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Effects of Adding Either a Leukotriene Receptor Antagonist or Low-Dose Theophylline to a Low or Medium Dose of Inhaled Corticosteroid in Patients With Persistent Asthma^*

^* From the Asthma and Allergy Research Group (Drs. Dempsey, Fowler, Wilson, and Lipworth), Department of Clinical Pharmacology & Therapeutics, and the Department of Medicine (Dr. Kennedy), Section of Vascular Medicine & Biology, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.

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

Study objectives: To evaluate the effect of adding zafirlukast or low-dose theophylline to a beclomethasone dipropionate (BDP) extra-fine hydrofluoroalkane aerosol on bronchial hyperresponsiveness as the primary outcome variable.

Methods: Twenty-four patients with mild-to-moderate asthma were studied using a randomized crossover design with the following three treatment blocks: (1) beclomethasone, 100 µg/d, alone for the first 2 weeks followed by 400 µg/d alone for the next 2 weeks; (2) beclomethasone, 100 µg/d, followed by 400 µg/d, with the addition of zafirlukast, 20 mg bid; (3) beclomethasone, 100 µg/d, followed by 400 µg/d, with the addition of theophylline, 200 to 300 mg bid. Measurements were made after 2 and 4 weeks of each treatment and at pretreatment baseline.

Results: The mean trough plasma theophylline concentration was 6.7 mg/L, coinciding with the anti-inflammatory target range (ie, 5 to 10 mg/L). The provocative dose of methacholine causing a 20% fall in FEV₁ (as doubling dose difference from baseline) was significantly (p < 0.05) greater with beclomethasone, 100 µg, plus zafirlukast (1.1 doubling dose) but not with beclomethasone, 100 µg, plus theophylline (0.7 doubling dose) compared to beclomethasone, 100 µg alone (0.4 doubling dose), but not compared to beclomethasone, 400 µg alone (1.1 doubling dose). There were also significant (p < 0.05) differences between beclomethasone, 100 µg, plus zafirlukast (but not BDP, 100 µg, plus theophylline) vs beclomethasone, 100 µg, alone in terms of nitric oxide level, midexpiratory phase of forced expiratory flow, and peak expiratory flow. There were no further significant improvements observed with the addition of zafirlukast or theophylline to beclomethasone, 400 µg.

Conclusions: A leukotriene receptor antagonist, but not low-dose theophylline, conferred significant additive anti-inflammatory effects to therapy with a low-dose inhaled corticosteroid but not to that with a medium dose of an inhaled corticosteroid. Thus, optimizing the dose of inhaled corticosteroid as monotherapy would seem to be the logical first step, which is in keeping with current guidelines.

Key Words: airway hyperresponsiveness • asthma • beclomethasone • theophylline • zafirlukast

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