NO in Exhaled Air of Asthmatic Children Is Reduced by the Leukotriene Receptor Antagonist Montelukast

Abstract

Nitric oxide in exhaled air (FENO) is increased in asthmatic children, probably reflecting aspects of airway inflammation. We have studied the effect of the leukotriene receptor antagonist (LTRA) montelukast on FENO with a view to elucidate potential anti-inflammatory properties of LTRAs. Twenty-six asthmatic children 6 to 15 yr of age completed a double-blind crossover trial of 2 wk of treatment with 5 mg montelukast once daily versus placebo. FENO was measured during single-breath exhalation at a constant flow rate of 0.1 to 0.13 L/s against a resistance of 10 kPa/L/s. Eleven children were receiving maintenance treatment with inhaled steroids during the study (mean daily dose, 273 microgram), whereas the other 15 used only inhaled beta(2)-agonists as required. The within-subject coefficient of variation of FENO over a 2-wk interval for the 26 children was 38%. FENO was significantly reduced by 20% after the 2-wk treatment with montelukast as compared with placebo as well as compared with baseline. This effect occurred rapidly with a 15% fall in FENO within 2 d. The effect of montelukast on FENO was independent of concurrent steroid treatment. The effect on FENO is probably not caused by bronchodilatation since FENO increased significantly after inhalation of terbutaline. In conclusion, FENO in asthmatic children was significantly decreased from montelukast, which corroborates anti- inflammatory properties of LTRA.

Exhaled NO: Determinants and Clinical Application in Children With Allergic Airway Disease

“…15,16 Medications, including inhaled or systemic corticosteroids or leukotriene receptor antagonists, need to be considered as they significantly reduce FeNO levels. 17,18 Serial measurements should be performed at approximately the same time of the day since circadian rhythms may affect FeNO levels. 5 Additionally, FeNO should be measured prior to spirometry or bronchial challenge tests.…”

“…51 Additionally, FeNO levels have been shown to decrease in response to asthma treatments, including systemic steroids, 17 ICS, 52 and montelukast. 18 Despite the evidence that FeNO or changes in FeNO can predict asthma exacerbation, there are conflicting results showing a negative correlation between FeNO levels and exacerbation rates/prediction of future asthma risk. 53 For example, some patients have persistently high FeNO levels despite treatment.…”

Montelukast exerts no acute direct effect on NO synthases

“…Taken together these assays clearly gave no evidence of any direct inhibitory effect of montelukast on NOS isoenzymes within the concentration range from 10 -7 to 10 -4 M, far exceeding that achieved during drug therapy (39). Therefore, alternative explanantions for the decreased NO levels measured in expired air from asthmatic subjects after treatment with montelukast should be considered (18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

“…Since no acute inhibitory effect on NO synthesis, neither directly on the three NOS isoenzymes, nor a suppression of the expression of iNOS was found, alternative explanantions for the decreased NO levels measured in expired air from asthmatic subjects after treatment with montelukast must be considered (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). They may be explained by changes in quantities or sites of NO generation, binding or more distal processes.…”

“…A number of studies in asthmatic subjects treated with montelukast have shown that such LTD 4 receptor blockade is associated with lower levels of exhaled NO (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). In a murine allergic asthma model in which inflammation was induced by injection of ovalbumin, no evidence for a change in inducible NOS (iNOS) mRNA levels following montelukast treatment was observed (28).…”