History of aspirin
Encyclopedia
The history of aspirin 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 other salicylate-rich plants date back at least to 400 BCE, 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 Aspirin
and 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 stroke
s.
trees and other salicylate-rich plants have been part of pharmacopoeia
s 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-inflammatory
properties 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 world
s, as a small part of a large, growing botanical pharmacopoeia.
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 the Spiraea 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 effect
s, particularly gastric irritation, limited their usefulness. By the 1880s, the German chemical industry, jump-started by the lucrative development of dye
s 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 firm Friedrich Bayer & Company, to start a systematic search for other chemical fever-reducers. Bayer chemists soon developed Phenacetin
, followed by the sedative
s Sulfonal and Trional
.
, 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 trial
s, 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.
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 to Aspirin 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.
s. 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 (filed 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 in Rensselaer, 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.
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
.
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.
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.
, many new aspirin brands and aspirin-based products entered the market. The Australian company Nicholas Proprietary Limited, through the aggressive marketing strategies
of George Davies, built Aspro
into a global brand, with particular strength in Australia, New Zealand, and the U.K.. American brands such as Burton's Aspirin, Molloy's Aspirin, Cal-Aspirin and St. Joseph Aspirin tried to compete with the American Bayer, while new products such Cafaspirin (aspirin with caffeine
) and Alka-Seltzer
(a soluble mix of aspirin and bicarbonate of soda) put aspirin to new uses. In 1925, the German Bayer became part of IG Farben
, a conglomerate of former dye companies; IG Farben's brands of Aspirin and, in Latin America
, the caffeinated Cafiaspirina (co-managed with Sterling Products) competed with less expensive aspirins such as Geniol.
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 label
s 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.
. 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 on guinea pig
s, 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
aorta
s). 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 drug
s 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 converting arachidonic acid
into a prostaglandin.
(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.
Ancient history
Ancient history is the study of the written past from the beginning of recorded human history to the Early Middle Ages. The span of recorded history is roughly 5,000 years, with Cuneiform script, the oldest discovered form of coherent writing, from the protoliterate period around the 30th century BC...
, though pure ASA has only been manufactured and marketed since 1899. Medicines made from willow
Willow
Willows, sallows, and osiers form the genus Salix, around 400 species of deciduous trees and shrubs, found primarily on moist soils in cold and temperate regions of the Northern Hemisphere...
and other salicylate-rich plants date back at least to 400 BCE, and were part of the pharmacopoeia of Western medicine in Classical antiquity
Classical antiquity
Classical antiquity is a broad term for a long period of cultural history centered on the Mediterranean Sea, comprising the interlocking civilizations of ancient Greece and ancient Rome, collectively known as the Greco-Roman world...
and the Middle Ages
Middle Ages
The Middle Ages is a periodization of European history from the 5th century to the 15th century. The Middle Ages follows the fall of the Western Roman Empire in 476 and precedes the Early Modern Era. It is the middle period of a three-period division of Western history: Classic, Medieval and Modern...
. 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
Salicylic acid
Salicylic acid is a monohydroxybenzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin...
, the active component of willow extract.
In 1853, chemist Charles Frédéric Gerhardt
Charles Frédéric Gerhardt
Charles Frédéric Gerhardt was a French chemist.-Biography:He was born in Strasbourg, where he attended the gymnasium. He then studied at the Karlsruhe Institute of Technology, where Friedrich Walchner's lectures first attracted his interest to chemistry...
reacted acetyl chloride
Acetyl chloride
Acetyl chloride, CH3COCl, also known as ethanoyl chloride or acyl chloride, is an acid chloride derived from acetic acid. It belongs to the class of organic compounds called acyl halides. It is a colorless liquid. Acetyl chloride does not exist in nature, because contact with water would hydrolyze...
with sodium salicylate
Sodium salicylate
Sodium salicylate is a sodium salt of salicylic acid. It can be prepared from sodium phenolate and carbon dioxide under higher temperature and pressure...
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
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...
began investigating acetylsalicylic acid as a less-irritating replacement for standard common salicylate medicines. By 1899, Bayer had dubbed this drug Aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , 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 discovered by Arthur Eichengrun, a chemist with the German company Bayer...
and 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 poisoning
Aspirin poisoning or salicylism can be acute or chronic. A single overdose may cause acute poisoning; continuous usage of an elevated dosage over long periods of time may cause chronic poisoning. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal with a mortality...
.
Aspirin's popularity declined after the development of acetaminophen/paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
in 1956 and ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....
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 stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
s.
Early history of salicylates
Medicines derived from willowWillow
Willows, sallows, and osiers form the genus Salix, around 400 species of deciduous trees and shrubs, found primarily on moist soils in cold and temperate regions of the Northern Hemisphere...
trees and other salicylate-rich plants have been part of pharmacopoeia
Pharmacopoeia
Pharmacopoeia, pharmacopeia, or pharmacopoea, , in its modern technical sense, is a book containing directions for the identification of samples and the preparation of compound medicines, and published by the authority of a government or a medical or pharmaceutical society.In a broader sense it is...
s at least dating back to ancient Sumer
Sumer
Sumer was a civilization and historical region in southern Mesopotamia, modern Iraq during the Chalcolithic and Early Bronze Age....
. A stone tablet of medical text from the Third Dynasty of Ur
Third Dynasty of Ur
The Third Dynasty of Ur, also known as the Neo-Sumerian Empire or the Ur III Empire refers simultaneously to a 21st to 20th century BC Sumerian ruling dynasty based in the city of Ur and a short-lived territorial-political state that some historians regard as a nascent empire...
, dated ca. 2000 BC, lists willow among other plant- and animal-based remedies; however, no indications
Indication (medicine)
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. The opposite of indication is contraindication.-Drugs:...
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
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
, anti-pyretic, and anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
properties comes from the Ebers Papyrus
Ebers papyrus
The Ebers Papyrus, also known as Papyrus Ebers, is an Egyptian medical papyrus dating to circa 1550 BC. Among the oldest and most important medical papyri of ancient Egypt, it was purchased at Luxor, in the winter of 1873–74 by Georg Ebers...
, 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
Materia medica
Materia medica is a Latin medical term for the body of collected knowledge about the therapeutic properties of any substance used for healing . The term 'materia medica' derived from the title of a work by the Ancient Greek physician Pedanius Dioscorides in the 1st century AD, De materia medica libre...
of Western medicine beginning at least with the Greek physician Hippocrates
Hippocrates
Hippocrates of Cos or Hippokrates of Kos was an ancient Greek physician of the Age of Pericles , and is considered one of the most outstanding figures in the history of medicine...
in the fifth century BC; he recommended it to ease the pain of child-bearing and to reduce fever. The Roman encyclopedist Celsus
Aulus Cornelius Celsus
Aulus Cornelius Celsus was a Roman encyclopedist, known for his extant medical work, De Medicina, which is believed to be the only surviving section of a much larger encyclopedia. The De Medicina is a primary source on diet, pharmacy, surgery and related fields, and it is one of the best sources...
, in his De Medicina
De Medicina
De Medicina is a 1st-century medical treatise by Aulus Cornelius Celsus, a Roman encyclopedist and possibly a practicing physician. It is the only surviving section of a much larger encyclopedia; only small parts still survive from sections on agriculture, military science, oratory, jurisprudence...
of ca. 30 AD, suggested willow leaf extract to treat the four signs of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
: redness, heat, swelling and pain. Willow treatments also appeared in Dioscorides's De Materia Medica, and Pliny the Elder
Pliny the Elder
Gaius Plinius Secundus , better known as Pliny the Elder, was a Roman author, naturalist, and natural philosopher, as well as naval and army commander of the early Roman Empire, and personal friend of the emperor Vespasian...
's Natural History. By the time of Galen
Galen
Aelius Galenus or Claudius Galenus , better known as Galen of Pergamon , was a prominent Roman physician, surgeon and philosopher...
, willow was commonly used throughout the Roman
Ancient Rome
Ancient Rome was a thriving civilization that grew on the Italian Peninsula as early as the 8th century BC. Located along the Mediterranean Sea and centered on the city of Rome, it expanded to one of the largest empires in the ancient world....
and Arab world
Arab world
The Arab world refers to Arabic-speaking states, territories and populations in North Africa, Western Asia and elsewhere.The standard definition of the Arab world comprises the 22 states and territories of the Arab League stretching from the Atlantic Ocean in the west to the Arabian Sea in the...
s, as a small part of a large, growing botanical pharmacopoeia.
18th and 19th centuries
Royal Society
The Royal Society of London for Improving Natural Knowledge, known simply as the Royal Society, is a learned society for science, and is possibly the oldest such society in existence. Founded in November 1660, it was granted a Royal Charter by King Charles II as the "Royal Society of London"...
, 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
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
. Inspired by the doctrine of signatures
Doctrine of signatures
The doctrine of signatures is a philosophy shared by herbalists from the time of Dioscurides and Galen. This doctrine states that herbs that resemble various parts of the body can be used to treat ailments of that part of the body. Examples include the plants liverwort; snakeroot, an antidote for...
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
Active ingredient
An active ingredient is the substance of a pharmaceutical drug or a pharmaceutical ingredient and bulk active in medicine; in pesticide formulations active substance may be used. Some medications and pesticide products may contain more than one active ingredient...
of Peruvian bark was quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
, 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
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
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
Salicylic acid
Salicylic acid is a monohydroxybenzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin...
. The German chemist who had been working to identify the Spiraea 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 effect
Adverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
s, particularly gastric irritation, limited their usefulness. By the 1880s, the German chemical industry, jump-started by the lucrative development of dye
Dye
A dye is a colored substance that has an affinity to the substrate to which it is being applied. The dye is generally applied in an aqueous solution, and requires a mordant to improve the fastness of the dye on the fiber....
s from coal tar
Coal tar
Coal tar is a brown or black liquid of extremely high viscosity, which smells of naphthalene and aromatic hydrocarbons. Coal tar is among the by-products when coal iscarbonized to make coke or gasified to make coal gas...
, 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
Carl Duisberg
Friedrich Carl Duisberg was a German chemist and industrialist.-Life:He was born in Barmen, Germany and from 1879 until 1882 he studied at the "Georg-August-Universität " and Friedrich Schiller University of Jena and received his doctorate .After military service in Munich, which he combined with...
, the head of research at the small dye firm Friedrich Bayer & Company, to start a systematic search for other chemical fever-reducers. Bayer chemists soon developed Phenacetin
Phenacetin
Phenacetin is an analgesic, once widely used; its use has declined because of its adverse effects.-History:Phenacetin was introduced in 1887, and was used principally as an analgesic, and was one of the first synthetic fever reducers to go on the market...
, followed by the sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
s Sulfonal and Trional
Trional
Trional is a sedative-hypnotic and anesthetic drug with GABAergic actions. It has similar effects to sulfonal, except it is faster acting.-History:Trional was prepared and introduced by Eugen Baumann and Alfred Kast in 1888....
.
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 EichengrünArthur Eichengrün
Arthur Eichengrün was a German chemist, best known through a controversy about who invented aspirin.- Life :Arthur Eichengrün was born in Aachen as the son of a Jewish cloth merchant and manufacturer...
, and a pharmacology group for testing the drugs, headed by Heinrich Dreser
Heinrich Dreser
Heinrich Dreser was a German chemist, responsible for the aspirin and heroin projects at Bayer AG. He was a key factor in the creation of the widely used modern drug, Codeine. On December 21, 1924, Dreser died of a stroke....
(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
Acetylation
Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...
salicylic acid to make acetylsalicylic acid (ASA). Charles Frederic Gerhardt
Charles Frédéric Gerhardt
Charles Frédéric Gerhardt was a French chemist.-Biography:He was born in Strasbourg, where he attended the gymnasium. He then studied at the Karlsruhe Institute of Technology, where Friedrich Walchner's lectures first attracted his interest to chemistry...
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
Acetyl chloride
Acetyl chloride, CH3COCl, also known as ethanoyl chloride or acyl chloride, is an acid chloride derived from acetic acid. It belongs to the class of organic compounds called acyl halides. It is a colorless liquid. Acetyl chloride does not exist in nature, because contact with water would hydrolyze...
with a sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
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
Sodium carbonate
Sodium carbonate , Na2CO3 is a sodium salt of carbonic acid. It most commonly occurs as a crystalline heptahydrate, which readily effloresces to form a white powder, the monohydrate. Sodium carbonate is domestically well-known for its everyday use as a water softener. It can be extracted from the...
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
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...
.
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 trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s, 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
Rheumatism
Rheumatism or rheumatic disorder is a non-specific term for medical problems affecting the joints and connective tissue. The study of, and therapeutic interventions in, such disorders is called rheumatology.-Terminology:...
. 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
Meadowsweet
Filipendula ulmaria, commonly known as Meadowsweet, is a perennial herb in the family Rosaceae that grows in damp meadows. It is native throughout most of Europe and Western Asia...
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 to Aspirin and Euspirin; Aspirin, they feared, might remind customers of aspiration
Pulmonary aspiration
Pulmonary aspiration is the entry of material from the oropharynx or gastrointestinal tract into the larynx and lower respiratory tract...
, 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 medicinePatent medicine
Patent medicine refers to medical compounds of questionable effectiveness sold under a variety of names and labels. The term "patent medicine" is somewhat of a misnomer because, in most cases, although many of the products were trademarked, they were never patented...
s. 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 (filed 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 in Rensselaer, New York
Rensselaer, New York
Rensselaer is a city in Rensselaer County, New York, United States, and is located on the Hudson River directly opposite Albany. As of the 2010 census, the city population was 9,392; in 1920, it was 10,832. The name is from Kiliaen van Rensselaer, the original landowner of the region in New...
, 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
American Medical Association
The American Medical Association , founded in 1847 and incorporated in 1897, is the largest association of medical doctors and medical students in the United States.-Scope and operations:...
, especially after the 1906 Pure Food and Drug Act
Pure Food and Drug Act
The Pure Food and Drug Act of June 30, 1906, is a United States federal law that provided federal inspection of meat products and forbade the manufacture, sale, or transportation of adulterated food products and poisonous patent medicines...
that prevented trademarked drugs from being listed in the United States Pharmacopeia
United States Pharmacopeia
The United States Pharmacopeia is the official pharmacopeia of the United States, published dually with the National Formulary as the USP-NF. The United States Pharmacopeial Convention is the nonprofit organization that owns the trademark and copyright to the USP-NF and publishes it every year...
; 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 IWorld War I
World War I , which was predominantly called the World War or the Great War from its occurrence until 1939, and the First World War or World War I thereafter, was a major war centred in Europe that began on 28 July 1914 and lasted until 11 November 1918...
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
Hoechst AG
Hoechst AG was a German chemicals then life-sciences company that became Aventis Deutschland after its merger with France's Rhône-Poulenc S.A. in 1999...
). The British market was immediately closed to the German companies, but British manufacturing could not meet the demand—especially with phenol
Phenol
Phenol, also known as carbolic acid, phenic acid, is an organic compound with the chemical formula C6H5OH. It is a white crystalline solid. The molecule consists of a phenyl , bonded to a hydroxyl group. It is produced on a large scale as a precursor to many materials and useful compounds...
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
Exclusive right
In Anglo-Saxon law, an exclusive right is a de facto, non-tangible prerogative existing in law to perform an action or acquire a benefit and to permit or deny others the right to perform the same action or to acquire the same benefit. A "prerogative" is in effect an 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
Atlantic Ocean
The Atlantic Ocean is the second-largest of the world's oceanic divisions. With a total area of about , it covers approximately 20% of the Earth's surface and about 26% of its water surface area...
were blocked by the Royal Navy
Royal Navy
The Royal Navy is the naval warfare service branch of the British Armed Forces. Founded in the 16th century, it is the oldest service branch and is known as the Senior Service...
.
Great Phenol Plot
Great Phenol Plot
The Great Phenol Plot was a conspiracy during the early years of World War I to divert American-produced phenol away from the manufacture of high explosives, and instead use it to produce Aspirin and bring profits to the German-owned Bayer company....
. 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
Brand management
Brand management is the application of marketing techniques to a specific product, product line, or brand.The discipline of brand management was started at Procter & Gamble as a result of a famous memo by Neil H...
strategy in preparation of the expiry of the aspirin patent in the United States. Thomas Edison
Thomas Edison
Thomas Alva Edison was an American inventor and businessman. He developed many devices that greatly influenced life around the world, including the phonograph, the motion picture camera, and a long-lasting, practical electric light bulb. In addition, he created the world’s first industrial...
, who needed phenol to manufacture phonograph
Phonograph
The phonograph record player, or gramophone is a device introduced in 1877 that has had continued common use for reproducing sound recordings, although when first developed, the phonograph was used to both record and reproduce sounds...
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
Johann Heinrich von Bernstorff
Johann Heinrich Graf von Bernstorff was a German politician and the ambassador to the United States and Mexico from 1908 to 1917.- Early life :...
and Interior Ministry official Heinrich Albert
Heinrich Albert
Heinrich Friedrich Albert was a German lawyer who served as commercial attaché to the Imperial German Ambassador to the United States Johann Heinrich von Bernstorff during World War I. He was also the paymaster for German espionage and sabotage operations in the United States...
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
United States Secret Service
The United States Secret Service is a United States federal law enforcement agency that is part of the United States Department of Homeland Security. The sworn members are divided among the Special Agents and the Uniformed Division. Until March 1, 2003, the Service was part of the United States...
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
New York World
The New York World was a newspaper published in New York City from 1860 until 1931. The paper played a major role in the history of American newspapers...
, 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 custodianAlien Property Custodian
An Alien Property Custodian was an office within the Government of the United States during World War I and again during World War II, serving as a Custodian of Enemy Property to property that belonged to US enemies.-World War I:...
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
Trading with the Enemy Act
The Trading with the Enemy Act, sometimes abbreviated as TWEA, is a United States federal law, , enacted in 1917 to restrict trade with countries hostile to the United States. The law gives the President the power to oversee or restrict any and all trade between the U.S. and its enemies in times of...
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.
Interwar years
Spanish flu
The 1918 flu pandemic was an influenza pandemic, and the first of the two pandemics involving H1N1 influenza virus . It was an unusually severe and deadly pandemic that spread across the world. Historical and epidemiological data are inadequate to identify the geographic origin...
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
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...
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
World War I reparations
World War I reparations refers to the payments and transfers of property and equipment that Germany was forced to make under the Treaty of Versailles following its defeat during World War I...
of the Treaty of Versailles
Treaty of Versailles
The Treaty of Versailles was one of the peace treaties at the end of World War I. It ended the state of war between Germany and the Allied Powers. It was signed on 28 June 1919, exactly five years after the assassination of Archduke Franz Ferdinand. The other Central Powers on the German side of...
, 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.
Diversification of market
Between World War I and World War IIWorld War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...
, many new aspirin brands and aspirin-based products entered the market. The Australian company Nicholas Proprietary Limited, through the aggressive marketing strategies
Marketing strategy
Marketing strategy is a process that can allow an organization to concentrate its limited resources on the greatest opportunities to increase sales and achieve a sustainable competitive advantage.-Developing a marketing strategy:...
of George Davies, built Aspro
Aspirin
Aspirin , also known as acetylsalicylic acid , 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 discovered by Arthur Eichengrun, a chemist with the German company Bayer...
into a global brand, with particular strength in Australia, New Zealand, and the U.K.. American brands such as Burton's Aspirin, Molloy's Aspirin, Cal-Aspirin and St. Joseph Aspirin tried to compete with the American Bayer, while new products such Cafaspirin (aspirin with caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
) and Alka-Seltzer
Alka-Seltzer
Alka-Seltzer is an effervescent antacid and pain reliever first marketed by the Dr. Miles Medicine Company. It was developed by Treneer in Elkhart Indiana. Alka-Seltzer is marketed for relief of minor aches, pains, inflammation, fever, headache, heartburn, sour stomach, indigestion, and hangovers,...
(a soluble mix of aspirin and bicarbonate of soda) put aspirin to new uses. In 1925, the German Bayer became part of IG Farben
IG Farben
I.G. Farbenindustrie AG was a German chemical industry conglomerate. Its name is taken from Interessen-Gemeinschaft Farbenindustrie AG . The company was formed in 1925 from a number of major companies that had been working together closely since World War I...
, a conglomerate of former dye companies; IG Farben's brands of Aspirin and, in Latin America
Latin America
Latin America is a region of the Americas where Romance languages – particularly Spanish and Portuguese, and variably French – are primarily spoken. Latin America has an area of approximately 21,069,500 km² , almost 3.9% of the Earth's surface or 14.1% of its land surface area...
, the caffeinated Cafiaspirina (co-managed with Sterling Products) competed with less expensive aspirins such as Geniol.
Competition from new drugs
After World War II, with the IG FarbenIG Farben
I.G. Farbenindustrie AG was a German chemical industry conglomerate. Its name is taken from Interessen-Gemeinschaft Farbenindustrie AG . The company was formed in 1925 from a number of major companies that had been working together closely since World War I...
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
Anadin
Anadin is a brand of painkiller sold in the UK and Ireland by Wyeth.Several different types of painkiller are sold under the brand. , these include:* Anadin Original - aspirin and caffeine based* Anadin paracetamol tablets - launched in 1988...
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
McNeil Laboratories
McNeil Consumer Healthcare is a medicals products company belonging to the Johnson & Johnson healthcare products group.-History:The company was founded on March 16, 1879 by 23-year-old Robert McNeil, who paid $167 for a drugstore complete with fixtures, inventory and soda fountain, as a retail...
with liquid Tylenol
Tylenol
Tylenol is a North American brand of drugs advertised for reducing pain, reducing fever, and relieving the symptoms of allergies, cold, cough, and flu. The active ingredient of its original, flagship product, paracetamol , is marketed as an analgesic and antipyretic...
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
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....
(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
Reye's syndrome
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...
, a potentially fatal disease. By 1986, the U.S. Food and Drug Administration required warning label
Warning label
A warning label is a label attached to an item, or contained in an item's instruction manual, warning the user about risks associated with the use of the item as intended by the manufacturer or seller. Most of them are intended to limit civil liability in lawsuits against the item's manufacturer...
s 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 systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. In 1958 Harry Collier, a biochemist in the London laboratory of pharmaceutical company Parke Davis, began investigating the relationship between kinins
Kinin-kallikrein system
The kinin-kallikrein system or simply kinin system is a poorly understood system of blood proteins that plays a role in inflammation, blood pressure control, coagulation and pain...
and the effects of aspirin. In tests on guinea pig
Guinea pig
The guinea pig , also called the cavy, is a species of rodent belonging to the family Caviidae and the genus Cavia. Despite their common name, these animals are not in the pig family, nor are they from Guinea...
s, Collier found that aspirin, if given beforehand, inhibited the bronchoconstriction
Bronchoconstriction
Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Bronchoconstriction can also be due to an accumulation of thick mucus....
effects of bradykinin
Bradykinin
Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...
. He found that cutting the guinea pigs' vagus nerve
Vagus nerve
The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...
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
University of London
-20th century:Shortly after 6 Burlington Gardens was vacated, the University went through a period of rapid expansion. Bedford College, Royal Holloway and the London School of Economics all joined in 1900, Regent's Park College, which had affiliated in 1841 became an official divinity school of the...
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
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
tests on removed animal tissues did not behave like in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
tests.
After five years of collaboration, Collier arranged for Piper to work with pharmacologist John Vane at the Royal College of Surgeons of England
Royal College of Surgeons of England
The Royal College of Surgeons of England is an independent professional body and registered charity committed to promoting and advancing the highest standards of surgical care for patients, regulating surgery, including dentistry, in England and Wales...
, in order to learn Vane's new bioassay
Bioassay
Bioassay , or biological standardization is a type of scientific experiment. Bioassays are typically conducted to measure the effects of a substance on a living organism and are essential in the development of new drugs and in monitoring environmental pollutants...
methods, which seemed like a possible solution to the in vitro testing failures. Vane and Piper tested the biochemical cascade
Biochemical cascade
A biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...
associated with anaphylactic shock (in extracts from guinea pig lungs, applied to tissue from rabbit
Rabbit
Rabbits are small mammals in the family Leporidae of the order Lagomorpha, found in several parts of the world...
aorta
Aorta
The aorta is the largest artery in the body, originating from the left ventricle of the heart and extending down to the abdomen, where it branches off into two smaller arteries...
s). 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
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
. In a June 23, 1971 paper in the journal Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...
, Vane and Piper suggested that aspirin and similar drugs (the non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
s or NSAIDs) worked by blocking the production of prostaglandins. Later research showed that NSAIDs such as aspirin worked by inhibiting cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
, the enzyme responsible for converting arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
into a prostaglandin.
Revival as heart drug
Aspirin's effects on blood clottingCoagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
(as an antiplatelet agent) were first noticed in 1950 by Lawrence Craven. Craven, a family doctor in California, had been directing tonsillectomy
Tonsillectomy
A tonsillectomy is a 3,000-year-old surgical procedure in which the tonsils are removed from either side of the throat. The procedure is performed in response to cases of repeated occurrence of acute tonsillitis or adenoiditis, obstructive sleep apnea, nasal airway obstruction, snoring, or...
patients to chew Aspergum
Aspergum
Aspergum is the United States trademark name for an analgesic chewing gum, whose active ingredient is aspirin.Aspergum contains 227 mg of aspirin, and is available in cherry and orange flavors. This product is generally used for the analgesic, anti-inflammatory, and anti-pyretic properties of...
, an aspirin-laced chewing gum
Chewing gum
Chewing gum is a type of gum traditionally made of chicle, a natural latex product, or synthetic rubber known as polyisobutylene. For economical and quality reasons, many modern chewing gums use rubber instead of chicle...
. 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
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
. However, Craven's studies were not taken seriously by the medical community, because he had not done a placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
-controlled
Scientific control
Scientific control allows for comparisons of concepts. It is a part of the scientific method. Scientific control is often used in discussion of natural experiments. For instance, during drug testing, scientists will try to control two groups to keep them as identical and normal as possible, then...
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
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
(and unlike other potential antiplatelet drugs, aspirin had low toxicity). Medical Research Council
Medical Research Council (UK)
The Medical Research Council is a publicly-funded agency responsible for co-ordinating and funding medical research in the United Kingdom. It is one of seven Research Councils in the UK and is answerable to, although politically independent from, the Department for Business, Innovation and Skills...
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
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
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
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
, statistician Richard Peto
Richard Peto
Sir Richard Peto FRS is Professor of Medical Statistics and Epidemiology at the University of Oxford.He attended Taunton's School in Southampton and subsequently studied Natural Sciences at Cambridge University....
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.
External links
- The Recent History of Platelets in Thrombosis and other Disorders - transcript of a "witness seminar" with historians and key figures in the development of aspirin therapy for thrombosis
- Aspirin Foundation - Bayer-funded website with historical content
- The History of aspirin - Bayer timeline of aspirin history
- The Aspirin Story - Multimedia presentation on the history of Bayer Aspirin