Dose selection for glycopyrrolate/eFlow® phase III clinical studies: results from GOLDEN (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer) phase II dose-finding studies

Abstract Background Long-acting muscarinic antagonists (LAMAs) are recommended for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrrolate/eFlow® is an investigational drug–device combination of the LAMA glycopyrrolate administered by an eFlow® Closed System (eFlow® CS) nebulizer. The GOLDEN 2 (NCT01706536) and GOLDEN 6 (NCT02038829) Phase II, multicenter studies were conducted to inform dose selection for the GOLDEN Phase III clinical trials. Bronchodilator responses and safety assessments supported dose selection. Methods Subjects with moderate-to-severe COPD were randomized into 28-day parallel-group (GOLDEN 2) or 7-day crossover (GOLDEN 6) studies and received placebo, glycopyrrolate (3, 6.25, 12.5, 25, 50 or 100 μg twice daily [BID]) or aclidinium bromide 400 μg BID. The primary endpoint of both studies was change from baseline in trough forced expiratory volume in 1 s (FEV1). Safety assessments included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events, and discontinuation due to TEAE. Lung function data collected in both studies were pooled. Results The combined GOLDEN 2 (n = 282) and GOLDEN 6 (n = 96) studies included 378 subjects. On Days 7 and 28 there were dose-ordered, statistically significant and clinically important lung function improvements in glycopyrrolate treatment groups. Specifically, on Day 7, glycopyrrolate produced >0.100 L placebo-adjusted changes from baseline in trough FEV1 (12.5 μg BID: 0.122 L; 25 μg BID: 0.123 L; 50 μg BID: 0.137 L) and FEV1 AUC0–12 (12.5 μg BID: 0.145 L; 25 μg BID: 0.178 L; 50 μg BID: 0.180 L). The improvements in lung function for the glycopyrrolate 25 and 50 μg BID doses were comparable to those with aclidinium bromide 400 μg BID (FEV1: 0.149 L; FEV1 AUC0−12: 0.172 L). Acceptable safety profiles were observed across all groups in both studies. Conclusions The efficacy and safety findings supported selection of glycopyrrolate 25 and 50 μg BID doses for the Phase III GOLDEN studies and provided preliminary evidence for the use of nebulized glycopyrrolate as a maintenance therapy for COPD

Modafinil treatment modulates functional connectivity in stroke survivors with severe fatigue

Post-stroke fatigue has a significant impact on stroke survivors’ mental and physical well-being. Our recent clinical trial showed significant reduction of post-stroke fatigue with modafinil treatment, however functional connectivity changes in response to modafinil have not yet been explored in stroke survivors with post-stroke fatigue. Twenty-eight participants (multidimensional fatigue inventory-20 ≥ 60) had MRI scans at baseline, and during modafinil and placebo treatment. Resting-state functional MRI data were obtained, and independent component analysis was used to extract functional networks. Resting-state functional connectivity (rsFC) was examined between baseline, modafinil and placebo treatment using permutation testing with threshold-free cluster enhancement. Overall twenty-eight participants (mean age: 6 +/-2 14.3, mean baseline MFI-20: 72.3 +/-9.24) were included. During modafinil treatment, increased rsFC was observed in the right hippocampus (p = 0.004, 11 voxels) compared to placebo. This coincided with lower rsFC in the left frontoparietal (inferior parietal lobule, p = 0.023, 13 voxels), somatosensory (primary somatosensory cortex; p = 0.009, 32 voxels) and mesolimbic network (temporal pole, p = 0.016, 35 voxels). In conclusion, modafinil treatment induces significant changes in rsFC in post-stroke fatigue. This modulation of rsFC may relate to a reduction of post-stroke fatigue; however, the relationship between sensory processing, neurotransmitter expression and fatigue requires further exploration

Assessment of potential cardiotoxic side effects of mitoxantrone in patients with multiple sclerosis

Previous studies showed that mitoxantrone can reduce disability progression in patients with multiple sclerosis (MS). There is, however, concern that it may cause irreversible cardiomyopathy with reduced left ventricular (LV) ejection fraction (EF) and congestive heart failure. The aim of this prospective study was to investigate cardiac side effects of mitoxantrone by repetitive cardiac monitoring in MS patients. The treatment protocol called for ten courses of a combined mitoxantrone (10 mg/m(2) body surface) and methylprednisolone therapy. Before each course, a transthoracic echocardiogram was performed to determine the LV end-diastolic diameter, the end-systolic diameter and the fractional shortening; the LV-EF was calculated. Seventy-three patients participated (32 males; age 48 +/- 12 years, range 20-75 years; 25 with primary progressive, 47 with secondary progressive and 1 with relapsing-remitting MS) who received at least four courses of mitoxantrone. Three of the 73 patients were excluded during the study (2 patients discontinued therapy; 1 patient with a previous history of ischemic heart disease developed atrial fibrillation after the second course of mitoxantrone). The mean cumulative dose of mitoxantrone was 114.0 +/- 33.8 mg. The mean follow-up time was 23.4 months (range 10-57 months). So far, there has been no significant change in any of the determined parameters (end-diastolic diameter, end-systolic diameter, fractional shortening, EF) over time during all follow-up investigations. Mitoxantrone did not cause signs of congestive heart failure in any of the patients. Further cardiac monitoring is, however, needed to determine the safety of mitoxantrone after longer follow-up times and at higher cumulative doses. Copyright (C) 2005 S. Karger AG, Basel

Beyond communication:The role of standardized protocols in a changing health care environment

Background: Communication errors have grave consequences in health care settings. The situationYbackgroundY assessmentYrecommendation (SBAR) protocol has been theorized to improve communication by creating a common language between nurses and physicians in acute care situations. This practice is gaining acceptance across the health care field. However, as yet, there has been little investigation of the ways in which SBAR may have an impact on how health care professionals operate beyond the creation of a common language. Purpose: The purposes of the study were to explore the implementation of the SBAR protocol and investigate the potential impact of SBAR on the day-to-day experiences of nurses. Methods: We performed a qualitative case study of 2 hospitals that were implementing the SBAR protocol. We collected data from 80 semistructured interviews with nurses, nurse manager, and physicians; observation of nursing and other hospital activities; and documents that pertained to the implementation of the SBAR protocol. Data were analyzed using a thematic approach. Findings: Our analysis revealed 4 dimensions of impact that SBAR has beyond its use as a communication tool: schema formation, development of legitimacy, development of social capital, and reinforcement of dominant logics

Глобалізація і нові виклики економічній дипломатії

У статті розглянуто вплив глобалізації на економічну дипломатію, відзначено основні виклики, пов’язані із фінансовою кризою 2008–2012 років. Визначено сучасний стан забезпечення української економічної дипломатії, наведено порівняння із досвідом провідних держав світу, в тому числі сусідніх країн. Виокремлено проблемні аспекти функціонування вітчизня- них дипломатичних представництв у частині забезпечення економічних інтересів України. Окреслено головні завдання для подальшої науково-теоретичної та практичної діяльності у сфері економічної дипломатії в Україні.В статье рассмотрено влияние глобализации на экономическую дипломатию, определены основные вызовы, связанные с финансовым кризисом 2008–2012 годов. Охарактеризовано современное состояние украинской экономической дипломатии, проведено сравнение с опытом ведущих стран мира, в том числе соседних. Выделены проблемные аспекты функционирования отечественных дипломатических представительств в части обеспечения экономических интересов Украины. Обозначены основные задания для дальнейшей научно-теоретической и практической деятельности в сфере экономической дипломатии Украины.The article discusses the impact of globalization on economic diplomacy, defined the key challenges that are associated with the continuing financial crisis of 2008–2012.Were defined the current situation with support of the Ukrainian economic diplomacy, a comparison with the experience of leading countries (including – neighbors).There were allocated the problematic aspects for the national diplomatic missions in support of Ukraine’s economic interests.Article denotes the main targets for further research and theoretical and practical activity in area of economic diplomacy in Ukraine

Facts, Principles, and (Real) Politics

Should our factual understanding of the world influence our normative theorising about it? G.A. Cohen has argued that our ultimate normative principles should not be constrained by facts. Many others have defended or are committed to various versions or subsets of that claim. In this paper I dispute those positions by arguing that, in order to resist the conclusion that ultimate normative principles rest on facts about possibility or conceivability, one has to embrace an unsatisfactory account of how principles generate normative political judgments. So political theorists have to choose between principles ostensibly unbiased by our current understanding of human motivation and political reality, or principles capable of reliably generating political judgments. I conclude with wider methodological observations in defence of the latter option, and so of a return to political philosophy’s traditional blend of normative and descriptive elements

An Experimental Approach to Examining Psychological Contributions to Multisite Musculoskeletal Pain.

The present study examined the prospective value of pain catastrophizing, fear of pain, and depression in the prediction of multisite musculoskeletal pain following experimentally induced delayed-onset muscle soreness (DOMS). The study sample consisted of 119 (63 females, 56 males) healthy university students. Measures of pain catastrophizing, fear of pain, and depression were completed prior to the DOMS induction procedure. Analyses revealed that pain catastrophizing and fear of pain prospectively predicted the experience of multisite pain following DOMS induction. Analyses also revealed that women were more likely to experience multisite pain than men. There was no significant relation between depressive symptoms and the experience of multisite pain. The discussion addresses the mechanisms by which pain catastrophizing and fear of pain might contribute to the spreading of pain. Clinical implications of the findings are also addressed. Perspective: The results of this experimental study suggest that pain catastrophizing and fear of pain might increase the risk of developing multisite pain following musculoskeletal injury