24-hour bronchodilation following a single dose of the novel ß(2)-agonist olodaterol in COPD.

BACKGROUND: Current guidelines recommend long-acting bronchodilators as maintenance therapy in COPD when symptoms are not adequately controlled with short-acting agents. Olodaterol is a novel long-acting ß(2)-adrenoceptor agonist with a pre-clinical profile that suggests 24-h bronchodilation may be achieved with once-daily administration. OBJECTIVE: To assess dose- and time-response in terms of bronchodilator efficacy, and to evaluate pharmacokinetics, safety and tolerability of single doses of olodaterol administered via Respimat(®) Soft Mist™ Inhaler in COPD patients. METHODS: A single-center, double-blind, placebo-controlled, 5-way crossover study including 24-h spirometry (FEV(1), FVC), safety, tolerability and pharmacokinetics (in a subset of patients) following dosing of olodaterol 2 µg, 5 µg, 10 µg and 20 µg; the washout period between test-days was at least 14 days. Primary endpoint of the study was the 24-h post-dosing FEV(1). Patients participating in the pharmacokinetic assessments continued in an open-label extension phase to establish pharmacokinetics of olodaterol 40 µg. RESULTS: 36 patients were assigned to treatment; mean baseline prebronchodilator FEV(1) was 1.01 L (37% predicted normal). All doses of olodaterol provided significantly greater bronchodilation compared to placebo in 24-h FEV(1) post-dose (p < 0.001); a clear dose-response relationship was observed, with values ranging from 0.070 L for olodaterol 2 µg to 0.119 L for olodaterol 20 µg. Similarly, olodaterol was superior to placebo (p < 0.001) in peak FEV(1) (0.121 L to 0.213 L) and average FEV(1) both during the daytime (0-12 h; ranging from 0.099 L to 0.184 L) and night-time (12-24 h; ranging from 0.074 L to 0.141 L). FVC results were consistent with those observed for FEV(1). Pharmacokinetic evaluation of the peak plasma concentrations and renal excretion suggested no obvious deviation from dose-proportionality over the investigated dose range of 2 µg-40 µg; in most patients, no plasma levels could be detected following the 2 µg dose. All treatments were well tolerated with no apparent dose relation in terms of adverse events. CONCLUSIONS: Olodaterol appears to be a promising long-acting ß(2)-adrenoceptor agonist,with bronchodilation maintained over 24 h that offers an opportunity for once-daily dosing in patients who require maintenance bronchodilator therapy for the management of COPD symptoms.

Closed intramedullary nailing for ununited femoral shaft fractures.

Fifteen cases of ununited diaphyseal fractures of femurs were treated successfully by intramedullary reaming and closed Küntscher nailing through the small gluteal incision. The equipment used is the same as for nailing fresh shaft fractures. The cases included 10 nonunions, 2 delayed unions and 3 miscellaneous problems. All but one case had been initially treated by open reduction with some form of internal skeletal fixation. Two cases had been treated by 2 open procedures befor the closed Küntscher nailing. No supplemental bone graft or external immobilization was necessary. Two cases were nailed successfully in the presence of infection, resulting in solid union and no recurrence of infection. Five nails have been removed after union and no refracture has occurred. No important postoperative complication or instances of the fat embolism syndrome were encountered. No rotational deformity or further shortening of the femur occurred. Postoperatively, the patients ambulated with protected weight-bearing as early as possible. The average hospital stay was 15 days. In general, the patients had a functional extremity even while the fracture lines were still visible on roentgenographs; all have returned to their previous work.