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dc.contributor.authorLombard, Marli C.
dc.contributor.authorN’Da, David D.
dc.contributor.authorVan Ba, Christophe Tran
dc.contributor.authorWein, Sharon
dc.contributor.authorNorman, Jennifer
dc.date.accessioned2015-10-05T06:22:50Z
dc.date.available2015-10-05T06:22:50Z
dc.date.issued2013
dc.identifier.citationLombard, M.C. et al. 2013. Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids. Malaria journal. 12(71):1-7. [http://www.malariajournal.com/]en_US
dc.identifier.issn1475-2875
dc.identifier.issn1475-2875 (Online)
dc.identifier.urihttp://hdl.handle.net/10394/14659
dc.description.abstractBackground: 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 0.8 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 15 mg/kg intraperitoneally (ip), or orally (per os) with 2.7 mg/kg, 8.3 mg/kg, 25 mg/kg or 50 mg/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 <0.8 mg/kg by the ip route and 12, 16 and 13 mg/kg per os, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15 mg/kg via ip route and at 50 mg/kg by oral route for hybrid 1 and 2, whereas artesunate was only able to provide a complete cure at 30 mg/kg ip and 80 mg/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_US
dc.description.urihttp://www.malariajournal.com/
dc.description.urihttp://www.malariajournal.com/content/12/1/71
dc.language.isoenen_US
dc.publisherBioMed Centralen_US
dc.subjectMalariaen_US
dc.subjectArtemisininen_US
dc.subjectQuinolineen_US
dc.subjecthybriden_US
dc.subjectpharmacokineticsen_US
dc.subjectIn vivo activityen_US
dc.titlePotent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybridsen_US
dc.typeArticleen_US
dc.contributor.researchID20883072 - N'Da, David Dago


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