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Mechanism of Action of Anti-Inflammatory Drugs

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Recent Advances in Prostaglandin, Thromboxane, and Leukotriene Research

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 433))

Abstract

25 years ago, Vane proposed that the mechanism of action of the aspirin-like drugs (non-steroid anti-inflammatory drugs; NSAIDs) was through the inhibition of prostaglandin biosynthesis1 and, there is now a general acceptance of the theory. The inhibition by aspirin is due to the irreversible acetylation of the cyclooxygenase (COX) site of prostaglandin endoperoxide synthase, leaving the peroxidase activity of the enzyme unaffected. In contrast to this unique irreversible action of aspirin, other NSAIDs such as ibuprofen or indomethacin produce reversible or irreversible COX inhibition by competing with the substrate, arachidonic acid, for the active site of the enzyme.

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References

  1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature; 231: 232–235 (1971).

    CAS  Google Scholar 

  2. Xie W, Robertson DL and Simmons DL. Mitogen-inducible prostaglandin G/H synthase: a new target for nonsteroidal antiinflammatory drugs. Drug Devel Res; 25: 249–265 (1992).

    Article  CAS  Google Scholar 

  3. Picot D, Loll PJ, Garavito RM. The x-ray crystal structure of the membrane protein prostaglandin H2synthase-1. Nature; 367: 243–249 (1994).

    Article  PubMed  CAS  Google Scholar 

  4. Luong, C., Miller, A., Barnett, J., Chow, J., Ramesha, C., and Browner, M.F. Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nature Structural Biology; 3: 927–933 (1996).

    Article  PubMed  CAS  Google Scholar 

  5. Gierse, J.K., McDonald, J.J., Hauser, S.D., Rangwala, S.H., Koboldt, C.M., and Seibert, K. A single amino acid difference between cyclooxygenase-1 (COX-1) and-2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J. Biol.Chem. 271: 15810–15814 (1996).

    Article  PubMed  CAS  Google Scholar 

  6. 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).

    Article  PubMed  CAS  Google Scholar 

  7. 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).

    Article  PubMed  CAS  Google Scholar 

  8. Funk, C.D., Funk, L.B., Kennedy, M.E., Pong, A.S., and Fitzgerald, G.A. Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J; 5: 2304–2312 (1991).

    PubMed  CAS  Google Scholar 

  9. Raz, A., Wyche, A., and Needleman, P. Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases. Proc Natl. Acad Sci USA; 86: 1657–1661 (1989).

    Article  PubMed  CAS  Google Scholar 

  10. Fu JY, Masferrer JL, Seibert K, Raz A and Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem; 265: 16737–16740 (1990).

    PubMed  CAS  Google Scholar 

  11. Masferrer JL, Zweifel BS, Seibert K and Needleman P. Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice. J Clin Invest; 86: 1375–1379 (1990).

    Article  PubMed  CAS  Google Scholar 

  12. Xie W, Chipman JG, Robertson DL, Erikson RL and Simmons DL Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl. Acad Sci USA; 88: 2692–2696 (1991).

    Article  PubMed  CAS  Google Scholar 

  13. O’Banion MK, Sadowski HB, Winn V and Young DA. A serum-and glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein. J Biol Chem; 266: 23261–23267 (1991).

    PubMed  Google Scholar 

  14. Kujubu DA, Fletcher BS, Varnum BC, Lim RW and Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem; 26: 12866–12872 (1991).

    Google Scholar 

  15. DeWitt, D.L. Prostaglandin endoperoxide synthase: Regulation of enzyme expression. Biochim.Biophys.Acta 1083: 121–134 (1991).

    Article  PubMed  CAS  Google Scholar 

  16. Wu, K.K., Sanduja, R., Tsai, A.-L., Ferhanoglu, B., and Loose-Mitchell, D.S. Aspirin inhibits interleukin 1-induced prostaglandin H synthase expression in cultured endothelial cells. Proc Natl. Acad Sci USA; 88: 2384–2387 (1991).

    Article  PubMed  CAS  Google Scholar 

  17. Kargman, S., Charleson, S., Cartwright, M., Frank, J., Riendeau, D., Mancini, J., Evans, J., and O’Neill, G.P. Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey and human gastrointestinal tracts. Gastroenterology; 111: 445–454 (1996).

    Article  PubMed  CAS  Google Scholar 

  18. Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, Mahler JF, Lee CA, Goulding EH, Kluckman KD, Kim HS and Smithies O. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell; 83: 483–492 (1995).

    Article  PubMed  CAS  Google Scholar 

  19. Kutchera, W., Jones, D.A., Matsunami, N., Groden, J., McIntyre, T.M., Zimmerman, G.A., White, R.L., and Prescott, S.M. Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: Evidence for a transcriptional effect. Proc Natl Acad Sci USA; 93: 4816–4820 (1996).

    Article  PubMed  CAS  Google Scholar 

  20. Gustafson-Svärd, C., Lilja, I., Hallböök, O., and Sjödahl, R. Cyclooxygenase-1 and cyclooxygenase-2 gene expression in human colorectal adenocarcinomas and in azoxymethane induced colonie tumours in rats. Gut; 38: 79–84 (1996).

    Article  PubMed  Google Scholar 

  21. Thun, M.J., Namboodiri, M.M., and Heath, C.W.J. Aspirin use and reduced risk of fatal colon cancer. New England Journal of Medicine; 325: 1593–1596 (1991).

    Article  PubMed  CAS  Google Scholar 

  22. Luk, G.D. Prevention of gastrointestinal cancer-the potential role of NS AIDs in colorectal cancer. Schweiz Med Wochenschr; 126: 801–812 (1996).

    PubMed  CAS  Google Scholar 

  23. Nugent, K.P., Spigelman, A.D., and Phillips, R.K.S. Tissue prostaglandin levels in familial adenomatous polyposis patients treated with sulindac. Dis Colon Rectum; 39: 659–662 (1996).

    Article  PubMed  CAS  Google Scholar 

  24. Oshima, M., Dinchuk, J.E., Kargman, S.L., Oshima, H., Hancock, B., Kwong, E., Trzaskos, J.M., Evans, J.F., Taketo, M.M. Suppression of intestinal polyposis in Apc Δ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell; 87: 803–809 (1996).

    Article  PubMed  CAS  Google Scholar 

  25. Harris, R.C., McKanna, I.A., Akai, Y., Jacobson, H.R., Dubois, R.N., and Breyer, M.D. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J. Clin. Invest.; 94: 2504–2510 (1994).

    Article  PubMed  CAS  Google Scholar 

  26. Nüsing, R.M., Klein, T., Pfeilschifter, J., and Ullrich, V. Effect of cyclic AMP and prostaglandin E2 on the induction of nitric oxide-and prostanoid-forming pathways in cultured rat mesangial cells. Biochem. J.; 313: 617–623 (1996).

    PubMed  Google Scholar 

  27. Morham, S.G., Langenbach, R., Loftin, C.D., Tiano, H.F., Vouloumanos, N., Jenette, J.C., Mahler, J.F., Kluckman, K.D., Ledford, A., Lee, C.A., and Smithies, O. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell; 83: 473–482 (1995).

    Article  PubMed  CAS  Google Scholar 

  28. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet; 343: 769–772 (1994).

    Article  PubMed  CAS  Google Scholar 

  29. Langman MJS, Weil J, Wainwright P, Lawson DH, Rawlins MD, Logan RFA, Murphy M, Vessey MP, Colin-Jones DG. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet; 343: 1075–1078 (1994).

    Article  PubMed  CAS  Google Scholar 

  30. Henry D, Lim LL-Y, Rodriguez LAG, Gutthann SP, Carson JL, Griffin M, Savage R, Logan R, Moride Y, Hawkey C, Hill S, Fries JT. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. Br Med J; 312: 1563–1566 (1996).

    Article  CAS  Google Scholar 

  31. Vane JR and Botting RM. New insights into the mode of action of anti-inflammatory drugs. Inflamm Res; 44: 1–10 (1995).

    Article  PubMed  CAS  Google Scholar 

  32. Grossman CJ, Wiseman J, Lucas FS, Trevethick MA, Birch P.J. Inhibition of constitutive and inducible cyclooxygenase activity in human platelets and mononuclear cells by NSAIDs and Cox 2 inhibitors. Inflamm Res; 44: 253–257 (1995).

    Article  PubMed  CAS  Google Scholar 

  33. Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl. Acad Sci USA; 90: 11693–11697 (1993).

    Article  PubMed  CAS  Google Scholar 

  34. Laneuville O, Breuer DK, DeWitt DL, Hla T, Funk CD and Smith WL. Differential inhibition of human prostaglandin endoperoxide H synthases-1 and-2 by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Therap; 271: 927–934 (1994).

    CAS  Google Scholar 

  35. Churchill L, Graham AG, Shih C-K, Pauletti D, Farina PR, Grob PM. Selective inhibition of human cyclo-oxygenase-2 by meloxicam. Inflammopharmacology; 4: 125–135 (1996).

    Article  CAS  Google Scholar 

  36. Barner A. Review of clinical trials and benefit/risk ratio of meloxicam. Scand J Rheumatol; 25(Suppl 102): 29–37 (1996).

    Article  Google Scholar 

  37. Rabasseda, X. Nimesulide: a selective cyclooxygenase 2 inhibitor antiinflammatory drug. Drugs of Today; 32(Suppl D): 1–23 (1996).

    Google Scholar 

  38. Glaser, K., Sung, M.-L., O’Neill, K., Belfast, M., Hartman, D., Carlson, R., Kreft, A., Kubrak, D., Hsiao, C.-L. and Weichman, B. Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-l. Eur J Pharmacol; 281: 107–111 (1995).

    Article  PubMed  CAS  Google Scholar 

  39. Laine, L., Sloane, R., Ferretti, M. and Comincili, F. A randomized double-blind comparison of placebo, etodolac and naproxen on gastrointestinal injury and prostaglandin production. Gastrointest Endosc; 42: 428–433 (1995).

    Article  PubMed  CAS  Google Scholar 

  40. Cummings, D.M. and Amadio, P. Jr. A review of selected newer nonsteroidal anti-inflammatory drugs. Am Fam Physician; 49: 1197–1202 (1994).

    PubMed  CAS  Google Scholar 

  41. Hubbard RC, Mehlisch DR, Jasper DR, Nugent MJ, Yu S, Isakson PC. SC-58635, a highly selective inhibitor of COX-2, is an effective analgesic in an acute post-surgical pain model. J Invest Med; 44: 293A (1996).

    Google Scholar 

  42. Parnham, M.J. COX-2 inhibitors at the 8th International Conference of the Inflammation Research Association. Exp. Opin. Invest. Drugs; 6: 79–82 (1997).

    Article  CAS  Google Scholar 

  43. Ford-Hutchinson, A. New highly selective COX-2 inhibitors. In: Selective COX-2 Inhibitors: Pharmacology, Clinical Effects and Therapeutic Potential. Abstracts of the William Harvey Research Conference, Cannes, p 23 (1997).

    Google Scholar 

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Author information

Authors and Affiliations

  1. The William Harvey Research Institute, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Charterhouse Square, London, ECIM 6BQ, UK

    John R. Vane & Regina M. Botting

Authors
  1. John R. Vane
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  2. Regina M. Botting
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Editor information

Editors and Affiliations

  1. Wilhelm Auerswald Atherosclerosis Research Group Vienna, University of Vienna, Vienna, Austria

    Helmut Sinzinger

  2. Karolinska Institutet, Stockholm, Sweden

    Bengt Samuelsson

  3. The William Harvey Research Institute, London, England

    John R. Vane

  4. University of Milan, Milan, Italy

    Rodolfo Paoletti

  5. Georgetown University Medical Center, Washington, DC, USA

    Peter Ramwell

  6. University of Medicine and Dentistry of New Jersey, Stratford, New Jersey, USA

    Patrick Y.-K. Wong

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© 1997 Springer Science+Business Media New York

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Vane, J.R., Botting, R.M. (1997). Mechanism of Action of Anti-Inflammatory Drugs. In: Sinzinger, H., Samuelsson, B., Vane, J.R., Paoletti, R., Ramwell, P., Wong, P.YK. (eds) Recent Advances in Prostaglandin, Thromboxane, and Leukotriene Research. Advances in Experimental Medicine and Biology, vol 433. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1810-9_27

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  • DOI: https://doi.org/10.1007/978-1-4899-1810-9_27

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4899-1812-3

  • Online ISBN: 978-1-4899-1810-9

  • eBook Packages: Springer Book Archive

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