Letter by Fürstenwerth Regarding Article, “Aspirin: A Historical and Contemporary Therapeutic Overview”
To the Editor:
I read with interest the article by Valentin Fuster and Joseph Sweeny, “Aspirin: A Historical and Contemporary Therapeutic Overview,”1 in which the discovery of the drug aspirin is presented as a logical sequence of activities inspired by the knowledge of pharmacological effects of willow extracts. In taking into account the scientific context in which the discovery of aspirin took place, I propose to revise this description. Neither Kolbe's synthesis of salicylic acid nor Gerhardt's synthesis of acetylsalicylic acid were performed in the context of drug development. The discovery of the drug aspirin only started with the efforts of chemists at Farbenfabriken Bayer to identify chemicals that could be used to treat diseases. In my view, the starting point of the discovery of aspirin was not the attempt “to modify the structure of salicylic acid in a way that effectively reduced the side effects of aspirin.” The starting point was the observation that acetanilide reduces fever in humans.
In the early 1880s, the clinicians Cahn and Hepp discovered that a substance, which they considered to be naphthalene, lowers the body temperature. To verify the chemical identity of naphthalene, they forwarded a sample to Kalle & Co. There, the structure of the naphthalene was determined as acetanilide. Subsequently, in 1886, Kalle & Co launched this fever-reducing agent as antifebrin. The common interpretation was that the acetyl moiety was responsible for the effects of this aniline derivative. Consequently, acetylation of all kinds of compounds became a standard approach to ennoble chemicals. At Farbenfabriken Bayer, the chemist Oscar Hinsberg prepared 4-ethoy-acetanilid, which Bayer in 1887 launched as a pain reliever under the brand name phenacetin. In 1894, Bayer introduced the drug tannigen, an acetylation product of tannic acid; in 1901, purgatol, anthrapurpurin-bis-acetat; and in 1904, exodin, another acetylated anthraquinone derivative.
Rosenthaler2 in 1906 accurately described the obsession to introduce acetyl groups into all kinds of compounds: “In many cases one dealt with it in entirely mechanical and spiritless manner, and many of the professional inventors of new medicines acetylated only for lack of other ideas. The whole mania for acetylation, of such one may well speak, has had its origin in acetanilide, because it showed better chemical properties than aniline.”
Felix Hoffman, too, was engaged in acetylation. According to Hoffman's laboratory journals,3 he acetylated a wide variety of compounds, not limited to a particular class of compounds.
In 1897, Hoffman prepared by acetylation some already known chemicals. On August 10, 1897, he prepared acetylsalicylic acid, and on August 21, 1897, he prepared bis-acetyl-morphin. The pharmacologist Heinrich Dreser tested the effects of these known compounds. He discovered the pain-relieving effect of acetylsalicylic acid and the cough suppressant effects of bis-acetyl-morphin. In 1898, Bayer launched bis-acetyl-morphin as heroin, and in 1899, acetylsalicylic acid as aspirin. Both drugs became commercial success. Unlike heroin, aspirin has become an integral part of the portfolio of essential drugs. Fuster and Sweeny document in their historical overview that the discovery of the therapeutic effects of acetylsalicylic acid has not ended yet. The discovery of aspirin continues to be an accidental sequence of events related only by serendipity.
Hauke Fürstenwerth, PhD
- © 2011 American Heart Association, Inc.