Effects of Montelukast on Surrogate Inflammatory Markers in Corticosteroid-treated Patients with Asthma

Abstract

We evaluated whether montelukast conferred additive effects in patients with asthma receiving fluticasone/salmeterol (FP/SM) combination and FP alone. Twenty-two patients with mild to moderate asthma completed a double-blind, placebo-controlled study. After a 2-week run-in using FP 250 microg/SM 50 microg 1 puff twice daily, patients entered a randomized crossover period to receive additional montelukast 10 mg daily or placebo for 3 weeks each. For the first 2 weeks, they received FP/SM 1 puff BID, and then they received FP 250 microg 1 puff BID for the 3rd week. The primary outcome was adenosine monophosphate challenge threshold and recovery time; secondary outcomes included surrogate inflammatory markers and lung function. Compared with FP/SM run-in, adding montelukast to FP/SM was better (p < 0.05) than placebo for inflammatory markers but not for lung function. For adenosine monophosphate threshold, recovery, exhaled nitric oxide, and blood eosinophils, there were 1.4 (95% confidence interval, 1.1-1.8) geometric mean fold, 10 minutes (3-17 minutes), 2.1 parts per billion (0.2-3.9 parts per billion), and 88 (34-172) x 10(6)/L differences, respectively. The combination of FP plus montelukast was superior to FP/SM for inflammatory markers but was inferior for lung function. Thus, in patients taking FP/SM or FP, montelukast conferred complimentary effects on surrogate inflammatory markers, which were dissociated from lung function. Further studies are required to evaluate whether these effects of montelukast translate into clinical benefits.

Montelukast improves regional air-trapping due to small airways obstruction in asthma

“…The 6.9¡12.4% pred FEV1 response noted after montelukast compared with placebo is comparable to findings from other studies, which showed improvements of ,7% pred from baseline [28][29][30]. The 6.5% pred improvement in FEF25-75% did not reach statistical significance, but agrees well with an 8% pred response seen in a prior study [28].…”

Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma

“…This, therefore, explains why there are additive effects of LTRAs to inhaled corticosteroids. In another study [26] in corticosteroid treated asthmatics, there was an additive effect on BHR to AMP plus blood eosinophils and exhaled NO. In other words, there is a nonsteroidal mediated component to BHR which can be attenuated 20 for LTRA minus placebo divided by log 10 2 (i.e.…”

Failure of montelukast to reduce sputum eosinophilia in high-dose corticosteroid-dependent asthma

“…The current authors do not believe that this is a weakness of the study, since montelukast binds reversibly to the leukotriene receptor, reaches steady state by day 2 and has a plasma terminal halflife of 5.3 h (up to 6.6 h in the elderly); this suggests that its clinical effects last, at most, for 33 h (five half-lives) [24]. Furthermore, several previous crossover trials examining the efficacy of adding montelukast to placebo in subjects on corticosteroids have omitted a washout period without evidence of carry-over interactions [25][26][27]. For example, a two-period, 16-week crossover trial, with a 2-week run-in phase, comparing the effect of adding montelukast or placebo to subjects with mild asthma already on fluticasone proprionate, found similar insignificant reductions in inflammatory cells on bronchial biopsy [27].…”