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 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.
Lazarus
S C
SC
Cardiovascular Research Institute, University of California, San Francisco, California 94143-0111, USA.
Wong
H H
HH
Watts
M J
MJ
Boushey
H A
HA
Lavins
B J
BJ
Minkwitz
M C
MC
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*
D018927:Anti-Asthmatic Agents; D007211:Indoles; D020024:Leukotriene Antagonists; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds; D013458:Sulfur Dioxide; C062735:zafirlukast