Objectives. Rifampin is a potent inducer of the cytochrome P450 3A4 isoenzyme (CYP3A4) that metabolizes most protease inhibitor (PI) antiretrovirals. This study was designed to evaluate the steady-state pharmacokinetics and tolerability of the coadministration of the PIs saquinavir and ritonavir (a CYP3A4 inhibitor used as a pharmacoenhancer of other PIs) and rifampin when coadministered in healthy HIV-negative volunteers. Methods.In an open-label, randomized, one sequence, two-period crossover study involving 28 healthy HIVnegative volunteers, arm 1 was randomized to receive saquinavir/ritonavir 1000/100 mg twice daily while arm 2 received rifampin 600 mg once daily for 14 days. Both arms were then to receive concomitant saquinavir/ritonavir and rifampin for 2 additional weeks. Vital signs, electrocardiography, laboratory analyses, and blood levels of total saquinavir, ritonavir, rifampin, and desacetyl-rifampin, the primary metabolite of rifampin, were measured. Results. In arm 1, 10/14 (71%) and, in arm 2, 11/14 (79%) participants completed the first study phase; eight participants in arm 1 and nine in arm 2 went on to receive both saquinavir/ritonavir and rifampin. Following substantial elevations (Ն grade 2) in hepatic transaminases in participants receiving the coadministered agents, the study was discontinued prematurely. Two participants in arm 1 displayed moderate elevations after five and four doses of rifampin, respectively. In arm 2, all participants experienced severe elevations within 4 days of initiating saquinavir/ritonavir. Clinical symptoms (e.g., nausea, vomiting, abdominal pain, and headache) were more common and severe in arm 2. Clinical symptoms abated and transaminases normalized following drug discontinuation. Limited pharmacokinetic data suggest a possible relationship between transaminase elevation and elevated rifampin and desacetyl-rifampin concentrations. Conclusions. Although not confirmed in HIV-infected patients, the data indicate that rifampin should not be coadministered with saquinavir/ritonavir.

Dispossession from social and ecological support systems is a major concern for many Indigenous communities. In response to community health challenges in these settings a number of initiatives such as youth mentorship programs have shown some value in enhancing adaptive capacity. The pilot Going Off, Growing Strong program provides opportunities for at-risk youth to engage in community- and land-based activities and build relationships with positive adult role models in Nain, Nunatsiavut (Labrador, Canada). This paper offers an interpretive description drawing from autobiographical accounts of the development of this innovative program. A collaboratively developed conceptual framework, based on the literature, is used to present and explain program operator’s experiences and rationale for program development. The emergent goals of Going Off, Growing Strong are to strengthen individual youth and collective community resilience through intergenerational exchange of land, social, and cultural skills and knowledge by drawing on social supports, such as a community freezer and experienced harvesters. We found that the process of collaborating over time with multiple stakeholders in creating this conceptual framework was an important one for solidifying the goals of Going Off, Growing Strong and creating context-specific, meaningful evaluation outcomes to enable future measurement of impacts on the community.De nombreuses communautés autochtones redoutent de se voir dépossédées de leurs systèmes de soutiens sociaux et écologiques. En réponse aux défis que pose la santé communautaire dans de tels contextes, un certain nombre d’initiatives, telles que les programmes de mentorat pour les jeunes, ont démontré une certaine valeur sur le plan de l’accroissement des capacités adaptatives. Le programme pilote Going Off, Growing Strong (« Sortir, grandir ») procure aux jeunes à risque des opportunités de s’engager dans des activités communautaires – et enracinées dans le territoire – et de nouer des relations avec des adultes jouant le rôle de modèles à Nain, au Nunatsiavut (Labrador, Canada). Cet article représente une description interprétative de l’élaboration de ce programme novateur à partir de récits autobiographiques. Nous utilisons un cadre conceptuel développé en collaboration et se basant sur de précédents travaux pour présenter et expliquer les expériences des acteurs et la raison d’être du développement de ce programme. Les objectifs émergents de Going Off, Growing Strong sont de renforcer la résilience des jeunes de la communauté au niveau individuel et collectif par l’intermédiaire des échanges intergénérationnels de compétences et de savoirs relatifs au territoire, à la société et à la culture, en se fondant sur des appuis sociaux tels qu’un congélateur communautaire et des chasseurs-pêcheurs...

This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single-blind, randomized, crossover, placebo-controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and well tolerated. R1663 did not affect bleeding time. Pharmacodynamic effects (prothrombin time [PT], activated partial thromboplastin time [aPTT]), parameters of thrombogram, and anti-factor Xa activity) and plasma concentrations of R1663 were dose-dependent and showed low to moderate (<40%) intersubject and intrasubject variability. Maximum factor Xa inhibition was achieved 3 hours post dose (time to maximum concentration of R1663): clotting times were prolonged up to 2.5-fold, whereas endogenous thrombin potential (ETP) and peak height were decreased by 48% and 85% from their baseline values, respectively. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations, with IC50 values of 182 and 2680 ng/mL for peak height and ETP, respectively. Oral doses of R1663 up to 480 mg were well tolerated, with predictable pharmacodynamics and pharmacokinetics. R1663 prolonged clotting times (PT, aPTT) and inhibited thrombin generation without increasing bleeding time.

These findings will allow the administration of R1663 without regard to food in the upcoming trials.

This study investigated the safety, pharmacokinetics and pharmacodynamics of multiple oral doses of R1663, a factor Xa inhibitor, and explored the influence of age and gender on pharmacokinetics and pharmacodynamics of R1663. This was a single-blind, randomised, placebo-controlled, dose escalation study in 48 healthy male volunteers aged 18 to 44 years. R1663 doses up to 300 mg twice daily or 400 mg once daily were administered for seven days. The exploration of gender and age effect was carried out in separate cohorts of eight male and eight female volunteers aged 45 to 65 years. Multiple oral doses of R1663 were safe and well tolerated. Pharmacokinetics was linear and showed moderate variability. Plasma concentrations peaked at 3 hour. Terminal half-life at steady state was 3-5 hours. Accumulation of R1663 was minimal. R1663 prolonged clotting times, inhibited thrombin generation (peak height and endogenous thrombin potential [ETP]) and anti-factor Xa activity in a concentration-dependent manner without increasing bleeding time. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations. The inhibition was more pronounced on peak height (IC₅₀ = 194 ng/ml) than on ETP (2790 ng/ml). Pharmacokinetics and pharmacodynamics of R1663 appeared not to be substantially affected by age or gender but remained to be confirmed in larger clinical trials including older patients. Meanwhile, dose adjustments based on age and gender are not anticipated.