A SINGLE-DOSE OF ZAFIRLUKAST REDUCES LTD4-INDUCED BRONCHOCONSTRICTIONIN PATIENTS ON MAINTENANCE INHALED CORTICOSTEROID-THERAPY

Background: Previous studies demonstrated that leukotriene receptor an tagonists (LTRAs) are effective in reducing asthma symptoms and the ai rway response to inhaled leukotriene D-4 (LTD4) in asthmatic patients receiving inhaled beta(2)-agonists alone. Objective: To investigate th e efficacy of a single 20-mg dose of the oral LTRA zafirlukast in redu cing the airway response to inhaled LTD4 in mild-to-moderate asthmatic patients receiving inhaled beta(2)-agonists and inhaled corticosteroi ds (ICS). Methods: In this double-blind, crossover trial, six patients on maintenance ICS (median dose 800 mu g/day; range 336 to 1600 mu g/ day), who had a 20% decrease in FEV1 following inhalation of a maximal concentration of 50 mu g/mL LTD4, received either zafirlukast or plac ebo on each of two study days. Two hours after dosing, patients underw ent bronchoprovocation challenges with increasing concentrations of LT D4 (0.1 to 1000 mu g/mL) at 10-minute intervals until either the patie nt's FEV1 decreased by 20% or the maximum concentration of LTD4 was gi ven. 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 dete rmine plasma concentrations of zafirlukast. Results: Compared with pla cebo, zafirlukast produced a 1.82-unit increase in logPC(20)FEV(1) and a 1.88-unit increase in logPD(20)FEV(1), representing a 66-fold highe r concentration and a 76-fold higher dose of LTD4, respectively, to pr oduce a 20% decrease in FEV1 (P <.001). Mean time to recovery after ch allenge was 36.7 versus 51.7 minutes when patients received zafirlukas t and placebo, respectively. No correlation between clinical effects a nd plasma drug levels was observed. Conclusions: This trial demonstrat ed that asthmatic patients on maintenance ICS can respond to exogenous ly administered LTD4 and that zafirlukast reduced the airway response to LTD4 in these patients.