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

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          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.

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          Most cited references16

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          Hapten-induced model of chronic inflammation and ulceration in the rat colon.

          We have developed a simple and reproducible rat model of chronic colonic inflammation by the intraluminal instillation of a solution containing a "barrier breaker" and a hapten. Administration of the hapten 2,4,6-trinitrobenzenesulfonic acid (5-30 mg) in 0.25 ml of 50% ethanol as the "barrier breaker" produced dose-dependent colonic ulceration and inflammation. At a dose of 30 mg, trinitrobenzenesulfonic acid/ethanol-induced ulceration and marked thickening of the bowel wall persisted for at least 8 wk. Histologically, the inflammatory response included mucosal and submucosal infiltration by polymorphonuclear leukocytes, macrophages, lymphocytes, connective tissue mast cells, and fibroblasts. Granulomas were observed in 57% of the rats killed 3 wk after induction of inflammation. Langhan's-type giant cells were also observed. Segmental ulceration and inflammation were common. The characteristics and relatively long duration of inflammation and ulceration induced in this model afford an opportunity to study the pathophysiology of colonic inflammatory disease in a specifically controlled fashion, and to evaluate new treatments potentially applicable to inflammatory bowel disease in humans.
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            5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.

            The efficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon. Seventy-six patients received active medication and 77 received a placebo. There were 20 dropouts (6 in the active group and 14 in the placebo group) during the study because of insufficient efficacy. After 6 wk of therapy, 48 of the 76 patients (63%) receiving 5-aminosalicylic acid were considered to be "much improved" by the study physician compared to 22 of the 77 patients (29%) on placebo (p = 0.001). A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mean disease activity index declined 55% for patients on 5-aminosalicylic acid and 24% for patients on placebo (p = 0.0001). Analysis of subgroups indicated that patients most likely to respond were those with disease confined to the 20-40 cm from the anus. Response was not affected by concurrent sulfasalazine, but patients requiring concurrent oral steroids had a diminished response. Rapid onset of efficacy was shown by a significant reduction in rectal bleeding within 3 days of treatment initiation. 5-Aminosalicylic acid enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon.
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              An experiment to determine the active therapeutic moiety of sulphasalazine.

              Sulphasalazine (S.A.S.P.) is of proven value in the treatment of ulcerative colitis, but its mode of action is unknown. When it is taken by mouth, nearly all the dose reaches the colon intact, where it is split by bacteria into sulphapyridine (S.P.) and 5-aminosalicylic acid (5-A.S.A.). An experiment was devised to determine whether the therapeutic property of S.A.S.P. is a function of the parent molecule or of these two principal metabolites. Retention enemas of S.A.S.P., S.P., and 5-A.S.A. were administered to volunteer patients with sigmoidoscopic evidence of active ulcerative colitis. The experiment was conducted as a blind controlled therapeutic trial, each patient having one of the test enemas daily for two weeks. Pronounced histological improvement was observed in approximately 30% of the patients receiving S.A.S.P. or 5-A.S.A., and in only 5% of those receiving S.P. It is concluded that the active therapeutic moiety of S.A.S.P. IS 5-A.S.A. and that the S.P. functions as a carrier ensuring that the 5-A.S.A. is liberated within the colon.
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                Author and article information

                Journal
                Digestive Diseases and Sciences
                Digest Dis Sci
                Springer Science and Business Media LLC
                0163-2116
                1573-2568
                September 1993
                September 1993
                : 38
                : 9
                : 1722-1734
                Article
                10.1007/BF01303184
                8359087
                0cdfa24f-0e5e-4a2b-aa42-b27b464849c8
                © 1993

                http://www.springer.com/tdm

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