Effects of Treatment with Formoterol on Bronchoprotection against Methacholine


      PURPOSE: In addition to their bronchodilatory effects, β2-agonists protect against bronchoconstriction, such as that caused by methacholine challenge. However, tachyphylaxis to this beneficial effect develops after chronic use of β2-agonists. We studied whether the frequency or dose of treatment with a long-acting β2-agonist (formoterol) affects the degree of bronchoprotection afforded against methacholine challenge and to compare this with the effects of a short-acting β2-agonist (terbutaline).
      PATIENTS AND METHODS: In a randomized, parallel group, double-blind study at two centers, patients with stable asthma of mild to moderate severity who were treated with inhaled corticosteroids were treated with formoterol 6 μg twice daily, 24 μg twice daily, 12 μg once daily; terbutaline 500 μg four times daily; or placebo. Treatments were given by dry powder inhaler for a period of 2 weeks. Of the 72 patients who were enrolled, 67 completed the study. Methacholine challenge was performed to calculate the provocative dose that caused a 20% fall in forced expiratory volume in 1 second at baseline (unprotected) after an initial 1-week run-in without β2-agonists, 1 hour after the first dose of study treatment, and again 1 hour after 7 and 14 days of study treatment.
      RESULTS: Each of the four active treatments exhibited significant tachyphylaxis (P <0.05) to protection against methacholine challenge when comparing first/last dose (as geometric mean protection ratio versus baseline): formoterol 24 μg twice daily (9.6-fold/1.6-fold), 12 μg once daily (7.1-fold/2.2-fold), 6 μg twice daily (6.2-fold/2.3-fold), and terbutaline 500 μg four times daily (2.9-fold/2.0-fold). There were no significant differences among treatments after 2 weeks in bronchoprotection against methacholine challenge. For all formoterol regimens, the bronchodilator response 1 hour after inhalation was maintained over the 2-week treatment period. Diurnal control of morning and evening peak flow was significantly better with formoterol 24 μg twice daily than with terbutaline.
      CONCLUSIONS: Tachyphylaxis to bronchoprotection against methacholine challenge develops after 2 weeks of therapy with formoterol, a long-acting β2-agonist, at all three dosage regimens that were tested. In contrast, the bronchodilator effects of formoterol were maintained during the 2 weeks of treatment.
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