(Redirected from Acetylsalicylic acid)
'Aspirin', or 'acetylsalicylic acid' (), (acetosal) is a
salicylate drug often used as an
analgesic (to relieve minor aches and pains),
antipyretic (to reduce
fever), and as an anti-
inflammatory. It also has an
antiplatelet ("blood-thinning") effect and is used in long-term, low doses to prevent
heart attacks and
blood clot formation in people at high risk for developing blood clots.
[1]
High doses of aspirin may also be given immediately after an acute heart attack; these doses may inhibit the synthesis of
prothrombin and therefore produce a second and different anticoagulant effect, although this is not well understood.
The main
undesirable side effects of aspirin are
gastrointestinal distress—including
ulcers and stomach bleeding—and
tinnitus, especially in higher doses. Another adverse effect is increased bleeding in
menstruating women, due to aspirin's anticoagulant properties. Aspirin is no longer used to control
flu-like symptoms or the symptoms of
chickenpox in children under 12 years of age due to the risk of
Reye's syndrome.
[2]
Aspirin was the first-discovered member of the class of drugs known as
non-steroidal anti-inflammatory drugs (NSAIDs), not all of which are salicylates, although they all have similar effects and a similar mechanism of action.
History
White willow (Salix alba) is a natural source of salicylic acid
Salicylic acid
The
Greek physician
Hippocrates wrote in the 5th century BC about a bitter powder extracted from
willow bark that could ease aches and pains and reduce fevers. This remedy was also mentioned in texts from ancient
Sumer,
Lebanon, and
Assyria. The
Cherokee and other Native Americans used an infusion of the bark for fever and other medicinal purposes for centuries.
[3] The medicinal part of the plant is the inner bark and was used as a pain reliever for a variety of ailments. The Reverend
Edward Stone, a vicar from
Chipping Norton, Oxfordshire,
England, noted in 1763 that the bark of the willow was effective in reducing a fever.
[4]
The active extract of the bark, called ''
salicin'', after the
Latin name for the white willow (''
Salix alba''), was isolated in crystalline form in 1828 by
Henri Leroux, a
French pharmacist, and
Raffaele Piria, an
Italian chemist. Piria was able to convert the substance into a sugar and a second component, which on oxidation becomes
salicylic acid.
Salicylic acid was also isolated from the herb
meadowsweet (''
Filipendula ulmaria'', formerly classified as ''
Spiraea ulmaria'') by German researchers in 1839. While their extract was somewhat effective, it also caused digestive problems such as
gastric irritation, bleeding,
diarrhea, and even death when consumed in high doses.
Modern development
A French chemist,
Charles Frederic Gerhardt, was first to prepare acetylsalicylic acid (named aspirin in 1899) 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.
[ Untersuchungen über die wasserfreien organischen Säuren, Gerhardt C, , , Annalen der Chemie und Pharmacie, 1853 ] Since no structural theory existed at that time Gerhardt called the compound he obtained "salicylic-acetic anhydride" (''wasserfreie Salicylsäure-Essigsäure''). When Gerhardt tried to dissolve the solid in a diluted solution of
sodium carbonate it immediately decomposed to sodium salts of salicylic and acetic acids.
[ 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 "acetylirte Salicylsäure", ''acetylated salicylic acid'') by a reaction of salicylic acid and acetyl chloride.[ Acetylderivate der Phloretin- und Salicylsäure, von Gilm H, , , Annalen der Chemie und Pharmacie, 1859 ] In 1869 Schröder, Prinzhorn and Kraut (Prinzhorn is credited in the paper with conducting the experiments) repeated both Gerhardt's (from sodium salicylate) and von Gilm's (from salicylic acid) syntheses and concluded that 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.[5]
In 1897, Felix Hoffmann, a chemist at Friedrich Bayer & Co., obtained acetylsalicylic acid[6] by a reaction of salicylic acid and acetic anhydride;[7] that is, essentially repeating the Gilm/Kraut procedure but substituting acetic anhydride for acetyl chloride. This synthesis served as the basis for Bayer claims to discovery of aspirin. According to a legend publicized by Bayer, Hoffmann made some of the formula and gave it to his father, who was suffering from the pain of arthritis and could not stand the side-effects of salicylic acid.
acetylsalicylic acid and that the latter had done so without knowing the purpose of the work".[ The discovery of aspirin: a reappraisal, Sneader W, , , BMJ, 2000 ] In 2000, Walter Sneader of University of Strathclyde in Glasgow reexamined the case and concluded that "Arthur Eichengrün was telling the truth when he wrote that acetylsalicylic acid was
synthesized under his direction and that the drug would not have been introduced in 1899 without his intervention".[ Subsequently, in his debate with Sneader, Axel Helmstaedter,]
General Secretary of the International Society for the History of Pharmacy, noted that Sneader did not credit several earlier publications which discussed the Hoffmann-Eichengrün controversy in detail, with most historians doubting Eichengrün's account.[8] Bayer also countered to Sneader in a press release that according to the records, Hoffmann and Eichengrün held equal positions, and Eichengrün was not Hoffmann's supervisor. Hoffmann was named on the US Patent as the inventor, which Sneader did not mention. Eichengrün, who left Bayer in 1908, had multiple opportunities to claim the priority and had never before 1949 done it; he neither claimed nor received any percentage of the profit from aspirin sales.[9] This argument did much to obscure the real history of aspirin, whose origin is not the pharmaceutical industry but earlier academic research. Despite the fact that pure aspirin was synthesized by von Gilm and by Kraut's group many years before Hoffmann, Bayer continues to insist that "The active ingredient in Aspirin®, acetylsalicylic acid, was synthesized for the first time in a chemically pure and thus stable form in 1897 by a young chemist working for Bayer, Dr. Felix Hoffmann."[10]
It was not until the 1970s that the mechanism of action of aspirin and other NSAIDs was elucidated.
Trademark issues
The brand name ''Aspirin'' was coined by the Bayer company of Germany. The name "aspirin" is composed of ''a-'' (from ''acetylirte'', meaning acetylated) ''-spir-'' (from the plant genus ''Spiraea'') and ''-in'' (a common, easily pronounceable ending for drug names at the time). On March 6, 1899, Bayer registered the name ''Aspirin'' as a trademark.
Bayer began marketing aspirin in July 1899. It was originally sold as a powder (which is still the preferred form in many European countries) and was an instant success; in 1914, Bayer introduced aspirin tablets.
Advertisement for Aspirin, Heroin, Lycetol, Salophen
Although Bayer had registered Aspirin as a trademark in 1899, the German Patent Office refused to grant Bayer a patent for the drug based on the grounds that neither the product nor the process of preparation were novel.
After World War II, Bayer lost the right to use the trademark in many countries because the Allies seized and resold its foreign assets. The right to use the aspirin trademark in the United States (along with all other Bayer trademarks) was purchased from the U.S. government by Sterling Drug in 1918. Even before the patent for the drug expired in 1917, Bayer had been unable to stop competitors from copying the formula and using the name elsewhere, so, with a flooded market, the public was unable to recognize aspirin as coming from only one manufacturer, and in 1921, a landmark ruling by Billings Learned Hand established "aspirin" as a genericized trademark.[11] Sterling was ultimately acquired by Bayer in 1994, but this did not restore the U.S. trademark. Other countries (such as Canada and many countries in Europe) still consider aspirin a protected trademark.
In some countries the name ''Aspirin'' is used as a generic name for the drug instead of the manufacturer's trademark. In countries in which Aspirin remains a trademark, the initialism 'ASA' (for ''acetylsalicylic acid''), or another initialism that matches the local-language term, is used as a generic term.
Synthesis
The synthesis of aspirin is classified as an esterification reaction, where the alcohol group from the salicylic acid reacts with an acid (acetyl anhydride) to form an ester. Aspirin is commercially synthesized using a two-step process. First, phenol (generally extracted from coal tar) is treated with a sodium base which generates sodium phenoxide, which is then reacted with carbon dioxide under high temperature and pressure to yield salicylate, which is acidified, yielding salicylic acid. This process is known as the Kolbe-Schmitt reaction.
:
Salicylic acid is then acetylated using acetic anhydride, yielding aspirin and acetic acid as a byproduct. This generally tends to produce low yields due to the relative difficulty of its extraction from an aqueous state. A method of extracting higher yields is to acidify with phosphoric acid and heat the reagents under reflux with a boiling water bath for between 40 to 60 minutes.
The original synthesis of aspirin from salicylic acid involved acetylation with acetyl chloride. Unfortunately, the byproduct from this is hydrochloric acid, which is corrosive and environmentally hazardous. As described above, it was then later found that acetic anhydride was a better acylating agent, with the byproduct acetic acid formed, which does not have the unwanted properties of hydrochloric acid and can also be recycled. The salicylic acid/acetic anhydride method is commonly employed in undergraduate teaching labs.
:
Formulations containing high concentrations of aspirin often smell like vinegar. This is because aspirin can undergo autocatalytic degradation to salicylic acid in moist conditions, yielding salicylic acid and acetic acid.
The acid dissociation constant (pKa) for Acetylsalicylic acid is 3.5 at 25 °C.[12] ASA, being a weak acid, dissociates as shown by the following reaction equation:
:
Therapeutic uses
Aspirin is one of the most frequently used drugs in the treatment of mild to moderate pain, including that of migraines,[13] and fever. It is often combined with other analgesics, even though this has never been shown to be more effective or less toxic than aspirin alone. Aspirin has, however, been used in addition to other non-steroidal anti-inflammatory drugs and opioid analgesics in the treatment of pain associated with cancer.[14]
In high doses, aspirin and other salicylates are used in the treatment of rheumatic fever, rheumatic arthritis, and other inflammatory joint conditions. In lower doses, aspirin also has properties as an inhibitor of platelet aggregation, and has been shown to decrease the incidence of transient ischemic attacks and unstable angina in men, and can be used prophylactically. It is also used in the treatment of Pericarditis, coronary artery disease, and acute myocardial infarction.
Veterinary uses
Aspirin has been used to treat pain and arthritis in veterinary medicine, primarily in cats and dogs, although it is not particularly recommended, as there are better medications available. Also, dogs are particularly susceptible to the gastrointestinal side effects associated with salicylates.[18] Horses have also been given aspirin for pain relief, although it is not commonly used due to its relatively short-lived analgesic effects. Horses are also fairly sensitive to the gastrointestinal side effects as well. Nevertheless, it has shown promise in its use as an anticoagulant, mostly in cases of laminitis.[19] Aspirin's use in animals should only be done under the direct supervision of a veterinarian.
Experimental uses
There have been some studies in the late 20th century indicating that aspirin may reduce cataract formation, although this is disputed.[20] The role of aspirin in reducing the rates of many forms of cancer has also been widely studied. One study suggests that aspirin can reduce the risk of breast cancer by almost 25%.[21] Additionally, aspirin may be effective in reduction of risk of other cancers as well, including those of the prostate,[22][23] colon,[24][25][26][27] pancreas,[28] upper GI tract,[29] and lung.[30][31] Its potency against tumors of the lung may be due to the fact that such tumors have high amounts of COX-2 enzymes expressed in them, especially adenocarcinomas and tumors caused by asbestosis, and aspirin is known to inhibit both the COX-1 and COX-2 enzymes.[32] Likewise, if there is a specific connection between COX-2 and lung cancer, other COX-2 inhibitors might also have the same effect. It should be pointed out, however, that this research is not complete, and there is currently no well-established medical recommendation on the use of aspirin or other NSAIDs for use in the treatment or prevention of cancer.
Contraindications
★ Aspirin should be avoided by those known to be allergic to ibuprofen or naproxen.
★ Caution should be exercised in those with asthma or NSAID-precipitated bronchospasm.
★ It is generally recommended that one seek medical help if symptoms do not improve after a few days of therapy.
★ Caution should be taken in patients with kidney disease, peptic ulcers, mild diabetes, gout or gastritis; manufacturers recommend talking to one's doctor before using this medicine.
★ Taking aspirin with alcohol or warfarin increases the chance of gastrointestinal hemorrhage (stomach bleeding).
★ Children under the age of 12 are discouraged from using aspirin in cold or flu symptoms as this has been linked with Reye's syndrome.
★ Patients with hemophilia or other bleeding tendencies should not take salicylates.
★ Some sources recommend that patients with hyperthyroidism avoid aspirin because it elevates T4 levels. [33]
★ Aspirin is known to cause hemolytic anemia in people who have the genetic disease glucose-6-phosphate dehydrogenase deficiency (G6PD), particularly in large doses and depending on the severity of the disease.
Adverse effects
★ Gastrointestinal complaints (stomach upset, dyspepsia, heartburn, small blood loss). To help avoid these problems, it is recommended that aspirin be taken at or after meals. Undetected blood loss may lead to hypochromic anemia.
★ Severe gastrointestinal complaints (gross bleeding and/or ulceration), requiring discontinuation and immediate treatment. Patients receiving high doses and/or long-term treatment should receive gastric protection with high-dosed antacids, ranitidine or omeprazole.
★ Frequently, central effects (dizziness, tinnitus, hearing loss, vertigo, centrally mediated vision disturbances, and headaches). The higher the daily dose is, the more likely it is that central nervous system side-effects will occur.
★ Sweating, seen with high doses, independent from antipyretic action
★ Long-term treatment with high doses (arthritis and rheumatic fever): often increased liver enzymes without symptoms, rarely reversible liver damage. The potentially fatal Reye's syndrome may occur, if given to pediatric patients with fever and other signs of infections. The syndrome is due to fatty degeneration of liver cells. Up to 30% of those afflicted will eventually die. Prompt hospital treatment may be life-saving.
★ Chronic nephritis with long-term use, usually if used in combination with certain other painkillers. This condition may lead to chronic renal failure.
★ Prolonged and more severe bleeding after operations and post-traumatic for up to 10 days after the last aspirin dose. If one wishes to counteract the bleeding tendency, fresh thrombocyte concentrate will usually work.
★ Skin reactions, angioedema, and bronchospasm have all been seen infrequently.
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 enhances the gastrointestinal bleeding associated with these types of drugs as well. Aspirin is known to displace a number of drugs from protein binding sites in the blood, including the anti-diabetic 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. The pharmacological activity of spironolactone may be reduced by taking aspirin, and aspirin is known to compete with Penicillin G for renal tubular secretion.[34] Aspirin may also inhibit the absorption of vitamin C.[35][36][37]
Dosage
For adults doses of 300 to 1000 mg are generally taken four times a day for fever or arthritis, with a maximum dose of 8000 mg (8 grams) a day.[38] The correct dose of aspirin depends on the disease or condition that is being treated. For instance, for the treatment of rheumatic fever, doses near the maximal daily dose have been used historically. For the prevention of myocardial infarction in someone with documented or suspected coronary artery disease, doses as low as 75 mg daily (or possibly even lower) are sufficient.
For those under 12 years of age, the dose previously varied with the age, but aspirin is no longer routinely used in children due to the association with Reye's syndrome; paracetamol (known in the United States as acetaminophen) or other NSAIDs, such as ibuprofen, are now used instead. Kawasaki disease remains one of the few indications for aspirin use in children, with aspirin initially started at 7.5–12.5 mg per kilogram of body weight, taken four times a day for up to two weeks and then continued at 5 mg/kg once daily for a further six to eight weeks.[39]
Overdose
Aspirin overdose can be acute or chronic. In acute poisoning, a single large dose is taken; in chronic poisoning, supratherapeutic 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.[40]
Symptoms
Aspirin overdose has potentially serious consequences, sometimes leading to significant morbidity and mortality. Patients with mild intoxication frequently have nausea and vomiting, abdominal pain, lethargy, tinnitus, and dizziness. More significant symptoms occur in more severe poisonings and include hyperthermia, tachypnea, respiratory alkalosis, metabolic acidosis, hyperkalemia, hypoglycemia, hallucinations, confusion, seizure, cerebral edema, and coma. The most common cause of death following an aspirin overdose is cardiopulmonary arrest usually due to pulmonary edema.[41]
Toxicity
The toxic dose of aspirin is generally considered greater than 150 mg per kg of body mass. Moderate toxicity occurs at doses up to 300 mg/kg, severe toxicity occurs between 300 to 500 mg/kg, and a potentially lethal dose is greater than 500 mg/kg.[42] This is the equivalent of many dozens of the common 325 mg tablets, depending on body weight. Note that children cannot tolerate as much aspirin per unit body weight as adults can, even when aspirin is indicated. Label-directions should be followed carefully.
Treatment
All overdose patients should be conveyed to hospital for assessment immediately. Initial treatment of an acute overdose includes gastric decontamination. This is achieved by administering activated charcoal which adsorbs the aspirin in the gastrointestinal tract. Stomach pumps are no longer routinely used in the treatment of poisonings but are sometimes considered if the patient has ingested a potentially lethal amount less than 1 hour previously.[ Position paper: gastric lavage., Vale JA, Kulig K; American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists., , , J Toxicol Clin Toxicol, 2004 ] Repeated doses of charcoal have been proposed to be beneficial in aspirin overdose.[43] A study performed found that repeat dose charcoal might not be of significant value.[44] However, most toxicologists will administer additional charcoal if serum salicylate levels are increasing.
Patients are monitored until their peak salicylate blood level has been determined.[45] Blood levels are usually performed 4 hours after ingestion and then every 2 hours after that to determine the maximum level. Maximum levels can be used as a guide to toxic effects expected.[46]
There is no antidote to salicylate poisoning. Frequent blood work is performed to check metabolic, salicylate, and blood sugar levels; arterial blood gas assessments are performed to test for respiratory alkalosis and metabolic acidosis. Patients are monitored and often treated according to their individual symptoms, patients may be given intravenous potassium chloride to counteract hypokalemia, glucose to restore blood sugar levels, benzodiazepines for any seizure activity, fluids for dehydration, and importantly sodium bicarbonate to restore the blood's sensitive pH balance. Sodium bicarbonate also has the effect of increasing the pH of urine, which in turn increases the elimination of salicylate. Additionally, hemodialysis can be implemented to enhance the removal of salicylate from the blood. Hemodialysis is usually used in severely poisoned patients; for example, patients with significantly high salicylate blood levels, significant neurotoxicity (agitation, coma, convulsions), renal failure, pulmonary edema, or cardiovascular instability are hemodialyzed.
If the overdose was intentional, the patient should undergo psychiatric evaluation, as with any suicide attempt.
Epidemiology
In the later part of the 20th century the number of salicylate poisonings has declined mainly due to the popularity of other over-the-counter analgesics such as paracetamol (acetaminophen). Fifty-two deaths involving single-ingredient aspirin were reported in the United States in the year 2000. However, in all but three cases, the reason for the ingestion of lethal doses was intentional, predominantly suicides.[47]
Mechanism of action
Structure of COX-2 inactivated by Aspirin. In the active site of each of the two monomers, Serine 530 has been acetylated. Also visible is the salicylic acid which has transferred the acyl group, and the heme cofactor.
In 1971, the British pharmacologist John Robert Vane, then employed by the Royal College of Surgeons in London, showed that aspirin suppresses the production of prostaglandins and thromboxanes.[48] For this discovery, he was awarded both a Nobel Prize in Physiology or Medicine in 1982 and a knighthood.
Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its competitive and irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is 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 COX 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 anticoagulant 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.[49]
Prostaglandins are local hormones (paracrine) produced in the body and have diverse effects in the body, including but not limited to 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 their reduction with the introduction of small amounts of aspirin has been seen to be an effective medical intervention. The side-effect of this is that the ability of the blood in general to clot is reduced, and excessive bleeding may result from the use of aspirin.
3D model of chemical structure of aspirin
There are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. Normally COX-2 produces prostanoids, most of which are pro-inflammatory. Aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called COX-2 selective inhibitors have been developed that inhibit only COX-2, with the hope for reduction of gastrointestinal side-effects.
However, several of the new COX-2 selective inhibitors have been recently withdrawn, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the microvasculature in the body express COX-2, and, by selectively inhibiting COX-2, prostaglandins (specifically PGI2; prostacyclin) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGI2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors.
Furthermore, aspirin has two additional modes of actions, contributing to its strong analgesic, antipyretic and anti-inflammatory properties:
★ It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons. In short, aspirin buffers and transports the protons. (Note: This effect in high doses of aspirin actually causes fever due to the heat released from the electron transport chain, instead of its normal antipyretic action.)
★ It induces the formation of NO-radicals in the body that enable the white blood cells (leukocytes) to fight infections more effectively. This has been found recently by Dr. Derek W. Gilroy, winning Bayer's International Aspirin Award 2005.[50]
More recent data suggest that salicylic acid and its derivatives will modulate signaling through NF-κB. NF-κB is a transcription factor complex that plays a central role in many biological processes, including inflammation.
See also
★ Aspergum
★ Copper aspirinate
★ Salicylic acid
References
1. http://www.americanheart.org/presenter.jhtml?identifier=4456 American Heart Association: ''Aspirin in Heart Attack and Stroke Prevention'' "The American Heart Association recommends aspirin use for patients who've had a myocardial infarction (heart attack), unstable angina, ischemic stroke (caused by blood clot) or transient ischemic attacks (TIAs or "little strokes"), if not contraindicated. This recommendation is based on sound evidence from clinical trials showing that aspirin helps prevent the recurrence of such events as heart attack, hospitalization for recurrent angina, second strokes, etc. (secondary prevention). Studies show aspirin also helps prevent these events from occurring in people at high risk (primary prevention)."
2. Aspirin use to be banned in under 16 year olds, Macdonald S, , , BMJ, 2002
3. Paul B. Hemel and Mary U. Chiltoskey, ''Cherokee Plants and Their Uses -- A 400 Year History,'' Sylva, NC: Herald Publishing Co. (1975); cited in Dan Moerman, A Database of Foods, Drugs, Dyes and Fibers of Native American Peoples, Derived from Plants.[1] A search of this database for "salix AND medicine" finds 63 entries.
4. An Account of the Success of the Bark of the Willow in the Cure of Agues, Stone, E, , , Philosophical Transactions, 1763
5. Uber Salicylverbindungen, Schröder, Prinzhorn, Kraut K, , , Annalen der Chemie und Pharmacie, 1869
6. The aspirin wars: money, medicine, and 100 years of rampant competition, by Charles C. Mann and Mark L. Plummer, , , Harvard Business School Press, 1991,
7. US Patent 644,077 dated February 27, 1900 Hoffmann H
8. Aspirin history: Is there a need for a reappraisal ? Helmstaedter A
9. Bayer AG: Zum Vortrag von Dr. Walter Sneader über die Entwicklung der Acetylsalicylsäure
10. Aspirin FAQ's
11. ''Bayer Co. v. United Drug Co.'', 272 F. 505 (S.D.N.Y. 1921). Free full text at Harvard Law School's Berkman Center for Internet & Society. Retrieved on 2007-09-07.
12. Acetylsalicylic acid
13. Management of the acute migraine headache, Aukerman G, Knutson D, Miser WF, , , Am Fam Physician, 2002 Free full text
14. Katzung, Bertram G. (1998). "Basic and Clinical Pharmacology", 7th ed., Stamford, Connecticut: Appleton & Lange. ISBN 0-8385-0565-1.
15. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2., ISIS-2 Collaborative group, , , Lancet, 1988
16. Aspirin may be less effective heart treatment for women than men Ann Arbor
17. Aspirin Resistance in Patients with Stable Coronary Artery Disease with and without a History of Myocardial Infarction, Dorsch MP, Lee JS, Lynch DR, Dunn SP, Rodgers JE, Schwartz T, Colby E, Montague D, Smyth SS, , , Ann Pharmacother., 2007
18. Veterinary Questions and Answers
19. Cambridge, H.; Lees, P.; Hooke, R.E.; Russell, C.S. "Antithrombotic actions of aspirin in the horse." 1991. ''Equine Vet. J.'' Vol. 23, Issue 2, 123-127.
20. Chew, E.Y. et al. "Aspirin effects on the development of cataracts in patients with diabetes mellitus. Early treatment diabetic retinopathy study report 16." 1992. ''Arch. Ophthalmol.'' Vol. 100. 339.
21. Staff Writer. "Aspirin use can cut breast cancer risk by nearly 25pct." ''Andhranews.net.'' September 7, 2007. Retrieved on September 7, 2007.
22. Aspirin and the risk of prostate cancer, Bosetti, ''et al.'', , , Eur J Cancer Prev, 2006
23. Regular use of aspirin and prostate cancer risk (United States), Menezes, ''et al.'', , , Cancer Causes Control, 2006
24. Thun, M.J.; Namboodiri, M.M.; Heath, C.W., Jr. "Aspirin use and reduced risk of fatal colon cancer." 1991. ''New Engl J Med.'' Vol. 325. 1593.
25. A randomized trial of aspirin to prevent colorectal adenomas, Baron, ''et al.'', , , N Engl J Med, 2003
26. A Prospective Study of Aspirin Use and the Risk for Colorectal Adenoma, Chan, ''et al.'', , , Ann Intern Med, 2004
27. Long-term Use of Aspirin and Nonsteroidal Anti-inflammatory Drugs and Risk of Colorectal Cancer, Chan, ''et al.'', , , JAMA, 2005
28. A Prospective Study of Aspirin Use and the Risk of Pancreatic Cancer in Women, Schernhammer, ''et al.'', , , J Natl Cancer Inst, 2004
29. Aspirin use and cancers of the upper aerodigestive tract, Bosetti, ''et al.'', , , Br J Cancer, 2003
30. Aspirin and lung cancer in women, Akhmedkhanov, ''et al.'', , , Br J cancer, 2002
31. Regular aspirin use and lung cancer risk, Moysich KB, Menezes RJ, Ronsani A, ''et al'', , , BMC Cancer, 2002 Free full text
32. Expression of cyclooxygenase-2 in human lung carcinoma, Wolff, ''et al.'', , , Cancer Research, 1998
33. [2]
34. Katzung, Bertram G. (1998), p. 584.
35. 'The Effects of Aspirin on the Metabolic Availability of Ascorbic Acid in Human Beings' The Journal of Clinical Pharmacology and New Drugs , 1973; 13:480–486 Published 1973. Accessed 31 July 2007.
36. 'Vitamin C-aspirin interactions' Int J Vitam Nutr Res Suppl. 1982;23:83–90. Published 1982. Accessed 31 July 2007.
37. 'Impairment of absorption of ascorbic acid following ingestion of aspirin in guinea pigs' Biochem Pharmacol. 1982 Dec 15;31(24):4035–8. Published 1982. Accessed 31 July 2007.
38. British National Formulary, , , , British Medical Journal and Royal Pharmaceutical Society of Great Britain, ,
39. British National Formulary for Children, , , , British Medical Journal and Royal Pharmaceutical Society of Great Britain, ,
40. The relative severity of acute versus chronic salicylate poisoning in children: a clinical comparison, Gaudreault P, Temple AR, Lovejoy FH Jr., , , Pediatrics, 1982
41. Acute salicylate self-poisoning in 177 consecutive patients treated in ICU, Thisted B, Krantz T, Stroom J, Sorensen MB., , , Acta Anaesthesiol Scand, 1987
42. Acute and chronic effects of aspirin toxicity and their treatment, Temple AR., , , Arch Intern Med, 1981
43. Treatment of salicylate poisoning with repeated oral charcoal, Hillman RJ, Prescott LF., , , Br Med J (Clin Res Ed), 1985
44. Does multiple-dose charcoal therapy enhance salicylate excretion?, Kirshenbaum LA, Mathews SC, Sitar DS, Tenenbein M., , , Arch Intern Med, 1990
45. An evidenced based flowchart to guide the management of acute salicylate (aspirin) overdose, Dargan PI, Wallace CI, Jones AL., , , Emerg Med J, 2002
46. Non-narcotic analgesics. Problems of overdosage, Meredith TJ, Vale JA., , , Drugs, 1986
47. 2000 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System, Litovitz TL, Klein-Schwartz W, White S, Cobaugh DJ, Youniss J, Omslaer JC, Drab A, Benson BE, , , Am J Emerg Med, 2001
48. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs., John Robert Vane, , , Nature - New Biology, 1971
49. Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin, , H, Tohgi, Stroke, 1992
50. "New mechanism of action of Aspirin discovered," in ''Medical News Today'', October 2, 2005.
External links
★ DrugBank Aspirin Entry
★ Reappraisal
★ An aspirin a day keeps the doctor away
★ Colour-enhanced scanning electron micrograph of aspirin crystals
★ Aspirin research in the 1990s
★ The History of Aspirin
★ Aspirin and heart disease
★ How Aspirin works
★ Molview from bluerhinos.co.uk See Aspirin in 3D
★ History of Aspro
★ The science behind aspirin
★ Aspirin How Products are Made
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