By the end of June 2020, the trial had published findings regarding  hydroxychloroquine  and  dexamethasone . [ 44 ] [ 219 ]  It had also announced results for  lopinavir/ritonavir  which were published in October 2020. The lopinavir-ritonavir and hydroxychloroquine arms were closed to new entrants after being shown to be ineffective. [ 44 ] [ 220 ] [ 221 ]  Dexamethasone was closed to new adult entries after positive results and by November 2020, was open to child entries.


Launched in December 2021, the  PANORAMIC  trial will test the effectiveness of  molnupiravir  and  nirmatrelvir/ritonavir  in preventing hospitalisation and helping faster recovery for people aged over 50 and those at higher risk due to underlying health conditions. [ 222 ] [ 223 ]  PANORAMIC is sponsored by the  University of Oxford  and funded by the  National Institute for Health Research  (NIHR). [ 222 ]  As of March 2022 has over 16,000 people enrolled as participants making it the largest study into COVID-19 antivirals. [ 224 ]


Drug cultures  are examples of  countercultures  that are primarily defined by  spiritual ,  medical , and  recreational drug use . They may be focused on a single drug, or endorse  polydrug  use. They sometimes eagerly or reluctantly initiate newcomers, but their main functions are to share drug experiences, to  reduce harm  by providing knowledge of how to use drugs as safely as possible, and to exchange information on suppliers and avoidance of  law enforcement .


Drug subcultures are groups of people united by a common understanding of the meaning, value, and risks of the incorporation into one's life of the drug(s) in question. Such unity can take many forms, from friends who take the drug together, possibly obeying certain rules of  etiquette , groups banding together to help each other obtain drugs and avoid arrest, [ 1 ]  to full-scale  political movements  for the reform of  drug laws . [ 2 ]  The sum of these parts can be considered an individual drug's "culture".


Many artists, writers, and musicians have used various drugs to facilitate or enhance their  creativity . Writers have explored their influence on human life in general and particularly on the creative process. There are many writings that portray drug culture.  Hunter S. Thompson 's 1971 novel  Fear and Loathing in Las Vegas  employs multiple drug use as a major theme and provides an example of the  drug culture of the 1960s .


After various drug cultures came to prominence during the 1960s, 1980s and early 2000s, the  internet  provided a new location and medium where drug cultures could be born and propagate. Technologies like  Tor  were able to offer anonymous  website hosting  and  browsing , which were used for the creation of the  darknet market   SilkRoad , the first of many to be used in the sale of psychoactive substances and other  illegal goods . There are  YouTube  channels devoted to recreational drug use and harm reduction, with the most popular being PsychedSubstance. Except for forums (like  Blue Light ) where individuals can post and discuss the properties and experiences of  psychoactive substances , there are websites and organizations specifically created to serve as  encyclopedias  of psychoactive drugs and drug culture, such as  Erowid  and PsychonautWiki.


Cannabis  has been used in the ancient past in places such as  ancient India , Romania, Egypt, and Mesopotamia. [ 3 ]  It was often used as medicine or for hemp. Its main route of consumption was smoking. Over time the culture became more international and a general "cannabis culture" formed.  Cannabis  culture has been responsible for the genre of films known as  stoner films  which has come to be accepted as a mainstream cinema movement. [ 4 ] [ 5 ]  In the  United States  the culture has also spawned its own celebrities (such as  Tommy Chong  and  Terence McKenna ), magazines ( Cannabis Culture  and  High Times ), and, in North America, its own distinct holiday:  April 20  (420), which is marked as a day for calling for the  legalization of cannabis  and celebration of cannabis. [ 6 ] [ 7 ]  The consumption of cannabis influenced many artistic movements such as  jazz ,  electronic music  and  hip hop . [ citation needed ]


Alcohol  (also known as ethanol) is a  psychoactive drug [ 8 ] [ 9 ]  found in  alcoholic beverages . Alcohol is one of the most commonly abused drugs in the world [ 10 ]  and is often used for  self-medication , [ 11 ]  and recreational use. [ 12 ] "


The  hip hop ,  hardcore rap , and  trap  scenes, alongside their  derivative subgenres  and  subcultures , are most notorious for having continuously celebrated and promoted  drug trafficking ,  gangster lifestyle , and the consumption of alcohol and other drugs since their inception in the United States during the late 1980s–early 1990s. [ 13 ] [ 14 ] [ 15 ] [ 16 ]


The drugs used in witchcraft are different depending on the culture. Most of the research done on drug use in witchcraft was done in the 60s during the hippie movement. Since then, the claim that ergot was taken in Salem has been disproven. However, because the research was done during the hippie and drug movement in the 70s, the theory is still a part of drug culture. [ 17 ]


Ancient Greek love magic used many rituals that show drug use in poisoning to deepen the emotion of love. Love magic would be used by ancient Greek women to gain or keep a man's love. Researchers of this period often look at the agency of the women. Greek love magic relates to drug culture as it deals with poisoning people. There can be similarities found in today's date rape drug. However, in ancient Greek time the women would slowly poison the men. Women would put the poisons on their robes to expose it to the men. [ 18 ]


Shamanism used hallucinogens to further their spirituality. These hallucinogens were used for different ceremonies of the Indians in the Northwest Amazon. These ceremonies include funerals and initiation of the young. Shamans had a wider range of use for these drugs. Shamans used these drugs to identify illnesses and find possible cures or to find an enemy. [ 19 ]


There is a theory, seemingly disproven due to timeline of events and number of those who experience the symptoms, that the Salem witch trials were caused by  ergot  poisoning. Ergot poisoning gives a similar effect to LSD, but like  ergine  the physical effects and dangers (including death due to higher toxicity of the  ergolines  in ergot) are much more substantial than the use of LSD for psychedelic research and ritual contexts. [ 20 ] [ 21 ]


A  cure  is a substance or procedure that ends a medical condition, such as a  medication , a  surgical operation , a change in lifestyle or even a philosophical mindset that helps end a person's sufferings; or the state of being healed, or cured. The medical condition could be a  disease ,  mental illness ,  genetic disorder , or simply a condition a person considers socially undesirable, such as  baldness  or lack of breast tissue.


An incurable disease may or may not be a  terminal illness ; conversely, a curable illness can still result in the patient's death.


The proportion of people with a disease that are cured by a given treatment, called the  cure fraction  or  cure rate , is determined by comparing  disease-free survival  of treated people against a matched control group that never had the disease. [ 1 ]


Another way of determining the cure fraction and/or "cure time" is by measuring when the hazard rate in a diseased group of individuals returns to the hazard rate measured in the general population. [ 2 ] [ 3 ]


Inherent in the idea of a cure is the permanent end to the specific instance of the disease. [ 4 ] [ 5 ]  When a person has the  common cold , and then recovers from it, the person is said to be  cured , even though the person might someday catch another cold. Conversely, a person that has successfully managed a disease, such as  diabetes mellitus , so that it produces no undesirable symptoms for the moment, but without actually permanently ending it, is not cured.


Related concepts, whose meaning can differ, include  response ,  remission  and  recovery .


In complex diseases, such as cancer, researchers rely on statistical comparisons of  disease-free survival  (DFS) of patients against matched, healthy control groups. This logically rigorous approach essentially equates  indefinite remission  with cure. [ 6 ]  The comparison is usually made through the  Kaplan-Meier estimator  approach. [ 7 ]


The simplest  cure rate model  was published by  Joseph Berkson  and  Robert P. Gage  in 1952. [ 7 ]  In this model, the survival at any given time is equal to those that are cured plus those that are not cured, but who have not yet died or, in the case of diseases that feature asymptomatic remissions, have not yet re-developed signs and symptoms of the disease. When all of the non-cured people have died or re-developed the disease, only the permanently cured members of the population will remain, and the DFS curve will be perfectly flat. The earliest point in time that the curve goes flat is the point at which all remaining disease-free survivors are declared to be permanently cured. If the curve never goes flat, then the disease is formally considered  incurable  (with the existing treatments).


The  Berkson and Gage equation  is

 S
 (
 t
 )
 =
 p
 +
 [
 (
 1
 −
 p
 )
 ×

 S

 ∗

 (
 t
 )
 ]

 {\displaystyle S(t)=p+[(1-p)\times S^{*}(t)]}


where

 S
 (
 t
 )

 {\displaystyle S(t)}

  is the proportion of people surviving at any given point in time,

 p

 {\displaystyle p}

  is the proportion that are permanently cured, and

 S

 ∗

 (
 t
 )

 {\displaystyle S^{*}(t)}

  is an exponential curve that represents the survival of the non-cured people.


Cure rate curves can be determined through an analysis of the data. [ 7 ]  The analysis allows the statistician to determine the proportion of people that are permanently cured by a given treatment, and also how long after treatment it is necessary to wait before declaring an asymptomatic individual to be cured. [ 3 ]


Several cure rate models exist, such as the  expectation-maximization algorithm  and  Markov chain Monte Carlo  model. [ 7 ]  It is possible to use cure rate models to compare the efficacy of different treatments. [ 7 ]  Generally, the  survival curves  are adjusted for the effects of normal aging on mortality, especially when diseases of older people are being studied. [ 8 ]


From the perspective of the patient, particularly one that has received a new treatment, the statistical model may be frustrating. [ 6 ]  It may take many years to accumulate sufficient information to determine the point at which the DFS curve flattens (and therefore no more relapses are expected). Some diseases may be discovered to be technically incurable, but also to require treatment so infrequently as to be not materially different from a cure. Other diseases may prove to have multiple plateaus, so that what was once hailed as a "cure" results unexpectedly in very late relapses. Consequently, patients, parents and psychologists developed the notion of  psychological cure , or the moment at which the patient decides that the treatment was sufficiently likely to be a cure as to be called a cure. [ 6 ]  For example, a patient may declare himself to be "cured", and to determine to live his life as if the cure were definitely confirmed, immediately after treatment.


Cures can take the form of natural  antibiotics  (for  bacterial infections ),  synthetic   antibiotics  such as the  sulphonamides , or  fluoroquinolones ,  antivirals  (for a very few  viral infections ),  antifungals ,  antitoxins ,  vitamins ,  gene therapy , surgery, chemotherapy, radiotherapy, and so on. Despite a number of cures being developed, the list of incurable diseases remains long.


Scurvy  became curable (as well as preventable) with doses of vitamin C (for example, in limes) when  James Lind  published  A Treatise on the Scurvy  (1753). [ 10 ]


Antitoxins to  diphtheria  and  tetanus toxins  were produced by  Emil Adolf von Behring  and his colleagues from 1890 onwards. The use of  diphtheria antitoxin  for the treatment of diphtheria was regarded by  The Lancet  as the "most important advance of the [19th] Century in the medical treatment of acute infectious disease". [ 11 ] [ 12 ]


Sulphonamides  become the first widely available cure for bacterial infections. [ citation needed ]


Antimalarials  were first synthesized, [ 13 ] [ 14 ] [ 15 ]  making  malaria  curable. [ 16 ]


Bacterial infections became curable with the development of antibiotics. [ 17 ]


Hepatitis C , a viral infection, became curable through treatment with antiviral medications. [ 18 ] [ 19 ]


Signs and symptoms Syndrome Disease


Medical diagnosis Differential diagnosis Prognosis


Acute Chronic Cure


Eponymous disease Acronym or abbreviation Remission


Deprescribing  is a process of tapering or stopping  medications  to achieve improved health outcomes by reducing exposure to  medications  that are potentially either harmful or no longer required. [ 1 ]  Deprescribing is important to consider with changing health and care goals over time, as well as  polypharmacy  and  adverse effects . [ 2 ]  Deprescribing can improve adherence, cost, and health outcomes but may have adverse drug withdrawal effects. More specifically, deprescribing is the planned and supervised process of intentionally stopping a  medication  or reducing its dose to improve the person's health or reduce the risk of adverse  side effects .  Deprescribing is usually done because the drug may be causing harm, may no longer be helping the patient, or may be inappropriate for the individual patient's current situation. [ 3 ] [ 4 ]  Deprescribing can help correct  polypharmacy  and  prescription cascade .


Deprescribing is often done with people who have  multiple long-term conditions  (multimorbidity), older people, and people who have a limited life expectancy. [ 5 ]  In all of these situations, certain medications may contribute to an increased risk of adverse events, and people may benefit from a reduction in the amount of  medication  taken.  Deprescribing aims to reduce medication burden and harm while maintaining or improving quality of life.  "Simply because a patient has tolerated a therapy for a long duration does not mean that it remains an appropriate treatment. Thoughtful review of a patient's medication regimen in the context of any changes in medical status and potential future benefits should occur regularly, and those agents that may no longer be necessary should be considered for a trial of medication discontinuation." [ 6 ]


The process of deprescribing is usually planned and supervised by healthcare professionals. [ 7 ]  To some, the definition of deprescribing includes only completely stopping a  medication , while to others, deprescribing also includes dose reduction, which can improve quality of life (minimize side effects) while maintaining benefits. [ 8 ]


The world’s first published use of the term “deprescribing” was described in 2003 by Michael Woodward in his article titled ‘Deprescribing: Achieving Better Health Outcomes for Older People through Reducing Medications.' It was published in the Society of Hospital Pharmacists of Australia's flagship  Journal of Pharmacy Practice and Research  (JPPR).’ [ 9 ] [ additional citation(s) needed ]


Older people are the heaviest users of medications and frequently take five or more medications (polypharmacy).   Polypharmacy  is associated with increased risks of adverse events, drug interactions,  falls , hospitalization, cognitive deficits, [ better source needed ]  and mortality. [ 10 ]  These effects are particularly seen in high-risk prescribing. [ 11 ]  Thus, optimizing medication through targeted deprescribing is a vital part of managing chronic conditions, avoiding adverse effects and improving outcomes.


Deprescribing is considered a potential intervention with reported safety and feasibility. [ 12 ] [ 13 ]  For a wide range of medications, including diuretics, blood pressure medication, sedatives, antidepressants, benzodiazepines and nitrates, adverse effects of deprescribing are rare. [ 14 ] [ 15 ]  While deprescribing has been shown to result in fewer medications, it is less certain if deprescribing is associated with significant changes in health outcomes. [ 12 ] [ 16 ]  Although it might be possible and safe to reduce the number of medicines that people use, reversing the potential harms associated with polypharmacy may not always be achievable. [ 17 ]  Early evidence suggested that deprescribing may reduce premature death, leading to calls to undertake a double-blind study.  A placebo-controlled, double-blind, randomized controlled trial was published in 2023.  This study undertook deprescribing in people over 65 years living in residential aged care. [ 18 ]   It found no change in mortality [ 19 ]  and that, if implemented in all residential aged care facilities across Australia, it could save up to $16 million annually. [ 20 ]


Deprescribing medications may improve patient function, generate a higher quality of life, and reduce bothersome signs and symptoms. Deprescribing has been shown to reduce the number of falls people experience but not to change the risk of having the first fall. [ 12 ]  Most health outcomes remain unchanged as an effect of deprescribing. The absence of a change has been viewed as a positive outcome, as the medications can often be safely withdrawn without altering health outcomes. This absence of an effect means that older people may not miss out on potentially beneficial effects of using medications due to deprescribing. [ 12 ]


Targeted deprescribing can improve adherence to other drugs. [ 5 ]  Deprescribing can reduce the complexity of medication schedules.  Complicated schedules are difficult for people to follow correctly.


The product information provided by drug companies provides much information on how to start medications and what to expect when using them. However, it provides little information on when and how to stop medications. [ 21 ]  Research into deprescribing is accumulating, with two papers showing a rapid acceleration in using the word since 2015. [ 8 ] [ 3 ]


In people with multiple long-term conditions and polypharmacy, deprescribing represents a complex challenge as clinical guidelines are usually developed for single conditions. In these cases, tools and guidelines like the  Beers Criteria  and STOPP/START could be used safely by clinicians, but not all patients might benefit from stopping their medication. There is a need for clarity about how much clinicians can do beyond the guidelines and the responsibility they need to take could help them prescribing and deprescribing for complex cases. Further factors that can help clinicians tailor their decisions to the individual are: access to detailed data on the people in their care (including their backgrounds and personal medical goals), discussing plans to stop a medicine already when it is first prescribed, and a good relationship that involves mutual trust and regular discussions on progress. Furthermore, longer appointments for prescribing and deprescribing would allow time to explain the process, explore related concerns, and support making the right decisions. [ 22 ] [ 23 ]


A review analysed way to improve deprescribing in  primary care . It concluded that clearly defined roles and responsibilities, with good communication between multidisciplinary team members, and pharmacists integrated within teams could aid deprescribing. Routine discussions about deprescribing when prescribing, with medication reviews tailored to patients’ needs and preferences could also help. Patients and informal carers should be involved in decisions, and trusted relationships should be built up with professionals allowing continuity of care. Clinicians would also benefit from training and education on deprescribing. [ 24 ] [ 25 ]


It is possible for the patient to develop adverse  drug withdrawal  events (ADWE). [ 26 ]  These symptoms may be related to the original reason why the medication was prescribed, to withdrawal symptoms or to underlying diseases that medications have masked. [ 27 ]   For some medications, ADWEs can generally be minimized or avoided by tapering the dose slowly and carefully monitoring for symptoms. Prescribers should be aware of which medications usually require tapering (such as  corticosteroids  and  benzodiazepines ) and which can be safely stopped suddenly (such as  antibiotics  and  nonsteroidal anti-inflammatory drugs ).


Deprescribing requires detailed follow-up and monitoring, not unlike the attention required when starting a new medication. It is recommended that prescribers frequently monitor "relevant signs, symptom, laboratory or diagnostic tests that were the original indications for starting the medication," as well as for potential withdrawal effects. [ 15 ]  The recommended schedule for monitoring during deprescribing is at two-week intervals. [ 28 ]


Several tools have been published to inform prescribers of inappropriate medications for various patient groups. The most common deprescribing algorithm is validated [ 29 ]  and has been tested in two RCTs. [ 16 ]   It is available for clinicians to identify medications that can be deprescribed. [ 29 ]  It prompts clinicians to consider if it is (1) an inappropriate prescription, (2) adverse effects or interactions that outweigh symptomatic effects or potential future benefits, (3) drugs taken for symptom relief but the symptoms are stable, and (4) drug intended to prevent future severe events but the potential benefit is unlikely to be realized due to limited life expectancy.  If the answer to any of the four prompts is yes, then the medication should be considered for deprescribing.


The CEASE algorithm prompts clinicians to consider if the treated condition remains a current concern for their patient.


The ERASE algorithm prompts clinicians to consider whether the treated condition still requires treatment. [ 30 ]  The ERASE mnemonic stands for " e valuate diagnostic parameters,"  " r esolved conditions," " a geing normally," " s elect targets," and " e liminate."


The  Beers Criteria  and the STOPP/START criteria present medications that may be inappropriate for use in older adults, [ 31 ]  including drugs associated with high risk of adverse reactions for this population or lacking evidence for their benefits when safer and more effective alternatives exist. [ 32 ]  Some countries, such as, Australia have their lists of Potentially Inappropriate Medicines. [ 33 ]  For people with dementia, the  Medication Appropriateness Tool for Comorbid Health Conditions in Dementia  (MATCH-D) [ 34 ]  can help clinicians identify when and what to consider deprescribing. [ 35 ]


RxFiles, an academic detailing group based in Saskatchewan, Canada, has developed a tool to help  long-term care  providers identify potentially inappropriate medications in their residents. [ 36 ]  Tasmanian Medicare Local has created resources to help clinicians deprescribe. [ 37 ]  Theoretical Underpinnings of a Model to Reduce Polypharmacy and Its Negative Health Effects: Introducing the Team Approach to Polypharmacy Evaluation and Reduction (TAPER) is a framework to support practitioners in deprescribing. [ 38 ]


An expert working group concluded that integrated healthcare provided by multidisciplinary patient-centred teams was the most appropriate approach to promote deprescribing and improve appropriate medication use. [ 39 ]  Deprescribing rounds in tertiary care hospitals have also been evaluated and shown to improve health-related outcomes. [ 40 ]


Although many trials have successfully resulted in a reduction in medication use, there are some barriers to deprescribing:


The prescriber and patients were shown to have the most significant influence on each other rather than external influences.  9 out of 10 older people said they would be willing to stop one or more medications if their doctor said it was okay.


Drug antagonism  refers to a medicine stopping the action or effect of another substance, preventing a biological response. [ 1 ] [ 2 ]  The stopping actions are carried out by four major mechanisms, namely chemical,  pharmacokinetic ,  receptor  and physiological  antagonism . [ 2 ]  The four mechanisms are widely used in reducing overstimulated physiological actions. Drug antagonists can be used in a variety of medications, including  anticholinergics ,  antihistamines , etc. The antagonistic effect can be quantified by  pharmacodynamics . Some can even serve as antidotes for toxicities and overdose.


Receptors  bind with endogenous  ligands  to produce a physiological effect and regulate the body and cellular homeostasis. In a ligand-receptor interaction, the ligand binds with the receptors to form a drug-receptor complex, producing a biological response. [ 3 ] [ 4 ]  The biological nature of receptors can be  enzymes ,  nucleic acids  or cellular proteins. Common types of receptors include  G-protein coupled receptors ,  nuclear receptors  and  ion channels . [ 4 ]


Functional antagonists would not produce a biological response after binding with a receptor. It blocks the binding of endogenous ligands to the receptors and thus inhibits the subsequent physiological effect. [ 3 ]


Both agonist and antagonist bond the same active site. Adding agonist dose can reverse the effect of reversible competitive antagonism. Irreversible competitive antagonism occurs when the antagonist binds to the same spot on the receptor as the agonist but dissociates from the receptors very slowly or not. As a result, when the agonist is delivered, there is no change in the antagonist occupancy. Since a receptor can only hold one molecule at a time, competitive antagonists can reduce the agonist occupancy (percentage of receptors to which the agonist is bound). Raising the agonist concentration can bring back the agonist occupancy and the subsequent tissue response due to their competition. Thus, the opposition is surmountable. The amount to which the competitive antagonist causes the agonist log concentration–effect curve to shift to the right while maintaining its maximum slope is a measure of the dosage ratio. The antagonist concentration causes the dosage ratio to rise linearly. [ 5 ] [ 6 ]


Different active sites are bonded by agonist and antagonist, which means in which the antagonist obstructs the chain of events that triggers the agonist to produce a response at a point downstream from the agonist binding site on the receptor. It irreversibly binds to the active site. [ 7 ]


One examples is when Ketamine enters the NMDA receptor's ion channel pore and blocks it, stopping ions from passing through the channels. Also, medication like nifedipine and verapamil stops Ca2+ from entering the cell membrane and so non-selectively prevent medications that act at any receptor that binds to these calcium channels from causing smooth muscle contraction. [ 8 ]


In the presence of a full agonist exerting its maximal effect,  a partial agonist  can behave like a competitive antagonist to lower the effect of receptor binding, generating merely a submaximal reaction. These variations can be evaluated regarding effectiveness, indicating the agonist-receptor complex's "strength" in causing a tissue response. It relies on  receptor occupancy  and  response . A particular medication of intermediate efficacy may appear as a partial agonist in one tissue (lower level of receptor expression) and a full agonist in another (high level of receptor expression) across distinct cell types expressing the same receptor but at varying densities. [ 5 ] [ 9 ]


Competitive antagonists are usually structurally similar to the active compound since they are structural analogues that have to bind to the same pocket. [ 10 ]  Examples of reversible competitive antagonists like  antihistamines  (Figure 1) compete with histamine (Figure 2) to bind to  histamine  receptors, blocking the allergic response by histamine. They are used in treating histamine-mediated allergies and  allergic rhinitis . [ 11 ]


Irreversible competitive antagonists like  phenoxybenzamine  do not dissociate from alpha-adrenergic receptors. It is used to block the activity of alpha receptors in sympathetic pathway and is used in the treatment of  paroxysmal hypertension  and sweating resulting from pheochromocytoma and  benign prostate hyperplasia . [ 12 ]


Chemical antagonism occurs when a chemical antagonist combines with a ligand to form an inactive product compound,  inhibiting the response. [ 8 ]  In chemical antagonism, the receptors are not involved in the process, and the antagonist directly binds with or removes the ligand. It prevents the ligand from binding to the receptor. As the ligand cannot stimulate the receptor, no physiological effect is generated by the receptors and thus provides an inhibitory effect. [ 13 ]  The common types of chemical antagonism include chelating agents, neutralising antibodies and salt aggregation.


Chelating agents  are organic compounds which are capable of linking to metal ions. [ 14 ]  They are usually useful for removing toxic heavy metal ions from body.  Dimercaprol  is a common chelating agent to treat toxic exposure to arsenic, mercury, gold, and lead. It is in the chelating class of drugs. [ 15 ]  From Figure 3, the SH-ligands of dimercaprol can compete with -SH groups in natural enzymes for heavy metal, forming a stable metal complex to be excreted through urine. [ 15 ]  The action antagonises the toxic metal ions and helps remove them from body circulation. However, dimercaprol has a narrow TI and is later replaced by its derivative, 2,3-dimercaptosuccinic acid ( DMSA ). [ 16 ]


Neutralising antibodies  block pathogen entry into cells to prevent further infection and replication. [ 17 ]   Infliximab  is a monoclonal antibody binding with tumour necrosis factor-alpha (TNF-alpha), inhibiting its pro-inflammatory action. [ 18 ]  Its efficacious anti-inflammatory action is clinically used in  Crohn's Disease , active rheumatoid arthritis,  psoriatic arthritis , and active ankylosing spondylitis.


Salt aggregation refers to reactions between a drug and an active compound forming a salt. Strongly anionic  unfractionated heparin  reacts with the positive cationic protamine arginine peptide to generate a salt aggregation. [ 19 ]  The resulting salt aggregate is not anticoagulant and is inactive.  Protamine  acts quickly, taking only five minutes to neutralize unfractionated heparin, and its half-life is only ten minutes. [ 8 ]


A drug which can affect the  pharmacokinetics  ( absorption, digestion, metabolism, excretion)  profile of another chemical (or drugs), thereby reducing the action of the target chemical. There could be a rise in the active drug's rate of metabolic breakdown. As an alternative, there may be a decrease in the rate at which the active medication is absorbed from the digestive system or a rise in the rate at which the drug is excreted by the kidneys. [ 8 ]


Most drugs are taken orally and are absorbed through the  gastrointestinal tract . [ 20 ]   Antacids  would increase the pH environment in the stomach and cause premature release of  enteric coated drugs , which are designed to be protected from an acidic environment in stomach. [ 21 ]  For example,  proton-pump inhibitors (PPIs)  are enteric coated to protect them from decomposition under an acidic environment. [ 22 ]  Co-administration of antacids with PPIs would lead to premature release into acidic gastric environments and inactivate PPIs before absorption. These types of pharmacokinetics antagonism should be carefully avoided to prevent loss of drug efficacy.


Since most drugs are either weakly acidic or weakly basic, modified pH would also affect the location at which the drug is deionised, thus affecting the required time for absorption and onset. [ 23 ]


Many drugs are metabolised by a set of liver enzymes called  CYP450s . [ 24 ]  The activity of these enzymes would determine the rate of pro-drug activation and the rate of inactivation of active drugs. For example,  warfarin , a commonly-used anticoagulant drug in atrial fibrillation, is metabolised by an enzyme called CYP2C9. Phenytoin, a CYP2C9 inducer, would increase its activity and the rate of warfarin breakdown, thereby reducing its efficacy. [ 25 ]  Patients should avoid the co-administration of warfarin and phenytoin. In cases where both drugs must be used together, warfarin dosing may be titrated up to cope with the reduced efficacy. [ 26 ]


The kidney excretes most drugs through urine. Since urine is weakly alkaline in nature, weakly acid drugs would ionise in urine, making it difficult for them to be reabsorbed. Therefore, in cases of aspirin (weak acid) toxicity, injecting intravenous sodium bicarbonate could increase urine pH, thereby increasing the excretion of aspirin through urine. [ 27 ]  A similar approach can be used in other weakly acidic drug toxicity.


Physiologic antagonism refers to the behaviour in which an antagonist behaves the opposite of the agonist but does not bind to the same active site as the agonist does. [ 8 ]  A physiologic antagonist binds to a different receptor but not the original agonist receptor.


Both  insulin  and  glucagon  are synthesised naturally in the human body to regulate blood glucose levels at homeostasis. [ 28 ]  Insulin binds to insulin receptors to decrease blood glucose levels, whilst glucagon binds to glucagon receptors to increase blood glucose levels. In cases of insulin-induced  hypoglycaemia , glucagon injection could help increase blood glucose levels. [ 8 ]


Another example is epinephrine (a bronchodilator) and histamine (a bronchoconstrictor). Epinephrine binds to adrenergic receptors to promote bronchodilation whilst histamine binds to histamine receptors which leads to bronchoconstriction. [ 29 ] [ 30 ]  Since they have opposite effects in different pathways, they are considered physiological antagonists, and they are not advised to be taken together.


Pharmacodynamics  (PD) is the core principle of quantifying the effects of antagonists by measuring the drug’s efficacy and safety. PD emphasises the relationship between the dose and response of a certain drug, which can be illustrated using a  dose-response curve . [ 31 ]


Efficacy is the maximal effect (Emax) that an agonist can produce. As a receptor antagonist does not affect receptors after binding, it is said to have zero efficacy.


A competitive antagonist does not affect the Emax of the agonist. This is because the effect of an agonist can be maximized by adding the dose of the agonist as the action of the antagonist is reversible. The maximum effect of the agonist can be achieved by adding the concentration of the agonist. [ 6 ] [ 31 ]


A non-competitive antagonist(or Allosteric antagonist) lowers the Emax of an agonist. The Emax of an agonist is inversely proportional to the concentration of the antagonist, which means a higher concentration of antagonist results in a lower Emax. The maximal efficacy of agonists is reduced as the inhibition cannot be reversed by adding the agonist concentration. [ 6 ] [ 31 ]


Potency is the amount of drug needed to give a certain therapeutic effect. It is affected by the drug’s affinity to the receptors and the number of receptors available. [ 32 ]  For antagonists,  half maximal inhibitory concentration (IC50)  is used to measure the potency of antagonists. IC50 means the concentration of antagonist needed to give a 50% inhibition. [ 33 ]  It can be directly compared with EC50, which is commonly used to measure the potency of an agonist.  EC50  means the concentration of agonist needed to give a 50% response.


IC50 is significant in determining the optimal dose of antagonist. A high concentration of an antagonist in the body may result in toxicity in the cell and damage the cell membrane. A lower IC50 means the inhibitory effect can be met with a lower concentration of antagonist and, therefore a lower risk of toxicity. For example, the IC50 of antagonists on cancer cell growth is essential for determining the optimal dose which inhibits cancer cells while inducing less harmful systemic effects in the body. [ 34 ]


The  therapeutic index  (TI) is used to quantify the risks and benefits of a certain drug. It describes the relationship between toxic dose and minimum effective dose, thus providing an important insight into the safety of a drug. [ 35 ]  The Therapeutic Index is calculated using the following equation:


TI = TD50 / ED50, where  TD50  is the dose at which toxicity presents in 50% of the population, and  ED50  is the dose needed to produce 50% of maximal response. [ 35 ]  From the equation, a high TI indicates that the drug needs a high dose to induce toxicity in 50% of the population or a low dose to achieve the minimum effective dose, and vice versa.


In the case of physiological antagonists, for example, insulin has a narrow TI. A narrow TI indicates that either excess or lack of insulin can cause significant risks. [ 31 ]  On one hand, lack of insulin may result in high blood glucose levels and kidney or cardiovascular damage. On the other hand, excess insulin may result in insulin-induced  hypoglycemia  as aforementioned. Another example is dimercaprol, a chemical antagonist in treating metal toxicity. Dimercaprol has a narrow TI so it is replaced by its derivative, 2,3-dimercaptosuccinic acid ( DMSA ). [ 16 ]


Upregulation of receptors  is the increase in receptor number or sensitivity of receptors. The receptors involved in functional antagonism are regulated in sensitivity, number and location. [ 36 ]  Therefore, changes in receptors are common. Using a long-term antagonist drug or continuous exposure to an antagonist may cause the upregulation and hypersensitivity of receptors, which means an increase in the number and sensitivity of receptors. [ 35 ]  The increase in the number of receptors is due to the increased expression of receptors after prolonged inhibition. The upregulation of receptors is important in the clinical aspect.


One example of upregulation of receptors is the upregulation of β-receptors caused by  β receptor antagonists  (also called β-blocker). The prolonged use of β-blockers results in the blockade of β-receptors, causing cells (mainly myocardial cells) to increase their expression of β-receptor. After removing the blockage, more receptors available for stimulation, resulting in higher sensitivity of β-receptors called the hypersensitivity of β-receptors. [ 37 ]  Abrupt discontinuation of β-blocker may potentially aggravate coronary artery disease, tachycardia, or even sudden cardiac death. [ 38 ]  Therefore, to prevent the adverse effects, doses of β-blocker must be reduced gradually over 10–14 days. [ 37 ]


Antidotes  are agents that can neutralise the effects of a poison or toxin. Antidotes counteract the effects of toxins in many ways, such as by blocking the absorption of the toxin, binding and neutralising the poison, opposing the toxin's end-organ function, or blocking the toxin's conversion to more hazardous metabolites. In addition to lowering the amount of free or active poison present, antidote delivery may also lessen the toxin's effects on organs through competitive inhibition, receptor blockage, or direct antagonistic interaction. [ 39 ] [ 40 ]


The therapeutic index or ratio (TD50/ED50), which is the ratio of the toxic dosage (TD) or fatal dose (LD) to the effective dose (ED), determines the level of safety associated with a substance. [ 31 ]


Agents that "bind" to the toxin can reduce free or active toxin present. It is possible for this binding to be nonspecific or specific.


Activated charcoal is the non-specific binding agent most frequently utilised as it has strong adsorption capacity and could prevent the toxin's enterohepatic recirculation. Chelation agents, immunotherapy, and bioscavenger therapy are examples of specific binders. Urinary alkalization or hemadsorption may improve elimination in some circumstances. [ 39 ]


It might occur either at the enzyme or receptor level. There are two possible outcomes at the enzyme level: competitive inhibition or enzyme activity reactivation.  Ethyl alcohol  or  fomepizole  used in methyl alcohol or ethylene glycol poisoning is a typical example of competitive enzyme inhibition. By posing competition for  alcohol dehydrogenase (ADH)  with methyl alcohol and ethylene glycol, these drugs reduce the production of harmful metabolites. [ 41 ]  For receptor level, the traditional antidotes include naloxone and flumazenil.  Flumazenil  functions as a competitive antagonist at the GABA-A receptor complex's benzodiazepine site. By doing this, the CNS and respiratory depression would reverse and the inward chloride current would reduce. Flumazenil is useful in treating and preventing benzodiazepine-induced coma from recurring. [ 42 ]


Antidotes can be employed to either mop up hazardous metabolites or change them into less toxic forms once they have developed. [ 39 ]   Hepatic glutathione  stores are replenished by N-acetyl cysteine, and this process is what leads to the conjugation of the poisonous metabolite  N-acetyl P-benzoquinone imine  (NAPQI). [ 43 ]


Drug detoxification  (informally,  detox )  is variously construed or interpreted as a type of "medical" intervention or technique in regards to a  physical dependence  mediated by a  drug ; as well as the process and experience of a  withdrawal syndrome  or any of the treatments for acute  drug overdose  (toxidrome). The first definition however, in relation to substance dependence and its treatment is arguably a  misnomer  and even directly contradictory since  withdrawal  is neither contingent upon nor alleviated through biological excretion or  clearance  of the drug. In fact, excretion of a given drug from the body is one of the very processes that leads to withdrawal since the syndrome arises largely due to the  cessation  itself and the drug being absent from the body; especially the  blood plasma , not from ‘leftover toxins’ or traces of the drug still being in the system.


Some  addiction medicine  practitioners use the term  withdrawal management  instead of  detoxification . [ 1 ] [ 2 ]


A detoxification program for physical dependence does not necessarily address the precedents of  addiction , social factors, psychological addiction, or the often-complex behavioral issues that intermingle with addiction. [ 3 ]


The  United States Department of Health and Human Services  acknowledges three steps in a drug detoxification process: [ 4 ]


Richard B. Resnick MD was the first scientist to investigate the idea of accelerated detox under anesthesia. In 1977, [ 6 ]  he published a paper detailing the first procedures using Naloxone and clonidine. Shortly afterward, physicians began discussing anesthesia to reduce pain during rapid detox. Norbert Loimer, MD, Ph.D. published a paper in the '80s outlining the success of opiate detoxification under general anesthesia. Resnick and Loimer's early research served as the foundation for all forms of detoxification under sedation procedures used today. While physicians' protocols significantly differ, they still adhere to the principles described in the early publications. [ 7 ]  The combined use of clonidine and naltrexone was found to be a rapid, safe, and effective treatment for abrupt withdrawal from methadone, as detailed in a paper published in The American Journal of Psychiatry in 1986. [ 8 ]


Since then, numerous clinics around the world have implemented detoxification under sedation procedures to assist patients in overcoming opioid use disorder. These procedures involve the administration of anesthesia and other medications to facilitate rapid detoxification of the body, effectively reducing the painful and uncomfortable symptoms of withdrawal. While the effectiveness of rapid detox has been a subject of debate, it remains a popular treatment option for certain individuals grappling with opioid addiction.


The concept of "detoxification" comes from the discredited autotoxin [ 9 ]  theory of  George E. Pettey  and others.   David F. Musto  says that "according to Pettey, opiates stimulated the production of toxins in the intestines, which had the physiological effect associated with withdrawal phenomena. [...] Therefore treatment would consist of purging the body of toxins and any lurking morphine that might remain to stimulate toxin production in the future." [ 10 ] [ 11 ]


Naltrexone therapy, which critics claim lacks long-term efficacy and can actually be detrimental to a patient's long-term recovery, has led to controversy. Additionally, there have been many questions raised about the ethics as well as safety of rapid detox following a number of deaths resulting from the procedure. [ 12 ] [ 13 ] [ 14 ]


Some researchers say that relapses to injection use of illicit opioids during or following repeated detoxification episodes carry the substantial potential for injury associated with uncontrolled drug use and include  drug overdose ,  infections , and death. [ 15 ]


A  drug reference standard  or  pharmaceutical reference standard  is a highly characterized material suitable to test the identity, strength, quality and purity of substances for pharmaceutical use and medicinal products. [ 1 ]


Pharmacopoeial reference standards are a subset of pharmaceutical reference standards. They are established for the intended use described in  pharmacopeial  texts (monographs and general chapters).  Pharmacopeial reference standards are available from various pharmacopoeias such as  United States Pharmacopeia  and the  European Pharmacopoeia .
Where pharmacopoeial tests or assays call for the use of a pharmacopoeial reference standard, only those results obtained using the specified pharmacopoeial reference standard are conclusive. [ citation needed ]


This  standards - or  measurement -related article is a  stub . You can help Wikipedia by  expanding it .


Drugs and sexual desire  is about sexual desire being manipulated through drugs from various approaches.  Sexual desire  is generated under the effects from  sex hormones  and microcircuits from brain regions. [ 1 ]   Neurotransmitters  play essential roles in stimulating and inhibiting the processes that lead to  libido  production in both men and women. For instance, a positive stimulation is modulated by  dopamine  from the medial  preoptic area  in the  hypothalamus [ 2 ]  and  norepinephrine . At the same time, inhibition occurs when  prolactin  and  serotonin  are released for action. [ 1 ]


Drugs acting on the above neurotransmitters can be used to upregulate or downregulate sexual desire due to diseased conditions. During  drug development  specialized for women, the Female Sexual Function Index-Desire Domain (FSFI-D) provides a reference measurement for researchers to evaluate recipients' responses and results. [ 3 ]  FSFI values allow researchers to monitor the change of sexual desire with a more solid definition, and at the same time, establish records for the  U.S. Food and Drug Administration (FDA)  to process applications for drug approval. Similarly, the Male Desire Scale (MDS) is used for men. [ 4 ]


After evaluating symptom severity using the scales, patients are then prescribed different types of drugs. Flibanserin [ 1 ]  and Bremelanotide [ 3 ]  were developed for raising sexual desire in women, whereas similar conditions in men are treated using medications for sexual dysfunction. [ 4 ]  On the other hand, down-regulation on libido comes in two approaches: a direct or an indirect mechanism. Multiple drugs from each category have been proven effective. [ 5 ]


Marketized drugs have encountered market demands, also boosted personalized medication developments aiming at a broader range of recipients. [ 6 ] [ 7 ] [ 8 ] [ 9 ]  Still, disease establishment dilemmas and FDA drug approvals give rise to ethical concerns, posing obstacles in the field's development. [ 10 ] [ 11 ]


These drugs are expected to restore a normal libido in patients. Targeting acquired and generalized  hypoactive sexual desire disorder (HSDD) , improvement in sexual desire, and alleviation of psychological stress are to relieve the correlated symptoms. [ 12 ]  However, the treatments cannot cope with medically or psychiatrically related conditions, nor the effects from other medications. [ 13 ]


Flibanserin  is the first pharmaceutical product from Sprout Pharmaceuticals [ 14 ]   for premenopausal women with HSDD. The drug was approved by the FDA in 2015. It compiles a  serotonin 1A receptor   agonist  and a  serotonin 2A receptor   antagonist . [ 15 ]  and is an  antidepressant [ 16 ]  that was originally developed for  depression . [ 12 ]  This weak partial agonist that acts on dopamine D4 receptors, [ 17 ]  is also postsynaptic and functions by modulating various neurotransmitters, including dopamine, norepinephrine, and serotonin.


Flibanserin contains centrally active  piperazine / benzimidazole -derived molecules, that aim to limit  forskolin -stimulated  cAMP  production. Thus, eliminating the  phosphatidyl-inositol  turnover, which  5-HT    stimulates typically in the brain cortex. [ 14 ]  However, the precise mechanism is oblique. It is estimated that the drug targets brain regions, especially in the medial  prefrontal cortex , hypothalamus,  limbic regions , and  brainstem . [ 14 ]


After its launch in 2015 and marketed as Addyi, the drug experienced controversies and rejection from being acknowledged after three reviews on the clinical trials. [ 10 ]  Regarding the eligible prescription criteria concluded from the trials, [ 18 ]  the patient should have a diagnosed psychological pathology, medical comorbidities, and the presence of personal relationship issues. [ 13 ]  Despite being the first drug, its efficacy was not significant for treatment less than at least four weeks. [ 19 ]  Treatment withdrawal is also practiced if recipients do not experience improvements in symptoms after eight weeks. [ 16 ]  Nevertheless, around 18% of the gain was observed after 24 weeks of treatment. [ 14 ]


Due to a wide range of observed side-effects, flibanserin's safety has been called into question. Clinical trials reported adverse reactions including  dizziness ,  nausea ,  fatigue , and  insomnia . [ 16 ]   Hypotension  and  central nervous system depression (somnolence)  leading to  sedation and sleepiness symptoms were also observed. [ 16 ]  In order to lower the chances of occurrence, the drug is usually prescribed to be taken only once per day before bed. [ 16 ]


On the other hand, the third stage of the trial suggests that risks are derived from any moderate or strong  cytochrome P-450 3A4 (CYP3A4)  inhibitors that are often present in  antihypertensive drugs ,  antiretroviral drugs ,  antibiotics , or  fluconazole . [ 18 ]  An alcohol-interaction study was also carried out. [ 20 ]  Instead of premenopausal women, the study was on male participants, with the conclusion that alcohol may pose a risk of  systolic  and  diastolic  blood pressure reduction to recipients. [ 20 ]


Flibanserin is delivered through oral administrations on a half-life of 11 hours. [ 21 ]  A steady state can be achieved after three days of treatment. [ 22 ]  The metabolites of the drug are predominantly eliminated through urination and defecation. [ 21 ]


Bremelanotide  was first developed by Palatin Technologies, then out-licensed to AMAG Pharmaceuticals Inc. after its approval by the FDA on 21 June 2019. [ 23 ]  Marked as VyleesiTM, it was primarily designed for both men and women in the form of an intranasal formulation, particularly for treating  male erectile dysfunction . [ 23 ]  However, the research was discontinued and focused on targeting female HSDD [ 23 ]  in a subcutaneous injection to increase  bioavailability . [ 3 ]  Bremelanotide is usually injected a minimum of 45 minutes before sexual activity. Despite having identical prescription criteria as that of flibanserin, bremelanotide is not recommended for pregnant patients. No trial was tested on pregnant patients. [ 24 ]  Therefore, patients at childbearing ages are recommended to use contraception continuously during treatment and should discontinue once they become pregnant. [ 24 ]


The  melanocortin receptor  agonist proposes to activate multiple receptor subtypes nonselectively, with the highest affinity with  MC1R , then  MC4R ,  MC3R ,  MC5R , and  MC2R  receptors. [ 23 ]  As MC4R receptors are present on neurons in the central nervous system, a function in modulating brain pathways is suggested, albeit a precise mechanism remains unknown. [ 23 ]


Sustained and significant improvement in FSFI scores throughout a 52-week extension was attained, indicating a high efficacy of the drug treating HSDD, most notably when anticipating the challenge in psychological distress. [ 25 ]


Mild or moderate adverse events are common, expressing symptoms like nausea, facial flushing, headache, and sunburn. [ 3 ] [ 23 ]  Unlike flibanserin, bremelanotide induces fewer side effects and is not affected nor develops severe complications with alcohol. [ 20 ]  However, the drug slows down gastric emptying, which can cause an impact on oral drug uptake and the subsequent drug effectiveness. [ 24 ]  As activation of MC1R gives rise to hyperpigmentation, [ 3 ]  treatment dosage is at a maximum of eight doses per month. [ 24 ]  Besides, to minimize the chances of cardiovascular complications, the prescribed daily dosage is at one dose. [ 24 ]


Bremelanotide is exposed through a single subcutaneous administration. [ 26 ]  With a half-life of an hour, the drug is excreted through urine and faeces. [ 27 ]


There are already 26 drugs available for men's  sexual dysfunction . [ 19 ]  Since HSDD in men is not acknowledged and was categorized to be a distinct sexual dysfunction, [ 4 ]  there are currently no drugs specialized for men in similar conditions as stated above.


Drugs down-regulating libido are generally either intended for libido suppression via direct down-regulating mechanisms or eliciting such side-effects by their unintended indirect mechanisms.


Two types of drugs are mainly prescribed to people suffering from overwhelming sexual desire:  gonadotropin-releasing hormone agonists (GnRH agonists)  and  steroidal anti-androgens .


GnRH  agonists are a group of drugs intended to activate  GnRH receptors  in the anterior pituitary gland. They are synthesized by replacing the sixth and tenth  amino acids  of the original gonadotropin-releasing  peptide  hormone. [ 28 ]  After the modification, they can bind to the GnRH receptors more strongly and are less degradable by enzymes when compared to the natural GnRH, making them more biologically active. [ 28 ] [ 29 ]  GnRH agonists commonly used are  leuprorelin ,  goserelin , and  triptorelin , which are marked as Lupron, Zoladex, and Decapetyl, respectively. [ 30 ]   Nafarelin , marked as Synarel, is also occasionally prescribed in the form of nasal spray. [ 31 ]  These drugs are all approved by the US FDA, and their working principles target both sexes equally.


This class of drugs initially stimulates the anterior pituitary gland to secrete more GnRH, leading to a temporary surge in GnRH level in the circulation. [ 32 ]  Yet, because of the  desensitization  effect on the receptors upon continuous stimulation, in the long term, its secretion will be inhibited if continual medication is prescribed. [ 28 ] [ 32 ] [ 33 ]  Particularly, GnRH is essential for the release of  gonadotropic hormones , such as LH and  follicle-stimulating hormone (FSH) , from the anterior pituitary-body. These hormones are responsible for the synthesis of steroid sex hormones (testosterone in men;  progesterone  and  estrogen  in women). Therefore, GnRH inhibition by these drugs, in turn, reduces the secretion of steroid sex hormones from the sex organs, eventually leading to libido suppression. [ 28 ]


Many studies have shown that leuprorelin, goserelin and triptorelin are effective in suppressing sexual desires and increasing control against sex. [ 5 ]  Patients who were prescribed with these drugs have sexual thoughts less frequently and strongly. [ 5 ]


Common adverse effects elicited by these drugs include hot flushes, bone loss, headache, unpredictable mood changes, depression, vaginal dryness, or even  atrophy  for females and penile atrophy for males. [ 34 ]  These adverse effects can be counteracted and treated by add-back therapy, also known as  hormone replacement therapy . People treated with GnRH agonists are suggested to undergo this therapy simultaneously by taking adequate  progestin ,  vitamin D , and calcium supplement pills daily. [ 34 ]


Gonadotropin-releasing hormone agonists are largely parenterally administered to the body, that is, via  subcutaneous  or  intramuscular injection . [ 30 ] [ 32 ] [ 35 ] [ 36 ] [ 37 ]  At the same time, nafarelin is an exception in which its prescription is a nasal spray, and some may be implanted into fats. [ 31 ]  In general, their half-lives are approximately two to four hours. [ 31 ] [ 35 ] [ 36 ] [ 37 ]  Some agonists are mainly excreted via urine while other agonists are mainly excreted via faeces. [ 31 ] [ 35 ] [ 36 ] [ 37 ]


Steroidal anti-androgens are a class of steroid drugs that inhibit the actions of  androgens .  Cyproterone acetate , a  17-hydroxyprogesterone acetate  derivative, is a very potent one and is widely used. [ 29 ]  Though it is not approved by the US FDA owing to its toxicity, it has been approved by Canada and a plethora of countries in Europe with the brand name Androcur in the market. [ 29 ] [ 38 ] [ 39 ]  This drug mainly targets men due to its mechanism of action.


Cyproterone acetate suppresses libido by directly reducing the level of active androgen,  testosterone , in males. The suppression of testosterone level results from its inhibition of the release of  luteinizing hormone (LH)  from the  anterior section of the pituitary gland , interfering with testosterone production from the testes as LH stimulates testosterone production. [ 32 ] [ 39 ] [ 40 ]  It also blocks the conversion of testosterone to  dihydrotestosterone  for action. [ 38 ] [ 41 ]  In addition to this mechanism, it also competes for the  androgen receptors  against testosterone and dihydrotestosterone, causing interference with the androgen-receptor interaction on the reproductive organ, thereby lowering sexual desire. [ 29 ] [ 38 ] [ 41 ]


Cyproterone acetate has been proven effective in restraining sexual drive and fantasies in patients with high libido. [ 5 ]  Its usage in treating hypersexuality has been advocated by the World Federation of Societies of Biological Psychiatry (WFSBP). [ 5 ]


Common adverse effects of cyproterone acetate include depression,  hepatotoxicity ,  dyspnea , change in body weight,  hot flushes , sweating, fatigue, and  gynaecomastia. [ 29 ] [ 39 ]


Cyproterone acetate is mainly orally administered to the body, and it has a  half-life  of 1.8 days. [ 29 ] [ 39 ] [ 42 ]  After  metabolism , its metabolites are predominantly excreted via faeces. [ 39 ]


There are many types of drugs that unintentionally lower sexual desire through indirect mechanisms. It is one of their side-effects as the outcome of libido suppression is not intended. However,  selective serotonin reuptake inhibitors (SSRIs) , being one of them, are indeed often prescribed to people who have immense sexual desire. SSRIs reduce the re-uptake of serotonin back to the neurons, leading to an increase in serotonin level in the body. Due to the fact that serotonin can interfere with other neurotransmitters and hormones, for instance, sex hormones, SSRIs can therefore lower sexual desire. [ 43 ]


Apart from SSRIs, other types of drugs that could lower sexual desire are not intended to suppress libido originally. Thus, sexually active people are suggested to avoid the usage of the following drugs: [ 44 ]


Postmenopausal women may also suffer from HSDD due to a decline in androgen production from menopause. [ 6 ]  A research proposed two combinations of drugs, each designed against the different causes of HSDD. One combination is to utilise  sublingual   testosterone  with a 5-HT1A receptor agonist to raise motivation for sex, by lifting the inhibition mechanisms in the brain's prefrontal regions. [ 6 ] [ 7 ] [ 8 ]  Testosterone is also proposed to be coupled with the PDE5 inhibitor, targeting an insensitive system for the production of sexual desire. [ 6 ] [ 7 ] [ 8 ]  As both clinical trials showed desirable results, this indicates the prosperity of further developing a single drug targeting HSDD for all women of different status, even though the FDA has not approved the two combinations. [ 9 ]


In fact, HSDD was defined shortly before the release of flibanserin to the market and its approval by the US FDA. This has brought up a controversy about whether it is appropriate and ethical to create a medical condition for the benefit of the sales of pharmaceutical products. [ 10 ]


Apart from this ethical issue, there is a dilemma of whether a medical doctor should prescribe drugs to sexual offenders whose libido is subpar. On the one hand, it is considered unethical for doctors not to treat them as they are expected to treat patients indiscriminately. On the other hand, treating sexual offenders may impose a risk to society. Physicians have been struggling with this dilemma, and it is still difficult for them to make a choice at this moment in time. [ 11 ]


Drugs.com  is an online pharmaceutical encyclopedia that provides drug information for consumers and healthcare professionals, primarily in the United States. It self-describes its information as "accurate and independent" yet limited to being "for educational purposes only and is not intended for medical advice, diagnosis or treatment." [ 1 ]


The Drugs.com website is owned and operated by the Drugsite Trust, a privately held Trust administered by two  New Zealand  pharmacists, Karen Ann and Phillip James Thornton. [ 2 ]  Operated on the  IBM Cloud , Drugs.com provides information on some 24,000 drugs, was visited by 50 million users per month in 2021, and has a  download  time of one second. [ 3 ]


The site contains a library of reference information which includes content from  Cerner Multum ,  Micromedex ,  Truven Health Analytics , U.S.  Food and Drug Administration  (FDA),  AHFS ,  Harvard Health Publications ,  Mayo Clinic , and Animalytics (a  veterinary  products database). [ 2 ] [ 4 ]


Drugs.com is certified by the  TRUSTe  online privacy certification program [ 5 ]  and the HONcode of  Health on the Net Foundation . [ 6 ]


The Drugs.com encyclopedia contains drug information for consumers, a portal for drugs based on diseases, a health professionals database of drug monographs, a  natural products  database, and a poison control center. [ 2 ]  Drugs.com is not affiliated with any  pharmaceutical companies . [ 2 ]


The domain Drugs.com was originally registered by Bonnie Neubeck in 1994. [ 7 ]  In 1999 at the height of the dotcom boom, Eric MacIver purchased an option to buy the domain from Neubeck. [ 8 ]  In August 1999, MacIver sold the domain at auction for US$823,666 to Venture Frogs, a startup incubator run by  Tony Hsieh  and  Alfred Lin , best known for their involvement in  LinkExchange  and later  Zappos.com . [ 9 ]  Venture Frogs sold the Drugs.com domain name to a private investor in June 2001, allowing Hsieh and Lin to focus on Zappos.com. [ 10 ]


The Drugs.com website was officially launched in September 2001. [ 3 ]  In March 2008, Drugs.com announced the release of Mednotes [ 11 ]  — an online personal medication record application which connected to  Google Health  (On June 24, 2011, Google announced it was retiring Google Health on January 1, 2012). [ 12 ]


In May 2010, U.S. FDA announced a collaboration with Drugs.com to distribute consumer health updates on the Drugs.com website and mobile platform. [ 13 ]


In February 2016,  comScore  stated that Drugs.com was the sixth most popular health network receiving approximately 23 million visitors for the month, while Searchmetrics listed Drugs.com in the top 100 US websites for search visibility. [ 14 ]


In April 2017,  The Harris Poll  listed Drugs.com as the Health Information Website Brand of the Year. [ 15 ]


Enisamium iodide  is a derivative of  isonicotinic acid . Based on its  systematic chemical name  of  N -benzyl-1-methylpyridin-1-ium-4-carboxamide iodide, the shortened name  carbabenzpiride  is sometimes used. Enisamium iodide is a registered antiviral drug sold in Ukraine,  Kazakhstan ,  Mongolia ,  Belarus , and other  Eastern European  countries under the trade names Amizon, Amizon Max, Amizonchik. [ 1 ]


In 2019, the  World Health Organization  assigned enisamium iodide  ATC code  – J05AX17 (Antivirals for systemic use of direct action) and included it in the ATC / DDD index. [ 2 ]


The compound enisamium iodide was first synthesized by scientists of the Institute of Pharmacology and Toxicology of the  National Academy of Medical Sciences of Ukraine . [ 3 ]  In 1997, enisamium iodide was registered as a non-narcotic analgesic and antipyretic. However, it is no longer used for these indications. Amizon is marketed as an antiviral drug for the treatment and prevention of influenza and SARS. [ 3 ] [ 4 ]


In 2005, Doctor of Medical Sciences, Professor, and a corresponding member of the  National Academy of Sciences  and the National Academy of Medical Sciences of Ukraine, Frolov was the first to demonstrate the antiviral activity of enisamium iodide in in vitro experiments. [ 2 ]


Recent studies have shown that the antiviral effect of enisamium is due to inhibition of viral  RNA  polymerase of influenza virus. [ 5 ] [ 6 ] [ 7 ]


Since 2008, the non-clinical program, which included a set of pharmacological, pharmacokinetic and toxicological studies, has been performed in several research institutes and laboratories in  Germany , the  United Kingdom , the  Czech Republic , the  Netherlands ,  Switzerland  and the  United States . [ 5 ]


The antiviral activity of enisamium iodide is associated with inhibition of influenza virus RNA polymerase. Enisamium iodide effectively inhibited SARS-CoV-2 virus replication in vitro in Caco-2 cells.


Enisamium has antiviral activity against various strains of influenza A (H1N1, H3N2, H5N1, H7N9), influenza B virus, respiratory syncytial virus, as well as strains of alpha-coronavirus NL-63 and beta-coronavirus SARS-CoV-2, etc. In vitro studies using influenza virus-infected normal human bronchial epithelial cells conducted at the Illinois Institute of Technology Research Institute (IITRI), Chicago, USA, showed a decrease in viral titers due to incubation with enisamium iodide (24 FAV00A). year on 3 log (1000 times). In addition, the polymerase chain reaction with reverse transcription revealed suppression of the expression of the M-gene of influenza virus by almost 2 orders of magnitude. [ 8 ] [ 9 ] [ 10 ]


Amizon tablets are indicated for the treatment and prevention of influenza and acute respiratory viral infections. Amizon Max and Amizonchik syrup according to the instructions for medicines are intended for the treatment of influenza and SARS. Amizon Max is also used to treat COVID-19 of moderate severity in combination with basic therapy.


In 2010, the third phase of clinical trials on the basis of FBDU "Research Institute of Influenza" of the Ministry of Health of the Russian Federation (St. Petersburg, Russia) was completed with 100 patients (60 patients with influenza and SARS received enisamium iodide, 40 – placebo). [ 7 ] [ 11 ]


In the enisamium iodide group, the mean duration of fever was shown to be 2.7 days, and in the placebo group, 3.8 days. Thus, as a result of taking enisamium iodide, the duration of fever was reduced by an average of 1.1 days. When assessing well-being, a significant improvement on the 3rd day of treatment was noted by 43.3% of patients in the main group and 15% in the control group (p <0.001). On day 7 of treatment, almost all patients (59 out of 60) who received enisamium iodide returned to their usual way of life, while 37.5% of those who took placebo continued to feel unwell and had not yet returned to normal. work and leisure.


Enisamium was more effective when treatment was started earlier. [ 7 ]


From May 2020 to March 2021, a batotocent clinical placebo-controlled, double-blind, randomized trial of enisamium iodide (Amizon Max) in patients with moderate to severe COVID-19 was conducted at 14 health care facilities in Ukraine. receiving inpatient treatment. [ 12 ] < [ 6 ]


The results of the clinical trial allowed to include in the instructions for medical use of the drug Amizon Max new indications for use, in particular - the treatment of COVID-19 moderate severity in combination with basic therapy. [ 13 ]


An  exercise mimetic  is a drug that mimics some of the biological effects of physical exercise. Exercise is known to have an effect in preventing, treating, or ameliorating the effects of a variety of serious illnesses, including  cancer ,  type 2 diabetes ,  cardiovascular disease , and psychiatric and neurological diseases such as  Alzheimer's disease . As of 2021, no drug is known to have the same benefits. [ 2 ] [ 3 ] [ 1 ]


Known biological targets affected by exercise have also been targets of  drug discovery , with limited results. These known targets include: [ 2 ]


The majority of the effect of exercise in reducing cardiovascular and all-cause mortality cannot be explained via improvements in quantifiable risk factors, such as blood cholesterol. This further increases the challenge of developing an effective exercise mimetic. [ 1 ]  Moreover, even if a broad spectrum exercise mimetic were invented, it is not necessarily the case that its public health effects would be superior to interventions to increase exercise in the population. [ 1 ]


Ketamine  has had a wide variety of medicinal and recreational uses since its discovery in 1962.


Ketamine  is the English  generic name  of the drug and its  INN Tooltip International Nonproprietary Name  and  BAN Tooltip British Approved Name , while  ketamine hydrochloride  is its  USAN Tooltip United States Adopted Name ,  USP Tooltip United States Pharmacopeia ,  BANM Tooltip British Approved Name , and  JAN Tooltip Japanese Accepted Name . [ 1 ] [ 2 ] [ 3 ]  Its generic name in Spanish and  Italian  and its  DCIT Tooltip Denominazione Comune Italiana  are  ketamina , in  French  and its  DCF Tooltip Dénomination Commune Française  are  kétamine , in  German  is  Ketamin , and in  Latin  is  ketaminum . [ 2 ]


The  S (+)  stereoisomer  of ketamine is known as  esketamine , and this is its  BAN Tooltip British Approved Name  while  esketamine hydrochloride  is its  BANM Tooltip British Approved Name . [ 4 ]


Ketamine is sold throughout the world primarily under the brand name Ketalar. [ 2 ] [ 3 ]  It is also marketed under a variety of other brand names, including Calypsol, Ketamin, Ketamina, Ketamine, Ketaminol, Ketanest, Ketaset, Tekam, and Vetalar among others. [ 2 ] [ 3 ]


Esketamine is sold mainly under the brand names Ketanest, Ketanest-S, and Spravato. [ 4 ]


After the publication of the  NIH -run antidepressant clinical trial, clinics began opening in which the intravenous ketamine is given for depression. [ 5 ] [ 6 ]  This practice is an  off label  use of IV ketamine in the United States, though the intranasal version of esketamine has been approved by the FDA for treatment of depression [ 5 ] [ 7 ]  In 2015 there were about 60 such clinics in the US; the procedure was not covered by insurance, and people paid between $400 and $1700  out of pocket  for a treatment. [ 8 ]  It was estimated in 2018 that there were approximately 300 of these clinics. [ 9 ]  The number of clinics has been increasing rapidly. [ 9 ]


A chain of such clinics in Australia, run by Aura Medical Corporation, was closed down by regulatory authorities in 2015. They found that the clinics' marketing was not supported by scientific research and the chain sent patients home with ketamine and needles to administer infusions to themselves. [ 10 ]


While ketamine is legally marketed in many countries worldwide, [ 2 ]  it is also a  controlled substance  in many countries. [ 11 ]


In Australia, ketamine is listed as a schedule 8-controlled drug under the  Poisons Standard  (October 2015). [ 12 ]  Schedule 8 drugs are outlined in the Poisons Act 1964 as "Substances which should be available for use but require restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence." [ 13 ]


In Canada, ketamine has been classified since 2005 as a Schedule I narcotic. [ 14 ]


In Hong Kong, since 2000, ketamine has been regulated under Schedule 1 of Hong Kong Chapter 134  Dangerous Drugs Ordinance . It can be used legally only by health professionals, for university research purposes, or with a physician's prescription. [ 15 ] [ 16 ]


By 2002, ketamine was classified as class III in  Taiwan ; given the recent rise of its prevalence in East Asia, however, rescheduling into class I or II is being considered. [ 17 ] [ 18 ]


In December 2013, the  government of India , in response to rising recreational use and the use of ketamine as a date rape drug, has added it to  Schedule X  of the  Drug and Cosmetics Act , requiring a special license for sale and maintenance for two years of records of all sales. [ 19 ] [ 20 ]


In the United Kingdom, it became labeled a  Class C drug  on 1 January 2006. [ 17 ] [ 21 ]  On 10 December 2013, the UK  Advisory Council on the Misuse of Drugs  (ACMD) recommended that the government reclassify ketamine to become a Class B drug. [ 22 ]  On 12 February 2014 the  Home Office  announced it would follow this advice "in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage". [ 23 ] [ 24 ]


The UK Minister of State for Crime Prevention,  Norman Baker , responding to the ACMD's advice, said the issue of ketamine's rescheduling for medical and veterinary use would be addressed "separately to allow for a period of consultation". [ 23 ]


Because of the increase in recreational use, ketamine was placed in Schedule III of the United States  Controlled Substance Act  in August 1999. [ 25 ]


Recreational use of ketamine was documented in the early 1970s in underground literature (e.g.,  The Fabulous Furry Freak Brothers ). [ 26 ]  It was used in  psychiatric  and other academic research through the 1970s, culminating in 1978 with the publishing of  psychonaut   John Lilly 's  The Scientist , and  Marcia Moore  and Howard Alltounian's  Journeys into the Bright World , which documented the unusual phenomenology of ketamine intoxication. [ 27 ]  The incidence of non-medical ketamine use increased through the end of the century, especially in the context of  raves  and other parties. [ 28 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ]  Its emergence as a  club drug  differs from other club drugs (e.g.,  MDMA ), however, due to its  anesthetic  properties (e.g., slurred speech, immobilization) at higher doses; [ 32 ]  in addition, reports are common of ketamine being sold as "ecstasy". [ 33 ]  In the 1993 book  E for Ecstasy [ 34 ]  (about the uses of the street drug  Ecstasy  in the UK), the writer, activist, and ecstasy advocate  Nicholas Saunders  highlighted test results showing that certain consignments of the drug also contained ketamine. Consignments of ecstasy known as "strawberry" contained what Saunders described as a "potentially dangerous combination of ketamine,  ephedrine , and  selegiline ", as did a consignment of "Sitting Duck" ecstasy tablets. [ 35 ]


The use of ketamine as part of a "post-clubbing experience" has also been documented. [ 36 ]  Ketamine's rise in the dance culture was most rapid in Hong Kong by the end of the 1990s. [ 32 ]


Ketamine use as a recreational drug has been implicated in deaths globally, with more than 90 deaths in England and Wales in the years of 2005–2013. [ 37 ]  They include accidental poisonings, drownings, traffic accidents, and suicides. [ 37 ]  The majority of deaths were among young people. [ 38 ]  This has led to increased regulation (e.g., upgrading ketamine from a Class C to a Class B banned substance in the U.K.). [ 39 ]


Unlike the other well-known dissociatives  phencyclidine  (PCP) and  dextromethorphan  (DXM), ketamine is very short-acting. It takes effect within about 10 minutes, [ 40 ]  while its  hallucinogenic  effects last 60 minutes when  insufflated  or injected, and up to two hours when ingested orally. [ 41 ]


At subanesthetic doses—under-dosaged from a medical point of view—ketamine produces a  dissociative state , characterised by a sense of detachment from one's physical body and the external world which is known as  depersonalization  and  derealization . [ 42 ]  At sufficiently high doses, users may experience what is called the "K-hole", a state of dissociation with visual and auditory hallucinations. [ 43 ]   John C. Lilly ,  Marcia Moore ,  D. M. Turner  and  David Woodard  (amongst others) have written extensively about their own  entheogenic  use of, and  psychonautic  experiences with, ketamine. [ 44 ]  Turner died prematurely due to drowning during presumed unsupervised ketamine use. [ 45 ]  In 2006 the Russian edition of  Adam Parfrey 's  Apocalypse Culture II  was banned and destroyed by authorities owing to its inclusion of an essay by Woodard about the entheogenic use of, and psychonautic experiences with, ketamine. [ 46 ] : 288–295


Because of its ability to cause confusion and  amnesia , ketamine has been used for  date rape . [ 40 ] [ 47 ]


Production for recreational use has been traced to 1967, when it was referred to as "mean green" and "rockmesc". [ 48 ]  Recreational names for ketamine include "Special K", [ 49 ]  "K", [ 50 ] [ 49 ]  "Kitty", "Ket", [ 51 ]  "K2", [ 50 ]  "Vitamin K", [ 49 ] [ 51 ]  "Super K", [ 49 ]  "Jet", [ 49 ] [ 52 ]  "Super acid", [ 49 ]  "Mauve", [ 49 ]  "Special LA coke", [ 49 ]  "Purple", [ 49 ]  "Cat Valium", [ 52 ] [ 53 ]  "Keller", [ 53 ]  "Kelly's Day", [ 53 ]  "New ecstasy", [ 54 ]  "Psychedelic heroin", [ 54 ]  "bump", [ 55 ]  "Majestic". [ 56 ]  A mixture of ketamine with  cocaine  is called "Calvin Klein" or "CK1". [ 57 ]  In Hong Kong, where illicit use of the drug is popular, ketamine is colloquially referred to as "kai-jai". [ 32 ]


According to the ongoing  Monitoring the Future  study conducted by  University of Michigan , prevalence rates of recreational ketamine use among American secondary school students (grades 8, 10, and 12) have varied between 0.8 and 2.5% since 1999, with recent rates at the lower end of this range. [ 58 ]  The  2006  National Survey on Drug Use and Health  (NSDUH) reports a rate of 0.1% for persons ages 12 or older with the highest rate (0.2%) in those ages 18–25. [ 59 ]  Further, 203,000 people are estimated to have used ketamine in 2006, and an estimated 2.3 million people used ketamine at least once in their life. [ 59 ]  A total of 529 emergency department visits in 2009 were ketamine-related. [ 60 ]


In 2003, the U.S.  Drug Enforcement Administration  conducted  Operation TKO , a probe into the quality of ketamine being imported from Mexico. [ 61 ]  As a result of operation TKO, U.S. and Mexican authorities shut down the Mexico City company Laboratorios Ttokkyo, which was the biggest producer of ketamine in Mexico. According to the DEA, over 80% of ketamine seized in the United States is of Mexican origin. As of 2011, it was mostly shipped from places like India, as cheap in cost as $5/gram. [ 61 ]  The  World Health Organization  Expert Committee on Drug Dependence, in its thirty-third report (2003), [ 62 ]  recommended research into ketamine's recreational use due to growing concerns about its rising popularity in Europe, Asia, and North America.


Cases of ketamine use in club venues have been observed in the Czech Republic, France, Italy, Hungary, The Netherlands, and the United Kingdom. [ 63 ]  Additional reports of use and dependence have been reported in Poland and Portugal. [ 64 ] [ 65 ]


Australia's  2019 National Drug Strategy Household Survey report  shows a prevalence of recent ketamine use of 0.3% in 2004, 0.2% in 2007 and 2010, 0.4% in 2016 and 0.9% in 2019 in persons aged 14 or older. [ 66 ]


In China, the small village of  Boshe  in eastern Guangdong was confirmed as a main production centre in 2013 when it was raided. [ 67 ]


Established by the Hong Kong Narcotics Division of the  Security Bureau , the Central Registry of Drug Abuse (CRDA) maintains a database of all the illicit drug users who have come into contact with law enforcement, treatment, health care, and social organizations. The compiled data are confidential under  The Dangerous Drugs Ordinance  of Hong Kong, and statistics are made freely available online on a quarterly basis. [ 68 ] [ 69 ]  Statistics from the CRDA show that the number of ketamine users (all ages) in Hong Kong has increased from 1605 (9.8% of total drug users) in 2000 to 5212 (37.6%) in 2009. [ 70 ]  Increasing trends of ketamine use among illicit drug users under the age of 21 were also reported, rising from 36.9% of young drug users in 2000 to 84.3% in 2009. [ 70 ]


A survey conducted among school-attending Taiwanese adolescents reported prevalence rates of 0.15% in 2004, 0.18% in 2005, and 0.15% in 2006 in middle-school (grades 7 and 9) students; in Taiwanese high-school (grades 10 and 12) students, prevalence was 1.13% in 2004, 0.66% in 2005, and 0.44% in 2006. [ 71 ]  From the same survey, a large portion (42.8%) of those who reported ecstasy use also reported ketamine use. [ 71 ]  Ketamine was the second-most used  illicit drug  (behind ecstasy) in absconding Taiwanese adolescents as reported by a multi-city street outreach survey. [ 72 ]  In a study comparing the reporting rates between web questionnaires and paper-and-pencil questionnaires, ketamine use was reported a higher rate in the web version. [ 73 ]  Urine samples taken at a club in Taipei, Taiwan, showed high rates of ketamine use at 47.0%; this prevalence was compared with that of detainees suspected of recreational drug use in the general public, of which 2.0% of the samples tested positive for ketamine use. [ 74 ]


In the late 2010s and early 2020s, law enforcement agencies in some U.S. states began directing paramedics to use ketamine to sedate people under arrest, sometimes under the auspices of treatment for the controversial diagnosis " excited delirium ". [ 75 ] [ 76 ] [ 77 ] [ 78 ] [ 79 ] [ 80 ]  The  American Society of Anesthesiologists  and  American College of Emergency Physicians  oppose the use of ketamine or any similar agent to incapacitate someone solely for a law enforcement purpose. [ 81 ]


The  Korea Oriental Instant Medicinal Centre ( Korean :  조선동방즉효성약물센터 or 조선동방즉효약물개발사 )  is a state-owned  North Korean   pharmaceutical company  founded in 1968. [ 1 ]  It is best known for selling  Neo-Viagra-Y.R. , an alleged  traditional Korean (Koryo)  medical supplement, [ 2 ] [ 3 ]  whose  active ingredient  is 50 mg of  Sildenafil  (Viagra), combined with Korean herbal medicines. [ 4 ]


This article about a North Korean company is a  stub . You can help Wikipedia by  expanding it .


This article about a  medical ,  pharmaceutical  or  biotechnological  corporation or company is a  stub . You can help Wikipedia by  expanding it .


Kumdang-2  is a cure for  AIDS ,  Ebola ,  MERS , and  tuberculosis  created in  North Korea . [ 1 ]  According to the website Minjok Tongshin, a version of the drug was originally produced in 1996. [ 2 ]  The name means "golden shower" in Korean. [ 3 ]


It is manufactured by the  Pugang Pharmaceutical Company . [ 4 ]  According to the  Korean Central News Agency , the drug's ingredients include  ginseng , small amounts of rare earth metals, [ 5 ]  and trace amounts of  gold  and  platinum . [ 6 ]  According to the KCNA, it can also cure cancer, morning sickness, and "harm from the use of computers". [ 7 ]  The drug was mentioned during the deadly  bird flu  outbreaks in 2006 and 2013. [ 2 ]


According to the chemical analysis by the South Korean  National Forensic Service , Kumdang-2 turned out to be mostly made of the anesthetic  Procaine . [ 8 ]


1EMR ,  1PVH ,  2Q7N


NM_001257135 NM_002309


NM_001039537 NM_008501


NP_001244064 NP_002300


NP_001034626 NP_032527


Leukemia inhibitory factor , or  LIF , is an  interleukin 6  class  cytokine  that affects  cell  growth by inhibiting differentiation. When LIF levels drop, the cells differentiate.


LIF derives its name from its ability to induce the terminal  differentiation  of  myeloid leukemic  cells, thus preventing their continued growth. Other properties attributed to the cytokine include: the growth promotion and cell differentiation of different types of target cells, influence on  bone   metabolism ,  cachexia ,  neural development ,  embryogenesis  and  inflammation .  p53  regulated LIF has been shown to facilitate  implantation  in the mouse model and possibly in humans. [ 5 ]  It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility. [ 6 ]


LIF binds to the specific LIF  receptor  ( LIFR -α) which forms a  heterodimer  with a specific subunit common to all members of that family of receptors, the  GP130  signal transducing subunit. This leads to activation of the  JAK / STAT  (Janus kinase/ signal transducer  and activator of  transcription ) and  MAPK  ( mitogen  activated  protein   kinase )  cascades . [ citation needed ]


LIF is normally expressed in the  trophectoderm  of the developing embryo, with its receptor LIFR expressed throughout the  inner cell mass . As embryonic stem cells are derived from the inner cell mass at the blastocyst stage, removing them from the inner cell mass also removes their source of LIF. Recombinant LIF has been produced in plants by InVitria.


LIF is often added to stem cell culture media as an alternative to feeder cell culture, due to the limitation that feeder cells present by only producing LIF on their cell surfaces. Feeder cells lacking the LIF  gene  do not effectively support stem cells. [ 7 ]  LIF promotes self-renewal by recruiting signal transducer and activator of transcription 3 ( Stat3 ). Stat3 is recruited to the activated LIF receptor and phosphorylated by  Janus kinase . It bears noting that LIF and Stat3 are not sufficient to inhibit stem cell differentiation, as cells will differentiate upon removal of serum. During the reversibility phase of differentiation from naive pluripotency, it is possible to revert cells back to naive pluripotency through the addition of LIF. [ 8 ]
Removal of LIF pushes stem cells toward  differentiation , however genetic manipulation of embryonic stem cells allows for LIF independent growth, notably overexpression of the gene  Nanog .


LIF is typically added to stem cell culture medium to reduce spontaneous differentiation. [ 9 ] [ 10 ]


Lifestyle drug  is an imprecise term commonly applied to  medications  which treat non–life-threatening and non-painful conditions such as  baldness ,  wrinkles ,  erectile dysfunction , or  acne , which the speaker perceives as either not medical problems at all or as minor medical conditions relative to others. It is sometimes intended as a pejorative, bearing the implication that the scarce medical research resources allocated to develop such drugs were spent frivolously when they could have been better spent researching cures for more serious medical conditions. Proponents, however, point out that improving the patient's subjective quality of life has always been a primary concern of  medicine , and argue that these drugs are doing just that. It finds broad use in both media and scholarly journals.


There is direct impact of lifestyle drugs on society, particularly in the developing world. Implications associated with labeling of indications and products sales of these lifestyle drugs may be varied. Drugs can, over time, switch from 'lifestyle' to 'mainstream' use. [ 1 ]


Though no precise widely accepted definition or criteria are associated with the term, there is much debate within the fields of  pharmacology  and  bioethics  around the propriety of developing such drugs, particularly after the commercial debut of  Viagra .


The German government's health insurance scheme has denied insurance coverage for some  Lifestyle-Medikament  ("lifestyle drugs") which they deem spurious. [ 2 ]


Critics of pharmaceutical firms claim that pharmaceutical firms actively  medicalize ; that is, they invent novel  disorders  and  diseases  which were not recognized as such before their "cures" could be profitably marketed, in effect pathologizing what were widely regarded as normal conditions of human existence. The consequences are said to include generally greater worries about health, misallocation of limited medical research resources to comparatively minor conditions while many serious diseases remain uncured, and needless health care expenditure. This  medicalization  of some element of human condition has significance, in principle, as a matter for  political discourse  or  dialogue  in  civil society  concerning  values or morals . [ 3 ]


Social critics also question the propriety of devoting huge research budgets towards creating these drugs when far more dangerous diseases like  cancer  and  AIDS  remain uncured. It is sometimes claimed that lifestyle drugs amount to little more than medically sanctioned  recreational drug use . [ citation needed ]


The term " me-too drug " or " follow-on drug " refers to a medication that is  similar  to a  pre-existing drug , usually by making minor modifications to the prototype, reflected in slight changes in the profiles of  side effects  or  activity , and used to treat conditions for which drugs already exist. [ 1 ] [ 2 ]  While pharmaceutical companies have justified the development of me-toos as offering incremental improvements in efficacy, side-effects, compliance and cost, critics have questioned the increasing  marketing  of me-toos, their absorption of  research and development  resources and their impact on the innovation of new treatments. [ 3 ] [ 4 ] [ 5 ]


In 1956,  Louis S. Goodman , co‐editor of  Goodman and Gilman , referred to “the problem of the introduction of ‘me too’ drugs, that is, drugs without signal advantage of any sort”. [ 1 ]  However, me-too drugs can be novel compounds themselves. [ 3 ] [ 6 ]  They are commonly used and include several  beta blockers ,  antidepressants  and  stomach acid reducing  and  cholesterol lowering  drugs. [ 1 ]


The term "me‐too drugs" was coined in the 1950s. In 1956,  Louis S. Goodman , co‐editor of  Goodman and Gilman , referred to “the problem of the introduction of ‘me too’ drugs, that is, drugs without signal advantage of any sort”. [ 1 ]  Once a new drug class was discovered, other major drug companies made efforts to produce their own similar versions. Pharmacologist  Milton Silverman  and physician  Philip R. Lee  noted "the great drug therapy era was marked not only by the introduction of new drugs in great profusion and by the launching of large promotional campaigns but also by the introduction of what are known as 'duplicative' or 'me-too' products". [ 7 ]


Between 1960 and 1962,  Estes Kefauver , then Senator of Tennessee, led a series of hearings enquiring about the pharmaceutical industry's motive to produce me-too drugs after it was noted that much of their time and resources were spent producing them. Subsequently, the FDA required drug companies to prove their drugs were safe and effective. [ 7 ]  In 1964,  Louis Lasagna  described me-too drugs as being “hard to justify putting into man at all, let alone on the market”. [ 1 ]  Three years later, the term appeared in the  Oxford English Dictionary . [ 1 ]  In the early 1970s, Silverman and Lee reported that there were almost 100  tranquillisers , 130  antihistamines , greater than 270  antibiotics  and more than 200  sulfonamides . [ 7 ]


In 1994,  Desmond Laurence's  textbook  Clinical Pharmacology  referred to me-too as "me-again". [ 1 ]


There is no agreed definition, however, several have been proposed, [ 1 ]  including:


Biosimilars  are compared with other biosimilars and are therefore not me-toos. [ 8 ] [ 9 ]


Me-too drugs include  diazepam ,  ranitidine  and  esketamine . [ 1 ]


The first-in-class β-blocker pronethalol was developed by  James Black  at  ICI Pharmaceuticals . It was followed by  propranolol ,  sotalol ,  practolol ,  metoprolol ,  labetalol ,  acebutolol  and  bisoprolol . Successive differences between β-blockers have had a combined cumulative effect and are seen as "innovative". [ 1 ]


15  benzodiazepines  were marketed in the UK between 1960 and 1982, of which seven were produced by Roche. [ 1 ]


The  proton-pump inhibitor   Nexium  by  AstraZeneca  is a me-too which was granted its patent by showing that it was effective for heartburn, not that it was better than its precursor,  Prilosec . [ 10 ]  It was shown to preserve revenues of Prilosec, whose U.S. patent expired in 2001. Considered a new drug by the FDA, Nexium was patented separately, sold for eight times the cost of its  generic   esomeprazole  and advertised as significantly better than its predecessor, a move the company received much criticism for, with a subsequent class action lawsuit filed against them. [ 11 ]


Both  Tagamet 's and  Zantac 's prices increased following the arrival of further me-too drugs  Pepcid  and  Axid . [ 4 ] [ 12 ]


Several me-toos followed the prototype of the  ace inhibitor ,  captopril , with  enalapril  being its first me-too. [ 1 ]  Most were as efficient as each other and had similar adverse effect profiles. [ 11 ]


When Merck's cholesterol-lowering statin Mevacor ( lovastatin ) was approved by the U.S.  Food and Drug Administration  (FDA) in 1987, the understanding of the link between cholesterol and heart disease was improving, and the potential market for the drug became significant. Subsequently, several other companies developed similar drugs: Merck developed Zocor ( simvastatin ) and Crestor ( rosuvastatin ),  Pfizer  developed Lipitor ( atorvastatin ),  Bristol-Myers Squibb  developed Pravachol ( pravastatin ), and  Novartis  developed Lescol ( fluvastatin ). [ 13 ] [ 14 ] [ 15 ]  Others include  pitavastatin  (Livalo). [ 1 ]


Imipramine  was the first-in-class of the tricyclic antidepressants.  Amitriptyline ,  Nortriptyline ,  Dosulepin  and  Doxepin  are some of the me-toos that followed. [ 1 ]  Several me-too  Selective serotonin reuptake inhibitors  have been developed for maintenance treatment in chronic depression. These include Paxil ( paroxetine ), Celexa ( citalopram ), Zoloft ( sertraline ), Lexapro ( escitalopram ) and Prozac ( fluoxetine ). [ 16 ]


For example, Celexa is a mixture of a left-handed and right-handed version of the same compound ("citalopram"), but only the left-handed version ("es-citalopram") is biologically active. Lexapro, the "me too" drug released several years after Celexa thus extending the patent life, is a purified form of just the left-handed version (the "es" in "es-citalopram"). [ 17 ]


Gilead Science's  Descovy  is a me-too drug of  Truvada , a popular Antiretroviral also used to prevent HIV infection in healthy people. Both versions are  prodrugs  that metabolize into the same active compound. Gilead has been accused in lawsuits of "slow walking" the development of the me-too drug; [ 18 ]  however, such lawsuits further a market perception the me-too drug is "safer." This drives sales of the more expensive me-too drug when both drugs have virtually identical safety profiles. Similarly,  Valtrex , first FDA approved in 2001 to treat persistent herpes outbreaks is a prodrug of  acyclovir , first FDA approved in the mid-1980s. Valtrex metabolizes into acyclovir in the liver, [ 19 ]  but when it first entered the market, it cost many times than the generic.


In 2005, a report by the  International Policy Network  defended me-toos, describing their development as "incremental improvements on already existing drugs". [ 20 ]  The report stated:


... this often represent(s) advances in safety and efficacy, along with providing new formulations and dosing options that significantly increase patient compliance. From an economic standpoint, expanding drug classes represent the possibility of lower drug prices as competition between manufacturers is increased. Additionally, pharmaceutical companies depend on incremental innovations to provide the revenue that will support the development of more risky “block-buster” drugs. Policies aimed at curbing incremental innovation will ultimately lead to a reduction in the overall quality of existing drug classes and may ultimately curb the creation of novel drugs. [ 20 ]


This incremental innovation has led to some referring to me-toos as "me-betters". [ 14 ] [ 21 ]


Many physicians are unaware that me-toos are compared to placebos rather than pre-existing drugs. [ 22 ]  Me-toos are seen as patentable new drugs and therefore substantial profit makers, where innovative drugs may be more risky to develop. [ 13 ] [ 23 ] [ 24 ]


Between 1998 and 2003, the U.S. Food and Drug Administration (FDA) approved 487 drugs, of which 78 per cent appeared to have similar characteristics to pre-existing marketed drugs. [ 25 ]


More than 60% of medicines listed on the World Health Organization's essential list are me‐too drugs. [ 1 ]


In September 2019, half of  antibiotics  under clinical development were “me-too” drugs. At the beginning of 2020, the WHO stated that only two of the 50 antibiotics in clinical development are active against serious drug resistant gram-negative bacteria, and most are not significant "upgrades" of drugs. [ 26 ] [ 27 ]


Medication discontinuation  is the ceasing of a  medication  treatment for a patient by either the  clinician  or the patient themself. [ 1 ] [ 2 ]  When initiated by the clinician, it is known as  deprescribing . [ 3 ]  Medication discontinuation is an important medical practice that may be motivated by a number of reasons: [ 4 ] [ 3 ]


Unlike the prescribing of medications, appropriate discontinuation has not attracted nearly as much attention or interest. [ 6 ]


Medications may be stopped in the context of  end-of-life care , such as medications that may affect  risk factors  for future disease. Medications that may be stopped as part of discussions about end-of-life care include  antihypertensives , medications for  diabetes , and drugs for  high cholesterol . [ 5 ]