A single dose of zafirlukast reduces LTD4-induced bronchoconstriction in patients on maintenance inhaled corticosteroid therapy.
BACKGROUND
Previous studies demonstrated that leukotriene receptor antagonists (LTRAs) are effective in reducing asthma symptoms and the airway response to inhaled leukotriene D4 (LTD4) in asthmatic patients receiving inhaled beta2-agonists alone.


OBJECTIVE
To investigate the efficacy of a single 20-mg dose of the oral LTRA zafirlukast in reducing the airway response to inhaled LTD4 in mild-to-moderate asthmatic patients receiving inhaled beta2-agonists and inhaled corticosteroids (ICS).


METHODS
In this double-blind, crossover trial, six patients on maintenance ICS (median dose 800 microg/day; range 336 to 1600 microg/day), who had a 20% decrease in FEV1 following inhalation of a maximal concentration of 50 microg/mL LTD4, received either zafirlukast or placebo on each of two study days. Two hours after dosing, patients underwent bronchoprovocation challenges with increasing concentrations of LTD4 (0.1 to 1000 microg/mL) at 10-minute intervals until either the patient's FEV1 decreased by 20% or the maximum concentration of LTD4 was given. Spirometric tests were done just before (baseline) and throughout the challenge phase until the patient's FEV1 returned to within 5% of baseline. Blood samples were collected two hours after dosing to determine plasma concentrations of zafirlukast.


RESULTS
Compared with placebo, zafirlukast produced a 1.82-unit increase in logPC20FEV1 and a 1.88-unit increase in logPD20FEV1, representing a 66-fold higher concentration and a 76-fold higher dose of LTD4, respectively, to produce a 20% decrease in FEV1 (P < .001). Mean time to recovery after challenge was 36.7 versus 51.7 minutes when patients received zafirlukast and placebo, respectively. No correlation between clinical effects and plasma drug levels was observed.


CONCLUSIONS
This trial demonstrated that asthmatic patients on maintenance ICS can respond to exogenously administered LTD4 and that zafirlukast reduced the airway response to LTD4 in these patients.
Northwestern University, Chicago, Illinois, USA.
L J
LJ
Smith
L A
LA
Hanby
B J
BJ
Lavins
S G
SG
Simonson
D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007211:Indoles; D017998:Leukotriene D4 / Q000494:pharmacology*; D008297:Male; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000097:blood / Q000627:therapeutic use*
D000305:Adrenal Cortex Hormones; D018927:Anti-Asthmatic Agents; D007211:Indoles; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds; D017998:Leukotriene D4; C062735:zafirlukast