Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids

 

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dc.contributor.author Lombard, Marli en_ZA
dc.contributor.author N'Da, David en_ZA
dc.contributor.author Tran Van Ba, Christophe en_ZA
dc.contributor.author Wein, Sharon en_ZA
dc.contributor.author Norman, Jennifer en_ZA
dc.contributor.author Wiesner, Lubbe en_ZA
dc.contributor.author Vial, Henri en_ZA
dc.date.accessioned 2015-10-30T09:34:06Z
dc.date.available 2015-10-30T09:34:06Z
dc.date.issued 2013 en_ZA
dc.identifier.citation Lombard, M. C., N’Da, D. D., Van Ba, C. T., Wein, S., Norman, J., Wiesner, L., & Vial, H. (2013). Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids. Malar J, 12, 71. en_ZA
dc.identifier.uri http://hdl.handle.net/11427/14525
dc.identifier.uri http://dx.doi.org/10.1186/1475-2875-12-71
dc.description.abstract BACKGROUND:Because Plasmodium falciparum displays increase tolerance against the recommended artemisinin combination therapies (ACT), new classes of anti-malarial drugs are urgently required. Previously synthesized artemisinin-aminoquinoline hybrids were evaluated to ascertain whether the potent low nanomolar in vitro anti-plasmodial activity would carry over in vivo against Plasmodium vinckei. A snapshot pharmacokinetic analysis was carried out on one of the hybrids to obtain an indication of the pharmacokinetic properties of this class of anti-malarial drugs. METHODS: In vitro activity of hybrids 2 and 3 were determined against the 3D7 strain of P. falciparum. Plasmodium vinckei-infected mice were treated with hybrids 1 - 3 for four days at a dosage of 0.8mg/kg, 2.5mg/kg, 7.5mg/kg or 15mg/kg intraperitoneally (ip), or orally (per os) with 2.7mg/kg, 8.3mg/kg, 25mg/kg or 50mg/kg. Artesunate was used as reference drug. A snapshot oral and IV pharmacokinetic study was performed on hybrid 2. RESULTS: Hybrids 1 - 3 displayed potent in vivo anti-malarial activity with ED50 of 1.1, 1.4 and <0.8mg/kg by the ip route and 12, 16 and 13mg/kg per os, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15mg/kg via ip route and at 50mg/kg by oral route for hybrid 1 and 2, whereas artesunate was only able to provide a complete cure at 30mg/kg ip and 80mg/kg per os. CONCLUSIONS: These compounds provide a new class of desperately needed anti-malarial drug. Despite a short half-life and moderate oral bioavailability, this class of compounds was able to cure malaria in mice at very low dosages. The optimum linker length for anti-malarial activity was found to be a diaminoalkyl chain consisting of two carbon atoms either methylated or unmethylated. en_ZA
dc.language.iso eng en_ZA
dc.publisher BioMed Central Ltd en_ZA
dc.rights This is an open access article distributed under the terms of the Creative Commons Attribution License en_ZA
dc.rights.uri http://creativecommons.org/licenses/by/2.0 en_ZA
dc.source Malaria Journal en_ZA
dc.source.uri http://www.malariajournal.com/ en_ZA
dc.subject.other Malaria en_ZA
dc.subject.other Artemisinin en_ZA
dc.subject.other Quinoline en_ZA
dc.subject.other Hybrid en_ZA
dc.subject.other Pharmacokinetics en_ZA
dc.subject.other In vivo activity en_ZA
dc.title Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids en_ZA
dc.type Journal Article en_ZA
dc.rights.holder 2013 Lombard et al; licensee BioMed Central Ltd. en_ZA
uct.type.publication Research en_ZA
uct.type.resource Article en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Health Sciences en_ZA
dc.publisher.department Division of Clinical Pharmacology en_ZA
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This is an open access article distributed under the terms of the Creative Commons Attribution License Except where otherwise noted, this item's license is described as This is an open access article distributed under the terms of the Creative Commons Attribution License