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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.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... 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 concentrationsPublication 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)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... 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 KPublication Open Access History of malaria treatment as a predictor of subsequent subclinical parasitaemia: a cross‑sectional survey and malaria case records from three villages in Pailin, western Cambodia(2016) Peto, Thomas J.; Kloprogge, Sabine E.; Tripura, Rupam; Chea Nguon; Nou Sanann; Sovann Yok; Chhouen Heng; Cholrawee Promnarate; Jeremy Chalk; Ngak Song; Lee, Sue J.; Yoel Lubell; Mallika Imwong; White, Nicholas J.; Seidlein, Lorenz von; Arjen Dondorp; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research UnitBackground: Treatment of the sub-clinical reservoir of malaria, which may maintain transmission, could be an important component of elimination strategies. The reliable detection of asymptomatic infections with low levels of parasitaemia requires high-volume quantitative polymerase chain reaction (uPCR), which is impractical to conduct on a large scale. It is unknown to what extent sub-clinical parasitaemias originate from recent or older clinical episodes. This study explored the association between clinical history of malaria and subsequent sub-clinical parasitaemia. Methods: In June 2013 a cross-sectional survey was conducted in three villages in Pailin, western Cambodia. Demographic and epidemiological data and blood samples were collected. Blood was tested for malaria by high-volume qPCR. Positive samples were analysed by nested PCR to determine the Plasmodium species. To identify previous episodes of malaria, case records were collected from village malaria workers and local health facilities and linked to study participants. Results: Among 1343 participants, 40/122 (32.8 %) with a history of clinical malaria were parasitaemic during the cross-sectional survey, compared to 172/1221 (14.1 %) without this history (p < 0.001). Among the 212 parasitaemic participants in the survey, 40 (18.9 %) had a history of clinical malaria, compared to 87 out of 1131 (7.7 %) parasitenegative participants; p < 0.001, adjusted OR 3.3 (95 % CI; 2.1–5.1). A history of Plasmodium vivax was associated with sub-clinical P. vivax parasitaemia in the survey (p < 0.001), but this association was not seen with Plasmodium falciparum (p = 0.253); only three participants had both P. falciparum parasites in the survey and a clinical history of P. falciparum. Conclusions: A clinical episode of vivax malaria was associated with subsequent sub-clinical parasitaemia. Treatment of P. vivax with artemisinin-based combination therapy without primaquine often resulted in recurrent episodes. Targeting individuals with a history of clinical malaria will be insufficient to eliminate the sub-clinical reservoir as they constitute a minority of parasitaemias.Publication Open Access Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized,non-inferiority, trial(2010-04) Awab, Ghulam Rahim; Sasithon Pukrittayakamee; ศศิธร ผู้กฤตยาคามี; Mallika Imwong; มัลลิกา อิ่มวงศ์; Dondorp, Arjen M.; Woodrow, Charles J.; Lee, Sue Jean; Day, Nicholas P.J.; Pratap Singhasivanon; ประตาป สิงหศิวานนท์; White, Nicholas J.; Kaker, Faizullah; White, Nicholas J.; Mahidol University. Faculty of Tropical MediicneBACKGROUND: Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail. METHODS: Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3) and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Delta = 5% difference in proportion of failures). RESULTS: Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1%) than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%), a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%). The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003). Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported. CONCLUSIONS: Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical therapy cannot be administered, dihydroartemisinin-piperaquine provides additional benefit in terms of post-treatment prophylaxis, reducing the incidence of recurrence from 4-8 weeks after treatment.Publication Open Access Clinically unapparent infantile thiamin deficiency in Vientiane, Laos.(2011-02-22) Khounnorath, Sengmanivong; Chamberlain, Karen; Taylor, Ann M.; Soukaloun, Douangdao; Mayxay, Mayfong; Lee, Sue J.; Phengdy, Bounthom; Luangxay, Khonsavanh; Sisouk, Kongkham; Soumphonphakdy, Bandit; Latsavong, Khaysy; Akkhavong, Kongsin; White, Nicholas J.; Newton, Paul N.; Newton, Paul N.; Mahidol University. Faculty of TropicalMedicine. Mahidol-Oxford Tropical Medicine Research Unit./PRINCIPAL FINDINGS: A cohort of 778 sick infants admitted during one year without clinical evidence of beriberi were studied prospectively and erythrocyte transketolase assays (ETK) performed. Biochemical thiamin deficiency was defined both in terms....7%) (P=0.045, relative risk=9.32 (95%CI 0.99 to 87.5)). Multivariate regression analysis indicated that infant age≥2 months and fewer maternal years of schooling were independently associated with infant basal ETK<0.59 micromoles/min/gHb. CONCLUSIONSPublication Open Access A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand(2005-09) Hutagalung, Robert; Paiphun, Lucy; Ashley, Elizabeth A.; McGready, Rose; Brockman, Alan; Thwai, Kaw L.; Pratap Singhasivanon; ประตาป สิงหศิวานนท์; Jelinek, Thomas; White, Nicholas J.; Nosten, François H.; Nosten, François H.; Mahidol University. Faculty of Tropical Medicine.BACKGROUND: The use of antimalarial drug combinations with artemisinin derivatives is recommended to overcome drug resistance in Plasmodium falciparum. The fixed combination of oral artemether-lumefantrine, an artemisinin combination therapy (ACT) is highly effective and well tolerated. It is the only registered fixed combination containing an artemisinin. The trial presented here was conducted to monitor the efficacy of the six-dose regimen of artemether-lumefantrine (ALN) in an area of multi-drug resistance, along the Thai-Myanmar border. METHODS: The trial was an open-label, two-arm, randomized study comparing artemether-lumefantrine and mefloquine-artesunate for the treatment of uncomplicated falciparum malaria with 42 days 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 490 patients with slide confirmed uncomplicated P. falciparum malaria were randomly assigned to receive artemether-lumefantrine (n = 245) or artesunate and mefloquine (n = 245) and were followed for 42 days. All patients had rapid initial clinical and parasitological responses. In both groups, the PCR adjusted cure rates by day 42 were high: 98.8% (95% CI 96.4, 99.6%) for artemether-lumefantrine and 96.3% (95% CI 93.1, 98.0%) for artesunate-mefloquine. Both regimens were very well tolerated with no serious adverse events observed attributable to either combination. CONCLUSION: Overall, this study confirms that these two artemisinin-based combinations remain highly effective and result in equivalent therapeutic responses in the treatment of highly drug-resistant falciparum malaria.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.BACKGROUND: Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda. METHODS: Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population 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 followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches. CONCLUSION: The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.Publication Open Access Efficacy of artemether-lumefantrine, the nationally-recommended artemisinin combination for the treatment of uncomplicated falciparum malaria, in southern Laos.(2012-06-8) Mayfong Mayxay; Maniphone Khanthavong; Odai Chanthongthip; Mallika Imwong; มัลลิกา อิ่มวงศ์; Tiengkham Pongvongsa; Bouasy Hongvanthong; Samalane Phompida; Viengxay Vanisaveth; White, Nicholas J.; Newton, Paul N; Mayfong Mayxay; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and Geneticsmalaria. RESULTS: Of 630 patients with P. falciparum enrolled in the trial of thiamin treatment, 549 (87%, 357 children ≤15 years and 192 adults) were included in this study. The per protocol 42-day cure rates were 97% (524/541) [96% (337/352... malaria five years after introduction in Laos. Regular monitoring is required in case artemisinin-resistant P. falciparum parasites should appear.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.