Am. J. Respir. Crit. Care Med., Volume 156, Number 6, December 1997, 1725-1730

The Leukotriene Receptor Antagonist Zafirlukast Inhibits Sulfur Dioxide-induced Bronchoconstriction in Patients with Asthma

STEPHEN C. LAZARUS, HOFER H. WONG, MICHAEL J. WATTS, HOMER A. BOUSHEY, BERNARD J. LAVINS, and MARGARET C. MINKWITZ

Cardiovascular Research Institute, University of California, San Francisco, California, and Zeneca Pharmaceuticals, Wilmington, Delaware

Inhalation of sulfur dioxide (SO₂) causes bronchoconstriction in most people with asthma. To examine the role of leukotrienes in this response, 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 12 subjects with mild-to-moderate asthma. Subjects had bronchial hyperresponsiveness, an FEV₁  70% of predicted, and a positive response to inhaled SO₂ (an 8-unit increase in specific airway resistance on inhaling an SO₂ concentration of  4 ppm (PC₈SRaw). Subjects were treated with zafirlukast (20 mg) or placebo on two treatment days 5 to 14 d apart. Two and 10 hours after treatment, subjects inhaled SO₂ (0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 ppm) during eucapnic hyperventilation at 20 L/min. PC₈SRaw was determined after each challenge. Blood samples were collected to assess zafirlukast plasma concentrations versus effect. PC₈SRaw was significantly 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 zafirlukast (2.7 versus 1.9 ppm; p = 0.09). An association was found between zafirlukast plasma concentrations and increases in PC₈SRaw 10 h after treatment (p = 0.001). The safety profile of zafirlukast was not clinically different from placebo. A single 20-mg dose of zafirlukast attenuated SO₂-induced bronchoconstriction. We conclude that SO₂-induced bronchoconstriction involves release of leukotrienes and that treatment with zafirlukast attenuates the bronchoconstrictor response.

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