title: 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.
authors.affiliation: Royal Brompton Clinical Studies Unit, Department of Thoracic Medicine, National Heart and Lung Institute at Imperial College School of Medicine, London, United Kingdom.
authors.forename: D A
authors.initials: DA
authors.lastname: Taylor
authors.forename: M W
authors.initials: MW
authors.lastname: Jensen
authors.forename: V
authors.initials: V
authors.lastname: Kanabar
authors.forename: R
authors.initials: R
authors.lastname: Engelstätter
authors.forename: V W
authors.initials: VW
authors.lastname: Steinijans
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: B J
authors.initials: BJ
authors.lastname: O'Connor
mesh_terms: D000249:Adenosine Monophosphate; D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000403:Airway Resistance / Q000187:drug effects*; D018927:Anti-Asthmatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy*; D001798:Blood Proteins / Q000032:analysis; D001985:Bronchial Provocation Tests; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D047091:Eosinophil Granule Proteins; D004804:Eosinophils / Q000187:drug effects; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011282:Pregnenediones / Q000009:adverse effects / Q000627:therapeutic use*; D012260:Ribonucleases; D013183:Sputum / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D001798:Blood Proteins; D047091:Eosinophil Granule Proteins; D011282:Pregnenediones; D000249:Adenosine Monophosphate; D012260:Ribonucleases; C120481:ciclesonide