Summary
The pro-inflammatory effects of prostaglandins have been clearly demonstrated with the use of various animal models of inflammation. Furthermore, the anti-inflammatory effects and some of the side effects of aspirin and other non-steroidal anti-inflammatory agents have been shown to depend on their ability to inhibit cyclo-oxygenase. These drugs, therefore, reduce the synthesis of prostaglandins, prostacyclin and thromboxane. They do not affect leukotriene production and there is no firm evidence to suggest that they alleviate inflammation through any other mechanism. In contrast, the corticosteroids facilitate the release of lipocortin which, through inhibition of phospholipase A2 reduces arachidonic acid release. These drugs possess potent anti-inflammatory properties and attempts have been made to develop non-steroidal drugs, such as BW755C, that display similar anti-inflammatory activity through inhibition of the 2 main pathways of the arachidonic acid cascade.
Administration of low dose aspirin 40 mg/day selectively inhibits production of thromboxane A2 without affecting prostacyclin. This may be because, firstly, about 60% of an administered dose of aspirin is deacylated to salicylate during first-pass metabolism and, secondly, platelets cannot regenerate cyclo-oxygenase. Thus, absorbed aspirin irreversibly affects platelet thromboxane production in the pre-systemic circulation, but the systemic plasma aspirin concentration is likely to be too low to affect prostacyclin synthesis. Studies in experimental inflammation have shown that after the administration of aspirin, the concentration of salicylate in inflammatory exudate is considerably higher than that of aspirin. In addition, a comparison of prostaglandin synthesis inhibitory potencies shows that the concentration of salicylate, but not of aspirin, at the inflammatory site is high enough to substantially inhibit prostaglandin synthesis.
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References
Blackwell GJ, Carnuccio R, di Rosa M, Flower RJ, Parente, et al. Macrocortin: a polyptetide causing the anti-phospholipase effect of glucocorticoids. Nature 287: 147–149, 1980
Cerletti C, Latini R, Dejana E, Tognoni G, Garattini S, et al. Inhibition of human platelet thromboxane generation by aspirin in the absence of measurable drug levels in peripheral blood. Biochemical Pharmacology 34: 1839–1841, 1985
Cloix JF, Colard O, Rothhut B, Russo-Marie F. Characterization and partial purification of ‘renocortins’: two polypeptides formed in renal cells causing the anti-phospholipase-like action of glucocorticoids. British Journal of Pharmacology 79: 313–321, 1983
Dreser H. Pharmakologisches über Aspirin (Acetylsalicyl-säure) Pflugers Arch 76: 360, 1899
Flower RJ. Drugs which inhibit prostaglandin biosynthesis. Pharmacological Reviews 26: 33–67, 1974
Flower RJ, Vane JR. Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol (4-acetamido-phenol). Nature 240: 410–411, 1972
Ford-Hutchinson AW, Brunet G, Savard P, Charleson S. Leukotriene B4, polymorphonuclear leukocytes and inflammatory exudates in the rat. Prostaglandins 28: 13–27, 1984
Gryglewski RJ, Bunting S, Moncada S, Flower RJ, Vane JR. Arterial walls are protected against deposition of platelet thrombi by a substance (prostaglandin X) which they make from prostaglandin endoperoxides. Prostaglandins 12: 685–713, 1976
Hamberg M, Svensson J, Samuelsson B. Prostaglandin endoperoxides. A new concept concerning the mode of action and release of prostaglandins. Proceedings of the National Academy of Sciences USA 71: 3824–3828, 1974
Hamberg M, Svensson J, Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proceedings of the National Academy of Sciences USA 72: 2994–2998, 1975
Heavey DJ, Barrow SE, Hickling NE, Ritter JM. Aspirin causes short-lived inhibition of bradykinin-stimulated prostacyclin production in man. Nature 318: 186–188, 1985
Higgs GA, Flower RJ, Vane JR. A new approach to anti-inflammatory drugs. Biochemical Pharmacology 28: 1959–1961, 1979
Higgs GA, Salmon JA, Henderson B, Vane JR. Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate,cyclo-oxygenase and anti-inflammatory activity. Proceedings of the National Academy of Sciences USA, in press, 1986
Hirata F, Schiffmann E, Venkatasubramanian K, Salomon D, Axelrod J. A Phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. Proceedings of the National Academy of Sciences USA 77: 2533–2536, 1980
Jaffe, EA, Weksler BB. Recovery of endothelial cell prostacyclin production after inhibition by low doses of aspirin. Journal of Clinical Investigation 63: 532–535, 1979
Moncada S, Ferreira SH, Vane JR. Prostaglandins, aspirin-like drugs and oedema of inflammation. Nature 246: 217–219, 1973
Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263: 663–665, 1976
Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low dose aspirin in healthy subjects. Journal of Clinical Investigation 69: 1366–1372, 1982
Rachmilewitz D. Role of endogenous prostanoids in pathogenesis of peptic ulcer. Postgraduate Medicine (Special Report): 79–83, 1985
Rachmilewitz D, Chapman JW, Nicholson PA. A multicenter controlled comparison of two dosage regimens of misoprostol with cimetidine in treatment of gastric ulcer in outpatients. Digestive Diseases and Sciences 31, No. 2 (Suppl.): 75S–80S, 1986
Samuelsson B. Endogenous synthesis of prostaglandins in guinea pig and men: effects of inhibitors. In Robinson & Vane (Eds) Prostaglandin synthetase inhibitors,pp. 99–106, Raven Press, New York, 1974
Samuelsson B, Borgeat P, Hammarstrom S, Murphy RC. Introduction of a nomenclature: leukotrienes. Prostaglandins 17: 785–787, 1979
Simmonds PM, Salmon JA, Moncada S. The release of leukotriene B4 during experimental inflammation. Biochemical Pharmacology 32: 1353–1359, 1983
Tolman EL, Fuller BL, Mariman BA, Capetola RJ, Levison S, et al. Tissue selectivity and variability of effects of acetaminophen in arachidonic acid metabolism. Prostaglandins, Leukotrienes and Medicine 12: 347–356, 1983
Tomlinson RV, Ringold HJ, Qureshi MC, Forchielli E. Relationship between inhibition of prostaglandin synthesis and drug efficacy: support for the current theory on mode of action of aspirin-like drugs. Biochemical and Biophysical Research Communications 46: 552–559, 1972
Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biology 231: 232–235, 1971
Vargaftig BB. Salicylic acid fails to inhibit generation of thromboxane A2 activity in platelets after in vivo administration to the rat. Journal of Pharmacy and Pharmacology 30: 101–104, 1978
Whittle BJR. Role of prostaglandins in the defense of the gastric mucosa. Brain Research Bulletin 5 (Suppl. 1): 7–14, 1980
Whittle BJR, Higgs GA, Eakins KE, Moncada S, Vane JR. Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa. Nature 284: 271–273, 1980
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Vane, J. The Evolution of Non-Steroidal Anti-Inflammatory Drugs and their Mechanisms of Action. Drugs 33 (Suppl 1), 18–27 (1987). https://doi.org/10.2165/00003495-198700331-00005
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DOI: https://doi.org/10.2165/00003495-198700331-00005