Skip to main content
SpringerLink
Log in

Treatment of dextran sulfate sodium-induced murine colitis by intracolonic cyclosporin

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

Abstract

The use of oral and intravenous cyclosporin represents a significant advance in the therapy of refractory inflammatory bowel diseases (IBD). However, oral administration of cyclosporin is fraught with improper delivery of cyclosporin to the colon for its topical action. Because of unpredictable metabolism by cytochrome P-450 IIIA, the targeted blood level for systemic effect is not reached at low doses. Furthermore, the doses that have been used for therapy of IBD have been shown to induce several adverse side effects. Thus, an alternate method of delivering cyclosporin to the colon is desirable. In this study, the effect of intracolonically administered cyclosporin was tested for its efficacy to heal mucosal erosions in dextran sulfate sodium (DSS)-induced colitis in mice. Both acute and chronic colitis was induced by feeding female Swiss-Webster mice with 5% DSS (30,000–40,000 mol wt) for five or seven days, respectively. Therapy was advocated prophylactically, prophylaxis plus therapy and therapeutically during the acute and chronic phase of the disease and therapeutically during the chronic phase of the disease. Intracolonic cyclosporin given prophylactically showed adverse effects by increasing the damage to the colonic mucosa. However, intracolonic cyclosporin given therapeutically in 2.5, 5, and 10 mg/kg after the induction of colitis resulted in dramatic responses in terms of reducing the disease activity and histologic scores, corroborated by complete histological resolution compared to oral cyclosporin given at identical doses. Intracolonic cyclosporin (5 mg/kg) was also very effective in reducing the chronic inflammation. The results of this study highlight the application of this animal model for therapeutic research. Furthermore, cyclosporin administered as an enema provides a new stratagem for the therapy of IBD because of its rapid onset of action at very low doses without the risk inherent in oral or systemic administration.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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. Riddell RH: Pathology of idiopathic inflammatory bowel diseases.In Inflammatory Bowel Diseases. JB Kirsner RG Shorter (ed). Philadelphia, Lea and Febiger, 1988, pp 329–350

    Google Scholar 

  2. Lauritsen K: Drug treatment and formation of eicosanoids in patients with chronic inflammatory bowel diseases. Danish Med Bull 36:378–393, 1989

    Google Scholar 

  3. Sutherland L, Singelton F, Sessions F, Hanauer S, Karwitt E, Ranking G, Summers R, Mekhjian H, Greenberger N, Kelly M, Levine L, Thomson A, Alpert E: Double blind placebo controlled trial of metronidazole in Crohn's disease. Gut 18:1071–1075, 1991

    Google Scholar 

  4. Present DH: 6-Mercaptopurine and other immunosuppressive agents in the treatment of Crohn's disease and ulcerative colitis. Gastroenterol Clin North Am 18:57–71, 1989

    Google Scholar 

  5. Stange EF, Fleig WE, Rekhlaw E, Ditschuneit H: Cyclosporin A treatment in inflammatory bowel diseases. Dig Dis Sci 34:1387–1392, 1989

    Google Scholar 

  6. Lichteger S, Present DH: Preliminary report: Cyclosporin in treatment of severe active ulcerative colitis. Lancet 336(8706):16–19, 1990

    Google Scholar 

  7. Porro GB, Panza E, Petrillo M: Cyclosporin A in acute ulcerative colitis. Lancet 2:1277–1278, 1984

    Google Scholar 

  8. Lobo AJ, Juby LD, Foster RN, Rothwell J, Smith AH, Axon ATR: Oral cyclosporin and renal function in Crohn's disease. Gut 30:A1480, 1989

    Google Scholar 

  9. Watkins PB: The role of cytochrome P-450 IIIA in cyclosporin metabolism. J Am Acad Dermatol 23:1309–1311, 1990

    Google Scholar 

  10. Sandborn WJ, Strong RM, Forland SC, Chase RL, Cutter RE: The pharmacokinetics and colonic tissue concentrations after IV, oral and enema administration. J Clin Pharmacol 31:76–80, 1991

    Google Scholar 

  11. Brynskov J, Freund L, Thomsen OO, Anderson CB, Rasmussen SN, Binder V: Treatment of refractory ulcerative colitis with cyclosporin enemas. Lancet 1:721–722, 1989

    Google Scholar 

  12. Sandborn WJ, Tremaine WJ, Schroeder KW, Batts KP, Lawson GM: Cyclosporine (CYA) enemas for treatment-resistant, ulcerative proctosignoiditis (UPS). Gastroenterology 102:A690, 1992

    Google Scholar 

  13. Winter T, Dalton HR, Merrett MN, Campbell A, Jewell DP: Cyclosporin A retention enemas in refractory distal ulcerative colitis: An open trial. Gastroenterology 102:A947, 1992

    Google Scholar 

  14. Ranzi T, Campanini MC, Velio P, Quarto di Palo F, Bianchi P: Treatment of chronic proctosigmoiditis with cyclosporin enemas. Lancet 2:97, 1989

    Google Scholar 

  15. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R: Novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98:694–702, 1990

    Google Scholar 

  16. Cooper HS, Murthy SNS, Shah RS, Sedergran DJ: Clinicopathological study of dextran sulfate sodium experimental murine colitis. Lab Invest (submitted)

  17. Dunnet CW: Multiple comparison tests. Biometrica 26:139–141, 1970

    Google Scholar 

  18. Newman D: The distribution of range in sample from a normal population expressed in terms of independent estimate of standard deviation. Biometrica 31:20–30, 1939

    Google Scholar 

  19. Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL: Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 96:795–803, 1989

    Google Scholar 

  20. Fitzpatric LR, Bostwick JS, Renzetti M, Pendleton RG, Dektor DL: Antiinflammatory effects of various drugs on acetic acid induced colitis in the rat. Agents Actions 30:399–411, 1990

    Google Scholar 

  21. Azad Khan AK, Piris J, Truelove SC: An experiment to determine the actual therapeutic moiety of sulphasalazine. Lancet 2:892–895, 1977

    Google Scholar 

  22. Meyers S, Sachar DB, Present DH, Janowitz HD: Olsalazine sodium in the treatment of ulcerative colitis among patients intolerant of sulfasalazine. A prospective, randomized placebo-controlled, double blind, dose ranging clinical trial. Gastroenterology 93:1255–1262, 1987

    Google Scholar 

  23. Robinson MG: New oral salicylates in the therapy of chronic idiopathic inflammatory bowel disease. Gastroenterol Clin North Am 18:43–49, 1989

    Google Scholar 

  24. Sutherland LR, Martin F, Greer S, Robinson MG, Greenberger N, Sarbid F, Martin T, Sparr J, Prokipchuk ED, Borgen L: 5-Aminosalicylic acid enemas in the treatment of distal ulcerative colitis, proctosigmoiditis and proctitis. Gastroenterology 92:1844–1848, 1987

    Google Scholar 

  25. Kolars JC, Duell EA, Schmiedlin-Ren P, Ellis CN, Voorhees JJ, Watkins PB: Cyclosporin metabolism by cytochrome P-450 IIIA in rat enterocytes: Another determinant of oral bioavailability. Gastroenterology 98:A192, 1990

    Google Scholar 

  26. Kronke M, Leonard WJ, Deeper JM, Green WC: Sequential expression of genes involved in human lymphocyte growth and differentiation. J Exp Med 161:1593–1598, 1985

    Google Scholar 

  27. Wagner H: Cyclosporin A: Mechanism action. Transplant Proc 15:523–526, 1983

    Google Scholar 

  28. Kubes P, Hunter J, Granger DN: Effects of cyclosporin A and FK 506 on ischemia/reperfusion-induced neutrophil infiltration in the cat. Dig Dis Sci 36:1469–1472, 1991

    Google Scholar 

  29. Thomson AW, Moon DK, Geczy CL, Nelson DS: Modification of delayed-hypersensitivity reactions to ovalbumin in cyclosporin A-treated guinea pigs. Immunology 48:301–308, 1983

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Krancer Center for Inflammatory Bowel Disease Research, Division of Gastroenterology, Department of Medicine, Hahnemann University, Broad and Vine Streets, Mail Stop 131, 19102-1192, Philadelphia, Pennsylvania

    S. N. S. Murthy PhD, Harry S. Cooper MD, Helen Shim MD, Rupal S. Shah BS, Samih A. Ibrahim MS & Deborah J. Sedergran MT (ASCP)

  2. Department of Pathology and Laboratory Medicine, Hahnemann University, Broad and Vine Streets, 19102-1192, Philadelphia, Pennsylvania

    S. N. S. Murthy PhD, Harry S. Cooper MD, Helen Shim MD, Rupal S. Shah BS, Samih A. Ibrahim MS & Deborah J. Sedergran MT (ASCP)

Authors
  1. S. N. S. Murthy PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harry S. Cooper MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helen Shim MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rupal S. Shah BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Samih A. Ibrahim MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Deborah J. Sedergran MT (ASCP)
    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

Murthy, S.N.S., Cooper, H.S., Shim, H. et al. Treatment of dextran sulfate sodium-induced murine colitis by intracolonic cyclosporin. Digest Dis Sci 38, 1722–1734 (1993). https://doi.org/10.1007/BF01303184

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01303184

Key Words

Search

Navigation