A randomized study of formoterol fumarate in a porous particle metered-dose inhaler in patients with moderate-to-severe COPD.

BACKGROUND: Formoterol fumarate (FF) is a well-established long-acting ß2-agonist. This represents the first clinical study of FF in a metered-dose inhaler (FF MDI) based on proprietary lipid-based porous-particle engineering technology. METHODS: In this randomized, double-blind, 5-period, crossover study (NCT00880490), subjects received 2.4, 4.8, and 9.6 µg of FF MDI, open-label Foradil(®) Aerolizer(®) (FA) 12 µg, and placebo. Spirometry was performed at baseline, 15 and 30 min, and 1, 2, 4, 6, 8, 10, 11.5, and 12 h post-dose. RESULTS: Thirty-four subjects were enrolled. Improvement in forced expiratory volume in 1 s (FEV1) was similar between FF MDI 9.6 µg and FA. Change in FEV1 area under the curve for 0-12 h (AUC0-12) for each FF MDI dose demonstrated superior efficacy versus placebo (P < .001 for all 3 doses). Over 12 h and at each time point, FF MDI 9.6 µg was non-inferior to FA for FEV1 AUC0-12 with the 95% CI's supporting a maximum difference of approximately 45 mL. Peak and trough FEV1, forced vital capacity, peak expiratory flow rate, peak inspiratory capacity, and pharmacokinetics confirmed the primary endpoint, with dose ordering of the FF MDI 2.4, 4.8, and 9.6 µg, and comparability of FF MDI 9.6 µg to FA. All 3 doses of FF MDI were safe and well-tolerated, with a safety profile similar to that of placebo and FA. CONCLUSIONS: The efficacy and pharmacokinetic profile of FF MDI 9.6 µg were comparable to FA 12 µg and with similar safety to placebo and FA. TRIAL REGISTRATION: This clinical trial was registered on ClinicalTrials.gov, Identifier: NCT NCT00880490.

Randomized study of the safety, pharmacokinetics, and bronchodilatory efficacy of a proprietary glycopyrronium metered-dose inhaler in study patients with chronic obstructive pulmonary disease.

BACKGROUND: Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary porous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting ß2-agonists, and a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges inherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers. METHODS: In this randomized, double-blind, 4-period, 6-treatment, placebo- and active-controlled, multicenter, crossover study, 4 ascending single doses of a proprietary glycopyrronium (GP) MDI were evaluated compared with Placebo MDI and open-label tiotropium (TIO) in study patients with COPD. Thirty-three study patients were enrolled and received single-dose administration of 4 of the 6 treatments (Placebo MDI, TIO 18 µg, or GP MDI at 14.4, 28.8, 57.6, and 115.2 µg ex-actuator) with an interval of 1 to 3 weeks between doses. The primary efficacy endpoint was peak change in forced expiratory volume in 1 second (FEV1). RESULTS: All 4 doses of GP MDI showed statistically superior efficacy compared with Placebo MDI for peak FEV1 (differences of 146 to 248 mL; P<.001), with a clear dose ordering of the response. Statistically significant differences compared with Placebo MDI were noted at almost all doses for the secondary FEV1 parameters (P ≤ .049) except 24-hour trough FEV1 at 28.8 µg. All doses were safe and well tolerated in this study; the most frequently reported adverse event was dry mouth (0-14.3% across doses; 9.5% for Placebo MDI, and 9.1% for TIO). CONCLUSIONS: This study demonstrated superior bronchodilatory efficacy of GP MDI compared with Placebo MDI at all doses tested, and no serious adverse events were reported. This study supports the further evaluation of GP MDI in study patients with COPD. In addition, these findings indicate that the correct dosage of glycopyrronium is no more than 115.2 µg total daily dose, or 57.6 µg twice daily based on comparisons with the active comparator. TRIAL REGISTRATION: This clinical trial was registered on ClinicalTrials.gov, Identifier: NCT00871182.

Evaluation of unexplained dyspnea in a young athletic male with pectus excavatum.

Pectus excavatum (PE) is a relatively common congenital deformity of the anterior chest wall associated with reduced exercise capacity. Uncertainty exists over the nature of physiologic impairment in PE. Evidence suggests that myocardial compression exerted by the displaced sternum on the right heart chambers, disables the ability of the heart to augment stroke volume during exercise. This case study describes the evaluation of an athletic 20 year old Caucasian male, lifelong non-smoker, with severe pectus deformity and previous fixation procedure to repair a sternal fracture. The patient performed an incremental cycle ergometer exercise test to determine the etiology of his dyspnea with exertion. The patient demonstrated normal work output and normal aerobic capacity but displayed dynamic hyperinflation. Mechanical restriction of tidal volume expansion appeared to be the major contributors to exercise limitation. These results are compared and contrasted with similar cases reported in the literature. Key PointsPectus excavatum (PE) is a relatively common phenomenon affecting approximately 1 in 300 births, with a 9:1 ratio of male to female rate of incidence.The etiology or exercise limitation is most frequently due to cardiovascular limitation due to the compression of the sternum upon the myocardium, impairing the ability to augment stroke volume.The Pectus Severity Index (PSI) is a useful indicator of pectus severity.Cardiopulmonary exercise testing provides useful data to distinguish between cardiovascular limitation, ventilatory limitation, or deconditioning in the evaluation of PE.In this case study, ventilatory limitation was due to the mechanical restriction of the thoracic cavity.