THE LEUKOTRIENE RECEPTOR ANTAGONIST ZAFIRLUKAST INHIBITS SULFUR DIOXIDE-INDUCED BRONCHOCONSTRICTION IN PATIENTS WITH ASTHMA

Inhalation of sulfur dioxide (SO2) causes bronchoconstriction in most people with asthma. To examine the role of leukotrienes in this respon se, the antagonism of SO2-induced bronchoconstriction by a single oral dose of the leukotriene receptor antagonist zafirlukast was assessed in a double-blind, placebo-controlled, two-period crossover trial in 1 2 subjects with mild-to-moderate asthma. Subjects had bronchial hyperr esponsiveness, an FEV1 greater than or equal to 70% of predicted, and a positive response to inhaled SO2 (an 8-unit increase in specific air way resistance on inhaling an SO2 concentration of less than or equal to 4 ppm (PC(8)SRaw). Subjects were treated with zafirlukast (20 mg) o r placebo on two treatment days 5 to 14 d apart. Two and 10 hours afte r treatment, subjects inhaled SO2 (0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 p pm) during eucapnic hyperventilation at 20 L/min. PC(8)SRaw was determ ined after each challenge. Blood samples were collected to assess zafi rlukast plasma concentrations versus effect. PC(8)SRaw was significant ly higher 2 h after zafirlukast compared with placebo (3.1 versus 1.5 ppm; p = 0.02) and remained higher 10 h after treatment with zafirluka st (2.7 versus 1.9 ppm; p = 0.09). An association was found between za firlukast plasma concentrations and increases in PC(8)SRaw 10 h after treatment (p = 0.001). The safety profile of zafirlukast was not clini cally different from placebo. A single 20-mg dose of zafirlukast atten uated SO2-induced bronchoconstriction. We conclude that SO2-induced br onchoconstriction involves release of leukotrienes and that treatment with zafirlukast attenuates the bronchoconstrictor response.