Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma

Shamsah Kazani, Jonathan Sadeh, Sreedhar Bunga, Michael E Wechsler, Elliot Israel, Shamsah Kazani, Jonathan Sadeh, Sreedhar Bunga, Michael E Wechsler, Elliot Israel

Abstract

Background: In asthma, cysteinyl leukotrienes (CysLTs) play varying roles in the bronchomotor response to multiple provocative stimuli. The contribution of CysLTs on the airway's response to hypertonic saline (HS) inhalation in asthma is unknown. Whether polymorphisms in the leukotriene biosynthetic pathway affect the contribution of CysLTs to this response is also unknown.

Methods: In a prospective, randomized, double-blind, placebo-controlled cross-over study, mild and moderate asymptomatic asthmatics underwent inhaled 3% HS challenge by doubling the duration of nebulization (0.5, 1, 2, 4, and 8 min) 2 h after one dose of montelukast (a CysLT receptor 1 [CysLTR1] antagonist) or placebo, and after three-week courses. We examined the effect of the leukotriene C(4) synthase (LTC(4)S) polymorphism (A-444C) on the efficacy of montelukast against HS inhalation in an exploratory manner.

Results: In 37 subjects, 2 h after administration of montelukast, the mean provocative dose of HS required to cause a 20% drop in FEV(1) (HS-PD(20)) increased by 59% (9.17 ml after placebo vs. 14.55 ml after montelukast, p=0.0154). Three weeks of cysLTR1 antagonism increased the HS-PD(20) by 84% (10.97 vs. 20.21 ml, p=0.0002). Three weeks of CysLTR1 antagonism appeared to produce greater effects on blocking bronchial hyper-responsiveness (2 h vs. three-week HS-PD(20) values 14.55 vs. 20.21 ml respectively, p=0.0898). We did not observe an effect of the LTC(4)S polymorphism on the response to CysLTR1 antagonism in this cohort.

Conclusions: A significant proportion of HS-induced bronchoconstriction is mediated by release of leukotrienes as evidenced by substantial acute inhibition with a CysLTR1 antagonist. There was a trend toward greater inhibition of bronchial responsiveness with three weeks of therapy as opposed to acute CysLTR1 antagonism. Clinicaltrials.gov registration number NCT00116324.

Copyright © 2010 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Study design
Figure 1. Study design
M = montelukast, P = placebo, HS = hypertonic saline challenge
Figure 2. Subject enrollment
Figure 2. Subject enrollment
Figure 3
Figure 3
Figure 3a Difference in HS-PD20 two hours after a single dose of study medications. Horizontal bars represent geometric means, 9.17 ml (95% CI 6.65 to 12.65 ml) and 14.55 ml (9.87 to 21.46 ml) respectively. N = 37 Figure 3b. Difference in HS-PD20 after three week courses of study medications. Horizontal bars represent geometric means, 10.97 ml (95% CI 7.36 to 16.35 ml) and 20.01 ml (13.15 to 31.06 ml) respectively. N = 35
Figure 3
Figure 3
Figure 3a Difference in HS-PD20 two hours after a single dose of study medications. Horizontal bars represent geometric means, 9.17 ml (95% CI 6.65 to 12.65 ml) and 14.55 ml (9.87 to 21.46 ml) respectively. N = 37 Figure 3b. Difference in HS-PD20 after three week courses of study medications. Horizontal bars represent geometric means, 10.97 ml (95% CI 7.36 to 16.35 ml) and 20.01 ml (13.15 to 31.06 ml) respectively. N = 35

Source: PubMed

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