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 methyl-oxy)-2H-indol-2yl)-2,2-dimethyl -propanoate) exerts its effect by binding to the 5-lipoxygenase activa ting 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 biosynt hesis 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 i n a double-blind, placebo-controlled parallel-design study before and after oral administration of a 250 mg dose of MK-0591 or placebo. Resu lts: 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 inh ibition 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 v ivo 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 ev ents were observed. Conclusion: These findings show that a single oral 250 mg dose of MK-0591 results in nearly complete blockade of systemi c leukotriene production and LTB(4) formation in the target tissue of inflammation (the rectum). Controlled multiple-dose trials to assess t he clinical efficacy of this novel 5-lipoxygenase-activating protein i nhibitor seem to be worthwhile.