Population pharmacokinetics of primaquine and its metabolites in African males.

BACKGROUND: Primaquine (PQ) is the prototype 8-aminoquinoline drug, a class which targets gametocytes and hypnozoites. The World Health Organization (WHO) recommends adding a single low dose of primaquine to the standard artemisinin-based combination therapy (ACT) in order to block malaria transmission in regions with low malaria transmission. However, the haemolytic toxicity is a major adverse outcome of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient subjects. This study aimed to characterize the pharmacokinetic properties of primaquine and its major metabolites in G6PD-deficient subjects. METHODS: A single low-dose of primaquine (0.4-0.5 mg/kg) was administered in twenty-eight African males. Venous and capillary plasma were sampled up to 24 h after the drug administration. Haemoglobin levels were observed up to 28 days after drug administration. Only PQ, carboxy-primaquine (CPQ), and primaquine carbamoyl-glucuronide (PQCG) were present in plasma samples and measured using liquid chromatography mass spectrometry. Drug and metabolites' pharmacokinetic properties were investigated using nonlinear mixed-effects modelling. RESULTS: Population pharmacokinetic properties of PQ, CPQ, and PQCG can be described by one-compartment disposition kinetics with a transit-absorption model. Body weight was implemented as an allometric function on the clearance and volume parameters for all compounds. None of the covariates significantly affected the pharmacokinetic parameters. No significant correlations were detected between the exposures of the measured compounds and the change in haemoglobin or methaemoglobin levels. There was no significant haemoglobin drop in the G6PD-deficient patients after administration of a single low dose of PQ. CONCLUSIONS: A single low-dose of PQ was haematologically safe in this population of G6PD-normal and G6PD-deficient African males without malaria. Trial registration NCT02535767.

Child Health and Infection with Low Density (CHILD) malaria: a protocol for a randomised controlled trial to assess the long-term health and socioeconomic impacts of testing and treating low-density malaria infection among children in Tanzania.

INTRODUCTION: As malaria declines, low-density malaria infections (LMIs) represent an increasing proportion of infections and may have negative impacts on child health and cognition, necessitating development of targeted and effective solutions. This trial assesses the health, cognitive and socioeconomic impact of two strategies for detecting and treating LMI in a low transmission setting. METHODS AND ANALYSIS: The study is a 3-arm open-label individually randomised controlled trial enrolling 600 children aged 6 months to 10 years in Bagamoyo district, Tanzania. Children are randomised to one of three arms: active case detection with molecular (ACDm) testing by high volume quantitative PCR (qPCR), passive case detection also with molecular testing (PCDm) and a control of standard PCD using rapid diagnostics tests (RDTs). Over the 2-year trial, ACDm participants receive malaria testing using RDT and qPCR three times annually, and malaria testing by RDT only when presenting with fever. PCDm and PCD participants receive malaria testing by RDT and qPCR or RDT only, respectively, when presenting with fever. RDT or qPCR positive participants with uncomplicated malaria are treated with artemether lumefantrine. The primary outcome is cumulative incidence of all-cause sick visits. Secondary outcomes include fever episodes, clinical failure after fever episodes, adverse events, malaria, non-malarial infection, antibiotic use, anaemia, growth faltering, cognition and attention, school outcomes, immune responses, and socioeconomic effects. Outcomes are assessed through monthly clinical assessments and testing, and baseline and endline neurodevelopmental testing. The trial is expected to provide key evidence and inform policy on health, cognitive and socioeconomic impact of interventions targeting LMI in children. ETHICS AND DISSEMINATION: Study is approved by Tanzania NatHREC and institutional review boards at University of California San Francisco and Ifakara Health Institute. Findings will be reported on ClinicalTrials.gov, in peer-reviewed journals and through stakeholder meetings. TRIAL REGISTRATION NUMBER: NCT05567016.

Implementation and mixed-methods evaluation of "Walk with a Doc" program at Stony Brook.

CONTEXT: Walking groups run by trained individuals, lasting under an hour in a natural environment, may be a cost-effective way by which to encourage sustainable changes in physical activity as well as foster companionship and a shared experience of wellness among participants. Walk with a Doc (WWaD) is a national program that provides a platform for medical professionals, including physicians and medical students, to deliver a short talk on a health topic prior to walking side by side with patients and community members. OBJECTIVES: To evaluate the WWaD Chapter at Stony Brook following implementation, a questionnaire was designed utilizing a mixed-methods approach (i.e., containing qualitative and quantitative items) and administered to all attendees monthly prior to the health discussion. The aim of the questionnaire was fourfold: first, to obtain participant demographics; second, to obtain information on attendees' own perceptions of their health status and the role exercise plays in their health; third, to gain data on physical activity levels, including lengths of exercise sessions and types of activities performed; and fourth, to learn more about attendees' motivations and goals for participating in the walks. METHODS: We received an IRB exemption. Physician and medical student volunteers were recruited from Stony Brook University Hospital, a suburban tertiary care center, to oversee program logistics. WWaD was scheduled to take place on the third Sunday of every month for 1 h at Heritage Park in Mount Sinai, New York. The event was advertised by volunteers to colleagues, peers, patients, and community members utilizing word of mouth, printed flyers, emails to listservs, and social media outlets. Each month, a physician volunteer oversaw a brief discussion (approximately 10 min in length). RESULTS: Over the course of the 5 month evaluation period, 91 individuals participated in the walks, including repeat attendees. After excluding duplicate or incomplete entries, data from 30 participants were included in this analysis. The majority of participants were female (n=24) with a mean age of 50 years (range, 23-98 years). Feedback on WWaD program elements was largely positive. Participants commended the monthly speakers for "informative talks" (n=6) on "interesting topics" (n=4), with plans to review the supplemental information in educational pamphlets following the walk (n=4). The brochures were also deemed "helpful." Overwhelmingly, patients referred to the community gathering and team building aspects of WWaD as the "most enjoyable" aspect of the program (n=8) and a key driver for participation. CONCLUSIONS: This mixed-methods study of the WWaD chapter at Stony Brook contributes to a growing body of evidence highlighting the value of walking groups as effective avenues for collaboration in producing accessible healthy behavior.