BETA(2)-ADRENOCEPTOR REGULATION AND BRONCHODILATOR SENSITIVITY AFTER REGULAR TREATMENT WITH FORMOTEROL IN SUBJECTS WITH STABLE ASTHMA

Objective: We have previously found that beta(2)-adrenoceptor downregu lation and bronchodilator desensitization to albuterol occurred at 36 hours after stopping regular treatment with twice daily salmeterol. In this study we have evaluated these same effects with formoterol given once or twice daily on a regular basis. Methods: In a randomized, pla cebo-controlled, double-blind, double-dummy crossover study, 16 subjec ts with mild-to-moderate stable asthma (mean [SD] age, 32.5 [15.3] yea rs; mean [SD] FEV1, 73.2 [12.1] percent predicted) receiving regular i nhaled corticosteroid therapy received 1 week of treatment with formot erol dry powder (24 mu g twice daily [8 AM/8 PM]), formoterol (24 mu g once daily [8 PM]), or identical placebo. Lymphocyte beta(2)-adrenoce ptor parameters and a dose-response curve to inhaled albuterol (200 to 1600 mu g) were evaluated at 36 hours after the last dose of each tre atment period. Results: There were no significant differences in the m ean values for albuterol dose-response effects among the three treatme nt regimens. Comparison of maximal bronchodilator responses between tr eatments (mean and SEM as change from baseline) revealed no significan t differences between treatments for FEV1 (0.47 L [0.06 L] for placebo vs 0.48 L [0.07 L] for 24 mu g once daily formoterol vs 0.51 L [0.08 L] for 24 mu g twice daily formoterol) or for forced expiratory flow, mid-expiratory phase (FEF25-75) (0.80 L/sec [0.12 L/sec] for placebo v s 0.80 L/sec [0.16 L/sec] for 24 mu g once daily formoterol vs 0.89 L/ sec [0.14 L/sec] for 24 mu g twice daily formoterol). Formoterol also had no significant effect on mean lymphocyte Pz-adrenoceptor density. However, in five of seven patients with the homozygous Gly-16 polymorp hism, beta(2)-adrenoceptor density was downregulated by twice daily fo rmoterol, whereas only two such cases exhibited a reduction in maximal FEV, response to albuterol. Conclusions: The results of this study sh owed that for patients taking inhaled corticosteroids, overall beta(2) -adrenoceptor regulation and associated bronchodilator sensitivity to inhaled albuterol were unaltered at 36 hours after stopping regular tr eatment with formoterol. However, in a subset of patients who were Gly -16 homozygous, there was a tendency towards downregulation but not de sensitization. Further studies in subjects with more severe asthma are required to assess the clinical relevance of these findings.