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 .


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 – leading to development of super-resistant bacteria. [ 3 ] [ 4 ]


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 ]


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 ]


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 .


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 ]


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 ]


The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are: [ 28 ] [ 29 ]


[ 30 ]
 [ 31 ]


Beta-lactam antibiotics (penicillin and cephalosporin)


Chloramphenicol


Binds to penicillin-binding proteins, Inhibiting peptidoglycan synthesis


Bind to 50S ribosome subunit, inhibiting formation of peptide bonds


Plasmid encode beta-lactamase, which open the beta-lactam ring, inactivating it.


Plasmid encode an enzyme that acetylate the drug, thereby inactivating it.


Erythromycin


Quinolones


Rifampin


Trimethoprim


Bind to 50S ribosome subunit, inhibiting protein synthesis


Binds to DNA topoisomerase, an enzyme essential for DNA synthesis


Binds to the RNA polymerase; inhibiting initiation of RNA synthesis


Inhibit the enzyme dihydrofolate reduces, blocking the folic acid pathway


Bacteria make an altered penicillin-binding proteins, that do not bind to the drug.


Bacteria make a form of 50S ribosome that does not binds to the drug.


Bacteria make an altered DNA topoisomerase that does not binds to the drug.


Bacteria make an altered polymerase that does not binds to the drug.


Bacteria make an altered enzyme that does not binds to the drug.


Tetracycline


Binds to 30S Ribosome subunit, inhibiting protein synthesis by blocking tRNA


New membrane transport system prevent drug from entering cell.


New membrane transport system pumps drug out of cell.


Biological cost  is a measure of the increased  energy metabolism  required to achieve a function. [ 32 ]


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 ]


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 ]


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 ]


Destruction of the resistant  bacteria  can also be achieved by  phage therapy , in which a specific  bacteriophage  (virus that kills bacteria) is used. [ 41 ]


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 .


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 ]
Since cancer is a genetic disease, two genomic events underlie acquired drug resistance: Genome alterations (e.g. gene amplification and deletion) and  epigenetic modifications .
Cancer cells are constantly using a variety of tools, involving genes, proteins, and altered pathways, to ensure their survival against antineoplastic drugs.


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 ]
Inherent 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 ]


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 ]


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 ]


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 .


Chromosomal rearrangement  due to  genome instability  can cause gene amplification and deletion.
 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 ]


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.
 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 ]


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 ]


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 ]


Studies on cancer cell lines have shown that hypomethylation (loss of methylation) of the  MDR1  gene promoter caused overexpression and the multidrug resistance. [ 13 ]


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 ]


Acquired resistance to the alkylating drug  fotemustine  in  melanoma  cell showed high MGMT activity related to the  hypermethylation  of the  MGMT  gene exons. [ 15 ]


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 ]


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 ]


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 ]


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 ]


MDR1  is activated through  NF-κB , a protein complex which acts as a transcription factor. [ 19 ] [ 20 ] [ 21 ] [ 22 ]  In the rat, an NF-κB binding site is adjacent to the  mdr1b  gene, [ 23 ]   NF-κB can be active in tumour cells because its mutated  NF-κB  gene or its inhibitory IκB gene mutated under chemotherapy. In  colorectal cancer  cells, inhibition of NF-κB or MDR1 caused increased  apoptosis  in response to a chemotherapeutic agent. [ 19 ]


Enhanced  DNA repair  plays an important role in the ability for cancer cells to overcome drug-induced DNA damages.


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


Aberrant  NF-κB  expression is found in many cancers, and NF-κB has been found to be involved in resistance to platinum-based chemotherapies, such as cisplatin. NF-κB 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-κB pathway can be difficult, as there can be many off-target and non-specific effects.


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 ]


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 ]


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 ]


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.


"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 ]


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 ]


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.


The Global Leaders Group on Antimicrobial Resistance is chaired by Her Excellency  Mia Amor Mottley , Prime Minister of  Barbados . [ 10 ]


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.


Current Group members: [ 12 ]


This  molecular  or  cell biology  article is a  stub . You can help Wikipedia by  expanding it .


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 ]


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 ]


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 .


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 ]


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.


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 1–14 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.


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 2–3 days and patients are not taken off their AEDs. [ 11 ] [ 12 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 .


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 ]


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.


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.


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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.


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 ]


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 ]


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 ]


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.


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 ]


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 ]


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 ]


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 ]


Common multidrug-resistant organisms, typically bacteria, include: [ 3 ]


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 ]


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:


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 ]


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 ]


Yeasts such as  Candida species  can become resistant under long-term treatment with  azole  preparations, requiring treatment with a different drug class.
 Lomentospora prolificans  infections are often fatal because of their resistance to multiple antifungal agents. [ 14 ]


HIV  is the prime example of MDR against antivirals, as it mutates rapidly under monotherapy.
 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 ]


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 ]
 Toxoplasma gondii  can also become resistant to  artemisinin , as well as  atovaquone  and  sulfadiazine , but is not usually MDR [ 17 ]
 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.


To limit the development of antimicrobial resistance, it has been suggested to: [ citation needed ]


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 ]


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 ]


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.


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 ]


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 ]


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.
 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.
 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.
Other psychiatric disorders that may predict treatment-resistant depression include  attention deficit hyperactivity disorder , [ 7 ]   personality disorders ,  obsessive compulsive disorder , and  eating disorders . [ 8 ]


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 .
Another factor is that medications used to treat comorbid medical disorders may lessen the effectiveness of  antidepressants  or cause  depression symptoms . [ 8 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


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 (8–12 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 ]


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 ]


A 2016  placebo   randomized controlled trial  evaluated the  rapid antidepressant  effects of the psychedelic  ayahuasca  in treatment-resistant depression with positive outcome. [ 26 ] [ 27 ]


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 ]


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 ]


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 ]


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 ]


Vagus nerve stimulation  has also been used for treatment-resistant depression. [ 37 ]


Deep brain stimulation  has been used in a small number of clinical trials to treat people with severe treatment-resistant depression. [ 38 ]


Magnetic seizure therapy  is currently being investigated for treating refractory depression.


Transcranial direct-current stimulation  is a form of  neuromodulation  that uses constant, low  direct current  delivered via electrodes on the head.


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 ]


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- (7–12 months) and long‐term (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 ]


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 ]


Another study saw just 8 of 124 patients in remission after two years of standard depression treatment. [ 43 ]


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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 ]


Morning glory:  Argyreia nervosa  (Hawaiian Baby Woodrose),  Ipomoea  spp. (Morning Glory, Tlitliltzin, Badoh Negro),  Rivea corymbosa  (Coaxihuitl, Ololiúqui)


2-Aminoacetophenone , also known as  β-ketophenethylamine ,  α-desmethylcathinone , or  phenacylamine , is a  substituted phenethylamine   derivative . [ 1 ] [ 2 ]  It is the phenethylamine homologue of  cathinone  (β-ketoamphetamine) and hence is a parent compound of a large number of  stimulant  and  entactogen   drugs . [ 1 ] [ 3 ] [ 4 ]


Phenacylamine is also  active  itself; it is a  potent   monoamine releasing agent  of  dopamine  ( EC 50 Tooltip half-maximal effective concentration  = 208   nM)  in vitro , whereas it was inactive for  serotonin  ( EC 50  > 10,000   nM) and the  EC 50  for  norepinephrine  was not assessed but the drug induced 96% release of norepinephrine at a concentration of 10,000   nM. [ 2 ] [ 5 ]  Hence, phenacylamine acts as a  norepinephrine–dopamine releasing agent  (NDRA). [ 2 ] [ 5 ]


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–brain barrier   permeability  and limited  central  activity due to its decreased  lipophilicity  relative to cathinone. [ 7 ]


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 ]


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 ]


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 ]


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  σ 2  subtype. It produces both  stimulant  and  dissociative  effects in animal behavioural studies. [ 1 ] [ 2 ] [ 3 ]


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 .


3F-PiHP  ( 3F-α-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 ]


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 ]


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 ]


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 ]


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 ]


4-HO-McPeT  ( 4-hydroxy- N -methyl- N -cyclopentyltryptamine ) is a  tryptamine  derivative which has  serotonergic  effects. [ 1 ]


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 ]


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 ]


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 ]


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? ]


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 ]


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 ]


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.


5-MeO-DBT was made schedule I at the state level in  Alabama  on September 13th, 2024. [ 5 ]


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 ]


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 α-methylated  AAZ-A-154  (DLX-001; ( R )-5-MeO-α-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 ]


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 ]


This  drug  article relating to the  nervous system  is a  stub . You can help Wikipedia by  expanding it .


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.


[11C]ME@HAPTHI  is a  radiotracer  of the  norepinephrine transporter  for  positron emission tomography . [ 1 ]


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 ]


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 ]


The new law aimed to reverse racial disparities in policing, and was projected to reduce black arrests by 94%. [ 6 ]


The new law came into effect on February 1, 2021. [ 7 ]


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 ]


This  Oregon elections -related article is a  stub . You can help Wikipedia by  expanding it .


This article about a  criminal law  topic is a  stub . You can help Wikipedia by  expanding it .


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 ]


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 ]


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 ]


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 ]


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 ]


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 ]


This article about an  organic compound  is a  stub . You can help Wikipedia by  expanding it .


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 −1 . [ 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 ]


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 ]


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   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 ]


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 ]


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 ]


AMCP is a member organization of the Alliance for a Stronger FDA. [ 6 ]


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 ]


In early 2021, AMCP received a $5,000 grant from  Pfizer  for a project titled “Emerging Patterns in the Adoption of New-to-Market Oncology Biosimilars.” [ 8 ]


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 ]


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 .


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 ]


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 ]


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 —work urging caution in its administration was published as early as 1959, [ 11 ]  after reports of adverse reactions ranging from hypersensitivity to brain damage—and was eventually replaced by other agents with higher efficacy and lower toxicity, such as  sodium diatrizoate , a closely related compound. [ 4 ]


Trade names include Urokon, Triurol and Salpix, as well as Gastrografina and Urografina in Portugal.


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 ]


N -Acetylcysteine amide  (abbrev. NACA, AD4 and also known as  acetylcysteinamide ) is an amide derivative of  N -acetylcysteine  that appears to have better  blood–brain barrier  permeability and  bioavailability  and a similar antioxidant capability. [ 1 ]


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 β   agonist   AC-186 . [ 3 ]  ACP-105 is an  aniline  SARM and is related to  AC-262536  and  vosilasarm  (RAD140). [ 5 ]


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 ]


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 ]
It is unclear whether jitteriness/anxiety syndrome predicts either good or poor prognosis (level D).  [ 4 ]


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 ]


The following are approved drugs that contain the acylsulfonamide functional group:


Several  investigational new drugs  contain also the acylsulfonamide functional group. Examples include:


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 ]


In 2023, adebrelimab was approved for use in China for the treatment of  small cell lung cancer . [ 3 ]


Adiphenine  is an inhibitor of  nicotinic receptors . [ 1 ]


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 ]


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 ]


As of 2024, admilparant is in Phase III clinical trials for both IPF and PPF. [ 2 ] [ 3 ]


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  § 1308.03(a).


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.


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  Betäubungsmittelgesetz  (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


For a complete list, see the list of schedules: [ 6 ]


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 ]


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 ]