Introduction Previous research has demonstrated the role that leukotrienes play in the processes of bronchial hyperactivity and inflammation. Since patients with CF display increased levels of leukotrienes in their lungs, reducing the production of leukotrienes should provide CF patients with some symptomatic relief through a decrease in bronchial hyperactivity and inflammation. Our study uses zileuton, a 5-lipooxygenase inhibitor, to block the formation of leukotrienes from arachidonic acid. It has been shown that zileuton is effective in reducing bronchial hyperactivity and inflammation in asthma patients, but there have been no studies measuring the effect of zileuton on CF patients. We hypothesize that upon treatment of zileuton, patients will show a decrease in sputum and urine leukotriene levels along with symptomatic and clinical improvement.
Methods A double-blinded, placebo-controlled, cross-over study was performed on 10 CF patients. For 4 weeks either placebo or zileuton (Zyflo) 600 mg qid was taken with a 2 week wash-out period between trials. Before and after each trial a methacholine challenge was performed and sputum and urine samples obtained and frozen before levels of leukotriene B4 (LTB4) and cysteinyl leukotrienes LTC4 and LTD4 (CLs) were measured by ELISA (R&D).
Results There was no difference in the PC20 during the zileuton-treated period although a subpopulation of patients (n=4) did show a significantly decreased value (20.0 6 3.3 to 13.8 6 2.9, p≤0.01) compared with no effect with placebo (18.3 6 2.1 to 26.6 6 10.0). In all patients, there were significant decreases in both LTB4 (7888 6 2739 [mean+sem] to 3475 6 1522 pg/mL, p≤0.01) and CLs concentrations (1408+177 to 699+134 pg/mL, p≤.005). However, there was no difference in the mean percentage of decrease between placebo (63.6 6 29.6%) and drug (50.1 6 21.1%) groups.
Conclusions Despite the decrease in leukotriene levels in the sputum, there was no change in bronchial hyperactivity in CF patients. Indeed, there was an increase in hyperactivity in some patients with zileuton. This would indicate that leukotrienes do not play a major role in the bronchial hyperactivity in patients with CF. Whether there is a clinical effect is not known and was not directly measured in this study. However, since zileuton only has marginal effectiveness in some asthma patients it may only be marginally efficacious in CF patients.