CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 86 NUMBER 1 | JULY 2009 49 REPORTS nature publishing group Smokers with asthma show a reduced response to inhaled corticosteroids. We hypothesized that a peroxisome proliferator–activated receptor-γ (PPAR-γ) agonist would be superior for the clinical treatment of these asthma patients. Forty-six smokers with asthma were randomized to inhaled beclometasone dipropionate (200 μg per day) or rosiglitazone (8 mg per day) for 4 weeks. Rosiglitazone produced improvements in lung function (forced expiratory volume in 1 s (FEV 1 ) = 183 ml, P = 0.051; forced expiratory flow between 25 and 75% of the forced vital capacity (FEF 25–75 ) = 0.24 l/s, P = 0.030) as compared with inhaled beclometasone dipropionate. Further trials using PPAR-γ agonists in steroid- resistant airway disease are indicated. Inhaled corticosteroids are recommended as the first line of treatment in patients with chronic persistent asthma. 1 Smokers with asthma, however, exhibit an impaired response to both inhaled and oral corticosteroids, 2–5 possibly because of noneosinophilic airway inlammation, impaired glucocorticoid receptor function, and/or reduced histone deacetylase activity. 6 Cigarette smoking in asthma patients is also associated with an accelerated decline in lung function, 7 increase in the number of emergency department visits for asthma (with associated costs) 7,8 and increase in severity of symptoms, as compared with nonsmoking asthmatic patients. 9 he prevalence of smoking in subjects with asthma relects the prevalence in the general population, and therefore smokers with asthma constitute a large group of patients with poorly controlled disease. 10 Smoking cessation is an efective therapy in this group, 11 but because sustained quitting rates are low, additional or alternative therapies are needed for individuals with asthma who continue to smoke. The glucocorticoid receptor is a member of the nuclear hormone receptor family, which includes the peroxisome proliferator–activated receptor-γ (PPAR-γ). PPAR-γ agonists exert anti-inlammatory efects on multiple inlammatory cell subtypes in vitro and reduce inlammation in animal models of asthma and neutrophilic airways disease. 12 On the basis of this evidence, we hypothesized that the PPAR-γ agonist rosiglitazone would have anti-inlammatory activity that would be of beneit in smokers with asthma. herefore, we undertook an exploratory clinical trial to examine the effect of rosiglitazone on lung function, Asthma Control Questionnaire (ACQ) score, and inlammatory end points in a group of smokers with asthma. RESULTS A total of 3,895 subjects with asthma were invited to participate in the study between August 2005 and May 2007, of whom 294 gave positive responses. Following screening through telephone calls, visits were arranged for 187 subjects. Ater a run-in period involving weaning from inhaled corticosteroids and assessment of bronchodilator reversibility, 91 subjects met the criteria for randomization (see Methods for further details). he trial contained four treatment arms, and subjects were randomly allocated to the various treatments. Forty- five subjects were randomized to other treatments, which are not discussed in this article. 13 he other 46 subjects were randomized equally to rosiglitazone and inhaled beclometasone dipropionate. he demographic, clinical (including previous inhaled corticosteroid and long-acting β 2 -agonist use), and inlammatory baseline characteristics of the recruited subjects in each group were well matched (Table 1). All the end points presented are the changes relative to the response in the group assigned to inhaled corticosteroids. Lung function At 2 weeks, rosiglitazone demonstrated a borderline improvement in prebronchodilator forced expiratory volume in 1 s (FEV 1 ) (164 ml, 95% conidence interval (CI), −1 to 329, P = 0.051) (Figure 1a and Table 2), a signiicant improvement in prebronchodilator peak expiratory low (32.7 l/min, 95% CI Bronchodilatory Effect of the PPAR-γ Agonist Rosiglitazone in Smokers With Asthma M Spears 1 , I Donnelly 2 , L Jolly 2 , M Brannigan 1 , K Ito 3 , C McSharry 2 , J Lafferty 1 , R Chaudhuri 1 , G Braganza 1 , P Bareille 4 , L Sweeney 4 , IM Adcock 3 , PJ Barnes 3 , S Wood 5 and NC Thomson 1 1 Department of Respiratory Medicine, Faculty of Medicine, University of Glasgow, Glasgow, UK; 2 Department of Immunology, Faculty of Medicine, University of Glasgow, Glasgow, UK; 3 Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK; 4 Discovery Medicine, GlaxoSmithKline, London, UK; 5 Department of General Practice, Faculty of Medicine, University of Glasgow, Glasgow, UK. Correspondence: NC Thomson (n.c.thomson@clinmed.gla.ac.uk) Received 24 January 2009; accepted 2 March 2009; advance online publication 8 April 2009. doi:10.1038/clpt.2009.41