Clinical Studies
Effects of Treatment with Formoterol on Bronchoprotection against Methacholine

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Abstract

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.

Section snippets

Patients

We studied patients between the ages of 16 and 65 years who had a diagnosis of asthma with minimum duration of 6 months according to American Thoracic Society criteria (6) and a forced expiratory volume in 1 second (FEV1) equal to or greater than 60% of predicted normal value. In all subjects, the provocative dose of methacholine that caused a 20% fall in FEV1 (PD20) was ≤1000 μg, and there was at least a fourfold increase in PD20 1 hour after inhaling 24 μg of formoterol from a dry powder

Results

A total of 72 subjects were enrolled into the study, of whom 67 completed the full protocol. Characteristics of the subjects who completed the study are summarized in Table 1. The geometric mean baseline unprotected PD20 after the initial run-in, before randomization (at visit 2), was 60 μg.

Discussion

This study of the development of tachyphylaxis with long-acting β2-agonists has three key findings. First, we found that the degree of protection after 14 days was not dependent upon the total daily dose of formoterol, when comparing 6 μg and 24 μg twice daily. Second, the degree of tachyphylaxis occurred to a comparable degree with once-daily and twice-daily administration of formoterol. Third, the residual degree of protection with formoterol was comparable to that observed with terbutaline.

Acknowledgements

The authors wish to acknowledge the technical assistance of C. L. Bromly (Newcastle), Y. Gnosspelius, and P. Larsson (Astra Draco AB, Sweden) for advice on study design and statistical analysis, G. Hamer (Astra Clinical Research Unit, Edinburgh) for monitoring the study, and for the grant support from Astra Draco.

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