A bolus of inhaled budesonide rapidly reverses airway subsensitivity and beta(2)-adrenoceptor down-regulation after regular inhaled formoterol

Background: Subsensitivity of airway beta(2)-adrenoceptors develops readily in asthmatics receiving regular long-acting beta(2)-agonists. This subsens itivity may be rapidly reversed by using systemic corticosteroids. The purp ose of the present study was to investigate whether the same acute facilita tory effects occur when using a bolus dose of inhaled corticosteroid. Methods: Ten subjects with stable mild-to-moderate asthma, with a mean age of 27 years, mean (+/-SD) FEV1 of 2.95 L (0.94 L), 81% (15%) of predicted, all receiving inhaled corticosteroids, reactive to adenosine monophosphate (AMP) with a provocative concentration producing a 20% fall in FEV1 (PC20) < 200 mg/mL, were recruited into a randomized double-blind crossover study. The subjects received two separate 1-week treatment periods with formotero l dry powder, 24 mu g bid, with an initial 1-week run-in and a 1-week washo ut period between the treatments. A single dose of placebo or budesonide tu rbuhaler, 1,600 mu g, was taken in conjunction with the last dose of both t reatment periods. AMP challenge was performed 2 h after the first and last dose of formoterol. Blood for lymphocyte beta(2)-adrenoceptor density (Bmax ) was also measured before and after treatment with formoterol. Results: There was no significant difference in the geometric mean PC20 aft er the first dose of formoterol comparing the two treatment periods: 362 mg /mL vs 391 mg/mL. The PC20 after the last dose of fomoterol was significant ly higher (p < 0.05) in conjunction with budesonide than with placebo: 427 mg/mL vs 99 mg/mL, amounting to a 4.3-fold difference (95% confidence inter val [CI], 1.1 to 16.6). For comparison within each treatment period, there was significant subsensitivity (p < 0.05) between the first and last dose o f formoterol when the latter was given,vith placebo: 391 mg/mL vs 99 mg/mL, a 3.9-fold fall (95% CI, 1.0 to 15.2), but not when the latter was given w ith budesonide: 362 mg/mL vs 427 mg/mL, a 1.2-fold rise (95% CI, 0.5 to 2.8 ). Lymphocyte beta(2)-adrenoceptor density (geometric mean B-max: fmol/10(6 ) cells) also showed significant down-regulation (p < 0.05) by formoterol g iven with placebo: preformoterol 2.53 vs postformoterol 1.91, but not by fo rmoterol given with budesonide: preformoterol 2.43 vs postformoterol 2.67. The Bmax was significantly higher (p < 0.05) with formoterol + budesonide a s compared to formoterol + placebo, amounting to a 1.40-fold difference (95 % CI, 1.09 to 1.80). Conclusion: We have shown that a bolus dose of inhaled budesonide rapidly r everses subsensitivity to AMP bronchoprotection and associated beta(2)-adre noceptor down-regulation in asthmatics taking regular formoterol. Further s tudies are indicated to assess whether high-dose inhaled corticosteroids sh ould be administered as soon as possible along with beta(2)-agonists during an acute episode of bronchoconstriction.