Intestinal anti-inflammatory activity of UR-12746, a novel 5-ASA conjugate, on acute and chronic experimental colitis in the rat

1 The present study was undertaken to investigate the intestinal anti-infla mmatory effects of UR-12746 on the acute and chronic stages of a trinitrobe nzene sulphonic acid (TNBS) experimental model of inflammatory bowel diseas e (IBD) in the rat. UR-12746 is a novel, locally-acting compound which comb ines, through an azo bond, 5-aminosalicylic (5-ASA) and UR-12715, a potent platelet activating factor (PAF)-antagonist. 2 UR-12746 oral pretreatment of colitic rats (50 and 100 mg kg(-1)) reduced acute colonic damage when evaluated 2 days after colonic insult. 3 Postreatment for 4 weeks with UR-12746 (50 and 100 mg kg(-1)) resulted in a faster recovery of the damaged colonic mucosa, which was macroscopically significant from the third week. 4 The intestinal anti-inflammatory effect of UR-12746 was associated with a decrease in leukocyte infiltration in the colonic mucosa, which was eviden ced both biochemically, by a reduction in myeloperoxidase activity, and his tologically, by a lower leukocyte count after morphometric analysis. This e ffect was higher than that seen with sulphasalazine, when assayed at the sa me doses and in the same experimental conditions. 5 Several mechanisms can be involved in the beneficial effects showed by UR -12746: inhibition of leukotriene Bq synthesis in the inflamed colon, impro vement of the altered colonic oxidative status, and reduction of colonic in terleukin-1 beta production. 6 The results suggest that the intestinal anti-inflammatory activity of UR- 12746 can be attributed to the additive effects exerted by 5-ASA and UR-127 15, the PAF antagonist compound, that are released in the colonic lumen aft er reduction of the azo bond by the intestinal bacteria.