The Centenary of Aspirin

The Centenary of Aspirin: Wonder Drug of the Twentieth Century Peter E. Childs
In 1997 the world celebrated the centenary of the discovery of aspirin by Felix Hoffmann, and in 1999 we celebrate the launching of aspirin commercially by Bayer as a pain-reliever. This event was marked by great celebrations at Bayer's headquarters at Leverkeusen in Germany, where their administration block was transformed into a giant packet of Bayer aspirin on March 6th. 1999. More than 40,000 tonnes and 100 billion aspirin tablets are produced worldwide each year! Americans consumed 80 billion tablets in 1994 and aspirin is found in at least 50 over-the-counter US drugs. Aspirin is probably the most successful medicine of all time and new uses are being discovered all the time. However, it does have side-effects and if it were introduced today it might not be licensed. (It is not recommended for children under 12 due to the slight possibility of a rare complication.) In some people it causes stomach bleeding. Large doses can kill. It is only in recent years that research has discovered how aspirin blocks pain. Every medicine cabinet (even on the Space Shuttle) has its bottle or packet of aspirin tablets (although though now there are many other analgesics), and 100+ billion tablets are produced each year worldwide. Dr. Felix Hoffmann (1868-1946) (Photo: Bayer AG)

It is a non-prescription drug and a generic drug, as its patent expired in the 1930s, so almost anyone can set up and make aspirin, as the chemistry is very simple (see below). However, its marketing is still licensed and its quality strictly controlled. History 1997 marks the centenary of the synthesis of the compound acetylsalicyclic acid, which came to be known as aspirin, by Felix Hoffmann at Bayer in Germany. 1999 marks the centenary of its marketing as a pain-relieving drug (an analgesic) by Bayer. Since then the name aspirin, originally a tradename, has passed into the popular vocabulary. The use of salicylic acid and its derivatives dates back at least to 400 BC when Hippocrates (440-377 B.C.) prescribed the bark and leaves of the willow tree (rich in salicin) to reduce pain and fever. In 100 AD Dioscorides mentioned willow leaves and a hundred years later Pliny and Galen also mentioned them. It was forgotten by doctors in the middle ages but lived on in folk medicine. The pain-relieving effects of Salix (willow) and Spiraea (meadow sweet) species was known in many cultures. In 1763 the first scientific study of willow bark extract was presented to the Royal Society in London by the Rev. Edward Stone, who tested it on 50 feverish patients. This was one of the earliest clinical trials but it was forgotten again for another 40 years. In 1828 a German chemist, J.A. Buchner (Professor of Pharmacy in Munich), experimented with salicin. Other people also worked on salicin and managed to extract salicylic acid from it. This has pain-reducing and anti-inflammatory properties but was too acidic. (It is also found in meadow sweet and oil of wintergreen, well-established herbal remedies.) Hermann Kolb‚ first identified its structure as ortho-oxybenzoic acid and managed to synthesise it. Artificial production of salicylic acid couldn't compete with the natural product until 1873. In 1876 its anti-rheumatic effects were clinically proven and its analgesic (pain-killing) and anti-pyretic (fever-relieving) effects were rediscovered. Although a useful drug salicylic acid was acidic and bitter, with severe side-effects, although its sodium salt was slightly easier on the stomach. Hoffmann's laboratory record for 10/10/1897 (Source: Bayer AG)

This was the setting in which Felix Hoffmann (1868-1946), a young chemist working for Friedr. Bayer & Co., first made the acetyl derivative to help his father's arthritis, by reducing the side-effects of taking salicylic acid. On 10/10/1897 he found the solution by acetylating salicylic acid to produce acetylsalicylic acid. (44 years earlier it had been made by Carl Friedrich Gerhardt see p. 26-27.) Together with Heinrich Dreser, a pharmacologist, Hoffmann tested the new product on animals to test its toxicity and activity - the first such studies carried out in industry. They also noted the effects on increasing the heart's performance. They also subjected it to a year-long clinical trial which it passed with flying colours. Finally a name had to be chosen to launch the new medicine on the market. On 23/1/1899 the name 'Aspirin' was selected and registered as a trade name. It was named for "a" from acetyl, 'spir' from the spirea plant, and 'in' a common ending for drugs. In May 1899 Bayer started marketing it and the 'Aspirin' story began in earnest. The US patent was granted in 1899 and it was patented and its name protected in many countries. The first water-soluble form was introduced in 1900. At first it was available only on prescription but became widely available over the counter from 1915. After WWI the trademark was lost by Germany in the USA, UK and France (the victors) where aspirin has entered the language as a generic name. In 1994 Bayer bought back the Bayer Aspirin trademark in the USA from Sterling Drug, who had held it since 1918. US Patent for Aspirin (1900) (Source: Bayer AG)

Chemistry Aspirin (acetylsalicylic acid) is made by the esterification of the phenolic -OH group of salicylic acid (see reaction scheme 2). The acid is itself made from phenol using the Kolb‚ synthesis (see reaction scheme 1). Reaction scheme 1: Synthesis of salicylic acid

Reaction scheme 2: Synthesis of acetylsalicylic acid

The synthesis and analysis of aspirin is a relatively easy experiment and features in A level and first year chemistry courses. A bottle of aspirin powder from 1900 (Photo: Bayer AG)

How aspirin works Aspirin was in use for decades before doctors understood how it worked and discovering the mechanism of its action won Sir John Vane, Sune Bergstrom and Bengt Samuelsson the Nobel Prize for Medicine in 1982. This work was first reported in 1971 and showed that aspirin inhibits an enzym,e used for the production of prostaglandins. The prostaglandins (a family of compounds) can cause inflammation and also vasoconstriction and platelet aggregation. Aspirin inhibits their formation and thus at low does aspirin thus thins the blood and reduces blood clotting; at higher doses it reduces fever and relieves aches and pains. Nobel Laureate, Sir John Vane comments: "No other medicine in the world can look back on such a fascinating, record-laden history - and it's not over yet. I'm proud to have helped write some chapters of this success story." A versatile drug Bayer's first clinical trials had shown that aspirin had an effect on the heart. In 1948 Dr. Lawrence Craven noticed that 400 men prescribed aspirin hadn't suffered heart attacks and he recommended it as a preventative for heart attack. The first clinical trials of aspirin to prevent heart attacks were published in 1974 (Elwood and Cochrane, BMJ, 1974, 1, 436). In 1980 the FDA approved the use of aspirin to reduce the risk of stroke in men after they have had mini-strokes. In 1985 the FDA approved aspirin for use in patients who have had heart attacks to prevent further attacks. Aspirin thins the blood, reducing blood pressure and thus reduces the chances of an attack. In 1971 the British pharmacologist John R. Vane and colleagues showed how aspirin works. They showed that aspirin works by inhibiting prostaglandin synthesis. The world-famous epidemiologist Sir Richard Peto has suggested that if all people at risk of vascular disease were put on a preventative regime of aspirin, 100,000 fatal and 200,000 non-fatal heart attacks and strokes would be prevented worldwide each year!! Studies are underway to see whether everyone should take aspirin as a primary method of preventing vascular disease. In 1989 US researchers reported that aspirin may help delay senile dementia, after finding reduced incidence in elderly patients taking aspirin to relieve rheumatoid arthritis. In 1994 Professor Henk C.S, Wallenburg in Rotterdam showed aspirin was useful in treating pre-eclampsia in pregnant women. In 1995 American researchers found evidence that aspirin protects against bowel cancer. Aspirin helps blood circulation in people with diabetes and can reduce a number of complications, including blindness, heart attack and kidney damage. No wonder that the humble aspirin, found in every medicine cupboard for 100 years, and one of the few surviving medicines of the Victorian era, has been described in the popular press as a 'wonder drug'. That is just what it is. In fact it seems that almost every year a new use is found for this old medicine. "Most of the drugs which would have been found alongside aspirin in a Victorian pharmacy have long since disappeared, replaced by newer and more effective drugs. But aspirin goes from strength to strength. And give the pace of current research into new uses of the drug it seems likely that it will still be available long into the next century." (G.N. Henderson, European Aspirin Foundation) Sources Publications: H.O.J. Collier, 'Aspirin', Scientific American, Nov. 1963, p.97 Uwe Zündorf, 'Aspirations for the new millennium', Bayer Report, #72, 1999, pp. 8-19 (including a detailed timeline for aspirin) Aspirin: the medicine of the century, Bayer, AG 1985 Aspirin (A curriculum resource for post-16 chemistry courses), compiled by David Lewis, edited by Colin Osborne; Royal Society of Chemistry 1998 Links: Bayer's own aspirin site: www.bayerus.com/aspirin/ The amazing story of aspirin (European Aspirin Foundation) www.aspirin-foundation.com America's 80 billion aspirin habit http://pharminfo.com/pubs/msb/aspirin.html Aspirin: a new look at an old drug www.fda.gov/opacom/catalog/aspirin.html