Effect of montelukast on time-course of exhaled nitric oxide in asthma: influence of LTC4 synthase A(-444)C polymorphism.
Leukotrienes (LT) mediate inflammation in asthma. The fraction of exhaled nitric oxide (FE(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 FE(NO) which can confound interpretation. The aims of this study were to characterize the time-course of FE(NO), determine the effect of montelukast on the time-course of FE(NO), and evaluate the influence of the LTC(4) synthase A(-444)C polymorphism on montelukast-evoked changes in FE(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. FE(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 FE(NO) was calculated (FE(NO)*), and % changes in FE(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. FE(NO) varied markedly as a function of time in each patient. Time-averaged values of FE(NO) (FE(NO)*) during placebo and montelukast treatment were similar. Montelukast significantly reduced the slope of the % change in FE(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 FE(NO). We conclude that assessment of inflammation or the anti-inflammatory effects of drugs in asthma based on single determinations of FE(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 FE(NO)* and warrants further study.
Whelan
Glenn J
GJ
Centers for Pediatric Pharmacology Research and Pharmacogenetics, Nemours Children's Clinic, Jacksonville, Florida 32207, USA.
Blake
Kathryn
K
Kissoon
Niranjan
N
Duckworth
Laurie J
LJ
Wang
Jainwei
J
Sylvester
James E
JE
Lima
John J
JJ
D000085:Acetates / Q000494:pharmacology*; D000293:Adolescent; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology*; D001944:Breath Tests; D002648:Child; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004311:Double-Blind Method; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000032:analysis*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011804:Quinolines / Q000494:pharmacology*; D013147:Spirometry; D013440:Sulfides; D013997:Time Factors
D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D011804:Quinolines; D013440:Sulfides; D009569:Nitric Oxide; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; C093875:montelukast