ANTIINFLAMMATORY ACTIVITY OF THE LEUKOTRIENE B-4 RECEPTOR ANTAGONIST,SC-41930, IN COLITIC COTTON-TOP TAMARINS

Cotton-top tamarins(CTTs) with histologically confirmed persistent and active colitis were given the leukotriene B-4 (LTB(4)) receptor antag onist, SC-41930, (10 mg/kg BW, by gavage b.i.d.) for eight weeks. Anti inflammatory activity was evaluated by colonic biopsy, stool consisten cy and the level of the lipid mediators LTB, and prostaglandin E(2) (P GE(2)) in rectal dialysates. Stool consistency did not improve with tr eatment but did not worsen. Blood chemistry (ALT, AST, LDH) and hemato logical parameters neither showed any untoward effects of SC-41930 tre atment nor was there any effect on body weight. In rectal dialysate LT B(4) levels were significantly reduced from pretreatment level of 4.87 +/- 1.46 ng/ml to 1.07 +/- 0.67 and 2.45 +/- 0.13 ng/ml at 4 and 8 we eks, respectively, and higher prostaglandin E(2) (PGE(2)) over time. H istologically, 5/7 improved, 1/7 remained the same and 1/7 worsened. O ral SC-41930 treatment was safe and associated with an anti-colitic ef fect. The reduced LTB(4) levels (affecting granulocyte degranulation a nd recruitment into tissues) and increased PGE(2) (perhaps exerting a mucosal protective effect) may, in part explain the observed efficacy of this compound in active tamarin colitis. Use of the CTT model could provide insight into the inflammatory mediator contribution to idiopa thic colitis and serve as a useful bridge between preclinical pharmaco logy and the assessment of these compounds in the medical management o f human inflammatory bowel disease.