Combined use of beta(2)-agonists and anticholinergic bronchodilators may have complementary benefits in patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to compare combination treatment with formoterol (FORM) plus tiotropium (TIO) versus treatment with TIO alone in patients with COPD. In this active-controlled, double-blind, multicenter trial, a total of 255 subjects with diagnosed COPD were randomized to 12 weeks of either a combination of FORM 12 microg twice-daily plus TIO 18 microg once-daily in the morning (QD AM) or monotherapy with TIO 18 microg QD AM. The primary efficacy variable was the area under the curve for forced expiratory volume in 1 second measured 0 to 4 hours after AM dosing (FEV(1) AUC(0-4h)). Significantly greater improvements in the FEV(1) AUC(0-4h) were seen with FORM + TIO (n = 116) versus TIO (n = 124) at all time points. The increase in FEV(1) 5 minutes after the first dose was 180 mL with FORM + TIO versus 40 mL with TIO (p < 0.001). At endpoint, FEV(1) AUC(0-4h) increased 340 mL with FORM + TIO versus 170 mL with TIO (p < 0.001). Improvements in trough FEV(1) with FORM + TIO versus TIO were 180 mL and 100 mL, respectively (p < 0.01). Significantly greater reductions from baseline in symptom scores (p < 0.05) and daytime albuterol use (p < 0.04) were seen at endpoint with combination FORM + TIO versus TIO monotherapy. Both treatments were well tolerated. This study demonstrated that concurrent treatment with FORM + TIO results in greater therapeutic benefits than TIO alone.
Intravenous/oral moxifloxacin therapy was efficacious and safe for hospitalized elderly patients with CAP, achieving > 90% cure in all severity and age subgroups, and was associated with faster clinical recovery than intravenous/oral levofloxacin therapy, with a comparable safety profile.
BackgroundThis study forms part of the first complete characterization of the dose–response curve for glycopyrrolate (GP) delivered using Co-Suspension™ Delivery Technology via a metered dose inhaler (MDI). We examined the lower GP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).MethodsThis randomized, double-blind, chronic-dosing, balanced incomplete-block, placebo-controlled, crossover study compared six doses of GP MDI (18, 9, 4.6, 2.4, 1.2, and 0.6 μg, twice daily [BID]) with placebo MDI BID and open-label tiotropium dry powder inhaler (18 μg, once daily [QD]) in patients with moderate-to-severe COPD. Patients were randomized into 1 of 120 treatment sequences. Each sequence included 4 of 8 treatments administered for 14-day periods separated by 7- to 21-day washout periods.The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0–12) on Day 14. Secondary efficacy endpoints included peak change from baseline (post-dose) in FEV1 and inspiratory capacity (IC) on Days 1, 7, and 14; change from baseline in morning pre-dose trough FEV1 on Days 7 and 14; change from baseline in 12-h post-dose trough FEV1 on Day 14; time to onset of action (≥10 % improvement in mean FEV1) and the proportion of patients achieving ≥12 % improvement in FEV1 on Day 1; and pre-dose trough IC on Days 7 and 14. Safety and tolerability were also assessed.ResultsGP MDI 18, 9, 4.6, and 2.4 μg demonstrated statistically significant and clinically relevant increases in FEV1 AUC0–12 compared with placebo MDI following 14 days of treatment (modified intent-to-treat population = 120). GP MDI 18 μg was non-inferior to open-label tiotropium for peak change in FEV1 on Day 1 and morning pre-dose trough FEV1 on Day 14. All doses of GP MDI were well tolerated with no unexpected safety findings.ConclusionsThese efficacy and safety results support GP MDI 18 μg BID as the most appropriate dose for evaluation in Phase III trials in patients with moderate-to-severe COPD.Trial registrationClinicalTrials.gov NCT01566773. Registered 27 March 2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0426-4) contains supplementary material, which is available to authorized users.
The effects of external elastic loading (EL) (19 cmH2O/l), applied continuously (C) and intermittently (I) during CO2 rebreathing, on diaphragmatic electromyogram (EMGdi), mouth occlusion pressure (P0.15), and ventilation (VI) were studied in normal subjects. EMGdi was analyzed as moving time average and quantitated in terms of peak (mean p) and average rate of rise of inspiratory activity (mean p/TI). CEL resulted in an increased mean p/TI response to CO2 in all subjects with P0.15 increasing in proportion to EMGdi. Tidal volume (VT) during rebreathing was decreased in all cases with VI being preserved in four of six runs due to increased breathing frequency (f). Although mean p was increased for a given end-tidal CO2 (PACO2) level during CEL, for a given rate of rise of inspiratory activity mean p was decreased in three of five subjects, indicating a diminished threshold for inspiratory "off-switch." CEL results in an augmented inspiratory drive that serves to increase muscle output and stabilize VT; the increased drive and decrease inspiratory off-switch threshold shorten TI mediating the compensatory increase in f. The first breath IEL resulted in decreased VT and mean p without change in mean p/TI, and all increased with subsequent loaded breaths independent of changes in PCO2. Load compensation for externally applied EL is mediated by neural mechanisms independent of chemical drive.
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