Aspirin and NSAIDs

Aspirin and NSAIDs - Another active principle soon extracted from plants was salicylic acid. Salicin, extracted from the willow tree, hasbeen launched in 1876 by a Scottish physician, Thomas John McLogan 31 . It was in extensive competition with Cinchona bark and quinine and never became a very popular treatment for fever or rheumatic symptoms. The Italian chemist Raffaele Piria, after having isolated salicylaldehyde (1839) 32 in Spireae species , prepared salicylic acid from salicin in Dumas’ laboratory in the Sorbonne, Paris. This acid was easier to use and was an ideal step before future syntheses. Its structure was closely related to benzoic acid, an effective preservative useful as an intestinal antiseptic for instance in typhoid fever. Acetylsalicylic acid has been fi rst synthesized by Charles Frederic Gerhardt in1853 33 and then, in a purer form, by Johann Kraut (1869).

Asetilsalsilat

Reaction aspirin and  salicylic cacid 

Acetylsalicylic acid synthesis with carbolic acid and carbon dioxide was improved by Hermann Kolbe in1874, but in fact nobody noticed its pharmacological interest. During the 1880s and 1890s, physicians became intensely interested in the possible adverse effects of fever on the human body and the use of antipyretics became one of the hottest fi elds in therapeutic research. The name of ArthurEichengrün, who performed the research and developmentbased pharmaceutical division where Felix Hoffmann worked, and Heinrich Dreser ( Figure 1.6 ) in charge of testing the drug with Kurt Witthauer and Julius Wohlgemuth are to be memorized for this historical discovery (1897). It is likely that acetylsalicylic acid was synthesized under

Arthur Eichengrün’s direction and that it would not have been introduced in 1899 without his intervention. 34 Dreser carried out comparative studies of aspirin and other salicylates to demonstrate that the former was less noxious and more benefi cial than the latter. 35 Bayer built his fortune upon this drug which received the name of “ Aspirin, ” the most familiar drug name. For the first time, an industrial group illustrated the close relationship between chemistry and practical therapeutics. It was not until the late 1970s that aspirin’s ability to inhibit prostaglandins production by the cyclo-oxygenase enzymes was identifi ed as the basis of its therapeutic activity. Prostaglandins are known as end-products of the so-called arachidonic acid cascade.

Arachidonic acid is normally stored in membrane-bound phospholipids and released by the action of phospholipases. Enzymatic conversion of released arachidonic acid into biologically active derivatives proceeds through several routes. First, cyclo-oxygenase converts arachidonic acid to unstable cyclic endoperoxides from which prostaglandins, prostacyclin and thromboxanes are derived. 36 Second, the production of the leukotrienes from arachidonic acid is initiated by the action of 5-lipoxygenase producing leukotrienes which are also believed to play an important pathophysiological role in allergic broncho-constriction ofasthma. Through pharmacological intervention in the arachidonic acid cascade various anti-infl ammatory agents have been developed. These include aspirin-like drugs, which inhibit cyclo-oxygenase. Corticosteroids appear to indirectly inhibit phospholipases thus preventing release of arachidonic acid. Future progress in this fi eld is likely to produce drugs which antagonize arachidonic acid derivatives or inhibit the enzymes involved in their synthesis with greater specifi city. 37 Using an ingenious “ real time ” biological assay of bloodstream hormones irrigating an isolated organ, called the “ blood-bathed organ cascade, ” John Vane ( Figure 1.7 ) developed a system for highly sensitive monitoring of several mediators like angiotensin, bradykinin and prostaglandins and discovered prostacyclin, a potent platelet aggregation inhibitor. John Vane explained anti-infl ammatory drugs effects (among which aspirin remains a true leader) through their activity on cyclo-oxygenase and inhibition of prostacyclin and thromboxane production. The impact of aspirin administration at low dose for the prevention of stroke or coronary attack resulted from its effect on enzymes regulating the production of prostaglandins.