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.

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Short-acting beta(2)-agonists provide greater protection to bronchoconstriction induced by adenosine-5'-monophosphate (AMP) than does methacholine. Because AMP produces bronchoconstriction through release of mediators from mast cells, and methacholine directly constricts airway smooth muscle, this suggests that beta(2)-agonists stabilize mast cells in vivo. This in vivo property has not been demonstrated with long-acting beta(2)-agonists. We undertook two double-blind, randomized, crossover, placebo-controlled studies to investigate the effects of salmeterol and albuterol on airway responsiveness (AR) to AMP and histamine in patients with mild asthma. In the first study, 19 patients attended on four occasions to inhale salmeterol 50 micrograms or placebo 2 h before challenge with AMP or histamine. In the second study 16 patients (13 of whom had participated in the first study) were studied in a similar fashion but inhaled albuterol 400 micrograms or placebo 30 min prior to challenge. Salmeterol reduced AR to AMP and histamine by 3.4 +/- 0.3 and 3.9 +/- 0.3 doubling doses, respectively (NS). In contrast, albuterol demonstrated a greater protective effect on AMP than on histamine, reducing AR by 5.1 +/- 0.3 and 3.8 +/- 0.2 doubling doses, respectively (p < 0.005). Thus, in contrast to albuterol, salmeterol did not demonstrate mast-cell stabilizing properties in vivo at a time corresponding to maximal bronchodilatation. These findings might be explained by the unique pharmacologic profile of salmeterol in combination with the differential beta(2)-adrenoceptor pharmacology of bronchial mast cells and bronchial smooth muscle.

Inhaled short-acting b 2 -agonists provide greater protection against airway responsiveness (AR) to the mast-cell stimulus, adenosine 59-monophosphate (AMP), than to histamine, a direct spasmogen. Both terbutaline and albuterol exhibit this mast-cell stabilizing property in a dose-dependent manner. A single dose of the long-acting b 2 -agonist formoterol has also been reported to have a mast cell-stabilizing effect, whereas salmeterol has not. To explore the dose-related actions of the longacting b 2 -agonist formoterol on AR, the authors compared the acute effects of three doses of formoterol and terbutaline on AR to AMP and histamine.In a double-blind, randomized, placebo-controlled, cross-over study, 25 mild, steroid naive, asthmatic subjects attended on 10 occasions. At each visit, subjects inhaled either a single dose of terbutaline (500 mg), formoterol (6, 12 or 24 mg) or a matched placebo, administered via Turbuhaler1, 30 min prior to challenge with both AMP and histamine.Each dose of b 2 -agonist reduced AR to AMP and histamine. The bronchoprotective effects of formoterol (6 mg) and terbutaline (500 mg) were similar in magnitude in reducing AR to histamine (mean¡SD: 3.6¡0.3 and 3.1¡0.3 doubling doses (DD)) and AR to AMP (3.5¡0.5 and 3.3¡0.4 DD, respectively). Overall, formoterol reduced AR to both spasmogens in a dose-dependent manner. In addition, formoterol (12 and 24 mg) provided a significantly greater protective effect against AMP than against histamine challenge. It decreased AR by 5.7¡0.6 and 6.3¡0.7 DD against AMP and 4.3¡0.4 and 4.8¡0.43 DD against histamine, respectively.The results of this study indirectly demonstrated an in vivo dose-dependent mast-cell stabilizing effect of formoterol, in addition to functional antagonism on airway smooth muscle. The long-acting b 2 -agonists formoterol and salmeterol are effective bronchodilators with a much longer duration of action than the short-acting b 2 -agonists albuterol and terbutaline [1]. Their addition to low-dose inhaled glucocorticosteroids (GCS) is now recommended as an alternative to the use of high-dose inhaled corticosteroids in asthma management, especially in patients with nocturnal asthma or exerciseinduced symptoms [2]. In a similar manner to short-acting b 2 -agonists, a single dose of formoterol may have a greater bronchoprotective effect on the indirect spasmogen, adenosine 59-monophosphate (AMP), than on the direct-acting spasmogen, histamine [3][4][5]. In vitro and in vivo evidence of mast-cell mediator release and the attenuation of the bronchoconstrictive effects of AMP by the cromones and antihistamines suggest that AMP acts primarily as a mast-cell stimulus [6][7][8]. This implies an in vivo mastcell stabilizing effect of formoterol, in addition to functional antagonism on airway smooth muscle, an observation which, to date, has not been demonstrated with salmeterol [9,10].To further evaluate the in vivo mechanisms of formoterol, the effects of a single dose of formoterol (6, 12 and 24 mg), terbutaline 500 mg (contro...

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