Australian Scientists Probe Aspirins Role in Cancer Treatment
Posted: February 14th, 2012 | Author: Verity Penfold | Filed under: Cankler Science News, Medicated | Tags: Aspirin, Cancer Research, Clinical Oncology, Non-steroidal Anti-inflammatories, NSAID, Peter MacCallum Cancer Institute | No Comments »
Researchers from Melbourne’s Peter MacCallum Cancer Institute – PMCI – say they have made an important discovery about how cancer spreads. A 2010 article published in the Journal of Clinical Oncology has previously suggested that 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”
Scientists have known for years that common drugs like aspirin can help cancer patients, but they weren’t sure why. PMCI researchers have now found a link between drugs like aspirin and the ability for cancer tumours to spread in the body.
PMCI’s associate professor Steven Stacker says the discovery unlocks a range of potential new pathways for treating cancer. “Hopefully this insight is going to be very important to understanding how these drugs may work and in fact how the lymphatic vessels may really contribute to a tumour metastasis,” he said.
Professor Stacker says scientists have learned more about how the lymphatic vessels in the body’s circulatory system function. Those vessels are often “hijacked” when a person has cancer. ”The blood vessels can be a conduit for cells to leave the primary tumour and go to other sites. The discovery we’ve found is that for the first time the major lymphatic vessels are seen to play their own individual role in this process,” he said.
Scientists found these vessels expand in the process of metastasis, increasing their volume and therefore allow cells and fluid to be transported more readily, a bit like a highway for cancer cells. The researchers have discovered that drugs like aspirin, known as non-steroidal anti-inflammatories (NSAIDs), can play a role in shutting down the dilation of these lymphatic vessels or cancer highways, effectively closing off a tumour’s supply lines.
“It does provide an opportunity now to try to inhibit that protein or inhibit that process, reduce the dilation of those lymphatic vessels and potentially reduce metastatic spread,” Professor Stacker said.
The researchers also think their findings could lead to an early warning system to help doctors work out if a tumour is likely to spread. The study is to be published today in the journal Cancer Cell.
RELATED:
Dr. Jennifer Ashton reports on a new study in the British Journal Lancet that shows a possible new link between aspirin and a lower rate of deaths from cancer: http://youtu.be/DEVliMVqQus
Professor John Burn: Aspirin ‘reduces cancer rates’ Regular doses of aspirin can cut bowel cancer rates by nearly two thirds in people suffering with Lynch Syndrome, a study has found: http://youtu.be/kpPIdJlEiwk
FACT! 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 (acetaminophen), 60 mg of codeine, or 5 mg of oxycodone. A combination of aspirin and caffeine, in general, affords greater pain relief than aspirin alone. Effervescent aspirin alleviates pain much faster than aspirin in tablets (15–30 min vs. 45–60 min).
Wiki
Aspirin (USAN), also known as acetylsalicylic acid (/əˌsɛtəlˌsælɨˈsɪlɨk/ ə-set-əl-sal-i-sil-ik; 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. It was first isolated by Arthur Eichengrün, a chemist with the German company Bayer.
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.
Chemical properties
Aspirin, an acetyl derivative of salicylic acid, is a white, crystalline, weakly acidic substance, with a melting point of 135 °C (275 °F). Acetylsalicylic acid decomposes rapidly in solutions of ammonium acetate or of the acetatee, carbonates, citrates or hydroxidesof 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 ester 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.
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 (pKa) for acetylsalicylic acid is 3.5 at 25 °C (77 °F)
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
Aspirin 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 of 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.
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 anacetyl 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 caused primarily 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: COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 normally 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.
However, several of the new COX 2 inhibitors, such as rofecoxib (Vioxx), have been withdrawn recently, after evidence emerged that PTGS2 inhibitors increase the risk of heart attack. Endothelial cells lining the microvasculature in the body are proposed to express PTGS2, and, by selectively inhibiting PTGS2, prostaglandin production (to be specific, PGI2; prostacyclin) is downregulated with respect to thromboxane levels, as PTGS1 in platelets is unaffected. Thus, the protective anticoagulative effect of PGI2 is removed, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new PTGS once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors.
Additional mechanisms
Aspirin has been shown to have at least three additional modes of action. 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. 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. In addition, 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 that aspirin helps to fight infection. More recent data also suggests that salicylic acid and its derivatives modulate signaling through NF-κB. NF-κB, atranscription 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.[127] 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.
Pharmacokinetics
Salicylic acid is a weak acid, and very little of it is ionized in the stomach after oral administration. Acetylsalicylic acid is poorly soluble in the acidic conditions of the stomach, which can delay absorption of high doses for eight to 24 hours. The increased pH and larger surface area of the small intestine causes aspirin to be absorbed rapidly there, which in turn allows more of the salicylate to dissolve. Owing to the issue of solubility, however, aspirin is absorbed much more slowly during overdose, and plasma concentrations can continue to rise for up to 24 hours after ingestion.
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.
As much as 80% of therapeutic doses of salicylic acid is metabolized in the liver. Conjugation with glycine forms salicyluric acid, and with glucuronic acid it forms salicyl acyl and phenolic glucuronide. These metabolic pathways have only a limited capacity. Small amounts of salicylic acid are also hydroxylated to gentisic acid. With large salicylate doses, the kinetics switch from first order to zero order, as metabolic pathways become saturated and renal excretion becomes increasingly important.
Salicylates are excreted mainly by the kidneys as salicyluric acid (75%), free salicylic acid (10%), salicylic phenol (10%), and acyl glucuronides (5%), gentisic acid (< 1%), and 2,3-dihydroxybenzoic acid. When small doses (less than 250 mg in an adult) are ingested, all pathways proceed by first-order kinetics, with an elimination half-life of about 2.0 to 4.5 hours. 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.
The main undesirable side-effects of aspirin taken by mouth are gastrointestinal ulcers, stomach bleeding, and tinnitus, especially in higher doses. In children and adolescents, aspirin is no longer indicated 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 medications called nonsteroidal anti-inflammatory drugs (NSAIDs), but differs from them in the mechanism of action. Though it, and others in its group called the salicylates, have similar effects (antipyretic, anti-inflammatory, analgesic) to the other NSAIDs and inhibit the same enzyme cyclooxygenase, aspirin (but not the other salicylates) does so in an irreversible manner and, unlike others, affect more the COX-1 variant than the COX-2 variant of the enzyme. For example, NSAIDs’ antiplatelet effects normally last in the order of hours, whereas aspirin’s effects last 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)
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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 andovarian 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.
History
The history of aspirin (also known as acetylsalicylic acid or ASA) and the medical use of it and related substances stretches back to antiquity, though pure ASA has only been manufactured and marketed since 1899. Medicines made from willow and othersalicylate-rich plants date back at least to 400 BCE[citation needed], and were part of the pharmacopoeia of Western medicine in Classical antiquity and the Middle Ages. Willow bark extract became recognized for its specific effects on fever, pain and inflammation in the mid-eighteenth century. Lewis and Clark allegedly used willow bark tea in 1803-1806 as a remedy for fever for members of the famous expedition. By the nineteenth century pharmacists were experimenting with and prescribing a variety of chemicals related to salicylic acid, the active component of willow extract.
In 1853, chemist Charles Frédéric Gerhardt reacted acetyl chloride with sodium salicylate to produce acetylsalicylic acid for the first time; in the second half of the nineteenth century, other academic chemists established the compound’s chemical structure and devised more efficient methods of synthesis. In 1897, scientists at the drug and dye firm Bayer began investigating acetylsalicylic acid as a less-irritating replacement for standard common salicylate medicines. By 1899, Bayer had dubbed this drug Aspirinand was selling it around the world. The word Aspirin was Bayer’s brand name, rather than the generic name of the drug; however, Bayer’s rights to the trademark were lost or sold in many countries. Aspirin’s popularity grew over the first half of the twentieth century, spurred by its effectiveness in the wake of Spanish flu pandemic of 1918, and aspirin’s profitability led to fierce competition and the proliferation of aspirin brands and products. Some of the 1918 flu deaths were probably due to Aspirin poisoning.
Aspirin’s popularity declined after the development of acetaminophen/paracetamol in 1956 and ibuprofen in 1962. 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 anti-clotting agent that reduces the risk of clotting diseases. Aspirin sales revived considerably in the last decades of the twentieth century, and remain strong in the twenty-first with widespread use as a preventive treatment for heart attacks and strokes.
Medicines derived from willow trees and other salicylate-rich plants have been part of pharmacopoeias at least dating back to ancient Sumer. A stone tablet of medical text from the Third Dynasty of Ur, dated ca. 2000 BC, lists willow among other plant- and animal-based remedies; however, no indications are given. The earliest specific reference to willow and myrtle (another salicylate-rich plant) being used for conditions that would likely be affected by their analgesic, anti-pyretic, and anti-inflammatoryproperties comes from the Ebers Papyrus, an Egyptian medical text from ca. 1543 BC, likely a copy of a text from around the time of the Ur tablet.
Willow bark preparations became a standard part of the materia medica of Western medicine beginning at least with the Greek physician Hippocrates in the fifth century BC; he recommended it to ease the pain of child-bearing and to reduce fever. The Roman encyclopedist Celsus, in his De Medicina of ca. 30 AD, suggested willow leaf extract to treat the four signs of inflammation: redness, heat, swelling and pain. Willow treatments also appeared in Dioscorides’s De Materia Medica, and Pliny the Elder’s Natural History. By the time of Galen, willow was commonly used throughout the Roman and Arab worlds, as a small part of a large, growing botanical pharmacopoeia.
18th and 19th centuries
The major turning point for salicylate medicines came in 1763, when a letter from English chaplain Edward Stone was read at a meeting of the Royal Society, describing the dramatic power of willow bark extract to cure ague—an ill-defined constellation of symptoms, including intermittent fever, pain, and fatigue, that primarily referred to malaria. Inspired by the doctrine of signatures to search for a treatment for agues near the brackish waters that were known to cause it, Stone had tasted the bark of a willow tree in 1758 and noticed an astringency reminiscent of the standard—and expensive—ague cure of Peruvian bark. He collected, dried, and powdered a substantial amount of willow bark, and over the next five years tested it on a number of people sick with fever and agues. In his letter, Stone reported consistent success, describing willow extract’s effects as identical to Peruvian bark, though a little less potent. (In fact, the active ingredient of Peruvian bark was quinine, which attacked the infectious cause of malaria, while the active ingredient of willow extract, salicin, relieved the symptoms of malaria but could not cure it.) Stone’s letter (mistakenly attributed to Edmund rather than Edward Stone) was printed in Philosophical Transactions, and by the end of the 18th century willow was gaining popularity as an inexpensive substitute for Peruvian bark.
In the 19th century, as the young discipline of organic chemistry began to grow in Europe, scientists attempted to isolate and purify the active components of many medicines, including willow bark. After unsuccessful attempts by Italian chemists Brugnatelli and Fontana in 1826, Joseph Buchner obtained relatively pure salicin crystals in 1828; the following year, Henri Leroux developed a better procedure for extracting modest yields of salicin. In 1830, Swiss pharmacist Johann Pagenstecher discovered what he thought was a new pain-reducing substance, isolated from the common remedy of meadowsweet (Spiraea ulmaria). By 1838, Italian chemist Raffaele Piria found a method of obtaining a more potent acid form of willow extract, which he named salicylic acid. The German chemist who had been working to identify theSpiraea extract, Karl Jacob Lowig, soon realized that it was in fact the same salicylic acid that Piria had found.
Through the middle decades of the 19th century, the use of salicylate medicines—including salicin, salicylic acid, and sodium salicylate grew considerably, and physicians increasingly knew what to expect from these medicines: reduction of pain, fever, and inflammation. However, the unpleasant side effects, particularly gastric irritation, limited their usefulness. By the 1880s, the German chemical industry, jump-started by the lucrative development of dyes from coal tar, was branching out to investigate the potential of new tar-derived medicines. The turning point was the advent of Kalle & Company’s Antifebrine, the branded version of the well-known dye derivative acetanilide—the anti-pyretic properties of which were discovered by accident in 1886. Antifebrine’s success inspired Carl Duisberg, the head of research at the small dye firmFriedrich Bayer & Company, to start a systematic search for other chemical fever-reducers. Bayer chemists soon developed Phenacetin, followed by the sedatives Sulfonal and Trional.
Synthesis of ASA
Upon taking control of Bayer’s overall management in 1890, Duisberg began to expand the company’s drug research program. He created a pharmaceutical group for creating new drugs, headed by former university chemist Arthur Eichengrün, and a pharmacology group for testing the drugs, headed by Heinrich Dreser (beginning in 1897, after periods under Wilhelm Siebel and Hermann Hildebrandt). In 1894, the young chemist Felix Hoffman joined the pharmaceutical group. Dreser, Eichengrün and Hoffman would be the key figures in the development of acetylsalicylic acid as the drug Aspirin (though their respective roles have been the subject of some contention).
In 1897, Hoffman started working to find a less irritating substitute for salicylic acid. It is generally accepted that he turned to this idea because his father was suffering the side effects of taking sodium salicylate for rheumatism. Other chemists had attempted this before as well, by acetylating salicylic acid to make acetylsalicylic acid (ASA). Charles Frederic Gerhardt was the 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. 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. In 1859, von Gilm produced ASA (which he called “acetylirte Salicylsäure”, acetylated salicylic acid) by a different method, the 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 that both reactions gave the same compound—acetylsalicylic acid. (Prinzhorn is credited in the paper with conducting the experiments.) They were first to assign to it the correct structure with the acetyl group connected to the phenolic oxygen. Kraut’s procedure was even being used by the drug company Heyden to make unbranded ASA. However, the published methods did not produce pure ASA—although Kraut’s method was efficient enough to be useful. It is likely that Hoffman started by recreating the published methods. On October 10, 1897 (according to his laboratory notebooks), Hoffman found a better method for making ASA, from salicylic acid refluxed with acetic anhydride.
Eichengrün sent ASA to Dreser’s pharmacology group for testing, and the initial results were very positive. The next step would normally have been clinical trials, but Dreser opposed further investigation of ASA because of salicylic acid’s reputation for weakening the heart—possibly a side effect of the high doses often used to treat rheumatism. Dreser’s group was soon busy testing Felix Hoffman’s next chemical success: diacetylmorphine (which the Bayer team soon branded as heroin because of the heroic feeling it gave them). Eichengrün, frustrated by Dreser’s rejection of ASA, went directly to Bayer’s Berlin representative Felix Goldmann to arrange low-profile trials with doctors. Though the results of those trials were also very positive, with no reports of the typical salicylic acid complications, Dreser still demurred. However, Carl Duisberg intervened and scheduled full testing. Soon, Dreser admitted ASA’s potential and Bayer decided to proceed with production. Dreser wrote a report of the findings to publicize the new drug; in it, he omitted any mention of Hoffman or Eichengrün. He would also be the only one of the three to receive royalties for the drug (for testing it), since it was ineligible for any patent the chemists might have taken out for creating it. For many years, however, he attributed Aspirin’s discovery solely to Hoffman.
The controversy over who was primarily responsible for aspirin’s development spread through much of the twentieth century and into the twenty-first. Although aspirin’s origin was in academic research and Bayer was not the first to produce it commercially, Bayer insists 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.” Historians and others have also challenged Bayer’s early accounts of Bayer’s synthesis, in which Hoffman was primarily responsible for the Bayer breakthrough. In 1949, shortly before his death, Eichengrün wrote an article, “Fifty Years of Asprin”, claiming that he had not told Hoffman the purpose of his research, meaning that Hoffman merely carried out Eichengrün’s research plan, and that the drug would never have gone to the market without his direction. This claim was later supported by research conducted by historian Walter Sneader. Axel Helmstaedter, General Secretary of the International Society for the History of Pharmacy, subsequently questioned the novelty of Sneader’s research, noting that several earlier articles discussed the Hoffmann-Eichengrün controversy in detail. Bayer countered Sneader in a press release stating 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.
Naming the drug
Spirea, or meadowsweet, is the German namesake of Spirsäure (salicylic acid), and ultimately aspirin.
The name Aspirin was derived from the name of the chemical ASA—Acetylspirsäure in German. Spirsäure (salicylic acid) was named for the meadowsweet plant, Spirea ulmaria, from which it could be derived. Aspirin took a- for the acetylation, -spir- from Spirsäure, and added -in as a typical drug name ending to make it easy to say. In the final round of naming proposals that circulated through Bayer, it came down toAspirin and Euspirin; Aspirin, they feared, might remind customers of aspiration, but Arthur Eichengrün argued that Eu- (meaning “good”) was inappropriate because it usually indicated an improvement over an earlier version of a similar drug. Since the substance itself was already known, Bayer intended to use the new name to establish their drug as something new; in January 1899 they settled on Aspirin.
Rights and Sale
Under Carl Duisberg’s leadership, Bayer was firmly committed to the standards of ethical drugs, as opposed to patent medicines. Ethical drugs were drugs that could be obtained only through a pharmacist, usually with a doctor’s prescription. Advertising directly to consumers was considered unethical and strongly opposed by many medical organizations; that was the domain of patent medicines. Therefore, Bayer was limited to marketing Aspirin directly to doctors.
When production of Aspirin began in 1899, Bayer sent out small packets of the drug to doctors, pharmacists and hospitals, advising them of Aspirin’s uses and encouraging them to publish about the drug’s effects and effectiveness. As positive results came in and enthusiasm grew, Bayer sought to secure patent and trademark wherever possible. It was ineligible for patent in Germany (despite being accepted briefly before the decision was overturned), but Aspirin was patented in Britain (filed December 22, 1898) and the United States (US Patent 644,077 issued February 27, 1900). The British patent was overturned in 1905, the American patent was also besieged but was ultimately upheld.
Faced with growing legal and illegal competition for the globally marketed ASA, Bayer worked to cement the connection between Bayer and Aspirin. One strategy it developed was to switch from distributing Aspirin powder for pharmacists to press into pill form to distributing standardized tablets—complete with the distinctive Bayer cross logo. In 1903 the company set up an American subsidiary, with a converted factory inRensselaer, New York, to produce Aspirin for the American market without paying import duties. Bayer also sued the most egregious patent violators and smugglers. The company’s attempts to hold onto its Aspirin sales incited criticism from muckraking journalists and the American Medical Association, especially after the 1906 Pure Food and Drug Act that prevented trademarked drugs from being listed in the United States Pharmacopeia; Bayer listed ASA with an intentionally convoluted generic name (monoacetic acid ester of salicylic acid) to discourage doctors referring to anything but Aspirin.
World War I and Bayer
By the outbreak of World War I in 1914, Bayer was facing competition in all its major markets from local ASA producers as well as other German drug firms (particularly Heyden and Hoechst). The British market was immediately closed to the German companies, but British manufacturing could not meet the demand—especially with phenol supplies, necessary for ASA synthesis, largely being used for explosives manufacture. On February 5, 1915, Bayer’s UK trademarks were voided, so that any company could use the term aspirin. The Australian market was taken over by Aspro, after the makers of Nicholas-Aspirin lost a short-lived exclusive right to the aspirin name there. In the United States, Bayer was still under German control—though the war disrupted the links between the American Bayer plant and the German Bayer headquarters—but phenol shortage threatened to reduce aspirin production to a trickle, and imports across the Atlantic Ocean were blocked by the Royal Navy.
The Great Phenol Plot
To secure phenol for aspirin production, and at the same time indirectly aid the German war effort, German agents in the United States orchestrated what became known as the Great Phenol Plot. By 1915, the price of phenol rose to the point that Bayer’s aspirin plant was forced to drastically cut production. This was especially problematic because Bayer was instituting a new branding strategy in preparation of the expiry of the aspirin patent in the United States. Thomas Edison, who needed phenol to manufacture phonograph records, was also facing supply problems; in response, he created a phenol factory capable of pumping out twelve tons per day. Edison’s excess phenol seemed destined for trinitrophenol production.
Although the United States remained officially neutral until April 1917, it was increasingly throwing its support to the Allies through trade. To counter this, German ambassador Johann Heinrich von Bernstorff and Interior Ministry official Heinrich Albert were tasked with undermining American industry and maintaining public support for Germany. One of their agents was a former Bayer employee, Hugo Schweitzer. Schweitzer set up a contract for a front company called the Chemical Exchange Association to buy all of Edison’s excess phenol. Much of the phenol would go to the German-owned Chemische Fabrik von Heyden’s American subsidiary; Heyden was the supplier of Bayer’s salicylic acid for aspirin manufacture. By July 1915, Edison’s plants were selling about three tons of phenol per day to Schweitzer; Heyden’s salicylic acid production was soon back on line, and in turn Bayer’s aspirin plant was running as well.
The plot only lasted a few months. On July 24, 1915, Heinrich Albert’s briefcase, containing details about the phenol plot, was recovered by a Secret Service agent. Although the activities were not illegal—since the United States was still officially neutral and still trading with Germany—the documents were soon leaked to the New York World, an anti-German newspaper. The World published an exposé on August 15, 1915. The public pressure soon forced Schweitzer and Edison to end the phenol deal—with the embarrassed Edison subsequently sending his excess phenol to the U.S. military—but by that time the deal had netted the plotters over two million dollars and there was already enough phenol to keep Bayer’s Aspirin plant running. Bayer’s reputation took a large hit, however, just as the company was preparing to launch an advertising campaign to secure the connection between aspirin and the Bayer brand.
Bayer loses foreign holdings
Beginning in 1915, Bayer set up a number of shell corporations and subsidiaries in the United States, to hedge against the possibility of losing control of its American assets if the U.S. should enter the war and to allow Bayer to enter other markets (e.g., army uniforms). After the U.S. declared war on Germany in April 1917, alien property custodian A. Mitchell Palmer began investigating German-owned businesses, and soon turned his attention to Bayer. To avoid having to surrender all profits and assets to the government, Bayer’s management shifted the stock to a new company, nominally owned by Americans but controlled by the German-American Bayer leaders. Palmer, however, soon uncovered this scheme and seized all of Bayer’s American holdings. After the Trading with the Enemy Act was amended to allow sale of these holdings, the government auctioned off the Rensselaer plant and all Bayer’s American patents and trademarks, including even the Bayer brand name and the Bayer cross logo. It was bought by a patent medicine company,Sterling Products, Inc. The rights to Bayer Aspirin and the U.S. rights to the Bayer name and trademarks, were sold back to Bayer AG in 1994 for US$1 billion.
With the coming of the deadly Spanish flu pandemic in 1918, aspirin—by whatever name—secured a reputation as one of the most powerful and effective drugs in the pharmacopeia of the time. Its fever-reducing properties gave many sick patients enough strength to fight through the infection, and aspirin companies large and small earned the loyalty of doctors and the public—when they could manufacture or purchase enough aspirin to meet demand. Despite this, some people believed that Germans put the Spanish flu bug in Bayer asprin, causing the pandemic as a war tactic.
The U.S. ASA patent expired in 1917, but Sterling owned the aspirin trademark, which was the only commonly used term for the drug. In 1920, United Drug Company challenged the Aspirin trademark, which became officially generic for public sale in the U.S. (although it remained trademarked when sold to wholesalers and pharmacists). With demand growing rapidly in the wake of the Spanish flu, there were soon hundreds of “aspirin” brands on sale in the United States.
Sterling Products, equipped with all of Bayer’s U.S. intellectual property, tried to take advantage of its new brand as quickly as possible, before generic ASAs took over. However, without German expertise to run the Rensselaer plant to make aspirin and the other Bayer pharmaceuticals, they had only a finite aspirin supply and were facing competition from other companies. Sterling president William E. Weiss had ambitions to sell Bayer aspirin not only in the U.S., but to compete with the German Bayer abroad as well. Taking advantage of the losses Farbenfabriken Bayer (the German Bayer company) suffered through the reparation provisions of the Treaty of Versailles, Weiss worked out a deal with Carl Duisberg to share profits in the Americas, Australia, South Africa and Great Britain for most Bayer drugs, in return for technical assistance in manufacturing the drugs.
Sterling also took over Bayer’s Canadian assets as well as ownership of the Aspirin trademark which is still valid in Canada and most of the world. Bayer bought Sterling Winthrop in 1994 restoring ownership of the Bayer name and Bayer cross trademark in the US and Canada as well as ownership of the Aspirin trademark in Canada.
Competition from new drugs
After World War II, with the IG Farben conglomerate dismantled because of its central role in the Nazi regime, Sterling Products bought half of Bayer Ltd, the British Bayer subsidiary—the other half of which it already owned. However, Bayer Aspirin made up only a small fraction of the British aspirin market because of competition from Aspro, Disprin (a soluble aspirin drug) and other brands. Bayer Ltd began searching for new pain relievers to compete more effectively. After several moderately successful compound drugs that mainly utilized aspirin (Anadin and Excedrin), Bayer Ltd’s manager Laurie Spalton ordered an investigation of a substance that scientists at Yale had, in 1946, found to be the metabolically active derivative of acetanilide: acetaminophen. After clinical trials, Bayer Ltd brought acetaminophen to market as Panadol in 1956.
However, Sterling Products did not market Panadol in the United States or other countries where Bayer Aspirin still dominated the aspirin market. Other firms began selling acetaminophen drugs, most significantly, McNeil Laboratories with liquid Tylenol in 1955, and Tylenol pills in 1958. By 1967, Tylenol was available without a prescription. Because it did not cause gastric irritation, acetaminophen rapidly displaced much of aspirin’s sales. Another analgesic, anti-inflammatory drug was introduced in 1962:ibuprofen (sold as Brufen in the U.K. and Motrin in the U.S.). By the 1970s, aspirin had a relatively small portion of the pain reliever market, and in the 1980s sales decreased even more when ibuprofen became available without prescription.
Also in the early 1980s, several studies suggested a link between children’s consumption of aspirin and Reye’s syndrome, a potentially fatal disease. By 1986, the U.S. Food and Drug Administration required warning labels on all aspirin, further suppressing sales. The makers of Tylenol also filed a lawsuit against Anacin aspirin maker American Home Products, claiming that the failure to add warning labels before 1986 had unfairly held back Tylenol sales, though this suit was eventually dismissed.
Investigating how aspirin works
The mechanism of aspirin’s analgesic, anti-inflammatory and antipyretic properties was unknown through the drug’s heyday in the early- to mid-twentieth century; Heinrich Dreser’s explanation, widely accepted since the drug was first brought to market, was that aspirin relieved pain by acting on the central nervous system. In 1958 Harry Collier, a biochemist in the London laboratory of pharmaceutical company Parke Davis, began investigating the relationship between kinins and the effects of aspirin. In tests onguinea pigs, Collier found that aspirin, if given beforehand, inhibited the bronchoconstriction effects of bradykinin. He found that cutting the guinea pigs’ vagus nerve did not affect the action of bradykinin or the inhibitory effect of aspirin—evidence that aspirin worked locally to combat pain and inflammation, rather than on the central nervous system. In 1963, Collier began working with University of London pharmacology graduate student Priscilla Piper to determine the precise mechanism of aspirin’s effects. However, it was difficult to pin down the precise biochemical goings-on in live research animals, and in vitro tests on removed animal tissues did not behave like in vivo tests.
After five years of collaboration, Collier arranged for Piper to work with pharmacologist John Vane at the Royal College of Surgeons of England, in order to learn Vane’s new bioassay methods, which seemed like a possible solution to the in vitro testing failures. Vane and Piper tested the biochemical cascade associated with anaphylactic shock (in extracts from guinea pig lungs, applied to tissue from rabbit aortas). They found that aspirin inhibited the release of an unidentified chemical generated by guinea pig lungs, a chemical that caused rabbit tissue to contract. By 1971, Vane identified the chemical (which they called “rabbit-aorta contracting substance,” or RCS) as a prostaglandin. In a June 23, 1971 paper in the journal Nature, Vane and Piper suggested that aspirin and similar drugs (the non-steroidal anti-inflammatory drugs or NSAIDs) worked by blocking the production of prostaglandins. Later research showed that NSAIDs such as aspirin worked by inhibiting cyclooxygenase, the enzyme responsible for convertingarachidonic acid into a prostaglandin.
Revival as heart drug
Aspirin’s effects on blood clotting (as an antiplatelet agent) were first noticed in 1950 by Lawrence Craven. Craven, a family doctor in California, had been directing tonsillectomy patients to chew Aspergum, an aspirin-laced chewing gum. He found that an unusual number of patients had to be hospitalized for severe bleeding, and that those patients had been using very high amounts of Aspergum. Craven began recommending daily aspirin to all his patients, and claimed that the patients who followed the aspirin regimen (about 8,000 people) had no signs of thrombosis. However, Craven’s studies were not taken seriously by the medical community, because he had not done a placebo-controlled study and had published only in obscure journals.
The idea of using aspirin to prevent clotting diseases (such as heart attacks and strokes) was revived in the 1960s, when medical researcher Harvey Weiss found that aspirin had an anti-adhesive effect on blood platelets (and unlike other potential antiplatelet drugs, aspirin had low toxicity). Medical Research Council haematologist John O’Brien picked up on Weiss’s finding and, in 1963, began working with epidemiologist Peter Elwood on aspirin’s anti-thrombosis drug potential. Elwood began a large-scale trial of aspirin as a preventive drug for heart attacks. Nicholas Laboratories agreed to provide aspirin tablets, and Elwood enlisted heart attack survivors in a double-blind controlled study—heart attack survivors were statistically more likely to suffer a second attack, greatly reducing the number of patients necessary to reliably detect whether aspirin had an effect on heart attacks. The study began in February 1971, though the researchers soon had to break the double-blinding when a study by American epidemiologist Herschel Jick suggested that aspirin either prevented heart attacks or made them more deadly. Jick had found that fewer aspirin-takers were admitted to his hospital for heart attacks than non-aspirin-takers, and one possible explanation was that aspirin caused heart attack sufferers to die before reaching the hospital; Elwood’s initial results ruled out that explanation. When the Elwood trial ended in 1973, it showed a modest but not statistically significant reduction in heart attacks among the group taking aspirin.
Several subsequent studies put aspirin’s effectiveness as a heart drug on firmer ground, but the evidence was not incontrovertible. However, in the mid-1980s, with the relatively new technique of meta-analysis, statistician Richard Peto convinced the U.S. FDA and much of the medical community that the aspirin studies, in aggregate, showed aspirin’s effectiveness with relative certainty. By the end of the 1980s, aspirin was widely used as a preventive drug for heart attacks and had regained its former position as the top-selling analgesic in the U.S.
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. It is used in the prevention of transient ischemic attacks, strokes, heart attacks, pregnancy loss, and cancer.
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 (acetaminophen), 60 mg of codeine, or 5 mg of oxycodone. A combination of aspirin and caffeine, in general, 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. A combination of aspirin and codeine may have a slightly higher analgesic effect than aspirin alone; however, this difference is not clinically meaningful. It appears ibuprofen is at least equally, and possibly more, effective than this combination.
According to a 1998 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 was very effective. Likewise, aspirin, codeine, or paracetamol was 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 an 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 (as found in the OTC brand Excedrin) is even more potent. For the treatment of migraine headache, this formulation works better than any of its three components taken separately, better than ibuprofen and better than sumatriptan. As with 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. Comparative clinical trials indicatedmetamizole and ibuprofen may relieve pain faster than aspirin, although the difference becomes insignificant after about two hours. The addition of caffeine in a dose of 60–130 mg to aspirin increases the analgesic effect in headache. The combination of aspirin, paracetamol (acetaminophen) and caffeine is still more effective, but at the cost of more stomach discomfort, nervousness and dizziness. There is some evidence low-dose aspirin 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.
For persons without cardiovascular problems, the benefits of aspirin are unclear. In the primary prevention trials, aspirin decreased the overall incidence of heart attacks and ischaemic strokes by about a tenth. However, since these events were rare, the absolute reduction of their rate was low: from 0.57% to 0.51% per year. In addition, the risks of hemorrhagic strokes and gastrointestinal bleeding almost completely offset the benefits of aspirin. Thus, in the primary prevention trials, aspirin did not change the overall mortality rate. Further trials are in progress.
The expert bodies diverge in their opinions regarding the use of aspirin for primary prevention, such as can be accomplished by including aspirin in a polypill for the general population. The US Government Preventive Services Task Force recommended making individual, case by case choices based on the estimated future risk and patients’ preferences. 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.
Coronary and carotid arteries, bypasses and stents
The coronary arteries supply blood to the heart. Aspirin is recommended for one to six months after placement of stents in the coronary arteries and for years after a coronary artery bypass graft.
The carotid arteries supply blood to the brain. Patients with mild carotid artery stenosis benefit from aspirin; it is recommended after a carotid endarterectomy or carotid artery stent.
After vascular surgery of the lower legs using artificial grafts that are sutured to the arteries to improve blood supply, aspirin is used to keep the grafts open because it serves as type of blood thinner, reducing the likelihood of clots forming.
Other uses
Although aspirin has been used to combat fever and pains associated with common cold for more than 100 years, its efficacy in this role was only recently confirmed in controlled clinical trials on adults. One gram of aspirin, on average, reduced the oral body temperature from 39.0 °C (102.2 °F) to 37.6 °C (99.7 °F) after three hours. The relief began after 30 minutes, and after six hours, the temperature still remained below 37.8 °C (100.0 °F). Aspirin also helped with “achiness”, discomfort, and headache, and with sore throat pain, for those who had it. The effects of aspirin were indistinguishable from those obtained using paracetamol in any respect, except for, possibly, a slightly higher incidence of sweating and gastrointestinal side-effects.
Fever and joint pain of acute rheumatic fever respond extremely well, often within three days, to high doses of aspirin. The therapy usually lasts for one to two weeks; and only in about 5% of the cases it has to continue for longer than six months. After fever and pain have subsided, the aspirin treatment is unnecessary, as it does not decrease the incidence of heart complications and residual rheumatic heart disease. 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. Naproxen was shown to be as effective as aspirin and less toxic; due to the limited clinical experience, however, naproxen is recommended only as a second-line treatment.
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 researchers. 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”
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; e.g. 75- and 81-milligram tablets are used; there is no medical significance in the slight difference. It is of historical interest that in the U.S., a 325 mg dose is equivalent to the historic 5-grain aspirin tablet in use prior to the metric system.
In general, for adults, doses are 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.
New recommendations from the US Preventive Services Task Force (USPSTF, March, 2009) on the use of aspirin for the primary prevention of coronary heart disease encourage men aged 45–79 and women aged 55–79 to use aspirin when the potential benefit of a reduction in myocardial infarction (MI) for men or stroke for women outweighs the potential harm of an increase in gastrointestinal hemorrhage. 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. Low dose aspirin use was also associated with a trend toward lower risk of cardiovascular events, and lower aspirin doses (75 or 81 mg/day) may optimize efficacy and safety for patients requiring aspirin for long-term prevention.
In children with Kawasaki disease, aspirin is taken at dosages based on body weight, initially four times a day for up to two weeks and then at a lower dose once daily for a further six to eight weeks.
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.
Adverse effects
Contraindications
Aspirin should not be taken by people who are allergic to ibuprofen or naproxen, or who have salicylate intolerance or a more generalized drug intolerance to NSAIDs, and caution should be exercised in those with asthma or NSAID-precipitatedbronchospasm. 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. Patients with hemophilia or other bleeding tendencies should not take aspirin or other salicylates. Aspirin is known to cause hemolytic anemia in people who have the genetic disease glucose-6-phosphate dehydrogenase deficiency (G6PD), in particular in large doses and depending on the severity of the disease. Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency. People withkidney 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.
Gastrointestinal
Aspirin use has been shown to increase the risk of gastrointestinal bleeding. 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. Combining aspirin with other NSAIDs has also been shown to further increase this risk. Using aspirin in combination with clopidogrel or warfarin also increases the risk of upper gastrointestinal bleeding.
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.
It is reported that deglycyrrhizinated licorice (DGL), an extract of the popular herb licorice, 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.
A study found that, in contrast to oral aspirin, intravenous injection of aspirin did not produce detectable histological damage or significantly alter gastric mucosal potential difference, and concluded that high blood levels of circulating salicylate did not acutely damage gastric mucosa, so that gastric mucosal damage produced acutely after single oral doses of aspirin are due to its topical, rather than systemic, action.
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. The United States Food and Drug Administration now recommends aspirin (or aspirin-containing products) should not be given to anyone under the age of 12 who has a fever, and the British Medicines and Healthcare products Regulatory Agency (MHRA) recommends children who are under 16 years of age should not take aspirin, unless it is on the advice of a doctor.
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.
A study of a group with a mean dosage of aspirin of 270 mg per day estimated that there was an average absolute risk increase in intracerebral hemorrhage (ICH) of 12 events per 10.000 persons. In comparison, there was an estimated absolute risk reduction in myocardial infarction of 137 events per 10.000 persons, and a reduction of 39 events per 10.000 persons in ischemic stroke. In cases where ICH already has occurred, aspirin use results in higher mortality, with a dose of approximately 250 mg per day resulting in a relative risk of death within three months after the ICH of approximately 2.5 (95% confidence interval 1.3 to 4.6).
Aspirin and other NSAIDs can cause hyperkalemia by inducing a hyporenin hypoaldosteronic state via inhibition of prostaglandin synthesis; however, these agents do not typically cause hyperkalemia by themselves in the setting of normal renal function and euvolemic state.
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 in general 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.[78][79] 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.
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