rural areas. [ 11 ]  In response to the need for alternative means of delivering pharmacy in services in rural communities lacking a full-time pharmacist, several  midwestern  and  northwestern  states with extensive rural areas have led much of the development of policy and implementation methods for telepharmacy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13076", "text": "In 2001, North Dakota became the first U.S. state to pass regulations allowing retail pharmacies to operate without requiring a pharmacist to be physically present. The next year, state agencies and grants established the North Dakota Telepharmacy Project, which now supports more than fifty remote retail and hospital pharmacy sites throughout North Dakota. [ 12 ]  In this program, a licensed pharmacist at a central site communicates with remote site  pharmacy technicians  and patients through  videoconferencing . A 2004 study of the program found that telepharmacy delivered the same quality of pharmacy services as traditional facilities, [ 13 ]  and a study of the operation of one North Dakota telepharmacy business from 2002 through 2004 found that, while medication inventory turnover was lower than the industry average, the remote sites were able to be operated profitably. [ 14 ]  The success and expansion of this program were an inspiration and model for programs and laws in other states. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13077", "text": "The Community Health Association of Spokane, a network of  community health centers  in  Spokane, Washington , started a telepharmacy program in 2001. The program delivers remote medication dispensing and health counseling to patients at six urban and rural clinics; remote site personnel are connected to pharmacists at the base site by  videoconferencing . A survey found that most patients at the remote sites strongly agreed or agreed that they would have had difficulty affording their medications without this program. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13078", "text": "The  Alaska Native Medical Center , a hospital in  Anchorage ,  Alaska , providing telehealth services to  Alaska Native  populations, established a telepharmacy program in 2003 to improve its pharmaceutical services in rural native settlements. The  American Society of Health-System Pharmacists  gave the program its 2006 Award for Excellence in Medication-Use Safety, concluding that the use of telepharmacy had improved access to pharmaceutical care and enabled pharmacists to monitor medication safety and encourage medication adherence, as well as making pharmacy care more cost-effective. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13079", "text": "The  U.S. Navy  Bureau of Medicine operates a large-scale telepharmacy program for the use of service personnel. After piloting the program in 2006 at  Naval Hospital Pensacola  in Florida and Naval Hospital Bremerton in Washington, in 2010 the Navy expanded it to more sites throughout the world. This program represents the largest implementation of telepharmacy to date. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13080", "text": "California  passed a Telehealth Advancement Act in 2011 to update the state's legal definitions of telehealth, simplify approval processes for telehealth services, and broaden the range of medical services that may be provided via telehealth. The law establishes legal parity between the direct and remote delivery of pharmacy care. [ 19 ]   Iowa 's first telepharmacy opened in September 2012 after receiving a three-year waiver from the Iowa Board of Pharmacy that allows the facility to operate without a pharmacist on-site. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13081", "text": "A 2010 study of the various American states'  rural health  offices found that telepharmacy in rural medical facilities varied in prevalence across the United States but was still not widespread, and that many states had not yet clearly defined regulations for telepharmacy in hospitals. [ 21 ]  Adoption and implementation of telepharmacy methods has been slow compared to the spread of the basic technologies involved ( internet access ,  audio/video compression  algorithms,  microphones  and  video cameras ), despite periodic predictions of a forthcoming boom in the industry. Aside from more intangible factors (such as physicians' and pharmacists' personal uneasiness with the lack of physical interaction with patients), the major obstacles to telepharmacy implementation appear to have been the lack of clear legal regulations for telepharmacy, and the lack of network and software systems to manage (and secure) all of the data used in a professional pharmacy. [ 22 ]  As of 2010, many of the telepharmacy facilities in active operation were operating as pilot programs or under temporary waivers issued by state regulators because many states still had no clear legal framework for the regulation of remote pharmaceutical sites without pharmacists. Even in states that had regulated retail telepharmacy practices, regulations were often not in place to permit the implementation of telepharmacy in hospital settings. [ 21 ] [ 23 ]  For some pharmacy facilities that might otherwise consider telepharmacy, the cost and complexity of the infrastructure needed to manage patient data across multiple sites can be prohibitive. In addition to the computer hardware required for patient data storage, distribution and teleconferencing, telepharmacy programs must deploy network security tools and procedures adequate to  protect patient medical information  in compliance with  HIPAA  and other patient privacy regulations. In 2010 the North Dakota Telepharmacy Project estimated that the computer hardware needed for a typical retail installation costs US$17,300 per site, with an additional cost of US$5,000 to buy a mobile cart for a hospital installation. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13082", "text": "Adoption of telepharmacy in  Canada  began as a response to a nationwide shortage of pharmacists. Canada's first telepharmacy service was started by a hospital in  Cranbrook, British Columbia , in June 2003 in order to assist a hospital in a nearby town that was unable to hire a pharmacist. To meet the need for service, a hospital pharmacist in Cranbrook began using telepharmacy technology to oversee pharmacy technicians at the other hospital. A similar service was subsequently extended to other small hospitals in the province; it is also used to provide coverage when a hospital's sole pharmacist is absent due to illness or vacation. [ 25 ]   Remote dispensing  machines for medication began operation in  Ontario , Canada, in 2007. After a patient inserts a prescription into the dispensing machine, the prescription is scanned and the patient is connected by telephone videoconference to a pharmacist at a remote site. The pharmacist reviews the prescription, discusses the patient's medication history, and authorizes the machine to dispense medication to the patient. The machines proved successful, with one assessment revealing that 96% of patients using them had their prescription filled in under five minutes. [ 26 ]  As of 2009, a hospital in  Ontario , Canada, was using telepharmacy services in addition to retaining a pharmacist at the hospital; the telepharmacist reviews medication orders, while the on-site pharmacist works with patients and oversees medication safety in the facility. Thus telepharmacy support allows the on-site pharmacist to focus on the more sensitive and nuanced tasks for which physical presence is most helpful. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13083", "text": "After their success in Canada, remote medication dispensing machines were scheduled to be tested at several hospital locations in the  United Kingdom  beginning in 2010. [ 26 ]  In 2013, Maxor National Pharmacy Services, a U.S. company, reported that its remote dispensing machines for medication were being used in  Bahrain ,  Belgium ,  Cuba ,  England ,  Germany ,  Guam ,  Italy ,  Japan ,  Spain  and  Venezuela . [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13084", "text": "In 2010,  Mannings  drugstores became the first in  Hong Kong  to use videoconferencing to allow patients at outlets without full-time pharmacists to consult with pharmacists at other sites. [ 29 ]  In Malaysia, a health startup called Esyms provides a telepharmacy service that has a live chat and video feature which allows you to speak to a licensed pharmacist. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13085", "text": "Nostradamus 's  Trait\u00e9 des fardemens et confitures , variously entitled  Moult utile opuscule...  and  Le vrai et parfaict embellissement de la face... , was first published in 1555, even though it contained a  Proem , or prologue, dated 1552. Clearly the work of an  apothecary , it contained recipes for preparing  cosmetics  and  preserves , the latter based largely on  sugar , which was controlled at the time by the apothecaries' guilds. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13086", "text": "Among the topics covered (which include removing spots from the face  with mercury ) were:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13087", "text": "A. THE COSMETICS MANUAL"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13088", "text": "B. THE COOKBOOK"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13089", "text": "The book was translated into  German  in 1574, then the German was revised in 1994, and finally the  German  was translated into  English  under the title  The Elixirs of Nostradamus  (Moyer Bell, 1996). Needless to say, the fourth-hand results of this process were unreliable, if not downright dangerous: the term  roses rouges incarn\u00e9es , for example, was routinely translated as 'black orchids', and  urines  (urine) came out as 'drinking wells'."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13090", "text": "USP 800  ( Hazardous Drugs\u2014Handling in Healthcare Settings ) is a guideline created by the  United States Pharmacopeia  Convention (USP), as one of their General Chapters through which the USP \"sets quality standards for medicines, dietary supplements and food ingredients\". USP 800 provides guidance about the handling of  hazardous drugs  (HDs) in the healthcare setting. It was published on February 1, 2016, and originally planned for implementation in December 2019; however, implementation has been delayed. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13091", "text": "USP 800 describes practice and quality standards for the handling of HDs involving but not limited to the receipt, storage,  compounding , dispensing, administration, and disposal of sterile and non-sterile products. This chapter applies to any personnel who may be exposed to HDs. Personnel likely to be exposed may include  pharmacists , pharmacy technicians,  nurses ,  physician assistants , home healthcare workers,  veterinarians , and  veterinary technicians . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13092", "text": "Facilities that handle HDs must follow the standards outlined in USP 800. At minimum the facilities's management system must include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13093", "text": "The National Institute for Occupational Safety and Health ( NIOSH ) maintains a list of  antineoplastic  and HDs that are used in healthcare settings. The site must maintain a list of any drugs they use that are on the NIOSH list and it must be updated every 12 months. If the facility begins using a new medication on the NIOSH list it must be added to their HD list."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13094", "text": "Each facility must have a designated person who develops, implements, and maintains USP 800 compliance. This person is also responsible for overseeing the training of personnel and reporting hazardous situations to the management team. All personnel who handle HDs must be trained on the fundamental practices and precautions to contain HDs. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13095", "text": "HDs must be handled in ways to limit contamination. HD storage areas must be separated from break rooms and refreshment areas.\nDesignated areas must be available for:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13096", "text": "Antineoplastic HDs and all HD active pharmaceutical ingredients (APIs) must be unpacked in an area that is neutral/normal or negative pressure. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13097", "text": "HDs must be stored properly to prevent spillage or breakage. HDs should not be stored on the floor or areas prone to natural disaster such as earthquakes. \nAntineoplastic HDs that require further manipulation other than repackaging or counting must be stored separately from non-HDs. Sterile and non-sterile HDs must not be stored together. Refrigerated HDs must be stored in a dedicated refrigerator located in a negative pressure area."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13098", "text": "The  World Pharmacy Council  (WPC) is an international non-profit organization dedicated to representing and advancing the role of community pharmacies in global healthcare systems.  Established in 2017, building upon the foundation of Pharmintercom (founded in 1987), the WPC aims to provide a unified voice for community pharmacists, advocating for their critical role in patient care and public health."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13099", "text": "The origins of the World Pharmacy Council date back to 1987 with the formation of Pharmintercom. [ 1 ]  This group consisted of community pharmacy organizations from seven countries that met annually to share information, discuss best practices, and address challenges facing community pharmacy. Recognizing the need for a more formal and influential global body, Pharmintercom members agreed to establish the World Pharmacy Council (WPC) in 2016, officially launching in 2017.  Since its inception, the WPC has expanded its membership to include numerous national community pharmacy organizations across Europe, North America, Asia and Australasia. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13100", "text": "The WPC's primary purpose is to advocate for the recognition and integration of community pharmacists' skills and services within healthcare systems worldwide. The organization strives to highlight the vital role community pharmacies play in providing accessible healthcare, managing medication therapies, delivering public health services, and contributing to positive patient outcomes. The WPC works to influence health policy at both national and international levels, promoting the full scope of practice for community pharmacists and their inclusion in integrated care models. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13101", "text": "The World Pharmacy Council operates as a not-for-profit public company registered in Australia, with its registered office located in Melbourne, Victoria. It is regulated by the Australian Securities & Investments Commission (ASIC). [ 4 ]  The WPC is governed by a Board of Directors composed of representatives from its member organizations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13102", "text": "Since 2021 the WPC's President has been Douglas Hoey, pharmacist and CEO of the USA's National Community Pharmacists Association. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13103", "text": "The WPC engages in various activities to achieve its objectives, including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13104", "text": "The WPC comprises full and affiliate members.  Full members are national pharmacy organizations representing community pharmacists in their respective countries. Affiliate members are companies and other organizations with an interest in the field of community pharmacy.  As of November 2024, the full members include [ 8 ] :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13105", "text": "Chamaelirium  is a genus of flowering plants containing the single species  Chamaelirium luteum , commonly known as  blazing-star , [ 2 ]   devil's bit , [ 2 ]   false unicorn , [ 2 ]   fairy wand , [ 2 ]  and  helonias . [ 2 ]  It is a  perennial  herb native to the eastern United States. It can be found in a variety of habitats, including wet  meadows  and  deciduous  woodlands."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13106", "text": "Chamaelirium luteum  has a basal rosette of around six 8\u201315\u00a0cm leaves, from which a single spike-like raceme  inflorescence  (1\u20131.5\u00a0cm diameter, 8\u201330\u00a0cm length) emerges. The plants are generally  dioecious , with male-biased gender ratios in a given population. This is due to higher mortality of female plants, and the tendency of female plants to flower less frequently. Female stalks tend to be taller, giving a total maximum plant height of about 1.2 m, but also tend to have about ten times fewer  flowers . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13107", "text": "Chamaelirium luteum  is the only member of its  monotypic  genus, and is quite rare at the fringes of its range. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13108", "text": "Chamaelirium luteum  can be found in temperate  North America , United States and Canada. It occurs in the east of the  Mississippi  and it is historically known from southern  Ontario . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13109", "text": "The  etymology  of  Chamaelirium luteum  comes from the Greek and means: chamai = \"on the ground\" and leirion = \"lilly\", and the Latin luteus = \"yellow\". [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13110", "text": "Because  Chamaelirium luteum  is normally collected wild, it is at risk of extinction. Cultivation techniques are still under development to satisfy the demand from the market. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13111", "text": "Chamaelirium luteum  prefers moist, well  drained  and  acidic soil  ( pH : 4.5 \u2013 6) with a high  humus  content. In open fields it should be shaded by a shading structure, to protect it from the direct radiation of the sun. For forest cultivation it should be preferably planted in an area with tall hardwood trees. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13112", "text": "Chamaelirium luteum  can be propagated through seeds or root division."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13113", "text": "For propagation through root division the  rhizomes  can be divided by cutting them into pieces of  1 \u2044 4  inch (6.4\u00a0mm). This disc-shaped pieces should be left to  callus  over night and can be planted in pots on the next day. The soil should be kept moist and shaded until the plants emerge. Young plants can be transplanted in a well prepared growing bed with a high organic matter in a planting distance of 6\u201310 inches (15\u201325 centimetres). To support the plants with nutrients, pine needles, rotted conifer-derived  sawdust  or bark mulch should be added to the top soil. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13114", "text": "For propagation through seeds, the seeds should be sown in late Fall or early Winter to a depth of  1 \u2044 8  inch (3.2\u00a0mm) in breeding beds with high humus content. For a good germination the seed should go through  stratification . [ 8 ]  The plants grow best in soil mixture of  peat moss  and decomposed  pine  needles. When the young plants emerge they should be left in undisturbed at least for one growing season. Then they can be transplanted as for the propagation method through root division. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13115", "text": "The plant should be moist and shaded and protected from herbivory by  snails  and  slugs  or  deer  in woods. Weeds should always be removed. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13116", "text": "Chamaelirium luteum  is used as ornamental or medical herb. Historically it has been used widely by  Indigenous peoples . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13117", "text": "It was traditionally used to prevent miscarriages and it has the reputation of improving fertility. [ 9 ] \nToday it is used to treat  menstrual  problems,  pregnancy  complaints,  fertility issues ,  ovarian cysts \nand  diuretic [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13118", "text": "The  rhizomes  can be harvested after six years and is done in Fall after collecting the mature seeds.\nAfter removing the soil and the roots from other plants, the rhizome should be stored unwashed until further processing. It should be prevented from drying out and also from too high moisture, which could lead to mold  infestation . Before processing, the rhizome should be washed carefully. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13119", "text": "The bioactive components are a mixture of steroidal  saponins , including chamaelirin and  aglycone   diosgenin . These bioactive substances act as an  emmenagogue ,  diuretic  and  emetic . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13120", "text": "Chinese herbology  ( traditional Chinese :  \u4e2d\u85e5\u5b78 ;  simplified Chinese :  \u4e2d\u836f\u5b66 ;  pinyin :  zh\u014dngy\u00e0o xu\u00e9 ) is the theory of traditional Chinese herbal therapy, which accounts for the majority of treatments in  traditional Chinese medicine  (TCM). A  Nature  editorial described TCM as \"fraught with  pseudoscience \", and said that the most obvious reason why it has not delivered many cures is that the majority of its treatments have no logical  mechanism of action . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13121", "text": "The term  herbology  is misleading in the sense that, while plant elements are by far the most commonly used substances, animal, human, and mineral products are also used, some of which are poisonous. In the  Huangdi Neijing  they are referred to as  \u6bd2\u85e5  (pinyin:  d\u00fay\u00e0o ) which means toxin, poison, or medicine.  Paul U. Unschuld  points out that this is similar etymology to the Greek  pharmakon  and so he uses the term  pharmaceutic . [ 2 ]  Thus, the term  medicinal  (instead of  herb ) is usually preferred as a translation for  \u85e5  (pinyin:  y\u00e0o ). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13122", "text": "Research into the effectiveness of traditional Chinese herbal therapy is of poor quality and often tainted by bias, [ 4 ]  with little or no rigorous evidence of efficacy. [ 5 ]  There are concerns over a number of potentially toxic Chinese herbs. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13123", "text": "Chinese herbs have been used for centuries. Among the earliest literature are lists of prescriptions for specific ailments, exemplified by the manuscript  Recipes for 52 Ailments , found in the  Mawangdui  which were sealed in 168 \u00a0 BCE."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13124", "text": "The first traditionally recognized herbalist is  Sh\u00e9nn\u00f3ng  ( \u795e\u8fb2 ,  lit. \u2009 ' Divine Farmer ' ), a mythical god-like figure, who is said to have lived around 2800 \u00a0 BCE. [ 7 ]  He allegedly tasted hundreds of herbs and imparted his knowledge of medicinal and poisonous plants to farmers. His  Sh\u00e9nn\u00f3ng B\u011bn C\u01ceo J\u012bng  ( \u795e\u8fb2\u672c\u8349\u7d93 ,  Shennong's  Materia Medica ) is considered as the oldest book on Chinese herbal medicine. It classifies 365 species of roots, grass, woods, furs, animals and stones into three categories of herbal medicine: [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13125", "text": "The original text of Shennong's  Materia Medica  has been lost; however, there are extant translations. [ 9 ]  The true date of origin is believed to fall into the late Western Han dynasty [ 7 ]  (i.e., the first century BCE)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13126", "text": "The  Treatise on Cold Damage Disorders and Miscellaneous Illnesses  was collated by  Zhang Zhongjing , also sometime at the end of the  Han dynasty , between 196 and 220 CE. Focusing on drug prescriptions, [ 10 ]  it was the first medical work to combine  Yinyang  and the  Five Phases  with drug therapy. [ 11 ]  This  formulary  was also the earliest Chinese medical text to group symptoms into clinically useful \"patterns\" ( zheng ,  \u8b49 ) that could serve as targets for therapy. Having gone through numerous changes over time, it now circulates as two distinct books: the  Treatise on Cold Damage Disorders  and the  Essential Prescriptions of the Golden Casket , which were edited separately in the eleventh century, under the  Song dynasty . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13127", "text": "Succeeding generations augmented these works, as in the  Yaoxing Lun  ( \u85e5\u6027\u8ad6 ;  \u836f\u6027\u8bba ; 'Treatise on the Nature of Medicinal Herbs'), a 7th-century  Tang dynasty  Chinese treatise on herbal medicine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13128", "text": "There was a shift in emphasis in treatment over several centuries. A section of the  Huangdi Neijing  Suwen including Chapter 74 was added by Wang Bing in his 765 edition. In which it says:  \u4e3b\u75c5\u4e4b\u8b02\u541b\uff0c\u4f50\u541b\u4e4b\u8b02\u81e3\uff0c\u61c9\u81e3\u4e4b\u8b02\u4f7f\uff0c\u975e\u4e0a\u4e0b\u4e09\u54c1\u4e4b\u8b02\u4e5f\u3002  \"Ruler of disease it called Sovereign, aid to Sovereign it called Minister, comply with Minister it called Envoy (Assistant), not upper lower three classes (qualities) it called.\"  The last part is interpreted as stating that these three rulers are not the three classes of Sh\u00e9nn\u00f3ng mentioned previously. This chapter in particular outlines a more forceful approach. Later on Zhang Zihe ( a.k.a.  Zhang Cong-zhen, 1156\u20131228) is credited with founding the 'Attacking School' which criticized the overuse of tonics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13129", "text": "Arguably the most important of these later works is the  Compendium of Materia Medica  ( Bencao Gangmu ,  \u672c\u8349\u7db1\u76ee ) compiled during the  Ming dynasty  by  Li Shizhen , which is still used today for consultation and reference."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13130", "text": "The use of Chinese herbs was popular during the  medieval age  in western Asian and Islamic countries. They were traded through the Silk Road from the East to the West.  Cinnamon ,  ginger ,  rhubarb ,  nutmeg  and  cubeb  are mentioned as Chinese herbs by medieval Islamic medical scholars Such as  Rhazes  (854\u2013925 CE),  Haly Abbas  (930\u2013994 CE) and  Avicenna  (980\u20131037 CE). There were also multiple similarities between the clinical uses of these herbs in Chinese and Islamic medicine. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13131", "text": "There are roughly 13,000 medicinals used in China and over 100,000 medicinal recipes recorded in the ancient literature. [ 14 ]  Plant elements and extracts are by far the most common elements used. [ 15 ]  In the classic  Handbook of Traditional Drugs  from 1941, 517 drugs were listed \u2013 out of these, only 45 were animal parts, and 30 were minerals. [ 15 ]  For many plants used as medicinals, detailed instructions have been handed down not only regarding the locations and areas where they grow best, but also regarding the best timing of planting and harvesting them. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13132", "text": "Some animal parts used as medicinals can be considered rather strange such as cows' gallstones. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13133", "text": "Furthermore, the classic  materia medica   Bencao Gangmu  describes the use of 35  traditional Chinese medicines derived from the human body , including bones, fingernail, hairs, dandruff, earwax, impurities on the teeth, feces, urine, sweat, and organs, but most are no longer in use. [ 18 ] [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13134", "text": "Typically, one batch of medicinals is prepared as a  decoction  of about 9 to 18 substances. [ 21 ]  Some of these are considered as main herbs, some as ancillary herbs; within the ancillary herbs, up to three categories can be distinguished. [ 22 ]  Some ingredients are added to cancel out toxicity or side-effects of the main ingredients; on top of that, some medicinals require the use of other substances as  catalysts ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13135", "text": "Chinese patent medicine ( \u4e2d\u6210\u85e5 ;  \u4e2d\u6210\u836f ;  zh\u014dngch\u00e9ng y\u00e0o ) is a kind of  traditional Chinese medicine . They are standardized  herbal  formulas. From ancient times, pills were formed by combining several herbs and other ingredients, which were dried and ground into a powder. They were then mixed with a binder and formed into pills by hand. The  binder  was traditionally honey. Modern teapills, however, are extracted in stainless steel extractors to create either a water decoction or water-alcohol decoction, depending on the herbs used. They are extracted at a low temperature (below 100\u00a0\u00b0C (212\u00a0\u00b0F)) to preserve essential ingredients. The extracted liquid is then further condensed, and some raw herb powder from one of the herbal ingredients is mixed in to form a herbal dough. This dough is then machine cut into tiny pieces, a small amount of excipients are added for a smooth and consistent exterior, and they are spun into pills. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13136", "text": "These medicines are not patented in the traditional sense of the word. No one has  exclusive rights  to the formula. Instead, \"patent\" refers to the  standardization  of the formula. In China, all Chinese patent medicines of the same name will have the same proportions of ingredients, and manufactured in accordance with the PRC Pharmacopoeia, which is mandated by law. However, in western countries there may be variations in the proportions of ingredients in patent medicines of the same name, and even different ingredients altogether. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13137", "text": "Several producers of Chinese herbal medicines are pursuing FDA clinical trials to market their products as drugs in U.S. and European markets. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13138", "text": "Chinese herbal extracts are herbal decoctions that have been condensed into a granular or powdered form. Herbal extracts, similar to patent medicines, are easier and more convenient for patients to take. The industry extraction standard is 5:1, meaning for every five pounds of raw materials, one pound of herbal extract is derived. [ 24 ] [ better\u00a0source\u00a0needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13139", "text": "There are several different methods to classify traditional Chinese medicinals:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13140", "text": "The Four Natures are: hot ( \u71b1 ;  \u70ed ), warm ( \u6eab ;  \u6e29 ), cool ( \u6dbc ), cold ( \u5bd2 ) or neutral ( \u5e73 ). [ 25 ]  Hot and warm herbs are used to treat  cold  diseases, while cool and cold herbs are used to treat hot diseases. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13141", "text": "The Five Flavors, sometimes also translated as  Five Tastes , are: acrid/pungent ( \u8f9b ), sweet ( \u7518 ), bitter ( \u82e6 ), sour ( \u9178 ), and salty ( \u9e79 ;  \u54b8 ). [ 25 ]  Substances may also have more than one flavor, or none (i.e., a bland ( \u6de1 ) flavor). [ 25 ]  Each of the Five Flavors corresponds to one of the  z\u00e0ng organs , which in turn corresponds to one of the  Five Phases : [ 26 ]  A flavor implies certain properties and presumed therapeutic \"actions\" of a substance: saltiness \"drains downward and softens hard masses\"; [ 25 ]  sweetness is \"supplementing, harmonizing, and moistening\"; [ 25 ]  pungent substances are thought to induce sweat and act on  qi  and  blood ; sourness tends to be astringent ( \u6f80 ;  \u6da9 ) in nature; bitterness \"drains  heat , purges the bowels, and eliminates dampness\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13142", "text": "These categories mainly include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13143", "text": "Many herbs earn their names from their unique physical appearance. Examples of such names include  Niu Xi  ( Radix cyathulae seu achyranthis ), 'cow's knees,' which has big joints that might look like cow knees;  Bai Mu Er  ( Fructificatio tremellae fuciformis ), 'white wood ear', which is white and resembles an ear;  Gou Ji  ( Rhizoma cibotii ), 'dog spine,' which resembles the spine of a dog. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13144", "text": "Color is not only a valuable means of identifying herbs, but in many cases also provides information about the therapeutic attributes of the herb. For example, yellow herbs are referred to as  huang  (yellow) or  jin  (gold).  Huang Bai  ( Cortex Phellodendri ) means 'yellow fir,\" and  Jin Yin Hua  ( Flos Lonicerae ) has the label 'golden silver flower.\" [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13145", "text": "Unique flavors define specific names for some substances.  Gan  means 'sweet,' so  Gan Cao  ( Radix glycyrrhizae ) is 'sweet herb,' an adequate description for the licorice root.  Ku  means 'bitter', thus  Ku Shen  ( Sophorae flavescentis ) translates as 'bitter herb.' [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13146", "text": "The locations or provinces in which herbs are grown often figure into herb names. For example,  Bei Sha Shen  ( Radix glehniae ) is grown and harvested in northern China, whereas  Nan Sha Shen  ( Radix adenophorae ) originated in southern China. And the Chinese words for north and south are respectively  bei  and  nan . [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13147", "text": "Chuan Bei Mu  ( Bulbus fritillariae cirrhosae ) and  Chuan Niu Xi  ( Radix cyathulae ) are both found in Sichuan province, as the character  chuan  indicates in their names. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13148", "text": "Some herbs, like  Fang Feng  ( Radix Saposhnikoviae ), literally 'prevent wind,' preventing or treating wind-related illnesses.  Xu Duan  ( Radix Dipsaci ), literally 'restore the broken,' treating torn soft tissues and broken bones. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13149", "text": "Many herbs indigenous to other countries have been incorporated into the Chinese materia medica.  Xi Yang Shen  ( Radix panacis quinquefolii ), imported from North American crops, translates as 'western ginseng,' while  Dong Yang Shen  ( Radix ginseng Japonica ), grown in and imported from North Asian countries, is 'eastern ginseng.' [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13150", "text": "From the earliest records regarding the use of medicinals to today, the toxicity of certain substances has been described in all Chinese materia medica. [ 31 ]  Since TCM has become more popular in the Western world, there are increasing concerns about the potential toxicity of many traditional Chinese medicinals including plants, animal parts and minerals. [ 6 ]  For most medicinals, efficacy and toxicity testing are based on traditional knowledge rather than laboratory analysis. [ 6 ]  The toxicity in some cases could be confirmed by modern research (i.e., in  scorpion ); in some cases it could not (i.e., in  Curculigo ). [ 32 ]  Further, ingredients may have different names in different locales or in historical texts, and different preparations may have similar names for the same reason, which can create inconsistencies and confusion in the creation of medicinals, [ 33 ]  with the possible danger of poisoning. [ 34 ] [ 35 ] [ 36 ] [ unreliable source? ]   Edzard Ernst  \"concluded that adverse effects of herbal medicines are an important albeit neglected subject in dermatology, which deserves further systematic investigation.\" [ 37 ]  Research suggests that the toxic heavy metals and undeclared drugs found in Chinese herbal medicines might be a serious health issue. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13151", "text": "Substances known to be potentially dangerous include  aconite , [ 32 ]  secretions from the  Asiatic toad , [ 39 ]  powdered centipede, [ 40 ]  the Chinese beetle ( Mylabris phalerata , Ban mao), [ 41 ]  and certain fungi. [ 42 ]  There are health problems associated with  Aristolochia . [ 6 ]  Toxic effects are also frequent with  Aconitum . [ 6 ]  To avoid its toxic adverse effects  Xanthium sibiricum  must be processed. [ 6 ]   Hepatotoxicity  has been reported with products containing  Reynoutria multiflora  ( synonym   Polygonum multiflorum ),  glycyrrhizin ,  Senecio  and  Symphytum . [ 6 ]  The evidence suggests that hepatotoxic herbs also include  Dictamnus dasycarpus ,  Astragalus membranaceus , and  Paeonia lactiflora ; although there is no evidence that they cause liver damage. [ 6 ] [ clarification needed ]  Contrary to popular belief,  Ganoderma lucidum  mushroom extract, as an adjuvant for cancer immunotherapy, appears to have the potential for toxicity. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13152", "text": "Also, adulteration of some herbal medicine preparations with conventional drugs which may cause serious adverse effects, such as  corticosteroids ,  phenylbutazone ,  phenytoin , and  glibenclamide , has been reported. [ 44 ] [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13153", "text": "However, many adverse reactions are due to misuse or abuse of Chinese medicine. [ 6 ]  For example, the misuse of the dietary supplement  Ephedra  (containing  ephedrine ) can lead to adverse events including gastrointestinal problems as well as sudden death from  cardiomyopathy . [ 6 ]  Products adulterated with  pharmaceuticals  for weight loss or erectile dysfunction are one of the main concerns. [ 6 ]  Chinese herbal medicine has been a major cause of  acute liver failure  in China. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13154", "text": "Most Chinese herbs are safe but some have shown not to be. Reports have shown products being contaminated with drugs, toxins, or false reporting of ingredients. Some herbs used in TCM may also react with drugs, have side effects, or be dangerous to people with certain medical conditions. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13155", "text": "Only a few trials exist that are considered to have adequate methodology by scientific standards. Proof of effectiveness is poorly documented or absent. [ 4 ]  A 2016  Cochrane review  found \"insufficient evidence that Chinese Herbal Medicines were any more or less effective than placebo or hormonal therapy\" for the relief of menopause related symptoms. [ 48 ]  A 2012 Cochrane review found no difference in decreased  mortality  for  SARS  patients when Chinese herbs were used alongside Western medicine versus Western medicine exclusively. [ 49 ]  A 2010 Cochrane review found there is not enough robust evidence to support the effectiveness of traditional Chinese medicine herbs to stop the bleeding from  haemorrhoids . [ 50 ]  A 2008 Cochrane review found promising evidence for the use of Chinese herbal medicine in relieving  painful menstruation , compared to conventional medicine such as  NSAIDs  and the oral contraceptive pill, but the findings are of low methodological quality. [ 51 ]  A 2012 Cochrane review found weak evidence suggesting that some Chinese medicinal herbs have a similar effect at preventing and treating  influenza  as  antiviral  medication. [ 52 ]  Due to the poor quality of these medical studies, there is insufficient evidence to support or dismiss the use of Chinese medicinal herbs for the treatment of influenza. [ 52 ]  There is a need for larger and higher quality randomized clinical trials to determine how effective Chinese herbal medicine is for treating people with influenza. [ 52 ]  A 2005 Cochrane review found that although the evidence was weak for the use of any single herb, there was low quality evidence that some Chinese medicinal herbs may be effective for the treatment of acute  pancreatitis . [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13156", "text": "The traditional practice of using now- endangered species  is controversial within TCM. Modern Materia Medicas such as Bensky, Clavey and Stoger's comprehensive Chinese herbal text discuss substances derived from endangered species in an appendix, emphasizing alternatives. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13157", "text": "Parts of endangered species used as TCM drugs include tiger bones [ 55 ]  and  rhinoceros horn . [ 56 ]  Poachers supply the  black market  with such substances, [ 57 ] [ 58 ]  and the black market in rhinoceros horn, for example, has reduced the world's rhino population by more than 90 percent over the past 40 years. [ 59 ]  Concerns have also arisen over the use of turtle  plastron [ 60 ]  and  seahorses . [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13158", "text": "TCM recognizes  bear bile  as a medicinal. In 1988, the Chinese Ministry of Health started controlling bile production, which previously used bears killed before winter. Now bears are fitted with a sort of permanent  catheter , which is more profitable than killing the bears. [ 62 ] [ verification needed ]  More than 12,000  asiatic black bears  are held in \"bear farms\", where they suffer cruel conditions while being held in tiny cages. The catheter leads through a permanent hole in the abdomen directly to the  gall bladder , which can cause severe pain.\nIncreased international attention has mostly stopped the use of bile outside of China; gallbladders from butchered cattle ( \u725b\u80c6 ;  \u725b\u81bd ;  ni\u00fa d\u01cen ) are recommended as a substitute for this ingredient. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13159", "text": "Collecting  American ginseng  to assist the Asian traditional medicine trade has made ginseng the most harvested wild plant in North America for the last two centuries, which eventually led to a listing on  CITES Appendix II . [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13160", "text": "Chinese medicinal plant materials (CMPMs) release chemicals that attracts the  Drugstore beetle , leading to the accumulation of this pest and further infestation and damage to these plants. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13161", "text": "Chinese herbology is a pseudoscientific practice with potentially unreliable product quality, safety hazards or misleading health advice. [ 65 ] [ 66 ] [ 67 ]  There are regulatory bodies, such as China GMP (Good Manufacturing Process) of herbal products. [ 68 ]  However, there have been notable cases of an absence of  quality control  during herbal product preparation. [ 69 ]  There is a lack of high-quality scientific research on herbology practices and product effectiveness for anti-disease activity. [ 65 ] [ 66 ]  In the herbal sources listed below, there is little or no evidence for efficacy or proof of safety across consumer age groups and disease conditions for which they are intended. [ 65 ] [ 66 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13162", "text": "There are over 300 herbs in common use. Some of the most commonly used herbs are  Ginseng  ( \u4eba\u53c2 ;  \u4eba\u53c3 ;  r\u00e9nsh\u0113n ),  wolfberry  ( \u67b8\u675e\u5b50 ;  g\u01d2uq\u01d0z\u01d0),  dong quai  ( Angelica sinensis ,  \u5f53\u5f52 ;  \u7576\u6b78 ;  d\u0101nggu\u012b ),  astragalus  ( \u9ec4\u8006 ;  \u9ec3\u8006 ;  hu\u00e1ngq\u00ed ),  atractylodes  ( \u767d\u672f ;  \u767d\u672e ;  b\u00e1izh\u00fa ), bupleurum ( \u67f4\u80e1 ;  ch\u00e1ih\u00fa ), cinnamon (cinnamon twigs ( \u6842\u679d ;  gu\u00eczh\u012b ) and cinnamon bark ( \u8089\u6842 ;  r\u00f2ugu\u00ec )),  coptis  ( \u9ec4\u8fde ;  \u9ec3\u9023 ;  hu\u00e1ngli\u00e1n ), ginger ( \u59dc ;  \u8591 ;  ji\u0101ng ), hoelen ( \u832f\u82d3 ;  f\u00fal\u00edng ),  licorice  ( \u7518\u8349 ;  g\u0101nc\u01ceo ),  ephedra sinica  ( \u9ebb\u9ec4 ;  \u9ebb\u9ec3 ;  m\u00e1hu\u00e1ng ),  peony  (white:  \u767d\u828d ;  b\u00e1ish\u00e1o  and reddish:  \u8d64\u828d ;  ch\u00ecsh\u00e1o ),  rehmannia  ( \u5730\u9ec4 ;  \u5730\u9ec3 ;  d\u00echu\u00e1ng ), rhubarb ( \u5927\u9ec4 ;  \u5927\u9ec3 ;  d\u00e0hu\u00e1ng ), and salvia ( \u4e39\u53c2 ;  \u4e39\u53c3 ;  d\u0101nsh\u0113n )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13163", "text": "In Chinese herbology, there are 50 \"fundamental\" herbs, as given in the reference text, [ 70 ]  although these herbs are not universally recognized as such in other texts. The herbs are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13164", "text": "In addition to the above, many other Chinese herbs and other substances are in common use, and these include:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13165", "text": "Traditional Chinese herbs are used either standalone, or in a grouping, jointly with other herbs. When several herbs are used together, this amalgamation is called a 'herbal formula'. [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13166", "text": "There are, generally speaking, three types of herbal formulas used in TCM:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13167", "text": "1.  Classic Formulas  - these are formulas which TCM practitioners believe have withstood the test of time over the centuries, and are mentioned in classical texts, such as the  Shanghan Lun ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13168", "text": "2. Patent Formulas - these are either classic formulas, or newer commonly-used formulas created in recent decades. The patent formulas stand out in that their usage is common enough, that they are frequently mass-produced by large companies, in China, the United States, and elsewhere."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13169", "text": "3. Custom-Made Formulas - these formulas are composed by a TCM Practitioner, to match the specific diagnosis and medical condition of a patient. These formulas are often partially-based on the older, classic formulas."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13170", "text": "The prescription of TCM formulas, is based on 4-tier system of hierarchy. [ 90 ]  The 4-tiers are: Jun (\u541b), Chen (\u81e3), Zuo (\u4f50) and Shi (\u4f7f). [ 91 ] [ 92 ]  These four tiers are often translated as: Sovereign, Minister, Assistant, Courier; or Monarch, Minister, Assistant, Envoy (also: 'Guide'). [ 93 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13171", "text": "This feudal-like hierarchy denotes the power and role of each herb in a given formula. [ 94 ] [ 95 ]  The Jun is the herb which is usually of the highest relative dosage, and leads the main action of the formula. In the majority of formulas, there is only one Jun (Monarch) herb. Sometimes, a formula may feature 2-3 Jun herbs, or lack a dominant Jun herb altogether. The Chen support the Jun in its actions, and provide additional uses for the medical purpose of the formula. The Zuo assist the Jun and Chen, but are given at a much lower dosage (relative to themselves), to deemphasize their influence, for various reasons. The Shi's main role is to help guide the formula to the correct bodily areas or organ systems inside of which it is meant to act. [ 96 ] [ 97 ] [ 98 ]  The Shi are also sometimes used \"to harmonize the properties of other herbs in the formula\". [ 99 ] [ 100 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13172", "text": "Most herbs can serve as either Jun (Monarch), Chen (Minister) or Zuo (Assistant) - the first three tiers in the herbal hierarchy. But only certain herbs, are considered fit to serve as Shi. This is because only some herbs are believed to have the ability, to guide other herbs into a given bodily area or organ system. [ 101 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13173", "text": "Within TCM formulas, there are also strict rules about which herbs pair well together (Dui Yao), and which are either contradictory, incompatible, or may cause a reaction amongst themselves, or with Western Medicine Drugs. [ 102 ]  For example: Gan Cao (Licorice) is incompatible with the herbs Yuan hua, Jing Da Ji, Hai Zao and Gan Sui. It may also alter the therapeutic effects of corticosteroids. [ 103 ] [ 104 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13174", "text": "Clerodendrum infortunatum , known as  bhat [ 2 ]  or  hill glory bower , is a  perennial   shrub  belonging to the  family   Lamiaceae , also sometimes classified under  Verbenaceae . It is the  type species  among ~150  species  of  Clerodendrum . It is one of the most well-known natural health remedies in traditional practices and  siddha medicine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13175", "text": "The species is native to  tropical  regions of  Asia  including  Bangladesh ,  India ,  Myanmar ,  Pakistan ,  Thailand ,  Malaysia , the  Andaman Islands , and  Sri Lanka . [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13176", "text": "Clerodendrum infortunatum  is a flowering  shrub  or small  tree , and is so named because of its rather ugly leaf  [ citation needed ] . The stem is erect, 0.5\u20134\u00a0m (1.6\u201313.1\u00a0ft) high, with no branches and produce circular leaves with 15\u00a0cm (5.9\u00a0in) diameter. Leaves are simple, opposite; both surfaces sparsely villous-pubescent, elliptic, broadly elliptic, ovate or elongate ovate, 3.5\u201320\u00a0cm (1.4\u20137.9\u00a0in) wide, 6\u201325\u00a0cm (2.4\u20139.8\u00a0in) long, dentate,  inflorescence  in terminal, peduncled, few-flowered cyme; flowers white with purplish pink or dull-purple throat, pubescent. Fruit  berry ,  globose , turned bluish-black or black when ripe, enclosed in the red accrescent fruiting- calyx . The stem is hollow and the leaves are 15\u201320\u00a0cm (5.9\u20137.9\u00a0in) long, borne in whorls of four on very short  petioles . The inflorescence is huge, consisting of many tubular snow white flowers in a terminal cluster up to 0.6\u00a0m (2\u00a0ft) long. The tubes of the flowers are about 10\u00a0cm (3.9\u00a0in) long and droop downward, and the expanded  corollas  are about 5\u00a0cm (2.0\u00a0in) across."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13177", "text": "The fruits are attractive dark metallic blue  drupes , about 1\u00a0cm (0.4\u00a0in) in diameter. Fruit usually with four dry nutlets and the seeds may be with or without  endosperm . It flowers from April to August. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13178", "text": "The major compounds are  sterols ,  sugars ,  flavonoids  and  saponins . Novel crystalline compounds such as  clerodolone ,  clerodone ,  clerodol , and a sterol designated  clerosterol  have been isolated from the root. Seven sugars namely  raffinose ,  lactose ,  maltose ,  sucrose ,  galactose ,  glucose  and  fructose  were identified. [ 2 ]   Fumaric acid ,  caffeic acid  esters,  \u03b2-sitosterol  and \u03b2-sitosterol glucoside were isolated from the flowers. [ 4 ]   Apigenin ,  acacetin  and a new flavone glycoside, characterised as the methyl ester of acacetin-7-0-glucuronide are isolated from the flowers. [ 5 ]  Saponin is one of the major compounds of the leaf. [ 6 ]  24 beta-ethylsterols, clerosterol and 22-dehydroclerosterol, 24-methyl-sterols (24-methylcholestanol, 24-methylcholesterol, 24-methyl-22-dehydrocholesterol, and 24-methyllathostero) and 24 beta-ethyl-22-dehydrocholestanol are found in the seeds. [ 7 ]   Scutellarin  and hispidulin-7-O-glucuronide are present in the leaf. [ 8 ]  Poriferasterol and  stigmasterol  are the components of the aerial parts. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13179", "text": "Clerodendrum infortunatum  is used in  Ayurvedic  and  Siddha   traditional medicines .  Fresh leaves are given for  diarrhea ,  liver  disorders, and  headache . [ 10 ]   The leaf and root are used as  antidandruff ,  antipyretic ,  ascaricide ,  laxative ,  vermifuge ,  anticonvulsant ,  antidiabetic , and for  gravel ,  malaria ,  scabies ,  skin diseases ,  sores ,  spasm ,  scorpion sting ,  snake bite , and  tumors . [ 11 ] [ 12 ]  In many traditional practices the leaves and root are widely used as  antihyperglycemic . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13180", "text": "Crude drugs  are drugs of plant, animal and microbial origin [ clarification needed ]  that contain natural substances that have undergone only the processes of collection and drying. [ dubious  \u2013  discuss ]  The term natural substances refers to those substances found in  nature  that have not had man-made changes made in their molecular structure. They are used as  medicine  for humans and animals, internally and externally for curing  diseases , e.g.,  Senna  and  Cinchona ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13181", "text": "A crude drug is any naturally occurring, unrefined substance derived from  organic  or  inorganic  sources such as plant, animal, bacteria, organs or whole organisms intended for use in the  diagnosis ,  cure , mitigation,  treatment , or prevention of disease in humans or other animals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13182", "text": "Crude drugs are unrefined natural  medications  in their raw forms.  Prior to the 1950s, every pharmacy student learned about crude drugs in  pharmacognosy  class. Pharmacognosy is the study of the proper  horticulture ,  harvesting  and uses of the raw medications found in nature."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13183", "text": "Raising, harvesting and selling crude drugs was how many large pharmaceutical companies started out.  Companies such as  Eli Lilly and Company  sold crude drugs to pharmacists to save them time and money, but the early pharmacy graduate would know how to raise their own crude drugs if need be. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13184", "text": "Identification of the crude drug by organoleptic characters is one of the important aspects of pharmacognostical study. Morphological study follows a special terminology which must be known to a pharmacognostist. The morphological terminology is derived from botany and zoology, depending upon the source of the crude drug. In general, color, odor, taste, size, shape, and special features, like touch, texture, fracture, presence of trichomes, and presence of ridges of crude drugs are studied under morphology. Aromatic odor of umbelliferous fruits and sweet taste of liquorice are the example of this type of evaluation. The study of form of a crude drug is  morphology , while description of the form is  morphography ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13185", "text": "However, shape and size of crude drugs as described in official books should only be considered as guidelines and may vary depending upon several factors. For example, color of the crude drug may fade if it gets exposed to sunlight for very long duration or if, the drug is not stored properly. Depending upon the condition under which the drug is growing or cultivated, i.e., availability of proper irrigation, fertilizers or even high temperature, may influence the size may be available and the crude drugs if grown in adverse conditions may be of small size."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13186", "text": "Color of the flowers as in case  Catharanthus roseus  and  Catharanthus alba,  presence of thorns in case of  Asparagus recemosus  and absence in  Asparagus officinalis , arrangement of flowers in case of  Withania semnifera   or   Witharia coagulens   can help in differentiating the varieties of the same plant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13187", "text": "Arrangement of cracks and wrinkles in case of stem bark of varieties of Cinchona bark, or the color of aloe can separate in varieties."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13188", "text": "The adulteration of seed of Strychnos nux-vomica with the seed of Strrychnos nux-blanda or Strychnos potatorum, caraway with Indian dill, Alexandrian senna with dog senna or palthe senna are identified by morphological means."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13189", "text": "In case of cellular products (unorganized drugs), form of the drug depends totally on the method of preparation of the drug. Thus, gum acacia is found in the form of ovoid tears, while tragacanth is marketed as vermiform ribbon with longitudinal striations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13190", "text": "To evaluate means to identify it and to determine its quality and purity, the identity of a drug can be established by actual collection of the drug from a plant or animal that has been positively identified. The evaluation of drug involves a number of methods that may be classified as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13191", "text": "The usage of crude drugs dates to  prehistoric times . Traditional medicine often incorporates the gathering and preparation of material from natural sources, particularly herbs. In such practice, the active ingredients and method of action are largely unknown to the practitioner."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13192", "text": "In recent history, the development of modern chemistry and application of the scientific method shaped the use of crude drugs. Eventually, the use of crude drugs reach a zenith in the early 1900s and eventually gave way to the use of purified active ingredients from the natural source. Currently the use and exploration of crude drugs has again gained prominence in the medical community. The realization that many completely unknown substances are yet to be discovered from crude drugs has created a new interest in pharmacognosy and has led to many medical breakthroughs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13193", "text": "In 1907, the  Pure Food and Drug Act  was implemented and standardization of crude drugs took place. Often the  USP  would specify what percentage of active ingredient was needed to claim a crude drug met USP standards."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13194", "text": "An example of standardization would be as follows (from the  United States Pharmacopeia ): [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13195", "text": "Opium  is the air-dried milky exudate obtained by incising the unripe capsules of  Papaver somniferum  Linne or its variety album De Candolle (Fam. Papaveraceae). Opium in its normal air-dried condition yields not less than 9.5 percent of anhydrous  morphine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13196", "text": "Crude medicine ( simplified Chinese :  \u836f\u6750 ;  traditional Chinese :  \u85e5\u6750 ;  pinyin :  y\u00e0oc\u00e1i ), (also known as crude drug in the  Chinese materia medica ) are bulk drugs from the Chinese materia medica basic processing and treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13197", "text": "Ethnobotany  is an interdisciplinary field at the interface of natural and social sciences that studies the relationships between humans and plants. [ 1 ] [ 2 ]  It focuses on  traditional knowledge  of how plants are used, managed, and perceived in  human societies . [ 3 ] [ 4 ]  Ethnobotany integrates knowledge from  botany ,  anthropology ,  ecology , and  chemistry  to study plant-related customs across cultures. Researchers in this field document and analyze how different societies use local  flora  for various purposes, including  medicine ,  food ,  religious use ,  intoxicants ,  building materials ,  fuels  and  clothing . [ 5 ]   Richard Evans Schultes , often referred to as the \"father of ethnobotany\", [ 6 ]  provided an early definition of the discipline:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13198", "text": "Ethnobotany simply means investigating plants used by primitive societies in various parts of the world. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13199", "text": "Since Schultes' time, ethnobotany has evolved from primarily documenting traditional plant knowledge to applying this information in modern contexts, particularly in  pharmaceutical development . [ 8 ]  The field now addresses complex issues such as  intellectual property  rights and equitable benefit-sharing arrangements arising from the use of traditional knowledge. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13200", "text": "The idea of ethnobotany was first proposed by the early 20th century botanist  John William Harshberger . [ 9 ]  While Harshberger did perform ethnobotanical research extensively, including in areas such as  North Africa ,  Mexico ,  Scandinavia , and  Pennsylvania , [ 9 ]  it was not until  Richard Evans Schultes  began his trips into the  Amazon  that ethnobotany became a more well known science. [ 10 ]  However, the practice of ethnobotany is thought to have much earlier origins in the first century AD when a Greek physician by the name of  Pedanius Dioscorides  wrote an extensive botanical text detailing the medical and culinary properties of \"over 600 mediterranean plants\" named  De Materia Medica . [ 5 ]  Historians note that Dioscorides wrote about traveling often throughout the Roman empire, including regions such as \" Greece ,  Crete ,  Egypt , and  Petra \", [ 11 ]  and in doing so obtained substantial knowledge about the local plants and their useful properties. European botanical knowledge drastically expanded once the New World was discovered due to ethnobotany. This expansion in knowledge can primarily be attributed to the substantial influx of new plants from the Americas, including crops such as potatoes, peanuts, avocados, and tomatoes. [ 12 ]  The French explorer  Jacques Cartier  learned a cure for scurvy (a tea made from the needles of a  coniferous  tree, likely  spruce ) from a local  Iroquois  tribe. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13201", "text": "During the medieval period, ethnobotanical studies were often conducted in connection with  monasticism . However, most botanical knowledge was kept in gardens, such as  physic gardens  attached to hospitals and religious buildings. It was thought of in practical use terms for culinary and medical purposes and the ethnographic element was not studied as a modern  anthropologist  might approach ethnobotany today. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13202", "text": "In 1732,  Carl Linnaeus  carried out a  research expedition  in Scandinavia asking the  Sami people  about their  ethnological  usage of plants. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13203", "text": "The  Age of Enlightenment  saw a rise in economic  botanical  exploration.  Alexander von Humboldt  collected data from the New World, and  James Cook 's voyages brought back collections and information on plants from the South Pacific. [ 16 ]  At this time major botanical gardens were started, for instance the  Royal Botanic Gardens, Kew  in 1759. The directors of the gardens sent out  gardener-botanist explorers  to care for and collect plants to add to their collections."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13204", "text": "As the 18th century became the 19th, ethnobotany saw expeditions undertaken with more colonial aims rather than trade economics such as that of  Lewis and Clarke  which recorded both plants and the peoples encountered use of them.  Edward Palmer  collected  material culture  artifacts and botanical specimens from people in the North American West ( Great Basin ) and Mexico from the 1860s to the 1890s. Through all of this research, the field of \"aboriginal botany\" was established\u2014the study of all forms of the vegetable world which  aboriginal peoples  use for food, medicine,  textiles , ornaments and more. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13205", "text": "The first individual to study the  emic  perspective of the plant world was a German physician working in Sarajevo at the end of the 19th century: Leopold Gl\u00fcck. His published work on traditional medical uses of plants done by rural people in Bosnia (1896) has to be considered the first modern ethnobotanical work. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13206", "text": "Other scholars analyzed uses of plants under an indigenous/local perspective in the 20th century:  Matilda Coxe Stevenson , Zuni plants (1915);  Frank Cushing , Zuni foods (1920);  Keewaydinoquay Peschel , Anishinaabe fungi (1998), and the team approach of Wilfred Robbins,  John Peabody Harrington , and  Barbara Freire-Marreco , Tewa pueblo plants (1916)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13207", "text": "In the beginning, ethonobotanical specimens and studies were not very reliable and sometimes not helpful. This is because the botanists and the anthropologists did not always collaborate in their work. The botanists focused on identifying species and how the plants were used instead of concentrating upon how plants fit into people's lives. On the other hand, anthropologists were interested in the cultural role of plants and treated other scientific aspects superficially. In the early 20th century, botanists and anthropologists better collaborated and the collection of reliable, detailed cross-disciplinary data began."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13208", "text": "Beginning in the 20th century, the field of ethnobotany experienced a shift from the raw compilation of data to a greater methodological and conceptual reorientation. This is also the beginning of academic ethnobotany. The so-called \"father\" of this discipline is  Richard Evans Schultes , even though he did not actually coin the term \"ethnobotany\". Today the field of ethnobotany requires a variety of skills: botanical training for the identification and preservation of plant specimens; anthropological training to understand the cultural concepts around the perception of plants; linguistic training, at least enough to transcribe local terms and understand native morphology, syntax, and semantics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13209", "text": "Mark Plotkin , who studied at  Harvard University , the  Yale School of Forestry  and  Tufts University , has contributed a number of books on ethnobotany. He completed a handbook for the  Tirio people  of  Suriname  detailing their medicinal plants;  Tales of a Shaman's Apprentice  (1994);  The Shaman's Apprentice,  a children's book with  Lynne Cherry  (1998); and  Medicine Quest: In Search of Nature's Healing Secrets  (2000)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13210", "text": "Plotkin was interviewed in 1998 by  South American Explorer  magazine, just after the release of  Tales of a Shaman's Apprentice  and the  IMAX  movie Amazonia. In the book, he stated that he saw wisdom in both traditional and Western forms of medicine:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13211", "text": "No medical system has all the answers\u2014no shaman that I've worked with has the equivalent of a polio vaccine and no dermatologist that I've been to could cure a fungal infection as effectively (and inexpensively) as some of my Amazonian mentors. It shouldn't be the doctor versus the witch doctor. It should be the best aspects of all medical systems ( ayurvedic ,  herbalism ,  homeopathic , and so on) combined in a way which makes health care more effective and more affordable for all. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13212", "text": "A great deal of information about the traditional uses of plants is still intact with tribal peoples. [ 20 ]  But the native healers are often reluctant to accurately share their knowledge to outsiders. Schultes actually apprenticed himself to an Amazonian shaman, which involves a long-term commitment and genuine relationship. In  Wind in the Blood: Mayan Healing & Chinese Medicine  by Garcia et al. the visiting acupuncturists were able to access levels of Mayan medicine that anthropologists could not because they had something to share in exchange. Cherokee medicine priest David Winston describes how his uncle would invent nonsense to satisfy visiting anthropologists. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13213", "text": "Another scholar, James W. Herrick, who studied under ethnologist  William N. Fenton , in his work  Iroquois Medical Ethnobotany  (1995) with Dean R. Snow (editor), professor of Anthropology at Penn State, explains that understanding herbal medicines in traditional Iroquois cultures is rooted in a strong and ancient  cosmological  belief system. [ 22 ]  Their work provides perceptions and conceptions of illness and imbalances which can manifest in physical forms from benign maladies to serious diseases. It also includes a large compilation of Herrick's field work from numerous Iroquois authorities of over 450 names, uses, and preparations of plants for various ailments. Traditional Iroquois practitioners had (and have) a sophisticated perspective on the plant world that contrast strikingly with that of modern medical science. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13214", "text": "Researcher Cassandra Quave at Emory University has used ethnobotany to address the problems that arise from antibiotic resistance. Quave notes that the advantage of medical ethnobotany over Western medicine rests in the difference in mechanism. For example, elmleaf blackberry extract focuses instead on the prevention of bacterial collaboration as opposed to directly exterminating them. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13215", "text": "Many instances of  gender bias  have occurred in ethnobotany, creating the risk of drawing erroneous conclusions. Anthropologists would often consult with primarily men. In Las Pavas, a small farming community in Panama, anthropologists drew conclusions about the entire community's use of plant from their conversations and lessons with mostly men. They consulted with 40 families, but the women only participated rarely in interviews and never joined them in the field. Due to the division of labor, the knowledge of wild plants for food, medicine, and fibers, among others, was left out of the picture, resulting in a distorted view of which plants were actually important to them. [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13216", "text": "Ethnobotanists have also assumed that ownership of a resource means familiarity with that resource. In some societies women are excluded from owning land, while being the ones who work it. Inaccurate data can come from interviewing only the owners. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13217", "text": "Other issues include ethical concerns regarding interactions with  indigenous populations , and the International Society of Ethnobiology has created a code of ethics to guide researchers. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13218", "text": "Media related to  Ethnobotany  at Wikimedia Commons"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13219", "text": "Crotalaria macrophylla   Willd. \n Flemingia angustifolia   Roxb. \n Flemingia bhottea   Buch.-Ham. \n Flemingia capitata   Buch.-Ham. \n Flemingia congesta   Roxb. ex  W. T. Aiton \n Flemingia latifolia   Benth. \n Flemingia nana   Roxb. \n Flemingia prostrata   Roxb. \n Flemingia semialata   W.T.Aiton \n Moghania cumingiana   (Benth.)  Kuntze \n Moghania macrophylla   ( Willd. ) Kuntze \n Moghania semialata   (W.T.Aiton) Mukerjee"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13220", "text": "Flemingia macrophylla  is a tropical woody  leguminous   shrub  in the family  Fabaceae . It is a multipurpose plant widely used in  agriculture ,  crop  improvement,  fodder ,  dyes  and for various  therapeutic  purposes.  Perhaps, it is the most versatile species of  Flemingia  in terms of  adaptation , medicinal and agricultural applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13221", "text": "Flemingia macrophylla  is a woody,  perennial , deep-rooting, and leafy shrub. It is about 0.6-2.4 m high (rarely 3 m).  The main  stem  is  prostrate  or erect, with numerous stems arising from a single base.  The young branches are greenish, ribbed, triangular in section and silky; while the old stems are brown, almost round in section. The leaves are  trifoliate .  leaflets  are papery, with a glabrous upper surface.  Inflorescences  are densely spicate- racemose  or paniculate, and  bracts  are foliaceous or dry, persistent or  deciduous . Pods are small and turn brown when ripening; they are  dehiscent , generally with two shiny black seeds in the vessel. Seeds are globular, 2\u20133\u00a0mm in diameter, and shiny black. The leaves are disproportionately large, hence origin of the  specific name ,  macrophylla  meaning \u2018large leaved\u2019 (Greek  makros  = large;  phyllon  = leaf). [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13222", "text": "It is a native plant of subhumid to humid (sub-)  tropics  where average annual rainfall is typically 1100\u20133500\u00a0mm with up to 6 dry months,  at  altitude  up to 2000 m above  msl . Thus its natural habitat is found in Asia including Bhutan, southern China, Cambodia, India, Indonesia, Laos, Myanmar, Malaysia, Nepal, northern Pakistan, Papua New Guinea, Philippines, Sri Lanka, Taiwan, Thailand and Vietnam.  It has been  cultivated  and  naturalised  in  sub-Saharan Africa  (such as C\u00f4te d'Ivoire, Ghana, Nigeria, Cameroon), Central and South America (e.g. Costa Rica, Panama, Colombia), and tropical Australia. [ 1 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13223", "text": "Its natural habitat is often in shaded locations, scrub,  woodlands ,  grasslands , gallery forest edges and alike, and on soils with fertility ranging from very low to intermediate (and even high) acidic contents. The shrubs are mostly seen under trees along watercourses and in  grasslands , on  clay  and  lateritic   soils . The plant is tolerant of light shade and is moderately able to survive fires. It can tolerate fairly long dry spells and is capable of surviving on very poorly drained soils with  waterlogging . It can strive well on a wide variety of soils within a  pH  range from 4\u20138, and high soluble  aluminium  (80% saturation). It requires a minimum rainfall of about 1,100\u00a0mm, and up to 3,500\u00a0mm/year for normal propagation, and is very  drought  tolerant. It can flower and fruit throughout the year. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13224", "text": "A number of  bioactive  compounds have been reported from  F. macrophylla . Like other members of  Fabaceae , it is rich in  Flavonoids .  Genistein , 5, 7,3\u2019, 4\u2019-tetrahydroxyisoflavone, 5, 7, 4\u2019-trihydroxyisoflavone-7-O-\u03b2-D-glucopyranoside, 5, 7,4\u2019-trihydroxy-8,3\u2019-diprenylflavanone, 5, 7,4\u2019-trihydroxy-6-prenylisoflavone, flemichin D, lespedezaflavanone A and ouratea-catechin are isolated from the root, in which genistein and its  isoflavones  analogs are the main constituents. [ 5 ] [ 6 ]  A novel  flavanone , named fleminone,  was isolated from a petrol extract of the stems. [ 7 ]   A new isoflavone, called flemiphyllin was also isolated. [ 8 ]  Three new flavonoids, fleminginin (1), flemingichromone (2), and flemingichalcone (3), and other twenty known compounds were isolated from the aerial parts. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13225", "text": "Flemingia macrophylla  is used in a variety of agricultural practices and by-products. Due to slow decomposition rate of its leaves, along with its dense growth, moderate drought tolerance, ability to withstand occasional  flooding , and  coppicing  ability, it is commonly used for  mulching ,  weed control  and  sod  protection. It is most commonly used in contour hedgerows for  erosion  control, often in association with  Desmodium cinereum .  Prunings are used for  mulch   and green  manure  in alley cropping systems. [ 1 ] [ 2 ]  Probably the most interesting feature of the species is the relative resistance of its leaves to decomposition. It is experimentally demonstrated that  F. macrophylla  is superior over the common  Leucaena leucocephala  as mulch for  plantain  production. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13226", "text": "It is also often used to shade young  coffee  and  cocoa  plants, for weed suppression and soil enrichment in  orchards , and to provide  fuel wood  and stakes for climbing crop species.  However, it is considered a poor  forage  since its leaves have a high  fibre  and  condensed tannin  concentrations and is not readily eaten by stock.  Yet it is used as dietary supplement by mixing with grasses and other legumes, particularly during dry season when regular forages are scarce. [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13227", "text": "In India it is used as a host plant to the  Lac insect , and is sometimes  intercropped  with food crops during its establishment period. It is also one of the major sources of the  resinous  powder, called in Arabic  \u0648\u0631\u0633  ( wars ), with variants  waras ,  wurs  and  wurus , obtained from fruits of the plant. It is a coarse purple or orange-brown powder, consisting of the glandular hairs rubbed from the dry pods, principally used for  dyeing   silk  to brilliant orange color; the active compound for it is flemingin. In  Arabia , the powder is used as cosmetic. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13228", "text": "Extracts from  Flemingia  species have been used as a traditional medicine for treating  rheumatism . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13229", "text": "Flemingia procumbens   Roxb. \n Moghania procumbens   (Roxb.) Mukerjee \n Moghania vestita   (Benth.) ex Baker Kuntze"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13230", "text": "Flemingia vestita ,  famously known as  sohphlang , is a  nitrogen fixing   herb  with characteristic  tuberous  root, belonging to the  genus   Flemingia .  The root is edible and is a common vegetable in some  Asian   tribal  communities. In addition, it has been traditionally used as an  anthelmintic , the basis of which is scientifically validated."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13231", "text": "It is found as a wild herb along the mountain slopes of  Himalayas . It is distributed in  Sichuan  and  Yunnan  provinces of  China ,  Nepal  and  Khasi hills ,  Jaintia Hills  of  Meghalaya  in Northeast  India . It is also sparsely found in  Laos ,  Philippines  and  Vietnam . [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13232", "text": "Flemingia vestita  is a  perennial  herb, having a prostrate but weak  stem , measuring about ~60\u00a0cm in average. It is highly branched with hairy  rhizome  and  hirsute  stems. The roots are tuberous (6\u00a0cm or longer). Leaves are  pinnately  compound with obovate-cuneate leaflets. Leaves are  digitately  3-foliolate; and also pubescent like the stem. Lateral leaflets are obliquely  elliptic , and slightly smaller.  Raceme  is axillary or terminal, about 2\u201310\u00a0cm, and densely pubescent;  bracts   lanceolate .  Calyx  is 5-lobed; lobes are linear-lanceolate, lower one is longest, longer than the tube.  Corolla  is slightly longer than calyx and elliptical. Fruits are hairy sub-cylindrical pods.  Seed  is  globose , brown or black in colour. Flowers are bright-red. It flowers during August and September. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13233", "text": "It is rich in bioactive  isoflavones  such as  genistein ,  daidzein ,  formononetin  and  pseudobaptigenin . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13234", "text": "This juicy tuber is a highly priced food   among the  Garo ,  Khasi  and  Jaintia  tribes of  Meghalaya , India. In fact its demand as foodstuff has increased so much that it has been cultivated as a  cash crop  and is regularly available in the local markets. [ 1 ]  The delicate skin is easily peeled off to expose a smooth cream-coloured flesh that has a sweet, nut-like flavour. In terms of nutritional value, it is particularly rich in  phosphorus  and  proteins ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13235", "text": "The tuber has been an indigenous  vermifuge  among the Khasis, to whom it is called  soh-phlang . The raw tuber or the root peel is directly consumed for the treatment of  soft-bodied   intestinal worms . [ 6 ]  Experimental investigation started in 1996 when the  in vitro  activity of tuber peel extract was tested against different  helminth  parasites, including the  nematodes  such as  Ascaris suum ,  Ascaris lumbricoides ,  Ascaridia galli ,  Heterakis gallinarum , a  cestode   Raillietina echinobothrida  and  trematodes  such as  Paramphistomum  sp., [ 7 ]   Artyfechinostomum sufrartyfex  and  Fasciolopsis buski . [ 8 ]  In 1991 an  isoflavone , genistein was isolated from the tuber extract [ 5 ]  which was demonstrated to be the major anthelmintic principle, highly potent against trematodes and cestodes. It was further demonstrated effective against the sheep liver fluke  Fasciola hepatica [ 9 ]  and  human tapeworms  such as  Echinococcus multilocularis  and  E. granulosus  metacestodes. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13236", "text": "Its property of nitrogen fixation has been put to experimental use. Mixed cropping with  F. vestita  was found to give better economic returns, mainly due to improved soil fertility with a net gain in  nitrogen  of up to 250\u00a0kg/ha/year. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13237", "text": "A traditional  glycerite  is a  fluid extract  of an herb or other medicinal substance made using  glycerin  as the majority of the fluid extraction medium."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13238", "text": "According to  King's American Dispensatory  (1898), glycerite is:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13239", "text": "Glycerita.\u2014Glycerites.\nBy this class of preparations is generally understood solutions of medicinal substances in glycerin, although in certain instances the various Pharmacopoeias deviate to an extent. The term Glycerita as here applied to fluid glycerines, or solutions of agents in glycerin, is preferable to the ordinary names, \"glyceroles,\" \"glycerates,\" or \"glycemates,\" etc., and includes all fluid preparations of the kind referred to, whether for internal administration or local application. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13240", "text": "Glycerites may consist of either  vegetable  source glycerin,  animal  source glycerin or a combination of the two.  In the case of liquid herbal products (a segment of the dietary supplements industry), the general rule is to utilize vegetable glycerin only, while  nutraceuticals  (another segment of the dietary supplements industry) might use a combination of both vegetable and animal source derived glycerin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13241", "text": "Alcohol-free (as opposed to alcohol-removed) glycerite products, in which alcohol is never used or added at any time, are preferred by those desiring or requiring that no alcohol be used in making products or added thereafter. The reasons are typically for personal or religious beliefs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13242", "text": "Muslims  for instance, represent the largest population requiring an alcohol-free standard.  Halal , the Islamic dietary law, lists alcohol as one of the 'explicitly forbidden substances' (called  Haram ) in which anything made with and/or at any time containing alcohol is forbidden.  USP grade  vegetable glycerin is acceptable for Halal certifying and in some instances a Halal standard may (but not always) accept  Kosher  certified USP Grade vegetable glycerin as meeting Halal standards (i.e. to be Halal 'compliant'). Where the issue of Halal Alcohol-Free versus Haram Alcohol-Removed glycerites is concerned, even though U.S. FDA Title 21 rules forbid referring to or labeling a product as being 'Alcohol-Free' that has at any time come into contact with alcohol, the Islamic community has taken the stance that products listed as alcohol-free often does not always mean \"Alcohol-Free\" as defined by Halal standards or U.S. FDA Title 21 rules, since many products listed as alcohol-free may in fact have been made using alcohol as an ingredient after which the alcohol is removed, which would still make any such products Haram by Islamic Dietary Law and in breach of U.S. FDA Title 21 labeling rules. The Islamic community is therefore encouraged to first ascertain whether a botanical glycerite is actually Halal 'Alcohol-Free' (e.g. Halal Certified or Halal compliant) or is Haram 'Alcohol-Removed' with glycerin thereafter added."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13243", "text": "Glycorandomization , is a  drug discovery  and  drug development  technology platform to enable the rapid diversification of bioactive small molecules, drug leads and/or approved drugs through the attachment of sugars. Initially developed as a facile method to manipulate carbohydrate substitutions of naturally occurring glycosides to afford the corresponding differentially glycosylated  natural product  libraries, [ 1 ] [ 2 ] [ 3 ]  glycorandomization  applications have expanded to include both small molecules (drug leads and approved drugs) and even macromolecules ( proteins ). [ 4 ]  Also referred to as 'glycodiversification', [ 5 ]  glycorandomization has led to the discovery of new glycoside analogs which display improvements in potency, selectivity and/or  ADMET  as compared to the parent molecule."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13244", "text": "The traditional method for attaching sugars to natural products, drugs or drug leads is by  chemical glycosylation . This classical approach typically requires multiple protection/deprotection steps in addition to the key anomeric activation/coupling reaction which, depending upon the glycosyl donor/acceptor pair, can lead to a mixture of  anomers . Unlike classical chemical glycosylation, glycorandomization methods are divergent ( i.e. , diverge from a common starting material, see  divergent synthesis ) and are not dependent upon sugar/ aglycon  protection/deprotection or sugar anomeric activation. Two complementary strategies to achieve glycorandomization/diversification have been developed: an enzyme-based strategy referred to as 'chemoenzymatic glycorandomization' and a chemoselective method known as 'neoglycorandomization'. Both methods start with free  reducing sugars  and a target  aglycon  to afford a library of compounds which differ solely by the sugars appended to the target natural product, drug or drug lead."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13245", "text": "Chemoenzymatic glycorandomization was inspired by the early pathway engineering work of Hutchinson and coworkers that suggested natural product glycosyltransferases were capable of utilizing non-native sugar nucleotide donors. [ 6 ]  The initial platform for chemoenzymatic glycorandomization was based upon a set of two highly permissive sugar activation enzymes (a sugar anomeric  kinase  and sugar-1-phosphate  nucleotidyltransferase ) to afford sugar nucleotide libraries as donors for these promiscuous  glycosyltransferases  where the permissivity of the corresponding sugar kinase [ 7 ]  and nucleotidyltransferase [ 8 ] [ 9 ]  was expanded by  enzyme engineering  and  directed evolution . The first application of this three enzyme (kinase, nucleotidyltransferase and glycosyltransferase) strategy enabled the product of a set of >30 differentially glycosylated  vancomycins , some members of which were further diversified chemoselectively by virtue of the installation of sugars bearing chemoselective handles. [ 10 ] [ 11 ] [ 12 ]  This enzymatic platform has been further advanced through glycosyltransferase evolution [ 13 ]  and capitalizing upon the discovery of the reversibility of glycosyltransferase-catalyzed reactions first discovered in the context of  calicheamicin  biosynthesis. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13246", "text": "Neoglycorandomization is a chemoselective glycodiversification method inspired by the alkoxyamine-based \u2018neoglycosylation\u2019 reaction first described Peri and Dumy. [ 16 ]  This reaction proceeds via an oxy-iminium intermediate to ultimately provide the more thermodynamically-favored closed ring neoglycoside. The neoglycosylation reaction is compatible with a wide range of saccharide and aglycon functionality where neoglycoside anomeric stereospecificity is a thermodynamically-driven. Importantly, structural and functional studies reveal neoglycosides to serve as good mimics of their  O -glycosidic comparators. The first neoglycorandomization proof of concept focused upon  digitoxin  where the rapid generation and cancer cell line cytotoxicity screening of 78 digitoxigenin neoglycosides revealed unique analogs with improved anticancer activity and reduced potential for cardiotoxicity. [ 17 ]  This platform has since been automated and used as an effective medicinal chemistry tool to modulate the properties of a range of  natural products  and  pharmaceutical drugs . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13247", "text": "Both chemoenzymatic glycorandomization and neoglycorandomization use free reducing sugars and unprotected aglycons and are thereby a notable advance over classical glycosylation methods. A notable advantage of the enzymatic approach is the use of the corresponding genes encoding for the permissive kinases, nucleotidyltransferases and/or glycosyltransferases for in vivo  synthetic biology  applications to afford in vivo glycorandomization. [ 19 ]  However, it is important to note the enzymatic platform is dependent upon the permissivity of the enzymes employed. In contrast, the main hurdle to chemoselective neoglycorandomization is installation of the alkoxylamine handle. Unlike the enzymatic approach, the anomeric stereoselectivity of the chemoselective method depends upon the reducing sugar used and can, in some cases, lead to anomeric mixtures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13248", "text": "Glycorandomization is used in the  pharmaceutical industry  and academic community to alter glycosylation patterns of sugar-containing natural products or to append sugars to drugs/drug leads. It provides a fast way to investigate the effect of subtle sugar modification on the pharmacological properties of the natural products analogues, [ 20 ]  thus, affording a new approach to drug discovery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13249", "text": "Herbal distillates , also known as  floral waters ,  hydrosols ,  hydrolates ,  herbal waters , and  essential waters , [ 1 ]  are aqueous products of  hydrodistillation . They are  colloidal suspensions  of  essential oils  as well as  water-soluble  components obtained by  steam distillation  or hydrodistillation (a variant of steam distillation) from plants and herbs. These herbal distillates have uses as  flavorings  and  cosmetics . Common herbal distillates for  skincare  include  rose water , [ 2 ]   orange flower water , [ 3 ]  and  witch hazel . [ 4 ]   Rosemary , [ 5 ]   oregano , [ 6 ]  and  thyme [ 7 ]  are hydrosols that may be used in  food manufacturing  industries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13250", "text": "Herbal distillates are produced in the same or similar manner as essential oils. However, essential oils will float to the top of the distillate where it can be removed, leaving behind the watery distillate. For this reason, the term  essential water  is an apt description. In the past, these essential waters were often considered a byproduct of distillation, but are now considered an important co-product. [ 8 ]  The produced herbal waters are essentially diluted essential oils at less than 1% concentration (typically 0.02% to 0.05%). [ 9 ]  Several factors, such as temperature and a herb's growth cycle, impact the characteristics of a distillate, and therefore influence the timing of the distillation. Rosemary, for example, should be distilled in the peak of  summer  before it flowers. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13251", "text": "1. Food industry:  Herbal distillates are often used in culinary applications to add subtle flavors to foods and beverages. Their mild nature makes them ideal for infusing delicate flavors into dishes without the overpowering intensity of essential oils. Commonly used distillates in this context include rose water, orange blossom water, and peppermint hydrosol. Herbal distillates are also used to preserve food, and have been shown to be effective in achieving desirable effects, like reducing the degree of oxidation of some meats. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13252", "text": "2. Cosmetics:  In the cosmetic industry, herbal distillates are prized for their gentle, skin-friendly properties. They are used in a variety of products, including:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13253", "text": "3. Herbal Treatments:  Herbal distillates are also employed in traditional and  holistic medicine  for their therapeutic benefits. Due to their lower concentration compared to essential oils, they are often used for:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13254", "text": "4. Agriculture:  Herbal distillates are also used as insecticides, herbicides, and antibacterial and antifungal agents in agriculture. Additionally, herbal distillates may be used in  allelopathy , with possible applications including the manipulation of the timing of sprouting (see  vivipary ) and  germination . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13255", "text": "5. Clothing:  Herbal distillates can be added to water in a  clothes iron  to add a delicate scent into clothing. Since herbal distillates do not contain hard minerals such as  plastic  and  metal , [ 13 ]  it will also help keep clothing irons working properly for much longer. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13256", "text": "The science of  distillation  is based on the fact that different substances  evaporate  at different temperatures. Unlike other extraction techniques based on  solubility  of a compound in either  water  or  oil , distillation will separate components regardless of their solubility. The distillate will contain compounds that vaporize at or below the temperature of distillation. The actual chemical components of these orange herbal distillates have not yet been fully identified, but plant distillates will usually contain essential oil compounds as well as organic acids and other water-soluble plant components. Compounds with a higher vaporization point will remain behind and will include many of the water-soluble  plant   pigments  and  flavonoids . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13257", "text": "Because hydrosols are produced at high temperatures and are somewhat acidic, they tend to inhibit  bacterial growth  but not  fungal growth . They are not  sterile , and should be kept refrigerated to preserve freshness. [ 15 ]  Herbal distillates degrade over time and will degrade faster than essential oils, which are more stable. [ 16 ]  Small-scale producers of hydrosols must be particularly aware of the risk of bacterial contamination and take steps to prevent it. Despite concerns that there may be significant amounts of  heavy metals  in popular herbal distillates, this has not shown to be the case. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13258", "text": "Iberogast , also known as  STW5 , is a liquid formulation of nine  herbs  used for  functional dyspepsia  and  irritable bowel syndrome .  A proprietary blend, it was developed in Germany in 1961 and is available (without prescription) in other countries.  Named after the genus ( Iberis ) of one of its ingredients, it is also claimed to possess  anti-inflammatory ,  antioxidative  and  free radical \u2013inhibiting properties as well as the ability to reduce  gastric acid  secretion. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13259", "text": "Iberogast is a mixture of extracts from bitter candytuft ( Iberis amara ), angelica root ( Angelicae radix ), milk thistle fruit ( Silybi mariani fructus ), celandine herb ( Chelidonium majus ), caraway fruit ( Carvi fructus ), liquorice root ( Liquiritiae radix ), peppermint herb ( Menthae piperitae folium ), balm leaf ( Melissae folium ), and chamomile flower ( Matricariae flos ). [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13260", "text": "A 2004  meta-analysis  comprising three randomized placebo-controlled studies with a total of 173 patients suggested that iberogast was more effective than placebo in relieving \"the most bothersome gastrointestinal symptom\" of  functional dyspepsia  as identified by each patient. Additionally, a single  reference-controlled study  was discussed, comparing iberogast to the prokinetic cisapride in the treatment of \"'functional dyspepsia of the dysmotility type'\" and finding no significant differences in efficacy or tolerability. This paper noted that, while iberogast seems to consistently provide symptomatic relief to patients, its efficacy is more evident \"with associated symptoms of  gastro-oesophageal reflux  or predominance of epigastric pain.\" It suggests a synergy of therapeutic mechanisms provided by the complex interactions between the GI tract and each individual component of iberogast. It also supports a promising safety profile for the formulation, but notes that its results must be confirmed in larger studies in order to provide any recommendations regarding the efficacy or safety of iberogast in the treatment of functional dyspepsia. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13261", "text": "In Germany, Iberogast has come under investigation after one patient died of liver failure. In 2018, the company producing Iberogast ( Bayer ) has been forced by authorities to print warnings about rare cases of liver toxicity. A former employee of Bayer was under criminal investigation related to Bayer's long resistance to declare the dangers of Iberogast. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13262", "text": "The  Boletin latinoamericano y del caribe de plantas medicinales y aromaticas  (English:  Latin American and Caribbean Bulletin of Medicinal and Aromatic Plants ) is a bimonthly  peer-reviewed   scientific journal  covering research on all aspects of  medicinal  and  aromatic plants . Articles are published in Spanish or English. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13263", "text": "The journal was established in 2002 as a communication tool to keep the Latin-American community informed on events and news related to medicinal and aromatic plants taking place around the world. This primary objective is still achieved by means of the so-called \"supplements\" issued in between each bulletin. The official launch of the publication took place in  Buenos Aires, Argentina , during the first  Latin-American Congress of Phytochemistry ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13264", "text": "The journal started to publish scientific contributions during its second year of publication. In 2007, the journal officially changed from a newsletter format to a more traditional journal format, typically publishing more than five original papers per issue. Articles are published under a  Creative Commons Attribution  license and access to its repository is free."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13265", "text": "Congreso Latinoamericano de Plantas Medicinales"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13266", "text": "This article about a  botany   journal  is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13267", "text": "Malabathrum ,  malabathron , or  malobathrum  is the name used in classical and medieval texts for certain  cinnamon -like aromatic plant leaves and an ointment prepared from those leaves.  Cinnamomum tamala  (sometimes given as  Cinnamomum tejpata ), grown most commonly in the eastern Himalayas, but also in the Western Ghats, is thought to be a notable source of these leaves, [ 1 ]  although other species of  Cinnamomum  and even plants in other genera [ 2 ]  may have been used. In ancient  Greece  and  Rome , the leaves were used to prepare a fragrant oil, called  oleum malabathri , and were therefore valuable."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13268", "text": "Malabathrum is mentioned in the first century  Greek  text  Periplus Maris Erythraei  and sourced to a people called 'S\u00easatai', identified with Kirradai ( Kirata ) of Ptolemy. [ 3 ]  Though malabathrum was a product of  Northeast India , it was rarely traded by the western traders at the mouth of the Ganges (which is much closer to the source) but at southwestern Indian ports of  Muziris / Nelcynda . [ 4 ]  It is mentioned in the  Periplus  that some people collected the green leaves after the S\u00easatai in the northeast prepared them and carried them to the ports of trade. [ 5 ]  In the language of Kerala, Malayalam, the plant is called  vazhana . It is also known as  edana  in Malayalam. The name malabathrum is used in mediaeval texts to describe the dried leaves of a number of trees of the genus  Cinnamomum , which were thought to have  medicinal  properties. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13269", "text": "The Greeks used  k\u00e1sia  ( cassia ) or  malabathron  to flavour wine, with absinth wormwood ( Artemisia absinthium ). Malabathrum leaves ( folia ) were used in cooking and for distilling an oil used in a caraway-sauce for oysters by the Roman gourmet Gaius Gavius  Apicius . [ 6 ]  Malabathrum is among the spices that, according to Apicius, any good kitchen should contain."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13270", "text": "Malabathrum from Egypt (Dioscorides I, 63) was based on beef fat and contained cinnamon, as well; one pound cost 300  denarii ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13271", "text": "The word \"malabathrum\" is the Hellenization of the  Sanskrit  word  tam\u0101lapattram  (\u0924\u092e\u093e\u0932\u092a\u0924\u094d\u0924\u094d\u0930\u092e\u094d), literally meaning \"dark-tree leaves\", with the  ta  being mistaken for the Greek definite article. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13272", "text": "Marine  pharmacognosy  is the investigation and identification of medically important plants and animals in the marine environment. It is a sub branch of terrestrial pharmacognosy. Generally the drugs are obtained from the marine species of bacteria, virus, algae, fungi and sponges. It is a relatively new field of study in western medicine, although many marine organisms were used in  traditional Chinese medicine . It was not until 2004 that the first FDA approval of a drug came directly from the sea:  ziconotide , which was isolated from a marine cone snail."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13273", "text": "With 79% of the Earth's surface covered by water, research into the chemistry of marine organisms is relatively unexplored and represents a vast resource for new medicines to combat major diseases such as  cancer ,  AIDS  or  malaria . Research typically focuses on sessile organisms or slow moving animals because of their inherent need for chemical defenses."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13274", "text": "Standard research involves an extraction of the organism in a suitable solvent followed by either an assay of this crude extract for a particular disease target or a rationally guided isolation of new chemical compounds using standard  chromatography  techniques."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13275", "text": "Over 70% of the Earth's surface is covered by oceans which contain 95% of the Earth's biosphere. [ 1 ]  It was over 3500 million years ago that organisms first appeared in the sea. Over time, they have evolved many different mechanisms to survive the various harsh environments which include extreme temperatures, salinity, pressure, different levels of aeration and radiation, overcoming effects of mutation, and combating infection, fouling and overgrowth by other organisms. [ 1 ] [ 2 ]  Adaptations to survive the different environments could be by physical or chemical adaptation. Organisms with no apparent physical defense, like  sessile  organisms, are believed to have evolved chemical defenses to protect themselves. [ 1 ]  It is also believed that the compounds would have to be extremely potent due to the dilution effect of seawater. This has been described to be analogues to pheromones but with the purpose of repelling instead of attracting. [ 3 ]  As well, predators have evolved chemical weapons in order to paralyze or kill prey.  Conus magus  is an example of a cone snail that has a poisoned harpoon-like projectile which it uses to paralyze prey like small fish. [ 4 ]  Some organisms, like the  Viperfish , are believed to attract small fish or prey by using its  photophore . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13276", "text": "Many different marine organisms have been explored for bioactive compounds. Some vertebrate animals include fish, sharks and snakes. Some examples of invertebrates are sponges, coelenterates, tunicates, echinoderms, corals, algae, molluscs and bryozoans. Some microorganisms include bacteria, fungi and cyanobacteria. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13277", "text": "There is an ongoing debate on what organisms are the actual true producers of some compounds. About 40% of the biomass of sponges can be from microorganisms. It's not surprising that some compounds may actually be produced by symbiotic microorganisms rather than the host."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13278", "text": "Marine environments are considered more biologically diverse than terrestrial environments. [ 4 ] [ 7 ]  Thirty-two different animal phyla are represented in the oceans of the 33 recognized phyla. Fifteen different phyla are represented only in marine environments, while only 1 is exclusively terrestrial. Marine phyla also contain functionally unique organisms such as filter feeders and sessile organisms which have no terrestrial counterpart. Also, marine autotrophs are more diverse than their terrestrial counterparts this is extremely important. Marine autotrophs are believed to stem from at least 8 ancient clades while terrestrial organisms mainly stem from one clade,  Embyrophyta . [ 7 ]  Marine environments may contain over 80% of the world's plant and animal species. [ 6 ]  The diversity of coral reefs can be extraordinary with species diversity reaching 1000 species per meter squared. The greatest marine tropical biodiversity is reported to be in the Indo-Pacific Ocean. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13279", "text": "Collecting marine samples can range from very simple and inexpensive to very complicated expensive. Samples from near or on shores are readily accessible via  beach combing ,  wading  or  snorkeling . [ 3 ] [ 9 ]  Sample collection from deep water can be completed via  dredging  however, this is a very invasive technique which destroys the local habitat, does not allow for repeated sampling from the same location and compromises sample integrity.  Corers  can be used for sediment sample collection from deep locations quickly, easily and inexpensively.  SCUBA diving  was introduced in the 1940s however, [ 3 ]  it was not widely used until it became popular in the 1970s. SCUBA diving is limited in the duration that divers can spend underwater when conducted from the surface. If prolonged dives were necessary, an underwater laboratory could be used.  Aquarius  is the only underwater laboratory dedicated to marine science. [ 10 ]  For sample collection from depths that cannot be achieved by SCUBA diving,  submersibles  may be used. Sample collection by submersibles can be extremely expensive with costs for a submersible, support ship, technicians and support staff ranging between $10,000 to $45,000 per day. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13280", "text": "For the isolation of biologically active compounds from organisms, several different steps need to be completed. The different steps required to obtain a biologically active compound are:  Extraction ,  chromatographic purification , dereplication,  structure elucidation  and  bioassay  testing. The steps do not have to follow that particular order and many steps may be completed simultaneously. In the first step, the sample may be  triturated  and  extracted  with a suitable solvent or  macerated . Some solvents used are  methanol : chloroform ,  ethanol ,  acetonitrile , or others. The purpose is to remove organic compounds that have a medium polarity which are considered more  \"drug-like\" . Ideally, polar compounds like  salts ,  peptides ,  sugars  as well as very non-polar compounds like  lipids  are left behind to simplify chromatography since they are not generally considered \"drug-like\". Drying of the sample could be completed before extraction by  lyophilisation  to remove any excess water and therefore limit the amount of highly polar compounds extracted."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13281", "text": "The next step depends on the methodology of individual laboratories. Bioassay-guided fractionation is a common method to find biologically active compounds. This involves testing the crude extract or preliminary fractions from chromatography in an assay or multiple assays, determining what fractions or crude extracts show activity in the specific assays, and further fractionating the active fractions or extracts. This step is than repeated where the new fractions are tested and the active fractions are further fractionated. This continues until the fraction only contains one compound. Dereplication is ideally performed as early as possible to determine if the active compound has been previously reported in order to prevent \"rediscovering\" a compound. This can be performed using  Liquid Chromatography- Mass Spectrometry  (LC-MS) data or  Nuclear Magnetic Resonance  (NMR) data obtained in the biological assay-guided process and then comparing the information to that found in databases of previously reported compounds."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13282", "text": "Structure elucidation is performed by using NMR data obtained of the compound and High Resolution Mass Spectrometry (HR-MS) Data.  Tandem Mass Spectrometry  can also be useful, especially for large molecules like  glycolipids ,  proteins ,  polysaccharides  or  peptides . Completed characterization for publication purposes may require  Infrared (IR) ,  Ultraviolet-visible (UV-vis) ,  specific rotation  and  melting point  data. Obtaining a  crystal structure  via  X-ray crystallography  can greatly accelerate and simplify structure elucidation however, obtaining crystals can be quite difficult."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13283", "text": "There are many different bioassays available for testing. There are  anticancer ,  antimicrobial ,  antiviral ,  anti-inflammatory ,  antiparasitic ,  anticholesterolemic , and many other differ assays. For  MTT assay  and  cytosolic   Lactate dehydrogenase (LDH)  release are common  cytotoxicity  or  cell viability assays ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13284", "text": "A common problem that plagues drug development is obtaining a sustainable supply of the compound. Compounds isolated from invertebrates can be difficult to obtain in sufficient quantity for clinical trials. Synthesis is an alternate source of the compound of interest if the compound is simple otherwise, it is generally not a viable alternative. Aqua culture is another alternative if the organism is readily grown otherwise, it may not be good sustainable source of a compound. Also, the small quantity the compound is usually found in from organisms makes this alternative even more expensive. For example,  ET-743  (INN name trabectedin, brand name Yondelis) can be isolated from the tunicate  Ecteinascidia turbinata  with a yield of 2 g per ton. [ 3 ]  This would require thousands of tons of tunicate to be grown and extracted to produce the kilograms of ET-743 that would be required for the treatment of thousands of people. Some success has been had in producing compounds of interest from microorganisms. Microorganisms can be used as a sustainable source for the production of compounds of interest. They can also be used for the production of intermediates so that semisynthesis can be used to produce the final compound. This has been achieved for ET-743 with the production of the intermediate Safracin B from  Pseudomonas fluoresens  and the subsequent semisynthesis into ET-743. This is currently the industrial production method for the production of Yondelis. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13285", "text": "\u03b1 Includes natural products or natural product derivatives or analogues;\n \u03b2 Number of active trials/number of total trials from  http://www.clinicaltrials.gov/  as of July 2011"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13286", "text": "Medical cannabis ,  medicinal cannabis  or  medical marijuana  ( MMJ ) refers to  cannabis products  and  cannabinoid molecules  that are  prescribed  by  physicians  for their patients. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The use of cannabis as medicine has a long history, but has not been as rigorously tested as other medicinal plants due to legal and governmental restrictions, resulting in limited  clinical research  to define the safety and efficacy of using cannabis to treat diseases. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13287", "text": "Preliminary evidence has indicated that cannabis might reduce  nausea  and  vomiting  during  chemotherapy  and reduce  chronic pain  and  muscle spasms . [ 6 ] [ 7 ]  Regarding non-inhaled cannabis or cannabinoids, a 2021 review found that it provided little relief against chronic pain and sleep disturbance, and caused several transient  adverse effects , such as cognitive impairment,  nausea , and  drowsiness . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13288", "text": "Short-term use increases the risk of minor and major adverse effects. [ 7 ]  Common side effects include  dizziness , feeling tired, vomiting, and  hallucinations . [ 7 ]  Long-term effects of cannabis are not clear. [ 7 ]  Concerns include memory and cognition problems, risk of addiction,  schizophrenia  in young people, and the risk of children taking it by accident. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13289", "text": "Many cultures have used cannabis for therapeutic purposes for thousands of years. [ 9 ]  Some American medical organizations have requested removal of cannabis from the list of  Schedule I controlled substances  maintained by the United States federal government, followed by regulatory and scientific review. [ 10 ] [ 11 ]  Others oppose its legalization, such as the  American Academy of Pediatrics . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13290", "text": "Medical cannabis can be administered through various methods, including  capsules ,  lozenges ,  tinctures ,  dermal patches , oral or dermal sprays,  cannabis edibles , and  vaporizing  or  smoking dried buds . Synthetic cannabinoids are available for prescription use in some countries, such as  synthetic delta-9-THC  and  nabilone . Countries that  allow the medical use of whole-plant cannabis  include Argentina, Australia, Canada, Chile, Colombia, Germany, Greece, Israel, Italy, the Netherlands, Peru, Poland, Portugal, Spain, and Uruguay. In the United States, 38 states and the District of Columbia have legalized cannabis for medical purposes, beginning with the passage of California's  Proposition 215  in 1996. [ 13 ]  Although cannabis remains prohibited for any use at the federal level, the  Rohrabacher\u2013Farr amendment  was enacted in December 2014, limiting the ability of federal law to be enforced in states where medical cannabis has been legalized."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13291", "text": "In the U.S., the  National Institute on Drug Abuse  defines medical cannabis as \"using the whole, unprocessed marijuana plant or its basic extracts to treat symptoms of illness and other conditions\". [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13292", "text": "A cannabis plant includes more than 400 different chemicals, of which about 70 are  cannabinoids . [ 15 ]  In comparison, typical government-approved medications contain only one or two chemicals. [ 15 ]  The number of active chemicals in cannabis is one reason why treatment with cannabis is difficult to classify and study. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13293", "text": "A 2014 review stated that the variations in ratio of CBD-to-THC in botanical and pharmaceutical preparations determines the therapeutic vs psychoactive effects (CBD attenuates THC's psychoactive effects [ 16 ] ) of cannabis products. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13294", "text": "Overall, research into the health effects of medical cannabis has been of low quality and it is not clear whether it is a useful treatment for any condition, or whether harms outweigh any benefit. [ 18 ]  There is no consistent evidence that it helps with  chronic pain  and  muscle spasms . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13295", "text": "Low quality evidence suggests its use for reducing  nausea  during  chemotherapy , improving appetite in  HIV/AIDS , improving sleep, and improving  tics  in  Tourette syndrome . [ 7 ]  When usual treatments are ineffective,  cannabinoids  have also been recommended for  anorexia ,  arthritis ,  glaucoma , [ 19 ]  and  migraine . [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13296", "text": "It is unclear whether American states might be able to mitigate the adverse effects of the  opioid epidemic  by prescribing medical cannabis as an alternative pain management drug. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13297", "text": "Cannabis should not be used in  pregnancy . [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13298", "text": "Research analyzing data from the National Health and Nutrition Examination Survey (NHANES) did not find significant differences in sleep duration between cannabis users and non-users. This suggests that while some individuals may perceive benefits from cannabis use in terms of sleep, it may not significantly change overall sleep patterns across the general population. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13299", "text": "A review of literature up to 2018 indicates that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia. CBD, a non-psychoactive component of cannabis, is of particular interest due to its potential to influence sleep without the psychoactive effects associated with tetrahydrocannabinol (THC). [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13300", "text": "Medical cannabis is somewhat effective in  chemotherapy-induced nausea and vomiting  (CINV) [ 6 ] [ 19 ]  and may be a reasonable option in those who do not improve following preferential treatment. [ 25 ]  Comparative studies have found cannabinoids to be more effective than some conventional antiemetics such as  prochlorperazine ,  promethazine , and  metoclopramide  in controlling CINV, [ 26 ]  but these are used less frequently because of side effects including dizziness, dysphoria, and hallucinations. [ 27 ] [ 28 ]  Long-term cannabis use may cause nausea and vomiting, a condition known as  cannabinoid hyperemesis syndrome  (CHS). [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13301", "text": "A 2016  Cochrane review  said that cannabinoids were \"probably effective\" in treating chemotherapy-induced nausea in children, but with a high side-effect profile (mainly drowsiness, dizziness, altered moods, and increased appetite). Less common side effects were \"ocular problems, orthostatic hypotension, muscle twitching, pruritus, vagueness, hallucinations, lightheadedness and dry mouth\". [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13302", "text": "Evidence is lacking for both efficacy and safety of cannabis and cannabinoids in treating patients with  HIV/AIDS  or for  anorexia  associated with AIDS. As of 2013, current studies suffer from the effects of bias, small sample size, and lack of long-term data. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13303", "text": "A 2021 review found little effect of using non-inhaled cannabis to relieve chronic pain. [ 8 ]  According to a 2019 systematic review, there have been inconsistent results of using cannabis for neuropathic pain, spasms associated with  multiple sclerosis  and pain from  rheumatic  disorders, but was not effective treating chronic cancer pain. The authors state that additional  randomized controlled trials  of different cannabis products are necessary to make conclusive recommendations. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13304", "text": "When cannabis is inhaled to relieve pain, blood levels of cannabinoids rise faster than when oral products are used, peaking within three minutes and attaining an analgesic effect in seven minutes. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13305", "text": "A 2011 review considered cannabis to be generally safe, [ 33 ]  and it appears safer than  opioids  in palliative care. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13306", "text": "A 2022 review concluded the pain relief experienced after using medical cannabis is due to the  placebo effect , especially given widespread media attention that sets the expectation for pain relief. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13307", "text": "Cannabis' efficacy is not clear in treating neurological problems, including  multiple sclerosis  (MS) and movement problems. [ 17 ]  Evidence also suggests that oral cannabis extract is effective for reducing patient-centered measures of spasticity. [ 17 ]  A trial of cannabis is deemed to be a reasonable option if other treatments have not been effective. [ 6 ] [ by whom? ]  Its use for MS is approved in ten countries. [ 6 ] [ 36 ] [ conflicted source? ]  A 2012 review found no problems with tolerance, abuse, or addiction. [ 37 ]   In the United States,  cannabidiol , one of the cannabinoids found in the marijuana plant, has been approved for treating two severe forms of epilepsy,  Lennox-Gastaut syndrome  and  Dravet syndrome . [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13308", "text": "A 2019 systematic review found that there is a lack of evidence that cannabinoids are effective in treating  depressive  or  anxiety disorders ,  attention-deficit hyperactivity disorder  (ADHD),  Tourette syndrome ,  post-traumatic stress disorder , or  psychosis . [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13309", "text": "Research indicates that cannabis, particularly CBD, may have anxiolytic (anxiety-reducing) effects. A study found that CBD significantly reduced anxiety during a simulated public speaking test for individuals with social anxiety disorder. However, the relationship between cannabis use and anxiety symptoms is complex, and while some users report relief, the overall evidence from observational studies and clinical trials remains inconclusive. Cannabis is often used by people to cope with anxiety, yet the efficacy and safety of cannabis for treating anxiety disorders is yet to be researched. [ 40 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13310", "text": "Cannabis use, especially at high doses, is associated with a higher risk of psychosis, particularly in individuals with a genetic predisposition to psychotic disorders like schizophrenia. Some studies have shown that cannabis can trigger a temporary psychotic episode, which may increase the risk of developing a psychotic disorder later. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13311", "text": "The impact of cannabis on depression is less clear. Some studies suggest a potential increase in depression risk among adolescents who use cannabis, though findings are inconsistent across studies. [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13312", "text": "There is insufficient data to draw strong conclusions about the safety of medical cannabis. [ 43 ]  Typically, adverse effects of medical cannabis use are not serious; [ 6 ]  they include tiredness, dizziness, increased appetite, and cardiovascular and psychoactive effects. Other effects can include impaired short-term memory; impaired motor coordination; altered judgment; and paranoia or psychosis at high doses. [ 44 ]  Tolerance to these effects develops over a period of days or weeks. The amount of cannabis normally used for medicinal purposes is not believed to cause any permanent cognitive impairment in adults, though long-term treatment in adolescents should be weighed carefully as they are more susceptible to these impairments. Withdrawal symptoms are rarely a problem with controlled medical administration of cannabinoids. The ability to drive vehicles or to operate machinery may be impaired until a tolerance is developed. [ 25 ]   Although supporters of medical cannabis say that it is safe, [ 43 ]  further research is required to assess the long-term safety of its use. [ 27 ] [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13313", "text": "Recreational use of cannabis is associated with cognitive deficits, especially for those who begin to use cannabis in adolescence. As of 2021 [update]  there is a lack of research into long-term cognitive effects of medical use of cannabis, but one 12-month observational study reported that \"MC patients demonstrated significant improvements on measures of  executive function  and clinical state over the course of 12 months\". [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13314", "text": "Exposure to THC can cause acute transient psychotic symptoms in healthy individuals and people with schizophrenia. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13315", "text": "A 2007 meta analysis concluded that cannabis use reduced the average age of onset of psychosis by 2.7 years relative to non-cannabis use. [ 47 ]   A 2005 meta analysis concluded that adolescent use of cannabis increases the risk of psychosis, and that the risk is dose-related. [ 48 ]  A 2004 literature review on the subject concluded that cannabis use is associated with a two-fold increase in the risk of psychosis, but that cannabis use is \"neither necessary nor sufficient\" to cause psychosis. [ 49 ]  A French review from 2009 came to a conclusion that cannabis use, particularly that before age 15, was a factor in the development of schizophrenic disorders. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13316", "text": "The  genus   Cannabis  contains two species which produce useful amounts of psychoactive cannabinoids:  Cannabis indica  and  Cannabis sativa , which are listed as Schedule I medicinal plants in the US; [ 6 ]  a third species,  Cannabis ruderalis , has few psychogenic properties. [ 6 ]  Cannabis contains more than 460 compounds; [ 9 ]  at least 80 of these are  cannabinoids [ 51 ] [ 52 ]  \u2013  chemical compounds  that interact with  cannabinoid receptors  in the brain. [ 6 ]  As of 2012, more than 20 cannabinoids were being studied by the U.S. FDA. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13317", "text": "The most psychoactive cannabinoid found in the cannabis plant is  tetrahydrocannabinol  (or delta-9-tetrahydrocannabinol, commonly known as THC). [ 9 ]  Other cannabinoids include  delta-8-tetrahydrocannabinol ,  cannabidiol  (CBD),  cannabinol  (CBN),  cannabicyclol  (CBL),  cannabichromene  (CBC) and  cannabigerol  (CBG); they have less psychotropic effects than THC, but may play a role in the overall effect of cannabis. [ 9 ]  The most studied are THC, CBD and CBN. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13318", "text": "CB1 and CB2 are the primary cannabinoid receptors responsible for several of the effects of cannabinoids, although other receptors may play a role as well. Both belong to a group of receptors called G protein-coupled receptors (GPCRs). CB1 receptors are found in very high levels in the brain and are thought to be responsible for psychoactive effects. [ 55 ]  CB2 receptors are found peripherally throughout the body and are thought to modulate pain and inflammation. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13319", "text": "Cannabinoid absorption is dependent on its route of administration."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13320", "text": "Inhaled and vaporized THC have similar absorption profiles to smoked THC, with a  bioavailability  ranging from 10 to 35%. Oral administration has the lowest bioavailability of approximately 6%, variable absorption depending on the vehicle used, and the longest time to peak plasma levels  (2 to 6 hours) compared to smoked or vaporized THC. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13321", "text": "Similar to THC, CBD has poor oral bioavailability, approximately 6%. The low bioavailability is largely attributed to significant first-pass metabolism in the liver and erratic absorption from the gastrointestinal tract. However, oral administration of CBD has a faster time to peak concentrations (2 hours) than THC. [ 57 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13322", "text": "Due to the poor bioavailability of oral preparations, alternative routes of administration have been studied, including sublingual and rectal. These alternative formulations maximize bioavailability and reduce first-pass metabolism. Sublingual administration in rabbits yielded bioavailability of 16% and time to peak concentration of 4 hours. [ 58 ]  Rectal administration in monkeys doubled bioavailability to 13.5% and achieved peak blood concentrations within 1 to 8 hours after administration. [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13323", "text": "Like cannabinoid absorption, distribution is also dependent on route of administration. Smoking and inhalation of vaporized cannabis have better absorption than do other routes of administration, and therefore also have more predictable distribution. [ 59 ] [ 60 ]  THC is highly protein bound once absorbed, with only 3% found unbound in the plasma. It distributes rapidly to highly vascularized organs such as the heart, lungs, liver, spleen, and kidneys, as well as to various glands. Low levels can be detected in the brain, testes, and unborn fetuses, all of which are protected from systemic circulation via barriers. [ 61 ]  THC further distributes into fatty tissues a few days after administration due to its high lipophilicity, and is found deposited in the spleen and fat after redistribution. [ 60 ] [ 62 ] [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13324", "text": "Delta-9-THC is the primary molecule responsible for the effects of cannabis. Delta-9-THC is metabolized in the liver and turns into 11-OH-THC. [ 64 ] \u00a011-OH-THC is the first metabolic product in this pathway. Both Delta-9-THC and 11-OH-THC are psychoactive. The metabolism of THC into 11-OH-THC plays a part in the heightened psychoactive effects of edible cannabis. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13325", "text": "Next, 11-OH-THC is metabolized in the liver into 11-COOH-THC, which is the second metabolic product of THC. [ 66 ] \u00a011-COOH-THC is not psychoactive. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13326", "text": "Ingestion of edible cannabis products lead to a slower onset of effect than the inhalation of it because the THC travels to the liver first through the blood before it travels to the rest of the body. Inhaled cannabis can result in THC going directly to the brain, where it then travels from the brain back to the liver in recirculation for metabolism. [ 64 ]  Eventually, both routes of metabolism result in the metabolism of psychoactive THC to inactive 11-COOH-THC."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13327", "text": "Due to substantial metabolism of THC and CBD, their metabolites are excreted mostly via  feces , rather than by urine. [ 57 ] [ 67 ]  After delta-9-THC is hydroxylated into 11-OH-THC via CYP2C9, CYP2C19, and CYP3A4, it undergoes phase II metabolism into more than 30 metabolites, a majority of which are products of  glucuronidation . Approximately 65% of THC is excreted in feces and 25% in the urine, while the remaining 10% is excreted by other means. [ 57 ]  The terminal half-life of THC is 25 to 36 hours, [ 68 ]  whereas for CBD it is 18 to 32 hours. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13328", "text": "CBD is hydroxylated by P450 liver enzymes into 7-OH-CBD. Its metabolites are products of primarily CYP2C19 and CYP3A4 activity, with potential activity of CYP1A1, CYP1A2, CYP2C9, and CYP2D6. [ 69 ]  Similar to delta-9-THC, a majority of CBD is excreted in feces and some in the urine. [ 57 ]  The terminal half-life is approximately 18\u201332 hours. [ 70 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13329", "text": "Smoking  has been the means of administration of cannabis for many users, but it is not suitable for the use of cannabis as a medicine. [ 71 ]  It was the most common method of medical cannabis consumption in the US as of 2013 [update] . [ 6 ]  It is difficult to predict the pharmacological response to cannabis because concentration of cannabinoids varies widely, as there are different ways of preparing it for consumption (smoked, applied as oils, eaten, infused into other foods,  or drunk) and a lack of production controls. [ 6 ]  The potential for adverse effects from smoke inhalation makes smoking a less viable option than oral preparations. [ 71 ]   Cannabis vaporizers  have gained popularity because of a perception among users that fewer harmful chemicals are ingested when components are inhaled via aerosol rather than smoke. [ 6 ]  Cannabinoid medicines are available in pill form ( dronabinol  and  nabilone ) and liquid extracts formulated into an oromucosal spray ( nabiximols ). [ 6 ]  Oral preparations are \"problematic due to the uptake of cannabinoids into fatty tissue, from which they are released slowly, and the significant first-pass liver metabolism, which breaks down \u03949THC and contributes further to the variability of plasma concentrations\". [ 71 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13330", "text": "The US Food and Drug Administration (FDA) has not approved smoked cannabis for any condition or disease, as it deems that evidence is lacking concerning safety and efficacy. [ 72 ]  The FDA issued a 2006 advisory against  smoked  medical cannabis stating: \"marijuana has a high potential for abuse, has no currently accepted medical use in treatment in the United States, and has a lack of accepted safety for use under medical supervision.\" [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13331", "text": "Cannabis, called  m\u00e1   \u9ebb  (meaning \"hemp; cannabis; numbness\") or  d\u00e0m\u00e1   \u5927\u9ebb  (with \"big; great\") in Chinese, was used in  Taiwan  for fiber starting about 10,000 years ago. [ 73 ]  The botanist  Hui-lin Li  wrote that in China, \"The use of Cannabis in medicine was probably a very early development. Since ancient humans used hemp seed as food, it was quite natural for them to also discover the medicinal properties of the plant.\" [ 74 ]  Emperor  Shen-Nung , who was also a pharmacologist, wrote a book on treatment methods in 2737 BCE that included the medical benefits of cannabis. He recommended the substance for many ailments, including constipation, gout, rheumatism, and absent-mindedness. [ 75 ]  Cannabis is one of the  50 \"fundamental\" herbs  in  traditional Chinese medicine . [ 76 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13332", "text": "The  Ebers Papyrus  ( c. \u20091550 BCE ) from  Ancient Egypt  describes medical cannabis. [ 77 ]  The ancient Egyptians used hemp (cannabis) in  suppositories  for relieving the pain of  hemorrhoids . [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13333", "text": "Surviving texts from  ancient India  confirm that cannabis' psychoactive properties were recognized, and doctors used it for treating a variety of illnesses and ailments, including insomnia, headaches, gastrointestinal disorders, and pain, including during childbirth. [ 79 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13334", "text": "The  Ancient Greeks  used cannabis to dress wounds and sores on their horses, [ 80 ]  and in humans, dried leaves of cannabis were used to treat nose bleeds, and cannabis seeds were used to expel tapeworms. [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13335", "text": "In the  medieval Islamic world ,  Arabic physicians  made use of the  diuretic ,  antiemetic ,  antiepileptic ,  anti-inflammatory ,  analgesic  and  antipyretic  properties of  Cannabis sativa , and used it extensively as medication from the 8th to 18th centuries. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13336", "text": "Cannabis seeds may have been used for food, rituals or religious practices in ancient Europe and China. [ 82 ] :\u200a19\u201322\u200a  Harvesting the plant led to the spread of cannabis throughout  Eurasia  about 10,000 to 5,000 years ago, with further distribution to the  Middle East  and Africa about 2,000 to 500 years ago. [ 82 ] :\u200a18\u201319\u200a  A  landrace   strain  of cannabis developed over centuries. [ 83 ]  They are cultivars of the plant that originated in one specific region."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13337", "text": "Widely cultivated strains of cannabis, such as \"Afghani\" or \"Hindu Kush\", are indigenous to the  Pakistan  and  Afghanistan  regions, while \"Durban Poison\" is native to Africa. [ 82 ] :\u200a45\u201348\u200a  There are approximately 16 landrace strains of cannabis identified from Pakistan, Jamaica, Africa, Mexico, Central America and Asia. [ 84 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13338", "text": "An Irish physician,  William Brooke O'Shaughnessy , is credited with introducing cannabis to Western medicine. [ 85 ]  O'Shaughnessy discovered cannabis in the 1830s while living abroad in  India , where he conducted numerous experiments investigating the drug's medical utility (noting in particular its  analgesic  and  anticonvulsant  effects). [ 86 ]   He returned to  England  with a supply of cannabis in 1842, after which its use spread through Europe and the United States. [ 87 ]   In 1845 French physician  Jacques-Joseph Moreau  published a book about the use of cannabis in psychiatry. [ 88 ]   In 1850 cannabis was entered into the  United States Pharmacopeia . [ 86 ]  An anecdotal report of  Cannabis indica  as a treatment for  tetanus  appeared in  Scientific American  in 1880. [ 89 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13339", "text": "The use of cannabis in medicine began to decline by the end of the 19th century, due to difficulty in controlling dosages and the rise in popularity of synthetic and  opium -derived drugs. [ 87 ]   Also, the advent of the hypodermic  syringe  allowed these drugs to be injected for immediate effect, in contrast to cannabis which is not water-soluble and therefore cannot be injected. [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13340", "text": "In the United States, the medical use of cannabis further declined with the passage of the  Marihuana Tax Act of 1937 , which imposed new regulations and fees on physicians prescribing cannabis. [ 90 ]   Cannabis was removed from the U.S. Pharmacopeia in 1941, and officially banned for any use with the passage of the  Controlled Substances Act  of 1970. [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13341", "text": "Cannabis began to attract renewed interest as medicine in the 1970s and 1980s, in particular due to its use by cancer and AIDS patients who reported relief from the effects of  chemotherapy  and  wasting syndrome . [ 91 ]   In 1996,  California  became the first U.S. state to legalize medical cannabis in defiance of federal law. [ 92 ]   In 2001,  Canada  became the first country to adopt a system regulating the medical use of cannabis. [ 93 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13342", "text": "Countries that have legalized the medical use of cannabis include  Argentina , [ 94 ]   Australia , [ 95 ]   Brazil , [ 96 ]   Canada , [ 97 ]   Chile , [ 97 ]   Colombia , [ 97 ]   Costa Rica , [ 98 ]   Croatia , [ 99 ]   Cyprus , [ 100 ]   Czech Republic , [ 97 ]   Finland , [ 101 ]   Germany , [ 102 ]   Greece , [ 103 ]   Israel , [ 104 ]   Italy , [ 105 ]   Jamaica , [ 106 ]   Lebanon , [ 107 ]   Luxembourg , [ 108 ]   Malta , [ 109 ]   Morocco , [ 110 ]  the  Netherlands , [ 97 ]   New Zealand , [ 111 ]   North Macedonia , [ 112 ]   Panama , [ 113 ]   Peru , [ 114 ]   Poland , [ 115 ]   Portugal , [ 116 ]   Rwanda , [ 117 ]   Sri Lanka , [ 118 ]   Switzerland , [ 119 ]   Thailand , [ 120 ]  the  United Kingdom , [ 121 ]  and  Uruguay . [ 97 ]   Other countries have more restrictive laws that allow only the use of isolated cannabinoid drugs such as  Sativex  or  Epidiolex . [ 122 ] [ 123 ]   Countries with the most relaxed policies include Canada, [ 124 ]  the Netherlands, [ 97 ]  Thailand, [ 125 ]  and Uruguay, [ 97 ]  where cannabis can be purchased without need for a prescription.  In  Mexico , THC content of medical cannabis is limited to one percent. [ 126 ]   In the  United States , the legality of medical cannabis varies by state. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13343", "text": "However, in many of these countries, access may not always be possible under the same conditions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13344", "text": "Cannabis and its derivatives are subject to regulation under three  United Nations   drug control treaties : the 1961  Single Convention on Narcotic Drugs , the 1971  Convention on Psychotropic Substances , and the 1988  Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances . [ 127 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13345", "text": "Cannabis and cannabis resin are classified as a Schedule I drug under the Single Convention treaty, meaning that medical use is considered \"indispensible for the relief of pain and suffering\" but that it is considered to be an addictive medication with risks of abuse. [ 128 ]  Countries have an obligation to provide access and sufficient availability of drugs listed in Schedule I for the purposes of medical uses. [ 129 ] [ 130 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13346", "text": "Prior to December 2020 cannabis and cannabis resin were also included in Schedule IV, a more restrictive level of control, which is for only the most dangerous drugs such as heroin and fentanyl. [ 131 ]  They were removed after an independent scientific assessment by the  World Health Organization  in 2018-1029."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13347", "text": "Member nations of the  UN Commission on Narcotic Drugs  voted 27\u201325 to remove it from Schedule IV on 2 December 2020, [ 132 ]  following a  World Health Organization  recommendation for removal in January 2019. [ 133 ] [ 134 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13348", "text": "In the United States, the use of cannabis for medical purposes is legal in 38 states, four out of five permanently inhabited  U.S. territories , and the  District of Columbia . [ 13 ]   An additional 10 states have more restrictive laws allowing the use of low-THC products. [ 13 ]   Cannabis remains illegal at the federal level under the  Controlled Substances Act , which classifies it as a Schedule I drug with a high potential for abuse and no accepted medical use.  In December 2014, however, the  Rohrabacher\u2013Farr amendment  was signed into law, prohibiting the  Justice Department  from prosecuting individuals acting in accordance with state medical cannabis laws. [ 135 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13349", "text": "In the US, the FDA has approved two oral cannabinoids for use as medicine in 1985: [ 136 ]   dronabinol  (pure delta-9-THC; brand name Marinol) and  nabilone  (a  synthetic neocannabinoid ; brand name Cesamet). [ 6 ]  In the US, they are both listed as Schedule II, indicating high potential for side effects and addiction. [ 53 ] [ 137 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13350", "text": "The method of obtaining medical cannabis varies by region and by legislation. In the US, most consumers grow their own or buy it from  cannabis dispensaries  in states where it is legal. [ 6 ] [ 138 ]   Marijuana vending machines  for selling or dispensing cannabis are in use in the United States and are planned to be used in Canada. [ 139 ]  In 2014, the startup Meadow began offering on-demand delivery of medical marijuana in the San Francisco Bay Area, through their mobile app. [ 140 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13351", "text": "Almost 70% of medical cannabis is exported from the United Kingdom, according to a 2017 United Nations report, with much of the remaining amount coming from Canada and the Netherlands. [ 141 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13352", "text": "In the United States, health insurance companies may not pay for a medical marijuana prescription as the  Food and Drug Administration  must approve any substance for medicinal purposes. Before this can happen, the FDA must first permit the study of the medical benefits and drawbacks of the substance, which it has not done since it was placed on Schedule I of the Controlled Substances Act in 1970. Therefore, all expenses incurred fulfilling a medical marijuana prescription will possibly be incurred as out-of-pocket. [ 142 ]   However, the  New Mexico Court of Appeals  has ruled that  workers' compensation  insurance must pay for prescribed marijuana as part of the state's Medical Cannabis Program. [ 143 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13353", "text": "Medical organizations that have issued statements in support of allowing access to medical cannabis include the  American Nurses Association , [ 10 ]   American Public Health Association , [ 144 ]   American Medical Student Association , [ 145 ]   National Multiple Sclerosis Society , [ 146 ]   Epilepsy Foundation , [ 147 ]  and  Leukemia & Lymphoma Society . [ 148 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13354", "text": "Organizations that oppose the legalization of medical cannabis include the  American Academy of Pediatrics  (AAP) [ 12 ]  and  American Psychiatric Association . [ 149 ]   However, the AAP also supports rescheduling for the purpose of facilitating research. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13355", "text": "The  American Medical Association [ 150 ]  and  American College of Physicians [ 151 ]  do not take a position on the legalization of medical cannabis, but have called for the Schedule I classification to be reviewed. The  American Academy of Family Physicians [ 11 ]  and  American Society of Addiction Medicine [ 152 ]  also do not take a position, but do support rescheduling to better facilitate research. The  American Heart Association  says that \"many of the concerning health implications of cannabis include cardiovascular diseases\" but that it supports rescheduling to allow \"more nuanced ... marijuana legislation and regulation\" and to \"reflect the existing science behind cannabis\". [ 153 ]   The  American Cancer Society [ 154 ]  and  American Psychological Association [ 155 ]  have noted the obstacles that exist for conducting research on cannabis, and have called on the federal government to better enable scientific study of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13356", "text": "Cancer Research UK  say that while cannabis is being studied for therapeutic potential, \"claims that there is solid \"proof\" that cannabis or cannabinoids can cure cancer is highly misleading to patients and their families, and builds a false picture of the state of progress in this area\". [ 156 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13357", "text": "There are three  International Nonproprietary Name  (INN) granted for cannabinoids: two plant-derived  phytocannabinoids  and one  neocannabinoid :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13358", "text": "Nabiximols  is the generic name (but not recognized as an INN) of a mixture of Cannabidiol and Dronabinol. Its most common form is the oromucosal spray derived from two strains of  Cannabis sativa  and containing THC and CBD traded under the brand name Sativex\u00ae. [ 53 ]  It is not approved in the United States, but is approved in several European countries, Canada, and New Zealand as of 2013. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13359", "text": "As an  antiemetic , these medications are usually used when conventional treatment for nausea and vomiting associated with cancer chemotherapy fail to work. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13360", "text": "Nabiximols  is used for treatment of spasticity associated with MS when other therapies have not worked, and when an initial trial demonstrates \"meaningful improvement\". [ 6 ]  Trials for FDA approval in the US are underway. [ 6 ]  It is also approved in several European countries for overactive bladder and  vomiting . [ 53 ]  When sold under the trade name Sativex as a mouth spray, the prescribed daily dose in Sweden delivers a maximum of 32.4\u00a0mg of  THC  and 30\u00a0mg of  CBD ; mild to moderate dizziness is common during the first few weeks. [ 162 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13361", "text": "Relative to inhaled consumption, peak concentration of oral THC is delayed, and it may be difficult to determine optimal dosage because of variability in patient absorption. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13362", "text": "In 1964, Albert Lockhart and  Manley West  began studying the health effects of traditional cannabis use in  Jamaican  communities. They developed, and in 1987 gained permission to market, the pharmaceutical \"Canasol\", one of the first cannabis extracts. [ 163 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13363", "text": "A 2022 review concluded that \"oral, synthetic cannabis products with high THC-to-CBD ratios and sublingual, extracted cannabis products with comparable THC-to-CBD ratios may be associated with short-term improvements in chronic pain and increased risk for dizziness and sedation.\" [ 164 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13364", "text": ", links to websites about medical cannabis"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13365", "text": "The  Medicines Discovery Catapult  ( MDC ) is the United Kingdom's  catapult centre  for medicine research and innovation, headquartered at  Alderley Park  in  Cheshire ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13366", "text": "The intention to form the company was announced by the Chancellor on 13 July 2015 with funding of \u00a35m, on a visit to Cheshire. It would be part of the  Northern Powerhouse  initiative. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13367", "text": "The Medicines Technologies Catapult was established in December 2015, [ 2 ]  funded by a \u00a310m grant from  Innovate UK  and based at the Alderley Park science park in Cheshire. [ 3 ]  On 1 March 2016 its name changed to the Medicines Discovery Catapult. [ 2 ]  Further funding of approximately \u00a310m per year was secured from Innovate UK for the years 2018 to 2023. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13368", "text": "The PMC was based in Cambridge and had regional centres of excellence at Belfast, Glasgow, Cardiff, Oxford, Leeds and Manchester. It worked with  precision medicine . It started from April 2015, and worked with regional parts of the Diagnostic Evidence Cooperative and  Academic Health Science Networks  (AHSN). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13369", "text": "On 26 June 2017 it was announced that the PMC would close, with most of its functions transferred to the MDC. [ 4 ]  The Leeds site is now the Leeds Centre for Personalised Medicine and Health."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13370", "text": "A not-for-profit company, the MDC works with a range of UK innovators to advance projects and products towards clinical impact. In 2019, the company stated that it worked in four sectors: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13371", "text": "In the same year, the number of staff increased from 40 to 75, and the company reported that its income comprised \u00a38.5m from Innovate UK and \u00a3152,000 from collaborative research and development. After charging \u00a37.1m to administrative expenses, the company reported a loss for the year of \u00a316,000. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13372", "text": "In 2020, the company was given the task of setting up one of the first PCR analysis centres for COVID-19 tests \u2013 known as  Lighthouse labs  \u2013 elsewhere at the Alderley Park site. [ 5 ] [ 6 ]  By 2021, this centre employed over 700 staff and had a stated capacity of 80,000 test samples per day. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13373", "text": "Dr Robin Brown has been the company's chairman since July 2018; [ 3 ]  he has a PhD in molecular biology and has worked in  venture capital  at  Advent Healthcare . [ 7 ]  The company has no shareholders. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13374", "text": "Previously, Professor Graham Boulnois was chairman from January 2016; he was head of research from 1992 to 2000 at  Zeneca Pharmaceuticals  in Cheshire, and Professor of Microbiology from 1984 to 1992 at the  University of Leicester . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13375", "text": "The  Nine Herbs Charm ,  Nigon Wyrta Galdor ,  Lay of the Nine Healing Herbs , or  Nine Wort Spell  (among other names) is an  Old English charm  recorded in the tenth century CE. [ 1 ]  It is part of the Anglo-Saxon medical compilation known as  Lacnunga , which survives in the manuscript Harley MS 585 in the British Library. [ 2 ]  The charm involves the preparation of nine plants."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13376", "text": "The poem contains one of two clear Old English mentions of the god  Woden  in Old English poetry; the other is  Maxims I  of the  Exeter Book .  Robert K. Gordon's  translation of the section reads as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13377", "text": "A snake came crawling, it bit a man. \nThen Woden took nine glory-twigs, \nSmote the serpent so that it flew into nine parts. \nThere apple brought this pass against poison, \nThat she nevermore would enter her house. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13378", "text": "Nine and three,  numbers significant in Germanic paganism  and later  Germanic folklore , are mentioned frequently throughout the charm. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13379", "text": "Scholars have proposed that this passage describes Woden coming to the assistance of the herbs through his use of nine twigs, each twig inscribed with the  runic  first-letter initial of a plant. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13380", "text": "According to Gordon, the poem is \"clearly an old heathen thing which has been subjected to Christian censorship.\" [ 1 ]  Malcolm Laurence Cameron states that chanting the poem aloud results in a \"marvellously incantatory effect\". [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13381", "text": "Paphiopedilum callosum  is a species of  orchid  found from  Vietnam  to northwestern  Peninsular Malaysia . It has been investigated and shown promising results in the treatment of cancer. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13382", "text": "This  Cypripedioideae -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13383", "text": "Pharmacognosy Communications  is a  peer-reviewed   open-access  pharmacy journal published by  EManuscript Services  on behalf of Pharmacognosy Network Worldwide. It is a quarterly publication edited by pharmacognosist Ian Edwin Cock,  Griffith University ,  Australia . It publishes articles on the subjects of  pharmacognosy ,  natural products ,  phytochemistry , and  phytomedicine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13384", "text": "The journal is indexed with CAB Abstracts,  Chemical Abstracts ,  EBSCO ,  Google Scholar , Index Copernicus, OpenJGate,  ProQuest , and  Ulrich's Periodicals Directory ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13385", "text": "Phcog.net (Pharmacognosy Network Worldwide) appeared on Beall's list from October 2012 [ 1 ]  through September 12, 2015. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13386", "text": "Pharmacognosy Research  is a  peer-reviewed   open-access   medical journal  published on behalf of the  Pharmacognosy Network Worldwide . The journal publishes articles on the subject of  pharmacognosy , natural products, and  phytochemistry  and is indexed with  CASPUR ,  EBSCO ,  ProQuest , and  Scopus ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13387", "text": "Pharmacognosy Reviews  is a  peer-reviewed   open-access   medical journal  published by Pharmacognosy Network Worldwide (Phcog.net). The journal publishes articles on the subject of  pharmacognosy , natural products, and  phytochemistry . It is indexed with Caspur,  EBSCO ,  ProQuest , and  Scopus ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13388", "text": "Phcog.net appeared on  Beall's list  of predatory open-access journals from October 2012 [ 1 ]  through September 12, 2015. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13389", "text": "Phytochemistry  is the study of  phytochemicals , which are chemicals derived from  plants . Phytochemists strive to describe the structures of the large number of  secondary metabolites  found in plants, the functions of these compounds in human and plant biology, and the biosynthesis of these compounds. Plants synthesize phytochemicals for many reasons, including to protect themselves against  insect  attacks and  plant diseases . The compounds found in plants are of many kinds, but most can be grouped into four major biosynthetic classes:  alkaloids ,  phenylpropanoids ,  polyketides , and  terpenoids ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13390", "text": "Phytochemistry can be considered a subfield of  botany  or  chemistry . Activities can be led in  botanical gardens  or in the wild with the aid of  ethnobotany . Phytochemical studies directed toward human (i.e. drug discovery) use may fall under the discipline of  pharmacognosy , whereas phytochemical studies focused on the ecological functions and evolution of phytochemicals likely fall under the discipline of  chemical ecology . Phytochemistry also has relevance to the field of  plant physiology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13391", "text": "Techniques commonly used in the field of phytochemistry are  extraction , isolation, and  structural elucidation  ( MS ,1D and 2D NMR) of  natural products , as well as various  chromatography  techniques (MPLC,  HPLC , and LC-MS)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13392", "text": "Many plants produce chemical compounds  for defence against herbivores . The major classes of pharmacologically active  phytochemicals  are described below, with examples of medicinal plants that contain them. [ 1 ]  Human settlements are often surrounded by weeds containing phytochemicals, such as  nettle ,  dandelion  and  chickweed . [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13393", "text": "Many phytochemicals, including  curcumin ,  epigallocatechin gallate ,  genistein , and  resveratrol  are  pan-assay interference compounds  and are not useful in  drug discovery . [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13394", "text": "Alkaloids  are bitter-tasting chemicals, widespread in nature, and often toxic. There are several classes with different modes of action as drugs, both recreational and pharmaceutical. Medicines of different classes include  atropine ,  scopolamine , and  hyoscyamine  (all from  nightshade ), [ 6 ]  the traditional medicine  berberine  (from plants such as  Berberis  and  Mahonia ),  caffeine  ( Coffea ),  cocaine  ( Coca ),  ephedrine  ( Ephedra ),  morphine  ( opium poppy ),   nicotine  ( tobacco ),  reserpine  ( Rauvolfia serpentina ),  quinidine  and  quinine  ( Cinchona ),  vincamine  ( Vinca minor ), and  vincristine  ( Catharanthus roseus ). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13395", "text": "Anthraquinone   glycosides  are found in  senna , [ 9 ]   rhubarb , and  Aloe . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13396", "text": "The  cardiac glycosides  are phytochemicals from plants including  foxglove  and  lily of the valley . They include  digoxin  and  digitoxin  which act as  diuretics . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13397", "text": "Polyphenols  of several classes are widespread in plants, including  anthocyanins ,  phytoestrogens , and  tannins . [ 13 ]  Polyphenols are secondary metabolites produced by almost every part of plants, including fruits, flowers, leaves and bark. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13398", "text": "Terpenes  and  terpenoids  of many kinds are found in  resinous  plants such as the  conifers . They are aromatic and serve to repel herbivores. Their scent makes them useful in  essential oils , whether for  perfumes  such as  rose  and  lavender , or for  aromatherapy . [ 14 ] [ 15 ]  Some have had medicinal uses:  thymol  is an antiseptic and was once used as a  vermifuge  (anti-worm medicine). [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13399", "text": "Contrary to bacteria and fungi, most plant  metabolic pathways  are not grouped into  biosynthetic gene clusters , but instead are scattered as individual genes. Some exceptions have been discovered:  steroidal glycoalkaloids  in  Solanum ,  polyketides  in  Pooideae , benzoxazinoids in  Zea mays ,  triterpenes  in  Avena sativa ,  Cucurbitaceae ,  Arabidopsis , and momilactone diterpenes in  Oryza sativa . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13400", "text": "Plant manufactured Pharmaceuticals  are pharmaceuticals derived from genetically modified plants used as therapeutic compounds. This can be used as the replacement for the traditional method of inoculating animals for  Cell Culture  production. We can use plants to cure and prevent diseases that may have once been deemed incurable. Through biotechnological advancements, we are able to produce complex therapeutic proteins from plant cells. [ 1 ]   Such  Therapeutic Proteins  are seen in brands like Enevrel and  Remicade  for rheumatoid arthritis, Herceptin, a breast cancer treatment. Plants like tobacco are hosts for protein production for applications such as; anemia, hepatitis C & B, hypertension, antimicrobial, and liver disease. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13401", "text": "With the advancement of Plant Manufactured Pharmaceuticals, comes the advancements of a new type production in industry. Companies such as  ZEA Biosciences  are developing cost-effective and scalable pharmaceutical ingredients using plants instead of cell culture. Unlike cell culture, plants can have a much larger production capacity, a mass quantity of plant hosts on site, and the ability to make specific antibodies that is used as a bio-reactor for specific patient needs. [ 1 ]  Indirectly, the need to grow plants that are being used as Plant Manufactured Pharmaceuticals will increase in geographic areas where certain plants naturally grow, for instance in developing countries. Increasing the need for agricultural societies in developing countries will help certain countries to export and make trade alliance with other countries and with the development of the therapies that can control diseases like  Cholera  and  HIV/AIDS . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13402", "text": "Landscape Gardens that must be grown for the production of the therapeutic proteins brings a new time of recovery for certain patients. Professor Roger Ulrich of Texas A&M University believes that  Therapeutic Gardens  can help the spiritual needs of patients and enhance stress recovery. This relieves the patient of stress and gives the patient a feeling of tranquility during their recovery. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13403", "text": "Many corporations are allowed to create  genetically modified organisms  and secure them through  intellectual property  rights creating monopolies, a fact that continues to evoke criticism . Awareness and education is needed for the public to understand how even GM plants have helped medical research. For instance, in 1992, a group of American students produced a  Hepatitis B  vaccine from a genetically modified  tobacco  plant showing the ability of produce pharmaceutical compounds. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13404", "text": "Stomachic  is a historic term for a medicine that serves to  tone  the  stomach , improving its function and increase appetite.  While many  herbal remedies  claim stomachic effects, modern  pharmacology  does not have an equivalent term for this type of action."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13405", "text": "Herbs with putative stomachic effects include: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13406", "text": "The purported stomachic  mechanism of action  of these substances is to stimulate the appetite by increasing the gastric secretions of the stomach; however, the actual therapeutic value of some of these compounds is dubious.  Some other important agents used are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13407", "text": "Swedish bitters , also called Swedish tincture, is a  bitter  and a traditional herbal tonic, the use of which dates back to the 15th century. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13408", "text": "Swedish bitters is said to have been formulated in a similar way to ancient  bitters  by  Paracelsus  and rediscovered by 18th century Swedish medics Dr.  Klaus Samst  and Dr.  Urban Hj\u00e4rne , though this appears to be mistaking the latter for his son, Kristian Henrik Hj\u00e4rne, who himself invented a bitter. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13409", "text": "In modern times, Swedish bitters have been popularized by  Maria Treben , an Austrian herbalist. [ 2 ]  The tonic is claimed to cure a large number of ailments, and to aid digestion. These claims are presented with little in the way of scientific evidence to support them, though  empirical evidence  provides for a very large database of positive results. [ 1 ] [ better\u00a0source\u00a0needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13410", "text": "The alcoholic  Swedish bitters  is purported to have a similar flavor to   Angostura bitters , though perhaps drier. Nowadays, it is more common to prepare  Swedish bitters  from a dry herbs mixture"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13411", "text": "The following herbs are added to alcohol to make Swedish bitters:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13412", "text": "There are variations on this recipe and herbal shops supply  alcoholic  and non-alcoholic versions of the drink. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13413", "text": "Maria Treben 's book contains nine pages on this bitter, with a description of many ailments and their cures. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13414", "text": "Christophe Wiart  (born August 12, 1967) is a French scientist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13415", "text": "His fields of expertise are  Asian   ethnopharmacology ,  chemotaxonomy  and  ethnobotany . [ 1 ]  \nHe has collected, identified and classified several hundred species of medicinal plants of  India ,  Southeast Asia  and  China . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13416", "text": "Ethnopharmacology of medicinal plants in Asia Pacific; [ 2 ]   bioprospection , collection and identification of medicinal botanical samples and  phytochemical  and  pharmacological  study for the identification of lead compounds as novel  antibacterial ,  anticancer , and  antioxidant  principles from rare plants from the  rainforest  of Southeast Asia. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13417", "text": "Christophe Wiart has authored several books of which:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13418", "text": "Dr. Christophe Wiart appeared on HBO's  Vice  in season 3, episode 6 (episode 28 of the series), titled \"The Post-Antibiotic World & Indonesia's Palm Bomb.\" This episode aired on April 17, 2015. [ 5 ]  This episode highlighted the need to find new treatments for infections that were previously treatable with antibiotics, but are now resistant to multiple drugs. \u201cThe last hope for the human race\u2019s survival, I believe, is in the rainforests of tropical Asia,\u201d said ethnopharmacologist Dr. Christophe Wiart. \u201cThe pharmaceutical wealth of this land is immense.\u201d  [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13419", "text": "Pharmacology  is the science of drugs and medications, [ 1 ]  including a substance's origin, composition,  pharmacokinetics ,  pharmacodynamics , therapeutic use, and  toxicology . More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal  biochemical  function. [ 2 ]  If substances have medicinal properties, they are considered  pharmaceuticals ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13420", "text": "The field encompasses drug composition and properties, functions, sources, synthesis and  drug design , molecular and cellular  mechanisms , organ/systems mechanisms, signal transduction/cellular communication,  molecular diagnostics ,  interactions ,  chemical biology , therapy, and medical applications and antipathogenic capabilities. The two main areas of pharmacology are  pharmacodynamics  and  pharmacokinetics . Pharmacodynamics studies the effects of a drug on biological systems, and pharmacokinetics studies the effects of biological systems on a drug. In broad terms, pharmacodynamics discusses the chemicals with biological  receptors , and pharmacokinetics discusses the  absorption , distribution,  metabolism , and  excretion  (ADME) of chemicals from the biological systems."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13421", "text": "Pharmacology is not synonymous with  pharmacy  and the two terms are frequently confused. Pharmacology, a  biomedical science , deals with the research, discovery, and characterization of chemicals which show biological effects and the elucidation of cellular and organismal function in relation to these chemicals. In contrast, pharmacy, a health services profession, is concerned with the application of the principles learned from pharmacology in its clinical settings; whether it be in a dispensing or clinical care role. In either field, the primary contrast between the two is their distinctions between direct-patient care, pharmacy practice, and the science-oriented research field, driven by pharmacology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13422", "text": "The word  pharmacology  is derived from  Greek  word  \u03c6\u03ac\u03c1\u03bc\u03b1\u03ba\u03bf\u03bd ,   pharmakon , meaning \"drug\" or \" poison \", together with another Greek word  -\u03bb\u03bf\u03b3\u03af\u03b1 ,  logia  with the meaning of \"study of\" or \"knowledge of\" [ 3 ] [ 4 ]  (cf. the  etymology of  pharmacy ). Pharmakon is related to  pharmakos , the ritualistic sacrifice or exile of a human  scapegoat  or victim in  Ancient Greek religion ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13423", "text": "The modern term  pharmacon  is used more broadly than the term  drug  because it includes  endogenous  substances, and biologically active substances which are not used as drugs.  Typically it includes pharmacological  agonists  and  antagonists , but also  enzyme  inhibitors (such as  monoamine oxidase  inhibitors). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13424", "text": "The origins of  clinical pharmacology  date back to the  Middle Ages , with  pharmacognosy  and  Avicenna 's  The Canon of Medicine ,  Peter of Spain 's  Commentary on Isaac , and  John of St Amand 's  Commentary on the Antedotary of Nicholas . [ 9 ]  Early pharmacology focused on  herbalism  and natural substances, mainly plant extracts. Medicines were compiled in books called  pharmacopoeias .  Crude drugs  have been used since prehistory as a preparation of substances from natural sources. However, the  active ingredient  of crude drugs are not purified and the substance is adulterated with other substances."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13425", "text": "Traditional medicine  varies between cultures and may be specific to a particular culture, such as in traditional  Chinese ,  Mongolian ,  Tibetan  and  Korean medicine . However much of this has since been regarded as  pseudoscience . Pharmacological substances known as  entheogens  may have spiritual and religious use and historical context."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13426", "text": "In the 17th century, the English physician  Nicholas Culpeper  translated and used pharmacological texts. Culpeper detailed plants and the conditions they could treat. In the 18th century, much of clinical pharmacology was established by the work of  William Withering . [ 10 ]  Pharmacology as a scientific discipline did not further advance until the mid-19th century amid the great biomedical resurgence of that period. [ 11 ]  Before the second half of the nineteenth century, the remarkable potency and specificity of the actions of drugs such as  morphine ,  quinine  and  digitalis  were explained vaguely and with reference to extraordinary chemical powers and affinities to certain organs or tissues. [ 12 ]  The first pharmacology department was set up by  Rudolf Buchheim  in 1847, at University of Tartu, in recognition of the need to understand how therapeutic drugs and poisons produced their effects. [ 11 ]  Subsequently, the first  pharmacology department  in  England  was set up in 1905 at  University College London ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13427", "text": "Pharmacology developed in the 19th century as a biomedical science that applied the principles of scientific experimentation to therapeutic contexts. [ 13 ]  The advancement of research techniques propelled pharmacological research and understanding. The development of the  organ bath  preparation, where tissue samples are connected to recording devices, such as a  myograph , and physiological responses are recorded after drug application, allowed analysis of drugs' effects on tissues. The development of the  ligand binding assay  in 1945 allowed quantification of the  binding affinity  of drugs at chemical targets. [ 14 ]  Modern pharmacologists use techniques from  genetics ,  molecular biology ,  biochemistry , and other advanced tools to transform information about molecular mechanisms and targets into therapies directed against disease, defects or pathogens, and create methods for preventive care, diagnostics, and ultimately  personalized medicine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13428", "text": "The discipline of pharmacology can be divided into many sub disciplines each with a specific focus."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13429", "text": "Pharmacology can also focus on specific  systems  comprising the body. Divisions related to bodily systems study the effects of drugs in different systems of the body. These include  neuropharmacology , in the  central  and  peripheral nervous systems ;  immunopharmacology  in the immune system. Other divisions include  cardiovascular ,  renal  and  endocrine  pharmacology.  Psychopharmacology  is the study of the use of drugs that affect the  psyche , mind and behavior (e.g. antidepressants) in treating mental disorders (e.g. depression). [ 15 ] [ 16 ]  It incorporates approaches and techniques from neuropharmacology, animal behavior and behavioral neuroscience, and is interested in the behavioral and neurobiological mechanisms of action of psychoactive drugs. [ citation needed ]  The related field of  neuropsychopharmacology  focuses on the effects of drugs at the overlap between the nervous system and the psyche."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13430", "text": "Pharmacometabolomics , also known as pharmacometabonomics, is a field which stems from  metabolomics , the quantification and analysis of  metabolites  produced by the body. [ 17 ] [ 18 ]  It refers to the direct measurement of  metabolites  in an individual's bodily fluids, in order to predict or evaluate the  metabolism  of  pharmaceutical  compounds, and to better understand the pharmacokinetic profile of a drug. [ 17 ] [ 18 ]  Pharmacometabolomics can be applied to measure  metabolite  levels following the administration of a drug, in order to monitor the effects of the drug on metabolic pathways.  Pharmacomicrobiomics  studies the effect of microbiome variations on drug disposition, action, and toxicity. [ 19 ]  Pharmacomicrobiomics is concerned with the interaction between drugs and the gut  microbiome .  Pharmacogenomics  is the application of genomic technologies to  drug discovery  and further characterization of drugs related to an organism's entire genome. [ citation needed ]  For pharmacology regarding individual genes,  pharmacogenetics  studies how genetic variation gives rise to differing responses to drugs. [ citation needed ]   Pharmacoepigenetics  studies the underlying  epigenetic  marking patterns that lead to variation in an individual's response to medical treatment. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13431", "text": "Pharmacology can be applied within clinical sciences.  Clinical pharmacology  is the application of pharmacological methods and principles in the study of drugs in humans. [ 21 ]  An example of this is posology, which is the study of dosage of medicines. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13432", "text": "Pharmacology is closely related to  toxicology . Both pharmacology and toxicology are scientific disciplines that focus on understanding the properties and actions of chemicals. [ 23 ]  However, pharmacology emphasizes the therapeutic effects of chemicals, usually drugs or compounds that could become drugs, whereas toxicology is the study of chemical's adverse effects and risk assessment. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13433", "text": "Pharmacological knowledge is used to advise  pharmacotherapy  in  medicine  and  pharmacy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13434", "text": "Drug discovery  is the field of study concerned with creating new drugs. It encompasses the subfields of  drug design  and  development . [ 24 ]  Drug discovery starts with drug design, which is the  inventive  process of finding new drugs. [ 25 ]  In the most basic sense, this involves the design of molecules that are complementary in  shape  and  charge  to a given biomolecular target. [ 26 ]  After a  lead compound  has been identified through drug discovery, drug development involves bringing the drug to the market. [ 24 ]  Drug discovery is related to  pharmacoeconomics , which is the sub-discipline of  health economics  that considers the value of drugs [ 27 ] [ 28 ]  Pharmacoeconomics evaluates the cost and benefits of drugs in order to guide optimal healthcare resource allocation. [ 29 ]  The techniques used for the  discovery ,  formulation , manufacturing and quality control of drugs discovery is studied by  pharmaceutical engineering , a branch of  engineering . [ 30 ]   Safety pharmacology  specialises in detecting and investigating potential undesirable effects of drugs. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13435", "text": "Development of medication  is a vital concern to  medicine , but also has strong  economical  and  political  implications. To protect the  consumer  and prevent abuse, many governments regulate the manufacture, sale, and administration of medication. In the  United States , the main body that regulates pharmaceuticals is the  Food and Drug Administration ; they enforce  standards  set by the  United States Pharmacopoeia . In the  European Union , the main body that regulates pharmaceuticals is the  EMA , and they enforce standards set by the  European Pharmacopoeia ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13436", "text": "The metabolic stability and the reactivity of a library of candidate drug compounds have to be assessed for drug metabolism and toxicological studies. Many methods have been proposed for quantitative predictions in drug metabolism; one example of a recent computational method is SPORCalc. [ 32 ]  A slight alteration to the chemical structure of a medicinal compound could alter its medicinal properties, depending on how the alteration relates to the structure of the substrate or receptor site on which it acts: this is called the structural activity relationship (SAR). When a useful activity has been identified, chemists will make many similar compounds called analogues, to try to maximize the desired medicinal effect(s). This can take anywhere from a few years to a decade or more, and is very expensive. [ 33 ]  One must also determine how safe the medicine is to consume, its stability in the human body and the best form for delivery to the desired organ system, such as tablet or aerosol. After extensive testing, which can take up to six years, the new medicine is ready for marketing and selling. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13437", "text": "Because of these long timescales, and because out of every 5000 potential new medicines typically only one will ever reach the open market, this is an expensive way of doing things, often costing over 1 billion dollars. To recoup this outlay pharmaceutical companies may do a number of things: [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13438", "text": "The  inverse benefit law  describes the relationship between a drugs therapeutic benefits and its marketing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13439", "text": "When designing drugs, the  placebo  effect must be considered to assess the drug's true therapeutic value."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13440", "text": "Drug development uses techniques from  medicinal chemistry  to chemically design drugs. This overlaps with the biological approach of finding targets and physiological effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13441", "text": "Pharmacology can be studied in relation to wider contexts than the physiology of individuals. For example,  pharmacoepidemiology  concerns the variations of the effects of drugs in or between populations, it is the bridge between  clinical pharmacology  and  epidemiology . [ 34 ] [ 35 ]   Pharmacoenvironmentology  or environmental pharmacology is the study of the effects of used pharmaceuticals and personal care products (PPCPs) on the environment after their elimination from the body. [ 36 ]  Human health and ecology are intimately related so environmental pharmacology studies the environmental effect of drugs and  pharmaceuticals and personal care products in the environment . [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13442", "text": "Drugs may also have ethnocultural importance, so  ethnopharmacology  studies the ethnic and cultural aspects of pharmacology. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13443", "text": "Photopharmacology  is an emerging approach in  medicine  in which drugs are activated and deactivated with  light . The energy of light is used to change for shape and chemical properties of the drug, resulting in different biological activity. [ 39 ]  This is done to ultimately achieve control when and where drugs are active in a reversible manner, to prevent  side effects  and pollution of drugs into the environment. [ 40 ] [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13444", "text": "The study of chemicals requires intimate knowledge of the biological system affected. With the knowledge of  cell biology  and  biochemistry  increasing, the field of pharmacology has also changed substantially. It has become possible, through molecular analysis of  receptors , to design chemicals that act on specific cellular signaling or  metabolic pathways  by affecting sites directly on cell-surface receptors (which modulate and mediate cellular signaling pathways controlling cellular function)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13445", "text": "Chemicals can have pharmacologically relevant properties and effects.  Pharmacokinetics  describes the effect of the body on the chemical (e.g.  half-life  and  volume of distribution ), and  pharmacodynamics  describes the chemical's effect on the body (desired or  toxic )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13446", "text": "Pharmacology is typically studied with respect to particular systems, for example endogenous  neurotransmitter systems . The major systems studied in pharmacology can be categorised by their  ligands  and include  acetylcholine ,  adrenaline ,  glutamate ,  GABA ,  dopamine ,  histamine ,  serotonin ,  cannabinoid  and  opioid ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13447", "text": "Molecular targets in pharmacology include  receptors ,  enzymes  and  membrane transport proteins . Enzymes can be targeted with  enzyme inhibitors . Receptors are typically categorised based on structure and function. Major receptor types studied in pharmacology include  G protein coupled receptors ,  ligand gated ion channels  and  receptor tyrosine kinases ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13448", "text": "Network pharmacology is a subfield of pharmacology that combines principles from pharmacology, systems biology, and network analysis to study the complex interactions between drugs and targets (e.g., receptors or enzymes etc.) in biological systems. The topology of a biochemical reaction network determines the shape of drug  dose-response curve [ 42 ]  as well as the type of drug-drug interactions, [ 43 ]  thus can help designing efficient and safe therapeutic strategies. The topology Network pharmacology utilizes computational tools and network analysis algorithms to identify drug targets, predict drug-drug interactions, elucidate signaling pathways, and explore the polypharmacology of drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13449", "text": "Pharmacodynamics is defined as how the body reacts to the drugs. Pharmacodynamics theory often investigates the  binding affinity  of  ligands  to their receptors. Ligands can be  agonists , partial agonists or  antagonists  at specific receptors in the body. Agonists bind to receptors and produce a biological response, a partial agonist produces a biological response lower than that of a full agonist, antagonists have affinity for a receptor but do not produce a biological response."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13450", "text": "The ability of a ligand to produce a biological response is termed  efficacy , in a dose-response profile it is indicated as percentage on the y-axis, where 100% is the maximal efficacy (all receptors are occupied)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13451", "text": "Binding affinity is the ability of a ligand to form a ligand-receptor complex either through  weak attractive forces  (reversible) or  covalent bond  (irreversible), therefore efficacy is dependent on binding affinity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13452", "text": "Potency  of drug is the measure of its effectiveness,  EC 50  is the drug concentration of a drug that produces an efficacy of 50% and the lower the concentration the higher the potency of the drug therefore EC 50  can be used to compare potencies of drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13453", "text": "Medication is said to have a narrow or wide  therapeutic index ,   certain safety factor  or  therapeutic window . This describes the ratio of desired effect to toxic effect. A compound with a narrow therapeutic index (close to one) exerts its desired effect at a dose close to its toxic dose. A compound with a wide therapeutic index (greater than five) exerts its desired effect at a dose substantially below its toxic dose. Those with a narrow margin are more difficult to dose and administer, and may require  therapeutic drug monitoring  (examples are  warfarin , some  antiepileptics ,  aminoglycoside   antibiotics ). Most anti- cancer  drugs have a narrow therapeutic margin: toxic side-effects are almost always encountered at doses used to kill  tumors ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13454", "text": "The effect of drugs can be described with  Loewe additivity  which is one of several common reference models. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13455", "text": "Other models include the  Hill equation ,  Cheng-Prusoff equation  and  Schild regression ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13456", "text": "Pharmacokinetics  is the study of the bodily absorption, distribution, metabolism, and excretion of drugs. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13457", "text": "When describing the pharmacokinetic properties of the chemical that is the active ingredient or  active pharmaceutical ingredient  (API), pharmacologists are often interested in  L-ADME :"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13458", "text": "Drug metabolism  is assessed in pharmacokinetics and is important in drug research and prescribing."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13459", "text": "Pharmacokinetics is the movement of the drug in the body, it is usually described as 'what the body does to the drug' the physico-chemical properties of a drug will affect the rate and extent of absorption, extent of distribution, metabolism and elimination. The drug needs to have the appropriate molecular weight, polarity etc. in order to be absorbed, the fraction of a drug the reaches the systemic circulation is termed bioavailability, this is simply a ratio of the peak plasma drug levels after oral administration and the drug concentration after an IV administration(first pass effect is avoided and therefore no amount drug is lost). A drug must be lipophilic (lipid soluble) in order to pass through biological membranes this is true because biological membranes are made up of a lipid bilayer (phospholipids etc.) Once the drug reaches the blood circulation it is then distributed throughout the body and being more concentrated in highly perfused organs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13460", "text": "In the  United States , the  Food and Drug Administration  (FDA) is responsible for creating guidelines for the approval and use of drugs. The FDA requires that all approved drugs fulfill two requirements:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13461", "text": "Gaining FDA approval usually takes several years. Testing done on animals must be extensive and must include several species to help in the evaluation of both the effectiveness and toxicity of the drug. The dosage of any drug approved for use is intended to fall within a range in which the drug produces a  therapeutic effect  or desired outcome. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13462", "text": "The safety and effectiveness of prescription drugs in the U.S. are regulated by the federal  Prescription Drug Marketing Act of 1987 ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13463", "text": "The  Medicines and Healthcare products Regulatory Agency  (MHRA) has a similar role in the UK."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13464", "text": "Medicare Part D  is a prescription drug plan in the U.S."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13465", "text": "The  Prescription Drug Marketing Act (PDMA)  is an act related to drug policy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13466", "text": "Prescription drugs  are drugs regulated by legislation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13467", "text": "The  International Union of Basic and Clinical Pharmacology ,  Federation of European Pharmacological Societies  and  European Association for Clinical Pharmacology and Therapeutics  are organisations representing standardisation and regulation of clinical and scientific pharmacology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13468", "text": "Systems for  medical classification  of drugs with  pharmaceutical codes  have been developed. These include the  National Drug Code  (NDC), administered by  Food and Drug Administration .; [ 46 ]   Drug Identification Number  (DIN), administered by  Health Canada  under the  Food and Drugs Act ;  Hong Kong Drug Registration , administered by the Pharmaceutical Service of the  Department of Health (Hong Kong)  and  National Pharmaceutical Product Index  in South Africa. Hierarchical systems have also been developed, including the  Anatomical Therapeutic Chemical Classification System  (AT, or ATC/DDD), administered by  World Health Organization ;  Generic Product Identifier  (GPI), a hierarchical classification number published by MediSpan and  SNOMED , C axis. Ingredients of drugs have been categorised by  Unique Ingredient Identifier ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13469", "text": "The study of pharmacology overlaps with  biomedical sciences  and is the study of the effects of drugs on living organisms. Pharmacological research can lead to new drug discoveries, and promote a better understanding of human  physiology . Students of pharmacology must have a detailed working knowledge of aspects in physiology, pathology, and chemistry. They may also require knowledge of plants as sources of pharmacologically active compounds. [ 38 ]   Modern pharmacology is interdisciplinary and involves biophysical and computational sciences, and analytical chemistry. A pharmacist needs to be well-equipped with knowledge on pharmacology for application in pharmaceutical research or pharmacy practice in hospitals or commercial organisations selling to customers. Pharmacologists, however, usually work in a laboratory undertaking research or development of new products. Pharmacological research is important in academic research (medical and non-medical), private industrial positions, science writing, scientific patents and law, consultation, biotech and pharmaceutical employment, the alcohol industry, food industry, forensics/law enforcement, public health, and environmental/ecological sciences. Pharmacology is often taught to pharmacy and medicine students as part of a  Medical School  curriculum."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13470", "text": "An  active ingredient  is any  ingredient  that provides  biologically active  or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13471", "text": "The similar terms  active pharmaceutical ingredient  (abbreviated as  API ) and  bulk active  are also used in medicine. [ 2 ] [ 3 ]  The term  active substance  may be used to describe the effective chemical used to control bacteria or pests. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13472", "text": "Some medication products can contain more than one active ingredient. The traditional word for the active pharmaceutical agent is  pharmacon  or  pharmakon  (from  Greek :  \u03c6\u03ac\u03c1\u03bc\u03b1\u03ba\u03bf\u03bd , adapted from  pharmacos ) which originally denoted a  magical substance  or drug. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13473", "text": "The terms  active constituent  or  active principle  are often chosen when referring to the active  substance  of interest in a plant (such as  salicylic acid  in  willow  bark or  arecoline  in  areca nuts ), since the word \"ingredient\" can be taken to  connote  a sense of human agency (that is, something that a person combines with other substances), whereas the natural products present in plants were not added by any human agency but rather occurred naturally (\"a plant doesn't have ingredients\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13474", "text": "In contrast with the active ingredients, the inactive ingredients are usually called  excipients  in pharmaceutical contexts. The main excipient that serves as a medium for conveying the active ingredient is usually called the  vehicle . For example,  petrolatum  and  mineral oil  are common vehicles. The term 'inactive' should not, however, be misconstrued as meaning  inert . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13475", "text": "The  dosage form  for a pharmaceutical contains the active pharmaceutical ingredient, which is the drug substance itself, and  excipients , which are the ingredients of the tablet, or the liquid in which the active agent is suspended, or other material that is pharmaceutically inert. Drugs are chosen primarily for their active ingredients."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13476", "text": "Patients often have difficulty identifying the active ingredients in their medication, as well as being unaware of the notion of an active ingredient. When patients are on multiple medications, active ingredients can interfere with each other, often resulting in severe or life-threatening complications. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13477", "text": "Many online services can help identify the active ingredient of most medications, such as the Medicines Database providing information on medications available in Australia. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13478", "text": "In phytopharmaceutical or  herbal medicine , the active ingredient may be either unknown or may require  cofactors  in order to achieve therapeutic goals. This leads to complications in labelling. One way manufacturers have attempted to indicate strength is to engage in  standardization  to a  marker  compound. Standardization has not been achieved yet, however, with different companies using different markers, or different levels of the same markers, or different methods of testing for marker compounds. For example,  St John's wort  is often standardized to the  hypericin  that is now known not to be the \"active ingredient\" for  antidepressant  use.  Other companies standardize to  hyperforin  or both, ignoring some 24 known additional possible active constituents. Many herbalists believe that the active ingredient in a plant is the plant itself. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13479", "text": "Additive effect  in  pharmacology  describes the situation when the combining effects of two drugs equal the sum of the effects of the two drugs acting independently. [ 1 ] [ 2 ]  The concept of additive effect is derived from the concept of  synergy . It was introduced by the scientists in pharmacology and  biochemistry  fields in the process of understanding the synergistic interaction between drugs and chemicals over the century."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13480", "text": "Additive effect often occurs when two similar drugs are taken together to achieve the same degree of therapeutic effect while reducing the specific  adverse effect  of one particular drug. For example,  aspirin, paracetamol, and caffeine  are formulated together to treat pain caused by tension headaches and  migraine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13481", "text": "Additive effect can be used to detect synergy as it can be considered as the baseline effect in methods determining whether drugs have synergistic effect. Synergistic effect is similar to additive effect, having a combination effect greater than additive effect. It can produce an effect of 2+2 > 4 when two drugs are used together. Additive effect can also be found in a majority of  combination therapies , although synergistic effect is more common. If the combination of two drugs in combination therapy has an effect lower than the sum of the effects of the two drugs acting independently, also known as  antagonistic effect , the drugs will seldom be prescribed together in the same therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13482", "text": "Drug or chemical combinations with additive effects can cause adverse effects. For example, co-administration of  non-steroidal anti-inflammatory drugs  (NSAIDs) and  glucocorticoids  increases the risk of gastric bleeding. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13483", "text": "The concept of additive effect is derived from the concept of drug synergy. Thus, the origin of additive effect dates back to the early twentieth century when the search for synergy started. During the search for synergy, the models of  Loewe additivity  and  Bliss independence  were proposed. [ 4 ]  These models are capable of measuring the effects of drug combinations. Hence, Loewe additivity and Bliss independence were developed to determine whether an effect of a drug combination is synergistic or antagonistic. During the construction of these models, the concept of additive effect was introduced as the baseline for the determination of synergy and antagonism."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13484", "text": "Additive effects can occur with drugs with either equivalent or overlapping actions, or independent actions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13485", "text": "Many of the drugs in the same class exert additive effect as they have a similar\u00a0therapeutic  mechanism of action . For example, the  calcium carbonate ,  magnesium , and  aluminium  salts are all  antacids  with the mechanism of using the  negative ion  to  neutralize  the acid in the stomach. [ 5 ]  The antacids have no interaction between them, so they would be considered to have additive effect when taken together."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13486", "text": "Drugs that are in the same class, but do not have the same target, may also act additively by interacting with different targets in the same pathway. For example,  propofol  and  sevoflurane  can both produce  anesthetic effects . [ 6 ]  Propofol can potentiate\u00a0the activity of  GABA A  receptor  and act on \u03b1, \u03b2 and \u03b3 subunits, [ 7 ] [ 8 ] [ 9 ]  while sevoflurane enhances the response of the\u00a0GABA A  receptor to endogenous GABA by binding to the \u03b11-subunit. [ 10 ]  By using Dixon up-down method, a trial has shown that the effect in producing anesthetic effects between propofol and sevoflurane is additive. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13487", "text": "Two drugs having different targets in unrelated pathways that ultimately result in the desired therapeutic result are considered to have additive effects with independent actions. For example,  artemisinin  and  curcumin  both exert  antimalarial  effects. Artemisinin works by being metabolized in the body into active metabolites. The metabolites would then create  reactive oxygen species(ROS)  that damage the parasites and kill them. [ 12 ]  The mechanism of action of curcumin remains largely unknown, but the antiparasitic effect is believed to be associated with the potentiation of innate and adaptive  immunological responses . [ 13 ] [ 14 ]  The combined effects of artemisinin and curcumin each contribute to the death of parasites via different mechanisms and the effect is shown to be additive by fractional inhibitory concentrations. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13488", "text": "Drugs with the same target in different sites that produce additive effects are also considered as independent action. For example,  doxorubicin  and  trabectedin  can both produce  anticancer effect . [ 16 ]  Doxorubicin is a  DNA intercalator  that prefers to bind to AT regions, [ 17 ]  while trabectedin forms  guanine  adduct in DNA to disrupt DNA repair system. [ 18 ]  A recent study has shown that doxorubicin and trabectedin do not hinder each other and could produce an additive anticancer effect. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13489", "text": "The concept of additive effect is analogous to the concept of simple addition in mathematics. However, the additive effect is not simply the  arithmetic summation  of two (or more) drugs in most cases. [ 20 ]  For an additive inhibition effect, drug A and drug B could each inhibit 20% individually, but the additive effect is not 40%. The effect cannot be simply arithmetic because if drug A and drug B each inhibits 60% cannot theoretically exert an inhibitory effect of 120%. With 60% inhibitory effect each, the remaining function would be at (1-60%)\u00d7(1-60%)=16%, meaning the additive inhibitory effect would be 84%. Since the application of additive effect is commonly seen in clinical practice, avoiding the common misconceptions of additive effect is crucial to understanding the clinical significance of additive effect. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13490", "text": "One of the typical uses of additive effect is to detect synergy. [ 21 ]  Additive effect can be considered as the baseline effect in methods of determining the presence of synergistic effect between two or more drugs. Synergistic effect is similar to additive effect. The only difference is it has a combination effect greater than additive effect. To be brief, synergy can produce an effect of 2 + 2 > 4 when drugs are used in combination. [ 22 ]  The combination of  angiotensin II receptor antagonist (ARB) ,  Candesartan-cilexetil , and  angiotensin-converting enzyme inhibitor (ACEI) , Ramipril, demonstrates a synergistic effect in reducing  systolic blood pressure . [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13491", "text": "The other use of additive effect is to detect antagonism. Similarly, additive effect can be considered as the baseline effect in methods of determining the presence of antagonistic effect between drugs. Pharmacists can confirm the presence of antagonism when the combination effect of drugs is less than additive effect. The combination of  acetylsalicylic acid  and  ibuprofen  demonstrates an antagonistic effect in relieving pain and  inflammation . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13492", "text": "The most common clinical usage of additive effect in pharmacology is combination therapy. Two or more therapeutic agents are used in combination therapy to treat a single disease. Different drugs in the same combination therapy act on different biological and biochemical pathways in the body to produce an additive effect."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13493", "text": "An example of combination therapy demonstrating additive effect is the use of  \u03b2-2 adrenergic receptor agonists  together with  inhaled corticosteroids . This is a treatment for two commonly seen  pulmonary diseases ,  asthma  and  chronic obstructive pulmonary disease . \u03b2-2 adrenergic receptor agonists act as  bronchodilators , having an effect of inducing bronchodilation to relieve bronchoconstriction; Inhaled corticosteroids act as anti-inflammatory drugs to decrease the inflammatory response. The two drugs act on different sites in the body. The corticosteroids also reverse and restore the function and number of \u03b2-2 adrenergic receptors in patients\u2019 lungs  in vivo . Meanwhile, the combined activity of two drugs resolves the problem of reduced sensitivity in some patients with chronic obstructive pulmonary disease towards inhaled corticosteroids. [ 24 ]  A common drug from this example can be found is  Seretide\u00ae , containing a long-acting \u03b2-2 adrenergic receptor agonist named as  Salmeterol  and a corticosteroid named as  Fluticasone . [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13494", "text": "Additive interaction can also be found in combination therapy for treating  hypertension . The combination of angiotensin II receptor blockers (ARBs) and  calcium channel blockers  (CCBs) is one of the suggested antihypertensive therapies. ARBs inhibit the action of  angiotensin II  to decrease fluid retention and blood volume to decrease blood pressure, reduce  vasoconstriction  to decrease  peripheral vascular resistance , and prevent vascular  fibrosis  to decrease vascular stiffness. CCBs are  vasodilators  inhibiting  L-type voltage-operated calcium channels  in the blood vessels to alleviate vasoconstriction resulting in a decrease in peripheral vascular resistance. The two types of drugs act on different pathways to produce an additive effect on lowering blood pressure without any increase in adverse effects. [ 26 ]  This combination, with ARB,  valsartan , and CCB,  amlodipine , is a common treatment in high-risk hypertensive patients, especially the elderly. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13495", "text": "The treatment for another common disease, primary  hypercholesterolemia , also demonstrates additive effect. Plant sterol-ester margarine and a common type of  antihyperlipidaemic  drug,  cerivastatin , have an additive effect in reducing  LDL cholesterol , without significant interaction between the two drugs. [ 28 ]  Another drug combination with additive effect for hypercholesterolemia is  niacin  ( vitamin B3 ) and  simvastatin . This drug combination is also known as  Simcor  commercially. Niacin can reduce the secretion of LDL cholesterol and very-low-density lipoprotein cholesterol (VLDL cholesterol). On the other hand, simvastatin can reduce the synthesis of LDL cholesterol and  triglycerides , and increase the level of  high-density lipoprotein cholesterol (HDL cholesterol) . Together, niacin and simvastatin reduce the level of LDL cholesterol and increases the level of HDL cholesterol, [ 23 ]  therefore managing hypercholesterolemia effectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13496", "text": "Additive interaction or additive effect can be found in the treatment of the majority of common diseases. The combination of drugs with different effects has the benefit of using each drug at its optimal dose. [ 29 ]  This decreases the possibility of using a higher dose of a single medication if the previous dose is ineffective in treating diseases or relieving symptoms. The significance of using drugs with optimal dose is lowering the occurrence of intolerable side effects, adverse reactions, and possible  drug toxicity  in patient's body. This increases the safe use of drugs and increases patient compliance with the therapy. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13497", "text": "One of the examples is the use of calcium channel blocker and beta-blocker. They are drugs that can be used to treat stable  angina . They can both decrease the frequency of angina, aiming to relieve the symptoms of angina. There are controlled, double blind clinical trials and studies involving patients with preserved left ventricular function demonstrating that the combination of calcium channel blocker and beta blocker has an additive cardio depressant effects when comparing with either drug class alone. [ 31 ]  The combination therapy is used when a single medication fails to produce a therapeutic effect. Choosing the optimal dose of the two medications in the combination therapy prevents the use of an extreme high dose of a single medication alone, leading to adverse effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13498", "text": "Drug combinations with additive effects have the potential to cause adverse effects. Adverse effects induced by drug combinations are not uncommon. The risk of having adverse effects is increased when the drug combination with additive effect has the same adverse effect. Thus, some drug combinations with additive effect are avoided. Below are commonly seen drug combinations with additive effect causing adverse effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13499", "text": "An example demonstrating how drug combination with additive effect can cause adverse effects is the co-administration of ACEI and  potassium-sparing diuretics . [ 3 ]  Despite having different mechanisms of action, the drugs are able to reduce potassium excretion from the body. Hence, both ACEI and potassium-sparing diuretics have the side effect of  hyperkalemia . When two drugs are used together, the risk of having hyperkalemia is doubled. Since hyperkalemia has the potential to cause  arrhythmia  and  metabolic acidosis , the combination of ACEI and potassium-sparing diuretics is avoided."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13500", "text": "Another example is the combination of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids. [ 3 ]  Although NSAIDs and glucocorticoids have different mechanisms of action, the drugs are able to diminish the protective effect of gastric mucosa from gastric acid. [ 32 ] [ 33 ]  As a result, the concomitant use of NSAIDs and glucocorticoids increases the risk of gastric bleeding and worsens  peptic ulcer disease . As a result, the combination of NSAIDs and glucocorticoids is not recommended."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13501", "text": "The  Antica Farmacia Sant'Anna  (Italian for \u201cAncient Pharmacy of Saint Anne\u201d) is a  pharmacy  and  herbal medicine   dispensary  in  Genoa , Italy, located in the quarter of  Castelletto . Founded by the  Discalced Carmelites  friars of the annex  Convent of Sant\u2019Anna  in 1650, it is the oldest commercial establishment still operating in Genoa [ 1 ]  and the only instance in Italy of a fully licensed pharmacy owned and operated by a religious institution. [ 2 ] [ 3 ]  While its ancient furniture and instruments are listed and protected as  cultural heritage , [ 4 ]  its modern  laboratories  are equipped with  state-of-the-art  technology for the preparation of medicines,  Galenic formulations ,  herbal medicine  products,  lotions , cosmetics and  dietary supplements  under the supervision of legally qualified personnel. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13502", "text": "The  Convent of Sant\u2019Anna  is the first foundation of the  Discalced Carmelites  outside of Spain, established in 1584 under the impulse of father Nicolas of Jesus and Mary Doria, a descendant of the prominent Doria family . Returned from Spain twenty years after the reformation of the  Carmelite Order  operated by  Saint Theresa of Avila  and  Saint John of the Cross , Father Doria established a monastery in his native city with the financial support of the noble families Doria,  Cattaneo ,  Spinola  e  Pallavicini ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13503", "text": "Soon after the foundation of the convent, the friars opened the pharmacy. [ 5 ]  At the end of the 16th century, one of the  cloisters  of the convent, presently known as 'the Cloister of the Roses', was used for the cultivation of curative  herbs .  Potatoes  imported from the Americas were planted there for the very first time on Italian soil, after the founder Father Doria had seen them at the court of  Philip II King of Spain . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13504", "text": "In the 17th century, noble and wealthy citizens usually resorted to a medical doctor in case of illness, while the underprivileged layers of society would usually seek medical support from religious institutions. By the mid-century Sant'Anna likely had a high influx of patients: testimony thereof is the construction of a large  wing  dedicated to the preparation and dispensation of medicines, separate from the friar's quarters. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13505", "text": "The oldest document mentioning the pharmacy, dated 1650, is stored at the  Vatican Apostolic Archives . [ 2 ]  Another document, dated 1652 and stored in the archives of the Convent of Sant'Anna, shows that the chief  chemist , brother Martino of Saint Anthony (1638\u20131721), would  \"go out every day to procure the ingredients for the medications [...], many patients came to him and not everyone could be healed in the same way [...], hence it was necessary to prepare different potions, medicines,and poultices\" . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13506", "text": "According to the historical registers of the pharmacy, a contract redacted in 1778 mentions that the Genoese surgeon and chemist Lorenzo Robello was tasked to procure ingredients for the pharmacy, prepare the medicines and administer them \" to the friars and to external patients \". At that time it was not possible to find a friar with the necessary qualifications; the resolve of the Carmelite Order, however, remained that the pharmacy was to be run primarily by friars and, by 1792, the fully-qualified chemist friar Giovanni della Croce assumed the direction of the pharmacy, updated its equipment and furnished the dispensary room with the  boiserie  which is still visible today. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13507", "text": "After the  annexation  of the Republic of Genoa to the  Kingdom of Sardinia  at the beginning of the 19th century, the pharmacy was further refurbished by brother Bernardino di Sant'Anna. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13508", "text": "In those years, the Pharmacy started a cooperation with the famous  Parisian  surgeon Louis Le Roy, author of the  treatise   Healing Medicine, aka Purgation , translated in Italian for the first time in  Bologna  in 1824. Although its content was later superseded by improvement in scientific research, the treatise enjoyed a great success at the time and was reprinted several times. A Genoese reprint in 1885 mentioned the cooperation with Sant'Anna's pharmacy in the back cover. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13509", "text": "A document stored in the library of the Convent shows that brother Modesto, whose lay name was Stefano Montabone, received his diploma of chemist in 1840, granting him permission to practice his profession in Genoa and all other territories of the Kingdom of Sardinia in accordance to  letter patents  issued by King  Victor Emmanuel I of Savoy . In 1882, however, the difficulties in securing chemist friars with appropriate legal  qualifications  appeared insurmountable. Therefore, keen to remain licensed according to the law, the Convent of Sant'Anna decided to enact a compromise solution and appointed a lay chemist \" to   ensure the regular preparation and administration of the medicines \", while the  business administration  of the pharmacy remained entrusted to a friar. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13510", "text": "At the end of the 19th century, the pharmacy had several prominent clients, including the main hospital of Genoa, the hospital of Pammatone. At the time, the most sought after products were  white sugar ,  quinine , English  salts ,  cinnamomum ,  rosolio ,  poppyseed  oil, medicines against  parasites  and a medicine against  demodicosis . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13511", "text": "At the end of the 19th century, the construction of the wealthy neighborhood of Circonvallazione a Monte significantly altered the area, when Corso Magenta and the  Sant'Anna funicular  were built immediately to the South of the convent. The religious buildings and the quaint village in which they are located have nonetheless remained intact and quiet to this day. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13512", "text": "The Pharmacy is still active today. Several ancient recipes are still prepared and updated when necessary. The laboratories have been refurbished to reflect modern needs and the latest regulatory requirements. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13513", "text": "After 1933, the Convent, the church and the pharmacy of Sant'Anna are accessible also with an elevator from the tunnel which connects Corso Magenta with the  Elevator Magenta-Crocco . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13514", "text": "Autopharmacology  relates to the  scientific  study of the  regulation  of body functions by the activity of its naturally existent (or  endogenous ) chemical factors of the  tissues . A more restricted definition would consider substances that were first identified as external agents which had a documented action on  physiological  functions, but later were discovered as existing as endogenous factors. [ 1 ]  The best example is the class of  endorphins , which, as its name implies, were discovered to exist in the  brain  and have specific  receptors  in it, [ 2 ]  by investigations on the mechanism of action of  opioids , such as  morphine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13515", "text": "Historically, the first approach to the concept of autopharmacology began with  British   physiologist  and  pharmacologist   Henry Dale  in the 1910s, discovered the role of  acetylcholine  in  synaptic transmission , [ 3 ]  and later proved by  Austrian  physiologist  Otto Loewi , to be the  neurotransmitter  involved in the proximal synapses of the  autonomic nervous system  (initially named  Vagusstoff  by Loewi, and later identified as acetylcholine). The same happened to another autonomic neurotransmitter,  noradrenaline  ( Akzeleransstoff  by Loewi), which later proved to be chemically similar to a long used pharmacological agent,  adrenaline , a hormone secreted by the  adrenal glands . Both scientists were awarded the 1936  Nobel Prize for Physiology or Medicine  for their pioneering and important contributions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13516", "text": "A research area where autopharmacology principles assumed great importance was that of  pain  and  inflammation , [ 4 ]  due to the great number of endogenous messengers, transmitters and modulators involved in their complex response at molecular and cellular level. The control and regulation mechanisms of the  circulatory system  and  renal  functions and their interactions (such as the  renin/angiotensin system ) are also greatly influenced by autopharmacological agents; One of the autopharmacology pioneers was Professor  Mauricio Rocha e Silva , leader of the team of  Brazilian  researchers who discovered  bradykinin  in 1948, an endogenous substance involved in  hypotension  in  circulatory shock . [ 5 ]  Of course, all these systems are of extreme importance for  clinical practice  and for the discovery of new  therapeutic drugs ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13517", "text": "Endogenous substances that could fall under the concept of autopharmacology are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13518", "text": "The main scientific criterion for an autopharmacological agent is the discovery of specific membrane receptors for it and, hopefully, its  transduction  and  cell signaling  mechanisms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13519", "text": "The term was never much of a mainstream concept, and has fallen into disuse, as research on basic mechanisms has advanced. In a  recent literature search  on  PubMed , only six titles refer to the term  autopharmacology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13520", "text": "A  bioassay  is an analytical method to determine the potency or effect of a substance by its effect on  living animals  or plants ( in vivo ), or on living cells or tissues ( in vitro ). [ 1 ] [ 2 ]  A bioassay can be either quantal or quantitative, direct or indirect. [ 3 ]  If the measured response is binary, the assay is  quantal ; if not, it is  quantitative . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13521", "text": "A bioassay may be used to detect biological hazards or to give an assessment of the quality of a mixture. [ 4 ]  A bioassay is often used to monitor  water quality  as well as  wastewater  discharges and its impact on the surroundings. [ 5 ]  It is also used to assess the environmental impact and safety of new technologies and facilities. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13522", "text": "Bioassays are essential in pharmaceutical, medical and agricultural sciences for development and launching of new drugs, vitamins, etc."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13523", "text": "A bioassay is a biochemical test to estimate the potency of a sample compound. Usually this potency can only be measured relative to a standard compound. [ 3 ] [ 1 ]  A typical bioassay involves a  stimulus  (ex. drugs) applied to a  subject  (ex. animals, tissues, plants). The corresponding  response  (ex. death) of the subject is thereby triggered and measured. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13524", "text": "The first use of a bioassay dates back to the late 19th century, when the foundation of bioassays was laid down by German physician Paul Ehrlich. [ 7 ]  He introduced the concept of standardization by the reactions of living matter. [ 7 ] [ 6 ]  His bioassay on  diphtheria  antitoxin was the first bioassay to receive recognition. [ 8 ]  His use of bioassay was able to discover that administration of gradually increasing dose of diphtheria in animals stimulated production of antiserum. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13525", "text": "One well known example of a bioassay is the \"canary in the coal mine\" experiment. [ 10 ]  To provide advance warning of dangerous levels of methane in the air, miners would take methane-sensitive canaries into coal mines. If the canary died due to a build-up of methane, the miners would leave the area as quickly as possible."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13526", "text": "Many early examples of bioassays used animals to test the   carcinogenicity  of chemicals. [ 11 ]  In 1915,  Yamaigiwa Katsusaburo  and Koichi Ichikawa tested the carcinogenicity of coal tar using the inner surface of rabbit's ears. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13527", "text": "From the 1940s to the 1960s, animal bioassays were primarily used to test the toxicity and safety of drugs, food additives, and pesticides. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13528", "text": "Beginning in the late 1960s and 1970s, reliance on bioassays increased as public concern for occupational and environmental hazards increased. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13529", "text": "Bioassay can be classified by how it is applied and how the response is recorded."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13530", "text": "One classical bioassay is the  Ames test . A strain of  Salmonella  that requires histidine to grow is put on two plates with growth medium containing minimal amounts of histidine and some rat liver extract (to mimick liver metabolism). A suspected  mutagen  is added to one plate. If the plate with the suspected mutagen grows more visible colonies, it is probably mutagenic: a mutagen might cause the strain of bacterium to regain the ability to make its own histidine. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13531", "text": "Most other forms of  toxicology testing  are also bioassays. Animals or cell cultures may be put under a number of levels of a suspected toxin to ascertain whether the substance causes harmful changes and at what level it does so. The  LD 50  value, a common measure of acute toxicity, describes the dose at which a substance is lethal to 50% of tested animals. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13532", "text": "The potency of a drug may be measured using a bioassay. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13533", "text": "Environmental bioassays are generally a broad-range survey of  toxicity . [ 16 ]  A toxicity identification evaluation is conducted to determine what the relevant  toxicants  are. Although bioassays are beneficial in determining the biological activity within an organism, they can often be time-consuming and laborious. Organism-specific factors may result in data that are not applicable to others in that species. For these reasons, other biological techniques are often employed, including  radioimmunoassays .  See  bioindicator ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13534", "text": "Water pollution  control requirements in the United States require some industrial dischargers and municipal  sewage treatment  plants to conduct bioassays. These procedures, called  whole effluent toxicity  tests, include acute toxicity tests as well as chronic test methods. [ 5 ]  The methods involve exposing living aquatic organisms to samples of wastewater for a specific length of time. [ 17 ] [ 18 ]  Another example is the bioassay ECOTOX, which uses the microalgae  Euglena gracilis  to test the toxicity of water samples. [ 19 ]  ( See   Bioindicator#Microalgae in water quality )"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13535", "text": "A  biological target  is anything within a living organism to which some other entity (like an endogenous  ligand  or a  drug ) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets are  proteins  and  nucleic acids . The definition is context-dependent, and can refer to the biological target of a   pharmacologically active   drug   compound , the receptor target of a  hormone  (like  insulin ), or some other target of an external stimulus.  Biological targets are most commonly proteins such as  enzymes ,  ion channels , and  receptors ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13536", "text": "The external stimulus ( i.e. , the drug or ligand) physically binds to (\"hits\") the biological target. [ 1 ] [ 2 ]  The interaction between the substance and the target may be:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13537", "text": "Depending on the nature of the stimulus, the following can occur: [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13538", "text": "The term \"biological target\" is frequently used in  pharmaceutical  research to describe the native protein in the body whose activity is modified by a drug resulting in a specific effect, which may be a desirable  therapeutic effect  or an unwanted  adverse effect .  In this context, the biological target is often referred to as a  drug target . The most common drug targets of currently marketed drugs include: [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13539", "text": "Identifying the biological origin of a disease, and the potential targets for intervention, is the first step in the discovery of a medicine using the  reverse pharmacology  approach. Potential drug targets are not necessarily disease causing but must by definition be disease modifying. [ 8 ]   An alternative means of identifying new drug targets is  forward pharmacology  based on phenotypic screening to identify \"orphan\" ligands [ 9 ]  whose targets are subsequently identified through target deconvolution. [ 10 ] [ 11 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13540", "text": "Databases containing biological targets information:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13541", "text": "These biological targets are conserved across species, making pharmaceutical pollution of the environment a danger to species who possess the same targets. [ 13 ]  For example, the synthetic  estrogen  in human  contraceptives ,  17-R-ethinylestradiol , has been shown to increase the  feminization  of fish downstream from sewage treatment plants, thereby unbalancing reproduction and creating an additional  selective pressure  on fish survival. [ 14 ]  Pharmaceuticals are usually found at ng/L to low-\u03bcg/L concentrations in the aquatic environment. [ 15 ]  Adverse effects may occur in non-target species as a consequence of specific drug target interactions. [ 16 ]  Therefore,  evolutionarily well-conserved  drug targets are likely to be associated with an increased risk for non-targeted pharmacological effects. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13542", "text": "A  British Approved Name  ( BAN ) is the official, non-proprietary, or generic name given to a  pharmaceutical   substance , as defined in the  British Pharmacopoeia (BP) . [ 1 ]  The BAN is also the official name used in some countries around the world, because starting in 1953, proposed new names were evaluated by a panel of experts from  WHO  in conjunction with the BP commission  to ensure naming consistency worldwide [ 2 ]  (an effort leading to the  International Nonproprietary Name  system). There is also a  British Approved Name (Modified)  ( BANM ). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13543", "text": "BANs are unique in that names are assigned for combination preparations as well as single-drug preparations. For example, the BAN  co-amoxiclav  is assigned to preparations containing  amoxicillin  and  clavulanic acid . Most other pharmacopoeias simply refer to combination products by both ingredients in the preparation, in this example \"amoxicillin with clavulanic acid\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13544", "text": "The prefix of \"co-\" is used for many combination drugs, including opioid with paracetamol or aspirin  analgesics  (e.g.,  co-codamol ,  co-codaprin ,  co-dydramol ,  co-proxamol ); the  anti-diarrhoeal , non-analgesic mixture of  diphenoxylate  and  atropine ,  co-phenotrope  (trade name  Lomotil );  antibiotics  (e.g.,  co-fluampicil  and  co-trimoxazole );  antihypertensives  (e.g.,  co-tenidone );  diuretics  (e.g.,  co-amilofruse  and  co-amilozide );  gastrointestinal  drugs (e.g.,  co-danthrusate ); and anti- Parkinsonism  agents such as  co-careldopa ,  co-beneldopa , and  co-cyprindiol . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13545", "text": "European Union  legislation from 2001 required harmonisation of the BP with the  European Pharmacopoeia (EP) , as well as the adoption of  International Nonproprietary Names  through directives (2001/82/EC [ 4 ]  and 2001/83/EC, [ 5 ]  as amended, and 2003/63/EC [ 6 ] ). Across the EU has meant that, with the notable exception of  adrenaline/epinephrine , [ 7 ]  BANs are now the same as the INNs. For example, the old BAN  methicillin  was replaced with the current BAN  meticillin , matching the INN."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13546", "text": "This has resulted in an interesting situation in other countries that use BANs. While the British Pharmacopoeia and BANs are the official pharmacopoeia/names defined by legislation in many of these countries, the former BANs often continue to be used, purportedly because of the difficulty of changeover.  Despite the importance of the BP, there appears to be little or no movement in the direction of changing these names. In Australia, the  Australian Approved Names  are generally the same as BANs, but a few exceptions remain."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13547", "text": "Cinacalcet , sold under the brand name  Sensipar  among others, is a medication used to treat  primary hyperparathyroidism ,  tertiary hyperparathyroidism  and  parathyroid carcinoma . [ 4 ] [ 6 ] [ 5 ]  Cinacalcet acts as a  calcimimetic  (i.e., it mimics the action of  calcium  on  tissues ) by  allosteric  activation of the  calcium-sensing receptor  that is expressed in various human organ tissues."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13548", "text": "The most common side effects include  nausea  and  vomiting . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13549", "text": "Cinacalcet was approved in the United States in March 2004, [ 4 ] [ 7 ] [ 8 ]  and in the European Union in October 2004. [ 5 ] [ 3 ]  It was the first allosteric G protein-coupled receptor modulator to enter the pharmaceutical market. [ 9 ]  In 2013, cinacalcet was the 76th most prescribed medicine in the United States. [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13550", "text": "In the United States, cinacalcet is indicated for the treatment of  secondary hyperparathyroidism  in people with chronic kidney disease on dialysis and  hypercalcemia  in people with parathyroid carcinoma. [ 4 ] [ 12 ]  Cinacalcet can also be used to treat severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo  parathyroidectomy . [ 4 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13551", "text": "In the European Union cinacalcet is indicated for:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13552", "text": "Cinacalcet has pregnancy category C in the US, meaning that adequate and well-controlled studies involving cinacalcet in pregnant women have not been done. [ 4 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13553", "text": "Studies have not been done in lactating women; therefore, it is not known whether cinacalcet is excreted into human milk. [ 4 ] [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13554", "text": "Hypocalcemia  (decreased calcium levels) is a contraindication to the use of cinacalcet. Those who have serum calcium levels less than 7.5\u00a0mg/dL should not be started on cinacalcet. Hypocalcemia symptoms include  paresthesias ,  myalgias , muscle cramping,  tetany , and  convulsions . Cinacalcet should not be administered until serum calcium levels are above 8.0\u00a0mg/dL and/or hypocalcemia symptoms are resolved. [ 4 ]  Cinacalcet is not approved for pediatric use in the United States. [ 6 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13555", "text": "Common side effects of cinacalcet include upset stomach, vomiting, diarrhea, dizziness, nausea, weakness, and chest pain. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13556", "text": "Clinical trials conducted in the United States by Amgen to determine whether the drug is safe in children were halted by the U.S.  Food and Drug Administration  (FDA) in February 2013, following the death of a 14-year-old participant. [ 6 ] [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13557", "text": "Serious side effects, including overdose symptoms, of cinacalcet include: [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13558", "text": "Cinacalcet is a strong inhibitor of the liver enzyme  CYP2D6  and is partially metabolized by  CYP3A4  and  CYP1A2 . Dose adjustments may be necessary if people are treated with CYP3A4 and CYP1A2 inhibitors and medications that are metabolized by CYP2D6. [ 4 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13559", "text": "Cinacalcet is a drug that acts as a  calcimimetic [ 4 ] [ 5 ]  (i.e. it mimics the action of calcium on tissues) by  allosteric activation  of the  calcium-sensing receptor  that is expressed in various human organ tissues. The calcium-sensing receptors on the surface of the chief cell of the  parathyroid gland  is the principal negative regulator of parathyroid hormone secretion. [ 15 ]  Cinacalcet increases the sensitivity of calcium receptors on parathyroid cells to reduce parathyroid hormone (PTH) levels and thus decrease serum calcium levels. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13560", "text": "In the field of  drug discovery ,  classical pharmacology , [ 1 ]  also known as  forward pharmacology , [ 2 ] [ 3 ] [ 4 ]  or  phenotypic drug discovery  (PDD), [ 5 ]  relies on  phenotypic screening  (screening in intact cells or whole organisms) of  chemical libraries  of synthetic  small molecules ,  natural products  or  extracts  to identify substances that have a desirable  therapeutic  effect. Using the techniques of  medicinal chemistry , the potency, selectivity, and other properties of these screening hits are optimized to produce candidate drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13561", "text": "Classical pharmacology traditionally has been the basis for the discovery of new drugs.  Compounds are screened in cellular or animal models of disease to identify compounds that cause a desirable change in phenotype.  Only after the compounds have been discovered, an effort is made to determine the  biological target  of the compounds through target validation experiments often involving  chemoproteomics . More recently it has become popular to develop a hypothesis that a certain biological target is disease modifying and  screen  for compounds that modulate the activity of this purified target.  Afterwards, these compounds are tested in animals to see if they have the desired effect.  This approach is known as \" reverse pharmacology \" [ 1 ]  or \"target based drug discovery\" (TDD). [ 5 ]  However, recent statistical analysis reveals that a disproportionate number of first-in-class drugs with novel mechanisms of action come from phenotypic screening, [ 6 ]  which has led to a resurgence of interest in this method. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13562", "text": "Pharmacognosy , the investigation of botanics used in indigenous medical traditions is essentially classical pharmacology. Pharmacognosy and classical pharmacology are both often contrasted with  reverse pharmacology , that is, working from the target backward to identify new drugs starting with screening libraries of compounds for affinity for particular target. In pharmacognosy,  folk medicines  are first tested in clinical trials for efficacy.  Only after efficacy has been established, is an effort made to determine the biologic target of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13563", "text": "Clozapine  N -oxide  (CNO) is a synthetic  drug  used mainly in  biomedical research  as a  ligand  to activate  Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) , [ 1 ]  despite the initial belief that it was biologically inert. However, it has been shown to not enter the brain after administration [ 2 ]  and to reverse metabolize in peripheral tissues to form clozapine. Clozapine can bind to a number of different serotonergic, dopaminergic and adrenergic receptors within the brain. [ 3 ]  These off-target effects mean behavioral data using the CNO-DREADD system have to be interpreted with caution. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13564", "text": "Alternatives to CNO with more affinity, more inert character, and faster kinetics include Compound 21 (C21) [ 5 ]  and deschloroclozapine (DCZ). [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13565", "text": "Coinduction  in  anesthesia  is a  pharmacological  tool whereby a combination of  sedative drugs  may be used to greater effect than a single agent, achieving a smoother onset of  general anesthesia . The use of coinduction allows lower doses of the same  anesthetic agents  to be used which provides enhanced safety, faster recovery, fewer side-effects, and more predictable  pharmacodynamics . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Coinduction is used in human medicine and  veterinary medicine [ 5 ]  as standard practice to provide optimum anesthetic induction. The onset or  induction  phase of anesthesia is a critical period involving the  loss of consciousness  and reactivity in the patient, and is arguably the most dangerous period of a general anesthetic. A great variety of coinduction combinations are in use and selection is dependent on the patient's age and health, the specific situation, and the indication for anesthesia. As with all forms of anesthesia the resources available in the environment are a key factor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13566", "text": "A standard coinduction regimen for an adult might consist of a  benzodiazepine  sedative  amnesic  such as  midazolam , followed by an  opioid   analgesic  with further sedating properties such as  fentanyl  which has a fast onset, then an  intravenous  induction agent:  propofol . A  muscle relaxant  such as  atracurium  would be administered after this, though this would not strictly be a part of coinduction. For a child on the other hand, a commonly used regimen would be  fentanyl ,  ketamin  and  rocuronium . In all cases the choice of agents would be tailored to the situation; for a  neonatal   intubation  the aforementioned regimes would be inappropriate as sedation and especially  amnesia  are less important.  Fentanyl  alone would be used, followed by the short-action muscle relaxant  suxamethonium : coinduction is typically not used in neonatal anesthesia. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13567", "text": "Combination therapy  or  polytherapy  is  therapy  that uses more than one  medication  or modality. Typically, the term refers to using multiple therapies to treat a  single   disease , and often all the therapies are pharmaceutical (although it can also involve non-medical therapy, such as the combination of medications and  talk therapy  to treat depression). 'Pharmaceutical' combination therapy may be achieved by prescribing/administering separate drugs, or, where available,  dosage forms  that contain more than one  active ingredient  (such as fixed-dose combinations)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13568", "text": "Polypharmacy  is a related term, referring to the use of multiple medications (without regard to whether they are for the same or separate conditions/diseases). Sometimes \"polymedicine\" is used to refer to pharmaceutical combination therapy. Most of these kinds of terms lack a universally consistent definition, so caution and clarification are often advisable."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13569", "text": "Conditions treated with combination therapy include  tuberculosis ,  leprosy ,  cancer ,  malaria , and  HIV / AIDS . One major benefit of combination therapies is that they reduce development of  drug resistance  since a pathogen or tumor is less likely to have resistance to multiple drugs simultaneously.   Artemisinin -based monotherapies for malaria are explicitly discouraged to avoid the problem of developing resistance to the newer treatment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13570", "text": "Combination therapy may seem costlier than monotherapy in the short term, but when it is used appropriately, it causes significant savings: lower treatment failure rate, lower case-fatality ratios, fewer side-effects than monotherapy, slower development of resistance, and thus less money needed for the development of new drugs. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13571", "text": "Combination therapy has gained momentum in oncology in recent years, with various studies demonstrating higher response rates with combinations of drugs compared to monotherapies, [ 2 ] [ 3 ]  and the FDA recently approving therapeutic combination regimens that demonstrated superior safety and efficacy to monotherapies. [ 4 ]  In a recent study about solid cancers,  Martin Nowak ,  Bert Vogelstein , and colleagues showed that in most clinical cases, combination therapies are needed to avoid the evolution of resistance to targeted drugs. Furthermore, they find that the simultaneous administration of multiple targeted drugs minimizes the chance of relapse when no single mutation confers cross-resistance to both drugs. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13572", "text": "Various systems biology methods must be used to discover combination therapies to overcome drug resistance in select cancer types. [ 5 ] [ 6 ]  Recent  precision medicine  approaches have focused on targeting multiple biomarkers found in individual tumors by using combinations of drugs. [ 7 ] [ 8 ]  However, with 300 FDA-approved cancer drugs on the market, there almost 45,000 possible two-drug combinations and almost 4.5 million three-drug combinations for to choose from. [ 9 ]  That level of complexity is one of the primary impediments to the growth of combination therapy in oncology. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13573", "text": "The  National Cancer Institute  has recently highlighted combination therapy as a top research priority in oncology. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13574", "text": "Combination therapy with two or more antibiotics are often used in an effort to treat multi-drug resistant Gram-negative bacteria. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13575", "text": "Monotherapy, or the use of a single therapy, can be applied to any therapeutic approach, but it is most commonly used to describe the use of a single  medication .  Normally, monotherapy is selected because a single medication is adequate to treat the medical condition.  However, monotherapies may also be used because of  unwanted side effects  or dangerous  drug interactions . [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13576", "text": "The  Department of Pharmacology at the University College London ,  the first of its kind in  England , was founded in 1905 and remained in existence until 2007."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13577", "text": "University College London  (UCL) was founded in 1826. It was born in the ferment of radical London in the 1820s and 1830s and was heavily influenced by the Scottish and French  Enlightenments . UCL was part of the radical opposition to the hegemony of  Oxford  and  Cambridge . [ 1 ]  In medicine, UCL was a force in combatting the conservative and religious monopoly of the  Royal Colleges of Physicians  and  Surgeons [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13578", "text": "Although Edinburgh University was well ahead at the time, [ 2 ]  UCL had a professor of Materia Medica and Pharmacy,  A.T.Thomson, from the start. Later this was renamed as the chair of Materia Medica and Therapeutics.  Its best known holder was  Sydney Ringer  (1878\u201387), who worked on the isolated beating heart and is renowned for his eponymous salt solution which he designed to maximise the  viability of isolated hearts. His textbook  \u2018Handbook of Therapeutics\u2019  ran for 13 editions between 1869 and 1897."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13579", "text": "In 1905. Pharmacology was established as a distinct discipline within basic medical sciences at UCL. It was the first Department of Pharmacology in England. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13580", "text": "Most of the people involved in the development of quantitative analysis of drug-receptor interactions worked at some time in UCL's Departments of Pharmacology, or of Physiology or of Biophysics. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13581", "text": "Arthur Cushny (1866\u20131926) was the first holder of the newly instituted Chair of Pharmacology, from 1905 until 1918.\nAfter graduating in medicine from Aberdeen, Cushny had studied in Berne, W\u00fcrzburg, and Strasbourg, where he became Assistant to the famed  Oswald Schmiedeberg . In 1893, at the age of 27, he was appointed Professor of Pharmacology at the  University of Michigan, Ann Arbor . Eight years later Cushny came to the chair at UCL where he soon expanded the department from the single room he had been given. He raised the funds for the building which the remnants of the department still occupies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13582", "text": "His main interests were in the heart and kidney. His work on the involvement of calcium in the action of digitalis was prescient.  He was interested in optical isomers. Data from an early clinical trial [ 4 ]  using hyoscine isomers was used by  William Sealy Gossett  who, under the pseudonym \"Student\" published in 1908 the first small-sample test of significance, Student's  t  test. [ 5 ]  His use of these data has given rise to much discussion. [ 6 ]  Later reanalysis of the same data by a randomisation tests [ 7 ] [ 8 ]  gave a similar result."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13583", "text": "Cushny published a textbook  Textbook of Pharmacology and Therapeutics  (eighth edition 1924). He introduced the Cushny  myograph , an ingenious  arrangement of  counterbalanced levers that allowed the faithful recording of the rate and force of contraction of the rapidly beating animal heart. It was still in use in practical classes at UCL, and elsewhere, in the 1960s."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13584", "text": "Cushny left UCL in 1918, to become Professor of Materia Medica and Pharmacology at Edinburgh. he was succeeded by A.J. Clark/"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13585", "text": "A.J. Clark , FRS (1885\u20131941) [ 9 ]  held the established Chair of Pharmacology from 1918 to 1926. After qualifying in medicine, and serving as a field medical officer throughout the First World War, Clark had been appointed Professor of Pharmacology at the  University of Cape Town  where he remained until accepting the Chair of Pharmacology at UCL in 1920. His influence on the subject was profound. The distinguished physiologist and Nobel laureate A.V. Hill ( Archibald Hill ) had begun the quantitative study of the action of agonists on an isolated tissue (frog skeletal muscle) some years earlier. Clark took this much further and extended it to examine the actions of antagonists. The data he gathered on the exact relationship between agonist concentration and response, and on how this changed in the presence of a competitive antagonist, were published in two classic papers in the  Journal of Physiology  in 1926,. [ 10 ] [ 11 ]   But he failed to work out a method for analysing properly the results of experiments with antagonists: that had to wait for his successor, Heinz Schild. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13586", "text": "Nevertheless, Clark was largely responsible for the transition of pharmacology from a descriptive subject to the quantitative science that it is today - this emphasis on quantitative approaches has remained strong throughout the subsequent history of the department. Clark's book  The Mode of Action of Drugs on Cells [ 12 ]  (Williams & Wilkins, 1933) is a classic and the following quotation from it set the tone for the department for many years."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13587", "text": "While at UCL Clark wrote the first edition of his textbook  Applied Pharmacology [ 13 ]  in 1923, a book that was to be updated by two of his successors as Head of department, first by H.O. Schild and later by H.P. Rang, and is still extant in the form of the widely used textbook  Rang & Dale's Pharmacology . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13588", "text": "In 1926 Clark followed his predecessor in moving to the University of Edinburgh."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13589", "text": "Ernest Basil Verney  (1894\u20131967) [ 15 ]  succeeded Clark. He held the Chair of Pharmacology from 1926 to 1934.\nWhile at UCL Verney discovered the antidiuretic hormone and also the mechanism by which structures in the brain sense minute changes in blood osmotic pressure.  Both findings were of profound importance for the understanding of water and electrolyte balance. Verney was also instrumental in arranging for  Otto Krayer  to come to the department, albeit for only a short period, following Krayer's exclusion from all academic positions in German universities because of his objection to the expulsion of Jewish scientists from their posts. Krayer was later to head the Department of Pharmacology at Harvard with the greatest distinction. \nIn 1934 Verney moved to an academic post at the University of Cambridge where he later became the first Sheild Professor of Pharmacology"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13590", "text": "John Gaddum  (1900\u20131965) held the Chair of Pharmacology from 1935 to 1938.\nLike A.J. Clark, he had a profound interest in quantitative methods."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13591", "text": "He extended A.J. Clark's work on competitive antagonism, and applied the law of mass action to describe the relationship (the Gaddum equation) between receptor occupancy and the concentrations of an agonist and a competitive antagonist at equilibrium with the receptors in a tissue. The theory for two or more competing ligands had been known since Michaelis & Menten (1914), [ 3 ]  but Gaddum was the first to apply it in a pharmacological context). Like Clark before him, Gaddum failed to spot how to use the theory to estimate equilibrium constants. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13592", "text": "Gaddum was also a master of bioassay which was then the preferred, and usually the only, way to determine the concentrations of biologically active molecules such as labile neurotransmitters and the neuropeptides."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13593", "text": "Frank Winton (1894\u20131985) [ 16 ]  held the Chair of Pharmacology from 1938 to 1961. His main scientific interest was in the control of blood flow to the kidney. Winton ran the department through the difficult war years when the Medical School was evacuated to  Leatherhead, Surrey ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13594", "text": "He appointed the first two female academics in the department. Mary Lockett (1911\u20131982) [ 17 ]  was a lecturer in the department from 1945 - 1950.  Hannah Steinberg  arrived in the UK from Vienna on a  Kindertransport  train while still a schoolgirl, and she eventually became Professor of Psychopharmacology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13595", "text": "Winton also worked hard and successfully to ensure that pharmacology had an appropriate place in the preclinical curriculum. He oversaw the extension of the department, including the Pharmacology Lecture Theatre (now the Schild Theatre)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13596", "text": "He was the author, with  Leonard Bayliss , of a widely used textbook  Human Physiology , first published in 1932. The 6th edition, 1968 was written by Olof J.C. Lippold and F.R Winton [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13597", "text": "Heinz Otto Schild (1906\u20131984) [ 19 ]  held the Chair of Pharmacology from 1961 to 1973."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13598", "text": "He was born in Fiume (now  Rijeka , Croatia), in 1908, when it was part of the  Austro-Hungarian empire . He qualified in medicine in Munich and then worked with Straub, the leading German pharmacologist of the time. By good fortune, Schild had been accepted as a visiting worker by  Sir Henry Dale  and was in England when the National Socialists came to power in Germany. He decided to stay in Britain and became an assistant in the Department of Pharmacology in Edinburgh, then headed by A.J. Clark. When J. H. Gaddum was appointed to the chair at UCL, he invited Schild to join him as a Demonstrator. So began his long association with UCL, interrupted only by his bizarre internment on the Isle of Man as an \u2018enemy alien\u2019 at the outbreak of the Second World War. Following his release (greatly aided by F.R Winton's and Sir  Henry Dale 's appeals to the Home Office) he returned to his work in the department, then based in Leatherhead, and in 1961 became Winton's successor as Head of Department and Professor of Pharmacology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13599", "text": "Schild made major contributions to receptor pharmacology, to the understanding of the mechanism of histamine release and to bioassay. Like Gaddum and Clark, he used quantitative approaches whenever possible. His name is immortalised by the Schild equation. [ 3 ]   He built on the work of Clark and Gaddum on competitive antagonism, by realising that the null method was key to extraction of physical equilibrium constants  from simple functional experiments. Rather than looking at the depression by antagonist of the response to a fixed agonist concentration, he measured the  dose-ratio , the factor by which the agonist concentration had to be increased in order to restore a given response in the presence of the antagonist. By measuring the dose-ratio as a function of antagonist, it was possible to estimate the dissociation equilibrium constant for the combination of the antagonist with its receptor. [ 3 ]  Crucially the estimate is not dependent on the nature of the agonist.  Although Schild's derivation used the simplest possible model, it was subsequently shown that his equation is valid under much more general conditions. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13600", "text": "A.J. Clark's textbook was continued by Schild as  Clark's Applied Pharmacology  by Wilson & Schild. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13601", "text": "Heinz Schild was a generous and kindly Head of department. He appointed the third female member of academic staff, Dr M. Maureen Dale, a co-author of Rang & Dales Pharmacology. [ 14 ]  He oversaw the planning and introduction of a three-year B.Sc. course in Pharmacology which began in 1967 and continues to this day. Medical students were able to enter its final year and Schild, who never lost sight of the roots of the subject in medicine, was delighted that many took this opportunity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13602", "text": "Sir James Whyte Black   OM   FRS   FRSE   FRCP  (1924\u20132010) held the Chair of Pharmacology from 1973 to 1978."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13603", "text": "Jim Black and Heinz Schild knew each other well because Schild had acted as a consultant to the then Smith, Kline & French company during the time when Black was leading the team that developed the histamine receptor antagonists, [ 22 ]   H 2  antagonists , which reduce secretion of gastric acid and which, at the time, transformed the treatment of gastric ulcers. Schild's methods for quantitative methods for analysis of drug antagonists [ 3 ] [ 20 ]  were crucial for this work."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13604", "text": "Black introduced many changes to teaching in the department. One of the most important was the introduction of a BSc course in Medicinal Chemistry. His long experience in the pharmaceutical industry had convinced him that organic and physical chemists working on drug development with pharmacologists and biochemists would benefit greatly from a substantial knowledge of biology, certainly enough to allow them to understand and assess the kinds of measurements that their biological colleagues undertook.  Though the students were based in the Department of Chemistry, they took also courses in physiology and pharmacology, particularly its molecular aspects. This BSc course, like that in Pharmacology, also flourished and continues today. Another important change was a sharp reduction in the number of experiments with animal tissues undertaken by medical students during their course in pharmacology. At the same time, the emphasis on the importance of observations on human subjects was increased."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13605", "text": "Black's appointment coincided with the onset of the straitened circumstances that all UK universities were to experience and that have continued in one form or another ever since. The changes he made helped the department to adjust to these harder times. To the regret of his Departmental staff, Black found that only the pharmaceutical industry could provide the facilities needed for the work he wished to pursue, and in 1978 he left to join the Wellcome Foundation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13606", "text": "Black was knighted in 1981 and in 1988 he got the  Nobel Prize in Physiology or Medicine  along with  Gertrude B. Elion  and  George H. Hitchings  for their work on drug development."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13607", "text": "Humphrey Rang (born 1936) held the Chair of Pharmacology from 1979 to 1983."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13608", "text": "Rang qualified in medicine at UCL and had worked in H.O.Schild's laboratory while a medical student. He was the author of the first successful ligand-binding experiment of the modern era. [ 23 ]  This was based on his PhD work in Oxford, under  William D.M. Paton . Rang had previously been the Professor of Pharmacology at Southampton and at St. George's Hospital Medical School. He brought with him  David Colquhoun  who was also returning to the department, having been appointed in 1964 as an assistant lecturer by H.O. Schild. These appointments greatly strengthened the interests and achievements of the department in fundamental aspects of pharmacology, particularly the study of ion channels and receptors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13609", "text": "In collaboration with M. Maureen Dale (also appointed during Schild's Headship), Rang prepared the first edition of  Pharmacology , [ 14 ]  the successor to Wilson & Schild's   Applied Pharmacology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13610", "text": "In 1983 Rang was offered and accepted the Directorship of the Sandoz Institute of Medical Research, a division of   Sandoz , then an independent pharmaceutical company. The new Institute was located in UCL and developed a close relationship with the department, both in teaching, to which members of the Institute contributed, and in research."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13611", "text": "After Rang's resignation, the Chair of Pharmacology became vacant.  The Head of department from 1983 to 1987 was  Donald.H Jenkinson   He had done his PhD under  Bernard Katz . in UCL's famous Department of Biophysics, and was yet  another member of staff who had been invited to join the Department by Heinz Schild.  During his tenure the Middlesex Hospital Medical School was merged with UCL's, including the two Departments of Pharmacology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13612", "text": "During the 1980s the traditional role of Heads of department was replaced by rotating headships that were no longer associated necessarily with an established chair.  Established chairs were,  de facto , abolished as part of the move to corporatise universities."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13613", "text": "David Colquhoun  FRS  was appointed to the established chair in 1985. It was subsequently dubbed the A.J. Clark chair, in honour of Clark's role in the establishment of quantitative pharmacology.  His work, with statistician Alan Hawkes and  Bert Sakmann  (Nobel prize 1991) established the department as the world leader in the theory and experiment of single ion channels. After retiring from the A.J.Clark chair in 2004, he worked on the misinterpretation of  p  values and its contribution to the irreproducibility that has come to light in some areas of science. [ 24 ] [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13614", "text": "D. A. Brown FRS  (1936 - 2023) was appointed in 1987 as head of department (he had previously held the same position at the School of Pharmacy). In 1987, the merger with the  Middlesex Hospital  Medical School was completed  and David Brown inherited the  title Astor Chair of Pharmacology from Professor F Hobbiger who had held that title at the Middlesex."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13615", "text": "Brown's appointment was intended initially to be the start of a 5-year rotating headship, but when Colquhoun's turn became due, he decided that the job of Head of department would not allow enough time to do the algebra and program development with which he was involved.  Donald Jenkinson likewise declined to take another turn. Luckily David Brown agreed to continue and he remained Head of department until 2002.  His tenure saw a second merger, this time with the Department of Pharmacology at the  Royal Free Medical School , headed by Professor  Annette Dolphin , FRS. David Brown is renowned for his discovery of the acetylcholine (muscarinic)-sensitive potassium channel (M channel)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13616", "text": "The Wellcome Lab for Molecular Pharmacology  \nThe growing importance of molecular biology led Brown & Colquhoun to apply to the  Wellcome Trust  in 1990. They funded the building of the Lab for Molecular Pharmacology  which Colquhoun directed until his retirement in 2004."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13617", "text": "Trevor G. Smart [ 27 ]  became Head of department in 2002, with the title of Schild Chair of Pharmacology.  He also works in the ion channel field. After the demise of the department in 2007. Smart became head of the new Research Department of Neuroscience, Physiology and Pharmacology. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13618", "text": "Stephanie Schorge . [ 29 ]  In 2021, Professor Schorge succeeded Trevor Smart as head of the Research Department of Neuroscience, Physiology and Pharmacology. She is the first female head of pharmacology since 1905."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13619", "text": "Stuart Cull-Candy  FRS . Stuart G. Cull-Candy works on glutamate-activated ion channels. He joined the Department from UCL's Department of Biophysics and holds the Gaddum Chair of Pharmacology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13620", "text": "Lucia Sivilotti  was appointed to the A.J. Clark chair in 2014.  She has run the UCL Single Ion Channel group after Colquhoun's retirement in 2004. She  continued and greatly extended the work in the field of single channel kinetics. She owns the web site OneMol  [1]  where the group's analysis programs and publications can be downloaded.  The association of the A.J. Clark chair with quantitative work on receptors has thus continued to the present day."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13621", "text": "The first of the nationwide  Research Assessment Exercises  took place in 1986. The UCL Department headed the list. It continued to be rated as the top Department of Pharmacology in each of the four research assessments that followed in 1989, 1992, 1996 and 2002.   But this performance was not enough to save the department."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13622", "text": "In 2004,  Malcolm Grant  became provost of UCL. He commissioned external reports on the reorganisation of the college. The distinguished vice-president of the University of Manchester,  Richard Alan North  FRS, was asked to assess several options for the reorganisation of the Faculty of Life Sciences. One was to create large Research Departments, including one of Neuroscience, Physiology and Pharmacology, from the existing academic Departments. Professor North's only comment on the options was that the proposed \"research departments in Life Sciences were too big\". Grant accepted the conclusions except for the part about the size of departments."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13623", "text": "On 24 May 2007 Grant persuaded the Academic Board to authorise him to act on its behalf [ 30 ]   and on 13 June 2007 the Department of Pharmacology was disestablished, after a century of distinction and innovation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13624", "text": "The academic staff at the time had three main concerns about the proposals. (a) The separation of teaching from research is bad, especially for teaching: the fact that a degree is offered in, for example, Pharmacology without a Pharmacology department to support it, means that there is no guarantee that there will be staff qualified or fully motivated to teach it. Moreover, the collegiality that comes from designing and providing a first-rate degree course is lost. (b) The size of the merged department of Neurosciences, Physiology and Pharmacology means less interaction between staff, and less collegiate spirit. (c) The changes created two extra levels of administration, so that now five levels existed between academics and the provost."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13625", "text": "Staff were told at the time that the new organisation would be rolled out to other Faculties across UCL, though this has not happened.    David Colquhoun  has kept a personal diary of the process on his blog:  In Memoriam Department of Pharmacology, UCL 1905 \u2013 2007 . [ 31 ]   On the positive side, UCL's current provost,  Michael Arthur , has put much emphasis on the quality of teaching, and maintaining its connections with research."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13626", "text": "As of 2019, UCL still offers pharmacology degrees, though within the now merged Neuroscience, Physiology and Pharmacology department."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13627", "text": "A history of the combined department appears on UCL's web site. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13628", "text": "Excretion  is elimination of  metabolic waste , which is an essential process in all  organisms . In  vertebrates , this is primarily carried out by the  lungs ,  kidneys , and  skin . [ 1 ]  This is in contrast with  secretion , where the substance may have specific tasks after leaving the  cell . For example,  placental mammals  expel  urine  from the  bladder  through the  urethra , [ 2 ]  which is part of the  excretory system .  Unicellular organisms  discharge waste products directly through the surface of the cell."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13629", "text": "During life activities such as  cellular respiration , several chemical reactions take place in the body. These are known as  metabolism . These chemical reactions produce waste products such as  carbon dioxide , water,  salts ,  urea  and  uric acid . Accumulation of these wastes beyond a level inside the body is harmful to the body. The excretory organs remove these wastes. This process of removal of metabolic waste from the body is known as excretion."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13630", "text": "Green  plants  excrete carbon dioxide and water as respiratory products. In green plants, the  carbon dioxide  released during respiration gets used during photosynthesis.  Oxygen  is a byproduct generated during  photosynthesis , and exits through  stomata , root cell walls, and other routes. Plants can get rid of excess water by transpiration and  guttation . It has been shown that the leaf acts as an 'excretophore' and, in addition to being a primary organ of photosynthesis, is also used as a method of excreting toxic wastes via diffusion. Other waste materials that are exuded by some plants\u00a0\u2014  resin , saps,  latex , etc. are forced from the interior of the plant by hydrostatic pressures inside the plant and by absorptive forces of plant cells. These latter processes do not need added energy, they act passively. However, during the pre-abscission phase, the metabolic levels of a leaf are high. [ 3 ] [ 4 ]  Plants also excrete some waste substances into the soil around them. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13631", "text": "In animals, the main excretory products are  carbon dioxide ,  ammonia  (in  ammoniotelics ),  urea  (in  ureotelics ),  uric acid  (in  uricotelics ),  guanine  (in  Arachnida ), and  creatine . The liver and kidneys  clear  many substances from the  blood  (for example, in  renal excretion ), and the cleared substances are then excreted from the body in the  urine  and  feces . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13632", "text": "Aquatic animals  usually excrete  ammonia  directly into the external environment, as this compound has high  solubility  and there is ample water available for dilution. In  terrestrial animals , ammonia-like compounds are converted into other nitrogenous materials, i.e.  urea , that are less harmful as there is less water in the environment and ammonia itself is  toxic . This process is called detoxification. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13633", "text": "Birds  excrete their nitrogenous wastes as  uric acid  in the form of a paste. Although this process is metabolically more expensive, it allows more efficient  water  retention and it can be stored more easily in the  egg . Many avian species, especially  seabirds , can also excrete salt via specialized nasal salt glands, the saline solution leaving through nostrils in the  beak ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13634", "text": "In  insects , a system involving  Malpighian tubules  is used to excrete  metabolic waste . Metabolic waste diffuses or is actively transported into the tubule, which transports the wastes to the intestines. The metabolic waste is then released from the body along with fecal matter."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13635", "text": "The excreted material may be called  ejecta . [ 8 ]  In  pathology  the word ejecta is more commonly used. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13636", "text": "FK962  is a compound which acts as an enhancer of  somatostatin  release. It stimulates nerve growth and  neurite  elongation, and has been researched in animal models for potential applications in the treatment of conditions such as  Alzheimer's disease  and  retinal neuropathy . [ 1 ] [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13637", "text": "This  hormonal preparation  article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13638", "text": "The  IUPHAR/BPS Guide to PHARMACOLOGY  is an  open-access  website, acting as a portal to information on the biological targets of licensed drugs and other small molecules. The Guide to PHARMACOLOGY (with GtoPdb being the standard abbreviation) is developed as a joint venture between the  International Union of Basic and Clinical Pharmacology  (IUPHAR) and the  British Pharmacological Society  (BPS). This replaces and expands upon the original 2009 IUPHAR Database (standard abbreviation IUPHAR-DB). The Guide to PHARMACOLOGY aims to provide a concise overview of all pharmacological targets, accessible to all members of the scientific and clinical communities and the interested public, with links to details on a selected set of targets. The information featured includes pharmacological data, target, and gene nomenclature, as well as curated chemical information for ligands. Overviews and commentaries on each target family are included, with links to key references."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13639", "text": "The  Guide to PHARMACOLOGY  was initially made available online in December 2011 with additional material released in July 2012. Maintained by a team of curators based at the University of Edinburgh, the Guide to PHARMACOLOGY is developed by an international network of contributors, including the editors of the  Concise Guide to PHARMACOLOGY . As with the original IUPHAR-DB, the International Union of Basic and Clinical Pharmacology (IUPHAR) Committee on Receptor Nomenclature and Drug Classification  (NC-IUPHAR), acts as the scientific advisory and editorial board for the database. Its network of over 500 specialist advisors (organized into ~90 subcommittees) contribute expertise and data. The current PI and Grant holder of the GtoPdb project is Prof.  Jamie A. Davies . The development and release of the first version of the GtoPdb in 2012 were described in an editorial published in the  British Journal of Pharmacology  entitled 'Guide to Pharmacology.org- an update'. [ 2 ]  The IUPHAR-DB is no longer being developed and all the information contained within this site is now available through the Guide to PHARMACOLOGY (IUPHAR-DB links should now re-direct)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13640", "text": "The target groups currently included on the Guide to PHARMACOLOGY are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13641", "text": "Information for each target group is subdivided into families based on classification, with a separate data page for each family. Within each page, targets are arranged into lists of tables, with each table including the protein and gene nomenclature for the target with links to gene nomenclature databases, and listing selected ligands with activity at the target, including agonists, antagonists, inhibitors and radioligands. Pharmacological data and references are given and each ligand is hyperlinked to a ligand page displaying nomenclature and a chemical structure or peptide sequence, along with synonyms and relevant database links. The Guide to PHARMACOLOGY also includes a list of all ligand molecules included on the site, subdivided into categories including small organic molecules (including mammalian  metabolites ,  hormones  and  neurotransmitters ), synthetic organic molecules,  natural products ,  peptides , inorganic molecules and  antibodies . A complete list of all the approved drugs included on the website is also available via the ligand list. The Guide to PHARMACOLOGY is being expanded to include clinical information on targets and ligands, in addition to educational resources.\nSearch features on the website include quick and advanced search options, and receptor and ligand searches, including support for ligand structures using chemical structures. Other features include 'Hot topic' news items and a recent receptor-ligand pairing list."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13642", "text": "Between November 2015 and October 2018, the  Wellcome Trust  supported a project to develop the IUPHAR Guide to IMMUNOPHARMACOLOGY [ 3 ]  (GtoImmuPdb), based on the GtoPdb schema. The GtoImmuPdb is an open-access resource that brings an immunological perspective to the high-quality, expert-curated pharmacological data found in the existing IUPHAR/BPS Guide to PHARMACOLOGY. Protein targets and ligands relevant to immunopharmacology have been tagged and curated into GtoImmuPdb. These have also been associated with new immunological data types such as immunological processes, cell types, and disease. GtoImmuPdb provides a knowledge base that connects immunology with pharmacology, bringing added value and supporting research and development of drugs targeted at modulating immune, inflammatory or infectious components of the disease. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13643", "text": "The Guide to PHARMACOLOGY includes an online, open-access database version of the  Concise Guide to PHARMACOLOGY , previously \"The Guide to Receptors and Channels\" [ 5 ]  available in HTML, PDF and printed formats. A hard copy summary of the online database is published as  The Concise Guide to Pharmacology 2017/2018 [ 6 ]  as a series of papers as a bi-annual supplement to the  British Journal of Pharmacology ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13644", "text": "The Guide to PHARMACOLOGY includes links to other relevant resources via target and ligand pages on both the concise and detailed view pages. Many of these resources maintain reciprocal links with the relevant Guide to PHARMACOLOGY pages."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13645", "text": "Following funding from the  Wellcome Trust , from 2012 to 2015 the Guide to PHARMACOLOGY was expanded to include the biological targets of all prescription drugs and other likely targets of future small molecule drugs. Overviews of the key features of a wide range of targets are provided on the summary view pages, with detailed view pages providing more in-depth information on the properties of a selected subset of targets. As of January 2018 the  Medicines for Malaria Venture  is supporting a new extension to develop the Guide to Malaria Pharmacology. [ 7 ]  The core GtoPdb continues to be supported by the  British Pharmacological Society ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13646", "text": "For over two millennia, texts in  Chinese herbology  and  traditional Chinese medicine  have recorded medicinal plants that are also  hallucinogens  and  psychedelics . Some are familiar  psychoactive plants  in Western  herbal medicine  (e.g.,  Chinese :  \u83a8\u83ea ;  pinyin :  l\u00e0ngd\u00e0ng , i.e.  Hyoscyamus niger ), but several Chinese plants have not been noted as hallucinogens in modern works (e.g., Chinese :  \u96f2\u5be6 ;  pinyin :  y\u00fansh\u00ed ;  lit.  'cloud seed', i.e.  Caesalpinia decapetala ). Chinese  herbals  are an important resource for the  history of botany , for instance,  Zhang Hua 's c. 290  Bowuzhi  is the earliest record of the  psilocybin mushroom   xi\u00e0oj\u00f9n   \u7b11\u83cc  (lit. \"laughing mushroom\", i.e.  Gymnopilus junonius )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13647", "text": "There is a  lexical gap  between Chinese names and descriptions of hallucinogenic plants and English pharmacological terminology for hallucinogens, which are commonly divided into psychedelics, dissociatives, and deliriants."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13648", "text": "The  English lexicon  has a complex  semantic field  for  psychoactive drugs , and most terms are  neologisms . [ a ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13649", "text": "Hallucination  (from Latin  alucinor  \"to wander in mind\") is defined as: \"The apparent, often strong subjective perception of an external object or event when no such stimulus or situation is present; may be visual, auditory, olfactory, gustatory, or tactile.\"  Hallucinogen  (coined in 1952 from Latin  alucinor  and  -gen  \"producing\"): \"A mind-altering chemical, drug, or agent, specifically a chemical the most prominent pharmacologic action of which is on the central nervous system (mescaline); in normal people, it elicits optic or auditory hallucinations, depersonalization, perceptual disturbances, and disturbances of thought processes.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_13650", "text": "Pharmacology  divides hallucinogens into three classes.  Psychedelic  (first used in 1956 from Greek  psyche-  \"mind; soul\" and  delein  \"to manifest\"): \"Pertaining to a rather imprecise category of drugs with mainly central nervous system action, and with effects said to be the expansion or heightening of consciousness, LSD, hashish, mescaline, psilocybin.\"  Dissociative  is a class of hallucinogen that produces feelings of  dissociation  (Latin  dissocioatus  \"to disjoin, separate\" from  socius  \"partner, ally\") meaning \"(3) An unconscious separation of a group of mental processes from the rest, resulting in an independent functioning of these processes and a loss of the usual associations, a separation of affect from cognition.\"  Dissociative disorders  is defined as \"a group of mental disorders characterized by disturbances in the functions of identity, memory, consciousness, or perception of the environment; this diagnostic group includes dissociative (older term, psychogenic) amnesia, dissociative fugue, dissociative identity (older term, multiple personality) disorder, and depersonalization disorder.\"  Deliriant  is a technical term introduced to distinguish hallucinogens that primarily cause  delirium  (1982, from Latin  deliro  \"to be crazy\" and  delira  \"go out of the furrow\"): \"An altered state of consciousness, consisting of confusion, distractibility, disorientation, disordered thinking and memory, defective perception (illusions and hallucinations), prominent hyperactivity, agitation, and autonomic nervous system overactivity; caused by illness, medication, or toxic, structural, and metabolic disorders.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_13651", "text": "The equivalent semantic field in the  Chinese lexicon  comprises contemporary  loanwords . [ b ]   Hu\u00e0nju\u00e9  ( \u5e7b\u89ba  \"hallucination; delusion; illusion\")  compounds   hu\u00e0n  ( \u5e7b  \"unreal; imaginary; illusory\") and ( ju\u00e9''   \u89ba  \"feeling; sensation; perception\").  Zh\u00echu\u00e0nj\u00ec  ( \u81f4\u5e7b\u5291  \"psychedelic; hallucinogen\") compounds  zh\u00ec  ( \u81f4  \"incur; cause\"),  hu\u00e0n  \"unreal; imaginary; illusory\", and  j\u00ec  ( \u5291  \"medicinal preparation; dose\").  Zh\u00echu\u00e0ny\u00e0o  ( \u81f4\u5e7b\u85e5  \"hallucinogenic drug\") with  y\u00e0o  ( \u85e5  \"medicine; drug\") is a less common synonym."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13652", "text": "M\u00edhu\u00e0ny\u00e0ow\u00f9  ( \u8ff7\u5e7b\u85e5\u7269  \"psychedelic\") combines  m\u00edhu\u00e0n  ( \u8ff7\u5e7b  \"phantasmagoric; surreal; mysterious; psychedelic\") and  y\u00e0ow\u00f9  ( \u85e5\u7269  \"medicine; pharmaceutical; medicament\"). The Chinese technical names for the last two classes of hallucinogens are rare:  Y\u00f3ul\u00edy\u00e0op\u01d0n  ( \u6e38\u79bb\u85e5\u54c1  \"dissociative\") compounds  y\u00f3ul\u00ed  ( \u6e38\u79bb  \"dissociated; drifting\") and  y\u00e0op\u01d0n  ( \u85e5\u54c1  \" medicine; chemical reagent; drug\"); and  Zh\u00eczh\u0101nw\u00e0ngy\u00e0o  ( \u81f4\u8c35\u5984\u85e5  \"deliriant\") combines  zh\u00ec  \"incur; cause\",  zh\u0101nw\u00e0ng  ( \u8b6b\u5984  \"(medical) delirium\"), and  y\u00e0o  \"medicine; drug\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13653", "text": "Chinese  pharmaceutical  literature mainly comprises texts called  bencao  ( Chinese :  \u672c\u8349 ;  pinyin :  b\u011bnc\u01ceo ;  Wade\u2013Giles :  pen-ts'ao ), translatable as English  herbal ,  pharmacopoeia , or  materia medica . This word  compounds   ben  \"(plant) root/stem; basis, origin; foundation; book\" and  cao  \"grass; herb; straw\". Although  bencao  is sometimes misinterpreted as \"roots and herbs\", the approximate meaning is \"[pharmaceutics whose] basis [ ben ] [is] herbs [ cao ]\". [ 1 ] [ failed verification ]  These works deal with drugs of all origins, mainly vegetable but also mineral, animal, and even the  human body ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13654", "text": "The Chinese  botanist , academic, and researcher  Hui-lin Li  (1911-2002) wrote seminal articles about the history and use of hallucinogenic plants in China. Li cites a story in  Li Shizhen 's 1596 magnum opus  Bencao gangmu  as the first discussion about the general use of psychoactive plants. In 1561, after horrific murders in  Changli , the  Ming dynasty   Jiajing Emperor  proclaimed a nationwide edict warning about the dangers of hallucinogens."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13655", "text": "Lang-tang ( Hyoscyamus niger ), Y\u00fcn-shih ( Caesalpinia Sepiaria ), Fang-k'uei ( Peucedanum japonica ) and Red Shanglu ( Phytolacca acinosa ) all can cause hallucination in peoples. In the past, this significance has not been fully divulged. Plants of this kind are all toxic, which can obscure the mind, alter one's consciousness, and confuse one's perception of sight and sound. In the T'ang times, An Lu-shan [a foreign warlord in the Chinese army service] once enticed the Kitan [tribesmen surrendered to his command] to drink Lang-tang wine and buried them alive while they were unconscious. Again in the second month of the 43rd year of the Chia-ch'in period (1561 A.D.), a wandering monk, Wu Ju-hsiang of Shensi province, who possessed wizardry, arrived at Ch'ang-li and stopped over at the house of a resident, Chang Shu. Upon finding the latter's wife being very beautiful, he asked that the entire family sit together at the table with him when he was being offered a meal. He put some reddish potion in the rice and after a while the whole family became unconscious and submitted to his assault. He then blew a magic spell into the ears of Chang Shu and the latter turned crazy and violent. Chang visualized his entire family as all devils and thereby killed them all, sixteen altogether, without any blood shed. The local authorities captured Chang Shu and kept him in prison. After ten days, he spat out nearly two spittoonsful of phlegm, became conscious, and found out himself that those he killed were his parents, brothers, sisters-in-law, his wife, sons, sisters, nephews. Both Chang and Wu were committed to the death sentence. The Emperor, Shih-tsung, proclaimed throughout the country about the case. The particular magic potion must be of the kind of Lang-tang or similar drugs. When the man was under the spell, he saw everyone else as a devil. It is thus very important to find out the remedy that counteracts such a thing. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13656", "text": "The following eight examples of confirmed and possible hallucinogens recorded in Chinese herbals are primarily based on the ten in Li Hui-Lin's 1977 article. [ 3 ]  Two edible plants, with only one Chinese source and no Western ones mentioning psychoactive properties, are omitted as unlikely:  fangfeng  ( \u9632\u98ce ;  \u9632\u98a8 ;  f\u00e1ngf\u0113ng ;  fang-feng  \" Saposhnikovia divaricata ;  Chinese parsnip \") and  longli  ( \u9f99\u8354 ;  \u9f8d\u8354 ;  l\u00f3ngl\u00ec ;  lung-li  \" Nephelium  topengii\"; a type of  lychee \"). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13657", "text": "The  l\u00e0ngd\u00e0ng  ( \u83a8\u83ea ;  l\u00e0ngd\u00e0ng ;  lang-tang  \" Hyoscyamus niger ; black henbane\") is one of the most famous hallucinogenic drugs in Chinese herbals. The seeds, which contain psychoactive  tropane alkaloids , are called  l\u00e0ngd\u00e0ngzi  ( \u83a8\u83ea\u5b50 , with  -zi  \"child; seed\") or  ti\u0101nxi\u0101nzi  ( \u5929\u4ed9\u5b50  \"heavenly  transcendent  seeds\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13658", "text": "For use in medicine, the seeds are supposedly treated by soaking in vinegar and milk to reduce their toxicity. The  Shennong Bencaojing  says, \"[The seeds] when taken [when properly prepared] for a prolonged period enable one to walk for long distances, benefiting to the mind and adding to the strength ... and to communicate with spirits and seeing devils. When taken in excess, it causes one to stagger madly.\" [ 5 ]  Lei Xiao's 470  Leigong paozhilun  ( \u96f7\u516c\u70ae\u7099\u8ad6  \"Master Lei's Treatise on the Decoction and Preparation of Drugs\") states that the seed \"is extremely poisonous, and when accidentally taken, it causes delirium and seeing sparks and flashes\", and Zhen Chuan's c. 620  Bencao yaoxing  ( \u672c\u8349\u85e5\u6027  \"Nature of Drugs in Materia Medica\") says the seeds \"should not be taken raw as it hurts people, causing them to see devils, acting madly like picking needles\". [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13659", "text": "The  yunshi  ( \u4e91\u5b9e ;  \u96f2\u5be6 ;  y\u00fansh\u00ed ;  yun-shih  \" Caesalpinia decapetala ; cat's claw\") was a versatile drug plant in the Chinese pharmacopeia, and the root, flowers, and seeds were all used in medicine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13660", "text": "The  Shennong Bencao  says, \"[The flowers] could enable one to see spirits, and when taken in excess, cause one to stagger madly. If taken over a prolonged period, they produce somatic levitation and effect communication with spirits.\"  Tao Hongjing , who edited the official  Shangqing Daoist  canon, also compiled the c. 510  Mingyi bielu  ( \u540d\u91ab\u5225\u9304  \"Supplementary Records of Famous Physicians\") that says \"[The flowers] will drive away evil spirits. When put in water and burned, spirits can be summoned\" and \"The seeds are like  langdang  ( Hyoscyamus niger ), if burned, spirits can be summoned; but this [sorcery] method has not been observed.\" [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13661", "text": "Li Hui-Lin notes this plant \"has not been noted as a hallucinogenic plant in modern works. In fact, as far as I am aware, it has not been investigated medicinally or chemically\". [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13662", "text": "The  fangkui  ( \u9632\u8475 ;  f\u00e1ngku\u00ed ;  fang-k'ui  \" Peucedanum japonicum \") root is used in Chinese medicine, and like the previous cat's claw, has not been noted as a hallucinogenic in modern works. The c. 510  Tao Hongjing mingyi bielu  states, \"Feverish people should not take it, because it causes one to be delirious and see spirits\"; and Chen Yanzhi's ( \u9673\u5ef6\u4e4b ) c. 454-473  Xiaoping fang  ( \u5c0f\u54c1\u65b9  \"Minor Prescriptions\") says that  fangkui , \"if taken in excess, makes one become delirious and act somewhat like mad\". [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13663", "text": "P. japonicum  is also used quite extensively in Korean cuisine - not only as a culinary herb, but also as a leaf vegetable, raising the question as to what constitutes consumption 'to excess'. It may be the case that the strain of plant grown in Korea is less toxic / medicinal than that found in China, or that very substantial quantities of the plant must be eaten before any psychoactive effects are manifested. Alternatively, the psychoactive components of the plant may be deactivated by the cooking processes employed in the preparation of the plant in Korea. [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13664", "text": "The  shanglu  ( \u5546\u9646 ;  \u5546\u9678 ;  sh\u0101ngl\u00f9 ;  shang-lu  \" Phytolacca  acinosa ; India pokeweed\") has edible leaves and poisonous roots. China's oldest extant dictionary, the c. 3rd-century BCE  Erya  (13: 110) gives two names for pokeweed:  ch\u00f9t\u0101ng  ( \u84eb\u859a ) and  m\u01cew\u011bi  ( \u99ac\u5c3e  \"horsetail\")."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13665", "text": "Chinese herbals distinguish two kinds of  shanglu , white with white flowers and white root, and red with red flowers and purple root. The white root is edible when cooked but the red root is extremely poisonous. The  Tao Hongjing mingyi bielu  records how Daoists used the red variety, \"By boiling or brewing and then taken, it can be used for abdominal parasitic worms and for seeing spirits\";  Su Song 's 1061  Bencao tujing  ( \u672c\u8349\u5716\u7d93  \"Illustrated Pharmacopeia\") says, \"It was much used by sorcerers in ancient times\". [ 12 ]  Su Gong's 659  Tang bencao  (\u5510\u672c\u8349 \" Tang dynasty  pharmacopeia\") says \"The red kind can be used to summon spirits; it is very poisonous. It can be only used as external application for inflammation. When ingested, it is extremely harmful, causing unceasing bloody stool. It may be fatal. It causes one to see spirits.\" [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13666", "text": "The 1406  Jiuhuang Bencao  \"Famine Relief Herbal\" lists pokeweed as a  famine food . It gives instructions for removing the poisonous phytolaccatoxin from the white roots and mentions Daoist  xian  using the flowers: \"Cut them up into slices, scald, then soak and wash repeatedly (throwing away the extract) until the material is clean; then just eat it with garlic. \u2026 Plants with white flowers can (it is said) confer longevity; the immortals collected them to make savouries to take with their wine.\" [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13667", "text": "Dama  ( \u5927\u9ebb ;  d\u00e0m\u00e1 ;  ta-ma  \" Cannabis sativa ; hemp; marijuana\") has been grown in China since  Neolithic  times. At a very early period the Chinese recognized the Cannabis plant as  dioecious , the male plants produce better fibers and the female plants produce more  cannabinoids . In modern usage, the names are  x\u01d0  ( \u67b2  \"male cannabis\") and  j\u016b  ( \u82f4  \"female cannabis\"). [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13668", "text": "Reflecting the importance of cannabis in ancient China, the ca. 3rd century BCE  Erya  dictionary (13) has four definitions:  f\u00e9n  ( \u9ec2 ;  \u8561 ) and  x\u01d0sh\u00ed  ( \u67b2\u5be6 ) mean \"cannabis flower\";  x\u01d0  ( \u67b2 ) and  m\u00e1  ( \u9ebb ) mean \"cannabis\" generally and not \"male cannabis\";  f\u00fa  ( \u83a9 , lit. \"reed membrane\") and  m\u00e1m\u01d4  ( \u9ebb\u6bcd , \"cannabis mother\") mean \"female cannabis\"; and  b\u00f2  ( \u859c ) and  sh\u0101nm\u00e1  ( \u5c71\u9ebb  \"mountain cannabis\") mean \"wild cannabis\", possibly  C. ruderalis ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13669", "text": "The  Shennong bencao  calls \"cannabis flowers/buds\"  mafen  ( \u9ebb\u8561 ) or  mabo  ( \u9ebb\u52c3 ) and says: \"To take much makes people see demons and throw themselves about like maniacs [ \u591a\u98df\u4ee4\u4eba\u898b\u9b3c\u72c2\u8d70 ]. But if one takes it over a long period of time one can communicate with the spirits, and one's body becomes light [ \u4e45\u670d\u901a\u795e\u660e\u8f15\u8eab ]\". [ 16 ]  The  Mingyi bielu  records that in the 6th century,  mabo  were, \"very little used in medicine, but the magician-technicians [ shujia   \u8853\u5bb6 ] say that if one consumes them with ginseng it will give one preternatural knowledge of events in the future.\" [ 17 ]  Meng Shen's c. 670  Shiliao bencao  ( \u98df\u7642\u672c\u8349  \"Nutritional Therapy Pharmacopeia\") says people will combine equal parts of raw cannabis flowers,  Japanese sweet flag , and  wild mandrake , \"pound them into pills of the size of marbles and take one facing the sun every day. After one hundred days, one can see spirits.\" [ 18 ]  Tang Shengwei's 1108  Zhenglei bencao  ( \u8b49\u985e\u672c\u8349  \"Reorganized Pharmacopeia\") gives a more complete account on the pharmaceutical uses of cannabis: \"Ma-fen has a spicy taste; it is toxic; it is used for waste diseases and injuries; it clears blood and cools temperature; it relieves fluxes; it undoes rheumatism; it discharges pus. If taken in excess, it produces hallucinations and a staggering gait. If taken over a long term, it causes one to communicate with spirits and lightens one's body.\" [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13670", "text": "According to the sinologists and historians  Joseph Needham  and  Lu Gwei-djen , some early Daoists adapted censers for the  religious and spiritual use of cannabis . The c. 570 Daoist encyclopedia  Wushang Biyao  ( \u7121\u4e0a\u79d8\u8981  \"Supreme Secret Essentials\") recorded adding cannabis into ritual censers, and they suggest  Yang Xi  (330-c. 386), who wrote the Shangqing scriptures during alleged visitations by Daoist  xian , was \"aided almost certainly by cannabis\". [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13671", "text": "The  mantuoluo  ( \u66fc\u9640\u7f57 ;  \u66fc\u9640\u7f85 ;  m\u00e0ntu\u00f3lu\u00f3 ;  man-t'o-lo  \" Datura stramonium ; jimsonweed\" or \"(Buddhism)  mandala \") contains highly  toxic   Tropane alkaloids . Several Datura species were introduced into China from India, and Li Shizhen's 1596  Bencao gangmu  was the first herbal to record the medicinal use of flowers and seeds. The drug is used in combination with  Cannabis sativa  and taken with wine as an anesthetic for small operations and cauterizations. Li Shizhen personally experimented with jimsonweed and recorded his experience as follows: \"According to traditions, it is alleged that when the flowers are picked for use with wine while one is laughing, the wine will cause one to produce laughing movements; and when the flowers are picked while one is dancing, the wine will cause one to produce dancing movements. [I have found out] that such movements will be produced when one becomes half-drunk with the wine and someone else laughs or dances to induce these actions.\" [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13672", "text": "The  maogen  ( \u6bdb\u831b ;  m\u00e1og\u00e8n ;  mao-ken  \" Ranunculus  japonicus ; buttercup\") is a poisonous plant with bright yellow flowers. The Daoist alchemist  Ge Hong 's c. 340  Zhouhou jiuzu fang  ( \u8098\u5f8c\u6551\u5352\u65b9  \"Remedies for Emergencies\", [ 22 ]  says, \"Among the herbs there is the Shui Lang (water Lang, a kind of Mao-ken) a plant with rounded leaves which grows along water courses and is eaten by crabs. It is poisonous to man and when eaten by mistake, it produces a maniacal delirium, appearing like a stroke and sometimes with blood-spitting. The remedy is to use licorice.\" Later herbals, which do not mention  maogen  as a deliriant, say the whole plant is considered poisonous and is should only be externally used as a medicine for irritation and inflammation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13673", "text": "The  xiaojun  ( \u7b11\u83cc ;  xi\u00e0oj\u00f9n ;  hsiao-ch'un  \"laughing mushroom\") was known to Chinese herbalists for centuries before modern botanists identified it as a type of  psilocybin mushroom , most likely either  Gymnopilus junonius  or Laughing Gym or  Panaeolus papilionaceus  or Petticoat Mottlegill."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13674", "text": "The earliest record of a mushroom that causes uncontrollable laughter appears in  Zhang Hua 's c. 290  Bowuzhi  compendium of natural wonders, in a context describing two unusual kinds of  j\u00f9n  ( \u83cc  \"mushroom; fungus\") that grow on tree bark."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13675", "text": "In all the mountain commanderies to the South of the Yangzi, there is a fungus which grows [ \u751f\u83cc ] throughout the spring and summer on the large trees that have fallen down; it is known as the Zhen [ \u6939  \"chopping block (for execution)\"]. If one eats it, it is tasty, but suddenly the poison takes effect and kills the eater. \u2026 If one eats Sweet gum tree growths [ \u751f\u8005 ], they will induce uncontrollable laughter. If one drinks \"earth sauce\" [ t\u01d4ji\u0101ng   \u571f\u6f3f ] one will recover. [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13676", "text": "The  Bencao gangmu  records Tao Hongjing's recipe for preparing \"earth sauce\": \"Dig out a pit three chi deep in a place where there is yellow earth. Take freshly-drawn water and pour it into the pit, stirring the water so as to make it turbid. After a short while, draw off the clear water and use this. It is called either 'soil sauce' or 'earth sauce'.\" [ 24 ]  Hui-lin Li quotes a Chinese-language study of \"laughing mushrooms\" that this \"soil infusion\" is the clear liquid after soil is mixed with water and allowed to settle, and an effective  antidote  for poisons. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13677", "text": "Subsequent Chinese authors give many similar records. Chen Renyu's ( \u9673\u4ec1\u7389 ) I245  J\u00f9np\u01d4  ( \u83cc\u8b5c  \"Mushroom Guidebook\") says this fungus is named   t\u01d4x\u00f9n  ( \u571f\u8548  \"earth mushroom\") or  d\u00f9x\u00f9n  ( \u675c\u8548  \"pear mushroom\") and \"grows in the ground. People believe it to be formed by the air from poisonous vermin, and kills people if taken.... Those poisoned by it will laugh. As an antidote, use strong tea, mixed with  alum  and fresh clear water. Upon swallowing this, it will cure immediately\". [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13678", "text": "The c. 304  Nanfang Caomu Zhuang  mentions sweetgum tree growths in a quite different context, the shamans in the southern state of  Yue  use a magical  f\u0113ngr\u00e9n  ( \u6953\u4eba  \"sweetgum person\") that is a kind of  li\u00fay\u01d0ng  ( \u7624\u766d  \" gall \") found growing on sweetgum trees. \"When aged they develop tumors. Sometimes in a violent thunder storm, the tree tumors grow suddenly three to five feet in one night, and these are called Feng-jen. The witches of Yueh collect these for witchcraft, saying that they have proof of their supernatural quality.\" [ 26 ]  Later sources gave two explanations of the sweetgum tree growths, either as galls that resemble humans and have magical powers or as parasitic plants with rain-giving powers. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13679", "text": "In Japan, both medieval and modern sources record laughing mushrooms. An 11th-century story in the  Konjaku Monogatarish\u016b  describes a group of Buddhist nuns who ate  maitake  ( \u821e\u8338  \"dancing mushrooms\") and began to laugh and dance uncontrollably. It is also known as the  waraitake  ( \u7b11\u8338  \"laughing mushroom\"), which scholars have identified as the  Panaeolus papilionaceus  or Petticoat Mottlegill; the related  Panaeolus cinctulus  or Banded Mottlegill; and the psilocybin mushroom  Gymnopilus junonius  or Laughing Cap also called  \u014dwaraitake  ( \u5927\u7b11\u8338  \"Big Laughing Mushroom\"). [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13680", "text": "In a study on early Daoist practitioners searching for the  elixir of Immortality , Needham and Lu mention the possible use of hallucinogenic plants, such as  Amanita muscaria  \"fly agaric\" and  xiaojun  \"laughing mushrooms\". Based on  Tang dynasty  and  Song dynasty  references, they tentatively identify it as a  Panaeolus  or  Pholiota  and suggest that the properties of at least some psychoactive mushrooms were widely known. They predict the further exploration of hallucinogenic fungi and other plants in Daoism and in Chinese culture in general \"will be an exciting task\". [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13681", "text": "Footnotes"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13682", "text": "In  biochemistry  and  pharmacology , the  Hill equation  refers to two closely related equations that reflect the binding of  ligands  to macromolecules, as a function of the ligand  concentration . A ligand is \"a substance that forms a complex with a biomolecule to serve a biological purpose\" ( ligand definition ), and a macromolecule is a very large molecule, such as a protein, with a complex structure of components ( macromolecule definition ).  Protein-ligand binding typically changes the structure of the target protein, thereby changing its function in a cell."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13683", "text": "The distinction between the two Hill equations is whether they measure  occupancy  or  response . The  Hill equation  reflects the occupancy of macromolecules: the fraction that is saturated or bound by the  ligand . [ 1 ] [ 2 ] [ nb 1 ]  This equation is formally equivalent to the  Langmuir isotherm . [ 3 ]  Conversely, the  Hill equation  proper reflects the cellular or tissue response to the ligand: the physiological output of the system, such as muscle contraction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13684", "text": "The Hill equation was originally formulated by  Archibald Hill  in 1910 to describe the  sigmoidal  O 2  binding curve of  haemoglobin . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13685", "text": "The binding of a  ligand  to a  macromolecule  is often enhanced if there are already other ligands present on the same macromolecule (this is known as  cooperative binding ). The Hill equation is useful for determining the degree of  cooperativity  of the ligand(s) binding to the enzyme or receptor. The  Hill coefficient  provides a way to quantify the degree of interaction between ligand binding sites. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13686", "text": "The Hill equation (for response) is important in the construction of  dose-response curves ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13687", "text": "The Hill equation is commonly expressed in the following ways. [ 2 ] [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13688", "text": "The special case where  \n \n \n \n n \n = \n 1 \n \n \n {\\displaystyle n=1} \n \n  is a  Monod equation ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13689", "text": "In pharmacology,  \n \n \n \n \u03b8 \n \n \n {\\displaystyle \\theta } \n \n  is often written as  \n \n \n \n \n p \n \n \n AR \n \n \n \n \n \n {\\displaystyle p_{{\\ce {AR}}}} \n \n , where  \n \n \n \n \n A \n \n \n \n {\\displaystyle {\\ce {A}}} \n \n  is the ligand, equivalent to L, and  \n \n \n \n \n R \n \n \n \n {\\displaystyle {\\ce {R}}} \n \n  is the receptor.  \n \n \n \n \u03b8 \n \n \n {\\displaystyle \\theta } \n \n  can be expressed in terms of the total amount of receptor and ligand-bound receptor concentrations:  \n \n \n \n \u03b8 \n = \n \n \n \n [ \n LR \n ] \n \n \n [ \n \n R \n \n \n total \n \n \n \n \n \n \n ] \n \n \n \n \n \n {\\displaystyle \\theta ={\\frac {\\ce {[LR]}}{\\ce {[R_{\\rm {total}}]}}}} \n \n .  \n \n \n \n \n K \n \n d \n \n \n \n \n {\\displaystyle K_{d}} \n \n  is equal to the ratio of the dissociation rate of the ligand-receptor complex to its association rate ( \n \n \n \n \n K \n \n \n d \n \n \n \n = \n \n \n \n k \n \n \n d \n \n \n \n \n k \n \n \n a \n \n \n \n \n \n \n \n {\\textstyle K_{\\rm {d}}={k_{\\rm {d}} \\over k_{\\rm {a}}}} \n \n ). [ 8 ]  Kd is the equilibrium constant for dissociation.  \n \n \n \n \n K \n \n A \n \n \n \n \n {\\textstyle K_{A}} \n \n  is defined so that  \n \n \n \n ( \n \n K \n \n A \n \n \n \n ) \n \n n \n \n \n = \n \n K \n \n \n d \n \n \n \n = \n \n \n \n k \n \n \n d \n \n \n \n \n k \n \n \n a \n \n \n \n \n \n \n \n {\\textstyle (K_{A})^{n}=K_{\\rm {d}}={k_{\\rm {d}} \\over k_{\\rm {a}}}} \n \n , this is also known as the microscopic  dissociation constant  and is the ligand concentration occupying half of the binding sites. In recent literature, this constant is sometimes referred to as  \n \n \n \n \n K \n \n D \n \n \n \n \n {\\textstyle K_{D}} \n \n . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13690", "text": "The  Gaddum  equation is a further generalisation of the Hill-equation, incorporating the presence of a reversible competitive antagonist. [ 1 ]  The Gaddum equation is derived similarly to the Hill-equation but with 2 equilibria: both the ligand with the receptor and the antagonist with the receptor. Hence, the Gaddum equation has 2 constants: the equilibrium constants of the ligand and that of the antagonist"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13691", "text": "The Hill plot is the rearrangement of the Hill equation into a straight line."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13692", "text": "Taking the reciprocal of both sides of the Hill equation, rearranging, and inverting again yields:  \n \n \n \n \n \n \u03b8 \n \n 1 \n \u2212 \n \u03b8 \n \n \n \n = \n \n \n \n [ \n \n L \n \n \n ] \n \n n \n \n \n \n \n K \n \n d \n \n \n \n \n = \n \n \n \n [ \n \n L \n \n \n ] \n \n n \n \n \n \n \n ( \n \n K \n \n A \n \n \n \n ) \n \n n \n \n \n \n \n \n \n \n {\\displaystyle {\\theta  \\over 1-\\theta }={[{\\ce {L}}]^{n} \\over K_{d}}={[{\\ce {L}}]^{n} \\over (K_{A})^{n}}} \n \n . Taking the logarithm of both sides of the equation leads to an alternative formulation of the Hill-Langmuir equation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13693", "text": "This last form of the Hill equation is advantageous because a plot of  \n \n \n \n log \n \u2061 \n \n ( \n \n \n \u03b8 \n \n 1 \n \u2212 \n \u03b8 \n \n \n \n ) \n \n \n \n {\\textstyle \\log \\left({\\theta  \\over 1-\\theta }\\right)} \n \n  versus  \n \n \n \n log \n \u2061 \n \n [ \n \n L \n \n ] \n \n \n \n {\\displaystyle \\log {[{\\ce {L}}]}} \n \n  yields a  linear plot , which is called a  Hill plot. [ 7 ] [ 8 ]  Because the slope of a Hill plot is equal to the Hill coefficient for the biochemical interaction, the slope is denoted by  \n \n \n \n \n n \n \n H \n \n \n \n \n {\\displaystyle n_{H}} \n \n . A slope greater than one thus indicates positively cooperative binding between the receptor and the ligand, while a slope less than one indicates negatively cooperative binding."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13694", "text": "Transformations of equations into linear forms such as this were very useful before the widespread use of computers, as they allowed researchers to determine parameters by fitting lines to data. However, these transformations affect error propagation, and this may result in undue weight to error in data points near 0 or 1. [ nb 2 ]  This impacts the parameters of linear regression lines fitted to the data. Furthermore, the use of computers enables more robust analysis involving  nonlinear regression ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13695", "text": "A distinction should be made between quantification of drugs binding to receptors and drugs producing responses. There may not necessarily be a linear relationship between the two values. In contrast to this article's previous definition of the Hill equation, the  IUPHAR  defines the Hill equation in terms of the tissue response  \n \n \n \n ( \n E \n ) \n \n \n {\\displaystyle (E)} \n \n , as [ 1 ] \n \n \n \n \n \n \n \n \n \n \n E \n \n E \n \n \n m \n a \n x \n \n \n \n \n \n \n \n \n = \n \n \n \n [ \n A \n \n ] \n \n n \n \n \n \n \n \n \n EC \n \n \n 50 \n \n \n n \n \n \n + \n [ \n A \n \n ] \n \n n \n \n \n \n \n \n \n \n \n \n \n \n = \n \n \n 1 \n \n 1 \n + \n \n \n ( \n \n \n \n \n EC \n \n \n 50 \n \n \n \n [ \n A \n ] \n \n \n \n ) \n \n \n n \n \n \n \n \n \n \n \n \n \n \n \n {\\displaystyle {\\begin{aligned}{\\frac {E}{E_{\\mathrm {max} }}}&={\\frac {[A]^{n}}{{\\text{EC}}_{50}^{n}+[A]^{n}}}\\\\&={\\frac {1}{1+\\left({\\frac {{\\text{EC}}_{50}}{[A]}}\\right)^{n}}}\\end{aligned}}} \n \n \nwhere  \n \n \n \n \n \n [ \n A \n ] \n \n \n \n \n {\\displaystyle {\\ce {[A]}}} \n \n  is the drug concentration,  \n \n \n \n n \n \n \n {\\displaystyle n} \n \n  is the Hill coefficient, and  \n \n \n \n \n \n EC \n \n \n 50 \n \n \n \n \n {\\displaystyle {\\text{EC}}_{50}} \n \n  is the drug concentration that produces a 50% maximal response. Dissociation constants (in the previous section) relate to ligand binding, while  \n \n \n \n \n \n EC \n \n \n 50 \n \n \n \n \n {\\displaystyle {\\text{EC}}_{50}} \n \n  reflects tissue response."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13696", "text": "This form of the equation can reflect tissue/cell/population responses to drugs and can be used to generate  dose response curves . The relationship between  \n \n \n \n \n K \n \n d \n \n \n \n \n {\\displaystyle K_{d}} \n \n  and EC50 may be quite complex as a biological response will be the sum of myriad factors; a drug will have a different biological effect if more receptors are present, regardless of its affinity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13697", "text": "The Del-Castillo Katz model is used to relate the Hill equation to receptor activation by including a second equilibrium of the ligand-bound receptor to an  activated  form of the ligand-bound receptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13698", "text": "Statistical analysis of response as a function of stimulus may be performed by regression methods such as the  probit model  or  logit model , or other methods such as the  Spearman\u2013K\u00e4rber method . [ 9 ]  Empirical models based on nonlinear regression are usually preferred over the use of some transformation of the data that linearizes the dose-response relationship. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13699", "text": "The Hill coefficient is a measure of  ultrasensitivity  (i.e. how steep is the response curve)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13700", "text": "The Hill coefficient,  \n \n \n \n n \n \n \n {\\displaystyle n} \n \n  or  \n \n \n \n \n n \n \n H \n \n \n \n \n {\\displaystyle n_{H}} \n \n , may describe cooperativity (or possibly other biochemical properties, depending on the context in which the Hill equation is being used). When appropriate, [ clarification needed ]  the value of the Hill coefficient describes the cooperativity of ligand binding in the following way:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13701", "text": "The Hill coefficient can be calculated approximately in terms of the  cooperativity index  of Taketa and Pogell [ 12 ]   as follows: [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13702", "text": "where  \n \n \n \n \n \n EC \n \n 90 \n \n \n \n \n \n \n \n \n {\\displaystyle {\\ce {EC90}}} \n \n  and  \n \n \n \n \n \n EC \n \n 10 \n \n \n \n \n \n \n \n \n {\\displaystyle {\\ce {EC10}}} \n \n  are the input values needed to produce the 10% and 90% of the maximal response, respectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13703", "text": "The most common form of the Hill equation is its irreversible form. However, when building computational models a reversible form is often required in order to model product inhibition.  For this reason, Hofmeyr and Cornish-Bowden devised the  reversible Hill equation . [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13704", "text": "The Hill coefficient is also intimately connected to the  elasticity coefficient  where the Hill coefficient can be shown to equal:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13705", "text": "n \n = \n \n \u03b5 \n \n s \n \n \n v \n \n \n \n \n 1 \n \n 1 \n \u2212 \n \u03b8 \n \n \n \n \n \n {\\displaystyle n=\\varepsilon _{s}^{v}{\\frac {1}{1-\\theta }}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13706", "text": "where  \n \n \n \n \u03b8 \n \n \n {\\displaystyle \\theta } \n \n  is the fractional saturation,  \n \n \n \n E \n S \n \n / \n \n \n E \n \n t \n \n \n \n \n {\\displaystyle ES/E_{t}} \n \n , and  \n \n \n \n \n \u03b5 \n \n s \n \n \n v \n \n \n \n \n {\\displaystyle \\varepsilon _{s}^{v}} \n \n  the elasticity coefficient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13707", "text": "This is derived by taking the slope of the Hill equation:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13708", "text": "n \n = \n \n \n \n d \n log \n \u2061 \n \n \n \u03b8 \n \n 1 \n \u2212 \n \u03b8 \n \n \n \n \n \n d \n log \n \u2061 \n s \n \n \n \n \n \n {\\displaystyle n={\\frac {d\\log {\\frac {\\theta }{1-\\theta }}}{d\\log s}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13709", "text": "and expanding the slope using the quotient rule. The result shows that the elasticity can never exceed  \n \n \n \n n \n \n \n {\\displaystyle n} \n \n  since the equation above can be rearranged to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13710", "text": "\u03b5 \n \n s \n \n \n v \n \n \n = \n n \n ( \n 1 \n \u2212 \n \u03b8 \n ) \n \n \n {\\displaystyle \\varepsilon _{s}^{v}=n(1-\\theta )}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13711", "text": "The Hill equation is used extensively in pharmacology to quantify the functional parameters of a drug [ citation needed ]  and are also used in other areas of biochemistry."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13712", "text": "The Hill equation can be used to describe dose-response relationships, for example  ion channel  open-probability (P-open) vs. ligand concentration. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13713", "text": "The Hill equation can be applied in modelling the rate at which a gene product is produced when its parent gene is being regulated by  transcription factors  (e.g.,  activators  and/or  repressors ). [ 11 ]  Doing so is appropriate when a gene is regulated by multiple binding sites for transcription factors, in which case the transcription factors may bind the DNA in a cooperative fashion. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13714", "text": "If the production of protein from gene  X  is up-regulated ( activated ) by a transcription factor  Y , then the rate of production of protein  X  can be modeled as a differential equation in terms of the concentration of activated  Y  protein:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13715", "text": "where  k  is the maximal transcription rate of gene  X ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13716", "text": "Likewise, if the production of protein from gene  Y  is down-regulated ( repressed ) by a transcription factor  Z , then the rate of production of protein  Y  can be modeled as a differential equation in terms of the concentration of activated  Z  protein:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13717", "text": "where  k  is the maximal transcription rate of gene  Y ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13718", "text": "Because of its assumption that ligand molecules bind to a receptor simultaneously, the Hill equation has been criticized as a physically unrealistic model. [ 5 ]  Moreover, the Hill coefficient should not be considered a reliable approximation of the number of cooperative ligand binding sites on a receptor [ 5 ] [ 17 ]  except when the binding of the first and subsequent ligands results in extreme positive cooperativity. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13719", "text": "Unlike more complex models, the relatively simple Hill equation provides little insight into underlying physiological mechanisms of protein-ligand interactions. This simplicity, however, is what makes the Hill equation a useful empirical model, since its use requires little  a priori  knowledge about the properties of either the protein or ligand being studied. [ 2 ]  Nevertheless, other, more complex models of cooperative binding have been proposed. [ 7 ]  For more information and examples of such models, see  Cooperative binding ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13720", "text": "Global sensitivity measure such as Hill coefficient do not characterise the local behaviours of the s-shaped curves. Instead, these features are well captured by the response coefficient measure. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13721", "text": "There is a link between Hill Coefficient and Response coefficient, as follows. Altszyler et al. (2017) have shown that these ultrasensitivity measures can be linked. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13722", "text": "An  International Nonproprietary Name  ( INN ) is an official  generic  and nonproprietary name given to a  pharmaceutical substance  or an  active ingredient , [ 1 ]  encompassing  compounds ,  peptides  and low-molecular-weight  proteins  (e.g.,  insulin ,  hormones ,  cytokines ), as well as complex biological products, such as those used for  gene therapy . [ 2 ]  INNs are intended to make communication more precise by providing a unique standard name for each active ingredient, to avoid  prescribing  errors. [ 3 ]  The INN system was initiated by the  World Health Organization  (WHO) in 1953. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13723", "text": "Having unambiguous standard names for each pharmaceutical substance ( standardization  of  drug nomenclature ) is important because a drug may be sold under many different brand names, or a branded medication may contain more than one drug. For example, the branded medications Celexa, Celapram and Citrol all contain the same active ingredient whose INN is  citalopram . The antibacterial medication known as  co-trimoxazole  as well as those under the brand names  Bactrim  and  Septran  all contain two active ingredients easily recognisable by their INN:  trimethoprim  and  sulfamethoxazole ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13724", "text": "The WHO publishes INNs in English,  Latin , French, Russian, Spanish,  Arabic , and  Chinese , and a drug's INNs are often  cognate  across most or all of the languages, with minor spelling or pronunciation differences, for example:  paracetamol  ( en )  paracetamolum  ( la ),  parac\u00e9tamol  ( fr ) and  \u043f\u0430\u0440\u0430\u0446\u0435\u0442\u0430\u043c\u043e\u043b  ( ru ). An established INN is known as a  recommended  INN  ( rINN ), while a name that is still being considered is called a  proposed  INN  ( pINN ). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13725", "text": "National nonproprietary names such as British Approved Names (BAN), D\u00e9nominations Communes Fran\u00e7aises (DCF), Japanese Adopted Names (JAN) and United States Adopted Names (USAN) are nowadays, with rare exceptions, identical to the INN. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13726", "text": "Mandate \nThe  World Health Organization  has a constitutional mandate to  \"develop, establish and promote international standards with respect to biological, pharmaceutical and similar products\". \nThe World Health Organization collaborates closely with INN experts and national nomenclature committees to select a single name of worldwide acceptability for each active substance that is to be marketed as a pharmaceutical. To avoid confusion, which could jeopardize the safety of patients, trade-marks should neither be derived from INNs nor contain common stems used in INNs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13727", "text": "Each drug's INN is unique but may contain a  stem  that is shared with other drugs of the same  class.  In this context, a stem is a syllable (or syllables) created to evoke in the name the pharmacological mechanism of action or the chemical structure of the substance. Stems are mostly placed word-finally (suffixes), but in some cases word-initial stems (prefixes) are used. For example, the  beta blocker  drugs  propranolol  and  atenolol  share the  stem  -olol  (as a  suffix ), and the benzodiazepine drugs  lorazepam  and  diazepam  share the stem  -azepam  (also a suffix)  The list of stems in use are collected in a publication informally known as the  Stem Book . [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13728", "text": "Some examples of stems are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13729", "text": "The  School of INN  is a WHO International Nonproprietary Name Programme initiative launched in 2019, [ 6 ]  which aims to provide information to pharmacy, medical and health students, as well as health professionals and other stakeholders on how an INN is designed and constructed. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13730", "text": "Users can take self-administered courses on several topics using this free and open source learning platform. For example, the course  An Introduction to Drug Nomenclature and INN  provides the user with a general overview of drug nomenclature and how INN are obtained and constructed. The course  Learning Clinical Pharmacology (ATC classification, INN system)  provides the student with the first steps to learn pharmacology using  INN stems ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13731", "text": "Registered students can take other courses provided by the School of INN, such as the  Stem in a pill  course,  in which each topic or course contains information correlating INN and pharmacology for a given stem, including  indications ,  mechanism of action ,  pharmacokinetics ,  contraindications , and  drug interactions  for the drugs sharing the stem. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13732", "text": "There is also a  \"How to ...\"  section about INN Programme services and  MedNet INN  which enables users to carry out searches in the INN database to retrieve information on INN, its chemical information and ATC codes amonsgt other things. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13733", "text": "The School of INN has created pilot sites in collaboration with several Universities around the globe:  University of the Western Cape (South Africa),  University of Eastern Piedmont  (Italy),  Universit\u00e9 Grenoble Alpes  (France) and  University Ramon Lull  and  University of Alcal\u00e1  in Spain. These pilot sites are involved in disseminating the use of INN, teaching based on INN and related research activities. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13734", "text": "The term  stem  is not used consistently in  linguistics . It has been defined as a form to which  affixes  (of any type) can be attached. [ 9 ]  Under a different and apparently more common view, this is the definition of a  root , [ 10 ]  while a stem consists of the root plus optional  derivational  affixes, meaning that it is the part of a word to which  inflectional  affixes are added. [ 11 ]  INN stems employ the first definition, while under the more common alternative they would be described as roots."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13735", "text": "Pharmacology  and  pharmacotherapy  (like  health care  generally) are universally relevant around the world, making  translingual communication  about them an important goal. An  interlingual  perspective is thus useful in  drug nomenclature . The WHO issues INNs in English, Latin, French, Russian, Spanish, Arabic, and Chinese. A drug's INNs are often  cognates  across most or all of the languages, but they also allow small  inflectional ,  diacritic , and  transliterational  differences that are usually transparent and trivial for nonspeakers (as is true of most  international scientific vocabulary ). For example, although  ibuprofenum  ( la ) has an inflectional difference from  ibuprofen  ( en ), and although  ibuprof\u00e8ne  ( fr ) has a diacritic difference, the differences are trivial; users can easily recognize the \"same word\". Although  \u0418\u0431\u0443\u043f\u0440\u043e\u0444\u0435\u0301\u043d   ( ru ) and  ibuprofen  ( en ) have a transliteration difference, they sound similar, and for Russian speakers who can recognize  Latin script  or English speakers who can recognize  Cyrillic script , they look similar; users can recognize the \"same word\". Thus, INNs make medicines bought anywhere in the world as easily identifiable as possible to people who do not speak that language. Notably, the \"same word\" principle allows health professionals and patients who do not speak the same language to communicate to some degree and to avoid potentially life-threatening confusions from drug interactions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13736", "text": "To facilitate the translation and pronunciation of INN, \"f\" should be used instead of \"ph\", \"t\" instead of \"th\", \"e\" instead of \"ae\" or \"oe\", and \"i\" instead of \"y\"; the use of the letters \"h\" and \"k\" should be avoided. [ 12 ]  Thus a predictable spelling system, approximating  phonemic orthography , is used, as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13737", "text": "Many drugs are supplied as  salts , with a cation and an anion. The way the INN system handles these is explained by the  WHO  at its \"Guidance on INN\" webpage. [ 1 ]  For example,  amfetamine  and  oxacillin  are INNs, whereas various salts of these compounds \u2013 e.g.,  amfetamine sulfate  and  oxacillin sodium  \u2013 are  modified INNs  ( INNM ). [ 1 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13738", "text": "Several countries had created their own nonproprietary naming system before the INN was created, and in many cases, the names created under the old systems continue to be used in those countries. As one example, in English the INN name for a common painkiller is  paracetamol ; the table below gives the alternative names for this in different systems:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13739", "text": "Other naming systems not listed above include  France 's  D\u00e9nomination Commune Fran\u00e7aise  (DCF) and  Italy 's  Denominazione Comune Italiana  (DCIT). [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13740", "text": "In the realms of  toxicology  and  pathology , the  Irwin screen  is utilised to determine whether the subject(s) show adverse effects from a course of  pharmaceutical  treatment or  environmental pollution . It is an  observational   methodology . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13741", "text": "Mice were first used systematically to determine a  drug 's  central nervous system   side effects  by  S. Irwin  in 1962 and then again in 1968. [ 1 ]   Its use in the  pharmaceutical industry  has become ingrained since then, as below."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13742", "text": "The  National Academy of Sciences  issued in 1975 a position paper on the \"Principles for Evaluating Chemicals in the Environment.\" This paper influenced government and academic circles, and was adopted by e.g.  Brimblecombe  for his study of  atmospheric   arsenic  levels. [ 2 ]  The critical review in 1982 by Mitchell and Tilson, [ 3 ]  caused the US  EPA  to develop guidelines for several behavioural tests including a test series based on the Irwin Screen, named the Functional Observational Battery (FOB) by Sette in 1989. [ 4 ]  In 1998, the FOB was published in the late 1990s as EPA Human Health 870 Series Test Guidelines, [ 1 ] [ 5 ] [ 6 ]  and in praxis the Irwin screen and the FOB \"overlap and to some extent are interchangeable.\" [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13743", "text": "The American batteries were harmonised with the  OECD 's from the same era. [ 7 ] [ 8 ] [ 9 ] [ 10 ]  Similar tests on food chemicals were recommended by the  FDA  in their  Red Book . [ 11 ]  Behavioural test batteries are now required for new drugs by the S7A group of the  International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use  (ICH). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13744", "text": "The Irwin screen was as of 2010 in the pharmaceutical industry almost exclusively used with  lab mice , whereas the FOB, or some modification thereof, was used with  lab rats  and other nonrodent species, such as  rabbits ,  dogs ,  guinea pigs  and  nonhuman primates . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13745", "text": "A sample Irwin screen [ 12 ]  includes overt behavior observations and autonomic observations:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13746", "text": "Overt Behavior"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13747", "text": "Autonomic Observations"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13748", "text": "The  John J. Abel Award  is an annual award presented by the  American Society for Pharmacology and Experimental Therapeutics  (ASPET). The award is given for outstanding research in the field of pharmacology and/or experimental therapeutics; which comes with a $5000 prize, An  engraved  plaque, and all travel expenses paid to attend the ASPET Annual Meeting at Experimental Biology. [ 1 ]  The Award is named after American  biochemist  and  pharmacologist ,  John Jacob Abel ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13749", "text": "Metreleptin , sold under the brand name  Myalept  among others, is a synthetic  analog  of the hormone  leptin  used to treat various forms of  dyslipidemia .  It has been approved in Japan for metabolic disorders including  lipodystrophy  and in the United States as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13750", "text": "The most common side effects include  hypoglycaemia  (low blood glucose) and weight loss. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13751", "text": "It was approved for medical use in Canada in January 2024. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13752", "text": "In the European Union, metreleptin is  indicated  in addition to diet to treat lipodystrophy, where people have a loss of fatty tissue under the skin and a build-up of fat elsewhere in the body such as in the liver and muscles. It is used in adults and children above the age of two years with  generalised lipodystrophy  ( Berardinelli-Seip syndrome  and  Lawrence syndrome ); and in adults and children above the age of twelve years with  partial lipodystrophy  (including  Barraquer-Simons syndrome ), when standard treatments have failed. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13753", "text": "In the United States, it is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in people with congenital or acquired generalized lipodystrophy. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13754", "text": "Metreleptin is being investigated for the treatment of diabetes and/or  hypertriglyceridemia , in patients with rare forms of lipodystrophy, syndromes characterized by abnormalities in adipose tissue distribution, and severe metabolic abnormalities. [ 10 ]  The FDA approved Metreleptin injection for treating complications of leptin deficiency in February 2014. [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13755", "text": "In a three-year study of metreleptin in patients with lipodystrophy organized by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health, metreleptin treatment was associated with a significant decrease in blood glucose (A1c decreased from 9.4% at baseline to 7.0% at study end) and triglyceride concentration (from 500\u00a0mg/dl at baseline to 200\u00a0mg/dl at study end). [ 11 ]  Metreleptin is effective in most patients with generalized lipodystrophy where circulating leptin levels are extremely low. Analogous to  insulin replacement  for patients with  type 1 Diabetes , metreleptin restores the function of a deficient hormone. However, in patients with partial lipodystrophy where there is only a relative leptin deficiency, the response to metreleptin is not universal. [ 12 ]  This may or may not be due to anti-leptin antibodies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13756", "text": "Metreleptin is undergoing research for its potential benefit in the treatment of anorexia nervosa. [ 13 ]  It is hypothesized that the gradual loss of body fat mass, and more specifically the ensuing low leptin levels, escalate the preexisting drive for thinness into an obsessive-compulsive-like and addictive-like state. It was shown that short-term metreleptin treatment of patients with anorexia nervosa had rapid on-set of beneficial cognitive, emotional, and behavioral effects. [ 14 ]   Among other things, depression, drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased rapidly. Whether metreleptin (or another leptin analogue) is a suitable treatment for anorexia nervosa remains to be seen. Potential side effects are weight loss and the development of anti-metreleptin antibodies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13757", "text": "In a clinical study, metreleptin treatment improved  non-alcoholic steatohepatitis  (fatty liver disease) both in patients with partial lipodystrophy and in those with relative leptin deficiency. Both  steatosis  and hepatic injury scores decreased. [ 15 ]  Metreleptin reduces body weight in overweight people with low leptin levels. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13758", "text": "Although it is not very effective as a weight loss drug, leptin levels are lowered in people who have lost weight and it is hypothesized that supplemental leptin could help them with  weight loss  maintenance. However, there is no regulatory pathway for drug approval for this indication. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13759", "text": "The  micro-atmosphere method  is an  antimicrobial sensitivity testing  method involving the use of potentially  bacteriostatic  or  fungicidal  compounds which are obtained from the volatile oils of plants, such as  citronella grass . This method involves the use of  essential oils , a  growth medium , a selection of bacterial or fungal cultures, and an  incubator ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13760", "text": "In this microbiological procedure, theoretically, the antibacterial or anti-fungal activity of the  volatile oils  from a chosen plant may be tested against a selection of  gram-positive  and  gram-negative bacteria  or a species of  fungus . The growth of the bacteria or fungi are then monitored on a timely basis to measure the  bacteriostatic  or anti-fungal activity of the volatile oils. In some cases, a complete inhibition of growth for the bacteria tested can be observed. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13761", "text": "Before it can be tested, the  essential oils  are first diluted to produce solutions of varying concentrations. In this way, the  minimum inhibitory concentration  can be calculated to obtain the most cost-effective antimicrobial agent. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13762", "text": "Until recently, the antibacterial activity of essential oils has been primarily evaluated through direct contact methods between the pathogen and the antimicrobial agent through diffusion and dilution methods, [ 1 ] [ 2 ]  however the role of essential oils in the vapour phase as antimicrobial agents is gaining increasing significance. [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13763", "text": "This method was developed on the premise that essential oil vapours exert critical biological activity. These methods offer rapid screening protocols for the antimicrobial assessment of plant essential oils. It has been suggested that essential oils in the vapour phase possess the greatest degree of antimicrobial activity since the active constituents are highly volatile in nature and thus, the vapour is therefore the contributing attribute for its biological activity. [ 8 ]  Each individual constituent has differing volatility, therefore when the mixtures are introduced into a free, non-saturated state in a closed micro-environment; the volatile constituents begin to disperse at differing rates in the vapour phase within the headspace according to their degree of volatility until they reach equilibrium. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13764", "text": "Preliminary research involving the essential oils of  citronella  yielded promising results when tested against a selection of Gram-positive bacteria and Gram-negative bacteria. The use of such extracts can be explored especially in the development of cost-effective treatments of  respiratory illness , specifically of those caused by bacterial or fungal infection. Preliminary tests exhibit complete inhibition of the growth of certain bacterial strains. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13765", "text": "In a separate research, the micro-atmosphere method was used to investigate the anti-fungal efficacy of the essential oils from the  cinnamon , a plant belonging to the genus  Cinnamomum ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13766", "text": "The procedure was employed to ensure that the active films, the material containing the active compound, does not come into direct contact to the tested fungal suspension. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13767", "text": "The micro-atmosphere method was performed, in order to evaluate the indirect effects of active films against  P. digitatum . Addition of 0.5% cinnamon essential oil, led to 12% inhibition of fungal growth. Higher anti-fungal effects were obtained by adding higher amounts of the essential oil. An inhibition of fungal growth between 28% and 50% were observed for the films incorporated with 1.5% and 3% essential oil, respectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13768", "text": "In this particular research, the potential anti-fungal agent was subjected to both  disk diffusion test  and the micro-atmosphere method for comparison and to get an idea of how the active compound may be utilized. The active compound exhibited higher anti-fungal effects in the disc diffusion test compared to the micro-atmosphere assays. This could be attributed to the fact that in the disc diffusion test, both direct contact and migration of active compounds from the film to the outside induced the observed antimicrobial effects. On the other hand, only the migration of the volatile compounds to the headspace, may cause the anti-fungal effect in the micro-atmosphere method. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13769", "text": "Neosaxitoxin  (NSTX) is included, as other  saxitoxin -analogs, in a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). The parent compound of PSTs, saxitoxin (STX), is a tricyclic perhydropurine alkaloid, which can be substituted at various positions, leading to more than 30 naturally occurring STX analogues. All of them are related imidazoline guanidinium derivatives. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13770", "text": "NSTX, and other PSTs, are produced by several species of marine dinoflagellates (eukaryotes) and freshwater cyanobacteria, blue-green algae (prokaryotes), which can form extensive blooms around the world. [ 4 ]  Under special conditions, during  harmful algal blooms  (HAB) or  red tide , all these toxins may build up in filter-feeding shellfish, such as mussels, clams and oysters, and can produce an outbreak of  Paralytic Shellfish Poisoning  (PSP). [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13771", "text": "Saxitoxin analogues associated to PSP can be divided into three categories: [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13772", "text": "NSTX is quite similar to saxitoxin, like all the neurotoxins associated to PSP, the only difference is that NSTX shows one hydroxyl group bonded to nitrogen \"1\", where saxitoxyn contains one hydrogen. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13773", "text": "This purine is highly hydrophilic [ 8 ]  and thermostable, it is not destroyed by cooking. [ 9 ]  Moreover, is very stable in usual storage, specially in acidic condition. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13774", "text": "NSTX blocks the extracellular portion, [ 11 ]  the outer vestibule, [ 12 ]  of some voltage gated sodium channels in a very powerful and reversible manner, without affection of other ion channels."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13775", "text": "\"Voltage-gated\", also called \"voltage-sensitive\" and \"voltage-dependent\"  sodium channel  also known as \"VGSCs\" or \"Nav channel\" are crucial elements of normal physiology in a variety of animals, including flies, leeches, squid and jellyfish, as well as mammalian and non-mammalian vertebrates. This large integral membrane protein plays an essential role in the initiation and propagation of action potentials in neurons, myocytes and other excitable cells. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13776", "text": "Nav channels form the basis for  electrical excitability  in animals. Nav channels evolved from Ca 2+  channels and were present in the common ancestor of choanoflagellates and animals, although this channel was likely permeable to both Na +  and Ca 2+ . Thus, like many other neuronal channels and receptors, Nav channels predated neurons. Invertebrates possess two Nav channels (Nav1 and Nav2), whereas vertebrate Nav channels are of the Nav1 family. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13777", "text": "Sodium-channel proteins in the mammalian brain are composed of an association that include one alpha subunit and one or more auxiliary beta subunits. Nine types of alpha subunits have been described (Na v 1.1 to Na v 1.9), and a tenth related isoform (Na x ) may also play some role as a Nav channel. Based in this information, ten Nav classes can be described: Na v 1.1 to Na v 1.9, and Na x . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13778", "text": "Former five, [ 16 ]  but more recently, six [ 17 ]  neurotoxin receptor sites have been recognized between the seven receptor site [ 18 ]  located in the vertebrate sodium channel receptor alpha subunit:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13779", "text": "NSTX and other site 1 blockers have high affinity (very low dissociation constant) and high specificity for Nav channels. The action of NSTX produces minimal effect on cardiac Nav, where it exhibits about 20\u201360 fold lesser affinity than in Nav channels from rat skeletal muscle and rat brain. [ 19 ]  Most data emphasize the role of \"STX resistant\" Na v  channel 1.5 in human heart. [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13780", "text": "Toxins such as neosaxitoxin and tetrodotoxin have less affinity for most cardiac Nav channels than for most Nav channels in nerve tissue. Moreover, NSTX is so active on nerve Nav channel than is roughly a million-fold more potent than lidocaine. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13781", "text": "This mechanism of action can produce two well known kinds of effects in humans:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13782", "text": "It can be approximately described using one of the classical model of neurotoxic disease, known from ancient times as red tide, the most harmful algal bloom (HAB). This well known clinical model is the \"paralytic shellfish poisoning\". [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13783", "text": "Of course, there are great differences between different algal blooms, [ 24 ] [ 25 ] [ 26 ] [ 27 ]  because of the mix of species included in each HAB, usually related to environmental conditions; [ 28 ]  because of the levels and quality of PSTs produced in each HAB, that may be modulated by concurrent microorganism; [ 29 ] [ 30 ] [ 31 ] [ 32 ]  and, last but not least, because of the specific properties of each kind of PST, for example:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13784", "text": "In spite of its heterogeneous and poorly understood epidemiology, the clinical picture of PSP could be useful to anticipate clinical effects of systemic NSTX."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13785", "text": "Usually, the victims of mild and severe acute intoxications eliminate the toxin in urine during the first 24 hours after ingestion, and improve to full recovery in the first day of intrahospital care (when vital support is provided in a timely manner). [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13786", "text": "When outbreaks of PSP occur in remote locations, where medical assistance is limited, reported lethality is under 10% in adults, but can reach 50% in children younger than six years old. This difference could be secondary to dissimilar doses and composition of involved mixes of PSTs; delay in medical support; or some kind of susceptibility of children. [ 41 ]  More recent information suggest that lethality could be around 1% of symptomatic patients, [ 42 ]  including cases where air transportation was required from remote locations of Alaska. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13787", "text": "Electrophysiologic observations demonstrated sub clinical abnormalities lasting for some days [ 44 ]  or weeks [ 45 ]  after clinical recovery ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13788", "text": "Some evidence suggest the presence of metabolic pathways for the sequential oxidation and glucuronidation of PST in vitro, both being the initial detoxication reactions for the excretion of these toxins in humans. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13789", "text": "Forensic analysis of fatalities after severe cases, conclude that PSP toxins are metabolically transformed by humans and that they are removed from the body by excretion in the urine and feces like any other xenobiotic compound. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13790", "text": "Considering the heterogeneous nature of toxins mixes contained in contaminated bivalve molluscs, the safe limit of toxin content in shellfish adequate for human ingestion is expressed in \"saxitoxin equivalents\". According to the Food and Agriculture Organization of the United Nations (FAO) and European Parliament, this limit is 80 microgram of saxitoxin equivalent per 100 gram of mussel meat (each mussel weights around 23\u00a0g). [ 48 ] [ 49 ]  The U.S. Food and Drug Administration extends the same definition to \"fish\" quality, but the term \"fish\" refers to fresh or saltwater fin fish, crustaceans, other forms of aquatic animal life other than birds or mammals, and all mollusks; and incorporate the use of \"ppm\" as another measure for saxitoxin equivalent concentration in mentioned foods. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13791", "text": "Paradoxically, the chronic and/or repeated exposure to marine seafood toxins, which is a much more realistic phenomenon, has not been fully examined. [ 51 ] [ 52 ]  One study in rats exposed to chronic (12 weeks) NSTX administration demonstrated some reduction in water and food intake, and a mild degree of transient cholestasis, probably associated to fasting, without other abnormalities. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13792", "text": "This action has been demonstrated in animals [ 54 ]  and humans. [ 55 ] [ 56 ] [ 57 ] [ 58 ] [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13793", "text": "The medical use of the NSTX anesthetic effect is supported by three reasons:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13794", "text": "In conclusion, NSTX is a well defined molecule with a long-lasting and sometimes dangerous relationship with human subjects. Recent investigations suggest a clinical application as a new local anesthetic that sounds \"too good to be true\", but more investigation is required. [ 86 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13795", "text": "Norethisterone acetate  ( NETA ), also known as  norethindrone acetate  and sold under the brand name  Primolut-Nor  among others, is a  progestin  medication which is used in  birth control pills ,  menopausal hormone therapy , and for the treatment of  gynecological disorders . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The medication available in low-dose and high-dose formulations and is used alone or in combination with an  estrogen . [ 5 ] [ 4 ] [ 6 ] [ 7 ]  It is  ingested orally . [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13796", "text": "Side effects  of NETA include  menstrual irregularities ,  headaches ,  nausea ,  breast tenderness ,  mood  changes,  acne ,  increased hair growth , and others. [ 6 ]  NETA is a progestin, or a  synthetic   progestogen , and hence is an  agonist  of the  progesterone receptor , the  biological target  of progestogens like  progesterone . [ 1 ]  It has weak  androgenic  and  estrogenic  activity and no other important  hormonal  activity. [ 1 ] [ 8 ]  The medication is a  prodrug  of  norethisterone  in the body. [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13797", "text": "NETA was  patented  in 1957 and was introduced for medical use in 1964. [ 11 ] [ 12 ]  It is sometimes referred to as a \"first-generation\" progestin. [ 13 ] [ 14 ]  NETA is marketed widely throughout the world. [ 4 ]  It is available as a  generic medication . [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13798", "text": "NETA is used as a  hormonal contraceptive  in combination with  estrogen , in the treatment of  gynecological disorders  such as  abnormal uterine bleeding , and as a component of  menopausal hormone therapy  for the treatment of  menopausal   symptoms . [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13799", "text": "NETA is available in the form of  tablets  for use  by mouth  both alone and in combination with  estrogens  including  estradiol ,  estradiol valerate , and  ethinylestradiol . [ 16 ] [ 4 ]   Transdermal patches  providing a combination of 50\u00a0\u03bcg/day estradiol and 0.14 or 0.25\u00a0mg/day NETA are available under the brand names CombiPatch and Estalis. [ 16 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13800", "text": "NETA was previously available for use by  intramuscular injection  in the form of  ampoules  containing 20\u00a0mg NETA, 5\u00a0mg  estradiol benzoate , 8\u00a0mg  estradiol valerate , and 180\u00a0mg  testosterone enanthate  in  oil solution  under the brand name  Ablacton  to suppress  lactation  in  postpartum  women. [ 17 ] [ 18 ] [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13801", "text": "Side effects  of NETA include  menstrual irregularities ,  headaches ,  nausea ,  breast tenderness ,  mood  changes,  acne ,  increased hair growth , and others. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13802", "text": "NETA is a  prodrug  of  norethisterone  in the body. [ 9 ]  Upon  oral ingestion , it is rapidly converted into norethisterone by  esterases  during  intestinal  and  first-pass   hepatic   metabolism . [ 10 ]  Hence, as a prodrug of norethisterone, NETA has essentially the same effects, acting as a potent  progestogen  with additional weak  androgenic  and  estrogenic  activity (the latter via its  metabolite   ethinylestradiol ). [ 1 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13803", "text": "In terms of dosage equivalence, norethisterone and NETA are typically used at respective dosages of 0.35\u00a0mg/day and 0.6\u00a0mg/day as  progestogen-only contraceptives , and at respective dosages of 0.5\u20131\u00a0mg/day and 1\u20131.5\u00a0mg/day in combination with ethinylestradiol in  combined oral contraceptives . [ 8 ]  Conversely, the two drugs have been used at about the same dosages in  menopausal hormone therapy  for the treatment of  menopausal   symptoms . [ 8 ]  NETA is of about 12% higher  molecular weight  than norethisterone due to the presence of its C17\u03b2  acetate   ester . [ 2 ]   Micronization  of NETA has been found to increase its potency by several-fold in animals and women. [ 21 ] [ 22 ] [ 23 ] [ 24 ]  The  endometrial transformation  dosage of micronized NETA per cycle is 12 to 14\u00a0mg, whereas that for non-micronized NETA is 30 to 60\u00a0mg. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13804", "text": "NETA metabolizes into  ethinylestradiol  at a rate of 0.20 to 0.33% across a dose range of 10 to 40\u00a0mg. [ 26 ] [ 27 ]  Peak levels of ethinylestradiol with a 10, 20, or 40\u00a0mg dose of NETA were 58, 178, and 231\u00a0pg/mL, respectively. [ 26 ] [ 27 ]  For comparison, a 30 to 40\u00a0\u03bcg dose of oral ethinylestradiol typically results in a peak ethinylestradiol level of 100 to 135\u00a0pg/mL. [ 27 ]  As such, in terms of ethinylestradiol exposure, 10 to 20\u00a0mg NETA may be equivalent to 20 to 30\u00a0\u03bcg ethinylestradiol and 40\u00a0mg NETA may be similar to 50\u00a0\u03bcg ethinylestradiol. [ 27 ]  In another study however, 5\u00a0mg NETA produced an equivalent of 28\u00a0\u03bcg ethinylestradiol (0.7% conversion rate) and 10\u00a0mg NETA produced an equivalent of 62\u00a0\u03bcg ethinylestradiol (1.0% conversion rate). [ 25 ] [ 28 ]  Due to its estrogenic activity via ethinylestradiol, high doses of NETA have been proposed for add-back in the treatment of  endometriosis  without estrogen supplementation. [ 26 ]  Generation of ethinylestradiol with high doses of NETA may increase the risk of  venous thromboembolism  but may also decrease  menstrual bleeding  relative to progestogen exposure alone. [ 27 ] [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13805", "text": "NETA has  antigonadotropic  effects via its progestogenic activity and can dose-dependently suppress  gonadotropin  and  sex hormone  levels in women and men. [ 1 ] [ 29 ] [ 30 ] [ 31 ]  The  ovulation -inhibiting dose of NETA is about 0.5\u00a0mg/day in women. [ 1 ]  In healthy young men, NETA alone at a dose of 5 to 10\u00a0mg/day orally for 2\u00a0weeks suppressed testosterone levels from ~527\u00a0ng/dL to ~231\u00a0ng/dL (\u201356%). [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13806", "text": "NETA, also known as norethinyltestosterone acetate, as well as 17\u03b1-ethynyl-19-nortestosterone 17\u03b2-acetate or 17\u03b1-ethynylestra-4-en-17\u03b2-ol-3-one 17\u03b2-acetate, is a progestin, or  synthetic  progestogen, of the  19-nortestosterone  group, and a synthetic  estrane   steroid . [ 2 ] [ 5 ]  It is the C17\u03b2  acetate   ester  of norethisterone. [ 2 ] [ 5 ]  NETA is a  derivative  of  testosterone  with an  ethynyl group  at the C17\u03b1 position, the  methyl group  at the C19 position removed, and an acetate ester attached at the C17\u03b2 position. [ 2 ] [ 5 ]  In addition to testosterone, it is a combined derivative of  nandrolone  (19-nortestosterone) and  ethisterone  (17\u03b1-ethynyltestosterone). [ 2 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13807", "text": "Chemical syntheses  of NETA have been published. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13808", "text": "Schering AG  filed for a patent for NETA in June 1957, and the patent was issued in December 1960. [ 11 ]  The drug was first marketed, by  Parke-Davis  as  Norlestrin  in the  United States , in March 1964. [ 11 ] [ 12 ]  This was a  combination formulation  of 2.5\u00a0mg NETA and 50\u00a0\u03bcg  ethinylestradiol  and was indicated as an  oral contraceptive . [ 11 ] [ 12 ]  Other early brand names of NETA used in oral contraceptives included  Minovlar  and  Anovlar . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13809", "text": "Norethisterone acetate  is the  INN Tooltip International Nonproprietary Name ,  BANM Tooltip British Approved Name , and  JAN Tooltip Japanese Accepted Name  of NETA while  norethindrone acetate  is its  USAN Tooltip United States Adopted Name  and  USP Tooltip United States Pharmacopeia . [ 2 ] [ 5 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13810", "text": "NETA is marketed under a variety of brand names throughout the world including Primolut-Nor (major), Aygestin ( US Tooltip United States ), Gestakadin, Milligynon, Monogest, Norlutate ( US Tooltip United States ,  CA Tooltip Canada ), Primolut N, SH-420 ( UK Tooltip United Kingdom ), Sovel, and Styptin among others. [ 2 ] [ 5 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13811", "text": "NETA is marketed in high-dose 5\u00a0mg oral tablets in the  United States  under the brand names Aygestin and Norlutate for the treatment of gynecological disorders. [ 35 ]  In addition, it is available under a large number of brand names at much lower dosages (0.1 to 1\u00a0mg) in combination with  estrogens  such as  ethinylestradiol  and  estradiol  as a  combined oral contraceptive  and for use in  menopausal hormone therapy  for the treatment of  menopausal   symptoms . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13812", "text": "NETA has been studied for use as a potential  male hormonal contraceptive  in combination with  testosterone  in men. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13813", "text": "The  n -octanol-water partition coefficient,   K ow  is a  partition coefficient  for the two-phase system consisting of  n -octanol  and water. [ 1 ]   K ow  is also frequently referred to by the symbol P, especially in the English literature. It is also called  n -octanol-water partition ratio . [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13814", "text": "K ow  serves as a measure of the relationship between  lipophilicity  (fat solubility) and  hydrophilicity  (water solubility) of a substance. The value is greater than one if a substance is more soluble in fat-like solvents such as n-octanol, and less than one if it is more soluble in water. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13815", "text": "If a substance is present as several  chemical species  in the octanol-water system due to  association  or  dissociation , each species is assigned its own  K ow  value. A related value, D, does not distinguish between different species, only indicating the concentration ratio of the substance between the two phases. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13816", "text": "In 1899,  Charles Ernest Overton  and  Hans Horst Meyer  independently proposed that the tadpole toxicity of non-ionizable organic compounds depends on their ability to partition into lipophilic compartments of cells. They further proposed the use of the partition coefficient in an olive oil/water mixture as an estimate of this lipophilic associated toxicity.  Corwin Hansch  later proposed the use of n-octanol as an inexpensive synthetic alcohol that could be obtained in a pure form as an alternative to olive oil. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13817", "text": "K ow  values are used, among others, to assess the environmental fate of  persistent organic pollutants . Chemicals with high partition coefficients, for example, tend to accumulate in the fatty tissue of organisms ( bioaccumulation ). Under the  Stockholm Convention , chemicals with a log  K ow  greater than 5 are considered to bioaccumulate. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13818", "text": "Furthermore, the parameter plays an important role in drug research ( Rule of Five ) and  toxicology .  Ernst Overton  and  Hans Meyer  discovered as early as 1900 that the  efficacy of an anaesthetic  increased with increasing  K ow  value (the so-called  Meyer-Overton rule ). [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13819", "text": "K ow  values also provide a good estimate of how a substance is distributed within a  cell  between the lipophilic  biomembranes  and the aqueous  cytosol . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13820", "text": "Since it is not possible to measure  K ow  for all substances, various models have been developed to allow for their prediction, e.g.  Quantitative structure\u2013activity relationships  (QSAR) or  linear free energy relationships  (LFER) [ 9 ] [ 10 ]  such as the  Hammett equation . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13821", "text": "A variant of the  UNIFAC  system can also be used to estimate octanol-water partition coefficients. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13822", "text": "Values for log  K ow  typically range between -3 (very hydrophilic) and +10 (extremely lipophilic/hydrophobic). [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13823", "text": "The values listed here [ 13 ]  are sorted by the partition coefficient. Acetamide is hydrophilic, and 2,2\u2032,4,4\u2032,5-Pentachlorobiphenyl is lipophilic."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13824", "text": "The  p-i concept  refers to the pharmacological interaction of drugs with immune receptors. It explains a form of  drug hypersensitivity , namely  T cell  stimulation, which can lead to various acute inflammatory manifestations such as  exanthems ,  eosinophilia and systemic symptoms ,  Stevens\u2013Johnson syndrome ,  toxic epidermal nercrolysis , and complications upon withdrawing the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13825", "text": "The p-i concept links  pharmacology  with  immunology : It implies that drugs bind directly, as an  off-target activity  to  immune receptors  which results in various forms of T cell stimulations. P-i thus starts with an off-target pharmacological activity of the drug followed by a cascade of immunological events which always starts with T cell activation, even if the drug did not bind to the T cell itself but to an  antigen presenting cell  (APC)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13826", "text": "The drug bindings occur by  non-covalent bonds  (e.g.  Hydrogen bonds ,  electrostatic interactions ,  van der Waals forces ) to some of the highly polymorphic  T cell receptors  for  antigen  (TCR) and / or  human leukocyte antigens  (HLA). The binding occurs mostly on the cell surface and is labile, reversible and transient. It interacts with the crucial molecules of antigen dependent T cell activation, which may alter the self-HLA to make it look like an allo-HLA-allele, to which T cells strongly react; Some drug binding to TCR itself may \u2013 together with HLA-peptide interaction \u2013 elicit TCR-CDR signalling or alter the TCR conformation, thereby enhancing its interaction with HLA-peptide (allogeneic effect). Certain drugs may not only interact with the immune receptors on the surface but also inside the cell ( endoplasmic reticulum  e.g.  Abacavir  to HLA-B*57:01). This may cause a change of presented peptides (altered peptide model)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13827", "text": "The polymorphism of the immune receptors explains to a large extent the notoriously unpredictable \u201c idiosyncrasy \u201d of drug hypersensitivity reactions (DHR), as some of the individually distinct protein sequences may bind the drug better than others. Thereby only those individuals react to the drug which express the fitting protein sequence, e.g. a certain HLA-allele."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13828", "text": "Until now, only  \u03b1\u03b2 TCR  and  HLA-class I and II  proteins were described as target structures for p-i mediated drug hypersensitivity, but it is likely that other immune receptors ( \u03b3\u03b4-TCR , HLA-Class Ib, etc.) are also possible off target structures."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13829", "text": "Originally, the immune stimulation by drugs were exclusively explained by the  hapten  concept, which was investigated in the early 1930s: [ 1 ] [ 2 ] [ 3 ] [ 4 ]  In these early studies it was found that drugs were too small to represent an antigen inherently. Only if they or their metabolites are haptens, thereby forming larger and stable drug-protein complexes, were they seen as new antigens. Such a formation of a complete antigen (drug-protein complexes, so-called  adducts ) were considered a necessary step to stimulate an immune response, since the drug alone remained unnoticed by the immune cells."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13830", "text": "One classical clinical model for a hapten reaction is  contact dermatitis . This is a skin disease based on a localized immune reaction in the skin to a chemically reactive, topical applied compound, which binds by covalent bonds to a carrier protein; many of the contact sensitizers also have a toxic effect, which may be important for the  costimulation  of the immune system. Extensive  in vitro  and  in vivo  data support the hapten concept in contact dermatitis."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13831", "text": "It was tempting to use the hapten model to explain generalized DH as well: The drug class most often involved in generalized DHR are  penicillins . When applied to the skin, they elicit contact dermatitis. Penicillins are classical haptens and penicillin modified proteins like  albumin  have been repeatedly found in patients after therapy. Thus it was assumed that the generalized DHR upon parenteral or oral application after penicillins is also due to the hapten-feature of this drug class."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13832", "text": "The \u201chapten-concept\u201d was soon extended to explain all immune mediated (adverse drug reactions): Only if the drug or a metabolite could act as hapten and bind covalently to proteins, then was the drug considered to be able to elicit immune reactions including generalized  exanthema ,  drug induced hepatitis ,  DRESS ,  SJS / TEN  etc. Consequently, during preclinical risk assessment of a new drug, the potential drug candidate may be screened carefully for hapten-features, and if the candidate drugs caused some adverse immune mediated reaction, it was linked to their hapten feature or, if the parent compound lacked hapten characteristics, a hapten feature of a drug metabolite as cause for the DHR was postulated. Importantly, the hapten theory as explanation for all generalized immune reactions was often disputed and hard to reconcile with many experimental or clinical findings."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13833", "text": "The p-i concept represents an alternative explanation of immune stimulation by drugs in DHR. It implies that no formation of a new antigen (hapten-protein complex) is needed to elicit an immune activation: T cells are stimulated by the drug binding to immune receptors directly, which leads to conformational changes of HLA and/or TCR as well as to signalling by the  TCR-CD3 complex : The p-i concept was created and formulated by Prof. emeritus Werner J. Pichler in early 2000, based on studies with drug specific T cell clones, derived from patients with DHR. The underlying investigations were performed by various PhD students in Pichler's research group at the  Inselspital / University of Bern  in  Bern ,  Switzerland . The essential, initial finding was that T cells from patients with DH showed a specific reaction to the incriminated drug in vitro ( proliferation ,  cytotoxicity ,  cytokine  release), and that this drug dependent stimulation of immune cells relied on labile (=non-covalent) binding of drugs to cell surface proteins, namely on antigen presenting cells and T cells, which were present in the cell culture."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13834", "text": "That a non-covalent, and drug binding was sufficient for T cell stimulation was shown by three main findings  underlying the lability of drug bindings: washing the cells in the cell culture (APCs, T cells) effectively removed the drugs, and the cells could not be stimulated any longer; This means that the drug was binding in a labile way, which was possible with the inert, parent compound; Transformation to a reactive metabolite was not needed to elicit a reaction:  blocking processing or metabolism by drugs did not interfere with reactivity and even fixing the antigen presenting cells by glutaraldehyde failed to eliminate T cell reactivity; And lastly by the speed of reaction: the reaction occurred within minutes, before metabolism could happen; addition of the drug to the cell culture containing drug reactive T cells resulted in a  Ca 2+  influx  in drug specific T cells within less than a minute."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13835", "text": "Over the years this p-i concept could be confirmed by many functional and structural studies including  crystallography  which localized the precise region of the immune receptor (HLA-B*57:01, TCRV\u03b220, etc.), to which a particular drug binds. Since crucial and highly sensitive molecules of T cell activation are targeted, complex and highly variable immunological consequences can develop: different types of T cells are activated to a variable degree, leading in inflammatory consequences with a highly polymorphic clinical picture of acute symptoms, followed by different late appearing complications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13836", "text": "The modification of the self-HLA, of TCR, or of the TCR-peptide-HLA complex by non-covalent, bindings of drugs is a reversible, transient process, whose effect is highly dependent on the affinity of drug-protein interactions. The drug can bind first to the HLA-peptide complex (p-i HLA) or the TCR complex (p-i TCR). Sometimes the drug may be trapped in between TCR and HLA."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13837", "text": "P-i HLA is often linked with a striking HLA-association of the DHR (shown for abacavir, carbamazepine, allopurinol, dapson, vancomycin etc.), since the drug binds to a certain HLA-allele with higher affinity than to other HLA-molecules. P-i TCR is less investigated. Drug binding to certain parts of the TCR V\u03b2 chains may be sufficient for full activation, if interaction with HLA-peptide complexes is possible; other p-i TCR bindings may require additional T cell activation (e.g. by viral infection) to lead to clinical symptoms."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13838", "text": "The in vitro analysis of p-i using drug specific T cell clones (TCC) or TCR-transfected cell lines generated from patients with DH revealed a strong stimulation: A high level of T cell mediated  cytotoxicity , a broad spectrum of secreted  cytokines  and polyclonality was observed; The p-i stimulation was unorthodox: some CD4+ T cells were uncharacteristically reacting to HLA-class I or CD8+ T cells to HLA-class II drug presentation or did not show strict HLA restriction, and some TCC were polyspecific (the reactive T cell clones reacted with various peptides): [ 5 ] [ 6 ] [ 7 ]  Altogether, the picture emerged that p-i induced T cell stimulations have features of allo-like immune stimulations (allo-stimulation)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13839", "text": "The two main clinical outcomes of acute p-i reactions are MPE/DRESS on one hand, and SJS/TEN on the other hand. In MPE/DRESS patients, high numbers of circulating, atypical (activated) lymphocytes and high levels of various cytokines can be found in the circulation. [ 8 ] [ 9 ]  In vitro drug stimulation reveals a proliferating, high cytokine secreting, cytotoxic CD4 and CD8 T cell reaction to the incriminated drug, which sometimes can be detected for many years.  \nQuite in contrast, patients with SJS/TEN may show lymphopenia, just the blister fluids are full of mainly CD8/NK+, cytotoxic T cells, which are able to kill keratinocytes. [ 10 ] [ 11 ] [ 12 ]  Cytotoxic molecules ( granzyme B ,  perforin ,  granulysin ) can be detected in vivo in blood and the blister fluid in the first few days of the disease. [ 12 ] [ 13 ]  During the acute disease (1\u20132 weeks), the T cells still react in in vitro assays, but after 3\u20134 weeks, the CD8 cell compartment, which is considered to be the main responsible cell population for the disease, appears to be exhausted and are refractory to drug stimulation. [ 14 ] [ 15 ]  How this CD8 exhaustion is achieved is unknown."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13840", "text": "If the p-i stimulation resulted in T cell expansion and activation (MPE, DRESS), some of the p-i-activated T cells might continue to react in the absence of drug: their TCR may be cross-reactive with unmodified, self HLA presenting exogenous peptides (mainly of herpes virus origin) or some self-peptides: this kind of cross-reactivity with exogenous or self peptides and self-HLA explain two late complications after severe DHR, mostly DRESS: one is viral reactivation: herpes viruses are permanently harboured in various cell types after infection (fibroblasts, endothelial cells, hematopoietic cells, brain cells, etc.) [ 16 ] [ 17 ] [ 18 ]  and are controlled by T cells. When these herpes-virus specific T cells are activated by p-i, they react with the herpes virus peptide expressing cells and damage them by their cytotoxic potential: [ 12 ] [ 19 ]  a consequence is the release virus particles into the circulation  [ 16 ] [ 17 ] [ 18 ]  and symptoms of viral reactivation (high virus load, possibly increase of liver enzymes and of activated lymphocytes) appear."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13841", "text": "A second wave of peptide reactivity may end up in autoimmunity: the abnormal stimulation by p-i includes T cells from the na\u00efve and memory T cell pool. It may include self-peptide reactive T cells, which, if the corresponding self-peptides are presented and are encountered, release cytokines and exert cytotoxicity - autoimmunity may arise. [ 20 ] [ 21 ]  As such self-peptide reactive T cells are present in relatively low amounts, they need >6\u20138 weeks to expand and appear after the virus-reactivations. Autoimmunity occurs in a minority of patients (<20%), and may is often manifested as autoimmune poly-endocrine syndrome. [ 20 ] [ 21 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13842", "text": "Multiple drug hypersensitivity (MDH): a further consequence of p-i stimulations like DRESS or severe MPE is MDH; such patients develop an additional DHR to a structurally different drug, with the same or different clinical manifestations. [ 23 ]  MDH occurs in ca. 20% of patients with DRESS, and can occur any time, from the start of DRESS (often to a combination therapy), during the initial activation, and can even appear years after the first DHR  [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13843", "text": "A main difficulty of DHR research and weak point of the p-i concept is the fact that it is cumbersome to demonstrate a p-i reactivity \u2013 namely that the T cell stimulation occurred due to non-covalent drug binding to immune receptors. In principle, a T cell mediated DHR was explained by p-i if the drug binding to the immune receptors was found to be labile."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13844", "text": "To demonstrate the lability of drug binding, drug specific T cell lines, T cell clones and TCR hybridoma cells were required. [ 25 ] [ 26 ] [ 27 ]  Washing of the cell mix of drug, APC and T cells abrogated p-i reactivity, while T cell reaction to haptens persisted. The presentation of peptides by HLA on APC takes > 4hr pulsing (uptake of hapten modified protein, processing and presentation), and may also require metabolism, if the stimulating drug was chemically inert and not a hapten. Therefore, an immediate reactivity of T cells (e.g. measured by rapid Ca 2+  influx) as well as reactivity to the drug in the presence of protein and metabolism inhibitors or by using glutaraldehyde-fixed antigen presenting cells was interpreted as p-i reaction. [ 25 ] [ 26 ] [ 27 ]  P-i reactivity was demonstrated for a number of drugs ( SMX ,  lidocain ,  lamotrigine ,  carbamazepine , various  radio contrast media ,  quinolones ,  vancomycin ,  dapsone , etc.), including some drugs which can act via p-i or as hapten ( piperacillin ,  flucloxacillin ,  amoxicillin ,  cephalosporins ,  monobactams ). In these cases the p-i reactivity was responsible for more severe reactions like hepatitis in flucloxacillin/B*57:01 carriers or DRESS with amoxicillin and piperacillin [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13845", "text": "DRESS/SJS/TEN (severe DHR) and HLA-linked DHR are p-i. Initially it was thought that p-i reactions were the exception while the hapten mechanism represented the main cause of systemic T cell mediated DHR. Conversely it seems to be the opposite as p-i appears to be the main mechanism in T cell mediated DHR: Whenever the mechanism was investigated how drugs cause severe DHR (DRESS, SJS/TEN), it was always found to be due to p-i. [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13846", "text": "It is unclear whether the majority of severe MPE is due to p-i. As the in vitro analysis of amoxicillin induced MPE (analysis of >150 amoxicillin induced MPE) regularly reveals high secretions of IL-5, IL-13, IFNg, granzyme B and granulysin upon drug exposure (very similar to DRESS cases), the in vitro drug stimulation in MPE is often strong and includes the secretion of Th1, Th2, and cytotoxic cytokines simultaneously. It is actually often stronger and broader than the cytokine secretion upon tetanus control, and is reminiscent of an in vitro mixed leukocyte reaction (MLR). [ 27 ]  Further work is needed, but most MPE appear to be mediated by p-i."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13847", "text": "Importantly, all drugs which develop DHR and have a strong HLA-linkage (e.g. allopurinol/oxypurinol and B*58:01) stimulate via p-i. Protein reactions are not HLA restricted: A protein is large and is processed into various small peptides. These peptides (including the hapten-modified peptides) fit into different HLA alleles and not in only one HLA like observed with drugs. Thus, the DHR-HLA linkage seen with certain drugs can only be explained by direct drug binding to an allele-typic region of the HLA-molecule. This was also confirmed in structural and computational studies. Importantly, if a drug can be stimulatory by p-i or by hapten mechanism (SMX/SMX-NO, beta-lactams), the severe T cell mediated symptoms are mediated by p-i and are HLA-allele restricted, [ 28 ]  while the hapten-reactions are not. Thus, the list of drugs acting via p-i and causing DHR is now longer than the list of hapten-like drugs (table)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13848", "text": "First hapten, then non covalent drug binding: A strong argument for a hapten-mechanism underlying DHR was the ability of the drug to cause all, namely IgG, IgE and T cell mediated DHR, since these different immune reactions required the immunogenic presentation of the drug in various ways. This is best achieved using hapten (and thus antigenic) features of a drug. Indeed, the classical hapten-drugs beta-lactam antibiotics, SMX-NO, or PPI are able to induce all forms of Gell and Coombs immune stimulations, while e.g. classical and exclusive p-i drugs like carbamazepine or abacavir induce only T cell reactions, but never anaphylaxis. [ 29 ]  Importantly, an ability to act as hapten does not rule out that non-covalent binding like in p-i plays a role in DHR. Actually, during a DHR the type of drug-protein binding may change: A drug may act as hapten in the induction phase causing asymptomatic immunity, but the effector mechanism of immunoglobulin-reactions and some severe T-cell mediated DHR may actually be due to non-covalent drug bindings. Thus, beta-lactam antibiotics \u2013 the classical hapten-drugs - are the main elicitor for \"fake antigen\" reactions, drug induced immune  thrombocytopenia  (DITP) and p-i stimulations, which are all based on non-covalent drug-protein interactions and are not antigen induced."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13849", "text": "The polyclonal T cells response stemming from the memory T cell pool includes T cells which are primed by prior immune responses. An important role play herpes viruses (HHV6, CMV, EBV, Herpes simplex I), where a relatively large amount of T cells are involved in the control of these herpes viruses. Indeed, herpes virus reactivation is so common, that it is part of the Japanese definition of DRESS. [ 30 ]   Since the precursor frequency of such herpes virus specific T cells is high (up to 10% of the CD8+ T cells in the elderly can be devoted to herpes virus control, [ 30 ] [ 31 ]  symptoms due to such T cells appear already after ca. 2\u20136 weeks."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13850", "text": "Penetration enhancers  (also called chemical penetration enhancers, absorption enhancers or sorption promotors) are chemical compounds that can facilitate the penetration of  active pharmaceutical ingredients  (API) into or through the poorly permeable biological membranes. These compounds are used in some pharmaceutical formulations to enhance the penetration of APIs in  transdermal drug delivery  and transmucosal drug delivery (for example, ocular, nasal, oral and buccal). [ 1 ]  They typically penetrate into the biological membranes and reversibly decrease their barrier properties."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13851", "text": "Human skin  is a very impermeable membrane that protects the body from ingress of harmful substances and prevents water loss from underlying organs. However, this seriously limits the use of skin as a site for drug administration. One of the approaches to facilitate  transdermal drug delivery  is the use of penetration enhancers. Many different compounds have been explored as potential penetration enhancers to facilitate transdermal drug delivery. These include  dimethylsulphoxide ,  azones  (such as  laurocapram ), pyrrolidones (for example  2-pyrrolidone ), alcohols ( ethanol  and  decanol ),  glycols  (for example  propylene glycol ), surfactants,  urea , various hydrocarbons and terpenes. [ 2 ] [ 3 ] [ 4 ]  Different potential skin site and modes of action were identified for penetration enhancement through the skin. In some cases, penetration enhancers may disrupt the packing motif of the  intercellular lipid matrix  or  keratin  domains. In other cases, drug penetration to the skin is facilitated because the penetration enhancer saturates the tissue and becomes a better system to dissolve the molecules of API."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13852", "text": "Topical administration to the eye is usually characterised by very poor  drug bioavailability  due to several natural defence mechanisms, including  nasolacrymal drainage ,  blinking , and poor permeability of the  cornea . Enhancement of the corneal permeability to drug molecules is one of the strategies to improve the efficiency of topical drug delivery to the eye. Several classes of compounds have been researched as potential penetration enhancers through ocular membranes. These include  chelating agents ,  cyclodextrins , surfactants,  bile acids  and salts, and  crown ethers . [ 5 ]  There are also reports on the use of cell penetrating peptides and chitosan as penetration enhancers in ocular drug delivery. [ 6 ]  The most commonly used penetration enhancers in ocular formulations are benzalkonium chloride and ethylenediamine tetraacetate (EDTA).  Benzalkonium chloride  is often used as an antimicrobial preservative in eye drops [ 7 ]  and EDTA is used as a chelating agent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13853", "text": "Cyclodextrins,  chitosan , some  surfactants ,  bile acids  and salts,  sodium tauro-24,25-dihydro-fusidate , and  phospholipids  were reported as penetration enhancers in nasal drug delivery both for humans and equines. [ 8 ]  Chitosan is one of the most widely researched penetration enhancers in nasal drug delivery and it enhances the penetration of drugs by opening the  tight junctions  in the cell membranes. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13854", "text": "Penetration enhancers have been applied to improve the absorption of poorly permeable, hydrophilic drugs or macromolecules. [ 10 ]  Permeation enhancers that have been used successfully for oral drug development include medium-chain fatty acids like caprylic acid [ 11 ]  or caprate, or its amino acid ester like Salcaprozate sodium (SNAC). [ 12 ]  The above-mentioned permeation/penetration enhancers have a surfactant-like activity where they perturb the intestinal epithelium, promoting transcellular or paracellular absorption. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13855", "text": "Peripherally acting  \u03bc-opioid receptor   antagonists  ( PAMORAs ) are a class of  chemical compounds  that are used to reverse  adverse effects  caused by  opioids  interacting with  receptors  outside the  central nervous system  (CNS), mainly those located in the  gastrointestinal tract . PAMORAs are designed to specifically inhibit certain  opioid receptors  in the gastrointestinal tract and with limited ability to cross the  blood\u2013brain barrier . Therefore, PAMORAs do not affect the  analgesic  effects of opioids within the central nervous system. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13856", "text": "Opioid drugs are known to cause  opioid-induced constipation  (OIC) by inhibiting  gastric emptying  and decreasing  peristaltic  waves leading to delayed absorption of medications and more water absorption from the  feces . That can result in hard and dry stool and  constipation  for some patients. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13857", "text": "OIC is one of the most common  adverse effects  caused by opioids, so the discovery of PAMORAs can prevent the effects that often compromise  pain management . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13858", "text": "Methylnaltrexone bromide  was the first medication in the  drug class  approved by the  FDA . [ 4 ]  It was discovered in 1979 by Leon Goldberg, a  pharmacologist  at the  University of Chicago . Having witnessed the suffering of a dying friend with OIC, Goldberg tested various  derivatives  of  naltrexone , a drug known to block the effects of opioids. His objective was to find a drug that could not pass the  blood brain barrier , without affecting the analgesic effects of the opioids. After Goldberg died, his colleagues at the university continued to develop the compound. It was approved by the FDA in April 2008, originally for OIC in adult patients with advanced illness and later in adult patients with chronic noncancer pain. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13859", "text": "In the late 1970s, Dennis M. Zimmerman and his co-workers from  Lilly Research Laboratories , Indiana, did research on structural concepts for narcotic antagonists defined in a 4-phenylpiperidine series. [ 6 ]  They reported  N -methyl- trans -3,4-dimethyl-4-phenylpiperidine to be pure opioid receptor  antagonist  with a new  pharmacophore . To increase the  potency  they attached a  phenolic group  to the  aromatic ring ,  N -methyl- trans -3,4-dimethyl-4-(3-hydroxyphenyl)piperidine. That structure was used to design and develop other opioid receptors antagonists such as  alvimopan . [ 5 ]  Alvimopan was approved later in 2008 for in-hospital use to increase the  gastrointestinal function  following a partial large or  small bowel  resection with primary  anastomosis .  Naloxegol  was approved in September 2014 and  naldemedine  in March 2017, both for the treatment of OIC in adult patients with chronic cancer. [ 7 ] [ 8 ] [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13860", "text": "PAMORAs act by inhibiting the binding of opioids  agonist  to the  \u03bc-opioid receptor  (MOR). The objective of PAMORAs treatment is to restore the  enteric nervous system  function (ENS). The MOR is found in several places in the body and PAMORAs is a  competitive antagonist  for binding to the receptor. The MORs in the gastrointestinal tract are the main receptors that PAMORAs are intended to block and prevent the binding of opioid agonists. [ 11 ]  PAMORAs are used in the treatment of opioid-induced bowel dysfunction (OIBD), a potential adverse effect caused by chronic opioid use. PAMORAs act on the three  pathophysiological  mechanisms of this adverse effect. They act on  gut motility ,  gut secretion  and  sphincter  function. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13861", "text": "PAMORAs effect on gut motility is that it can increase the resting tone in the circular muscle layer. The antagonist enhances the effect on tonic inhibition of the  muscle tone . This will normalize the tone in the circular muscle layer and therefore prevent opioid-induced rhythmic contractions.  When these two factors are combined, it results in decreased  transit time . Impliedly these effects will decrease the passive absorption of fluids which helps with decreasing OIBD symptoms such as constipation,  gut spasm  and  abdominal cramp . [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13862", "text": "PAMORAs effect on gut secretion will help reverse the decreased  cAMP  formation that opioid agonists induce. [ 14 ]  Also, the antagonist will establish a normal secretion of  chloride . Opioids agonists can also reduce the  secretion  of  peptides  by increasing the  sympathetic nervous system  through the \u03bc-receptors in the ENS, which can lead to drier and harder stool. PAMORAs work against it so the stool becomes softer and less dry. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13863", "text": "PAMORAs effect on the function of the  sphincter  is in theory to regulate the movement coordination. The antagonist can prevent  sphincter of Oddi dysfunction  that is caused by opioids. [ 15 ]  Antagonists can also reduce opioid-induced anal sphincter dysfunction. The dysfunction is tied to  straining ,  hemorrhoids  and incomplete emptying. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13864", "text": "Even though \u03bc-opioid receptor (MOR) targeting drugs have been used for a long time, not much is known about the  structure-activity relationship  and the  ligand -receptor interactions on the basis of well-defined  biological effects  on receptor activation or inhibition. Also, the distinction in the receptor-ligand interaction patterns of agonists and antagonists is not known for sure. One theory states that the  morphinans  biological activity could be determined by the size of the N-substituents. For example, antagonists usually have larger substituents, such as  allyl - or  cyclopropyl methyl  at the morphinan nitrogen, while agonists generally contain a  methyl group . On the other hand, agonist activity is also shown in ligands with larger groups at the morphinan nitrogen, and therefore this hypothesis is challenged. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13865", "text": "Methylnaltrexone bromide, naloxegol, and naldemedine all have similar structures, which is not far away from the chemical structure of  morphine  and other MOR-agonists. All contain a rigid  pentacyclic  structure that involves  benzene ring  (A),  tetrahydrofuran  ring (B), two  cyclohexane  rings (C and D) and a  piperidine  ring (E). [ 18 ]  The most important functional groups for the biological action of opioids are the  hydroxyl group  on the  phenol , N-methyl group,  ether  bridge between C4 and C5, the  double bond  between  carbon  number C7 and C8 and the hydroxyl groups at C3 and C6. The phenolic ring and its 3-hydroxyl group is vital for the analgesic effects as the removal of the OH group decrease the analgesic activity 10-fold. There is another principle for the hydroxyl group on C6 as the removal enhances its activity. The increased activity is mainly because of the increased  lipophilicity  and the increased ability to cross the blood\u2013brain barrier. Naldemedine has the hydroxyl group while methylnaltrexone bromide has a  ketone  group and naloxegol has an  ester . The double bond between C7 and C8 is not required for the analgesic effect and reduction of the double bond will increase the activity. None of the antagonists has a double bond in their structure. The N-substituent on the skeleton is thought to determine the pharmacological behavior and its interaction with MOR. It is also thought to play a key role in distinguishing antagonists from agonists. Allyl group, a  methylcyclopropyl group  or a  methylcyclobutyl  as N-substituent groups are thought to lead antagonist activity. [ 19 ] [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13866", "text": "Agonists and antagonists form certain  chemical bonds  with  amino acids  that construct the MOR. The majority of antagonists, as well as agonists, are predicted to form  charged interaction  with Asp147 and a  hydrogen bond  with Tyr148. However, majority of antagonists also form additional  polar interactions  with other amino acid residues such as Lys233, Gln124, Gln229, Asn150, Trp318 and Tyr128. Only a small minority of agonists form the same additional polar interactions. Both agonists and antagonists are known to form hydrogen bonds with His297. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13867", "text": "It can be concluded that interactions with the amino acid residues, Asp147 and Tyr148 are essential for the  ligand  to bind to the receptor and the molecules that form additional polar interactions with other residues are more often antagonists than agonists. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13868", "text": "The N-substituent group can form  hydrophobic  bonds with Tyr326 and Trp293 and the aromatic and cyclohexane rings can form similar bonds to Met151. The backside of the ligand can also form a hydrophobic bond, but with Val300 and Ile296. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13869", "text": "Methylnaltrexone bromide is the  bromide  salt form of methylnaltrexone, a  quaternary  methyl derivative of  noroxymorphone . The methyl group and the quaternary salt formation increase the  polarity  and reduce the  lipid solubility  thereby restricts the blood\u2013brain-barrier penetration. Methylnaltrexone has eight times higher  affinity  for MOR than for  \u03ba-opioid receptor  (KOR) and  \u03b4-opioid receptor  (DOR). [ 23 ]  Naltrexone forms interaction with Asp147 and Tyr148 along with a  hydrogen bond  with Lys233. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13870", "text": "Peripherally selective trans-3,4-dimethyl-4-(3-hydroxylphenyl)piperidine opioid antagonists were developed for the treatment of  gastrointestinal motility  disorder by Zimmerman and his coworkers. From that, they derived the 4-(3-hydroxyphenyl)-3,4-dimethylpiperidine scaffold with functional groups spanning various sizes, charge, and polarity to reach peripheral opioid receptor antagonism while decreasing CNS drug exposure. The  in vitro  \u03bc-Ki,  in vivo   AD50 , and  ED50  and peripheral index (ratio) was examined for several selective analogs, and from that, they found out that the trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, Alvimopan, gave the best results. [ 5 ]  The large  zwitterionic  structure and the high polarity prevents Alvimopan from crossing the blood\u2013brain barrier, potency at binding peripheral MORs is thereby 200 times that of central MORs. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13871", "text": "Naloxegol is a  polyethylene glycol -modified derivative of \u03b1- naloxol . Naloxegol has a similar form as  naloxone  as a  heteropentacyclic  compound both of which have an  allyl group  attached to the  amine  of the  piperidine  ring. However, naloxegol has a monomethoxy-terminated n=7  oligomer  of  PEG  connected to the 6-alpha-hydroxyl group of \u0251-naloxol via an  ether  linkage. The PEG moiety increases the  molecular weight  and therefore restricts the uptake of naloxegol into the  CNS . [ 26 ]  Furthermore, pegylated naloxegol becomes a  substrate  for the  P-glycoprotein   efflux  transporter that transports the compound out of the CNS. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13872", "text": "Naldemedine has a similar chemical structure as naltrexone but with an additional side chain that increases the  molecular weight  and  polar surface area  of the substance. Like naloxegol, naldemedine is a substrate of the P-glycoprotein efflux transporter. These properties result in less penetration into the CNS and decrease possible inference with the effects of opioid agonists. [ 28 ] \nNaldemedine is a dual antagonist for MOR and DOR. Activation of the DOR has been known to cause nausea and/or vomiting, so a dual antagonist can decrease both OIC and nausea/vomiting. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13873", "text": "The  molecular weight ,  bioavailability ,  protein binding ,  elimination half-life , the  time to achieve maximum plasma concentration  and  binding affinity  are present in the table below. [ 26 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13874", "text": "Methylnaltrexone bromide has poor oral bioavailability, and for that reason, every other day it is administered  subcutaneously . About half of the dose is excreted in the urine and somewhat less in feces with 85% eliminated unchanged. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13875", "text": "Alvimopan has considerable low bioavailability (6%) due to its high  binding affinity  and low  dissociation rate . Essentially, alvimopan is mediated by  biliary secretion  with an average plasma clearance of 400 ml/min.  Metabolism  of alvimopan is via  intestinal flora  resulting in  hydrolysis  of alvimopan to the active amide metabolite (ADL 08-0011). However, the metabolite is considered clinically irrelevant due to its low binding affinity. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13876", "text": "When naloxegol is given with a fatty meal,  absorption  increases. Clearance is mostly via  hepatic metabolism  (P450-CYP3A) with unknown actions of the metabolites. Naloxegol has small fragments eliminated by  renal excretion . [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13877", "text": "Naldemedine metabolites mainly via  CYP3A  to nor-naldemedine, it also metabolites via  UDP-glucuronosyltransferase  1A3 to naldemedine 3-G, but in a lesser extent. Those metabolites are both opioid receptor antagonists but are less potent than the  parent compound . [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13878", "text": "Axelopran  is an oral PAMORA which is under development by Theravane Biopharma. It has completed phase II in  clinical trials  in more than 400 patients with OIC. Axelopran has a different chemical structure from other PAMORAs but with a similar  mechanism of action . It acts as an antagonist for MOR, KOR and DOR, but with higher affinity for MOR and KOR than for DOR. Like other PAMORAs, the main goal is the treatment of OIC. [ 34 ] \nAxelopran is also being investigated in fixed-dose combination (FDC) with  oxycodone . It is done by using spray coating technology to create an FDC of axelopran and controlled-release oxycodone. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13879", "text": "There is a demand for optimization of the receptor  selectivity  and affinity accompanied by an exploration of candidate compounds regarding their  route of administration . These are the main objectives and future strategies for drug discovery and the development of PAMORAs.\nPredominantly, the MORs exhibit functionally selective agonism. Therefore, future possible candidate compounds that target OIC are PAMORAs with optimized selectivity and affinity. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13880", "text": "Pharmacoepidemiology  is the study of the uses and effects of drugs in well-defined populations. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13881", "text": "To accomplish this study, pharmacoepidemiology borrows from both  pharmacology  and  epidemiology . Thus, pharmacoepidemiology is the bridge between both pharmacology and epidemiology. Pharmacology is the study of the effect of drugs and clinical pharmacology is the study of effect of  drugs  on clinical humans. Part of the task of clinical pharmacology is to provide a risk benefit assessment by effects of drugs in patients: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13882", "text": "Other parameters relating to drug use may benefit epidemiological methodology. Pharmacoepidemiology then can also be defined as the transparent application of epidemiological methods through pharmacological treatment of conditions to better understand the conditions to be treated. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13883", "text": "Epidemiology  is the study of the distribution and determinants of diseases and other health states in populations. Epidemiological studies can be divided into two main types: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13884", "text": "Pharmacoepidemiology benefits from the  methodology  developed in general epidemiology and may further develop them for applications of methodology unique to needs of pharmacoepidemiology. There are also some areas that are altogether unique to pharmacoepidemiology, e.g., pharmacovigilance. Pharmacovigilance is a type of continual monitoring of unwanted effects and other safety-related aspects of drugs that are already placed in current growing integrating markets. In practice, pharmacovigilance refers almost exclusively to spontaneous reporting systems which allow health care professionals and others to report adverse drug reactions to the central agency. The central agency combines reports from many sources to produce a more informative profile for drug products than could be done based on reports from fewer health care professionals. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13885", "text": "In Australia, a 10% sample of all people eligible for government-subsidised medicines by the Pharmaceutical Benefits Scheme (PBS) are made available for research purposes.  Licences are held between Services Australia, who hold the data for the PBS, and academics at Monash University, University of New South Wales, University of South Australia and the University of Western Australia to use the 10% sample for research purposes. Research outputs from these data have to be approved by Services Australia prior to publication.  These data create a useful picture of all dispensed medicines in Australia and allow for pharmacovigilance and to explore trends in medicines usage. [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13886", "text": "Pharmacological cardiotoxicity  is defined as  cardiac damage  that occurs under the action of a  drug . This can occur both through damage of  cardiac muscle  as well as through alteration of the  ion  currents of  cardiomyocytes . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13887", "text": "Two distinct drug classes in which cardiotoxicity can occur are in  anti-cancer  and  antiarrhythmic drugs .  Anti-cancer  drug classes that cause cardiotoxicity include  anthracyclines ,  monoclonal antibodies , and  antimetabolites . This form generally manifests as a progressive form of  heart failure , but can also manifest as an harmful  arrhythmia . [ 2 ]  In contrast, in  antiarrhythmic drugs , cardiotoxicity is due to a risk of  arrhythmias  resulting from treated-induced  ion current  imbalance. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13888", "text": "Other types of drugs are also known for cardiotoxicity, such as  clozapine  being associated with myocarditis. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13889", "text": "The cardiotoxicity of anticancer drugs has been well documented, with an entire sub-speciality of  cardio-oncology  dedicated towards investigating and treating these serious side effects. Two well known anticancer drug families that cause cardiotoxicity are  anthracyclines  and  monoclonal antibodies targeting HER2.  Other types of anticancer drugs that can lead to cardiotoxicity include alkylating agents such as  cyclophosphamide , BCR-ABL1 targeting receptor tyrosine kinases such as  imatinib , and VEGF antibodies such as  bevicizumab . [ 5 ]  This section of the article will focus on  anthracyclines  and  HER2 monoclonal antibodies  due to the prominence of cardiotoxicity in these compounds."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13890", "text": "The mechanism of anthracycline-induced cardiotoxicity is unknown and is under active research. However, multiple theories exist. One well supported mechanism is related to the production of superoxide anion  radicals  that in turn damage cardiac myocytes.  [ 6 ]  Recent research suggests that Top2b (topoisomerase-II\u03b2) helps\u00a0mediate the production of oxygen radicals, representing a potential biomarker for this serious side effect. [ 7 ]    Other proposed mechanisms include interference with cardiac  ATP  production, mitochondria-related stress, and lipid peroxidation. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13891", "text": "On the other hand, the mechanism of  HER2  antibody cardiotoxicity is more well known.  [ 8 ]   HER2  is a protein expressed on the cell membranes of HER2 positive breast cancer cells.  However, HER2 is also expressed on the surface of cardiac myocytes. It is hypothesized that HER2 expressed in these cardiac cells have a cardioprotective mechanism, and the targeting of these proteins in this context leads to the cardiotoxicity associated with  HER2 monoclonal antibodies. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13892", "text": "The cardiotoxicity of anthracyclines can be classified into three categories: early, early onset chronic, and late onset chronic.  Early cardiotoxicity is rare, but manifests as arrthymias, myocarditis, and pericarditis. This type of toxicity occurs directly after treatment with anthracycline. Early onset chronic cardiotoxicity is defined as cardiotoxicity manifesting within one year of the completion of treatment, while late onset chronic cardiotoxicity occurs after one year.  [ 10 ]  The cardiotoxicity of anthracyclines is dose dependent.  At total exposure levels lower than 400 mg/m2, the incidence of heart failure is between 3%-5%.  At a exposure rate of 700 mg/m2, the heart failure rate is at 48%. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13893", "text": "Cardiotoxicity involving  HER2 monoclonal antibodies  manifests as decrease left ventricular ejection fraction and resulting heart failure. [ 12 ]  The cardiotoxicity of  HER2 monoclonal antibodies  is dose independent. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13894", "text": "The immediate intervention for the development of cardiotoxicity is discontinuation of the drug. Preventative measures for anthracycline induced cardiomyopathy include  dexrazoxane , which is the only preventative drug approved by the FDA for prevention of anthracycline cardiomyopathy. [ 14 ]   Overall, there are no specific treatments targeted towards the cardiotoxicity of anticancer drugs. Rather, treatment is of the resultant heart failure. This often takes the form o f ACE inhibitors  or  beta blockers .  [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13895", "text": "Antiarrhythmics  are broad class of drugs that are used treat heart rhythm irregularities.  [ 16 ]  Utilizing the Vaughan-Williams (VW) system, antiarrhymic drugs are classified into four main classes based on their mechanism of action. Class I antiarrhymics lead to blockage of sodium channels. Class II antiarrhymatics are  beta-adrenoceptor blockers . Class III antiarrhymics act as  potassium channel blockers , while Class IV antiarrhymics are  non-dihydropyridine calcium channel blockers . While the effects of these drugs may be antiarrhymic, they can also be proarrhymic in other contexts."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13896", "text": "The pharmacological cardiotoxicity of antiarrhymic compounds is related to their electrophysiological mechanism. In particular, because antiarrhymics drugs act on the opening/closing of ion channels, the modification of the electrical currents can lead to adverse cardiac events such  torsade de pointes  or  ventricular fibrillation . Due to the case-by-case basis in which these medication lead to cardiotoxicity and the development of specific adverse rhythms, it has become increasingly important to assess compounds in a preclinical environment (See  Pharmacological cardiotoxicity#In Silico Cardiotoxicity Assessment )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13897", "text": "The manifestation of antiarrhymic cardiotoxicity may manifest as worsening of the pre-existent arrhythmia or the development of a new arrhythmia."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13898", "text": "Female sex at birth has been associated with an increased risk of the development of new arrhythmia, and other risk factors include age, kidney disease, drug-drug interactions, and other underlying heart problems. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13899", "text": "Like with anticancer drugs, the most common intervention for the development of cardiotoxicity is discontinuation of the causative drug. Individual risk factors, such as risk of arrhythmia re-emergence, are considered when deciding final courses of action. Adjacent devices, such as pacemakers, or ablation therapy may also be considered as alternatives to medical treatment for the primary arrhythmia. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13900", "text": "The treatment of  torsade de pointes  is typically with intravenous magnesium sulfate, which helps stabilize cardiac membranes. [ 19 ]  For  ventricular fibrillation  cases, either/or  defibrillation ,  amiodarone , or  epinephrine  is used dependent on the ACLS algorithm.  [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13901", "text": "In the last years, in silico models have aided scientists and clinicians to cure several diseases. [ 21 ]  Computational modeling in particular has helped scientists to alter parameters that otherwise could have not been investigated. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13902", "text": "In the field of  electrophysiology , pharmacological cardiotoxicity can be carried out by leveraging specific computational models. Recently, it has become possible to analyze the pharmacological effect on  atria  and  ventricles  separately. [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13903", "text": "Since the two cardiac chambers are very different each other and play a key role both on a functional and anatomical basis, suitable computational models have to be accounted for to describe their different behavior. During the years, several models have been developed to best characterize and replicate the cellular action potential behavior of the most relevant anatomical region of the heart, such as Courtemanche model for atria or O'Hara model for ventricles. [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13904", "text": "In this way, it has been possible to create a virtual cellular population of cardiomyocytes and vary their  conductances  that are related to the main ionic currents which contribute to the action potential morphology, and is reflective of a specific anatomical region of the heart. [ 24 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13905", "text": "In order to create a stable population of cellular  action potentials , several biomarkers have been developed to best characterize the instability of cellular action potentials. Examples of biomarkers reported include: [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13906", "text": "A \n P \n \n D \n \n 90 \n \n \n = \n \n t \n \n 90 \n \n \n \u2212 \n \n t \n \n 0 \n \n \n \n \n {\\displaystyle APD_{90}=t_{90}-t_{0}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13907", "text": "A \n P \n \n D \n \n 50 \n \n \n = \n \n t \n \n 50 \n \n \n \u2212 \n \n t \n \n 0 \n \n \n \n \n {\\displaystyle APD_{50}=t_{50}-t_{0}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13908", "text": "A \n P \n \n D \n \n 20 \n \n \n = \n \n t \n \n 20 \n \n \n \u2212 \n \n t \n \n 0 \n \n \n \n \n {\\displaystyle APD_{20}=t_{20}-t_{0}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13909", "text": "T \n r \n i \n a \n n \n g \n u \n l \n a \n t \n i \n o \n n \n = \n A \n P \n \n D \n \n 90 \n \n \n \u2212 \n A \n P \n \n D \n \n 50 \n \n \n \n \n {\\displaystyle Triangulation=APD_{90}-APD_{50}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13910", "text": "A \n P \n A \n = \n \n V \n \n M \n a \n x \n \n \n \u2212 \n \n V \n \n 0 \n \n \n \n \n {\\displaystyle APA=V_{Max}-V_{0}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13911", "text": "Once the cellular population is stable, all action potential are then compared to physiological data related to the most relevant anatomical regions to appropriately filter the action potential, aiming to consider just the physiologically relevant ones. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13912", "text": "At the atrial level, clusterization occurs with data associated to: [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13913", "text": "According to  pharmacokinetic  and  pharmacodynamic  ideals, pharmacological action is integrated in the model. By means of specific electrical stimuli protocols, [ 28 ]  the pharmacological effect of a new drug can be investigated in a completely safe, and controlled computational environment, providing preliminary important considerations concerning the cardiotoxicity of new pharmacological compounds. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13914", "text": "According to the outcome of the simulations, several aspects can be investigated to identify the proarrhythmicity of a new pharmacological compound. [ 30 ] [ 31 ]  The typical changes, known as repolarization abnormalities, that are considered pro-arrhythmic include: [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13915", "text": "Simulation can be carried out at different effective plasmatic therapeutic level of the drugs to identify the level at which cardiotoxicity cannot be neglected. The data collected could be finally managed to create a score system aimed to define the torsadogenic risk, namely the risk of inducing torsade de pointes, of the new drugs. [ 32 ] [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13916", "text": "A possible torsade de point risk score to assess cardiotoxicity could be: [ 33 ] \n \n \n \n \n T \n d \n P \n R \n S \n = \n \n \n \n \n \u2211 \n \n c \n \n \n ( \n \n W \n \n c \n \n \n \u22c5 \n n \n R \n \n A \n \n c \n \n \n ) \n \n \n N \n \u22c5 \n \n \u2211 \n \n c \n \n \n \n W \n \n c \n \n \n ) \n \n \n \n \n \n {\\displaystyle TdPRS={\\frac {\\sum _{c}(W_{c}\\cdot nRA_{c})}{N\\cdot \\sum _{c}W_{c})}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13917", "text": "where  \n \n \n \n \n \u2211 \n \n c \n \n \n \n \n {\\displaystyle \\sum _{c}} \n \n  is the sum of all concentrations, [C] is the concentration taken into account,  \n \n \n \n \n W \n \n c \n \n \n = \n \n \n \n E \n F \n T \n P \n C \n \n \n [ \n C \n ] \n \n \n \n \n \n {\\displaystyle W_{c}={\\frac {EFTPC}{[C]}}} \n \n  ,  \n \n \n \n N \n \n \n {\\displaystyle N} \n \n  is the total number of models in the population, and  \n \n \n \n n \n R \n \n A \n \n c \n \n \n \n \n {\\displaystyle nRA_{c}} \n \n  represents the number of models showing repolarization abnormalities. [ 33 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13918", "text": "More detailed computation simulations can be carried out accounting for not cellular models, but taking into consideration the functional  syncytium  and enabling the cells to mutually interact, the so-called electrotonic coupling. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13919", "text": "In case of tissue simulation or in wider cases, such as in whole organ simulations, all the cellular models are note applicable anymore, and several corrections have to be made. Firstly, the governing equations can not be just  ordinary differential equations , but a system of  partial differential equations  has to be accounted for. [ 35 ]  A suitable choice may be the monodomain model: [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13920", "text": "\u25bd \n \u22c5 \n ( \n D \n \u2207 \n V \n ) \n = \n ( \n \n C \n \n m \n \n \n \n \n \n \u2202 \n V \n \n \n \u2202 \n t \n \n \n \n + \n \n I \n \n i \n o \n n \n \n \n ( \n V \n , \n u \n ) \n ) \n \n \n {\\displaystyle \\triangledown \\cdot (D\\nabla V)=(C_{m}{\\frac {\\partial V}{\\partial t}}+I_{ion}(V,u))} \n \n   \n \n \n \n i \n n \n \n \n {\\displaystyle in} \n \n   \n \n \n \n \u03a9 \n \n \n {\\displaystyle \\Omega }"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13921", "text": "n \n \u22c5 \n ( \n D \n \u2207 \n V \n ) \n = \n 0 \n \n \n {\\displaystyle n\\cdot (D\\nabla V)=0} \n \n   \n \n \n \n i \n n \n \n \n {\\displaystyle in} \n \n   \n \n \n \n \u2202 \n \u03a9 \n \n \n {\\displaystyle \\partial \\Omega }"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13922", "text": "where  \n \n \n \n D \n \n \n {\\displaystyle D} \n \n  is the effective conductivity tensor,  \n \n \n \n \n C \n \n m \n \n \n \n \n {\\displaystyle C_{m}} \n \n is the capacitance of the cellular membrane,  \n \n \n \n \n I \n \n i \n o \n n \n \n \n \n \n {\\displaystyle I_{ion}} \n \n  the transmembrane ionic current,  \n \n \n \n \u03a9 \n \n \n {\\displaystyle \\Omega } \n \n  and  \n \n \n \n \u2202 \n \u03a9 \n \n \n {\\displaystyle \\partial \\Omega } \n \n \u00a0are the domain of interest and its boundary, respectively, with  \n \n \n \n n \n \n \n {\\displaystyle n} \n \n  the outward boundary of  \n \n \n \n \u2202 \n \u03a9 \n \n \n {\\displaystyle \\partial \\Omega } \n \n . [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13923", "text": "Photopharmacology is an emerging multidisciplinary field that combines  photochemistry  and  pharmacology . [ 1 ]  Built upon the ability of light to change the  pharmacokinetics  and  pharmacodynamics  of bioactive molecules, it aims at regulating the activity of drugs in vivo by using light. [ 2 ]  The light-based modulation is achieved by incorporating molecular photoswitches such as azobenzene and diarylethenes or photocages such as o-nitrobenzyl, coumarin, and BODIPY compounds into the pharmacophore. [ 3 ]  This selective activation of the biomolecules helps prevent or minimize off-target activity and systemic side effects. Moreover, light being the regulatory element offers additional advantages such as the ability to be delivered with high spatiotemporal precision, low to negligible toxicity, and the ability to be controlled both qualitatively and quantitatively by tuning its wavelength and intensity. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13924", "text": "Though photopharmacology is a relatively new field, the concept of using light in therapeutic applications came into practice a few decades ago.  Photodynamic therapy  (PDT) is a well-established clinically practiced protocol in which  photosensitizers  are used to produce singlet oxygen for destroying diseased or damaged cells or tissues. [ 2 ]   Optogenetics  is another method that relies on light for dynamically controlling biological functions especially brain and neural. [ 4 ]  Though this approach has proven useful as a research tool, its clinical implementation is limited by the requirement for genetic manipulation. Mainly, these two techniques laid the foundation for photopharmacology. Today, it is a rapidly evolving field with diverse applications in both basic research and clinical medicine which has the potential to overcome some of the challenges limiting the range of applications of the other light-guided therapies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13925", "text": "Figure 1.  Schematic representation of the mechanism of (a) photopharmacology (b) photodynamic therapy, and (c) optogenetics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13926", "text": "The discovery of natural photoreceptors such as  rhodopsins  in the eye inspired the biomedical and pharmacology research community to engineer light-sensitive proteins for therapeutic applications. [ 2 ]  The development of synthetic  photoswitchable  molecules is the most significant milestone in the history of light-delivery systems. Scientists are continuing with their efforts to explore new photoswitches and delivery strategies with enhanced performance to target different biological molecules such as ion channels, nucleic acid, and enzyme receptors. Photopharmacology research progressed from in vitro to in vivo studies in a significantly short period of time yielding promising results in both forms. Clinical trials are underway to assess the safety and efficacy of these photopharmacological therapies further and validate their potential as an innovative drug delivery approach."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13927", "text": "Molecular  photoswitches  are utilized in the field of photopharmacology, where the energetics of a molecule can be reversibly controlled with light to achieve spatial and temporal resolution of a particular effect. Photoswitches may function by undergoing  photoisomerization  through which light is used to conformationally adapt a molecule to a biological site, or through an environmental effect where an external factor such as a solvent effect or hydrogen bonding can selectively allow or quench an emissive state within a molecule. To visualize photophysical processes, a useful depiction is the  Jablonski diagram . This is a diagram which depicts electronic and vibrational energy levels within a molecule as vertical levels and shows the possible relaxation pathways from excited states. Typically, the ground state is referred to as S 0 , and is drawn at the bottom of the figure with nearby vibrational excitations just above it. An absorption will promote an electron into the S 1  state at any vibrational energy level, or into a higher order excited state if the absorbed energy has enough magnitude. The excited state can then undergo internal conversion which is the electronic relaxation to a lower state with the same vibrational energetics or vibrational relaxation within a state. This may be followed by an intersystem crossing wherein the electron undergoes a spin flip, or a radiative or nonradiative decay back to the ground state. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13928", "text": "One example of an organic compound that undergoes photoisomerization is  azobenzene . The structure is two phenyl rings joined with a N=N double bond and is the simplest aryl azo compound. Azobenzene and its derivatives have two accessible absorbance bands: the S 1  state from a n-\u03c0* transition which can be excited into using blue light, and the S 2  state from a \u03c0-\u03c0* transition that can be excited into using ultraviolet light. [ 6 ]  Azobenzene and its derivatives have two isomers, trans and cis. The trans isomer, having the phenyl rings on opposite sides of the azo double bond, is the thermally preferred isomer as there is less stereoelectronic distortion and more delocalization present. However, excitation of the trans isomer to the S 2  state facilitates a shift to the cis isomer. The S 1  absorption is associated with a conversion back to the trans isomer. In this way, azobenzene and its derivatives can act as reversible stores of energy by maintaining a strained configuration in the cis isomer. Modifications of the substituents on azobenzene allow the energetics of these absorptions to be tuned, and if they are engineered such that the two absorption bands overlap a single wavelength of light can be used to flip between them. There are a number of similar photoswitches which isomerize between E and Z configurations across an azo group (for instance, azobenzene and azopyrazole) or an ethylene bridge (for instance, stilbene and hemithioindigo). [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13929", "text": "Alternatively, photoswitches may themselves be emissive and exhibit environmental control over their properties. One such example is a class of ruthenium polypyridyl coordination complexes. Typically they contain two bidentate bipyridine or phenanthroline ligands and an extended phenanthroline-phenazine bidentate ligand such as dipyrido[3,2-a:2,3-c]phenazine (dppz). [ 8 ]  These complexes have an accessible metal to ligand charge transfer excited state ( 1 MLCT) which undergoes rapid intersystem crossing to a  3 MLCT state due to the strong spin-orbit coupling of the ruthenium center. These excited states are localized on the extended ligand phenazine nitrogens, and emission occurs from the  3 MLCT state. Hydrogen bonding interactions such as the presence of water around these nitrogen atoms stabilizes the  3 MLCT state, quenching the emission process. Thus, by controlling whether an aqueous or otherwise protic polar solvent is present, emissive behaviors can be \u201cturned on/off\u201d, and alternation between \u201cbright states\u201d and \u201cdark states\u201d is facilitated. This light switch behavior makes these and similar complexes of recent interest in photopharmacological applications such as photodynamic therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13930", "text": "As previously mentioned, photopharmacology relies on the use of molecular photoswitches being incorporated into the structure of biologically active molecules which allows their potency to be controlled optically. [ 7 ]  They are introduced into the structure of bioactive compounds via insertion, extension, or bioisosteric replacement. [ 7 ]  These incorporations can be supported by structural considerations of the molecule or SAR (structure-activity relationship) analysis to determine the optimal position. [ 7 ]  Some examples of photoswitchable molecules commonly used in photopharmacology are azobenzenes, diarylethenes, and photocages. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13931", "text": "Azobenzenes are a class of photoswitchable molecules and are used in photopharmalogical applications for their reversible photoisomerization, as described in the previous section. An example of a photoswitchable molecule that uses azobenzene is phototrexate.  Phototrexate  is an inhibitor of human dihydrofolate reductase and is an analogue of  methotrexate , a chemotherapy agent. [ 10 ]  When in its photoactive cis form, phototrexate has been shown to be a potent antifolate and is relatively inactive when in the trans form. [ 10 ]  The azologization, or incorporation of azobenzene, of methotrexate allows for control of cytotoxic activity and is considered a step forward in developing targeted anticancer drugs with localized efficacy. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13932", "text": "Diarylethene  photoswitches have reversible cyclization and cycloreversion reactions that are photoinduced. [ 11 ]  They are a class of compounds that have aromatic functional groups bonded to each end of a carbon-carbon double bond. An example of this class of molecule that is used in photopharmacology is  stilbene . Under the influence of light, stilbene switches between its two isomers (E and Z)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13933", "text": "Figure 4. Figure showing stilbene isomerizations under light from E to Z."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13934", "text": "Diarylethenes have been shown to have some advantages over the more researched azobenzenes switches, such as thermal irreversibility, high photoswitching efficiency, favorable cellular stability, and low toxicity. [ 11 ]  Diarylethenes have been shown to have promise in fields other than photopharmacology as well. These fields include optical data storage, optoelectronic devices, supramolecular self-assembly and anti-counterfeiting. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13935", "text": "A class of substances known as photocages contain \u201cphotosensitive groups, also known as 'photoremovable protecting groups\", from which target substances are released upon exposure to specific wavelengths of light\u201d. [ 12 ]  The photosensitive groups physically and chemically protect the target from being released until the molecule undergoes photoreaction. [ 12 ]  Due to these interactions with light, they are commonly used molecules in photopharmacology. More recently, they have played an important role in photoactivated  chemotherapy  (PACT). In PACT, photocages utilize a photoremovable protecting group that protects cytotoxic drugs until the bond is cleaved via light interaction and the cytotoxic drug is released. [ 13 ]  Some well-known photocages include \u201co-nitrobenzyl derivatives, coumarin derivatives, BODIPY, xanthene derivatives, quinone and diarylenes derivatives\u201d. [ 12 ]  However, there are limitations with using photocages in clinical applications as there are not many PPGs that can be used in vivo. This is due to PPG-payload conjugates needing to have acceptable solubility and biological inertness for biocompatibility and the need for efficient uncaging above 600\u00a0nm. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13936", "text": "Figure 5. Example of a photocage release system activated by NIR. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13937", "text": "Photopharmacology, the use of light to control the activity of drugs, has emerged as a promising approach to drug delivery and therapy. By harnessing the power of light, researchers can achieve precise control over drug release and activation, offering new possibilities for targeted and personalized treatments. This subsection explores the application of photopharmacology in drug delivery, focusing on recent advancements and potential clinical applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13938", "text": "In one study, [ 15 ]  researchers designed HDAC inhibitors which can be activated or deactivated with light, providing precise therapeutic control. This approach could reduce the side effects of traditional chemotherapy by targeting inhibitors to specific body areas, potentially leading to more effective and personalized cancer treatments."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13939", "text": "In another study, [ 16 ]  the researchers developed a strategy to attach a photoswitchable group to a common antibiotic; ciprofloxacin. By attaching the photoswitchable group, researchers can control the activity of ciprofloxacin with light. This approach could potentially lead to new ways of treating bacterial infections, with the ability to switch the antibiotic's activity on and off as needed.\nIn this paper [ 17 ]  an in vitro protocol to test different light wavelengths on human cancer cell lines is developed, finding that blue light most effectively inhibited cell growth. This suggests that photopharmacology could offer new cancer treatment options by targeting specific light wavelengths to modulate drug activity in tumor cells."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13940", "text": "Another application of photopharmacology [ 18 ]  is developing a luminescent photoCORM grafted on carboxymethyl chitosan, which, when exposed to light, releases carbon monoxide (CO) to induce apoptotic death in colorectal cancer cells, demonstrating precise control over CO release for targeted cancer therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13941", "text": "Researchers developed a toolbox of photoswitchable antagonists that can interact with GPCRs, a class of proteins involved in various cellular processes. [ 19 ]  By using light to switch the activity of these antagonists, researchers can control the interaction between the antagonists and GPCRs in real time. This approach allows for precise modulation of GPCR activity, which could lead to new insights into cellular signaling pathways and potential therapeutic applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13942", "text": "In another application [ 20 ]  by using light to control the assembly of nanopores, researchers can potentially regulate the flow of ions or molecules through these nanopores. This approach could have applications in various fields, including sensing, drug delivery, and nanotechnology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13943", "text": "Another paper [ 21 ]  reports on the use of photopharmacology to control drug activity; multifunctional fibers in the study deliver light and drugs to specific body areas. Implanted fibers activate light-responsive drugs, altering their structure, and offering precise drug delivery for conditions needing exact timing or dosage."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13944", "text": "In another study, [ 22 ]  ligands were designed to switch their binding mode to G-quadruplex DNA upon exposure to visible light. This method could potentially modulate the activity of G-quadruplex DNA, crucial in gene expression and telomere maintenance, offering new therapeutic avenues, particularly in cancer treatment. The study underscores photopharmacology's promise in targeting specific DNA structures, suggesting G-quadruplex DNA as a viable target for future photopharmacological interventions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13945", "text": "Another study [ 23 ]  developed photoactivatable antibody-photoCORM conjugates targeting human ovarian cancer cells, releasing CO upon light exposure to diminish cell viability. This approach offers precise cancer cell targeting while minimizing harm to healthy tissue, showcasing the potential of photopharmacology in cancer therapy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13946", "text": "In another paper, [ 24 ]  a photoactivatable compound that binds to and modulates the activity of the CRY1 protein, regulating the mammalian circadian clock, was developed. By using light to control the compound's activity, researchers can potentially treat circadian rhythm disorders and related health conditions by modulating the function of CRY1. Photopharmacology involves using light to control the activity of drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13947", "text": "In another application [ 25 ]  researchers used photopharmacology to control drug release and focus on a drug interacting with tubulin, visualizing its release in real time with time-resolved serial crystallography. This technique offers insights into drug-tubulin interactions and demonstrates the potential for designing drugs with precise actions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13948", "text": "The future of photopharmacology holds immense promise. It has the potential to revolutionize conventional drug therapy offering new avenues for precision medicine, treating neurological disorders, and in the field of  oncology  and  ophthalmology . [ 1 ]  Additionally, it holds promise for the field of  regenerative medicine  where photoswitches can be used to modulate the activity of signaling pathways for targeted tissue repair and regeneration. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13949", "text": "Photopharmacology will continue to grow and expand with the new discoveries and advances happening in other related fields such as synthetic chemistry, biology, nanotechnology, pharmacology, and bioengineering. While the potential of photopharmacology is vast, some challenges must be addressed to make it a clinical reality.\u00a0One challenge is the development of stable and biocompatible photoswitches that are selective for their target receptors without cross-activity. [ 2 ]  It is particularly important that these photoswitchables have their absorbance bands fall within the wavelength range of 650\u00a0nm to 900\u00a0nm. [ 2 ]  Hence, optimum molecular designing of photoswitches is required to achieve the characteristics mentioned above and desired level of performance. At present, photopharmacology uses a rational drug design approach based on studying the structure-activity relationship, however, a phenotypic screening for photoswitchable drugs could also be beneficial."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13950", "text": "In order to achieve good spatial-temporal control over drug activity there should be a significant difference between the activity of isomers. However, understanding the structural changes during the biological effects induced by photoswitching is limited. This scarcity of knowledge is also a challenge for the growth of this field, as it hampers the optimization of the activity and potency of the isomers to obtain the expected outcomes during applications. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13951", "text": "The biggest challenge in photopharmacology is finding appropriate and effective ways to deliver light to deep tissues in the body and tissues avoiding issues such as scattering and absorption. Various strategies have been attempted in this regard, one being the development of photoswitchable ligands that respond to deep-tissue penetrating wavelengths like red or infrared light. Moreover, some recent preclinical studies have spurred the development of wireless, compact or injectable, and remotely controllable devices capable of delivering light to neural tissues with minimal damage. [ 26 ]  There are novel optofluidic systems that can simultaneously regulate both drug delivery and light activity at specific sites.\u00a0Although external delivery of light is the most preferred method, the use of internal exogenous light sources such as luminescent compounds where light would be delivered directly at the site of action. This could avoid the issues related to light penetration and also enhance the degree of selectivity. In addition, this creates the opportunity to use photopharmacology as a theranostic approach that combines targeted drug delivery and molecular imaging. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13952", "text": "In  pharmacology ,  pleiotropy  includes all of a drug's actions other than those for which the agent was specifically developed. [ 1 ]  It may include  adverse effects  which are detrimental ones, [ 1 ]  but is often used to denote additional beneficial effects. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13953", "text": "For example,  statins  are  HMG-CoA reductase  inhibitors that primarily act by decreasing cholesterol synthesis, but which are believed to have other beneficial effects, including acting as  antioxidants  and stabilizing  atherosclerotic plaques . [ 1 ]  Steroid drugs, such as  prednisone  and  prednisolone , have pleiotropic effects, including  systemic  ones, for the same reason that endogenous  steroid hormones  do: cells throughout the body have receptors that can respond to them, because the endogenous ones are  endocrine  messengers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13954", "text": "Another example is melatonin, which has a wide range of effects on biological systems on multiple scales, from modulating the circadian rhythm and inducing sleep via the activation of melatoninergic receptors, to recepto-independent antioxydative and anti-inflammatory effects over all organs down to cells. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13955", "text": "Polymer-protein hybrids  are a class of  nanostructure  composed of  protein - polymer  conjugates (i.e. complexes composed of one protein attached to one or more  polymer chains ). [ 1 ] [ 2 ]  The protein component generally gives the advantages of biocompatibility and  biodegradability , as many proteins are produced naturally by the body and are therefore well tolerated and metabolized. [ 3 ]  Although proteins are used as targeted therapy drugs, the main limitations\u2014the lack of stability and insufficient circulation times still \u00a0remain. [ 4 ]  Therefore, protein-polymer conjugates have been investigated to further enhance pharmacologic behavior and stability. [ 5 ]  By adjusting the chemical structure of the protein-polymer conjugates, polymer-protein particles with unique structures and functions, such as stimulus responsiveness, enrichment in specific tissue types, and enzyme activity, [ 6 ]  can be synthesized. Polymer-protein particles have been the focus of much research recently because they possess potential uses including bioseparations, imaging, biosensing, gene and drug delivery. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13956", "text": "Attaching a single polymer chain to a specific site away from the active center of the protein has less impact on protein activity compared with random attachments. [ 8 ] [ 9 ]  In practice, attaching a single polymer chain can be used to adjust chemical properties of the therapeutic protein. For example, conjugation of a single chain of the hydrophilic polyethylene glycol (PEG) can increase the hydrodynamic radius of the protein conjugate by 5-10 fold. [ 10 ]  Attachment to PEG was mainly achieved by covalent conjugation via the grafting to strategy, targeting chemo-selective anchor groups. Other polymers, such as oligosaccharides and polypeptides, offer different properties to the enzymes attached to them."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13957", "text": "Researchers conjugated the thermo-responsive polymer poly(N-isopropylacrylamide) (pNIPAm) with the biotin-recognizing protein streptavidin close to its recognition site. [ 11 ]  At temperatures above the lower critical solution temperature (LCST), the polymer collapses and blocks the binding site, thus reversibly preventing biotin from binding to streptavidin. By copolymerization with two different thermosensitive polymers  poly(sulfobetaine methacrylamide)  (pSBAm) and pNIPAm together, researchers can control enzyme activity in a small temperature window. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13958", "text": "((N,N'-dimethylacrylamide)-co-4-phenylazophenyl acrylate) at the active site of endoglycanase creates a photoswitchable protein hybrid. [ 13 ]  The resulting hybrid catalyzes the hydrolysis of glycoside when irradiated by 350\u00a0nm UV light, but turns inactive under 420\u00a0nm visible light depending on the conformation of the conjugated polymer. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13959", "text": "A polymer shell is formed by conjugation of multiple molecules of polymers onto the protein core. The polymer shell can either protect the protein core from unwanted degradation or create desired interactive sites for guest molecules. The first generation of polymer shell protein core structures mainly used of Polyethylene glycol (PEG) chains to increase the hydrodynamic radius and reduce immune response to proteins. [ 14 ]  However, the PEG shell can reduce protein activity in the inner core. More advanced designs use biodegradable linkers to achieve programmed release of the protein core in specific tissues. Several therapeutic designs with biodegradable PEG shells are already being developed  in vivo . [ 15 ] [ 16 ] [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13960", "text": "Direct conjugation of polymers (\"grafting to\" strategy) can efficiently construct a polymer shell with diverse polymer types, however, it has low polymer density, especially with large polymers. In contrast, \"grafting from\" strategy allows the formation of a dense and uniform polymer shell. The protein core can also function as a carrier for other therapeutic molecules, such as plasmid DNA. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13961", "text": "Dendrite polymer shells have a high volume to molecular weight ratio compared with traditional polymer shells. Using branched carbohydrates can give unique biological properties while maintaining molecular definition. [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13962", "text": "Although covalent conjugation has been the dominant strategy for constructing polymer-protein hybrids, noncovalent chemistry can add another level of complexity and provides the opportunity to create higher-ordered structures. Specifically, self-assembly by non-covalent interactions is progressing rapidly. [ 21 ] [ 22 ] [ 23 ]  Supra molecular self-assembly  can create  nanoparticles , vesicles/micelles, protein cages, etc. Metal-binding interactions, host-guest, and boronic acid-based chemistries are widely studied as non-covalent conjugation methods to create polymer-protein hybrids. [ 24 ] [ 25 ] [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13963", "text": "Streptavidin is a protein purified from the bacterium  Streptomyces avidinii , which has a high affinity for biotin. By covalently linking streptavidin and polymers, well defined supramolecular constructs can be created due to the high specificity of"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13964", "text": "Streptavidin for both biotin and its analogues. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13965", "text": "Building upon the covalent core shell strategy, several polymer\u2013streptavidin systems have been developed for affinity separation, bio-sensors and diagnostic applications due to the robust binding conditions and stability of the protein. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13966", "text": "Streptavidin can be used as a macro-initiator for  in situ ATRP , through grafting from strategy, a stoichiometrically well defined polymer-protein conjugate can be synthesized. Polymer streptavidin systems can also be empowered to cross the cellular membrane by conjugating with cell penetrating molecules such as peptides and membrane disturbing polymers."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13967", "text": "Polymer streptavidin systems can also be modulated to respond to certain environmental changes such as pH. By incorporating pH responsive poly(propylacrylic acid) (PPAAc) into the system, tumor cell suppressor p53 and cytochrome C can be delivered into cancer cells efficiently. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13968", "text": "For biomolecules that are not hampered by the biotin-streptavidin interaction, iminobiotin, an analogue of biotin, has been applied as a pH-sensitive linker that allows the controlled and reversible assembly and intracellular release of cargo molecules in acidic intracellular compartments. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13969", "text": "Polymer-protein conjugates can also form a higher ordered supramolecular structure via self-assembly of amphiphilic polymers into micelles and microcapsules, which is one of the most promising strategies to generate drug delivery systems. Such systems have the innate advantage of rapid preparation, a high drug loading capacity, ease of surface decoration, and the potential to be stimuli responsive."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13970", "text": "Micelles refers to a type of supramolecular structure consisting of amphiphilic molecules self-assemblies, usually hollow centered. Researchers successfully conjugated a diblock copolymer site specifically onto GFP, the resulting amphiphilic polymer-protein conjugate is capable of reversible self-assembly into micelles. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13971", "text": "In addition to retaining the native globular shape of proteins, the polypeptide backbone of denatured proteins can also be utilized to be conjugated with hydrophilic polymer chains to generate higher ordered structure through hydrophobic interactions. For example, nanoconjugates of poly-ethylene glycol(PEG) and denatured bovine serum albumin(BSA) will spontaneously self-assemble into a micellar structure, whose protein core can adsorb high numbers of hydrophobic drugs. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13972", "text": "An efficient way to synthesize protein-polymer hybrid nanoparticles is to take advantage of photoinitiated reversible addition\u2212fragmentation chain transfer (RAFT) polymerization-induced self-assembly(PISA) by using multi-RAFT modified bovine serum albumin (BSA) as a macromolecular chain transfer agent. RAFT mediated growth of the PHPMA chains will graft from the BSA-RAFT, and increase the hydrophobicity of the star BSA\u2212PHPMA conjugates. \u00a0At the critical aggregation concentration, they form nanoparticles due to the hydrophobic interactions. [ 33 ]  The resulting nanoparticles show excellent encapsulation capability for both hydrophobic and hydrophilic molecules, such as cancer drugs and DNA."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13973", "text": "A rather easy method to prepare protein-polymer hybrid nanoparticles is nanoprecipitation. Spherical nanoparticles composed of BSA-PMMA with diameters of around 100\u00a0nm were obtained and the water insoluble chemotherapeutic drug camptothecin was encapsulated within the hydrophobic core consisting of PMMA. [ 6 ]  Such protein-polymer hybrid nanoparticles possess tunable sizes and surface charges, have attractive bio-compatibilities and allow efficient cell uptake. Camptothecin-encapsulated BSA-PMMA nanoparticles revealed enhanced anti-tumor activity both in vitro and in animals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13974", "text": "Beyond the nanoscale, protein-polymer conjugate could also be used as building blocks for constructing more complicated structures such as microcapsules through hydrophobic interactions. By performing  pickering emulsion technique  to process BSA\u2013pNIPAm nanoconjugates into hollowed microcapsules consisting of a closely packed monolayer of conjugated protein\u2013polymer building blocks (named proteinosomes). [ 34 ]  These proteinosomes exhibit protocellular properties such as guest molecule encapsulation, selective permeability, controllable mobilization, gene-directed protein synthesis and membrane-gated internalized enzyme catalysis. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13975", "text": "Based on the above-mentioned method, a multi responsive microcapsule has been synthesized by incorporating photoswitchable spiropyran units and the thermoresponsive monomer N-isopropylacrylamide into the membrane. [ 36 ]  Stimuli responsive membrane exhibited advantages in the capture and release of different-molecular-weight products by opening and closing the photoresponsive spiropyran ligands, under body temperature, room temperature, UV, redox."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13976", "text": "Another effective way to modulate the permeability of microcapsules was based on a  self-sacrificing  strategy. By selectively using lysozyme and BSA as building blocks as well as  self-sacrificing  components, the corresponding pores could be generated in the membrane, and then the permeability of the generated microcapsules could be increased from10 kDa to 22 kDa and then to 71 kDa. By loading FITC-Lys (14 kDa), RBITCdextran (70 kDa) and DNA (90 kDa) into the microcapsules, a programmed release of the encapsulants from low molecular weight to high molecular weight was realized. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13977", "text": "Using similar strategy, pH-sensitive protein-polymer microcapsules were developed. Both doxycycline (DOX) and folic acid were incorporated onto the surface of protein covalently. The very low toxicity of polymer-protein nanoconjugates effectively avoided the high toxicity of DOX, which is expected to not only reduce toxic side effects, but also improve anticancer efficiency in vitro examinations. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13978", "text": "Protein nanocages are natural nanocarriers composed of protein subunits with a porous structure. They benefit from monodispersity, intrinsic high stability for protection of internalized drugs from enzymatic degradation and controllable assembly for cargo loading and release."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13979", "text": "However, their application might be blocked by immunogenicity, broad biodistribution and significant function and property variations. The incorporation of polymer chains by performing in situ ATRP on the outer surface of or inside the protein nanocages can be an effective way to mitigate those drawbacks. For example, increased loading density of cargo molecules and enhanced stability of the cage assembly can be obtained via internal ATRP inside the cavity of the virus capsid. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13980", "text": "Beyond virus type particles, large multimeric proteins such as the iron storage protein ferritin have emerged as attractive tools to be used as well-defined nano-containers. Using a grafting from strategy, polymers can be introduced to ferritin in a highly regular fashion for precise spatial control. [ 40 ]  These polymer\u2013ferritin constructs exhibited protease resistance, enabling longer retention time within the bloodstream while reducing possible antibody interactions."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13981", "text": "Polymer-Protein nanoparticles not only contain the traditional properties of nanoparticles, but also have their own unique properties based on the properties of specific proteins. Because they are proteinaceous, they have high biocompatibility,  biodegradability  and biofunctionality. [ 35 ]   Protein-polymer bioconjugates which is the building block of Polymer-Protein hybrids exhibit a unique array of properties such as: \u00a0light-switching effects, [ 41 ] [ 42 ]  acoustic signal capture, thermal energy transfer, and magnetic signal response. [ 43 ] [ 44 ] [ 45 ] [ 6 ] [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13982", "text": "Generally, Polymer-Protein hybrids can be synthesized by interfacial self-assembly of protein\u2013polymer conjugates in emulsions. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13983", "text": "Grafting to approach which is the most common and straightforward methodology refers to directly attaching the synthetic polymers to the target protein. This technique can be engineered for site-specific or random conjugation and, when compared to other conjugation methods, provides simple and thorough characterization of polymer before conjugation. And when using this method, the protein remains unaffected by polymerization methods."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13984", "text": "As shown in the figure, a protein is firstly conjugated with the initiator and the polymer chain then grows from the protein core in a controlled manner via living polymerization. Likewise, to the earlier discussed methods, grafting from approach can be designed for site-specific or random attachment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13985", "text": "Not like the grafting from and grafting to approach which can conjugate several polymers onto one protein core, the grafting through approach enables several proteins to connect to one polymer chain due to the multivalent nature of protein."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13986", "text": "Thermoresponsive conjugates have been exploited for the subsequent separation of proteins from a complex mixture. This method has been utilized to purify polyclonal antibodies in serum samples. This method of purification is rapid, sensitive, inexpensive and could be used to purify various types of antibodies. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13987", "text": "Thermoresponsive conjugates can also be exploited to mediate bioactivity. One of the utilities of the method is demonstrated temperature control of biotin binding and release. Biotin binding was observed below the LCST, while above the LCST the conjugates aggregated, and the biotin binding affinity was reduced by ~20%. By changing the temperature, the recovery of the biotinylated molecules can be achieved. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13988", "text": "The absorption of proteins for particles in physiological fluids can greatly affect the subsequent medical performance of particles in vivo. Nonspecific protein adsorption can be controlled in vivo by modifying the nanoparticle surface with a non-toxic, biocompatible protein possessing tolerable antigenic properties such as albumin. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13989", "text": "The high recognition ability of proteins can enable high delivery efficiency. Protein-polymer particles have potential to deliver drugs to specific regions of the body using the inherent biorecognition property at the protein interface. [ 51 ]  Additionally, in some cases the presentation of specific proteins on nanoparticle surfaces can be useful for aiding passage through impermeable biological barriers. [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13990", "text": "Enzyme-catalyzed reactions can be performed at higher temperatures using enzyme-immobilized nanoparticles, in which the presence of multiple proteins at the nanoparticle surface facilitates the retention of water molecules limiting the denaturation of the attached proteins. After modification with poly(amide), protein activity could remain unchanged over 500 min at 50\u00a0\u00b0C, while the half-life time of the native lipase at 50\u00a0\u00b0C is only 30 min in aqueous solution. [ 53 ]  Immobilized enzymes on nanoparticles can significantly improve the efficiency of enzyme reactions by increasing tolerance to a wider range of experimental conditions without significantly reducing biological activity. Besides, polymer-protein particles are reported to control the activity of proteins [ 54 ]  and compartmentalize different enzymes to perform multi-step reactions. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13991", "text": "By immobilizing proteins to polymer nanoparticles or polymer/inorganic hybrid nanoparticles (such as polymer-stabilized iron oxide nanoparticles), proteins or their affinity ligands can be separated from complex solutions by applying magnetic fields or centrifugation. Lipase attached to iron oxide nanoparticles maintained 85% biological activity after 30 reaction and separation cycles. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13992", "text": "As the appropriate target is combined with magnetic nanoparticles, the selected target can be magnetically separated directly from natural biological fluids, [ 57 ]  which offers a fast, gentle, extensible, and easy to automate separation technique. The simplicity of magnetic separation has been applied in a number of disciplines, including mineral processing wastewater treatment, molecular biology, cell sorting, and clinical diagnostics. [ 58 ] [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13993", "text": "Microcapsules termed protocells prepared by polymer-protein hybrids are the hotspot of the research area recently, enabling various functions such as bioreactors, [ 45 ]  cascade system [ 60 ]  and multiresponsive membranes, etc. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13994", "text": "Polypharmacology  is the design or use of pharmaceutical agents that act on multiple targets or disease pathways. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13995", "text": "Despite scientific advancements and an increase of global  R&D  spending, drugs are frequently withdrawn from markets. This is primarily due to their  side effects  or toxicities. Drug molecules often interact with multiple targets and the unintended  drug-target  interactions can cause side effects. Polypharmacology remains to be one of the major challenges in drug development, and it opens novel avenues to rationally design the next generation of more effective but less toxic therapeutic agents. [ 2 ]  Polypharmacology suggests that more effective drugs can be developed by specifically modulating multiple targets. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13996", "text": "It is generally thought that complex diseases such as cancer and central nervous system diseases may require complex therapeutic approaches. In this respect, a drug that \"hits\" multiple sensitive nodes belonging to a network of interacting targets offers the potential for higher efficacy and may limit drawbacks generally arising from the use of a single-target drug or a combination of multiple drugs. [ 5 ]  In contrast,  chemical biology  continues to be a reductionist discipline, still regarding chemical probes as highly selective small molecules that enable the modulation and study of one specific target. Chemical biology cannot continue to overlook the existence of polypharmacology text [ according to whom? ]  and its urge to become a more holistic discipline that looks at the use of tool compounds from a systems perspective. [ 6 ]  The use of  chemoproteomics  offers strategies to develop a more holistic understanding of the proteome-wide range of targets a drug interacts with. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13997", "text": "The primordial idea of polypharmacology was first proposed in 2004 by  Bryan Roth . [ 8 ]  He reasoned that most common central nervous system disorders are polygenic in origin, and attempts to develop more effective treatments for diseases such as schizophrenia and depression by discovering drugs selective for single molecular targets ('magic bullets') have been largely unsuccessful. He therefore proposed a proof of concept that designing selectively non-selective drugs (that is, 'magic shotguns') that interact with several molecular targets will lead to new and more effective medications for a variety of central nervous system disorders."}
{"_id": "WikiPedia_Pharmacology$$$corpus_13998", "text": "A similar concept was independently proposed in the year of 2006 by Professor Zhiguo Wang [ 9 ]  who used the term 'single agent\u2013multiple targets' (SAMT) to describe the same principle as 'magic shotguns' and his research team provided the first experimental evidence for the feasibility, effectiveness and advantages of SAMT, specifically the 'complex decoy oligodeoxynucleotides technology cdODN' attacking multiple target transcription factors, in the treatment of xenograft breast cancer in mice. Subsequently, Wang's team extended the SAMT to designing single agent that can act on multiple miRNAs targeting cancer cells and cardiac pacemaker channel genes and calcium channel genes as a new therapeutic approach. [ 10 ] [ 11 ] [ 12 ]  Wang has published two monographs on polypharmacology:<Polypharmacology: Principles and Methodologies> [ 13 ]  and <Anti-Aging Polypharmacology> Wang's work is now categorized as 'Epigenetic Polypharmacology' or 'Targeted Polypharmacology', a branch of Polypharmacology. [ 14 ]  In 2008, Professor Keven Shokat and his colleagues described a single compound that blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases and termed it 'multitargeted drug' along with the concept of 'Polypharmacology'. [ 15 ]  Since then, Polypharmacology has become a new branch of Pharmacology discipline and research field as well as one of the new direction and strategies for drug development. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_13999", "text": "The  Sheild Professorship of Pharmacology  is the senior  professorship  in  pharmacology  at the  University of Cambridge . It is named in honour of  Marmaduke Sheild . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14000", "text": "The position was originally established on 7 June 1946 as a personal chair for the tenure of  Ernest Basil Verney . On 11 March 1961 the professorship was re-established on a permanent basis. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14001", "text": "A  proteolysis targeting chimera  ( PROTAC ) [ 2 ]  is a molecule that can remove specific unwanted proteins. Rather than acting as a conventional  enzyme inhibitor , a PROTAC works by inducing selective  intracellular   proteolysis . A heterobifunctional molecule with two active domains and a linker, PROTACs consist of two covalently linked protein-binding molecules: one capable of engaging an  E3 ubiquitin ligase , and another that binds to a target protein meant for degradation. Recruitment of the E3 ligase to the target protein results in  ubiquitination  and subsequent degradation of the target protein via the  proteasome . Because PROTACs need only to bind their targets with high selectivity (rather than inhibit the target protein's enzymatic activity), there are currently many efforts to retool previously ineffective inhibitor molecules as PROTACs for next-generation drugs. [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14002", "text": "Initially described by Kathleen Sakamoto,  Craig Crews  and Ray Deshaies in 2001, [ 5 ]  the PROTAC technology has been applied by a number of drug discovery labs using various E3 ligases, [ 6 ]  including  pVHL , [ 7 ] [ 8 ] [ 9 ]   CRBN , [ 10 ] [ 11 ]   Mdm2 , [ 12 ]   beta-TrCP1 , [ 5 ]   DCAF11 , [ 13 ] [ 14 ]   DCAF15 , [ 15 ]  DCAF16, [ 15 ]   RNF114 , [ 15 ]  and  c-IAP1 . [ 16 ]   Yale University  licensed the PROTAC technology to Arvinas in 2013\u201314. [ 17 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14003", "text": "In 2019, Arvinas put two PROTACs into clinical trials:  bavdegalutamide  (ARV-110), an  androgen receptor  degrader, and  vepdegestrant  (ARV-471), an  estrogen receptor  degrader. [ 19 ] [ 20 ]  In 2021, Arvinas put a second androgen receptor PROTAC,  Luxdegalutamide  (ARV-766), into the clinic. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14004", "text": "PROTACs achieve degradation through \"hijacking\" the cell's ubiquitin\u2013proteasome system (UPS) by bringing together the target protein and an E3 ligase. [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14005", "text": "First, the E1 activates and conjugates the ubiquitin to the E2. [ 15 ]  The E2 then forms a complex with the E3 ligase. The E3 ligase targets proteins and covalently attaches the ubiquitin to the protein of interest. [ 22 ]  Eventually, after a ubiquitin chain is formed, the protein is recognized and degraded by the  26S proteasome . [ 19 ]  PROTACs take advantage of this cellular system by putting the protein of interest in close proximity to the E3 ligase to catalyze degradation. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14006", "text": "Unlike traditional inhibitors, PROTACs have a  catalytic mechanism , with the PROTAC itself being recycled after the target protein is degraded. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14007", "text": "The protein targeting warhead, E3 ligase, and linker must all be considered for PROTAC development. Formation of a  ternary complex  between the protein of interest, PROTAC, and E3 ligase may be evaluated to characterize PROTAC activity because it often leads to ubiquitination and subsequent degradation of the targeted protein. [ 15 ]  A  hook effect  is commonly observed with high concentrations of PROTACs due to the bifunctional nature of the degrader. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14008", "text": "Currently,  pVHL  and  CRBN  have been used in preclinical trials as E3 ligases. [ 15 ]  However, there still remains hundreds of E3 ligases to be explored, with some giving the opportunity for cell specificity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14009", "text": "Compared to traditional inhibitors, PROTACs display multiple benefits that make them desirable drug candidates. Due to their catalytic mechanism, PROTACs can be administered at lower doses compared to their inhibitor analogues, [ 20 ]  though care needs to be taken in achieving oral bioavailability if administered by that route. [ 23 ]  Some PROTACs have been shown to be more selective than their inhibitor analogues, reducing off-target effects. [ 20 ]  PROTACs have the ability to target previously undruggable proteins, as they do not need to target catalytic pockets. [ 20 ]  This also helps prevent mutation-driven  drug resistance  often found with enzymatic inhibitors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14010", "text": "Pullulan bioconjugates  are systems that use  pullulan  as a scaffold to attach biological materials to, such as drugs. These systems can be used to enhance the delivery of drugs to specific environments or the mechanism of delivery. These systems can be used in order to deliver drugs in response to stimuli, create a more controlled and sustained release, and provide a more targeted delivery of certain drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14011", "text": "Pullulan is generated by the microbial  A. pullulans  through the processing mainly of glucose, but can also be produced from  maltose ,  fructose ,  galactose ,  sucrose , and  mannose . [ 1 ]  In a commercial setting, pullulan is obtained from a strain of  A. pullulans  that is non-toxic, non-pathogenic, and unmodified genetically that is given a liquid form of starch in a set environment. [ 1 ]  The pullulan produced can be modified by different conditions such as the nutrients provided, temperature, pH, oxygen content, and other supplements. The microbial needs to be provided with a source of carbon and nitrogen in order to produce pullulan and the ratio of carbon to nitrogen needs to be precise in order to maximize pullulan production. Higher levels of nitrogen than carbon are required as excess carbon can decrease the efficiency of the enzymes and excess nitrogen can increase the production of  biomass , but does not affect the pullulan production. [ 1 ]  Oxygen is also important for the proliferation of the  A. pullulans  cells and the production of pullulan. [ 1 ]  Further supplements can be used in order to increase the level of pullulan production, such as olive oil and tween 80. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14012", "text": "While the manufacturing conditions of pullulan can be altered in order to increase yield, chemical modifications of pullulan can also be used to alter the properties of the pullulan. The unmodified structure of pullulan contains nine  hydroxyl  groups attached to the backbone of the molecule, and these hydroxyl groups can be replaced with other functional groups. [ 1 ]  Some examples of processes that can modify the functional groups of pullulan include  sulfation ,  esterification ,  oxidation ,  etherification ,  copolymerization , amidification, and others. [ 1 ]  Pullulan can be given a negative charge through creating an ester linkage that attaches a carboxylate group to the hydroxyl, which yields a carboxymethyl pullulan. [ 1 ]  Pullulan is hydrophilic and can be modified to have hydrophobic functionality by adding a cholesterol group. [ 1 ]  The main benefit of the added hydrophobic functionality is that it makes it so the pullulan can form self assembling  micelles. [ 1 ]  Another notable modification to pullulan is the  acetylation  of pullulan in order to create pullulan acetate (PA), which also has a hydrophobic functionality. [ 2 ]  PA has the benefit of forming self-assembled  nanoparticles , which can simplify manufacturing of certain pullulan bioconjugates. [ 2 ]  Pullulan and pullulan derivatives can also be folated in order to improve cancer cell targeting as the nanoparticle can be endocytosed into the cancer cells through folate-mediated  endocytosis . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14013", "text": "Pullulan bioconjugate systems can be formed to respond to many different stimuli to enhance the release of the drug to the target tissue. These stimuli include pH, temperature, photothermal, electrical, ultrasonic, magnetic, and enzymatic. [ 1 ]  The pH is often used to target tumor tissues, as the extracellular pH of tumors is more acidic than the normal cells. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14014", "text": "A pullulan and polydopamine hydrogel loaded with crystal violet demonstrated pH responsive behavior due to the  protonation  of the  polydopamine , which increased the release of the  crystal violet  in the acidic environment. [ 4 ]  The study showed that at a pH of a normal cell's extracellular environment, 7.4, about 60% of the crystal violet was released compared to the 87% release when in a pH of 5.0. [ 4 ]  The use of pH responsive systems for the treatment of cancer may aid in the ability to overcome resistance of the drug as well as prevent excess damage to healthy tissue. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14015", "text": "Another pH responsive pullulan system was formed with pullulan and  doxorubicin  where the doxorubicin is attached to the pullulan by  hydrazone  bonds. [ 6 ]  The drug release of the doxorubicin was tested at two pHs, 7.4 and 5, where the hydrazine is stable at 7.4 and cleaves in acidic environments. [ 6 ]  The results from this study supported the results from the pullulan and polydopamine study, as doxorubicin was released faster in the acidic environment than the pH that reflected a normal cell's extracellular environment. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14016", "text": "Temperature can also be used as a trigger to control the drug release from pullulan systems. Thermal responsive pullulan systems can be used in conjunction with thermal generating treatments for cancer in order to improve the treatment. [ 1 ]  Nanoparticles composed of periodate oxidized carboxymethyl pullulan crosslinked with two Jeffamines were synthesized and demonstrated that the nanoparticle size could be decreased with increased temperature. [ 7 ]  The nanoparticles decrease in size with increasing temperature due to the increased temperature promoting the hydrophobic interactions of the structure. [ 7 ]  Altering the temperature can induce heating or cooling dynamics that are reversible, which allows for unique properties in terms of drug release. [ 3 ]  Pullulan can be altered with  photosensitizers  in order to provide a controlled thermal reaction in a target area. [ 1 ]   Spiropyrane  can be added to pullulan in order to act as a photosensitizer. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14017", "text": "Electrical stimuli can be used to alter the delivery of drugs through pullulan constructs. A copolymer polyacrylamide-graft-pullulan was synthesized and used for transdermal delivery of rivastigmine tartarate. [ 8 ]  In this study, the use of electric stimuli demonstrated the ability to increase the diffusion rate and in a way acted as a controllable switch to control diffusion rate. [ 8 ]  Pullulan systems can be used to enhance ultrasound imaging, as pullulan-graft-poly(carboxybetaine methacrylate) demonstrated the ability to generate carbon dioxide in response to ultrasound, which enhanced the contrast. [ 1 ]   Superparamagnetic iron oxide nanoparticles (SPIONs)  have been generated which have magnetic properties, which showed to improve uptake and also decrease the cytotoxicity. [ 1 ]  Enzymes can also be used to trigger drug release mechanisms, such as how esterase has been used to cleave photosensitizers from pullulan in order to increase the photodynamic reaction. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14018", "text": "As demonstrated in the last example, these stimuli response mechanisms do not have to be independent. They can be used in combinations in order to improve the efficacy of the drug delivery."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14019", "text": "When pullulan is modified with a hydrophobic functionality, such as cholesterol, the pullulan derivative forms self-assembled vesicles that can encapsulate a hydrophobic drug. [ 1 ]  With the hydrophobic functional group, the pullulan derivative is an amphiphilic molecule, which when in an aqueous environment forms a  micelle . This micelle has a hydrophilic exterior with the pullulan backbone and a hydrophobic core due to the functional group added to the pullulan. [ 3 ]  The nanoparticles formed are spherical, have an average size of 20-30 nanometers according to dynamic light scattering measurements, and are able to be maintained in physiological conditions. [ 9 ]  Cholesteryl-pullulan (CHP) is an example of a pullulan derivative that is capable of forming self-assembled mechanisms and has been used to anticancer drugs. [ 5 ]  The size of the self-assembled nanoparticle can be adjusted by changing the amount of cholesterol attached to the pullulan. The higher the number of cholesterol substitutions, the smaller the nanoparticle created. [ 3 ] \u00a0 PA and folated PA (FPA) have been created and form self-assembled nanoparticles, which have been used to deliver  epirubicin . [ 2 ]  Pullulan derivatives have been combined with gold to form self-assembled nanoparticles that were capable of loading doxorubicin. [ 10 ]  Pullulan-dexamethasone bioconjugates have been created which also exhibit self-assembling nanoparticles that have an approximate size of 400 nanometers and have shown to extend the release of the  dexamethasone . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14020", "text": "Pullulan is used as a bioconjugate platform in order to enhance the delivery of  chemotherapeutics . Pullulan derivatives can be created in order to specifically target cancer cells. In terms of cancer therapeutics, pullulan can be used to encapsulate hydrophobic cancer therapeutics through self assembled micelles, can be linked to drugs in the form of a bioconjugate, and can be utilized for its pH responsive nature. [ 12 ]  Cancer drugs that have been used with pullulan include doxorubicin,  paclitaxel , epirubicin,  mitoxantrone , and 10-hydroxycamptothecin. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14021", "text": "Pullulan derivatives can be folated in order to take advantage of the higher density of folate receptors on cancer cells. [ 5 ]  Doxorubicin has been loaded into pullulan micelles and folated micelles for targeted delivery to cancer cells through folate mediated endocytosis. [ 5 ]  The use of folated pullulan nanoparticles shows lower toxicity and higher levels of drug accumulation within the cancer cells. [ 5 ]  The pH sensitivity of pullulan also makes pullulan a good candidate for chemotherapeutic delivery, as the pullulan can be altered by the acidic environment of the tumor to provide targeted release. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14022", "text": "Pullulan nanoparticles have also been used to deliver paclitaxel and proved to be stable under different environmental conditions. [ 5 ]   Curcumin  pullulan derivatives have a great effect in targeting  hepatocarcinoma  cells, as the pullulan increases the ability of curcumin to solubilize, and therefore allows for the cells to properly uptake the curcumin. [ 5 ]  Pullulan micelles can also be used to deliver genes, such as  p53 , in order to suppress tumor development. [ 5 ]  The pullulan protects the RNA or DNA from degradation from enzymes within the body, which enables the ability of gene therapy for treatment of cancer. [ 5 ]  The addition of ascorbic acid to pullulan bioconjugates has demonstrated antimetastic properties, which can improve cation modified pullulan derivatives. [ 5 ]  There are many factors that make pullulan a suitable drug delivery platform for cancer therapeutics. Some of these factors include the chemical modifications, the pH responsiveness, as well as the ability for the pullulan to form self-assembled micelles that can protect the therapeutics from the immune system. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14023", "text": "In vitro research has been conducted that synthesized pullulan acetate nanoparticles altered with folate and then loaded with epirubicin. [ 2 ]   This study showed that the use of folate modification to pullulan increased the cytotoxicity of the drug as well as released the drug at a faster rate than unfolated pullulan acetate. [ 2 ]  Another pullulan folated system was researched, where pullulan gold nanoparticles were folated and encapsulated doxorubicin. [ 10 ]  The pullulan gold nanoparticle provided pH controlled release of the doxorubicin and demonstrated lower toxicity to non cancer cells than doxorubicin without a carrier platform. [ 10 ]  CHP systems have been developed to deliver protein vaccines and have shown success in generating different degrees of immune responses mostly with  CD4 T  cells. [ 3 ]  Biotinylated pullulan acetate (BPA) have been created as they have vitamin H functionality, which helps increase the level of interaction with cancer cells. [ 13 ]  The drawback with vitamin H is that increasing the vitamin H increases the interaction of the nanoparticles with cancer cells, but also lowers the concentration of the drug in the nanoparticle due to the altered hydrophobicity. [ 13 ]  Modifications to pullulan can be made to enhance the controlled release of drugs, such as pullulan-g-poly(L-lactide) due to the water insoluble nature of the polymeric component. [ 13 ] \u00a0 Doxorubicin has been conjugated to pullulan through hydrazone bonds, but was shown to have lower cytotoxic activity than doxorubicin without a delivery platform. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14024", "text": "The ocular space is a difficult area to deliver drugs into and therefore special drug delivery considerations need to be taken into account.  Intravitreal injections  are a common method of delivery drugs to the eye. Pullulan systems can be utilized in intravitreal injections in order to develop drugs that are long lasting and therefore require less frequent injections. [ 11 ]  One study looked at different chemical linkers to pullulan to test efficacy of said linkers in extending the release of  rhodamine B  (RhB). [ 9 ]  This study used ether (Pull-Et-RhB), hydrazone (Pull-Hy-RhB), and ester (Pull-Es-RhB) linkers to generate pullulan bioconjugates. [ 9 ]  Ex vivo modeling of the drug release indicated that the drug diffuses slower in the vitreous humor than in water. [ 9 ]  The ether bond was stable at differing pH, while the hydrazone and ester bond released the drug faster in more acidic pH, that reflected the pH of endosomes. [ 9 ]  The Pull-Hy-RhB demonstrated that this drug delivery system was capable of delivering the drug to the retina through testing of the blood in the vessels of the retina. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14025", "text": "Further studies have investigated the creation and efficacy of pullulan-dexamethasone bioconjugates for intravitreal injections. [ 14 ]  The study synthesized self-assembling pullulan nanoparticles with dexamethasone attached through hydrazone bonds. [ 11 ]   This study reiterated that the drug release was fast in acidic pH that mimicked the pH of  lysosomes. [ 11 ]  The variation in drug release was that at the pH of the vitreous humor the drug took two weeks to release half of the drug, while took only two days, when in a lysosomal pH. [ 11 ]   Pharmacokinetic  analysis was performed on this bioconjugate system and revealed that dexamethasone was released in the vitreous humor and that it remained for sixteen days and that a substantial amount of the bioconjugate left the vitreous humor intact. [ 14 ]  Overall the studies regarding pullulan bioconjugates for the application in intravitreal injections demonstrate that pullulan can provide sustained release as well as allow the drug to reach the retina."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14026", "text": "Pullulan has many other applications. Pullulan can be used as a scaffold material for stem cells, such as  mesenchymal stem cells . [ 1 ]  Pullulan can be conjugated with photosensitive molecules in order to be used with photodynamic therapy. [ 1 ]  Pullulan can be modified to be a contrast agent for MRI in multiple ways such as oxidation, iron-oxide conjugates, and cation conjugates. [ 1 ]  Pullulan has been thiolated in order to generate mucoadhesive properties. [ 15 ]  This mucoadhesive system has been further modified by polyaminating pullulan to provide sustained drug release. [ 15 ]  A study developed a transdermal pullulan system that is capable of delivering rivastigmine tartarate in response to external electrical stimuli. [ 8 ]  Pullulan systems can be loaded with a plethora of different drugs including anti-inflammatory, antilipidemic, and antiglycemic drugs. [ 12 ]  Pullulan systems can be used to treat heart conditions through the delivery of  beta blockers  and inhibitors of  angiotensin-converting enzyme . [ 12 ]  Pullulan can also be utilized in regards to bone disease as they can be used to deliver  bisphosphonates  and can help to image bone regeneration through MRI. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14027", "text": "Quantitative systems pharmacology  (QSP) is a discipline within biomedical research that uses mathematical computer models to characterize biological systems, disease processes and drug pharmacology. [ 1 ] [ 2 ]  QSP can be viewed as a sub-discipline of  pharmacometrics  that focuses on modeling the mechanisms of drug  pharmacokinetics  (PK),  pharmacodynamics  (PD), and disease processes using a  systems pharmacology  point of view.  QSP models are typically defined by systems of  ordinary differential equations  (ODE) that depict the dynamical properties of the interaction between the drug and the biological system."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14028", "text": "QSP can be used to generate biological/pharmacological hypotheses  in silico  to aid in the design of  in vitro  or  in vivo  non-clinical and clinical experiments.  This can help to guide biomedical experiments so that they yield more meaningful data.  QSP is increasingly being used for this purpose in pharmaceutical research & development to help guide the discovery and development of new therapies. [ 3 ] [ 4 ]  QSP has been used by the FDA in a clinical pharmacology review. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14029", "text": "QSP emerged as a discipline through two workshops held at the National Institutes of Health (NIH) in 2008 and 2010, with the goal of merging of systems biology and pharmacology. The workshops outlined a need for a mathematical discipline to aid in translational medicine. QSP proposed integrating concepts, methods, and investigators from computational biology, systems biology, and biological engineering into pharmacology.  [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14030", "text": "A review of the history and future of QSP identified areas where it has advanced understanding of drug mechanisms, supported preclinical to clinical translation, and in general aided in drug development. The FDA has included QSP as a component of the Model-Informed Drug Development Program.  [ 6 ]   [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14031", "text": "Receptor theory  is the application of receptor models to explain drug behavior. [ 1 ]  Pharmacological receptor models preceded accurate knowledge of  receptors  by many years. [ 2 ]   John Newport Langley  and  Paul Ehrlich  introduced the concept that receptors can mediate drug action at the beginning of the 20th century.  Alfred Joseph Clark  was the first to quantify drug-induced biological responses (specifically, f-mediated receptor activation). So far, nearly all of the quantitative theoretical modelling of receptor function has centred on  ligand-gated ion channels  and  G protein-coupled receptors . [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14032", "text": "In 1901, Langley challenged the  dominant hypothesis  that drugs act at nerve endings by demonstrating that nicotine acted at sympathetic ganglia even after the degeneration of the severed preganglionic nerve endings. [ 4 ]  In 1905 he introduced the concept of a receptive substance on the surface of skeletal muscle that mediated the action of a drug. Langley postulated that these receptive substances were different in different species (citing the fact that nicotine-induced muscle paralysis in mammals was absent in crayfish). [ 5 ]  Around the same time,  Ehrlich  was trying to understand the basis of selectivity of agents. [ 6 ]  He theorized that selectivity was the basis of a preferential distribution of lead and dyes in different body tissues. However, he later modified the theory in order to explain immune reactions and the selectivity of the immune response. [ 6 ]  Thinking that selectivity was derived from interaction with the tissues themselves, Ehrlich envisaged molecules extending from cells that the body could use to distinguish and mount an immune response to foreign objects. However, it was only after Ahlquist demonstrated the differential effects of adrenaline on two distinct receptor populations, that the theory of receptor-mediated drug interactions gained acceptance. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14033", "text": "The receptor occupancy model, which describes agonist and competitive antagonists, was built on the work of Langley,  Hill , and Clark. The occupancy model was the first model put forward by Clark to explain the activity of drugs at receptors and quantified the relationship between drug concentration and observed effect. It is based on mass-action kinetics and attempts to link the action of a drug to the proportion of receptors occupied by that drug at equilibrium. [ 9 ] [ 10 ]   In particular, the magnitude of the response is directly proportional to the amount of drug bound, and the maximum response would be elicited once all receptors were occupied at equilibrium. He applied mathematical approaches used in enzyme kinetics systematically to the effects of chemicals on tissues. [ 2 ] \nHe showed that for many drugs, the relationship between drug concentration and biological effect corresponded to a hyperbolic curve, similar to that representing the adsorption of a gas onto a metal surface [ 11 ]  and fitted the  Hill\u2013Langmuir equation . [ 3 ]  Clark, together with  Gaddum , was the first to introduce the  log concentration\u2013effect curve  and described the now-familiar 'parallel shift' of the log concentration\u2013effect curve produced by a competitive antagonist. [ 3 ]  Attempts to separate the binding phenomenon and activation phenomenon were made by  Ari\u00ebns  in 1954 and by Stephenson in 1956 to account for the intrinsic activity (efficacy) of a drug (that is, its ability to induce an effect after binding). [ 9 ] [ 12 ] [ 13 ]  Classic occupational models of receptor activation failed to provide evidence to directly support the idea that receptor occupancy follows a Langmuir curve as the model assumed leading to the development of alternative models to explain drug behaviour. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14034", "text": "The development of the classic theory of drug antagonism by Gaddum, Schild and Arunlakshana built on the work of Langley,  Hill  and Clark. [ 12 ]   Gaddum  described a model for the competitive binding of two ligands to the same receptor in short communication to  The Physiological Society  in 1937. The description referred only to binding, it was not immediately useful for the analysis of experimental measurements of the effects of antagonists on the response to agonists. [ 14 ]  It was Heinz Otto Schild who made measurement of the equilibrium constant for the binding of an antagonist possible.  He developed the  Schild equation  to determine a dose ratio, a measure of the potency of a drug. In Schild regression, the change in the dose ratio, the ratio of the EC 50  of an agonist alone compared to the EC 50  in the presence of a competitive antagonist as determined on a dose response curve used to determine the affinity of an antagonist for its receptor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14035", "text": "The flaw in Clark's receptor-occupancy model was that it was insufficient to explain the concept of a  partial agonist . This led to the development of agonist models of drug action by Ariens in 1954 and by Stephenson in 1956 to account for the intrinsic activity (efficacy) of a drug (that is, its ability to induce an effect after binding). [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14036", "text": "The two-state model is a simple linear model to describe the interaction between a ligand and its receptor, but also the active receptor (R * ). [ 15 ]  The model uses an equilibrium dissociation constant to describe the interaction between ligand and receptor.  It proposes that ligand binding results in a change in receptor state from an inactive to an active state based on the  receptor's conformation . A receptor in its active state will ultimately elicit its biological response. It was first described by Black and Leff in 1983 as an alternative model of receptor activation. [ 16 ]  Similar to the receptor occupancy model, the theory originated from earlier work by del Castillo & Katz on observations relating to ligand-gated ion channels. [ 3 ]  In this model,  agonists  and  inverse agonists  are thought to have selective binding affinity for the pre-existing resting and active states [ 3 ] [ 17 ]  or can induce a conformational change to a different receptor state.  Whereas  antagonists  have no preference in their affinity for a receptor state. [ 18 ] [ 19 ]  The fact that receptor conformation (state) would affect binding affinity of a ligand was used to explain a mechanism of partial agonism of receptors by del Castillo & Katz in 1957 was based on their work on the action of acetylcholine at the motor endplate [ 3 ]  build on similar work by Wyman & Allen in 1951 on conformational-induced changes in hemoglobin's oxygen binding affinity occurring as a result of oxygen binding. [ 20 ]  The del Castillo-Katz mechanism divorces the binding step (that can be made by agonists as well as antagonists) from the receptor activation step (that can be only exerted by agonists), describing them as two independent events. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14037", "text": "The original Ternary complex model was used to describe ligand, receptor, and G-protein interactions.  It uses equilibrium dissociation constants for the interactions between the receptor and each ligand (K a  for ligand A; K b  for ligand B), as well as a cooperativity factor (\u03b1) that denotes the mutual effect of the two ligands on each other's affinity for the receptor. An \u03b1 > 1.0 refers to positive allosteric modulation, an \u03b1 < 1.0 refers to negative allosteric modulation, and an \u03b1 = 1.0 means that binding of either ligand to the receptor does not alter the affinity of the other ligand for the receptor (i.e., a neutral modulator). [ 15 ]  Further, the \u03b1 parameter can be added as a subtle but highly useful extension to the ATCM in order to include effects of an allosteric modulator on the efficacy (as distinct from the affinity) of another ligand that binds the receptor, such as the orthosteric agonist. Some ligands can reduce the efficacy but increase the affinity of the orthosteric agonist for the receptor. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14038", "text": "Although it is a simple assumption that the proportional amount of an active receptor state should correlate with the biological response, the experimental evidence for receptor overexpression and spare receptors suggests that the calculation of the net change in the active receptor state is a much better measure for response than is the fractional or proportional change. This is demonstrated by the effects of agonist/ antagonist combinations on the desensitization of receptors. This is also demonstrated by receptors that are activated by overexpression, since this requires a change between R and R* that is difficult to understand in terms of a proportional rather than a net change, and for the molecular model that fits with the mathematical model. [ 21 ] [ 22 ] [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14039", "text": "The classic  Monod\u2013Wyman\u2013Changeux model  (MWC) for cooperativity is generally published in an irreversible form. That is, there are no product terms in the rate equation which can be problematic for those wishing to build metabolic models since there are no product inhibition terms. [ 1 ]  However, a series of publications by Popova and Sel'kov [ 2 ]  derived the MWC rate equation for the reversible, multi-substrate, multi-product reaction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14040", "text": "The same problem applies to the classic  Hill equation  which is almost always shown in an irreversible form. Hofmeyr and Cornish-Bowden first published the reversible form of the Hill equation. [ 1 ]  The equation  has since been discussed elsewhere [ 3 ] [ 4 ]  and the model has also been used in a number of kinetic models such as a model of Phosphofructokinase and Glycolytic Oscillations in the Pancreatic \u03b2-cells [ 5 ]  or a model of a glucose-xylose co-utilizing S. cerevisiae strain. [ 6 ]  The model has also been discussed in modern enzyme kinetics textbooks. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14041", "text": "Consider the simpler case where there are two binding sites. See the scheme shown below. Each site is assumed to bind either molecule of substrate S or product P. The catalytic reaction is shown by the two reactions at the base of the scheme triangle, that is S to P and P to S. The model assumes the binding steps are always at equilibrium. The reaction rate is given by:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14042", "text": "v \n = \n \n k \n \n 1 \n \n \n \n ( \n \n E \n S \n + \n 2 \n E \n \n S \n \n 2 \n \n \n + \n E \n S \n P \n \n ) \n \n \u2212 \n \n k \n \n 2 \n \n \n \n ( \n \n E \n P \n + \n 2 \n E \n \n P \n \n 2 \n \n \n + \n E \n S \n P \n \n ) \n \n \n \n {\\displaystyle v=k_{1}\\left(ES+2ES_{2}+ESP\\right)-k_{2}\\left(EP+2EP_{2}+ESP\\right)}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14043", "text": "Invoking the  rapid-equilibrium assumption  we can write the various complexes in terms of equilibrium constants to give:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14044", "text": "v \n = \n \n \n \n \n V \n \n f \n \n \n \u03c3 \n ( \n 1 \n \u2212 \n \u03c1 \n ) \n ( \n \u03c3 \n + \n \u03c0 \n ) \n \n \n 1 \n + \n ( \n \u03c3 \n + \n \u03c0 \n \n ) \n \n 2 \n \n \n \n \n \n \n \n {\\displaystyle v={\\frac {V_{f}\\sigma (1-\\rho )(\\sigma +\\pi )}{1+(\\sigma +\\pi )^{2}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14045", "text": "where  \n \n \n \n \u03c1 \n = \n \u0393 \n \n / \n \n \n K \n \n e \n q \n \n \n \n \n {\\displaystyle \\rho =\\Gamma /K_{eq}} \n \n . The  \n \n \n \n \u03c3 \n \n \n {\\displaystyle \\sigma } \n \n  and  \n \n \n \n \u03c0 \n \n \n {\\displaystyle \\pi } \n \n  terms are the ratio of substrate and product to their respective half-saturation constants, namely  \n \n \n \n \u03c3 \n = \n S \n \n / \n \n \n S \n \n 0.5 \n \n \n \n \n {\\displaystyle \\sigma =S/S_{0.5}} \n \n  and  \n \n \n \n \u03c0 \n = \n P \n \n / \n \n \n P \n \n 0.5 \n \n \n \n \n {\\displaystyle \\pi =P/P_{0.5}} \n \n  and"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14046", "text": "Using the author's own notation, if an enzyme has  \n \n \n \n h \n \n \n {\\displaystyle h} \n \n  sites that can bind ligand, the form, in the general case, can be shown to be:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14047", "text": "v \n = \n \n \n \n \n V \n \n f \n \n \n \u03c3 \n ( \n 1 \n \u2212 \n \u03c1 \n ) \n ( \n \u03c3 \n + \n \u03c0 \n \n ) \n \n h \n \u2212 \n 1 \n \n \n \n \n 1 \n + \n ( \n \u03c3 \n + \n \u03c0 \n \n ) \n \n h \n \n \n \n \n \n \n \n {\\displaystyle v={\\frac {V_{f}\\sigma (1-\\rho )(\\sigma +\\pi )^{h-1}}{1+(\\sigma +\\pi )^{h}}}}"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14048", "text": "The non-cooperative reversible Michaelis-Menten equation can be seen to emerge when we set the Hill coefficient to one."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14049", "text": "If the enzyme is irreversible the equation turns into the simple Michaelis-Menten equation that is irreversible. When setting the equilibrium constant to infinity, the equation can be seen to revert to the simpler case where the product inhibits the reverse step."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14050", "text": "A comparison has been made between the MWC and reversible Hill equation. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14051", "text": "A modification of the reversible Hill equation was published by Westermark et al [ 10 ]  where modifiers affected the catalytic properties instead.  This variant was shown to provide a much better fit for describing the kinetics of muscle  phosphofructokinase ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14052", "text": "Ro05-4082  ( N-methylclonazepam ,  ID-690 ) is a  benzodiazepine  derivative developed in the 1970s. It has  sedative  and  hypnotic  properties, and has around the same potency as  clonazepam  itself. [ 1 ]  It was never introduced into clinical use. It is a  structural isomer  of  meclonazepam  (3-methylclonazepam), and similarly has been sold as a  designer drug , first being identified in Sweden in 2017. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14053", "text": "This  sedative -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14054", "text": "Safety pharmacology  is a branch of  pharmacology  specialising in detecting and investigating potential undesirable  pharmacodynamic  effects of  new chemical entities  (NCEs) on physiological functions in relation to exposure in the therapeutic range and above. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14055", "text": "Primary organ systems (so-called core battery systems) are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14056", "text": "Secondary organ systems of interest are:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14057", "text": "Safety pharmacology studies are required to be completed prior to human exposure (i.e., Phase I clinical trials), and regulatory guidance is provided in ICH S7A and other documents. [ 2 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14058", "text": "The aims of nonclinical safety pharmacology evaluations are three-fold:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14059", "text": "The following key issues have to be considered within safety pharmacology: [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14060", "text": "The first appearance of the term \u2018safety pharmacology\u2019 in the published literature dates back to 1980. [ 5 ]  The term was certainly in common usage in the 1980s within the pharmaceutical industry to describe nonclinical pharmacological evaluation of unintended effects of candidate drugs for regulatory submissions. [ 6 ]  Back then, it was part of a wider \u2018general pharmacology\u2019 assessment, which addressed actions of a drug candidate beyond the therapeutically intended effects. The only detailed guidelines indicating the requirements from drug regulatory authorities for general pharmacology studies were from the  Ministry of Health, Labour, and Welfare . Nowadays, the term \u2018general pharmacology\u2019 is no longer used, and the ICH S7A guidelines [ 7 ]  distinguish between primary pharmacodynamics (\u201cstudies on the mode of action and/or effects of a substance in relation to its desired therapeutic target\u201d), secondary pharmacodynamics (\u201cstudies on the mode of action and/or effects of a substance not related to its desired therapeutic target\u201d) and safety pharmacology (\u201cstudies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above.\u201d).\nA major stimulus to the discipline of safety pharmacology was the release in 1996 of a draft \u2018Points to Consider\u2019 document on QT prolongation by the European Medicines Agency's Committee for Proprietary Medicinal Products (CPMP), issued in final form the following year. [ 8 ]  This initiative had been prompted by growing concern of sudden death caused by drug-induced torsade de pointes, a potentially lethal cardiac tachyarrhythmia. Later, in 2005,  this concern was addressed by issue of the ICH S7B guidelines. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14061", "text": "Preclinical safety pharmacology integrates  in silico ,  in vitro ,  and  in vivo  approaches. [ 10 ]   In vitro  safety pharmacology studies are focused on early hazard identification and subsequent compound profiling in order to guide preclinical  in vivo   safety and toxicity studies. Early compound profiling can flag for receptor-, enzyme-, transporter-, and ion channel-related liabilities of NCEs (e.g., inhibition of the human ether-a-go-go related gene protein ( hERG )). Classically,  in vivo  investigations comprise the use of young adult conscious animals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14062", "text": "Safety pharmacology studies have to be designed for defining the  dose-response relationship  of the adverse effect observed. Justification should be provided for the selection of the particular animal model or test system. The time course (e.g., onset and duration of response) of the adverse effect is investigated through selected time points for the measurements based on pharmacodynamic and pharmacokinetic considerations. Generally, the doses eliciting the adverse effect have to be compared to the doses eliciting the primary pharmacodynamic effect in the test species or the proposed therapeutic effect in humans."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14063", "text": "The primary reference document for safety pharmacology is ICH S7A, followed by many key regulatory documents which either focus on or mention safety pharmacology:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14064", "text": "A  subunit vaccine  is a  vaccine  that contains purified parts of the  pathogen  that are  antigenic , or necessary to elicit a protective  immune response . [ 1 ] [ 2 ]  Subunit vaccine can be made from dissembled viral particles in cell culture or  recombinant DNA  expression, [ 3 ]  in which case it is a  recombinant subunit vaccine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14065", "text": "A \"subunit\" vaccine doesn't contain the whole pathogen, unlike  live attenuated  or  inactivated vaccine , but contains only the antigenic parts such as  proteins ,  polysaccharides [ 1 ] [ 2 ]  or  peptides . [ 4 ]  Because the vaccine doesn't contain \"live\" components of the pathogen, there is no risk of introducing the disease, and is safer and more stable than vaccines containing whole pathogens. [ 1 ] \nOther advantages include being well-established technology and being suitable for  immunocompromised  individuals. [ 2 ]  Disadvantages include being relatively complex to manufacture compared to some vaccines, possibly requiring  adjuvants  and  booster shots , and requiring time to examine which antigenic combinations may work best. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14066", "text": "The first recombinant subunit vaccine was produced in the mid-1980s to protect people from  Hepatitis B . Other recombinant subunit vaccines\u00a0licensed include  Engerix-B  ( hepatitis B ),  Gardasil 9 [ 5 ]  ( Human Papillomavirus ),  Flublok [ 6 ]  ( influenza ),  Shingrix [ 7 ]  ( Herpes zoster ) and  Nuvaxovid [ 8 ]  ( Coronavirus disease 2019 )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14067", "text": "After  injection , antigens trigger the production of antigen-specific  antibodies , which are responsible for recognising and neutralising foreign substances. Basic components of recombinant subunit vaccines include recombinant subunits, adjuvants and carriers. Additionally, recombinant subunit vaccines are popular candidates for the development of  vaccines  against  infectious diseases  (e.g.  tuberculosis , [ 9 ]   dengue [ 10 ] )."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14068", "text": "Recombinant subunit vaccines are considered to be safe for injection. The chances of  adverse effects  vary depending on the specific type of  vaccine  being administered. Minor side effects include injection site pain, fever, and  fatigue , and serious  adverse effects  consist of  anaphylaxis  and potentially fatal  allergic reaction . The  contraindications  are also vaccine-specific; they are generally not recommended for people with the previous history of  anaphylaxis  to any component of the vaccines. Advice from medical professionals should be sought before receiving any vaccination."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14069", "text": "The first certified subunit vaccine by clinical trials on humans is the hepatitis B vaccine, containing the surface antigens of the hepatitis B virus itself from infected patients and adjusted by newly developed technology aiming to enhance the vaccine safety and eliminate possible contamination through individuals plasma. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14070", "text": "Subunit vaccines contain fragments of the pathogen, such as protein or polysaccharide, whose combinations are carefully selected to induce a strong and effective immune response. Because the immune system interacts with the pathogen in a limited way, the risk of  side effects  is minimal. [ 2 ] \nAn effective vaccine would elicit the immune response to the antigens and form  immunological memory  that allows quick recognition of the pathogens and quick response to future infections. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14071", "text": "A drawback is that the specific antigens used in a subunit vaccine may lack  pathogen-associated molecular patterns  which are common to a class of pathogen. These  molecular structures  may be used by  immune cells  for danger recognition, so without them, the immune response may be weaker.  Another drawback is that the antigens do not infect  cells , so the immune response to the subunit vaccines may only be  antibody-mediated , not  cell-mediated , and as a result, is weaker than those elicited by other types of vaccines.\nTo increase immune response,  adjuvants  may be used with the subunit vaccines, or booster doses may be required. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14072", "text": "A  protein subunit  is a  polypeptide chain  or  protein  molecule that assembles (or \" coassembles \") with other protein molecules to form a  protein complex . [ 12 ] [ 13 ] [ 14 ]  Large assemblies of proteins such as  viruses  often use a small number of types of protein subunits as building blocks. [ 15 ]   A key step in creating a recombinant protein vaccine is the identification and isolation of a protein subunit from the pathogen which is likely to trigger a strong and effective immune response, without including the parts of the virus or bacterium that enable the pathogen to reproduce.  Parts of the protein shell or  capsid  of a virus are often suitable.  The goal is for the protein subunit to prime the immune system response by mimicking the appearance but not the action of the pathogen. [ 16 ]  Another protein-based approach involves self\u2010assembly of multiple protein subunits into a  virus-like particle  (VLP) or nanoparticle. The purpose of increasing the vaccine's surface similarity to a whole virus particle (but not its ability to spread) is to trigger a stronger immune response. [ 17 ] [ 16 ] [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14073", "text": "Protein subunit vaccines are generally made through  protein production , manipulating the  gene expression  of an organism so that it  expresses  large amounts of a  recombinant gene . [ 16 ] [ 19 ]  A variety of approaches can be used for development depending on the vaccine involved. [ 17 ]   Yeast ,  baculovirus , or  mammalian  cell cultures can be used to produce large amounts of proteins in vitro. [ 16 ] [ 19 ] [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14074", "text": "Protein-based vaccines are being used for  hepatitis B  and for  human papillomavirus  (HPV). [ 17 ] [ 16 ]   The approach is being used to try to develop vaccines for difficult-to-vaccinate-against viruses such as  ebolavirus  and  HIV . [ 21 ]  Protein-based vaccines for COVID-19 tend to target either its spike protein or its receptor binding domain. [ 17 ]  As of 2021, the most researched vaccine platform for COVID-19 worldwide was reported to be recombinant protein subunit vaccines. [ 16 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14075", "text": "Vi capsular polysaccharide vaccine  (ViCPS) against  typhoid  caused by the Typhi serotype of  Salmonella enterica . [ 23 ]  Instead of being a protein, the Vi antigen is a  bacterial capsule  polysacchide, made up of a long sugar chain linked to a lipid. [ 24 ]  Capsular vaccines like ViCPS tend to be weak at eliciting immune responses in children. Making a  conjugate vaccine  by linking the polysacchide with a  toxoid  increases the efficacy. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14076", "text": "A  conjugate vaccine  is a type of  vaccine  which combines a weak  antigen  with a strong antigen as a carrier so that the  immune system  has a stronger response to the weak antigen. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14077", "text": "A  peptide-based subunit vaccine  employs a  peptide  instead of a full  protein . [ 27 ]  Peptide-based subunit vaccine mostly used due to many reasons,such as, it is easy and affordable for massive production. Adding to that, its greatest stability, purity and exposed composition. [ 28 ]  Three steps occur leading to creation of peptide subunit vaccine; [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14078", "text": "When compared with conventional  attenuated vaccines  and  inactivated vaccines , recombinant subunit vaccines have the following special characteristics:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14079", "text": "However, there are also some drawbacks regarding recombinant subunit vaccines:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14080", "text": "Vaccination  is a potent way to protect individuals against  infectious diseases . [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14081", "text": "Active immunity  can be acquired artificially by  vaccination  as a result of the body's own defense mechanism being triggered by the exposure of a small, controlled amount of  pathogenic  substances to produce its own antibodies and memory cells without being infected by the real pathogen. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14082", "text": "The processes involved in primary immune response are as follows:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14083", "text": "Under specific circumstances, low doses of  vaccines  are given initially, followed by additional doses named  booster doses . Boosters can effectively maintain the level of  memory cells  in the human body, hence extending a person's  immunity . [ 33 ] [ 34 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14084", "text": "The manufacturing process of recombinant subunit  vaccines  are as follows: [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14085", "text": "Candidate subunits will be selected primarily by their  immunogenicity . [ 44 ]  To be  immunogenic , they should be of foreign nature and of sufficient complexity for the reaction between different components of the  immune system  and the candidates to occur. [ 45 ]  Candidates are also selected based on size, nature of function (e.g.  signalling ) and cellular location (e.g.  transmembrane ). [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14086", "text": "Upon identifying the target subunit and its encoding  gene , the  gene  will be isolated and transferred to a second, non-pathogenic organism, and cultured for  mass production . [ 46 ]  The process is also known as  heterologous expression . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14087", "text": "A suitable  expression system  is selected based on the requirement of  post-translational modifications , costs, ease of product extraction and production efficiency. Commonly used systems for both licensed and developing recombinant subunit  vaccines  include  bacteria ,  yeast ,  mammalian  cells,  insect  cells. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14088", "text": "Bacterial cells  are widely used for  cloning processes ,  genetic modification  and small-scale productions. [ 48 ]   Escherichia coli (E. Coli)  is widely utilised due to its highly explored  genetics , widely available genetic tools for  gene expression , accurate profiling and its ability to grow in inexpensive  media  at high cell densities. [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14089", "text": "E. Coli is mostly appropriate for structurally simple proteins owing to its inability to carry out  post-translational modifications , lack of  protein secretary system  and the potential for producing  inclusion bodies  that require additional solubilisation. [ 48 ] [ 49 ] [ 50 ]  Regarding application,  E.Coli  is being utilised as the  expression system  of the  dengue vaccine . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14090", "text": "Yeast  matches  bacterial cells'  cost-effectiveness, efficiency and technical feasibility. [ 48 ]  Moreover,  yeast  secretes  soluble   proteins  and has the ability to perform  post-translational modifications  similar to  mammalian  cells. [ 50 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14091", "text": "Notably, yeast incorporates more  mannose  molecules during  N-glycosylation  when compared with other  eukaryotes , [ 51 ]  which may trigger  cellular conformational stress responses . Such responses may result in failure in reaching native protein conformation, implying potential reduction of  serum half-life  and  immunogenicity . [ 48 ]  Regarding application, both the  hepatitis B virus surface antigen  ( HBsAg ) and the  virus-like particles  ( VLPs ) of the major capsid protein L1 of  human papillomavirus  type 6, 11, 16, 18 are produced by  Saccharomyces cerevisiae . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14092", "text": "Mammalian  cells are well known for their ability to perform therapeutically essential  post-translational modifications  and express properly folded,  glycosylated  and functionally active proteins. [ 49 ] [ 52 ] [ 53 ]  However, efficacy of mammalian cells may be limited by  epigenetic   gene silencing  and  aggresome  formation (recombinant protein aggregation). [ 49 ]  For mammalian cells, synthesised proteins were reported to be secreted into chemically defined media, potentially simplifying protein extraction and purification. [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14093", "text": "The most prominent example under this class is  Chinese Hamster Ovary (CHO)  cells utilised for the synthesis of recombinant  varicella zoster virus  surface glycoprotein (gE) antigen for  SHINGRIX . [ 7 ]   CHO cells  are recognised for rapid growth and their ability to offer process versatility. They can also be cultured in suspension-adapted culture in protein-free medium, hence reducing risk of  prion -induced contamination. [ 48 ] [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14094", "text": "The  baculovirus - insect  cell  expression system  has the ability to express a variety of  recombinant proteins  at high levels and provide significant eukaryotic protein processing capabilities, including  phosphorylation ,  glycosylation ,  myristoylation  and  palmitoylation . [ 54 ]  Similar to  mammalian  cells, proteins expressed are mostly  soluble , accurately folded, and biologically active. [ 55 ]  However, it has slower growth rate and requires higher cost of  growth medium  than  bacteria  and  yeast , and confers  toxicological  risks. [ 48 ]  A notable feature is the existence of elements of control that allow for the expression of secreted and  membrane -bound proteins in Baculovirus-insect cells. [ 48 ] [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14095", "text": "Licensed recombinant subunit  vaccines  that utilises  baculovirus - insect  cells include  Cervarix  (papillomavirus C-terminal truncated major capsid protein L1 types 16 and 18) [ 48 ] [ 56 ]  and  Flublok Quadrivalent  ( hemagglutinin  ( HA ) proteins from four strains of  influenza viruses ). [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14096", "text": "Throughout history, extraction and  purification  methods have evolved from standard  chromatographic methods  to the utilisation of  affinity tags . [ 57 ]  However, the final extraction and purification process undertaken highly depends on the chosen  expression system . Please refer to subunit expression and synthesis for more insights. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14097", "text": "Adjuvants  are materials added to improve  immunogenicity  of recombinant subunit  vaccines . [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14098", "text": "Adjuvants increase the magnitude of  adaptive response  to the  vaccine  and guide the activation of the most effective forms of  immunity  for each specific  pathogen  (e.g. increasing generation of T cell memory). [ 58 ] [ 59 ] [ 60 ] [ 61 ]  Addition of adjuvants may confer benefits including dose sparing and stabilisation of final vaccine formulation. [ 58 ] [ 61 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14099", "text": "Appropriate adjuvants are chosen based on safety, tolerance, compatibility of antigen and  manufacturing  considerations. [ 58 ]  Commonly used adjuvants for recombinant subunit  vaccines  are  Alum  adjuvants (e.g.  aluminium hydroxide ),  Emulsions  (e.g.  MF59 ) and  Liposomes  combined with  immunostimulatory  molecules (e.g. AS01 B ). [ 58 ] [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14100", "text": "Delivery systems  are primarily divided into polymer-based  delivery systems  ( microspheres  and  liposomes ) and live  delivery systems  ( gram-positive bacteria ,  gram-negative bacteria  and  viruses ) [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14101", "text": "Vaccine antigens  are often encapsulated within  microspheres  or  liposomes . Common microspheres made using  Poly-lactic acid (PLA) [ 62 ]  and  poly-lactic-co-glycolic acid (PLGA) [ 62 ]  allow for controlled  antigen  release by degrading in vivo while  liposomes  including multilamellar or unilamellar vesicles allow for prolonged release. [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14102", "text": "Polymer-based  delivery systems  confer advantages such as increased resistance to degradation in  GI tract , controlled  antigen  release, raised particle uptake by  immune cells  and enhanced ability to induce  cytotoxic T cell  responses. [ 60 ]  An example of licensed recombinant vaccine utilising  liposomal  delivery is  Shringrix ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14103", "text": "Live  delivery systems , also known as  vectors , are cells modified with  ligands  or  antigens  to improve the  immunogenicity  of recombinant subunits via altering  antigen presentation ,  biodistribution  and trafficking. [ 63 ]  Subunits may either be inserted within the carrier or  genetically engineered  to be expressed on the surface of the  vectors  for efficient presentation to the  mucosal immune system . [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14104", "text": "Recombinant subunit  vaccines  are safe for administration. [ 67 ] [ 68 ] \u00a0However, mild local reactions, including  induration  and  swelling  of the injection site, along with  fever ,  fatigue  and  headache  may be encountered after vaccination. [ 67 ] [ 69 ] [ 70 ]  Occurrence of severe  hypersensitivity  reactions and  anaphylaxis  is rare, [ 71 ]  but can possibly lead to  deaths  of individuals.  Adverse effects  can vary among populations depending on their  physical health  condition, age,  gender  and  genetic  predisposition. [ 72 ] [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14105", "text": "Recombinant subunit  vaccines  are  contraindicated  to people who have experienced  allergic reactions  and  anaphylaxis  to  antigens  or other components of the  vaccines  previously. [ 74 ] [ 75 ]  Furthermore, precautions should be taken when administering  vaccines  to people who are in  diseased  state and during  pregnancy , [ 74 ]  in which their injections should be delayed until their conditions become stable and after childbirth respectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14106", "text": "ENGERIX-B  (produced by GSK) and  RECOMBIVAX HB  (produced by merck) are two recombinant subunit  vaccines  licensed for the protection against  hepatitis B . Both contain  HBsAg  harvested and purified from  Saccharomyces cerevisiae  and are formulated as a suspension of the  antigen  adjuvanted with  alum . [ 76 ] [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14107", "text": "Antibody  concentration \u226510mIU/mL against  HBsAg  are recognized as conferring protection against hepatitis B infection. [ 76 ] [ 77 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14108", "text": "It has been shown that primary 3-dose  vaccination  of healthy individuals is associated with \u226590% seroprotection rates for  ENGERIX-B , despite decreasing with older age. Lower seroprotection rates are also associated with presence of underlying  chronic diseases  and  immunodeficiency . Yet, GSK HepB still has a clinically acceptable  safety profile  in all studied populations. [ 78 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14109", "text": "Cervarix ,  GARDASIL  and  GARDASIL9  are three recombinant subunit  vaccines  licensed for the protection against  HPV  infection. They differ in the  strains  which they protect the patients from as  Cervarix  confers protection against type 16 and 18, [ 56 ]   Gardasil  confers protection against type 6, 11, 16 and 18, [ 79 ]  and Gardasil 9 confers protection against type 6, 11, 16, 18, 31, 33, 45, 52, 58 [ 5 ]  respectively.\u00a0 The  vaccines  contain purified  VLP  of the major capsid L1 protein produced by recombinant  Saccharomyces cerevisiae . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14110", "text": "It has been shown in a 2014 systematic quantitative review that the bivalent HPV vaccine ( Cervarix ) is associated with  pain  (OR 3.29; 95% CI: 3.00\u20133.60),  swelling  (OR 3.14; 95% CI: 2.79\u20133.53) and  redness  (OR 2.41; 95% CI: 2.17\u20132.68) being the most frequently reported adverse effects. For Gardasil, the most frequently reported events were  pain  (OR 2.88; 95% CI: 2.42\u20133.43) and  swelling  (OR 2.65; 95% CI: 2.0\u20133.44). [ 80 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14111", "text": "Gardasil was discontinued in the U.S. on May 8, 2017, after the introduction of Gardasil 9 [ 81 ]  and Cervarix was also voluntarily withdrawn in the U.S. on August 8, 2016. [ 82 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14112", "text": "Flublok Quadrivalent  is a licensed recombinant subunit  vaccine  for active  immunisation  against  influenza . It contains  HA  proteins of four  strains  of  influenza  virus purified and extracted using the  Baculovirus - insect   expression system . The four viral strains are standardised annually according to  United States Public Health Services (USPHS)  requirements. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14113", "text": "Flublok Quadrivalent  has a comparable safety profile to traditional trivalent and quadrivalent vaccine equivalents. Flublok is also associated with less local reactions (RR = 0.94, 95% CI 0.90\u20130.98, three RCTs, FEM, I2 = 0%, low\u2010 certainty evidence) and higher risk of  chills \u00a0(RR = 1.33, 95% CI 1.03\u20131.72, three RCTs, FEM, I2 = 14%, low\u2010certainty evidence). [ 83 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14114", "text": "SHINGRIX  is a licensed recombinant subunit  vaccine  for protection against  Herpes Zoster , whose risk of developing increases with decline of  varicella zoster virus (VZV)  specific  immunity . The vaccine contains  VZV  gE antigen component extracted from  CHO cells , which is to be reconstituted with  adjuvant  suspension AS01 B . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14115", "text": "Systematic reviews  and  meta-analyses  have been conducted on the efficacy, effectiveness and safety of  SHINGRIX  in  immunocompromised  18\u201349 year old patients and healthy adults aged 50 and over. These studies reported  humoral  and  cell-mediated immunity  rate ranged between 65.4 and 96.2% and 50.0\u201393.0% while efficacy in patients (18\u201349 yo) with  haematological malignancies  was estimated at 87.2% (95%CI, 44.3\u201398.6%) up to 13 months post-vaccination with an acceptable  safety profile . [ 84 ] [ 85 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14116", "text": "NUVAXOVID  is a recombinant subunit vaccine licensed for the prevention of  SARS-CoV-2 infection . Market authorization was issued on 20 December 2021. [ 86 ]  The vaccine contains the  SARS-CoV-2 spike  protein produced using the  baculovirus   expression system , which is eventually adjuvanted with the  Matrix M  adjuvant. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14117", "text": "While the practice of  immunisation  can be traced back to the  12th century , in which ancient  Chinese  at that time employed the technique of  variolation  to confer  immunity  to  smallpox  infection, [ citation needed ]  the modern era of vaccination has a short history of around 200 years. It began with the  invention  of a vaccine by Edward Jenner in 1798 to eradicate  smallpox  by injecting relatively weaker  cowpox  virus into the human body. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14118", "text": "The middle of the 20th century marked the golden age of vaccine science. [ citation needed ]  Rapid technological advancements during this period of time enabled scientists to cultivate  cell culture  under controlled environments in laboratories, [ 87 ]  subsequently giving rise to the production of vaccines against  poliomyelitis ,  measles  and various  communicable diseases . [ citation needed ]  Conjugated vaccines were also developed using  immunologic  markers including capsular  polysaccharide  and  proteins . [ 87 ]  Creation of products targeting common illnesses successfully lowered infection-related  mortality  and reduced  public healthcare  burden."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14119", "text": "Emergence of  genetic engineering techniques  revolutionised the creation of vaccines. By the end of the 20th century, researchers had the ability to create  recombinant vaccines  apart from traditional  whole-cell vaccine , for instance  Hepatitis B vaccine , which uses the viral  antigens  to initiate  immune responses . [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14120", "text": "As the  manufacturing  methods continue to evolve, vaccines with more complex constitutions will inevitably be generated in the future to extend their therapeutic applications to both infectious and  non-infectious diseases , [ citation needed ]  in order to safeguard the health of more people."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14121", "text": "Recombinant subunit  vaccines  are used in development for  tuberculosis , [ 9 ]   dengue fever , [ 10 ]   soil-transmitted helminths , [ 88 ]   feline leukaemia [ 89 ]  and  COVID-19 . [ 90 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14122", "text": "Subunit vaccines are not only considered effective for SARS-COV-2, but also as candidates for evolving immunizations against malaria, tetanus, salmonella enterica, and other diseases. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14123", "text": "Research has been conducted to explore the possibility of developing a heterologous  SARS-CoV  receptor-binding domain (RBD) recombinant protein as a human  vaccine  against  COVID-19 . The theory is supported by evidence that  convalescent   serum  from  SARS-CoV  patients have the ability to neutralise  SARS-CoV-2  (corresponding virus for  COVID-19 ) and that amino acid similarity between  SARS-CoV  and  SARS-CoV-2 spike  and RBD protein is high (82%). [ 90 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14124", "text": "Toxicity  is the degree to which a  chemical substance  or a particular  mixture  of substances can damage an  organism . [ 1 ]  Toxicity can refer to the effect on a whole organism, such as an  animal ,  bacterium , or  plant , as well as the effect on a substructure of the organism, such as a  cell  ( cytotoxicity ) or an organ such as the  liver  ( hepatotoxicity ). Sometimes the word is more or less synonymous with  poisoning  in everyday usage."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14125", "text": "A central concept of  toxicology  is that the effects of a  toxicant  are  dose -dependent; even  water  can lead to  water intoxication  when taken in too high a dose, whereas for even a very toxic substance such as  snake venom  there is a dose below which there is no detectable toxic effect. Toxicity is species-specific, making cross-species analysis problematic. Newer  paradigms  and metrics are evolving to bypass  animal testing , while maintaining the concept of toxicity endpoints. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14126", "text": "In  Ancient Greek  medical literature, the adjective  \u03c4\u03bf\u03be\u03b9\u03ba\u03cc\u03bd  (meaning \"toxic\") was used to describe substances which had the ability of \"causing death or serious debilitation or exhibiting symptoms of infection.\" [ 3 ]  The word draws its origins from the Greek noun \u03c4\u03cc\u03be\u03bf\u03bd  toxon  (meaning \"arc\"), in reference to the use of bows and  poisoned arrows  as weapons. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14127", "text": "English-speaking American culture has adopted several figurative usages for  toxicity , often when describing harmful inter-personal relationships or character traits (e.g. \" toxic masculinity \"). [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14128", "text": "Humans have a deeply rooted history of not only being aware of toxicity, but also taking advantage of it as a tool. Archaeologists studying bone arrows from caves of Southern Africa have noted the likelihood that some aging 72,000 to 80,000 years old were dipped in specially prepared poisons to increase their lethality. [ 5 ]  Although scientific instrumentation limitations make it difficult to prove concretely, archaeologists hypothesize the practice of making poison arrows was widespread in cultures as early as the paleolithic era. [ 6 ] [ 7 ]  The San people of Southern Africa have managed to preserved this practice into the modern era, with the knowledge base to form complex mixtures from poisonous beetles and plant derived extracts, yielding an arrow-tip product with a shelf life beyond several months to a year. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14129", "text": "There are generally five types of toxicities: chemical, biological, physical, radioactive and behavioural."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14130", "text": "Disease-causing microorganisms and parasites are toxic in a broad sense but are generally called  pathogens  rather than toxicants. The biological toxicity of pathogens can be difficult to measure because the  threshold dose  may be a single organism. Theoretically one  virus , bacterium or  worm  can reproduce to cause a serious  infection . If a host has an intact  immune system , the inherent toxicity of the organism is balanced by the host's response; the effective toxicity is then a combination. In some cases, e.g.  cholera toxin , the disease is chiefly caused by a nonliving substance secreted by the organism, rather than the organism itself. Such nonliving biological toxicants are generally called  toxins  if produced by a microorganism, plant, or fungus, and  venoms  if produced by an animal."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14131", "text": "Physical toxicants are substances that, due to their physical nature, interfere with biological processes. Examples include  coal  dust,  asbestos  fibres or finely divided  silicon dioxide , all of which can ultimately be fatal if inhaled. Corrosive chemicals possess physical toxicity because they destroy tissues, but are not directly poisonous unless they interfere directly with biological activity. Water can act as a physical toxicant if taken in extremely high doses because the concentration of vital ions decreases dramatically with too much water in the body. Asphyxiant gases can be considered physical toxicants because they act by displacing oxygen in the environment but they are inert, not chemically toxic gases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14132", "text": "Radiation can have a toxic effect on organisms. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14133", "text": "Behavioral toxicity refers to the undesirable effects of essentially therapeutic levels of medication clinically indicated for a given disorder (DiMascio, Soltys and Shader, 1970). These undesirable effects include anticholinergic effects, alpha-adrenergic blockade, and dopaminergic effects, among others. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14134", "text": "Toxicity can be measured by its effects on the target (organism, organ, tissue or cell).  Because individuals typically have different levels of response to the same dose of a toxic substance, a population-level measure of toxicity is often used which relates the probabilities of an outcome for a given individual in a population.  One such measure is the  LD 50 . When such data does not exist, estimates are made by comparison to known similar toxic things, or to similar exposures in similar organisms. Then, \" safety factors \" are added to account for uncertainties in data and evaluation processes. For example, if a dose of a toxic substance is safe for a laboratory rat, one might assume that one-tenth that dose would be safe for a human, allowing a safety factor of 10 to allow for interspecies differences between two mammals; if the data are from fish, one might use a factor of 100 to account for the greater difference between two chordate classes (fish and mammals). Similarly, an extra protection factor may be used for individuals believed to be more susceptible to toxic effects such as in pregnancy or with certain diseases. Or, a newly synthesized and previously unstudied chemical that is believed to be very similar in effect to another compound could be assigned an additional protection factor of 10 to account for possible differences in effects that are probably much smaller. This approach is very approximate, but such protection factors are deliberately very conservative, and the method has been found to be useful in a wide variety of applications."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14135", "text": "Assessing all aspects of the toxicity of cancer-causing agents involves additional issues, since it is not certain if there is a minimal effective dose for  carcinogens , or whether the risk is just too small to see. In addition, it is possible that a single cell transformed into a cancer cell is all it takes to develop the full effect (the \"one hit\" theory)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14136", "text": "It is more difficult to determine the toxicity of chemical mixtures than a pure chemical because each component displays its own toxicity, and components may interact to produce enhanced or diminished effects. Common mixtures include  gasoline ,  cigarette smoke , and  industrial waste .  Even more complex are situations with more than one type of toxic entity, such as the discharge from a malfunctioning sewage treatment plant, with both chemical and biological agents."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14137", "text": "The preclinical toxicity testing on various biological systems reveals the species-, organ- and dose-specific toxic effects of an investigational product. The toxicity of substances can be observed by (a) studying the accidental exposures to a substance (b) in vitro studies using cells/ cell lines (c) in vivo exposure on experimental animals. Toxicity tests are mostly used to examine specific adverse events or specific endpoints such as cancer, cardiotoxicity, and skin/eye irritation. Toxicity testing also helps calculate the No Observed Adverse Effect Level (NOAEL) dose and is helpful for clinical studies. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14138", "text": "For substances to be regulated and handled appropriately they must be properly classified and labelled. Classification is determined by approved testing measures or calculations and has determined cut-off levels set by governments and scientists (for example,  no-observed-adverse-effect levels ,  threshold limit values , and  tolerable daily intake  levels).  Pesticides  provide the example of well-established  toxicity class  systems and  toxicity labels . While currently many countries have different regulations regarding the types of tests, numbers of tests and cut-off levels, the implementation of the  Globally Harmonized System [ 12 ] [ 13 ]  has begun unifying these countries."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14139", "text": "Global classification looks at three areas: Physical Hazards (explosions and pyrotechnics), [ citation needed ]  Health Hazards [ citation needed ]  and  environmental hazards . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14140", "text": "The types of toxicities where substances may cause lethality to the entire body, lethality to specific organs, major/minor damage, or cause cancer. These are globally accepted definitions of what toxicity is. [ citation needed ]  Anything falling outside of the definition cannot be classified as that type of toxicant. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14141", "text": "Acute toxicity looks at lethal effects following oral, dermal or inhalation exposure. It is split into five categories of severity where Category 1 requires the least amount of exposure to be lethal and Category 5 requires the most exposure to be lethal. The table below shows the upper limits for each category."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14142", "text": "Note: The undefined values are expected to be roughly equivalent to the category 5 values for oral and dermal administration. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14143", "text": "Skin corrosion and irritation are determined through a skin patch test analysis, similar to an  allergic inflammation patch test . This examines the severity of the damage done; when it is incurred and how long it remains; whether it is reversible and how many test subjects were affected."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14144", "text": "Skin corrosion  from a substance must penetrate through the epidermis into the dermis within four hours of application and must not reverse the damage within 14 days.  Skin irritation  shows damage less severe than corrosion if: the damage occurs within 72 hours of application; or for three consecutive days after application within a 14-day period; or causes  inflammation  which lasts for 14 days in two test subjects.  Mild skin irritation  is minor damage (less severe than irritation) within 72 hours of application or for three consecutive days after application."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14145", "text": "Serious  eye  damage  involves tissue damage or degradation of vision which does not fully reverse in 21 days. Eye irritation involves changes to the eye which do fully reverse within 21 days."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14146", "text": "An Environmental hazard can be defined as any condition, process, or state adversely affecting the environment. These hazards can be physical or chemical, and present in air, water, and/or soil. These conditions can cause extensive harm to humans and other organisms within an ecosystem."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14147", "text": "The EPA maintains a list of priority pollutants for testing and regulation. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14148", "text": "Workers in various occupations may be at a greater level of risk for several types of toxicity, including neurotoxicity. [ 16 ]   The expression \"Mad as a hatter\" and the \"Mad Hatter\" of the book  Alice in Wonderland  derive from the known occupational toxicity of  hatters  who used a toxic chemical for controlling the shape of hats. Exposure to chemicals in the workplace environment may be required for evaluation by industrial hygiene professionals. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14149", "text": "Hazards in the arts have been an issue for artists for centuries, even though the toxicity of their tools, methods, and materials was not always adequately realized. Lead and cadmium, among other toxic elements, were often incorporated into the names of artist's oil paints and pigments, for example, \"lead white\" and \"cadmium red\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14150", "text": "20th-century printmakers and other artists began to be aware of the toxic substances, toxic techniques, and toxic fumes in glues, painting mediums, pigments, and solvents, many of which in their labelling gave no indication of their toxicity. An example was the use of  xylol  for cleaning  silk screens . Painters began to notice the dangers of breathing painting mediums and thinners such as  turpentine . Aware of toxicants in studios and workshops, in 1998 printmaker  Keith Howard  published  Non-Toxic Intaglio Printmaking  which detailed twelve innovative  Intaglio -type printmaking techniques including  photo etching ,  digital imaging ,  acrylic -resist hand-etching methods, and introducing a new method of  non-toxic   lithography . [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14151", "text": "There are many environmental health mapping tools.  TOXMAP  is a Geographic Information System (GIS) from the Division of Specialized Information Services [ 19 ]  of the  United States National Library of Medicine  (NLM) that uses maps of the United States to help users visually explore data from the  United States Environmental Protection Agency 's (EPA)  Toxics Release Inventory  and  Superfund  programs. TOXMAP is a resource funded by the US Federal Government. TOXMAP's chemical and environmental health information is taken from NLM's Toxicology Data Network \n(TOXNET) [ 20 ]  and  PubMed , and from other authoritative sources."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14152", "text": "Aquatic toxicity  testing subjects key indicator species of  fish  or  crustacea  to certain concentrations of a substance in their environment to determine the lethality level. Fish are exposed for 96 hours while crustacea are exposed for 48 hours. While GHS does not define toxicity past 100\u00a0mg/L, the EPA currently lists aquatic toxicity as \"practically non-toxic\" in concentrations greater than 100 ppm. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14153", "text": "Note: A category 4 is established for chronic exposure, but simply contains any toxic substance which is mostly insoluble, or has no data for acute toxicity."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14154", "text": "Toxicity of a substance can be affected by many different factors, such as the pathway of administration (whether the toxicant is applied to the skin, ingested, inhaled, injected), the time of exposure (a brief encounter or long term), the number of exposures (a single dose or multiple doses over time), the physical form of the toxicant (solid, liquid, gas), the concentration of the substance, and in the case of gases, the partial pressure (at high ambient pressure, partial pressure will increase for a given concentration as a gas fraction), the genetic makeup of an individual, an individual's overall health, and many others.  Several of the terms used to describe these factors have been included here."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14155", "text": "Considering the limitations of the  dose-response  concept, a novel Abstract Drug Toxicity Index (DTI) has been proposed recently. [ 22 ]   DTI redefines drug toxicity, identifies hepatotoxic drugs, gives mechanistic insights, predicts clinical outcomes and has potential as a screening tool."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14156", "text": "Venom in medicine  is the medicinal use of  venoms  for  therapeutic  benefit in treating  diseases ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14157", "text": "Venom is any  poisonous  compound secreted by an animal intended to harm or disable another. When an organism produces a venom, its final form may contain hundreds of different  bioactive elements  that interact with each other inevitably producing its  toxic  effects. [ 1 ]  This mixture of ingredients includes various  proteins ,  peptides , and non-peptidic  small molecules . [ 2 ]  The active components of these venoms are isolated, purified, and screened in  assays .  These may be either  phenotypic assays  to identify component that may have desirable therapeutic properties ( forward pharmacology ) or target directed assays to identify their  biological target  and  mechanism of action  ( reverse pharmacology ). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14158", "text": "Venoms are  naturally occurring  substances that organisms evolved to deploy against other organisms, in defense or attack. [ 2 ]   They are often mixtures of   proteins  that act together or singly to attack their specific  targets  within the organism against which they are used, generally with high  specificity  and generally easily accessible through the vascular system. [ 2 ]   This has made venoms a subject of study for people who work in  drug discovery . [ 2 ]   With developments in  omic  technologies ( proteomics ,  genomics , etc.), researchers in this field became able to identify genes that produce certain elements in an animal's venom, as well as  protein domains  that have been used as building blocks across many species. [ 2 ]  In conjunction with methods of separation and purification of compounds, scientists are able to study each individual compound that exists within a venom \"concoction\", looking for compounds to serve as drug leads or other use. [ 2 ]  Each venomous organism produces thousands of different proteins giving access to millions of different molecules that still have potential uses. In addition, nature is continuously evolving; as prey develop resistance to these venoms, the predators also evolve as well, creating novel toxins that can continue to act upon its respective prey. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14159", "text": "The earliest known use of venom in medicine dates back to 380 B.C. in ancient Greece. [ 5 ]   Aristotle 's \"Historia Animalium\", describes how venom can be used in the production of antidotes for the venom. [ 5 ]  During the height of the Roman empire, there is evidence of venom being added into medicine used to treat smallpox, leprosy, fever, and wounds. [ 5 ]  Despite this, early uses of venom were primarily involved in the process of making antidotes. This use of venom continued into the Middle Ages and well into the 19th century. The first modern study of venom in a medical light occurred in the late 19th century. A scientist, Albert Calmatte, injected animals with small amounts of venom, using their blood as the antidote. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14160", "text": "Captopril  emulates the function of the toxin found in Brazilian pit viper ( Bothrops jararaca ) venom and is generally accepted as the first venom \"success\" story.  Captopril is an  ACE inhibitor  (angiotensin-converting enzyme) that was approved by the FDA approved in April 1981. It lowers blood pressure by inhibiting the production of  angiotensin II  which acts in a pathway that leads to  vasoconstriction  which raises blood pressure. After the creation of this drug, many analogues ( enalapril ,  lisinopril ,  perindopril ,  ramipril , etc.) were produced. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14161", "text": "Ziconotide  is a synthetically made version of the \u03c9- conotoxin  made by the  cone snail , [ 7 ]  that is used to treat severe pain and is delivered as an infusion into the  cerebrospinal fluid  using an  intrathecal   pump system . [ 8 ]   Ziconitide acts presynaptically on  N-type calcium channels , blocking the receptors of this channel with high selectivity and affinity, [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14162", "text": "Eptifibatide  was modeled after a component in  southeastern pygmy rattlesnake  venom and is used in anticoagulation therapies in an effort to reduce the risk of  heart attacks ; it is used in only severe cases because of the possible side effect of  thrombocytopenia , a condition where platelets are unable to aggregate at all. [ 9 ] [ 10 ] [ 11 ]  Eptifibatide binds reversibly to platelets reducing the risk of  thrombosis . It is an antagonist of  glycoprotein IIb/IIIa . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14163", "text": "Exenatide  is a 39- amino-acid   peptide  that is a synthetic version of exendin-4, a  hormone  found in the saliva of the  Gila monster . [ 12 ]  It is used to treat  Type II Diabetes  as an adjunct to insulin and other drugs. [ 13 ] [ 14 ]  It is  GLP-1 receptor agonist  that was first isolated by John Eng in 1992 while working at the Veterans Administration Medical Center in the Bronx, New York. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14164", "text": "Batroxobin , is a  serine protease  found in  snake venom  produced by  Bothrops atrox  and  Bothrops moojeni , venomous species of  pit viper  found east of the Andes in South America. It cleaves  fibrinogen , similarly to  thrombin .  Batroxobin from  B atrox  is used as a drug called \"Reptilase\" that is used to stop bleeding,  while batroxobin from  B moojeni  is a drug called \"Defibrase\", used to break up blood clots.  It is also used in a system called \"Vivostat\", where a person's blood is taken just before surgery and exposed to batroxobin; the resulting clots are then harvested, and then dissolved, forming a  fibrin glue  that is then used on the person during the surgery. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14165", "text": "Advil  is primarily a brand of  ibuprofen  (a  pain reliever  in the  nonsteroidal anti-inflammatory drug  category). [ 1 ]  Advil has been called a \"megabrand\" because it offers various \"products for a wide range of pain, head cold, and sleep problems.\" [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14166", "text": "The brand first entered the American market in 1984 through  Whitehall [ 3 ]  (itself a division of  Wyeth , which was purchased by  Pfizer  in 2009), [ 4 ]  the same year ibuprofen gained  Food and Drug Administration  (FDA) approval for  over-the-counter  (OTC) sales in the United States (being available via prescription since 1974). [ 5 ]  Within ten years of having a market presence, it outsold  Bayer Aspirin  and was a fierce competitor to  Tylenol  (primarily a brand of  acetaminophen ). [ 6 ]  In the mid-1990s, for example, it held 13% of the multibillion-dollar over-the-counter American market for  analgesics . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14167", "text": "In 2023, there were 23 varieties of Advil available on the U.S. market including: [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14168", "text": "Marketing campaigns for the brand (some including celebrities like  Regis Philbin ) have pushed slogans such as \"Take Action. Take Advil.\" and have been presented under the premise of \"True Advil Stories\"; [ 9 ]  the brand has also been involved in sponsorship deals such as with  Major League Pickleball . [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14169", "text": "Amrutanjan  is an  analgesic   balm  manufactured and distributed by  Amrutanjan Healthcare . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14170", "text": "Amrutanjan was founded in 1893 by journalist and freedom fighter,  Kasinathuni Nageswara Rao . [ 2 ]  He popularized the balm by distributing it free-of-cost at music concerts. Even today, the words \"Bombay\" are inscribed along with Amrutanjan on the lid of its most well-known product, the pain balm. In 1936, Amrutanjan became a  public limited company  with the name Amrutanjan Limited. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14171", "text": "It is used as a balm for:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14172", "text": "The brand is owned by the parent  Amrutanjan Healthcare . It is now headed by Sambhu Prasad, the grandson of Nageshwara Rao. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14173", "text": "Anacin  is an American brand of  analgesic  that is manufactured by  Prestige Consumer Healthcare . Anacin's active ingredients are  aspirin  and  caffeine . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14174", "text": "Anacin was invented by William Milton Knight and was first to be used  c. \u20091916  as stated in the patent. [ 2 ]  Trademarked in 1918, Anacin is one of the oldest brands of pain relievers in the United States. It originally contained  acetophenetidin  (phenacetin) and was promoted as \"aspirin-free relief,\" but was reformulated in the 1980s following the FDA's ruling to withdraw phenacetin from the market in 1983 due to concerns over its carcinogenic properties. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14175", "text": "It was originally sold by the Anacin Co. (\"Pharmaceutical Chemists\") in  Chicago, Illinois .  American Home Products , now known as Wyeth, purchased the manufacturing rights in 1930. [ 4 ]  Anacin was reportedly their most popular product. [ 5 ]  Insight Pharmaceuticals acquired the brand in 2003. [ citation needed ]  In 2014,  Prestige Consumer Healthcare  signed an agreement with Insight to acquire the company; it was Prestige's largest acquisition to that point. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14176", "text": "In 1939, Anacin sponsored a daytime serial called  Our Gal Sunday . Their sponsorship spanned 18 of the program's 23 years on the air. [ 5 ]  Early Anacin radio commercials appeared in radio shows and dramas of the 1940s and '50s. These \"formulaic\" commercials usually claimed that Anacin was being actively prescribed by doctors and dentists at the time, treated \" headaches ,  neuritis  and  neuralgia \", and that it contained \"a combination of medically proven ingredients, like a doctor's prescription\", without specifying those ingredients. Sometimes the announcer would mention that there were four active ingredients in Anacin, one of which was the medicine the consumer was already taking. It also claimed to help with depression. The announcer then reminded the listener that Anacin was available \"at any drug counter\", and \"comes in handy (tin) boxes of 12 and 30, and economical family-size bottles of 50 and 100\", usually spelling out its name at the end of the commercial. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14177", "text": "Anacin sponsored the first made-for-television  sitcom ,  Mary Kay and Johnny . Unsure of how many viewers would be watching when they sponsored the show in 1947, Anacin ran a simple test, offering a free mirror to the first 200 viewers to write for one. The offer drew over 9,000 responses, overwhelming the sponsor but proving television was a viable advertising medium. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14178", "text": "Anacin was also a leading sponsor of the television soaps  Love of Life ,  The Secret Storm  and the early years of  The Young and the Restless ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14179", "text": "Anacin is one of the earliest and best examples of a concerted television marketing campaign, created for them in the late 1950s by  Rosser Reeves  of the  Ted Bates  ad agency.  Many people remember the commercials advertising \"tension producing\" situations, and the \"hammers in the head\" advertisement with the slogan \"Tension. Pressure. Pain.\""}
{"_id": "WikiPedia_Pharmacology$$$corpus_14180", "text": "An Anacin advertisement in 1962 featured a mother trying to assist her grown daughter with various chores, such as preparing a meal. \"Don't you think it needs a little salt?\", the mother would say, only to have her nerve-racked daughter shout, \"Mother, please, I'd rather do it myself!\" As the mother wilted, the daughter would emote and rub her head, with her inner voice saying, \"Control yourself! Sure, you've got a headache, you're tense, irritable, but don't take it out on her!\"  Another commercial had a wife greeting her husband as he pulled into their driveway in his car; the husband responded by yelling \"Helen, can't you keep Billy's bike  out of the driveway?!? \" These advertisement scenarios became popular and were parodied a number of times, including in the  Allan Sherman  song \"Headaches\", the 1966 film  The Silencers  and the 1980 film  Airplane ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14181", "text": "Anacin had a large billboard behind the center field fence of  Yankee Stadium  from the 1950s through 1973, until the stadium's 1974-75 renovation."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14182", "text": "Anacin covers a family of pain relievers. There are currently two different formulations:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14183", "text": "Anacin's side effects may include dizziness,  heartburn , irritability,  nausea , nervousness, rashes, hives, bloody stools, drowsiness, hearing loss, ringing in the ears, and trouble sleeping. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14184", "text": "B&O Supprettes  is the  brand name  for a  prescription  medication containing powdered  opium  and  belladonna   alkaloids  in a  suppository  form.  They are indicated for the treatment of moderate to severe  pain  from  urethral   spasm , and for extending the interval(s) between injections of opiates. [ 1 ]  The drug has various \"off label\" uses, including  renal colic ,  intestinal   cramps ,  tenesmus  and  diarrhea . They are also often prescribed after urinary bladder  surgery . [ 2 ]   B&O Supprettes was unique in the  United States  because they were the only drug containing opium that is for suppository use sold in the US  and, in fact, one of the very few medications that contains opium in any form in the US along with  paregoric  and  opium tincture  ( laudanum ). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14185", "text": "B&O Supprettes (the name is derived from the generic term 'belladonna/opium suppository') is an \"unapproved\" drug according to the  Food and Drug Administration  (FDA) \u2013 that is, the drug existed before the  Food, Drug and Cosmetic Act of 1938 . Accordingly, the compound has never undergone specific medical trials, and its  efficacy  has never been required to be demonstrated. The FDA has put pressure on the manufacturers of this drug for this reason. The original manufacturer of the Supprettes,  Eli Lilly and Company , has long since lost any patent to the drug. Amerifit, which manufactured generic Supprettes prior to 2008, was cautioned by the FDA due to the unapproved nature of the drug combination. [ 4 ]   Since 2008, Paddock Laboratories has manufactured a generic version of the Supprettes after working with the FDA on marketing issues related to the unapproved nature of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14186", "text": "The drug and its  generic  counterparts are supplied in packages of 12, and available in two strengths:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14187", "text": "Each B&O Supprettes suppository  #15 A  contains 16.2\u00a0mg (1/4  grain ) of belladonna and 30\u00a0mg (1/2 grain) of opium."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14188", "text": "Each B&O Supprettes suppository  #16 A  contains 16.2\u00a0mg of belladonna and 60\u00a0mg (1 grain) of opium."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14189", "text": "The usual dose is one suppository  rectally  once or twice daily  PRN  - (as needed), not to exceed four Supprettes in a 24-hour period. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14190", "text": "In the United States, B&O Supprettes is a  Schedule II  drug under the  Controlled Substances Act  of 1970; a written prescription is mandatory, and no refills are permitted. [ 5 ]  Refrigerated storage is preferable, but not required. Most pharmacies consider B&O Supprettes to be a \"special order\" item, and as such are not normally kept in inventory.  Compounding  pharmacies have the capability of producing a generic form of the medication, and can modify the dosage(s) of the active ingredients (for pediatric or elderly patients, and those with  chronic kidney disease ) or the carrier (usually substituting  cocoa butter ) to best meet the needs of the patient at the request of the prescriber."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14191", "text": "Biodyl  is a  trademark  of  Merial  for a  dietary supplement  used in animals.  It is manufactured in two formulations: a powder for use in an individual animal's drinking water, and an  injectable  solution.  The injectable solution is available by  veterinary   prescription  in some countries and  over the counter  in others."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14192", "text": "Biodyl is formulated as a powder to be given in water, and as an injectable solution.  The injectable solution is given  under the skin ,  in the muscle , or  in a vein , depending on the species of animal. [ 1 ]   Its intended uses include reducing physiological stress such as due to being transported, and preventing  azoturia  in performance animals.  The manufacturer's own product information describes Biodyl as an \"injection solution containing metabolic constituents ( adenosine triphosphoric acid  or ATP, magnesium aspartate,  potassium aspartate ,  sodium selenite  and vitamin B 12) for debility, convalescence and myopathies.\" [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14193", "text": "Composition: [ 1 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14194", "text": "In the United States, Biodyl is not  FDA approved , \"in that there is not in effect an approval of an application filed with respect to its intended use or uses\". [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14195", "text": "The manufacturer however, states that \"Biodyl is safe when used as directed. It has been around from the 1950s and adverse reactions have been exceedingly rare over many years of tracking. Less than one animal in over 2 million doses.\" [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14196", "text": "In April 2009, the sudden deaths of 21  polo ponies  at  Palm Beach International Polo Club  in  Florida  were attributed by a polo team captain to error or tampering in the team's supply of Biodyl. [ 6 ] [ 7 ]   A newspaper in Argentina reported 3 similar deaths of horses at an international competition in Uruguay. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14197", "text": "In the United States, concerns about a possible manufacturing error or tampering were lost amid a media outcry about the \"illegal\" use of \"illegal\" drugs not approved by the FDA, even \"banned\" by the FDA. [ 8 ]   In the US, Biodyl is neither an illegal drug nor a banned drug, but it is an unapproved drug.  Although Biodyl is a  dietary supplement , a type of product that normally is not subject to FDA approval, FDA approval is required to market injectable solutions (except animal vaccines, which are subject to USDA approval).  An Associated Press story misreported an October 2008 FDA refusal to permit commercial importation of the solution as a refusal to approve the solution.  In fact, Biodyl is not FDA-approved because the manufacturer has never submitted an application for FDA approval. [ 9 ]   Also, the FDA may permit the importation of unapproved drugs for personal use for pets. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14198", "text": "However, on April 23 a new concern emerged when a reputable pharmacy in  Ocala, Florida  disclosed that in  compounding  a preparation for the polo ponies which may have been intended to substitute for Biodyl, the pharmacy accidentally used an incorrect quantity of one of the ingredients. [ 11 ]   Compounding of drugs for use in animals is a subject of concern for the FDA. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14199", "text": "Daflon  is an oral micronized purified phlebotonic  flavonoid  fraction containing 90%  diosmin  and 10%  hesperidin . It is manufactured by  Laboratoires Servier  and often used to treat or manage disorders of the blood vessels. [ 1 ] [ 2 ]  Flavonoids are a type of  phytochemical  that have been associated with various effects on human health and are a component of many different  pharmaceutical ,  nutraceutical , and  cosmetic  preparations. [ 3 ]  Diosmin is a flavone  glycoside  that is derived from hesperidin. Hesperidin is a flavone that is extracted from citrus fruits. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14200", "text": "Daflon is not an FDA-approved medication, and therefore it cannot be advertised for treatment of diseases in the United States. Daflon is under preliminary research for its potential use in treating  vein  diseases, [ 5 ]  or  hemorrhoids . [ 6 ]  It is sold as a drug in  France , [ 7 ] [ 8 ]  Spain, [ 9 ]   Malaysia [ 10 ] [ 11 ]  and Belgium."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14201", "text": "There is moderate certainty evidence for the effectiveness of daflon for slightly reducing oedema compared to placebo in the treatment of  chronic venous insufficiency . [ 12 ]   Little to no differences in quality of life after treatment with Daflon were found and there is low certainty evidence that this class of drugs do not influence ulcer healing. [ 12 ]   Diosmiplex, a micronized purified flavonoid fraction of daflon, with similar venous insufficiency indication, is sold as a prescription  medical food  in the US. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14202", "text": "Daflon plays a crucial role in the prevention of  perivascular   edema  formation and treatment of  venous stasis . This activity can be explained by its antagonist activity against  prostaglandin E2  (PgE2) and  thromboxane  (TxA2) biosynthesis leading to inhibition of inflammatory process. Moreover, it also has a contraction activity on the lymphatic vessels which cause the lymphatic flow maximal. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14203", "text": "For venous insufficiency, the dosage is 2 tablets of 500mg daily. For acute hemorrhoidal attack, the dosage is 6 tablets daily for 4 days, followed by 4 tablets daily over the next 3 days. [ 15 ]  For chronic venous disease, the dosage is 2 tablets a day for at least 2 months. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14204", "text": "Possible side effects include routine  gastric disorders  and neurovegetative disorders, however, toxicology studies indicate that diosmin is quite safe. [ 2 ]  Diosmin interacts in an inhibitory manner with some metabolic enzymes so  drug-interactions  are probable. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14205", "text": "Excedrin  is an  over-the-counter   headache   pain reliever , typically in the form of  tablets or caplets . It contains  paracetamol, aspirin and caffeine . It was manufactured by  Bristol-Myers Squibb  until it was purchased by  Novartis  in July 2005 along with other products from BMS's over-the-counter business. As of March 2015,  GSK  holds majority ownership of Excedrin through a joint venture transaction with  Novartis . [ 1 ]  On July 18, 2022, GSK spun off its consumer healthcare business (including Excedrin) to  Haleon ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14206", "text": "The brand became known for advertisements where it cured especially unpleasant and excruciating headaches (called \"Excedrin headaches\" in the ads of 1970s, [ 2 ]  and later called \"Excedrin  tension headaches \"). In 2007, the brand branched out into marketing for other types of pains with the introduction of Excedrin Back & Body, without caffeine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14207", "text": "Excedrin is a combination medication composed of  acetaminophen ,  aspirin , and  caffeine . These medications treat migraine headache in a variety of ways."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14208", "text": "Acetaminophen  is a fever reducer and painkiller. Its precise mechanism is unknown. It is known that it mostly affects the  brain  and  spinal cord , which are parts of the central nervous system. By lowering the quantity of  prostaglandins  the body produces, acetaminophen raises the threshold for pain."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14209", "text": "Aspirin  is a nonsteroidal anti-inflammatory drug (NSAID). It lessens irritation and swelling as well as discomfort and inflammation. The amount of prostaglandins the body produces is also decreased by aspirin, but not in the same way that acetaminophen does."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14210", "text": "Caffeine  acts as a  vasoconstrictor , [ 3 ]  causing blood vessels to become smaller. This helps to restrict the blood vessels in the brain. As a result, the amount of blood that may pass through the blood arteries at once is reduced. There are several theories regarding the cause and exacerbation of headaches, and it is thought by some that  vasodilation  may contribute to symptoms. [ 4 ]  If a headache is brought on by caffeine withdrawal, the caffeine content of Excedrin may relieve it. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14211", "text": "Over the years, different forms of the drug have been introduced: [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14212", "text": "Excedrin is no longer sold in Canada. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14213", "text": "Previously, Excedrin Migraine and Excedrin Extra Strength sold in Canada had a different formulation compared to the United States. In Canada the product sold with those names contained 500 mg of acetaminophen and 65 mg of caffeine per tablet. The reason was that the  combination of acetaminophen with aspirin  creates the risk of  renal papillary necrosis  if large doses are taken chronically."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14214", "text": "In 2005, Bristol-Myers Squibb announced the sale of its North American consumer medicine business (including Excedrin,  Comtrex  and Keri brands) to  Novartis  for $660 million, in order to focus on drugs for the ten most profitable disease areas. [ 12 ]  As of March 2015,  GlaxoSmithKline  held majority ownership through a joint venture transaction with  Novartis . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14215", "text": "On January 9, 2012, Novartis announced that it was voluntarily recalling all lots of select bottle-packaging configurations of Excedrin products with expiration dates of December 20, 2014, or earlier as a precautionary measure because the products may contain stray tablets, capsules, or caplets from other Novartis products, or contain broken or chipped tablets. The recall was conducted with the knowledge of the U.S.  Food and Drug Administration . [ 13 ]  Wholesalers and retailers were instructed to stop distribution and return the affected product. Consumers in possession of recalled Excedrin were instructed to stop using the product and contact Novartis. Novartis stated that Excedrin would be shipping to stores on October 15, 2012, and that customers would start seeing it by the first of November. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14216", "text": "On January 21, 2020, GlaxoSmithKline announced that production and distribution of caplets and gel tabs of Excedrin Extra Strength and Excedrin Migraine would be stopped temporarily. Their statement said, \"Through routine quality control and assurance measures, we discovered inconsistencies in how we transfer and weigh ingredients\" for the recalled products, and that production would restart \"shortly\". [ 15 ] [ 16 ]  However, GSK acknowledged that they \"cannot confirm a definite date as to when supply will resume\". [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14217", "text": "On December 26, 2020,  the U.S. Consumer Product Safety Commission  announced the recall of 400,000 bottles of Excedrin due to the containers of the drug allegedly having holes in the bottom. The concern behind the recall was that the plastic bottles, if they had a hole, could allow children to access the painkiller caplets and lead to dangerous overdose or poisoning. [ 18 ]  The recall involved bottles containing 50, 80, 100, 152, 200, 250, or 300 caplets. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14218", "text": "Levolet  may refer to:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14219", "text": "The  Merck Group , branded and commonly known as  Merck , is a German  multinational  science and technology company headquartered in  Darmstadt , with about 60,000 employees and a presence in 66 countries. The group includes around 250 companies; the main company is Merck  KGaA  in Germany. The company is divided into three business lines: Healthcare, Life Sciences and Electronics. Merck was founded in 1668 and is the world's oldest operating chemical and pharmaceutical company, as well as one of the largest pharmaceutical companies globally. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14220", "text": "Merck operates in  Europe ,  Africa ,  Asia ,  Oceania  and the  Americas . It has major  research and development  centres in  Darmstadt ,  Boston ,  Tokyo  and  Beijing , as well as other Research and Development units in  Taiwan ,  France ,  Israel ,  South Korea ,  India , and the  UK . [ 8 ]  Merck pioneered the commercial manufacture of  morphine  in the 19th century and for a time held a virtual monopoly on  cocaine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14221", "text": "Merck was privately owned until going public on the  Frankfurt Stock Exchange  in 1995 and is listed on the  DAX  index of Germany's top companies. The  Merck family  still controls a majority of 70.3% of the company's shares. The Merck Group includes around 250 companies in 180 countries; the current main parent company of the group, since 1995, is named  Merck  KGaA , and is itself mainly owned by the former main parent company,  E. Merck  oHG , which now operates as a  holding company ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14222", "text": "The American pharmaceutical company  Merck & Co.  was established as a subsidiary of Merck in 1891, but was  nationalized  by the United States in 1917, before being privatized again when  George W. Merck , a member of an American branch of the Merck family, repurchased the stock in 1919. [ 9 ]  It is known as MSD ( Merck Sharp and Dohme ) outside of North America. The original Merck of Darmstadt holds the rights to the name Merck in all countries except the U.S. and Canada, where it is known as EMD ( Emanuel Merck, Darmstadt ), and the life science business specifically is known as MilliporeSigma. In 2015 Merck adopted a uniform brand identity for all its subsidiaries, and the company has stressed its intention to protect the brand of \"the real Merck\" globally and initiated litigation against its former subsidiary over use of the name. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14223", "text": "In 2018, the company celebrated their 350th anniversary. [ 11 ]  Merck has formed a strategic alliance with the  Technische Universit\u00e4t Darmstadt , which is located in the same town as Merck. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14224", "text": "The roots of Merck reach back as far as the 17th century in the  Landgraviate of Hesse-Darmstadt  (now a part of Germany). In 1668,  Friedrich Jacob Merck , an  apothecary , assumed ownership of the  Engel-Apotheke  ( lit. \u2009 ' Angel Pharmacy ' ) in  Darmstadt . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14225", "text": "In 1816,  Emanuel Merck , a descendant of the original founder, took over the pharmacy. Thanks to his scientific education he was successful in isolating and characterizing several different  alkaloids  in the  pharmacy 's laboratory, and by doing so also invented a number of drugs. He began the manufacture of these substances \"in bulk\" in 1827, touting them as a \"Cabinet of Pharmaceutical and Chemical Innovations\". He and his successors gradually built up a  chemical - pharmaceutical  factory that produced \u2014 in addition to raw materials for pharmaceutical preparations \u2014 a multitude of other chemicals and (from 1890) medicines. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14226", "text": "In 1891, Georg(e) Merck established himself in the United States and set up  Merck & Co.  with Theodore Weicker in New York. Merck & Co. was confiscated following the  First World War  and set up as an independent company in the United States. [ 14 ] [ 15 ]   Today, the US company, which operates as Merck Sharp and Dohme (MSD) outside the U.S. and Canada, has about 68,000 employees (December 2021) in 120 countries. It is one of the top 5 pharmaceutical companies worldwide, larger than its German ancestor, which employs 60,334 people in 67 countries (December 2021). While Merck in Darmstadt is the legal successor of the original Merck and retains the rights to the name \"Merck\" in all countries except the U.S. and Canada, it is sometimes known as the \"German Merck\" or \"Merck Darmstadt\" in North America. The company was formerly also referred to as \"E. Merck\" (Emanuel Merck). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14227", "text": "In the years of the  Nazi rule , the company was led by Karl Emanuel Merck who became a member of the  Nazi Party  in 1933 and subsequently received the title of  Wehrwirtschaftsf\u00fchrer . In addition, Merck was president of the Hessian Chamber of Commerce and Industry as well as performing an advisory function in the Expert Advisory Council for National Health (\"Sachverst\u00e4ndigenrat f\u00fcr  Volksgesundheit \") of the  Nazi Party . [ 16 ]  During World War II, Merck was manufacturing war essential products such as narcotics, vitamins,  biocides  and other chemicals. According to the company's account, 265  forced laborers  were working in the plant in Darmstadt, most of them women from Russia and Poland. [ 17 ]  Additionally, several hundred  Fremdarbeiter  (\"foreign workers\") from France and Belgium were employed throughout the war years. An air raid on 12 December 1944 destroyed nearly 70 percent of the plant and killed 55 employees. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14228", "text": "In 1973, Merck Ltd. acquired BDH Chemicals [ 19 ]  from the  Glaxo Group ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14229", "text": "In the early 1980s Merck Group built a visitor center at its Darmstadt headquarters that featured a pyramid. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14230", "text": "Merck was legally named  E. Merck  oHG  until 1995. In 1995 it was listed on the  Frankfurt Stock Exchange  and became a  KGaA , legally named  Merck KGaA . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14231", "text": "On 13 March 2006, Merck announced a takeover bid for  Schering AG , the world's largest producer of oral contraceptives. On 23 March 2006,  Bayer  AG made a supported offer for Schering and Merck decided to drop out of the bidding for the company. [ 20 ]  Schering is not to be confused with  Schering-Plough  which was once part of Schering AG but was acquired by Merck & Co. in 2009. In September 2006 the company announced a takeover bid of $13.2 billion for  Serono  SA, Switzerland's largest biotech firm. The deal included a buy-out of the  Bertarelli  family's 64.5% stake in Serono to be followed by a public tender offer for the remaining shares starting in November 2006. [ 21 ] [ 22 ]  The combined company has an R&D budget of approximately $1.1 billion and sales of approximately $4.6 billion. Its approximately $2 billion in sales of  biologics  would make it seventh among pharmaceutical/biotech companies. The new entity,  Merck Serono , began operations in 2007."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14232", "text": "Merck KGaA established its philanthropic foundation in 2008 called Merck Foundation.  Rasha Kelej  currently serves as its CEO. [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14233", "text": "In 2010, Merck took over  Billerica  (MA) based  Millipore Corporation  for EUR 5.3 billion (US$7.2 billion). [ 25 ] [ 26 ]  It is now Merck's life science business unit. With the acquisition of Millipore, Merck is consolidating its US holdings and shutting down the Gibbstown facility and warehouse. Gibbstown operations will be transferred to the new Philadelphia office and Millipore headquarters. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14234", "text": "Merck Korea received the \"Leading Investor Award\" at the 5th Korea-EU  Industrial Cooperation Day  in 2011. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14235", "text": "In December 2013, the company bought  AZ Electronic Materials  SA (AZEM) for about $2.6 billion in cash to increase its offering of specialty chemicals to the electronics industry. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14236", "text": "In September 2014 Merck halted the clinical development of two drug candidates in development with  Oxygen Biotherapeutics . One drug candidate suffered a lack of success in  patient recruitment , with its MUC1 antigen-specific cancer  immunotherapy  drug,  tecemotide  (L-BLP25), missing its Phase I/II endpoint of increasing overall survival in patients with Stage III  non-small cell lung cancer . [ 29 ]  Later in September it was announced that the company would acquire  Sigma-Aldrich  for $17 billion. [ 30 ]  After the acquisition was completed in 2015, Merck had around 50,000 employees. [ 31 ]  In November 2014, Merck and  Pfizer  agreed a deal for the latter to sell the former sharing rights to develop an experimental immunotherapy drug for a fee of $850 million. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14237", "text": "In October 2015, Merck revealed it would return the rights of the Kuvan drug to  BioMarin Pharmaceutical Inc.  The drug is effective in the treatment of the rare genetic disorder  PKU , however Merck is moving away from genetics into  cancer treatment ,  immunology  and  neurology . [ 33 ]  In October, it was announced that  Karl-Ludwig Kley , CEO of Merck since April 2007, would retire in April 2016, and be succeeded by  Stefan Oschmann , who has been a member of the executive board since 2011. [ 34 ]  The company started building new facilities for its R&D operations and a new visitor center at its Darmstadt site in the early 2010s. By 2015 the site's pyramid had been torn down as part of the renovations. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14238", "text": "In April 2017, the company announced it had completed the acquisition of food safety testing company,  BioControl Systems Inc. [ 36 ]  In August of the same year the company announced the acquisition of Natrix Separations for an undisclosed sum. [ 37 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14239", "text": "In April 2019, Merck announced it would acquire  Versum Materials . [ 38 ]  The acquisition was completed in October 2019 and represented an equity value of about U$5.8 billion. [ 39 ]  In the same year, Merck has also announced the acquisition of Intermolecular Inc, the California-based company for advanced materials. The acquisition was completed in September 2019 and represented an equity value of U$62 million. [ 40 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14240", "text": "In February 2020, Merck announced the divestment of its Allergopharma Business to Dermapharm, under an unspecified fee. The deal includes Merck's Portfolio in Europe and parts of Asia, including China and India. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14241", "text": "In January 2021,  MilliporeSigma  announced it would acquire AmpTec to expand and enhance the businesses mRNA vaccine capabilities as well as its treatment and diagnostics offerings. [ 42 ]  In March, its Performance Materials division changed name to Electronics division. [ 43 ]  In December of the same year, EMD Serono (Merck Group operations in the US and Canada) announced it would acquire Swiss-based  Chord Therapeutics  and its lead drug  cladribine , used in generalised  myasthenia gravis  and  neuromyelitis optica spectrum disorder . [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14242", "text": "In September 2017, Merck said it is considering options for its consumer-health division, including a potential full or partial sale, or strategic partnership. An  equity analyst  estimated the unit could command a purchase price of \u20ac1.8 billion to \u20ac2.7 billion from a full sale. [ 45 ]  In December  Reuters  reported that both  Nestl\u00e9  and private equity owners of  Stada [ 46 ]  were preparing bids for Merck's consumer health group. Days later, Reuters again reported that  Perrigo  was also preparing a bid for the division in the region of \u20ac4 billion ($4.7 billion to $4.8 billion). [ 47 ]  In April 2018, Reuters reported that generic drug manufacturer,  Mylan  was in advanced discussions to acquire the consumer health business for between  \u20ac3.5\u20134 billion (\u00a33\u20133.4 billion). [ 48 ]  Later in the month, Reuters reported that  Procter & Gamble  would purchase the division for \u20ac3.4 billion euros (\u00a32.96 billion; $4.2 billion). [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14243", "text": "Merck in Darmstadt is the sole legal successor of the original Merck and retains the rights to the trademark \"Merck\" in all countries except the U.S. and Canada, where \"EMD\" brand is mostly used (it was introduced alongside Merck's 2001 logo [ 50 ] ). In recent branding campaigns, the company has referred to itself as \"the original Merck\" and \"the real Merck\". The company was legally known as  E. Merck  oHG  until 1995, when  Merck  KGaA  became the main parent company and the former a  holding company . Both oHG and KGaA are generic business entity type designations and not used in everyday speech or branding. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14244", "text": "In 2015 Merck adopted a new logo to increase the visual differences between both companies, while also visualizing \"vibrant science and technology\" as the new company's brand. [ 51 ]  It has initiated litigation in several countries against its former subsidiary  Merck & Co.  (MSD) over infringing use of the Merck name. In 2016, the  High Court of Justice  in the United Kingdom ruled that MSD had breached an agreement with its former parent company and that only Merck of Darmstadt is entitled to use the Merck name in the United Kingdom; the judge also held that MSD's use of \"Merck\" as part of branding on its global websites were directed to the UK and infringed Merck's trade mark rights in the UK. [ 52 ]  In response, MSD has initiated counter-litigation in the United States. [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14245", "text": "After those controversies, Merck also adopted a new logo for EMD. The same look was also given to the logos of EMD Serono, MilliporeSigma, and EMD Performance Materials (renamed EMD Electronics in March 2021) divisions. Its corporate website is  merckgroup.com  in the world excluding U.S. and Canada, displaying normal Merck logo in the header, and  emdgroup.com  in U.S. and Canada, displaying use of its corporate name, Merck KGaA, Darmstadt, Germany, in the header and additionally displaying a disclaimer about trademark ownership in the footer. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14246", "text": "On 7 December 2021, Merck, which uses the name EMD Electronics in North America, announced they would be investing $1 billion in a U.S. operations joint venture with  Palantir Technologies  to assist in solving some of the chip industries supply chain problems. The plan is for sites in Pennsylvania, Texas, California, and Arizona. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14247", "text": "Generics UK (Merck's former British subsidiary, the global Generics business being sold on 2 October 2007) paid a \u00a312M  out-of-court settlement  with the  Department of Health and Social Care  of the UK over involvement in an alleged  price and supply fixing  cartel. [ 55 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14248", "text": "The  NHS  alleges various drugs companies exploited the  oligopolistic market  conditions, forcing the NHS to pay inflated prices. NHS fraud investigators believe there was a  conspiracy  to limit the supply of 30 of its most commonly prescribed drugs, including a class of  penicillin   antibiotics  and to a  generic  version of best-selling  ulcer  treatment  Zantac . [ 56 ]  The NHS has so far filed claims in relation to just three drugs, seeking damages of more than \u00a3150m, while the  Serious Fraud Office  (SFO) is conducting a parallel investigation into the price-fixing allegations limited to the supply of blood-thinning pill  warfarin  and  penicillin -based  antibiotics . Homes and offices of  executives  at six firms, including  Ranbaxy , Generics UK,  Norton Healthcare , Goldshield and Regent-GM were raided by the SFO in May 2002. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14249", "text": "The following is an illustration of the company's mergers, acquisitions,  spin-offs  and historical predecessors:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14250", "text": "After Wilhelm Adam Sert\u00fcrner's isolation of  morphine  from  opium  in 1805, Merck pioneered (from 1827) the commercial manufacture of morphine for an expanding global market. From 1884 onwards, Merck also played role in the production and marketing of  cocaine .  Sigmund Freud , author of  \u00dcber Coca  (1884), was an enthusiastic collaborator in Merck's cocaine research, though the methodological sophistication of his  self-experimentation  studies has been challenged.\nAttention was directed at  vitamins  as a new  product  category, and  Vigantol  was introduced in 1927, followed by Cebion in 1934. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14251", "text": "Following the defeat of Germany in  World War II , Merck was granted permission by the military government to produce drugs, pesticides, food preservatives, reagents, and fine chemicals for laboratory use. Soon afterward the boom that is commonly known as the \" Wirtschaftswunder \" (economic miracle) set in. For Merck, this meant two-digit sales-growth figures for many years. Products of this time included  corticoid  preparations \u2014 for example  Fortecortin , which is still used today \u2014 the cold remedy Nasivin or the hormone preparations Gestafortin and Mantova. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14252", "text": "Merck currently employs over 2,500 people in its 4 R&D hubs via.  Boston ,  Darmstadt , Beijing and Tokyo. [ 57 ] [ 58 ]  In the year 2018, Merck invested over \u20ac1,6 billion in its R&D operations. [ 59 ] \nThe focus of Merck's current pharmaceutical R&D is on  oncology , neurology and immunology. In oncology, its first marketed product is  Erbitux  ( cetuximab ), for which it has marketing rights worldwide, apart from North America. [ 60 ]  (Cetuximab was discovered by  Imclone Systems , and is marketed in North America by  Bristol-Myers Squibb .) Other areas of Expertise from Merck Healthcare include Fertility, Endocrinology and General Medicine, the later focusing on treatments for Diabetes, Thyroid disease and Cardiovascular diseases. Some products from Merck include  Metformin ,  Bisoprolol ,  Levothyroxine  and  Digitoxin . Merck's  clinical research  strategy consists of a partnership with  Quintiles  in which the latter helps the former in the clinical development of all its compounds. [ 61 ]  In February 2019, Merck also announced a partnership with GSK to develop and commercialize M7824 (bintrafusp alfa*), a new Immunotherapy with potential in various difficult-to-treat cancers. [ 62 ]  In 2020, Merck launched partnership with  Pechoin  in China to develop \"high-tech herbal\"  skincare products . [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14253", "text": "The life science business of Merck, formerly known as Merck Millipore, was created in July 2010 following the completed acquisition of the US company Millipore. It employs around 19,000 people in 66 countries and runs 65 manufacturing sites and uses the brands Sigma-Aldrich, Milli-Q and Millipore. [ 64 ]  This division comprises all Millipore activities and major segments of the former Merck division Performance & Life Science Chemicals.Merck Millipore had three business units: Bioscience, Lab Solutions and Process Solutions. The Bioscience business unit is dedicated to  solutions  and reagents for protein research and cell biology, cell culture  solutions , as well as to products and services for the development of biopharmaceutical agents. The scope of activities of Lab Solutions included laboratory chemicals and other materials for research, science and industry, products and services for sampling, and test kits for the pharmaceutical, foods and diagnostics industries, along with products, consumables and services surrounding highly purified laboratory water for science and industry. Process Solutions focused on products and services for the production of chemical and biopharmaceutical agents. In 2022 the business was restructured and consisted afterwards of the entities Life Science Services, Science & Lab Solutions, and Process Solutions. The Life Science Services include the Contract Development and Manufacturing Organization (CDMO) and contract testing services. Science & Lab Solutions includes products for Laboratories and Quality Control organizations. Process Solutions supports the biopharma manufacturing processes of its clients with single-use products. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14254", "text": "In 2015, Merck acquired  SigmaAldrich  and combined it with Merck Millipore. [ 66 ]  The company was branded Merck globally and MilliporeSigma in the United States and Canada [ 64 ]  The newly established life science business of Merck has 300,000 products and three business units: Research Solutions, Process Solutions and Applied Solutions. The company serves customers in biotech, pharma, diagnostics, food safety, academia, and environmental. Matthias Heinzel serves as the CEO of the life science business of Merck."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14255", "text": "The Life Science business sponsors several award programs for graduate students. One of these awards, the Alfred R. Bader Award for Student Innovation recognizes advanced chemistry graduate students, typically in the field of synthetic organic chemistry. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14256", "text": "Semiconductor Solutions is the largest business unit within Merck's Electronics business sector. It provides materials, delivery systems, and services for the semiconductor industry. The business unit supplies products for every major production step in the wafer processing, including doping, lithography, patterning, deposition, planarization, etching, and cleaning. After the acquisition of Intermolecular, its capabilities allow material combinations to be tested directly in the specific application environment accelerating learning cycles. Since the acquisition of Versum and Intermolecular, inc., the company's portfolio in electronic materials was significantly expanded. The launch of the integrated organization was done on 1 June 2020. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14257", "text": "Merck started working on effect pigments in 1957. The business unit is called Surface Solutions. The core markets for Surface Solutions are automotive coatings, cosmetics, and, to a smaller extent, industrials. An example of its pigments is alumina effect pigments sold under the brand name  Xirallic . Currently, this business unit pools all activities for pigments in lacquering, printing, and plastic applications, in the field of security technology (for instance counterfeiting protection), pigments for applications in the food and pharmaceutical areas, functional materials, and active substances and pigments for cosmetics. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14258", "text": "M Ventures  is a  venture capital  fund of Merck. In 2021, the funds available for investment were increased by Eur 600M to enable investments Biotechnology and Technology. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14259", "text": "The award was jointly established by Merck and the  Technische Universit\u00e4t Darmstadt  in 1992. It recognizes scientists who have made contributions to chemical and pharmaceutical research. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14260", "text": "During the company's 350th anniversary in 2018, Merck announced the Future Insight Prize The prize consists of a research grant of \u20ac1,000,000 ($1.1 million) every year through the next 35 years, to motivate innovation in areas that could solve humanity's most pressing issues. [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14261", "text": "Nurofen  is a  brand  of range of pain-relief medication containing  ibuprofen  made by the  English - Dutch  company  Reckitt Benckiser . [ 1 ]   Introduced in 1983, the Nurofen brand was acquired following Reckitt Benckiser's acquisition of  Boots healthcare international  in 2005 for \u00a31.93 billion, which included Nurofen,  Strepsils , and  Clearasil . [ 2 ]   The brand is primarily marketed and sold in the  United Kingdom , [ 1 ]  other parts of  Europe ,  South Africa ,  Australia  and  New Zealand .  In 2016, it was the biggest selling branded over-the-counter medication sold in Great Britain, with sales of \u00a3116.8 million. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14262", "text": "There are 11 variants of Nurofen, all of which contain ibuprofen as an active ingredient. [ 4 ]   The ibuprofen is variously formulated as the  free acid , or the  lysine   salt .  For oral formulations, i.e., taken by mouth, it is available in the conventional solid round tablet, a torpedo-shaped solid caplet, or may alternatively be in the form of a soft gel cap.  It is also available as a  topical gel , which is applied directly to the surface of the skin. [ 5 ]   In some cases these are marketed as being useful for treating specific types of pain; such as  back pain  or  period pain . The primary difference among the various formulations is speed and duration of ibuprofen absorption.  According to the UK  Medicines and Healthcare products Regulatory Agency  (UK MHRA), the form of ibuprofen in 'Nurofen Tension Headache' ( ibuprofen lysine ) is absorbed nearly twice as fast as the form in 'Nurofen Period Pain' (ibuprofen free acid), with the former reaching peak blood concentrations in 38\u00a0minutes, compared to 80\u00a0minutes for the latter. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14263", "text": "Some variants of Nurofen contain additional active ingredients; for example, 'Nurofen Cold & Flu' contains the non- sedating   decongestant   pseudoephedrine .  Others are advertised as being targeted for specific pain types, for example  period pain . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14264", "text": "Nurofen Plus is a pain relief medication based on  codeine  and  ibuprofen . [ 7 ]  It contains 12.8\u00a0 mg  of  codeine phosphate  (a mild  opioid analgesic ) and 200\u00a0mg of ibuprofen, [ 7 ]  which is an  NSAID . Nurofen Plus is the only product in the Nurofen range that contains codeine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14265", "text": "The original Nurofen Plus tablet was manufactured in two equal parts, joined, and then coated.  One part contained 12.8\u00a0mg of codeine phosphate, and the other part contained 200\u00a0mg of ibuprofen. The tablets could be forcefully split into their two constituent active ingredients, thus isolating the codeine for recreational use. Such drugs have a potential for misuse because they are available freely to the public. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14266", "text": "On 25 August 2011, it was reported that several packs of Nurofen Plus were found to contain  Seroquel XR  \u2014 an  anti-psychotic  drug used to treat  schizophrenia  \u2014 in  Boots  stores across London. [ 9 ] [ 10 ] [ 11 ]   The next day, a safety alert was issued by the  Medicines and Healthcare products Regulatory Agency  (MHRA). Pharmacists were told to check each package of Nurofen Plus to look for anti-psychotic drugs. Three batches of Nurofen Plus were affected by the alert. Reckitt Benckiser, manufacturer of Nurofen Plus, said that it did not know where the drugs had been switched. The product was re-released in October in cellophane-sealed packs. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14267", "text": "In 2010, the Australian consumer advocate  Choice  awarded Nurofen a \"Shonky award\" for charging more for \"targeted\" products, all of which had the same active ingredient as the base product. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14268", "text": "In 2012, the Australian  Therapeutic Goods Administration  upheld a complaint that Nurofen's advertising of different products for different pain was \"misleading or likely to be misleading\", and ordered that \"any representation that refers to two or more Nurofen products that contain equivalent quantities of ibuprofen and include the same product specific indications on the Australian Register of Therapeutic Goods must clearly indicate, in the body of the advertisement, that the two products can be used for the same purposes and are interchangeable (or words to that effect)\". [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14269", "text": "In April 2013, the Australian consumer affairs television programme  The Checkout  ran a story about Nurofen's claims about targeting specific pain.  Edelman , the PR company for Reckitt Benckiser provided a statement, some of which was used in the programme. Included in the information provided by Edelman were photocopies of some 'sciencey looking documents' that confirmed that Ibuprofen was 'Non-selective'. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14270", "text": "In March 2015, the  Australian Competition & Consumer Commission  (ACCC) launched proceedings against Reckitt Benckiser; for misleading advertising for its targeted pain range. In December 2015, the  Federal Court of Australia  found that Reckitt Benckiser, which makes Nurofen, had misled consumers with its \"Nurofen Specific pain range\", and ordered that all Nurofen specific pain products be removed from retail sale within three months. [ 15 ]   A spokeswoman for Reckitt Benckiser argued that, \"[This] specific-pain range\" was intended \"to help consumers navigate their pain relief options, particularly within the grocery environment where there is no healthcare professional to assist decision making\". [ 16 ]   The ACCC said that the products were found to be \"no more effective at treating the type of pain described on its packaging than any of the other Nurofen specific pain products\", and sold for almost twice the price. [ 17 ]   Specific pain range painkillers include Nurofen Back Pain, Nurofen Period Pain, Nurofen Migraine Pain and Nurofen Tension; and all contain the \"same active ingredient, 342\u00a0milligrams of ibuprofen lysine\". [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14271", "text": "In April 2016, the Federal Court imposed a $1.7 million fine on Reckitt Benckiser. [ 18 ]  The ACCC appealed the decision in May arguing that $1.7 million in penalties did not act as an adequate deterrent for a company the size of Reckitt Benckiser. [ 19 ]  In December 2016, the Federal Court increased the fine to $6 million, the highest corporate penalty ever awarded for misleading conduct under the  Australian Consumer Law . [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14272", "text": "Following the 2015 Australian decision, the UK  Advertising Standards Authority  (ASA) said that it was investigating earlier complaints about a television advertisement for Nurofen Express, which was alleged to be misleading, as it implied that the medicine targeted muscles in the head. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14273", "text": "Tiger Balm  ( Chinese :  \u864e \u6a19 \u842c \u91d1 \u6cb9 ;  pinyin :  H\u01d4biao W\u00e0nj\u012bny\u00f3u ;  Pe\u030dh-\u014de-j\u012b :  H\u00f3\u0358-phiau B\u0101n-kim-i\u00fb ) is an  analgesic   heat rub  manufactured and distributed by  Singaporean  company  Haw Par Healthcare . It is used for external pain relief."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14274", "text": "A precursor to Tiger Balm called Ban Kin Yu ( Chinese :  \u842c\u91d1\u6cb9 ;  lit.  'Ten Thousand Golden Oil') was developed in the 1870s in  Rangoon ,  Burma , during the  British colonial era  by the practising Chinese herbalist  Aw Chu Kin , [ 1 ]  son of Aw Leng Fan, a Chinese  Hakka  herbalist in  Zhongchuan ,  Fujian Province ,  China . [ 2 ]  His father had sent him to Rangoon in the 1860s to help in his uncle's herbal shop. Eventually, Aw Chu Kin himself set up a family business named Eng Aun Tong \u6c38\u5b89\u5802 (\"Hall of Everlasting Peace\"). On his deathbed in 1908, he asked his sons  Aw Boon Haw  and  Aw Boon Par  to perfect the product. In 1918, the product was renamed \"Tiger Balm\" in order to gain broader appeal. [ 2 ]  By 1918, the Aw family had become one of the wealthiest families in Rangoon. [ 3 ]  By the 1920s, the brothers had turned Eng Aun Tong into a very successful business empire that produced and marketed pharmaceutical products, including the Tiger Balm medicinal ointment. [ 4 ]  Tiger Balm sold well in Burma, and was exported to China, Japan, and Southeast Asia. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14275", "text": "The brothers moved to Singapore in the 1920s due to problems with the  colonial British government . [ 5 ]  They set up a branch first at  Amoy Street , then moved to Cecil Street and finally to  89 Neil Road  between 1924 and 1926, at the junction of Neil and Craig Road. The Aw family founded the  Tiger Balm Gardens  in Hong Kong in 1935, Singapore in 1937 and Fujian Province in 1946 [ 6 ]  to promote the product. Boon Haw also established newspapers in China and Singapore; his daughter said that he spent so much money on advertising that \"he thought it would be cheaper to just open a few newspapers\". [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14276", "text": "In 2013, a lawsuit filed by Haw Par against the Indian company  Rangoon Chemical Works , asserting that the latter's \"Flying Tiger\" balm with similar branding infringed on the Tiger Balm trademark, reached the  Supreme Court of India . [ 8 ]  As a result, Rangoon Chemical Works made changes in the branding of its product and redesigned packaging. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14277", "text": "In 2018, there were 10 products being sold under the Tiger Balm brand, [ 10 ]  in over 100 countries. [ 11 ]  Tiger Balm generated  S$ 152 million ( US$ 110.56 million) in revenues in 2015. [ 12 ]  Haw Par's revenues from Tiger Balm sales in India were  \u20b9 85 crore  (US$12.43 million) in 2018. [ 13 ]  The product sold in India is manufactured in  Hyderabad  by Makson [ 14 ]  and marketed by  Alkem Laboratories . [ 15 ]  Between 1993 and 2011, it had been manufactured and marketed by  Elder Pharmaceuticals . [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14278", "text": "The remainder is a  petroleum jelly  and  paraffin  base.  The packaging label states that the active ingredients are menthol and camphor."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14279", "text": "The Camphor concentration varies by country of sale; as of Nov 2023 Tiger Balm Red and Tiger Balm White both contain 25% Camphor in Singapore and Cambodia, but only 11% in Australia as an example.  This is likely due to different regulatory requirements. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14280", "text": "A new product named  Tiger Balm White HR  uses eucalyptus oil instead of cajuput oil. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14281", "text": "Venalex  is a micronized purified  flavenoid  fraction (MPFF). It is a  vegan ,  gluten-free  nutritional supplement. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14282", "text": "Venalex is used to treat chronic functional or structural  venous insufficiency  of the lower limbs. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14283", "text": "No results of clinical trials have been published. [ citation needed ]  Venalex is not currently approved by the FDA. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14284", "text": "Venalex is made with a 9-1 ratio of  diosmin  and  hesperidin . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14285", "text": "Hydroxypropol methylcellulose ,  magnesium stearate ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14286", "text": "Zam-Buk  is a  patent medicine  which was produced by the Zam-Buk Company of  Leeds , England, founded by Charles Edward Fulford. It was first sold by his  Bile Beans  company in 1902, [ 1 ]  as a herbal balm and antiseptic ointment; the use of a complementary Zam-Buk soap was recommended to augment the treatment. The ointment was advertised as being effective against a wide range of conditions, including cuts, bruises, sprains, ulcers, bleeding  piles  and even colds and toothache. It could also be used as an  embrocation  by rubbing it into the muscles of the back, legs or feet. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14287", "text": "The source of the name is uncertain, but a link to South Africa has been suggested.  It remains very widely popular in South Africa. [ 3 ]  The brand name was at one time used to refer to ambulance-men and first aiders at rugby league matches in Australia and New Zealand. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14288", "text": "The product is still manufactured today, often by  Bayer , who now owns the trade mark [ 5 ]  in some, but not all, countries. It is available in Southern Africa, Malaysia, Indonesia and Thailand."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14289", "text": "In the early 20th century, it was reported that the formulation comprised 66%  paraffin wax , 20% pale resin ( colophony ), and 14%  eucalyptus oil , with small amounts of other ingredients. [ 2 ]  More recently, the composition eucalyptus oil, 1.8%  camphor , 0.5%  thyme oil , and 0.65%  sassafras oil . The English and Thai varieties do not contain sassafras oil. [ 6 ]  A 1908 report published in  The British Medical Journal  estimated that the cost of ingredients for a standard 0.6-ounce (17\u00a0g) box was one  farthing , yet its retail price was 1 s  1\u00bd  d . [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14290", "text": "Widely used in earlier times as an all-round antiseptic and healing ointment, particularly with rugby players worldwide. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14291", "text": "When  Radio Luxembourg  started  longwave   commercial radio  broadcasts in English in 1933, its first advertisers were Fulford's Zam-Buk and  Bile Beans . [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14292", "text": "The Zam-Buk brand and trademark were eventually acquired by  Fisons , but production ceased in 1994 after the business was sold to  Rhone-Poulenc ; the product was revived in the United Kingdom by Rose & Co. in 1996. [ 9 ]  After the original trademarks expired, Rose & Co successfully resisted a new application by a third party to register Zam-Buk as a trademark in 2008. [ 10 ]  As of 2015, the trademark for Zam-Buk is registered to  Bayer Consumer Care AG  in Australia, Canada and the United States. [ 11 ] [ 12 ] [ 13 ] . Zam Buk is manufactured for Bayer in Thailand by Interthai Pharmaceutical Manufacturing and is distributed in Malaysia, Thailand, Singapore, Indonesia and South Africa."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14293", "text": "In Leeds, the tin boxes used for Zam-buk were printed in Hunslet by Charles Lightowler, at their Hunslet Printing Sheds on Jack Lane.  They also printed the Peps and Bile Beans tins, which were delivered by horse and cart to the Fulford's factory on Carlton Hill, off Woodhouse Lane. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14294", "text": "The  Bencao gangmu , known in English as the  Compendium of Materia Medica  or  Great Pharmacopoeia , [ 1 ]  is an encyclopedic gathering of medicine, natural history, and  Chinese herbology  compiled and edited by  Li Shizhen  and published in the late 16th century, during the  Ming dynasty . Its first draft was completed in 1578 and printed in  Nanjing  in 1596. The  Compendium  lists the  materia medica  of  traditional Chinese medicine  known at the time, including plants, animals, and minerals that were believed to have medicinal properties."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14295", "text": "Li compiled his entries not only from hundreds of earlier works in the  bencao  medical tradition, but from literary and historical texts. He reasoned that a poem might have better value than a medical work and that a  tale of the strange  could illustrate a drug's effects. [ 2 ]  The Ming dynasty emperors did not pay too much attention to his work, and it was ignored. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14296", "text": "Li's work contained errors and mistakes due to his limited scientific knowledge at the time. For example, Li claimed that all otters were male [ 4 ]  and that  quicksilver  (mercury) was not toxic. [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14297", "text": "The title, translated as \" Materia Medica , Arranged according to Drug Descriptions and Technical Aspects\", [ 7 ]  uses two  Chinese   compound words .  Bencao  ( Pen-ts'ao ; \"roots and herbs; based on herbs, pharmacopeia,  materia medica \") combines  ben  ( \u672c  'origin, basis') and  cao  ( \u8349  'grass, plant, herb').  Gangmu  ( Kang-mu ; 'detailed outline; table of contents') combines  gang  ( kang ;  \u7db1  'main rope, hawser; main threads, essential principles') and  mu  ( \u76ee  'eye, look; category, division')."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14298", "text": "The characters  \u7db1  and  \u76ee  were later used as ' class ' and ' order ', respectively, in  biological classification ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14299", "text": "Li Shizhen  travelled widely for field study, combed through more than 800 works of literature, and compiled material from the copious historical  bencao  literature. He modelled his work on a  Song dynasty  compilation, especially its use of non-medical texts. He worked for more than three decades, with the help of his son, Li Jianyuan, who drew the illustrations. He finished a draft of the text in 1578, the printer began to carve the blocks in 1593, but it was not published until 1596, three years after Li died. Li Jianyuan presented a copy to the  Ming dynasty  emperor, who saw it but did not pay much attention. Further editions were then published in 1603, 1606, 1640, and then in many editions, with increasing numbers of illustrations, down to the 21st century. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14300", "text": "The text consists of 1,892 entries, each entry with its own name called a  gang . The  mu  in the title refers to the synonyms of each name. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14301", "text": "The  Compendium  has 53 volumes in total:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14302", "text": "The text is written in almost 2 million  Chinese characters , classified into 16 divisions and 60 orders.  For every herb there are entries on their names, a detailed description of their appearance and odor, nature, medical function, side effects, recipes, etc."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14303", "text": "The text contains information that was proven to be wrong due to Li's limited scientific and technical knowledge. For example, it is claimed that  quicksilver  (mercury) and  lead  were not  toxic . [ 5 ]  Li also claimed that  otters  are always male [ 4 ]  and that the Moupin  langur  is ten-foot (three-metre) tall, has backwards feet and can be caught when it draws its upper lip over its eyes. [ 4 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14304", "text": "The British historian  Joseph Needham  writes about the Compendium in his  Science and Civilisation in China . [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14305", "text": "The text provided classification of how traditional medicine was compiled and formatted, as well as biology classification of both plants and animals."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14306", "text": "The text corrected some mistakes in the knowledge of herbs and diseases at the time. Several new herbs and more details from experiments were also included. It also has notes and records on general medical data and medical history."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14307", "text": "The text includes information on pharmaceutics,  biology ,  chemistry ,  geography ,  mineralogy ,  geology ,  history , and even  mining  and  astronomy ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14308", "text": "The  Biopharmaceutics Classification System  ( BCS ) is a system to differentiate drugs on the basis of their solubility and permeability. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14309", "text": "This system restricts the prediction using the parameters  solubility  and  intestinal permeability . The solubility classification is based on a  United States Pharmacopoeia  (USP) aperture. The intestinal permeability classification is based on a comparison to the  intravenous injection . All those factors are highly important because 85% of the most sold drugs in the  United States  and  Europe  are  orally administered . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14310", "text": "According to the Biopharmaceutics Classification System (BCS) drug substances are classified to four classes upon their solubility and permeability: [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14311", "text": "The drugs are classified in BCS on the basis of solubility and permeability."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14312", "text": "Solubility class boundaries are based on the highest dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 to 6.8. The volume estimate of 250 ml is derived from typical  bioequivalence  study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14313", "text": "Permeability class boundaries are based indirectly on the extent of absorption of a drug substance in humans and directly on the measurement of rates of mass transfer across human intestinal membrane. Alternatively non-human systems capable of predicting drug absorption in humans can be used (such as in-vitro culture methods).  A drug substance is considered highly permeable when the extent of absorption in humans is determined to be 85% or more of the administered dose based on a mass-balance determination or in comparison to an  intravenous  dose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14314", "text": "The  Brazilian Nonproprietary Name  or  DCB , from the Portuguese  Denomina\u00e7\u00e3o Comum Brasileira  is the official Portuguese nomenclature for  drugs  or  active ingredients  that have been approved by the  Brazilian Health Regulatory Agency (ANVISA)  for use in  Brazil . [ 1 ] [ 2 ]  The consolidated list from October 2021 contains just over 12,300 items. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14315", "text": "Every record has a numerical  identifier  known as the  DCB Number , used in contexts such as registrations, tenders and official documentation. [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14316", "text": "In 1970 Andrejus Korolkovas, from the Faculty of Pharmaceutical Sciences,  University of S\u00e3o Paulo , was already publishing about the importance of a nomenclature to harmonize the names of drugs. [ 6 ]  In the year 1981, a list of generic names that would be mandatory for a new registration of a medicine was published in the Official Gazette of the Union, by the Ministry of Health. A standardization of nomenclature was carried out, and the introduction of numerical codes that would allow the identification of the substances. In 1983 the use of the standard nomenclature in official documents was made mandatory. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14317", "text": "The  Classification of Pharmaco-Therapeutic Referrals  ( CPR ) is a  taxonomy  focused on defining and grouping together situations requiring a  referral  from  pharmacists  to  physicians  (and vice versa) regarding the  pharmacotherapy  used by the  patients . It has been published in 2008. It is bilingual: English/Spanish ( Clasificaci\u00f3n de Derivaciones F\u00e1rmaco-terap\u00e9uticas ). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14318", "text": "It is a simple and efficient classification of pharmaco-therapeutic referrals between physicians and pharmacists permitting a common inter-professional language. [ 2 ]  It is adapted to any type of referrals among health professionals, and to increase its specificity it can be combined with  ATC codes ,  ICD-10 , and  ICPC-2 PLUS . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14319", "text": "It is a part of the  MEDAFAR Project , whose objective is to improve, through different scientific activities, the coordination processes between physicians and pharmacists working in  primary health care . [ 3 ] [ 4 ] [ 5 ] [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14320", "text": "It is structured in 4 chapters (E, I, N, S) and 38 rubrics. The terminology used follows the rules of ICPC-2. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14321", "text": "Each rubric consists in an alphanumeric code (the letter corresponds to the chapters and the number to the component) and each title of the rubric (the assigned name) is expressed and explained by:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14322", "text": "\u2013 A series of terms  related with  the title of the rubric."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14323", "text": "\u2013 A  definition  expressing the meaning of the rubric."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14324", "text": "\u2013 A list of  inclusion criteria  and another list with  exclusion criteria  to select and qualify the contents corresponding to a rubric."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14325", "text": "\u2013 Some  example  to illustrate every term."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14326", "text": "It also includes a glossary of 51 terms defined by consensus, an alphabetical index with 350 words used in the rubrics; and a standardized model of inter-professional referral form, to facilitate referrals from community pharmacists to primary care physicians."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14327", "text": "The  Coding Symbols for a Thesaurus of Adverse Reaction Terms  ( COSTART ) was developed by the  United States   Food and Drug Administration  (FDA) for the coding, filing and retrieving of post-marketing  adverse reaction  reports. [ 1 ]  COSTART provides a method to deal with the variation in vocabulary used by those who submit adverse event reports to the FDA. Use of this dictionary allowed for standardization of adverse reaction reporting towards the FDA in a consistent way."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14328", "text": "COSTART was last updated in 1999. It has been replaced by the Medical Dictionary for Regulatory Activities,  MedDRA . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14329", "text": "The  national drug code  ( NDC ) is a unique product identifier used in the  United States  for drugs intended for  human  use. The Drug Listing Act of 1972 [ 1 ] [ 2 ]  requires registered drug establishments to provide the  Food and Drug Administration  (FDA) with a current list of all drugs manufactured, prepared, propagated, compounded, or processed by it for commercial distribution. Drug products are identified and reported using the NDC."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14330", "text": "There are several alternative drug classification systems in addition to NDC that are also commonly used when analyzing drug data, such as  Generic Product Identifier (GPI) ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14331", "text": "The national drug code is a unique 10 or 11 digit, 3-segment numeric identifier assigned to each  medication  listed under Section 510 of the US Federal  Food, Drug, and Cosmetic Act . The segments identify the labeler or  vendor , product (within the scope of the labeler), and trade  package  (of this product)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14332", "text": "While the labeler code is assigned by the FDA, both the product and package segments are assigned by the labeler. [ 5 ]  While in the past labelers may have had the opportunity to reassign old product codes no longer used to new products, according to the new FDA validation procedures, once an NDC code is assigned to one product (defined by key properties including active ingredients, strength, and dosage form) it may not be later reassigned to a different product."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14333", "text": "NDC codes exist in one of the following groupings of digits into segments: 4-4-2, 5-3-2, 5-4-1, 6-3-2, or 6-4-1. [ 5 ] [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14334", "text": "The following NDC structure rules apply depending on the length of certain segments.  These rules include the 11 digit format.  Unless stated otherwise, search for drug codes using the 10 digit format."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14335", "text": "The official FDA format for NDCs separates the 3 segments with dashes. This is the format in which the NDC must be submitted by labelers since mandatory electronic listing was established in June 2009. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14336", "text": "While the NDC is a 10-digit identifier, confusion exists because of a proliferation of different notations and variants."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14337", "text": "The previous NDC directory, populated by a paper-based listing system, sometimes inserted an  asterisk  in either a product code or a package code in addition to the dashes. This format is easily transformed to the official format in effect today by deleting the asterisk (if any)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14338", "text": "Each NDC-coded product package in the US bears a  barcode  with a  Universal Product Code  that begins with a 3 ( UPC-A ) or 03 ( EAN-13 ). [ 7 ]  The remainder of the numbers can be the 10 NDC digits, plus the  check digit , but this is not required. If the NDC is used in the UPC it is the most minimal form of the NDC code with 10 digits only. Because the NDC code has been linked with product barcodes in this way, the NDC code could contain ambiguities in this form. For example, 1234-5678-90, 12345-678-90, and 12345-6789-0 could all be entirely different products with the same barcode 1234567890. To prevent any actual ambiguity from impacting the marketplace, ambiguity checks are part of the new electronic listing process."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14339", "text": "The pure 10-digit NDC format cannot be transformed back into the standard format with dashes without the help of the product listing database."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14340", "text": "The  Centers for Medicare and Medicaid Services  (CMS) had created an 11-digit NDC derivative, which pads the labeler, product, or package code segments of the NDC with leading zeroes wherever they are needed to result in a fixed length 5-4-2 configuration (but always written without dashes). [ 8 ]  This format was adopted by data standards selected pursuant to  HIPAA  regulation, thus other government agencies' lists and databases (such as the  UMLS ) may contain the 11-digit derivative of the original NDC."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14341", "text": "The 11-digit NDC format cannot be transformed back into the 10-digit standard format without the help of a product listing database."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14342", "text": "In some applications, the fully expanded 5+4 digit labeler+product code is used as a 9-digit number to identify a product regardless of packaging.  Thus an 11-digit NDC can be transformed into a 9-digit NDC product code by removing the last two digits.  This does not work reliably for 10-digit NDCs where the packaging code might be one digit and not two."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14343", "text": "In 2022, the FDA proposed revising the NDC regulations to require use of a uniform 12-digit NDC with the same three functional segments but with uniform segment lengths of 6, 4, and 2 digits. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14344", "text": "The  National Pharmaceutical Product Index  or  NAPPI  is a comprehensive database of  pharmaceutical codes  for  medical products classification  used in  South Africa . Each product has a unique  NAPPI code  which enables  electronic data interchange  throughout the health care delivery chain."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14345", "text": "NAPPI is governed by the NAPPI Advisory Board (NAB), a non-profit organisation representing hospitals, medical schemes, medical scheme administrators, and medical and dental associations. MediKredit is responsible for the management and maintenance of the NAPPI Product File."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14346", "text": "This South Africa-related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14347", "text": "This  database -related article is a  stub . You can help Wikipedia by  expanding it ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14348", "text": "The  pregnancy category  of a medication is an assessment of the risk of  fetal  injury due to the pharmaceutical, if it is used as directed by the mother during  pregnancy . It does  not  include any  risks conferred by pharmaceutical agents or their metabolites in breast milk ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14349", "text": "Every drug has specific information listed in its product literature. The  British National Formulary  used to provide a table of drugs to be avoided or used with caution in pregnancy, and did so using a limited number of key phrases, but now Appendix 4 (which was the Pregnancy table) has been removed. Appendix 4 is now titled \"Intravenous Additives\". [ 1 ]  However, information that was previously available in the former Appendix 4 (pregnancy) and Appendix 5 (breastfeeding) is now available in the individual drug monographs. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14350", "text": "American law requires that certain drugs and biological products must be labelled very specifically.  Title 21, Part 201.57 (9)(i)  of the  Code of Federal Regulations  lists specific requirements regarding the labeling of drugs with respect to their effects on pregnant populations, including a definition of a \"pregnancy category\". These rules are enforced by the  Food and Drug Administration ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14351", "text": "To supplement this information, the  FDA  publishes additional rules regarding pregnancy and lactation labeling. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14352", "text": "The FDA does not regulate labeling for all hazardous and non-hazardous substances. Many substances, including  alcohol , are widely known to cause serious hazards to pregnant women and their fetuses, including  fetal alcohol syndrome . Many other  pollutants  and  hazardous materials  are similarly known to cause reproductive harm. However, some of these substances are not subject to drug labeling laws, and are therefore not assigned a \"Pregnancy Category\" per 21 CFR 201.57."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14353", "text": "One characteristic of the FDA definitions of the pregnancy categories is that the FDA requires a relatively large amount of high-quality data on a pharmaceutical for it to be defined as Pregnancy Category A. As a result of this, many drugs that would be labelled as safe in other countries are allocated to Category C by the FDA."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14354", "text": "On December 13, 2014, the FDA published the Pregnancy and Lactation Labeling Final Rule (PLLR), which changed the labeling requirements for the pregnancy and lactation sections for prescription drugs and biological agents. [ 3 ]  The final rule removed the pregnancy letter categories, and created descriptive subsections for pregnancy exposure and risk, lactation, and effects to reproductive potential for females and males.   Labeling changes from this rule began on June 30, 2015, with all submissions for prescription drugs and biological agents using the labeling changes immediately. Previously approved drugs from June 30, 2001, will switch to the new labeling gradually. The rule does not affect the labeling of over-the-counter drugs or of drugs approved prior to June 30, 2001."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14355", "text": "Australia  has a slightly different pregnancy category system from the United States. The categorisation of medicines for use in pregnancy does not follow a hierarchical structure. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14356", "text": "The system, as outlined below, was developed by medical and scientific experts based on available evidence of risks associated with taking particular medicines while pregnant. Being general in nature, it is not presented as medical advice to health professionals or the public. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14357", "text": "Some prescribing guides, such as the  Australian Medicines Handbook , are shifting away from using pregnancy categories since, inherent in these categories, there is an implied assumption that the alphabetical code is one of safety when this is not always the case. Categorisation does not indicate which stages of fetal development might be affected and does not convey information about the balance between risks and benefits in a particular situation. Additionally, categories are not necessarily maintained or updated with availability of new data. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14358", "text": "The data presented is for comparative and illustrative purposes only, and may have been superseded by updated data."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14359", "text": "The  Unique Ingredient Identifier  ( UNII ) is an alphanumeric identifier linked to a substance's  molecular structure  or descriptive information and is generated by the  Global Substance Registration System  (GSRS) of the  Food and Drug Administration  (FDA). It classifies substances as  chemical ,  protein ,  nucleic acid ,  polymer ,  structurally diverse , or  mixture [ 1 ] [ 2 ]  according to the standards outlined by the  International Organization for Standardization  in ISO 11238 [ 3 ]  and ISO DTS 19844. [ 4 ]  UNIIs are non-proprietary, unique, unambiguous, and free to generate and use. [ 2 ]  A UNII can be generated for substances at any level of complexity, being broad enough to include \"any substance, from an atom to an organism.\" [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14360", "text": "The GSRS is used to generate permanent, unique identifiers for substances in regulated products, such as ingredients in drug and biological products. The GSRS uses molecular structure, protein and nucleic sequences and descriptive information to generate the UNII. The preferred means for defining a chemical substance is by its two-dimensional molecular structure since it is pertinent to a substance's identity and information regarding a substance's  stereochemistry  is readily available. [ 5 ]  Nucleic acids are defined by their sequences and by any modifications that may be present. In the case of proteins only end-group modifications will be uniquely identified, along with any other modifications that are essential for activity. This is because of the inherently heterogenous nature of proteins. Therefore, two different protein substances can share the same UNII and yet have no biosimilarity or therapeutic equivalence. [ 5 ]  Polymers are defined by their structural repeating units and  physical properties  such as  molecular weight  or properties related to molecular weight (e.g.  viscosity ). Structurally diverse materials are inherently heterogenous preparations from natural materials such as  plant   extract  and  vaccines. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14361", "text": "The GSRS is a freely distributable software system provided through a collaboration between the FDA, the  National Center for Advancing Translational Sciences  (NCATS) and the  European Medicines Agency  (EMA). [ 1 ]  The GSRS was developed to implement the ISO 11238 standard which is one of the core ISO  Identification of Medicinal Product  (IDMP) standards. The GSRS Board which governs the GSRS includes experts from FDA, European Regulatory Agencies, and the  United States Pharmacopoeia  (USP). [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14362", "text": "A  United States Adopted Name  ( USAN ) is a unique nonproprietary name assigned to a  medication  marketed in the  United States .  Each name is assigned by the USAN Council, which is co-sponsored by the  American Medical Association  (AMA), the  United States Pharmacopeial Convention  (USP), and the  American Pharmacists Association  (APhA)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14363", "text": "The USAN Program states that its goal is to select simple, informative, and unique nonproprietary names (also called generic names) for drugs by establishing logical nomenclature classifications based on pharmacological or chemical relationships. [ 1 ]   In addition to drugs, the USAN Council names agents for  gene therapy  and cell therapy,  contact lens polymers , surgical materials, diagnostics, carriers, and substances used as an  excipient .  The USAN Council works in conjunction with the  World Health Organization  (WHO)  international nonproprietary name  (INN) Expert Committee and national nomenclature groups to standardize  drug nomenclature  and establish rules governing the classification of new substances. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14364", "text": "The USAN Council began in June 1961 after the AMA and the USP jointly formed the AMA-USP Nomenclature Committee. [ 3 ]   The American Pharmacists Association (APhA) became the third sponsoring organization in 1964, at which point the name of the committee was changed to the USAN Council, and United States Adopted Name became the official term to describe any nonproprietary name negotiated and formally adopted by the Council.  In 1967, a liaison representative from the  Food and Drug Administration  (FDA) was appointed to serve on the USAN Council. The FDA announced in 1984 that it would discontinue adding drug names to its official list and use the USAN as the established name for labeling and advertising new single-entity  drugs  marketed in the United States. [ 4 ] [ 5 ]  The AMA Council on Drugs no longer exists as a separate entity. The FDA now has a representative on the USAN Council, which has moved away from chemically derived names."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14365", "text": "Currently, the USAN Council has five members, one from each sponsoring organization, one from the FDA, and a member-at-large.  One member is nominated to the USAN Council annually by each sponsoring organization; the FDA nominates one liaison member annually.  The member-at-large is selected by the sponsoring organizations from a list of candidates proposed by the AMA, APhA, and the USP.  The five nominees to the Council must be approved annually by the  board of trustees  of the three sponsoring organizations."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14366", "text": "By definition, nonproprietary names are not subject to proprietary  trademark  rights but are entirely in the public domain. This distinguishes them from the trademarked names that have been registered for private use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14367", "text": "Assignment of a USAN takes into account practical considerations, such as the existence of  trademarks , international harmonization of drug nomenclature, the development of new classes of drugs, and the fact that the intended uses of substances for which names are being selected may change. [ 7 ] [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14368", "text": "USANs assigned today reflect both present nomenclature practices and older methods used to name drug entities.  Early drug nomenclature was based on the  chemical structure .  As newer drugs became chemically more complex and numerous, nonproprietary names based on chemistry became long and difficult to spell, pronounce, or remember.  Additionally, chemically derived names provided little useful information to non-chemist health practitioners.  Considering the needs of health professionals led to a system in which USANs reflect relationships between new entities and older drugs, and avoid names that might suggest non-existent relationships."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14369", "text": "Current nomenclature practices involve the adoption of standardized syllables called \"stems\" that relate new chemical entities to existing drug families. Stems may be  prefixes ,  suffixes , or  interfixes  in the nonproprietary name.  Each stem can emphasize a specific  chemical structure  type, a pharmacologic property, or a combination of these attributes. The recommended list of USAN stems is updated regularly to keep pace to accommodate drugs with new  chemical  and pharmacologic properties. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14370", "text": "As a general rule, the application for a USAN should be forwarded to the USAN Council after the  Investigational New Drug  (IND) is active and  clinical trials  have begun."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14371", "text": "Many drug manufacturers seeking a USAN are multinational companies with  subsidiaries  in various parts of the world or contractual agreements with drug firms outside the  United States .  Therefore, it is highly desirable to the  pharmaceutical company , the various nomenclature committees, and the medical community in general that a global name be established for each new single-entity compound introduced.  Assigning a USAN and standardizing names internationally can take anywhere from several months to a few years."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14372", "text": "Examples of drugs for which the USAN differs from the INN include: [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14373", "text": "VigiBase  is a  World Health Organization 's (WHO) global Individual Case Safety Report (ICSR) database that contains ICSRs submitted by the participating member states enrolled under WHO's international drug monitoring programme. It is the single largest drug safety data repository in the world. Since 1978, the  Uppsala Monitoring Centre  (UMC; established in  Uppsala ,  Sweden ) on behalf of WHO, have been maintaining VigiBase. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14374", "text": "Vigibase is used to obtain the information about a safety profile of a medicinal product. These data are used by pharmaceutical industries, academic institutions and regulatory authorities for statistical signal detection, updating periodic reports, ICSR comparisons with company databases and studying the reporting patterns. [ 2 ] \nThe data (pre-dominantly post-marketing serious and non-serious cases) is collected from each of its 110 member states which currently comprises to over 10 million ICSRs (October 2014). [ 2 ]  About a hundred thousand ICSRs are added each year."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14375", "text": "It is mandatory for all the participating countries (125 members states and 28 associate members) to submit ICSRs to UMC via its appointed national centre based in the respective member states, authorized by its  competent authority  or the  health authority  itself. \nThese reports are usually sent to the respective national centre by marketing authorization holders, health care professionals (HCP), consumers or any regional centre. Most of participating member have a well established system for collection of ICSRs. [ 3 ] \nThese submissions are in  ICH  E2B format and are reported more than once a month or at least every quarter. For some member states that lack an E2B compatible database for ICSR management, UMC in collaboration with  Swissmedic  has developed  VigiFlow , a web-based ICSR management system. VigiFlow functions as a national ICSR database management system and analysis tool, through which cases are sent to UMC. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14376", "text": "With primary objective of identify the earliest possible  pharmacovigilance  signals, the usage of VigiBase is permitted and accessed by the following authorities: [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14377", "text": "VigiBase is a  relational database management system  (RDMS) which is compatible with ODBC ( open database connectivity ) and uses  SQL  for the database communication. The RDMS can be accessed through client server applications, ODBC, and Internet applications. Apart from data management, the VigiBase system includes an automated signal detection process using advanced data mining tools ( VigiMine - a Bayesian Confidence Propagation Neural Network (BCPNN) data mining tool). [ 1 ]  VigiBase further includes a WHO Drug Dictionaries (WHO-DD and -DDE), and medical terminology dictionary such as WHO Adverse Reaction Terminology (WHO-ART),  International Classification of Diseases  (ICD), and the  Medical Dictionary for Regulatory Activities  (MedDRA). [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14378", "text": "Type of reports: Most preferred data includes post-marketing spontaneous serious and non-serious cases ICSRs. Case reports from studies,  clinical trials  or special monitoring and literature are sometimes included, but are flagged. [ 4 ] \nType of medicine: Database includes ICSRs on ordinary  allopathic  medicines, traditional medicines (herbals), biologics,  vaccines  and  medical devices . In addition, ICSRs on medication errors, therapeutic failure and counterfeit/substandard medicines are also considered. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14379", "text": "The  WHODrug Dictionary  is an international classification of  medicines  created by the WHO Programme for International Drug Monitoring and managed by the  Uppsala Monitoring Centre . [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14380", "text": "It is used by  pharmaceutical companies ,  clinical trial  organizations and  drug regulatory  authorities for identifying drug names in spontaneous  ADR  reporting (and  pharmacovigilance ) and in clinical trials. [ 2 ]  Created in 1968 and regularly updated, since 2005 there have been major developments in the form of a WHO Drug Dictionary Enhanced (with considerably more  fields  and data entries) and a WHO Herbal Dictionary, which covers traditional and  herbal  medicines. Since 2016 all of the WHODrug products have been available in a single subscription service called WHODrug Global. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14381", "text": "Organization\nWHODrug drug code consist of 11 characters (alphanumeric code). It has 3 parts: Drug Record Number(Drug Rec No), Sequence number 1(Seq1) and Sequence number 2 (Seq2). Drug Rec No consists of 6 characters. It uniquely identifies active  moieties , regardless of salt form or plant part and extract. \nSeq1 is used to uniquely identify different variations (e.g. salts and esters), plant parts and extraction methods, thereby defining active substances or a combination of active substances. WHODrug records sharing the same Drug Rec No and Seq1 contain the same variation/plant part/extract variation of the same active moiety. For single-ingredient records, Seq1=01 identifies a specific active moiety. If Seq1 is higher than 01 it refers to variations of that active moiety. For multi-ingredient records, Seq1=01 identifies a combination of active moieties. If Seq1 is higher than 01 it refers to variations of one or more of the active moieties in the combination. Finally, Seq2 uniquely identifies the name of the record in WHODrug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14382", "text": "Example\nThe Drug Code for the substance  Ibuprofen  is 001092 01 001. The Drug Code for the trade name Advil infants pain & fever relief is 001092 01 A3D."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14383", "text": "WHODrug records are classified with at least one code from  Anatomical Therapeutic Chemical Classification System  (including the HATC which stands for Herbal ATC and which is treated as part of ATC for mapping purposes). Preferably, a fourth level ATC code is assigned. ATC assignments in WHODrug are marked as 'official' or 'UMC-assigned'. Official ATC codes are classifications included in the official ATC index, while UMC-assigned ATC codes are classifications NOT included in the official ATC index."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14384", "text": "In addition, a separate cross reference called \"Cross Reference ATC 5\". In this additional reference, WHODrug records are matched to fifth level ATC codes where applicable."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14385", "text": "WHODrug is offered in Four formats (called B3 and C3). B3 format is brief while C3 format contains additional columns on top of B3 format."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14386", "text": "WHODrug concepts can be organized into groups. Standardised Drug Groupings (SDGs) define groups of drugs. For example, diuretics, corticosteroids, drugs used in diabetes. Groups are also defined based on interaction, for example, drugs interacting with CYP2C8 or drugs interacting with UGT.\nR,Lee"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14387", "text": "[ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14388", "text": "The  WHO Adverse Reactions Terminology  (WHOART) was a dictionary meant to serve as a basis for rational coding of  adverse reaction  terms. The system was maintained by the  Uppsala Monitoring Centre  (UMC), the  World Health Organization  Collaborating Centre for International Drug Monitoring. The system is no longer actively maintained since 2015. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14389", "text": "S -Adenosyl methionine  ( SAM ), also known under the commercial names of  SAMe ,  SAM-e , or  AdoMet , is a common  cosubstrate  involved in  methyl group  transfers, transsulfuration, and aminopropylation. Although these  anabolic  reactions occur throughout the body, most SAM is produced and consumed in the liver. [ 1 ]  More than 40 methyl transfers from SAM are known, to various substrates such as  nucleic acids ,  proteins ,  lipids  and  secondary metabolites . It is made from  adenosine triphosphate  (ATP) and  methionine  by  methionine adenosyltransferase . SAM was first discovered by  Giulio Cantoni  in 1952. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14390", "text": "In  bacteria , SAM is bound by the  SAM riboswitch , which regulates  genes  involved in methionine or  cysteine  biosynthesis. In  eukaryotic  cells, SAM serves as a regulator of a variety of processes including  DNA ,  tRNA , and  rRNA   methylation ;  immune response ; [ 2 ]  amino acid metabolism;  transsulfuration ; and more. In plants, SAM is crucial to the biosynthesis of  ethylene , an important  plant hormone  and signaling molecule. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14391", "text": "S -Adenosyl methionine consists of the adenosyl group attached to the sulfur of methionine, providing it with a positive charge. It is synthesized from ATP and methionine by  S -Adenosylmethionine synthetase enzyme  through the following reaction:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14392", "text": "The  sulfonium  functional group present in  S -adenosyl methionine is the center of its peculiar reactivity. Depending on the enzyme,  S -adenosyl methionine can be converted into one of three  products:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14393", "text": "The reactions that produce, consume, and regenerate SAM are called the SAM cycle. In the first step of this cycle, the SAM-dependent  methylases  (EC 2.1.1) that use SAM as a substrate produce  S -adenosyl homocysteine as a product. [ 4 ]   S -Adenosyl homocysteine is a strong negative regulator of nearly all SAM-dependent methylases despite their biological diversity. This is hydrolysed to  homocysteine  and  adenosine  by  S -adenosylhomocysteine hydrolase   EC 3.3.1.1  and the homocysteine recycled back to  methionine  through transfer of a methyl group from  5-methyltetrahydrofolate , by one of the two classes of  methionine synthases  (i.e.  cobalamin -dependent ( EC 2.1.1.13 ) or cobalamin-independent ( EC 2.1.1.14 )). This methionine can then be converted back to SAM, completing the cycle. [ 5 ]  In the rate-limiting step of the SAM cycle, MTHFR (methylenetetrahydrofolate reductase) irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14394", "text": "A large number of enzymes cleave SAM reductively to produce radicals:   5\u2032-deoxyadenosyl 5\u2032-radical , methyl radical, and others.  These enzymes are called  radical SAMs .  They all feature  iron-sulfur cluster  at their active sites. [ 7 ]  Most enzymes with this capability share a region of sequence homology that includes the motif CxxxCxxC or a close variant. This sequence provides three cysteinyl thiolate ligands that bind to three of the four metals in the 4Fe-4S cluster.  The fourth Fe binds the SAM."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14395", "text": "The radical intermediates generated by these enzymes perform a wide variety of unusual chemical reactions. Examples of radical SAM enzymes include  spore photoproduct lyase ,  activases of  pyruvate formate lyase  and anaerobic sulfatases,  lysine 2,3-aminomutase , and various enzymes of cofactor biosynthesis, peptide modification,  metalloprotein  cluster formation,  tRNA  modification, lipid metabolism, etc. Some radical SAM enzymes use a second SAM as a methyl donor. Radical SAM enzymes are much more abundant in anaerobic bacteria than in aerobic organisms. They can be found in all domains of life and are largely unexplored. A recent bioinformatics study concluded that this family of enzymes includes at least 114,000 sequences including 65 unique reactions. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14396", "text": "Deficiencies in radical SAM enzymes have been associated with a variety of diseases including  congenital heart disease ,  amyotrophic lateral sclerosis , and increased viral susceptibility. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14397", "text": "Another major role of SAM is in  polyamine  biosynthesis. Here, SAM is decarboxylated by  adenosylmethionine decarboxylase  ( EC 4.1.1.50 ) to form  S -adenosylmethioninamine . This compound then donates its  n -propylamine group in the biosynthesis of polyamines such as  spermidine  and  spermine  from  putrescine . [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14398", "text": "SAM is required for cellular growth and repair. It is also involved in the biosynthesis of several hormones and neurotransmitters that affect mood, such as  epinephrine .   Methyltransferases  are also responsible for the addition of methyl groups to the 2\u2032 hydroxyls of the first and second  nucleotides  next to the 5\u2032 cap in  messenger RNA . [ 10 ] [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14399", "text": "As of 2012, the evidence was inconclusive as to whether SAM can mitigate the pain of  osteoarthritis ; clinical trials that had been conducted were too small from which to generalize. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14400", "text": "The SAM cycle has been closely tied to the liver since 1947 because people with  alcoholic cirrhosis  of the liver would accumulate large amounts of methionine in their blood. [ 13 ]  While multiple lines of evidence from laboratory tests on cells and  animal models  suggest that SAM might be useful to treat various  liver diseases , as of 2012 SAM had not been studied in any large randomized placebo-controlled clinical trials that would allow an assessment of its efficacy and safety. [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14401", "text": "A 2016 Cochrane review concluded that for  major depressive disorder , \"Given the absence of high quality evidence and the inability to draw firm conclusions based on that evidence, the use of SAMe for the treatment of depression in adults should be investigated further.\" [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14402", "text": "A 2020 systematic review found that it performed significantly better than placebo, and  had similar outcomes to other commonly used antidepressants ( imipramine  and  escitalopram ). [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14403", "text": "SAM has recently been shown to play a role in  epigenetic  regulation. DNA methylation is a key regulator in epigenetic modification during mammalian cell development and differentiation. In mouse models, excess levels of SAM have been implicated in erroneous methylation patterns associated with diabetic neuropathy. SAM serves as the methyl donor in cytosine methylation, which is a key epigenetic regulatory process. [ 18 ]  Because of this impact on epigenetic regulation, SAM has been tested as an anti-cancer treatment. In many cancers, proliferation is dependent on having low levels of DNA methylation. In vitro addition in such cancers has been shown to remethylate oncogene promoter sequences and decrease the production of proto-oncogenes. [ 19 ]  In cancers such as colorectal cancer, aberrant global hypermethylation can inhibit promoter regions of tumor-suppressing genes. Contrary to the former information, colorectal cancers (CRCs) are characterized by global hypomethylation and promoter-specific DNA methylation. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14404", "text": "Oral SAM achieves peak plasma concentrations three to five hours after ingestion of an enteric-coated tablet (400\u20131000\u00a0mg). The half-life is about 100 minutes. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14405", "text": "In Canada, the UK, [ 22 ]  and the United States, SAM is sold as a  dietary supplement  under the marketing name SAM-e (also spelled SAME or SAMe). [ 23 ]  It was introduced in the US in 1999, after the  Dietary Supplement Health and Education Act  was passed in 1994. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14406", "text": "It was introduced as a  prescription drug  in Italy in 1979, in Spain in 1985, and in Germany in 1989. [ 24 ]  As of 2012, it was sold as a prescription drug in Russia, India, China, Italy, Germany, Vietnam, and Mexico. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14407", "text": "Gastrointestinal disorder,  dyspepsia  and  anxiety  can occur with SAM consumption. [ 21 ]  Long-term effects are unknown. SAM is a weak DNA- alkylating  agent. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14408", "text": "Another reported side effect of SAM is  insomnia ; therefore, the supplement is often taken in the morning. Other reports of mild side effects include lack of appetite, constipation, nausea, dry mouth, sweating, and anxiety/nervousness, but in placebo-controlled studies, these side effects occur at about the same incidence in the placebo groups. [ medical citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14409", "text": "Taking SAM at the same time as some drugs may increase the risk of  serotonin syndrome , a potentially dangerous condition caused by having too much serotonin. These drugs include, but are certainly not limited to,  dextromethorphan  (Robitussin),  meperidine  (Demerol),  pentazocine  (Talwin), and  tramadol  (Ultram). [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14410", "text": "SAM can also interact with many antidepressant medications \u2014 including  tryptophan  and the herbal medicine  Hypericum perforatum  (St. John's wort) \u2014 increasing the potential for serotonin syndrome or other side effects, and may reduce the effectiveness of  levodopa  for Parkinson's disease. [ 27 ]  SAM can increase the risk of manic episodes in people who have  bipolar disorder . [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14411", "text": "A 2022 study concluded that SAMe could be toxic. Jean-Michel Fustin of  Manchester University  said that the researchers found that excess SAMe breaks down into  adenine  and  methylthioadenosine  in the body, both producing the  paradoxical effect  of inhibiting methylation. This was found in  laboratory mice , causing harm to health, and in  in vitro  tests on human cells. [ 28 ] [ 22 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14412", "text": "Alcohol withdrawal syndrome  ( AWS ) is a set of symptoms that can occur following a reduction in  alcohol  use after a period of excessive use. [ 1 ]  Symptoms typically include  anxiety ,  shakiness , sweating, vomiting,  fast heart rate , and a mild fever. [ 1 ]  More severe symptoms may include  seizures , and  delirium tremens  (DTs); which can be fatal in untreated patients. [ 1 ]  Symptoms start at around 6 hours after the last drink. [ 2 ]  Peak incidence of seizures occurs at 24 to 36 hours [ 5 ]  and peak incidence of  delirium tremens  is at 48 to 72 hours. [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14413", "text": "Alcohol withdrawal may occur in those who are alcohol  dependent . [ 1 ]  This may occur following a planned or unplanned decrease in alcohol intake. [ 1 ]  The underlying mechanism involves a decreased responsiveness of  GABA receptors  in the brain. [ 3 ]  The withdrawal process is typically followed using the  Clinical Institute Withdrawal Assessment for Alcohol  scale (CIWA-Ar). [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14414", "text": "The typical treatment of alcohol withdrawal is with  benzodiazepines  such as  chlordiazepoxide  or  diazepam . [ 2 ]  Often the amounts given are based on a person's symptoms. [ 2 ]   Thiamine  is recommended routinely. [ 2 ]   Electrolyte problems  and  low blood sugar  should also be treated. [ 2 ]  Early treatment improves outcomes. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14415", "text": "In the Western world about 15% of people have problems with  alcoholism  at some point in time. [ 3 ]  Alcohol depresses the central nervous system, slowing cerebral messaging and altering the way signals are sent and received. Progressively larger amounts of alcohol are needed to achieve the same physical and emotional results. The drinker eventually must consume alcohol just to avoid the physical cravings and withdrawal symptoms. About half of people with alcoholism will develop withdrawal symptoms upon reducing their use, with four percent developing severe symptoms. [ 3 ]  Among those with severe symptoms up to 15% die. [ 2 ]  Symptoms of alcohol withdrawal have been described at least as early as 400 BC by  Hippocrates . [ 7 ] [ 8 ]  It is not believed to have become a widespread problem until the 1700s. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14416", "text": "Signs and symptoms of alcohol withdrawal occur primarily in the central nervous system. The severity of withdrawal can vary from mild symptoms such as insomnia, trembling, and anxiety to severe and life-threatening symptoms such as  alcoholic hallucinosis ,  delirium tremens , and  autonomic instability . [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14417", "text": "Withdrawal usually begins 6 to 24 hours after the last drink. [ 11 ]  Symptoms are worst at 24 to 72 hours, and improve by seven days. [ 2 ] [ 3 ]  To be classified as alcohol withdrawal syndrome, patients must exhibit at least two of the following symptoms: increased hand tremor, insomnia, nausea or vomiting, transient hallucinations (auditory, visual or tactile),  psychomotor agitation , anxiety,  generalized tonic\u2013clonic seizures , and autonomic instability. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14418", "text": "The severity of symptoms is dictated by a number of factors, the most important of which are degree of alcohol intake, length of time the individual has been using alcohol, and previous history of alcohol withdrawal. [ 12 ] [ 13 ]  Symptoms are also grouped together and classified:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14419", "text": "Six to 12 hours after the ingestion of the last drink, withdrawal symptoms such as shaking, headache, sweating, anxiety, nausea or vomiting may occur. [ 15 ]  Twelve to 24 hours after cessation, the condition may progress to such major symptoms as confusion, hallucinations [ 15 ]  (with awareness of reality), while less severe symptoms may persist and develop including tremor, agitation, hyperactivity and insomnia. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14420", "text": "At 12 to 48 hours following the last ethanol ingestion, the possibility of  generalized tonic\u2013clonic seizures  should be anticipated, occurring in 3\u20135% of cases. [ 13 ]  Meanwhile, none of the earlier withdrawal symptoms will typically have abated. Seizures carry the risk of major complications and death for individuals with an alcohol use disorder. [ 16 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14421", "text": "Although the person's condition usually begins to improve after 48 hours, withdrawal symptoms sometimes continue to increase in severity and advance to the most severe stage of withdrawal,  delirium tremens . This occurs in 5\u201320% of patients experiencing detoxification and one third of untreated cases, [ 14 ] [ 13 ]  which is characterized by hallucinations that are indistinguishable from reality, severe confusion, seizures, high blood pressure, and fever that can persist anywhere from 4 to 12 days. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14422", "text": "A protracted alcohol withdrawal syndrome occurs in many alcoholics when withdrawal symptoms continue beyond the acute withdrawal stage but usually at a subacute level of intensity and gradually decreasing with severity over time. This syndrome is sometimes referred to as the  post-acute-withdrawal syndrome . Some withdrawal symptoms can linger for at least a year after discontinuation of alcohol. Symptoms can include a craving for alcohol, inability to feel pleasure from normally pleasurable things (known as  anhedonia ), clouding of  sensorium , disorientation, nausea and vomiting or headache. [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14423", "text": "Insomnia is a common  protracted withdrawal  symptom that persists after the acute withdrawal phase of alcohol. Insomnia has also been found to influence relapse rate. Studies have found that  magnesium  or  trazodone  can help treat the persisting withdrawal symptom of insomnia in recovering alcoholics. Insomnia can be difficult to treat in these individuals because many of the traditional sleep aids (e.g., benzodiazepine receptor agonists and barbiturate receptor agonists) work via a GABA A  receptor mechanism and are cross-tolerant with alcohol. However,  trazodone  is not cross-tolerant with alcohol. [ 18 ] [ 19 ] [ 20 ]  The acute phase of the alcohol withdrawal syndrome can occasionally be protracted. Protracted  delirium tremens  has been reported in the medical literature as a possible but unusual feature of alcohol withdrawal. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14424", "text": "Chronic use of  alcohol  leads to changes in brain chemistry especially in the GABAergic system. Various adaptations occur such as changes in  gene expression  and down regulation of  GABA A  receptors . During acute alcohol withdrawal, changes also occur such as upregulation of alpha4 containing GABA A  receptors and downregulation of alpha1 and alpha3 containing GABA A  receptors. Neurochemical changes occurring during alcohol withdrawal can be minimized with drugs which are used for acute detoxification. With abstinence from alcohol and cross-tolerant drugs these changes in neurochemistry may gradually return towards normal. [ 22 ] [ 23 ]  Adaptations to the  NMDA  system also occur as a result of repeated alcohol intoxication and are involved in the hyper-excitability of the central nervous system during the alcohol withdrawal syndrome.  Homocysteine  levels, which are elevated during chronic drinking, increase even further during the withdrawal state, and may result in  excitotoxicity . [ 24 ]  Alterations in  ECG  (in particular an increase in  QT interval ) and  EEG  abnormalities (including abnormal quantified EEG) may occur during early withdrawal. [ 24 ]  Dysfunction of the  hypothalamic\u2013pituitary\u2013adrenal axis  and increased release of  corticotropin-releasing hormone  occur during both acute as well as protracted abstinence from alcohol and contribute to both acute and protracted withdrawal symptoms.  Anhedonia / dysphoria  symptoms, which can persist as part of a  protracted withdrawal , may be due to  dopamine  underactivity. [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14425", "text": "Kindling is a phenomenon where repeated alcohol detoxifications leads to an increased severity of the withdrawal syndrome. For example, binge drinkers may initially experience no withdrawal symptoms, but with each period of alcohol use followed by cessation, their withdrawal symptoms intensify in severity and may eventually result in full-blown  delirium tremens  with convulsive seizures. Alcoholics who experience seizures during detoxification are more likely to have had previous episodes of alcohol detoxification than patients who did not have seizures during withdrawal. In addition, people with previous withdrawal syndromes are more likely to have more medically complicated alcohol withdrawal symptoms. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14426", "text": "Kindling can cause complications and may increase the risk of relapse,  alcohol-related brain damage  and cognitive deficits. Chronic alcohol misuse and kindling via multiple alcohol withdrawals may lead to permanent alterations in the GABA A  receptors. [ 27 ]  The mechanism behind kindling is sensitization of some neuronal systems and desensitization of other neuronal systems which leads to increasingly gross neurochemical imbalances. This in turn leads to more profound withdrawal symptoms including  anxiety ,  convulsions  and  neurotoxicity . [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14427", "text": "Binge drinking is associated with increased impulsivity, impairments in  spatial working memory  and impaired  emotional learning . These adverse effects are believed to be due to the neurotoxic effects of repeated withdrawal from alcohol on aberrant neuronal plasticity and cortical damage. Repeated periods of acute intoxication followed by acute detoxification has profound effects on the brain and is associated with an increased risk of seizures as well as cognitive deficits. The effects on the brain are similar to those seen in alcoholics who have detoxified repeatedly but not as severe as in alcoholics who have no history of prior detox. Thus, the acute withdrawal syndrome appears to be the most important factor in causing damage or impairment to brain function. The brain regions most sensitive to harm from binge drinking are the  amygdala  and  prefrontal cortex . [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14428", "text": "People in adolescence who experience repeated withdrawals from  binge drinking  show impairments of long-term nonverbal memory. Alcoholics who have had two or more alcohol withdrawals show more frontal lobe cognitive dysfunction than those who have experienced one or no prior withdrawals. Kindling of neurons is the proposed cause of withdrawal-related cognitive damage. Kindling from repeated withdrawals leads to accumulating neuroadaptive changes. Kindling may also be the reason for cognitive damage seen in binge drinkers. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14429", "text": "Many hospitals use the  Clinical Institute Withdrawal Assessment for Alcohol  (CIWA) protocol in order to assess the level of withdrawal present and therefore the amount of medication needed. [ 12 ]  When overuse of alcohol is suspected but drinking history is unclear, testing for elevated values of carbohydrate-deficient transferrin or gammaglutamyl transferase can help make the diagnosis of alcohol overuse and dependence more clear. The CIWA has also been shortened (now called the CIWA-Ar), while retaining its validity and reliability, to help assess patients more efficiently due to the life-threatening nature of alcohol withdrawal. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14430", "text": "Benzodiazepines   are effective for the management of symptoms as well as the prevention of seizures. [ 31 ]  Certain vitamins are also an important part of the management of alcohol withdrawal syndrome. In those with severe symptoms inpatient care is often required. [ 11 ]  In those with lesser symptoms treatment at home may be possible with daily visits with a health care provider. [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14431", "text": "Cohort studies  have demonstrated that the combination of  anticonvulsants  and  benzodiazepines  is more effective than other treatments in reducing alcohol withdrawal scores and shortening the duration of  intensive care unit  stays. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14432", "text": "Benzodiazepines are the most commonly used medication for the treatment of alcohol withdrawal and are generally safe and effective in suppressing symptoms of alcohol withdrawal. [ 33 ]  This class of medication is generally effective in symptoms control, but needs to be used carefully. Although benzodiazepines have a long history of successfully treating and preventing withdrawal, there is no consensus on the ideal one to use. The most commonly used agents are long-acting benzodiazepines, such as  chlordiazepoxide  and  diazepam . These are believed to be superior to other benzodiazepines for treatment of delirium and allow for longer periods between doses. However, benzodiazepines with intermediate half-lives like  lorazepam  may be safer in people with liver problems. [ 34 ]  Benzodiazepines showed a protective benefit against alcohol withdrawal symptoms, in particular seizure, compared to other common methods of treatment. [ 35 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14433", "text": "The primary debate between use of long-acting benzodiazepines and short-acting is that of ease of use. Longer-acting drugs, such as diazepam, can be administered less frequently. However, evidence does exist that \"symptom-triggered regimens\" such as those used when treating with lorazepam, are as safe and effective, but have decreased treatment duration and medication quantity used. [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14434", "text": "Although benzodiazepines are very effective at treating alcohol withdrawal, they should be carefully used. Benzodiazepines should only be used for brief periods in alcoholics who are not already dependent on them, as they share cross tolerance with alcohol. There is a risk of replacing an alcohol addiction with benzodiazepine dependence or adding another addiction. Furthermore, disrupted GABA benzodiazepine receptor function is part of  alcohol dependence  and chronic benzodiazepines may prevent full recovery from alcohol induced mental effects. [ 36 ] [ 37 ]  The combination of benzodiazepines and alcohol can amplify the adverse psychological effects of each other causing enhanced depressive effects on mood and increase suicidal actions and are generally contraindicated except for alcohol withdrawal. [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14435", "text": "Alcoholics are often deficient in various nutrients, which can cause severe complications during alcohol withdrawal, such as the development of  Wernicke syndrome . To help to prevent Wernicke syndrome, these individuals should be administered a multivitamin preparation with sufficient quantities of thiamine and folic acid. During alcohol withdrawal, the prophylactic administration of  thiamine ,  folic acid , and  pyridoxine  intravenously is recommended before starting any carbohydrate-containing fluids or food. These vitamins are often combined into a  banana bag  for intravenous administration. [ 39 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14436", "text": "Very limited evidence indicates that  topiramate  or  pregabalin  may be useful in the treatment of alcohol withdrawal syndrome. [ 40 ]  Limited evidence supports the use of  gabapentin  or  carbamazepine  for the treatment of mild or moderate alcohol withdrawal as the sole treatment or as combination therapy with other medications; however, gabapentin does not appear to be effective for treatment of severe alcohol withdrawal and is therefore not recommended for use in this setting. [ 40 ] [ 41 ]  A 2010  Cochrane review  similarly reported that the evidence to support the role of anticonvulsants over benzodiazepines in the treatment of alcohol withdrawal is not supported. [ 42 ]   Paraldehyde  combined with  chloral hydrate  showed superiority over chlordiazepoxide with regard to life-threatening side effects and carbamazepine may have advantages for certain symptoms. [ 42 ]  Long term anticonvulsant medications are not usually recommended in those who have had prior seizures due to withdrawal. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14437", "text": "There are three medications used to help prevent a return to drinking:  naltrexone ,  acamprosate , and  disulfiram . They are used after withdrawal has occurred. [ 44 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14438", "text": "Clonidine  may be used in combination with benzodiazepines to help some of the symptoms. [ 12 ]  No conclusions can be drawn concerning the efficacy or safety of  baclofen  for alcohol withdrawal syndrome due to the insufficiency and low quality of the evidence. [ 45 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14439", "text": "Antipsychotics , such as  haloperidol , are sometimes used in addition to benzodiazepines to control agitation or psychosis. [ 12 ]  Antipsychotics may potentially worsen alcohol withdrawal as they lower the seizure threshold.  Clozapine ,  olanzapine , or low-potency  phenothiazines  (such as  chlorpromazine ) are particularly risky; if used, extreme caution is required. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14440", "text": "While intravenous  ethanol  could theoretically be used, evidence to support this use, at least in those who are very sick, is insufficient. [ 47 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14441", "text": "Hypertension is common, and some doctors also prescribe beta blockers during withdrawal."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14442", "text": "Failure to manage the alcohol withdrawal syndrome appropriately can lead to permanent brain damage or death. [ 48 ]  It has been proposed that brain damage due to alcohol withdrawal may be prevented by the administration of  NMDA antagonists ,  calcium antagonists , and  glucocorticoid antagonists . [ 49 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14443", "text": "Continued use of benzodiazepines may impair recovery from psychomotor and cognitive impairments from alcohol. [ 50 ]  Cigarette smoking may slow down or interfere with recovery of brain pathways in recovering alcoholics. [ 51 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14444", "text": "The  atypical antipsychotics  ( AAP ), also known as  second generation antipsychotics  ( SGAs ) and  serotonin \u2013dopamine antagonists  ( SDAs ), [ 1 ] [ 2 ]  are a group of  antipsychotic  drugs (antipsychotic drugs in general are also known as  tranquilizers  and  neuroleptics , although the latter is usually reserved for the  typical antipsychotics ) largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval (e.g. by the  FDA  of the  US , the  TGA  of  Australia , the  MHRA  of the  UK ) for  schizophrenia ,  bipolar disorder , irritability in  autism , and as an  adjunct  in  major depressive disorder ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14445", "text": "Both generations of medication tend to block receptors in the brain's  dopamine pathways . Atypicals are less likely than  haloperidol \u2014the most widely used  typical antipsychotic \u2014to cause  extrapyramidal   motor control   disabilities  in patients such as unsteady  Parkinson's disease \u2013type movements, body  rigidity , and involuntary  tremors . However, only a few of the atypicals have been demonstrated to be superior to lesser-used, low- potency  first-generation antipsychotics in this regard. [ 3 ] [ 4 ] [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14446", "text": "As experience with these agents has grown, several studies have questioned the utility of broadly characterizing antipsychotic drugs as \"atypical/second generation\" as opposed to \"first generation\", noting that each agent has its own efficacy and side-effect profile. It has been argued that a more nuanced view in which the needs of individual patients are matched to the properties of individual drugs is more appropriate. [ 4 ] [ 3 ]  Although atypical antipsychotics are thought to be safer than typical antipsychotics, they still have severe side effects, including  tardive dyskinesia  (a serious movement disorder),  neuroleptic malignant syndrome , and increased risk of  stroke ,  sudden cardiac death ,  blood clots , and  diabetes .  Significant weight gain  may occur. Critics have argued that \"the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.\" [ 6 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14447", "text": "Atypical antipsychotics are typically used to treat  schizophrenia  or  bipolar disorder . [ 7 ]  They are also frequently used to treat  agitation  associated with  dementia ,  anxiety disorder ,  autism spectrum disorder ,  persecutory delusion  and  obsessive-compulsive disorder  (an  off-label use ). [ 8 ] [ 9 ]  In dementia, they should only be considered after other treatments have failed and if the patient is a risk to themselves and/or others. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14448", "text": "The first-line psychiatric treatment for schizophrenia is antipsychotic medication, [ 11 ]  which can reduce the positive symptoms of schizophrenia in about 8\u201315 days. Antipsychotics only appear to improve secondary  negative symptoms  of schizophrenia in the short term and may worsen negative symptoms overall. [ 12 ]  Overall there is no good evidence that atypical antipsychotics have any therapeutic benefit for treating the negative symptoms of schizophrenia. [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14449", "text": "There is very little evidence on which to base a risk and benefit assessment of using antipsychotics for long-term treatment. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14450", "text": "The choice of which antipsychotic to use for a specific patient is based on benefits, risks, and costs. [ 15 ]  It is debatable whether, as a class,  typical  or atypical antipsychotics are better. [ 16 ]  Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. [ 17 ]  There is a good response in 40\u201350% of patients, a partial response in 30\u201340%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two of three different antipsychotics) in the remaining 20%. [ 18 ]   Clozapine  is considered a first choice treatment for  treatment resistant schizophrenia , especially in the short term; in the longer-terms the risks of adverse effects complicate the choice. [ 19 ]  In turn, risperidone, olanzapine, and  aripiprazole  have been recommended for the treatment of first-episode psychosis. [ 20 ] [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14451", "text": "The utility of broadly grouping the antipsychotics into first generation and atypical categories has been challenged. It has been argued that a more nuanced view, matching the properties of individual drugs to the needs of specific patients is preferable. [ 3 ]  While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and  extrapyramidal symptoms  in particular) than typical medications, the results showing these effects often lacked robustness, and the assumption was increasingly challenged even as atypical prescriptions were soaring. [ 22 ] [ 23 ]  In 2005 the US government body  NIMH  published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind study (the CATIE project). [ 24 ]  This study compared several atypical antipsychotics to an older, mid-potency typical antipsychotic,  perphenazine , among 1,493 persons with schizophrenia. The study found that only  olanzapine  outperformed perphenazine in discontinuation rate (the rate at which people stopped taking it due to its effects). The authors noted an apparent superior efficacy of olanzapine to the other drugs in terms of reduction in psychopathology and rate of hospitalizations, but olanzapine was associated with relatively severe  metabolic  effects such as a major weight gain problem (averaging 9.4\u00a0lbs over 18 months) and increases in  glucose ,  cholesterol , and  triglycerides . No other atypical studied ( risperidone ,  quetiapine , and  ziprasidone ) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine (a result supported by a meta-analysis [ 3 ]  by Leucht  et al.  published in  The Lancet ), although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%, P=0.002). A phase 2 part of this CATIE study roughly replicated these findings. [ 25 ]  Compliance has not been shown to be different between the two types. [ 26 ]  Overall evaluations of the CATIE and other studies have led many researchers to question the first-line prescribing of atypicals over typicals, or even to question the distinction between the two classes. [ 27 ] [ 28 ] [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14452", "text": "It has been suggested that there is no validity to the term \"second-generation antipsychotic drugs\" and that the drugs that currently occupy this category are not identical to each other in mechanism, efficacy, and side-effect profiles. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14453", "text": "Each drug has its own mechanism, as Dr. Rif S. El-Mallakh, explained regarding the binding site and occupancy with a focus on the dopamine D2 receptor:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14454", "text": "In general, when an antagonist of a neurotransmitter receptor is used, it must occupy a minimum of 65% to 70% of the target receptor to be effective. This is clearly the case when the target is a postsynaptic receptor, such as the dopamine D2 receptor. Similarly, despite significant variability in antidepressant response, blockade of 65% to 80% of presynaptic transport proteins\u2014such as the serotonin reuptake pumps when considering serotoninergic antidepressants, or the norepinephrine reuptake pumps when considering noradrenergic agents such as nortriptyline\u2014is necessary for these medications to be effective.... Depending on the level of intrinsic activity of a partial agonist and clinical goal, the clinician may aim for a different level of receptor occupancy. For example,  aripiprazole  will act as a dopamine agonist at lower concentrations, but blocks the receptor at higher concentrations. Unlike antagonist antipsychotics, which require only 65% to 70% D2  receptor occupancy  to be effective, aripiprazole receptor binding at effective antipsychotic doses is 90% to 95%. Since aripiprazole has an intrinsic activity of approximately 30% (i.e., when it binds, it stimulates the D2 receptor to about 30% of the effect of dopamine binding to the receptor), binding to 90% of the receptors, and displacing endogenous dopamine, allows aripiprazole to replace the background or tonic tone of dopamine, which has been measured at 19% in people with schizophrenia and 9% in controls. Clinically, this still appears as the minimal effective dose achieving maximal response without significant parkinsonism despite >90% receptor occupancy. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14455", "text": "In bipolar disorder, SGAs are most commonly used to rapidly control  acute mania  and  mixed episodes , often in conjunction with mood stabilizers (which tend to have a delayed onset of action in such cases) such as  lithium  and  valproate . In milder cases of mania or mixed episodes, mood stabilizer monotherapy may be attempted first. [ 32 ]  SGAs are also used to treat other aspects of the disorder (such as acute bipolar depression or as a prophylactic treatment) as adjuncts or as a monotherapy, depending on the drug. Both  quetiapine  and  olanzapine  have demonstrated significant efficacy in all three treatment phases of bipolar disorder.  Lurasidone  (trade name Latuda) has demonstrated some efficacy in the acute depressive phase of bipolar disorder. [ 32 ] [ 33 ] [ 34 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14456", "text": "In  non-psychotic   major depressive disorder  (MDD), some SGAs have demonstrated significant efficacy as adjunctive agents; and, such agents include: [ 35 ] [ 36 ] [ 37 ] [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14457", "text": "whereas only quetiapine has demonstrated efficacy as a monotherapy in non-psychotic MDD. [ 40 ]   Olanzapine/fluoxetine  is an efficacious treatment in both  psychotic  and  non-psychotic  MDD. [ 41 ] [ 42 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14458", "text": "Aripiprazole ,  brexpiprazole ,  cariprazine ,  olanzapine , and  quetiapine  have been approved as adjunct treatment for MDD by the FDA in the United States. [ 43 ] [ 44 ]   Cariprazine ,  Quetiapine ,  lurasidone , and  lumateperone [ 45 ]  have been approved, as monotherapies, for  bipolar depression , but as of present, lurasidone has not been approved for MDD. [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14459", "text": "Both  risperidone  and  aripiprazole  have received FDA approval for irritability in autism. [ 41 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14460", "text": "Between May 2007 and April 2008, Dementia and Alzheimer's together accounted for 28% of atypical antipsychotic use in patients aged 65 or older. [ 46 ]  The U.S.  Food and Drug Administration  requires that all atypical antipsychotics carry a  black box warning  that the medication has been associated with an increased risk of mortality in elderly patients. [ 46 ]  In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia. [ 47 ]  In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%. [ 47 ]  As of now, the only FDA-approved atypical antipsychotic for alzheimer-related dementia is  brexpiprazole ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14461", "text": "Legend:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14462", "text": "The side effects reportedly associated with the various atypical antipsychotics vary and are medication-specific. Generally speaking, atypical antipsychotics are widely believed to have a lower likelihood for the development of  tardive dyskinesia  than the typical antipsychotics. However, tardive dyskinesia typically develops after long-term (possibly decades) use of antipsychotics. It is not clear if atypical antipsychotics, having been in use for a relatively short time, produce a lower incidence of tardive dyskinesia. [ 32 ] [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14463", "text": "Among the other side effects that have been suggested is that atypical antipsychotics increase the risk of cardiovascular disease. [ 54 ]  Kabinoff and colleagues (2003) found that the increase in cardiovascular disease is seen regardless of the treatment received, and that it is instead caused by many different factors such as lifestyle or diet. [ 54 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14464", "text": "Sexual side effects have also been reported when taking atypical antipsychotics. [ 55 ]  In males antipsychotics reduce sexual interest, impair sexual performance with the main difficulties being failure to ejaculate. [ 56 ]  In females there may be abnormal menstrual cycles and infertility. [ 56 ]  In both males and females the breasts may become enlarged and a fluid will sometimes ooze from the nipples. [ 56 ]  Sexual adverse effects caused by some antipsychotics are a result of an increase of  prolactin . Sulpiride and Amisulpiride, as well as Risperdone and paliperidone (to a lesser extent), cause a high increase of prolactin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14465", "text": "In April 2005, the US Food and Drug Administration (FDA) issued an advisory and subsequent black box warning regarding the risks of atypical antipsychotic use among elderly patients with dementia. The FDA advisory was associated with decreases in the use of atypical antipsychotics, especially among elderly patients with dementia. [ 57 ]  Subsequent research reports confirmed the mortality risks associated with the use of both conventional and atypical antipsychotics to treat patients with dementia. Consequently, in 2008 the FDA issued although a black box warning for classical neuroleptics. Data on treatment efficacies are strongest for atypical antipsychotics. Adverse effects in patients with  dementia  include an increased risk of mortality and cerebrovascular events, as well as metabolic effects, extrapyramidal symptoms, falls, cognitive worsening, cardiac arrhythmia, and pneumonia. [ 58 ]  Conventional antipsychotics may pose an even greater safety risk. No clear efficacy evidence exists to support the use of alternative psychotropic classes (e.g. antidepressants, anticonvulsants). [ 59 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14466", "text": "Many different types of medication can induce in patients that have never had symptoms before. A new chapter about OCD in the  DSM-5  (2013) now specifically includes drug-induced OCD."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14467", "text": "There are reports that some atypical antipsychotics could cause drug-induced OCD in already schizophrenic patients. [ 60 ] [ 61 ] [ 62 ] [ 63 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14468", "text": "All of the atypical antipsychotics warn about the possibility of  tardive dyskinesia  in their package inserts and in the  PDR . It is not possible to truly know the risks of tardive dyskinesia when taking atypicals, because tardive dyskinesia can take many decades to develop and the atypical antipsychotics are not old enough to have been tested over a long enough period of time to determine all of the long-term risks. One hypothesis as to why atypicals have a lower risk of tardive dyskinesia is because they are much less fat-soluble than the typical antipsychotics and because they are readily released from D2 receptor and brain tissue. [ 64 ]  The typical antipsychotics remain attached to the D2 receptors and accumulate in the brain tissue which may lead to TD. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14469", "text": "Both typical and atypical antipsychotics can cause tardive dyskinesia. [ 65 ]  According to one study, rates are lower with the atypicals at 3.9% per year as opposed to the typicals at 5.5% per year. [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14470", "text": "Recently, metabolic side effects have been of considerable concern to clinicians, patients and the FDA. In 2003, the  Food and Drug Administration  (FDA) required all manufacturers of atypical antipsychotics to change their labeling to include a warning about the risks of  hyperglycemia  and  diabetes  with atypical antipsychotics. It must also be pointed out that although all atypicals must carry the warning on their labeling, some evidence shows that atypicals are not equal in their effects on weight and  insulin sensitivity . [ 66 ]  The general consensus is that clozapine and olanzapine are associated with the greatest effects on weight gain and decreased insulin sensitivity, followed by risperidone and quetiapine. [ 66 ]  Ziprasidone and aripiprazole are thought to have the smallest effects on weight and  insulin resistance , but clinical experience with these newer agents is not as developed as that with the older agents. [ 66 ]  The mechanism of these adverse effects is not completely understood but it is believed to result from a complex interaction between a number of pharmacologic actions of these drugs. Their effects on weight are believed to mostly derive from their actions on the  H 1  and  5-HT 2C  receptors, while their effects on insulin sensitivity are believed to be the result of a combination of their effects on body weight (as increased body mass is known to be a risk factor for insulin resistance) and their antagonistic effects on the  M 3  receptor . Some of the newer agents, however, such as risperidone and its metabolite paliperidone, ziprasidone, lurasidone, aripiprazole, asenapine and iloperidone, have clinically insignificant effects on the  M 3  receptor and appear to carry a lower risk of insulin resistance. Whereas clozapine, olanzapine and quetiapine (indirectly via its active metabolite, norquetiapine) all antagonise the M 3  receptor at therapeutic-relevant concentrations. [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14471", "text": "Recent evidence suggests a role of the  \u03b1 1  adrenoceptor  and  5-HT 2A  receptor  in the metabolic effects of atypical antipsychotics. The  5-HT 2A  receptor , however, is also believed to play a crucial role in the therapeutic advantages of atypical antipsychotics over their predecessors, the typical antipsychotics. [ 68 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14472", "text": "The two atypical antipsychotics with trials showing that had a low incidence of weight gain in large meta-analysis were lurasidone and aripiprazole. [ 69 ]  In a meta-analysis of 18 antipsychotics, olanzapine and clozapine exhibited the worst metabolic parameters and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign parameters. [ 70 ]   Aripiprazole ,  asenapine ,  ziprasidone  and  lurasidone  have low propensity to cause weight gain. [ 71 ]  Lumateperone was found to cause minimal weight gain in a long-term 12 month follow-up study. [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14473", "text": "A study by Sernyak and colleagues found that the prevalence of diabetes in atypical antipsychotic treatments was statistically significantly higher than that of conventional treatment. [ 54 ]  The authors of this study suggest that it is a causal relationship the Kabinoff et al. suggest the findings only suggest a temporal association. [ 54 ]  Kabinoff et al. suggest that there is insufficient data from large studies to demonstrate a consistent or significant difference in the risk of insulin resistance during treatment with various atypical antipsychotics. [ 54 ]  Prescribing  topiramate ,  zonisamide ,  metformin ,  GLP-1 receptor agonists , or  nizatidine  alongside an antipsychotic significantly reduces weight gain. [ 73 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14474", "text": "Despite increasing some  risk factors , SGAs are not associated with excess cardiovascular mortality when used to treat serious psychiatric disorders. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14475", "text": "The  British National Formulary  recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. [ 80 ]  Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. [ 81 ]  Other symptoms may include restlessness, increased sweating, and trouble sleeping. [ 81 ]  Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. [ 81 ]  Symptoms generally resolve after a short period of time. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14476", "text": "There is tentative evidence that discontinuation of antipsychotics can result in psychosis. [ 82 ]  It may also result in reoccurrence of the condition that is being treated. [ 83 ]  Rarely tardive dyskinesia can occur when the medication is stopped. [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14477", "text": "The atypical antipsychotics integrate with the  serotonin  (5-HT),  norepinephrine  (\u03b1, \u03b2), and  dopamine  (DA) receptors in order to effectively treat schizophrenia. [ 84 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14478", "text": "D 2  Receptor : Hyperactive dopaminergic activity on  D 2  receptors  in the mesolimbic pathway is responsible for the positive symptoms of schizophrenia (hallucinations, delusions, paranoia). After taking an antipsychotic,  antagonism  of D 2  receptors occurs throughout the entire brain, leading to a number of deleterious side effects from D 2  receptor antagonism throughout the entire  dopamine pathway  system. It's not possible to affect D 2  receptors only in the  mesolimbic pathway , [ 85 ] [ Stahl AP Explained 1 - 1 ]  but  5-HT 2A  receptor  antagonism reverses these side effects to some extent. [ Stahl AP Explained 1 - 2 ]  Reducing D 2  dopaminergic activity in the mesolimbic pathway also results in an  anhedonic  effect, reducing pleasure and motivation. In the mesocortical pathway to the  DLPFC  and  VMPFC , endogenous D 2  receptor dopamine activity is sometimes low in schizophrenia, resulting in cognitive, affective, and, broadly, the negative symptoms of schizophrenia. D 2  receptor antagonism further compounds these problems. In the  nigrostriatal pathway , D 2  receptor antagonism results in  extrapyramidal symptoms . If this antagonism occurs long enough, symptoms of EPS may become permanent, even if antipsychotic use is discontinued. In the  tuberoinfundibular pathway , D 2  receptor antagonism results in elevated  prolactin . If prolactin levels become high enough,  hyperprolactinaemia  may occur, resulting in sexual dysfunction, weight gain, more rapid demineralization of bones, and possibly  galactorrhea  and  amenorrhea . [ Stahl AP Explained 1 - 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14479", "text": "5-HT 2A  Receptor : When  serotonin  is released on to  postsynaptic  5-HT 2A  receptors, the dopamine neuron is inhibited, thus acting as a brake on dopamine release. [ Stahl AP Explained 1 - 2 ]  This brake is disrupted through action of a 5-HT 2A  antagonist, which disinhibits the dopamine neuron, stimulating dopamine release. The result of this is that dopamine competes with antipsychotic D 2  antagonistic action at D 2  receptors, thereby reducing antagonistic binding there and eliminating or lowering D 2  antagonistic effects in several pathways of the dopamine system. [ Stahl AP Explained 1 - 2 ]  In the nigrostratial pathway, it reduces EPS. In the tuberoinfundibular pathway, it reduces or eliminates prolactin elevation. [ Stahl AP Explained 1 - 3 ]  Dopamine release in the mesolimbic pathway from 5-HT 2A  antagonism does not appear to be as robust as in the other pathways of the dopamine system, thereby accounting for why atypical antipsychotics still retain part of their efficacy against the positive symptoms of schizophrenia through their D 2  antagonism. [ Stahl AP Explained 1 - 3 ]  When 5-HT 2A  antagonistic agent particles occupy 5-HT 2A  receptors in the mesocortical pathway and in the prefrontal cortex, the negative symptoms of schizophrenia, affective symptoms, and cognitive deficits and abnormalities are treated and reduced. [ Stahl AP Explained 1 - 3 ]  Furthermore, 5-HT 2A  receptor antagonism blocks the serotonergic excitation of cortical pyramidal cells, reducing  glutamate  release, which in turn lowers hyperactive dopaminergic D 2  receptor activity in the mesolimbic pathway, reducing or eliminating the positive symptoms of schizophrenia. [ Stahl AP Explained 1 - 3 ] [ 86 ] [ 87 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14480", "text": "Brexpiprazole , approved by the US FDA in 2015, has a similar binding profile to  aripiprazole  as a partial D2  agonist  with moderate  histamine  binding, but with brexipiprazole has a higher affinity for serotonin receptor  5-HT 2A ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14481", "text": "Some effects of  5-HT 1A  receptor activation include decreased aggressive behavior/ideation, [ 88 ]  increased sociability, and decreased anxiety and depression. [ non-primary source needed ]  Blockade of the 5-HT 2C  receptor increases  serotonin , releasing norepinephrine and dopamine within the brain. [ 85 ]  But neuronal  reuptake  of norepinephrine is  limited sharply  by some antipsychotics, e.g.  ziprasidone . Increased norepinephrine can cause increased glucose(blood sugar) levels. [ 89 ] [ 90 ] [ 91 ]  Increased blood sugar levels by increased norepinephrine causes hunger in many humans, which is why weight gain occurs with some antipsychotics if the norepinephrine is not inhibited. [ 92 ] [ 93 ] [ 94 ] [ 95 ] [ 96 ]  Inhibition of norepinephrine stabilizes mood in humans. [ 97 ]   5-HT 6  receptor antagonists improve cognition, learning, and memory. [ 98 ]  The  5-HT 7  receptor is very potent for the mitigation of bipolar conditions and also yields an antidepressant effect. The antipsychotics  asenapine , [ 99 ]   lurasidone , [ 100 ] [ 101 ]   risperidone , [ 102 ]  and  aripiprazole [ 103 ]  are very potent at the 5-HT 7  receptor.  Antagonistic affinity  for the  H 1  receptor also has an antidepressant effect. H 1  antagonism blocks serotonin and norepinephrine reuptake. Patients with increased histamine levels have been observed to have lower serotonin levels. [ 104 ]  However, the H 1  receptor is linked to weight gain. To have partial agonism at the  5-HT 1A  receptor can yield absence of weight gain in an antipsychotic. This is very relevant for ziprasidone, [ 105 ] [ 106 ]  but it creates a risk for a prolonged QTc interval. [ 107 ] [ 108 ]  On the other hand, blockade of the  5-HT 3  receptor removes the risk for a prolonged QTc interval, [ 100 ]  but then creates a larger risk for weight gain. Relation to the 5-HT 3  receptor increases caloric uptake and glucose, [ 109 ]  which is seen in clozapine and olanzapine. [ 110 ] [ 111 ]  Other ways for dopamine to resolve is to have agonism at both the D 2  receptor and 5-HT 1A  receptor, which normalizes the dopamine level in the brain. This occurs with  cariprazine  and  aripiprazole ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14482", "text": "Whether the anhedonic, loss of pleasure and motivation effect resulting from dopamine insufficiency or blockade at D 2  receptors in the mesolimbic pathway, which is mediated in some part by antipsychotics (and despite dopamine release in the mesocortical pathway from 5-HT 2A  antagonism, which is seen in atypical antipsychotics), or the positive mood, mood stabilization, and cognitive improvement effect resulting from atypical antipsychotic serotonergic activity is greater for the overall quality of life effect of an atypical antipsychotic is a question that is variable between individual experience and the atypical antipsychotic(s) being used. [ 85 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14483", "text": "Inhibition.  Disinhibition: The opposite process of inhibition, the turning on of a biological function.  Release : Causes the appropriate neurotransmitters to be discharged in vesicles into the synapse where they attempt to bind to and activate a receptor.  Downregulation and Upregulation . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14484", "text": "Note:  Unless otherwise specified, the drugs below serve as antagonists/inverse agonists at the receptors listed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14485", "text": "Atypical antipsychotics are most commonly administered orally. [ 56 ]  Antipsychotics can also be injected, but this method is not as common. [ 56 ]  They are lipid-soluble, are readily absorbed from the digestive tract, and can easily pass the blood\u2013brain barrier and placental barriers. [ 56 ]  Once in the brain, the antipsychotics work at the synapse by binding to the receptor. [ 113 ]  Antipsychotics are completely metabolized in the body and the metabolites are excreted in urine. [ 56 ]  These drugs have relatively long half-lives. [ 56 ]  Each drug has a different half-life, but the occupancy of the D2 receptor falls off within 24 hours with atypical antipsychotics, while lasting over 24 hours for the typical antipsychotics. [ 64 ]  This may explain why relapse into psychosis happens quicker with atypical antipsychotics than with typical antipsychotics, as the drug is excreted faster and is no longer working in the brain. [ 64 ]  Physical dependence with these drugs is very rare. [ 56 ]  However, if the drug is abruptly discontinued, psychotic symptoms, movement disorders, and sleep difficulty may be observed. [ 56 ]  It is possible that withdrawal is rarely seen because the AAP are stored in body fat tissues and slowly released. [ 56 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14486", "text": "Acronyms used: \nIR - Immediate release formulation. \nXR - Extended release formulation. \nEM - Extensive metabolisers. \nPM - Poor metabolisers.  \nC max  - maximum plasma concentrations of the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14487", "text": "The first major tranquilizer or antipsychotic medication,  chlorpromazine  (Thorazine), a typical antipsychotic, was discovered in 1951 and introduced into clinical practice shortly thereafter. Clozapine (Clozaril), an atypical antipsychotic, fell out of favor due to concerns over drug-induced  agranulocytosis . Following research indicating its effectiveness in treatment-resistant  schizophrenia  and the development of an adverse event monitoring system, clozapine re-emerged as a viable antipsychotic. According to Barker (2003), the three most-accepted atypical drugs are clozapine, risperidone, and olanzapine. However, he goes on to explain that clozapine is usually the last resort when other drugs fail. Clozapine can cause agranulocytosis (a decreased number of white blood cells), requiring blood monitoring for the patient. Despite the effectiveness of clozapine for treatment-resistant schizophrenia, agents with a more favorable side-effect profile were sought for widespread use. During the 1990s,  olanzapine ,  risperidone , and  quetiapine  were introduced, with  ziprasidone  and  aripiprazole  following in the early 2000s. The atypical antipsychotic  paliperidone  was approved by the FDA in late 2006. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14488", "text": "The atypical antipsychotics have found favor among clinicians and are now considered to be  first-line treatments  for schizophrenia and are gradually replacing the  typical antipsychotics . In the past, most researchers have agreed that the defining characteristics of atypical antipsychotics are the decreased incidence of  extrapyramidal  side effects (EPS) [ 132 ]  and an absence of sustained prolactin elevation. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14489", "text": "The terminology can still be imprecise. The definition of \"atypicality\" was based upon the absence of extrapyramidal side effects, but there is now a clear understanding that atypical antipsychotics can still induce these effects (though to a lesser degree than typical antipsychotics). [ 133 ]  Recent literature focuses more upon specific pharmacological actions and less upon categorization of an agent as \"typical\" or \"atypical\". There is no clear dividing line between the typical and atypical antipsychotics therefore categorization based on the action is difficult. [ 64 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14490", "text": "More recent research is questioning the notion that second-generation antipsychotics are superior to first generation typical antipsychotics. Using a number of parameters to assess quality of life,  Manchester University  researchers found that typical antipsychotics were no worse than atypical antipsychotics. The research was funded by the  National Health Service  (NHS) of the UK. [ 134 ]  Because each medication (whether first or second generation) has its own profile of desirable and adverse effects, a neuropsychopharmacologist may recommend one of the older (\"typical\" or first generation) or newer (\"atypical\" or second generation) antipsychotics alone or in combination with other medications, based on the symptom profile, response pattern, and adverse effects history of the individual patient."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14491", "text": "Between May 2007 and April 2008, 5.5 million Americans filled at least one prescription for an atypical antipsychotic. [ 46 ]  In patients under the age of 65, 71% of patients were prescribed an atypical antipsychotic to treat Schizophrenia or Bipolar Disorder where this dropped to 38% in patients aged 65 or above. [ 46 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14492", "text": "Despite the name \"antipsychotics\", the drugs are commonly used for a variety of conditions that do not involve  psychosis . Some healthcare professionals reported avoiding the name \"atypical antipsychotic\" when prescribing the drug to patients who had bipolar disorder. [ 135 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14493", "text": "Stahl: AP Explained 1"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14494", "text": "6CM4"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14495", "text": "1813"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14496", "text": "13489"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14497", "text": "ENSG00000149295"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14498", "text": "ENSMUSG00000032259"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14499", "text": "P14416"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14500", "text": "P61168"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14501", "text": "NM_016574 NM_000795"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14502", "text": "NM_010077"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14503", "text": "NP_000786 NP_057658 NP_000786.1"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14504", "text": "NP_034207"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14505", "text": "Dopamine receptor D 2 , also known as  D 2 R , is a  protein  that, in humans, is encoded by the  DRD2   gene . After work from  Paul Greengard 's lab had suggested that  dopamine receptors  were the site of action of antipsychotic drugs, several groups, including those of  Solomon H. Snyder  and  Philip Seeman  used a radiolabeled antipsychotic drug to identify what is now known as the  dopamine  D 2  receptor. [ 5 ]  The dopamine D 2  receptor is the main  receptor  for most  antipsychotic drugs .  The structure of DRD2 in complex with the atypical antipsychotic  risperidone  has been determined. [ 6 ] [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14506", "text": "D 2  receptors are coupled to  G i  subtype of  G protein . This  G protein-coupled receptor  inhibits  adenylyl cyclase  activity. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14507", "text": "In mice, regulation of D 2 R surface expression by the  neuronal calcium sensor-1  (NCS-1) in the  dentate gyrus  is involved in exploration,  synaptic plasticity  and memory formation. [ 9 ]  Studies have shown potential roles for D 2 R in retrieval of fear memories in the  prelimbic cortex [ 10 ]  and in discrimination learning in the  nucleus accumbens . [ 11 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14508", "text": "In flies, activation of the D 2   autoreceptor  protected dopamine neurons from cell death induced by  MPP + , a toxin mimicking  Parkinson's disease  pathology. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14509", "text": "While optimal dopamine levels favor D 1 R cognitive stabilization, it is the D 2 R that mediates the cognitive flexibility in humans. [ 13 ] [ 14 ] [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14510", "text": "Alternative splicing  of this gene results in three transcript variants encoding different  isoforms . [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14511", "text": "The long form ( D2Lh ) has the \"canonical\" sequence and functions as a classic post- synaptic  receptor. [ 17 ]  The short form ( D2Sh ) is pre-synaptic and functions as an  autoreceptor  that regulates the levels of dopamine in the synaptic cleft. [ 17 ]   Agonism  of D2sh receptors inhibits dopamine release; antagonism increases  dopaminergic  release. [ 17 ]  A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14512", "text": "D 2 R conformers are equilibrated between two full active (D 2 High R) and inactive (D 2 Low R) states, while in complex with an  agonist  and  antagonist  ligand, respectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14513", "text": "The monomeric inactive conformer of D 2 R in binding with  risperidone  was reported in 2018 ( PDB  ID: 6CM4). However, the active form which is generally bound to an agonist, is not available yet and in most of the studies the  homology modeling  of the structure is implemented. The difference between the active and inactive of  G protein-coupled receptor  is mainly observed as conformational changes at the cytoplasmic half of the structure, particularly at the  transmembrane domains  (TM) 5 and 6. The conformational transitions occurred at the cytoplasmic ends are due to the coupling of  G protein  to the cytoplasmic loop between the TM 5 and 6. [ 19 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14514", "text": "It was observed that either D 2 R agonist or antagonist ligands revealed better  binding affinities  inside the ligand-binding domain of the active D 2 R in comparison with the inactive state. It demonstrated that ligand-binding domain of D 2 R is affected by the conformational changes occurring at the cytoplasmic domains of the TM 5 and 6. In consequence, the D 2 R activation reflects a positive cooperation on the ligand-binding domain."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14515", "text": "In drug discovery studies in order to calculate the binding affinities of the D 2 R ligands inside the binding domain, it's important to work on which form of D 2 R. It's known that the full active and inactive states are recommended to be used for the agonist and antagonist studies, respectively."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14516", "text": "Any disordering in equilibration of D 2 R states, which causes problems in signal transferring between the nervous systems, may lead to diverse serious disorders, such as  schizophrenia , [ 20 ]   autism [ citation needed ]  and  Parkinson's disease . [ citation needed ]  In order to assist in the management of these conditions, equilibration between the D 2 R states is controlled by implementing of agonist and antagonist D 2 R ligands. [ citation needed ]  In most cases, it was observed that the problems regarding the D 2 R states may have genetic roots and are controlled by drug therapies. [ citation needed ]  So far, there is no certain treatment for these mental disorders."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14517", "text": "There is an orthosteric binding site (OBS), as well as a secondary binding pocket (SBP) on the dopamine 2 receptor, and interaction with the SBP is a requirement for allosteric pharmacology. The compound SB269652 is a negative allosteric modulator of the D 2 R. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14518", "text": "It was observed that D 2 R exists in dimeric forms or higher order oligomers. [ 22 ]  There are some experimental and molecular modeling evidences that demonstrated the D 2 R monomers cross link from their TM 4 and TM 5 to form dimeric conformers. [ 23 ] [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14519", "text": "Allelic  variants:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14520", "text": "Some researchers have previously associated the  polymorphism  Taq 1A ( rs1800497 ) to the  DRD2  gene.\nHowever, the polymorphism resides in  exon  8 of the  ANKK1  gene. [ 28 ]  DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor\nfluctuations but not hallucinations in Parkinson's disease. [ 29 ] [ 30 ]  A splice variant in Dopamine receptor D2(rs1076560) was found to be associated with limb truncal  tardive dyskinesia  and diminished expression factor of  Positive and Negative Syndrome Scale  (PANSS) in  schizophrenia  subjects. [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14521", "text": "Most of the older  antipsychotic  drugs such as  chlorpromazine  and  haloperidol  are antagonists for the dopamine D 2  receptor, but are, in general, very unselective, at best selective only for the \"D 2 -like family\" receptors and so binding to D 2 , D 3  and D 4 , and often also to many other receptors such as those for  serotonin  and  histamine , resulting in a range of side-effects and making them poor agents for scientific research. In similar manner, older dopamine agonists used for  Parkinson's disease  such as  bromocriptine  and  cabergoline  are poorly selective for one dopamine receptor over another, and, although most of these agents do act as D 2  agonists, they affect other subtypes as well. Several selective D 2   ligands  are, however, now available, and this number is likely to increase as further research progresses."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14522", "text": "The dopamine receptor D 2  has been shown to  interact  with  EPB41L1 , [ 50 ]   PPP1R9B [ 51 ]  and  NCS-1 . [ 52 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14523", "text": "The D 2  receptor forms  receptor heterodimers   in vivo  (i.e., in living animals) with other  G protein-coupled receptors ; these include: [ 53 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14524", "text": "The D 2  receptor has been shown to form heterodimers  in vitro  (and possibly  in vivo ) with  DRD 3 , [ 56 ]   DRD 5 , [ 57 ]  and  5-HT 2A . [ 58 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14525", "text": "Insulin shock therapy  or  insulin coma therapy  was a form of  psychiatric  treatment in which patients were repeatedly injected with large doses of  insulin  in order to produce daily  comas  over several weeks. [ 1 ]  It was introduced in 1927 by Austrian-American  psychiatrist   Manfred Sakel  and used extensively in the 1940s and 1950s, mainly for  schizophrenia , before falling out of favour and being replaced by  neuroleptic  drugs in the 1960s. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14526", "text": "It was one of a number of physical treatments introduced into psychiatry in the first four decades of the 20th century. These included the convulsive therapies ( cardiazol/metrazol  therapy and  electroconvulsive therapy ),  deep sleep therapy , and  psychosurgery . Insulin coma therapy and the convulsive therapies are collectively known as the  shock therapies ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14527", "text": "In 1927, Sakel, who had recently qualified as a medical doctor in  Vienna  and was working in a psychiatric clinic in  Berlin , began to use low (sub-coma) doses of insulin to treat drug addicts and psychopaths, and when one of the patients experienced improved mental clarity after having slipped into an accidental coma, Sakel reasoned the treatment might work for mentally ill patients. [ 3 ]  Having returned to Vienna, he treated schizophrenic patients with larger doses of insulin in order to deliberately produce coma and sometimes convulsions. [ 3 ]  Sakel made his results public in 1933, and his methods were soon taken up by other psychiatrists. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14528", "text": "Joseph Wortis , after seeing Sakel practice it in 1935, introduced it to the US. British psychiatrists from the  Board of Control  visited Vienna in 1935 and 1936, and by 1938, 31 hospitals in England and Wales had insulin treatment units. [ 2 ]  In 1936, Sakel moved to New York and promoted the use of insulin coma treatment in US psychiatric hospitals. [ 3 ]  By the late 1940s, the majority of psychiatric hospitals in the US were using insulin coma treatment. [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14529", "text": "Insulin coma therapy was a labour-intensive treatment that required trained staff and a special unit. [ 2 ]  Patients, who were almost invariably diagnosed with  schizophrenia , were selected on the basis of having a good  prognosis  and the physical strength to withstand an arduous treatment. [ 5 ]  There were no standard guidelines for treatment. Different hospitals and psychiatrists developed their own protocols. [ 5 ]  Typically, injections were administered six days a week for about two months. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14530", "text": "The daily insulin dose was gradually increased to 100\u2013150 units (1 unit = 34.7  \u03bcg [ 6 ] ) until comas were produced, at which point the dose would be levelled out. [ 1 ]  Occasionally doses of up to 450 units were used. [ 7 ]  After about 50 or 60 comas, or earlier if the psychiatrist thought that maximum benefit had been achieved, the dose of insulin was rapidly reduced before treatment was stopped. [ 5 ] [ 8 ]  Courses of up to 2 years have been documented. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14531", "text": "After the insulin injection patients would experience various symptoms of decreased blood glucose: flushing, pallor, perspiration, salivation, drowsiness or restlessness. [ 8 ]   Sopor  and coma\u2014if the dose was high enough\u2014would follow. [ 8 ]  Each coma would last for up to an hour and be terminated by intravenous glucose or via naso-gastric tube. [ 1 ]  Seizures occurred before or during the coma. [ 9 ]  Many would be tossing, rolling, moaning, twitching, spasming or thrashing around. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14532", "text": "Some psychiatrists regarded seizures as therapeutic and patients were sometimes also given  electroconvulsive therapy  or cardiazol/metrazol convulsive therapy during the coma, or on the day of the week when they didn't have insulin treatment. [ 8 ] [ 9 ]  When they were not in a coma, insulin coma patients were kept together in a group and given special treatment and attention. One handbook for psychiatric nurses, written by British psychiatrist  Eric Cunningham Dax , instructs nurses to take their insulin patients out walking and occupy them with games and competitions, flower-picking and map-reading, etc. [ 10 ]  Patients required continuous supervision as there was a danger of hypoglycemic aftershocks after the coma. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14533", "text": "In \"modified insulin therapy\", used in the treatment of neurosis, patients were given lower (sub-coma) doses of insulin. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14534", "text": "A few psychiatrists (including Sakel) claimed success rates for insulin coma therapy of over 80% in the treatment of schizophrenia. [ 11 ]  A few others argued that it merely accelerated remission in those patients who were undergoing remission anyway. The consensus at the time was somewhere in between, claiming a success rate of about 50% in patients who had been ill for less than a year (about double the spontaneous remission rate) with no influence on relapse. [ 3 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14535", "text": "Sakel suggested the therapy worked by \"causing an intensification of the tonus of the parasympathetic end of the autonomic nervous system, by blockading the nerve cell, and by strengthening the anabolic force which induces the restoration of the normal function of the nerve cell and the recovery of the patient.\" [ 3 ]  The shock therapies in general had developed on the erroneous premise that  epilepsy  and schizophrenia rarely occurred in the same patient. The premise was supported by neuropathologic studies that found a dearth of glia in the brains of schizophrenic patients and a surplus of glia in epileptic brains. These observations led the Hungarian neuropsychiatrist  Ladislas Meduna  to induce seizures in schizophrenic patients with injections of camphor, soon replaced by pentylenetetrazol (Metrazole). [ 13 ]  Another theory was that patients were somehow \"jolted\" out of their mental illness. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14536", "text": "The  hypoglycemia  (pathologically low  glucose  levels) that resulted from insulin coma therapy made patients extremely restless, sweaty, and liable to further convulsions and \"after-shocks\". In addition, patients invariably emerged from the long course of treatment \"grossly  obese \", [ 5 ]  probably due to glucose rescue-induced  glycogen storage disease . The most severe risks of insulin coma therapy were death and brain damage, resulting from irreversible or prolonged coma respectively. [ 1 ] [ 7 ]  A study at the time claimed that many of the cases of brain damage were actually therapeutic improvement because they showed \"loss of tension and hostility\". [ 15 ]  Mortality risk estimates varied from about 1% [ 2 ]  to 4.9%. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14537", "text": "Respected singer-songwriter  Townes Van Zandt  was said to have lost much of his long-term memory from this treatment, performed on him for  bipolar disorder , preceding a life of  substance abuse  and  depression . [ 17 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14538", "text": "Insulin coma therapy was used in most hospitals in the US and the UK during the 1940s and 1950s. The numbers of patients were restricted by the requirement for intensive medical and nursing supervision and the length of time it took to complete a course of treatment. For example, at one typical large British psychiatric hospital,  Severalls Hospital  in  Essex , insulin coma treatment was given to 39 patients in 1956. In the same year, 18 patients received modified insulin treatment, while 432 patients were given electroconvulsive treatment. [ 18 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14539", "text": "In 1953, British psychiatrist Harold Bourne published a paper entitled \"The insulin myth\" in the  Lancet , in which he argued that there was no sound basis for believing that insulin coma therapy counteracted the schizophrenic process in a specific way. If treatment worked, he said, it was because patients were chosen for their good prognosis and were given special treatment: \"insulin patients tend to be an elite group sharing common privileges and perils\". [ 19 ]  Prior to publishing \"The insulin myth\" in  The Lancet , Bourne had tried to submit the article to the  Journal of Mental Science ; after a 12-month delay, the Journal informed Bourne they had rejected the article, telling him to \"get more experience\". [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14540", "text": "In 1957, when insulin coma treatment use was declining,  The Lancet  published the results of a randomized, controlled trial in which patients were either given insulin coma treatment or identical treatment but with unconsciousness produced by  barbiturates . There was no difference in outcome between the groups and the authors concluded that, whatever the benefits of the coma regimen, insulin was not the specific therapeutic agent. [ 21 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14541", "text": "In 1958, American neuropsychiatrist Max Fink published in the Journal of the American Medical Association the results of a random controlled comparison in 60 patients treated with 50 iatrogenic insulin-induced comas or chlorpromazine in doses from 300\u00a0mg to 2000\u00a0mg/day. [ 22 ]  The results were essentially the same in relief and discharge ratings but chlorpromazine was safer with fewer side-effects, easier to administer, and better suited to long-term care. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14542", "text": "In 1958, Bourne published a paper on increasing disillusionment in the psychiatric literature about insulin coma therapy for schizophrenia. He suggested there were several reasons it had received almost universal uncritical acceptance by reviews and textbooks for several decades despite the occasional disquieting negative finding, including that, by the 1930s when it all started, schizophrenics were considered inherently unable to engage in  psychotherapy , and insulin coma therapy \"provided a personal approach to the schizophrenic, suitably disguised as a physical treatment so as to slip past the prejudices of the age.\" [ 23 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14543", "text": "By the 1970s, insulin shock therapy had mostly fallen out of use in the United States, though was still practiced in some hospitals. [ 24 ]  Its use may have continued longer in China, India, and the Soviet Union. [ 20 ] [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14544", "text": "Recent articles about insulin coma treatment have attempted to explain why it was given such uncritical acceptance. In the US, Deborah Doroshow wrote that insulin coma therapy secured its foothold in psychiatry not because of scientific evidence or knowledge of any mechanism of therapeutic action, but due to the impressions it made on the minds of the medical practitioners within the local world in which it was administered and the dramatic recoveries observed in some patients. Today, she writes, those who were involved are often ashamed, recalling it as unscientific and inhumane. Administering insulin coma therapy made psychiatry seem a more legitimate medical field. Harold Bourne, who questioned the treatment at the time, said: \"It meant that psychiatrists had something to do. It made them feel like real doctors instead of just institutional attendants\". [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14545", "text": "One retired psychiatrist who was interviewed by Doroshow \"described being won over because his patients were so sick and alternative treatments did not exist\". [ 5 ]  Doroshow argues that \"psychiatrists used complications to exert their practical and intellectual expertise in a hospital setting\" and that collective risk-taking established \"especially tight bonds among unit staff members\". [ 5 ]  She finds it ironic that psychiatrists \"who were willing to take large therapeutic risks were extremely careful in their handling of adverse effects\". Psychiatrists interviewed by Doroshow recalled how insulin coma patients were provided with various routines and recreational and group-therapeutic activities, to a much greater extent than most psychiatric patients. Insulin coma specialists often chose patients whose problems were the most recent and who had the best  prognosis ; in one case discussed by Doroshow a patient had already started to show improvement before insulin coma treatment, and after the treatment denied that it had helped, but the psychiatrists nevertheless argued that it had. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14546", "text": "In 1959, the 1994  Nobel Prize  winner in Economics,  John Nash , was diagnosed with schizophrenia and was initially treated at McLean Hospital. When he relapsed, he was admitted to  Trenton Psychiatric Hospital  in  New Jersey .\u00a0His associates at  Princeton University  pleaded with the hospital director to have Nash admitted to the insulin coma unit, recognizing that it was better staffed than other hospital units. He responded to treatment and was subsequently medicated with  neuroleptics . [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14547", "text": "Nash's life story was presented in the film  A Beautiful Mind , which accurately portrayed the seizures associated with his treatments. [ 27 ]   In a review of\u00a0the Nash history, Fink ascribed the success of coma treatments to the 10% of associated seizures, noting that physicians often augmented the comas by convulsions induced by  ECT . He envisioned insulin coma treatment as a weak form of convulsive therapy. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14548", "text": "In the UK, psychiatrist Kingsley Jones sees the support of the Board of Control as important in persuading psychiatrists to use insulin coma therapy. The treatment then acquired the privileged status of a standard procedure, protected by professional organizational interests. He also notes that it has been suggested that the  Mental Treatment Act 1930  encouraged psychiatrists to experiment with physical treatments. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14549", "text": "British lawyer Phil Fennell notes that patients \"must have been terrified\" by the insulin coma therapy procedures and the effects of the massive overdoses of insulin, and were often rendered more compliant and easier to manage after a course. [ 14 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14550", "text": "Leonard Roy Frank , an American activist from the  psychiatric survivors movement  who underwent 50 forced insulin coma treatments combined with ECT, described the treatment as \"the most devastating, painful and humiliating experience of my life\", a \"flat-out atrocity\" glossed over by psychiatric  euphemism , and a violation of basic human rights. [ 29 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14551", "text": "In 2013, French physician-and-novelist  Laurent Seksik  wrote an historical novel about the tragic life of  Eduard Einstein :  Le cas Eduard Einstein . He related the encounter between Dr Sakel and  Mileva Maric ,  Albert Einstein 's first wife (and Eduard's mother), and the way Sakel's therapy had been given to Eduard, who had  schizophrenia . [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14552", "text": "Like many new medical treatments for diseases previously considered incurable, depictions of insulin coma therapy in the media were initially favorable. In the 1940 film  Dr. Kildare's Strange Case , young Kildare uses the new \"insulin shock cure for schizophrenia\" to bring a man back from insanity. The film dramatically shows a five-hour treatment that ends with a patient eating jelly sandwiches and reconnecting with his wife. Other films of the era began to show a more sinister approach, beginning with the 1946 film  Shock , in which actor  Vincent Price  plays a doctor who plots to murder a patient using an overdose of insulin in order to keep the fact that he was a murderer a secret. More recent films include  Frances  (1982) in which actress  Frances Farmer  undergoes insulin coma treatment, and  A Beautiful Mind , which depicted genius  John Nash  undergoing insulin treatment. In an episode of the medical drama  House M.D. , House puts himself in an insulin shock to try to make his hallucinations disappear. [ 31 ]   Sylvia Plath 's  The Bell Jar  refers to insulin coma therapy in chapter 15. In  Kelly Rimmer 's book,  The German Wife , the character Henry Davis undergoes insulin shock therapy to treat 'combat fatigue'."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14553", "text": "The  Journal of Child and Adolescent Psychopharmacology  is a  peer-reviewed   medical journal  covering  psychopharmacology  in  children  and  adolescents . It was established in 1990 and is published ten times per year by  Mary Ann Liebert . The  editor-in-chief  is  Harold S. Koplewicz  (Child Mind Institute). According to the  Journal Citation Reports , the journal has a 2017  impact factor  of 2.901. [ 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14554", "text": "Electroencephalography  (EEG) is the science of recording the spontaneous rhythmic electrical activity of a living brain through electrodes on the scalp. Brain rhythms have origins similar to the electrical activity of the heart.  The rhythmic activity varies in frequency and amplitude with age, attention, sleep, and chemical concentrations of oxygen, carbon dioxide, glucose, ammonia, and hormones. Chemicals that affect brain functions change brain rhythms in systematic and identifiable ways. As new psychoactive drugs were discovered that changed behavior, the basis for the science of  psychopharmacology , the accompanying changes in the rhythms were found to be drug class specific.  The measurement of the changes in rhythms became the basis for the science of pharmaco-EEG."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14555", "text": "Definitions of the changes in EEG rhythms were developed that identified and classified psychoactive drugs, monitored the depth of anesthesia, and evaluated the efficacy of the seizures induced in convulsive therapy (electroshock)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14556", "text": "The first recordings of electrical activity from the brain were reported from exposed animal brain tissues in the 1870s. In 1929 Hans Berger, a German psychiatrist, reported continuous electrical rhythms from the intact human head using electrodes on the scalp.  The continuous electrical activity varied in frequencies and amplitude with drowsiness and sleep, and with mental problem solving.  Episodic runs and bursts of high voltage slow frequencies were recorded in patients with epilepsy."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14557", "text": "In his third report in 1931 Berger recorded changes in the rhythms with cocaine, morphine, scopolamine, and chloroform. Each chemical elicited different frequency and amplitude patterns and different behaviors."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14558", "text": "The first clinical applications were in identifying the sudden bursts of high voltage slow frequencies during seizures, both spontaneous and induced by the chemical pentylenetetrazol (Metrazol), by electricity in electroshock, and in the coma induced by insulin.  When reserpine was studied in 1953, chlorpromazine in 1954, and imipramine in 1957, individual rhythmic patterns were described."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14559", "text": "The EEG patterns of new psychoactive drugs predicted their clinical activity.  By the 1960s, EEG analysis of psychoactive drugs was a feature of the NIMH Early Clinical Drug Evaluation (ECDEU) program that evaluated and identified new psychiatric treatments. Proposed psychoactive drugs developed in chemical laboratories were first tested in animals and then tested in man.  The changes in the EEG became the basis for a classification of new drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14560", "text": "Assessment methods in human volunteers were developed that recorded the changes in the resting subject at different dosages, both on acute single administrations and repeated daily dosing. The observed changes were compared to those for known drugs and predicted their behavioral effects. When no systematic changes were recorded, the agents were considered not to have a clinical use."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14561", "text": "Dosing schedules were optimized.  In patients who failed to respond to prescribed treatments, those who were considered \"pharmacotherapy resistant,\" EEG studies showed that the chemicals did not elicit identifiable brain changes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14562", "text": "In pre-clinical animal trials EEG recordings were associated the changes with vigilance and motor measures, concluding that the EEG patterns were \"dissociated,\" that is, bearing little relationship to the changes in behavior.  In human trials, however, when the EEG measures could be related to vigilance, mood, memory, and psychological tests, a theory of \"association of EEG and behavior\" developed and sustained pharmaco-EEG studies of new drugs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14563", "text": "The technology was applied in anesthesia, identifying the efficacy of individual seizures in convulsive therapy, in studies of sleep patterns, and the relation of evoked potentials to speech and psychological tests."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14564", "text": "Social changes in attitudes to the ethics of testing drugs and treatments in patients, prisoners, children, and volunteers inhibited the continued development of the science and its abandonment."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14565", "text": "Polypharmacy and the widespread use of active psychiatric drugs made the study of individual compounds in psychiatric patients difficult.  The science then successfully focused on alert male volunteers (since the EEG varied with menstrual cycles in women). [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14566", "text": "Vigilance.  The scalp recorded EEG is sensitive to changes in vigilance.  Different methods developed to sustain a monitored level of alertness using hand held buzzers that sounded off when the subject relaxed and dozed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14567", "text": "Volunteer Baseline and Placebo training.  As the EEG is sensitive to anxiety, an initial training session became standard procedure. The baseline recording identified subjects whose records were unique."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14568", "text": "EEG recording.  Different electrode placements were tested. Commonly the recordings were made using the frontal-occipital or the bifrontal leads. Standard EEG amplifiers were used."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14569", "text": "Quantification and analyses. In the beginning the EEG recordings were made on paper and changes measured visually, scored by ruler and calipers. By the 1960s, electronic analyzers of 10 second epochs measured changes in \"power.\"   Digital computer methods using period analysis, power spectral density, and amplitude analyses followed."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14570", "text": "The quantitative changes in mean frequency, mean amplitudes, percent time delta (1\u20133\u00a0Hz), theta (3.5 - 7.5\u00a0Hz), alpha (8-12.5\u00a0Hz), beta1 (13\u201321\u00a0Hz), and beta2 (>21\u00a0Hz), and the presence of bursts in 10-second epochs were commonly used to identify patterns."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14571", "text": "Predictive patterns.  The measures related the EEG changes to the common classes of psychoactive drugs\u2014antidepressant,  anxiolytic ,  antipsychotic , hallucinogen,  deliriant ,  euphoriant , and mood stabilizer being the most frequent.  For a time, the pharmaco-EEG profiles of different classes of drugs were actively used to identify active psychotropic agents."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14572", "text": "Psychopharmacology.  Pharmaco-EEG studies were economically useful in clinically classifying new agents, dosage ranges and durations of effects, and separating active from inactive substances.  The list of successful applications is extensive; some specific examples are the identification of mianserin (GB-94) and doxepin as antidepressants of the imipramine class; of the inactivity of flutroline as a proposed antipsychotic in man despite activity in dogs; and of equivalent EEG activity of the laevo and dextro enantiomers of 6-azamianserin (mirtazapine) despite differences in preclinical trials."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14573", "text": "Studies of different cannabis formulations (hashish, marijuana, tetrahydrocannabinol-\u2206-9 extract each showed the same patterns in EEG, cardiovascular, and clinical profiles. Tolerance development was marked in acute administration of cannabis in chronic hashish users."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14574", "text": "In testing narcotic antagonists ( naloxone ,  cyclazocine ) and opioid substitutes ( methadone ,  levomethadyl ) in the treatment of opioid dependence, the quantitative EEG experiments showed the efficiency of antagonistic and replacement activity of different dosing schedules. Dose finding trials of naloxone showed no specific CNS effect when administered alone but very effective antagonistic action in opioid dose and overdose."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14575", "text": "Convulsive therapy.  The grandmal seizure is the central event in electroshock (electroconvulsive therapy, ECT) and insulin coma.  It was introduced in 1934 and by the 1940s EEG recordings during the treatment showed the classic sequence of epileptic seizure events recognized as the \"grand mal seizure.\"  In the 1950s, recordings of interseizure records, on days after an induced seizure, showed progressive slowing of mean frequencies and increased amplitudes during the treatment course.  These changes were necessary accompaniments of effective courses of treatment\u2014patients without progressive slowing failed to recover."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14576", "text": "In the early 1980s, commercial ECT devices were equipped with a 2-channel EEG recorder that measured the EEG characteristics and duration.  The quality of the EEG record became the standard for an \"effective\" treatment.  The same quantitative measures used in psychopharmacology were established in clinical ECT."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14577", "text": "Anesthesia.  Specialized equipment to monitor ongoing identification of anesthesia stages are common in modern surgical units."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14578", "text": "History."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14579", "text": "Fink M. Pharmacoelectroenephalography: A note on its history. Neuropsychobiology 1984; 12:173-178"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14580", "text": "Fink M. A clinician-researcher and ECDEU: 1959-1980. In: T. Ban, D. Healy, E. Shorter (Eds.):  The Triumph of Psychopharmacology and the Story of the CINP. Budapest, Animula,  82-96, 2000."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14581", "text": "Fink M. Pharmaco-Electroencephalography: A  Selective History of the Study of Brain Responses to Psychoactive Drugs. In: T. Ban, E. Shorter, D. Healy (Eds.):  History of CINP, IV: 661-672, 2004."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14582", "text": "Galderisi S, Sannita WG. Pharmaco-EEG: A history of progress and missed opportunity. Clinical EEG and Neuroscience  37:61-65, 2006;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14583", "text": "Fink M. Remembering the lost science of pharmaco-EEG. Acta psychiatr Scand.,  121:161-173. 2010"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14584", "text": "Methodology"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14585", "text": "Brazier MAB (Ed): Computer Techniques in EEG Analysis. EEG Journal, Supplement 20, 1-98, 1961."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14586", "text": "Stille G, Herrmann W, Bente D, Fink M, Itil T, Koella WP, Kubicki S, K\u00fcnkel H, Kugler J, Matejcek M, Petsche H. Guidelines for pharmaco-EEG studies in man. Pharmacopsychiatry 15:107-108;1982"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14587", "text": "Herrmann WM, Abt K, Coppola R, et al. International Pharmaco-EEG Group (IPEG). Recommendations for EEG and evoked potential mapping. Neuropsychobiology  22:170-176. 1989"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14588", "text": "Association or dissociation?"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14589", "text": "Wikler A.  Pharmacologic dissociation of behavior and EEG 'sleep patterns' in dogs: Morphine, n-allynormorphine and atropine. Proc Soc exp Biol 79:261-264, 1952;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14590", "text": "Wikler A. Clinical and electroencephalographic studies on the effect of mescaline, n-allyInormorphine and morphine in man. J nerv ment Dis 120:157-175, 1954."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14591", "text": "Fink M. EEG classification of psychoactive compounds in man: Review and theory of behavioral association. In: Efron D, Cole JO, Levine J, Wittenborn JR. (Eds): Psychopharmacology: A Review of Progress 1957-1967 U.S.G.P.O., Washington, D.C., 497-507, 1968;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14592", "text": "Fink M., Itil T. Neurophysiology of the phantastica: EEG and behavioral relations in man. In: Efron D, Cole JO, Levine J, Wittenborn JR. (Eds): Psychopharmacology: A Review of Progress 1957-1967. U.S.G.P.O., Washington, D.C., 1231-1239, 1968;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14593", "text": "Fink M.  Itil T. EEG and human psychopharmacology: IV: Clinical antidepressants. In: Efron D, Cole JO, Levine J, Wittenborn JR. (Eds): Psychopharmacology: A Review of Progress 1957-1967. U.S.G.P.O., Washington, D.C., 671-682, 1968;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14594", "text": "Fink M. EEG and human psychopharmacology.  Annu Rev Pharmacol 9:241-258, 1969;"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14595", "text": "Bradley P and Fink M. (Eds): Anticholinergic Drugs and Brain Functions in Animals and Man. Prog Brain Res 28, 184 pp., 1968."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14596", "text": "Fink M. EEG and behavior: Association or dissociation in man? Integrative Psychiatry  9:108-123, 1993."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14597", "text": "Examples of human studies."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14598", "text": "Fink M, Kahn RL. Relation of EEG delta activity to behavioral response in electroshock: Quantitative serial studies. Arch Neurol & Psychiatry 78:516-525,1957"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14599", "text": "Fink M. Electroencephalographic  and behavioral effects of Tofranil. Canad Psychiat Assoc J, 4 (suppl) 166-71, 1959."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14600", "text": "Itil TM, Polvan N, Hsu W. Clinical and EEG effects of GB-94, a tetracyclic antidepressant: EEG model in the discovery of a new psychotropic drug. Curr Ther Res 14:395-413, 1972."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14601", "text": "Volavka J, Levine R, Feldstein S, Fink M. Short-term effects of heroin in man. Arch Gen Psychiatry 30:677-684,1974."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14602", "text": "Itil TM, Cora R, Akpinar S, Herrmann WH, Patterson CJ. \"Psychotropic\" action of sex hormones:  Computerized EEG in establishing the immediate CNS effects of steroid hormones. Curr Therapeutic Res 16:1147-1170, 1974."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14603", "text": "Fink M, Kety S, McGaugh J (Eds.): Psychobiology of Convulsive Therapy. Washington DC: VH Winston & Sons, 1974."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14604", "text": "Volavka J, Fink M, Panayiotopoulos CP. Acute EEG effects of cannabis preparations in long-term users. In: C. Stefanis, R. Dornbush, M Fink (Eds): Hashish- A Study of Long-Term Use. NY: Raven Press, 1977."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14605", "text": "American Psychiatric Association Electroconvulsive therapy. Task Force Report #14. Washington, DC: American Psychiatric Association. (1978). (200 pp.)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14606", "text": "Fink M, Irwin P, Sannita W, Papakostas Y, Green MA. Phenytoin: EEG effects and plasma levels in volunteers. Therap Drug Monitoring 1: 93-104, 1979."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14607", "text": "Fink M and Irwin P. EEG and behavioral profile of flutroline (CP-36,584), a novel antipsychotic drug. Psychopharmacology 72: 67-71, 1981."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14608", "text": "Fink M and Irwin P. Pharmaco-EEG study of 6-azamianserin (ORG-3770): Dissociation  of EEG and pharmacologic predictors of antidepressant activity. Psychopharmacology 78: 44-48, 1982."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14609", "text": "Fink M, Irwin P. CNS effects of acetylsalicylic acid (Aspirin). Clin Pharm Therap 32:362-365, 1982."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14610", "text": "Additional notes."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14611", "text": "This is a  list of  psychiatric medications  used by  psychiatrists  and other  physicians  to treat  mental illness  or distress."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14612", "text": "The list is ordered alphabetically according to the condition or conditions, then by the  generic  name of each medication. The list is not exhaustive and not all drugs are used regularly in all countries. Some medications treat multiple conditions and appear multiple times."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14613", "text": "The  psychopharmacology revolution  covers the introduction of various psychiatric drugs into clinical practice as well as their continued development. Although not exclusively limited to the 1950s period, the literature tends to suggest that this decade was a particularly fruitful time for  CNS  drug discovery and it has been referred to as a \"golden era\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14614", "text": "The history of  chlorpromazine  can be traced back to the work of  BASF  who were creating dyes at around the turn of the 20th century (c.f.  methylene blue ). It was found that attaching basic side chains to the tricyclic  phenothiazine  residue resulted in compounds that functioned as reliable  antihistamines ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14615", "text": "Henri Laborit  was first using chlorpromazine to treat the anxiety of patients prior to surgery. He noted the so-called \"indifference\" that this agent causes and suggested that it be used on agitated psychotic patients. [ 1 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14616", "text": "Chlorpromazine has H1, M1, and \u03b11 receptor antagonist activity. This causes sedation, anticholinergic effects, as well as orthostatic hypotension. It also functions as a blocker of D2 receptors, although it is much weaker and less selective than  haloperidol  in this respect. Blockade of the D2 receptors is thought to underlie the antipsychotic effect of the  typical antipsychotics . However, in the case of atypicals such as  clozapine  and  risperidone , blockade of 5HT2A receptors are thought to also account for an important part of their pharmacology."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14617", "text": "Minor chemical manipulations in the chemical structure of chlorpromazine was used to create novel antipsychotic agents such as  thioridazine  and  fluoperazine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14618", "text": "Minor chemical manipulations in the structure of chlorpromazine led to the first  tricyclic antidepressant  (TCA),  imipramine  (Tofranil), whose structure is iminodibenzyl ( dibenzazepine ) based. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14619", "text": "Imipramine was first used on agitated psychotic patients, but it was shown that in the majority of cases their condition did not improve and actually worsened slightly. However, it was noted that a few of the patients who were depressed became more animated so its use in the treatment of depression became apparent."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14620", "text": "Due to the chemical similarity of imipramine to chlorpromazine, this agent also functions as a H1, M1, and \u03b11 receptor antagonist. Imipramine is also known to function as a fast sodium channel blocker, which is said to account for the cardiotoxicity of this agent. The collective effect of imipramine on these receptors is not thought to contribute to its therapeutic activity in the treatment of depression, although it is believed to account for mostly all of its side effects."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14621", "text": "The usefulness of the TCAs in treating depression is thought to stem from their ability to inhibit the uptake of the neurotransmitters serotonin (5-HT) and noradrenaline (NA). It was proposed that designing agents that were more selective for 5-HT and/or NA would lower the incidence of side effects. This in turn has led to the development/discovery of the SSRIs and SNRIs."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14622", "text": "The so-called golden era also covers the discovery of the first  monoamine oxidase inhibitor ,  iproniazid  (Marsilid), which is  hydrazine  based. Like imipramine, this also was used in the treatment of depression. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14623", "text": "Iproniazid  was the result of a failed medicinal chemistry attempt to improve on the anti-tubercular activity of  isoniazid . It was first given to patients with  tuberculosis  where a surprising but wholly unexpected improvement in mood was noticed.  Nathan Kline  coined the term \"psychic energizer\" to account for this effect and posited that they be used in the treatment of depression."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14624", "text": "Iproniazid is no longer used because it caused an unacceptable incidence in  jaundice . Nevertheless, related agents such as  phenelzine  and  isocarboxazid  are still on the market."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14625", "text": "In addition,  tranylcypromine  is a non-hydrazine containing irreversible inhibitor of MAO which is also available. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14626", "text": "A limitation of these agents is their potential to cause hypertension so their safety is not guaranteed. However, it seems that the selective inhibitor of the B isoform of MAO, selegiline, is much less likely to cause hypertension."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14627", "text": "The investigations into the mechanism of activity of these agents that followed their discovery led to the proposal of the \" chemical imbalance \" of  neurotransmitters  theory of mood disorders, which is supposed to account for the  pathophysiology  and/or  pathogenesis  of these states. It follows that these so-called \"imbalances\" can be corrected by the judicious application of appropriately selected  psychotropic  medication(s)."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14628", "text": "An excess of dopamine is cited as the cause of schizophrenia, [ 4 ]  whereas a deficiency of noradrenaline and serotonin were cited as the cause for depression."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14629", "text": "The discovery of  reserpine  was also of great significance to the development of the monoamine amine theory of depression."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14630", "text": "Prior to the introduction of these agents, the management of mental disorders in America relied mainly on \" psychoanalytic \" methods said to be deriving from a \" Freudian \" understanding of the subject area. [ 3 ] [ 5 ]  Apparently, there was great resistance to the use of medicine in the treatment of mental disorders prior to the 1950s. It is, however, known that various other agents including amphetamine and opium have documented use in the history of treating depression, [ 6 ] [ 7 ]  and that barbiturates, lithium salts, bromide salts, various  anticholinergic  alkaloids, as well as opium, were all used in the history of the treatment of schizophrenia. [ 8 ] [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14631", "text": "A  reuptake enhancer  ( RE ), also sometimes referred to as a  reuptake activator , is a type of  reuptake modulator  which enhances the  plasmalemmal   transporter -mediated  reuptake  of a  neurotransmitter  from the  synapse  into the  pre-synaptic   neuron , leading to a decrease in the  extracellular   concentrations  of the neurotransmitter and therefore a decrease in  neurotransmission ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14632", "text": "The  antidepressant   tianeptine  was once claimed to be a  (selective)  serotonin  reuptake enhancer  (SRE or SSRE), but the role of serotonin reuptake in its mechanism is doubtful. Tianeptine has no affinity for the  serotonin transporter , neither increases nor decreases extracellular levels of serotonin in  cortico - limbic  structures of conscious rats, and it didn't show any other long-term effect on the serotonin pathway. [ 1 ]  Ultimately, tianeptine was determined to be a selective mu opioid receptor agonist."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14633", "text": "Coluracetam  is a choline-reuptake enhancer. [ 2 ]  The  flavone   luteoline  as well as some of its  derivatives  enhance the reuptake at the  dopamine transporter , [ 3 ] [ 4 ]  extracts of  Caulis Sinomenii  activate DA/NE transporters. [ 5 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14634", "text": "The  Scandinavian College of Neuropsychopharmacology  ( SCNP ) is a Nordic  psychopharmacology  organisation. The SCNP publishes the journal,  Acta Neuropsychiatrica ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14635", "text": "Stimulants  (also known as  central nervous system stimulants , or  psychostimulants , or colloquially as  uppers ) are a class of drugs that increase  alertness . They are used for various purposes, such as enhancing  attention ,  motivation ,  cognition ,  mood , and  physical performance . Some stimulants occur naturally, while others are exclusively synthetic. Common stimulants include  caffeine ,  nicotine ,  amphetamines ,  cocaine ,  methylphenidate , and  modafinil . Stimulants may be subject to varying forms of regulation, or outright prohibition, depending on jurisdiction."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14636", "text": "Stimulants increase activity in the  sympathetic nervous system , either directly or indirectly. Prototypical stimulants increase synaptic concentrations of  excitatory neurotransmitters , particularly  norepinephrine  and  dopamine  (e.g., methylphenidate). Other stimulants work by binding to the  receptors  of excitatory neurotransmitters (e.g., nicotine) or by blocking the activity of endogenous agents that promote sleep (e.g., caffeine). Stimulants can affect various functions, including  arousal ,  attention , the  reward system ,  learning ,  memory , and  emotion . Effects range from mild stimulation to  euphoria , depending on the specific drug, dose, route of administration, and inter-individual characteristics."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14637", "text": "Stimulants have a long history of use, both for medical and non-medical purposes. Archeological evidence from Peru shows that cocaine use dates back as far as 8000 B.C.E. [ 1 ]  Stimulants have been used to treat various conditions, such as  narcolepsy ,  attention deficit hyperactivity disorder  (ADHD),  obesity ,  depression , and  fatigue . They have also been used as  recreational drugs ,  performance-enhancing substances , and  cognitive enhancers , by various groups of people, such as students, athletes, artists, and workers. They have also been used to promote aggression of combatants in wartime, both historically and in the present day. [ 2 ] [ 3 ] [ 4 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14638", "text": "Simulants have potential risks and side effects, such as  addiction ,  tolerance ,  withdrawal ,  psychosis ,  anxiety ,  insomnia ,  cardiovascular problems , and  neurotoxicity . The misuse and abuse of stimulants can lead to serious health and social consequences, such as  overdose ,  dependence ,  crime , and  violence . Therefore, the use of stimulants is regulated by laws and policies in most countries, and requires medical supervision and prescription in some cases."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14639", "text": "A  stimulant  is an overarching term that covers many  drugs  including those that increase the activity of the  central nervous system  and the body, [ 5 ]  drugs that are pleasurable and invigorating, or drugs that have  sympathomimetic  effects. [ 6 ]  Sympathomimetic effects are those effects that mimic or copy the actions of the  sympathetic nervous system . The sympathetic nervous system is a part of the nervous system that prepares the body for action, such as increasing the heart rate, blood pressure, and breathing rate. Stimulants can activate the same receptors as the natural chemicals released by the sympathetic nervous system (namely  epinephrine  and  norepinephrine ) and cause similar effects. [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14640", "text": "Stimulants in therapeutic doses, such as those given to patients with  attention deficit hyperactivity disorder  (ADHD), increase ability to focus, vigor, sociability, libido and may elevate mood. However, in higher doses, stimulants may actually decrease the ability to focus, a principle of the  Yerkes-Dodson Law . [ 8 ]  In higher doses, stimulants may also produce euphoria, vigor, and a decreased need for sleep."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14641", "text": "Many, but not all, stimulants have  ergogenic  effects; that is, they enhance physical performance. Drugs such as ephedrine, pseudoephedrine, amphetamine and methylphenidate have well documented ergogenic effects, while cocaine has the opposite effect. [ 9 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14642", "text": "Neurocognitive enhancing effects of stimulants, specifically  modafinil , amphetamine and methylphenidate have been reported in healthy adolescents by some studies, [ 10 ]  and is a commonly cited reason among illicit drug users for use, particularly among college students in the context of studying. [ 10 ]  Still, results of these studies is inconclusive: assessing the potential overall neurocognitive benefits of stimulants among healthy youth is challenging due to the diversity within the population, the variability in cognitive task characteristics, and the absence of replication of studies. [ 10 ]  Research on the cognitive enhancement effects of modafinil in healthy non-sleep-deprived individuals has yielded mixed results, with some studies suggesting modest improvements in attention and executive functions while others show no significant benefits or even a decline in cognitive functions. [ 11 ] [ 12 ] [ 13 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14643", "text": "In some cases, psychiatric phenomena may emerge such as  stimulant psychosis ,  paranoia , and  suicidal ideation . Acute toxicity has been reportedly associated with hyperhydrosis, panic attacks, severe anxiety, mydriasis, paranoia, aggressive behavior, excessive motor activity, psychosis, rhabdomyolysis,  and  punding . The violent and aggressive behavior associated with acute stimulant toxicity may partially be driven by paranoia. [ 14 ]  Most drugs classified as stimulants are  sympathomimetic , meaning that they stimulate the sympathetic branch of the autonomic nervous system. This leads to effects such as  mydriasis  (dilation of the pupils), increased heart rate, blood pressure, respiratory rate and body temperature. [ 6 ]  When these changes become pathological, they are called  arrhythmia ,  hypertension , and  hyperthermia , and may lead to  rhabdomyolysis ,  stroke ,  cardiac arrest , or  seizures . However, given the complexity of the mechanisms that underlie these potentially fatal outcomes of acute stimulant toxicity, it is impossible to determine what dose may be lethal. [ 15 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14644", "text": "Assessment of the effects of stimulants is relevant given the large population currently taking stimulants. A systematic review of cardiovascular effects of prescription stimulants found no association in children, but found a correlation between prescription stimulant use and  ischemic   heart attacks . [ 16 ]   A review over a four-year period found that there were few negative effects of stimulant treatment, but stressed the need for longer-term studies. [ 17 ]  A review of a year long period of prescription stimulant use in those with  ADHD  found that cardiovascular side effects were limited to transient increases in blood pressure only. [ 18 ]  However, a 2024 systematic review of the evidence found that stimulants overall improve ADHD symptoms and broadband behavioral measures in children and adolescents, though they carry risks of side effects like appetite suppression and other adverse events. [ 19 ]  Initiation of stimulant treatment in those with ADHD in early childhood appears to carry benefits into adulthood with regard to social and cognitive functioning, and appears to be relatively safe. [ 20 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14645", "text": "Abuse of prescription stimulants (not following physician instruction) or of illicit stimulants carries many negative health risks. Abuse of cocaine, depending upon route of administration, increases risk of cardiorespiratory disease,  stroke , and  sepsis . [ 21 ]  Some effects are dependent upon the route of administration, with intravenous use associated with the transmission of many disease such as  Hepatitis C ,  HIV/AIDS  and potential medical emergencies such as  infection ,  thrombosis  or  pseudoaneurysm , [ 22 ]  while inhalation may be associated with increased  lower respiratory tract infection ,  lung cancer , and pathological restricting of lung tissue. [ 23 ]  Cocaine may also increase risk for autoimmune disease [ 24 ] [ 25 ] [ 26 ]  and damage nasal cartilage. Abuse of methamphetamine produces similar effects as well as marked degeneration of dopaminergic neurons, resulting in an increased risk for  Parkinson's disease . [ 27 ] [ 28 ] [ 29 ] [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14646", "text": "Stimulants are widely used throughout the world as  prescription medicines  as well as without a prescription (either legally or  illicitly ) as  performance-enhancing  or  recreational  drugs. Among narcotics, stimulants produce a noticeable crash or  comedown  at the end of their effects. In the US, the most frequently prescribed stimulants as of 2013 were  lisdexamfetamine  (Vyvanse),  methylphenidate  (Ritalin), and  amphetamine  (Adderall). [ 31 ]  It was estimated in 2015 that the percentage of the world population that had used  cocaine  during a year was 0.4%. For the category \"amphetamines and prescription stimulants\" (with \"amphetamines\" including  amphetamine  and  methamphetamine ) the value was 0.7%, and for  MDMA  0.4%. [ 32 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14647", "text": "Stimulants have been used in medicine for many conditions including  obesity ,  sleep disorders ,  mood disorders ,  impulse control disorders ,  asthma ,  nasal congestion  and, in case of cocaine, as  local anesthetics . [ 33 ]   Drugs used to treat obesity are called  anorectics  and generally include drugs that follow the general definition of a stimulant, but other drugs such as  cannabinoid receptor antagonists  also belong to this group. [ 34 ] [ 35 ]   Eugeroics  are used in management of sleep disorders characterized by  excessive daytime sleepiness , such as  narcolepsy , and include stimulants such as  modafinil  and  pitolisant . [ 36 ] [ 37 ]  Stimulants are used in impulse control disorders such as  ADHD [ 38 ]  and  off-label  in  mood disorders  such as  major depressive disorder  to increase  energy , focus and elevate mood. [ 39 ]   Stimulants such as  epinephrine , [ 40 ]   theophylline  and  salbutamol [ 41 ]  orally have been used to treat asthma, but inhaled  adrenergic drugs  are now preferred due to less systemic side effects.  Pseudoephedrine  is used to relieve nasal or sinus congestion caused by the common cold, sinusitis, hay fever and other respiratory allergies; it is also used to relieve ear congestion caused by ear inflammation or infection. [ 42 ] [ 43 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14648", "text": "Stimulants were one of the first classes of drugs to be used in the treatment of  depression , beginning after the introduction of the amphetamines in the 1930s. [ 44 ] [ 45 ] [ 46 ]  However, they were largely abandoned for treatment of depression following the introduction of conventional  antidepressants  in the 1950s. [ 44 ] [ 45 ]  Subsequent to this, there has been a resurgence in interest in stimulants for depression in recent years. [ 47 ] [ 48 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14649", "text": "Stimulants produce a fast-acting and pronounced but transient and short-lived  mood lift . [ 49 ] [ 50 ] [ 47 ] [ 45 ]  In relation to this, they are minimally effective in the treatment of depression when administered continuously. [ 49 ] [ 50 ]  In addition, tolerance to the mood-lifting effects of amphetamine has led to dose escalation and  dependence . [ 48 ]  Although the efficacy for depression with continuous administration is modest, it may still reach  statistical significance  over  placebo  and provide benefits similar in magnitude to those of conventional antidepressants. [ 51 ] [ 52 ] [ 53 ] [ 54 ]  The reasons for the short-term mood-improving effects of stimulants are unclear, but may relate to rapid  tolerance . [ 49 ] [ 50 ] [ 45 ] [ 55 ]  Tolerance to the effects of stimulants has been studied and characterized both in animals [ 55 ] [ 56 ] [ 57 ] [ 58 ]  and humans. [ 59 ] [ 60 ] [ 61 ] [ 62 ]  Stimulant  withdrawal  is remarkably similar in its symptoms to those of  major depressive disorder . [ 63 ] [ 55 ] [ 64 ] [ 65 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14650", "text": "Classifying stimulants is difficult, because of the large number of classes the drugs occupy, and the fact that they may belong to multiple classes; for example,  ecstasy  can be classified as a  substituted methylenedioxyphenethylamine , a  substituted amphetamine  and consequently, a  substituted phenethylamine . [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14651", "text": "Major stimulant classes include  phenethylamines  and their daughter class  substituted amphetamines . [ 66 ] [ 67 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14652", "text": "Substituted amphetamines  are a  class of compounds  based upon the  amphetamine  structure; [ 68 ]  it includes all  derivative  compounds which are formed by replacing, or  substituting , one or more  hydrogen atoms  in the amphetamine core structure with  substituents . [ 68 ] [ 69 ] [ 70 ]  Examples of substituted amphetamines are amphetamine (itself), [ 68 ] [ 69 ]   methamphetamine , [ 68 ]   ephedrine , [ 68 ]   cathinone , [ 68 ]   phentermine , [ 68 ]   mephentermine , [ 68 ]   bupropion , [ 68 ]   methoxyphenamine , [ 68 ]   selegiline , [ 68 ]   amfepramone , [ 68 ]   pyrovalerone , [ 68 ]   MDMA  (ecstasy), and  DOM  (STP). Many drugs in this class work primarily by activating  trace amine-associated receptor 1  (TAAR1); [ 71 ]  in turn, this causes  reuptake inhibition  and effluxion, or release, of  dopamine ,  norepinephrine , and  serotonin . [ 71 ]  An additional mechanism of some substituted amphetamines is the release of  vesicular stores  of  monoamine neurotransmitters  through  VMAT2 , thereby increasing the concentration of these neurotransmitters in the  cytosol , or intracellular fluid, of the  presynaptic neuron . [ 72 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14653", "text": "Amphetamines-type stimulants are often used for their therapeutic effects. Physicians sometimes prescribe amphetamine to treat  major depression , where subjects do not respond well to traditional  SSRI  medications, [ citation needed ]  but evidence supporting this use is poor/mixed. [ 48 ]  Notably, two recent large  phase III  studies of  lisdexamfetamine  (a  prodrug  to amphetamine) as an adjunct to an  SSRI  or  SNRI  in the treatment of  major depressive disorder  showed no further benefit relative to  placebo  in effectiveness. [ 73 ]  Numerous studies have demonstrated the effectiveness of drugs such as  Adderall  (a mixture of  salts  of  amphetamine  and  dextroamphetamine ) in controlling symptoms associated with  ADHD . Due to their availability and fast-acting effects, substituted amphetamines are prime candidates for abuse. [ 74 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14654", "text": "Hundreds of cocaine analogs have been created, all of them usually maintaining a benzyloxy connected to the 3 carbon of a  tropane . Various modifications include substitutions on the  benzene ring , as well as additions or substitutions in place of the normal carboxylate on the tropane 2 carbon. Various compound with similar structure activity relationships to cocaine that aren't technically analogs have been developed as well."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14655", "text": "Most stimulants exert their activating effects by enhancing  catecholamine  neurotransmission. Catecholamine neurotransmitters are employed in regulatory pathways implicated in attention, arousal, motivation, task salience and reward anticipation. Classical stimulants either  block the reuptake  or  stimulate the efflux  of these catecholamines, resulting in increased activity of their circuits. Some stimulants, specifically those with  empathogenic  and  hallucinogenic  effects, also affect  serotonergic  transmission. Some stimulants, such as some amphetamine derivatives [ which? ]  and, notably,  yohimbine , can decrease  negative feedback  by antagonizing regulatory  autoreceptors . [ 75 ]   Adrenergic agonists , such as, in part,  ephedrine , act by directly binding to and activating  adrenergic receptors , producing sympathomimetic effects. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14656", "text": "There are also more indirect  mechanisms of action  by which a drug can elicit activating effects. Caffeine is an  adenosine receptor antagonist , and only indirectly increases catecholamine transmission in the brain. [ 76 ]   Pitolisant  is an  histamine 3 (H 3 )-receptor inverse agonist . As  histamine 3 (H 3 ) receptors  mainly act as  autoreceptors , pitolisant decreases negative feedback to  histaminergic  neurons, enhancing histaminergic transmission."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14657", "text": "The precise  mechanism of action  of some stimulants, such as modafinil, for treating symptoms of narcolepsy and other sleep disorders, remains unknown. [ 77 ] [ 78 ] [ 79 ] [ 80 ] [ 81 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14658", "text": "Amphetamine is a potent  central nervous system  (CNS) stimulant of the  phenethylamine class  that is approved for the treatment of  attention deficit hyperactivity disorder  (ADHD) and  narcolepsy . [ 82 ]  Amphetamine is also used off-label as a  performance  and  cognitive enhancer , and recreationally as an  aphrodisiac  and  euphoriant . [ 83 ] [ 84 ] [ 85 ] [ 86 ]  Although it is a prescription medication in many countries, unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use. [ 87 ] [ 88 ]  As a consequence, amphetamine is illegally manufactured in  clandestine labs  to be trafficked and sold to users. [ 89 ]  Based upon drug and  drug precursor  seizures worldwide, illicit amphetamine production and trafficking is much less prevalent than that of  methamphetamine . [ 89 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14659", "text": "The first pharmaceutical amphetamine was  Benzedrine , a brand of inhalers used to treat a variety of conditions. [ 90 ] [ 91 ]  Because the dextrorotary isomer has greater stimulant properties, Benzedrine was gradually discontinued in favor of formulations containing all or mostly dextroamphetamine. Presently, it is typically prescribed as  mixed amphetamine salts ,  dextroamphetamine , and  lisdexamfetamine . [ 90 ] [ 92 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14660", "text": "Amphetamine is a  norepinephrine-dopamine releasing agent  (NDRA). It enters neurons through  dopamine  and  norepinephrine transporters  and facilitates neurotransmitter efflux by activating  TAAR1  and inhibiting  VMAT2 . [ 71 ]  At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved  cognitive control . [ 84 ] [ 85 ] [ 93 ]  Likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength. [ 83 ]  In contrast, supratherapeutic doses of amphetamine are likely to impair cognitive function and induce rapid  muscle breakdown . [ 82 ] [ 84 ] [ 94 ]  Very high doses can result in  psychosis  (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use. [ 95 ] [ 96 ]  As recreational doses are generally much larger than prescribed therapeutic doses, recreational use carries a far greater risk of serious side effects, such as dependence, which only rarely arises with therapeutic amphetamine use. [ 82 ] [ 94 ] [ 95 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14661", "text": "Caffeine is a stimulant compound belonging to the  xanthine  class of chemicals naturally found in  coffee ,  tea , and (to a lesser degree)  cocoa  or  chocolate . It is included in many  soft drinks , as well as a larger amount in  energy drinks . Caffeine is the world's most widely used psychoactive drug and by far the most common stimulant. In  North America , 90% of adults consume caffeine daily. [ 97 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14662", "text": "A few jurisdictions restrict the sale and use of caffeine. In the United States, the FDA has banned the sale of pure and highly concentrated caffeine products for personal consumption, due to the risk of overdose and death. [ 98 ]  The Australian Government has announced a ban on the sale of pure and highly concentrated caffeine food products for personal consumption, following the death of a young man from acute caffeine toxicity. [ 99 ] [ 100 ]  In Canada, Health Canada has proposed to limit the amount of caffeine in energy drinks to 180\u00a0mg per serving, and to require warning labels and other safety measures on these products. [ 99 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14663", "text": "Caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient, [ 101 ]  or reducing one of its side-effects (especially drowsiness). [ 102 ]  Tablets containing standardized doses of caffeine are also widely available. [ 103 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14664", "text": "Caffeine's mechanism of action differs from many stimulants, as it produces stimulant effects by inhibiting adenosine receptors. [ 104 ]   Adenosine receptors are thought to be a large driver of drowsiness and sleep, and their action increases with extended wakefulness. [ 105 ]   Caffeine has been found to increase striatal dopamine in animal models, [ 106 ]  as well as inhibit the inhibitory effect of adenosine receptors on dopamine receptors, [ 107 ]  however the implications for humans are unknown.  Unlike most stimulants, caffeine has no addictive potential.  Caffeine does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur, per a study on drug abuse liability published in an NIDA research monograph that described a group preferring placebo over caffeine. [ 108 ]  In large telephone surveys only 11% reported dependence symptoms.  However, when people were tested in labs, only half of those who claim dependence actually experienced it, casting doubt on caffeine's ability to produce dependence and putting societal pressures in the spotlight. [ 109 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14665", "text": "Coffee consumption is associated with a lower overall risk of  cancer . [ 110 ]  This is primarily due to a decrease in the risks of  hepatocellular  and  endometrial cancer , but it may also have a modest effect on colorectal cancer. [ 111 ]  There does not appear to be a significant protective effect against other types of cancers, and heavy coffee consumption may increase the risk of  bladder cancer . [ 111 ]  A protective effect of caffeine against  Alzheimer's disease  is possible,  but the evidence is inconclusive. [ 112 ] [ 113 ] [ 114 ]  Moderate coffee consumption may decrease the risk of  cardiovascular disease , [ 115 ]  and it may somewhat reduce the risk of  type 2 diabetes . [ 116 ]  Drinking 1-3 cups of coffee per day does not affect the risk of  hypertension  compared to drinking little or no coffee. However those who drink 2\u20134 cups per day may be at a slightly increased risk. [ 117 ]  Caffeine increases  intraocular pressure  in those with  glaucoma  but does not appear to affect normal individuals. [ 118 ]  It may protect people from  liver cirrhosis . [ 119 ]  There is no evidence that coffee stunts a child's growth. [ 120 ]  Caffeine may increase the effectiveness of some medications including ones used to treat  headaches . [ 121 ]   Caffeine may lessen the severity of  acute mountain sickness  if taken a few hours prior to attaining a high altitude. [ 122 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14666", "text": "Ephedrine is a  sympathomimetic   amine  similar in molecular structure to the well-known drugs  phenylpropanolamine  and  methamphetamine , as well as to the important  neurotransmitter   epinephrine  (adrenaline). Ephedrine is commonly used as a stimulant,  appetite suppressant , concentration aid, and  decongestant , and to treat  hypotension  associated with anesthesia. [ citation needed ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14667", "text": "In chemical terms, it is an  alkaloid  with a  phenethylamine  skeleton found in various plants in the genus  Ephedra  (family  Ephedraceae ). It works mainly by increasing the activity of  norepinephrine  (noradrenaline) on  adrenergic receptors . [ 123 ]  It is most usually marketed as the  hydrochloride  or  sulfate  salt."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14668", "text": "The herb  m\u00e1 hu\u00e1ng  ( Ephedra sinica ), used in  traditional Chinese medicine  (TCM), contains ephedrine and  pseudoephedrine  as its principal active constituents. The same may be true of other herbal products containing extracts from other  Ephedra  species."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14669", "text": "3,4-Methylenedioxymethamphetamine (MDMA, ecstasy, or molly) is a euphoriant,  empathogen , and stimulant of the amphetamine class. [ 124 ]  Briefly used by some psychotherapists as an adjunct to therapy, the drug became popular recreationally and the  DEA  listed MDMA as a  Schedule I controlled substance , prohibiting most medical studies and applications. MDMA is known for its  entactogenic  properties. The stimulant effects of MDMA include  hypertension ,  anorexia  (appetite loss),  euphoria , social disinhibition,  insomnia  (enhanced wakefulness/inability to sleep), improved  energy , increased arousal, and increased  perspiration , among others. Relative to catecholaminergic transmission, MDMA enhances serotonergic transmission significantly more, when compared to classical stimulants like amphetamine. MDMA does not appear to be significantly addictive or dependence forming. [ 125 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14670", "text": "Due to the relative safety of MDMA, some researchers such as  David Nutt  have criticized the scheduling level, writing a satirical article finding MDMA to be 28 times less dangerous than horseriding, a condition he termed \"equasy\" or \"Equine Addiction Syndrome\". [ 126 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14671", "text": "Methylenedioxypyrovalerone (MDPV) is a  psychoactive drug  with stimulant properties that acts as a  norepinephrine-dopamine reuptake inhibitor  (NDRI). [ 127 ]  It was first developed in the 1960s by a team at Boehringer Ingelheim. [ 128 ]  MDPV remained an obscure stimulant until around 2004, when it was reported to be sold as a  designer drug . Products labeled as  bath salts  containing MDPV were previously sold as recreational drugs in gas stations and convenience stores in the United States, similar to the marketing for  Spice  and  K2  as incense. [ 129 ] [ 130 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14672", "text": "Incidents of psychological and physical harm have been attributed to MDPV use. [ 131 ] [ 132 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14673", "text": "Mephedrone is a  synthetic  stimulant drug of the  amphetamine  and  cathinone  classes. Slang names include drone [ 133 ]  and MCAT. [ 134 ]  It is reported to be manufactured in China and is chemically similar to the cathinone compounds found in the  khat  plant of  eastern Africa . It comes in the form of tablets or a powder, which users can swallow, snort, or inject, producing similar effects to  MDMA ,  amphetamines , and  cocaine ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14674", "text": "Mephedrone was first synthesized in 1929, but did not become widely known until it was rediscovered in 2003. By 2007, mephedrone was reported to be available for sale on the Internet; by 2008 law enforcement agencies had become aware of the compound; and, by 2010, it had been reported in most of Europe, becoming particularly prevalent in the United Kingdom. Mephedrone was first made illegal in Israel in 2008, followed by Sweden later that year. In 2010, it was made illegal in many European countries, and, in December 2010, the EU ruled it illegal. In Australia, New Zealand, and the US, it is considered an  analog  of other illegal drugs and can be controlled by laws similar to the  Federal Analog Act . In September 2011, the USA temporarily classified mephedrone as illegal, in effect from October 2011."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14675", "text": "Mephedrone is neurotoxic and has abuse potential, predominantly exerted on 5-hydroxytryptamine (5-HT) terminals, mimicking that of MDMA with which it shares the same subjective sensations on abusers. [ 135 ] [ 136 ] [ 137 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14676", "text": "Methamphetamine (contracted from  N - meth yl - a lpha- m ethyl ph en et hyl amine ) is a potent psychostimulant of the  phenethylamine  and  amphetamine   classes  that is used to treat  attention deficit hyperactivity disorder  (ADHD) and  obesity . [ 138 ] [ 139 ] [ 140 ]  Methamphetamine exists as two  enantiomers ,  dextrorotary  and  levorotary . [ 141 ] [ 142 ]  Dextromethamphetamine is a stronger CNS stimulant than  levomethamphetamine ; [ 94 ] [ 141 ] [ 142 ]  however, both are addictive and produce the same toxicity symptoms at high doses. [ 142 ]  Although rarely prescribed due to the potential risks, methamphetamine hydrochloride is approved by the  United States Food and Drug Administration  (USFDA) under the trade name  Desoxyn . [ 139 ]  Recreationally, methamphetamine is used to  increase sexual desire ,  lift the mood , and increase  energy , allowing some users to engage in sexual activity continuously for several days straight. [ 139 ] [ failed verification ] [ 143 ] [ unreliable source? ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14677", "text": "Methamphetamine may be sold illicitly, either as pure dextromethamphetamine or in an  equal parts  mixture of the right- and left-handed molecules (i.e., 50%\u00a0levomethamphetamine and 50%\u00a0dextromethamphetamine). [ 143 ]  Both dextromethamphetamine and racemic methamphetamine are  schedule II  controlled substances in the United States. [ 139 ]  Also, the production, distribution, sale, and possession of methamphetamine is restricted or illegal in many other countries due to its placement in schedule II of the  United Nations Convention on Psychotropic Substances  treaty. [ 144 ] [ 145 ]   In contrast,  levomethamphetamine  is an  over-the-counter drug  in the United States. [ note 1 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14678", "text": "In low doses, methamphetamine can cause an  elevated mood  and increase alertness, concentration, and energy in fatigued individuals. [ 94 ] [ 139 ]  At higher doses, it can induce  psychosis ,  rhabdomyolysis , and  cerebral hemorrhage . [ 94 ] [ 139 ]  Methamphetamine is known to have a high potential for  abuse  and  addiction . [ 94 ] [ 139 ]  Recreational use of methamphetamine may result in psychosis or lead to  post-withdrawal syndrome , a withdrawal syndrome that can persist for months beyond the typical withdrawal period. [ 148 ]  Unlike  amphetamine  and  cocaine , methamphetamine is  neurotoxic  to humans, damaging both  dopamine  and  serotonin  neurons in the  central nervous system  (CNS). [ 138 ] [ 140 ]  Unlike the long-term use of amphetamine in prescription doses, which may improve certain brain regions in individuals with ADHD, there is evidence that methamphetamine causes brain damage from long-term use in humans; [ 138 ] [ 140 ]  this damage includes adverse changes in brain structure and function, such as reductions in  gray matter  volume in several brain regions and adverse changes in markers of metabolic integrity. [ 149 ] [ 150 ] [ 140 ]  However, recreational amphetamine doses may also be neurotoxic. [ 151 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14679", "text": "Methylphenidate is a stimulant drug that is often used in the treatment of ADHD and narcolepsy and occasionally to treat obesity in combination with diet restraints and exercise. Its effects at therapeutic doses include increased focus, increased alertness, decreased appetite, decreased need for sleep and decreased impulsivity. Methylphenidate is not usually used recreationally, but when it is used, its effects are very similar to those of amphetamines."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14680", "text": "Methylphenidate acts as a  norepinephrine-dopamine reuptake inhibitor  (NDRI), by blocking the  norepinephrine transporter  (NET) and the  dopamine transporter  (DAT). Methylphenidate has a higher affinity for the dopamine transporter than for the norepinephrine transporter, and so its effects are mainly due to elevated dopamine levels caused by the inhibited reuptake  of dopamine, however increased norepinephrine levels also contribute to various of the effects caused by the drug."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14681", "text": "Methylphenidate is sold under a number of brand names including Ritalin. Other versions include the long lasting tablet Concerta and the long lasting transdermal patch Daytrana."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14682", "text": "Cocaine is an  SNDRI . Cocaine is made from the leaves of the  coca  shrub, which grows in the mountain regions of South American countries such as  Bolivia ,  Colombia , and  Peru , regions in which it was cultivated and used for centuries mainly by the  Aymara people . In Europe, North America, and some parts of Asia, the most common form of cocaine is a white crystalline powder. Cocaine is a stimulant but is not normally prescribed therapeutically for its stimulant properties, although it sees clinical use as a local anesthetic, in particular in  ophthalmology . [ 152 ]  Most cocaine use is recreational and its abuse potential is high (higher than amphetamine), and so its sale and possession are strictly controlled in most jurisdictions. Other  tropane  derivative drugs related to cocaine are also known such as  troparil  and  lometopane  but have not been widely sold or used recreationally. [ 153 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14683", "text": "Nicotine  is the active chemical constituent in  tobacco , which is available in many forms, including  cigarettes ,  cigars ,  chewing tobacco , and  smoking cessation  aids such as  nicotine patches ,  nicotine gum , and  electronic cigarettes . Nicotine is used widely throughout the world for its stimulating and relaxing effects.  Nicotine exerts its effects through the agonism of  nicotinic acetylcholine receptors , resulting in multiple downstream effects such as increase in activity of dopaminergic neurons in the midbrain  reward system , and acetaldehyde one of the tobacco constituent decreased the expression of  monoamine oxidase  in the brain. [ 154 ]   Nicotine is addictive and dependence forming. Tobacco, the most common source of nicotine, has an overall harm to user and self score 3 percent below cocaine, and 13 percent above amphetamines, ranking 6th most harmful of the 20 drugs assessed, as determined by a multi-criteria decision analysis. [ 155 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14684", "text": "Phenylpropanolamine (PPA; Accutrim; \u03b2-hydroxyamphetamine), also known as the  stereoisomers  norephedrine and norpseudoephedrine, is a  psychoactive drug  of the  phenethylamine  and  amphetamine   chemical classes  that is used as a stimulant,  decongestant , and  anorectic  agent. [ 156 ]  It is commonly used in  prescription  and  over-the-counter   cough and cold preparations . In  veterinary medicine , it is used to control  urinary incontinence  in dogs under  trade names  Propalin and Proin."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14685", "text": "In the United States, PPA is no longer sold without a prescription due to a possible increased risk of  stroke  in younger women. In a few countries in Europe, however, it is still available either by prescription or sometimes over-the-counter. In Canada, it was withdrawn from the market on 31 May 2001. [ 157 ]  In India, human use of PPA and its formulations were banned on 10 February 2011. [ 158 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14686", "text": "Lisdexamfetamine (Vyvanse, etc.) is an amphetamine-type medication, sold for use in treating  ADHD . [ 159 ]  Its effects typically last around 14 hours. [ 160 ]  Lisdexamfetamine is inactive on its own and is metabolized into  dextroamphetamine  in the body. [ 60 ]  Consequently, it has a lower abuse potential. [ 60 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14687", "text": "Pseudoephedrine is a  sympathomimetic   drug  of the  phenethylamine  and  amphetamine   chemical classes . It may be used as a  nasal/sinus decongestant , as a stimulant, [ 161 ]  or as a  wakefulness-promoting agent . [ 162 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14688", "text": "The  salts  pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many  over-the-counter   preparations , either as a single ingredient or (more commonly) in combination with  antihistamines ,  guaifenesin ,  dextromethorphan , and/or  paracetamol  (acetaminophen) or another  NSAID  (such as  aspirin  or  ibuprofen ). It is also used as a precursor chemical in the illegal production of methamphetamine."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14689", "text": "Khat is a  flowering plant  native to the  Horn of Africa  and the  Arabian Peninsula . [ 163 ] [ 164 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14690", "text": "Khat contains a  monoamine   alkaloid  called  cathinone , a \"keto-amphetamine\". This alkaloid causes excitement,  loss of appetite , and  euphoria . In 1980, the  World Health Organization  (WHO) classified it as a  drug of abuse  that can produce mild to moderate  psychological dependence  (less than tobacco or  alcohol ), [ 165 ]  although the WHO does not consider khat to be seriously addictive. [ 164 ]  It is banned in some countries, such as the United States, Canada, and Germany, while its production, sale, and consumption are legal in other countries, including  Djibouti ,  Ethiopia ,  Somalia , Kenya and  Yemen . [ 166 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14691", "text": "Modafinil  is an  eugeroic  medication, which means that it promotes wakefulness and alertness. Modafinil is sold under the brand name Provigil among others. Modafinil is used to treat  excessive daytime sleepiness  due to  narcolepsy ,  shift work sleep disorder , or  obstructive sleep apnea . While it has seen off-label use as a purported cognitive enhancer, the research on its effectiveness for this use is not conclusive. [ 167 ]  Despite being a CNS stimulant, the addiction and  dependence  liabilities of modafinil are considered very low. [ 168 ] [ 169 ] [ 170 ]  Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have  mood-elevating properties . [ 169 ]  The similarities in effects with  caffeine  are not clearly established. [ 171 ] [ 172 ]  Unlike other stimulants, modafinil does not induce a subjective  feeling of pleasure or reward , which is commonly associated with  euphoria , an intense feeling of well-being. Euphoria is a potential indicator of  drug abuse , which is the compulsive and excessive use of a substance despite adverse consequences. In clinical trials, modafinil has shown no evidence of abuse potential, that is why modafinil is considered to have a low risk of addiction and dependence, however, caution is advised. [ 173 ] [ 174 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14692", "text": "Pitolisant is an  inverse agonist  (antagonist) of the  histamine 3 (H 3 ) autoreceptor . As such, pitolisant is an  antihistamine medication  that also belongs to the class of CNS stimulants. [ 175 ] [ 176 ] [ 177 ] [ 178 ]  Pitolisant is also considered a medication of  eugeroic  class, which means that it promotes wakefulness and alertness. Pitolisant is the first  wakefulness-promoting agent  that acts by blocking the  H 3  autoreceptor . [ 179 ] [ 180 ] [ 181 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14693", "text": "Pitolisant has been shown to be effective and well-tolerated for the treatment of  narcolepsy  with or without cataplexy. [ 181 ] [ 180 ] [ 179 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14694", "text": "Pitolisant is the only non-controlled anti-narcoleptic drug in the  US . [ 179 ]  It has shown minimal abuse risk in studies. [ 179 ] [ 182 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14695", "text": "Blocking the  histamine 3 (H 3 ) autoreceptor  increases the activity of histamine  neurons  in the brain. The H 3  autoreceptors regulate  histaminergic activity  in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting  histamine  biosynthesis and release upon binding to endogenous histamine. [ 183 ]  By preventing the binding of endogenous histamine at the H 3 , as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain. [ 184 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14696", "text": "Stimulants enhance the activity of the  central  and  peripheral nervous systems . Common effects may include increased  alertness ,  awareness ,  wakefulness ,  endurance ,  productivity , and  motivation ,  arousal ,  locomotion ,  heart rate , and  blood pressure , and a diminished desire for  food  and  sleep . Use of stimulants may cause the body to reduce significantly its production of natural body chemicals that fulfill similar functions. Until the body reestablishes its normal state, once the effect of the ingested stimulant has worn off the user may feel depressed, lethargic, confused, and miserable. This is referred to as a \" crash \", and may provoke reuse of the stimulant."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14697", "text": "Abuse  of  central nervous system  (CNS) stimulants is common.  Addiction  to some CNS stimulants can quickly lead to  medical ,  psychiatric , and  psychosocial  deterioration.  Drug tolerance ,  dependence , and  sensitization  as well as a  withdrawal  syndrome can occur. [ 185 ]  Stimulants may be screened for in animal discrimination and self-administration models which have high sensitivity albeit low specificity. [ 186 ]   Research on a progressive ratio  self-administration  protocol has found amphetamine, methylphenidate, modafinil, cocaine, and nicotine to all have a higher break point than placebo that scales with dose indicating reinforcing effects. [ 187 ]  A progressive ratio self-administration protocol is a way of testing how much an animal or a human wants a drug by making them do a certain action (like pressing a lever or poking a nose device) to get the drug. The number of actions needed to get the drug increases every time, so it becomes harder and harder to get the drug. The highest number of actions that the animal or human is willing to do to get the drug is called the break point. The higher the break point, the more the animal or human wants the drug. In contrast to the classical stimulants such as amphetamine, the effects of modafinil depend on what the animals or humans have to do after getting the drug. If they have to do a performance task, like solving a puzzle or remembering something, modafinil makes them work harder for it than placebo, and the subjects wanted to self-administer modafinil. But if they had to do a relaxation task, like listening to music or watching a video, the subjects did not want to self-administer modafinil. This suggests that modafinil is more rewarding when it helps the animals or humans do something better or faster, especially considering that modafinil is not commonly abused or depended on by people, unlike other stimulants. [ 187 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14698", "text": "Psychosocial treatments, such as  contingency management , have demonstrated improved effectiveness when added to treatment as usual consisting of counseling and/or case-management.  This is demonstrated with a decrease in dropout rates and a lengthening of periods of abstinence. [ 188 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14699", "text": "The presence of stimulants in the body may be tested by a variety of procedures. Serum and urine are the common sources of testing material although saliva is sometimes used. Commonly used tests include chromatography, immunologic assay, and mass spectrometry. [ 189 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14700", "text": "Sulfozinum  ( sulfazin ) is a pharmaceutical drug that causes a  pyrogenic reaction  (body temperature elevation) [ 1 ] [ 2 ]   and severe pain. [ 3 ]  Sulfozinum is a 0.37 \u2013 2% sterilized solution of purified elemental  sulfur  in  peach oil  or  olive oil  for intramuscular injections. The preparation is unstable, so it was prepared only in local hospital pharmacies. In the  Soviet Union , it was used in the pyrogenic treatment of syphilitic encephalitis (mostly in the pre-antibiotics era), various psychiatric conditions, [ 4 ] [ 5 ]  and alcoholism. [ 6 ]  Sulfozin was not used in American psychiatry. [ 3 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14701", "text": "The American delegation during its visit to the USSR in 1989 confirmed charges of the use of sulfozine injections. [ 7 ]  Psychiatrists in the USSR employed sulfozine treatment allegedly to increase treatment response to neuroleptic administration but were unable to present any research evidence of its efficiency for this purpose. [ 8 ]  The muscle necrosis, fever, immobility, and severe pain caused by sulfozine, as well as the pattern of its use in 10 persons, suggest that the medication was applied for  punitive  rather than therapeutic purposes. [ 8 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14702", "text": "Real benefits of its use in psychiatry are disputable, but it was widely used due to its extremely painful action, lasting from several hours to 2\u20133 days, as a punishment for psychiatric patients and in  political abuse of psychiatry . [ 9 ]  Sulfozine symbolised Soviet punitive psychiatry. [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14703", "text": "In 1989, during  Perestroika , its use was restricted only to cases when its prescription was confirmed both by consilium [ clarification needed ]  and by informed consent of the patient or his representatives. [ 11 ]  Its present use is not known."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14704", "text": "Some psychiatrists in post-Soviet Russia call the criticism of sulfozin attacks on psychiatry and still believe that sulfozin was sometimes the only effective treatment when all other ones were ineffective in calming down violent patients. [ 12 ]  The psychiatrists say that sulfozin really brought a psychosis to remission. [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14705", "text": "\" Truth serum \" is a colloquial name for any of a range of psychoactive drugs used in an effort to obtain information from subjects who are unable or unwilling to provide it otherwise. These include  ethanol ,  scopolamine ,  3-quinuclidinyl benzilate ,  midazolam ,  flunitrazepam ,  sodium thiopental , and  amobarbital , among others."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14706", "text": "Although a variety of such substances have been tested, serious issues have been raised about their use scientifically, ethically and legally. There is currently no drug proven to cause consistent or predictable enhancement of truth-telling. [ 1 ]  Subjects questioned under the influence of such substances have been found to be suggestible and their memories subject to reconstruction and fabrication. When such drugs have been used in the course of investigating civil and criminal cases, they have not been accepted by Western legal systems and legal experts as genuine investigative tools. [ 2 ]  In the United States, it has been suggested that their use is a potential violation of the  Fifth Amendment  of the  U.S. Constitution  (the  right to remain silent ). [ 3 ] [ 4 ]  Concerns have also been raised through the  European Court of Human Rights  arguing that use of a truth serum could be considered a violation of a human right to be free from degrading treatment, [ 5 ]  or could be considered a form of  torture . [ 6 ]  It has been noted to be a violation of the  Inter-American Convention to Prevent and Punish Torture . [ 7 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14707", "text": "\"Truth serum\" was previously used in the management of  psychotic  patients in the practice of  psychiatry . [ 8 ]  In a therapeutic context, the controlled administration of  intravenous   hypnotic  medications is called \" narcosynthesis \" or \"narcoanalysis\". Such application was first documented by Dr.  William Bleckwenn . Reliability and suggestibility of patients are concerns, and the practice of chemically inducing an involuntary mental state is now widely considered to be a form of torture. [ 9 ] [ 10 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14708", "text": "Sedatives  or  hypnotics  that alter higher cognitive function include  ethanol ,  scopolamine ,  3-quinuclidinyl benzilate , potent short or intermediate acting hypnotic  benzodiazepines  such as  midazolam ,  flunitrazepam , and various short and ultra-short acting  barbiturates , including  sodium thiopental  (commonly known by the brand name Pentothal) and  amobarbital  (formerly known as sodium amytal). [ 11 ] [ 2 ] [ 12 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14709", "text": "While there have been many clinical studies of the efficacy of narcoanalysis in interrogation or  lie detection , there is dispute whether any of them qualify as a  randomized ,  controlled study , that would meet scientific standards for determining effectiveness. [ 13 ] [ 14 ] [ 15 ] [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14710", "text": "India's  Central Bureau of Investigation  has used intravenous barbiturates for interrogation, often in high-profile cases. [ 2 ]  One such case was the interrogation of  Ajmal Kasab , the only terrorist captured alive by police in the  2008 attacks  in  Mumbai, India . [ 17 ] [ 18 ]  Kasab was a  Pakistani [ 19 ] [ 20 ]  militant and a member of the  Lashkar-e-Taiba  terrorist group. [ 21 ] [ 22 ]  On 3 May 2010, Kasab was found guilty of 80 offences, including murder, waging war against India, possessing explosives, and other charges. [ 23 ]  On 6 May 2010, the same trial court sentenced him to death on four counts and to a life sentence on five counts. [ 24 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14711", "text": "The Central Bureau of Investigation also conducted this test on Krishna, a key witness and suspect in the high-profile  2008 Aarushi-Hemraj Murder Case  to seek more information from Krishna and also determine his credibility as a witness with key information, yet not known to the investigating authorities. Per unverified various media sources, Krishna had purported to have deemed Hemraj (the prime suspect) as not guilty of Aarushi's murder, claiming he [Hemraj] \"treated Aarushi like his own daughter\"."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14712", "text": "On May 5, 2010 the Supreme Court Judge Balasubramaniam in the case \"Smt. Selvi vs. State of Karnataka\" held that narcoanalysis,  polygraph  and  brain mapping  tests were to be allowed with the consent of the accused. The judge stated: \"We are of the considered opinion that no individual can be forced and subjected to such techniques involuntarily, and by doing so it amounts to unwarranted intrusion of personal liberty.\" [ 25 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14713", "text": "In  Gujarat , Madhya Pradesh High Court permitted narcoanalysis in the investigation of a killing of a tiger that occurred in May 2010. The Jhurjhura Tigress at  Bandhavgarh National Park , a mother of three cubs, was found dead as a result of being hit by a vehicle. A Special Task Force requested the narcoanalysis testing of four persons, one of whom refused to consent on grounds of potential post-test complications. [ 26 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14714", "text": "In 2004,  Novaya Gazeta , with reference to  KGB  General  Oleg Kalugin , published an article that said that since the end of the 1980s the  First  and Second Directorates of the KGB had used, in exceptional cases and mostly on foreign citizens, a soluble odourless, colourless and tasteless substance code-named SP-117, an improved successor to similar drugs used by the KGB prior, that was effective in making a subject lose control of oneself 15 minutes after intake. [ 27 ]  Most importantly, a person who would be given, consecutively, two parts of the drug, i.e. both the \"dote\" and \"antidote\", would have no recollection of what had occurred in between and feel afterward as though he had suddenly fallen asleep, the preferable way to administer the \"dote\" being in an alcoholic drink, as that would serve as a plausible explanation of the sudden onset of drowsiness. [ 27 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14715", "text": "Other reports state that SP-117 was just a form of concentrated alcohol meant to be added to alcoholic drinks such as champagne. [ 28 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14716", "text": "According to the Russian  Foreign Intelligence Service  (SVR) officer, Alexander Kouzminov, who quit the service in the early 1990s, the officers of SVR\u2032s Directorate S, which runs SVR's \" illegals \", primarily used the drug to verify fidelity and trustworthiness of their agents who operated overseas, such as  Vitaly Yurchenko . [ 29 ]  According to  Alexander Litvinenko ,  Russian presidential candidate   Ivan Rybkin  was drugged with the same substance by FSB agents during his kidnapping in 2004. [ 30 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14717", "text": "Scopolamine  was promoted by obstetrician Robert Ernest House as an advance that would prevent false convictions, beginning in 1922. He had noted that women in childbirth who were given scopolamine could answer questions accurately even while in a state of  twilight sleep , and were oftentimes \"exceedingly candid\" in their remarks. House proposed that scopolamine could be used when interrogating suspected criminals. He even arranged to administer scopolamine to prisoners in the  Dallas County  jail. Both men were believed to be guilty, both denied guilt under scopolamine, and both were eventually acquitted. [ 16 ]  In 1926, the use of scopolamine was rejected in a court case, by Judge Robert Walker Franklin, who questioned both its scientific origin, and the uncertainty of its effect. [ 12 ] [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14718", "text": "The United States  Office of Strategic Services  (OSS) experimented with the use of  mescaline ,  scopolamine , and  marijuana  as possible truth drugs during  World War II . They concluded that the effects were not much different from those of  alcohol : subjects became more talkative but that did not mean they were more truthful. Like  hypnosis , there were also issues of suggestibility and interviewer influence. Cases involving scopolamine resulted in a mixture of testimonies both for and against those suspected, at times directly contradicting each other. [ 2 ] [ 31 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14719", "text": "LSD  was also considered as a possible truth serum, but found unreliable. [ 2 ]  During the 1950s and 1960s, the United States  Central Intelligence Agency  (CIA) carried out a number of investigations including  Project MKUltra [ 32 ]  and  Project MKDELTA [ citation needed ] , which involved illegal use of truth drugs including LSD. [ 33 ] [ 31 ] [ 34 ]  A CIA report from 1961, released in 1993, concludes:"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14720", "text": "The salient points that emerge from this discussion are the following. No such magic brew as the popular notion of truth serum exists. The barbiturates, by disrupting defensive patterns, may sometimes be helpful in interrogation, but even under the best conditions they will elicit an output contaminated by deception, fantasy, garbled speech, etc. A major vulnerability they produce in the subject is a tendency to believe he has revealed more than he has. It is possible, however, for both normal individuals and psychopaths to resist drug interrogation; it seems likely that any individual who can withstand ordinary intensive interrogation can hold out in narcosis. The best aid to a defense against narco-interrogation is foreknowledge of the process and its limitations. There is an acute need for controlled experimental studies of drug reaction, not only to depressants but also to stimulants and to combinations of depressants, stimulants, and ataraxics. [ 16 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14721", "text": "In 1963, the  U.S. Supreme Court  ruled, in  Townsend v. Sain , that confessions produced as a result of ingestion of truth serum were \"unconstitutionally coerced\" and therefore inadmissible. [ 35 ]  The viability of forensic evidence produced from truth sera has been addressed in lower courts \u2013 judges and expert witnesses have generally agreed that they are not reliable for lie detection. [ 36 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14722", "text": "In 1967, during his investigation into the  assassination of President John F. Kennedy ,  New Orleans  District Attorney  Jim Garrison  arranged for his key witness,  Perry Russo , to be administered sodium pentothal before being questioned about his knowledge regarding an alleged  conspiracy . [ 37 ]  Russo would later describe \"his conditioning by the DA's office as a complete brainwashing job.\" [ 38 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14723", "text": "In 1995, during the search for evidence that could acquit  Andres English-Howard , his defense attorney employed  methohexital ."}
{"_id": "WikiPedia_Pharmacology$$$corpus_14724", "text": "More recently, a judge approved the use of narcoanalysis in the  2012 Aurora, Colorado shooting  trial to evaluate whether  James Eagan Holmes 's state of mind was valid for an  insanity plea . [ 39 ]  Judge William Sylvester ruled that prosecutors would be allowed to interrogate Holmes \"under the influence of a medical drug designed to loosen him up and get him to talk\", such as sodium amytal, if he filed an insanity plea. [ 3 ]  The hope was that a 'narcoanalytic interview' could confirm whether or not he had been legally insane on 20 July, the date of the shootings. [ 3 ]  It is not known whether such an examination was carried out. [ 2 ]"}
{"_id": "WikiPedia_Pharmacology$$$corpus_14725", "text": "William Shepherd, chair of the criminal justice section of the  American Bar Association , stated, with respect to the Holmes case, that use of a \"truth drug\" as proposed, \"to ascertain the veracity of a defendant's plea of insanity... would provoke intense legal argument relating to Holmes's right to remain silent under the fifth amendment of the US constitution.\" [ 3 ]  Discussing possible effectiveness of such an examination, psychiatrist August Piper stated that \"amytal's inhibition-lowering effects in no way prompt the subject to offer up true statements or memories.\" [ 40 ]   Psychology Today 's  Scott Linfield noted, as per Piper, that \"there's good reason to believe that truth serums merely lower the threshold for reporting virtually all information, both true and false.\" [ 40 ]"}
{"_id": "drug_clean$$$corpus_1", "text": "The use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sj\u00f6qvist et al, 2008) (Thirumalai and Anawalt, 2023). Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sj\u00f6qvist et al, 2008) (Thirumalai and Anawalt, 2023). The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023). The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001). The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (Garc\u00eda-Arn\u00e9s and Garc\u00eda-Casares, 2023). Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)"}
{"_id": "drug_clean$$$corpus_2", "text": "The use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sj\u00f6qvist et al, 2008) (Thirumalai and Anawalt, 2023). Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sj\u00f6qvist et al, 2008) (Thirumalai and Anawalt, 2023). The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023). The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001). The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (Garc\u00eda-Arn\u00e9s and Garc\u00eda-Casares, 2023). Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)"}
{"_id": "drug_clean$$$corpus_3", "text": "The use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sj\u00f6qvist et al, 2008) (Thirumalai and Anawalt, 2023). Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sj\u00f6qvist et al, 2008) (Thirumalai and Anawalt, 2023). The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023). The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001). The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (Garc\u00eda-Arn\u00e9s and Garc\u00eda-Casares, 2023). Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)"}
{"_id": "drug_clean$$$corpus_4", "text": "The use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sj\u00f6qvist et al, 2008) (Thirumalai and Anawalt, 2023). Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sj\u00f6qvist et al, 2008) (Thirumalai and Anawalt, 2023). The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023). The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001). The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (Garc\u00eda-Arn\u00e9s and Garc\u00eda-Casares, 2023). Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)"}
{"_id": "drug_clean$$$corpus_5", "text": "The use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sj\u00f6qvist et al, 2008) (Thirumalai and Anawalt, 2023). Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sj\u00f6qvist et al, 2008) (Thirumalai and Anawalt, 2023). The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023). The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001). The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (Garc\u00eda-Arn\u00e9s and Garc\u00eda-Casares, 2023). Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)"}
{"_id": "drug_clean$$$corpus_6", "text": "Methampetamine is a stimulant drug with inotropic effects upon the cardiovascular system. Methamphetamine is metabolized to amphetamine, which is also a stimulant. Methamphetamine and amphetamine have similar effects to cocaine on the cardiovascular system. The heart may have such stress placed upon it that there are ischemic changes to the myocardial fibers. Chronic use leads to hypertrophy, interstitial fibrosis and microvascular disease. The myocardial effects are made worse by concomitant ethanol use.\u00a0"}
{"_id": "drug_clean$$$corpus_7", "text": "Cocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Cerebral infarction can occur within 3\u2003hours of cocaine use even in young persons. Subarachnoid haemorrhage is often associated with rupture of a berry aneurysm. Intraparenchymal haemorrhage can occur in the basal ganglia and thalamus. (Milroy and Parai, 2011). Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. With chronic usage, the myocardium develops interstitial fibrosis, and the heart becomes enlarged. Atheroma formation in artereis as well as arterial dissection can occur. (Milroy and Parai, 2011) Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010). Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007). Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with \"excited delerium\" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008)"}
{"_id": "drug_clean$$$corpus_8", "text": "Cocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Cerebral infarction can occur within 3\u2003hours of cocaine use even in young persons. Subarachnoid haemorrhage is often associated with rupture of a berry aneurysm. Intraparenchymal haemorrhage can occur in the basal ganglia and thalamus. (Milroy and Parai, 2011). Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. With chronic usage, the myocardium develops interstitial fibrosis, and the heart becomes enlarged. Atheroma formation in artereis as well as arterial dissection can occur. (Milroy and Parai, 2011) Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010). Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007). Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with \"excited delerium\" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008)"}
{"_id": "drug_clean$$$corpus_9", "text": "Cocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Cerebral infarction can occur within 3\u2003hours of cocaine use even in young persons. Subarachnoid haemorrhage is often associated with rupture of a berry aneurysm. Intraparenchymal haemorrhage can occur in the basal ganglia and thalamus. (Milroy and Parai, 2011). Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. With chronic usage, the myocardium develops interstitial fibrosis, and the heart becomes enlarged. Atheroma formation in artereis as well as arterial dissection can occur. (Milroy and Parai, 2011) Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010). Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007). Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with \"excited delerium\" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008)"}
{"_id": "drug_clean$$$corpus_10", "text": "Cocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Cerebral infarction can occur within 3\u2003hours of cocaine use even in young persons. Subarachnoid haemorrhage is often associated with rupture of a berry aneurysm. Intraparenchymal haemorrhage can occur in the basal ganglia and thalamus. (Milroy and Parai, 2011). Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. With chronic usage, the myocardium develops interstitial fibrosis, and the heart becomes enlarged. Atheroma formation in artereis as well as arterial dissection can occur. (Milroy and Parai, 2011) Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010). Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007). Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with \"excited delerium\" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008)"}
{"_id": "drug_clean$$$corpus_11", "text": "Cocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Cerebral infarction can occur within 3\u2003hours of cocaine use even in young persons. Subarachnoid haemorrhage is often associated with rupture of a berry aneurysm. Intraparenchymal haemorrhage can occur in the basal ganglia and thalamus. (Milroy and Parai, 2011). Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. With chronic usage, the myocardium develops interstitial fibrosis, and the heart becomes enlarged. Atheroma formation in artereis as well as arterial dissection can occur. (Milroy and Parai, 2011) Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010). Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007). Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with \"excited delerium\" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008)"}
{"_id": "drug_clean$$$corpus_12", "text": "Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022). Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a \"talc granulomatosis\" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to \"cut\" or dilute the amount of drug. (Milroy and Parai, 2011)"}
{"_id": "drug_clean$$$corpus_13", "text": "Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022). Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a \"talc granulomatosis\" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to \"cut\" or dilute the amount of drug. (Milroy and Parai, 2011)"}
{"_id": "drug_clean$$$corpus_14", "text": "Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022). Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a \"talc granulomatosis\" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to \"cut\" or dilute the amount of drug. (Milroy and Parai, 2011)"}
{"_id": "drug_clean$$$corpus_15", "text": "Mycobacterium tuberculosis infection of the lung has resulted in upper lung field granulomatous and cavitary disease.Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022). Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a \"talc granulomatosis\" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to \"cut\" or dilute the amount of drug. (Milroy and Parai, 2011)"}
{"_id": "drug_clean$$$corpus_16", "text": "Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022). Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a \"talc granulomatosis\" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to \"cut\" or dilute the amount of drug. (Milroy and Parai, 2011)"}
{"_id": "drug_clean$$$corpus_17", "text": "Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022). Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a \"talc granulomatosis\" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to \"cut\" or dilute the amount of drug. (Milroy and Parai, 2011)"}
{"_id": "drug_clean$$$corpus_18", "text": "Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022). Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a \"talc granulomatosis\" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to \"cut\" or dilute the amount of drug. (Milroy and Parai, 2011)"}
{"_id": "drug_clean$$$corpus_19", "text": "Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022). Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a \"talc granulomatosis\" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to \"cut\" or dilute the amount of drug. (Milroy and Parai, 2011)"}
{"_id": "drug_clean$$$corpus_20", "text": "Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022). Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a \"talc granulomatosis\" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to \"cut\" or dilute the amount of drug. (Milroy and Parai, 2011)"}
{"_id": "drug_clean$$$corpus_21", "text": "The abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states). Chronic alcohol abuse leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023). In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke\u2013Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff\u2019s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol abuse leads to permanent brain damage. (Nutt et al, 2021). Abrupt cessation of alcohol ingestion in persons who are chronic alcohol abusers predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022). Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023). Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)"}
{"_id": "drug_clean$$$corpus_22", "text": "The abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states). Chronic alcohol abuse leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023). In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke\u2013Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff\u2019s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol abuse leads to permanent brain damage. (Nutt et al, 2021). Abrupt cessation of alcohol ingestion in persons who are chronic alcohol abusers predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022). Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023). Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)"}
{"_id": "drug_clean$$$corpus_23", "text": "The abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states). Chronic alcohol abuse leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023). In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke\u2013Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff\u2019s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol abuse leads to permanent brain damage. (Nutt et al, 2021). Abrupt cessation of alcohol ingestion in persons who are chronic alcohol abusers predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022). Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023). Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)"}
{"_id": "drug_clean$$$corpus_24", "text": "The abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states). Chronic alcohol abuse leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023). In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke\u2013Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff\u2019s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol abuse leads to permanent brain damage. (Nutt et al, 2021). Abrupt cessation of alcohol ingestion in persons who are chronic alcohol abusers predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022). Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023). Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)"}
{"_id": "drug_clean$$$corpus_25", "text": "The abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states). Chronic alcohol abuse leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023). In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke\u2013Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff\u2019s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol abuse leads to permanent brain damage. (Nutt et al, 2021). Abrupt cessation of alcohol ingestion in persons who are chronic alcohol abusers predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022). Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023). Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)"}
{"_id": "drug_clean$$$corpus_26", "text": "The abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states). Chronic alcohol abuse leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023). In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke\u2013Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff\u2019s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol abuse leads to permanent brain damage. (Nutt et al, 2021). Abrupt cessation of alcohol ingestion in persons who are chronic alcohol abusers predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022). Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023). Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)"}
{"_id": "drug_clean$$$corpus_27", "text": "The abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states). Chronic alcohol abuse leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023). In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke\u2013Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff\u2019s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol abuse leads to permanent brain damage. (Nutt et al, 2021). Abrupt cessation of alcohol ingestion in persons who are chronic alcohol abusers predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022). Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023). Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)"}
{"_id": "drug_clean$$$corpus_28", "text": "Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)"}
{"_id": "drug_clean$$$corpus_29", "text": "Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)"}
{"_id": "drug_clean$$$corpus_30", "text": "Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)"}
{"_id": "drug_clean$$$corpus_31", "text": "Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)"}
{"_id": "drug_clean$$$corpus_32", "text": "Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)"}
{"_id": "drug_clean$$$corpus_33", "text": "Emphysema, of the centrilobular type, with numerous enlarged air spaces as a result of the loss of lung tissue from smoking is demonstrated here grossly.Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)"}
{"_id": "drug_clean$$$corpus_34", "text": "A large squamous cell carcinoma of the lung in a smoker is shown here. The incidence of both squamous cell carcinomas and small cell anaplastic carcinomas of lung is far greater in smokers than non-smokers.Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)"}
{"_id": "drug_clean$$$corpus_35", "text": "Small cell anaplastic (oat cell) carcinoma of the lung appears here in a smoker. Smokers who stop will diminish their risk for lung cancer, even after just a couple of years.Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)"}
{"_id": "drug_clean$$$corpus_36", "text": "The normal gross appearance of a lung in cross section is shown here for comparison.Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)"}