Skip to main content
SpringerLink
Log in

Nabumetone, in contrast to etodolac, lacks gastrointestinal irritancy in the rat: Assessment by the inflammatory marker, haptoglobin, and blood loss

  • Published:
InflammoPharmacology Aims and scope Submit manuscript

Abstract

The aim of the present study was to compare the effects of the non-acidic anti-inflammatory drug, nabumetone, with those of etodolac on gastrointestinal mucosal integrity and blood loss in the rat. Gastrointestinal damage was absent in nabumetone-treated animals even at a high anti-inflammatory dose (79 mg/kg). Plasma haptoglobin, a marker of mucosal integrity, and caecal haemoglobin, a measure of blood loss, were also unchanged compared with controls. In contrast, etodolac induced both gastric (ED50 30 mg/kg) and ileal (ED50 4.5 mg/kg) ulceration in a dose-related manner. Accompany-ing these changes were increases in haptoglobin concentration and blood loss. It is suggested that nabumetone’s lack of gastrointestinal irritancy may relate, in part, to its non-acidic nature and to its active metabolite’s (6MNA) differential effects on prostanoid production and lack of enterohepatic circulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Roth SH, Bennett, RE. Nonsteroidal anti-inflammatory drug gastropathy. Arch Intern Med. 1987;147:2039–100.

    Google Scholar 

  2. Armstrong CP, Blower AL. Nonsteroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut. 1987;28:527–32.

    PubMed  CAS  Google Scholar 

  3. Aabakken L, Osnes M. Non-steroidal anti-inflammatory drug-induced disease in the distal ileum and large bowel. Scand J Gastroenterol. 1989;24(Suppl.163):48–55.

    Google Scholar 

  4. Grebb WH, Von Schrader HW, Cerlek S et al. Endoscopic studies of nabumetone in patients with rheumatoid arthritis. Am J Med. 1987;83(Supp..4B):19–24.

    Article  Google Scholar 

  5. Lussier A, Davis A, Lussier Y et al. Comparative gastrointestinal blood loss associated with placebo, aspirin and nabumetone as assessed by radiochromium. J Clin Pharmacol. 1989;29:225–9.

    PubMed  CAS  Google Scholar 

  6. Lemmel EM, Stroehmann I. Experience with nabumetone in the treatment of rheumatic conditions - results of an application study in 18,047 patients. Fortschr Med. 1988;106:63–8.

    Google Scholar 

  7. Fleischmann RM. Clinical efficacy and safety of nabumetone in rheumatoid arthritis and osteoarthritis. J Rheumatol. 199219(Suppl.36):32–40.

    Google Scholar 

  8. Roth SH. Upper gastrointestinal safety with nabumetone. J Rheumatol. 199219(Suppl.36):74–9.

    Google Scholar 

  9. Melarange R, Rashbrook LC. Comparison of the effects of nabumetone with indomethacin on rat gastric mucosal 6-keto-PGF1α production and on bile salt-induced changes in gastric mucosal function. J Pharm Pharmacol. 1987;39:717–20.

    PubMed  CAS  Google Scholar 

  10. Dandona P, Jeremy JY. Nonsteroidal anti-inflammatory drug therapy and gastric side effects. Does nabumetone provide a solution? Drugs. 1990;40(Suppl.5):16–24.

    PubMed  CAS  Google Scholar 

  11. Melarange R, Blower PR, Gentry C et al. Nabumetone, an effective anti-inflammatory agent, lacks the gastric irritancy potential of piroxicam or ibuprofen. Br J Pharmacol. 1990;99:172P.

    Google Scholar 

  12. Melarange R, Gentry C, O’Connell C et al. The anti-inflammatory drug nabumetone lacks the gastrointestinal damaging potential of loxoprofen or naproxen. Jap J Inflam. 1991;11:607–14.

    CAS  Google Scholar 

  13. Melarange R, Gentry C, O’Connell C et al. Antiinflammatory and gastrointestinal effects of nabumetone or its active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA). Comparative studies with indomethacin. Dig Dis Sci. 1992;37:1847–52.

    Article  PubMed  CAS  Google Scholar 

  14. Robert A. Cytoprotection by prostaglandins. Gastroenterology. 1979;77:761–7.

    PubMed  CAS  Google Scholar 

  15. Lee D, Dvornik D. Etodolac: effect on prostaglandin concentrations in the gastric mucosa of rats. Life Sci. 1985;36:1157–62.

    Article  PubMed  CAS  Google Scholar 

  16. Lee DKH, Chau TT, Weichmann BM et al. Temporal relationships of the anti-inflammatory effect of etodolac in the adjuvant arthritic rat. Proc Soc Exp Biol Med. 1988;187:273–7.

    PubMed  CAS  Google Scholar 

  17. Dvornik D, Lee DKH. Theoretical mechanism for the gastrointestinal safety of etodolac: Selective sparing of cytoprotective prostaglandins. Clin Rheumatol. 1989;8:16–24.

    Article  PubMed  Google Scholar 

  18. Clarke BS. A method for occult blood in faeces using non-carcinogenic reagents. Med Lab Tech. 1971;28:187–90.

    CAS  Google Scholar 

  19. Martel RR, Klicius J. Comparison in rats of the anti-inflammatory and gastric irritant effects of etodolac with several clinically effective anti-inflammatory drugs. Agents Actions. 1982;12:295–7.

    Article  PubMed  CAS  Google Scholar 

  20. Kent TH, Cardelli RM, Stamler FW. Small intestinal ulcers and intestinal flora in rats given indomethacin. Am J Pathol. 1969;54:237–49.

    PubMed  CAS  Google Scholar 

  21. Satoh H, Inada I, Hirata T et al. Indomethacin produces gastric antral ulcers in the refed rat. Gastroenterology. 1981;81:719–25.

    PubMed  CAS  Google Scholar 

  22. Bonney RJ, Glinka S, Hopple S et al. Assessment of gastric bleeding in rats: effects of cyclooxygenase inhibitors and 16,16-dimethyl prostaglandin E2 on gastric bleeding. Agents Actions. 1987;21:310–13.

    Article  PubMed  CAS  Google Scholar 

  23. Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nature (London) New Biol. 1971;231:235–7.

    CAS  Google Scholar 

  24. Nadell J, Bruno J, Varady J et al. Effect of naproxen and of aspirin on bleeding time and platelet aggregation. J Clin Pharmacol. 1974;14:176–82.

    PubMed  CAS  Google Scholar 

  25. Patrono C, Ciabattoni G, Pugliese F et al. Inhibition of platelet cyclooxygenase by aspirin-like drugs: methods forin vitro andex vivo assessment. In: Brune K, Baggliolini M, eds. Arachidonic Acid Metabolism in Inflammation and Thrombosis. Agents Actions Suppl. Basel: Birkhauser; 1979;4:138–44.

    Google Scholar 

  26. Billingham MEJ, Tucker MJ. Correlation between the rise in acute phase proteins and histological evidence of ulceration in the rat following indomethacin treatment. Br J Pharmacol. 1979;67:450P.

    PubMed  CAS  Google Scholar 

  27. Melarange R, Gentry C, Durie M et al. Gastrointestinal irritancy, antiinflammatory activity, and prostaglandin inhibition in the rat Differentiation of effects between nabumetone and etodolac. Dig Dis Sci. 1994;39:601–8.

    Article  PubMed  CAS  Google Scholar 

  28. Amos RS, Crockson RA, Crockson AP et al. Rheumatoid arthritis: C-reactive protein and erythrocyte sedimentation rate during initial treatment. Br Med J. 1978;1:1396.

    Article  PubMed  CAS  Google Scholar 

  29. Thoen J, Helgetveit K, Forre O et al. Effects of piroxicam and D-penicillamine on T lymphocyte subpopulations, natural killer cells and rheumatoid factor population in rheumatoid arthritis. Scand J Rheumatol. 1988;17:91–102.

    PubMed  CAS  Google Scholar 

  30. Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1993;268:6610–4.

    PubMed  CAS  Google Scholar 

  31. Laneuville O, Breuer DK, DeWitt DL et al. Differential inhibition of human prostaglandin endoper- oxide H synthases-1 and -2 by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther. 1994;271:927–34.

    PubMed  CAS  Google Scholar 

  32. Patrignani P, Panara MR, Greco A et al. Biochemical and pharmacological characterisation of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther. 1994;271:1705–12.

    PubMed  CAS  Google Scholar 

  33. Duggan DE, Hooke KF, Noll RM et al. Enterohepatic circulation of indomethacin and its role in intestinal irritation. Biochem Pharmacol. 1975;25:1749–54.

    Article  Google Scholar 

  34. Whittle BJR. Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology. 1981;80:94–8.

    PubMed  CAS  Google Scholar 

  35. Allison MC, Howatson AG, Torrance CJ et al. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med. 1992;327:749–54.

    Article  PubMed  CAS  Google Scholar 

  36. Morris AJ, Madhok R, Sturrock RD et al. Enteroscopic diagnosis of small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs. Lancet. 1991;337:520.

    Article  PubMed  CAS  Google Scholar 

  37. Cayen MN, Kraml M, Ferdinandi ES et al. The metabolic disposition of etodolac in rats, dogs and man. Drug Metab Rev. 1981;12:339–62.

    PubMed  CAS  Google Scholar 

  38. Brune K, Nurnberg B, Szelenyi I et al. The enterohepatic circulation of some anti-inflammatory drugs may cause intestinal ulcerations. In: Rainsford KD, Velo GP, eds. Side Effects of Anti-Inflammatory Drugs, Vol.3 (Part 2). Lancaster: MTP Press; 1985:29–40

    Google Scholar 

  39. Brett MA, Grebb WH, Kurth HJ et al. Absence of enterohepatic circulation of the active metabolite of nabumetone. Forsch Med. 1988;106:736–7.

    CAS  Google Scholar 

  40. Bjarnason I. Non-steroidal anti-inflammatory drug-induced enteropathy. In: Peters TJ, ed. The Cell Biology of Inflammation in the Gastrointestinal Tract. Hull: Corner & Co; 1990:345–60.

    Google Scholar 

  41. Bjarnason I, Fehilly B, Smethurst P et al. Importance of localversus systemic effects of non-steroidal anti-inflammatory drugs in increasing small intestinal permeability in man. Gut. 1991;32:275–7.

    PubMed  CAS  Google Scholar 

  42. Melarange R, Moore G, Blower PR et al. A comparison of indomethacin with ibuprofen on gastrointestinal mucosal integrity in conventional and germ-free rats. Aliment Pharmacol Ther. 1992;6:67–77.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. SmithKline Beecham Pharmaceuticals, Research and Development Technologies, CM19 5AD, Harlow, Essex, UK

    R. Melarange, C. Gentry & P. R. Blower

  2. Research and Development Technologies, SmithKline Beecham Pharmaceuticals, AL6 9AR, The Frythe, Welwyn, Herts, UK

    C. D. N. Toseland

  3. Worldwide Strategic Product Development, Four Falls Corporate Center, SmithKline Beecham Corporation, Conshohocken, PA, USA

    R. Spangler

Authors
  1. R. Melarange
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Gentry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. R. Blower
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. D. N. Toseland
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Spangler
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Melarange, R., Gentry, C., Blower, P.R. et al. Nabumetone, in contrast to etodolac, lacks gastrointestinal irritancy in the rat: Assessment by the inflammatory marker, haptoglobin, and blood loss. Inflammopharmacology 3, 259–270 (1995). https://doi.org/10.1007/BF02659123

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02659123

Keywords

Search

Navigation