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COX-2 Chronology C J Hawkey 1509 LEADING ARTICLE Gut: first published as 10.1136/gut.2005.065003 on 13 October 2005. Downloaded from COX-2 chronology C J Hawkey ............................................................................................................................... Gut 2005;54:1509–1514. doi: 10.1136/gut.2005.065003 The role of selective cyclooxygenase (COX)-2 inhibitors in N 1859 Hammond Kolbe synthesises salicylic acid, with industrial scale production in 1874.7 medical practice has become controversial since evidence Salicylic acid is bitter and irritates the mouth emerged that their use is associated with an increased risk and stomach. of myocardial infarction. Selective COX-2 inhibitors were N 1863 Friedrich Bayer and Friedrich Weskott found a dye manufacturing company employ- seen as successor to non-selective non-steroidal anti- ing six people in Wuppertal-Barmen.8 inflammatory drugs, in turn successors to aspirin. The N 1886 Bayer manufacture phenacetin from a importance of pain relief means that such drugs have waste product of a benzo dye. What starts as a always attracted attention. The fact that they work through supplement to dye manufacture is to become the company’s more profitable and dominant inhibition of cyclooxygenase, are widespread, and have activity18 multiple effects also means that adverse effects that were unanticipated (even though predictable) have always THE ASPIRIN YEARS emerged. In this paper I therefore present an historical N 1897 Motivated by his father’s intolerance of perspective so that the lessons of the past may be applied salicylic acid, Felix Hoffman synthesises acetyl salicylic acid, named aspirin (derived from to the present. Acetyl Spirea).12910 This had been done ........................................................................... before in 1853 (Carl Friedrich Gerhardt) and 1869 (Kraut) but Hoffman’s method is quan- titative (mixing salicylic acid and acetic hydride 2:3 before adding acetic acid) and yields pure stable aspirin.12 Aspirin causes 1066 AND ALL THAT less dyspepsia than salicylic acid. When I was 10 years old, history involved N 1897 Eleven days later Hoffman synthesises learning by rote 150 entries on a date chart. I another new compound also by acetylation (of remember memorising AD 735: Venerable Bede di acetyl morphine).12 Bayer employees try http://gut.bmj.com/ (À) Jarrow, with not even an inkling of what it the new substance and find it makes them meant. My history date chart was almost entirely feel heroic so it is called heroin. Heinrich about kings and battles (although individualised Dreser prefers to market heroin than aspirin. with my own birth date of 1947) and contained N 1898 Aspirin is shown to have a negative nothing about medical or drug development inotropic affect on frogs’ hearts.12 Despite apart from the Black Death (1349). In a belated this, a secret clinical trial is conducted which attempt to rectify this, and in recognition that all shows effectiveness against pain, inflamma- on September 30, 2021 by guest. Protected copyright. known non-steroidal anti-inflammatory drugs tion, and fever. (NSAIDs) are cyclooxygenase (COX)-2 inhibi- tors, I present a COX-2 chronology intended to N 1899 Aspirin is registered as a tradename. help the reader put current controversies into N 1900 Aspirin is patented in the USA and UK. perspective. Patents are refused in Germany. Aspirin rapidly becomes popular, endorsed by Caruso and Kafka (who claimed it eased the unbear- THE CHRONOLOGY able pain of being).1 N 1500BC Ebers papyrus recommends dried N 1903 Bayer production plant is established in 1–3 myrtle leaves for rheumatic and back pain. Albany, New York. Bootleg sales are rising. N C 400BC Hipocrates (460–377BC) recom- N 1905 Bayer bring lawsuit for patent infringe- 1–3 mends willow tree bark for fever and pain. ment in England (unsuccessfully) and in the N 1763AD Edward Stone uses willow bark for USA (successfully). They lose their patent in fever in 50 patients, based on the doctrine of England because Kraut had synthesised signatures3 (malady and cure—fever and aspirin in 1869.12 ....................... willow—are found in similar places). A mis- N 1911 Aspirin becomes available over the Correspondence to: print means his report to the Royal Society is counter. Professor C J Hawkey, attributed to the mathematician Edmund N 1914–16 In anticipation of loss of patent Wolfson Digestive Stone.4 Diseases Centre, University (1917) Bayer brand aspirin is marketed aggres- of Nottingham, University N 1828 Johann Andreas Buchner prepares sal- sively with direct to consumer advertisements Hospital, Nottingham, icin, a partially purified extract of willow NG7 2UH, UK; bark.5 cj.hawkey@ Abbreviations: COX, cyclooxygenase; NSAIDs, non- nottingham.ac.uk N 1838 Raffaelle Piria splits salicin to yield steroidal anti-inflammatory drugs; PPIs, proton pump ....................... salicylic acid.6 inhibitors www.gutjnl.com 1510 Hawkey in the USA. Promotion includes promotional fans with N 1971 Sir John Vane shows inhibition of prostaglandin product names printed on them. The American Medical synthesis to be the mode of action of aspirin and NSAIDs.20 Gut: first published as 10.1136/gut.2005.065003 on 13 October 2005. Downloaded from Association objects strongly. N 1970s Numerous experiments show that prostaglandins N 1917 Marketing of aspirin by Montsanto provokes legal protect the stomach even against boiling water.21 battle, leading to US Supreme Court verdict that the name aspirin is now so widespread that Bayer do not own it.12 – Systematic data showing that aspirin use is associated with a reduction in myocardial infarction and stroke – Bayer USA essentially separates from Bayer, Leverkusen emerge.22 to avoid anticipated war related sanctions. One week – New possibly safer NSAIDs are launched. They include later, USA enters the first World War azapropazone and piroxicam. Use is later restricted – Six months later ‘‘Trading with the Enemy’’ Act creates when they are associated with a particularly high level the Office of Alien Property Custodian to take over of ulcer complications.23 The problem with piroxicam is German assets and hold in trust during the war.1 thought to be that its long half life precludes recovery of gastric cyclooxygenase activity. N 1918 Bayer, USA accused of having subsidiary, secretly 1 poisoning Americans with contaminated dye. N 1980s FDA announce that one aspirin a day helps prevent a second heart attacks but objects to Sterling advertising – Sales of Bayer aspirin collapse in USA claims to that effect.12 – ‘‘Trading with the Enemy’’ Act amended to allow N 1989 Phillip Needleman identifies a steroid suppressible German property to be sold to Americans. cyclooxygenase—COX-2.24 In the same year molecular – Bayer US is sold for $5.31 million to Sterling Products biologists identify an immediate early gene, with homol- who add it to their portfolio of laxatives, dandruff ogy to COX-1 that is responsible for this activity.25 26 When treatments, and impotence cures (advertisement: told by an excited researcher that they have identified a ‘‘Makes old men boys again’’).1 cyclooxygenase, one of them (Herschman) retires to his room and consults a student textbook to find out what a N 1920s Sterling reach agreement with Bayer, Leverkusen to cyclooxygenase is.27–29 market Bayer aspirin in the USA. Advertisements claim that aspirin ‘‘does not affect the heart’’. US administration N 1991–93 Intensive drug development activity results in forces company to withdraw this claim.1 first generation of selective COX-2 inhibitors. The phar- macology is unusual because inhibition shows delayed N 1938 Douthwaite and Lintott use rigid endoscopy to show onset and is semi irreversible.27 28 At least one company gastric damage with aspirin, illustrating their Lancet paper misses out on a blockbuster because their pharmacological with watercolour paintings.11 screening does not take account of these properties N 1940 Nana Svartz develops sulphasalazine for arthritis on spurious theoretical grounds (sulpapyridine for bacteria, a N 1992 Non-selective NSAIDs and selective COX-2 inhibitors shown to act by obstructing entrance of precursor salicylate to penetrate connective tissue), thereby inad- 28 vertently recreating an[azo] dye in the process. arachidonic acid. Sulphasalazine has little obvious effect on arthritis but N 1994 Bayer takes over Sterling Winthrop and is able to sell Svartz is an observant physician who notices improve- Bayer aspirin in the USA for the first time in 75 years.2 http://gut.bmj.com/ ments in the underlying bowel symptoms of patients with N 1994 Crystal structure of COX-1 published.29 enteropathic arthritis.12 N 1940 Karl Link shows aspirin increases bleeding and advises caution in his article ‘‘Is aspirin a safe medicine?’’ THE COX-2 YEARS 13 in the Journal of the American Medical Association. N 1995 First generation of selective COX-2 inhibitors enter N 1948 In the Lancet, cardiologist Paul Gibson recommends clinical trials, with celecoxib (made by Montsanto) and on September 30, 2021 by guest. Protected copyright. aspirin for prevention of coronary thrombosis.14 rofecoxib (made by Merck). Over the next four years N 1950 Lawrence Craven recommends aspirin, having given numerous trials show selective COX-2 inhibitors to reduce it to more than 400 male patients, none of whom has a pain and inflammation both acutely and chronically and heart attack. Craven’s recommendation is ignored.15 to be as effective as NSAIDs in this activity.30 In the same
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