page_title: History of aspirin
section_title: 18th and 19th centuries
hierarchical_section_title: History of aspirin / 18th and 19th centuries
caption_attribution_description: Eesti: Angervaks (Filipendula ulmaria) Keilas.English: Meadowsweet (Filipendula ulmaria). Keila, Northwestern Estonia.
context_page_description: The history of aspirin begins with its synthesis and manufacture in 1899. Before that, salicylic acid had been used medicinally since antiquity. Medicines made from willow and other salicylate-rich plants appear in clay tablets from ancient Sumer as well as the Ebers Papyrus from ancient Egypt. Hippocrates referred to the use of salicylic tea to reduce fevers around 400 BC, and willow bark preparations were part of the pharmacopoeia of Western medicine in classical antiquity and the Middle Ages. Willow bark extract became recognized for its specific effects on fever, pain, and inflammation in the mid-eighteenth century. By the nineteenth century pharmacists were experimenting with and prescribing a variety of chemicals related to salicin, the active component of willow extract.
  In 1853, chemist Charles Frédéric Gerhardt treated acetyl chloride with sodium salicylate to produce acetylsalicylic acid for the first time; in the second half of the nineteenth century, other academic chemists established the compound's chemical structure and devised more efficient methods of synthesis.
context_section_description: The major turning point for salicylate medicines came in 1763, when a letter from English chaplain Edward Stone was read at a meeting of the Royal Society, describing the dramatic power of willow bark extract to cure ague—an ill-defined constellation of symptoms, including intermittent fever, pain, and fatigue, that primarily referred to malaria. Inspired by the doctrine of signatures to search for a treatment for agues near the brackish waters that were known to cause it, Stone had tasted the bark of a willow tree in 1758 and noticed an astringency reminiscent of the standard—and expensive—ague cure of Peruvian bark. He collected, dried, and powdered a substantial amount of willow bark, and over the next five years tested it on a number of people sick with fever and agues. In his letter, Stone reported consistent success, describing willow extract's effects as identical to Peruvian bark, though a little less potent. (In fact, the active ingredient of Peruvian bark was quinine, which attacked the infectious cause of malaria, while the active ingredient of willow extract, salicin, relieved the symptoms of malaria but could not cure it.) Stone's letter (mistakenly attributed to Edmund rather than Edward Stone) was printed in Philosophical Transactions, and by the end of the 18th century willow was gaining popularity as an inexpensive substitute for Peruvian bark.
  In the 19th century, as the young discipline of organic chemistry began to grow in Europe, scientists attempted to isolate and purify the active components of many medicines, including willow bark. After unsuccessful attempts by Italian chemists Brugnatelli and Fontana in 1826, Johann Buchner obtained relatively pure salicin crystals in 1828; the following year, Henri Leroux developed another procedure for extracting modest yields of salicin. In 1834, Swiss pharmacist Johann Pagenstecher discovered what he thought was a new pain-reducing substance, isolated from the common remedy of meadowsweet (Spiraea ulmaria). By 1838, Italian chemist Raffaele Piria found a method of obtaining a more potent acid form of willow extract, which he named salicylic acid. The German chemist who had been working to identify the Spiraea extract, Karl Jacob Löwig, soon realized that it was in fact the same salicylic acid that Piria had found.
  Salicylate medicines—including salicin, salicylic acid, and sodium salicylate— were difficult and wasteful to extract from plants, and in 1860 Hermann Kolbe worked out a way to synthesize salicylic acid. Throughout the late 1800s use of salicylates grew considerably, and physicians increasingly knew what to expect from these medicines: reduction of pain, fever, and inflammation. However, the unpleasant side effects, particularly gastric irritation, limited their usefulness, as did their intense bitterness. By the 1880s, the German chemical industry, jump-started by the lucrative development of dyes from coal tar, was branching out to investigate the potential of new tar-derived medicines. The turning point was the advent of Kalle & Company's Antifebrine, the branded version of the well-known dye derivative acetanilide—the fever-reducing properties of which were discovered by accident in 1886. Antifebrine's success inspired Carl Duisberg, the head of research at the small dye firm Friedrich Bayer & Company, to start a systematic search for other chemical fever-reducers. Bayer chemists soon developed Phenacetin, followed by the sedatives Sulfonal and Trional.
caption: Meadowsweet (Filipendula ulmaria). Tea made from its flowers are an old folk remedy against fever and pain.
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