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ABSTRACT: Background: The use of amodiaquine in prophylaxis is associated with serious toxicity, resulting from its meta-bolic conversion into a reactive quinone-imine metabolite by the hepatic cytochrome P450. To circumvent this toxicity, several amodiaquine analogues that lack the potential to form a quinone-imine derivative, while retaining antimalarial activity, have been designed. Isoquine is one of these promising molecules that has already reached Phase I clinical trials in humans. Methods: We analysed the in vitro activity of isoquine against 62 Plasmodium falciparum isolates collected in Kenya and the association of this activity with polymorphisms in pfcrt and pfmdr1 genes. Results: The median concentration of isoquine that inhibited 50% of parasite growth (IC 50) was 9 nM, com-pared with 56 nM chloroquine, 8 nM amodiaquine, 10 nM desethylamodiaquine, 69 nM lumefantrine and 1 nM dihydroartemisinin. Isoquine activity was correlated with polymorphisms in pfcrt at codon 76, but not in pfmdr1 at codon 86. Conclusions: The high activity of isoquine against field isolates, including chloroquine-resistant isolates, with IC 50 ,10 nM, warrants its further development as an antimalarial.
Journal of Antimicrobial Chemotherapy 11/2012; · 5.07 Impact Factor
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Magnus Manske,
Olivo Miotto,
Susana Campino,
Sarah Auburn,
Jacob Almagro-Garcia,
Gareth Maslen,
Jack O'Brien,
Abdoulaye Djimde,
Ogobara Doumbo,
Issaka Zongo, [......],
David J Conway,
Shannon Takala-Harrison,
Christopher V Plowe,
Julian C Rayner,
Kirk A Rockett,
Taane G Clark,
Chris I Newbold,
Matthew Berriman,
Bronwyn MacInnis,
Dominic P Kwiatkowski
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ABSTRACT: Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome.
Nature 06/2012; 487(7407):375-9. · 36.28 Impact Factor
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ABSTRACT: The worldwide burden of malaria can be substantially reduced using existing public health interventions. However, elimination of Plasmodium will require fundamentally different approaches. Novel experimental attenuation strategies for active immunization using knockout strains have recently stimulated renewed interest in whole-parasite vaccine approaches. Preventive drug administration during transmission of wild-type sporozoites is a complementary strategy for eliciting protective immune responses. These whole-cell immunization strategies are based on one fundamental principle: inducing protection by blocking parasite conversion from the clinically silent liver phase to the pathogenic intra-erythrocytic replication cycle. Here, we review the basis, evidence and targets for whole-cell-based vaccination strategies against the liver stage bottleneck in Plasmodium infections and discuss preclinical and clinical research opportunities.
Trends in Molecular Medicine 07/2011; 17(9):527-36. · 10.35 Impact Factor
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ABSTRACT: Plasmodium undergoes an obligate liver phase before the onset of malaria, which is caused exclusively by cyclic propagation of the parasite inside erythrocytes. The diagnostically inaccessible and clinically silent pre-erythrocytic expansion phase is a promising target for inducing sterilizing immunity against reinfections. Recent studies in rodent and human malaria models called attention to the induction of potent protective immunity by administration of anti-malarial drugs during sporozoite exposure. Here, we review the concept of drug-mediated pathogen arrest as a natural immunization strategy. This previously unrecognized immunological benefit might also open new opportunities for population-wide presumptive drug administration as an adjunct malaria control tool.
Current opinion in immunology 06/2011; 23(4):500-8. · 10.88 Impact Factor
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ABSTRACT: The pharmacokinetic and pharmacodynamic properties of a new pediatric formulation of artemether-lumefantrine, dispersible tablet, were determined within the context of a multicenter, randomized, parallel-group study. In an exploratory approach, we compared a new pediatric formulation with the tablet formulation administered crushed in the treatment of African children with uncomplicated Plasmodium falciparum malaria. Patients were randomized to 3 different dosing groups (weights of 5 to <15 kg, 15 and <25 kg, and 25 to <35 kg). Treatment was administered twice daily over 3 days. Plasma concentrations of artemether and its active metabolite, dihydroartemisinin (DHA), were determined at 1 and 2 h after the first dose of dispersible (n = 91) and crushed (n = 93) tablets. A full pharmacokinetic profile of lumefantrine was reconstituted on the basis of 310 (dispersible tablet) and 315 (crushed tablet) plasma samples, collected at 6 different time points (1 sample per patient). Dispersible and crushed tablets showed similar artemether and DHA maximum concentrations in plasma (C(max)) for the different body weight groups, with overall means of 175 ± 168 and 190 ± 168 ng/ml, respectively, for artemether and 64.7 ± 58.1 and 63.7 ± 65.0 ng/ml, respectively, for DHA. For lumefantrine, the population C(max) were 6.3 μg/ml (dispersible tablet) and 7.7 μg/ml (crushed tablet), whereas the areas under the concentration-time curves from time zero to the time of the last quantifiable plasma concentration measured were 574 and 636 μg · h/ml, respectively. For both formulations, descriptive quintile analyses showed no apparent association between artemether/DHA C(max) and parasite clearance time or between the lumefantrine C(max) and the occurrence of adverse events or corrected QT interval changes. The results suggest that the dispersible tablet provides adequate systemic exposure to artemether, DHA, and lumefantrine in African children with uncomplicated P. falciparum malaria.
Antimicrobial Agents and Chemotherapy 06/2011; 55(9):3994-9. · 4.84 Impact Factor
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ABSTRACT: Each year, infections with the protozoan parasite Plasmodium falciparum kill 1 million people, mostly children in Africa. Intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) reduces the incidence of malaria and aims to prevent mortality in infants, children, and pregnant women. There is contradictory evidence as to whether this strategy may generate additional protection against reinfection beyond the limited duration of the intervention. Previous work established that ablation of either liver-stage maturation or subsequent life cycle conversion by causal prophylactic drugs elicits protective immune responses against reinfections when drugs are no longer present. Here we show in the rodent malaria model that pyrimethamine, a component of SP, inhibits liver-stage development in vitro and in vivo, confirming the causal prophylactic activity of pyrimethamine. Repeated exposure to high doses of Plasmodium berghei sporozoites during pyrimethamine prophylaxis induced complete protection in C57BL/6 mice against challenge with high doses of sporozoites delivered intravenously 35 to 199 days later. Immunizations by infectious mosquito bites induced limited, inoculation-dependent protection against subsequent challenge by infected mosquito bites but provided partial protection against experimental cerebral malaria. Short-term pyrimethamine prophylaxis during intravenous transmission of sporozoites from a pyrimethamine-resistant strain delayed, but did not prevent, blood-stage infection. Our data provide a rationale for the notion of sustained protective efficacy of IPT based on the capacity of arrested, drug-sensitive liver-stage and/or suppressed blood-stage parasites to mount lasting protection.
Antimicrobial Agents and Chemotherapy 03/2011; 55(6):2760-7. · 4.84 Impact Factor
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ABSTRACT: Eukaryotic pathogens typically follow a complex life cycle, including host switch and morphologically distinct forms. Parasite stage conversion offers exceptional opportunities for whole organism vaccine development. In case of Plasmodium, the causative agent of malaria, disease is exclusively caused by asexual blood stages that invade and replicate within erythrocytes. Pathogenic blood stage infections are preceded by a silent parasite growth phase inside the liver. Two alternative experimental whole organisms vaccine strategies that lead to arrested Plasmodium liver stages elicit potent, lasting immunity against re-infection. Live irradiation- or genetically arrested parasites are metabolically active and correspond to classical attenuated vaccines. Specific antimalarial treatment during experimental natural sporozoite infections prevents a febrile malaria episode and, simultaneously, induces effective anti-liver stage immunity. Translation of these strategies into a safe, affordable, and accessible pediatric anti-malaria vaccine requires major bioengineering and pharmaceutical improvements, respectively, but holds promise for a truly effective immunization scheme against the most prevalent and fatal vector-borne disease.
Human vaccines 01/2011; 7 Suppl:16-21. · 3.58 Impact Factor
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PLoS ONE 01/2011; 6(2). · 4.09 Impact Factor
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Susana Campino,
Sarah Auburn,
Katja Kivinen,
Issaka Zongo,
Jean-Bosco Ouedraogo,
Valentina Mangano,
Abdoulaye Djimde,
Ogobara K Doumbo,
Steven M Kiara,
Alexis Nzila, [......],
Timothy Anderson,
François Nosten,
Nicholas J White,
Rhian Gwilliam,
Panos Deloukas,
Bronwyn MacInnis,
Christopher I Newbold,
Kirk Rockett,
Taane G Clark,
Dominic P Kwiatkowski
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ABSTRACT: The diversity in the Plasmodium falciparum genome can be used to explore parasite population dynamics, with practical applications to malaria control. The ability to identify the geographic origin and trace the migratory patterns of parasites with clinically important phenotypes such as drug resistance is particularly relevant. With increasing single-nucleotide polymorphism (SNP) discovery from ongoing Plasmodium genome sequencing projects, a demand for high SNP and sample throughput genotyping platforms for large-scale population genetic studies is required. Low parasitaemias and multiple clone infections present a number of challenges to genotyping P. falciparum. We addressed some of these issues using a custom 384-SNP Illumina GoldenGate assay on P. falciparum DNA from laboratory clones (long-term cultured adapted parasite clones), short-term cultured parasite isolates and clinical (non-cultured isolates) samples from East and West Africa, Southeast Asia and Oceania. Eighty percent of the SNPs (n = 306) produced reliable genotype calls on samples containing as little as 2 ng of total genomic DNA and on whole genome amplified DNA. Analysis of artificial mixtures of laboratory clones demonstrated high genotype calling specificity and moderate sensitivity to call minor frequency alleles. Clear resolution of geographically distinct populations was demonstrated using Principal Components Analysis (PCA), and global patterns of population genetic diversity were consistent with previous reports. These results validate the utility of the platform in performing population genetic studies of P. falciparum.
PLoS ONE 01/2011; 6(6):e20251. · 4.09 Impact Factor
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ABSTRACT: In sub-Saharan Africa, Plasmodium falciparum and hepatitis A (HAV) infections are common, especially in children. Co-infections with these two pathogens may therefore occur, but it is unknown if temporal clustering exists.
We studied the pattern of co-infection of P. falciparum malaria and acute HAV in Kenyan children under the age of 5 years in a cohort of children presenting with uncomplicated P. falciparum malaria. HAV status was determined during a 3-month follow-up period.
Among 222 cases of uncomplicated malaria, 10 patients were anti-HAV IgM positive. The incidence of HAV infections during P. falciparum malaria was 1.7 (95% CI 0.81-3.1) infections/person-year while the cumulative incidence of HAV over the 3-month follow-up period was 0.27 (95% CI 0.14-0.50) infections/person-year. Children with or without HAV co-infections had similar mean P. falciparum asexual parasite densities at presentation (31,000/µL vs. 34,000/µL, respectively), largely exceeding the pyrogenic threshold of 2,500 parasites/µL in this population and minimizing risk of over-diagnosis of malaria as an explanation.
The observed temporal association between acute HAV and P. falciparum malaria suggests that co-infections of these two hepatotrophic human pathogens may result from changes in host susceptibility. Testing this hypothesis will require larger prospective studies.
PLoS ONE 01/2011; 6(7):e21013. · 4.09 Impact Factor
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Steffen Borrmann,
Philip Sasi,
Leah Mwai,
Mahfudh Bashraheil,
Ahmed Abdallah,
Steven Muriithi,
Henrike Frühauf,
Barbara Schaub,
Johannes Pfeil,
Judy Peshu, [......],
Benjamin Tsofa,
Moses Mosobo,
Brett Lowe,
Faith Osier,
Greg Fegan,
Niklas Lindegårdh,
Alexis Nzila,
Norbert Peshu,
Margaret Mackinnon,
Kevin Marsh
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ABSTRACT: The emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies.
On the Kenyan coast we studied the treatment responses in 474 children 6-59 months old with uncomplicated P. falciparum malaria in a randomized controlled trial of dihydroartemisinin-piperaquine vs. artemether-lumefantrine from 2005 to 2008. (ISRCTN88705995).
The proportion of patients with residual parasitemia on day 1 rose from 55% in 2005-2006 to 87% in 2007-2008 (odds ratio, 5.4, 95%CI, 2.7-11.1; P<0.001) and from 81% to 95% (OR, 4.1, 95%CI, 1.7-9.9; P = 0.002) in the DHA-PPQ and AM-LM groups, respectively. In parallel, Kaplan-Meier estimated risks of apparent recrudescent infection by day 84 increased from 7% to 14% (P = 0.1) and from 6% to 15% (P = 0.05) with DHA-PPQ and AM-LM, respectively. Coinciding with decreasing transmission in the study area, clinical tolerance to parasitemia (defined as absence of fever) declined between 2005-2006 and 2007-2008 (OR body temperature >37.5°C, 2.8, 1.9-4.1; P<0.001). Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof.
The significant, albeit small, decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity, to the coincident reduction in population-level clinical immunity, or both. Maintaining the efficacy of artemisinin-based therapy in Africa would benefit from a better understanding of the mechanisms underlying reduced parasite clearance rates.
Controlled-Trials.com ISRCTN88705995.
PLoS ONE 01/2011; 6(11):e26005. · 4.09 Impact Factor
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ABSTRACT: Previous epidemiological studies have demonstrated a protective association between the NOS2G-954C (NOS2(Lambaréné)) polymorphism in inducible nitric oxide synthase and severe malaria. The polymorphism is commoner in children with uncomplicated compared with severe malaria. We now show that the likely mechanism for such protection is increased flux of nitrogen from arginine to nitric oxide (NO) during episodes of malaria. Forty-seven boys with uncomplicated malaria received an infusion of (15)N-arginine to measure directly whole body in vivo NO production. The NOS2G-954C genotype previously associated with reduced risk of severe malaria in Gabon was also assessed. Evaluable data were obtained from 40 boys, of whom 6 were NOS2G-954C heterozygotes. Heterozygotes had higher urinary (15)N nitrate enrichments, 2.3 ± 0.6 vs. 1.4 ± 0.5 atoms percent excess (P = 0.001) and higher ratios of (15)N between urine nitrate and plasma arginine (87 ± 11 vs. 57 ± 18%, P = 0.001) consistent with accelerated NO production. We also derived total NO production rates, combining data with total urine production rate and nitrate concentration; these showed no difference by genotype (0.62 ± 0.36, n = 6 vs. 0.83 ± 0.50 μmol/kg·h, n = 16; P = 0.36), but data were confounded by very high variability in measurements of urine output and nitrate concentrations. This study supports the idea that NOS2 genotype protects against severe malaria by increasing NO production during episodes of uncomplicated malaria.
AJP Regulatory Integrative and Comparative Physiology 11/2010; 299(5):R1248-53. · 3.34 Impact Factor
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ABSTRACT: Resistance to the amino alcohol quinine has been associated with polymorphisms in pfnhe, a sodium hydrogen exchanger. We investigated the role of this gene in quinine resistance in vitro in isolates from Kenya. We analyzed pfnhe whole-gene polymorphisms, using capillary sequencing, and pfcrt at codon 76 (pfcrt-76) and pfmdr1 at codon 86 (pfmdr1-86), using PCR-enzyme restriction methodology, in 29 isolates from Kilifi, Kenya, for association with the in vitro activities of quinine and 2 amino alcohols, mefloquine and halofantrine. In vitro activity was assessed as the drug concentration that inhibits 50% of parasite growth (IC50). The median IC50s of quinine, halofantrine, and mefloquine were 92, 22, and 18 nM, respectively. The presence of 2 DNNND repeats in microsatellite ms4760 of pfnhe was associated with reduced susceptibility to quinine (60 versus 227 nM for 1 and 2 repeats, respectively; P<0.05), while 3 repeats were associated with restoration of susceptibility. The decrease in susceptibility conferred by the 2 DNNND repeats was more pronounced in parasites harboring the pfmdr1-86 mutation. No association was found between susceptibility to quinine and the pfcrt-76 mutation or between susceptibility to mefloquine or halofantrine and the pfnhe gene and the pfcrt-76 and pfmdr1-86 mutations. Using previously published data on the in vitro activities of chloroquine, lumefantrine, piperaquine, and dihydroartemisinin, we investigated the association of their activities with pfnhe polymorphism. With the exception of a modulation of the activity of lumefantrine by a mutation at position 1437, pfnhe did not modulate their activities. Two DNNND repeats combined with the pfmdr1-86 mutation could be used as an indicator of reduced susceptibility to quinine.
Antimicrobial Agents and Chemotherapy 08/2010; 54(8):3302-7. · 4.84 Impact Factor
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ABSTRACT: Malaria remains the most prevalent vector-borne infectious disease and has the highest rates of fatality. Current antimalarial drug strategies cure malaria or prevent infections but lack a sustained public health impact because they fail to expedite the acquisition of protective immunity. We show that antibiotic administration during transmission of the parasite Plasmodium berghei results in swift acquisition of long-lived, life cycle-specific protection against reinfection with live sporozoites in mice. Antibiotic treatment specifically inhibits the biogenesis and inheritance of the apicoplast in Plasmodium liver stages, resulting in continued liver-stage maturation but subsequent failure to establish blood-stage infection. Exponential expansion of these attenuated liver-stage merozoites from a single sporozoite induces potent immune protection against malaria. If confirmed in residents of malaria-endemic areas, periodic prophylaxis with safe and affordable antibiotics may offer a powerful shortcut toward a needle-free surrogate malaria immunization strategy.
Science translational medicine 07/2010; 2(40):40ra49. · 7.80 Impact Factor
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The Journal of Infectious Diseases 04/2010; 201(8):1271-2. · 6.41 Impact Factor
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Steffen Borrmann,
William M. Sallas,
Sonia Machevo,
Raquel González,
Anders Björkman,
Andreas Mårtensson,
Mary Hamel,
Elizabeth Juma,
Judy Peshu,
Bernhards Ogutu,
Abdoulaye Djimdé,
Umberto D’Alessandro,
Anne-Claire Marrast,
Gilbert Lefèvre,
Steven E. Kern
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ABSTRACT: Objectives Artemether–lumefantrine (AL) is first-line treatment for uncomplicated malaria in many African countries. Concomitant food consumption may affect absorption of lumefantrine but data in the most important target population, i.e. children, are lacking. Therefore, we evaluated the effect of food intake on oral lumefantrine bioavailability in African children with malaria.Methods In a randomised, investigator-blinded, multicentre phase III efficacy trial, 899 infants and children with acute uncomplicated Plasmodium falciparum malaria received six doses of AL according to body weight over 3 days either as crushed tablets (Coartem®) or as dispersible tablets. Single blood samples were obtained for lumefantrine plasma concentration determination in a subset of 621 patients, and a two-compartment pharmacokinetic model was constructed.Results The mean observed lumefantrine plasma concentration for crushed tablet and dispersible tablet, respectively, was 100% and 55% higher with a concomitant meal at the time of dose intake than when taken alone. Similarly, consumption of milk (the most common meal) increased model-estimated lumefantrine bioavailability by 57% (90% CI: 29–96%) with crushed tablets and 65% (90% CI: 28–109%) with dispersible tablets compared to no food. The 28-day PCR-corrected cure rate (primary study endpoint) in the evaluable population was 582/587 [99.1% (95% CI: 98.0–99.7%)] and was not related to food intake.Conclusions AL was highly efficacious. Concomitant food intake increased lumefantrine absorption in children with malaria.Effet de la nourriture sur la biodisponibilité du luméfantrine chez des enfants africains recevant des comprimés écrasés ou dispersibles d’artéméther-luméfantrine (Coartem®) contre la malaria aigüe non compliquée à Plasmodium falciparumObjectifs: l’artéméther-luméfantrine (AL) est un traitement de première intention contre la malaria sans complications dans de nombreux pays africains. La consommation concomitante d’aliments peu affecter l’absorption de la luméfantrine, mais des données sur la population cible la plus importante i.e. les enfants, font défaut. Par conséquent, nous avons évalué l’effet de la prise alimentaire sur la biodisponibilité orale de la luméfantrine chez des enfants africains atteints de malaria.Méthodes: Dans une étude d’efficacité randomisée, aveugle pour l’investigateur, multicentrique de phase III, 899 nourrissons et enfants atteints de malaria aigüe àPlasmodium falciparum non compliquée ont reçu six doses d’AL en fonction du poids du corps pendant 3 jours, soit en comprimés écrasés (Coartem®) ou sous forme de comprimés dispersibles. Des échantillons uniques de sang ont été prélevés pour la détermination de la concentration plasmatique de luméfantrine dans un sous-ensemble de 621 patients et un modèle pharmacocinétique bi compartimental a été construit.Résultats: Les concentrations plasmatiques moyennes de luméfantrine observées pour les comprimés écrasés et les comprimés dispersibles étaient de 100% et 55% respectivement plus élevée avec un repas concomitant au moment de la prise de la dose que lorsqu’ils étaient pris seuls. De même, la consommation de lait (le repas le plus commun) augmentait la biodisponibilité luméfantrine estimée par le model de 57% (IC90%: 29-96) avec les comprimés écrasés et 65% (IC90%: 28-109) avec les comprimés dispersibles, comparativement à l’absence de nourriture. Le taux de guérison au jour 28 corrigé par la PCR (critère d’évaluation primaire de l’étude) dans la population évaluable était de 582/587 (99,1% (IC95%: 98.0-99.7%)) et n’était pas liéà la prise alimentaire.Conclusions: AL était très efficace. La prise concomitante d’aliments augmente l’absorption de la luméfantrine chez les enfants atteints de malaria.Efecto de la consumición de comida sobre la biodisponibilidad de la lumefantrina en niños Africanos que reciben comprimidos de artemeter-lumefantrina (Coartem®) triturados o dispersables para malaria aguda no complicada por Plasmodium falciparumObjetivos: La artemeter+lumefantrina (AL) es la primera línea de tratamiento para malaria no complicada en muchos países africanos. La consumición concomitante de comida puede afectar la absorción de la lumefantrina pero los datos en la población diana más importante, es decir, en niños, no existe. Por lo tanto, hemos evaluado el efecto de la toma de comidas sobre la biodisponibilidad de lumefantrina oral en niños africanos con malaria.Métodos: En un ensayo aleatorizado, cegado para el investigador, multicéntrico de fase 3, 899 bebés y niños con malaria aguda no complicada por Plasmodium falciparum recibieron seis dosis de AL según su peso corporal durante 3 días, bien como comprimidos triturados (Coartem®) o como comprimidos dispersables. Se obtuvieron dosis individuales de sangre para determinar la concentración de lumefantrina en sangre en un subgrupo de 621 pacientes y se construyó un modelo farmacocinético de dos compartimientos.Resultados: La concentración media observada de lumefantrina en sangre para los comprimidos triturados y los dispersables fué, respectivamente, de un 100% y un 55% más alto con una comida concomitante en el momento de tomar la dosis, que cuando se tomaba sola. De forma similar, la consumición de leche (la comida más común) aumentó la biodisponibilidad de lumefantrina según la estimación del modelo en un 57% (90% IC: 29% a 96%) con comprimidos triturados y del 65% (90% IC: 28% a 109%) con comprimidos dispersables comparado con el no haber tomado alimento alguno. La tasa de curación a día 28 corregida por PCR (resultado primario del estudio) en la población evaluada era 582/587 (99.1% (95% IC: 98.0-99.7%)) y no estaba relacionada con la toma de alimentos.Conclusiones: AL era altamente eficaz. La toma concomitante de comida aumentó la absorción de lumefantrina en niños con malaria.
Tropical Medicine & International Health 03/2010; 15(4):434 - 441. · 2.80 Impact Factor
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Steffen Borrmann,
William M Sallas,
Sonia Machevo,
Raquel González,
Anders Björkman,
Andreas Mårtensson,
Mary Hamel,
Elizabeth Juma,
Judy Peshu,
Bernhards Ogutu,
Abdoulaye Djimdé,
Umberto D'Alessandro,
Anne-Claire Marrast,
Gilbert Lefèvre,
Steven E Kern
[show abstract]
[hide abstract]
ABSTRACT: Artemether-lumefantrine (AL) is first-line treatment for uncomplicated malaria in many African countries. Concomitant food consumption may affect absorption of lumefantrine but data in the most important target population, i.e. children, are lacking. Therefore, we evaluated the effect of food intake on oral lumefantrine bioavailability in African children with malaria.
In a randomised, investigator-blinded, multicentre phase III efficacy trial, 899 infants and children with acute uncomplicated Plasmodium falciparum malaria received six doses of AL according to body weight over 3 days either as crushed tablets (Coartem) or as dispersible tablets. Single blood samples were obtained for lumefantrine plasma concentration determination in a subset of 621 patients, and a two-compartment pharmacokinetic model was constructed.
The mean observed lumefantrine plasma concentration for crushed tablet and dispersible tablet, respectively, was 100% and 55% higher with a concomitant meal at the time of dose intake than when taken alone. Similarly, consumption of milk (the most common meal) increased model-estimated lumefantrine bioavailability by 57% (90% CI: 29-96%) with crushed tablets and 65% (90% CI: 28-109%) with dispersible tablets compared to no food. The 28-day PCR-corrected cure rate (primary study endpoint) in the evaluable population was 582/587 [99.1% (95% CI: 98.0-99.7%)] and was not related to food intake.
AL was highly efficacious. Concomitant food intake increased lumefantrine absorption in children with malaria.
Tropical Medicine & International Health 02/2010; 15(4):434-41. · 2.80 Impact Factor
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ABSTRACT: Febrile malaria is the most common clinical manifestation of P. falciparum infection, and is often the primary endpoint in clinical trials and epidemiological studies. Subjective and objective fevers are both used to define the endpoint, but have not been carefully compared, and the relative incidence of clinical malaria by active and passive case detection is unknown.
We analyzed data from cohorts under active and passive surveillance, including 19,462 presentations with fever and 5,551 blood tests for asymptomatic parasitaemia. A logistic regression model was used to calculate Malaria Attributable Fractions (MAFs) for various case definitions. Incidences of febrile malaria by active and passive surveillance were compared in a subset of children matched for age and location.
Active surveillance identified three times the incidence of clinical malaria as passive surveillance in a subset of children matched for age and location. Objective fever (temperature≥37.5°C) gave consistently higher MAFs than case definitions based on subjective fever.
The endpoints from active and passive surveillance have high specificity, but the incidence of endpoints is lower on passive surveillance. Subjective fever had low specificity and should not be used in primary endpoint. Passive surveillance will reduce the power of clinical trials but may cost-effectively deliver acceptable sensitivity in studies of large populations.
PLoS ONE 01/2010; 5(12):e15569. · 4.09 Impact Factor
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ABSTRACT: We have analyzed the in vitro chemosensitivity profiles of 115 Kenyan isolates for chloroquine (CQ), piperaquine, lumefantrine (LM), and dihydroartemisinin in association with polymorphisms in pfcrt at codon 76 and pfmdr1 at codon 86, as well as with variations of the copy number of pfmdr1. The median drug concentrations that inhibit 50% of parasite growth (IC(50)s) were 41 nM (interquartile range [IQR], 18 to 73 nM), 50 nM (IQR, 29 to 96 nM), 32 nM (IQR, 17 to 46 nM), and 2 nM (IQR, 1 to 3 nM) for CQ, LM, piperaquine, and dihydroartemisinin, respectively. The activity of CQ correlated inversely with that of LM (r(2) = -0.26; P = 0.02). Interestingly, parasites for which LM IC(50)s were higher were wild type for pfcrt-76 and pfmdr1-86. All isolates had one pfmdr1 copy. Thus, the decrease in LM activity is associated with the selection of wild-type pfcrt-76 and pfmdr1-86 parasites, a feature that accounts for the inverse relationship between CQ and LM. Therefore, the use of LM-artemether is likely to lead to the selection of more CQ-susceptible parasites.
Antimicrobial Agents and Chemotherapy 09/2009; 53(12):5069-73. · 4.84 Impact Factor
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Zul Premji,
Rich E. Umeh,
Seth Owusu-Agyei,
Fabian Esamai,
Emmanuel U. Ezedinachi,
Stephen Oguche, Steffen Borrmann,
Akintunde Sowunmi,
Stephan Duparc,
Paula L. Kirby,
Allan Pamba,
Lynda Kellam,
Robert Guiguemdé,
Brian Greenwood,
Stephen A. Ward,
Peter A. Winstanley
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ABSTRACT: Background
Chlorproguanil−dapsone−artesunate (CDA) was developed as an affordable, simple, fixed-dose artemisinin-based combination therapy for use in Africa. This trial was a randomized parallel-group, double-blind, double-dummy study to compare CDA and artemether−lumefantrine (AL) efficacy in uncomplicated Plasmodium falciparum malaria and further define the CDA safety profile, particularly its hematological safety in glucose-6-phosphate dehydrogenase (G6PD) -deficient patients.
Methods and Findings
The trial was conducted at medical centers at 11 sites in five African countries between June 2006 and August 2007. 1372 patients (≥1 to
PLoS ONE 08/2009; 4(8). · 4.09 Impact Factor
