An imbalance between oxidative stress and antioxidative capacity is thought to piay an important role in the development and progression of chronic obstructive pulmonary disease (COPD). To assess the lung oxidative status in patients with COPD, we studied whether exhaled hydrogen peroxide (H2O2) is increased in breath condensate of patients with stable COPD (n = 12, mean FEV1 51% pred) and in patients with exacerbated COPD (n = 19, actual FEVi 36% pred) compared with a healthy control group (n = 10, FEVi 108% pred). Expired breath condensate during 15 min of tidal breathing was collected by cooling. The concentration of H2O2 was measured spectrophotometrically by means of horse radish peroxidase-catalyzed oxidation of tetramethylbenzidine. Concentrations of H2O2 (mean ± SEM) were significantly elevated at 0.205 ± 0.054 nM in patients with stable COPD compared with 0.029 ± 0.012 n.M in the control group (p < 0.05) and were further increased to 0.600 ± 0.075 nM in patients with acutely exacerbated COPD (p < 0.001 compared with patients with stable COPD). Patients with pulmonary infiltrates on chest radiograph showed similar values compared with patients without obvious infiltrates. These findings demonstrate that patients with stable COPD exhibit increased oxidant production in the airways and that oxidant production increases further during exacerbations.
GSK961081 is a bifunctional molecule demonstrating both muscarinic antagonist and β-agonist activities.This was a 4-week, multicentre, randomised, double-blind, double-dummy, placebo and salmeterol controlled parallel group study. Doses ranging across three twice-daily doses and three once-daily doses were assessed in moderate and severe chronic obstructive pulmonary disease (COPD) patients. Trough forced expiratory volume in 1 s (FEV1) at day 29 was the primary end-point. At days 1 and 28, 12-h FEV1 spirometry was performed in all patients. A subset of patients underwent complete 24-h spirometry at day 28.The study recruited 436 patients. GSK961081 showed statistically and clinically significant differences from placebo in all doses and regimens for trough FEV1 on day 29 (155–277 mL). The optimal total daily dose was 400 μg, either as 400 μg once daily or as 200 μg twice daily, with an improvement in day 29 trough FEV1 of 215 mL and 249 mL, respectively. Other efficacy end-points also showed improvement. No effects were observed on glucose, potassium, heart rate, blood pressure and no dose–response effect was seen on corrected QT elongation.This study showed that GSK961081 is an effective bronchodilator in COPD and appeared to be safe and well tolerated.
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