The pharmacokinetics of chloroquine in healthy and<i>Plasmodium chabaudi</i>-infected mice: implications for chronotherapy

Cambiè, Giulia; Verdier, F.; Gaudebout, C.; Clavier, F.; Ginsburg, Hagaï

doi:10.1051/parasite/1994013219

Cited by 14 publications

(14 citation statements)

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“…Whole-blood CQ concentration was measured for the pharmacokinetic determinations, but the sampling period was only 4 h postdose, therefore limiting the findings to the distribution phase of the pharmacokinetic profile. Nevertheless, Cambie et al (11) found that malaria infection (particularly high parasitemia of Ͼ20% in mice) increased the half-life and V/F, which suggests a decreased CL/F (Tables 1 and 2). One other investigation of CQ pharmacokinetics in healthy mice has been reported, in the context of grapefruit juice interaction (4).…”

Section: Discussionmentioning

confidence: 99%

“…However, pharmacokinetic data for CQ in mice were notably deficient. The only specific murine study of CQ pharmacokinetics was an investigation in healthy and malaria-infected (Plasmodium chabaudi) mice (11). Whole-blood CQ concentration was measured for the pharmacokinetic determinations, but the sampling period was only 4 h postdose, therefore limiting the findings to the distribution phase of the pharmacokinetic profile.…”

Section: Discussionmentioning

confidence: 99%

“…Based on previous reports (9,11,13) and a pilot study (data not shown), CQ doses of 0, 300, 600, 900, and 1,500 g CQ (approximately 0, 10, 20, 30, and 50 mg/kg, respectively, for a 30-g mouse) were selected for the dose ranging studies. The CQ solutions were administered to each mouse by i.p.…”

Section: Maymentioning

confidence: 99%

“…Remarkably, there is a paucity of pharmacokinetic and pharmacodynamic data for CQ in preclinical animal models, particularly in murine malaria models (4,11,29).…”

mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Maymentioning

confidence: 99%

“…Remarkably, there is a paucity of pharmacokinetic and pharmacodynamic data for CQ in preclinical animal models, particularly in murine malaria models (4,11,29).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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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“…First, stage-specific mortality caused by C cannot be involved. The half-life of whole blood Cconcentration in mice heavily infected with P. chabaudi (21-25 % parasitized RBCs) is in the order of 7 h (Cambie et al 1994). Parasite numbers were first assayed at least 2 d after treatment, when the C level must have been less than 0.5 mg kg −" ; preliminary experiments revealed twice this concentration to have no noticeable effect on parasite numbers or infection dynamics.…”

Section: Discussionmentioning

confidence: 99%

Adaptive changes in Plasmodium transmission strategies following chloroquine chemotherapy

Buckling

Taylor

Carlton

et al. 1997

Proc. R. Soc. Lond. B

110

102

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SUMMARYBoth theory and data suggest that malaria parasites divert resources from within-host replication to the production of transmission stages (gametocytes) when conditions deteriorate. Increased investment into transmission stages should therefore follow subcurative treatment with antimalarial drugs, but relevant clinical studies necessarily lack adequate control groups. We therefore carried out controlled experiments to test this hypothesis, using a rodent malaria (Plasmodium chabaudi) model. Infections treated with a subcurative dose of the antimalarial chloroquine showed an earlier peak and a greater rate of gametocyte production relative to untreated controls. These alterations led to correlated changes in infectivity to mosquitoes, with the consequence that chloroquine treatment had no effect on the proportion of mosquitoes infected. Treatment of human malaria commonly does not result in complete parasite clearance. If surviving parasites produce compensatory increases in their rate of gametocyte production similar to those reported here, such treatment may have minimal effect on decreasing, and may actually increase, transmission. Importantly, if increased investment in transmission is a generalized stress response, the effect might be observed following a variety of antimalarial treatments, including other drugs and potential vaccines. Similar parasite life history counter-adaptations to intervention strategies are likely to occur in many disease-causing organisms.

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Transmission model of endemic human malaria in a partially immune population

Chiyaka

Garira

Dube

2007

Mathematical and Computer Modelling

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The pharmacokinetics of chloroquine in healthy andPlasmodium chabaudi-infected mice: implications for chronotherapy

Cited by 14 publications

References 2 publications

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

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

Adaptive changes in Plasmodium transmission strategies following chloroquine chemotherapy

Transmission model of endemic human malaria in a partially immune population

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