A Dose-dependent Effect of the Novel Inhaled Corticosteroid Ciclesonide on Airway Responsiveness to Adenosine-5 ′ -Monophosphate in Asthmatic Patients

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Abstract
Inhaled corticosteroids decrease airway responsiveness in asthma partly through suppression of airway inflammation. We have previously demonstrated that inhaled budesonide reduced airway responsiveness to the mast cell stimulus adenosine-5 ′ -monophosphate (AMP) to a threefold greater extent than to methacholine and sodium metabisulfite, suggesting that AMP responsiveness may be a more sensitive marker of airway inflammation and steroid action in order to assess a dose–response relationship. To investigate this, we studied the effects of three doses of the novel corticosteroid ciclesonide (50 μ g, 200 μ g, and 800 μ g) inhaled as a dry powder twice daily on airway responsiveness to AMP and inflammatory parameters in induced sputum. In a three-parallel-dose group, double-blind, placebo-controlled, randomized, crossover study, with a washout period of 3 to 8 wk, a total of 29 patients with mild to moderate allergic asthma underwent AMP challenge and sputum induction before and after 14 d of treatment with ciclesonide or matched placebo. Compared with placebo, ciclesonide 100 μ g, 400 μ g, and 1,600 μ g daily reduced airway responsiveness to AMP by 1.6 (95% confidence interval [CI], − 0.1 to 3.4, not significant [NS]), 2.0 (95% CI, 0.4 to 3.6, p < 0.05), and 3.4 (95% CI, 2.3 to 4.4, p < 0.05) doubling doses, respectively, and this reduction in airway responsiveness was dose-dependent (p = 0.039). A significant reduction in the percentage of eosinophils in induced sputum was observed after 400 μ g and 1,600 μ g daily ciclesonide (p < 0.05), but this was not dose-dependent. Sputum eosinophil cationic protein (ECP) was significantly reduced after 400 μ g daily ciclesonide only (p < 0.05). Thus, in patients with mild to moderate asthma, assessment of airway responsiveness to AMP, rather than inflammatory parameters in induced sputum, represents a sensitive method to evaluate a dose–response relationship of an inhaled corticosteroid and may have applications in evaluating other novel inhaled corticosteroids.