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Bronchodilator Response to Albuterol After Regular Formoterol and Effects of Acute Corticosteroid Administration^*

^* From the Departments of Clinical Pharmacology and Therapeutics (Drs. Aziz and Lipworth) and Respiratory Medicine (Dr. Lipworth), Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.

Correspondence to: Brian J. Lipworth, MD, Asthma and Allergy Research Group, Department of Clinical Pharmacology and Respiratory Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland UK; e-mail: b.j.lipworth{at}dundee.ac.uk

Background: There is controversy about the development of bronchodilator subsensitivity after regular administration of long-acting ß₂-agonists.

Objectives: The purpose of the study was to evaluate whether regular treatment with formoterol affects the bronchodilator response to repeated puffs of albuterol, and also to assess the effects of acute administration of a bolus dose of IV or inhaled corticosteroid.

Materials and methods: Twelve patients (mean [SD] age, 43 [15] years; FEV₁, 57 [17] % predicted) with stable, moderate to severe persistent asthma who were all taking inhaled corticosteroids were evaluated in a randomized, placebo-controlled, double-blind, double-dummy, crossover study. Patients received treatments each for 2 weeks followed by a bolus (IV/inhaled) of corticosteroid or placebo: (1) placebo inhaler bid + bolus placebo; (2) formoterol Turbuhaler 24 µg metered dosage bid (delivered dosage 18 µg bid) + placebo; (3) formoterol 24 µg bid + bolus IV hydrocortisone, 200 mg; or (4) formoterol 24 µg bid + bolus inhaled budesonide, 1,600 µg. Bronchodilator response to repeated puffs of albuterol (200 to 1,600 µg) for > 80 min was measured at 2 h after bolus administration of placebo or corticosteroid. The study was powered at the 80% level to detect a 20% difference in area under curve between 20 and 80 min (AUC) for FEV₁ response to albuterol as change from baseline (primary end point).

Results: There was significant subsensitivity (p = 0.01) of the mean albuterol FEV₁ response (as AUC, L x s) after formoterol alone (737) as compared to placebo (1,453) along with partial reversal by steroid administration: formoterol + hydrocortisone (1,050), and formoterol + budesonide (942). There was a similar pattern of subsensitivity (p = 0.03) for the mean albuterol forced expiratory flow between 25% and 75% of vital capacity response (as AUC, L): placebo (2,149), formoterol alone (1,002), formoterol + hydrocortisone (1,402), and formoterol + budesonide (1,271).

Conclusion: Regular treatment with formoterol produced significant bronchodilator subsensitivity to repeated puffs of albuterol, which was partially reversed by a bolus dose of systemic or inhaled corticosteroid.

Key Words: ß₂-adrenoceptor • albuterol • asthma • bronchodilator • corticosteroids • formoterol • genetic polymorphism • subsensitivity • tachyphylaxis

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