Novel ocular antihypertensive compounds in clinical trials

June Chen1, Stephen A Runyan1, Michael R Robinson21Department of Biological Sciences, 2Ophthalmology Clinical Research, Allergan, Inc, Irvine, CA, USAIntroduction: Glaucoma is a multifactorial disease characterized by progressive optic nerve injury and visual field defects. Elevated intraocular pressure (IOP) is the most widely recognized risk factor for the onset and progression of open-angle glaucoma, and IOP-lowering medications comprise the primary treatment strategy. IOP elevation in glaucoma is associated with diminished or obstructed aqueous humor outflow. Pharmacotherapy reduces IOP by suppressing aqueous inflow and/or increasing aqueous outflow.Purpose: This review focuses on novel non-FDA approved ocular antihypertensive compounds being investigated for IOP reduction in ocular hypertensive and glaucoma patients in active clinical trials within approximately the past 2 years.Methods: The mode of IOP reduction, pharmacology, efficacy, and safety of these new agents were assessed. Relevant drug efficacy and safety trials were identified from searches of various scientific literature databases and clinical trial registries. Compounds with no specified drug class, insufficient background information, reformulations, and fixed-combinations of marketed drugs were not considered.Results: The investigational agents identified comprise those that act on the same targets of established drug classes approved by the FDA (ie, prostaglandin analogs and β-adrenergic blockers) as well as agents belonging to novel drug classes with unique mechanisms of action. Novel targets and compounds evaluated in clinical trials include an actin polymerization inhibitor (ie, latrunculin), Rho-associated protein kinase inhibitors, adenosine receptor analogs, an angiotensin II type 1 receptor antagonist, cannabinoid receptor agonists, and a serotonin receptor antagonist.Conclusion: The clinical value of novel compounds for the treatment of glaucoma will depend ultimately on demonstrating favorable efficacy and benefit-to-risk ratios relative to currently approved prostaglandin analogs and β-blockers and/or having complementary modes of action.Keywords: intraocular pressure, glaucoma progression, clinical trials, drug development, aqueous humor dynamics, antihypertensiv

Family social support, community “social capital” and adolescents’ mental health and educational outcomes: a longitudinal study in England

Purpose To examine the associations between family social support, community “social capital” and mental health and educational outcomes. Methods The data come from the Longitudinal Study of Young People in England, a multi-stage stratified nationally representative random sample. Family social support (parental relationships, evening meal with family, parental surveillance) and community social capital (parental involvement at school, sociability, involvement in activities outside the home) were measured at baseline (age 13–14), using a variety of instruments. Mental health was measured at age 14–15 (GHQ-12). Educational achievement was measured at age 15–16 by achievement at the General Certificate of Secondary Education. Results After adjustments, good paternal (OR = 0.70, 95% CI 0.56–0.86) and maternal (OR = 0.65, 95% CI 0.53–0.81) relationships, high parental surveillance (OR = 0.81, 95% CI 0.69–0.94) and frequency of evening meal with family (6 or 7 times a week: OR = 0.77, 95% CI 0.61–0.96) were associated with lower odds of poor mental health. A good paternal relationship (OR = 1.27, 95% CI 1.06–1.51), high parental surveillance (OR = 1.37, 95% CI 1.20–1.58), high frequency of evening meal with family (OR = 1.64, 95% CI 1.33–2.03) high involvement in extra-curricular activities (OR = 2.57, 95% CI 2.11–3.13) and parental involvement at school (OR = 1.60, 95% CI 1.37–1.87) were associated with higher odds of reaching the educational benchmark. Participating in non-directed activities was associated with lower odds of reaching the benchmark (OR = 0.79, 95% CI 0.70–0.89). Conclusions Building social capital in deprived communities may be one way in which both mental health and educational outcomes could be improved. In particular, there is a need to focus on the family as a provider of support

Use of Discretionary Protective Equipment in High School Athletes: Prevalence and Determinants

Objectives. We sought to describe the use of discretionary protective equipment among high school athletes and to examine social and behavioral determinants contributing to equipment usage. Methods. We analyzed data from a 3-year (1996–1999), stratified, 2-stage cluster sample of athletes engaged in 12 organized sports in 100 North Carolina high schools (n=19728 athlete-seasons) (an athlete-season represents an individual student who participates in a particular sport in a particular season). We used generalized logistic regression to model the association of social and behavioral determinants and demographic variables with discretionary protective equipment use. Results. About one third of high school athletes self-reported using lower extremity discretionary protective equipment. Girls, seniors, those who played limited-contact sports, and those who played multiple sports reported higher usage. Small school size, low player/coach ratio, high proportion of team usage, and history of previous lower extremity injury were important predictors of usage. Coaches’ experience, qualifications, and training, however, were not predictive of usage. Conclusions. Intervention efforts to promote use of discretionary protective equipment need to target school-level factors and should consider both team requirements and the role of peers in setting and reinforcing norms

Adipose-derived human stem/stromal cells: comparative organ specific mitochondrial bioenergy profiles

BACKGROUND: Adipose-derived stem/stromal cells (ASCs) isolated from the stromal vascular fraction are a source of mesenchymal stem cells that have been shown to be beneficial in many regenerative medicine applications. ASCs are an attractive source of stem cells in particular, due to their lack of immunogenicity. This study examines differences between mitochondrial bioenergetic profiles of ASCs isolated from adipose tissue of five peri-organ regions: pericardial, thymic, knee, shoulder, and abdomen. RESULTS: Flow cytometry showed that the majority of each ASC population isolated from the adipose tissue of 12 donors, with an n = 3 for each tissue type, were positive for MSC markers CD90, CD73, and CD105, and negative for hematopoietic markers CD34, CD11B, CD19, and CD45. Bioenergetic profiles were obtained for ASCs with an n = 4 for each tissue type and graphed together for comparison. Mitochondrial stress tests provided the following measurements: basal respiration rate (measured as oxygen consumption rate [pmol O2/min], ATP production, proton leak, maximal respiration, respiratory control ratio, coupling efficiency, and non-mitochondrial respiration. Glycolytic stress tests provided the following measurements: basal glycolysis rate (measured as extracellular acidification rate [mpH/min]), glycolytic capacity, glycolytic reserve, and non-glycolytic acidification. CONCLUSIONS: The main goal of this manuscript was to provide baseline reference values for future experiments and to compare bioenergetic potentials of ASCs isolated from adipose tissue harvested from different anatomical locations. Through an investigation of mitochondrial respiration and glycolysis, it was demonstrated that bioenergetic profiles do not significantly differ by region due to depot-dependent and donor-dependent variability. Thus, although the physiological function, microenvironment and anatomical harvest site may directly affect the characteristics of ASCs isolated from different organ regions, the ultimate utility of ASCs remains independent of the anatomical harvest site

TOMMORROW neuropsychological battery: German language validation and normative study

Assessment of preclinical Alzheimer's disease (AD) requires reliable and validated methods to detect subtle cognitive changes. The battery of standardized cognitive assessments that is used for diagnostic criteria for mild cognitive impairment due to AD in the TOMMORROW study have only been fully validated in English-speaking countries. We conducted a validation and normative study of the German language version of the TOMMORROW neuropsychological test battery, which tests episodic memory, language, visuospatial ability, executive function, and attention.; German-speaking cognitively healthy controls (NCs) and subjects with AD were recruited from a memory clinic at a Swiss medical center. Construct validity, test-retest, and alternate form reliability were assessed in NCs. Criterion and discriminant validities of the cognitive measures were tested using logistic regression and discriminant analysis. Cross-cultural equivalency of performance of the German language tests was compared with English language tests.; A total of 198 NCs and 25 subjects with AD (aged 65-88 years) were analyzed. All German language tests discriminated NCs from persons with AD. Episodic memory tests had the highest potential to discriminate with almost twice the predictive power of any other domain. Test-retest reliability of the test battery was adequate, and alternate form reliability for episodic memory tests was supported. For most tests, age was a significant predictor of group effect sizes; therefore, normative data were stratified by age. Validity and reliability results were similar to those in the published US cognitive testing literature.; This study establishes the reliability and validity of the German language TOMMORROW test battery, which performed similarly to the English language tests. Some variations in test performance underscore the importance of regional normative values. The German language battery and normative data will improve the precision of measuring cognition and diagnosing incident mild cognitive impairment due to AD in clinical settings in German-speaking countries