THE EFFECT OF AEROSOLIZED SK-AND-F-104353-Z2 ON THE BRONCHOCONSTRICTOR EFFECT OF LEUKOTRIENE-D4 IN ASTHMATICS

Leukotriene D4 (LTD4) is a potent bronchoconstrictor and vasoactive mediator that has been implicated in the pathogenesis of bronchial asthma. We have studied the effect of SK&F 104353-Z2, a specific LTD4 antagonist, on LTD4-induced bronchoconstriction in asthmatics. A total of 12 mild asthmatics (mean baseline FEV1 ± SEM: 85.9% ± 2.6) received on 2 separate days, double-blind and cross-over, 800 μg SK&F 104353-Z2 or placebo via aerosol. After 30 min, doubling concentrations of LTD4 (0.078 to 20.1 μM in the first 4 patients and up 80.4 μM in the other patients) were inhaled with intervals of 30 min. Specific airways conductance (sGaw) and forced expiratory volume in 1 s (FEV1) were measured. On the placebo-day LTD4 inhalation caused a concentration dependent bronchoconstriction. The effect of SK&F 104353-Z2 on baseline sGaw and FEV1 could be evaluated in 10 patients. After inhalation of SK&F 104353-Z2 a small, but significant increase, in sGaw (0.107 ± 0.013 to 0.132 ± 0.011 cm H2O-1s-1) and FEV1 (3.39 ±0.23 to 3.56 ±0.25 liter) was observed. The effect of SK&F 104353-Z2 on the dose-response curve for LTD4 was evaluated in the six patients who inhaled concentrations of LTD4 up to 80 μM. On the active treatment day, the dose-response curve for LTD4 was significantly shifted to the right. Geometric mean PC20 LTD4 (FEV1) (μM) was 4.4 (range 1.5-11.6) on the placebo and 54.1 (2.8-81) on the active treatment day (p < 0.05). Geometric mean PC35 LTD4 (sGaw) (μM) was 2.75 (0.2-80.4) on the placebo and 22.7 (0.1-81.0) on the active treatment day (NS). We conclude that inhaled SK&F 104353-Z2 is able to antagonize the bronchoconstrictor effect of inhaled LTD4 in asthmatics. © 1991.