Sertraline hydrochloride for reducing impulsive behaviour in male, repeat-violent offenders (ReINVEST): protocol for a phase IV, double-blind, placebo-controlled, randomised clinical trial.

INTRODUCTION: Considerable evidence supports an association between poor impulse control (impulsivity) and violent crime. Furthermore, impulsivity and aggression has been associated with reduced levels of serotonergic activity in the brain. Selective serotonin reuptake inhibitors (SSRIs) are a class of anti-depressants that aim to regulate brain serotonin concentrations. Several small studies in psychiatric populations have administered SSRIs to impulsive--aggressive individuals, resulting in reduced impulsivity, anger, aggression and depression. However, no clinical trial has been undertaken in a criminal justice population. This protocol describes the design and implementation of the first systematic study of the potential benefits of SSRIs in impulsive---violent offenders who are at high risk of reoffending. METHODS AND ANALYSIS: A randomised, double-blinded, multicentre trial to test the clinical efficacy of an SSRI, sertraline hydrochloride, compared with placebo on recidivism and behavioural measures (including impulsivity, anger, aggression, depression and self-reported offending) over 12 months. 460 participants with histories of violence and screening positive for impulsivity are recruited at several local courts and correctional service offices in New South Wales, Australia. ETHICS AND DISSEMINATION: Results will be submitted for publication in a peer-reviewed journal. Possible implications of the effectiveness of this pharmacological intervention include economic benefits of reducing prison costs and societal benefits of improving safety. This study has received ethical approval from the University of New South Wales, Aboriginal Health & Medical Research Council, Corrective Services NSW and the NSW Justice Health and Forensic Mental Health Network. TRIAL REGISTRATION NUMBER: ACTRN12613000442707.

Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660).

AIMS: Cathepsin C (CTSC) is necessary for the activation of several serine proteases including neutrophil elastase (NE), cathepsin G and proteinase 3. GSK2793660 is an oral, irreversible inhibitor of CTSC that is hypothesized to provide an alternative route to achieve NE inhibition and was tested in a Phase I study. METHODS: Single escalating oral doses of GSK2793660 from 0.5 to 20 mg or placebo were administered in a randomized crossover design to healthy male subjects; a separate cohort received once daily doses of 12 mg or placebo for 21 days. Data were collected on safety, pharmacokinetics, CTSC enzyme inhibition and blood biomarkers. RESULTS: Single, oral doses of GSK2793660 were able to dose-dependently inhibit whole blood CTSC activity. Once daily dosing of 12 mg GSK2793660 for 21 days achieved ≥90% inhibition (95% CI: 56, 130) of CTSC within 3 h on day 1. Only modest reductions of whole blood enzyme activity of approximately 20% were observed for NE, cathepsin G and proteinase 3. Seven of 10 subjects receiving repeat doses of GSK2793660 manifested epidermal desquamation on palmar and plantar surfaces beginning 7-10 days after dosing commencement. There were no other clinically important safety findings. CONCLUSIONS: GSK2793660 inhibited CTSC activity but not the activity of downstream neutrophil serine proteases. The palmar-plantar epidermal desquamation suggests a previously unidentified role for CTSC or one of its target proteins in the maintenance and integrity of the epidermis at these sites, with some similarities to the phenotype of CTSC-deficient humans.

Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice.

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene that encodes α-galactosidase A and is characterized by pathological accumulation of globotriaosylceramide and globotriaosylsphingosine. Earlier, the authors demonstrated that oral coadministration of the pharmacological chaperone AT1001 (migalastat HCl; 1-deoxygalactonojirimycin HCl) prior to intravenous administration of enzyme replacement therapy improved the pharmacological properties of the enzyme. In this study, the authors investigated the effects of coformulating AT1001 with a proprietary recombinant human α-galactosidase A (ATB100) into a single intravenous formulation. AT1001 increased the physical stability and reduced aggregation of ATB100 at neutral pH in vitro, and increased the potency for ATB100-mediated globotriaosylceramide reduction in cultured Fabry fibroblasts. In Fabry mice, AT1001 coformulation increased the total exposure of active enzyme, and increased ATB100 levels in cardiomyocytes, cardiac vascular endothelial cells, renal distal tubular epithelial cells, and glomerular cells, cell types that do not show substantial uptake with enzyme replacement therapy alone. Notably, AT1001 coformulation also leads to greater tissue globotriaosylceramide reduction when compared with ATB100 alone, which was positively correlated with reductions in plasma globotriaosylsphingosine. Collectively, these data indicate that intravenous administration of ATB100 coformulated with AT1001 may provide an improved therapy for Fabry disease and thus warrants further investigation.