Assessment of physical functioning in patients with chronic obstructive pulmonary disease (COPD) requiring long-acting dual bronchodilation in routine clinical practice.

OBJECTIVE: We aim to determine the effect of a fixed-dose combination (FDC) of tiotropium/olodaterol on Physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) in a real world setting. METHODS: COPD patients were prospectively enrolled to evaluate the effect of a FDC of tiotropium/olodaterol inhaler therapy via the Respimat® Soft Mist™ inhaler (SMI) on the physical functioning scale (PF-10), and the general condition of the patient as assessed by the physician (Physician's Global Evaluation, PGE), and the patient's satisfaction after 6 weeks of treatment. The primary end-point was the percentage of patients with therapeutic success at 6th week follow-up, defined as a ≥10-points increase in the standardised PF-10 score from baseline. RESULTS: A total of 257 patients from 57 sites were enrolled, and 234 completed the follow up. After 6 weeks of treatment, 155 out of 234 patients (66.2%) showed therapeutic success in the physical functioning score, coupled with significant improvement in PGE score: 78 (33.3%) patients with good/excellent PGE score at baseline, increasing to 172 (73.5%) at 6th week (p<0.0001). The patient's satisfaction was excellent: 77.2% reporting to be satisfied/very satisfied with the treatment, 79.9% with inhaling and 79.0% with the handling of SMI device. 1.6% of patients reported an investigator-defined drug-related adverse event. CONCLUSION: Treatment of COPD patients with a FDC of tiotropium/olodaterol SMI for 6 weeks resulted in significant improvements in the patients' condition as assessed by patients and physicians, with no new safety findings.

Subcellular localization of the voltage-gated potassium channels Kv3.1b and Kv3.3 in the cerebellar dentate nucleus of glutamic acid decarboxylase 67-green fluorescent protein transgenic mice.

Deep cerebellar dentate nuclei are in a key position to control motor planning as a result of an integration of cerebropontine inputs and hemispheric Purkinje neurons signals, and their influence through synaptic outputs onto extracerebellar hubs. GABAergic dentate neurons exhibit broader action potentials and slower afterhyperpolarization than non-GABAergic (presumably glutamatergic) neurons. Specific potassium channels may be involved in these distinct firing profiles, particularly, Kv3.1 and Kv3.3 subunits which rapidly activate at relatively positive potentials to support the generation of fast action potentials. To investigate the subcellular localization of Kv3.1b and Kv3.3 in GAD- and GAD+ dentate neurons of glutamic acid decarboxylase 67-green fluorescent protein (GAD67-GFP) knock-in mice a preembedding immunocytochemical method for electron microscopy was used. Kv3.1b and Kv3.3 were in membranes of cell somata, dendrites, axons and synaptic terminals of both GAD- and GAD+ dentate neurons. The vast majority of GAD- somatodendritic membrane segments domains labeled for Kv3.1b and Kv3.3 (96.1% and 84.7%, respectively) whereas 56.2% and 69.8% of GAD- axonal membrane segments were immunopositive for these subunits. Furthermore, density of Kv3.1b immunoparticles was much higher in GAD- somatodendritic than axonal domains. As to GAD+ neurons, only 70.6% and 50% of somatodendritic membrane segments, and 53.3% and 59.5% of axonal membranes exhibited Kv3.1b and Kv3.3 labeling, respectively. In contrast to GAD- cells, GAD+ cells exhibited a higher density labeling for both Kv3 subunits at their axonal than at their somatodendritic membranes. Taken together, Kv3.1b and Kv3.3 potassium subunits are expressed in both GAD- and GAD+ cells, albeit at different densities and distribution. They likely contribute to the distinct biophysical properties of both GAD- and GAD+ neurons in the dentate nucleus.