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 antagonist, SC-41930, (10 mg/kg BW, by gavage b.i.d.) for eight weeks. Antiinflammatory activity was evaluated by colonic biopsy, stool consistency and the level of the lipid mediators LTB, and prostaglandin E(2) (PGE(2)) in rectal dialysates. Stool consistency did not improve with treatment but did not worsen. Blood chemistry (ALT, AST, LDH) and hematological parameters neither showed any untoward effects of SC-41930 treatment nor was there any effect on body weight. In rectal dialysate LTB(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 weeks, respectively, and higher prostaglandin E(2) (PGE(2)) over time. Histologically, 5/7 improved, 1/7 remained the same and 1/7 worsened. Oral SC-41930 treatment was safe and associated with an anti-colitic effect. The reduced LTB(4) levels (affecting granulocyte degranulation and 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 idiopathic colitis and serve as a useful bridge between preclinical pharmacology and the assessment of these compounds in the medical management of human inflammatory bowel disease.