The Addition of Artesunate to Chloroquine for Treatment of Plasmodium Falciparum Malaria in Gambian Children Delays, but Does Not Prevent Treatment Failure

Sutherland, Colin J.; Drakeley, Christopher J.; Obisike, Uche; Coleman, Rosalind; Jawara, Musa; Targett, G. A. T.; Milligan, Paul; Pinder, Margaret; Walraven, Gijs

doi:10.4269/ajtmh.2003.69.19

Cited by 29 publications

(30 citation statements)

References 21 publications

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“…These may be remnants of the starting parasite population that survived the artemether concentrations present in the host in the first few days of treatment, and therefore, these genotypes have not only survived lumefantrine but may also bear a signal of artemisinin selection. Evidence to support this comes from our previous in vivo study of the combination CQ plus artesunate (CQϩAS) (27). Molecular analysis of the transmission potential of different genotypes demonstrated a fourfold reduction in transmissibility to mosquitoes of parasites harboring the 86Y allele compared to those with the 86N allele among children treated with CQϩAS.…”

Section: Discussionsupporting

confidence: 51%

Amodiaquine and Artemether-Lumefantrine Select Distinct Alleles of the Plasmodium falciparum mdr1 Gene in Tanzanian Children Treated for Uncomplicated Malaria

Humphreys

Merinopoulos

Ahmed

et al. 2007

Antimicrob Agents Chemother

223

249

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The artemisinin-based combination therapies artemether-lumefantrine (AL) and amodiaquine (AQ) plus artesunate have been adopted for treatment of Plasmodium falciparum malaria in many African countries. Molecular markers of parasite resistance suitable for surveillance have not been established for any of the component drugs in either of these combinations. We assessed P. falciparum mdr1 (Pfmdr1) alleles present in 300 Tanzanian children presenting with uncomplicated falciparum malaria, who were enrolled in a clinical trial of antimalarial therapy. Pfmdr1 genotype analysis was also performed with isolates from 182 children who failed AQ monotherapy and 54 children who failed AL treatment. Pfmdr1 alleles 86Y, 184Y, and 1246Y were more common among treatment failures in the AQ group than among pretreatment infections. The converse was found in the AL-treated group. Children presenting with the 86Y/184Y/1246Y Pfmdr1 haplotype and treated with AQ were significantly more likely to retain this haplotype if they were parasite positive during posttreatment follow-up than were children treated with AL (odds ratio, 33.25; 95% confidence interval, 4.17 to 1441; P, <0.001). We conclude that AL and AQ exert opposite within-host selective effects on the Pfmdr1 gene of P. falciparum.

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Section: Discussionsupporting

confidence: 51%

Amodiaquine and Artemether-Lumefantrine Select Distinct Alleles of the Plasmodium falciparum mdr1 Gene in Tanzanian Children Treated for Uncomplicated Malaria

Humphreys

Merinopoulos

Ahmed

et al. 2007

Antimicrob Agents Chemother

223

249

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“…3). There are few clinical studies of CQ in combination with artemisinin drugs (48), but reports of CQ-artesunate treatment in West Africa and Vietnam suggest that beneficial outcomes can be achieved (24,33,49,63).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics, and Allometric Scaling of Chloroquine in a Murine Malaria Model

Moore

Page‐Sharp

Stoney

et al. 2011

Antimicrob Agents Chemother

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Chloroquine (CQ) is an important antimalarial drug for the treatment of special patient groups and as a comparator for preclinical testing of new drugs. Pharmacokinetic data for CQ in animal models are limited; thus, we conducted a three-part investigation, comprising (i) pharmacodynamic studies of CQ and CQ plus dihydroartemisinin (DHA) in Plasmodium berghei-infected mice, (ii) pharmacokinetic studies of CQ in healthy and malaria-infected mice, and (iii) interspecies allometric scaling for CQ from 6 animal and 12 human studies. The single-dose pharmacodynamic study (10 to 50 mg CQ/kg of body weight) showed dose-related reduction in parasitemia (5-to >500-fold) and a nadir 2 days after the dose. Multiple-dose regimens (total dose, 50 mg/kg CQ) demonstrated a lower nadir and longer survival time than did the same single dose. The CQ-DHA combination provided an additive effect compared to each drug alone. The elimination half-life (t 1/2 ), clearance (CL), and volume of distribution (V) of CQ were 46.6 h, 9.9 liters/h/kg, and 667 liters/kg, respectively, in healthy mice and 99.3 h, 7.9 liters/h/kg, and 1,122 liters/kg, respectively, in malaria-infected mice. The allometric equations for CQ in healthy mammals (CL ‫؍‬ 3.86 ؋ W 0.56 , V ‫؍‬ 230 ؋ W 0.94 , and t 1/2 ‫؍‬ 123 ؋ W 0.2 ) were similar to those for malaria-infected groups. CQ showed a delayed dose-response relationship in the murine malaria model and additive efficacy when combined with DHA. The biphasic pharmacokinetic profiles of CQ are similar across mammalian species, and scaling of specific parameters is plausible for preclinical investigations.Chloroquine (CQ) was introduced 50 years ago as an alternative to quinine (25,70). It became the drug of choice for both prophylaxis and treatment of malaria, but resistance has caused a decline in the contemporary clinical use of chloroquine (25,35,40,70,72). Nevertheless, CQ remains one of the most important antimalarial drugs, especially in the treatment of vivax malaria and special patient groups, such as children and pregnant women (32,37,48,51,73), not least because it is inexpensive and well tolerated and has a rapid onset of action. Recent studies have clarified the mechanism of CQ resistance and shown that clinical efficacy of CQ may return at least a decade after it has been withdrawn from use, prompting suggestions that CQ could reemerge as an important therapeutic option for malaria, most likely in combination with artemisinin compounds or chemosensitizing agents (25,28,36,42,45,70).Notwithstanding its clinical status, CQ has a prominent role as a comparator for in vitro and in vivo preclinical testing of new antimalarial drugs (54,56,68,74). Remarkably, there is a paucity of pharmacokinetic and pharmacodynamic data for CQ in preclinical animal models, particularly in murine malaria models (4,11,29).The pharmacokinetic parameters for CQ exhibit wide interindividual variation, although limitations in study design and analytical procedures have been contributing factors (18,64,65). Recent clinical stud...

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“…In 2000 and 2001, pediatric treatment trials for uncomplicated malaria conducted in The Gambia included CQ comparison arms (14,37). We have used plasma and data from these trials and examined whether antibodies to AMA-1 and MSP-1 19 are associated with clinical recovery and elimination of parasites.…”

mentioning

confidence: 99%

Immunoglobulin G Antibodies to Merozoite Surface Antigens Are Associated with Recovery from Chloroquine-ResistantPlasmodium falciparumin Gambian Children

et al. 2006

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We examined the hypothesis that recovery from uncomplicated malaria in patients carrying drug-resistant Plasmodium falciparum is a measure of acquired functional immunity and may therefore be associated with humoral responses to candidate vaccine antigens. Gambian children with malaria were treated with chloroquine in 28-day trials, and recovery was defined primarily as the absence of severe clinical malaria at any time and absence of parasitemia with fever after 3 days. Plasma samples from these children were assayed by enzyme-linked immunosorbent assay for immunoglobulin G (

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The Addition of Artesunate to Chloroquine for Treatment of Plasmodium Falciparum Malaria in Gambian Children Delays, but Does Not Prevent Treatment Failure

Cited by 29 publications

References 21 publications

Amodiaquine and Artemether-Lumefantrine Select Distinct Alleles of the Plasmodium falciparum mdr1 Gene in Tanzanian Children Treated for Uncomplicated Malaria

Amodiaquine and Artemether-Lumefantrine Select Distinct Alleles of the Plasmodium falciparum mdr1 Gene in Tanzanian Children Treated for Uncomplicated Malaria

Pharmacokinetics, Pharmacodynamics, and Allometric Scaling of Chloroquine in a Murine Malaria Model

Immunoglobulin G Antibodies to Merozoite Surface Antigens Are Associated with Recovery from Chloroquine-ResistantPlasmodium falciparumin Gambian Children

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