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Comparative effects of etodolac, indomethacin, and benoxaprofen on icosanoid biosynthesis

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Abstract

Etodolac (Ultradol®) is a new tetrahydropyrano-indole derivative which has shown pronounced analgesic and antiinflammatory properties. Its effects on the different pathways of metabolism of arachidonic acid have been studied and compared to the effects of indomethacin and benoxaprofen. All three drugs tested inhibited the cyclooxygenase activity of the parenchyma as assessed by inhibition of LTB4- and LTD4-induced contraction. However, the activity of human polymorphonuclear leukocyte 5-lipoxygenase and of human platelet 12-lipoxygenase was inhibited only by very high concentrations (1×10−4 M and over) of these compounds, whereas nordihydroguaiaretic acid (NDGA) was active at concentrations 100 times lower. In the Schultz-Dale reaction of the guinea pig trachea, etodolac, benoxaprofen, and indomethacin produced increases of the myotropic contractile activity of the tissues sensitized to qvalbumin. Our results do not lend support to the hypothesis that the mechanism of action of these antiinflammatory drugs is linked to the inhibition of lipoxygenases.

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References

  1. Vane, J. R. 1971. Inhibition of prostaglandin synthesis as a mechanism of action of aspirinlike drugs.Nature 231:232–235.

    Google Scholar 

  2. Borgeat, P., M. Hamberg, andB. Samuelsson. 1976. Transformation of arachidonic acid and homo-γ-linoleic acid by rabbit polymorphonuclear leukocytes. Monohydroxy acids from novel lipoxygenases.J. Biol. Chem. 251:7816–7820.

    Google Scholar 

  3. Borgeat, P., andB. Samuelsson. 1979. Transformation of Arachidonic acid by Rabbit polymorphonuclear leukocytes. Formation of a novel dihydroxyeicosatetraenoic acid.J. Biol. Chem. 254:2643–2646.

    Google Scholar 

  4. Sirois, P., andP. Borgeat. 1980. From slow reacting substance of anaphylaxis (SRS-A) to leukotriene D4 (LTD4).Int. J. Immunopharmacol. 2:281–293.

    Google Scholar 

  5. Borgeat, P., andP. Sirois. 1981. Leukotrienes: A major step in the understanding of immediate hypersensitivity reactions.J. Med. Chem. 24:121–126.

    Google Scholar 

  6. Sirois, P., andP. Borgeat. 1982. Mediators of immediate hypersensitivity.In Immunopharmacology. P. Sirois and M. Rola-Pleszczynski, editors. Elsevier/North-Holland, Amsterdam. 201–222.

    Google Scholar 

  7. Demerson, C. A., L. G. Humber, A. H. Philipp, andR. R. Martel. 1976. Etodolic acid and related compounds. Chemistry and antiinflammatory actions of some potent di- and trisubstituted 1,3,4,9-tetrahydropyrano [3,4-b]indole-l-acetic acids.J. Med. Chem. 19:391–395.

    Google Scholar 

  8. Joubert, L., J. F. Mullane, M. Merlo, R. R. Martel, J. Arnold, G. Rolly, andG. Vetter. 1982. Clinical pharmacological profile of Ultradol®, a new nonsteroidal anti-inflammatory drug.Curr. Ther. Res. 32:74–88.

    Google Scholar 

  9. Martel, R. R., andJ. Klicius. 1976, Antiinflammatory and analgesic properties of etodolic acid in rats.Can. J. Physiol. Pharmacol. 54:245–248.

    Google Scholar 

  10. Cashin, C. H., W. Dawson, andE. A. Kitchen. 1977. The pharmacology of benoxaprofen [2-(4-chlorophenyl)-α-methyl-5-benzoxazole acetic acid], LRCL 3794, a new compound with antiinflammatory activity apparently unrelated to inhibition of prostaglandin synthesis.J. Pharm. Pharmacol. 29:330–336.

    Google Scholar 

  11. Walker, J. R., J. R. Boot, B. Cox, andW. Dawson. 1980. Inhibition of the release of slow-reacting substance of anaphylaxis by inhibitors of lipoxygenase activity.J. Pharm. Pharmacol,32:866–867.

    Google Scholar 

  12. Sirois, P., P. Borgeat, A. Jeanson, S. Roy, andG. Girard. 1980. The action of leukotriene B4 (LTB4 on the lung.Prostaglandins Med,5:429–444.

    Google Scholar 

  13. Sirois, P., S. Roy, P. Borgeat, S. Picard, andP. Vallerand. 1982. Evidence for a mediator role of thromboxane A2 in the myotropic action of leukotriene B4 (LTB4) on the guinea pig lung.Prostaglandins Leukotrienes andMed. 8:157–170.

    Google Scholar 

  14. Sirois, P., S. Roy, andP. Borgeat, 1981. The lung parenchymal strip as a sensitive assay for leukotriene B4.Prostaglandins Med. 6:153–159.

    Google Scholar 

  15. Borgeat, P., andB. Samuelsson. 1979. Arachidonic acid metabolism in Polymorphonuclear leukocytes: Effect of ionophore A23187.Proc. Natl. Acad. Sci. U.S.A. 76:2148–2152.

    Google Scholar 

  16. Borgeat, P., B.Fruteau de Laclos, H.Rabinovitch, S.Picard, P.Braquet, J.Hébert, and M.Laviolette. 1984. Eosinophil-rich human polymorphonuclear leukocyte preparations characteristically release ieukotriene C4 upon ionophore A23187 challenge.J. Allergy Clin, Immunol, (in press).

  17. Piper, P. J., andM. Samhoun. 1981. The mechanism of action of leukotrienes C4 and D4 in guinea pig isolated perfused lung and parenchymal strips of guinea pig, rabbit, and rat.Prostaglandins 21:793–802.

    Google Scholar 

  18. Rossoni, G., C. Omini, T. Vigano, V. Mandelli, G. C. Folco, andF. Berti. 1980. Bronchoconstriction by histamine and bradykinin in guinea pigs: Relationship to thromboxane A2 generation and the effect of aspirin.Prostaglandins 20:547–557.

    Google Scholar 

  19. Ferdinandi, E. S., M. N. Cayen, andC. Pace-Asciak. 1982. Disposition of etodolac, other antiinflammatory pyranoindole-1-acetic acids and furobufen in normal and adjuvant arthritic rats.J. Pharmacol. Exp. Ther. 220:417–426.

    Google Scholar 

  20. Salari, H., P. Braquet, andP. Borgeat. 1984. Comparative effects of indomethacin, acetylenic acids, 15-HETE, nordihydroguaiaretic acid, and BW755C on the metabolism of arachidonic acid in human leukocytes and platelets,Prostaglandins Leukotrienes Med. 13:53–60.

    Google Scholar 

  21. Walker, J. L. 1973. The regulatory function of prostaglandins in the release of histamine and SRS-A from passively sensitized human lung tissue.In Advances in the Biosciences 9, S. Bergstrom and S. Bernhard, editors. Pergamon Press, Braunschweig. 235–239.

    Google Scholar 

  22. Engineer, D. M., U. Neiderhauser, P. J. Piper, andP. Sirois. 1978. Release of mediators of anaphylaxis: Inhibition of prostaglandin synthesis and the modification of release of slow-reacting substance of anaphylaxis and histamine.Br. J. Pharmacol. 62:61–66.

    Google Scholar 

  23. Yen, S. S., andW. Kreutner. 1980. Effect of inhibition of arachidonic acid metabolism on anaplylaxis of guinea pig lung strips.Agents Actions 10:274–278.

    Google Scholar 

  24. Benslay, D. N., andR. Nickander. 1982. The comparative effects of benoxaprofen and other antiinflammatory drugs on bone dammage in the adjuvant arthritic rats.Agents Actions 12:313–319.

    Google Scholar 

  25. Martel, R. R., andJ. K. Licius. 1982. Comparison in rats of the antiinflammatory and gastric irritant effects of etodolac with several clinically effective antiinflammatory drugs.Agents Actions 12:295–297.

    Google Scholar 

  26. Shen, T. Y., andC. A. Winter. 1977. Chemical and biological studies on indomethacin, sulindac, and their analogs.Adv. Drug Res. 12:89–245.

    Google Scholar 

  27. Littler, T. R. 1981. Antirheumatic drugs.Pharmacol. Ther. 15:45–68.

    Google Scholar 

  28. Jacob, G. B., K. K. Hart, J. F. Mullane, S. Lutins, andT. Y. Lee. 1983. Placebo control study of etodolac and aspirin in the treatment of rheumatoid arthritis.Curr. Ther. Res. 33:703–713.

    Google Scholar 

  29. Gordon, G. V., andB. G. Polsky. 1983. Three month trial of etodolac (Ultradol®) compared with aspirin and placebo in patients with rheumatoid arthritis.Curr. Ther. Res. 33:89–99.

    Google Scholar 

  30. Borgeat, P., P. Sirois, P. Braquet, andM. Rola-Pleszczynski. 1984. Evidence of a role for Leukotrienes in inflammation.In Protective Role of Prostaglandins. Ed. M. M. Cohen, editor. CRC Press, Boca Raton (in press).

    Google Scholar 

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Authors and Affiliations

  1. Département de Pédiatrie et de Pharmacologie, Faculté de Médecine Université de Sherbrooke, J1H 5N4, Sherbrooke, Québec, Canada

    P. Sirois & C. Saura

  2. Groupe de Recherche sur les Leucotriènes Laboratoire d'Endocrinologie Moléculaire, Le Centre Hospitalier de I'Université Laval Québec, G1V4G2, Québec, Canada

    H. Salari & P. Borgeat

Authors
  1. P. Sirois
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  2. C. Saura
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  3. H. Salari
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  4. P. Borgeat
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Sirois, P., Saura, C., Salari, H. et al. Comparative effects of etodolac, indomethacin, and benoxaprofen on icosanoid biosynthesis. Inflammation 8, 353–364 (1984). https://doi.org/10.1007/BF00918212

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