The discovery and development of antiinflammatory drugs

Inflammation was one of the earliest recognized and defined disease entities. Celsus characterized inflammation by the 4 cardinal signs, namely, pain (dolor), redness (rubor), warmth (calor), and swelling (tumor); Galenius (others say Virchow) added “loss of function” (functio laesa). These signs are still valid. Attempts to modify these symptoms by drug therapy are at least as old as the cardinal signs themselves. Dioscourides, a Greek physician of the Roman army, prescribed extracts of willow bark for joint pain, an approach that was later propagated by Hildegard von Bingen in continental Europe and, of course, by the Reverend Stone in his famous letter to the Royal Society of Medicine in London (1,2). The physicians of those times recognized that local inflammation often accompanies “general inflammation” manifested by fever and malaise. The reason for this association was only recently uncovered, namely, the release of the pyrogenic cytokines, such as tumor necrosis factor (TNF ) and interleukin-1, that are produced by inflamed tissue and mediate generalized symptoms. Fever, along with malaise, was regarded by the Hippocratic School as a cardinal sign of an imbalance in the body fluids, resulting in disease (3). Based on this Hippocratic concept, purgation, sweating, and bloodletting were employed to alleviate inflammation and other diseases on the assumption that these procedures could change the composition of the body fluids. Such practices were continued until the 19th century and were used to cure all types of diseases, including mental disorders (4). Not surprisingly, these measures yielded limited success. A more rational approach to treating inflammation became possible after the invention of the thermometer (5). As soon as fever could be measured, it lent itself to therapeutic trials. The bark of the cinchona tree (containing quinine) was one of the earliest drugs discovered to be effective against fever. In the 18th century, malaria was a prominent disease in many parts of Europe. Since cinchona bark turned out to be effective, why shouldn’t European barks be tested? The results are well known. First, willow bark was confirmed to be effective, and then the natural ester of salicylic acid (salicin) was isolated as the willow’s active ingredient (1,2). Later, salicylic acid itself was isolated. Eventually, Kolbe described the complete synthesis of pure salicylic acid. To provide sufficient amounts, the first “scale up” of a synthetic process was invented, and the first drug factory was built (Salicylic Acid Works, founded by von Heyden in Dresden in 1874) (see ref. 6). Earlier (in 1806), a young pharmacist in Einbeck, Germany had made another major discovery. W. Serturner, an admirer of the French Revolution and the scientific discoveries that followed it, had used his large pharmacy (apothecary) to extract the active ingredient of opium, the sap of the poppy. Serturner had checked his extracts for sedative activity in his pack of dogs and was able to isolate a pure substance that he named morphine, after the god of sleep (7). The importance of this discovery is hard to appreciate even now. Until the discovery of morphine, a drug effect was always the consequence of the combined ingredients of a plant or animal product and the suggestive effect of the “healer” (physician, apothecary, witch doctor). With morphine, for the first time, a pure (crystalline) substance mediated the effect. Since the substance could be reliably dosed, the physician was now less important. Caventou and Pelletier in Paris adapted this method and isolated several alkaloids, among them quinine (8). This molecule was the target for many new chemical syntheses. While Serturner, Caventou and Pelletier, and others isolated the active ingredients from different plants (among them strychnine, veratrine, and others), Magendie in Paris introduced the first pharmacopeia based Kay Brune, MD, Burkhard Hinz, PhD: Friedrich-Alexander University, Erlangen, Germany. Address correspondence and reprint requests to Kay Brune, MD, Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander University, Fahrstrasse 17, D-91054 Erlangen, Germany. E-mail: brune@pharmakologie.uni-erlangen.de. Submitted for publication December 18, 2003; accepted in revised form April 29, 2004.