History of acetylsalicylic acid

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The history of aspirin begins with their synthesis and production in 1899. As a shorthand for A cetyl s alicyl s äure ASA is used in the English language ASA for a cetyl s alicylic a cid. Aspirin, a registered trademark of Bayer AG , has partly become a generic name or a synonym for acetylsalicylic acid.

Salicylic acid has been used medicinally since ancient times . Medicines made from willow wood and other salicylate-rich plants appear in clay tablets from ancient Sumer and in the Ebers papyrus from ancient Egypt. Hippocrates referred to in 400 BC. On the use of salicylic tea to lower fever . Salicylate-rich plants were part of the pharmacopoeia of Western medicine in classical antiquity and in the Middle Ages. Willow bark extract was known for its specific effects on fever, pain and inflammation in the mid-18th century . In the 19th century, pharmacists experimented and prescribed a variety of chemicals associated with salicin, the active component of willow extract.

Aspirinum

In 1853, the chemist Charles Frédéric Gerhardt treated acetyl chloride with sodium salicylate for the first time to produce acetylsalicylic acid. In the second half of the 19th century, other academic chemists established the chemical structure of the compound and developed more efficient synthetic methods. In 1897, scientists at Bayer Arzneimittel- und Farbenfabriken began to investigate acetylsalicylic acid as a less irritating substitute for common salicylate standard drugs and developed a new synthetic route. Bayer had called this aspirin until 1899 and sold it worldwide. The word aspirin was the brand name of Bayer rather than the generic name of the drug. However, Bayer's trademark rights have been lost or sold in many countries. The popularity of acetylsalicylic acid grew in the first half of the 20th century and resulted in fierce competition with the distribution of ASA products and brands.

After the development of paracetamol (acetaminophen) in 1956 and ibuprofen in 1962, the frequency of ASA intake decreased. In the 1960s and 1970s discovered John Vane and others the basic mechanisms of action of acetylsalicylic acid, while clinical trials and other studies from the 1960s, the effectiveness of the drug to the 1980s as anticoagulant were (anticoagulants), the risk of clotting disorders (coagulopathy) reduced . ASA sales picked up significantly in the last decades of the 20th century and remained widely used in the preventive treatment of heart attacks and strokes into the 21st century .

Early history of salicylates

Medicines derived from willow trees and other salicylate-rich plants are part of pharmacopoeias that date back to ancient times. Willow leaves for medical purposes are already described on Sumerian clay tablets (3rd millennium BC). The Ebers papyrus , an Egyptian medical text from around 1543 BC. BC, mentions the use of willow and myrtle (another plant rich in salicylates) to treat fever and pain.

Edward Stone found that the bark of the white willow (Salix alba) could replace the Peruvian bark in the treatment of chills.

Willow bark preparations became a standard part of Western medicine starting with the Greek physician Hippocrates in the fifth century BC. He recommended chewing on willow bark to relieve pain or fever, and making tea for it, also to relieve pain during childbirth . The Roman encyclopaedist Aulus Cornelius Celsus published in his work De Medicina around 30 AD the recommendation to use willow leaf extract for the treatment of the four signs of inflammation, rubor (redness), calor (warming), tumor (swelling) and dolor (pain), to use. Willow treatments also appeared in Pedanios Dioscurides De Materia Medica and in Naturalis historia by Pliny the Elder around AD 100 . In the time of Galen (circa 130-200 AD), willow bark was widely used in ancient Rome and the Arab world, within a large, growing botanical pharmacopoeia.

Outside Europe, the Nama , a people native to South Africa and Namibia , may have used willow bark against rheumatic diseases.

18th and 19th centuries

Honor plaque for Edward Stone

The most important turning point for salicylate drugs came in 1763 when a letter from the English chaplain Edward Stone was read at a meeting of the Royal Society describing the special potential of willow bark extract for curing chills, although the description was rather incoherent was a poorly defined hodgepodge of symptoms, including intermittent fever, pain, and fatigue, probably related primarily to malaria . Inspired by the doctrine of signatures , which were used to search for pathogens in the vicinity of brackish water after a treatment against chills, Edward Stone tried the bark of a willow tree in 1758 and found an astringency that was reminiscent of the usual and expensive healing method of the Peruvian bark. He collected, dried, and pulverized a considerable amount of willow bark and tested it on a number of people who had fever and pain over the next five years. In his letter, Stone reported continued success and described the effects of willow extract as identical to that of Peruvian bark, albeit a little less effective. In fact, the active ingredient in Peruvian bark was quinine , which attacked the infectious cause of malaria, while the active ingredient in willow extract, salicin, relieved the symptoms of malaria. Stone's letter (incorrectly attributed to Edmund Stone instead of Edward Stone) was printed in the Philosophical Transactions of the Royal Society , which made willow bark an inexpensive substitute for cinchona trees in the late 18th century .

Real meadowsweet ( Filipendula ulmaria ). Tea made from its flowers is an ancient folk remedy for fever and pain.

In the 19th century, as the fledgling discipline of organic chemistry began to develop in Europe, scientists tried to isolate and purify the active components of many drugs, including willow bark. After unsuccessful attempts by the Italian chemists Luigi Valentino Brugnatelli and Felice Fontana , Johann Andreas Buchner succeeded in 1828 in producing relatively pure salicin crystals. In the following year, Henri Leroux developed another method for obtaining salicin, but with a low yield. In 1834 the Swiss pharmacist Johann Pagenstecher discovered what he thought was a new pain reliever substance isolated from the widespread plant true meadowsweet (formerly called Spiraea ulmaria). The full name of the author is Johann Samuel Friedrich Pagenstecher (1783-1856). In 1838 the Italian chemist Raffaele Piria found a method for obtaining a stronger acid form of the willow extract, which he called salicylic acid. The German chemist who worked on the identification of the "Spiraea" extract, Carl Löwig , soon realized that it was, in fact, the same salicylic acid that Piria had found.

Salicylate drugs - including salicin, salicylic acid, and sodium salicylate - have been difficult and laborious to extract from plants. In 1860 Hermann Kolbe worked out a way to synthesize salicylic acid. During the late 19th century, the use of salicylates increased dramatically, and doctors began to understand what to expect from these drugs: reducing pain, lowering fever, and reducing inflammation. However, the unpleasant side effects, particularly stomach irritation, limited their use, as did their intense bitter taste. In the 1880s, stimulated by the lucrative development of colorants from coal tar, the German chemical industry began looking for the potential of new tar-derived drugs.

Bayer on the way to aspirin

The turning point was the invention of Antifebrin by Chemischen Fabrik Kalle , the branded version of the well-known dye derivative acetanilide , whose antipyretic properties were discovered by chance in 1886. The success of antifebrin prompted Carl Duisberg , head of research at the small paint factory Friedrich Bayer - today's Bayer AG - to systematically search for other chemical fever reducers. Bayer chemists soon developed phenacetin , followed by the sedative sulfonal . The sulfonals were replaced by the development of barbiturates .

Synthesis of acetylsalicylic acid

Synthesis steps from phenol to salicylic acid to acetylsalicylic acid

In 1853 Charles Frédéric Gerhardt published the first methods for the production of acetylsalicylic acid. In the second half of the 19th century, other academic chemists established the chemical structure of the compound and developed more efficient synthetic methods. While working on the synthesis and researching the properties of various acid anhydrides, he mixed acetyl chloride with a sodium salt of salicylic acid (sodium salicylate). A violent reaction ensued and the resulting melt soon solidified. Since there was no structural theory at that time, Gerhardt called the compound salicylacetic anhydride ("anhydrous salicylic acid-acetic acid"). When Gerhardt tried to dissolve the solid in a dilute sodium carbonate solution , it immediately disintegrated into the sodium salts of salicylic acid and acetic acid . In 1859, an Austrian chemist, Hugo von Gilm , obtained an analytically pure substance acetylsalicylic acid (which he called acetylated salicylic acid ) through a reaction of salicylic acid and acetyl chloride. In 1869, Schröder, Prinzhorn, and Kraut repeated the synthesis of Gerhardt (from sodium salicylate) and von Gilm (from salicylic acid) and concluded that both reactions gave the same compound - acetylsalicylic acid. (The work ascribes the conduct of the experiments to Prinzhorn.) First, the correct structure with the acetyl group, which is bound to the phenolic oxygen , was assigned.

After Duisberg took control of the overall management of Bayer in 1890, he began expanding the company's drug discovery program. He founded a pharmaceutical group for the production of new drugs under the direction of the former university chemist Arthur Eichengrün and a pharmacological group for the testing of drugs under the direction of Heinrich Dreser (from 1897, after periods under Wilhelm Siebel and Dr. Hermann Hildebrandt). In 1894 the young chemist Felix Hoffmann joined the pharmaceutical group. Dreser, Eichengrün and Hoffmann were the key figures in the development of the active ingredient acetylsalicylic acid into the drug aspirin (although their respective roles were controversial).

Aspirin bottles from paint factories vorm. Friedrich Bayer & Co., Elberfeld

In 1897 Hoffmann began to look for a substitute for salicylic acid that was less irritating to the stomach. It is widely believed that he turned to this idea because his father suffered from the side effects of taking sodium salicylate for rheumatism . It is likely that Hoffmann did what most chemists always did by studying the literature and mimicking the published methods. On August 10, 1897, Hoffmann finally found, according to his laboratory notebooks, a better method for producing ASA from salicylic acid with acetic anhydride.

Structural formula of acetylsalicylic acid

Eichengrün sent the ASS to the Dresden pharmacology group for testing. The first results were very positive. The next step would normally have been a clinical trial, but Dreser declined further investigation of ASA because salicylic acid had a reputation for weakening the heart - possibly a side effect of the high doses commonly used to treat rheumatism. Dreser's group was soon busy testing Felix Hoffmann's next chemical hit: diacetylmorphine (which the Bayer team soon referred to as " heroin " because of the heroic feeling it gave them ). Eichengrün was frustrated by Dresden's rejection of the ASS and went straight to Bayer representative Felix Goldmann to arrange low-profile studies with doctors. Although the results of these studies were also very positive and there were no reports of the typical salicylic acid complications, Dreser still refused. However, Carl Duisberg intervened and planned full tests. Dreser soon acknowledged the potential of ASS and Bayer decided to continue production. Dreser wrote a report on the results to publicize the new drug. He left out any mention of Hoffmann or Eichengrün. He would also be the only one of the three to receive royalties on the drug (to test it) because it wasn't patent approved, and one that chemists may have filed for making the drug. For many years, however, he attributed the discovery of acetylsalicylic acid exclusively to Hoffmann.

Title page of Kurt Witthauer 's first clinical report on aspirin

Kurt Witthauer was the senior physician and internist at the Diakonissenhaus Halle / Saale and was the first to conduct a clinical study of the substance acetylsalicylic acid. He examined the effect of the drug on fifty patients and coined the name aspirin in the professional world by being the first to publish a scientific report on the use of acetylsalicylic acid.

The controversy over who was primarily responsible for developing aspirin spread throughout much of the 20th century into the 21st century. Although the origins of acetylsalicylic acid lay in academic research and Bayer was not the first to synthesize it, Bayer still described Hoffman from 2016 onwards as the "discoverer of an analgesic, antipyretic and anti-inflammatory substance". Historians and others have also questioned Bayer's early reports of the Bayer synthesis that Hoffmann was primarily responsible for the Bayer breakthrough. In 1949, shortly before his death, Eichengrün wrote an article entitled Fifty Years of Asprin , in which he claimed that he had failed to tell Hoffmann the purpose of his research, which meant that Hoffmann was merely carrying out Eichengrün's research plan and that the drug was without his Instructions would never have hit the market. This claim was later supported by research by historian Walter Sneader . Axel Helmstaedter , General Secretary of the International Society for the History of Pharmacy, questioned Sneader's new findings and noted that several earlier articles discussed the Hoffmann-Eichengrün controversy in detail. Bayer countered Sneader in a press release stating that Hoffmann and Eichengrün held the same positions and Eichengrün was not Hoffmann's superior. Hoffmann was named as the inventor in the US patent, which Sneader did not mention. Eichengrün, who left Bayer in 1908, had several options for making use of his initial description, but had never done so before 1949. Also, he has not claimed or received any royalties on profits from the sale of aspirin.

Name of the drug

Spirea or meadowsweet contains spiric acid (salicylic acid) and is part of the name of aspirin.

The name aspirin is derived from the name of the chemical ASA - acetylspiric acid. Liquoric acid (salicylic acid) was derived from the plant Spirea ulmaria . Aspirin was created as a letter combination from an "A" - for acetylation, "spir" - from spiric acid and the ending "in" - as a typical end of a drug name to simplify the complicated name acetylsalicylic acid . In the last voting round on name proposals at Bayer, two names were still in the running: Aspirin and Euspirin . "Aspirin" was feared that it might remind customers of " aspiration ", but Arthur Eichengrün argued that ancient Greek εὖ eu - (in ancient Greek meaning "good") was inappropriate because there is usually an improvement over it an earlier version of a similar drug. Since the substance itself was already known, Bayer wanted to use the new name to establish the drug as something new. In January 1899 they agreed on "Aspirin".

Rights and sales

Display of aspirin in a Galician Tui pharmacy

Under the leadership of Carl Duisberg, Bayer was determined to follow the standards of prescription drugs that were only available at a pharmacy. Direct marketing to consumers, so-called OTC drugs , was decidedly rejected by many medical organizations. Bayer therefore limited itself to marketing aspirin directly to doctors. The brand name Aspirin was incorporated into the trademark role of the Imperial Patent Office in Berlin, which had existed since 1877, for the paint factories on March 6, 1899 . Friedr. Bayer & Co. registered. When production of aspirin began in 1899, Bayer sent small packets of the medicine to doctors, pharmacists and hospitals, informed them about the use of aspirin and encouraged them to publish information about the drug's effects and effectiveness. When positive results came in and enthusiasm increased, Bayer sought patent and trademark rights wherever possible. It was not patentable in Germany because the Saxon chemical factory v. Heyden in Radebeul already manufactured the active ingredient on a large scale and sold it as a drug (name acetylin ). Aspirin was patented in the United Kingdom (filed December 22, 1898) and the United States (US Patent 644,077, issued February 27, 1900). The British patent was revoked in 1905 after a patent lawsuit by Chemische Fabrik von Heyden; the American patent was also challenged, but ultimately upheld.

In view of the growing legal and illegal competition for ASA, which is marketed around the world, Bayer worked to strengthen the link between Bayer and aspirin. One strategy that was developed was to switch from delivering aspirin powder to pharmacists who pressed it into tablets or dispensed it in packaged powder sachets, to distributing standardized tablets - complete with the unmistakable Bayer cross logo. In 1903 the company founded an American subsidiary with a converted factory in Rensselaer, NY , to produce aspirin for the American market and not have to pay import duties. Bayer sued the identified patent infringers and smugglers. The company's attempts to hold on to its aspirin sales have met with criticism from fraudulent journalists and the American Medical Association , particularly under the Pure Food and Drug Act of 1906, which prevented drugs from being trademarked in the United States Pharmacopeia (comparable to the Red List ) were listed. Bayer listed ASA with an intentionally interleaved generic name, "monoacetic acid ester of salicylic acid," to discourage doctors from referring to anything other than aspirin.

World War I and aspirin

Envelope from Nicholas Pty Ltd of Melbourne, Victoria, Australia advertising their ASS product

Until the outbreak of World War I in 1914, Bayer was exposed to competition from local ASA manufacturers and other German drug manufacturers (particularly Heyden and Hoechst ) in all major markets . The UK market was immediately closed to German companies, but UK manufacturing was unable to meet demand - particularly with phenol supplies, which are required for ASA synthesis and are mainly used to make explosives . On February 5, 1915, Bayer's UK trademarks became invalid and any company could use the term “aspirin”. The Australian market was taken over by Aspro ("Aspirin protectAspro") after the makers of Nicholas aspirin lost a short-lived right to the name Aspirin. In the United States, Bayer was still under German control - even though the war cut ties between Bayer's American plant and Bayer's German headquarters. Nevertheless, the phenol deficiency threatened to reduce aspirin production to a minimum and imports across the Atlantic were blocked by the Royal Navy .

The great phenol conspiracy

The August 15, 1915 issue of New York World brought the news of the great phenol conspiracy and other secret operations organized by Johann Heinrich von Bernstorff and Heinrich Albert .

In order to secure the phenol for aspirin production and at the same time indirectly support the German war effort, German agents in the USA orchestrated what became known as the Great Phenol Plot (great phenol conspiracy). By 1915, the price of phenol had soared that Bayer's aspirin production facility was forced to cut production dramatically. This was particularly problematic as Bayer put in place a new branding strategy to prepare for the expirin of the Aspirin patent in the US. Thomas Alva Edison , who used phenol to make panels, also faced supply problems. In response, he created a phenol factory that can pump twelve tons per day. Edison's excess phenol appeared to be destined for the production of trinitrophenol .

Although the United States remained officially neutral until April 1917, it increasingly supported the Allies through trade. To counteract this, the German Ambassador Johann Heinrich von Bernstorff and Interior Minister 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 signed a deal with a front-line company called the Chemical Exchange Association to buy all of Edison's excess phenol. A large part of the phenol would be sold to the American subsidiary of Chemischen Fabrik v. Heyden go. Heyden was the supplier of Bayer salicylic acid for aspirin production. By July 1915, Edison's plants were selling about three tons of phenol per day to Schweitzer. Heyden's salicylic acid production was soon up and running again, and Bayer's aspirin plant was also up and running.

The plot lasted only a few months. On July 24, 1915, Heinrich Albert's briefcase, which contained details of the phenol conspiracy, was retrieved by an intelligence agent. Although the activities were not illegal - the United States was still officially neutral and still trading with Germany - the documents were soon leaked to New York World , an anti-German newspaper. The New York World published an exposé on August 15, 1915. Public pressure soon forced Schweitzer and Edison to end the plot, whereupon Edison sent his excess phenol to the US military. At the time, the deal had cost over $ 2 million and there was already enough phenol to keep the Bayer aspirin plant going. Bayer's reputation now saw great success as the company prepared for an advertising campaign to secure the link between Aspirin and the Bayer brand.

Bayer loses foreign investments

Bayer began advertising to American consumers just before the aspirin patent expired. In this February 19, 1917 New York Times advertisement, Bayer is featured as "One Real Aspirin" in view of legal competition in the US market.

Beginning in 1915, Bayer established a number of mailbox companies and subsidiaries in the United States to protect itself against the possibility of losing control of its American assets should the US enter the war and to open up other market segments for Bayer (e.g. B. the production of army uniforms). After the USA declared war on Germany in April 1917, the Office of Alien Property Custodian was founded, an authority to control the property of opponents of the war. As head of the agency, A. Mitchell Palmer began researching German companies and soon turned to Bayer. In order not to have to surrender all profits and assets to the government, Bayer management had moved the inventory to a new company nominally owned by Americans but controlled by the German-American Bayer leaders. However, Palmer soon uncovered this plan and confiscated all of Bayer's American holdings. After the Trading with the Enemy Act was amended to allow these stocks to be sold, the government auctioned the Rensselaer plant and all of Bayer's American patents and trademarks, including the Bayer brand name and the Bayer cross logo. It was purchased by a drug company, Sterling Drug , Inc. The rights to Bayer-Aspirin and the US-American rights to the name Bayer including the cross logo and the other brands were bought back by Bayer AG in 1994 for one billion US dollars.

Interwar years

With the outbreak of the deadly Spanish flu pandemic in 1918, acetylsalicylic acid secured its reputation as one of the most powerful and effective drugs in the drug directory of the time. Its antipyretic properties gave many sick patients enough strength to fight the infection. Pharmaceutical companies big and small forged the loyalty of doctors and the public - if only they could make or buy enough ASA to meet demand. Even so, some people believed the Germans put the Spanish flu in Bayer aspirin and started the pandemic as a war tactic.

Newspaper advertisement for Bayer Aspirin from April 1918. The patent for aspirin has expired. Bayer remained in control of the Aspirin brand, which can be seen at the bottom of the ad. The ad includes a "patriotic" slogan to buy war bonds. It also shows the factory in New York State.

The US ASA patent expired in 1917, but Sterling Drug owned the brand "Aspirin," which was the only commonly used term for the drug. In a legal dispute between the American Bayer and the United Drug Company over the brand "Aspirin", the judge found that "Aspirin" had meanwhile become the generic name for acetylsalicylic acid-containing drugs in sales to end consumers Pharmacist. With the rapidly growing demand for Spanish flu, hundreds of brands of "aspirin" were soon offered in the United States.

l'Aspirine (1923) from Usines du Rhône, a predecessor of Sanofi

After the First World War , Bayer was forced under the Versailles Treaty to give up the rights to the Aspirin brand for the territory of the victorious powers USA , France and Great Britain . In the USA, the US authorities "Alien Property Custodian" seized the pharmaceutical company in 1917 when the US entered the war. It was sold two years later to Sterling Drug for 5.3 million US dollars, including the trademark rights and the rights to the company name including the Bayer logo. Sterling Drug also acquired Bayer’s Canadian assets and ownership of the Aspirin brand, which continues to operate in Canada and much of the world. In the United States, the name "Aspirin" became public domain through a court order in 1921.

Sterling Drug, which held all of Bayer's US intellectual property, was trying to take advantage of its new brand as soon as possible before adopting generic ASA supplements began. Without German know-how to operate the Rensselaer plant for the production of aspirin and other Bayer drugs, they only had a limited aspirin supply and were exposed to competition from other companies. Sterling President William E. Weiss had ambitions not only to sell Bayer aspirin in the USA but also to compete with the German Bayer Group abroad. Taking advantage of the losses suffered by Farbenfabriken Bayer (the German Bayer company) as a result of the reparations provisions of the Versailles Treaty , Weiss concluded an agreement with Carl Duisberg to gain shares in America, Australia, South Africa and the UK for most Bayer drugs in return for technical support in the manufacture of the drugs.

Tubes with ASA the German Red Cross, as during the Second World War was used

Bayer bought Sterling Winthrop's North American OTC business from then owner Kodak for $ 1 billion in 1994, restoring ownership of the Bayer name and brand in the United States and Canada and ownership of the Aspirin brand, including the trademark in Canada.

Market diversification for acetylsalicylic acid

Empirin 1939

Many new brands of aspirin and ASA-based products appeared on the market between World War I and World War II. The Australian company Nicholas Proprietary Limited built a global brand with particular strength in Australia, New Zealand and the UK through the aggressive marketing strategy of George Davies. This is how American brands such as Burton's Aspirin , Molloys Aspirin , Cal-Aspirin and St. Joseph Aspirin emerged , which competed with the American Bayer, while new products such as Cafaspirin (aspirin with caffeine ) and Alka-Seltzer (a soluble mixture of aspirin, sodium bicarbonate and Citric acid) ASA for new indications. In 1925, Deutsche Bayer became part of IG Farben, a conglomerate of former dye companies. The aspirin brands from IG Farben, in Latin America the caffeinated Cafiaspirina and the products serviced by Sterling competed with less expensive ASS products such as B. Geniol .

Competition from new drugs

Aspirin / acetylsalicylic acid tablet pack from Warrick Bros Ltd, England

After the Second World War, when the IG Farben conglomerate was dismantled because of its central role in the Nazi regime, Sterling Products bought half of Bayer Ltd, Bayer's British subsidiary previously held by IG Farben. However, due to competition from Aspro, Disprin (a soluble aspirin drug) and other brands, Bayer Aspirin made up only a small part of the UK acetylsalicylic acid market. Bayer AG was looking for new pain relievers in order to be able to compete better. After several moderately successful compound drugs (e.g. Anadin and Excedrin), which mainly used ASA, Bayer Ltd manager Laurie Spalton ordered a study of a substance that scientists at Yale had found in 1946, the metabolically active derivative of acetanilide : Acetaminophen. Following clinical studies, Bayer Ltd (UK) launched paracetamol as Panadol in 1956 . However, parent company Sterling Products did not market Panadol in the United States or in any other country where Bayer aspirin still dominated the ASA market.

In the GDR and later in the new federal states, acetylsalicylic acid was sold under the trade name Acesal by the manufacturer Dr. Kade Pharmaceutical Factory from Berlin in various concentrations, which is also known as "East Aspirin". It is still on sale as the Acesal 500. Dr. Kade acquired Acesal from Takeda Pharmaceutical in 2013 . The brand was created using the mosaic method . It is the most frequently used method for creating trade names. In the course of this, one or more words are taken apart and the components reassembled. So Acesal arose from Ace -tyl- sal -icylsäure.

Other companies - notably McNeil Laboratories - began selling acetaminophen drugs as liquid Tylenol in 1955 and Tylenol pills in 1958. Tylenol was available without a prescription until 1967. Since it did not cause stomach irritation, acetaminophen quickly replaced a large part of ASA sales. Another pain reliever , anti-inflammatory drug was introduced in 1962: ibuprofen (sold as Brufen in the UK and Motrin in the US). In the 1970s, acetylsalicylic acid had a relatively small share of the pain reliever market, and sales fell even further in the 1980s when ibuprofen became available without a prescription.

Bayer aspirin and RITE AID aspirin

Also in the early 1980s, several studies suggested a link between the use of ASA in children and Reye's syndrome , a potentially fatal disease. By 1986, the Food and Drug Administration , the highest drug authority in the United States, required pharmaceutical manufacturers to attach a warning to all ASS products, which further reduced sales. The paracetamol makers also filed a lawsuit against aspirin maker Anacin, alleging that the failure to put up warning signs before 1986 wrongly affected Tylenol's sales. This action was ultimately dismissed.

Research into the mode of action

The mechanism of the analgesic, anti-inflammatory and antipyretic properties of ASA was unknown in the drug's heyday in the early to mid-20th centuries. Heinrich Dresden's explanation was that aspirin relieves pain by acting on the central nervous system and has been widely accepted since the drug was first introduced. In 1958, Harry Collier , a biochemist in the London laboratory of the pharmaceutical company Parke-Davis , began to investigate the relationship between the kinin-kallikrein system kinins and the effects of acetylsalicylic acid. In animal studies with guinea pigs , Collier found that ASA, when given beforehand, inhibited the effects of bradykinin . He found that severing the guinea pigs' vagus nerve did not affect the effects of bradykinin or the inhibitory effects of acetylsalicylic acid - evidence that ASA acts locally against pain and inflammation and not against the central nervous system . In 1963, Collier began working with PhD student in pharmacology, Priscilla Piper, to determine the exact mechanism of ASA effects. However, it was difficult to determine the exact biochemical processes in living test animals, and tests on extracted animal tissues did not behave like tests in vivo .

John Robert Vane

After five years of working together, Collier arranged for Piper to work with pharmacologist John Robert Vane at the Royal College of Surgeons of England to learn Vane's new bioassay methods. These methods could be a possible solution to the previous errors in in vitro studies . Vane and Piper tested the biochemical cascade associated with anaphylactic shock (excerpts from guinea pig lungs applied to tissue from rabbits). They found that acetylsalicylic acid inhibits the release of an unidentified chemical that is produced by the guinea pig's lungs. This chemical caused rabbit tissue to contract, and they called it Rabbit-Aorta Contracting Substance (RCS). By 1971, Vane identified the chemical as prostaglandin . In a June 23, 1971 Nature article, Vane suggested that aspirin and similar nonsteroidal anti-inflammatory drugs suppress the production of prostaglandins. Later research showed that it inhibits the enzyme cyclooxygenase , which is responsible for converting arachidonic acid into prostaglandin. For his discoveries about the mechanisms of action of acetylsalicylic acid on prostaglandin synthesis, Vane received the Nobel Prize in 1982.

Revitalization of acetylsalicylic acid as a heart drug

Effects of ASA on blood clotting (as a platelet inhibitor ) were first noted by Lawrence Craven in 1950 . Craven, a family doctor in California, had instructed tonsillectomy patients to chew aspergum , an aspirin -containing chewing gum . He found that an unusual number of patients had to be hospitalized for severe bleeding and that these patients used very high amounts of Aspergum. Craven began recommending acetylsalicylic acid daily to all of his patients, claiming that the patients who followed the ASA treatment regimen (approximately 8,000 people) had no evidence of thrombosis . However, Craven's studies were not taken seriously by the medical community because he did not conduct a study and only published it in dubious journals.

The idea of ​​using acetylsalicylic acid to prevent blood clotting diseases such as heart attacks and strokes was revived in the 1960s when medical researcher Harvey Weiss discovered that ASA had an anti-adhesive effect on blood platelets and, unlike other potential antiplatelet agents, ASA was low in toxicity. The hematologist John O'Brien of the Medical Research Council in Great Britain took up the findings of Weiss and began working in 1963 with the epidemiologist Peter Elwood on the potential of acetylsalicylic acid against thrombosis. Elwood started a large-scale ASA study as a heart attack preventive drug. Nicholas Laboratories agreed to provide aspirin tablets, and Elwood enrolled heart attack survivors in a double-blind study. From a statistical point of view, heart attack survivors were more likely to have a second attack, which significantly reduced the number of patients required and whether acetylsalicylic acid had an effect on the prevention of the heart attack. The study began in February 1971, although researchers soon had to abandon double blindness when a study by American epidemiologist Hershel Jick found that acetylsalicylic acid prevented heart attacks but found the heart attacks were more deadly. Jick found that fewer ASA users were hospitalized for a heart attack than non-ASA users. One possible explanation was that ASA users died of heart attacks before reaching the hospital; Elwood's first results precluded this explanation. When the Elwood study ended in 1973, there was a modest, but not statistically significant, decrease in heart attacks in the group that took acetylsalicylic acid.

Several subsequent studies put the efficacy of acetylsalicylic acid as a heart medication on firmer ground, but the evidence has been controversial. In the mid-1980s, statistician Richard Peto convinced the US FDA and much of the medical community that the ASA studies as a whole showed the effectiveness of acetylsalicylic acid with relative certainty. As of the late 1980s, ASA was widely used as a preventive drug against heart attacks and had regained its former position as the best-selling analgesic in the United States.

In the meantime, three large studies in 2018 have shown that ASA is not suitable for the primary prevention of healthy patients with an increased cardiovascular risk. The American Heart Association and the American College of Cardiology decided in 2019 to change the relevant guidelines for clinical practice. Nevertheless, millions of people continue to take low-dose acetylsalicylic acid daily, even without a doctor's prescription.

Trivia

"What do ordinary people care that they are not richer than others when the world provides them with roads, railways, hotels, telegraphs, physical security and aspirin."

- Ortega y Gasset, revolt of the masses
  • Aspirin is one of the "Brands of the Century". The project honors those brands that are emblematic in their own product category, i.e. that are exemplary for the entire category.
  • The aspirin rose is a type of white rose presented by the rose breeding company Rosen Tantau in 1997 , which was named after the drug on the occasion of the 100th anniversary of the aspirin invention. In 1995 the rose species received an award as Recognized German Rose (ADR Rose).

literature

Web links

Commons : Acetylsalicylic acid  - Collection of pictures, videos and audio files
Commons : Aspirin  - collection of pictures, videos and audio files
Wiktionary: Aspirin  - explanations of meanings, word origins, synonyms, translations

Individual evidence

  1. ↑ a b c d aspirin . In: Chemical & Engineering News . Retrieved August 12, 2019.
  2. ↑ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj Diarmuid Jeffreys. Aspirin: The Remarkable Story of a Wonder Drug . Chemical Heritage Foundation, 2008. ISBN 9781596918160
  3. ↑ a b c d Aspirin: Turn of the Century Miracle Drug . In: Chemical Heritage Magazine . 27, No. 2, September, pp. 26-30. Retrieved August 12, 2019.
  4. ↑ The History of Aspirin , August 12, 2019.
  5. ↑ a b c d e f g h i j k l Charles C. Mann and Mark L. Plummer. The Aspirin Wars: Money, Medicine, and 100 Years of Rampant Competition . New York: Alfred A. Knopf, 1991. ISBN 0-394-57894-5
  6. ↑ a b c Karsten Schrör: Acetylsalicylic Acid . Wiley-Blackwell, Weinheim 2009, ISBN 978-3-527-32109-4 , pp. 5 (English).
  7. ↑ John F. Nunn: Ancient Egyptian Medicine . University of Oklahoma Press, Norman, OK, USA 1996, ISBN 978-0-8061-2831-3 (Chapter 7, Table 7.2).
  8. ^ T. Maclagan: The Treatment of Rheumatism by Salicin and Salicylic Acid . In: BMJ . tape 1 , no. 803 , May 20, 1876, p. 627 , doi : 10.1136 / bmj.1.803.627 (English, In an answer from Dr. Ensor, Cape of Good Hope, to this publication).
  9. ^ A b c d e Alan Jones: Chemistry: An Introduction for Medical and Health Sciences . John Wiley & Sons, 2015, ISBN 978-0-470-09290-3 , pp. 5–9 (English, limited preview in Google Book Search).
  10. ^ Edmund Stone (1763) "An account of the success of the bark of the willow in the cure of the ague," Philosophical Transactions of the Royal Society of London , 53  : 195-200. Available on-line at: Royal Society Publishing.
  11. ↑ A. Buchner (1828) [ https://books.google.com/books?id=r-40AQAAMAAJ&pg=PA405#v=onepage&q&f=false On Rigatelli's antipyretic (i.e. anti-fever drug and on an alkaloid discovered in willow bark ), Repertory for Pharmacy, 29: 405-420.
  12. ↑ (Leroux, H.) (1830) "Mémoire relatif à l'analyse de l'écorce de saule et à la découverte d'un principe immédiat propre à remplacer le sulfate de quinine" (Memoir concerning the analysis of willow bark and the discovery of a substance immediately likely to replace quinine sulfate), Journal de chimie médicale, de pharmacie et de toxicologie , 6  : 340–342.
  13. ↑ F. Pagenstecher (1834) "About the distilled water and oil of the flowers of Spiraea Ulmaria" the flowers of Spiraea ulmaria), Repertorium für die Pharmacie, 49: 337-367.
  14. ↑ Piria (1838) "Sur de nouveaux produits extraits de la salicine" (For new products obtained from salicine): Comptes rendus… 6: 620–624. On page 622, Piria mentions "Hydrure de salicyle" (hydrogen salicylate, ie salicylic acid).
  15. ^ C. Löwig & S. Weidmann (1839) Contributions to Organic Chemistry Annals of Physics and Chemistry, 46: 45–91. From page 82: is the salicylic hydrogen from Piria (Compt. Rend. VI, p. 620). (So ​​far only one organic compound is known that can be compared to Spiraea acid (i.e. salicylic acid) the hydrogen salicylate from Piria (Compt. Rend. VI, p. 620).)
  16. ↑ Entry on sulfonal. In: Römpp Online . Georg Thieme Verlag, accessed on August 12, 2019.
  17. ↑ a b c Overview of the relatives of acetylsalicylic acid, explanations of publications on the synthesis of acetylsalicylic acid . In: Revue d'Histoire de la Pharmacie . 84, No. 310, 1996, pp. 269-273. doi : 10.3406 / pharm . 1996.4350 . PMID 11624864 .
  18. ↑ Ch. Gerhardt: Investigations on the anhydrous organic acids. In: Annals of Chemistry and Pharmacy. 87, 1853, p. 57, doi : 10.1002 / jlac.18530870107 .
  19. ↑ Ch. Gerhardt: Investigations on the anhydrous organic acids. In: Annals of Chemistry and Pharmacy. 87, 1853, p. 57, doi : 10.1002 / jlac.18530870107 .
  20. ↑ by Gilm H .: Acetyl derivatives of phloretinic and salicylic acid . In: Annals of Chemistry and Pharmacy . 112, No. 2, 1859, pp. 180-185. doi : 10.1002 / jlac.18591120207 .
  21. ↑ A. d. Schröder, A. d. Prinzhorn, K. Kraut: About salicylic compounds ;. In: Annals of Chemistry and Pharmacy. 150, 1869, p. 1, doi : 10.1002 / jlac.18691500102 .
  22. ↑ a b Sneader W: The discovery of aspirin: a reassessment . In: BMJ . 321, No. 7276, 2000, pp. 1591-4. doi : 10.1136 / bmj.321.7276.1591 . PMID 11124191 .
  23. ^ Anne AJ Andermann, " Physicians, Fads, and Pharmaceuticals: A History of Aspirin , McGill Journal of Medicine, vol. 2, no. 2 (1996). Retrieved August 12, 2019.
  24. ↑ Karsten Schrör, HK Breddin: Acetylsalicylic acid in the cardiovascular system: 50 years after Felix Hoffmann. Springer-Verlag 1996, ISBN 3-764-35646-4 , p. 8. ( preview in Google book search)
  25. ^ Felix Hoffmann - Personalities of Bayer's History . Bayer. Archived from the original on November 16, 2016.
  26. ↑ Walter Sneader, Re: Aspirin anamnesis: Is there a need for a reassessment? BMJ , March 16, 2001.
  27. ^ Bayer AG: On the lecture by Dr. Walter Sneader on the development of acetylsalicylic acid . Retrieved August 12, 2019. (Archive)
  28. ↑ Bayer patents aspirin . History Channel . Retrieved August 12, 2019.
  29. ↑ Registered 120 years ago , German Patent and Trademark Office, August 10, 2019. Retrieved on August 12, 2019.
  30. ↑ Patent US644077 : Acetyl Salicyl Acid. Registered on August 1, 1898 , published on February 27, 1900 , applicant: Farbenfabriken of Elberfeld Co, New York, inventor: Felix HOFFMANN. ‌
  31. ↑ Kuehmsted vs Farbenfabriken of Elberfeld, 179 F. 701 (7th Cir. 1910)
  32. ^ "Against using the word 'Aspirin' in correspondence, invoices, bills of lading, and the like, or upon cartons, labels, or other marking, in any sales of 'acetyl salicylic acid' to manufacturing chemists, wholesale or retail druggists, or physicians. The defendant will be free to sell 'acetyl salicylic acid' direct to consumers under the name 'Aspirin' without suffix or qualification. The defendant in sales to retail druggists will also be free to pack tablets in bottles and boxes of fifty or less, labeled, 'Aspirin,' provided these bottles or boxes be wrapped or boxed in containers marked 'acetyl salicylic acid manufactured by UD Co. , 'without the word' Aspirin, 'and that in making such sales the correspondence, invoices, bills of lading, and the like refer to the drug so sold only as' acetyl salicylic acid.' "( Learned HAND, District Judge : Bayer Co. v. United Drug Co., 272 F. 505 (SDNY 1921), 1921-04-14)
  33. ^ Désirée Kietzmann: Trademark rights: Aspirin as reparation payment. In: apotheke adhoc. EL PATO Medien, June 28, 2010, accessed on September 3, 2019 .
  34. ↑ Aspirin: A Brand . In: Canadian Family Physician . 27, 1981, p. 1202. PMID 21289783 .
  35. ↑ Aspirin Brand or Aspirin Tablets? Avoid the "Genericide" headache in the US . Archived from the original on May 30, 2008. Retrieved November 13, 2008.
  36. ↑ Learned Hand: Bayer Co. v. United Drug Co. , 272 F. 505 (SDNY 1921), 1921-04-21
  37. ↑ Acesal 250 mg: Farewell to "Eastern Aspirin" , March 11, 2017. Retrieved on August 12, 2019.
  38. ^ John Robert Vane: Inhibition of Prostaglandin Synthesis as a Mechanism of Action for Aspirin-like Drugs . In: Nature New Biology . tape 231 , June 23, 1971, p. 232-235 , doi : 10.1038 / newbio231232a0 .
  39. ^ Information from the Nobel Foundation on the 1982 award ceremony for John Robert Vane (English)
  40. ↑ Miner J, Hoffhines A: The discovery of aspirin's antithrombotic effects . In: Tex Heart Inst J . 34, No. 2, 2007, pp. 179-86. PMID 17622365 .
  41. ↑ Richard J. Sundberg: The chemical century: Molecular manipulation and its effects on the 20th century . CRC, 2017, ISBN 978-1-315-34203-0 , pp. 491 ( limited preview in Google Book Search [accessed August 16, 2019]).
  42. ↑ Widespread aspirin use despite few benefits, high risks m Science Daily , July 22, 2019. Retrieved August 12, 2019.
  43. ↑ Brands of the Century , Publishing Group Die Zeit. Retrieved August 12, 2019.
  44. ^ Peter Schneider: Right Rose, Right Place . Storey Publishing, 2009, ISBN 978-1-60342-438-7 , pp. 69 (English).
  45. ↑ Aspirin Rose (ADR - Rose 1995). Federation of German Tree Nurseries (BdB) eV, accessed on August 14, 2019 (ADR no .: 9233).