Inactivation of artemisinin by thalassemic erythrocytes

Charoenteeraboon, Juree; Kamchonwongpaisan, Sumalee; Wilairat, Prapon; Vattanaviboon, Paiboon; Yuthavong, Yongyuth

doi:10.1016/s0006-2952(00)00271-9

Cited by 12 publications

(19 citation statements)

References 27 publications

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“…In vitro studies have demonstrated markedly increased 50% inhibitory concentrations of artemisinin drugs in parasite cultures with thalassemic red blood cells (10,22,34,37,38). The determinants of reduced parasite susceptibility to artemisinin drugs in thalassemic cells remain unclear but may relate to competitive uptake and inactivation of drug by thalassemic host cell components, the abnormal hemoglobin itself (38), erythrocyte membrane-bound heme (37), or alterations in oxidative stress within parasitized thalassemic erythrocytes (34).…”

Section: Discussionmentioning

confidence: 99%

“…However, the applicability of dose regimens developed in studies with other racial groups is uncertain. In addition, hemoglobin variants that result in conditions such as ␣-thalassemia and that may alter the dispositions and efficacies of artemisinin drugs (10,20,22,34,38) have a high prevalence in some Melanesian populations (1). There have been no previous pharmacokinetic studies of rectal ARTS in patients with hemoglobinopathies.…”

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confidence: 99%

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Disposition of Artesunate and Dihydroartemisinin after Administration of Artesunate Suppositories in Children from Papua New Guinea with Uncomplicated Malaria

Karunajeewa

Ilett

Dufall³

et al. 2004

Antimicrob Agents Chemother

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A detailed pharmacokinetic analysis was performed with 47 children from Papua New Guinea with uncomplicated falciparum or vivax malaria treated with artesunate (ARTS) suppositories (Rectocaps) given in two doses of approximately 13 mg/kg of body weight 12 h apart. Following an intensive sampling protocol, samples were assayed for ARTS and its primary active metabolite, dihydroartemisinin (DHA), by liquid chromatography-mass spectrometry. A population pharmacokinetic model was developed to describe the data. Following administration of the first dose, the mean maximal concentrations of ARTS and DHA were 1,085 nmol/liter at 0.9 h and 2,525 nmol/liter at 2.3 h, respectively. The absorption half-life for ARTS was 2.3 h, and the conversion half-life (ARTS to DHA) was 0.27 h, while the elimination half-life of DHA was 0.71 h. The mean common volumes of distribution for ARTS and DHA relative to bioavailability were 42.8 and 2.04 liters/kg, respectively, and the mean clearance values relative to bioavailability were 6 and 2.2 liters/h/kg for ARTS and DHA, respectively. Substantial interpatient variability was observed, and the bioavailability of the second dose relative to that of the first was estimated to be 0.72. The covariates age, sex, and ␣-thalassemia genotype were not influential in the pharmacokinetic model development; but the inclusion of weight as a covariate significantly improved the performance of the model. An ARTS suppositories dose of 10 of 20 mg/kg is appropriate for use in children with uncomplicated malaria.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Disposition of Artesunate and Dihydroartemisinin after Administration of Artesunate Suppositories in Children from Papua New Guinea with Uncomplicated Malaria

Karunajeewa

Ilett

Dufall³

et al. 2004

Antimicrob Agents Chemother

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“…The reduced metabolic activity at the ring stage is reflected further in ARTinduced temporary arrest of growth (dormancy) at this stage (10,62). Whereas this may partially explain the prolonged parasite clearance observed in clinical studies (46), the possibility of host factors that may play a crucial role in determining prolonged parasite clearance times observed in vivo has not been investigated (9,58). In addition, it has been proposed that ARTs may interfere with the mitochondrial function of the parasite (36,59).…”

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confidence: 99%

Lack of Association of the S769N Mutation in Plasmodium falciparum SERCA (PfATP6) with Resistance to Artemisinins

Cui

Wang

Jiang

et al. 2012

Antimicrob Agents Chemother

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The recent emergence of artemisinin (ART) resistance in Plasmodium falciparum in western Cambodia, manifested as delayed parasite clearance, is a big threat to the long-term efficacy of this family of antimalarial drugs. Among the multiple candidate genes associated with ART resistance in P. falciparum, the sarcoplasmic/endoplasmic reticulum Ca 2؉ -ATPase PfATP6 has been postulated as a specific target of ARTs. The PfATP6 gene harbors multiple single-nucleotide polymorphisms in field parasite populations, and S769N has been associated with decreased sensitivity to artemether in parasite populations from French Guiana. In this study, we used an allelic exchange strategy to engineer parasite lines carrying the S769N mutations in P. falciparum strain 3D7 and evaluated whether introduction of this mutation modulated parasite sensitivity to ART derivatives. Using three transgenic lines carrying the 769N mutation and two transgenic lines carrying the wild-type 769S as controls, we found that S769N did not affect PfATP6 gene expression. We compared the sensitivities of these parasite lines to three ART derivatives, artemether, artesunate, and dihydroartemisinin, in 18 biological experiments and detected no significant effect of the S769N mutation on parasite response to these ART derivatives. This study provides further evidence for the lack of association of PfATP6 with ART resistance.

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“…Erythrocyte polymorphisms are common in the southeast Asian region [67,68,69]. Host-dependent artemisinin resistance has been shown in P. falciparum infecting α-thalassemic hemoglobin (Hb) H alone (α-thal1/α-thal2) or Hb H with Hb Constant Spring (CS) (Hb H/Hb CS or α-thal1/Hb CS) erythro cytes [70][71][72][73]. These genetically variant erythrocytes are capable of taking up a large portion of artemisinin drugs owing to a higher binding affinity of the drugs to Hb H in α-thalassemic erythrocytes than to Hb A, thereby reducing artemisinin effectiveness [72,73].…”

Section: Factors Contributing To Artemisinin Resistancementioning

confidence: 99%

Emerging artemisinin resistance in the border areas of Thailand

Na‐Bangchang¹,

Karbwang

2013

Expert Review of Clinical Pharmacology

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Emergence of artemisinin resistance has been confirmed in Cambodia and the border areas of Thailand, the well-known hotspots of multidrug resistance Plasmodium falciparum. It appears to be spreading to the western border of Thailand along the Thai-Myanmar border, and will probably spread to other endemic areas of the world in the near future. This raises a serious concern on the long-term efficacy of artemisinin-based combination therapies, as these combination therapies currently constitute the last effective and most tolerable treatment for multidrug-resistant Plasmodium falciparum. Attempts have been made by a diverse array of stakeholders to prevent the emergence of new foci of artemisinin resistance, as well as to limit the spread of resistance to the original foci. The success in achieving this goal depends on effective integration of containment and surveillance programs with other malaria control measures, with support from both basic and operational research.

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Inactivation of artemisinin by thalassemic erythrocytes

Cited by 12 publications

References 27 publications

Disposition of Artesunate and Dihydroartemisinin after Administration of Artesunate Suppositories in Children from Papua New Guinea with Uncomplicated Malaria

Disposition of Artesunate and Dihydroartemisinin after Administration of Artesunate Suppositories in Children from Papua New Guinea with Uncomplicated Malaria

Lack of Association of the S769N Mutation in Plasmodium falciparum SERCA (PfATP6) with Resistance to Artemisinins

Emerging artemisinin resistance in the border areas of Thailand

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