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Publication Open Access Chloroquine is grossly under dosed in young children with malaria: implications for drug resistance.(2014-01-23) Ursing, Johan; Eksborg, Staffan; Rombo, Lars; Bergqvist, Yngve; Blessborn, Daniel; Rodrigues, Amabelia; Kofoed, Poul-Erik; Ursing, Johan; Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Research Unit.BACKGROUND: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations. METHODS AND FINDINGS: Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m(2) were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10-14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662-988) and 758 (95% CI 640-876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10-14 taking 50 mg/kg and children aged 0-2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent. CONCLUSIONS: CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10-14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa.Publication Open Access Poor quality vital anti-malarials in Africa - an urgent neglected public health priority(2011-12-13) Newton, Paul N.; Green, Michael D.; Mildenhall, Dallas C.; Plançon, Aline; Nettey, Henry; Nyadong, Leonard; Hostetler, Dana M.; Swamidoss, Isabel; Harris, Glenn A.; Powell, Kristen; Timmermans, Ans E.; Amin, Abdinasir A.; Opuni, Stephen K.; Barbereau, Serge; Faurant, Claude; Soong, Ray C.W.; Faure, Kevin; Jonarthan Thevanayagam; Fernandes, Peter; Kaur, Harparkash; Angus, Brian; Stepniewska, Kasia; Guerin, Philippe J.; Fernández, Facundo M.; Newton, Paul N.; Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU).BACKGROUND: Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. METHODS: Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis) and botanical investigations were performed. RESULTS: Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA) containing paracetamol (acetaminophen), counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. CONCLUSIONS: Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.Publication Open Access Directly-observed therapy (DOT) for the radical 14-day primaquine treatment of Plasmodium vivax malaria on the Thai-Myanmar border(2010-11-01) Takeuchi, Rie; Saranath Lawpoolsri; สารนาถ ล้อพูลศรี; Mallika Imwong; มัลลิกา อิ่มวงศ์; Kobayashi, Jun; Jaranit Kaewkungwal; จรณิต แก้วกังวาล; Sasithon Pukrittayakamee; ศศิธร ผู้กฤตยาคามี; Supalap Puangsa-art; ศุภลาภ พวงสอาด; Nipon Thanyavanich; นิพนธ์ ธัญญวานิช; Wanchai Maneeboonyang; วรรณไชย มณีบุญยัง; Day, Nicholas P.J.; Pratap Singhasivanon; ประตาป สิงหศิวานนท์; Pratap Singhasivanon; Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical Medicine; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit (MORU); Mahidol University. Faculty of Tropical Medicine. Department of Tropical Hygiene.BACKGROUND: Plasmodium vivax has a dormant hepatic stage, called the hypnozoite, which can cause relapse months after the initial attack. For 50 years, primaquine has been used as a hypnozoitocide to radically cure P. vivax infection, but major concerns remain regarding the side-effects of the drug and adherence to the 14-day regimen. This study examined the effectiveness of using the directly-observed therapy (DOT) method for the radical treatment of P. vivax malaria infection, to prevent reappearance of the parasite within the 90-day follow-up period. Other potential risk factors for the reappearance of P. vivax were also explored. METHODS: A randomized trial was conducted from May 2007 to January 2009 in a low malaria transmission area along the Thai-Myanmar border. Patients aged ≥ 3 years diagnosed with P. vivax by microscopy, were recruited. All patients were treated with the national standard regimen of chloroquine for three days followed by primaquine for 14 days. Patients were randomized to receive DOT or self-administered therapy (SAT). All patients were followed for three months to check for any reappearance of P. vivax. RESULTS: Of the 216 patients enrolled, 109 were randomized to DOT and 107 to SAT. All patients recovered without serious adverse effects. The vivax reappearance rate was significantly lower in the DOT group than the SAT group (3.4/10,000 person-days vs. 13.5/10,000 person-days, p = 0.021). Factors related to the reappearance of vivax malaria included inadequate total primaquine dosage received (< 2.75 mg/kg), duration of fever ≤ 2 days before initiation of treatment, parasite count on admission ≥ 10,000/µl, multiple P. vivax-genotype infection, and presence of P. falciparum infection during the follow-up period. CONCLUSIONS: Adherence to the 14-day primaquine regimen is important for the radical cure of P. vivax malaria infection. Implementation of DOT reduces the reappearance rate of the parasite, and may subsequently decrease P. vivax transmission in the area.