Skip to main content
SpringerLink
Log in

In Vivo Selectivity of Nonsteroidal Antiinflammatory Drugs and Gastrointestinal Ulcers in Rats

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

The aim of the present work was to study in vivo COX-2–COX-1 selectivity of 16 nonsteroidal anti-inflammatory drugs (NSAIDs) in equipotent ulcerogenic doses in two in vivo experimental models. Indomethacin, ibuprofen, nimesulide, aceclofenac, aspirin, sodium diclofenac, meloxicam, naproxene, paracetamol, piroxicam, tenoxicam, nabumetone, ketoprofen, mefenamic acid, etodolac, and ketorolac were administered to female Wistar rats (N = 10 each group). In experiment I, solid food plus subcutaneous NSAIDs were given. In experiment II, NSAIDs were given by oral gavage and in bolus. Macroscopic gastric antral ulcer area (30%) and intestinal erosiva area (295 mm2) in experiment I and necrotic gastric fundus area (65%) and erosive intestinal area (182 mm2), “in vivo” the NSAIDs COX-1 was showed. Neutrofilia assessed in gastric intestinal mucosa where also ibuprofen and paracetamol not given neotrophilic infiltration. In conclusion, COX-2–COX-1 selectivity was demonstrated in vivo with the drugs aceclofenac, nabumetone, meloxicam, nimesulide, and paracetamol.

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

    Google Scholar 

  2. Xie W., Chipman JG, Roberstson DL, Erikson RL, Simmons DL: Expression of a mitogen-responsive gene enconding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 88:1692–1696, 1991

    Google Scholar 

  3. Seibert K, Zhang Y, Leahy K, Hanser S, Masferrer JL, Perkins W, Lee L, Isakson P: Pharmacological and biochemical demonstration of the role cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA 91:12013–12017, 1994

    Google Scholar 

  4. Hla T, Neilson K: Human ciclooxygenase 2 cDNA. Proc Natl Acad Sci USA 266:7384–7388, 1992

    Google Scholar 

  5. Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR: Selectivity of nonsteroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci USA 90:11693–11697, 1993

    Google Scholar 

  6. Meade EA, Smith WL, Dewitt DL: Differential inhibition of prostaglandin endoperoxidase synthase (cyclooxigenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 95(suppl 2A):40–45, 1993

    Google Scholar 

  7. Masferrer JL, Zweifel BS, Manning PT, Hanser SD, Leahy KM, Smith WG, Isakson PC, Serbert K: Selective inhibition of inducible cyclooxigenase 2 in vivo is antiinflammatory and nonulcerogenic. Proc Natl Acad Sci USA 91:3228–3232, 1994

    Google Scholar 

  8. Scheiman J: NSAID, gastrointestinal injury and cytoprotection. Gastroenterol Clin North Am 25:(2)279–363, 1996

    Google Scholar 

  9. Akarasereenont P, Mitchell JA, Thimermann C, Vane JR: Relative potency of nonsteroid antiinflammatory drugs and inhibitors of cyclooxigenase-1 or cyclooxigenase-2. Br J Pharmacol 112:183–190, 1994

    Google Scholar 

  10. Vane JR: Introduction: Mechanism of action of NSAIDS. Br J Rheumatol 35(suppl 1):1–3, 1996

    Google Scholar 

  11. Engelhardt G: Meloxicam inhibits preferentially COX-2. Eur J Clin Pharmacol 47:A98, 1994

    Google Scholar 

  12. Henry D, Lim LLY, García Rodríguez LA, Pérez Gutthann S, Carson JL, Griffin M, Savage R, Logan R, Moride Y, Hawokey C, Hill S, Fries JT: Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: Results of collaborative meta-analysis. Br Med J 312:1563–1566, 1996

    Google Scholar 

  13. García Rodríguez LA, Jick H: Risk of upper gastrointestinal bleeding and perforation associated with individual nonsteroidal anti-inflammatory drugs. Lancet 340:769–772, 1994

    Google Scholar 

  14. Aabakken L, Bjombeth BA, Hofstad B, Olaussen B, Larsen S, Osnes M: Comparison of the gastrointestinal side effects of naproxen formulated as plain tablets, enteric-coated tablets, or enteric-coated granulos in capsules. Scand J Gastroenterol 24(suppl):65–73, 1989

    Google Scholar 

  15. Gabriel SE, Jaakkimainen L, Bombardier C: Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta analysis. Ann Intern Med 115:787–796, 1991

    Google Scholar 

  16. Hawkey CJ: Non-steroidal anti-inflammatory drugs and peptic ulcers. BMJ 300:278–284, 1990

    Google Scholar 

  17. Langman MJ: Epidemiologic evidence on the association between peptic ulceration and anti inflammatory drug use. Gastroenterology 96:640–646, 1989

    Google Scholar 

  18. Satoh H, Inada I, Hirata T, Maki Y: Indomethacin produces gastric antral ulcers in the refed rat. Gastroenterology 81:719–725, 1981

    Google Scholar 

  19. Satoh H, Guth PH. Gastric antral ulcers produced by indomethacin in the rat. III. Role of acid and prostaglandin. Gastroenterology 80:1272, 1981

    Google Scholar 

  20. Laudanno OM, Cesolari J, Flaherty P, Esnarriaga J: AINEs selectivos COX-1 vs COX-2 y úlceras gastrointestinales, en ratas. Medicina 5(suppl 4):51, 1997

    Google Scholar 

  21. Oi M, Oshida K, Sugimura S: The location of gastric ulcer. Gastroenterology, 36:45–56, 1959

    Google Scholar 

  22. Oi M, Itoh Y, Kumagai F: A possible dual control mechanism in the origin of peptic ulcer. Gastroenterology 57:280–293, 1969

    Google Scholar 

  23. Lippman W: Inhibition of indomethacin-induced gastric ulceration in the rat by perorally-administered synthetic and natural prostaglandin analogues. Prostaglandins 7:1–10, 1974

    Google Scholar 

  24. Robert A: An intestinal disease produced experimentally by a prostaglandin deficiency. Gastroenterology 69:1045–1047, 1975

    Google Scholar 

  25. Vane JR: Towards a better aspirin. Nature 367:215–216, 1994

    Google Scholar 

  26. Whittle BJR, Higgs GA, Fakins KE, Moncada S, Vane JR: Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa. Nature 284:271–273, 1980

    Google Scholar 

  27. Engelhardt G, Bogel R, Schnitzler C, Utzmann R: Meloxicam: Influence on arachidonic acid metabolism. Part II. In vivo findings. Biochem Pharmacol 51:29–38, 1996

    Google Scholar 

  28. Roth GJ, Stanford N, Hejems PN. Acetylation of prostaglandin synthetase by aspirin. Proc Natl Acad Sci USA 72:3073, 1995

    Google Scholar 

  29. Kolbasa KP, Lancaster C, Olafsson AS, Gilbertson SK, Robert A: Indomethacin-induced gastric antral ulcers in hamsters. Gastroenterology 95:932–934, 1988

    Google Scholar 

  30. Laudanno OM: La prostaglandina E1 (Misoprostol) y el SAME en la prevención de la gastrifis hemorrágica inducida por aspidna, en el hombre. Acta Gastroenterol Latinoam 14:289–295, 1984

    Google Scholar 

  31. Whittle BJR: Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis in the rat. Gastroenterology 180:94–98, 1981

    Google Scholar 

  32. Anthony A, Dillon AP, Pounder RE, Wakefield A: Gastric mucosal contraction and vascular injury induced by indomethacin precede neutrophil infiltration in the rat. Gut 39:363–368, 1996

    Google Scholar 

  33. Havison PJ, Egan RW, Gale PH, Christian GD, Hill BS, Nelson SD: Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase. Chem Biol Interact 64(3):251–266, 1988

    Google Scholar 

  34. Pairet M, Engelhardt G: The preferential inhibition of COX-2 by meloxicam is highly dependent on the structure of the drugs. Rheumatol Eur 24(suppl 3):272, 1995

    Google Scholar 

  35. Mizuno H, Sakamoto C, Matsuda K, Wada K, Uchida T, Noguchi H, Alkamatsu T, Kasuga M. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by specific antagonist delays healing in mice. Gastroenterology 112:387–397, 1997

    Google Scholar 

  36. Uchida M, Kawano O, Misa Ki N, Saitoh K, Inno O: Healing of gastric acid induced gastric ulcer and gastric mucosal PGI2 levels in rats. Dig Dis Sci 35:80–85, 1990

    Google Scholar 

  37. Bedini OA, Laudanno OM, Naves P, San Miguel P, Cesolari J: Alteración de la angiogenesis y retardo de la reparación de la úlcera gástrica por ácido acético en ratas tratadas con meloxicam. Acta Gastroent Latinoam 27(suppl 3):183, 1997

    Google Scholar 

  38. Laudanno OM, Cesolari JA, Esnarriaga J, Vada J, Flaherty P, Guastalli G, San Miguel P, Bedini O: Meloxicam (COX-2) vs indomethacin (COX-1) and gastrointestinal ulcers. Biocell (in press)

  39. Laudanno OM, Cesolari JA, Esnarriaga J, Guastalli G: Meloxicam vs nabumetone on the gastrointestinal mucosa injury. Com Biol 14:(3):320, 1996

    Google Scholar 

  40. Bennet A, Tavares IA: NSAIDs, COX-2 inhibitors and the gut. Lancet 346:1105, 1995

    Google Scholar 

  41. Tavares IA, Bishai PM, Bennet A: Activity of nimesulide on constitutive and inducible cyclooxygenases. Arzneim Forsch 45:1093–1095, 1995

    Google Scholar 

  42. Hayllar J, Bjarnason I: NSAIDs, COX-2 inhibitors, and the gut. Lancet 346:521–522, 1995

    Google Scholar 

  43. Lichtenberger LM, Wang ZM, Romero JJ, Ulloa C, Pérez JC, Giraud MN, Barreto JC: Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: Insight into the mechanism and reversal of NSAID-induced gastrointestinal injury. Nat Med 1:154–158, 1995

    Google Scholar 

  44. Lugea A, Antolin M, Mourelle M, Guarner F, Malagelada JR: Deranged hydrophobic barrier of the rat gastroduodenal mucosa after parenteral nonsteroid anti-inflammatory drugs. Gastroenterology 112:1931–1939, 1997

    Google Scholar 

  45. Insel PA: Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In JG Hardman, LE Limbird (eds). Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed. New York, McGraw-Hill, pp 617–658, 1996

    Google Scholar 

  46. Schneider HT, Nuernberg B, Dietzel K, Brune K. Biliary elimination of nonsteroidal antiinflammatory drugs in patients. Br J Clin Pharmacol 29:127–131, 1990

    Google Scholar 

  47. Futaki N, Takahashi S, Yokoyama M, Ara I, Higuchi S, Otomo S: NS 398, a new antiinflammatory agent, inhibits prostaglandin G/H synthase-cyclooxygenase (COX-2) activity in vitro. Prostaglandin 47:55–59, 1994

    Google Scholar 

  48. Gans KR, Gabraight W, Roman RJ: Anti-inflammatory and safety profile of Dup 6976, a novel ovally effective prostaglandin synthesis inhibitor. J Pharmacol Exp Ther 254:180–187, 1990

    Google Scholar 

  49. Chan CC, Boyce S, Brideau C: Pharmacology of a selective cyclooxygenase-2 inhibitors, L-745–337: A novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in the rat and nonhuman primate stomach. J Exp Pharmacol Ther 33:1609–1611, 1995

    Google Scholar 

  50. Riese J, Hoff T, Nordhoff A, De Witt DL, Resch K, Kaever V: Transient expression of prostaglandin endoperoxidase synthase-2 during mouse macrophage activation. J Leuk Biol 55:476–482, 1994

    Google Scholar 

  51. Lanza FL: A review of gastric ulcer and gastroduodenal injury in normal volunters receiving aspirin and other non-steroidal anti-inflammatory drugs. Scand J Gastroenterol 24(suppl 163):24–31, 1989

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental Gastroenterology, Cathedras of Gastroenterology and Histology, Faculty of M´edicine, U.N.R. Rosario, Argentina

    O.M. Laudanno, J.A. Cesolari, J. Esnarriaga, P. San Miguel & O.A. Bedini

Authors
  1. O.M. Laudanno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J.A. Cesolari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Esnarriaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. San Miguel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O.A. Bedini
    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

Laudanno, O., Cesolari, J., Esnarriaga, J. et al. In Vivo Selectivity of Nonsteroidal Antiinflammatory Drugs and Gastrointestinal Ulcers in Rats. Dig Dis Sci 45, 1359–1365 (2000). https://doi.org/10.1023/A:1005508120776

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1005508120776

Search

Navigation