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

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 micrograms, 200 micrograms, and 800 micrograms) 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 micrograms, 400 micrograms, and 1,600 micrograms 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 micrograms and 1,600 micrograms daily ciclesonide (p < 0. 05), but this was not dose-dependent. Sputum eosinophil cationic protein (ECP) was significantly reduced after 400 micrograms 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.

Effects of hydrofluoroalkane formulations of ciclesonide 400 µg once daily vs fluticasone 250 µg twice daily on methacholine hyper‐responsiveness in mild‐to‐moderate persistent asthma

“…We performed our challenges in the morning when the airway exhibits enhanced diurnal hyper-responsiveness, so as to coincide with trough protection at the end of the 24-h dosing interval with CIC. Previous data with twice daily CIC have shown a doseresponse against adenosine monophosphate challenge with doses of 100, 400 and 1600 mg daily given each for 2 weeks [21]. In summary, our results showed no significant difference between HFA formulations of once daily CIC 400 mg and twice daily FP 250 mg over 4 weeks for effects on the primary outcome of methacholine hyperresponsiveness in mild-to-moderate asthma.…”

Dose-related effect of inhaled fluticasone on allergen-induced airway changes in rats

“…To date, the dose-dependent effect of ICS on airway eosinophilia has mainly been assessed on induced sputum samples. These studies also indicate that ICS are effective, from low doses onwards, at reducing eosinophil number, and that the dose-response curve is relatively flat [17][18][19][20]. To what extent this is paralleled by changes in mucosal eosinophil number has not been fully established in humans.…”

Preclinical Profile of Ciclesonide, a Novel Corticosteroid for the Treatment of Asthma

“…The first clinical data on ciclesonide have already been published and have demonstrated that ciclesonide reduces airway responsiveness to adenosine-5Ј-monophosphate in a dose-dependent manner when compared with placebo in patients with mildto-moderate asthma. A reduction in eosinophils was also observed in induced sputum from the same patients (Taylor et al, 1999). Another study has shown that ciclesonide produces a significant inhibition of early and late phase reaction after allergen challenge (Dahl et al, 1998).…”