The efficacy of BAY y 1015 in dextran sulfate model of mouse colitis

Abstract

Objective and Design: There is crucial evidence that leukotrienes are significant mediators of inflammation in inflammatory bowel diseases (IBD). Thus, selective inhibition of leukotriene synthesis is believed to provide a novel approach to therapy of IBD. The aim of the study is to study the efficacy of a potent 5-lipoxygenase activating protein inhibitor (FLAP), BAY y 1015 in a dextran sulfate model of mouse colitis.¶Material: Outbred female mice weighing approximately 25 grams were used to produce acute or chronic colitis by feeding 5% dextran sulfate in drinking water.¶Treatment: Colitic mice were treated with placebo (3% starch suspension, 0.1 ml. p.o., bid) or BAY y 1015 at 8 or 24 mg/kg, p.o., bid or olsalazine, 150 mg/kg/day, p.o.¶Methods: Efficacy was determined by measuring daily disease activity index (DAI), quantitative histological scores, qualitative histology and measurement of tissue myeloperoxidase (MPO) and leukotriene B₄ (LTB₄) levels.¶Results: BAY y 1015 was significantly more effective in improving the qualitative histology, inhibiting the DAI, inflammation scores (37–79%), crypt scores (28–71%), MPO (49–57%) and LTB₄ levels (56–63%) compared to placebo treatment at all levels of colitis. The two doses of BAY y 1015 were equipotent in decreasing TLB₄ levels. BAY y 1015 was significantly better than olsalazine in two of the three protocols used in this study. In the advanced disease level both doses of BAY y 1015 were equipotent in inhibiting crypt and (28–32%) inflammation scores (34–36%), LTB4 (34–56%) and MPO 41–49%) compared to olsalazine.¶Conclusion: This study suggests the possibility of investigating the use of this compound for the treatment of human inflammatory bowel diseases.