BLOCKADE OF LEUKOTRIENE PRODUCTION BY A SINGLE ORAL DOSE OF MK-0591 IN ACTIVE ULCERATIVE-COLITIS

Background: 5-Lipoxygenase products of arachidonic acid metabolism are thought to play a central role in the secondary amplification of the inflammatory response in a number of human inflammatory diseases, such as ulcerative colitis. MK-0591 (3-(1((4-chlorophenyl)methyl)-3((1,1-dimethyl-ethyl)thio-5(guinolin-2ylmethyl-oxy)-2H-indol-2yl)-2,2-dimethyl-propanoate) exerts its effect by binding to the 5-lipoxygenase activating protein, thereby inhibiting the translocation and activation of 5-lipoxygenase. Methods: Concentrations of leukotriene B-4 (LTB(4)) and prostaglandin E(2) (PGE(2)) in rectal dialysis fluid, ex vivo biosynthesis of LTB(4) in whole blood, and urinary excretion of leukotriene E(4) (LTE(4)) from 16 patients with mild to moderately active distally located ulcerative colitis were measured by use of radioimmunoassays in a double-blind, placebo-controlled parallel-design study before and after oral administration of a 250 mg dose of MK-0591 or placebo. Results: The mean LTB, concentration in rectal dialysis fluid was lowered after MK-0591 by >90% (P < 0.05) from 4 to 8 hours, with a maximum inhibition of 97.5% +/- 3.4% (mean +/- SD) at 20 to 24 hours after dosing, whereas PGE(2) was unchanged. In whole blood, MK-0591 decreased ex vivo biosynthesis of LTB(4) (p < 0.01), with a maximum inhibition of 96.4% +/- 2.1% at 4 hours after dosing. Urinary excretion of LTE(4) was reduced by more than 85% (p < 0.001) from 4 to 48 hours. No adverse events were observed. Conclusion: These findings show that a single oral 250 mg dose of MK-0591 results in nearly complete blockade of systemic leukotriene production and LTB(4) formation in the target tissue of inflammation (the rectum). Controlled multiple-dose trials to assess the clinical efficacy of this novel 5-lipoxygenase-activating protein inhibitor seem to be worthwhile.