Dose-related antagonism of leukotriene D4-induced bronchoconstriction by p.o. administration of LY-171883 in nonasthmatic subjects

Leukotriene D4 (LTD4) has been suggested as a proinflammatory mediator in asthma. We have investigated the inhibitory activity of the p.o. LTD4 antagonist LY-171883 (1-[2-hydroxy-3-propyl]-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl]et hanone) on LTD4-induced bronchoconstriction in nonasthmatic subjects, in a double-blind, placebo controlled, randomized, cross-over study. Twelve subjects, mean age 26.3 +/- 1.7 years, participated. On 4 separate days, base-line measurements of forced expiratory volume in 1 second (FEV1) and maximum flow at 70% of vital capacity below total lung capacity (Vp30) were performed, after which subjects ingested either 50 or 200 or 400 mg of LY-171883, and then undertook a dose-response study with inhaled LTD4. Measurements of FEV1 and Vp30 were made at intervals for 8 min after inhalation of each dose of LTD4, and increasing doses administered until FEV1 had fallen by greater than 20% or the maximum cumulative dose of LTD4 (88.2 nmol) had been given. Cumulative dose-response curves were constructed on a logarithmic scale, and the provocation doses of LTD4 producing a 12% fall in FEV1 (PD12 FEV1) and a 30% fall in Vp30 (PD30Vp30) after placebo determined by linear interpolation to be 5.5 (0.9-176.4) and 1.2 (0.1-6.2) nmol, respectively. Following the 50-, 200- and 400-mg doses of LY-171883, the geometric mean PD12 FEV1 values were 7.0 (NS), 10.5 (NS) and 25.3 (P less than .01) nmol, respectively, whereas corresponding values for PD30Vp30 were 1.7 (NS), 2.6 (NS) and 6.1 (P less than .01) nmol.(ABSTRACT TRUNCATED AT 250 WORDS)