VAPCO  Manufacturing CO. Ltd. is a company based in  Amman ,  Jordan , that produces veterinary and agrochemical products.  It was established in 1975. [ 1 ]


This article related to a  manufacturing  company is a  stub . You can help Wikipedia by  expanding it .


Vaping cessation , usually called "quitting  vaping ", is the process of stopping using  electronic cigarettes , usually those containing  nicotine . Professional assistance for quitting is similar to that given for stopping smoking, though stopping vaping may have unique challenges; as noted by  Harvard Medical School , "'vapes' can deliver a much higher dose much faster than traditional cigarettes." This can make vapes harder to quit than cigarettes. [ 1 ]


While the strength of addiction may be stronger, the nature of withdrawal symptoms appears similar to that seen with smoking. These symptoms can include depression, irritability, anxiety, and strong, focus-consuming cravings. However, smoking cessation training sometimes emphasizes avoiding environments that can trigger the urge to smoke. Because smoking is successfully prohibited in many public areas, the relatively few areas where it is allowed can remind a former smoker of the tempting behavior. However, vapers report vaping in many of these same places where smoking is prohibited, so such physically identified trigger warnings and avoidance, can be ineffective for people who use these smoke free devices.
 [ 2 ]


To address the fact that nicotine cravings can happen anywhere, designers of "serious games" have created  cessation apps for phones, available for download online.
 [ 3 ]


In 2024, the CDC started promoting  online cessation programs specifically designed for people addicted to vaping nicotine. [ 4 ]


A  vasoactive  substance is an  endogenous  agent or  pharmaceutical drug  that has the effect of either increasing or decreasing  blood pressure  and/or  heart rate  through its  vasoactivity , that is, vascular activity (effect on  blood vessels ). By adjusting  vascular compliance  and  vascular resistance , typically through  vasodilation  and  vasoconstriction , it helps the body's  homeostatic  mechanisms (such as the  renin–angiotensin system ) to keep  hemodynamics  under control. For example,  angiotensin ,  bradykinin ,  histamine ,  nitric oxide , and  vasoactive intestinal peptide  are important endogenous vasoactive substances. Vasoactive drug therapy is typically used when a patient has the blood pressure and heart rate  monitored  constantly. The  dosage  is typically titrated (adjusted up or down) to achieve a desired effect or  range of values  as determined by competent clinicians.


Vasoactive drugs are typically administered using a volumetric infusion device (IV pump).  This category of  drugs  require close observation of the patient with near immediate intervention required by the  clinicians  in charge of the patient's care. Important vasoactive substances are  angiotensin -11,  endothelin -1, and alpha- adrenergic agonists .


Various vasoactive agents, such as  prostanoids ,  phosphodiesterase inhibitors , and endothelin antagonists, are approved for the treatment of  pulmonary arterial hypertension . The use of vasoactive agents for patients with pulmonary hypertension may cause harm and unnecessary expense to persons with  left heart disease  or  hypoxemic  types of  lung diseases . [ 1 ]


The  Verified-Accredited Wholesale Distributors  ( VAWD ) program was established in 2004 to help protect the public from the
threat of  counterfeit drugs . [ 1 ]   The VAWD program was developed and is administered by the  National Association of Boards of Pharmacy  (NABP). [ 1 ]   The program offers an accreditation to  wholesale distribution facilities  by offering an objective, third-party audit system.


The criteria to earn VAWD accreditation program includes a compliance review, criteria including: licensure verification, on-site survey and examination, screening through NABP's Clearinghouse, and  criminal background checks  for responsible persons.  The facility must employ security and best practices for safe distribution.  Resurveys of accredited sites will be performed by trained NABP surveyors before accreditation may be renewed.


Verosudil  ( AR-12286 ) is a drug which acts as a potent and selective inhibitor of the  enzyme   Rho kinase , and has been investigated for the treatment of  glaucoma . [ 1 ] [ 2 ]


Vesamicol  is an experimental drug, acting  presynaptically  by inhibiting  acetylcholine  (ACh) uptake into synaptic vesicles and reducing its release. [ 1 ]  Vesamicol may have applications for the treatment of  adenocarcinoma in situ of the lung . [ 2 ]


Vesamicol can be broadly categorized as a cholinergic  physiological antagonist , because it reduces the apparent activity of cholinergic  neurons , but does not act at the postsynaptic ACh receptor. Vesamicol causes a non-competitive and reversible block of the intracellular transporter  VAChT  responsible for carrying newly synthesized ACh into secretory vesicles in the presynaptic nerve terminal. This transport process is driven by a proton gradient between cell organelles and the cytoplasm.  Blocking of acetylcholine loading leads to empty vesicles fusing with neuron membranes, decreasing ACh release. [ 3 ]


Vesatolimod  ( GS-9620 ) is an  antiviral  drug developed by  Gilead Sciences , which acts as a potent and selective agonist of  Toll-like receptor 7  (TLR7), a receptor involved in the regulation of the  immune system . It is used to stimulate the immune system, which can increase its ability to combat chronic viral infections. Vesatolimod is in  clinical trials  to determine whether it is safe and effective in patients with  Hepatitis B  and  HIV/AIDS , [ 1 ] [ 2 ]  and has also shown activity against other viral diseases such as  norovirus  and  enterovirus 71 . [ 3 ] [ 4 ]


VGX-1027  ( GIT-27 ) is a drug which acts as an  immunomodulator . It acts by blocking downstream signalling of the  Toll-like receptors   TLR2 ,  TLR4  and  TLR6 , and thereby reducing production of various  cytokines , including  interleukins  and  TNF-α . In animal studies it has  antiinflammatory  effects and has been investigated for conditions such as  arthritis  and lung inflammation. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]


Vicenistatin  is a macrolactam antibiotic synthesized by  Streptomyces halstedii  HC34. It was originally isolated from this bacterium in 1993. [ 1 ]   It includes the unusual starter unit   methylaspartate . [ 2 ]


Vidofludimus  is an  investigational new drug  that is being evaluated to treat  Crohn's disease  and  ulcerative colitis . [ 1 ]  It is a  dihydroorotate dehydrogenase  inhibitor. [ 2 ]


Vilobelimab , sold under the brand name  Gohibic , is an investigational  medication  that is used for the treatment of  COVID-19 . [ 1 ]  It is a human-mouse chimeric  IgG4   kappa  antibody that targets human  C5a  in plasma. [ 3 ]


The most common adverse reactions include pneumonia, sepsis, delirium, pulmonary embolism, hypertension, pneumothorax, deep vein thrombosis, herpes simplex, enterococcal infection, bronchopulmonary aspergillosis, hepatic enzyme increased, urinary tract infection, hypoxia, thrombocytopenia, pneumomediastinum, respiratory tract infection, supraventricular tachycardia, constipation, and rash. [ 1 ]


Vilobelimab is a recombinant chimeric monoclonal IgG4 antibody that specifically binds to the soluble human complement split product C5a after cleavage from C5 to block its interaction with the C5a receptor, both of which are components of the complement system thought to contribute to inflammation and worsening of COVID-19. [ 2 ]  Vilobelimab was granted an  emergency use authorization  (EUA) by the US  Food and Drug Administration  (FDA) in April 2023. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]


In the US, vilobelimab is authorized for use in hospitalized adults when initiated within 48 hours of receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (artificial life support). [ 1 ]  Vilobelimab is not approved by the FDA for any indication, including for the treatment of COVID-19. [ 2 ]


The clinical trial supporting the authorization showed that participants treated with vilobelimab had a lower risk of death by day 28 and day 60 of treatment compared to placebo. [ 1 ]


In November 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Gohibic intended for the treatment of adults with SARS‑CoV2‑induced acute respiratory distress syndrome (ARDS) who are receiving systemic corticosteroids. [ 6 ]  The applicant for this medicinal product is InflaRx GmbH. [ 6 ] [ 7 ]


Vilobelimab is the  international nonproprietary name . [ 8 ]


Vimseltinib  is an  investigational new drug  that is being evaluated to treat  tenosynovial giant cell tumor . [ 1 ]  It is a  macrophage colony-stimulating factor receptor  antagonist. [ 2 ]


Vishnevsky liniment  or  balsamic liniment  ( Russian :  мазь Вишневского ,  Latin :  Linimentum balsamicum Wishnevsky ) is a  topical medication  which has been used to treat  wounds ,  burns ,  skin ulcers  and  suppurations . Developed by  Russian   surgeon   Alexander Vishnevsky  in 1927, the  liniment  contains  birch tar ,  xeroformium  ( bismuth  tribromophenolate) and  castor oil  which have been broadly used as a topical medication in the former  Soviet Union . [ 1 ]


Vishnevsky liniment was broadly used in the  Soviet army  during   World War II . [ 1 ]  It was later shown that a prolonged application of Vishnevsky liniment for chronic skin ulcers, wounds or burns can be associated with higher risk of  skin cancer ,  hematologic  or other malignancy. [ 1 ]


Vitusapotek  is a chain of 300  pharmacies  in Norway owned and run by  Norsk Medisinaldepot , a subsidiary of   McKesson Europe . The pharmacy chain is based in  Oslo , and is the second largest in Norway, after  Apotek1 .


The chain was established in 2001 after the deregulation of the pharmacy market in Norway. The sister company  Ditt Apotek  is a  franchise  chain for independent pharmacies. Until 2007 the chain was a separate company, but is now merged into the parent company along with the wholesaler  NMD Grossisthandel . NMD is one of the largest suppliers of pharmaceuticals and health-related products via pharmacies. NMD currently has a distribution center in Oslo and a branch in  Harstad .


Vixarelimab  (KPL-716) is a fully human  monoclonal antibody  that works by binding to the  oncostatin M receptor  β, thus inhibiting both  interleukin 31  and  oncostatin M . It is developed by Kiniksa Pharmaceuticals for  prurigo nodularis . [ 1 ] [ 2 ] [ 3 ]


Vofopitant  ( GR205171 ) is a drug which acts as an  NK 1  receptor   antagonist . It has  antiemetic  effects as with other NK 1  antagonists, [ 1 ]  and also shows  anxiolytic  actions in animals. [ 2 ]  It was studied for applications such as the treatment of  social phobia  and  post-traumatic stress disorder , but did not prove sufficiently effective to be marketed. [ 3 ] [ 4 ]


Volagidemab  (development name REMD-477) is a  monoclonal antibody  that targets the  glucagon receptor . It is developed by REMD Biotherapeutics for type 1 and type 2 diabetes. A phase II trial did not meet its primary endpoint. [ 1 ] [ 2 ] [ 3 ]


A systematic review and meta-analysis of volagidemab, published in 2024, found it to be potentially beneficial in the treatment of type   1 diabetes. [ 4 ]


Volenrelaxin  (LY3540378) is a long-acting, synthetic analogue of  relaxin  developed by  Eli Lilly and Company  to treat  heart failure . [ 1 ] [ 2 ]


Voxtalisib  ( XL-765 ,  SAR245409 ) is a drug which acts as a dual  inhibitor  of the  kinase  enzymes  phosphatidylinositol 3-kinase  (PI3K) and  mechanistic target of rapamycin  (mTOR). It is in  clinical trials  for the treatment of various types of  cancer . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]


VUF-5681  is a potent and selective  histamine antagonist  which binds selectively to the  H 3  subtype . [ 1 ]  However while VUF-5681 blocks the activity of more potent H 3  agonists, recent studies suggest that it may have some weak  partial agonist  activity when administered by itself. [ 2 ]


VUF-8430  is a  histamine agonist [ 1 ]  selective for the  H 4  subtype. [ 2 ]


Vutiglabridin  ( HSG4112 ) is an experimental anti-obesity drug that is a synthetic structural analog of  glabridin . [ 1 ] [ 2 ] [ 3 ]


VVD-118313  is a chemical compound which acts as a potent and selective negative  allosteric modulator  of  JAK1 , and was developed for research into the treatment of inflammatory diseases, especially chronic inflammation involved in the development of  cancer . [ 1 ] [ 2 ] [ 3 ] [ 4 ]


WB-4101  is a compound which acts as an  antagonist  at the  α 1B -adrenergic receptor . It was one of the first selective antagonists developed for this receptor and was invented in 1969, but is still commonly used in research into adrenergic receptors, especially as a  lead compound  from which to develop more selective drugs. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]


WEDINOS  (an acronym for  Welsh Emerging Drugs and Identification of Novel Substances ) is a  public health laboratory  in  Cardiff, Wales  devoted to  drug checking  and  epidemiological surveillance  of  recreational drugs  and  prescription drugs  obtained from unsanctioned sources. It is the only fixed-site facility in the  United Kingdom  devoted to this task. [ 1 ] [ 2 ]  It was established in 2013, and is funded by  Public Health Wales . [ 1 ] [ 3 ]


Although based and funded in Wales, WEDINOS analyzes samples sent from anywhere in the United Kingdom. [ 1 ] [ 4 ]


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


Western Norway Pharmaceutical Trust  ( Norwegian :  Apotekene Vest HF ) is a  health trust  owned by  Western Norway Regional Health Authority  that operates four hospital  pharmacies  at  Haukeland University Hospital  in  Bergen ,  Stavanger Hospital ,  Haugesund Hospital  and  Førde Hospital . The pharmacies are part of the  Ditt Apotek  chain and use  Norsk Medisinaldepot  as  wholesaler .


Harvey A.K. Whitney  (1894-1957) was an American  pharmacist . He was instrumental in the formation and was the first chairman and President of the  American Society of Health-System Pharmacists , [ 1 ]  where he served from 1942 to 1943. He also co-founded The Bulletin of the ASHP in 1943 which later became the  American Journal of Health-System Pharmacy . [ 2 ]  The  Harvey A.K. Whitney Lecture Award , considered to be the highest award in health-system pharmacy, is named after him. [ 3 ]


Whitney was born on November 7, 1894, in  Adrian, Michigan . During high school, he worked part-time at a local drugstore. Whitney graduated high school in 1912 and in the following year, he went to work for the Rupp & Bowman Drug Company after high school. [ 4 ]  During  World War I , he served in the  Army Medical Corps  before being  honorably discharged  and later attended the  College of Pharmacy at the University of Michigan . He graduated in 1923 with his Ph.C. degree. [ 4 ]


Harvey A.K. Whitney passed away in 1957.


The award was established in 1950 by the Michigan Society of Hospital Pharmacists and is considered one of the highest awards in health-system pharmacy. [ 2 ]  The award is given out annually.


Wholesale acquisition cost  is the price of a medication set by a pharmaceutical manufacturer in the United States when selling to a wholesaler. [ 1 ]  Generally 20% is added to create the  average wholesale price . [ 1 ]


The  Wushi'er Bingfang  ( Chinese :  五十二病方 ;  pinyin :  Wǔshí’èr Bìngfāng ), or  Recipes for Fifty-Two Ailments , is an  ancient Chinese  medical text that was discovered in 1973 in  Mawangdui  in a tomb that was sealed in 168 BCE under the  Han dynasty . [ 4 ]  The text was copied in  seal script  on  sheets of silk  around 215 BCE, under the  Qin dynasty , but might have dated from even earlier. [ 5 ]  Modern editors chose its title because the text starts with a list of fifty-two ailments for which recipes are given. [ 6 ]  The  formulary  presents more than 250  exorcistic  and drug-based cures for ailments such as  warts ,  hemorrhoids ,  inguinal swellings , and  snake bites . [ 7 ]  Among other medical treatments, the text also recommends  lancing  and  cauterization , but mention neither  acupuncture  nor  moxibustion  (cauterization with moxa). [ 8 ]


With roughly 9,950 characters,  Wushi'er bingfang  is the longest of the medical texts that have been found in ancient Chinese tombs. [ 9 ]  Along with other excavated manuscripts (from  Zhangjiashan  and  Wuwei , among others), it has shed light on the early development of  Chinese medicine . [ 10 ]  It illustrates, for instance, that magical  incantations  were a common therapeutic method among the  social elite of the time . [ 11 ]  And because it shows the development of  channel theory  in a primitive stage and does not mention the doctrine of  Yinyang  and the  Five Phases , it has pushed historians to date the more sophisticated  Huangdi Neijing  ( Yellow Emperor's Inner Canon ) to the first century BCE. [ 12 ]


The original manuscript of  Wushi'er bingfang  is kept at the  Hunan Provincial Museum  in  Changsha . [ 13 ]


WYE-687  is a drug which acts as an  inhibitor  of both subtypes of the  mechanistic target of rapamycin  (mTOR),  mTORC1  and  mTORC2 . It is being researched for potential applications in the treatment of various forms of  cancer . [ 1 ] [ 2 ] [ 3 ]


Xeligekimab  (GR1501) is a  monoclonal antibody  that neutralizes  interleukin-17A ; [ 1 ]  it is being developed for  plaque psoriasis , [ 2 ]   axial spondyloarthritis , [ 3 ]  and  lupus nephritis . [ 4 ]  It is in a Phase III trial in 2023. [ 5 ]


Xevinapant  is an  investigational new drug  that is being evaluated to treat  squamous cell cancer . [ 1 ]  By acting as a  SMAC mimetic , it functions as an inhibitor of several members of the  IAP  protein family (including  XIAP ,  c-IAP1 , and  c-IAP2 ). [ 2 ]


XF-73 (Exeporfinium chloride)  is an experimental drug candidate. It is an  anti-microbial  that works via weakening bacteria cell walls. [ 1 ]  It is a potential treatment for  methicillin-resistant  Staphylococcus aureus  (MRSA) and possibly  Clostridioides difficile . It is being  developed  by Destiny Pharma Ltd. [ 2 ] [ 3 ] [ 4 ]


Structurally, it is a dicationic  porphyrin . [ 5 ]


It has completed a phase I clinical trial for nasal decolonisation of MRSA—being tested against 5 bacterial strains. It seems unlikely to cause MRSA to develop resistance to it. [ 1 ] [ 6 ]


In 2014, a phase 1 clinical trial for nasal administration was run. [ 7 ]


As of June 2022 [update] , another phase 1 clinical trial (for nasal administration) completed recruiting in 2016 but no results have been posted. [ 8 ]


XL-388  is a drug which acts as a potent and selective  inhibitor  of both subtypes of the  mechanistic target of rapamycin  (mTOR),  mTORC1  and  mTORC2 . [ 1 ]  It is being researched for the treatment of various forms of  cancer , [ 2 ] [ 3 ] [ 4 ]  and has also been used to demonstrate a potential application for mTOR inhibitors in the treatment of  neuropathic pain . [ 5 ] [ 6 ]


XL-413  is a drug which acts as a selective inhibitor of the  enzyme   cell division cycle 7-related protein kinase  (CDC7). It is being researched for the treatment of some forms of  cancer , and also has applications in  genetic engineering . [ 1 ] [ 2 ] [ 3 ] [ 4 ]


This  genetics  article is a  stub . You can help Wikipedia by  expanding it .


This article about  biological engineering  is a  stub . You can help Wikipedia by  expanding it .


YM-254890  is a  macrolide antibiotic  derived from  Chromobacterium  species. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It is used as a pharmacological research compound which acts as a selective inhibitor of  G q  mediated signalling. [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]  However the claimed selectivity for G q  has been disputed. [ 10 ]


Yoda1  is a chemical compound which is the first  agonist  developed for the  mechanosensitive ion channel   PIEZO1 . This protein is involved in regulation of  blood pressure  and  red blood cell  volume, and Yoda1 is used in scientific research in these areas. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]


Z583  ( GLXC-26150 ) is a chemical compound which acts as a potent and highly selective  inhibitor  of  JAK3 , and was developed for the treatment of  rheumatoid arthritis . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]


Zandelisib  is an  investigational new drug  that is being evaluated to treat  follicular lymphoma . [ 1 ]  It is a  phosphatidylinositol 3 kinase delta  inhibitor. [ 2 ]


Zanidatamab , sold under the brand name  Ziihera , is a  humanized monoclonal antibody  used for the treatment of HER2-positive  biliary tract cancer . [ 1 ] [ 2 ]  It is an IgG-like  bispecific HER2-directed antibody  directed against two non-overlapping domains of HER2. [ 1 ] [ 2 ] [ 3 ]  Zanidatamab is produced in  Chinese hamster ovary cells . [ 1 ]


The most common adverse reactions include  diarrhea ,  infusion-related reaction ,  abdominal pain , and  fatigue . [ 2 ]


Zanidatamab was approved for medical use in the United States in November 2024. [ 2 ] [ 4 ]


Zanidatamab is  indicated  for the treatment of adults with previously treated, unresectable or  metastatic  HER2-positive (IHC 3+)  biliary tract cancer , as detected by an FDA-approved test. [ 1 ] [ 2 ]


The US  Food and Drug Administration  prescribing information contains a  boxed warning  for embryo-fetal toxicity. [ 2 ]


The most common adverse reactions include diarrhea, infusion-related reactions, abdominal pain, and fatigue. [ 2 ]


Efficacy was evaluated in HERIZON-BTC-01 (NCT04466891), an open-label multicenter, single-arm trial in 62 participants with unresectable or metastatic HER2-positive (IHC3+)  biliary tract cancer . [ 2 ]  Participants were required to have received at least one prior  gemcitabine -containing regimen in the advanced disease setting. [ 2 ]


The US  Food and Drug Administration  (FDA) granted the application for zanidatamab  priority review ,  breakthrough therapy , and  orphan drug  designations. [ 2 ]


Zanidatamab was approved for medical use in the United States in November 2024. [ 2 ] [ 5 ] [ 6 ]


Zanidatamab is the  international nonproprietary name . [ 7 ]


Zanidatamab is sold under the brand name Ziihera. [ 1 ]


Zapomeran , sold under the brand name  Kostaive  is a self-amplifying  mRNA-based   COVID-19 vaccine . [ 1 ]  It contains a self-amplifying mRNA that encodes the  SARS-CoV-2  spike protein. [ 1 ]  Self-amplifying means that the mRNA also carries instructions to make a protein called  replicase . [ 1 ]


Kostaive was approved for medical use in Japan in November 2023, and it is the first self-amplifying mRNA-based COVID-19 vaccine to be approved. [ 2 ] [ 3 ]


Zapomeran is used to provide protection against  COVID-19 , caused by infection with the  SARS-CoV-2  virus. [ 1 ]


Kostaive was approved for medical use in Japan in November 2023. [ 4 ] [ 5 ] [ 6 ]


In December 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kostaive, a vaccine intended for the prevention of COVID-19 in adults. [ 1 ]  The applicant for this medicinal product is Arcturus Therapeutics Europe B.V. [ 1 ]


Zapomeran is the  international nonproprietary name . [ 7 ] [ 8 ]


Zaprinast  was an unsuccessful clinical drug candidate that was a precursor to the chemically related  PDE5 inhibitors , such as  sildenafil  (Viagra), which successfully reached the market. It is a  phosphodiesterase inhibitor , [ 1 ]  selective for the subtypes  PDE5 ,  PDE6 ,  PDE9  and  PDE11 .   IC 50  values are 0.76, 0.15, 29.0, and 12.0  μ M, respectively. [ 2 ] [ 3 ]


Zaprinast inhibits the growth of asexual blood-stage  malaria  parasites ( P. falciparum )  in vitro  with an  ED 50  value of 35  μ M, and inhibits PfPDE1, a  P. falciparum  cGMP-specific phosphodiesterase, with an IC 50  value of 3.8  μ M. [ 4 ]


Zaprinast has also been shown to activate the orphan  G-protein coupled receptor  known as  GPR35 , both in rats and humans, [ 5 ]  and to inhibit the mitochondrial  pyruvate  carrier.  [ 6 ]


Zasocitinib  ( TAK-279 ,  NDI-034858 ) is a drug which is an orally active, highly selective  tyrosine kinase 2  (TYK2)  inhibitor . It has been researched for various inflammatory conditions including  psoriatic arthritis  and  Crohn's disease . [ 1 ] [ 2 ] [ 3 ]   It is significantly more selective than earlier compounds over side targets such as  JAK1 , which is hoped to give it an improved side effect profile. [ 4 ]


Zatolmilast  is a  investigational new drug  that is being evaluated to treat  fragile X syndrome . [ 1 ]  It is a  PDE4D  allosteric inhibitor. [ 2 ]


Zeteletinib  ( BOS-172738 ,  DS-5010 ) is an experimental  anticancer medication  which acts as a  RET inhibitor . [ 1 ] [ 2 ]


Zicronapine  ( / z aɪ ˈ k r ɒ n ə p iː n /   zye- KRON -ə-peen , previously known as  Lu 31-130 ) is an  atypical antipsychotic  medication [ 1 ]  formerly under development by  H. Lundbeck A/S . In  phase II studies  zicronapine showed statistically significant separation from placebo and convincing efficacy and safety data when compared to  olanzapine . [ 2 ]


Zicronapine exhibits monoaminergic activity and has a multi-receptorial profile.  In vitro  and  in vivo  it has shown potent antagonistic effects at dopamine  D 1 ,  D 2  and serotonin  5HT 2A  receptors. [ 3 ]


In 2014 Lundbeck removed zicronapine from its development portfolio in favor of pursuing the more promising antipsychotic  Lu AF35700  (a  prodrug  of  Lu AF356152 ). [ 4 ]


Zimlovisertib  ( PF-06650833 ) is a drug which acts as a selective inhibitor of the enzyme  Interleukin-1 receptor-associated kinase 4  (IRAK-4). It has  antiinflammatory  effects and has been trialed for various indications including  hidradenitis suppurativa  and treatment of  COVID-19  infection, and while it has not been adopted into clinical use it continues to be used for research in this area. [ 1 ] [ 2 ] [ 3 ]


ZINC17988990  is a drug which acts as a potent and selective inhibitor for the  TRPV5  calcium channel, with an IC 50  of 177 nM and high selectivity for TRPV5 over  TRPV6  and the other subtypes of  TRPV . It is the first selective inhibitor to be developed for TRPV5, and may be useful for modulating calcium reabsorption in the kidneys. [ 1 ]


Zinterol  is a  beta-adrenergic agonist . [ 1 ]


Its structure is based on  soterenol  ( antiarrhythmic ) and phentermine.


Zipalertinib  is an  investigational new drug  that is being evaluated for the treatment of  non-small cell lung cancer  (NSCLC) with  EGFR  mutations, particularly  exon  20 insertion mutations. [ 1 ] [ 2 ] [ 3 ]


Ziritaxestat  is a small-molecule, selective  autotaxin  inhibitor that was investigated as a potential treatment for  idiopathic pulmonary fibrosis  (IPF). [ 1 ]  Initially showing promise in early-phase studies, ziritaxestat underwent evaluation in two large-scale phase 3 clinical trials, ISABELA 1 and ISABELA 2. [ 1 ] [ 2 ]  These trials aimed to assess the efficacy and safety of ziritaxestat in patients with IPF, including those receiving standard of care treatment with pirfenidone or nintedanib. [ 1 ]  However, both trials were prematurely terminated due to a lack of efficacy, as ziritaxestat failed to demonstrate significant improvement in lung function or other clinical outcomes compared to placebo. [ 1 ] [ 2 ] [ 3 ]


ZLY18  is an experimental drug that acts as an agonist of the  free fatty acid receptor 1  (FFA1) and all three types of  peroxisome proliferator-activated receptor  ( alpha ,  delta , and  gamma ). It is in development for the treatment of  non-alcoholic fatty liver disease . [ 1 ] [ 2 ] [ 3 ] [ 4 ]


ZM447439  is an  aurora inhibitor . [ 1 ]


Zofenoprilat  is an  angiotensin-converting enzyme inhibitor , and is the free  sulfhydryl   active metabolite  of  zofenopril . [ 1 ]


Zolertine  is an  alpha-1 adrenoceptor antagonist . [ 1 ]


α-Eucaine  ( alpha -eucaine) is a drug that was previously used as a  local anesthetic . [ 1 ]  It was designed as an  analog  of  cocaine  and was one of the first synthetic chemical compounds to find general use as an anesthetic. [ 2 ]


The  Aldol condensation  between two equivalents of acetone gives  Mesityl oxide  [141-79-7] ( 1 ) ( isophorone  is a side-product of this reaction). Ammonolysis of mesityl oxide formed diacetonamine [625-04-7] ( 2 ). The reaction of this product with acetone then gives 2,2,6,6-tetramethyl-4-piperidone [826-36-8] ( 3 ).  N -methylation of the secondary amine gives 1,2,2,6,6-pentamethylpiperidin-4-one [5554-54-1] ( 4 ). Cyanohydrin formation gives  CID:434556  ( 5 ). Esterification of the tertiary alcohol with benzoyl chloride gives ( 6 ). Pinner reaction of the nitrile with EtOH/H+ affords alpha-eucaine ( 7 ).


α3IA , also known as  GTPL4094 , is an inverse agonist of the  GABA A  receptor . It is more selective for the  α3  subunit, hence its name.


Agonism of the α3 subunit shows anxiolytic properties. However, by being an inverse agonist, α3IA has the opposite action: it shows  anxiogenic  properties. [ 2 ]


This compound also has affinity for the other subunits of the  GABA A  receptor , but it is more selective for the α3 subunit. [ 3 ]


Δ-3-Tetrahydrocannabinol  (often abbreviated as  delta-3-THC  or  Δ 3 -THC ) is a synthetic  isomer  of  tetrahydrocannabinol  (THC) developed during the original research in the 1940s to develop synthetic routes to the  natural products   Δ 8 -THC  and Δ 9 -THC found in the  cannabis . [ 1 ]  While the normal  trans  configuration of THC is in this case flattened by the double bond, it still has two  enantiomers  as the 9-methyl group can exist in an (R) or (S) conformation. The (S) enantiomer has similar effects to Δ 9 -THC though with several times lower potency, while the (R) enantiomer is many times less active or inactive, depending on the assay used. [ 2 ] [ 3 ] [ 4 ]  It has been identified as a component of  vaping  liquid products. [ 5 ]


Δ-7-Tetrahydrocannabinol  ( Delta-5-THC ,  Δ 5 -THC ; alternatively numbered as  Δ-5-Tetrahydrocannabinol ,  Δ 7 -THC ) is a synthetic isomer of  tetrahydrocannabinol . The (6aR,9S,10aR)-Δ 7 -THC epimer is only slightly less potent than Δ 9 -THC itself, while the (9R) epimer is much less potent. [ 1 ] [ 2 ]


Clinical pharmacology  is "that discipline that teaches, does research, frames policy, gives information and advice about the actions and proper uses of medicines in humans and implements that knowledge in clinical practice". [ 1 ] [ 2 ]  Clinical pharmacology is inherently a translational discipline underpinned by the basic science of  pharmacology , engaged in the experimental and observational study of the disposition and effects of drugs in humans, and committed to the translation of science into evidence-based therapeutics. [ 3 ]  It has a broad scope, from the discovery of new target  molecules  to the effects of drug usage in whole  populations . [ 4 ]  The main aim of clinical pharmacology is to generate data for optimum use of drugs and the practice of ' evidence-based medicine '.


Clinical pharmacologists have  medical  and scientific training that enables them to evaluate  evidence  and produce new data through well-designed  studies .  Clinical pharmacologists must have access to enough patients for  clinical care , teaching and education, and research. Their responsibilities to patients include, but are not limited to, detecting and analysing adverse drug effects and reactions, therapeutics, and toxicology including reproductive toxicology, perioperative drug management, and  psychopharmacology .


Modern clinical pharmacologists are also trained in data analysis skills. Their approaches to analyse data can include modelling and simulation techniques (e.g. population analysis, non-linear mixed-effects modelling).


Clinical pharmacology consists of multiple branches listed below:


Medicinal uses of plant and animal resources have been common since prehistoric times. Many countries, such as China, Egypt, and India, have written documentation of many traditional remedies. A few of these remedies are still regarded as helpful today, but most have them have been discarded,  because they  were ineffective and potentially harmful.


For many years, therapeutic practices were based on Hippocratic  humoral theory , popularized by the Greek physician  Galen  (129 – c. AD 216) and not on experimentation.


In around the 17th century physicians started to apply use methods to study traditional remedies, although they still lacked methods to test the hypotheses they had about how drugs worked. [ 8 ]


By the late 18th century and early 19th century, methods of experimental physiology and pharmacology began to be developed by scientists such as François Magendie and his student Claude Bernard.


From the late 18th century to the early 20th century, advances were made in chemistry and physiology that laid the foundations needed to understand how drugs act at the tissue and organ levels.  The advances that were made at this time gave manufacturers the ability to make and sell medicines that they claimed to be effective, but were in many cases worthless. There were no methods for evaluating such claims until rational therapeutic concepts were established in medicine, starting at about the end of the 19th century.


The development of receptor theory at the start of the 20th century and later developments led to better understanding of how medicines act and the development of many new medicines that are both safe and effective. Expansion of the scientific principles of pharmacology and clinical pharmacology continues today. [ 9 ] [ 7 ]


" Addiction Rare in Patients Treated with Narcotics " is the title of a  letter to the editor  written by Jane Porter and  Hershel Jick  and published in the January 10, 1980, issue of  The New England Journal of Medicine . The letter analyzed data on patients who had been treated with  opioids  in a hospital setting, and concluded that addiction was uncommon among such patients. It has since been frequently misrepresented to claim that opioids are not addictive when prescribed for use at home. This misrepresentation has been blamed for contributing to the  opioid epidemic in the United States .


The letter reported on an examination of medical files of patients who had been hospitalized and treated with small doses of  opioids . The authors concluded that of the 11,882 patients who received at least one narcotic drug, only four of them had developed a "reasonably well documented" addiction among patients who had no history of addiction. Its text read, in its entirety:


Recently, we examined our current files to determine the incidence of narcotic addiction in 39,946 hospitalized medical patients who were monitored consecutively. Although there were 11,882 patients who received at least one narcotic preparation, there were only four cases of reasonably well documented addiction in patients who had no history of addiction. The addiction was considered major in only one instance. The drugs implicated were meperidine in two patients, Percodan in one, and hydromorphone in one. We conclude that despite widespread use of narcotic drugs in hospitals, the development of addiction is rare in medical patients with no history of addiction. [ 1 ]


The article has been cited extensively as evidence that addiction was very rare among patients who were prescribed narcotics (more specifically, opioids). [ 2 ] [ 3 ]  It became so well known that it is sometimes referred to simply as  Porter and Jick . [ 4 ]


Methodological limitations from which the letter suffered included that the patients it reported on were all given opioids in small doses in a hospital. [ 2 ] [ 3 ]  Additionally, in 2003, Jick told  The New York Times  that the study did not follow patients after they left the hospital. [ 5 ]


In 2017, the letter attracted renewed interest because the  New England Journal of Medicine  published a bibliographic analysis of the letter showing that it had been cited 608 times since it was published. In comparison, the other letters to the editor in the same issue of the  Journal  as Porter and Jick's letter had been cited a median of 11 times. [ 6 ]  Of these 608 citations, the analysis also showed that 72.2% of them cited it in support of the claim that patients treated with opioids rarely developed addiction, and 80.8% did not mention that the letter only included data on prescriptions given to hospitalized patients. [ 7 ]  It was also misrepresented in the popular media; a 1990  Scientific American  article described it as an "extensive study," and a 2001  Time  story dubbed it a "landmark study" showing that concerns about opioid addiction were "basically unwarranted." [ 8 ]  In addition,  Purdue Pharma , the manufacturer of  OxyContin , trained its sales representatives to say that the risk of addiction among patients using the drug was less than 1 percent, citing Porter and Jick's letter as one of their sources. [ 9 ]


Because the letter has been frequently misrepresented to argue that opioids were rarely addictive, these misrepresentations have been blamed for contributing to the opioid epidemic. [ 3 ] [ 10 ]  For example, a co-author of the 2017 bibliographic analysis,  David Juurlink , has stated that he thinks the letter's appearance in a prestigious journal helped convince doctors that opioids were safe, saying, "I think it's fair to say that this letter went quite a long way." [ 11 ]  Jick, who wrote the letter, has since said that "The letter wasn't of value to health and medicine in and of itself. So if I could take it back—if I knew then what I know now, I would never have published it. It wasn't worth it." [ 12 ]


In medicine,  patient compliance  (also  adherence ,  capacitance ) describes the degree to which a patient correctly follows medical advice. Most commonly, it refers to medication or drug compliance, but it can also apply to other situations such as medical device use,  self care , self-directed exercises, or therapy sessions. Both patient and health-care provider affect compliance, and a positive physician-patient relationship is the most important factor in improving compliance. [ 1 ]  Access to care plays a role in patient adherence, whereby greater wait times to access care contributing to greater absenteeism. [ 2 ]  The  cost of prescription medication  also plays a major role. [ 3 ]


Compliance can be confused with  concordance , which is the process by which a patient and clinician make decisions together about treatment. [ 4 ]


Worldwide, non-compliance is a major obstacle to the effective delivery of health care. 2003 estimates from the  World Health Organization  indicated that only about 50% of patients with chronic diseases living in  developed countries  follow treatment recommendations with particularly low rates of adherence to therapies for  asthma ,  diabetes , and  hypertension . [ 1 ]  Major barriers to compliance are thought to include the complexity of modern medication regimens, poor  health literacy  and not understanding treatment benefits, the occurrence of undiscussed side effects, poor treatment satisfaction, cost of prescription medicine, and poor communication or lack of trust between a patient and his or her health-care provider. [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]  Efforts to improve compliance have been aimed at simplifying medication packaging, providing effective medication reminders, improving patient education, and limiting the number of medications prescribed simultaneously. Studies show a great variation in terms of characteristics and effects of interventions to improve medicine adherence. [ 10 ]  It is still unclear how adherence can consistently be improved in order to promote clinically important effects. [ 10 ]


In medicine, compliance (synonymous with adherence, capacitance) describes the degree to which a patient correctly follows medical advice. Most commonly, it refers to medication or drug compliance, but it can also apply to medical device use,  self care , self-directed exercises, or therapy sessions. Both patient and health-care provider affect compliance, and a positive physician-patient relationship is the most important factor in improving compliance. [ 1 ]


As of 2003, US health care professionals more commonly used the term "adherence" to a regimen rather than "compliance", because it has been thought to reflect better the diverse reasons for patients not following treatment directions in part or in full. [ 6 ] [ 11 ]  Additionally, the term adherence includes the ability of the patient to take medications as prescribed by their physician with regards to the correct drug, dose, route, timing, and frequency. [ 12 ]  It has been noted that compliance may only refer to passively following orders. [ 13 ]  The term  adherence  is often used to imply a collaborative approach to decision-making and treatment between a patient and clinician. [ 14 ]


The term concordance has been used in the  United Kingdom  to involve a patient in the treatment process to improve compliance, and refers to a 2003  NHS  initiative. In this context, the patient is informed about their condition and treatment options, involved in the decision as to which course of action to take, and partially responsible for monitoring and reporting back to the team. [ 15 ]  Informed intentional non-adherence is when the patient, after understanding the risks and benefits, chooses not to take the treatment. [ 16 ]


As of 2005, the preferred terminology remained a matter of debate. [ 17 ]  As of 2007, concordance has been used to refer specifically to patient adherence to a treatment regimen which the physician sets up collaboratively with the patient, to differentiate it from adherence to a physician-only prescribed treatment regimen. [ 18 ] [ 19 ] [ 20 ]  Despite the ongoing debate, adherence has been the preferred term for the  World Health Organization , [ 1 ]  The  American Pharmacists Association , [ 5 ]  and the U.S.  National Institutes of Health  Adherence Research Network. [ 21 ]  The  Medical Subject Headings  of the  United States National Library of Medicine  defines various terms with the words  adherence  and  compliance .  Patient Compliance   and  Medication Adherence  are distinguished under the MeSH tree of  Treatment Adherence and Compliance .


An estimated half of those for whom treatment regimens are prescribed do not follow them as directed. [ 1 ]


Negative side effects of a medicine can influence adherence. [ 22 ] : 280


Cost and poor understanding of the directions for the treatment, referred to as ' health literacy ' have been known to be major barriers to treatment adherence. [ 23 ] [ 6 ] [ 24 ]   There is robust evidence that education and physical health are correlated. Poor educational attainment is a key factor in the cycle of health inequalities. [ 25 ] [ 26 ] [ 27 ]


Educational qualifications help to determine an individual's position in the labour market, their level of income and therefore their access to resources. [ citation needed ]


In 1999 one fifth of UK adults, nearly seven million people, had problems with basic skills, especially  functional literacy  and functional numeracy, described as: "The ability to read, write and speak in English, and to use mathematics at a level necessary to function at work and in society in general." This made it impossible for them to effectively take medication, read labels, follow drug regimes, and find out more. [ 28 ]


In 2003, 20% of adults in the UK had a long-standing illness or disability and a national study for the UK  Department of Health , found more than one-third of people with poor or very poor health had literary skills of Entry Level 3 or below. [ 29 ]


Low levels of literacy and numeracy were found to be associated with socio-economic deprivation. [ 29 ]  Adults in more deprived areas, such as the North East of England, performed at a lower level than those in less deprived areas such as the South East. Local authority tenants and those in poor health were particularly likely to lack basic skills. [ 29 ]


A 2002 analysis of over 100 UK  local education authority  areas found educational attainment at 15–16 years of age to be strongly associated with coronary heart disease and subsequent infant mortality. [ 30 ]


A study of the relationship of literacy to asthma knowledge revealed that 31% of asthma patients with a reading level of a ten-year-old knew they needed to see the doctors, even when they were not having an asthma attack, compared to 90% with a high school graduate reading level. [ 31 ]


In 2013 the US National Community Pharmacists Association sampled for one month 1,020 Americans above age 40 for with an ongoing prescription to take medication for a chronic condition and gave a grade C+ on adherence. [ 32 ] [ better source needed ]  In 2009, this contributed to an estimated cost of $290 billion annually. [ 33 ]  In 2012, increase in patient medication cost share was found to be associated with low adherence to medication. [ 34 ]


The United States is among the countries with the highest  prices of prescription drugs  mainly attributed to the government's lack of negotiating lower prices with monopolies in the pharmaceutical industry especially with brand name drugs. [ 35 ]  In order to manage medication costs, many US patients on long term therapies fail to fill their prescription, skip or reduce doses. According to a Kaiser Family Foundation survey in 2015, about three quarters (73%) of the public think drug prices are unreasonable and blame pharmaceutical companies for setting prices so high. [ 36 ]  In the same report, half of the public reported that they are taking prescription drugs and a "quarter (25%) of those currently taking prescription medicine report they or a family member have not filled a prescription in the past 12 months due to cost, and 18 percent report cutting pills in half or skipping doses". [ 36 ]  In a 2009 comparison to Canada, only 8% of adults reported to have skipped their doses or not filling their prescriptions due to the cost of their prescribed medications. [ 37 ]


The elderly often have multiple health conditions, and around half of all  NHS  medicines are prescribed for people over retirement age, despite representing only about 20% of the UK population. [ 38 ] [ 39 ]  The recent  National Service Framework  on the care of older people highlighted the importance of taking and effectively managing medicines in this population. However, elderly individuals may face challenges, including multiple medications with frequent dosing, and potentially decreased dexterity or cognitive functioning. Patient knowledge is a concern that has been observed.


In 1999 Cline et al. identified several gaps in knowledge about medication in elderly patients discharged from hospital. [ 40 ]  Despite receiving written and verbal information, 27% of older people discharged after heart failure were classed as non-adherent within 30 days. Half the patients surveyed could not recall the dose of the medication that they were prescribed and nearly two-thirds did not know what time of day to take them. A 2001 study by Barat et al. evaluated the medical knowledge and factors of adherence in a population of 75-year-olds living at home. They found that 40% of elderly patients do not know the purpose of their regimen and only 20% knew the consequences of non-adherence. [ 41 ]  Comprehension,  polypharmacy , living arrangement, multiple doctors, and use of compliance aids was correlated with adherence.


In children with asthma, self-management compliance is critical and co-morbidities have been noted to affect outcomes; in 2013 it has been suggested that electronic monitoring may help adherence. [ 42 ]


People of different ethnic backgrounds have unique adherence issues through literacy, physiology, culture or poverty. [ citation needed ]  There are few published studies on adherence in medicine taking in ethnic minority communities. Ethnicity and culture influence some health-determining behaviour, such as participation in screening programmes and attendance at follow-up appointments. [ 43 ] [ 44 ]


Prieto  et al  emphasised the influence of ethnic and cultural factors on adherence. They pointed out that groups differ in their attitudes, values and beliefs about health and illness. This view could affect adherence, particularly with preventive treatments and medication for asymptomatic conditions. Additionally, some cultures fatalistically attribute their good or poor health to their god(s), and attach less importance to self-care than others. [ 45 ]


Measures of adherence may need to be modified for different ethnic or cultural groups. In some cases, it may be advisable to assess patients from a cultural perspective before making decisions about their individual treatment. [ citation needed ]


Recent studies have shown that black patients and those with non-private insurance are more likely to be labeled as non-adherent. [ 46 ]  The increased risk is observed even in patients with a controlled A1c, and after controlling for other socioeconomic factors. [ 47 ]


Not all patients will fill the prescription at a pharmacy. In a 2010 U.S. study, 20–30% of prescriptions were never filled at the pharmacy. [ 48 ] [ 49 ]  Reasons people do not fill prescriptions include the cost of the medication, [ 3 ] [ 5 ]  A US nationwide survey of 1,010 adults in 2001 found that 22% chose not to fill prescriptions because of the price, which is similar to the 20–30% overall rate of unfilled prescriptions. [ 3 ]  Other factors are doubting the need for medication, or preference for self-care measures other than medication. [ 50 ] [ 51 ]  Convenience, side effects and lack of demonstrated benefit are also factors. [ citation needed ]


Prescription medical claims records can be used to estimate medication adherence based on fill rate. Patients can be routinely defined as being 'Adherent Patients' if the amount of medication furnished is at least 80% based on days' supply of medication divided by the number of days patient should be consuming the medication. This percentage is called the medication possession ratio (MPR). 2013 work has suggested that a medication possession ratio of 90% or above may be a better threshold for deeming consumption as 'Adherent'. [ 52 ]


Two forms of MPR can be calculated, fixed and variable. [ 53 ]  Calculating either is relatively straightforward, for Variable MPR (VMPR) it is calculated as the number of days' supply divided by the number of elapsed days including the last prescription.


V
 M
 P
 R
 =

 All days' supply
 Elapsed days (inclusive of last prescription)

 {\displaystyle VMPR={\dfrac {\text{All days' supply}}{\text{Elapsed days (inclusive of last prescription)}}}}


For the Fixed MPR (FMPR) the calculation is similar but the denominator is the number of days in a year whilst the numerator is constrained to be the number of days' supply within the year that the patient has been prescribed.


F
 M
 P
 R
 =

 All days' supply

 ≤
 365

 365

 {\displaystyle FMPR={\dfrac {{\text{All days' supply}}\leq 365}{365}}}


For medication in tablet form it is relatively straightforward to calculate the number of days' supply based on a prescription. Some medications are less straightforward though because a prescription of a given number of doses may have a variable number of days' supply because the number of doses to be taken per day varies, for example with preventative corticosteroid inhalers prescribed for asthma where the number of inhalations to be taken daily may vary between individuals based on the severity of the disease. [ citation needed ]


Contextual factors along with intrapersonal circumstances such as mental states affect decisions. They can accurately predict decisions where most contextual information is identified. [ 54 ]  General compliance with recommendations to follow isolation is influenced beliefs such as taking health precaution to be protected against infection, perceived vulnerability, getting COVID-19 and trust in the government. [ 55 ]  Mobility reduction, compliance with quarantine regulations in European regions where level of trust in policymakers is high can influence whether one complies with isolation rules. [ 56 ]  In addition, perceived infectiousness of COVID-19 is a strong predictor of rule compliance such that the more contagious people think COVID-19 is, the less willing social distancing measures are taken, while the sense of duty and fear of the virus contribute to staying at home. [ 57 ] [ 58 ] [ 59 ]  People might not leave their homes due to trusting regulations to be effective or placing it in a higher power such that individuals who trust others demonstrate more compliance than those who do not. [ 60 ] [ 61 ]  Compliant individuals see protective measures as effective, while non-compliant people see them as problematic. [ 62 ]


Once started, patients seldom follow treatment regimens as directed, and seldom complete the course of treatment. [ 5 ] [ 6 ]  In respect of hypertension, 50% of patients completely drop out of care within a year of diagnosis. [ 63 ]  Persistence with first-line single antihypertensive drugs is extremely low during the first year of treatment. [ 64 ]  As far as lipid-lowering treatment is concerned, only one third of patients are compliant with at least 90% of their treatment. [ 65 ]  Intensification of patient care interventions (e.g. electronic reminders, pharmacist-led interventions, healthcare professional  education  of patients) improves patient adherence rates to lipid-lowering medicines, as well as total cholesterol and LDL-cholesterol levels. [ 66 ]


The World Health Organization (WHO) estimated in 2003 that only 50% of people complete long-term therapy for chronic illnesses as they were prescribed, which puts patient health at risk. [ 67 ]  For example, in 2002  statin  compliance dropped to between 25 and 40% after two years of treatment, with patients taking statins for what they perceive to be preventative reasons being unusually poor compliers. [ 68 ]


A wide variety of packaging approaches have been proposed to help patients complete prescribed treatments. These approaches include formats that increase the ease of remembering the dosage regimen as well as different labels for increasing patient understanding of directions. [ 69 ] [ 70 ]  For example, medications are sometimes packed with reminder systems for the day and/or time of the week to take the medicine. [ 70 ]  Some evidence shows that reminder packaging may improve clinical outcomes such as blood pressure. [ 70 ]


A not-for-profit organisation called the Healthcare Compliance Packaging Council of Europe] (HCPC-Europe) was set up [ when? ]  between the pharmaceutical industry, the packaging industry with representatives of European patients organisations. The mission of HCPC-Europe is to assist and to educate the healthcare sector in the improvement of patient compliance through the use of packaging solutions. A variety of packaging solutions have been developed by this collaboration. [ 71 ]


The World Health Organization (WHO) groups barriers to medication adherence into five categories; health care team and system-related factors, social and economic factors, condition-related factors, therapy-related factors, and patient-related factors. Common barriers include: [ 72 ]


Health care providers play a great role in improving adherence issues. Providers can improve patient interactions through  motivational interviewing  and active listening. [ 73 ]  Health care providers should work with patients to devise a plan that is meaningful for the patient's needs. A relationship that offers trust, cooperation, and mutual responsibility can greatly improve the connection between provider and patient for a positive impact. [ 13 ]  The wording that health care professionals take when sharing health advice may have an impact on adherence and health behaviours, however, further research is needed to understand if positive framing (e.g., the chance of surviving is improved if you go for screening) versus negative framing (e.g., the chance of dying is higher if you do not go for screening) is more effective for specific conditions. [ 74 ]


In 2012 it was predicted that as telemedicine technology improves, physicians will have better capabilities to remotely monitor patients in real-time and to communicate recommendations and medication adjustments using personal mobile devices, such as smartphones, rather than waiting until the next office visit. [ 75 ]


Medication Event Monitoring Systems (MEMS), as in the form of smart medicine bottle tops, smart pharmacy vials or smart blister packages as used in clinical trials and other applications where exact compliance data are required, work without any patient input, and record the time and date the bottle or vial was accessed, or the medication removed from a blister package. The data can be read via proprietary readers, or NFC enabled devices, such as smartphones or tablets. A 2009 study stated that such devices can help improve adherence. [ 76 ]  More recently a 2016 scoping review suggested that in comparison to MEMS, median mediction adherence was grossly overestimated by 17% using self-report, by 8% using pill count and by 6% using rating as alternative methods for measuring medication adherence. [ 77 ]


The effectiveness of two-way email communication between health care professionals and their patients has not been adequately assessed. [ 78 ]


As of 2019 [update] , 5.15 billion people, which equates to 67% of the global population, have a mobile device and this number is growing. [ 79 ]  Mobile phones have been used in healthcare and has fostered its own term,  mHealth . They have also played a role in improving adherence to medication. [ 80 ]  For example, text messaging has been used to remind patients to take medication in patients with chronic conditions such as  asthma  and  hypertension . [ 81 ]  Other examples include the use of smartphones for synchronous and asynchronous Video Observed Therapy (VOT) as a replacement for the currently resource intensive [ 82 ]  standard of  Directly Observed Therapy  (DOT) (recommended by the WHO [ 83 ] ) for Tuberculosis management. [ 84 ]  Other mHealth interventions for improving adherence to medication include smartphone applications, [ 85 ]  voice recognition in interactive phone calls [ 86 ]  and  Telepharmacy . [ 87 ]  Some results show that the use of mHealth improves adherence to medication and is cost-effective, [ 87 ]  though some reviews report mixed results. [ 88 ]  Studies show that using mHealth to improve adherence to medication is feasible and accepted by patients. [ 88 ] [ 87 ]  Specific mobile applications might also support adherence. [ 89 ] [ 90 ]  mHealth interventions have also been used alongside other  telehealth  interventions such as wearable wireless pill sensors, [ 91 ]  smart pillboxes [ 91 ]  and smart inhalers [ 92 ]


Depot injections  need to be taken less regularly than other forms of medication and a medical professional is involved in the administration of drugs so can increase compliance. Depot's are used for  oral contraceptive pill [ 93 ]  and  antipsychotic  medication used to treat  schizophrenia [ 94 ]  and  bipolar disorder . [ 95 ]


Sometimes drugs are given  involuntarily  to ensure compliance. This can occur if an individual has been  involuntarily committed [ 96 ]  or are subjected to an  outpatient commitment  order, where failure to take medication will result in detention and involuntary administration of treatment. [ 97 ] : 16   This can also occur if a patient is not deemed to have  mental capacity  to consent to treatment in an  informed  way. [ 98 ]


A  WHO  study estimates that only 50% of patients with chronic diseases in developed countries follow treatment recommendations. [ 1 ]


Asthma non-compliance (28–70% worldwide) increases the risk of severe asthma attacks requiring preventable ER visits and hospitalisations; compliance issues with asthma can be caused by a variety of reasons including: difficult inhaler use, side effects of medications, and cost of the treatment. [ 99 ]


200,000 new cases of cancer are diagnosed each year in the UK. One in three adults in the UK will develop cancer that can be life-threatening, and 120,000 people will be killed by their cancer each year. This accounts for 25% of all deaths in the UK. However while 90% of cancer pain can be effectively treated, only 40% of patients adhere to their medicines due to poor understanding. [ citation needed ]


Results of a recent (2016) systematic review found a large proportion of patients struggle to take their oral antineoplastic medications as prescribed. This presents opportunities and challenges for patient education, reviewing and documenting treatment plans, and patient monitoring, especially with the increase in patient cancer treatments at home. [ 14 ]


The reasons for non-adherence have been given by patients as follows:


Partridge  et al  (2002) identified evidence to show that adherence rates in cancer treatment are variable, and sometimes surprisingly poor. The following table is a summary of their findings: [ 100 ]


In 1998, trials evaluating  Tamoxifen  as a preventative agent have shown dropout rates of around one-third:


In March 1999, the "Adherence in the International Breast Cancer Intervention Study" evaluating the effect of a daily dose of Tamoxifen for five years in at-risk women aged 35–70 years was [ 103 ]


Patients with diabetes are at high risk of developing coronary heart disease and usually have related conditions that make their treatment regimens even more complex, such as hypertension, obesity and depression [ 104 ]  which are also characterised by poor rates of adherence. [ 105 ]


Other aspects that drive medicine adherence rates is the idea of perceived  self-efficacy  and risk assessment in managing diabetes symptoms and decision making surrounding rigorous medication regiments. Perceived control and self-efficacy not only significantly correlate with each other, but also with diabetes distress psychological symptoms and have been directly related to better medication adherence outcomes. [ 107 ]  Various external factors also impact diabetic patients' self-management behaviors including health-related knowledge/beliefs, problem-solving skills, and self-regulatory skills, which all impact perceived control over diabetic symptoms. [ 108 ]


Additionally, it is crucial to understand the decision-making processes that drive diabetics in their choices surrounding risks of not adhering to their medication. While patient decision aids (PtDAs), sets of tools used to help individuals engage with their clinicians in making decisions about their healthcare options, have been useful in decreasing decisional conflict, improving transfer of diabetes treatment knowledge, and achieving greater risk perception for disease complications, their efficacy in medication adherence has been less substantial. [ 109 ]  Therefore, the risk perception and decision-making processes surrounding diabetes medication adherence are multi-faceted and complex with socioeconomic implications as well. For example, immigrant health disparities in diabetic outcomes have been associated with a lower risk perception amongst foreign-born adults in the United States compared to their native-born counterparts, which leads to fewer protective lifestyle and treatment changes crucial for combatting diabetes. [ 110 ]  Additionally, variations in patients' perceptions of time (i.e. taking rigorous, costly medication in the present for abstract beneficial future outcomes can conflict with patients' preferences for immediate versus delayed gratification) may also present severe consequences for adherence as diabetes medication often requires systematic, routine administration. [ 111 ]


As a result of poor compliance, [ citation needed ]  75% of patients with a diagnosis of hypertension do not achieve optimum blood-pressure control. [ citation needed ]


A 2003 review found that 41–59% of patients prescribed antipsychotics took the medication prescribed to them infrequently or not at all. [ 113 ]  Sometimes non-adherence is due to  lack of insight , [ 114 ]  but psychotic disorders can be episodic and antipsychotics are then use prophylactically to reduce the likelihood of relapse rather than treat symptoms and in some cases individuals will have no further episodes despite not using antipsychotics. [ 115 ]   A 2006 review investigated the effects of compliance therapy for schizophrenia: and found no clear evidence to suggest that compliance therapy was beneficial for people with schizophrenia and related syndromes. [ 116 ]


A longitudinal study has shown that adherence with treatment about 60%. [ 117 ]  The predictors of adherence were found to be more of psychological, communication and logistic nature rather than sociodemographic or clinical factors. The following factors were identified as independent predictors of adherence:


An  adverse drug reaction  ( ADR ) is a harmful, unintended result caused by taking  medication . [ 1 ] : 1.1 Adverse Drug Reaction (ADR)  [ 2 ]  ADRs may occur following a single dose or prolonged administration of a  drug  or may result from the combination of two or more drugs. The meaning of this term differs from the term " side effect " because side effects can be beneficial as well as detrimental. [ 3 ]  The study of ADRs is the concern of the field known as  pharmacovigilance . [ 3 ]  An  adverse event  (AE) refers to any unexpected and inappropriate occurrence at the time a drug is used, whether or not the event is associated with the administration of the drug. [ 1 ] : 1.2 Adverse Event (AE)   An ADR is a special type of AE in which a causative relationship can be shown. [ 3 ]  ADRs are only one type of medication-related harm. Another type of medication-related harm type includes not taking prescribed medications, known as  non-adherence . [ 4 ]  Non-adherence to medications can lead to death and other negative outcomes. [ 4 ]  Adverse drug reactions require the use of a  medication . [ 3 ]


Types A and B were proposed in the 1970s, [ 8 ]  and the other types were proposed subsequently when the first two proved insufficient to classify ADRs. [ 9 ]


Other types of adverse drug reactions are Type C, Type D, Type E, and Type F. [ 10 ]  Type C was categorized for chronic adverse drug reactions, Type D  for delayed adverse drug reactions, Type E for withdrawal adverse drug reactions, and Type F for failure of therapy as an adverse drug reaction. Adverse drug reactions can also be categorized using time-relatedness, dose-relatedness, and susceptibility, which collectively are called the DoTS classification. [ 10 ]


The U.S  Food and Drug Administration  defines a serious  adverse event  as one when the patient outcome is one of the following: [ 11 ]


Severity is a measure of the intensity of the adverse event in question. [ 12 ]  The terms "severe" and "serious", when applied to adverse events, are technically very different. [ 12 ]  They are easily confused but can not be used interchangeably, requiring care in usage. [ 12 ]  Seriousness usually indicates patient outcome (such as negative outcomes including disability, long-term effects, and death). [ 12 ]


In adverse drug reactions, the seriousness of the reaction is important for reporting. [ 12 ]


Some  ocular antihypertensives  cause systemic effects, [ 13 ]  although they are administered locally as  eye drops , since a fraction escapes to the systemic circulation.


Various diseases, especially those that cause  renal  or  hepatic  insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states. [ 14 ]


The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia [ 15 ]  ( MATCH-D ) criteria warns that people with  dementia  are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms. [ 16 ]


Pharmacogenomics  includes how genes can predict potential adverse drug reactions. [ 17 ]  However, pharmacogenomics is not limited to adverse events (of any type), but also looks at how genes may impact other responses to medications, such as low/no effect or expected/normal responses (especially based on drug metabolism). [ 17 ]


Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation. [ 18 ] [ 19 ]


Phase I reactions include metabolism by cytochrome P450. [ 20 ]  Patients have abnormal metabolism by  cytochrome P450  due to either inheriting abnormal  alleles  or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions. [ 21 ] [ 22 ]


Inheriting abnormal  butyrylcholinesterase  ( pseudocholinesterase ) may affect metabolism of drugs such as  succinylcholine . [ 23 ]


Inheriting abnormal  N -acetyltransferase  which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as  isoniazid ,  hydralazine , and  procainamide . [ 22 ] [ 23 ]


Inheriting abnormal  thiopurine  S -methyltransferase  may affect the metabolism of the  thiopurine  drugs  mercaptopurine  and  azathioprine . [ 22 ]


Protein binding interactions are usually transient and mild until a new steady state is achieved. [ 24 ] [ 25 ]  These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are: [ 26 ]


Some drug interactions with  warfarin  are due to changes in protein binding. [ 26 ]


The risk of  drug interactions  is increased with  polypharmacy , especially in older adults. [ 27 ]


Two or more drugs that contribute to the same mechanism in the body can have additive  toxic  or adverse effects. One example of this is multiple medications administered concurrently that prolong the  QT interval , such as  antiarrhythmics  like  sotalol  and some  macrolide antibiotics , such as systemic  azithromycin . [ 28 ]  Another example of additive effects for adverse drug reactions is in  serotonin toxicity  ( serotonin syndrome ). [ 29 ]  If medications that cause increased  serotonin  levels are combined, they can cause  serotonin toxicity  (though therapeutic doses of one agent that increases  serotonin  levels can cause  serotonin toxicity  in certain cases and individuals). [ 29 ]  Some of the medications that can contribute to  serotonin toxicity  include  MAO inhibitors ,  SSRIs , and  tricyclic antidepressants . [ 29 ]


Some medications can either  inhibit  or  induce  key  drug metabolizing   enzymes  or  drug transporters , which when combined with other medications that utilize the same proteins can lead to either toxic or sub-therapeutic adverse effects. One example of this is a patient taking a  cytochrome P450 3A4  (CYP3A4) inhibitor such as the  antibiotic   clarithromycin , as well as another medication metabolized by CYP3A4 such as the  anticoagulant   apixaban , which results in elevated blood concentrations of apixaban and greater risk of serious bleeds. [ 30 ]  Additionally, Clarithromycin is a  permeability glycoprotein  (P-gp) efflux pump inhibitor, which when given with apixaban (a substrate for P-gp) will lead to increased absorption of apixaban, resulting in the same adverse effects as with CYP3A4 inhibition. [ 30 ]


Causality  assessment is used to determine the likelihood that a drug caused a suspected ADR. [ 3 ]  There are a number of different methods used to judge causation, including the  Naranjo algorithm , the Venulet algorithm and the WHO causality term assessment criteria. Each have pros and cons associated with their use and most require some level of expert judgement to apply. [ 31 ]
An ADR should not be labeled as 'certain' unless the ADR abates with a  challenge-dechallenge-rechallenge  protocol (stopping and starting the agent in question). [ 3 ]  The  chronology  of the onset of the suspected ADR is important, as another substance or factor may be implicated as a cause; co-prescribed medications and underlying  psychiatric conditions  may be factors in the ADR. [ 3 ]


Assigning  causality  to a specific agent often proves difficult, unless the event is found during a clinical study or large databases are used. Both methods have difficulties and can be fraught with error. Even in clinical studies, some ADRs may be missed as large numbers of test individuals are required to find a specific adverse drug reaction, especially for rare ADRs. Psychiatric ADRs are often missed as they are grouped together in the questionnaires used to assess the population. [ 32 ] [ 33 ]


Many countries have official bodies that monitor drug safety and reactions. On an international level, the  WHO  runs the  Uppsala Monitoring Centre . [ 34 ]  The  European Union  runs the  European Medicines Agency  (EMA). [ 35 ]  In the  United States , the  Food and Drug Administration  (FDA) is responsible for monitoring post-marketing studies. [ 36 ]  The FDA has a reporting system called the  FDA Adverse Event Reporting System , where individuals can report adverse drug events. [ 36 ]  Healthcare professionals, consumers, and the pharmaceutical industry can all submit information to this system. [ 36 ]  For health products marketed in  Canada , a branch of  Health Canada  called The Canada Vigilance Program is responsible for surveillance. [ 37 ]  Both healthcare professionals and consumers can report to this program. [ 37 ]  In  Australia , the  Therapeutic Goods Administration  (TGA) conducts postmarket monitoring of therapeutic products. [ 38 ]  In the UK, a monitoring system called the  Yellow Card Scheme  was established in 1964. [ 39 ]  The  Yellow Card Scheme  was set up to surveil medications and other health products. [ 40 ]


A study by the  Agency for Healthcare Research and Quality  (AHRQ) found that in 2011,  sedatives  and  hypnotics  were a leading source for adverse drug events seen in the  hospital  setting.  Approximately 2.8% of all ADEs present on admission and 4.4% of ADEs that originated during a hospital stay were caused by a sedative or hypnotic drug. [ 41 ]   A second study by AHRQ found that in 2011, the most common specifically identified causes of adverse drug events that originated during hospital stays in the U.S. were  steroids ,  antibiotics , opiates/narcotics, and  anticoagulants . Patients treated in urban teaching hospitals had higher rates of ADEs involving  antibiotics  and opiates/narcotics compared to those treated in urban nonteaching hospitals.  Those treated in private, nonprofit hospitals had higher rates of most ADE causes compared to patients treated in public or private, for-profit hospitals. [ 42 ]


Medication related harm (MRH) is common after hospital discharge in older adults, but methodological inconsistencies between studies and a paucity of data on risk factors limits clear understanding of the epidemiology. There was a wide range in incidence, from 0.4% to 51.2% of participants, and 35% to 59% of harm was preventable. Medication related harm incidence within 30 days after discharge ranged from 167 to 500 events per 1,000 individuals discharged (17–51% of individuals). [ 43 ]


In the U.S., females had a higher rate of ADEs involving  opiates  and  narcotics  than males in 2011, while male patients had a higher rate of  anticoagulant  ADEs.  Nearly 8 in 1,000 adults aged 65 years or older experienced one of the four most common ADEs (steroids, antibiotics, opiates/narcotics, and anticoagulants) during hospitalization. [ 42 ]  A study showed that 48% of patients had an adverse drug reaction to at least one drug, and pharmacist involvement helps to pick up adverse drug reactions. [ 44 ]


In 2012,  McKinsey & Company  concluded that the cost of the 50-100 million preventable error-related adverse drug events would be between US$18–115 billion. [ 45 ]


An article published in  The Journal of the American Medical Association  (JAMA) in 2016 reported adverse drug event statistics from  emergency departments  around the  United States  in 2013-2014. [ 46 ]  From this article, an estimated prevalence of adverse drug events that were presented to the emergency department (ED) was 4 events out of every 1000 people. [ 46 ]  This article reported that 57.1% of these adverse drug events presented to the ED were in females. [ 46 ]  As well, out of all of the adverse drug events presented to the emergency department documented in this article, 17.6% were from  anticoagulants , 16.1% were from  antibiotics , and 13.3% from  diabetic  agents. [ 46 ]


An  adverse effect  is an undesired harmful effect resulting from a  medication  or other  intervention , such as  surgery . [ 1 ]  An adverse effect may be termed a " side effect ", when judged to be secondary to a main or  therapeutic effect . The term  complication  is similar to adverse effect, but the latter is typically used in pharmacological contexts, or when the negative effect is expected or common. If the negative effect results from an unsuitable or incorrect  dosage  or procedure, this is called a  medical error  and not an adverse effect. Adverse effects are sometimes referred to as " iatrogenic " because they are generated by a  physician /treatment. Some adverse effects occur only when starting, increasing or discontinuing a treatment.
Using a drug or other medical intervention which is  contraindicated  may increase the  risk  of adverse effects. Adverse effects may cause complications of a  disease  or procedure and negatively affect its  prognosis . They may also lead to  non-compliance  with a treatment regimen. Adverse effects of medical treatment resulted in 142,000 deaths in 2013 up from 94,000 deaths in 1990 globally. [ 2 ]


The harmful outcome is usually indicated by some result such as  morbidity ,  mortality , alteration in  body weight , levels of  enzymes , loss of function, or as a  pathological  change detected at the microscopic, macroscopic or physiological level. It may also be indicated by  symptoms  reported by a patient. Adverse effects may cause a reversible or irreversible change, including an increase or decrease in the susceptibility of the individual to other chemicals,  foods , or procedures, such as  drug interactions .


In terms of drugs, adverse events may be defined as: "Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment." [ 3 ]


In  clinical trials , a distinction
is made between an  adverse event  and a  serious adverse event . Generally, any event which causes death, permanent damage,  birth defects , or requires  hospitalization  is considered a serious adverse event. [ 4 ]  The results of trials are often included in the labelling of the medication to provide information both for patients and the prescribing physicians.


The term "life-threatening" in the context of a serious adverse event refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. [ 3 ]


In many countries, adverse effects are required by law to be reported, researched in  clinical trials  and included into the patient information accompanying  medical devices  and  drugs  for sale to the public. Investigators in human clinical trials are obligated to report these events in  clinical study reports . [ 5 ]  Research suggests that these events are often inadequately reported in publicly available reports. [ 6 ]  Because of the lack of these data and uncertainty about methods for synthesising them, individuals conducting  systematic reviews  and meta-analyses of therapeutic interventions often unknowingly overemphasise health benefit. [ 7 ]  To balance the overemphasis on benefit, scholars have called for more complete reporting of harm from clinical trials. [ 8 ]


The  Yellow Card Scheme  is a  United Kingdom  initiative run by the  Medicines and Healthcare products Regulatory Agency (MHRA)  and the  Commission on Human Medicines (CHM)  to gather information on adverse effects to  medicines . This includes all licensed medicines, from medicines issued on  prescription  to medicines bought  over the counter  from a supermarket. The scheme also includes all  herbal supplements  and unlicensed medicines found in cosmetic treatments. Adverse drug reactions (ADRs) can be reported by a number of health care professionals including  physicians ,  pharmacists  and  nurses , as well as  patients .


In the  United States  several reporting systems have been built, such as the  Vaccine Adverse Event Reporting System  (VAERS), the Manufacturer and User Facility Device Experience Database (MAUDE) and the Special Nutritionals Adverse Event Monitoring System.  MedWatch  is the main reporting center, operated by the  Food and Drug Administration .


In  Australia , adverse effect reporting is administered by the  Adverse Drug Reactions Advisory Committee  (ADRAC), a subcommittee of the  Australian Drug Evaluation Committee  (ADEC). Reporting is voluntary, and ADRAC requests healthcare professionals to report all adverse reactions to its current drugs of interest, and serious adverse reactions to any drug. ADRAC publishes the Australian Adverse Drug Reactions Bulletin every two months. The Government's  Quality Use of Medicines  program is tasked with acting on this reporting to reduce and minimize the number of preventable adverse effects each year.


Adverse reaction reporting is an important component of New Zealand's  pharmacovigilance  activities. The  Centre for Adverse Reactions Monitoring (CARM)  in Dunedin is New Zealand's national monitoring centre for adverse reactions. It collects and evaluates spontaneous reports of adverse reactions to medicines, vaccines, herbal products and dietary supplements from health professionals in New Zealand. Currently the CARM database holds over 80,000 reports and provides New Zealand-specific information on adverse reactions to these products, and serves to support clinical decision making when unusual symptoms are thought to be therapy related


In Canada, adverse reaction reporting is an important component of the surveillance of marketed health products conducted by the Health Products and Food Branch (HPFB) of Health Canada. Within HPFB, the Marketed Health Products Directorate leads the coordination and implementation of consistent monitoring practices with regards to assessment of signals and safety trends, and risk communications concerning regulated marketed health products.


MHPD also works closely with international organizations to facilitate the sharing of information.  Adverse reaction reporting is mandatory for the industry and voluntary for consumers and health professionals.


In principle, medical professionals are required to report all adverse effects related to a specific form of therapy. In practice, it is at the discretion of the professional to determine whether a medical event is at all related to the therapy. As a result, routine adverse effects reporting often may not include long-term and subtle effects that may ultimately be attributed to a therapy. [ 9 ]


Part of the difficulty is identifying the source of a complaint. A headache in a patient taking medication for  influenza  may be caused by the underlying disease or may be an adverse effect of the treatment. In patients with end-stage  cancer , death is a very likely outcome and whether the drug is the cause or a bystander is often difficult to discern. [ citation needed ]


Surgery  may have a number of undesirable or harmful effects, such as  infection ,  hemorrhage ,  inflammation ,  scarring , loss of function, or changes in local  blood flow . They can be reversible or irreversible, and a compromise must be found by the physician and the patient between the beneficial or life-saving consequences of surgery versus its adverse effects. For example, a limb may be lost to  amputation  in case of untreatable  gangrene , but the patient's life is saved. Presently, one of the greatest advantages of  minimally invasive  surgery, such as  laparoscopic surgery , is the reduction of adverse effects.


Other nonsurgical physical procedures, such as high-intensity  radiation therapy , may cause  burns  and alterations in the  skin . In general, these therapies try to avoid damage to healthy  tissues  while maximizing the therapeutic effect.


Vaccination  may have adverse effects due to the nature of its biological preparation, sometimes using  attenuated   pathogens  and  toxins . Common adverse effects may be  fever ,  malaise  and local reactions in the vaccination site. Very rarely, there is a serious adverse effect, such as  eczema vaccinatum , a severe, sometimes fatal complication which may result in persons who have  eczema  or atopic  dermatitis .


Diagnostic  procedures may also have adverse effects, depending much on whether they are  invasive ,  minimally invasive  or  noninvasive . For example,  allergic  reactions to  radiocontrast  materials often occur, and a  colonoscopy  may cause the perforation of the  intestinal  wall.


Adverse effects can occur as a collateral or side effect of many interventions, but they are particularly important in  pharmacology , due to its wider, and sometimes uncontrollable, use by way of  self-medication . Thus,  responsible drug use  becomes an important issue here. Adverse effects, like  therapeutic effects  of drugs, are a function of  dosage  or drug levels at the target  organs , so they may be avoided or decreased by means of careful and precise  pharmacokinetics , the change of drug levels in the organism in function of time after administration.


Adverse effects may also be caused by  drug interaction . This often occurs when patients fail to inform their physician and pharmacist of all the medications they are taking, including herbal and dietary supplements. The new medication may interact agonistically or antagonistically (potentiate or decrease the intended therapeutic effect), causing significant  morbidity  and mortality around the world. Drug-drug and food-drug interactions may occur, and so-called "natural drugs" used in  alternative medicine  can have dangerous adverse effects. For example, extracts of  St John's wort  ( Hypericum perforatum ), a  phytotherapic  used for treating mild  depression  are known to cause an increase in the  cytochrome P450   enzymes  responsible for the  metabolism  and elimination of many drugs, so patients taking it are likely to experience a reduction in  blood  levels of drugs they are taking for other purposes, such as  cancer   chemotherapeutic  drugs,  protease inhibitors  for  HIV  and  hormonal contraceptives .


The scientific field of activity associated with drug safety is increasingly government-regulated, and is of major concern for the public, as well as to  drug manufacturers . The distinction between adverse and nonadverse effects is a major undertaking when a new drug is developed and tested before  marketing  it. This is done in  toxicity  studies to determine the nonadverse effect level (NOAEL). These studies are used to define the dosage to be used in human testing (phase I), as well as to calculate the maximum admissible daily intake. Imperfections in clinical trials, such as insufficient number of patients or short duration, sometimes lead to  public health  disasters, such as those of  fenfluramine  (the so-called  fen-phen  episode),  thalidomide  and, more recently, of  cerivastatin  (Baycol, Lipobay) and  rofecoxib  (Vioxx), where drastic adverse effects were observed, such as  teratogenesis ,  pulmonary hypertension ,  stroke ,  heart disease ,  neuropathy , and a significant number of deaths, causing the forced or voluntary  withdrawal  of the drug from the market.


Most drugs have a large list of nonsevere or mild adverse effects which do not rule out continued usage. These effects, which have a widely variable incidence according to individual sensitivity, include  nausea ,  dizziness ,  diarrhea ,  malaise ,  vomiting ,  headache ,  dermatitis , dry mouth, etc. These can be considered a form of pseudo-allergic reaction, as not all users experience these effects; many users experience none at all.


The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia [ 10 ]  ( MATCH-D ) warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms. [ 11 ]


Sometimes, putative medical adverse effects are regarded as controversial and generate heated discussions in society and  lawsuits  against drug manufacturers. One example is the recent controversy as to whether  autism  was linked to the  MMR vaccine  (or to  thiomersal , a  mercury -based preservative used in some  vaccines ). No link has been found in several large studies, and despite removal of thimerosal from most early childhood vaccines beginning with those manufactured in 2003, the rate of autism has not decreased as would be expected if it had been the causative agent. [ 40 ] [ 41 ]


Another instance is the potential adverse effects of  silicone   breast implants , which led to class actions brought by tens of thousands of plaintiffs against manufacturers of gel-based implants, due to allegations of damage to the  immune system  which have not yet been conclusively proven. [ 42 ]  In 1998, Dow Corning settled its remaining suits for $3.2 Billion and went into bankruptcy. [ 43 ]


Due to the exceedingly high impact on public health of widely used medications, such as  hormonal contraception  and  hormone replacement therapy , which may affect millions of users, even marginal probabilities of adverse effects of a severe nature, such as  breast cancer , have led to public outcry and changes in medical therapy, although its benefits largely surpassed the statistical risks.


The  antimicrobial spectrum  of an  antibiotic  means the range of  microorganisms  it can kill or inhibit. Antibiotics can be divided into  broad-spectrum antibiotics , extended-spectrum antibiotics and  narrow-spectrum antibiotics  based on their spectrum of activity. Detailedly, broad-spectrum antibiotics can kill or inhibit a wide range of microorganisms; extended-spectrum antibiotic can kill or inhibit  Gram positive bacteria  and some  Gram negative bacteria ; narrow-spectrum antibiotic can only kill or inhibit limited species of bacteria. [ 1 ] [ 2 ] [ 3 ]


Currently no antibiotic's spectrum can completely cover all types of microorganisms. [ 4 ]


The antimicrobial spectrum of an antibiotic can be determined by testing its antimicrobial activity against a wide range of microbes  in vitro   . Nonetheless, the range of microorganisms which an antibiotic can kill or inhibit  in vivo  may not always be the same as the antimicrobial spectrum based on data collected in vitro. [ 2 ] [ 5 ]


Narrow-spectrum antibiotics  have low propensity to induce  bacterial resistance  and are less likely to disrupt the  microbiome  (normal  microflora ). [ 3 ]   On the other hand, indiscriminate use of  broad-spectrum antibiotics  may not only induce the development of bacterial resistance and promote the emergency of  multidrug-resistant  organisms, but also cause off-target effects due to  dysbiosis . [ 3 ] [ 6 ]  They may also have side effects, such as diarrhea or rash. [ 7 ]  Generally, a broad antibiotic has more clinical indications, and therefore are more widely used. [ 2 ] [ 8 ]   The Healthcare Infection Control Practices Advisory Committee (HICPAC) recommends the use of narrow-spectrum antibiotics whenever possible. [ 9 ]


Augmentation , in the context of the pharmacological management of  psychiatry , refers to the combination of two or more  drugs  to achieve better treatment results. Examples include:


In  pharmacology , the term is occasionally used to describe treatments that increase (augment) the concentration of some substance in the body. This might be done when someone is deficient in a hormone, enzyme, or other endogenous substance. For example:


The  Cancer Trials Support Unit   (CTSU)  is a service of the  National Cancer Institute  (NCI)  in the United States.


The CTSU facilitates access to NCI-funded  clinical trials  for qualified clinical sites and supports the management and conduct of those clinical trials.


The NCI launched the CTSU in 1999 to streamline and harmonize support services for Phase III Cooperative Group cancer clinical trials funded by the NCI.


CTSU now supports multiple NCI-funded networks and clinical trials of all phases and types.  These include  cancer treatment , prevention and control,  advanced imaging  and correlative science studies.  The CTSU collaborates with the NCI and its funded organizations to develop and support operational processes and  informatics  solutions leading to cost-effective solutions that reduce administrative burden on clinical sites. [ 1 ] [ 2 ]


The CTSU supports the following NCI cancer research networks: [ 3 ] [ 4 ]


Additional NCI and NIH services that work in conjunction with the CTSU include:


Clinical trials  are prospective biomedical or behavioral research studies on  human participants  designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel  vaccines ,  drugs ,  dietary choices ,  dietary supplements , and  medical devices ) and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. [ 1 ] [ 2 ]  They are conducted only after they have received  health authority/ethics committee  approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the  risk/benefit ratio  of the trial—their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted.


Depending on product type and development stage, investigators initially enroll volunteers or patients into small  pilot studies , and subsequently conduct progressively larger scale comparative studies. Clinical trials can vary in size and cost, and they can involve a single research center or  multiple centers , in one country or in multiple countries.  Clinical study design  aims to ensure the  scientific validity  and  reproducibility  of the results.


Costs for clinical trials can range into the billions of dollars per approved drug, [ 3 ]  and the complete trial process to approval may require 7–15 years. [ 4 ] [ 5 ]  The sponsor may be a governmental organization or a  pharmaceutical ,  biotechnology  or medical-device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a  contract research organization  or a central laboratory. Only 10 percent of all drugs started in human clinical trials become  approved drugs . [ 6 ]


Some clinical trials involve healthy subjects with no  pre-existing medical conditions . Other clinical trials pertain to people with specific health conditions who are willing to try an experimental treatment. Pilot experiments are conducted to gain insights for design of the clinical trial to follow. [ citation needed ]


There are two goals to testing medical treatments: to learn whether they work well enough, called "efficacy", or "effectiveness"; and to learn whether they are safe enough, called "safety". [ 1 ]  Neither is an absolute criterion; both safety and efficacy are evaluated relative to how the treatment is intended to be used, what other treatments are available, and the severity of the disease or condition. The benefits must outweigh the risks. [ 7 ] [ 8 ] : 8   For example, many drugs to treat cancer have severe side effects that would not be acceptable for an over-the-counter pain medication, yet the cancer drugs have been approved since they are used under a physician's care and are used for a life-threatening condition. [ 9 ]


In the US the elderly constitute 14% of the population, while they consume over one-third of drugs. [ 10 ]  People over 55 (or a similar cutoff age) are often excluded from trials because their greater health issues and drug use complicate data interpretation, and because they have different physiological capacity than younger people. Children and people with unrelated medical conditions are also frequently excluded. [ 11 ]  Pregnant women are often excluded due to potential risks to the  fetus .


The sponsor designs the trial in coordination with a panel of expert clinical investigators, including what alternative or existing treatments to compare to the new drug and what type(s) of patients might benefit. If the sponsor cannot obtain enough test subjects at one location investigators at other locations are recruited to join the study. [ citation needed ]


During the trial, investigators recruit subjects with the predetermined characteristics, administer the treatment(s) and collect data on the subjects' health for a defined time period. Data include measurements such as  vital signs , concentration of the study drug in the blood or tissues, changes to symptoms, and whether improvement or worsening of the condition targeted by the study drug occurs. The researchers send the data to the trial sponsor, who then analyzes the pooled data using  statistical tests . [ citation needed ]


Examples of clinical trial goals include assessing the safety and relative effectiveness of a medication or device: [ citation needed ]


While most clinical trials test one alternative to the novel intervention, some expand to three or four and may include a  placebo . [ citation needed ]


Except for small, single-location trials, the design and objectives are specified in a document called a  clinical trial protocol . The protocol is the trial's "operating manual" and ensures all researchers perform the trial in the same way on similar subjects and that the data is comparable across all subjects. [ citation needed ]


As a trial is designed to test  hypotheses  and rigorously monitor and assess outcomes, it can be seen as an application of the  scientific method , specifically the experimental step. [ citation needed ]


The most common clinical trials evaluate new pharmaceutical products, medical devices,  biologics ,  diagnostic assays ,  psychological therapies , or other interventions. [ 12 ]  Clinical trials may be required before a national  regulatory authority [ 13 ]  approves marketing of the innovation.