Search

Abstract: 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 β2-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 (FEV1, 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 FEV1. 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 FEV1 was 1.01 L (37% predicted normal). All doses of olodaterol provided significantly greater bronchodilation compared to placebo in 24-h FEV1 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 FEV1 (0.121 L to 0.213 L) and average FEV1 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 FEV1. 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 β2-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. [Copyright &y& Elsevier]

Aims: The aim of this work is to compare empagliflozin systemic exposure between patients with heart failure (HF) and patients with type 2 diabetes (T2D)., Methods: Analysis of covariance (ANCOVA) compared steady state trough concentrations of empagliflozin 10 mg in EMPEROR-reduced (patients with HF with reduced ejection fraction [HFrEF]) and EMPA-REG OUTCOME (patients with T2D at high cardiovascular risk) after adjusting for eGFR and body weight., Results: The difference in geometric Mean (gMean) empagliflozin steady state trough concentration of 10 mg empagliflozin between EMPEROR-reduced and EMPA-REG OUTCOME was 1.47-fold (95% confidence interval [CI]: 1.33, 1.63). Additionally, ANCOVA for the sub-group of patients with both T2D and HF conditions revealed a difference in gMean steady state trough concentration of 1.53-fold (95% CI: 1.26, 1.85). In both patients with HFrEF and HF with preserved EF (HFpEF), there was no major difference in empagliflozin steady state trough exposure by New York Heart Association (NYHA) classification or by use of angiotensin receptor-neprilysin inhibitor as comedication. A weak positive correlation was observed for NT-proBNP at Week 12 and empagliflozin steady state trough concentration in both patients with HFrEF and HFpEF (Pearson correlation r = 0.19)., Conclusions: Plasma concentrations of empagliflozin in patients with HF were higher compared to patients with T2D, but the exposure resulting from the 10 mg dose was still below the exposure resulting from the dose of 25 mg approved in patients with T2D. The difference in exposure was attributable to demographic characteristics and HF-induced pathophysiological changes. Overall, the results confirm 10 mg as the appropriate empagliflozin dose in patients with HF., (© 2024 Boehringer Ingelheim Pharma GmbH & Co. KG. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Inhibition of the epithelial sodium channel (ENaC) represents a mutation-agnostic therapeutic approach to restore airway surface liquid hydration and mucociliary clearance in patients with cystic fibrosis. BI 1265162 is an inhaled ENaC inhibitor with demonstrated preclinical efficacy., Methods: Three phase I trials of BI 1265162 in healthy male subjects are presented: NCT03349723 (single-rising-dose trial evaluating safety, tolerability and pharmacokinetics (PK)); NCT03576144 (multiple-rising-dose trial evaluating safety, tolerability and PK); and NCT03907280 (absolute bioavailability trial)., Results: BI 1265162 single doses ≤1200 µg and multiple doses of 600 µg were well tolerated. Adverse events were balanced across treatment groups, were of mainly mild or moderate intensity and resolved by trial-end. One subject discontinued from trial medication on day 7 (asymptomatic hyperkalaemia adverse event; recovered day 8). One subject experienced a serious adverse event (neuropathia vestibularis) leading to hospitalisation and missed one of the four dosing periods. Both events were not considered to be drug-related and subjects recovered. BI 1265162 displayed dose-proportional, time-independent PK; maximum accumulation was 1.6-fold; calculated effective elimination half-life was 3.6-8.7 h over the dose ranges tested. Renal excretion was not a major drug elimination route. Oral and inhaled dosing (±activated oral charcoal) absolute bioavailability was 0.50% and ∼40%, respectively., Conclusion: BI 1265162 single or multiple doses up to 6.5 days were well tolerated. Systemic exposures mainly represent drug absorbed through the lungs and not the gastrointestinal tract, with ∼40% of the inhaled dose reaching the systemic circulation. Accumulation was minimal. Twice-daily dosing is supported for future development., Competing Interests: Conflict of interest: A. Mackie is an employee of Boehringer Ingelheim. Conflict of interest: J. Rascher has nothing to disclose. Conflict of interest: M. Schmid is an employee of Boehringer Ingelheim. Conflict of interest: V. Endriss is an employee of Boehringer Ingelheim. Conflict of interest: T. Brand is an employee of Boehringer Ingelheim. Conflict of interest: W. Seibold is an employee of Boehringer Ingelheim., (Copyright ©ERS 2021.)

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5-300 mg/day; Arm A), BI 860585 (40-220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80-220 mg/day; Arm C) with 60-80 mg/m 2 /week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash ( n = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash ( n = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.

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.