In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol,☆☆,

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Abstract

Background: It has been shown in vitro that prior treatment with salmeterol and formoterol antagonizes the relaxant effect of albuterol in carbachol-contracted human bronchi. Objectives: The primary aim of this study was to evaluate whether there is a potential in vivo interaction between long- and short-acting β2 -agonists in the presence of increased airway tone induced by methacholine. In addition, a post hoc analysis was made to evaluate the effects of β2 -adrenoceptor polymorphisms. Methods: Sixteen asthmatic subjects (mean age [±SD], 39 [13] years; FEV1 , 81% [17%] of predicted value), all taking inhaled corticosteroids and having methacholine PD20 values of less than 500 μg, were randomized in double-blind, double-dummy, cross-over fashion to receive single doses of inhaled placebo, inhaled formoterol 12 μg, or inhaled salmeterol 50 μg followed 12 hours later by a single dose of inhaled albuterol 400 μg (low dose) or 1600 μg (high dose). Methacholine challenges were performed on each of 6 separate occasions 1 hour after albuterol. Results: There was a greater numerical difference in geometric mean PD20 values between low- and high-dose albuterol after placebo dosing (671 μg vs 1080 μg, a 1.61-fold difference; P < .05) compared with low- and high-dose albuterol after formoterol dosing (660 μg vs 799 μg, a 1.21-fold difference; P = .4), or after salmeterol dosing (568 μg vs 847 μg, a 1.49-fold difference; P = .055). PD20 values with high-dose albuterol in combination with formoterol or salmeterol were numerically lower than those found with high-dose albuterol in combination with placebo, but they were not significantly different. There was a significant difference between PD20 values with low-dose albuterol after dosing with formoterol (PD20 = 660 μg, a 1.6-fold difference; P < .05) or with salmeterol (PD20 = 568 μg, a 1.9-fold difference; P < .05) compared with PD20 with high-dose albuterol after placebo dosing (PD20 = 1080 μg). Post hoc polymorphism analysis for pooled pretreatment with formoterol and salmeterol (excluding placebo pretreatment) showed significantly (P < .05) lower PD20 values with homozygous glycine-16 compared with heterozygous glycine/arginine-16 and significantly (P < .05) lower PD20 values with homozygous glutamate-27 compared with either heterozygous glutamate/glutamine-27 or homozygous glutamine-27. Conclusion: Compared with placebo, both salmeterol and formoterol caused a significant degree of antagonism of albuterol-induced bronchorelaxation in methacholine-contracted bronchi in vivo. This interaction could be caused by prolonged occupancy of airway β2 -adrenoceptors by long-acting β2 -agonists or by early tachyphylaxis 12 hours after a single-dose exposure. The degree of albuterol protection was also related to β2 -adrenoceptor polymorphism. (J Allergy Clin Immunol 1999;103:816-22.)

Section snippets

Subjects

Sixteen subjects (13 women and 3 men; mean [±SD] age, 39 [13] years) with mild-to-moderate asthma, all taking inhaled corticosteroids with a median dose of 450 μg/day (Table I), were recruited to take part in a randomized, double-blind, cross-over study.All patients were reactive to methacholine with PD20 values of less than 500 μg and exhibited at least a 2 doubling-dose improvement in PD20 at 20 minutes after inhalation of 400 μg of albuterol at initial screening (Table I). All had stable

Prechallenge spirometry

FEV1 was significantly (P < .05) higher 12 hours after the inhalation of formoterol or salmeterol as compared with placebo, apart from one salmeterol treatment in which the numerical trend did not achieve statistical significance before inhalation of albuterol (Fig 2).

. Mean (SE) FEV1 values before (open symbols) and 1 hour after (filled symbols) inhalation of albuterol (ALB) and at 12 hours after a single dose of placebo, formoterol 12 μg, or salmeterol 50 μg. Prealbuterol and postalbuterol

DISCUSSION

Our results have demonstrated that prior treatment with a single dose of salmeterol and formoterol antagonized the protective effect of albuterol against methacholine-induced bronchoconstriction. This was evident by the greater degree of improvement in PD20 between low- and high-dose albuterol alone when given on a background of placebo compared with responses on a background of formoterol or salmeterol. Furthermore, the response to high-dose albuterol in conjunction with formoterol and

Acknowledgements

We thank Dr Ian Hall (University Hospital, Nottingham, UK) for performing the genotype analysis.

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    Supported by a University of Dundee research grant.

    ☆☆

    Reprint requests: Brian Lipworth, MD, Professor of Allergy and Respiratory Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK.

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