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Molecular Mechanisms of the Gastric Toxicity of Antirheumatic Drugs

  • U. Aehringhaus
  • H. Weiler
  • B. A. Peskar
  • B. M. Peskar
Part of the Archives of Toxicology book series (TOXICOLOGY, volume 7)

Abstract

Gastric toxicity of non-steroidal antiinflammatory drugs has been suggested to be due to inhibition of prostaglandin synthesis. Proquazone, which is less ulcerogenic than indomethacin, however, is a more potent inhibitor of gastric mucosal prostaglandin synthesis than indomethacin in vitro and equally effective in vivo. These results indicate that additional factors such as pharmacokinetic properties contribute to the gastric toxicity of non-steroidal antiinflammatory drugs. Furthermore, lipoxygenase products of arachidonic acid metabolism might modulate the effects of inhibition of prostaglandin synthesis by non-steroidal antiinflammatory drugs. Using a radioimmunoassay for leukotriene C4 the capacity of ovalbumin-sensitized guinea pig gastric mucosa to release leukotriene C4-like immunoreactivity after antigenic challenge has been demonstrated.

Key words

Non-steroidal antiinflammatory drugs Prostaglandins Cyclooxygenase Lipoxygenase Leukotrienes Proquazone Indomethacin 

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References

  1. Aehringhaus U, Wölbung RH, König W, Patrono C, Peskar BM, Peskar BA (1982) Release of leukotriene C4 from human polymorphonuclear leucocytes as determined by radioimmunoassay. FEBS Lett 146: 111–114PubMedCrossRefGoogle Scholar
  2. Allen R, Bleicher M (1977) Die Behandlung degenerativer Gelenkerkrankungen mit Biarison. Schweiz Rundschau Med 46: 1481–1489Google Scholar
  3. Augstein J, Farmer JB, Lee TB, Sheard P, Tattersall ML (1973) Selective inhibitor of slow-reacting substance of anaphylaxis. Nature (New Biol) 245: 215–217CrossRefGoogle Scholar
  4. Bennett A, Hensby CN, Sanger GJ, Stamford IF (1981) Metabolites of arachidonic acid formed by human gastrointestinal tissues and their actions on the muscle layers. Br J Pharmacol 74:435–444PubMedGoogle Scholar
  5. Brune K, Gubler H, Schweitzer A (1979) Autoradiographic methods for the evaluation of ulcerogenic effects of anti-inflammatory drugs. Pharmacol Ther 5: 199–207CrossRefGoogle Scholar
  6. Gubler HU, Baggiolini M (1978) Pharmacological properties of proquazone. Scand J Rheumatol 21:8–11CrossRefGoogle Scholar
  7. Liebig R, Bernauer W, Peskar BA (1974) Release of prostaglandins, a prostaglandin metabolite, slow-reacting substance and histamine from anaphylactic lungs, and its modification by catecholamines. Naunyn-Schmiedebergs Arch Pharmacol 284:279–293PubMedCrossRefGoogle Scholar
  8. Morris HR, Piper PJ, Taylor GW, Tippins JR (1980) The role of arachidonate lipoxygenase in the release of SRS-A from guinea-pig chopped lung. Prostaglandins 19: 371–383PubMedCrossRefGoogle Scholar
  9. Peskar BM (1977) On the synthesis of prostaglandins by human gastric mucosa and its modification by drugs. Biochim Biophys Acta 487: 307–314PubMedGoogle Scholar
  10. Peskar BM, Seyberth HW, Peskar BA (1980) Synthesis and metabolism of endogenous prostaglandins by human gastric mucosa. Adv Prostaglandin Thromboxane Res 8: 1511PubMedGoogle Scholar
  11. Peskar BM, Weiler H, Peskar BA (1982) Effect of BW 755C on prostaglandin synthesis in the rat stomach. Biochem Pharmacol 31: 1652–1653PubMedCrossRefGoogle Scholar
  12. Takesue EI, Perrine JW, Trapold JH (1976) The antiinflammatory profile of proquazone. Arch Int Pharmacodyn 221: 122–131PubMedGoogle Scholar
  13. Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (New Biol) 231: 232–235Google Scholar
  14. Weiler H, Meier C, Fröhlich J, Peskar BM (1984) Effect of proquazone and indomethacin on gastric prostaglandin synthesis in vitro and in vivo. Agents Actions (in press)Google Scholar
  15. Whittle BJR, Higgs GA, Eakins KE, Moncada S, Vane JR (1980) Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa. Nature 284:271–273PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1984

Authors and Affiliations

  • U. Aehringhaus
    • 1
  • H. Weiler
    • 1
  • B. A. Peskar
    • 1
  • B. M. Peskar
    • 2
  1. 1.Department of Pharmacology and ToxicologyRuhr-Universität BochumBochumFederal Republic of Germany
  2. 2.Department of GastroenterologyUniversity of EssenEssenFederal Republic of Germany

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