Hull, England, United Kingdom
|Fig 1. Proc Royal Soc 1763, Salix Edmund Stone Willow bark. Source.|
In the short period between the years 1946-1950, three highly effective new drugs became available for clinical use in the newly established National Health Service. They were penicillin, streptomycin, and cortisone. Before this there were few potent drugs of proven benefit in the remedy of symptoms or disease. Since inflammation was a frequent cause of pain and fever, anti-inflammatory drugs were and remain of great importance. Many of the synthetic analgesic non-steroidal anti-inflammatory drugs (NSAIDs) now available originated in the salicylates. Aspirin (acetylsalicylic acid) was contained in over one hundred and forty products, and each year over sixty billion aspirin tablets are taken worldwide, perhaps the most widely used remedy of all time. In the 1980s aspirin was linked to the rare Reye’s syndrome in children in whom it was banned; subsequently, it was largely replaced by paracetamol (acetaminophen), which has little anti-inflammatory activity, and non-steroidal anti-inflammatory drugs such as ibuprofen. Aspirin’s anticoagulant action is widely used in prevention of heart attacks and strokes.
Hippocrates (440-377 B.C.) prescribed the bark and leaves of salix, the willow tree (rich in salicin), to reduce pain and fever. It also was mentioned by Dioscorides (c. 100 A.D.) and later by Pliny the Elder and Galen. However, it then fell into clinical disuse for centuries until the Reverend Edward (aka Edwin) Stone (1702–1768) rediscovered its efficacy. Stone was born in Lacey Green, Princes Risborough, Buckinghamshire. He attended Wadham College, Oxford in 1720 and in 1728 was ordained for the curacy of Charlton-on-Otmoor, where he remained until 1730 when he was elected a Fellow of Wadham. In 1745 he moved to Chipping Norton as chaplain at Bruern Abbey until it was destroyed by fire.
On April 25, 1763, Stone wrote to the president of the Royal Society, George Parker, second earl of Macclesfield, and in his letter read before the Royal Society on June 2, 1763, he described the use of dried willow bark [salix alba] as a remedy for fevers and agues. (Fig 1) This landmark paper1 initiated the discovery of the actions and chemical structure of aspirin2 and the development of other non-steroidal anti-inflammatory drugs used worldwide in treating pain, inflammation, and fevers.3
|Fig 2. Felix Hoffmann. Source.|
Stone explained that he had suffered from “aguistic intermitting disorders,” and had “accidentally” tasted willow bark and noted its extreme bitterness. He argued from the doctrine of signatures—that the shape, color, and other attributes of a medicinal plant indicated its use in healing, for instance, the liver-shaped leaf of Hepatica acutiloba used to treat liver disorders.4 Stone stated: “their remedies lie not far from their causes,” and concluded that the willow tree that “delights in a moist or wet soil might provide an antidote for agues that chiefly abound in that environment.” He gathered a pound of willow bark, dried it near a baker’s oven for three months, and then pulverized the bark into a fine powder. He dosed himself, and to his delight “the ague was soon removed.” Over the next five years, Stone tested the powder on about fifty people who benefited from it. It seems likely that many suffered from malaria, and he later added Peruvian (Jesuit) bark, which contained quinine, and “the ague was completely routed.”3
The mechanism was unknown until John Vane and Priscilla Piper between 1969 and 1971 showed that aspirin and related drugs inhibited the action of cyclo-oxygenase (COX) enzymes that catalyse peroxidation of arachidonic acid to prostaglandins that modulate inflammation.
“Medical truants” who have deserted medical practice and found fame in the arts or other endeavors are well known. Edmund Stone represents the converse situation: a non-medical man who has made important contributions to medicine: an inverse “medical truant.”
The aspirin controversy
It is usually stated that the chemist Felix Hoffmann (1868-1946) (Figure 2) at the Bayer Company developed aspirin to help his rheumatic father. This was based on an anecdotal footnote in an encyclopedia published in Nazi Germany in 1934. In 1895 Arthur Eichengrün (1867–1949), (Fig 3) the head of chemical research at Bayer, assigned the task of developing a “better” salicylic acid to Felix Hoffmann. Hoffmann had examined several derivatives of salicylic acid, not just aspirin, its acetyl ester. Aspirin had fewer side effects than salicylates. However, its development was arrested when Hoffmann’s associate, Heinrich Dreser (1860-1924), derided its potential. A Bayer publication noted that Hoffmann had repeatedly told his colleagues that Dreser had “set aside” acetylsalicylic acid.5 He was more occupied with Bayer’s new drug—heroin.
|Fig 3. Arthur Eichengrün. circa 1900. Scan from Aspirin and Related Drugs, Fig. 1.7. Via Wikimedia.|
Eichengrün refused to accept Dreser’s rejection of acetylsalicylic acid and successfully proceeded with its development,6 though he made no personal claims for priority.7 It was not until 1897, under instruction from Eichengrün, that Hoffmann synthesized acetylsalicylic acid, which was named aspirin, for Bayer.2
Eichengrün was made head of pharmacology research at Bayer. Sneader6 brought to light the fact that fifty years later, in his 1949 paper, Eichengrün claimed8 that he had instructed Hoffmann to synthesize acetylsalicylic acid and Hoffmann had done so without understanding its clinical potential. That Eichengrün led this research is shown in his correspondence with the chemist Carl Duisberg, who was the managing director of Bayer and IG Farben.9 The Bayer historical section and biographies in 202010 make no mention of Eichengrün. As a Jew, he had been unable to challenge this omission under the Hitler regime.
In 1944, confined in Theresienstadt concentration camp, Eichengrün had typed a letter (now hidden in the Bayer archives)11 very similar to his 1949 paper.8 He said that he tried to obtain a salicylate analgesic that would not give rise to the gastric side effects associated with sodium salicylate. For obvious reasons during the Nazi era, he was unable to refute Bayer’s American public patent of 1900 that attributed the invention of aspirin to Hoffmann.
Eichengrün had tested aspirin on himself, experiencing no ill effects. He gave a supply to Dr. Felix Goldmann, Bayer’s representative in Berlin, who recruited several leading clinics to assess it, with encouraging results.12 A dentist had given the drug to a patient with a fever and raging toothache; he dramatically exclaimed, “My toothache’s gone!” After confirmation in other patients, Goldmann sent a report to the Bayer management. According to Eichengrün, when Dreser was asked to comment, he scribbled on it, “This is the usual Berlin boasting, the product has no value.”13
Eichengrün was the first director of pharmaceutical research at Bayer. He produced a new silver-protein complex Protargol that was the drug of choice for treating gonorrhea until the 1940s. He left Bayer in 1908 and established his own research in Berlin to manufacture materials based on cellulose acetate. He introduced a variety of products, including the rapidly acting photographic developer Edinol, and a plastic Cellon, used for pilots’ goggles and gas masks. The lab also created a cellulose acetate coating for the fabric used on aircraft in his own manufacturing plant, Cellon-Werke. In 1933 the Nazis forced him to abandon his company. He was released from Theresienstadt in May 1945, and died in Bavaria in 1949.
In the discovery of aspirin, Edmund Stone’s observations in the eighteenth century were crucial. Hoffmann’s role in the synthesis of aspirin was undoubtedly important, but was initiated by the self-effacing Eichengrün. It is Eichengrün who deserves credit for prompting Hoffman’s synthesis of aspirin and more importantly for initiating its clinical uses.
- Stone E. An account of the success of the bark of the willow in the cure of agues. Phil. Trans. 1763;53, 195–200. https://royalsocietypublishing.org/doi/10.1098/rstl.1763.0033.
- Pearce JMS. Edward Stone and aspirin. World Federation of Neurology Dec 2014. https://worldneurologyonline.com/article/controversial-story-aspirin/.
- Wood JN. From plant extract to molecular panacea: a commentary on Stone (1763) ‘An account of the success of the bark of the willow in the cure of the agues’. Philosophical transactions of the Royal Society of London. Series B, Biological sciences vol. 370,1666 (2015): 20140317.
- Pearce JMS. The doctrine of signatures. Eur Neurol 2008;60:51-52
- Zündorf U. Leverkusen: Bayer; 1997. 100 Years of aspirin: the future has just begun; p. 33. cited by Sneader6.
- Sneader, W. The discovery of aspirin: a reappraisal. BMJ 2000;321: 1591-4.
- Eichengrün A. Geschichte und Entwicklung der Farbenfabriken vorm Friedr Bayer & Co, Elberfield, in den ersten 50 Jahren. Munich: Meisenbach-Riffrath; 1918. Pharmaceutisch-wissenschafliche Abteilung; pp. 409–416. cited by Sneader6.
- Eichengrün A. 50 Jahre Aspirin. Pharmazie 1949; 4: 582-584.
- Rinsema TJ. One Hundred Years of Aspirin. Medical History 1999;43:502-507.
- Bayer, Biographies. Felix Hoffmann (2020). https://www.bayer.com/en/history/felix-hoffmann.
- Bayer-Archiv. 271/2.1 Personal data on Eichengrün. Dr A. Eichengrün, Aspirin, KZ Theresienstadt. 1944:2. cited by Sneader6.
- Witthauer K. Aspirin, eine neues Salicylpräparat. Die Heilkunde 1899;3:396. cited by Sneader.6.
- Dreser H. Pharmakologisches über aspirin (Acetylsalicylsäure). Pflugers Arch 1899; 76: 306-318.
JMS PEARCE, MD, FRCP, is emeritus consultant neurologist in the Department of Neurology at the Hull Royal Infirmary, England.