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Interaction studies of tilomisole, aspirin, and naproxen in acute and chronic inflammation with assessment of gastrointestinal irritancy in the rat

  • Inflammation and Immunomodulation
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Abstract

The effect of combination NSAID therapy of tilomisole with aspirin or naproxen was studied in rats with carrageenan-induced paw edema and established adjuvant arthritis. Inflamed paws were measured using mercury plethysmography and the arthritic paws were X-rayed to determine any bony/soft tissue changes. The gastrointestinal tract was also examined for bleeding and ulceration. Tilomisole had a less potent acute anti-inflammatory effect than aspirin or naproxen, but produced no significant gastrointestinal damage. A significant reduction in anti-inflammatory activity was observed with the tilomisole/aspirin combination in acute inflammation. Only additive interactions were observed with the naproxen inhibition. In the established arthritis assay, a significant synergistic anti-inflammatory response, i.e. both inhibition of paw edema and bone erosion, was also observed with the 80 and 93% tilomisole/naproxen combinations. The gastric ulcerogenic effect of the combination paralleled its increased activity. The synergism between tilomisole and naproxen in thischronic arthritic model may be due to enhanced cyclooxygenase inhibitory activity. These drug interaction studies suggest possible interactions in human clinical trials of rheumatoid arthritis.

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References

  1. A. Bartelink,Clinical drug interactions in the gastrointestinal tract in man. In Clinical Effects of Interaction between Drugs. (Eds. L. T. Cluff and J. C. Petrie) pp. 103–116, American Elsevier, New York, 1974.

    Google Scholar 

  2. P. M. Brooks, J. J. Walker, M. A. Bell, W. W. Buchanan and A. R. Rhymer,Indomethacin-aspirin interaction: A clinical appraisal. Br. Med. J.3, 69–71 (1975).

    PubMed  Google Scholar 

  3. R. F. Willkens and E. J. Segre,Combination therapy with naproxen and aspirin in rheumatoid arthritis. Arth. Rheum.19, 677–682 (1976).

    Google Scholar 

  4. Y. Pawlotsky, J. Y. Louboutin, G. Chales, B. Flouvat and A. Roux,Ketoprofen-aspirin interactions. Sem. Hop. Paris,59, 3218–3220 (1983).

    PubMed  Google Scholar 

  5. D. M. Grennan, D. G. Ferry, M. E. Ashworth, R. E. Kenny and M. MacKinnon,The aspirin-ibuprofen interaction in rheumatoid arthritis. Br. J. Clin. Pharmacol.8, 497–503 (1979).

    PubMed  Google Scholar 

  6. C. G. Van Arman, G. W. Nuss and E. A. Risley,Interactions of aspirin, indomethacin and other drugs in adjuvant-induced arthritis in the rat. J. Pharmacol. Exp. Ther.187, 400–413 (1973).

    PubMed  Google Scholar 

  7. H. Bekemeier and R. Hirschelmann,On steroid-saving combinations in carrageenan paw edema and adjuvant arthritis. Arzenim-Forsch/Drug Res.36, 1521–1524 (1986).

    Google Scholar 

  8. R. L. Fenichel, H. E. Alburn, P. A. Schreck, R. Bloom and F. J. Gregory,Immunomodulating and antimetastatic activity of 3-(p-clorophenyl)thiazolo[3,2-a]benzeimidazole-2-acetic acid (WY-18,251, NSC-310,633). J. Immunopharmacol.2, 491–508 (1980).

    PubMed  Google Scholar 

  9. R. L. Fenichel, S. K. Dheer, N. H. Grant, D. P. Scott, R. Bloom and F. J. Gregory,Immunomodulating activity of 3(p-chlorophenyl)-thiazolo[3,2-a]benzimidazole-2-acetic acid (WY-18,251, NSC-310,663) in mice implanted with Lewis lung tumor. Effect of WY-18,251 on lymphocyte proliferation and phagocytosis. J. Immunopharmacol.5, 333–340 (1983).

    PubMed  Google Scholar 

  10. S. C. Gilman, R. P. Carlson, J. Chang and A. J. Lewis,The antiinflammatory activity of the immunomodulator WY-18,251(3-(p-chlorophenyl)thiazolo[3,2-a]-benzimidazole-2-acetic acid). Agents and Actions17, 53–59 (1985).

    PubMed  Google Scholar 

  11. D. J. Finney,Probit Analysis, pp. 232–292, Cambridge University Press, Boston, MA 1971.

    Google Scholar 

  12. D. J. Finney, Statistical Method in Biological Assay, pp. 69–96 Griffin & Co., London 1978.

    Google Scholar 

  13. Z. E. Mielens, H. P. Drobeck, J. Rozitis and V. J. Sansone,Interaction of aspirin with non-steroidal antiinflammatory drugs in rats. J. Pharm. Pharmacol.20, 567–569 (1968).

    PubMed  Google Scholar 

  14. K. F. Swingle, T. J. Grant, L. W. Jaques and D. C. Kvam,Interactions of antiinflammatory drugs in carrageenan-induced foot edema of the rat. J. Pharmacol. Exp. Ther.172, 423–425 (1970).

    PubMed  Google Scholar 

  15. D. G. Palmer, J. Highton, M. J. MacKinnon and D. B. MyersNon-steroidal antiinflammatory drugs in combination: Experimental observations. Clin. Exp. Rheum.3, 111–116 (1985).

    Google Scholar 

  16. R. J. Flower,Drugs which inhibit prostaglandin biosynthesis. Pharmacol. Rev.26, 33–66 (1974).

    PubMed  Google Scholar 

  17. U. Klotz,Interactions of analgesics with other drugs. Am. J. Med.75, 133–138 (1983).

    Google Scholar 

  18. K. D. Rainsford,Gastric ulcerogenecity of non-steroidal antiinflammatory drugs in mice with mucosa sensitized by cholinomimetic treatment. J. Pharm. Pharmacol.39, 669–672 (1987).

    PubMed  Google Scholar 

  19. A. Robert,Effects of prostaglandins on the stomach and the intestine. Prostaglandins6, 523–532 (1974).

    PubMed  Google Scholar 

  20. E. Ezer, E. Palosi, G. Hajos and L. Szporny,Antagonism of the gastrointestinal ulcerogenic effect of some non-steroidal antiinflammatory agents by sodium salicylate. J. Pharm. Pharmacol.28, 655–656 (1976).

    PubMed  Google Scholar 

  21. T. Suwa, H. Urano, Y. Kohno, A. Suzuki and T. Amano,Comparative studies on the gastrointestinal lesions caused by several non-steroidal antiinflammatory agents in rats. Agents and Actions21, 167–172 (1987).

    PubMed  Google Scholar 

  22. T. Corell and K. M. Jensen,Interactions of salicylates and other non-steroidal antiinflammatory agents in rats as shown by gastro-ulcerogenic and antiiflammatory activities and plasma concentrations. Acta Pharmacol. Toxicol.45, 225–231 (1979).

    Google Scholar 

  23. J. L. Humes, C. A. Winter, S. J. Sadowski and F. A. Kuehl Jr.,Multiple sites on prostaglandin cyclooxygenase are determinants in the action of nonsteroidal antiinflammatory agents. Proc. Natl. Acad. Sci.4, 2053–2056 (1981).

    Google Scholar 

  24. R. S. Jones and J. R. Ward,Studies of polyarthritis and other lesions induced in rats by injection of mycobacterial adjuvant: General clinical and pathological characteristics and some modifying factors. Arth. Rheum.6, 23–35 (1963).

    Google Scholar 

  25. C. M. Pearson and F. D. Ward,Studies of polyarthritis and other lesions induced in rats by injection of mycobacterial adjuvant: General clinical and pathological characteristics and some modifying factors. Arth. Rheum.2, 440–459 (1959).

    Google Scholar 

  26. N. R. Ackerman, W. H. Rooks, L. Shott, H. Genant, P. Maloney and P. West,Effects of naproxen in connective tissue changes in the adjuvant arthritic rat. Arth. Rheum.22, 1365–1374 (1979).

    Google Scholar 

  27. S. Wanwimolruk, D. J. Birkett and P. M. Brooks,Protein binding of some nonsteroidal antiinflammatory drugs in rheumatoid arthritis. Clin. Pharmacokinet.7, 85–92 (1982).

    PubMed  Google Scholar 

  28. C. W. Denko, D. B. Purser and R. M. Johnson,Amino acid composition of serum albumin in normal individuals and in patients with rheumatoid arthritis. Clin. Chem.16, 54–57 (1970).

    PubMed  Google Scholar 

  29. J. S. Lowe,Serum protein changes in rats with arthritis induced by mycobacterial adjuvant. Biochem. Pharmacol.13, 633–641 (1964).

    PubMed  Google Scholar 

  30. C. Higham, L. Aarons, P. J. L. Holt, M. Lynch and M. Rowland,A chronic dose-ranging study of the pharmacokinetics of phenylbutazone in rheumatoid arthritic patients. Br. J. Clin. Pharmacol.12, 123–129 (1981).

    PubMed  Google Scholar 

  31. F. A. Van Den Ouweland, M. J. A. M. Fransseen, L. B. A. Van DePutte, Y. Tan, C. A. M. Van Ginneken and F. W. J. Gribnau,Naproxen pharmacokinetics in patients with rheumatoid arthritis during active polyarticular inflammation. Br. J. Clin. Pharmacol.23, 189–193 (1987).

    PubMed  Google Scholar 

  32. E. Segre, H. Sevelius, M. Chaplin, E. Rorchielli, R. Runkel and W. Rooks,Interactions of naproxen and aspirin in the rat and man. Scand. J. Rheum.2, (Suppl.) 37–42 (1973).

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Experimental Therapeutics, Wyeth-Ayerst Research, CN 8000, 08543-8000, Princeton, NJ, USA

    W. Calhoun, S. C. Gilman, L. J. Datko, T. W. Copenhaver & R. P. Carlson

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  1. W. Calhoun
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  2. S. C. Gilman
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  3. L. J. Datko
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  4. T. W. Copenhaver
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  5. R. P. Carlson
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Calhoun, W., Gilman, S.C., Datko, L.J. et al. Interaction studies of tilomisole, aspirin, and naproxen in acute and chronic inflammation with assessment of gastrointestinal irritancy in the rat. Agents and Actions 36, 99–106 (1992). https://doi.org/10.1007/BF01991236

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  • DOI: https://doi.org/10.1007/BF01991236

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