Fexofenadine Decreases Sensitivity to and Montelukast Improves Recovery from Inhaled Mannitol

Abstract

We studied, separately, the effects of the histamine antagonist, fexofenadine hydrochloride, and the leukotriene antagonist, montelukast sodium, and their placebos on airway sensitivity to and recovery from inhaled mannitol in subjects with asthma. Two 180-mg doses of fexofenadine were taken over 14 h, and three 10-mg doses of montelukast over 36 h, with the last dose 5 h before challenge. Fexofenadine reduced sensitivity to mannitol and the PD(15) was (mean [95% confidence interval] 138 [95, 201]) mg versus placebo (51 [25, 106] mg) (p < 0.001). The final percent reduction in FEV(1) with fexofenadine was 20.8 +/- 5.4% and not different from placebo (20.1 +/- 5.3%) (p = 0.7); however, recovery was slower with fexofenadine compared with placebo (p < 0.001). By contrast, montelukast had no effect on sensitivity to mannitol and the PD(15) was 71 [36, 144] mg versus placebo (87 [51, 148] mg (p = 0.35). The total dose of mannitol delivered and the final percent reduction in FEV(1) with montelukast were 171 +/- 142 mg and 21 +/- 4% and for placebo were 182 +/- 144 mg and 20 +/- 5% (p = 0.35, p = 0.59, respectively). However, recovery of FEV(1) to baseline was faster with montelukast, with the area under the percent reduction FEV(1)-versus-time curve reduced (220 +/- 121% change.min) compared with placebo (513 +/- 182% change.min) (p < 0.001). We conclude that whereas histamine is important for the initial airway response, leukotrienes are important in sustaining the airway response to inhaled mannitol.

Evidence of mast cell activation and leukotriene release after mannitol inhalation

“…The finding is consistent with the previous demonstration that the LT antagonist montelukast inhibited the airway response to mannitol, as demonstrated by a faster recovery of the lung function to baseline after challenge [14]. Moreover, the observations add to the similarities with EIB, as it is well established that recovery of lung function to baseline after EIB is also much faster with antagonists of the cysteinyl-LT [2,5,27,28].…”

“…Mannitol is known to induce the release of histamine from lung mast cells in vitro [12]. Furthermore, the histamine antagonist, fexofenadine, is effective in reducing airway sensitivity to mannitol [14]. This suggests that preformed histamine is involved in the response to mannitol and its source is likely to be mast cells.…”

“…It is known that mediator secretion from mast cells, basophils and human lung fragments is triggered by increased osmolarity [11,12] and this release is inhibited with nedocromil sodium [13]. As with EIB, the airway response to mannitol may be modified by specific mediator antagonists [14]. However, there is no direct evidence for mediator release from mast cells or other cells occurring in response to inhaled mannitol.…”

“…To this end the urinary levels of the PGD 2 metabolite 9a,11b-PGF 2 were measured before and after a mannitol challenge in atopic asthmatics and in nonasthmatic nonatopic subjects who served as controls. The urinary excretion of N t -methylhistamine was also measured, as well as LTE 4 , in view of pharmacological data supporting the role for cysteinyl-LTs and histamine in the bronchoconstriction following the inhalation of mannitol [14].…”

The Effect of Omega-3 Fatty Acids on Bronchial Hyperresponsiveness, Sputum Eosinophilia, and Mast Cell Mediators in Asthma

“…[8][9][10][11] Mannitol causes bronchoconstriction through an increase in the osmolarity of the airway surface fl uid, leading to mediator release from mast cells similar to the proposed mechanism for EIB. 12 Evidence for mediator release to mannitol is an increase in urinary eicosanoids 11 b -PGF 2 a and LTE 4 following a mannitol challenge 11 similar to what has been observed with exercise and EVH.…”