Aspirin and other anti-inflammatory drugs.

Historical introduction Salicylic acid, the active substance in plants used for thousands of years as medicaments, was synthesised by Kolbe in Germany in 1874. MacLagan and Stricker showed that it was eVective in rheumatic fever. A few years later sodium salicylate was also in use as a treatment for chronic rheumatoid arthritis and gout as well as an antiseptic compound. Felix HoVman was a young chemist working at Bayer. Legend has it that his father, who was taking salicylic acid to treat his arthritis, complained to his son about its bitter taste. Felix responded by adding an acetyl group to salicylic acid to make acetylsalicylic acid. Heinrich Dreser, the Company’s head of pharmacology, showed it to be analgesic, antipyretic, and anti-inflammatory. Bayer introduced the new drug as “aspirin” in 1899 and sales have increased ever since. In the latter part of the 20th century several other non-steroidal anti-inflammatory drugs (NSAIDs) were discovered, including antipyrine, phenacetin, phenylbutazone and, more recently, the fenamates, indomethacin and naproxen. Despite the diversity of their chemical structures, these drugs all share the same therapeutic properties. They alleviate the swelling, redness and pain of inflammation, reduce a general fever, and cure a headache. They also share, but not equally, a number of side eVects including damage to the gastric mucosa, delay in the birth process, and damage to the kidney. A particularly interesting “side eVect”, now used prophylactically, is the anti-thrombotic eVect. Many clinical trials have shown that aspirin given once a day in doses as low as 75 mg will help to prevent heart attacks or strokes. When a chemically diverse group of drugs shares not only the same therapeutic qualities (which in themselves have not much connection with each other), but also the same side eVects, it is a fairly safe bet that their actions are based on a single biochemical intervention. For many years pharmacologists and biochemists searched for such a common mode of action without finding one that was satisfactory. It was against this background that, using a crude preparation of prostaglandin synthase (now known as cyclo-oxygenase or COX), Vane found a dose dependent inhibition of prostaglandin formation by aspirin, salicylate, and indomethacin but not by morphine. Two other reports from the same laboratory lent support to his findings. Smith and Willis showed that aspirin prevented the release of prostaglandins from aggregating human platelets and Ferreira et al demonstrated that aspirin-like drugs blocked prostaglandin release from the perfused, isolated spleen of the dog. Vane proposed that all NSAIDs act by inhibiting COX, thereby reducing prostaglandin formation, providing a unifying explanation for their therapeutic actions and their side eVects. This also firmly established certain prostaglandins as important mediators of inflammatory disease (see reviews by Vane and Botting and Vane et al). COX first cyclises arachidonic acid to form prostaglandin (PG) G2 and the peroxidase part of the enzyme then reduces PGG2 to PGH2.