In June 1997, India declared its stock of chemical weapons of 1,044 tonnes (1,151 short tons) of mustard gas. [ 57 ] [ 58 ]  By the end of 2006, India had destroyed more than 75 percent of its chemical weapons/material stockpile and was granted extension for destroying the remaining stocks by April 2009 and was expected to achieve 100 percent destruction within that time frame. [ 57 ]  India informed the United Nations in May 2009 that it had destroyed its stockpile of chemical weapons in compliance with the international Chemical Weapons Convention. With this India has become the third country after South Korea and Albania to do so. [ 59 ] [ 60 ]  This was cross-checked by inspectors of the United Nations.


Producing or stockpiling mustard gas is prohibited by the  Chemical Weapons Convention . When the convention entered force in 1997, the parties declared worldwide stockpiles of 17,440 tonnes of mustard gas. As of December 2015, 86% of these stockpiles had been destroyed. [ 61 ]


A significant portion of the United States' mustard agent  stockpile  was stored at the Edgewood Area of  Aberdeen Proving Ground  in  Maryland . Approximately 1,621 tons of mustard agents were stored in one-ton containers on the base under heavy guard. A chemical neutralization plant was built on the proving ground and neutralized the last of this stockpile in February 2005. This stockpile had priority because of the potential for quick reduction of risk to the community. The nearest schools were fitted with overpressurization machinery to protect the students and faculty in the event of a catastrophic explosion and fire at the site. These projects, as well as planning, equipment, and training assistance, were provided to the surrounding community as a part of the Chemical Stockpile Emergency Preparedness Program (CSEPP), a joint program of the Army and the  Federal Emergency Management Agency  (FEMA). [ 62 ]  Unexploded shells containing mustard gases and other chemical agents are still present in several test ranges in proximity to schools in the Edgewood area, but the smaller amounts of poison gas (4 to 14 pounds (1.8 to 6.4 kg)) present considerably lower risks. These remnants are being detected and excavated systematically for disposal. The U.S. Army Chemical Materials Agency oversaw disposal of several other chemical weapons stockpiles located across the United States in compliance with international chemical weapons treaties. These include the complete incineration of the chemical weapons stockpiled in  Alabama ,  Arkansas ,  Indiana , and  Oregon . Earlier, this agency had also completed destruction of the chemical weapons stockpile located on  Johnston Atoll  located south of  Hawaii  in the  Pacific Ocean . [ 63 ]  The largest mustard agent stockpile, at approximately 6,200  short tons , was stored at the  Deseret Chemical Depot  in northern  Utah . The incineration of this stockpile began in 2006. In May 2011, the last of the mustard agents in the stockpile were incinerated at the Deseret Chemical Depot, and the last artillery shells containing mustard gas were incinerated in January 2012.


In 2008, many empty  aerial bombs  that contained mustard gas were found in an excavation at the  Marrangaroo Army Base  just west of Sydney, Australia. [ 64 ] [ 65 ]  In 2009, a mining survey near  Chinchilla, Queensland , uncovered 144 105-millimeter  howitzer  shells, some containing "Mustard H", that had been buried by the U.S. Army during World War II. [ 65 ] [ 66 ]


In 2014, a collection of 200 bombs was found near the  Flemish  villages of  Passendale  and  Moorslede . The majority of the bombs were filled with mustard agents. The bombs were left over from the German army and were meant to be used in the  Battle of Passchendaele  in World War I. It was the largest collection of chemical weapons ever found in Belgium. [ 67 ]


A large amount of chemical weapons, including mustard gas, was found in a neighborhood of  Washington, D.C.  The cleanup was completed in 2021. [ 68 ]


In 2002, an archaeologist at the Presidio Trust archaeology lab in San Francisco was exposed to mustard gas, which had been dug up at the  Presidio of San Francisco , a former military base. [ 69 ]


In 2010, a clamming boat pulled up some old  artillery  shells of World War I from the  Atlantic Ocean  south of  Long Island, New York . Multiple fishermen suffered from blistering and respiratory irritation severe enough to require hospitalization. [ 70 ]


From 1943 to 1944, mustard agent experiments were performed on Australian service volunteers in tropical  Queensland, Australia , by  Royal Australian Engineers ,  British Army  and American experimenters, resulting in some severe injuries. One test site, the  Brook Islands National Park , was chosen to simulate Pacific islands held by the  Imperial Japanese Army . [ 71 ] [ 72 ]  These experiments were the subject of the documentary film  Keen as Mustard . [ 73 ]


The United States tested sulfur mustards and other chemical agents including  nitrogen mustards  and  lewisite  on up to 60,000 servicemen during and after WWII. The experiments were classified secret and as with  Agent Orange [ broken anchor ] , claims for medical care and compensation were routinely denied, even after the WWII-era tests were declassified in 1993. The  Department of Veterans Affairs  stated that it would contact 4,000 surviving test subjects but failed to do so, eventually only contacting 600. Skin cancer, severe eczema, leukemia, and chronic breathing problems plagued the test subjects, some of whom were as young as 19 at the time of the tests, until their deaths, but even those who had previously filed claims with the VA went without compensation. [ 74 ]


African American servicemen  were tested alongside white men in separate trials to determine whether their skin color would afford them a degree of immunity to the agents, and  Nisei  servicemen, some of whom had joined after their release from  Japanese American Internment Camps  were tested to determine susceptibility of  Japanese military personnel  to these agents. These tests also included  Puerto Rican  subjects. [ 75 ]


Concentrations of thiodiglycol in urine have been used to confirm a diagnosis of chemical poisoning in hospitalized victims. The presence in urine of 1,1'-sulfonylbismethylthioethane (SBMTE), a conjugation product with glutathione, is considered a more specific marker, since this metabolite is not found in specimens from unexposed persons. In one case, intact mustard gas was detected in postmortem fluids and tissues of a man who died one week post-exposure. [ 76 ]


Notes


Nevirapine  ( NVP ), sold under the brand name  Viramune  among others, is a medication used to treat and prevent  HIV/AIDS , specifically  HIV-1 . [ 5 ]  It is generally recommended for use with other  antiretroviral medications . [ 5 ]  It may be used to prevent  mother to child spread during birth  but is not recommended following other exposures. [ 5 ]  It is taken by mouth. [ 5 ]


Common side effects include rash, headache, nausea, feeling tired, and  liver problems . [ 5 ]  The liver problems and skin rash may be severe and should be checked for during the first few months of treatment. [ 5 ] [ 6 ]  It appears to be safe for use during  pregnancy . [ 5 ]  It is a non-nucleoside  reverse transcriptase inhibitor  (NNRTI) and works by blocking the function of  reverse transcriptase . [ 5 ]


Nevirapine was approved for medical use in the United States in 1996. [ 5 ]  It is on the  World Health Organization's List of Essential Medicines . [ 7 ]  It is available as a  generic medication . [ 5 ]


Nevirapine is used in people six years of age and older infected with HIV-1 as part of combination antiretroviral treatment (ART or cART). Monotherapy with nevirapine is not indicated due to rapid emergence of resistance. [ 3 ] [ 4 ]


Nevirapine in triple combination therapy has been shown to suppress  viral load  effectively when used as initial antiretroviral therapy ( i.e. , in antiretroviral-naive patients). [ 8 ]  Some clinical trials have demonstrated comparable HIV suppression with nevirapine-based regimens to that achieved with regimens based on a  protease inhibitor  (PI) [ 9 ] [ 10 ]  or  efavirenz . [ 11 ]


This drug is generally only to be considered for use if the CD4 cell count is very low. [ 3 ]


Although concerns have been raised about nevirapine-based regimens in those starting therapy with high viral load or low CD4 count, some analyses suggest that nevirapine may be effective in this group of people. [ 11 ]


Nevirapine may also form a useful component of salvage regimens after virological failure, usually in combination with one or more PIs as well as  nucleotide reverse transcriptase inhibitor  (NRTIs), especially in those who have not previously taken an NNRTI.


Dosing in children is based on  body surface area  (BSA), [ 3 ]  however, weight-based dosing algorithms have been released. These guidelines include dosing algorithms for as young as newborn babies. [ 12 ]


Although a single dose of nevirapine given to both mother and child reduced the rate of HIV transmission by almost 50% compared with a very short course of  zidovudine  (AZT) prophylaxis, in a clinical trial in  Uganda ., [ 13 ]  that trial was found in an Associated Press investigation to be riddled with "sloppy recordkeeping" and possibly fraud. [ 14 ]  A subsequent study in  Thailand  showed that prophylaxis with single-dose nevirapine in addition to zidovudine is more effective than zidovudine alone. [ 15 ]  These and other trials have led the  World Health Organization  to endorse the use of single-dose nevirapine prophylaxis in many developing world settings as a cost-effective way of reducing mother-to-child transmission. However, in the United States the Ugandan study was deemed flawed  [ 16 ]  and as of 2006 the FDA has not approved of such nevirapine prophylaxis. [ 17 ]  However, supporters of HIVNET 012 experiment argued that the flaws in this experiment were largely due to bureaucratic incompetence, while the findings regarding the safety and efficacy of single-dose nevirapine from this study were scientifically solid and too important to discard. [ 18 ]  Moreover, it was argued that holding African researchers who operated under resource-poor situations to the same moral and procedural standards to their Western counterparts was unrealistic, and would further marginalize African researchers' role in the science community and impede the progress of African science. [ 19 ]  Another clinical trial,  Using Nevirapine to Prevent Mother-to-Child HIV Transmission During Breastfeeding , was completed in September 2013. [ 20 ]


A major concern with this approach is that NNRTI resistance mutations are commonly observed in both mothers and infants after single-dose nevirapine, [ 21 ]  and may compromise the response to future NNRTI-containing regimens. [ 22 ]  A short course of maternal  Lamivudine/zidovudine  is recommended by the U.S. Public Health Service Task Force to reduce this risk. [ 23 ]


Nevirapine is contraindicated for non-occupational post-exposure-prophylaxis including for pregnant and nonpregnant women due to severe liver toxicity. [ 24 ]


The most common adverse effect of nevirapine is the development of mild or moderate rash (13%). [ 25 ] [ 26 ]  Severe or life-threatening skin reactions have been observed in 1.5% of patients, including  Stevens–Johnson syndrome ,  toxic epidermal necrolysis  and  hypersensitivity . [ 25 ]


Nevirapine may cause severe or life-threatening liver toxicity, usually emerging in the first six weeks of treatment. [ 25 ] [ 27 ]  In 2000, the U.S.  Food and Drug Administration  issued a  black box warning  on nevirapine, warning that it could cause life-threatening liver toxicity and skin reactions. [ 4 ]  Unacceptably high risk of serious liver symptoms in certain patient groups (women with CD4 count >250 and men >400) [ 11 ] [ 28 ]  has led the U.S. DHHS to recommend the restriction of nevirapine use to those at lower risk, unless the benefit to the patient clearly outweighs the risk; [ 27 ]  although in the 2NN study which found these CD4 limits, the effect was seen only in patients recruited from Thailand. More recent studies on the use of Nevirapine in people with higher CD4 cell counts have come to the following conclusion: Treatment-experienced patients who start NVP-based combination therapy with low pre–ART and high current CD4 cell counts and an undetectable VL have a similar likelihood for discontinuing NVP therapy because of hypersensitivity reactions (HSRs), compared with treatment-naive patients with low CD4 cell counts. This suggests that NVP-based combination therapy may be safely initiated in such patients. However, in similar patients with a detectable VL, it is prudent to continue to adhere to current CD4 cell count thresholds. [ 29 ]  The U.S. Public Health Service Task Force advocates caution in the use of nevirapine in pregnancy due to toxicity issues, which may be exacerbated during pregnancy. [ 23 ]


Cases of  immune reconstitution syndrome  and  fat redistribution  have also been observed with this drug. [ 4 ]


The U.S. Food and Drug Administration recommends stopping nevirapine if a person experiences: [ 4 ]


Additionally, the U.S.  FDA  recommends close monitoring during the first 6 weeks of therapy for the above symptoms as there is high risk during this time. Continued monitoring is recommended for up to the first 18 weeks of treatment. If a patient experiences hepatitis plus rash or other systemic symptoms, or severe hypersensitivity or skin rash, nevirapine should not be restarted. [ 4 ]


Nevirapine is a substrate for liver  CYP3A  and  CYP2B6  enzymes. Concomitant administration of drugs that are inhibitors of these enzymes may increase serum nevirapine levels significantly. Some examples of these drugs include  ritonavir ,  fosamprenavir , and  fluconazole . On the other hand, drugs that are  inducers  of these enzymes such as  rifampicin  may lower serum nevirapine levels. [ 30 ] [18]


In addition, concomitant use of   St. John's wort   (Hypericum perforatum , which has been shown to induce  CYP3A4  and  CYP1A2 [ 31 ] ) or St. John's wort containing products may significantly lower nevirapine levels. [ 30 ]


Nevirapine is an inducer of  cytochrome P450  isoenzymes  CYP3A4  and  CYP2B6 . It may reduce levels of several co-administered drugs including the antiretrovirals  efavirenz ,  indinavir ,  lopinavir ,  nelfinavir  and  saquinavir , as well as  clarithromycin ,  ketoconazole , forms of  hormonal contraception , and  methadone . [ 25 ]


Nevirapine falls in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretrovirals. [ 32 ]   Both nucleoside and non-nucleoside RTIs inhibit the same target, the  reverse transcriptase  enzyme, an essential viral enzyme which transcribes viral RNA into DNA. Unlike  nucleoside  RTIs, which bind at the polymerase active site, NNRTIs bind to a hydrophobic pocket in the subdomain of p66 which is about 10 angstrom away from the active site (known as the NNRTI pocket). Therefore, this NNRTI-binding pocket will inhibit reverse transcription in a way that is distinct to the NRTIs. [ 33 ]


Nevirapine is not effective against HIV-2, as the pocket of the HIV-2 reverse transcriptase has a different structure, which confers intrinsic resistance to the NNRTI class. [ 34 ]


Resistance to nevirapine develops rapidly if viral replication is not completely suppressed. [ 8 ]  The most common mutations observed after nevirapine treatment are Y181C and K103N, which are also observed with other NNRTIs. [ 25 ] [ 35 ]  As all NNRTIs bind within the same pocket, viral strains which are resistant to nevirapine are usually also resistant to the other NNRTIs,  efavirenz  and  delavirdine . However, second generation NNRTIs like  rilpivirine  and  etravirine  are effective in treatment for HIV strains resistant to nevirapine and other first generation drugs in that same class.


Nevirapine was discovered by Karl D. Hargrave and colleagues at Boehringer Ingelheim Pharmaceuticals, Inc., one of the  Boehringer Ingelheim  group of companies. It is covered by  U.S. Patent 5,366,972   Archived  2018-09-20 at the  Wayback Machine  and corresponding foreign patents.  Nevirapine was the first NNRTI approved by the  U.S. Food and Drug Administration  (FDA). It was approved June 21, 1996 for adults and September 11, 1998, for children. It was also approved in Europe in 1997.


Former U.S. President  George W. Bush 's  PEPFAR funding  of $500 million to help combat the African AIDS epidemic included nevirapine, among other medications and programs.


In South Africa, the  Treatment Action Campaign  successfully sued the government over its failure to make nevirapine widely available. In  Minister of Health v Treatment Action Campaign  the  Constitutional Court of South Africa  ordered the government to immediately "remove the restrictions that prevent Nevirapine from being made available for the purpose of reducing the risk of mother-to-child transmission of HIV at public hospitals and clinics that are not research and training sites [and] permit and facilitate the use of Nevirapine for the purpose of reducing the risk of mother-to-child transmission of HIV and to make it available for this purpose at hospitals and clinics when in the judgement of the attending medical practitioner acting in consultation with the medical superintendent of the facility concerned this is medically indicated, which shall if necessary include that the mother concerned has been appropriately tested and counselled." [ 36 ] [ 37 ]


Non-steroidal anti-inflammatory drugs [ 1 ] [ 3 ]  ( NSAID ) [ 1 ]  are members of a  therapeutic   drug class  which  reduces pain , [ 4 ]   decreases inflammation ,  decreases fever , [ 1 ]  and  prevents blood clots . Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of  gastrointestinal ulcers and bleeds ,  heart attack , and  kidney disease . [ 5 ] [ 6 ]


The term  non-steroidal , common from around 1960, distinguishes these drugs from  corticosteroids , another class of  anti-inflammatory  drugs, [ 7 ]  which during the 1950s had acquired a bad reputation due to overuse and side-effect problems after their introduction in 1948. [ 8 ] [ 9 ] [ 10 ]


NSAIDs work by inhibiting the activity of  cyclooxygenase   enzymes  (the  COX-1  and  COX-2   isoenzymes ). In cells, these enzymes are involved in the synthesis of key biological mediators, namely  prostaglandins , which are involved in  inflammation , and  thromboxanes , which are involved in  blood clotting .


There are two general types of NSAIDs available: non-selective and  COX-2 selective . [ 11 ]  Most NSAIDs are non-selective, and inhibit the activity of both COX-1 and COX-2. These NSAIDs, while reducing inflammation, also inhibit platelet aggregation and increase the risk of  gastrointestinal ulcers  and bleeds. [ 11 ]  COX-2 selective inhibitors have fewer gastrointestinal side effects, but promote  thrombosis , and some of these agents substantially increase the risk of  heart attack . As a result, certain COX-2 selective inhibitors—such as  rofecoxib —are no longer used due to the high risk of undiagnosed  vascular disease . [ 11 ]  These differential effects are due to the different roles and tissue localisations of each COX isoenzyme. [ 11 ]  By inhibiting physiological COX activity, NSAIDs may cause deleterious effects on kidney function, [ 12 ]  and, perhaps as a result of water and sodium retention and decreases in renal blood flow, may lead to heart problems. [ 13 ]  In addition, NSAIDs can blunt the production of  erythropoietin , resulting in anaemia, since haemoglobin needs this hormone to be produced.


The most prominent NSAIDs are  aspirin ,  ibuprofen , and  naproxen ; all available  over the counter  (OTC) in most countries. [ 14 ]   Paracetamol  (acetaminophen) is generally not considered an NSAID because it has only minor anti-inflammatory activity. Paracetamol treats pain mainly by blocking COX-2 and inhibiting  endocannabinoid  reuptake almost exclusively within the brain, and only minimally in the rest of the body. [ 15 ] [ 16 ]


NSAIDs are often suggested for the treatment of acute or chronic conditions where  pain  and inflammation are present. NSAIDs are generally used for the symptomatic relief of the following conditions: [ 17 ] [ 18 ] [ 19 ]


The effectiveness of NSAIDs for treating non-cancer chronic pain and cancer-related pain in children and adolescents is not clear. [ 27 ] [ 28 ]  There have not been sufficient numbers of high-quality randomised controlled trials conducted. [ 27 ] [ 28 ]


Differences in anti-inflammatory activity between the various individual NSAIDs are small, but there is considerable variation among individual patients in therapeutic response and tolerance to these drugs. About 60% of patients will respond to any NSAID; of the others, those who do not respond to one may well respond to another. Pain relief starts soon after taking the first dose, and a full analgesic effect should normally be obtained within a week, whereas an anti-inflammatory effect may not be achieved (or may not be clinically assessable) for up to three weeks. If appropriate responses are not obtained within these times, another NSAID should be tried. [ 3 ]


Pain following  surgery  can be significant, and many people require strong pain medications such as opioids. There is some low-certainty evidence that starting NSAID painkiller medications in adults early, before surgery, may help reduce post-operative pain, and also reduce the dose or quantity of opioid medications required after surgery. [ 29 ]  Any increase risk of surgical bleeding, bleeding in the gastrointestinal system, myocardial infarctions, or injury to the kidneys has not been well studied. [ 29 ]  When used in combination with paracetamol, the analgesic effect on post-operative pain may be improved. [ 30 ]


Aspirin , the only NSAID able to irreversibly inhibit  COX-1 , is also indicated for  antithrombosis  through  inhibition of platelet aggregation . This is useful for the management of arterial  thrombosis , and prevention of adverse cardiovascular events like heart attacks. Aspirin inhibits platelet aggregation by inhibiting the action of  thromboxane A 2 . [ 31 ]


NSAIDs are useful in the management of post-operative  dental pain  following invasive dental procedures such as  dental extraction . When not contra-indicated, they are favoured over the use of  paracetamol  alone due to the anti-inflammatory effect they provide. [ 32 ]  There is weak evidence suggesting that taking pre-operative analgesia can reduce the length of post operative pain associated with placing orthodontic spacers under local anaesthetic. [ 33 ]


Based on  observational studies  and  randomized controlled trials , NSAID use is not effective for the treatment or prevention of  Alzheimer's disease . [ 34 ] [ 35 ]


NSAIDs may be used with caution by people with the following conditions:


NSAIDs should usually be avoided by people with the following conditions:


The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly common. Use of NSAIDs increases risk of a range of  gastrointestinal  (GI) problems, kidney disease and adverse cardiovascular events. [ 40 ] [ 41 ]  As commonly used for post-operative pain, there is evidence of increased risk of kidney complications. [ 42 ]  Their use following gastrointestinal surgery remains controversial, given mixed evidence of increased risk of leakage from any bowel  anastomosis  created. [ 43 ] [ 44 ] [ 45 ]


An estimated 10–20% of people taking NSAIDs experience  indigestion . In the 1990s, high doses of prescription NSAIDs were associated with serious upper gastrointestinal adverse events, including bleeding. [ 46 ]


NSAIDs, like all medications, may interact with other medications. For example, concurrent use of NSAIDs and  quinolone antibiotics  may increase the risk of quinolones' adverse  central nervous system  effects, including seizure. [ 47 ] [ 48 ]


There is an argument over the benefits and risks of NSAIDs for treating chronic musculoskeletal pain. Each drug has a benefit-risk profile and balancing the risk of no treatment with the competing potential risks of various therapies should be considered. [ 49 ]  For people over the age of 65 years old, the balance between the benefits of pain-relief medications such as NSAIDS and the potential for adverse effects has not been well determined. [ 50 ]


There is some evidence suggesting that, for some people, use of NSAIDs (or other anti-inflammatories) may contribute to the initiation of chronic pain. [ 51 ]


Side effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy. An estimated 10–20% of NSAID patient's experience  dyspepsia , and NSAID-associated upper gastrointestinal adverse events are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States, and represent 43% of drug-related emergency visits. Many of these events are avoidable; a review of physician visits and prescriptions estimated that unnecessary prescriptions for NSAIDs were written in 42% of visits. [ 52 ]


Aspirin should not be taken by people who have  salicylate intolerance [ 53 ] [ 54 ]  or a more generalized  drug intolerance  to NSAIDs, and caution should be exercised in those with  asthma  or  NSAID -precipitated  bronchospasm . Owing to its effect on the stomach lining, manufacturers recommend people with  peptic ulcers , mild  diabetes , or  gastritis  seek medical advice before using aspirin. [ 55 ] [ 56 ]  Use of aspirin during  dengue fever  is not recommended owing to increased bleeding tendency. [ 57 ]  People with  kidney disease ,  hyperuricemia , or  gout  should not take aspirin because it inhibits the kidneys' ability to excrete  uric acid , and thus may exacerbate these conditions.


If a  COX-2 inhibitor  is taken, a traditional NSAID (prescription or over-the-counter) should not be taken at the same time. [ 58 ]


Rofecoxib  (Vioxx) was shown to produce significantly fewer gastrointestinal adverse drug reactions ( ADRs ) compared with naproxen. [ 59 ]  The study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs (COX-2 inhibitors). A statistically significant increase in the incidence of  myocardial infarctions  was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a statistically significant relative risk of cardiovascular events of 1.97 versus placebo [ 60 ] —which caused a worldwide withdrawal of rofecoxib in October 2004. [ 61 ]


Use of methotrexate together with NSAIDs in  rheumatoid arthritis  is safe, if adequate monitoring is done. [ 62 ]


NSAIDs, aside from aspirin, increase the risk of  myocardial infarction  and  stroke . [ 63 ] [ 64 ]  This occurs at least within a week of use. [ 5 ]  They are not recommended in those who have had a previous heart attack as they increase the risk of death or recurrent MI. [ 65 ]  Evidence indicates that  naproxen  may be the least harmful out of these. [ 64 ] [ 66 ]


NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of  heart failure  in people without a history of cardiac disease. [ 66 ]  In people with such a history, use of NSAIDs (aside from low-dose aspirin) was associated with a more than 10-fold increase in heart failure. [ 67 ]  If this link is proven causal, researchers estimate that NSAIDs would be responsible for up to 20 percent of hospital admissions for congestive heart failure. In people with heart failure, NSAIDs increase mortality risk ( hazard ratio ) by approximately 1.2–1.3 for naproxen and ibuprofen, 1.7 for rofecoxib and celecoxib, and 2.1 for diclofenac. [ 68 ]


On 9 July 2015, the  Food and Drug Administration  (FDA) toughened warnings of increased  heart attack  and  stroke  risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs)  other than  aspirin . [ 69 ]


A 2005 Finnish survey study found an association between long term (over three months) use of NSAIDs and  erectile dysfunction . [ 70 ]


A 2011 publication [ 71 ]  in  The Journal of Urology  received widespread publicity. [ 72 ]  According to the study, men who used NSAIDs regularly were at significantly increased risk of erectile dysfunction. A link between NSAID use and erectile dysfunction still existed after controlling for several conditions. However, the study was observational and not controlled, with low original participation rate, potential participation bias, and other uncontrolled factors. The authors warned against drawing any conclusion regarding cause. [ 73 ]


The main  adverse drug reactions  (ADRs) associated with NSAID use relate to direct and indirect irritation of the  gastrointestinal (GI) tract . NSAIDs cause a dual assault on the GI tract: the acidic molecules directly irritate the  gastric mucosa , and inhibition of COX-1 and COX-2 reduces the levels of protective  prostaglandins . [ 40 ]  Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucus secretion and diminished trophic effects on the epithelial mucosa. [ 74 ]


Common gastrointestinal side effects include: [ 17 ]


Clinical NSAID ulcers are related to the systemic effects of NSAID administration. Such damage occurs irrespective of the route of administration of the NSAID (e.g., oral, rectal, or parenteral) and can occur even in people who have  achlorhydria . [ 76 ]


Ulceration risk increases with therapy duration, and with higher doses. To minimize GI side effects, it is prudent to use the lowest effective dose for the shortest period of time—a practice that studies show is often not followed. Over 50% of patients who take NSAIDs have sustained some mucosal damage to their small intestine. [ 77 ]


The risk and rate of gastric adverse effects is different depending on the type of NSAID medication a person is taking.  Indomethacin ,  ketoprofen , and  piroxicam  use appear to lead to the highest rate of gastric adverse effects, while  ibuprofen  (lower doses) and  diclofenac  appear to have lower rates. [ 17 ]


Certain NSAIDs, such as aspirin, have been marketed in  enteric-coated  formulations that manufacturers claim reduce the incidence of gastrointestinal ADRs. Similarly, some believe that rectal formulations may reduce gastrointestinal ADRs. However, consistent with the systemic mechanism of such ADRs, and in clinical practice, these formulations have not demonstrated a reduced risk of GI ulceration. [ 17 ]


Numerous "gastro-protective" drugs have been developed with the goal of preventing gastrointestinal toxicity in people who need to take NSAIDs on a regular basis. [ 40 ]  Gastric adverse effects may be reduced by taking medications that suppress acid production such as  proton pump inhibitors  (e.g.:  omeprazole  and  esomeprazole ), or by treatment with a drug that mimics  prostaglandin  in order to restore the lining of the GI tract (e.g.: a prostaglandin analog  misoprostol ). [ 40 ]  Diarrhea is a common side effect of misoprostol; however, higher doses of misoprostol have been shown to reduce the risk of a person having a complication related to a gastric ulcer while taking NSAIDs. [ 40 ]  While these techniques may be effective, they are expensive for maintenance therapy. [ 78 ]


Hydrogen sulfide  NSAID hybrids prevent the gastric ulceration/bleeding associated with taking the NSAIDs alone. Hydrogen sulfide is known to have a protective effect on the cardiovascular and gastrointestinal system. [ 79 ]


NSAIDs should be used with caution in individuals with  inflammatory bowel disease  (e.g.,  Crohn's disease  or  ulcerative colitis ) due to their tendency to cause gastric bleeding and form ulceration in the gastric lining. [ 80 ]


NSAIDs are also associated with a fairly high incidence of adverse drug reactions ( ADRs ) on the kidney and over time can lead to  chronic kidney disease . The mechanism of these kidney ADRs is due to changes in kidney blood flow. Prostaglandins normally dilate the  afferent arterioles  of the  glomeruli . This helps maintain normal glomerular perfusion and  glomerular filtration rate  (GFR), an indicator of  kidney function . This is particularly important in kidney failure where the kidney is trying to maintain renal perfusion pressure by elevated angiotensin II levels. At these elevated levels, angiotensin II also constricts the afferent arteriole into the glomerulus in addition to the efferent arteriole it normally constricts. Since NSAIDs block this prostaglandin-mediated effect of afferent arteriole dilation, particularly in kidney failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased RPF (renal perfusion flow) and GFR. [ 81 ]


Common ADRs associated with altered kidney function include: [ 17 ]


These agents may also cause kidney impairment, especially in combination with other nephrotoxic agents. Kidney failure is especially a risk if the patient is also concomitantly taking an  ACE inhibitor  (which removes angiotensin II's vasoconstriction of the efferent arteriole) and a  diuretic  (which drops plasma volume, and thereby RPF)—the so-called "triple whammy" effect. [ 82 ]


In rarer instances NSAIDs may also cause more severe kidney conditions: [ 17 ]


NSAIDs in combination with excessive use of  phenacetin  or  paracetamol  (acetaminophen) may lead to  analgesic nephropathy . [ 83 ]


Photosensitivity  is a commonly overlooked adverse effect of many of the NSAIDs. [ 84 ]  The 2-arylpropionic acids are the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including  piroxicam ,  diclofenac , and  benzydamine . [ 85 ]


Benoxaprofen , since withdrawn due to its  liver toxicity , was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready  decarboxylation  of the  carboxylic acid   moiety . The specific absorbance characteristics of the different  chromophoric  2-aryl substituents, affects the decarboxylation mechanism. [ 86 ]


While NSAIDs as a class are not direct  teratogens , use of NSAIDs in late pregnancy can cause premature closure of the fetal  ductus arteriosus  and kidney ADRs in the fetus. [ 87 ]  Thus, NSAIDs are not recommended during the third trimester of pregnancy because of the increased risk of premature constriction of the ductus arteriosus. [ 87 ]  Additionally, they are linked with  premature birth [ 88 ]  and  miscarriage . [ 89 ]  Aspirin, however, is used together with  heparin  in pregnant women with  antiphospholipid syndrome . [ 90 ]  Additionally,  indomethacin  can be used in pregnancy to treat  polyhydramnios  by reducing fetal urine production via inhibiting fetal renal blood flow. [ 91 ]


In contrast,  paracetamol  (acetaminophen) is regarded as being safe and well tolerated during pregnancy, but Leffers et al. released a study in 2010, indicating that there may be associated male infertility in the unborn. [ 92 ] [ 93 ]  Doses should be taken as prescribed, due to risk of liver toxicity with overdoses. [ 94 ]


In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy. [ 95 ]


In October 2020, the U.S.  Food and Drug Administration  (FDA) required the  drug label  to be updated for all nonsteroidal anti-inflammatory medications, to describe the risk of kidney problems in unborn babies which can then lead to low amniotic fluid levels, as a result of the use of NSAIDs. [ 96 ] [ 97 ]  They are recommending avoiding the use of NSAIDs by pregnant women at 20 weeks or later in pregnancy. [ 96 ] [ 97 ]


A variety of allergic or allergic-like  NSAID hypersensitivity reactions  follow the ingestion of NSAIDs. These hypersensitivity reactions differ from the other adverse reactions listed here which are toxicity reactions, i.e. unwanted reactions that result from the pharmacological action of a drug, are dose-related, and can occur in any treated individual; hypersensitivity reactions are idiosyncratic reactions to a drug. [ 98 ]  Some NSAID hypersensitivity reactions are truly allergic in origin:  1)  repetitive  IgE -mediated  urticarial  skin eruptions,  angioedema , and  anaphylaxis  following immediately to hours after ingesting one structural type of NSAID but not after ingesting structurally unrelated NSAIDs; and  2)  Comparatively mild to moderately severe  T cell -mediated delayed onset (usually more than 24 hour), skin reactions such as  maculopapular rash ,  fixed drug eruptions ,  photosensitivity reactions , delayed  urticaria , and  contact dermatitis ; or  3)  far more severe and potentially life-threatening t-cell-mediated delayed systemic reactions such as the  DRESS syndrome ,  acute generalized exanthematous pustulosis , the  Stevens–Johnson syndrome , and  toxic epidermal necrolysis . Other NSAID hypersensitivity reactions are allergy-like symptoms but do not involve true allergic mechanisms; rather, they appear due to the ability of NSAIDs to alter the metabolism of arachidonic acid in favor of forming metabolites that promote allergic symptoms. Affected individuals may be abnormally sensitive to these provocative metabolites or overproduce them and typically are susceptible to a wide range of structurally dissimilar NSAIDs, particularly those that inhibit COX1. Symptoms, which develop immediately to hours after ingesting any of various NSAIDs that inhibit COX-1, are:  1)  exacerbations of asthmatic and rhinitis (see  aspirin-exacerbated respiratory disease ) symptoms in individuals with a history of  asthma  or  rhinitis  and  2)  exacerbation or first-time development of  wheals  or  angioedema  in individuals with or without a history of chronic  urticarial  lesions or angioedema. [ 39 ]


It has been hypothesized that NSAIDs may delay healing from  bone  and  soft-tissue injuries  by inhibiting inflammation. [ 99 ]  On the other hand, it has also been hypothesized that NSAIDs might speed recovery from soft tissue injuries by preventing inflammatory processes from damaging adjacent, non-injured muscles. [ 100 ]


There is moderate evidence that they delay bone healing. [ 101 ]  Their overall effect on soft-tissue healing is unclear. [ 100 ] [ 99 ] [ 102 ]


Long-term use of NSAID analgesics and paracetamol is associated with an increased risk of hearing loss. [ 103 ] [ 104 ] [ 105 ]


The use of NSAIDs for analgesia following gastrointestinal surgery remains controversial, given mixed evidence of an increased risk of leakage from any bowel  anastomosis  created. This risk may vary according to the class of NSAID prescribed. [ 43 ] [ 44 ] [ 45 ]


Common adverse drug reactions (ADR), other than listed above, include: raised liver  enzymes ,  headache ,  dizziness . [ 17 ]  Uncommon ADRs include an  abnormally high level of potassium in the blood , confusion,  spasm of the airways , and rash. [ 17 ]  Ibuprofen may also rarely cause  irritable bowel syndrome  symptoms. NSAIDs are also implicated in some cases of  Stevens–Johnson syndrome . [ 106 ]


Most NSAIDs penetrate poorly into the  central nervous system  (CNS). However, the COX enzymes are expressed constitutively in some areas of the CNS, meaning that even limited penetration may cause adverse effects such as somnolence and dizziness. [ 107 ]


NSAIDs may increase the risk of bleeding in patients with  Dengue fever [ 108 ]  For this reason, NSAIDs are only available with a prescription in India. [ 109 ]


In very rare cases, ibuprofen can cause  aseptic meningitis . [ 110 ]


As with other drugs,  allergies  to NSAIDs might exist. While many allergies are specific to one NSAID, up to 1 in 5 people may have unpredictable cross-reactive allergic responses to other NSAIDs as well. [ 111 ]


Although small doses generally have little to no effect on the immune system, large doses of NSAIDs significantly suppress the production of immune cells. [ 112 ]  As NSAIDs affect prostaglandins, they affect the production of most fast growing cells. [ 112 ]  This includes immune cells. [ 112 ]  Unlike  corticosteroids , they do not directly suppress the immune system and so their effect on the immune system is not immediately obvious. [ 112 ]  They suppress the production of new immune cells, but leave existing immune cells functional. [ 112 ]  Large doses slowly reduce the immune response as the immune cells are renewed at a much lower rate. [ 112 ]  Causing a gradual reduction of the immune system, much slower and less noticeable than the immediate effect of Corticosteroids. [ 112 ]  The effect significantly increases with dosage, in a nearly exponential rate. [ 112 ]  Doubling of dose reduced cells by nearly four times. [ 112 ]  Increasing dose by five times reduced cell counts to only a few percent of normal levels. [ 112 ]  This is likely why the effect was not immediately obvious in low dose trials, as the effect is not apparent until much higher dosages are tested. [ 112 ]


NSAIDs reduce kidney blood flow and thereby decrease the efficacy of  diuretics , and inhibit the elimination of  lithium  and  methotrexate . [ 113 ]


NSAIDs cause  decreased ability to form blood clots , which can increase the risk of bleeding when combined with other drugs that also decrease blood clotting, such as  warfarin . [ 113 ]


NSAIDs may aggravate  hypertension  (high blood pressure) and thereby antagonize the effect of  antihypertensives , [ 113 ]  such as  ACE inhibitors . [ 114 ]


NSAIDs may interfere and reduce effectiveness of  SSRI  antidepressants through inhibiting  TNFα  and  IFNγ , both of which are cytokine derivatives. [ 115 ] [ 116 ]  NSAIDs, when used in combination with SSRIs, increase the risk of adverse gastrointestinal effects. [ 117 ]  NSAIDs, when used in combination with SSRIs, increase the risk of internal bleeding and brain hemorrhages. [ 118 ]


Various widely used NSAIDs enhance  endocannabinoid  signaling by blocking the anandamide-degrading membrane enzyme  fatty acid amide hydrolase  ( FAAH ). [ 119 ]


NSAIDs may reduce the effectiveness of  antibiotics . An  in-vitro  study on cultured  bacteria  found that adding NSAIDs to antibiotics reduced their effectiveness by around 20%. [ 120 ]


The concomitant use of NSAIDs with  alcohol  and/or  tobacco  products significantly increases the already elevated risk of  peptic ulcers  during NSAID therapy. [ 121 ] [ better source needed ]


Most NSAIDs act as nonselective inhibitors of the  cyclooxygenase  (COX)  enzymes , inhibiting both the cyclooxygenase-1 ( COX-1 ) and cyclooxygenase-2 ( COX-2 )  isoenzymes . This inhibition is competitively  reversible  (albeit at varying degrees of reversibility), as opposed to the mechanism of  aspirin , which is irreversible inhibition. [ 122 ]  COX catalyzes the formation of  prostaglandins  and  thromboxane  from  arachidonic acid  (itself derived from the cellular  phospholipid  bilayer by  phospholipase A 2 ). Prostaglandins act (among other things) as messenger molecules in the process of  inflammation . This  mechanism of action  was elucidated in 1970 by  John Vane  (1927–2004), who received a  Nobel Prize  for his work (see  Mechanism of action of aspirin ). [ 123 ] [ 124 ]


COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the  stomach  lining, where prostaglandins serve a protective role, preventing the stomach  mucosa  from being eroded by its own acid. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs. [ 125 ]


When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels,  ulcers  of the stomach or  duodenum  and internal  bleeding  can result. [ 126 ]  The discovery of COX-2 led to research to the development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs. [ 127 ]


NSAIDs have been studied in various assays to understand how they affect each of these enzymes. While the assays reveal differences, unfortunately, different assays provide differing ratios. [ 128 ]


Paracetamol  (acetaminophen) is not considered an NSAID because it has little anti-inflammatory activity. It treats pain mainly by blocking COX-2 mostly in the central nervous system, but not much in the rest of the body. [ 15 ]


However, many aspects of the mechanism of action of NSAIDs remain unexplained, and for this reason, further COX pathways are hypothesized. The  COX-3  pathway was believed to fill some of this gap but recent findings make it appear unlikely that it plays any significant role in humans and alternative explanation models are proposed. [ 15 ]


NSAIDs interact with the  endocannabinoid system  and its  endocannabinoids , as COX2 have been shown to utilize endocannabinoids as substrates, and may have a key role in both the  therapeutic effects  and  adverse effects  of NSAIDs, as well as in NSAID-induced  placebo  responses. [ 129 ] [ 130 ] [ 131 ]


NSAIDs are also used in the acute pain caused by  gout  because they inhibit  urate  crystal  phagocytosis  besides inhibition of prostaglandin synthase. [ 132 ]


NSAIDs have  antipyretic  activity and can be used to treat fever. [ 133 ] [ 134 ]  Fever is caused by elevated levels of  prostaglandin E2  (PGE2), which alters the firing rate of neurons within the  hypothalamus  that control thermoregulation. [ 133 ] [ 135 ]  Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of  prostanoid  biosynthesis (PGE2) within the hypothalamus. [ 133 ] [ 134 ]  PGE2 signals to the hypothalamus to increase the body's thermal setpoint. [ 134 ] [ 136 ]   Ibuprofen  has been shown more effective as an  antipyretic  than  paracetamol  (acetaminophen). [ 135 ] [ 137 ]
 Arachidonic acid  is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D, and E. [ 138 ]


NSAIDs can be classified based on their chemical structure or mechanism of action. Older NSAIDs were known long before their mechanism of action was elucidated and were for this reason classified by chemical structure or origin. Newer substances are more often classified by mechanism of action. [ 139 ]


The following NSAIDs are derived from  fenamic acid , which is a derivative of  anthranilic acid , [ 143 ] : 235   which in turn is a nitrogen  isostere  of  salicylic acid , which is the  active metabolite  of  aspirin . [ 143 ] : 235  [ 144 ] : 17


Most NSAIDs are  chiral  molecules;  diclofenac  and the  oxicams  are exceptions. However, the majority are prepared as  racemic mixtures . Typically, only a single  enantiomer  is pharmacologically active. For some drugs (typically profens), an  isomerase   enzyme   in vivo  converts the inactive enantiomer into the active form, although its activity varies widely in individuals. This phenomenon is likely responsible for the poor correlation between NSAID efficacy and plasma concentration observed in older studies when specific analysis of the active enantiomer was not performed. [ 151 ]


Ibuprofen  and  ketoprofen  are now available in single-enantiomer preparations (dexibuprofen and dexketoprofen), which purport to offer quicker onset and an improved side-effect profile.  Naproxen  has always been marketed as the single active enantiomer. [ 152 ]


NSAIDs within a group tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. [ 153 ]  Rather, differences among compounds usually relate to dosing regimens (related to the compound's  elimination half-life ), route of administration, and tolerability profile. [ medical citation needed ]


Regarding adverse effects, selective  COX-2 inhibitors  have lower risk of gastrointestinal bleeding. [ 153 ]  With the exception of  naproxen , nonselective NSAIDs increase the risk of having a heart attack. [ 153 ]  Some data also supports that the partially selective  nabumetone  is less likely to cause gastrointestinal events. [ 153 ]


A consumer report noted that  ibuprofen , naproxen, and  salsalate  are less expensive than other NSAIDs, and essentially as effective and safe when used appropriately to treat osteoarthritis and pain. [ 154 ]


Most nonsteroidal anti-inflammatory drugs are weak acids, [ 155 ]  with a pKa of 3–5. They are absorbed well from the  stomach  and intestinal mucosa. They are highly protein-bound in plasma (typically >95%), usually to  albumin , so that their  volume of distribution  typically approximates to plasma volume. Most NSAIDs are metabolized in the  liver  by  oxidation  and conjugation to inactive metabolites that typically are excreted in the  urine , though some drugs are partially excreted in  bile . Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage. [ medical citation needed ]


Ibuprofen and diclofenac have short half-lives (2–3 hours). Some NSAIDs (typically oxicams) have very long half-lives (e.g., 20–60 hours). [ medical citation needed ]


It is widely believed that naturally occurring salicin in  willow  trees and other plants was used by the ancients as a form of analgesic or anti-inflammatory drug, [ 156 ]  but this story, although compelling, is not entirely true. [ 157 ] [ 158 ]  Hippocrates does not mention willow at all. [ 159 ]   Dioscorides 's  De materia medica  was arguably the most influential herbal from Roman to Medieval times but, if he mentions willow at all (there is doubt about the identity of 'Itea'), then he used the ashes, steeped in vinegar, as a treatment for corns, [ 160 ]  which corresponds well with modern uses of  salicylic acid .


Willow bark (from trees of the  Salix  genus) was widely known to be used as a medicine by multiple First Nations communities. [ 161 ]  The bark would be chewed or steeped in water for its pain relieving and antipyretic effects. The effects are a result of the bark's salicin content. Meadowsweet, another plant to contain salicin, has strong roots in British folk medicine for the same maladies. Willow bark was first reported in Western science by Edward Stone in 1763 as a treatment for  ague  (fever) according to the pseudoscientific  doctrine of signatures . [ 162 ]


In the body, salicin is turned into salicylic acid, which produces the antipyretic and analgesic effects that the plants are known for.


Salicin was first isolated by  Johann Andreas Buchner  in 1827. By 1829, French chemist Henri Leroux had improved the extraction process to obtain about 30g of purified salicin from 1.5   kg of willow bark. [ 163 ]  By  hydrolysis , salicin releases  glucose  and  salicyl alcohol  which can be converted into  salicylic acid , both  in vivo  and through chemical methods. [ 164 ]  In 1869,  Hermann Kolbe  synthesised salicylic acid, although it was too acidic for the  gastric mucosa . [ 164 ]  The reaction used to synthesise  aromatic  acid from a  phenol  in the presence of CO 2  is known as the  Kolbe-Schmitt reaction . [ 165 ] [ 166 ] [ 167 ]


By 1897, the German chemist  Felix Hoffmann  and the  Bayer  company prompted a new age of pharmacology by converting salicylic acid into acetylsalicylic acid—named  aspirin  by  Heinrich Dreser . Other NSAIDs like  ibuprofen  were developed from the 1950s forward. [ 163 ]
In 2001, NSAIDs accounted for 70,000,000 prescriptions and 30   billion  over-the-counter  doses sold annually in the  United States . [ 46 ]


Research supports the use of NSAIDs for the control of pain associated with veterinary procedures such as dehorning and castration of calves. [ citation needed ]  The best effect is obtained by combining a short-term local anesthetic such as  lidocaine  with an NSAID acting as a longer term analgesic. [ citation needed ]  However, as different species have varying reactions to different medications in the NSAID family, little of the existing research data can be extrapolated to animal species other than those specifically studied, and the relevant government agency in one area sometimes prohibits uses approved in other jurisdictions. [ citation needed ]


In the United States,  meloxicam  is approved for use only in canines, whereas (due to concerns about liver damage) it carries warnings against its use in cats [ 168 ] [ 169 ]  except for one-time use during surgery. [ 170 ]  In spite of these warnings, meloxicam is frequently prescribed "off-label" for non-canine animals including cats and livestock species. [ 171 ]  In other countries, for example  The European Union  (EU), there is a label claim for use in cats. [ 172 ]


Nystatin , sold under the brand name  Mycostatin  among others, is an  antifungal medication . [ 1 ]  It is used to treat  Candida  infections of the skin including  diaper rash ,  thrush ,  esophageal candidiasis , and  vaginal yeast infections . [ 1 ]  It may also be used to prevent candidiasis in those who are at high risk. [ 1 ]  Nystatin may be used by mouth, in the vagina, or applied to the skin. [ 1 ]


Common side effects when applied to the skin include burning, itching, and a rash. [ 1 ]  Common side effects when taken by mouth include vomiting and diarrhea. [ 1 ]  During  pregnancy  use in the vagina is safe while other formulations have not been studied in this group. [ 1 ]  It works by disrupting the  cell membrane  of the fungal cells. [ 1 ]


Nystatin was discovered in 1950 by  Rachel Fuller Brown  and  Elizabeth Lee Hazen . [ 2 ]  It was the first polyene macrolide antifungal. [ 3 ]  It is on the  World Health Organization's List of Essential Medicines . [ 4 ]  It is available as a  generic medication . [ 1 ]  It is made from the bacterium  Streptomyces noursei . [ 2 ]  In 2022, it was the 236th most commonly prescribed medication in the United States, with more than 1   million prescriptions. [ 5 ] [ 6 ]


Skin ,  vaginal ,  mouth , and  esophageal   Candida  infections usually respond well to treatment with nystatin. Infections of nails or  hyperkeratinized  skin do not respond well. [ 7 ]


When given parenterally, its activity is reduced due to presence of plasma. [ 8 ]


Oral nystatin is often used as a preventive treatment in people who are at risk for fungal infections, such as  AIDS  patients with a low CD4 +  count and people receiving  chemotherapy . It has been investigated for use in patients after liver transplantation, but  fluconazole  was found to be much more effective for preventing colonization, invasive infection, and death. [ 9 ]  It is effective in treating oral candidiasis in elderly people who wear dentures. [ 10 ]


It is also used in very low birth-weight (less than 1500 g or 3 lb 5oz o) infants to prevent invasive fungal infections, although fluconazole is the preferred treatment. It has been found to reduce the rate of invasive fungal infections and also reduce deaths when used in these babies. [ 11 ]


Liposomal nystatin is not commercially available, but investigational use has shown greater  in vitro  activity than colloidal formulations of  amphotericin B , and demonstrated effectiveness against some amphotericin B-resistant forms of fungi. [ 12 ]  It offers an intriguing possibility for difficult-to-treat systemic infections, such as invasive aspergillosis, or infections that demonstrate resistance to amphotericin B.  Cryptococcus  is also sensitive to nystatin. Additionally, liposomal nystatin appears to cause fewer cases of and less severe nephrotoxicity than observed with amphotericin B. [ 12 ]


Bitter taste and nausea are more common than most other adverse effects. [ 7 ]


The oral suspension form produces a number of adverse effects including but not limited to: [ 13 ]


Both the oral suspension and the topical form can cause:


Too high of a dosage can potentially lead to additional side effects such as: [ 16 ]


Like  amphotericin B  and  natamycin , nystatin is an  ionophore . [ 17 ]  It binds to  ergosterol , a major component of the fungal  cell membrane . When present in sufficient concentrations, it forms pores in the membrane that lead to  K +  leakage, acidification, and death of the fungus. [ 18 ]  Ergosterol is a  sterol  unique to fungi, so the drug does not have such catastrophic effects on animals or plants. However, many of the systemic/toxic effects of nystatin in humans are attributable to its binding to mammalian sterols, namely  cholesterol . This is the effect that accounts for the  nephrotoxicity  observed when high serum levels of nystatin are achieved. [ 16 ]  Despite the molecular similarities and differences of ergosterol and cholesterol, there is currently no consensus as to why nystatin has a higher binding affinity for ergosterol because it remains unclear how the nystatin pores are formed. [ 16 ]  Researchers have concluded thus far that nystatin pores are formed from 4-12 nystatin molecules, with an unknown number of the necessary sterol interactions. [ 19 ]


Nystatin also impacts cell membrane potential and transport by  lipid peroxidation . [ 20 ]   Conjugated  double bonds in nystatin's structure steal  electron density  from ergosterol in fungal cell membranes. Lipid peroxidation alters the  hydrophilicity  of the interior of  channels  in the membrane, which is necessary to transport ions and  polar  molecules. Disruption of  membrane transport  from nystatin results in rapid cell death. Lipid peroxidation by nystatin also contributes significantly to  K +  leakage due to structural modifications of the membrane. [ 21 ]


Nystatin A 1  (often called nystatin) is biosynthesized by a bacterial strain,  Streptomyces noursei . [ 22 ]  The structure of this active compound is characterized as a polyene macrolide with a deoxysugar  D - mycosamine , an  aminoglycoside . [ 22 ]  The genomic sequence of nystatin reveals the presence of the polyketide loading module (nysA), six polyketide syntheses modules (nysB, nysC, nysI, nysJ, and nysK) and two thioesterase modules (nysK and nysE). [ 22 ]  It is evident that the biosynthesis of the macrolide functionality follows the  polyketide synthase  I pathway. [ 23 ]


Following the biosynthesis of the macrolide, the compound undergoes post-synthetic modifications, which are aided by the following enzymes: GDP-mannose dehydratase (nysIII), P450 monooxygenase (nysL and nysN), aminotransferase (nysDII), and glycosyltransferase (nysDI). [ 22 ]  The biosynthetic pathway is thought to proceed as shown to yield nystatin.


The melting point of nystatin is 44 - 46 °C. [ 24 ]


Like many other antifungals and antibiotics, nystatin has  bacterial  origin. It was isolated from  Streptomyces noursei  in 1950 by  Elizabeth Lee Hazen  and  Rachel Fuller Brown , who were doing research for the Division of Laboratories and Research of the New York State Department of Health. Hazen found a promising micro-organism in the soil of a friend's dairy farm. She named it  Streptomyces noursei , after Jessie Nourse, the wife of the farm's owner. [ 25 ]  Hazen and Brown named nystatin after the  New York  State Health Department in 1954. [ 26 ]  The two discoverers patented the drug, and then donated the $13 million in profits to a foundation to fund similar research. [ 27 ]


It is also used in cellular biology as an inhibitor of the  lipid raft - caveolae   endocytosis pathway  on mammalian cells, at concentrations around 3 μg/ml. [ citation needed ]


In certain cases, a nystatin derivative has been used to prevent the spread of mold on objects such as works of art. For example, it was applied to wood panel paintings damaged as a result of  the Arno River Flood of 1966 in Florence, Italy . [ 28 ]


Nystatin is also used as a tool by scientists performing  "perforated" patch-clamp  electrophysiological recordings of cells. When loaded in the recording pipette, it allows for measurement of electrical currents without washing out the intracellular contents, because it forms pores in the cell membrane that are permeable to only  monovalent   ions , [ 29 ]  preferably cations such as sodium, potassium, lithium, and cesium. [ 30 ]


Another electrophysiological measurement that can be made is fusion event duration in a nystatin-ergosterol based system. Fusions are measured while the voltage is held constant, and is characterized by a spike in the current that then returns to the baseline current as the nystatin channels close. When present in smaller concentrations, nystatin momentarily forms pores that allows a vesicle fusion to occur more easily; that fusion then interrupts the pore stability and the nystatin and ergosterol disperse from each other. [ 31 ]  Conversely, researchers have found that the half-life of these nystatin pores increase with an increased dosage level of nystatin to the membrane systems. This indicates a lower energy of both the lipid membrane and the ionophores when there is a higher concentration of nystatin. [ 32 ]


Due to its  toxicity  profile when high levels in the serum are obtained, no injectable formulations of nystatin are on the US market. However, injectable formulations have been investigated in the past. [ 12 ]


Oseltamivir , sold under the brand name  Tamiflu  among others, is an  antiviral medication  used to treat and prevent  influenza A  and  influenza B , viruses that cause  the flu . [ 5 ]  Many medical organizations recommend it in people who have complications or are at high risk of complications within 48 hours of first symptoms of infection. [ 6 ]  They recommend it to prevent infection in those at high risk, but not the general population. [ 6 ]  The  Centers for Disease Control and Prevention  (CDC) recommends that clinicians use their discretion to treat those at lower risk who present within 48 hours of first symptoms of infection. [ 6 ] [ 7 ] [ 8 ]  It is taken by mouth, either as a pill or liquid. [ 5 ]


Recommendations regarding oseltamivir are controversial as are criticisms of the recommendations. [ 6 ] [ 9 ] [ 10 ] [ 11 ]  A 2014  Cochrane Review  concluded that oseltamivir does not reduce hospitalizations, and that there is no evidence of reduction in complications of influenza. [ 11 ]  Two  meta-analyses  have concluded that benefits in those who are otherwise healthy do not outweigh its risks. [ 12 ] [ 13 ]  They also found little evidence regarding whether treatment changes the risk of hospitalization or death in high risk populations. [ 12 ] [ 13 ]  However, another meta-analysis found that oseltamivir was effective for prevention of influenza at the individual and household levels. [ 14 ]


Common side effects include  vomiting ,  diarrhea , headache, and trouble sleeping. [ 5 ]  Other side effects may include  psychiatric symptoms  and  seizures . [ 5 ] [ 15 ] [ 16 ]  In the United States it is recommended for influenza infection during pregnancy. [ 1 ]  It has been taken by a small number of pregnant women without signs of problems. [ 1 ]  Dose adjustment may be needed in those with kidney problems. [ 5 ]


Oseltamivir was approved for medical use in the US in 1999. [ 5 ]  It was the first  neuraminidase inhibitor  available by mouth. [ 17 ]  It is on the  World Health Organization's List of Essential Medicines  but was downgraded to "complementary" status in 2017. [ 18 ] [ 19 ] [ 20 ]  A  generic version  was approved in the US in 2016. [ 21 ] [ 22 ]  In 2022, it was the 205th most commonly prescribed medication in the United States, with more than 1   million prescriptions. [ 23 ] [ 24 ]


Oseltamivir is used for the prevention and treatment of  influenza  caused by influenza A and B viruses. [ 5 ] [ 25 ]  It is on the  World Health Organization's List of Essential Medicines . [ 20 ]  The WHO supports its use for severe illness due to confirmed or suspected influenza virus infection in critically ill people who have been hospitalized. [ 20 ]  Oseltamivir's risk-benefit ratio is controversial. [ 10 ] [ 11 ]  In 2017, it was moved from the core to the complementary list based on its lower cost-effectiveness. [ 26 ]  The Expert Committee did not recommend the deletion of oseltamivir from the EML and EMLc, recognizing that it is the only medicine included on the Model Lists for critically ill patients with influenza and for influenza pandemic preparedness. [ 18 ]  However, the Committee noted that, since the inclusion of oseltamivir on the Model List in 2009, new evidence in seasonal and pandemic influenza has lowered earlier estimates of the magnitude of effect of oseltamivir on relevant clinical outcomes. [ 18 ]  The Committee recommended that the listing of oseltamivir be amended, moving the medicine from the core to the Complementary List, and that its use be restricted to severe illness due to confirmed or suspected influenza virus infection in critically ill hospitalized patients. [ 18 ]  The Expert Committee noted that WHO guidelines for pharmacological management of pandemic and seasonal influenza would be updated in 2017: unless new information is provided to support the use of oseltamivir in seasonal and pandemic outbreaks, the next Expert Committee might consider oseltamivir for deletion. [ 18 ]


The US  Centers for Disease Control and Prevention  (CDC),  European Centre for Disease Prevention and Control  (ECDC),  Public Health England  and the  American Academy of Pediatrics  (AAP) recommend the use of oseltamivir for people who have complications or are at high risk for complications. [ 6 ] [ 7 ] [ 27 ] [ 28 ] [ 29 ]  This includes those who are hospitalized, young children, those over the age of 65, people with other significant health problems, those who are pregnant, and  Indigenous peoples of the Americas  among others. [ 27 ]  The  Infectious Disease Society of America  takes the same position as the CDC. [ 9 ]


A systematic review of  systematic reviews  in  PLoS One  did not find evidence for benefits in people who are at risk, noting that "the trials were not designed or powered to give results regarding serious complications, hospitalization and mortality", [ 12 ]  as did a 2014 Cochrane Review. [ 30 ]  The Cochrane Review further recommended: "On the basis of the findings of this review, clinicians and healthcare policy-makers should urgently revise current recommendations for use of the neuraminidase inhibitors (NIs) for individuals with influenza." [ 30 ]  That is not utilizing NIs for prevention or treatment "Based on these findings there appears to be no evidence for patients, clinicians or policy-makers to use these drugs to prevent serious outcomes, both in annual influenza and pandemic influenza outbreaks." [ 30 ]


The CDC, ECDC, Public Health England, Infectious Disease Society of America, the AAP, and  Roche  (the originator) reject the conclusions of the Cochrane Review, arguing in part that the analysis inappropriately forms conclusions about outcomes in people who are seriously ill based on results obtained primarily in healthy populations, and that the analysis inappropriately included results from people not infected with influenza. [ 6 ] [ 7 ] [ 9 ] [ 28 ] [ 29 ]  The EMA did not change its labeling of the drug in response to the Cochrane study. [ 31 ]


A 2014 review recommended that all people admitted to intensive care units during influenza outbreaks with a diagnosis of  community-acquired pneumonia  receive oseltamivir until the absence of influenza infection is established by  polymerase chain reaction  (PCR) testing. [ 32 ]


A 2015 systematic review and meta-analysis found oseltamivir effective at treating the symptoms of influenza, reducing the length of hospitalization, and reducing the risk of  otitis media . The same review found that oseltamivir did not significantly increase the risk of adverse events. [ 33 ]  A 2016 systematic review found that oseltamivir slightly reduced the time it takes for the symptoms of influenza to be alleviated, and that it also increased the risk of "nausea, vomiting, [and] psychiatric events in adults and vomiting in children." [ 34 ]  The decrease in duration of sickness was about 18 hours. [ 35 ]


In those who are otherwise healthy the CDC states that antivirals may be considered within the first 48 hours. [ 27 ]  A German clinical practice guideline recommends against its use. [ 36 ]


Two 2013  meta-analyses  have concluded that benefits in those who are otherwise healthy do not outweigh its risks. [ 12 ] [ 13 ]  When the analysis was restricted to people with confirmed infection, the same 2014 Cochrane Review (see above) found unclear evidence of change in the risk of complications such as  pneumonia , [ 30 ]  while three other reviews found a decreased risk. [ 13 ] [ 37 ] [ 38 ]  Together, published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1.0 day. [ 39 ]  Any benefit of treatment must be balanced against side effects, which include psychiatric symptoms and increased rates of vomiting. [ 16 ]


The 2014  Cochrane Collaboration  review concluded that oseltamivir did not affect the need for hospitalizations, and that there is no proof of reduction of complications of influenza (such as pneumonia) because of a lack of diagnostic definitions, or reduction of the spread of the virus. There was also evidence that suggested that oseltamivir prevented some people from producing sufficient numbers of their own antibodies to fight infection. The authors recommended that guidance should be revised to take account of the evidence of small benefit and increased risk of harms. [ 30 ] [ 40 ]


The US  Centers for Disease Control and Prevention  (CDC), the  European Centre for Disease Prevention and Control  (ECDC), the  Public Health England  (PHE), the  Infectious Disease Society of America  (IDSA), the  American Academy of Pediatrics  (AAP), and Roche (the originator) rejected the recommendations of the 2014 Cochrane Review to urgently change treatment guidelines and drug labels. [ 6 ] [ 7 ] [ 9 ] [ 28 ] [ 29 ] [ 31 ]


As of 2017 [update] , the CDC does not recommend to use oseltamivir generally for prevention due to concerns that widespread use will encourage resistance development. [ 27 ]  They recommend that it be considered in those at high risk, who have been exposed to influenza within 48 hours and have not received or only recently been vaccinated. [ 27 ]  They recommended it during outbreaks in  long term care facilities  and in those who are significantly immunosuppressed. [ 27 ]


As of 2011 [update] , reviews concluded that when oseltamivir is used preventatively it decreases the risk of exposed people developing symptomatic disease. [ 30 ] [ 41 ]  A systematic review of systematic reviews found low to moderate evidence that it decreases the risk of getting symptomatic influenza by 1 to 12% (a relative decrease of 64 to 92%). [ 12 ]  It recommended against its use in healthy, low-risk persons due to cost, the risk of resistance development, and side effects and concluded it might be useful for prevention in unvaccinated  high risk persons. [ 12 ]


Common  adverse drug reactions  (ADRs) associated with oseltamivir therapy (occurring in over 1 percent of people) include nausea and vomiting. In adults, oseltamivir increased the risk of nausea for which the  number needed to harm  was 28 and for vomiting was 22. So, for every 22 adult people on oseltamivir one experienced vomiting. In the treatment of children, oseltamivir also induced vomiting. The number needed to harm was 19. So, for every 19 children on oseltamivir one experienced vomiting. In prevention there were more headaches, kidney, and psychiatric events. Oseltamivir's effect on the heart is unclear: it may reduce cardiac symptoms, but may also induce serious arrhythmias. [ 30 ]


Postmarketing reports include  liver inflammation  and elevated liver enzymes, rash, allergic reactions including  anaphylaxis ,  toxic epidermal necrolysis ,  abnormal heart rhythms , seizure, confusion, aggravation of diabetes, and  haemorrhagic   colitis  and  Stevens–Johnson syndrome . [ 42 ] [ 43 ]  Neuropsychiatric symptoms and body pain, followed by skin problems, were identified as the side effects most significantly reducing patient satisfaction on a drug review platform. [ 44 ]


The US and EU package inserts for oseltamivir contain a warning of psychiatric effects observed in post-marketing surveillance. [ 45 ] [ 46 ]  The frequency of these appears to be low and a causative role for oseltamivir has not been established. [ 46 ] [ 47 ]  The 2014 Cochrane Review found a dose-response effect on psychiatric events. In trials of prevention in adults one person was harmed for every 94 treated. [ 30 ]  Neither of the two most cited published treatment trials of oseltamivir reported any drug-attributable serious adverse events. [ 45 ]


It is  pregnancy category  B in Australia, meaning that it has been taken by a small number of women without signs of problems and in animal studies it looks safe. [ 48 ]  Dose adjustment may be needed in those with kidney problems. [ 5 ]


Oseltamivir is a  neuraminidase inhibitor , a  competitive inhibitor  of influenza's  neuraminidase  enzyme. The enzyme cleaves the  sialic acid  which is found on  glycoproteins  on the surface of human cells that helps new virions to exit the cell, preventing new viral particles from being released. [ 25 ]


The vast majority of mutations conferring resistance are single  amino acid  residue substitutions (His274Tyr in N1) in the  neuraminidase  enzyme. [ 49 ]  A 2011 meta-analysis of 15 studies found a pooled incidence rate for oseltamivir resistance of 2.6%. Subgroup analyses detected higher rates among influenza A patients, especially the H1N1 subtype. It was found that a substantial number of patients might become oseltamivir-resistant as a result of oseltamivir use, and that oseltamivir resistance might be significantly associated with pneumonia. [ 49 ]  In severely immunocompromised patients there were reports of prolonged shedding of oseltamivir- (or  zanamivir )-resistant virus, even after oseltamivir treatment was stopped. [ 6 ]


As of December 15, 2010 [update] , the  World Health Organization  (WHO) reported 314 samples of the prevalent  2009 pandemic H1N1 flu  tested worldwide showed resistance to oseltamivir. [ 50 ]


The CDC found sporadic oseltamivir-resistant 2009 H1N1 virus infections had been identified, including with rare episodes of limited transmission, but the public health impact had been limited. Those sporadic cases of resistance were found in immunosuppressed patients during oseltamivir treatment and persons who developed illness while receiving oseltamivir chemoprophylaxis. [ 51 ]


During 2011, a new influenza A(H1N1)2009 variant with mildly reduced oseltamivir (and zanamivir) sensitivity was detected in more than 10% of community specimens in Singapore and more than 30% of samples from northern Australia. [ 52 ]


While there is concern that antiviral resistance may develop in people with haematologic malignancies due to their inability to reduce viral loads and several surveillance studies found oseltamivir-resistant pH1N1 after administration of oseltamivir in those people, as of November 2013 [update] , widespread transmission of oseltamivir-resistant pH1N1 has not occurred. [ 53 ]


During the 2007–08 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant. [ 54 ]  In the 2008–09 season, the proportion of resistant H1N1 increased to 99.4%, while no other seasonal strains (H3N2, B) showed resistance. [ 55 ]


From 2009 to 2014, oseltamivir resistance was very low in seasonal flu. In the 2010–11 flu season, 99.1% of H1N1, 99.8% of H3N, and 100% of Influenza B remained oseltamivir susceptible in the US. [ 56 ]  In January 2012, the US and European CDCs reported all seasonal flu samples tested since October 2011 to be oseltamivir susceptible. [ 57 ] [ 58 ]  In the 2013–14 season only 1% of 2009 H1N1 viruses showed oseltamivir resistance. No other influenza viruses were resistant to oseltamivir. [ 59 ]


Three studies have found resistance in 0%, 3.3%, and 18% of subjects. [ 49 ]  In the study with the 18% resistance rate, the subjects were children, many of whom had not been previously exposed to influenza virus and therefore had a weakened immune response; the results suggest that higher and earlier dosing may be necessary in such populations. [ 60 ]


In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals not treated with these drugs. The prevalence was 1.7%. [ 61 ]  According to the CDC, As of 2019 [update] , transmission of oseltamivir-resistant influenza B virus strains—from persons treated with the drug—is rare. [ 62 ]


As of 2013 [update] , H274Y and N294S mutations that confer resistance to oseltamivir have been identified in a few H5N1 isolates from infected patients treated with oseltamivir, and have emerged spontaneously in Egypt. [ 63 ]


As of 2013 [update] , two of 14 adults infected with A(H7N9) and treated with oseltamivir developed oseltamivir-resistant virus with the Arg292Lys mutation. [ 64 ]


Its oral bioavailability is over 80% and is extensively metabolised to its active form upon first-pass through the liver. [ 4 ]  It has a  volume of distribution  of 23–26 litres. [ 4 ]  Its  half-life  is about 1–3 hours and its active carboxylate metabolite has a half-life of 6–10 hours. [ 4 ]  More than 90% of the oral dose is eliminated in the urine as the active metabolite. [ 4 ]


Oseltamivir was discovered by scientists at  Gilead Sciences  using  shikimic acid  as a starting point for  synthesis ; shikimic acid was originally available only as an extract of  Chinese star anise ; but by 2006, 30% of the supply was manufactured  recombinantly  in  E. coli. [ 65 ] [ 66 ]  Gilead exclusively licensed their relevant patents to  Roche  in 1996. [ 67 ]  The drug has not been patent-protected in Thailand, the Philippines, Indonesia, and several other countries. [ 67 ]


In 1999, the FDA approved oseltamivir phosphate for the treatment of influenza in adults [ 68 ]  based on two double-blind, randomized, placebo-controlled clinical trials. [ 69 ]  In June 2002, the  European Medicines Agency  (EMA) approved oseltamivir phosphate for prophylaxis and treatment of influenza. In 2003, a pooled analysis of ten randomised clinical trials concluded that oseltamivir reduced the risk of lower respiratory tract infections resulting in antibiotic use and hospital admissions in adults. [ 70 ]


Oseltamivir (as Tamiflu) was widely used during the H5N1 avian influenza  epidemic  in Southeast Asia in 2005. [ medical citation needed ]  In response to the epidemic, various governments – including those of the United Kingdom, Canada, Israel, United States, and Australia – stockpiled quantities of oseltamivir in preparation for a possible  pandemic [ 71 ]  and there were worldwide shortages of the drug, driven by the high demand for stockpiling. [ 65 ]  In November 2005, US President  George W. Bush  requested that Congress fund US$1 billion for the production and stockpile of oseltamivir, after Congress had already approved $1.8 billion for military use of the drug. Defense Secretary Donald Rumsfeld, who was a past chairman of Gilead Sciences, recused himself from all government decisions regarding the drug. [ 72 ]


In 2006, a Cochrane Review (since withdrawn) raised controversy by concluding that oseltamivir should not be used during routine seasonal influenza because of its low effectiveness. [ 73 ]


In December 2008, the Indian drug company  Cipla  won a case in India's court system allowing it to manufacture a cheaper generic version of Tamiflu, called Antiflu. In May 2009, Cipla won approval from the World Health Organization (WHO) certifying that its drug Antiflu was as effective as Tamiflu, and Antiflu is included in the WHO list of prequalified medicinal products. [ 74 ]


In 2009, a new A/H1N1 influenza virus was discovered to be spreading in North America. In June 2009, the WHO declared the A/H1N1 influenza a pandemic. [ 75 ]  The  National Institute for Health and Care Excellence  (NICE), the CDC, the WHO, and the ECDC maintained their recommendation to use oseltamivir. [ 8 ] [ 76 ]


From 2010 to 2012, Cochrane requested Roche's full clinical study reports of their trials, which they did not provide. [ 77 ]  In 2011, a  freedom of information request  to the European Medicines Agency (EMA) provided Cochrane with reports from 16 Roche oseltamivir trials. In 2012, the Cochrane team published an interim review based on those reports. In 2013, Roche released 74 full clinical study reports of oseltamivir trials after GSK released the data on  zanamivir  studies. [ 78 ]  In 2014, Cochrane published an updated review based solely on full clinical study reports and regulatory documents. [ 30 ] [ 77 ]  In 2016, Roche's oseltamivir patents began to expire. [ 67 ]


There have been [ when? ]  reports of oseltamivir reducing disease severity and hospitalization time in  canine parvovirus  infection. [ 79 ]  The drug may limit the ability of the virus to invade the  crypt  cells of the  small intestine  and decrease gastrointestinal  bacterial  colonization and toxin production. [ 80 ]


Oseltamivir has been deemed ineffective at treating  COVID-19 , consistent with the  SARS-CoV-2 virus  lacking influenza's neuraminidase enzyme. [ 81 ]


Oxicam  is a class of  non-steroidal anti-inflammatory drugs  (NSAIDs), [ 2 ]  meaning that they have  anti-inflammatory ,  analgesic , and antipyretic therapeutic effects.  Oxicams bind closely to  plasma proteins . [ 1 ]   Most oxicams are unselective inhibitors of the  cyclooxygenase  (COX) enzymes.  The exception is  meloxicam  with a slight (10:1) preference for  COX-2 , which, however, is only clinically relevant at low doses. [ 3 ]


The most popular drug of the oxicam class is  piroxicam . [ 1 ]   Other examples include:  ampiroxicam ,  droxicam ,  pivoxicam ,  tenoxicam ,  lornoxicam , [ 1 ]  and  meloxicam .


Isoxicam  has been suspended as a result of fatal skin reactions. [ 1 ]


The physico-chemical characteristics of these molecules vary greatly depending upon the environment. [ 4 ]


In contrast to most other NSAIDs, oxicams are not  carboxylic acids .  They are  tautomeric , and can exist as a number of tautomers ( keto-enol tautomerism ), here exemplified by piroxicam: [ 2 ]


The oxicams are associated with drug-related  erythema multiforme  (EM),  Stevens–Johnson syndrome , and  toxic epidermal necrolysis  (TEN).  This association is one of the reasons oxicams are not regularly prescribed.


Paracetamol , [ a ]  or  acetaminophen , [ b ]  is a non-opioid  analgesic  and  antipyretic  agent used to treat  fever  and mild to moderate  pain . [ 13 ] [ 14 ] [ 15 ]  It is a widely available  over-the-counter drug  sold under various brand names, including  Tylenol  and  Panadol .


Paracetamol relieves pain in both acute mild  migraine  and episodic  tension headache . [ 16 ] [ 17 ]  At a standard dose, paracetamol slightly reduces fever; [ 14 ] [ 18 ] [ 19 ]  it is inferior to  ibuprofen  in that respect, [ 20 ]  and the benefits of its use for fever are unclear, particularly in the context of fever of viral origins. [ 14 ] [ 21 ] [ 22 ]   The  aspirin/paracetamol/caffeine  combination also helps with both conditions where the pain is mild and is recommended as a  first-line treatment  for them. [ 23 ] [ 24 ]  Paracetamol is effective for post- surgical  pain, but it is inferior to ibuprofen. [ 25 ]  The  paracetamol/ibuprofen  combination provides further increase in potency and is superior to either drug alone. [ 25 ] [ 26 ]  The pain relief paracetamol provides in  osteoarthritis  is small and clinically insignificant. [ 15 ] [ 27 ] [ 28 ]  The evidence in its favor for the use in low back pain,  cancer pain , and  neuropathic pain  is insufficient. [ 15 ] [ 27 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ]


In the short term, paracetamol is safe and effective when used as directed. [ 33 ]  Short term adverse effects are uncommon and similar to ibuprofen, [ 34 ]  but paracetamol is typically safer than  nonsteroidal anti-inflammatory drugs  (NSAIDs) for long-term use. [ 35 ]  Paracetamol is also often used in patients who cannot tolerate NSAIDs like ibuprofen. [ 36 ] [ 37 ]  Chronic consumption of paracetamol may result in a drop in  hemoglobin  level, indicating possible  gastrointestinal bleeding , [ 38 ]  and  abnormal liver function tests . The recommended maximum daily dose for an adult is three to four grams. [ 27 ] [ 39 ]  Higher doses may lead to toxicity, including  liver failure . [ 40 ]   Paracetamol poisoning  is the foremost cause of  acute liver failure  in the  Western world , and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. [ 41 ] [ 42 ] [ 43 ]


Paracetamol was first made in 1878 by  Harmon Northrop Morse  or possibly in 1852 by  Charles Frédéric Gerhardt . [ 44 ] [ 45 ] [ 46 ]  It is the most commonly used medication for pain and fever in both the United States and Europe. [ 47 ]  It is on the  World Health Organization's List of Essential Medicines . [ 48 ]  Paracetamol is available as a  generic medication , with brand names including  Tylenol  and  Panadol  among  others . [ 49 ]  In 2022, it was the 114th most commonly prescribed medication in the United States, with more than 5   million prescriptions. [ 50 ] [ 51 ]


Paracetamol is used for reducing fever. [ 13 ]  However, there has been a lack of research on its  antipyretic  properties, particularly in adults, and thus its benefits are unclear. [ 14 ]  As a result, it has been described as  over-prescribed  for this application. [ 14 ]  In addition, low-quality  clinical data  indicates that when used for the  common cold , paracetamol may relieve a  stuffed  or  runny  nose, but not other cold symptoms such as  sore throat ,  malaise ,  sneezing , or  cough . [ 52 ]


For people in  critical care , paracetamol decreases body temperature by only 0.2–0.3   °C more than control interventions and has no effect on their  mortality . [ 18 ]  It did not change the outcome in febrile patients with stroke. [ 53 ]  The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported. [ 18 ]  Paracetamol offered no benefit in the treatment of  dengue fever  and was accompanied by a higher rate of liver enzyme elevation: a sign of potential liver damage. [ 54 ]  Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection. [ 22 ]


The efficacy of paracetamol in children with fever is unclear. [ 55 ]  Paracetamol should not be used solely to reduce body temperature; however, it may be considered for children with fever who appear distressed. [ 56 ]  It does not prevent  febrile seizures . [ 56 ] [ 57 ]  It appears that 0.2   °C decrease of the body temperature in children after a standard dose of paracetamol is of questionable value, particularly in emergencies. [ 14 ]  Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7   °C. [ 19 ]  Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis [ 58 ] ), including children younger than 2 years old, [ 59 ]  with equivalent safety. [ 20 ]   Exacerbation  of asthma occurs with similar frequency for both medications. [ 60 ]  Giving paracetamol and ibuprofen together at the same time to children under 5 is not recommended; however, doses may be alternated if required. [ 56 ]


Paracetamol is used for the relief of mild to moderate pain such as headache, muscle aches, minor arthritis pain, toothache as well as pain caused by cold, flu, sprains, and  dysmenorrhea . [ 61 ]  It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient. [ 15 ]


The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain. [ 15 ]


It appears to provide only small and not clinically important benefits in  osteoarthritis . [ 15 ] [ 27 ]   American College of Rheumatology  and  Arthritis Foundation  guideline for the management of osteoarthritis notes that the  effect size  in  clinical trials  of paracetamol has been very small, which suggests that for most individuals it is ineffective. [ 28 ]  The guideline conditionally recommends paracetamol for short-term and episodic use to those who do not tolerate nonsteroidal anti-inflammatory drugs. For people taking it regularly, monitoring for liver toxicity is required. [ 28 ]  Essentially the same recommendation was issued by  EULAR  for hand osteoarthritis. [ 62 ]  Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only. [ 63 ]


Paracetamol is ineffective for acute low back pain. [ 15 ] [ 29 ]  No randomized clinical trials evaluated its use for chronic or  radicular  back pain, and the evidence in favor of paracetamol is lacking. [ 30 ] [ 27 ] [ 29 ]


Paracetamol is effective for acute migraine: [ 16 ]  39 % of people experience pain relief at one hour compared with 20 % in the control group. [ 64 ]  The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a  first-line treatment  for migraine". [ 23 ]  Paracetamol on its own only slightly alleviates episodic  tension headache  in those who have them frequently. [ 17 ]  However, the aspirin/paracetamol/caffeine combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache: two hours after administering the medication, 29 % of those who took the combination were pain-free as compared with 21 % on paracetamol and 18 % on placebo. [ 65 ]  The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend this combination as a "highlighted" one for self-medication of tension headache, with paracetamol/caffeine combination being a "remedy of first choice", and paracetamol a "remedy of second choice". [ 24 ]


Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain. [ 66 ]  For the relief of such pain, paracetamol is inferior to ibuprofen. [ 25 ]  Full therapeutic doses of nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen,  naproxen  or  diclofenac  are clearly more efficacious than the paracetamol/codeine combination which is frequently prescribed for dental pain. [ 67 ]  The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone. [ 25 ] [ 26 ] [ 68 ] [ 69 ]  Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations. [ 26 ]


A meta-analysis of general post-surgical pain, which included dental and other surgery, showed the paracetamol/codeine combination to be more effective than paracetamol alone: it provided significant pain relief to as much as 53 % of the participants, while the placebo helped only 7 %. [ 70 ]


Paracetamol fails to relieve procedural pain in  newborn babies . [ 71 ] [ 72 ]  For  perineal  pain  postpartum  paracetamol appears to be less effective than  nonsteroidal anti-inflammatory drugs  (NSAIDs). [ 73 ]


The studies to support or refute the use of paracetamol for cancer pain and neuropathic pain are lacking. [ 31 ] [ 32 ]  There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department. [ 74 ]  The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain. [ 75 ]


Paracetamol helps ductal closure in  patent ductus arteriosus . It is as effective for this purpose as ibuprofen or  indomethacin , but results in less frequent gastrointestinal bleeding than ibuprofen. [ 76 ]  Its use for extremely low birth weight and gestational age infants however requires further study. [ 76 ]


Gastrointestinal adverse effects such as nausea and  abdominal pain  are extremely uncommon, and their frequency is nothing
like that of ibuprofen. [ 37 ]  Increase in risk-taking behavior is possible. [ 77 ]  According to the U.S.  Food and Drug Administration  (FDA), the drug may cause rare and possibly fatal skin reactions such as  Stevens–Johnson syndrome  and  toxic epidermal necrolysis , [ 78 ]   Rechallenge  tests and an analysis of American but not French  pharmacovigilance  databases indicated a risk of these reactions. [ 78 ] [ 79 ]


In clinical trials for  osteoarthritis , the number of participants reporting adverse effects was similar for those on paracetamol and on placebo. However, the abnormal liver function tests (meaning there was some inflammation or damage to the liver) were almost four times more likely in those on paracetamol, although the clinical importance of this effect is uncertain. [ 80 ]  After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicating  gastrointestinal bleeding  was observed in 20 % of participants, this rate being similar to the ibuprofen group. [ 38 ]


Due to the absence of  controlled studies , most of the information about the long-term safety of paracetamol comes from  observational studies . [ 37 ]  These indicate a consistent pattern of increased  mortality  as well as  cardiovascular  ( stroke ,  myocardial infarction ), gastrointestinal ( ulcers ,  bleeding ) and  renal  adverse effects with increased dose of paracetamol. [ 38 ] [ 37 ] [ 81 ]  Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer. [ 37 ]  Those who take it regularly at a higher dose (more than 2–3   g daily) are at much higher risk (3.6–3.7 times) of gastrointestinal bleeding and other bleeding events. [ 82 ]  Meta-analyses suggest that paracetamol may increase the risk of  kidney impairment  by 23 % [ 83 ]  and kidney cancer by 28 %. [ 81 ]  Paracetamol slightly but significantly increases  blood pressure  and heart rate. [ 37 ]  A 2022 double-blind, placebo-controlled, crossover study has provided evidence that daily, high-dose use (4 g per day) of paracetamol increases systolic BP. [ 84 ] [ non-primary source needed ]   A review of available research has suggested that increase in systolic blood pressure and increased risk of gastrointestinal bleeding associated with chronic paracetamol use shows a degree of dose dependence. [ 82 ]


The association between paracetamol use and  asthma  in children has been a matter of controversy. [ 85 ]  However, the most recent research suggests that there is no association, [ 86 ]  and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer, ibuprofen. [ 60 ]


In recommended doses, the  side effects  of paracetamol are mild to non-existent. [ 87 ]  In contrast to aspirin, it is not a  blood thinner  (and thus may be used in patients where bleeding is a concern), and it does not cause gastric irritation. [ 88 ]  Compared to Ibuprofen—which can have adverse effects that include diarrhea, vomiting, and abdominal pain—paracetamol is well tolerated with fewer side effects. [ 89 ]  Prolonged daily use may cause kidney or liver damage. [ 88 ] [ 90 ]  Paracetamol is metabolized by the liver and is  hepatotoxic ; side effects may be more likely in  chronic alcoholics  or patients with liver damage. [ 87 ] [ 91 ]


Until 2010 paracetamol was believed safe in pregnancy however, in a study published in October 2010 it has been linked to  infertility  in the adult life of the unborn. [ 92 ]  Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood. One recent research study showed evidence that paracetamol can ease psychological pain, but more studies are needed to draw a stronger conclusion. [ 93 ]  Unlike aspirin, it is safe for children, as paracetamol is not associated with a risk of  Reye's syndrome  in children with viral illnesses. [ 94 ]  Chronic users of paracetamol may have a higher risk of developing  blood cancer . [ 95 ]


Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or  birth defects . However, indications exist of a possible increase in the risk of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy. [ 82 ]


Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood  asthma , [ 96 ] [ 97 ]  but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult. [ 82 ]  Paracetamol, in a small-scale meta-analysis was also associated with a 20–30 % increase in  autism spectrum disorder ,  attention deficit hyperactivity disorder , and  conduct disorder , with the association being lower in a meta-analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and whether there was potential bias in the findings. [ 82 ] [ 98 ] [ 99 ]  There is also an argument that the large number, consistency, and robust designs of the studies provide strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders. [ 100 ] [ 101 ]  In animal experiments, paracetamol disrupts fetal  testosterone  production, and several epidemiological studies linked  cryptorchidism  with mother's paracetamol use for more than two weeks in the second trimester. On the other hand, several studies did not find any association. [ 82 ]


The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at the lowest effective dosage, and for the shortest time. [ 82 ] [ 102 ] [ 103 ]


In pregnancy, paracetamol and  metoclopramide  are deemed safe as are NSAIDs until the  third trimester . [ 104 ]


Overdose  of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams), [ 39 ]  and can cause potentially fatal  liver damage . [ 105 ] [ 106 ]  A single dose should not exceed 1000 mg, doses should be taken no sooner than four hours apart, and no more than four doses (4000 mg) in 24 hours. [ 39 ]  While a majority of adult overdoses are linked to suicide attempts, many cases are accidental, often due to the use of more than one paracetamol-containing product over an extended period. [ 107 ]