Efficacy of the Inflammatory Cell Infiltration Inhibitor IS-741 on Colitis Induced by Dextran Sulfate Sodium in the Rat

Abstract

ABSTRACT-We examined the therapeutic effects of the inflammatory cell infiltration inhibitor IS-741 (N-(2-((ethylsulfonyl)amino)-5-(trifluoromethyl)-3-pyridinyl)-cyclohexanecarboxamide monosodium salt monohydrate) on a rat colitis model. As a result of its effects on leukocyte infiltration, IS-741 inhibits cell adhesion, alleviates symptoms and signs of pancreatitis and multiple organ failure and demonstrates a lifesaving effect in a model of severe acute pancreatitis. A rat model was prepared by inducing colitis with 3% dextran sodium sulfate (DSS) and maintaining pathology with 1% DSS. Repeated oral administration of IS-741 at 1, 10 or 100 mg/kg per day was conducted for 2 weeks (during treatment with 1% DSS). IS-741 at each dose decreased the area of erosion in the large intestine, thickening of the wall of the large intestine and anemia caused by melena. Some effects of IS-741 were nearly equivalent to those of the control compound salazosulfapyridine. Furthermore, IS-741 markedly alleviated inflammatory cell infiltration into the intestinal wall. IS-741 improved lesions in a rat DSS model by inhibiting leukocyte infiltration, suggesting the possibility of clinical application of this drug for IBD.

Muscularis mucosae - the forgotten sibling

“…In the experimental rat model for colitis, pathological changes such as inflammatory cell infiltration, edema, hemorrhage and metaplasia were observed in the muscularis mucosae of the large intestine (Yotsuya et al, 2001). As a new therapeutic target for inflammatory bowel diseases such as diarrhea, constipation, irritable bowel syndrome and Crohn's disease (Kirsner, 2000;Van Montfrans et al, 2002;Lembo and Camilleri, 2003;Mertz, 2003), much attention should be attracted to the motor regulation of the intestinal muscularis mucosae.…”

IS-741 Attenuates Local Migration of Monocytes and Subsequent Pancreatic Fibrosis in Experimental Chronic Pancreatitis Induced by Dibutyltin Dichloride in Rats

“…29 Yamauchi et al 20 reported that IS-741 inhibited the leukocyte adherence to pancreatic collecting venules, accompanied by a reduction in Mac-1 expression on circulating neutrophils in acute necrotizing pancreatitis animals. Yotsuya et al 30 suggested that IS-741 inhibited the cluster formation of LFA-1 with activation of LFA-1. In previous studies, IS-741 has been proven to have therapeutic effects in some animal models of acute pancreatitis, 20,22 ileitis, 23 and colitis, 19,24 and it is supposed that the mechanism by which IS-741 prevents the development of inflammation might be due to its inhibitory effects on the adhesion of neutrophils to endothelial cells and subsequent neutrophil infiltration into the tissue.…”

A novel diamino-pyridine derivative (IS-741) attenuates rat ileitis induced by trinitrobenzene sulfonic acid

“…Recently, Yotsuya et al 19 reported that the administration of IS-741 (1, 10, or 100mg/kg) led to the attenuation of dextran sodium sulfate (DSS)-induced colitis, which is useful for the evaluation of therapeutic effects against ulcerative colitis. They showed that IS-741 decreased the area of erosion in the large intestine and decreased the thickening of the large intestinal wall, as well as attenuating anemia, due to its inhibitory effects on the inflammatory cell infiltration into the intestinal wall.…”

“…[15][16][17][18] However, there are only few reports about the efficacy of leukocyte-endothelial interaction inhibitors against intestinal inflammation. 19 In the present study, we investigated the effects of oral IS-741 on rat experimental ileitis. A trinitrobenzene sulfonic acid (TNBS) colitis model was reported by Morris et al, 20 and it has been used as a Crohn's disease colitis model.…”