Determinants of Primaquine and Carboxyprimaquine Exposures in Children and Adults with Plasmodium vivax Malaria.

Primaquine is the only widely available drug for radical cure of Plasmodium vivax malaria. There is uncertainty whether the pharmacokinetic properties of primaquine are altered significantly in childhood or not. Patients with uncomplicated P. vivax malaria and with normal glucose-6-phosphate dehydrogenase were randomized to receive either chloroquine (25 mg base/kg of body weight) or dihydroartemisinin-piperaquine (dihydroartemisinin at 7 mg/kg and piperaquine at 55 mg/kg) plus primaquine, given either as 0.5 mg base/kg/day for 14 days or 1 mg/kg/day for 7 days. Predose day 7 venous plasma concentrations of chloroquine, desethylchloroquine, piperaquine, primaquine, and carboxyprimaquine were measured. Methemoglobin levels were measured at frequent intervals. Day 7 primaquine and carboxyprimaquine concentrations were available for 641 patients. After adjustment for the milligram-per-kilogram primaquine daily dose, day of sampling, partner drug, and fever clearance, there was a significant nonlinear relationship between age and trough primaquine and carboxyprimaquine concentrations and daily methemoglobin levels. Compared to adults 30 years of age, children 5 years of age had trough primaquine concentrations that were 0.53 (95% confidence interval [CI], 0.39 to 0.73)-fold lower, trough carboxyprimaquine concentrations that were 0.45 (95% CI, 0.35 to 0.55)-fold lower, and day 7 methemoglobin levels that were 0.87 (95% CI, 0.58 to 1.27)-fold lower. Increasing plasma concentrations of piperaquine and chloroquine and poor metabolizer CYP 2D6 alleles were associated with higher day 7 primaquine and carboxyprimaquine plasma concentrations. Higher blood methemoglobin concentrations were associated with a lower risk of recurrence. Young children have lower primaquine and carboxyprimaquine exposures and lower levels of methemoglobinemia than adults. Young children may need higher weight-adjusted primaquine doses than adults. (This study has been registered at ClinicalTrials.gov under identifier NCT01640574.).

Comparison of the Cumulative Efficacy and Safety of Chloroquine, Artesunate, and Chloroquine-Primaquine in Plasmodium vivax Malaria.

Background: Chloroquine has been recommended for Plasmodium vivax infections for >60 years, but resistance is increasing. To guide future therapies, the cumulative benefits of using slowly eliminated (chloroquine) vs rapidly eliminated (artesunate) antimalarials, and the risks and benefits of adding radical cure (primaquine) were assessed in a 3-way randomized comparison conducted on the Thailand-Myanmar border. Methods: Patients with uncomplicated P. vivax malaria were given artesunate (2 mg/kg/day for 5 days), chloroquine (25 mg base/kg over 3 days), or chloroquine-primaquine (0.5 mg/kg/day for 14 days) and were followed for 1 year. Recurrence rates and their effects on anemia were compared. Results: Between May 2010 and October 2012, 644 patients were enrolled. Artesunate cleared parasitemia significantly faster than chloroquine. Day 28 recurrence rates were 50% with artesunate (112/224), 8% with chloroquine (18/222; P < .001), and 0.5% with chloroquine-primaquine (1/198; P < .001). Median times to first recurrence were 28 days (interquartile range [IQR], 21-42) with artesunate, 49 days (IQR, 35-74) with chloroquine, and 195 days (IQR, 82-281) with chloroquine-primaquine. Recurrence by day 28, was associated with a mean absolute reduction in hematocrit of 1% (95% confidence interval [CI], .3%-2.0%; P = .009). Primaquine radical cure reduced the total recurrences by 92.4%. One-year recurrence rates were 4.51 (95% CI, 4.19-4.85) per person-year with artesunate, 3.45 (95% CI, 3.18-3.75) with chloroquine (P = .002), and 0.26 (95% CI, .19-.36) with chloroquine-primaquine (P < .001). Conclusions: Vivax malaria relapses are predominantly delayed by chloroquine but prevented by primaquine. Clinical Trials Registration: NCT01074905.

The Association between Betel Quid Chewing and Metabolic Syndrome Among Urban Adults in Mandalay District of Myanmar.

Background: As the prevalence of metabolic syndrome, obesity and diabetes increase worldwide, the need to identify modifiable lifestyle risk factors also increases, especially those that may be relatively unique to a specific population. To explore a possible association between betel quid chewing and metabolic syndrome, a community-based cross-sectional study was conducted. Methodology: Three hundred ninety-one (391) adults were interviewed and the following parameters were measured: triglycerides, HDL-cholesterol, glucose, waist circumference, body mass index and blood pressure. Multiple logistic regression was used to determine the association between betel quid chewing and metabolic syndrome while controlling for confounders. Results: The prevalence of metabolic syndrome was similar in chewers and non-chewers, 50% and 49%, respectively. After controlling for other factors, development of metabolic syndrome was positively associated with number of betel quids chewed per day, age greater than 40 years, and a positive family history of hypertension and diabetes. Regarding the duration of betel chewing, when analyzed by sex, the risk was doubled in men compared to non-chewers (OR 2.15; 95% CI = 1.21, 3.84). As a result, a man chewing more than 10 pieces (OR 2.49; 95% CI = 1.36, 4.57) of betel quids per day for more than 10 years had a two-fold increased chance of developing the metabolic syndrome. Conclusions: Frequency and duration of betel quid chewing may represent a behavioral lifestyle target for approaches to reduce the incidence of metabolic syndrome.

AFES A.S.-O.N.E.: ASEAN Survey Of Needs in Endocrinology in the Time of the COVID-19 Pandemic.

OBJECTIVES: The COVID-19 pandemic has made a major impact on hospital services globally, including the care of persons with diabetes and endocrine disorders. The aim of this study is to describe the epidemiology of COVID-19 in the ASEAN Federation of Endocrine Societies (AFES) member countries; to describe challenges, changes and opportunities in caring for patients with endocrine diseases, as well as in fellowship training programs, and endocrinerelated research in the AFES countries. METHODOLOGY: The AFES ASEAN Survey Of Needs in Endocrinology (AFES A.S.-O.N.E.) was an open-ended questionnaire that was sent to the presidents and representatives of the AFES member countries by email. Responses from Societies were collated and synthesized to obtain perspectives on the emergent issues in endocrinology in the Southeast Asian region during this pandemic. RESULTS: The burden of COVID-19 cases varied widely across the AFES member countries, with the least number of cases in Vietnam and Myanmar, and the greatest number of cases in either the most populous countries (Indonesia and the Philippines), or a country with the highest capability for testing (Singapore). The case fatality rate was also the highest for Indonesia and the Philippines at around 6%, and lowest for Vietnam at no fatalities. The percentage with diabetes among patients with COVID-19 ranged from 5% in Indonesia to 20% in Singapore, approximating the reported percentages in China and the United States. The major challenges in managing patients with endocrine diseases involved inaccessibility of health care providers, clinics and hospitals due to the implementation of lockdowns, community quarantines or movement control among the member countries. This led to disruptions in the continuity of care, testing and monitoring, and for some, provision of both preventive care and active management including surgery for thyroid cancer or pituitary and adrenal tumors, and radioactive iodine therapy. Major disruptions in the endocrine fellowship training programs were also noted across the region, so that some countries have had to freeze hiring of new trainees or to revise both program requirements and approaches to training due to the closure of outpatient endocrine clinics. The same observations are seen for endocrine-related researches, as most research papers have focused on the pandemic. Finally, the report ends by describing innovative approaches to fill in the gap in training and in improving patient access to endocrine services by Telemedicine. CONCLUSION: The burden of COVID-19 cases and its case fatality rate varies across the AFES member countries but its impact is almost uniform: it has disrupted the provision of care for patients with endocrine diseases, and has also disrupted endocrine fellowship training and endocrine-related research across the region. Telemedicine and innovations in training have been operationalized across the AFES countries in an attempt to cope with the disruptions from COVID-19, but its over-all impact on the practice of endocrinology across the region will only become apparent once we conquer this pandemic.