title: The leukotriene receptor antagonist zafirlukast inhibits sulfur dioxide-induced bronchoconstriction in patients with asthma.
abstract: 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 < or = 70% of predicted, and a positive response to inhaled SO2 (an 8-unit increase in specific airway resistance on inhaling an SO2 concentration of < or = 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 S02-induced bronchoconstriction involves release of leukotrienes and that treatment with zafirlukast attenuates the bronchoconstrictor response.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, California 94143-0111, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Lazarus
authors.forename: H H
authors.initials: HH
authors.lastname: Wong
authors.forename: M J
authors.initials: MJ
authors.lastname: Watts
authors.forename: H A
authors.initials: HA
authors.lastname: Boushey
authors.forename: B J
authors.initials: BJ
authors.lastname: Lavins
authors.forename: M C
authors.initials: MC
authors.lastname: Minkwitz
mesh_terms: D000328:Adult; D000403:Airway Resistance; D018927:Anti-Asthmatic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001249:Asthma / Q000503:physiopathology*; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007211:Indoles; D020024:Leukotriene Antagonists; D008297:Male; D048448:Phenylcarbamates; D013449:Sulfonamides; D013458:Sulfur Dioxide / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D018927:Anti-Asthmatic Agents; D007211:Indoles; D020024:Leukotriene Antagonists; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds; D013458:Sulfur Dioxide; C062735:zafirlukast