A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5'-monophosphate in asthmatic patients.
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.
Taylor
D A
DA
Royal Brompton Clinical Studies Unit, Department of Thoracic Medicine, National Heart and Lung Institute at Imperial College School of Medicine, London, United Kingdom.
Jensen
M W
MW
Kanabar
V
V
Engelstätter
R
R
Steinijans
V W
VW
Barnes
P J
PJ
O'Connor
B J
BJ
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
D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D001798:Blood Proteins; D047091:Eosinophil Granule Proteins; D011282:Pregnenediones; D000249:Adenosine Monophosphate; D012260:Ribonucleases; C120481:ciclesonide