Theophylline Plus Inhaled Beclomethasone Better Than Beclomethasone Alone in Smokers With Asthma: Presented at ERS

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Title: Theophylline Plus Inhaled Beclomethasone Better Than Beclomethasone Alone in Smokers With Asthma: Presented at ERS
URL: http://www.pslgroup.com/dg/22E78A.htm
Doctor's Guide
October 9, 2008

By Chris Berrie

BERLIN -- October 9, 2008 -- The combination of low-dose theophylline and inhaled beclomethasone promotes improvements over inhaled beclomethasone alone for lung function, asthma symptoms, and sputum differential count for smokers with stable mild to moderate asthma, according to a randomised, double-blind, active-comparator, parallel-group trial.

The study was presented here on October 7 at the European Respiratory Society (ERS) 18th Annual Congress by principal investigator Mark Spears, PhD, Respiratory Medicine, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom.

"Smokers with asthma display reduced responses to normal therapeutic doses of inhaled corticosteroids, so we are trying to understand why, and how to overcome this in subjects who don't stop smoking," Dr. Spears said.

Similarly, smoking in patients with asthma is associated with increased asthma symptoms, accelerated decline in lung function, and increased emergency department visits.

Previously, in vitro studies demonstrated that cigarette smoke can reduce histone deacetylase (HDAC) activity, which can be restored to normal by low-dose theophylline.

Therefore, Dr. Spears and colleagues hypothesised that use of low-dose theophylline in combination with corticosteroid in smokers with asthma would produce improvements in lung function that are greater than those with inhaled corticosteroid alone due to increased HDAC activity restoring corticosteroid sensitivity.

The researchers enrolled 68 smokers with stable mild to moderate asthma and, where appropriate, weaned patients from inhaled corticosteroids over more than 4 weeks. The inclusion criteria were baseline forced expiratory volume at 1 second (FEV₁) >50% predicted and postbronchodilation FEV₁ improvement of 12% or greater.

Patients were randomised to 28 days of treatment with oral theophylline 200 mg twice daily (n = 23), inhaled hydrofluroalkane beclomethasone dipropionate 100 mcg twice daily (n = 23), or the combination (n = 22). Median ages in the 3 groups were 46, 42, and 44 years, respectively. Males made up 34.8%, 39.1%, and 45.5% of the groups, respectively.

Baseline clinical characteristics across these patient groups were similar for asthma duration (16, 16, 15 years, respectively), pack years (30, 24, 25 years), and prebronchodilator percent FEV₁ predicted (73%, 75%, 78%).

The primary endpoint was change in prebronchodilator FEV₁ from baseline to day 28 as combination treatment relative to beclomethasone alone. Secondary outcomes were peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow at 25% to 75% vital capacity, Asthma Control Questionnaire (ACQ) score, induced sputum differential, and HDAC activity.

While theophylline treatment was not associated with statistically significant changes in prebronchodilator lung function at day 28, its combination with beclomethasone was superior to beclomethasone alone for PEF (difference: 40 L/min; P < .05) and FVC (difference: 254 L/second; P < .05).

For ACQ score, significant reductions were obtained for theophylline alone (0.55; P = .016) and combination treatment (0.47; P = .033).

With sputum samples, combination treatment was associated with a significant reduction in sputum lymphocytes (-0.8%; 95% CI, -1.4% to -0.1%), while theophylline alone resulted in significant reductions in sputum supernatant concentrations of interleukin 8 (-1201.3 pg/mL; P = .009) and myeloperoxidase (-215.0 ng/mL; P = .026).

Dr. Spears indicated, however, that for HDAC activity, it was not possible to detect differences in sputum macrophages both at baseline and with treatment.

Overall, combination treatment with low-dose theophylline and inhaled beclomethasone was more effective than inhaled beclomethasone alone for lung function, asthma symptoms, and sputum differential count. At the same time, theophylline alone versus inhaled beclomethasone alone improved asthma symptoms and sputum cytokines.

However, the mechanism by which theophylline contributes to these changes in lung function remains to be identified, according to the researchers.

Funding for this study was provided by GlaxoSmithKline.

[Presentation title: Efficacy of Low Dose Theophylline and Inhaled Corticosteroids in Smokers With Asthma. Abstract P3617]

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