For people with a life-shortening or  terminal illness , such as a dementia, it is important to consider when to discontinue medications used to prevent future serious events.  The  Medication Appropriateness Tool for Comorbid Health conditions during Dementia  ( MATCH-D ) provides guidance for clinicians and consumers on how to manage medications. [ 7 ]


Drug discontinuation may cause  rebound effects  (return of the symptoms the drug relieved, and that, to a degree stronger than they were before treatment first began) and  withdrawal syndromes  (symptoms caused by the discontinuation by the drug itself).


Drug discontinuation may be difficult to adjust to, owing to the long term use and the symbolism associated with ceasing medications, such as the decision to stop  chemotherapy . [ 5 ]


Recent research (Nixon & Vendelø, 2016) shows that General Practitioners (GPs) who actively consider discontinuation, are reluctant to do so, as they experience that the safest decision is to continue prescriptions, rather than discontinue them. In part this is due to the ambiguity about the appropriateness of discontinuing medication. The clinical guidelines available to GPs do not encourage discontinuation of medication, and thus, they offer GPs a weak frame for discontinuation.


Withdrawal of anti-hypertensive drugs in older people


The latest evidence does not have evidence of an effect due to discontinuing vs continuing medications used for treating elevated blood pressure or prevention of heart disease in older adults on all-case mortality and incidence of heart attack. [ 8 ]  The findings are based on low quality evidence suggesting it may be safe to stop anti-hypertensive medications. However, older adults should not stop any of their medications without talking to a healthcare professional. [ 8 ]


Membrane-mediated  anesthesia  or anaesthesia (UK) is a  mechanism of action  that involves an  anesthetic agent  exerting its  pharmaceutical  effects primarily through interaction with the  lipid bilayer membrane .


The relationship between  volatile  ( inhalable )  general anesthetics  and the cellular  lipid  membrane has been well established since around 1900, based on the  Meyer-Overton Correlation . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  Since 1900 there have been extensive research efforts to characterize these membrane-mediated  effects  of anesthesia, leading to many  theories  but few answers. During the 1980s the focus of anesthetic research shifted from  membrane lipids  to  membrane proteins , [ 5 ] [ 6 ] [ 7 ]  where it currently remains. [ 8 ] [ 9 ] [ 10 ] [ 11 ]  Accordingly, the specific membrane-mediated anesthetic effects remain mostly undiscovered. [ 9 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ]


Recent research has demonstrated promising mechanisms of membrane- mediated  anesthetic action for both  general  and  Local anesthetics . These studies suggest that  t he anesthetic  binding site  in the membrane is within ordered lipids. This  binding  disrupts the function of the ordered lipids, forming  lipid rafts  that dislodge a membrane-bound  phospholipase  involved in a  metabolic pathway  that actives anesthetic-sensitive  potassium channels . [ 15 ] [ 16 ] [ 17 ]  Other recent studies show similar lipid-raft-specific anesthetic effects on  sodium channels . [ 17 ] [ 18 ]


See  Theories of general anaesthetic action  for a broader discussion of purely theoretical mechanisms.


At the turn of the twentieth century, one of the most important anesthetic-based  theories  began to take shape. At the time, the research of both German  pharmacologist   Hans Horst Meyer  (1899) [ 1 ]  and British-Swedish  physiologist   Charles Ernest Overton  (1901) [ 2 ]  reached the same conclusion about  general anesthetics  and  lipids :


There is a direct  correlation  between  anesthetic agents  and lipid  solubility . The more  lipophillic   the anesthetic  agent  is, the more  potent  the anesthetic agent is. [ 3 ] [ 8 ] [ 18 ]


This principle became known as the  Meyer-Overton Correlation . It originally compared the anesthetic  partition coefficient  in  olive oil  (X-axis) to the  effective dose  that induced anesthesia in 50% (i.e.,  EC50 ) of the  tadpole   research  subjects (Y-axis). [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Modern renditions of the Meyer-Overton  plot  usually compare olive oil partition coefficent of the  Inhalational  or  Intravenous   drug  ( X-axis ) to the  minimum alveolar concentration  (MAC) or the  effective dose  50 (i.e., ED50) of the anesthetic agent ( Y-axis ). [ citation needed ]


Despite more than 175 years of  anesthetic  use and research, the exact connection between  phospholipids , the  bilayer membrane , and  general anesthetic agents  remains mostly unknown. [ 4 ] [ 9 ] [ 10 ]  Accordingly, the means of membrane-mediated anesthesia remain mostly theoretical. [ 4 ] [ 19 ] [ 20 ]


The Lateral Pressure Profile theory suggests that anesthetic agents partition into the  lipid bilayer , increasing the horizontal ( lateral )  pressure  on  proteins  imbedded in the membrane. The added pressure causes a  conformational change  in  protein structure , forcing the  neuronal   channel  into an open or closed  state  (e.g.,  hyperpolarization ) that generates the  Inhibitory  state of  general anesthesia  in the  central nervous system  (CNS). [ 20 ] [ 21 ] [ citation needed ]


This is the first hypothesis to explain the correlations of anesthetic potency with lipid bilayer  structural characteristics , describing both  mechanistic  and  thermodynamic  rationale for the effects of general anesthesia. [ citation needed ]


Inhaled anesthetics  partition into the membrane and disrupt the function of ordered lipids. [ 15 ]  Membranes, like proteins, are composed of ordered and disordered regions. [ 14 ]  The ordered region of the membrane contains a  palmitate  binding site that drives the association of  palmitoylated  proteins to clusters of GM1 lipids (sometimes referred to as  lipid rafts ). Palmitate's binding to lipid rafts regulates the affinity of most proteins to lipid rafts. [ 22 ]


Inhaled anesthetics partition into the lipid membrane and disrupt the binding of palmitate to GM1 lipids (see figure). The anesthetic binds to a specific palmitate site nonspecifically. The clusters of GM1 lipids persist, but they lose their ability to bind palmitoylated proteins. [ 23 ]


Phospholipase D2 (PLD2) is a palmitoylated protein that is activated by  substrate presentation . [ 24 ]  Anesthetics cause PLD2 to move from GM1 lipids, where it lacks access to its substrate, to a  PIP2 domain  which has abundant PLD2 substrate. [ 23 ]  Animals with genetically depleted PLD2 were significantly resistant to anesthetics. The anesthetics xenon, chloroform, isofluorane, and propofol all activate PLD in cultured cells.


Twik-related potassium channel ( TREK-1 ) is localized to ordered lipids through its interaction with PLD2. Displacement of the complex from GM1 lipids causes the complex to move to clusters. The product of PLD2,  phosphatidic acid  (PA) directly activates TREK-1. [ 25 ]  The anesthetic sensitivity of TREK-1 was shown to be through PLD2, and the sensitivity could be transferred to TRAAK, an otherwise anesthetic insensitive channel. [ 15 ]


The membrane mediated mechanism is still being investigated. Nonetheless, the GABAAR gamma subunit is palmitoylated and the alpha subunit binds to PIP2. When the agonist GABA binds to GABAAR it causes a translocation to thin lipids near PIP2. [ 26 ]  Anesthetic disruption of  Palmitate mediated localization  should therefore cause the channel to move the same as an agonist, but this has not yet been confirmed.


Endocytosis helps regulate the time an ion channel spends on the surface of the membrane. GM1 lipids are the site of endocytosis. The anesthetics hydroxychloroquine,  tetracaine , and  lidocaine  blocked entry of palmitoylated protein into the endocytic pathway. [ 27 ]  By blocking access to GM1 lipids, anesthetics block access to endocytosis through a membrane-mediated mechanism.


Local anesthetics disrupt ordered lipid domains and this can cause PLD2 to leave a lipid raft. [ 16 ]  They also disrupt protein interactions with PIP2. [ 27 ]


More than 100 years ago, a unifying theory of anesthesia was proposed based on the oil partition coefficient. In the 70s this concept was extended to the disruption of lipid partitioning. [ 28 ]  Partitioning itself is an integral part of forming the ordered domains in the membrane, and the proposed mechanism is very close to the current thinking, but the partitioning itself is not the target of the anesthetics. At clinical concentration, the anesthetics do not inhibit lipid partitioning. [ 15 ]  Rather they inhibit the order within the partition and/or compete for the palmitate binding site. Nonetheless, several of the early conceptual ideas about how disruption of lipid partitioning could affect an ion channel have merit.


Occupational health concerns over the use of cannabis among workers are becoming increasingly important as cannabis becomes legal in more areas of the US. [ 1 ] [ 2 ]   [1]   Of note, employers have concerns of workers either coming to work acutely impaired or recent use of cannabis still being detected in the body. Employment issues such as  ADA  law as it relates to accommodations for cannabis, paying unemployment benefits or paying out workers compensation benefits and disability claims are all important issues. While federal law still prohibits use, employers in different states have taken different stances based on whether they are federal contractors, perform safety sensitive work or whether the cannabis use is acutely impairing the employee.


Cannabis  is currently the most commonly used illicit drug in the world and one of the earliest plants cultivated by humans. Early evidence of cannabis use in medicine has been found in China and India for religious and medicinal uses. Archaeological research shows early civilization cultivation of hemp in India to create a variety of products from ropes, textiles and paper. In countries, such as  Nepal  and  China , cannabis seeds are still used today both as a pharmaceutical as well as a food enhancer. [ 3 ]  Lack of concentration, impaired learning and memory, alterations in thought formation, expression and sedation have been associated with cannabis use. Physiological signs include  tachycardia , dilated pupils with injected  conjunctiva , dry mouth and increased appetite Studies have also confirmed that impairment is related on a dose response relationship.


As cannabis use increases and more states  legalize use in the US , there are concerns surrounding the use of cannabis and its effects on job performance and safety. [2]  There are also concerns that the concentration of  THC  have increased over the past 50 years, thereby increasing the effects of the drug. [ 4 ]  The  Controlled Substances Act  of 1970 currently lists cannabis as a Schedule 1 drug, deeming it to be a substance with high risk of dependence, abuse and no (supervised) medical uses. The  CATO  institute estimates that legalizing drugs would save $41 billion per year along with $46.7 billion in revenue, if taxed at the same rates as alcohol and tobacco. [ 5 ]


Employers and employees have faced new challenges in the workplace with the increasing legislation of cannabis. State law can have provisions, for an employer to refuse to hire based on marijuana use, under the concern of safety, productivity and company reputation. Companies that have “ safety sensitive work ” or include operating machinery or large vehicles are also free to institute a zero-tolerance policy for its employees. For the approximate 10 million  CDL  (Commercial Drivers Licenses) drivers in the USA, federal law requires they pass employer drug tests under the Omnibus Transportation Employee Safety Act of 1991.


Individual states in response to the federal government differed in how they dealt with cannabis. California was the first state to pass medical marijuana in 1996, followed by 23 other states currently permitting the use of medical marijuana.


In the case of U.S. v. Stacey among several others, the legality of cannabis use has been contested since citizens who argue for protection under state law, are always subject to federal charges [ 6 ]  While there has been some guidance from the Department of Justice to the DEA to reassess its priorities in the drug war and to target larger threats and substances, the interpretation is still subjective and has not prevented large scale raids on medical marijuana facilities across the country. [ 4 ]


California was the first state to pass medical marijuana in 1996, followed by 23 other states currently permitting the use of medical marijuana [ 7 ]  For the states that have legalized medical marijuana, employees and employers have had to face new challenges in the workplace. State law can have provisions, for an employer to refuse to hire based on marijuana use, under the concern of safety, productivity and company reputation. Companies that have a lot of “safety sensitive work” or include operating machinery or large vehicles are also free to institute a zero-tolerance policy for its employees. For the approximate 10 million CDL ( Commercial Drivers Licenses ) drivers in the USA, federal law requires they pass employer drug tests under the  Omnibus Transportation Employee Safety Act  of 1991.


Drivers that use cannabis show impairment both in simulator and on the road tests, mainly on the abilities to “..concentrate and maintain attention, estimate time and distance, and demonstrate coordination on divided attention tasks—all important requirements for operating a motor vehicle” [ 4 ]


The Department of Transportation (DOT) has also stated in its Drug and Alcohol Testing Regulations that cannabis is not acceptable for any employee engaged in safety sensitive work. Currently, there are federal laws that give employers guidance and protection on how to ensure a drug free workplace despite the increase in cannabis use. According to the  National Association of Attorneys General  (NAAG), in Colorado the number of positive drug tests for marijuana went up by 20% between 2012-2013, compared to the national average increase of 5% [ 8 ]


For those companies that have received federal grants and have federal contracts over $100,000, they follow  The Drug Free Workplace Act  of 1988, a comprehensive policy, which includes drug prevention methods, information about employee assistance programs and disciplinary consequences of drug use in the workplace [ 9 ]  Federal agencies are required to use the Substance Abuse and Mental health Services Administration ( SAMHSA ) procedures for testing and recommend private employers use the same criteria for consistency. [ 10 ]   The policy requires employees to report any criminal drug violations in the workplace to the employer within 5 calendar days which may subsequently result in discipline including termination, regardless of state law. [ 11 ]


The  Occupational and Safety Act of 1970  includes a  general duty clause  for employers to protect employees from exposure for those compounds with no regulated standards of safe exposure. It has been defined broadly as to “maintain conditions or adopt practices reasonably necessary and appropriate to protect workers on the job. [ 12 ]  The ADA prohibits employers from discriminating against disabled individuals, which is defined as “a physical or mental impairment that substantially limits one or more major life activities, a person who has a history or record of such an impairment, or a person who is perceived by others as having such an impairment.”


Employers under this law have an obligation to provide “reasonable accommodations” to the disabled employee, so they may perform the essential duties of the job, as long as those accommodations don’t pose an undue hardship on the employer". [ 13 ]  The ADA section 12114(a) however states that these rights are not granted to employee or applicant who is currently engaging in the illegal use of drugs [ 13 ]  The ADA does not require employer coverage when the employee is engaging in the “illegal use of drugs”, including marijuana which is still illegal under the  Controlled Substance Act.


Coats v. Dish Network LLC, held that a “state’s lawful activities statute does not protect a worker’s off-duty use of medical marijuana because this activity is not lawful under federal law” under the ordinary meaning of “permitted by law” [ 14 ]


The  Federal Employees Compensation Act  (FECA) provides for the payment of workers’ compensation benefits, including wages and medical benefits, to civilian officers and employees of all branches of the federal government, whereas state law has oversight over its own workers’ compensation program


FECA  prohibits employees from receiving compensation when the injury “was proximately… caused by the intoxication by… illegal drugs.” [ 15 ] [ 16 ]


Colorado Court of Appeals in Beinor v Industrial Claim Appeals [ 17 ]  agreed with the employer and held that unemployment insurance benefits could be withheld due to the violation of the employer’s zero tolerance drug policy. Worker was a sweeper using cannabis legally outside of working hours. Colorado State statue “disqualifies an individual from receiving unemployment benefits after the presence of a controlled substance was not medically prescribed was found in the worker’s system during worker hours.”


Cannabis has unique  pharmacokinetics  and metabolism which makes it a challenge to drug test for acute impairment vs recent use.  THC  is deposited in fat and can be detectable in urine for up to a month or more. However, it is not always an indicator of acute impairment. Further there are privacy concerns, from invasive blood testing for compounds, under the  4th Amendment  of the US constitution. Variability in study designs, ethical dilemma of safety and productivity, work type and drug metabolism in users. When smoked, blood levels of THC immediately rise and are distributed primarily in the lungs and brain. THC is metabolized to the transient psychoactive substance THC-OH, which is finally converted to THC-COOH, the physiologically inactive metabolite.  The immediate euphoria and subsequent impairment from THC-OH, as suggested by older studies may last about 6 hours, with some limited studies showing impairment lasting as long as 24 to 48 hours [ 18 ]  Specific studies that assess driving and impairment show a return to "...nonimpaired state within 3-6 hours.“ [ 4 ]


The method of testing cannabis in urine can be misleading, due to the potential for interpreting a positive result for THC-COOH, as an indicator of acute impairment. [ citation needed ]


FSMB ( Federal State Medical Boards ) after reviewing over 50 major studies in the field, have offered these 10 recommendations: [ 19 ]


1)Thoroughly document patient’s visit prior to considering cannabis use for those with good compliance. Information on the inadequacy of response to other treatment, comprehensive history and physical condition should be included.


2) Don’t treat close friends or family.


3) Inform risks and benefits.


4) Compliance Contract, concerns of diversion.


5) Regular Visits are recommended.


6) No relationships with dispensaries or cannabis companies.


A large study in France of over 10,000 crashes, concluded an odds ratio of 2.18 for THC level less than 1 ng/ml up to 4.72 for THC 5 ng/ml for being involved in a crash. [ 20 ]   Some researchers such as  Donzé N ,  Ménétrey  have considered categorizing impairment as the sum of THC, THC-OH and THC-COOH, which would be more accurate for assessing impairment since it would include the active metabolite; however, more research is needed along with better point of care detection. Some Norwegian studies have suggested that individuals with levels of 2-5 ng/mL experienced “moderate established impairment” and levels of THC above 5 -10 ng/ml was likely to be severe impairment. [ 20 ]


The consensus from a meta-analysis study shows that serum levels of an average of 3.8 (ranging from 3.1 to 4.5) for oral cannabis and an average of 3.8 (ranging from 3.3 to 4.5) for smoker cannabis cause a similar impairment to a BAC of around 0.05g/dL, i.e. a 5 ng/mL cutoff would resemble the level of impairment allowed for alcohol under federal testing laws. [ 21 ]   However, since the presence of metabolites does not automatically indicate impairment, an immediate physical exam by a physician is advised to correlate findings clinically to diagnose impairment. [ 21 ]


Over-the-counter  ( OTC )  drugs  are  medicines  sold directly to a consumer without a requirement for a  prescription  from a healthcare professional, [ 1 ]  as opposed to  prescription drugs , which may be supplied only to consumers possessing a valid prescription. In many countries, OTC drugs are selected by a  regulatory agency  to ensure that they contain ingredients that are safe and effective when used without a  physician 's care. OTC drugs are usually regulated according to their  active pharmaceutical ingredient  (API) and strengths of final products. [ 2 ]


The term  over-the-counter  ( OTC ) refers to a medication that can be purchased without a medical prescription. [ 3 ]  In contrast,  prescription drugs  require a prescription from a doctor or other health care professional and should only be used by the prescribed individual. [ 4 ]  Some drugs may be legally classified as over-the-counter (i.e. no prescription is required), but may only be dispensed by a  pharmacist  after an assessment of the patient's needs or the provision of  patient education . Regulations detailing the establishments where drugs may be sold, who is authorized to dispense them, and whether a prescription is required vary considerably from country to country.


As of 2011, around a third of older adults in the U.S. reportedly used OTC drugs, and this number is increasing. [ 5 ] [ 6 ] [ 7 ] [ 8 ]  By 2018, the prevalence of use by adults in the U.S. as first-line treatment for minor illnesses had reached 81%: however, there is some debate as to whether this figure relates to an actual improvement of health. [ 9 ] [ 1 ] [ 10 ]


In  Canada , there are four drug schedules: [ 11 ]


All medications other than Schedule 1 may be considered an OTC drug, as they do not require prescriptions for sale. While the National Association of Pharmacy Regulatory Authorities provides recommendations on the scheduling of drugs for sale in Canada, each province may determine its own scheduling. [ 12 ]  The drugs found in each schedule may vary from province to province. [ citation needed ]


In November 2016, India's Drug Consultative Committee announced it was embarking on establishing a definition of drugs which could be dispensed without a prescription. [ 1 ]  Prior to this, the general assumption was that any drug which did not fall into a prescription schedule could be purchased without a prescription. [ 1 ]   However, the needed definition had not been enacted by early 2018. The lack of a legal definition for OTC drugs has led to this  US$4 billion  market segment being effectively unregulated. [ 1 ]


In the  Netherlands , there are four categories: [ 13 ]


A drug that is UA may be sold OTC but only by pharmacists. The drug can be on the shelves like any other product. Examples are  domperidone , 400 mg  ibuprofen  up to 50 tablets and  dextromethorphan . A drug that is UAD can also be sold at drugstores which are stores where no prescription can be filled. The drugs are usually on the shelves, and the store also sells items like toys, gadgets, perfumes and homeopathic products. The drugs in this category have limited risk and addiction potential. Examples are  naproxen  and  diclofenac  in small amounts,  cinnarizine , 400 mg ibuprofen up to 20 tablets and also 500 mg  paracetamol  up to 50 tablets. Drugs in the AV category can be sold at  supermarkets , gas stations, etc. and include only drugs with minimal risk to the public, like paracetamol up to 20 tablets, 200 mg ibuprofen up to 10 tablets,  cetirizine  and  loperamide .


In the  United States , the manufacture and sale of OTC substances are regulated by the  Food and Drug Administration . The FDA requires that all "new drugs" obtain a  New Drug Application  (NDA) before entering interstate commerce, but the act exempts any drugs  generally recognized as safe and effective  (GRAS/E). [ 14 ]  To deal with the vast number of OTC drugs that were already on the market before the requirement that all drugs obtain an NDA, the FDA created the OTC monograph system to review classes of drugs and to categorize them as GRAS/E after review by expert panels. Certain classes of OTC drugs would not be required to obtain an NDA and could remain on the market if they conformed to the monograph guidelines for doses, labeling, and warnings finalized in the  Code of Federal Regulations [ 15 ]


Thus, an OTC drug product is allowed to be marketed either (1) pursuant to an  FDA monograph  or (2) pursuant to an NDA for products that do not fit within a specific monograph. [ 16 ]  There is also the possibility that certain OTC drug products are marketed under the grandfathering provisions of the  Federal Food, Drug, and Cosmetic Act , but the FDA has never formally acknowledged that any legitimate grandfathered OTC drug exists.


Examples of OTC substances approved in the United States are sunscreens, anti-microbial and anti-fungal products, external and internal analgesics such as  lidocaine  and  aspirin ,  psoriasis  and  eczema  topical treatments, anti- dandruff  shampoos containing  coal tar , and other topical products with a therapeutic effect.


The  Federal Trade Commission  regulates advertising of OTC products, in contrast to prescription drug advertising, which is regulated by the FDA. [ 17 ]


The FDA requires OTC products to be labeled with an approved "Drug Facts" label to educate consumers about their medications. The labels comply to a standard format and are intended to be easy for typical consumers to understand. Drug Facts labels include information on the product's  active ingredient(s) ,  indications  and purpose, safety warnings, directions for use, and  inactive ingredients . [ 18 ]


The 2020  Coronavirus Aid, Relief, and Economic Security Act  (CARES Act) includes reforms that modernize the way certain OTC drugs are regulated in the United States. [ 19 ] [ 20 ]  Many OTC monographs need to be updated but updating or changing an OTC monograph requires the slow and burdensome notice-and-comment rulemaking process. [ 19 ]  The CARES Act includes OTC monograph reform provisions that replace the rulemaking process with an administrative order process. [ 19 ]


An ill-defined third category of substances is products having over-the-counter status from the FDA while being simultaneously subject to other restrictions on sale. While they are legally classified as OTC drugs, they are typically stored behind the counter and are sold only in stores that are registered with their state. They may be unavailable in convenience and grocery stores that stock other non-restricted OTC medications.


For example, many drugstores have moved products containing  pseudoephedrine , an OTC product, into locations where customers must ask a pharmacist for them. A prescription is not required; the change has been made in an effort to reduce  methamphetamine  production. Since the passage of the  Illinois Methamphetamine Precursor Control Act  and the subsequent federal  Combat Methamphetamine Epidemic Act of 2005 , the purchase of pseudoephedrine is restricted. Sellers of pseudoephedrine must obtain and record the identity of the purchaser and enforce  quantity restrictions . After initial attempts to control methamphetamine use (by requiring documentation of sale with government issued ID as well as limits on the quantity an individual could purchase) failed to realize meaningful reductions in methamphetamine use and production,  Mississippi  passed House Bill 512 in the State Senate on February 2, 2010 "to require a prescription from a licensed medical professional to purchase over-the-counter medicines with pseudoephedrine,  ephedrine , or any other precursor chemical that can readily and illicitly be converted into  methamphetamine ,  methcathinone  or any active/scheduled analogs of  phenylethylamines /  amphetamine ." [ citation needed ]  However, products containing the substance are still OTC in most states, since no prescription is required.


A similar regulation once applied to some forms of  emergency contraception . However, on February 25, 2014, the FDA approved generic one-pill emergency contraception products for unrestricted sale on the shelf. There is no age limit or need for ID to purchase. [ 21 ]


Furthermore, some  Schedule V  controlled substances may be classified as OTC products in certain states. Such drugs are sold without a prescription but are subject to record-keeping rules and quantity and/or age restrictions, and they must be dispensed by a  pharmacy . [ 22 ]  Finally, pharmacies frequently require a prescription for Schedule V drugs as a matter of policy, despite their OTC status according to applicable laws and regulations.  [ citation needed ]


In the United Kingdom, medication is governed by the Medicines Regulations 2012. Medication falls into one of three categories: [ 1 ] [ 23 ]


If it is not appropriate to sell a 'P' medication – i.e. the condition is not suitable for self-management and requires referral to a medical prescriber – then a sale should not occur and the pharmacist has a legal and professional obligation to refer this on to an appropriate service.


Examples of these include some sleep aid tablets such as  diphenhydramine , human  deworming  tablets such as  mebendazole , painkillers with small amounts of  codeine  (up to 12.8 mg per tablet), and  pseudoephedrine . Medication available only with a prescription is marked somewhere on the box/container with [POM]. Pharmacy-only products are marked with [P]. A prescription is not required for [P] medicines, and pharmacy sales assistants are required by  Royal Pharmaceutical Society  codes to ask certain questions, which varies for what the customer says. If they ask for a specific product, the pharmacy assistant must ask "Who is it for?", "How long have you had the symptoms?", "Are you allergic to any medication?", "Are you taking any medication?" ('WHAM' questions). If a customer asks for a remedy, e.g., hay fever, then the '2WHAM questions' must be asked "Who is it for?", "What are the symptoms?", "How long have you had the symptoms?", "Have you taken any action towards your symptoms?", and "Are you taking any other medication?". It is with this information that the pharmacist can halt the sale, if need be. No [POM], [P] or [GSL] products that are stocked in a pharmacy can be sold, dispensed, or pre-made until a responsible pharmacist is signed in and on the premises. Some medication available in supermarkets and petrol stations is sold only in smaller packet sizes. Often, larger packs will be marked as [P] and available only from a pharmacy. Frequently, customers buying larger-than-usual doses of [P] medicines (such as  DXM , promethazine, codeine or  Gee's Linctus ) will be queried, due to the possibility of abuse. [ 24 ]


As a general rule, over-the-counter drugs have to be used primarily to treat a condition that does not require the direct supervision of a doctor and must be proven to be reasonably safe and well tolerated. [ 25 ]  OTC drugs are usually also required to have little or no abuse potential, although in some areas drugs such as  codeine  are available OTC (usually in strictly limited formulations or requiring paperwork or identification to be submitted during purchase). [ 26 ]


Over time, often 3–6 years, drugs that prove themselves safe and appropriate as prescription medicines may be switched from prescription to OTC. [ citation needed ]  An example of this is  diphenhydramine  (Benadryl), an anti-histamine which once required a prescription but now is available OTC nearly everywhere. [ citation needed ]  More recent [ when? ]  examples are  cimetidine  and  loratadine  in the United States, and  ibuprofen  in Australia. [ citation needed ]


It is somewhat unusual for an OTC drug to be withdrawn from the market as a result of safety concerns, rather than market forces, though it does happen occasionally. For example,  phenylpropanolamine  was removed from sale in the United States over concern regarding  strokes  in young women. [ 27 ]  A study has been done examining consumer's perceptions about the risk of and access to nonprescription medication. The study concluded that a small percentage of consumers prefer having access to medication over potential risks of taking non-prescribed medication. [ 28 ]   Ranitidine  was suspended in multiple markets due to concerns over the presence of the  carcinogen   N -nitrosodimethylamine  (NDMA). [ 29 ] [ 30 ] [ 31 ] [ 32 ]


In the United Kingdom, it was announced in February 2007 that  Boots the Chemist  would try over-the-counter sales of Viagra in stores in  Manchester, England  (previous available as prescription only). Men aged between 30 and 65 could buy four tablets after a consultation with a  pharmacist . [ 33 ]


Overmedication  describes the excessive use of  over-the-counter  or  prescription medicines  for a person. Overmedication can have harmful effects, such as non-adherence or  interactions  with multiple prescription drugs.


Over-the-counter (OTC) medications are generally first-line therapies that people may choose to treat common acute illnesses, such as fevers, colds, allergies, headaches, or other pain. Many of these medications can be bought in retail pharmacies or grocery stores without a prescription. OTC medication overuse is most prevalent in adolescents and young adults. [ 1 ]  This overuse is common due to the relatively low cost, widespread availability, low perceived dangers, and internet culture associated with OTC medications. [ 2 ]  OTC medications may be combination formulations that contain multiple drugs. These combination formulations are often used with other substances, which complicates treatment for these types of overdoses. Furthermore, the easy access to information online can sometimes lead to self-diagnosis and self-medication, contributing to the potential for misuse and overuse.


Overuse of  acetaminophen  is the leading cause of  liver failure  in the  Western world . [ 3 ]  The maximum daily limit of acetaminophen is 4 grams per day for someone with a healthy liver. It is also highly recommended to not go over the maximum daily limit. Exceeding the maximum daily limit could involve severe  liver toxicity , liver failure,  kidney failure , or even death. [ 4 ]  People who have poor liver function or with chronic alcohol use disorder should either limit or not ingest acetaminophen to prevent morbidities. [ 5 ]  Additionally, acetaminophen is an ingredient in many combination medications, increasing the risk of unintentional overdose. Consumers should read labels carefully and consult healthcare providers to ensure they are not consuming excessive doses. In cases of suspected overdose, immediate medical attention is needed to mitigate potential life-threatening consequences. [ 4 ]


Codeine  is an  opioid  and shares similarities to other opioid overuse. Many OTC medications for cough have formulations that contain codeine, which people may seek to overuse. The common effects of codeine include  miosis ,  respiratory depression ,  CNS depression , and decreased bowel motility. [ 6 ]  Despite the risk of death, dependence is another significant issue related to codeine overuse. Tolerance can cause users to use more opioid, leading to dependence, especially with chronic daily use of codeine. [ 1 ]  Additionally, the misuse of codeine-containing cough syrups has become a public health concern, as it can serve as a gateway to stronger opioids. [ citation needed ]  Education about the risks and signs of opioid addiction can play a role in prevention and early intervention.


Dextromethorphan , also shortened to DXM, affects the  NMDA receptor  and serotonin receptors which is believed to give its psychoactive effects at high doses. Similarly to codeine, DXM comes primarily in formulations that contain other OTC medications and is not common to find DXM on its own. Moreso, people who use DXM tend to use it concomitantly with other substances such as alcohol,  hallucinogens ,   sedative drugs , and opioids. [ 1 ]  DXM has dose dependent psychoactive effects with lower dose leading to more restlessness and  euphoria  and higher doses causing hallucinations, delusional beliefs, paranoia, perceptual distortions,  ataxia , and out of body experiences. [ 1 ]


Diphenhydramine  is typically used for allergy relief, although it may be used to alleviate sleeping problems, anxiety, and overall restlessness. [ 7 ]  Effects may include euphoria, hallucinations, or  psychosis . [ 7 ]  The anticholinergic activity of diphenhydramine may lead to  tachycardia ,  dry mouth , blurred vision,  mydriasis ,  depression, and urinary retention. [ 7 ]


In 2020, purposeful overmedication with Benadryl (diphenhydramine) was a concern due to use of social media by teenagers in the United States, with the FDA issuing a public warning about the possibility of seizures, hallucinations, breathing difficulty or loss of consciousness. [ 8 ]


Pseudoephedrine ,  ephedrine  or  phenylpropanolamine  can be overused with the intent for weight loss or improving athletic performance, possibly causing  insomnia , diminished sense of fatigue, euphoria, and psychotic behavior. [ 1 ]  The habitual use of the medication has led to  dependence , with symptoms of restlessness, dysphoria, and distorted perceptions on withdrawal. [ 1 ]


Seniors (65 years old and up) are possible users of overmedication. [ 9 ]  Seniors are disproportionately affected by not only adverse drug events, but also  drug interactions  and more hospital admissions. [ medical citation needed ]


The term for individuals taking five or more medications is  polypharmacy , which commonly occurs in elderly people, increasing their risk of overmedication. [ 10 ]  Medical providers are generally hesitant to prescribe polypharmacy in the elderly due to the risk of harmful drug interactions. Concerns with polypharmacy and elderly groups are reduced medication adherence, increased fall risk, cognitive function impairment, and adverse drug reaction. [ 11 ]  Almost 75% of clinic visits result in people obtaining a written prescription. [ 12 ] [ 13 ]


More careful prescribing practices could increase medication adherence in elderly people. [ 14 ] [ 15 ]  Single-pill combination formulations make it easier for a person to monitor medications. [ 15 ]


Opioids are used for pain management acutely or prescribed after a surgical procedure. While opioids aid in short- and long-term pain management, overprescription or constant opioid-exposure increases the risk for addiction. [ 16 ]  There is a rise within healthcare systems to manage prescription of opioids. [ 16 ]  Children prescribed opioids may become susceptible to the harms of addiction. [ 17 ] [ 18 ]


Reducing or withdrawing prescribed opioids, such as for people with chronic non-cancerous pain, using  either dose-reduction or stopping opioid prescriptions, may be effective, but standards are absent for managing withdrawal symptoms and deprescribing coprescription of sedatives. [ 19 ] [ 20 ]  Studies found a significant increase in opioid surplus disposal when individuals were provided with the necessary education or disposal kits. [ 21 ] [ 22 ]


As antibiotics inhibit bacterial infections, they are a commonly prescribed medication. Overuse of these medications over the years has contributed to reduced efficacy against certain bacteria due to  antimicrobial resistance , [ 23 ]  a global medical concern. [ 24 ]  Antibiotic overprescription is a potential problem in acute care, primary hospitals, and dental offices. [ 24 ]


Antibiotic-resistant bacterial infections are increasing. [ 23 ]  A systemic review of admitted  COVID-19  patients who were prescribed antibiotics showed that 80% of the admitted people were given antibiotics upon admission without confirmed bacterial coinfections. [ 25 ]


Physicians prescribe antibiotics for non-indicated diagnoses, such as viral infections, possibly cntributing to more antibiotic-resistant infections, greater adverse drug events, more drug-drug interactions, and deaths. [ 26 ]  Dentists may prescribe antibiotics for non-indicated conditions that could otherwise be treated with other interventions, according to clinical guidelines. [ 27 ]


Premedication  is using  medication  before some other  therapy  (usually  surgery  or  chemotherapy ) to prepare for that forthcoming therapy. Typical examples include premedicating with a  sedative  or  analgesic  before surgery; using  prophylactic (preventive)  antibiotics before surgery; and using  antiemetics  or  antihistamines  before chemotherapy.


Premedication before chemotherapy for cancer often consists of drug regimens (usually 2  or more drugs, e.g.  dexamethasone ,  diphenhydramine  and  omeprazole ) given to a patient minutes to hours before the chemotherapy to avert side effects or   hypersensitivity  reactions (i.e. allergic reactions). [ citation needed ]


Melatonin  has been found to be effective as a premedication in both adults and children due to its pharmacological properties of  hypnotic ,  antinociceptive  and  anticonvulsant  which produce effective  anxiolysis  and sedation. Unlike midazolam, melatonin does not impair psychomotor skills or adversely affect the quality of recovery. It has a faster recovery time compared to midazolam and has a reduced incidence of post-operative excitement and results in a reduction in dose required of  propofol  and  thiopental . [ 1 ]


Midazolam  is effective in children in reducing anxiety associated with separation from parents and induction of  anesthesia . [ 2 ]   Sufentanil  is also sometimes used as a premedication.  Clonidine  is becoming increasingly popular as a premedication for children. One drawback of clonidine is that it can take up to 45 minutes to take full effect. [ 3 ]  In children, clonidine has been found to be equal to and possibly superior to benzodiazepines as a premedication. It has a more favourable side effect profile. It also reduces the need for an  induction  agent. It improves post-operative pain relief, is better at inducing sedation at induction, reduces  agitated emergence , reduces shivering and  post-operative nausea and vomiting  and reduces post-operative delirium associated with  sevoflurane  anaesthesia.  Benzodiazepines  such as  midazolam  are more commonly used due largely to a lack of a marketing effort by the pharmaceutical companies. As a result, clonidine is becoming increasingly popular with  anesthesiologists . [ 4 ] [ 5 ]   Dexmedetomidine  and  atypical antipsychotic agents  are other premedications which are used particularly in very uncooperative children. [ 6 ]


Non-drug interventions for children include playing relaxing music, massages, reducing noise and controlling light to maintain the sleep wake cycle. [ 7 ]  Other non-pharmacological options for children who refuse or cannot tolerate premedication include clown doctors; low sensory stimulation and hand-held video games may also help reduce anxiety during induction of general anesthesia. [ 8 ]


Proprietary drug  are  chemicals  used for medicinal purposes which are formulated or manufactured under a name protected from competition through  trademark  or  patent . [ 1 ]  The invented drug is usually still considered proprietary even if the patent expired. [ 2 ]  When  a patent  expires,  generic drugs  may be developed and released legally. Some international and national  governmental organizations  have set up  laws  to enforce  intellectual property  to protect proprietary drugs, but some also highlight the importance of  public health  disregarding  legal regulations . [ 3 ] [ 4 ]  Proprietary drugs affect the world in various aspects including  medicine ,  public health  and  economy .


Not all proprietary drugs have their  generic replacements  available.  Biologics  are often produced by  in vivo  preparation and direct extraction of substances from  living organisms. [ 5 ]   Pharma  is not extensively involved in searching for ready-to-sell generic  biologics  due to the complexity of manufacture and hurdles in extraction processes. [ 6 ]  Besides  vaccines , these endogenous origin chemicals are prescribed to patients with severe conditions, such as complications including  asthma ,  rheumatoid arthritis , [ 7 ]  or  cancer . Patients taking a particular brand of  biologics  are unable to interchange between one and another to prevent underlying exposure to more side effects and/or suboptimal treatment. [ 6 ]  It is believed that  generic biopharmaceutical products  will not be released in the near future until all technical difficulties are overcome. [ 8 ]


The table below shows some examples of pharma and their past/current proprietary medications:


Broadly defined as  drugs  that are marketed under  trade names  and have  patents , [ 15 ]  which can be a synonym of proprietary drugs in daily use. Strictly speaking, every  drug  with a  trade name  is a brand name drug, [ 16 ]  such as  Panadol , a  GSK  branded  paracetamol .


Generic drugs  are  drugs  that have the same  active ingredient  with a patent-expired drug, and are virtually bio-equivalent. The official names are often used to market these drugs, which are called unbranded  generic drug , [ 17 ]  such as Panamax, a generic form of  paracetamol .


A term specifically used to describe past proprietary drugs by referring to their off-patent status. [ 18 ]


To support scientific investigation and protect  intellectual properties ,  patents  are granted to companies and individuals who invented the drug. [ 19 ]  Most entities in the world have established corresponding agendas legally. Global and regional governmental organizations have various extents of advancements and approaches in their  intellectual property rights  protection  laws . Below are some examples for comparison:


The Agreement on Trade-Related Aspects of Intellectual Property Rights  ( TRIPS Agreement ) [ 20 ]  set up in 1994 suggested a standard on  Intellectual Property Rights , which proprietary drug, a type of pharmaceutical and scientific inventions, is covered in this agreement. Basic principles such as the minimal duration of patent and part of the exclusive rights of  patent  owners are included by  WTO  member states in their respective  national regulations . By 5 years and 10 years after the effectiveness of  TRIPS Agreement ,  developed countries  and  developing countries  were required to comply with it. [ 21 ]


Trying to alleviate worldwide divide in  accessibility of medical resources , members from the  WTO  endorsed the  Doha Declaration  on the  TRIPS Agreement  and Public Health in 2001. The basics of this Declaration is that "the TRIPS Agreement does not and should not prevent Members from taking measures to protect  public health ". [ 4 ]  It legalized the participating members to ignore the restriction from the  patent  of the proprietary medicine when they are controlling a significant  public health  crisis, namely  human immunodeficiency virus  ( HIV ),  malaria  and  tuberculosis . Thus, affordable  generic medicine  can be provided for the populations in the  developing countries  in emergency situations.


In the  United States , proprietary drugs are associated with two status:  patent  and  exclusivity .  Patent  is managed by the  United States Patent and Trademark Office , [ 3 ]  granting inventors of new drugs rights for 20 years. [ 21 ]  It is open to all drugs, regardless of its research or commercialization status. [ 22 ]  To enjoy the benefits brought by  patenting , pharmaceutical companies are obliged to disclose all research data on that drug to the public for further progression. [ 23 ]   Exclusivity , given by  the U.S. Food and Drug Association  (FDA), means a period of time in which no other competitor drugs can be approved. [ 23 ]  Commercialized and clinically used drugs are the targets of exclusivity. The length of exclusivity depends on the nature of application, and ranges from one to seven years. [ 23 ]  Practically exclusivity is granted for proprietary drugs that have been granted with  patents , but it is not mandatory. Legalwise,  generic counterparts  have to wait for at least 2 decades for  patent  expiration to sell a copy . This system is said to aim for a balance between gaining  public access  to  generic drugs  and encouraging drug research and development. [ 23 ]


Despite the  US  having a legal system regarding to drug patenting, litigation have taken place. In the past, it is common for drug manufacturers challenging the validity of patents. [ 24 ]  In 2018,  Mylan  attempted to revoke the patent of  Symbicort  owned by  AstraZeneca  through the court. [ 25 ]  Now  pharma  suing on deliberately infringing  generic drugs  has become more prominent. [ 24 ]   AstraZeneca  then took follow-up actions against  Mylan  for premature submission of  Abbreviated New Drug Application  (ANDA) for generic  Symbicort  and won the  lawsuit . [ 25 ]  The introduction of  biopharmaceuticals  and the subsequent establishment of new drug laws may also bring more litigation. [ 25 ]


According to the  Patent  Law in India, drug can apply for a  patent  since 2005. [ 26 ]  Registering a drug for  patents  in  India  is more limiting than developed countries.  India  was removed from  the least developed member states  list of the  WTO  and is therefore no longer eligible for the waiver, [ 27 ]  it has modified its  patent  law [ 26 ]  to satisfy  TRIPS Agreement  with its  intellectual property rights   legal system . An Indian  patent  lasts for 20 years. [ 28 ]  To ensure the interest of public, a  compulsory license  can be issued by the government if a  pharma  is suspected for violating the  public health  principles. [ 26 ]


Introducing new drug  patenting  regulations after 35 years [ 29 ]  could possibly lead to today's disputes, such as the  Novartis v. Union of India  incident. Generic  Gleevec , a  formulation  that can substitute  Glivec , were distributed in the local market since 1993. [ 30 ]  Novartis had filed a  patent  for  Glivec  in 1997. [ 30 ]  An exclusive marketing right was also granted for  Novartis  in 2003 and the application were approved in 2005 . [ 30 ]  In 2013,  the Supreme Court of India  upheld the rejection of the patent application of  Glivec  by  Novartis , [ 31 ]  ending the 10-years battle between the proprietary drug tycoon and the local  patent law . Since 1993,  Novartis  has started to register  patent  for  Glivec  and its active ingredients worldwide without defeats. [ 31 ]  However,  the Supreme Court of India  rejected the  patent registration  of  Glivec  on 2006 [ 31 ]  according to the interpretations on the  patent law  and  TRIPS agreement  by the Court. By then, the local  generic drugs  in  India  are protected. [ 31 ]  This incident is referred as a challenge to the  intellectual property  laws. [ 31 ]


Patent cliff  refers to a dramatic dip in the revenue of a merchandise upon  patent expiry . [ 32 ]  It is a prominent phenomenon in the proprietary drug industry due to the vast gap of prices between the proprietary drug and the  generic drug . [ 33 ]  Since 2010, numerous pharmaceutical board busters have started to become off-patent. [ 34 ]  As seen in the figure below, the top five off-patent proprietary drug before 2017 have a combined lifetime sale of around US$588.4 Billion, [ 35 ]  which is enormous enough to surpass the bottom 5% countries'  GDP  in 2020. [ 36 ]


Figure 1: Five best-selling proprietary drug which lost their patents before 2017 [ 35 ]


Proprietary drug is a substantial business protected by its respective  patent . They are usually sold at a higher price, to compensate for the  clinical trial  cost and sometimes for the  manufacturing  of new  technology . [ 37 ]  For example, an widely used average proprietary drug is 18 times more expensive than a common  generic drug . [ 33 ]   Lyrica , a recent off-patent  painkiller  for  nervous systems , had a sale of 5B USD in 2019, [ 38 ]  out of the 51.8B USD annual sale of the corresponding company. [ 39 ]


However, once the proprietary drug become off-patent, there will soon be immense competition from the  generic drugs  produced by their business rivals. [ 40 ]  As cheaper pharmaceutical alternatives are launched, the surge in supply disrupts the market  supply-and-demand  status. [ 34 ]  The declining dependence on the original proprietary drug will cause its sales decreases. On top of that, the original company usually will have their prices tuned down for improving competitiveness. [ 34 ]  Resulting in a significant drop of revenue of the proprietary drug. [ 40 ]


Below showed the graph which represented the yearly revenue of  Lipitor , a proprietary drug which lost its  patent  on 2011. [ 41 ]  As it can be seen, a significant  patent cliff  happened from 2011 to 2012(58.8% drop in yearly revenue) and it is very possibly due to its newly off-patent status. [ 34 ]


Figure 2: The yearly revenue of  Lipitor  by  Pfizer  (million US dollars) from 2004 to 2019 [ 41 ]


Proprietary drug market is protected by its patent. As a result, its market exclusivity basis allows proprietary drugs to be highly profitable and commercially successful. [ 42 ]  Usually,  pharmaceutical research  is a lengthy, highly demanding, rarely successful, costly and risky investment. [ 43 ]  It is usually associated with a disinterested  merchandise  in the economic world. [ 43 ]  However, once a successful experimental drug candidate is registered as a proprietary drug product, the  patent  legally ensures a long-term dominance in the exclusive market which is free of imitative  generic drug . Generating a stable and considerable net income to cover the cost. [ 44 ]


The huge earning of the proprietary drug can circulate back to fund future  medical research . Providing more resources and manpower to the research and development of another drug candidates. [ 42 ]  As well as attracting new investments to the  pharmaceutical research  industry due to its exclusive market potential. They encourage efforts on  biopharmaceutical  innovations and newborn medical breakthroughs. [ 42 ]


Being required for successful  patent  registration, detailed  pharmaceutical formulations  of the proprietary drug are disclosed on its  patent  registration application, [ 45 ]  which promote the spillover of research efforts among the medical world. [ 46 ]  In order to inspect the safety and efficacy of the proprietary drug candidate, pharmaceutical companies need to list all  clinical trial  data and formulation method as detailed as possible to prove the drug candidate's validity to the patent registration committee. [ 45 ]  Once the  patent  is rewarded, these data will later be published on  medical literature  and  public domains  as common knowledge. [ 46 ]


Researchers can capitalise on the previous successes and establish their own project on top of the current statistics. These cooperatively help exploit more unknown drug candidates without repeating previous progresses. [ 46 ]  Speeding up future medical advancements. [ 46 ]


According to  World Health Organisation(WHO) ,  equitable access to medicines  refers to an affordable and reasonable ability for patients to get their required drug to achieve  health . [ 47 ]   WHO  member states shall fulfill their  moral responsibility  to improve the delivery of and access to the needed drugs. [ 47 ]


However, the  monopolisation  of some expensive proprietary drug in the market is hindering poor patients' access to their best available medications. [ 48 ]  Leading to suboptimal treatments of diseases and lowering of health standard of these patients. [ 48 ]  This phenomenon is very prominent in the underdeveloped countries which usually have a large proportion of underprivileged citizens. [ 48 ] [ 49 ]


Some proprietary drugs(mainly speciality proprietary drug) are criticised for their price-gouging commercial tactics. [ 37 ] [ 50 ]  To illustrate, the world's most expensive drug,  Zolgensma , costs over US$2.1 million per year of treatment, which are generally considered as unaffordable. [ 51 ]  Since  Zolgensma  is the only approved drug for curing  Spinal Muscular Atrophy  in childhood, patients who cannot afford  Zolgensma  will be physically disabled for the rest of their lives. Creating inequity among patients with varying financial capacitances.


According to the  TRIPS Agreement , the  term of patent  of the proprietary drug usually can last for 20 years counting from the filing date. [ 52 ]  After that, approved  generic drugs  can enter the market legally with fair competition. [ 52 ]


However, in order to achieve longer dominance in the market,  pharmaceutical manufacturer  (especially  big pharma ) may apply for  patent  extension or even new  patent  registration based on various reasons. [ 53 ]  Including modifying the formulations, dosage form or maneuvering legal system. [ 30 ] [ 54 ]  To illustrate,  AbbVie , a pharmaceutical tycoon, had attempted 247 proprietary drug  patent  extension applications for extending their exclusivity for 39 years in the  USA  on 2018 alone. [ 55 ]  Among them, 137 applications were successful in extending the  patent .


The abusing of  patent  extension system leads to a much longer  terms of patent  than that stated in both local regulations and  TRIPS Agreement . [ 3 ] [ 53 ]  Providing a long period of competition-free market to their proprietary drug. It creates an unfair competition environment in the  pharmaceutical market . [ 53 ]  Since the  generic drug  companies are excluded from that particular market, they cannot release new pharmaceutical products for public use on the same field. [ 53 ]  Resulting enduring monopolisation of proprietary drug market by the  big pharma  which are already stockpiling proprietary drug. [ 55 ]


Royal Blood-Fresh  ( Korean :  혈궁불로정 ) is a  traditional Korean medicine  ( Koryo medicine )  health supplement  derived from  soybeans . [ 1 ]  It is manufactured in North Korea [ 2 ]  and is the most famous product sold by the North Korean company,  Pugang Pharmaceutic . [ 3 ]


It is marketed as a "blood purifier" and a preventative against  deep-vein thrombosis . [ 1 ]  It is marketed to foreigners during  Air Koryo  flights [ 3 ]  and has been sold at  Pyongyang Gwan , a North Korean restaurant in Hanoi, Vietnam. [ 4 ]  It has been dismissed outside of North Korea as a non-scientific "miracle cure". [ 3 ]


In 2017, three Russian nationals were arrested in  South Korea  for selling North Korean drugs, which included Royal Blood-Fresh,  Kumdang-2 , and  Neo-Viagra-Y.R. [ 5 ]


The Seed  was a controversial  drug rehabilitation  program in the  United States  that operated between 1970 and 2001. [ 1 ]  Aimed at youths, the program was modeled after adult treatment programs, with its techniques having been compared to those of the cult  Synanon . [ 2 ]  In a 1974 U.S Senate report, its techniques were also compared to the  North Korean   brainwashing  technique used on  Prisoners of War  during the  Korean War . [ 3 ] [ 4 ]  At its height in the 1970s The Seed had locations in  Fort Lauderdale ,  Fort Myers ,  Dade County , [ 5 ]  and  St. Petersburg . [ 6 ] [ 7 ]  The organisation widely marketed itself as "spectacularly successful", "teaching love", and received wide press coverage. [ 8 ]   There was also a location in Cleveland, Ohio.  Art Barker and his entourage would travel back and forth a couple times a month.


Following the release of the Senate report, along with criticisms from experts about the techniques and high suicide rate of the attendees, The Seed began to decline over the next two decades. By 2001, only the original Fort Lauderdale location remained, and the founder, Arthur Barker, retired and dissolved the organisation. [ 2 ]  Several other similar drug rehabilitation programs were founded in its image after The Seed's decline, most notably  Straight, Incorporated . [ 2 ]


Sepsivac  is a drug developed by  Cadila Pharmaceuticals  to treat  gram-negative   sepsis .  The active ingredient is heat-killed Mycobacterium w, a non-pathogenic strain of  Mycobacterium .  As an  immunomodulatory , it modulates the immune system of the body and hence significantly reduces mortality rate in patients with gram negative sepsis. Sepsivac is a drug developed by  CSIR  and Cadila Pharmaceuticals under New Millennium Indian Technology Leadership Initiative (NMITLI) programme. [ 1 ]  In many cases, Sepsivac has proven to provide effective care and relief to COVID patients. [ 2 ]


Sepsivac is approved by the  Drug Controller General of India  (DCGI) for treatment of  sepsis  or septic shock. [ 3 ] [ better source needed ]


In patients with sepsis, in response to an  infection , a lot of  pro-inflammatory  and  anti-inflammatory   cytokines  are generated in the body. However, some of the cytokines also cause inflammation in the organs of the body, which might be harmful.  Immunomodulator  drugs such as Sepsivac regulate this host immune response. [ 4 ]  Sepsivac is found to be safe in patients with no systematic side-effects. It can be used in combination with other treatments to manage a patient in critical care setting. [ 5 ]


Scientists at CSIR found similarities between the clinical characteristics of patients with gram-negative sepsis and  COVID-19 . In association with Cadila Pharmaceuticals, the researchers are now working on initiating a randomised, blinded, controlled  clinical trial  to evaluate Sepsivac's efficacy to reduce mortality in critically ill COVID-19 patients. [ 1 ]  The repurposed drug will boost the immunity of the body and limit the spread of COVID-19 and increase the recovery rate. [ 6 ]  The clinical trials will be conducted at national hospitals including  PGIMER Chandigarh ,  AIIMS New Delhi , and  AIIMS , Bhopal. [ 7 ]


A  sialogogue  (also spelled  sialagogue ,  ptysmagogue  or  ptyalagogue ) is a  substance , especially a  medication , that increases the flow rate of  saliva . [ 1 ]  The definition focuses on substances that promote  production or secretion of saliva  (proximal causation) rather than any food that is  mouthwatering  (distal causation that triggers proximal causation).


Sialogogues can be used in the treatment of  xerostomia  (the subjective feeling of having a dry mouth), to stimulate any functioning  salivary gland  tissue to produce more saliva. Saliva has a bactericidal effect, so when low levels of it are secreted, the risk of  caries  increases. [ 2 ]  Not only this, but fungal infections such as oral  candidosis  also can be a consequence of low salivary flow rates. The  buffer  effect of saliva is also important, neutralising acids that cause tooth enamel demineralisation.


The following are used in dentistry to treat xerostomia: [ 3 ]


A tincture is prepared from the root of the pyrethrium ( pyrethrum ) or pellitory (a number of plants in the  Chrysanthemum  family). It is found growing in Levant and parts of Limerick and Clare in  Ireland . The root powder was used as flavouring in tooth powders in the past. [ 5 ]


Skin pop scars  are a cutaneous condition caused by intravenous drug abuse. [ 1 ]


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


The  Solidarity trial for treatments  is a multinational  Phase III-IV clinical trial  organized by the  World Health Organization  (WHO) and partners to compare four untested treatments for hospitalized people with severe  COVID-19  illness. [ 1 ] [ 2 ]  The trial was announced 18 March 2020, [ 1 ]  and as of 6 August 2021, 12,000 patients in 30 countries had been recruited to participate in the trial. [ 3 ]


In May, the WHO announced an international coalition for simultaneously developing several candidate  vaccines  to prevent COVID-19 disease, calling this effort the  Solidarity trial for vaccines . [ 4 ]


The treatments being investigated are  remdesivir ,  lopinavir/ritonavir  combined, lopinavir/ritonavir combined with  interferon-beta , and  hydroxychloroquine  or  chloroquine . Hydroxychloroquine or chloroquine investigation was discontinued in June 2020 due to concluding that it provided no benefit. [ citation needed ]


The trial intends to rapidly assess thousands of COVID-19 infected people for the potential efficacy of existing antiviral and  anti-inflammatory  agents not yet evaluated specifically for COVID-19 illness, a process called "repurposing" or "repositioning" an already-approved drug for a different disease. [ 2 ] [ 5 ]


The Solidarity project is designed to give rapid insights to key clinical questions: [ 2 ] [ 5 ]


Enrolling people with COVID-19 infection is simplified by gathering   informed consent , and capturing data on an online clinical trial platform (Castor EDC). [ 6 ] [ 2 ]  After the trial staff determine the drugs available at the hospital, the platform  randomizes  the hospitalized subject to one of the trial drugs or to the hospital standard of care for treating COVID-19. The trial physician records and submits follow-up information about the subject status and treatment, completing data input via the Castor EDC Platform. [ 6 ]  The design of the Solidarity trial is not  double-blind  – which is normally the standard in a high-quality clinical trial – but WHO needed speed with quality for the trial across many hospitals and countries. [ 2 ]  A global  safety monitoring board of WHO physicians  examine  interim results  to assist decisions on safety and effectiveness of the trial drugs, and alter the trial design or recommend an effective therapy. [ 2 ] [ 5 ]  A similar web-based study to Solidarity, called "Discovery", was initiated in March across seven countries by  INSERM  ( Paris ,  France ). [ 2 ] [ 7 ]


The Solidarity trial seeks to implement coordination across hundreds of hospital sites in different countries – including those with poorly-developed infrastructure for clinical trials – yet needs to be conducted rapidly. According to  John-Arne Røttingen , chief executive of the  Research Council of Norway  and chairman of the Solidarity trial international  steering committee , the trial would be considered effective if therapies are determined to "reduce the proportion of patients that need ventilators by, say, 20%, that could have a huge impact on our national health-care systems." [ 8 ]


According to the WHO Director General, the aim of the trial is to "dramatically cut down the time needed to generate robust evidence about what drugs work", [ 9 ]  a process using an "adaptive design". [ 10 ] [ 11 ]  The Solidarity and European Discovery trials apply adaptive design to rapidly alter trial parameters when results from the four experimental therapeutic strategies emerge. [ 7 ] [ 12 ]


Adaptive designs within ongoing Phase III-IV clinical trials – such as the Solidarity and Discovery projects – may shorten the trial duration and use fewer subjects, possibly expediting decisions for early termination to save costs if interim results are negative. [ 7 ] [ 10 ] [ 11 ]  If the Solidarity project shows early evidence of success, design changes across the project's international locations can be made rapidly to enhance overall outcomes of affected people and hasten use of the therapeutic drug. [ 1 ] [ 7 ]


The individual or combined drugs being studied in the Solidarity and Discovery projects are already approved for other diseases. [ 2 ]  They are: [ 2 ] [ 7 ]


Due to safety concerns and evidence of  heart arrhythmias  leading to higher death rates, the WHO suspended the hydroxychloroquine arm of the Solidarity trial in late May 2020, [ 14 ] [ 15 ]  then reinstated it, [ 16 ]  then withdrew it again when an interim analysis in June showed that hydroxychloroquine provided no benefit to hospitalized people severely infected with COVID-19. [ 13 ]


In October 2020, the World Health Organization Solidarity trial produced an interim report concluding that its "remdesivir, hydroxychloroquine, lopinavir and interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay." [ 17 ]  Gilead – the manufacturer of remdesivir – criticized the Solidarity trial methodology after it showed no benefit of the treatments, claiming that the international nature of the Solidarity trial was a weakness, whereas many experts regard the multinational study as a strength. [ 18 ]  Purchase agreements between the EU and Gilead for remdesivir and granting of its  Emergency Use Authorization  by the US FDA during October were questioned by Solidarity trial scientists as not based on positive clinical trial data, when the interim analysis of the Solidarity trial had found remdesivir to be ineffective. [ 18 ]


In January 2022, the Canadian component of the Solidarity trial reported that in-hospital people with COVID-19 treated with remdesivir had lower death rates (by about 4%) and reduced need for oxygen (less by 5%) and mechanical ventilation (less by 7%) compared to people receiving standard-of-care treatments. [ 19 ]


During March, funding for the Solidarity trial reached  US$108  million from 203,000 individual donations,  charitable organizations  and governments, with 45 countries involved in financing or trial management. [ 1 ] [ 20 ]  As of 1 July 2020, nearly 5,500 patients in 21 countries of 39 that have approval to recruit were recruited to participate in the trial. More than 100 countries in all 6 WHO regions have expressed interest in participating. [ 3 ]


The WHO has developed a multinational coalition of vaccine scientists defining a  Global Target Product Profile  (TPP) for COVID-19, identifying favorable attributes of safe and effective vaccines under two broad categories: "vaccines for the long-term protection of people at higher risk of COVID-19, such as healthcare workers", and other vaccines to provide rapid-response immunity for new outbreaks. [ 4 ]  The international TPP team was formed to 1) assess the development of the most promising candidate vaccines; 2) map candidate vaccines and their clinical trial worldwide, publishing a frequently-updated "landscape" of vaccines in development; [ 21 ]  3) rapidly evaluate and screen for the most promising candidate vaccines simultaneously before they are tested in humans; and 4) design and coordinate a multiple-site, international  randomized controlled trial   –  the Solidarity trial for vaccines [ 22 ]   –  to enable simultaneous evaluation of the benefits and risks of different vaccine candidates under clinical trials in countries where there are high rates of COVID-19 disease, ensuring fast interpretation and sharing of results around the world. [ 4 ]  The WHO vaccine coalition will prioritize which vaccines should go into Phase II and III clinical trials, and determine harmonized Phase III protocols for all vaccines achieving the  pivotal trial  stage. [ 4 ]


The WHO announced in August 2021 that it will roll out the next phase Solidarity trial under the name  Solidarity PLUS  trial in 52 countries. The trial will enroll hospitalized patients to test three new drugs for potential treatment of COVID-19. These drugs include  artesunate ,  imatinib  and  infliximab . The selection of these therapies was done by an independent expert panel of WHO. These drugs are already used for other indications: artesunate is used for malaria, imatinib for cancers, and infliximab, an  anti-TNF  agent is used for Crohn's Disease and rheumatoid arthritis. The drugs will be donated for the purpose of trial by their manufacturers. [ citation needed ]


Sucrosomial iron  is a new  oral iron  preparation containing  ferric pyrophosphate  covered by  phospholipids  plus  sucrose   ester  of  fatty acid  matrix. This allows the molecule to be absorbed in the  gastrointestinal  tract by trans-cellular, para-cellular and M-cells independently of  hepcidin  and due to gastro-resistant properties, it does not cause the side effects such as gastric irritation which is commonly associated to oral iron. [ 1 ] [ 2 ] [ 3 ]


Targeted therapy  or  molecularly targeted therapy  is one of the major modalities of medical treatment ( pharmacotherapy ) for  cancer , [ 1 ]  others being  hormonal therapy  and  cytotoxic   chemotherapy . As a form of  molecular medicine , targeted therapy blocks the growth of  cancer cells  by interfering with specific targeted  molecules  needed for  carcinogenesis  and  tumor  growth, [ 2 ]  rather than by simply interfering with all  rapidly dividing cells  (e.g. with traditional  chemotherapy ). Because most agents for targeted therapy are  biopharmaceuticals , the term  biologic therapy  is sometimes synonymous with  targeted therapy  when used in the context of cancer therapy (and thus distinguished from chemotherapy, that is, cytotoxic therapy). However, the modalities can be combined;  antibody-drug conjugates  combine biologic and cytotoxic mechanisms into one targeted therapy.


Another form of targeted therapy involves the use of nanoengineered enzymes to bind to a tumor cell such that the body's natural cell degradation process can digest the cell, effectively eliminating it from the body.


Targeted cancer therapies are expected to be more effective than older forms of treatments and less harmful to normal cells. Many targeted therapies are examples of  immunotherapy  (using immune mechanisms for therapeutic goals) developed by the field of  cancer immunology . Thus, as  immunomodulators , they are one type of  biological response modifiers .


The most successful targeted therapies are chemical entities that target or preferentially target a protein or enzyme that carries a mutation or other genetic alteration that is specific to cancer cells and not found in normal host tissue. [ 3 ]  One of the most successful molecular targeted therapeutics is  imatinib , marketed as Gleevec, which is a kinase inhibitor with exceptional affinity for the oncofusion protein  BCR-Abl  which is a strong driver of tumorigenesis in  chronic myelogenous leukemia . Although employed in other indications, imatinib is most effective targeting BCR-Abl. Other examples of molecular targeted therapeutics targeting mutated oncogenes, include PLX27892 which targets mutant B-raf in melanoma.


There are targeted therapies for  lung cancer ,  colorectal cancer ,  head and neck cancer ,  breast cancer ,  multiple myeloma ,  lymphoma ,  prostate cancer ,  melanoma  and other cancers. [ 1 ] [ 4 ] [ 5 ]


Biomarkers are usually required to aid the selection of patients who will likely respond to a given targeted therapy. [ 6 ]


Co-targeted therapy involves the use of one or more therapeutics aimed at multiple targets, for example PI3K and MEK, in an attempt to generate a synergistic response [ 5 ]  and prevent the development of drug resistance. [ 7 ] [ 8 ]


The definitive experiments that showed that targeted therapy would reverse the malignant phenotype of tumor cells involved treating Her2/neu transformed cells with monoclonal antibodies in vitro and in vivo by Mark Greene's laboratory and reported from 1985. [ 9 ]


Some have challenged the use of the term, stating that drugs usually associated with the term are insufficiently selective. [ 10 ]  The phrase occasionally appears in  scare quotes : "targeted therapy". [ 11 ]   Targeted therapies may also be described as "chemotherapy" or "non-cytotoxic chemotherapy", as "chemotherapy" strictly means only "treatment by chemicals". But in typical medical and general usage "chemotherapy" is now mostly used specifically for "traditional" cytotoxic chemotherapy.


The main categories of targeted therapy are currently  small molecules  and  monoclonal antibodies .


Many are  tyrosine-kinase inhibitors .


Several are in development and a few have been licensed by the FDA and the European Commission. Examples of licensed monoclonal antibodies include:


Many  antibody-drug conjugates  (ADCs) are being developed. See also  antibody-directed enzyme prodrug therapy  (ADEPT).


In the U.S., the  National Cancer Institute 's   Molecular Targets Development Program  (MTDP) aims to identify and evaluate molecular targets that may be candidates for drug development.


Tetrodocain  ( Korean :  테트로도카인주사약 ) is medical injection produced by the  Korea Jangsaeng Joint Venture Company  ( 조선장생합영회사 ) in  North Korea . The injection was first claimed to be invented by the company in 2004. [ 1 ]  According to the state-run  Korean Central News Agency  (KCNA), the main ingredient of the injection is  tetrodotoxin , isolated from  puffer  poisons, and operates as an  anaesthetic . [ 2 ]  It has been sold for international export on sites based in Russia and China. [ 3 ]


KCNA described the medicine as efficacious in treating a wide range of diseases, including  cancer ,  tuberculosis , chronic  hepatitis ,  pancreatitis  and  HIV/AIDS . [ 4 ] [ 5 ]  These claims have been deemed to be either exaggerated or false. [ 3 ]  The North Korean government also marketed its use in  drug detoxification  from  narcotics  such as  opium ,  cocaine  and  heroin . [ 6 ]


North Korea released a supposed clinical research thesis about the usage of tetrodocain for anesthetics in 2015. [ 7 ]


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


Pharmacogenomics , often abbreviated "PGx," is the study of the role of the  genome  in  drug  response. Its name ( pharmaco-  +  genomics ) reflects its combining of  pharmacology  and  genomics . Pharmacogenomics analyzes how the genetic makeup of a patient affects their response to drugs. [ 1 ]  It deals with the influence of  acquired  and  inherited  genetic variation on drug response, by correlating DNA  mutations  (including  point mutations ,  copy number variations , and  structural variations ) with  pharmacokinetic  (drug  absorption ,  distribution ,  metabolism , and  elimination ),  pharmacodynamic  (effects mediated through a drug's  biological targets ), and/or  immunogenic  endpoints. [ 2 ] [ 3 ] [ 4 ]


Pharmacogenomics aims to develop rational means to optimize  drug therapy , with regard to the patients'  genotype , to achieve maximum efficiency with minimal  adverse effects . [ 5 ]  It is hoped that by using pharmacogenomics,  pharmaceutical drug  treatments can deviate from what is dubbed as the "one-dose-fits-all" approach. Pharmacogenomics also attempts to eliminate trial-and-error in prescribing, allowing physicians to take into consideration their patient's genes, the functionality of these genes, and how this may affect the effectiveness of the patient's current or future treatments (and where applicable, provide an explanation for the failure of past treatments). [ 6 ] [ 7 ]  Such approaches promise the advent of  precision medicine  and even  personalized medicine , in which drugs and drug combinations are optimized for narrow subsets of patients or even for each individual's unique genetic makeup. [ 8 ] [ 9 ]


Whether used to explain a patient's response (or lack of it) to a treatment, or to act as a predictive tool, it hopes to achieve better treatment outcomes and greater efficacy, and reduce drug toxicities and adverse drug reactions (ADRs). For patients who do not respond to a treatment, alternative therapies can be prescribed that would best suit their requirements. In order to provide pharmacogenomic recommendations for a given drug, two possible types of input can be used:  genotyping , or  exome  or whole  genome   sequencing . [ 10 ]  Sequencing provides many more data points, including detection of mutations that prematurely terminate the synthesized protein (early  stop codon ). [ 10 ]


The term  pharmacogenomics  is often used interchangeably with  pharmacogenetics . Although both terms relate to drug response based on genetic influences, there are differences between the two.  Pharmacogenetics  is limited to  monogenic  phenotypes (i.e., single gene-drug interactions).  Pharmacogenomics  refers to polygenic drug response phenotypes and encompasses  transcriptomics ,  proteomics , and  metabolomics .


Pharmacokinetics  involves the absorption, distribution, metabolism, and elimination of pharmaceutics. These processes are often facilitated by enzymes such as drug transporters or drug metabolizing enzymes (discussed in-depth below). Variation in DNA loci responsible for producing these enzymes can alter their expression or activity so that their functional status changes. An increase, decrease, or loss of function for transporters or metabolizing enzymes can ultimately alter the amount of medication in the body and at the site of action. This may result in deviation from the medication's  therapeutic window  and result in either toxicity or loss of effectiveness.


The majority of clinically actionable pharmacogenetic variation occurs in genes that code for drug-metabolizing enzymes, including those involved in both  phase I  and  phase II  metabolism. The  cytochrome P450  enzyme family is responsible for metabolism of 70-80% of all medications used clinically. [ 11 ]   CYP3A4 ,  CYP2C9 ,  CYP2C19 , and  CYP2D6  are major CYP enzymes involved in drug metabolism and are all known to be highly polymorphic. [ 11 ]  Additional drug-metabolizing enzymes that have been implicated in pharmacogenetic interactions include  UGT1A1  (a  UDP-glucuronosyltransferase ),  DPYD , and  TPMT . [ 12 ]


Many medications rely on  transporters  to cross cellular membranes in order to move between body fluid compartments such as the blood, gut lumen, bile, urine, brain, and cerebrospinal fluid. [ 13 ]  The major transporters include the  solute carrier ,  ATP-binding cassette , and  organic anion transporters . [ 13 ]  Transporters that have been shown to influence response to medications include  OATP1B1  ( SLCO1B1 ) and breast cancer resistance protein (BCRP) ( ABCG2 ). [ 14 ]


Pharmacodynamics  refers to the impact a medication has on the body, or its mechanism of action.


Drug targets are the specific sites where a medication carries out its pharmacological activity. The interaction between the drug and this site results in a modification of the target that may include inhibition or potentiation. [ 15 ]  Most of the pharmacogenetic interactions that involve drug targets are within the field of  oncology  and include  targeted therapeutics  designed to address  somatic mutations  (see also  Cancer Pharmacogenomics ). For example,  EGFR  inhibitors like  gefitinib  (Iressa) or  erlotinib  (Tarceva) are only indicated in patients carrying specific mutations to  EGFR . [ 16 ] [ 17 ]


Germline mutations  in drug targets can also influence response to medications, though this is an emerging subfield within pharmacogenomics. One well-established gene-drug interaction involving a germline mutation to a drug target is  warfarin  (Coumadin) and  VKORC1 , which codes for  vitamin K epoxide reductase (VKOR) . Warfarin binds to and inhibits VKOR, which is an important enzyme in the vitamin K cycle. [ 18 ]  Inhibition of VKOR prevents  reduction  of  vitamin K , which is a  cofactor  required in the formation of  coagulation  factors  II ,  VII ,  IX  and  X , and inhibitors  protein C  and  S . [ 18 ] [ 19 ]


Medications can have off-target effects (typically unfavorable) that arise from an interaction between the medication and/or its metabolites and a site other than the intended target. [ 20 ]  Genetic variation in the off-target sites can influence this interaction. The main example of this type of pharmacogenomic interaction is  glucose-6-phosphate-dehydrogenase (G6PD) . G6PD is the enzyme involved in the first step of the  pentose phosphate pathway  which generates NADPH (from NADP). NADPH is required for the production of reduced  glutathione  in  erythrocytes  and it is essential for the function of  catalase . [ 21 ]  Glutathione and catalase protect cells from oxidative stress that would otherwise result in cell  lysis . Certain variants in  G6PD  result in  G6PD deficiency , in which cells are more susceptible to oxidative stress. When medications that have a significant oxidative effect are administered to individuals who are G6PD deficient, they are at an increased risk of erythrocyte lysis that presents as  hemolytic anemia . [ 22 ]


The  human leukocyte antigen  (HLA) system, also referred to as the  major histocompatibility complex  (MHC), is a complex of genes important for the  adaptive immune system . Mutations in the HLA complex have been associated with an increased risk of developing hypersensitivity reactions in response to certain medications. [ 23 ]


The  Clinical Pharmacogenetics Implementation Consortium  (CPIC) is "an international consortium of individual volunteers and a small dedicated staff who are interested in facilitating use of pharmacogenetic tests for patient care. CPIC’s goal is to address barriers to clinical implementation of pharmacogenetic tests by creating, curating, and posting freely available, peer-reviewed, evidence-based, updatable, and detailed gene/drug clinical practice guidelines. CPIC guidelines follow standardized formats, include systematic grading of evidence and clinical recommendations, use standardized terminology, are peer-reviewed, and are published in a journal (in partnership with Clinical Pharmacology and Therapeutics) with simultaneous posting to cpicpgx.org, where they are regularly updated." [ 12 ]


The CPIC guidelines are "designed to help clinicians understand HOW available genetic test results should be used to optimize drug therapy, rather than WHETHER tests should be ordered. A key assumption underlying the CPIC guidelines is that clinical high-throughput and pre-emptive (pre-prescription) genotyping will become more widespread, and that clinicians will be faced with having patients’ genotypes available even if they have not explicitly ordered a test with a specific drug in mind. CPIC's guidelines, processes and projects have been endorsed by several professional societies." [ 12 ]


In February 2020 the  FDA  published the Table of Pharmacogenetic Associations. [ 24 ]  For the gene-drug pairs included in the table, "the FDA has evaluated and believes there is sufficient scientific evidence to suggest that subgroups of patients with certain genetic variants, or genetic variant-inferred phenotypes (such as affected subgroup in the table below), are likely to have altered drug metabolism, and in certain cases, differential therapeutic effects, including differences in risks of adverse events." [ 25 ]


"The information in this Table is intended primarily for prescribers, and patients should not adjust their medications without consulting their prescriber. This version of the table is limited to pharmacogenetic associations that are related to drug metabolizing enzyme gene variants, drug transporter gene variants, and gene variants that have been related to a predisposition for certain adverse events. The FDA recognizes that various other pharmacogenetic associations exist that are not listed here, and this table will be updated periodically with additional pharmacogenetic associations supported by sufficient scientific evidence." [ 25 ]


The FDA Table of Pharmacogenomic Biomarkers in Drug Labeling lists FDA-approved drugs with pharmacogenomic information found in the drug labeling. "Biomarkers in the table include but are not limited to germline or somatic gene variants (polymorphisms, mutations), functional deficiencies with a genetic etiology, gene expression differences, and chromosomal abnormalities; selected protein biomarkers that are used to select treatments for patients are also included." [ 26 ]


The  Pharmacogenomics Knowledgebase (PharmGKB)  is an " NIH -funded resource that provides information about how human genetic variation affects response to medications. PharmGKB collects, curates and disseminates knowledge about clinically actionable gene-drug associations and genotype-phenotype relationships." [ 27 ]


There are many commercial laboratories around the world who offer pharmacogenomic testing as a  laboratory developed test (LDTs) . The tests offered can vary significantly from one lab to another, including genes and alleles tested for, phenotype assignment, and any clinical annotations provided. With the exception of a few direct-to-consumer tests, all pharmacogenetic testing requires an order from an authorized healthcare professional. In order for the results to be used in a clinical setting in the  United States , the laboratory performing the test much be  CLIA -certified. Other regulations may vary by country and state.


Direct-to-consumer  (DTC) pharmacogenetic tests allow consumers to obtain pharmacogenetic testing without an order from a prescriber. DTC pharmacogenetic tests are generally reviewed by the FDA to determine the validity of test claims. [ 28 ]  The FDA maintains a  list of DTC genetic tests  that have been approved.


There are multiple ways to represent a pharmacogenomic  genotype . A commonly used  nomenclature  system is to report  haplotypes  using a star (*) allele (e.g.,  CYP2C19  *1/*2).  Single-nucleotide polymorphisms  (SNPs) may be described using their assignment reference SNP cluster ID (rsID) or based on the location of the  base pair  or  amino acid  impacted. [ 29 ]


In 2017 CPIC published results of an expert  survey  to standardize terms related to clinical pharmacogenetic test results. [ 30 ]  Consensus for terms to describe allele functional status,  phenotype  for drug metabolizing enzymes, phenotype for drug transporters, and phenotype for high-risk genotype status was reached.


The list below provides a few more commonly known applications of pharmacogenomics: [ 31 ]


Pharmacogenomics may be applied to several areas of medicine, including  pain management ,  cardiology ,  oncology , and  psychiatry . A place may also exist in  forensic pathology , in which pharmacogenomics can be used to determine the cause of death in drug-related deaths where no findings emerge using  autopsy . [ citation needed ]


In  cancer treatment , pharmacogenomics tests are used to identify which patients are most likely to respond to certain  cancer drugs . In behavioral health, pharmacogenomic tests provide tools for physicians and care givers to better manage medication selection and side effect amelioration. Pharmacogenomics is also known as companion diagnostics, meaning tests being bundled with drugs. Examples include  KRAS  test with  cetuximab  and  EGFR  test with  gefitinib . Beside efficacy, germline pharmacogenetics can help to identify patients likely to undergo severe toxicities when given cytotoxics showing impaired detoxification in relation with genetic polymorphism, such as canonical 5-FU. [ 32 ]  In particular, genetic deregulations affecting genes coding for  DPD ,  UGT1A1 ,  TPMT ,  CDA  and  CYP2D6  are now considered as critical issues for patients treated with 5-FU/capecitabine, irinotecan, mercaptopurine/azathioprine, gemcitabine/capecitabine/AraC and tamoxifen, respectively. [ 33 ]


In  cardiovascular disorders , the main concern is response to drugs including  warfarin ,  clopidogrel ,  beta blockers , and  statins . [ 10 ]  In patients with CYP2C19, who take clopidogrel, cardiovascular risk is elevated, leading to  medication package insert  updates by regulators. [ 34 ]  In patients with  type 2 diabetes ,  haptoglobin  (Hp) genotyping shows an effect on cardiovascular disease, with Hp2-2 at higher risk and supplemental vitamin E reducing risk by affecting  HDL . [ 35 ]


In psychiatry, as of 2010, research has focused particularly on  5-HTTLPR  and  DRD2 . [ 36 ]


Initiatives to spur adoption by clinicians include the  Ubiquitous Pharmacogenomics (U-PGx)  program in  Europe  and the Clinical Pharmacogenetics Implementation Consortium (CPIC) in the United States. [ 37 ]  In a 2017 survey of European clinicians, in the prior year two-thirds had not ordered a pharmacogenetic test. [ 38 ]


In 2010,  Vanderbilt University Medical Center  launched Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment (PREDICT); [ 39 ]  in 2015 survey, two-thirds of the clinicians had ordered a pharmacogenetic test. [ 40 ]


In 2019, the largest private health insurer,  UnitedHealthcare , announced that it would pay for genetic testing to predict response to psychiatric drugs. [ 41 ]


In 2020,  Canada's  4th largest health and dental insurer,  Green Shield Canada , announced that it would pay for pharmacogenetic testing and its associated clinical decision support software to optimize and personalize mental health prescriptions. [ 42 ]


A potential role for pharmacogenomics is to reduce the occurrence of  polypharmacy : it is theorized that with tailored drug treatments, patients will not need to take several medications to treat the same condition. Thus they could potentially reduce the occurrence of  adverse drug reactions , improve treatment outcomes, and save costs by avoiding purchase of some medications. For example, maybe due to inappropriate prescribing,  psychiatric  patients tend to receive more medications than age-matched non-psychiatric patients. [ 43 ]


The need for pharmacogenomically tailored drug therapies may be most evident in a survey conducted by the Slone Epidemiology Center at  Boston University  from February 1998 to April 2007. The study elucidated that an average of 82% of adults in the United States are taking at least one medication (prescription or nonprescription drug, vitamin/mineral, herbal/natural supplement), and 29% are taking five or more. The study suggested that those aged 65 years or older continue to be the biggest consumers of medications, with 17-19% in this age group taking at least ten medications in a given week. Polypharmacy has also shown to have increased since 2000 from 23% to 29%. [ 44 ]


Case A – Antipsychotic adverse reaction [ 45 ]


Patient A has schizophrenia. Their treatment included a combination of ziprasidone, olanzapine, trazodone and  benztropine . The patient experienced dizziness and sedation, so they were tapered off ziprasidone and olanzapine, and transitioned to quetiapine. Trazodone was discontinued. The patient then experienced excessive sweating, tachycardia and neck pain, gained considerable weight and had hallucinations. Five months later, quetiapine was tapered and discontinued, with ziprasidone re-introduced into their treatment, due to the excessive weight gain. Although the patient lost the excessive weight they had gained, they then developed muscle stiffness,  cogwheeling , tremors and night sweats. When benztropine was added they experienced blurry vision. After an additional five months, the patient was switched from ziprasidone to aripiprazole. Over the course of 8 months, patient A gradually experienced more weight gain and sedation, and developed difficulty with their gait, stiffness, cogwheeling and dyskinetic ocular movements. A pharmacogenomics test later proved the patient had a CYP2D6 *1/*41, which has a predicted phenotype of IM and CYP2C19 *1/*2 with a predicted phenotype of IM as well.


Case B – Pain Management [ 46 ]


Patient B is a woman who gave birth by caesarian section. Her physician prescribed codeine for post-caesarian pain. She took the standard prescribed dose, but she experienced nausea and dizziness while she was taking codeine. She also noticed that her breastfed infant was lethargic and feeding poorly. When the patient mentioned these symptoms to her physician, they recommended that she discontinue codeine use. Within a few days, both the patient's and her infant's symptoms were no longer present. It is assumed that if the patient had undergone a pharmacogenomic test, it would have revealed she may have had a duplication of the gene CYP2D6, placing her in the Ultra-rapid metabolizer (UM) category, explaining her reactions to codeine use.


Case C – FDA Warning on Codeine Overdose for Infants [ 47 ]


On February 20, 2013, the  FDA  released a statement addressing a serious concern regarding the connection between children who are known as CYP2D6 UM, and fatal reactions to codeine following  tonsillectomy  and/or  adenoidectomy  (surgery to remove the tonsils and/or adenoids). They released their strongest Boxed Warning to elucidate the dangers of CYP2D6 UMs consuming codeine. Codeine is converted to morphine by CYP2D6, and those who have UM phenotypes are in danger of producing large amounts of morphine due to the increased function of the gene. The morphine can elevate to life-threatening or fatal amounts, as became evident with the death of three children in August 2012.


Although there appears to be a general acceptance of the basic tenet of pharmacogenomics amongst physicians and healthcare professionals, [ 49 ]  several challenges exist that slow the uptake, implementation, and standardization of pharmacogenomics. Some of the concerns raised by physicians include: [ 50 ] [ 49 ] [ 51 ]


Issues surrounding the availability of the test include: [ 48 ]


Although other factors contribute to the slow progression of pharmacogenomics (such as developing guidelines for clinical use), the above factors appear to be the most prevalent. Increasingly substantial evidence and industry body guidelines for clinical use of pharmacogenetics have made it a population wide approach to precision medicine. Cost, reimbursement, education, and easy use at the point of care remain significant barriers to widescale adoption.


There has been call to move away from race and ethnicity in medicine and instead use genetic ancestry as a way to categorize patients. [ 52 ]  Some  alleles  that vary in frequency between specific populations have been shown to be associated with differential responses to specific  drugs . As a result, some disease-specific guidelines only recommend pharmacogenetic testing for populations where high-risk alleles are more common [ 53 ]  and, similarly, certain insurance companies will only pay for pharmacogenetic testing for beneficiaries of high-risk populations. [ 54 ]


In the early 2000s, handling genetic information as exceptional, including legal or regulatory protections, garnered strong support. It was argued that genomic information may need special policy and practice protections within the context of electronic health records (EHRs). [ 55 ]  In 2008, the  Genetic Information Nondiscrimination Act (GINA)  was enacted to protect patients from health insurance companies discriminating against an individual based on genetic information. [ 56 ] [ 57 ]