薬理と治療

Abstract

[Objectives Mesalazine is widely used as a drug for the treatment of inflammatory bowel disease（IBD）. In this study, we evaluated its pharmacological properties in vitro and in two rat models of IBD. Methods We examined the effects of mesalazine to scavenge various radicals and to inhibit leukotriene B4 biosynthesis in vitro. The anti−inflammatory activity of mesalazine was investigated in rat models of acetic acid−induced and 2, 4, 6−trinitrobenzenesulfonic acid（TNBS）−induced colitis. Results Mesalazine scavenged hydrogen peroxide（IC50：2.2μmol／L）, but had no effect on superoxide. It scavenged hypochlorite（IC50：35.7μmol／L）and reduced free radical, 1,1−diphenyl−2−picrylhydrazyl（IC50：6.5μmol／L）. Mesalazine also inhibited the biosynthesis of leukotriene B4 in rat peritoneal neutrophils（IC50：599μmol／L）. In a rat model of acetic acidinduced colitis, intrarectal administration of mesalazine significantly reduced the ulcer area and wet weight of damaged colon at doses of 3, 10, and 30 mg／kg. Finally, the ulcer area of TNBS−induced colitis in rats was significantly reduced by intrarectal administration of mesalazine at doses of 10, 30, and 100 mg／kg. Conclusions Mesalazine ameliorated colitis in typical rat models of IBD. These findings suggest that mesalazine is useful for the treatment of IBD by reducing hydrogen peroxide, hypochlorite, free radicals, and leukotriene B4.（Jpn Pharmacol Ther 2008；36：293−301）KEY WORDS Mesalazine, Inflammatory bowel disease, Colitis, Objectives Mesalazine is widely used as a drug for the treatment of inflammatory bowel disease（IBD）. In this study, we evaluated its pharmacological properties in vitro and in two rat models of IBD. Methods We examined the effects of mesalazine to scavenge various radicals and to inhibit leukotriene B4 biosynthesis in vitro. The anti−inflammatory activity of mesalazine was investigated in rat models of acetic acid−induced and 2, 4, 6−trinitrobenzenesulfonic acid（TNBS）−induced colitis. Results Mesalazine scavenged hydrogen peroxide（IC50：2.2μmol／L）, but had no effect on superoxide. It scavenged hypochlorite（IC50：35.7μmol／L）and reduced free radical, 1,1−diphenyl−2−picrylhydrazyl（IC50：6.5μmol／L）. Mesalazine also inhibited the biosynthesis of leukotriene B4 in rat peritoneal neutrophils（IC50：599μmol／L）. In a rat model of acetic acidinduced colitis, intrarectal administration of mesalazine significantly reduced the ulcer area and wet weight of damaged colon at doses of 3, 10, and 30 mg／kg. Finally, the ulcer area of TNBS−induced colitis in rats was significantly reduced by intrarectal administration of mesalazine at doses of 10, 30, and 100 mg／kg. Conclusions Mesalazine ameliorated colitis in typical rat models of IBD. These findings suggest that mesalazine is useful for the treatment of IBD by reducing hydrogen peroxide, hypochlorite, free radicals, and leukotriene B4.（Jpn Pharmacol Ther 2008；36：293−301）KEY WORDS Mesalazine, Inflammatory bowel disease, Colitis]