Effect of montelukast on time‐course of exhaled nitric oxide in asthma: Influence of LTC 4 synthase A −444 C polymorphism

Leukotrienes (LT) mediate inflammation in asthma. The fraction of exhaled nitric oxide (F E NO ) is thought to be a sensitive and reproducible method for assessing airway inflammation in asthmatics and the anti‐inflammatory effects of drugs. A number of factors are known to contribute to intrapatient variation in F E NO which can confound interpretation. The aims of this study were to characterize the time‐course of F E NO , determine the effect of montelukast on the time‐course of F E NO , and evaluate the influence of the LTC 4 synthase A −444 C polymorphism on montelukast‐evoked changes in F E NO . Following a 2‐week run‐in, 7 males and 5 females with asthma, 10–16 years old, received 5 or 10 mg of montelukast or an identical placebo at bedtime for 7 days in double‐blind, crossover fashion, followed by a 7‐day washout. F E NO was quantified every 30 min for 3 or 6 hr at baseline and on days 1, 2, 3, and 7 of treatment. A time‐averaged value for F E NO was calculated (F E NO *), and % changes in F E NO * relative to baseline vs. time following placebo and montelukast were compared. The genotype of the A −444 C polymorphism was determined by PCR and RFLP. F E NO varied markedly as a function of time in each patient. Time‐averaged values of F E NO (F E NO *) during placebo and montelukast treatment were similar. Montelukast significantly reduced the slope of the % change in F E NO * vs. time curve in heterozygotes (n = 4), but not in A/A homozygotes (n = 8). These data suggest that heterozygotes respond better to montelukast compared to A/A homozygotes, at least with respect to changes in F E NO . We conclude that assessment of inflammation or the anti‐inflammatory effects of drugs in asthma based on single determinations of F E NO can be misleading. We further conclude that the A −444 C polymorphism in the LTC 4 synthase gene probably contributes to interpatient variability in montelukast‐evoked changes in F E NO * and warrants further study. Pediatr Pulmonol. 2003; 36:413–420. © 2003 Wiley‐Liss, Inc.