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


METHODS
Outbred female mice weighing approximately 25 grams were used to produce acute or chronic colitis by feeding 5% dextran sulfate in drinking water.


METHODS
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.


CONCLUSIONS
This study suggests the possibility of investigating the use of this compound for the treatment of human inflammatory bowel diseases.
Murthy
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Krancer Center for IBD Research, Division of Gastroenterology and Hepatology, Allegheny University of the Health Sciences, Philadelphia, PA 19102-1192, USA. murthys@allegheny.edu
Murthy
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NS
Coppola
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Wood
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D000818:Animals; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D007975:Leukotriene B4 / Q000032:analysis; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D051379:Mice; D009195:Peroxidase / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use*
C099016:Bay y 1015; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; D007975:Leukotriene B4; D016264:Dextran Sulfate; D009195:Peroxidase