Bronchodilation and safety of supratherapeutic doses of salbutamol or ipratropium bromide added to single dose GSK961081 in patients with moderate to severe COPD

BackgroundThere are few data on the bronchodilatory effects of adding short-acting bronchodilators (SABA) to maintenance, long-acting bronchodilator therapy. This study assessed the additional bronchodilation and safety of adding supratherapeutic doses of salbutamol (SALB) or ipratropium bromide (IPR) to the novel bi-functional molecule (or dual pharmacophore) GSK961081 400 μg (MABA 400) or 1200 μg (MABA 1200).MethodsThis randomised, double-blind, complete, crossover study in 44 patients with moderate to severe COPD, evaluated 6 treatments with a washout of at least 7 days between treatments: single doses of MABA 400 or MABA 1200 followed by cumulative doses of either SALB (3× 200 μg at 20 min intervals), IPR (20 μg, 20 μg and 40 μg at 20 min intervals) or placebo (PLA) (three doses at 20 min intervals) at 1 h, 12 h and 24 h post-MABA dose. The primary endpoint was maximal increase in FEV₁, from pre-dose bronchodilator (SABA/PLA), measured 15 min after each cumulative dose of SALB, IPR or PLA. Systemic pharmacodynamics (potassium, heart rate, glucose and QTc), adverse events and systemic pharmacokinetics were also assessed.ResultsThe additional bronchodilatory effects at 12 h and 24 h for both SALB and IPR were of a similar magnitude and statistically significant relative to PLA; mean differences (SE) (L) following MABA 400 dosing: 0.139 (0.023) after SALB at 12 h; 0.123 (0.022) after SALB at 24 h; 0.124 (0.023) after IPR at 12 h; 0.141 (0.021) after IPR at 24 h; and after MABA 1200 dosing: 0.091 (0.023) after SALB at 12 h; 0.126 (0.022) after SALB at 24 h; 0.055 (0.023) after IPR at 12 h; 0.122 (0.022) after IPR at 24 h. Any additional bronchodilator effects at 1 h were small and not clinically significantly different from PLA. There were small, non-clinically significant increases in mean heart rate after both MABA doses plus SALB, and decreased potassium levels in four patients after MABA 1200 plus SALB (×3) or PLA (×1) were observed but overall all treatments were well tolerated and raised no significant safety signals.ConclusionThe additional bronchodilation achieved following supratherapeutic doses of SALB and IPR on top of single doses of MABA 400 or 1200 was comparable for the two agents and neither were associated with any clinically relevant systemic pharmacodynamic effects other than the small transient hypokalemic effect in a 3 out of 41 patients receiving additional high dose salbutamol and MABA 1200. Either short-acting bronchodilator could potentially be used as rescue medication on top of MABA therapy.     

Age-dependent alteration in muscle regeneration: the critical role of tissue niche

Although adult skeletal muscle is composed of fully differentiated fibers, it retains the capacity to regenerate in response to injury and to modify its contractile and metabolic properties in response to changing demands. The major role in the growth, remodeling and regeneration is played by satellite cells, a quiescent population of myogenic precursor cells that reside between the basal lamina and plasmalemma and that are rapidly activated in response to appropriate stimuli. However, in pathologic conditions or during aging, the complete regenerative program can be precluded by fibrotic tissue formation and resulting in functional impairment of the skeletal muscle. Our study, along with other studies, demonstrated that although the regenerative program can also be impaired by the limited proliferative capacity of satellite cells, this limit is not reached during normal aging, and it is more likely that the restricted muscle repair program in aging is presumably due to missing signals that usually render the damaged muscle a permissive environment for regenerative activity.     

Nebulous margins: Sexuality and social constructions of risks in rural areas of Central Mexico

This paper reports on research conducted among young people in two rural communities in the state of Morelos, Central Mexico. Methods used included participant observation, indepth interviews and focus groups. Findings suggest that a person's constitution or 'nature', their gender and perceived risks during agricultural work were strongly associated with riskrelated sexual behaviour. Those who perceive themselves as having a strong constitution see themselves at low risk of acquiring STIs/AIDS. Young people reported receiving little information about reproductive matters at school, including condom use. When information was provided, it was often in a form disassociated from its cultural context. Efforts to control female sexuality between puberty and marriage were particularly marked in the communities studied and may interfere with risk reduction among both young women and young men. Policy recommendations for the future development of sexual education in rural areas in Mexico are outlined.     

Life Course Epidemiology in Nutrition and Chronic Disease Research: A Timely Discussion

Humans are exposed to a complex and changing combination of nutritional factors during the life course, necessitating their investigation over time to capture “critical periods of sensitivity.” A life course approach provides a framework to examine trajectories and long-term effects of nutritional and other risk factors, particularly the role of timing, accumulation, and temporal relationships of these exposures in relation to chronic disease development. Currently, most epidemiologic research does not sufficiently address this issue in relation to disease etiology. Although applying a life course approach would augment our knowledge about disease development, this approach presents major challenges in designing, conducting, and analyzing studies. A scientific symposium was held that reviewed emerging research and discussed methodological concerns in applying the life course approach. The research presented at this session focused on the role of timing, with the pre- and postnatal and pubertal periods as critical windows of exposure for chronic conditions. Methodological issues and complexities in analyzing and selecting datasets were highlighted. This symposium elucidated unique study designs and statistical strategies to demonstrate the strengths of this methodology, and served as a catalyst for new research in the area of nutrition and chronic disease epidemiology.     

PSYCHOTHERAPY APPROACHES FOR ADULT SURVIVORS OF CHILDHOOD SEXUAL ABUSE: AN INTEGRATIVE REVIEW OF OUTCOMES RESEARCH

This review synthesized results of 26 outcomes research studies and two meta-analyses that evaluated abuse-focused psychotherapy techniques for survivors of childhood sexual abuse. Different therapeutic approaches delivered in individual, group, or combination formats were evaluated with pre/post test, quasi-experimental, or randomized control designs. Accumulated research findings suggest that abuse-focused psychotherapy for adults sexually abused as children is generally beneficial in reducing psychiatric distress, depression, and trauma-specific symptoms. No one therapeutic approach was demonstrated to be superior. There was little evidence about the effectiveness of individual versus group therapy or the optimal treatment duration.