Skip to main content
SpringerLink
Log in

Copper-Indomethacinate Associated with Zwitterionic Phospholipids Prevents Enteropathy in Rats (Effect on Inducible NO Synthase)

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

Abstract

Intestinal toxicity exerted by indomethacin wascompared to that induced by copperindomethacinate, freeor associated to zwitterionic phospholipids. A singlehigh dose of indomethacin (15 or 20 mg/kg), copper-indomethacinate (15 or 20 mg/kg), orcopperindomethacinate liposomes or nanocapsules (15mg/kg) was orally administered. Then 24 hr laterjejunoileal tissue was taken for macroscopicobservation, ex vivo nitrite production, and determinationof myeloperoxydase and iNOS activities. Antiinflammatoryactivity of the drugs was investigated using thecarrageenan-induced paw edema model. Indomethacin induced penetrating ulcerations of theintestine that were maximal at hour 24.Copperindomethacinate induced significantly lessulceration than indomethacin with no significantdifference in MPO and iNOS activities. The injurious action ofindomethacin on the small intestine was further reducedwhen copper-indomethacinate was administered as thephospholipid-associated state while similaranti-inflammatory action was observed on rat paw edema. Theantiulcerogen effect of copper-indomethacinate seems tobe linked to its free radical scavenging effect withoutany modification of nitric oxide release.

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. Garner A: Adaptation in the pharmaceutical industry, with particular reference to gastrointestinal drugs and disease. Scand J Gastroenterol 27:83–89, 1992

    Google Scholar 

  2. Bjarnasson I, Hayllar J, Mac Pherson AJ, Russel AS: Side effects of nonsteroid anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 104:1832–1847, 1993

    Google Scholar 

  3. Yamada Y, Deitch E, Specian RD, Perry MA, Sartor RB, Grisham MB: Mechanisms of acute and chronic intestinal inflammation induced by indomethacin. Inflammation 17:641–662, 1993

    Google Scholar 

  4. Wallace JL, Keenan CM, Gale D, Shoupe TS: Exacerbation of experimental colitis by nonsteroidal anti-inflammatory drugs is not related to elevated leukotriene B4 synthesis. Gastroenterology 102:18–27, 1992

    Google Scholar 

  5. Davies NM, Wright MR, Jamali F: Antiinflammatory druginduced small intestinal permeability: The rat is a suitable model. Pharmacol Res 11:1652–1656, 1994

    Google Scholar 

  6. Hills BA, Butler BD, Lichtenberger LM: Gastric mucosal barrier: Hydrophobic lining to the lumen of the stomach. Am J Physiol 244:G561–G568, 1983

    Google Scholar 

  7. Anthony A, Pounder RE, Dhillon AP, Wakefield AJ: Vascular anatomy defines sites of indomethacin induced jejunal ulceration along the mesenteric margin. Gut 41:763–770, 1997

    Google Scholar 

  8. Lichtenberger LM, Wang ZM, Giraud MN, Romero JJ, Barreto JC: Effect of naproxen gastric mucosal hydrophobicity. Gastroenterology 108:A149, 1995

    Google Scholar 

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

    Google Scholar 

  10. Goddard PJ, Hills BA, Lichtenberger LM: Does aspirin damage canine gastric mucosa by reducing its surface hydrophobicity? Am J Physiol 252:G421–G430, 1987

    Google Scholar 

  11. Lichtenberger LM, Graziani LA, Dial EJ, Butler BD, Hills DA: Role of surface-active phospholipids in gastric cytoprotection. Science 219:1327–1329, 1983

    Google Scholar 

  12. Moncada S, Higgs A: The L-arginine nitric oxide pathway. N Engl J Med 27:2002–2012, 1993

    Google Scholar 

  13. Salvemini D, Settle SL, Masferrer JL, Seibert K, Currie MG, Needleman P: Regulation of prostaglandin production by nitric oxide: An in-vivo analysis. Br J Pharmacol 114:1171–1178, 1995

    Google Scholar 

  14. Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P: Nitric oxide activates cyclooxyge nase enzymes. Proc Natl Acad Sci USA 90:7240–7244, 1993

    Google Scholar 

  15. Salvemini D, Misko TP, Masferrer J, Seibert K, Currie MG, Needleman P: In Biology of Nitric Oxide, vol 4. S Moncada, M Feelish, R Busse (eds). London, Portland Press, 1995, chap 8, pp 304–315

    Google Scholar 

  16. Alican I, Kubes P: A critical role for nitric oxide in intestinal barrier function and dysfunction. Am J Physiol 270:G225–G237, 1996

    Google Scholar 

  17. McCall TB, Boughton-Smith NK, Palmer RM, Whittle BJR, Moncada S: Synthesis of nitric oxide from L-arginine by neutrophils. Release and interaction with superoxide anion. Biochem J 261:293–296, 1989

    Google Scholar 

  18. Wink DA, Cook JA, Pacelli R, Liebmann J, Krishna MC, Mitchell JB: Nitric oxide (NO) protects against cellular damage by reactive oxygen species. Toxicol Lett 82/83:221–226, 1995

    Google Scholar 

  19. Wallace JL, Reuter BK, Cicala C, Mc Knight W, Grisham MB, Cirino G: A diclofenac derivative without ulcerogenic properties. Eur J Pharmacol 257:249–255, 1994

    Google Scholar 

  20. Wallace JL, Reuter BK, Cirino G: Nitric-oxide-releasing NSAIDs: A novel approach for reducing gastrointestinal toxicity. Gastroenterol Hepatol 9:S40–S44, 1994

    Google Scholar 

  21. Bertrand V, Guimbaud R, Tulliez M, Mauping C, Sogni P, Couturier D, Giroud JP, Chaussade S, Chauvelot-Moadon L: Increase in tumour necrosis factor-a production linked to the toxicity of indomethacin for the rat small intestine. Br J Pharmacol 124:1385–1394, 1998

    Google Scholar 

  22. Bertrand V, Guimbaud R, Sogni P, Lamrani A, Mauprivez C, Giroud JP, Couturei D, Chauvelot-Moadon L, Chaussade S: Role of tumour necrosis factor-a and inducible nitric oxide synthase in the prevention of nitro-flurbiprofen small intestine toxicity. Eur J Pharmacol 356:245–253, 1998

    Google Scholar 

  23. Somasundaram S, Rafi S, Hayllar J, Sigthorsson G, Jacal H, Price AB, McPherson A, Mahmod T, Scott D, Wrigglesworth JM, Bjarnassan I: Mitochondrial damage: A possible mechanism of the “topical” phase of NSAID induced injury in the rat intestine. Gut 41:344–353, 1997

    Google Scholar 

  24. Kurose I, Miura S, Higuchi H, Watanabe N, Kamejaya Y, Tkaishi H, Tomita K, Fukumusa D, Kato S, Ishü H: Increased nitric oxide synthase activity as a cause of mitochondrial dysfunction in rat hepatocytes: role of TNF-a. Hepatology 24:1185–1192, 1996

    Google Scholar 

  25. Sorenson JRJ: Copper chelates as possible active forms of antiarthritic agents. J Med Chem 19:135–148, 1976

    Google Scholar 

  26. Sorenson JR: Copper-complexes offer physiologic approach to treatment of ulcers. In Ulcer Diseases. New Aspects of Pathogenesis and Pharmacology. S Szabo, CJ Pfeiffer (eds). Boca Raton, Florida, CRC Press, 1989, pp 357–372

    Google Scholar 

  27. Roch-Arveiller M, Pham Huy D, Maman L, Giroud JP, Sorenson JRJ: Nonsteroidal anti-inflammatory drug-copper complex modulation of polymorphonuclear leukocyte migration. Biochem Pharmacol 39:569–574, 1990

    Google Scholar 

  28. Roch-Arveiller M, Revelant V, Pham Huy D, Mamau L, Fontague J, Sorenson JRJ, Giroud JP: Effects of some nonsteroidal anti-inflammatory drug-copper complexes on polymorphonuclear leukocyte oxidative metabolism. Agents Actions 31:65-71, 1990

    Google Scholar 

  29. Weissenborn U, Maedge S, Buettner D, Swing KF: Indomethacin induced gastrointestinal lesions in relation to tissue concentration, food intake and bacterial invasion in the rat. Pharmacology 30:32–39, 1985

    Google Scholar 

  30. Stainmesse S, Fessi H, Devissaguet JP, Puisieux F: Procédeés de préparation de systè mes colloidaux dispersibles de lipides amphiphiles sous forme de liposomes submicroniques. European patent no. 894018571

  31. Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S: Nanocapsule formation by interfacial polymer deposition following solvent deplacement. Int J Pharmacol 55:R1–R4, 1989

    Google Scholar 

  32. Wallace JL, Mc Knight W, Miyasaka M, Tamatano T, Paulson J, Anderson DC, Granger DN, Kuber P: Role of endothelial adhesion molecules in NSAID-induced gastric mucosal injury. Am J Physiol 265:G993–G998, 1993

    Google Scholar 

  33. Maehly AC, Chance B: The assay of catalases and peroxidases. In Methods of Biochemical Analysis. D Glick (ed). New York, Interscience, 1954, pp 357–408

    Google Scholar 

  34. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275, 1951

    Google Scholar 

  35. Bush PA, Gonzalez NE, Griscavage JM, Ignarro LJ: Nitric oxide synthase from cerebellum catalyzes the formation of equimolar quantities of nitric oxide and citrulline from L-arginine. Biochem Biophys Res Commun 185:960-–966, 1992

    Google Scholar 

  36. Marletta MA, Yoon PS, Iyengar R, Leaf CD, Wishnok JS: Macrophage oxidation of L-arginine to nitrite and nitrate: Nitric oxide is an intermediate. Biochemistry 27:8706–8711, 1988

    Google Scholar 

  37. Worthington Biochemical Corp: Worthington Enzyme Manual. Worthington Biochemical Corp, Freehold, New Jersey. 1972, 43 pp

  38. Scarpignato C: NSAID-induced gastro-duodenal damage: from pathogenesis to prevention. In Recent Advances in the Pathophysiology of GastroIntestinal and Liver Diseases. JP Galmiche, J Gournay (eds). Paris, John Libbey Eurotext, 1997, pp 47–84

    Google Scholar 

  39. Wallace JL, Keenan Ch, Granger DN: Gastric ulceration by non-steroidal anti-inflammatory drugs is a neutrophildependent process. Am J Physiol 259:G462–G467, 1990

    Google Scholar 

  40. Shoehgen EC, Godin-Ostro E, Fielder FG, Ginsberg RS, Slusher MA, Weiner AL: Encapsulation of indomethacin in liposomes provides protection against both gastric and intestinal ulceration when orally administered to rats. Arthritis Rheum 31:412–421, 1989

    Google Scholar 

  41. Ammoury N, Fessi H, Devissaguet JP, Dubrasquet M, Benita S: Jejunal absorption, pharmacological activity and pharmacokinetic evaluation of indomethacin loaded poly (D, L-lactide) and poly(isobutylcyanoacrylate ) nanocapsules in rats. Pharm Res 8:101–105, 1991

    Google Scholar 

  42. Ammoury N, Dubrasquet M, Fessi H, Devissaguet JP, Puisieux F, Benita S: Indomethacin-loaded poly(D,L-lactide) nanocapsules: Protection from gastrointestinal ulceration and antiin-flammatory activity evaluation in rats. Clin Mater 13:121–130, 1993

    Google Scholar 

  43. Konturek SK, Konturek PC: Role of nitric oxide in the digestive system. Digestion 51:1–13, 1995

    Google Scholar 

  44. Kubes P, Wallace JL: Nitric oxide as a mediator of gastrointestinal mucosal injury? Mediators Inflamm 4:397–405, 1995

    Google Scholar 

  45. Elliott SN, McKnight W, Cirino G, Wallace JL: A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats. Gastroenterology 109:524–530, 1995

    Google Scholar 

  46. Smalley WE, Griffin MR: The risks and costs of upper gastrointestinal disease attributable to NSAIDs. Gastroenterol Clin North Am 25:373–396, 1996

    Google Scholar 

Download references

Authors
  1. Viviane Bertrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fadila Guessous
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anne-Laure Le Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernard Viossat
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hatem Fessi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ahmed El Abbouyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jean-Paul Giroud
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Monique Roch-Arveiller
    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

Bertrand, V., Guessous, F., Roy, AL.L. et al. Copper-Indomethacinate Associated with Zwitterionic Phospholipids Prevents Enteropathy in Rats (Effect on Inducible NO Synthase). Dig Dis Sci 44, 991–999 (1999). https://doi.org/10.1023/A:1026668816189

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026668816189

Search

Navigation