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Publication Open Access Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda.(2012-08-22) Tarning, Joel; Kloprogge, Frank; Piola, Patrice; Dhorda, Mehul; Muwanga, Sulaiman; Turyakira, Eleanor; Nitra Nuengchamnong; นิทรา เนื่องจำนงค์; Nosten, François; Day, Nicholas P.J.; White, Nicholas J.; Guerin, Philippe J.; Lindegardh, Niklas; Tarning, Joel; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit.pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a... comparison with literature values and different modeling strategies. RESULTS: The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followedPublication Open Access Comparative genome‑wide analysis and evolutionary history of haemoglobin‑processing and haem detoxification enzymes in malarial parasites(2016) Patrath Ponsuwanna; Theerarat Kochakarn; Duangkamon Bunditvorapoom; Krittikorn Kümpornsin; Otto, Thomas D.; Chase Ridenour; Kesinee Chotivanich; Prapon Wilairat; White, Nicholas J.; Olivo Miotto; Thanat Chookajorn; Mahidol University. Faculty of Tropical Medicine. Genomic and Evolutionary Medicine Unit, Centre of Excellence in MalariaBackground: Malaria parasites have evolved a series of intricate mechanisms to survive and propagate within host red blood cells. Intra-erythrocytic parasitism requires these organisms to digest haemoglobin and detoxify ironbound haem. These tasks are executed by haemoglobin-specific proteases and haem biocrystallization factors that are components of a large multi-subunit complex. Since haemoglobin processing machineries are functionally and genetically linked to the modes of action and resistance mechanisms of several anti-malarial drugs, an understanding of their evolutionary history is important for drug development and drug resistance prevention. Methods: Maximum likelihood trees of genetic repertoires encoding haemoglobin processing machineries within Plasmodium species, and with the representatives of Apicomplexan species with various host tropisms, were created. Genetic variants were mapped onto existing three-dimensional structures. Genome-wide single nucleotide polymorphism data were used to analyse the selective pressure and the effect of these mutations at the structural level. Results: Recent expansions in the falcipain and plasmepsin repertoires are unique to human malaria parasites especially in the Plasmodium falciparum and P. reichenowi lineage. Expansion of haemoglobin-specific plasmepsins occurred after the separation event of Plasmodium species, but the other members of the plasmepsin family were evolutionarily conserved with one copy for each sub-group in every Apicomplexan species. Haemoglobin-specific falcipains are separated from invasion-related falcipain, and their expansions within one specific locus arose independently in both P. falciparum and P. vivax lineages. Gene conversion between P. falciparum falcipain 2A and 2B was observed in artemisinin-resistant strains. Comparison between the numbers of non-synonymous and synonymous mutations suggests a strong selective pressure at falcipain and plasmepsin genes. The locations of amino acid changes from non-synonymous mutations mapped onto protein structures revealed clusters of amino acid residues in close proximity or near the active sites of proteases. Conclusion: A high degree of polymorphism at the haemoglobin processing genes implicates an imposition of selective pressure. The identification in recent years of functional redundancy of haemoglobin-specific proteases makes them less appealing as potential drug targets, but their expansions, especially in the human malaria parasite lineages, unequivocally point toward their functional significance during the independent and repetitive adaptation events in malaria parasite evolutionary history.Publication Open Access Rapid clinical assessment to facilitate the triage of adults with falciparum malaria, a retrospective analysis.(2014-01-29) Hanson, Josh; Lee, Sue J.; Mohanty, Sanjib; Faiz, M. Abul; Anstey, Nicholas M.; Price, Ric N.; Prakaykaew Charunwatthana; ประกายแก้ว จรูญวรรธนะ; Yunus, Emran Bin; Mishra, Saroj K.; Tjitra, Emiliana; Ridwanur Rahman; Francois Nosten; Htut, Ye; Maude, Richard J.; Chau, Tran Thi Hong; Phu, Nguyen Hoan; Hien, Tran Tinh; White, Nicholas J.; Day, Nicholas P. J.; Dondorp, Arjen M.; Hanson, Josh; Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit.BACKGROUND: Most adults dying from falciparum malaria will die within 48 hours of their hospitalisation. An essential component of early supportive care is the rapid identification of patients at greatest risk. In resource-poor settings, where most patients with falciparum malaria are managed, decisions regarding patient care must frequently be made using clinical evaluation alone. METHODS: We retrospectively analysed 4 studies of 1801 adults with severe falciparum malaria to determine whether the presence of simple clinical findings might assist patient triage. RESULTS: If present on admission, shock, oligo-anuria, hypo- or hyperglycaemia, an increased respiratory rate, a decreased Glasgow Coma Score and an absence of fever were independently predictive of death. The variables were used to construct a simple clinical algorithm. When applied to the 1801 patients, this algorithm's positive predictive value for survival to 48 hours was 99.4 (95% confidence interval (CI) 97.8-99.9) and for survival to discharge 96.9% (95% CI 94.3-98.5). In the 712 patients receiving artesunate, the algorithm's positive predictive value for survival to 48 hours was 100% (95% CI 97.3-100) and to discharge was 98.5% (95% CI 94.8-99.8). CONCLUSIONS: Simple clinical findings are closely linked to the pathophysiology of severe falciparum malaria in adults. A basic algorithm employing these indices can facilitate the triage of patients in settings where intensive care services are limited. Patients classified as low-risk by this algorithm can be safely managed initially on a general ward whilst awaiting senior clinical review and laboratory data.Publication Open Access Genetic variability of Plasmodium malariae dihydropteroate synthase (dhps) in four Asian countries.(2014-04-03) Naowarat Tanomsing; เนาวรัตน์ ถนอมสิงห์; Mayxay, Mayfong; Newton, Paul N.; Nosten, Francois; Dolecek, Christiane; Hien, Tran Tinh; White, Nicholas J.; Day, Nicholas P. J.; Dondorp, Arjen M.; Mallika Imwong; มัลลิกา อิ่มวงศ์; Mallika Imwong; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and Genetics; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit; Mahidol University. Faculty of Tropical Medicine. Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Uni.The dihydropteroate synthase (dhps) genes of 44 P. malariae strains from four Asian countries were isolated. Only a limited number of polymorphisms were observed. Comparison with homologous mutations in other Plasmodium species showed that these polymorphisms are unlikely to be associated with sulfadoxine resistance.Publication Open Access Geographic distribution of amino acid mutations in DHFR and DHPS in Plasmodium vivax isolates from Lao PDR, India and Colombia(2016) Naowarat Saralamba; Supatchara Nakeesathit; Mayfong Mayxay; Newton, Paul N.; Lyda Osorio; Kim, Jung‑Ryong; White, Nicholas J.; Day, Nicholas P. J.; Dondorp, Arjen M.; Mallika Imwong; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and Geneticsthe corresponding wild-type amino acids were found at high frequencies in Lao PDR during 2001–2004 (57.8 %). Size polymorphism analysis of the tandem repeats within pvdhfr revealed that 74.3 % of all the isolates carried the type B variant. Eighty-nine per centPublication Open Access Intervals to Plasmodium falciparum recurrence after anti-malarial treatment in pregnancy: a longitudinal prospective cohort(2015) Natthapon Laochan; Zaloumis, Sophie G.; Mallika Imwong; Usa Lek-Uthai; Alan Brockman; Kanlaya Sriprawat; Jacher Wiladphaingern; White, Nicholas J.; François Nosten; McGready, Rose; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit (MORU)Background: Plasmodium falciparum infections adversely affect pregnancy. Anti-malarial treatment failure is common. The objective of this study was to examine the duration of persistent parasite carriage following anti-malarial treatment in pregnancy. Methods: The data presented here are a collation from previous studies carried out since 1994 in the Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border and performed using the same unique methodology detailed in the Materials and Methods section. Screening for malaria by microscopy is a routine part of weekly antenatal care (ANC) visits and therapeutic responses to anti-malarials were assessed in P. falciparum malaria cases. Women with microscopy confirmed P. falciparum malaria had a PCR blood spot from a finger-prick sample collected. Parasite DNA was extracted from the blood-spot samples using saponin lysis/Chelex extraction method and genotyped using polymorphic segments of MSP1, MSP2 and GLURP. Recurrent infections were classified by genotyping as novel, recrudescent or indeterminate. Factors associated with time to microscopy-detected recrudescence were analysed using multivariable regression techniques. Results: From December 1994 to November 2009, 700 women were treated for P. falciparum and there were 909 recurrent episodes (481 novel and 428 recrudescent) confirmed by PCR genotyping. Most of the recurrences, 85 % (770/909), occurred after treatment with quinine monotherapy, artesunate monotherapy or artesunate-clindamycin. The geometric mean number of days to recurrence was significantly shorter in women with recrudescent infection, 24.5 (95 %: 23.4-25.8), compared to re-infection, 49.7 (95 %: 46.9-52.7), P <0.001. The proportion of recrudescent P. falciparum infections that occurred after days 28, 42 and 63 from the start of treatment was 29.1 % (124/428), 13.3 % (57/428) and 5.6 % (24/428). Recrudescent infections ≥100 days after treatment occurred with quinine and mefloquine monotherapy, and quinine + clindamycin and artesunate + atovaquone-proguanil combination therapy. Treatments containing an artemisinin derivative or an intercalated Plasmodium vivax infection increased the geometric mean interval to recrudescence by 1.28-fold (95 % CI: 1.09-1.51) and 2.19-fold (1.77-2.72), respectively. Intervals to recrudescence were decreased 0.83-fold (0.73-0.95) if treatment was not fully supervised (suggesting incomplete adherence) and 0.98-fold (0.96-0.99) for each doubling in baseline parasitaemia. Conclusions: Prolonged time to recrudescence may occur in pregnancy, regardless of anti-malarial treatment. Long intervals to recrudescence are more likely with the use of artemisinin-containing treatments and also observed with intercalated P. vivax infections treated with chloroquine. Accurate determination of drug efficacy in pregnancy requires longer duration of follow-up, preferably until delivery or day 63, whichever occurs last.Publication Open Access The threat of antimalarial drug resistance(2016) Borimas Hanboonkunupakarn; White, Nicholas J.; Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical MedicineThe battle between man and malaria has continued for thousands of years. Antimalarial drugs are essential weapons to fight the disease, but their efficacy is threatened by drug resistance which continues to emerge creating a major obstacle to malaria control and jeopardizing renewed hopes for elimination. As 2016 is the first year under WHO Global Technical Strategy for Malaria 2016–2030, it is a good time to ponder the progress of both sides and plan for the future.Publication Open Access Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria(2016) Thanaporn Wattanakul; Pramote Teerapong; Plewes, Katherine; Newton, Paul N.; Wirongrong Chierakul; Kamolrat Silamut; Kesinee Chotivanich; Ronnatrai Ruengweerayut; White, Nicholas J.; Dondorp, Arjen M.; Tarning, Joel; Mahidol University. Faculty of Tropical Medicine. Mahidol‑Oxford Tropical Medicine Research Unit.Background: Fever is an inherent symptom of malaria in both adults and children. Paracetamol (acetaminophen) is the recommended antipyretic as it is inexpensive, widely available and has a good safety profile, but patients may not be able to take the oral drug reliably. A comparison between the pharmacokinetics of oral syrup and intramuscular paracetamol given to patients with acute falciparum malaria and high body temperature was performed. Methods: A randomized, open-label, two-treatment, crossover, pharmacokinetic study of paracetamol dosed orally and intramuscularly was conducted. Twenty-one adult patients with uncomplicated falciparum malaria were randomized to receive a single 600 mg dose of paracetamol either as syrup or intramuscular injection on day 0 followed by a single dose administered by the alternative route on day 1. Paracetamol plasma concentrations were quantified frequently and modelled simultaneously using nonlinear mixed-effects modelling. The final population pharmacokinetic model was used for dose optimization simulations. Relationships between paracetamol concentrations with temperature and parasite half-life were investigated using linear and non-linear regression analyses. Results: The population pharmacokinetic properties of paracetamol were best described by a two-compartment disposition model, with zero-order and first-order absorption for intramuscular and oral syrup administration, respectively. The relative bioavailability of oral syrup was 84.4 % (95 % CI 68.2–95.1 %) compared to intramuscular administration. Dosing simulations showed that 1000 mg of intramuscular or oral syrup administered six-hourly reached therapeutic steady state concentrations for antipyresis, but more favourable concentration–time profiles were achieved with a loading dose of 1500 mg, followed by a 1000 mg maintenance dose. This ensured that maximum therapeutic concentrations were reached rapidly during the first 6 h. No significant relationships between paracetamol concentrations and temperature or parasite half-life were found. Conclusions: Paracetamol plasma concentrations after oral syrup and intramuscular administration in patients with acute falciparum malaria were described successfully by a two-compartment disposition model. Relative oral bioavailability compared to intramuscular dosing was estimated as 84.4 % (95 % CI 68.2–95.1 %). Dosing simulations showed that a loading dose followed by six-hourly dosing intervals reduced the time delay to reach therapeutic drug levels after both routes of administration. The safety and efficacy of loading dose paracetamol antipyretic regimens now needs to be established in larger studies.Publication Open Access Practical PCR genotyping protocols for Plasmodium vivax using Pvcs and Pvmsp1.(2005-04-27) Mallika Imwong; มัลลิกา อิ่มวงศ์; Sasithon Pukrittayakamee; Grüner, Anne Charlotte; Rénia, Laurent; Letourneur, Frank; Sornchai Looareesuwan; ศรชัย หลูอารีย์สุวรรณ; White, Nicholas J.; Snounou, Georges; Mallika Imwong; Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical Medicine.of follow up. Parasite genotyping by polymerase chain reaction (PCR) was used to distinguish recrudescent from newly acquired P. falciparum infections. The PCR adjusted cure rates were evaluated by survival analysis. RESULTS: In 2001-2002 a total of 490Publication Open Access Clinical trials of artesunate plus sulfadoxine‑pyrimethamine for Plasmodium falciparum malaria in Afghanistan: maintained efficacy a decade after introduction(2016) Ghulam Rahim Awab; Mallika Imwong; Sasithon Pukrittayakamee; Fazel Alim; Warunee Hanpithakpong; Joel Tarning; Dondorp, Arjen M.; Day, Nicholas P. J.; White, Nicholas J.; Woodrow, Charles J.; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit (MORU)Background: Combination therapy with artesunate plus sulfadoxine-pyrimethamine (SP) was adopted as recommended treatment for Plasmodium falciparum infection in Afghanistan in 2003. Methods: A series of prospective clinical studies examining the efficacy of artesunate plus sulfadoxine-pyrimethamine (AS + SP) against P. falciparum were undertaken in sentinel sites in Afghanistan from 2007 to 2014, accompanied by relevant molecular studies. The first study was a randomized trial of AS + SP versus dihydroartemisinin-piperaquine, while two subsequent studies were standard therapeutic efficacy studies of AS + SP. Results: Three hundred and three patients were enrolled across four provinces in the north and east of the country. Curative efficacy was high in all the trials, with an adequate clinical and parasitological response (ACPR) of more than 95 % in all groups and trial stages. Genotyping for drug-resistance alleles at dhfr indicated fixation of the S108 N mutation and a prevalence of the C59R mutation of approximately 95 % across all sites. Other mutations in dhfr and dhps remained rare or absent entirely, although five isolates from the first trial carried the dhps triple mutant SGEGA haplotype. In the last study undertaken in 2012–2014 the K13 artemisinin resistance marker was examined; only two of 60 successfully sequenced samples carried a K13-propeller mutation. Conclusions: These data confirm maintained efficacy 10 years after introduction of artesunate plus SP as combination treatment of P. falciparum in Afghanistan. The molecular data indicate that despite a substantial fall in incidence, resistance has not developed to artemisinins, or intensified to the ACT partner drug components. Trial Registration http://www.clinicaltrials.gov/ct NCT00682578, NCT01115439 and NCT01707199