Aspirin

Aspirin (USAN), also known as acetylsalicylic acid ( ; abbreviated ASA), is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication.

Salicylic acid, the main metabolite of aspirin, is an integral part of human and animal metabolism. While much of it is attributable to diet, a substantial part is synthesized endogenously.

Aspirin also has an antiplatelet effect by inhibiting the production of thromboxane, which under normal circumstances binds platelet molecules together to create a patch over damaged walls of blood vessels. Because the platelet patch can become too large and also block blood flow, locally and downstream, aspirin is also used long-term, at low doses, to help prevent heart attacks, strokes, and blood clot formation in people at high risk for developing blood clots. It has also been established that low doses of aspirin may be given immediately after a heart attack to reduce the risk of another heart attack or of the death of cardiac tissue.

The main undesirable side effects of aspirin are gastrointestinal ulcers, stomach bleeding, and tinnitus, especially in higher doses. In children and adolescents, aspirin is no longer used to control flu-like symptoms or the symptoms of chickenpox or other viral illnesses, because of the risk of Reye's syndrome.

Aspirin is part of a group of medication called nonsteroidal anti-inflammatory drugs (NSAIDs). Though it, and other in its group called the salicylates, have similar effects (antipyretic, anti-inflammatory, analgesic) and inhibit the same enzyme cyclooxygenase as their mechanism of action, they do so in a irreversible manner (see NSAID mechanism of action). For example, NSAIDs antiplatelet effects last in the order of hours, whereas aspirin's effect lasts for days (until the body replaces the suppressed platelets). Hence, when physicians tell patients to stop taking NSAIDs, they usually imply aspirin as well.

Today, aspirin is one of the most widely used medications in the world, with an estimated 40,000 tonnes of it being consumed each year. In countries where Aspirin is a registered trademark owned by Bayer, the generic term is acetylsalicylic acid (ASA).

Medical uses

Aspirin is used for the treatment of a number of conditions including: fever, pain, rheumatic fever, inflammatory diseases such as rheumatoid arthritis, pericarditis, and Kawasaki disease.

Pain

In general, aspirin works well for dull, throbbing pain; it is ineffective for pain caused by most muscle cramps, bloating, gastric distension and acute skin irritation. The most studied example is pain after surgery, such as tooth extraction, for which the highest allowed dose of aspirin (1 g) is equivalent to 1 g of paracetamol, 60 mg of codeine and 5 mg of oxycodone. A combination of aspirin and caffeine, generally, affords greater pain relief than aspirin alone. Effervescent aspirin alleviates pain much faster than aspirin in tablets (15–30 min vs. 45–60 min).

Nevertheless, as a postsurgery painkiller, aspirin is inferior to ibuprofen and has higher gastrointestinal toxicity. The maximum dose of aspirin (1 g) provides weaker pain relief than an intermediate dose of ibuprofen (400 mg), and this relief does not last as long. It appears ibuprofen is at least equally, and possibly more, effective than this combination.

According to a meta-analysis of clinical trials for menstrual pain, aspirin demonstrated higher efficacy than placebo, but lower than ibuprofen or naproxen, although maximum doses of aspirin were never used in these trials. The authors concluded ibuprofen has the best risk-benefit ratio.

Aspirin did not ease pain during cycling exercise, while caffeine, surprisingly, was very effective. Similarly, aspirin, codeine or paracetamol were not better than placebo for muscle soreness after exercise.

Headache

Aspirin is a first-line drug in the treatment of migraine, bringing relief in 50–60% of the cases. When used at a high dose of 1000 mg (as compared to 275–325 mg when used as a pain killer or 81 mg as a antiplatelet therapy). no significant differences were seen as compared to triptan medication, sumatriptan (Imitrex) and other painkillers such as paracetamol(acetaminophen) or ibuprofen. The combination of aspirin, paracetamol (acetaminophen) and caffeine (Excedrin) is even more potent. For the treatment of migraine headache, this formulation works better than any of its three components taken separately, and better than sumatriptan. Similarly to all other medications for migraine, it is recommended to take aspirin at the first signs of the headache, and it is the way these medications were used in the comparative clinical trials.

Aspirin alleviates pain in 60–75% of patients with episodic tension headaches. It is equivalent to paracetamol (acetaminophen) in that respect, except for the higher frequency of gastrointestinal side effects. The combination of aspirin, paracetamol (acetaminophen) and caffeine (Excedrin) is still more effective, but at the cost of more stomach discomfort, nervousness and dizziness.

There is some evidence low-dose asprin has benefit for reducing the occurrence of migraines in susceptible individuals.

Prevention of heart attacks and strokes

There are two distinct uses of aspirin for prophylaxis of cardiovascular events: primary prevention and secondary prevention. Primary prevention is about decreasing strokes and heart attacks in the general population of those who have no diagnosed heart or vascular problems. Secondary prevention concerns patients with known cardiovascular disease.

Low doses of aspirin are recommended for the secondary prevention of strokes and heart attacks. For both males and females diagnosed with cardiovascular disease, aspirin reduces the chance of a heart attack and ischaemic stroke by about a fifth. This translates to an absolute rate reduction from 8.2% to 6.7% of such events per year for people already with cardiovascular disease. Although aspirin also raises the risk of hemorrhagic stroke and other major bleeds by about twofold, these events are rare, and the balance of aspirin's effects is positive. Thus, in secondary prevention trials, aspirin reduced the overall mortality by about a tenth. On the other hand, Antithrombotic Trialists’ Collaboration argued such recommendations are unjustified, since the relative reduction of risk in the primary prevention trials of aspirin was same for persons in high- and low-risk groups and did not depend on the blood pressure. The Collaboration suggested statins as the alternative and more effective preventive medication. and with sore throat pain, for those who had it. Aspirin was indistinguishable from paracetamol in any respect, except for, possibly, slightly higher rate of sweating and gastrointestinal side effects. In addition, the high doses of aspirin used caused liver toxicity in about 20% of the treated children, who are the majority of rheumatic fever patients, and increased the risk of their developing Reye's syndrome.

Along with rheumatic fever, Kawasaki disease remains one of the few indications for aspirin use in children, although even this use has been questioned by some authors. In the United Kingdom, the only indications for aspirin use in children and adolescents under 16 are Kawasaki disease and prevention of blood clot formation.

Aspirin is also used in the treatment of pericarditis, coronary artery disease, and acute myocardial infarction.

Taking aspirin before air travel in cramped conditions has been suggested to decrease the risk of deep-vein thrombosis (DVT). The reason for taking aspirin is the long period of sitting without exercise, not air travel itself. A large, randomized, controlled trial in 2000 of aspirin against placebo in 13,000 patients with hip fractures found "a 29% relative risk reduction in DVT with 160 mg of aspirin taken daily for five weeks. Although there are obvious problems with extrapolating the data to long-distance travelers, this is the best evidence we could find to justify aspirin use".

Experimental

Aspirin has been theorized to reduce cataract formation in diabetic patients, but one study showed it was ineffective for this purpose. The role of aspirin in reducing the incidence of many forms of cancer has also been widely studied. In several studies, its use did not reduce the incidence of prostate cancer. Its effects on the incidence of pancreatic cancer are mixed; one study published in 2004 found a statistically significant increase in the risk of pancreatic cancer among women, while a meta-analysis of several studies, published in 2006, found no evidence aspirin or other NSAIDs are associated with an increased risk for the disease. The drug may be effective in reduction of risk of various cancers, including those of the colon, lung, and possibly the upper GI tract, though some evidence of its effectiveness in preventing cancer of the upper GI tract has been inconclusive. Its preventative effect against adenocarcinomas may be explained by its inhibition of PTGS2 (COX-2) enzymes expressed in them.

A 2009 article published by the Journal of Clinical Investigation suggested that aspirin might prevent liver damage. In their experiment, scientists from Yale University and The University of Iowa induced damage in certain liver cells (hepatocytes) using excessive doses of acetaminophen. This caused hepatoxicity and hepatocyte death, which triggered an increase in the production of TLR9. The expression of TLR9 caused an inflammatory cascade involving pro–IL-1β and pro-IL-18. Aspirin was found to have a protective effect on hepatocytes because it led to the "downregulation of proinflammatory cytokines".

In another 2009 article published by the Journal of the American Medical Association, men and women who regularly took aspirin after colorectal cancer diagnosis were found to have lower risks of overall and colorectal cancer death compared to patients not using aspirin.

A 2010 article in the Journal of Clinical Oncology has suggested aspirin may reduce the risk of death from breast cancer. While the information has been well-circulated by the media, official health bodies and medical groups have expressed concern over the touting of aspirin as a "miracle drug".

A 2010 study by Oxford University involving over 25000 patients showed taking a small (75 mg) daily dose of aspirin for between four and eight years substantially reduces death rates from a range of common cancers by at least a fifth and the reduction of risk continued for 20 years in both men and women. For specific cancers the, reduction was about 40% for bowel cancer, 30% for lung cancer, 10% for prostate cancer and 60% for oesophageal cancer, while the reductions in pancreas, stomach, brain, breast and ovarian cancers were difficult to quantify because there were not enough data, but other studies are in progress. However, taking aspirin doubles the annual risk of major internal bleeding that normally has a very low incidence (about 1 in 1000) in middle age, but increased dramatically after 75 years old.

Resistance

For some people, aspirin does not have as strong an effect on platelets as for others, an effect known as aspirin resistance or insensitivity. One study has suggested women are more likely to be resistant than men, and a different, aggregate study of 2,930 patients found 28% to be resistant. A study in 100 Italian patients found that of the apparent 31% aspirin-resistant subjects, only 5% were truly resistant, and the others were noncompliant.

Dosage

Adult aspirin tablets are produced in standardised sizes which vary slightly from country to country, for example 300 mg in Britain and 325 mg in the USA. Smaller doses are based on these standards; thus 75 and 81 mg tablets are used—there is no medical significance in the slight difference. It is of historical interest that the US 325 mg dose is almost exactly equivalent to the historic 5 grain aspirin tablet that preceded the metric dosage.

For adults, doses are generally taken four times a day for fever or arthritis, with doses near the maximal daily dose used historically for the treatment of rheumatic fever. For the prevention of myocardial infarction in someone with documented or suspected coronary artery disease, much lower doses are taken once daily. The WHI study said regular low dose (75 or 81 mg) aspirin female users had a 25% lower risk of death from cardiovascular disease and a 14% lower risk of death from any cause.

Adverse effects

Contraindications

Aspirin should not be taken by people who are allergic to ibuprofen or naproxen, 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. Even if none of these conditions is present, there is still an increased risk of stomach bleeding when aspirin is taken with alcohol or warfarin. Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency. 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. Aspirin should not be given to children or adolescents to control cold or influenza symptoms, as this has been linked with Reye's syndrome. Although some enteric coated formulations of aspirin are advertised as being "gentle to the stomach", in one study enteric coating did not seem to reduce this risk.

In addition to enteric coating, "buffering" is the other main method companies have used to try to mitigate the problem of gastrointestinal bleeding. Buffering agents are intended to work by preventing the aspirin from concentrating in the walls of the stomach, although the benefits of buffered aspirin are disputed. Almost any buffering agent used in antacids can be used; Bufferin, for example, uses MgO. Other preparations use CaCO₃.

Taking it with vitamin C is a more recently investigated method of protecting the stomach lining. According to research done at a German university, taking equal doses of vitamin C and aspirin decreases the amount of stomach damage that occurs compared to taking aspirin alone.

Deglycyrrhizinated licorice (DGL), an extract of the popular herb licorice, reportedly helps relieve the symptoms of gastritis. In a 1979 research study, a dose of 350 milligrams of DGL was shown to decrease the amount of gastrointestinal bleeding induced by three adult-strength aspirin tablets (750 milligrams).

A dose of 500 milligrams of S-adenosyl-methionine (SAMe, an amino acid naturally formed in the body) given together with a large dose of aspirin (1300 milligrams) in a research study reduced the amount of stomach damage by 90 percent.

Central effects

Large doses of salicylate, a metabolite of aspirin, have been proposed to cause tinnitus (ringing in the ears) based on experiments in rats, via the action on arachidonic acid and NMDA receptors cascade.

Reye's syndrome

Reye's syndrome, a rare but severe illness characterized by acute encephalopathy and fatty liver, can occur when children or adolescents are given aspirin for a fever or other illnesses or infections. From 1981 through 1997, 1207 cases of Reye's syndrome in under-18 patients were reported to the U.S. Centers for Disease Control and Prevention. Of these, 93% reported being ill in the three weeks preceding onset of Reye's syndrome, most commonly with a respiratory infection, chickenpox, or diarrhea. Salicylates were detectable in 81.9% of children for whom test results were reported. After the association between Reye's syndrome and aspirin was reported and safety measures to prevent it (including a Surgeon General's warning and changes to the labeling of aspirin-containing drugs) were implemented, aspirin taken by children declined considerably in the United States, as did the number of reported cases of Reye's syndrome; a similar decline was found in the United Kingdom after warnings against pediatric aspirin use were issued.

Hives and swelling

For a small number of people, taking aspirin can result in symptoms that resemble an allergic reaction, including hives, swelling and headache. The reaction is caused by salicylate intolerance and is not a true allergy, but rather an inability to metabolize even small amounts of aspirin, resulting in an overdose.

Other effects

Aspirin can induce angioedema (swelling of skin tissues) in some people. In one study, angioedema appeared one to six hours after ingesting aspirin in some of the patients participating in the study. However, when the aspirin was taken alone, it did not cause angioedema in these patients; the aspirin had been taken in combination with another NSAID-induced drug when angioedema appeared.

Aspirin causes an increased risk of cerebral microbleeds having the appearance on MRI scans of 5–10 mm or smaller hypointense (dark holes) patches. Such cerebral microbleeds are important since they often occur prior to ischemic stroke or intracerebral hemorrhage, Binswanger disease and Alzheimer's disease.

Aspirin can cause prolonged bleeding after operations for up to 10 days. In one study, 30 of 6499 elective surgical patients required reoperations to control bleeding. Twenty had diffuse bleeding and 10 had bleeding from a site. Diffuse, but not discrete, bleeding was associated with the preoperative use of aspirin alone or in combination with other NSAIDS in 19 of the 20 diffuse bleeding patients.

Overdose

Aspirin overdose can be acute or chronic. In acute poisoning, a single large dose is taken; in chronic poisoning, higher than normal doses are taken over a period of time. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal, with a mortality rate of 25%; chronic overdose may be especially severe in children. Toxicity is managed with a number of potential treatments, including activated charcoal, intravenous dextrose and normal saline, sodium bicarbonate, and dialysis. The diagnosis of poisoning usually involves measurement of plasma salicylate, the active metabolite of aspirin, by automated spectrophotometric methods. Plasma salicylate levels generally range from 30–100 mg/L after usual therapeutic doses, 50–300 mg/L in patients taking high doses and 700–1400 mg/L following acute overdose. Salicylate is also produced as a result of exposure to bismuth subsalicylate, methyl salicylate and sodium salicylate.

Interactions

Aspirin is known to interact with other drugs. For example, acetazolamide and ammonium chloride have been known to enhance the intoxicating effect of salicyclates, and alcohol also increases the gastrointestinal bleeding associated with these types of drugs. Aspirin is known to displace a number of drugs from protein binding sites in the blood, including the antidiabetic drugs tolbutamide and chlorpropamide, the immunosuppressant methotrexate, phenytoin, probenecid, valproic acid (as well as interfering with beta oxidation, an important part of valproate metabolism) and any nonsteroidal anti-inflammatory drug. Corticosteroids may also reduce the concentration of aspirin. Ibuprofen can negate the antiplatelet effect of aspirin used for cardioprotection and stroke prevention. The pharmacological activity of spironolactone may be reduced by taking aspirin, and aspirin is known to compete with Penicillin G for renal tubular secretion. Aspirin may also inhibit the absorption of vitamin C.

Chemical properties

Aspirin, an acetyl derivative of salicylic acid, is a white, crystalline, weakly acidic substance, with a melting point of . Acetylsalicylic acid decomposes rapidly in solutions of ammonium acetate or of the acetates, carbonates, citrates or hydroxides of the alkali metals. Acetylsalicylic acid is stable in dry air, but gradually hydrolyses in contact with moisture to acetic and salicylic acids. In solution with alkalis, the hydrolysis proceeds rapidly and the clear solutions formed may consist entirely of acetate and salicylate.

Synthesis

The synthesis of aspirin is classified as an esterification reaction. Salicylic acid is treated with acetic anhydride, an acid derivative, causing a chemical reaction that turns salicylic acid's hydroxyl group into an acetyl group, (R-OH → R-OCOCH3). This process yields aspirin and acetic acid, which is considered a byproduct of this reaction. Small amounts of sulfuric acid (and occasionally phosphoric acid) are almost always used as a catalyst. This method is commonly employed in undergraduate teaching labs.

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Formulations containing high concentrations of aspirin often smell like vinegar. because aspirin can decompose through hydrolysis in moist conditions, yielding salicylic acid and acetic acid.

The acid dissociation constant (pK_a) for acetylsalicylic acid is 3.5 at .

Polymorphism

Polymorphism, or the ability of a substance to form more than one crystal structure, is important in the development of pharmaceutical ingredients. Many drugs are receiving regulatory approval for only a single crystal form or polymorph. For a long time, only one crystal structure for aspirin was known, although there had been indications aspirin might have a second crystalline form since the 1960s. The elusive second polymorph was first discovered by Vishweshwar and coworkers in 2005, and fine structural details were given by Bond et al. A new crystal type was found after attempted cocrystallization of aspirin and levetiracetam from hot acetonitrile. The form II is only stable at 100 K and reverts to form I at ambient temperature. In the (unambiguous) form I, two salicylic molecules form centrosymmetric dimers through the acetyl groups with the (acidic) methyl proton to carbonyl hydrogen bonds, and in the newly claimed form II, each salicylic molecule forms the same hydrogen bonds with two neighboring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid groups both polymorphs form identical dimer structures.

Mechanism of action

Discovery of the mechanism

In 1971, British pharmacologist John Robert Vane, then employed by the Royal College of Surgeons in London, showed aspirin suppressed the production of prostaglandins and thromboxanes. For this discovery, he was awarded both a Nobel Prize in Physiology or Medicine in 1982 and a knighthood.

Suppression of prostaglandins and thromboxanes

Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (PTGS) enzyme required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the PTGS enzyme. This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors.

Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A₂ in platelets, producing an inhibitory effect on platelet aggregation. This antithrombotic property makes aspirin useful for reducing the incidence of heart attacks. 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A₂ release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.

Prostaglandins are local hormones produced in the body and have diverse effects, including the transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are primarily caused by blood clots, and low doses of aspirin are seen as an effective medical intervention for acute myocardial infarction. An unwanted side effect of the effective anticlotting action of aspirin is that it may cause excessive bleeding.

COX-1 and COX-2 inhibition

There are at least two different types of cyclooxygenase: PTGS1 and PTGS2. Aspirin irreversibly inhibits PTGS1 and modifies the enzymatic activity of PTGS2. Normally, PTGS2 produces prostanoids, most of which are proinflammatory. Aspirin-modified PTGS2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs, COX 2 inhibitors, have been developed to inhibit only PTGS2, with the intent to reduce the incidence of gastrointestinal side effects. In short, aspirin buffers and transports the protons. When high doses of aspirin are given, it may actually cause fever owing to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. Additionally, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion, which is an important step in immune response to infection; however, there is currently insufficient evidence to show aspirin helps to fight infection. More recent data also suggests that salicylic acid and its derivatives modulate signaling through NF-κB. NF-κB, a transcription factor complex, plays a central role in many biological processes, including inflammation.

Effects upon hypothalamic-pituitary-adrenal activity

Aspirin, like other medications affecting prostaglandin synthesis, has profound effects on the pituitary gland, which indirectly affects a number of other hormones and physiological functions.Effects on growth hormone, prolactin and TSH (with relevant effect on T3 and T4) were observed directly. Aspirin reduces the effects of vasopressin and increases those of naloxone upon the secretion of ACTH and cortisol by the hypothalamic-pituitary-adrenal axis (HPA axis), which has been suggested to occur through an interaction with endogenous prostaglandins and their role in regulating the HPA axis.

About 50–80% of salicylate in the blood is bound by protein, while the rest remains in the active, ionized state; protein binding is concentration-dependent. Saturation of binding sites leads to more free salicylate and increased toxicity. The volume of distribution is 0.1–0.2 l/kg. Acidosis increases the volume of distribution because of enhancement of tissue penetration of salicylates. When higher doses of salicylate are ingested (more than 4 g), the half-life becomes much longer (15–30 hours), because the biotransformation pathways concerned with the formation of salicyluric acid and salicyl phenolic glucuronide become saturated. Renal excretion of salicylic acid becomes increasingly important as the metabolic pathways become saturated, because it is extremely sensitive to changes in urinary pH. There is a 10- to 20-fold increase in renal clearance when urine pH is increased from 5 to 8. The use of urinary alkalinization exploits this particular aspect of salicylate elimination.

History

Plant extracts, including willow bark and spiraea, of which salicylic acid was the active ingredient, had been known to help alleviate headaches, pains and fevers since antiquity. The father of modern medicine, Hippocrates, who lived sometime between 460 BC and 377 BC, left historical records describing the use of powder made from the bark and leaves of the willow tree to help these symptoms.

A French chemist, Charles Frederic Gerhardt, was the first to prepare acetylsalicylic acid in 1853. In the course of his work on the synthesis and properties of various acid anhydrides, he mixed acetyl chloride with a sodium salt of salicylic acid (sodium salicylate). A vigorous reaction ensued, and the resulting melt soon solidified. Since no structural theory existed at that time, Gerhardt called the compound he obtained "salicylic-acetic anhydride" (wasserfreie Salicylsäure-Essigsäure). This preparation of aspirin ("salicylic-acetic anhydride") was one of the many reactions Gerhardt conducted for his paper on anhydrides and he did not pursue it further.

Six years later, in 1859, von Gilm obtained analytically pure acetylsalicylic acid (which he called acetylierte Salicylsäure, acetylated salicylic acid) by a reaction of salicylic acid and acetyl chloride. In 1869, Schröder, Prinzhorn and Kraut repeated both Gerhardt's (from sodium salicylate) and von Gilm's (from salicylic acid) syntheses and concluded both reactions gave the same compound—acetylsalicylic acid. They were first to assign to it the correct structure with the acetyl group connected to the phenolic oxygen.

In 1897, chemists working at Bayer AG produced a synthetically altered version of salicin, derived from the species, which caused less digestive upset than pure salicylic acid. The identity of the lead chemist on this project is a matter of controversy. Bayer's official story is the work was done by Felix Hoffmann, but the Jewish chemist Arthur Eichengrün later claimed he was the lead investigator and records of his contribution were expunged under the Nazi regime. The new drug, formally acetylsalicylic acid, was named Aspirin by Bayer AG after the old botanical name for meadowsweet, Spiraea ulmaria. By 1899, Bayer was selling it around the world. The name Aspirin is derived from acetyl and spirsäure, an old German name for salicylic acid. The popularity of aspirin grew over the first half of the 20th century, spurred by its supposed effectiveness in the wake of the Spanish flu pandemic of 1918. However, recent research suggests the high death toll of the 1918 flu was partly due to aspirin, as the doses used at times can lead to toxicity, fluid in the lungs, and, in some cases, contribute to secondary bacterial infections and mortality. Aspirin's profitability led to fierce competition and the proliferation of aspirin brands and products, especially after the American patent held by Bayer expired in 1917.

The popularity of aspirin declined after the market releases of paracetamol (acetaminophen) in 1956 and ibuprofen in 1969. In the 1960s and 1970s, John Vane and others discovered the basic mechanism of aspirin's effects, while clinical trials and other studies from the 1960s to the 1980s established aspirin's efficacy as an anticlotting agent that reduces the risk of clotting diseases. Aspirin sales revived considerably in the last decades of the 20th century, and remain strong in the 21st century, because of its widespread use as a preventive treatment for heart attacks and strokes.

Trademark

As part of war reparations specified in the 1919 Treaty of Versailles following Germany's surrender after World War I, Aspirin (along with heroin) lost its status as a registered trademark in France, Russia, the United Kingdom, and the United States, where it became a generic name. Today, "aspirin" is a generic word in Australia, France, India, Ireland, New Zealand, Pakistan, Jamaica, the Philippines, South Africa, United Kingdom and the United States. Aspirin, with a capital "A", remains a registered trademark of Bayer in Germany, Canada, Mexico, and in over 80 other countries, where the trademark is owned by Bayer, using acetylsalicylic acid in all markets, but using different packaging and physical aspects for each.

Compendial status

United States Pharmacopeia British Pharmacopoeia

Veterinary use

Aspirin is sometimes used for pain relief or as an anti-coagulant in veterinary medicine, primarily in dogs and sometimes horses, although newer medications with fewer side effects are generally used instead. Both dogs and horse are susceptible to the gastrointestinal side effects associated with salicylates, but it is a convenient treatment for arthritis in older dogs and has shown some promise in cases of laminitis in horses. Aspirin should only be used in animals under the direct supervision of a veterinarian; in particular, cats lack the glucuronide conjugates that aid in the excretion of aspirin, making even low doses potentially toxic.

References

External links

NextBio Aspirin Entry

Interactive 3D-structure of aspirin with detailed x-ray crystal structure data

The History of Aspirin

How Aspirin works

The science behind aspirin

Take two: Aspirin, New uses and new dangers are still being discovered as aspirin enters its 2nd century. Shauna Roberts, American Chemical Society

U.S. National Library of Medicine: Drug Information Portal - Aspirin

Category:Non-steroidal anti-inflammatory drugs Category:Antiplatelet drugs Category:Benzoic acids Category:Equine medications Category:Salicylates Category:World Health Organization essential medicines Category:Acetate esters