Isoform-selective NADPH oxidase inhibitor panel for pharmacological target validation.

Dysfunctional reactive oxygen species (ROS) signaling is considered an important disease mechanism. Therapeutically, non-selective scavenging of ROS by antioxidants, however, has failed in multiple clinical trials to provide patient benefit. Instead, pharmacological modulation of disease-relevant, enzymatic sources of ROS appears to be an alternative, more promising and meanwhile successfully validated approach. With respect to targets, the family of NADPH oxidases (NOX) stands out as main and dedicated ROS sources. Validation of the different NOX isoforms has been mainly through genetically modified rodent models and is lagging behind in other species. It is unclear whether the different NOX isoforms are sufficiently distinct to allow selective pharmacological modulation. Here we show for five widely used NOX inhibitors that isoform selectivity can be achieved, although individual compound specificity is as yet insufficient. NOX1 was most potently (IC50) targeted by ML171 (0.1 µM); NOX2, by VAS2870 (0.7 µM); NOX4, by M13 (0.01 µM) and NOX5, by ML090 (0.01 µM). In addition, some non-specific antioxidant and assay artefacts may limit the interpretation of data, which included, surprisingly, the clinically advanced NOX inhibitor, GKT136901. In a human ischemic blood-brain barrier hyperpermeability model where genetic target validation is not an option, we provide proof-of-principle that pharmacological target validation for different NOX isoforms is possible by applying an inhibitor panel at IC50 concentrations. Moreover, our findings encourage further lead optimization and development efforts for isoform-selective NOX inhibitors in different indications.

Reactive Oxygen Comes of Age: Mechanism-Based Therapy of Diabetic End-Organ Damage.

Reactive oxygen species (ROS) have been mainly viewed as unwanted by-products of cellular metabolism, oxidative stress, a sign of a cellular redox imbalance, and potential disease mechanisms, such as in diabetes mellitus (DM). Antioxidant therapies, however, have failed to provide clinical benefit. This paradox can be explained by recent discoveries that ROS have mainly essential signaling and metabolic functions and evolutionally conserved physiological enzymatic sources. Disease can occur when ROS accumulate in nonphysiological concentrations, locations, or forms. By focusing on disease-relevant sources and targets of ROS, and leaving ROS physiology intact, precise therapeutic interventions are now possible and are entering clinical trials. Their outcomes are likely to profoundly change our concepts of ROS in DM and in medicine in general.

Satisfaction and burden of mental health personnel: data from healthcare services for substance users and their families

Objective: To evaluate satisfaction and burden of mental health personnel providing mental health services for substance users and their families. Method: Five hundred twenty-seven mental health workers who provide treatment for substance users in five Brazilian states were interviewed. Data on sociodemographic characteristics and measures of satisfaction (SATIS-BR) and burden of mental health personnel (IMPACTO-BR) were collected. Results: Type of mental health service and educational attainment were associated with degree of satisfaction and burden. Therapeutic community workers and those with a primary education level reported being more satisfied with the treatment offered to patients, their engagement in service activities, and working conditions. Workers from psychosocial care centers, psychosocial care centers focused on alcohol and other drugs, and social care referral centers (both general and specialized), as well as workers with a higher education, reported feeling overburdened. Conclusion: This study offers important information regarding the relationship of mental health personnel with their work. Care providers within this sample reported an overall high level of job satisfaction, while perceived burden differed by type of service and educational attainment. To our knowledge, this is the first study with a sample of mental health professionals working with substance users across five Brazilian states.

Satisfaction and burden of mental health personnel: data from healthcare services for substance users and their families.

OBJECTIVE: To evaluate satisfaction and burden of mental health personnel providing mental health services for substance users and their families. METHOD: Five hundred twenty-seven mental health workers who provide treatment for substance users in five Brazilian states were interviewed. Data on sociodemographic characteristics and measures of satisfaction (SATIS-BR) and burden of mental health personnel (IMPACTO-BR) were collected. RESULTS: Type of mental health service and educational attainment were associated with degree of satisfaction and burden. Therapeutic community workers and those with a primary education level reported being more satisfied with the treatment offered to patients, their engagement in service activities, and working conditions. Workers from psychosocial care centers, psychosocial care centers focused on alcohol and other drugs, and social care referral centers (both general and specialized), as well as workers with a higher education, reported feeling overburdened. CONCLUSION: This study offers important information regarding the relationship of mental health personnel with their work. Care providers within this sample reported an overall high level of job satisfaction, while perceived burden differed by type of service and educational attainment. To our knowledge, this is the first study with a sample of mental health professionals working with substance users across five Brazilian states.

Crack-cocaine users have less family cohesion than alcohol users

Objective: Many studies correlate characteristics of family functioning and the development of drug addiction. This study sought to evaluate and compare the family environment styles of two groups of psychoactive substance users: 1) alcohol-only users and 2) crack-cocaine users. Methods: Three hundred and sixty-four users of alcohol, crack-cocaine, and other drugs, recruited from research centers in four Brazilian capitals participated in this study. Subjects were evaluated through the Family Environment Scale and the Addiction Severity Index, 6th version (ASI-6). ASI-6 t-scores were compared by analysis of variance (ANOVA) and post-hoc tests. A final model was obtained using a logistic regression analysis. All analyses were adjusted for partner, age, and psychiatric t-score. Results: We found a significant difference between groups in the cohesion subscale (p = 0.044). The post-hoc test revealed a difference of 1.06 points (95%CI 0.11-2.01) between groups 1 (6.45±0.28) and 2 (5.38±0.20). No significant between-group differences were observed in the other subscales. However, categorical analyses of variables regarding family dynamic showed that crack users more often reported that sometimes people in their family hit each other (30.4% vs. 13.2%, p = 0.007) and that people in their family frequently compared each other regarding work and/or school achievement (57.2% vs. 42.6%, p = 0.041). Conclusion: These results suggest that families of crack-cocaine users are less cohesive than families of alcohol users. This type of family environment may affect treatment outcome, and should thus be adequately approached.

Crack-cocaine users have less family cohesion than alcohol users.

OBJECTIVE: Many studies correlate characteristics of family functioning and the development of drug addiction. This study sought to evaluate and compare the family environment styles of two groups of psychoactive substance users: 1) alcohol-only users and 2) crack-cocaine users. METHODS: Three hundred and sixty-four users of alcohol, crack-cocaine, and other drugs, recruited from research centers in four Brazilian capitals participated in this study. Subjects were evaluated through the Family Environment Scale and the Addiction Severity Index, 6th version (ASI-6). ASI-6 t-scores were compared by analysis of variance (ANOVA) and post-hoc tests. A final model was obtained using a logistic regression analysis. All analyses were adjusted for partner, age, and psychiatric t-score. RESULTS: We found a significant difference between groups in the cohesion subscale (p = 0.044). The post-hoc test revealed a difference of 1.06 points (95%CI 0.11-2.01) between groups 1 (6.45±0.28) and 2 (5.38±0.20). No significant between-group differences were observed in the other subscales. However, categorical analyses of variables regarding family dynamic showed that crack users more often reported that sometimes people in their family hit each other (30.4% vs. 13.2%, p = 0.007) and that people in their family frequently compared each other regarding work and/or school achievement (57.2% vs. 42.6%, p = 0.041). CONCLUSION: These results suggest that families of crack-cocaine users are less cohesive than families of alcohol users. This type of family environment may affect treatment outcome, and should thus be adequately approached.