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Effects of Once-Daily Formoterol and Budesonide Given Alone or in Combination on Surrogate Inflammatory Markers in Asthmatic Adults^*

^* From the Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK.

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

Objectives: We wished to evaluate the effects of once-daily combination therapy on surrogate inflammatory markers.

Methods: Fifteen patients with atopic persistent asthma were evaluated (mean age, 32.4 years; FEV₁, 75.2% predicted) in a randomized, double-blind, double-dummy, placebo-controlled crossover study with a 1-week placebo washout period, comparing the following once-daily nighttime treatments: (1) formoterol (FM), 12 µg, for 2 weeks and FM, 24 µg, for 2 weeks; or (2) budesonide (BUD), 400 µg, for 2 weeks and BUD, 800 µg, for 2 weeks; or (3) FM, 12 µg, plus BUD, 400 µg, for 2 weeks and FM, 24 µg, plus BUD, 800 µg, for 2 weeks. Adenosine monophosphate (AMP) bronchial challenge, exhaled nitric oxide (NO), and serum eosinophilic cationic protein (ECP) were evaluated at 12 h postdosing after administration of each placebo and after 2 and 4 weeks of each treatment.

Results: The results of AMP challenge (provocative concentration causing a 20% fall in FEV₁) at 4 weeks showed significant (p < 0.05) improvements after patients had received all active treatments compared to placebo (20 mg/mL), with FM plus BUD, 261 mg/mL, being superior (p < 0.05) to FM alone, 82 mg/mL, but not to BUD, 201 mg/mL. NO and ECP showed significant (p < 0.05) reductions compared to placebo with FM plus BUD or BUD alone but not with FM alone. Combination therapy was associated with optimal patient preference (rank order, FM plus BUD > FM > BUD; p < 0.0005), highest domiciliary peak expiratory flow, and lowest rescue inhaler usage. All three treatments produced equivalent improvements in spirometry.

Conclusions: Patients preferred once-daily combination therapy, but this had no greater effect on inflammatory markers than therapy with BUD alone. FM alone had no anti-inflammatory activity but exhibited bronchoprotection. This emphasizes the importance of first optimizing anti-inflammatory control with inhaled corticosteroids before considering adding a regular long-acting ß₂-agonist.

Key Words: adenosine monophosphate • bronchial hyperresponsiveness • budesonide • exhaled nitric oxide • formoterol • inflammation

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