Proposals as long as Mode of Action of Aspirin-like Drugs 1960s 1971 Clues to COX-2

Proposals as long as Mode of Action of Aspirin-like Drugs 1960s 1971 Clues to COX-2

Proposals as long as Mode of Action of Aspirin-like Drugs 1960s 1971 Clues to COX-2

Briggs, Lisa, Morning Producer has reference to this Academic Journal, PHwiki organized this Journal COX-2, eicosanoids in addition to the resolution of inflammation Paul Colville-Nash Department of Experimental Pathology William Harvey Research Institute Spector, W.G. & Willoughby, D.A. (1968) Pharmacology of Inflammation. 1500 B.C. Ebers papyrus recommended dried leaves of myrtle to expel rheumatic pains from womb

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In Roman times in Asia, China, the Americas in addition to Africa, salicylate-containing plants were used

Salicylic acid was synthesized in 1859 by Hermann Kolbe at Marburg University in Germany. His student, von Heyden, adapted the synthesis as long as industrial production in 1874. In 1876 the anti-rheumatic effect of salicylic acid was demonstrated in a clinical trial. Aspirin consumption worldwide 15×1012 tablets per year or 45,000 tons per year (in as long as mation from Bayer AG)

Proposals as long as Mode of Action of Aspirin-like Drugs Northover in addition to Subramanian (1961) Inhibit kallikrein Whitehouse (1962) Interfere with oxidative metabolism Smith MJH (1966) Stabilise capiliary permeability Collier HOJ (1969) Block a route to mediator receptors, or block release of an intermediate McArthur (1971) Displace endogenous anti inflammatory peptides from plasma proteins Di Rosa et al (1971) Interfere with migration of leukocytes Barker (1971) Hyperpolarise nerve membranes Northover (1971, 1973) Inhibit Ca++ uptake or binding to cellular membranes Chang et al (1972) Inhibit leukocyte phagocytosis Ignarro (1972) Stabilise lysosomal membranes Sharma (1972) Inhibit generation of lipoperoxides 1960s Prostagl in addition to ins are a family of potent lipid mediators derived from arachidonic acid They are made by all cells in the body except the red blood cells Roles of Prostagl in addition to ins in the 1970’s Pyretic (Feldberg & Gupta, 1973; Milton & Wendl in addition to t, 1973) Pro-inflammatory (Willis, 1969) Hyperalgesic (Ferreira, 1972) Inhibit gastric acid secretion (Robert, 1968) Contract the uterus (Bergstrom et al .,1968) Increase renal blood flow (Lonigro et al., 1973) 1971 Discovered that aspirin in addition to similar drugs inhibit the biosynthesis of prostagl in addition to ins proposed that this was their mode of action Inhibition (%) Indomethacin Aspirin Salicylic acid Log concentration (µg/mL) (Vane, 1971) 100 80 60 40 20 0 0.1 1.0 10 100 1000 4 3 1 2 3 1 1 3 3 4 4 1

Clues to COX-2 Flower in addition to Vane (1972) found paracetamol more active on brain COX than on spleen COX. “Our results support the idea that a study of prostagl in addition to ins synthetase systems from different systems will lead to aspirin-like drugs with a greater specificity of action.” Clues to COX-2 “Selective inhibition of prostagl in addition to in production in inflammatory exudates in addition to the gastric mucosa.” Whittle et al. Nature, London (1980) COX selectivity to explain the lack of toxicity of salicylate in addition to BW755 on the stomach. Discovery of COX-2 Cells may contain two pools of COX, a constitutive COX enzyme in addition to a different COX which is LPS-inducible in addition to the expression of which is sensitive to glucocorticoid inhibition Fu, Masferrer, Seibert, Raz in addition to Needleman J Biol Chem, 1990 In 1991, Dan Simmons published the structure of a protein encoded by an early response gene which was 60% homologous with COX in ram seminal vesicles Xie et al. Proc. Natl. Acad. Sci. USA 88 2692-2696 April 1991

The three dimensional structure of COX-1 has been published by Garavito et al. in addition to that of COX-2 by Browner et al. Comparison of NSAID Binding Sites COX-1 COX-2 M. Browner, et al, 1998 Roche Bioscience Aspirin-like drugs are anti-inflammatory by inhibition of prostagl in addition to in biosynthesis by COX-2 in addition to are ulcerogenic through inhibition of COX-1 COX-1 constitutive Physiological Stimulus PGI2 endothelium stomach mucosa COX-2 Induced Macrophages/Other Cells PGs Inflammation Inflammatory Stimulus Proteases Other Inflammatory Mediators PGE2 Kidney TXA2 platelets

Summary of COX Selectivities in WHRI Blood / A549 Assay COX-1 selective COX-2 selective L745337 nimesulide NS398 meloxicam celecoxib etodolac sulindac salicylate diclofenac Ibuprofen Diflunisal Aspirin Flurbiprofen (IC50 ratio (COX-2/COX-1) 100 1 0.1 0.01 0.001 10 ketoprofen Indomethacin Tolmetin Naproxen NSAIDs clinically efficacious: reduce joint pain in addition to swelling But NSAIDs may promote joint damage: Newman in addition to Ling, Lancet, 1985; De Brito et al, Br J Rheum, 1986 Br in addition to t, Am J Med, 1987; Bottomley et al, Br J Pharm, 1988; Pettipher et al, Ann Rheum Dis, 1989; Bulstra et al, Clin Orthop, 1992. NSAIDs in addition to Joint Destruction:

A role in the resolution of inflammation Cyclooxygenase (COX) A key enzyme in prostagl in addition to in synthesis Two iso as long as ms: COX-1, constitutive, maintenance of physiological processes COX-2, inducible, major target as long as new generation NSAIDs with reduced side effects e.g. less injurious to normal gastric mucosa BUT COX-2 associated with wound healing phase of gastric ulcers COX-2 selective inhibitors delay healing of gastric ulcers in rodents Willoughby, D.A. (1975). Annals of Rheumatic Disease, 34.

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COX-1, COX-2, in addition to COX-3 in addition to the future treatment of chronic inflammatory disease Derek A Willoughby, Adrian R Moore in addition to Paul Colville-Nash Department of Experimental Pathology, William Harvey Research Institute Barts in addition to The London, Queen Mary’s School of Medicine in addition to Dentistry Charterhouse Square, London, EC1M 6BQ. United Kingdom Lancet, 355 (9204), p646, 2000. Treatment during disease flare with NSAIDs beneficial Treatment during periods of disease remission perhaps less desirable Options: a) Stop NSAID treatment during remission – difficult b) Replace endogenous mechanisms – not available yet c) Block reactivated pro-inflammatory systems Alternative approaches Arachidonic acid release in addition to metabolism

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