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

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dc.contributor.authorLombard, Marlien_ZA
dc.contributor.authorN'Da, Daviden_ZA
dc.contributor.authorTran Van Ba, Christopheen_ZA
dc.contributor.authorWein, Sharonen_ZA
dc.contributor.authorNorman, Jenniferen_ZA
dc.contributor.authorWiesner, Lubbeen_ZA
dc.contributor.authorVial, Henrien_ZA
dc.date.accessioned2015-10-30T09:34:06Z
dc.date.available2015-10-30T09:34:06Z
dc.date.issued2013en_ZA
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 0.8mg/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.identifier.apacitationLombard, M., N'Da, D., Tran Van Ba, C., Wein, S., Norman, J., Wiesner, L., & Vial, H. (2013). Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids. <i>Malaria Journal</i>, http://hdl.handle.net/11427/14525en_ZA
dc.identifier.chicagocitationLombard, Marli, David N'Da, Christophe Tran Van Ba, Sharon Wein, Jennifer Norman, Lubbe Wiesner, and Henri Vial "Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids." <i>Malaria Journal</i> (2013) http://hdl.handle.net/11427/14525en_ZA
dc.identifier.citationLombard, 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.ris TY - Journal Article AU - Lombard, Marli AU - N'Da, David AU - Tran Van Ba, Christophe AU - Wein, Sharon AU - Norman, Jennifer AU - Wiesner, Lubbe AU - Vial, Henri AB - 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. DA - 2013 DB - OpenUCT DO - 10.1186/1475-2875-12-71 DP - University of Cape Town J1 - Malaria Journal LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids TI - Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids UR - http://hdl.handle.net/11427/14525 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/14525
dc.identifier.urihttp://dx.doi.org/10.1186/1475-2875-12-71
dc.identifier.vancouvercitationLombard M, N'Da D, Tran Van Ba C, Wein S, Norman J, Wiesner L, et al. Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids. Malaria Journal. 2013; http://hdl.handle.net/11427/14525.en_ZA
dc.language.isoengen_ZA
dc.publisherBioMed Central Ltden_ZA
dc.publisher.departmentDivision of Clinical Pharmacologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open access article distributed under the terms of the Creative Commons Attribution Licenseen_ZA
dc.rights.holder2013 Lombard et al; licensee BioMed Central Ltd.en_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en_ZA
dc.sourceMalaria Journalen_ZA
dc.source.urihttp://www.malariajournal.com/en_ZA
dc.subject.otherMalariaen_ZA
dc.subject.otherArtemisininen_ZA
dc.subject.otherQuinolineen_ZA
dc.subject.otherHybriden_ZA
dc.subject.otherPharmacokineticsen_ZA
dc.subject.otherIn vivo activityen_ZA
dc.titlePotent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybridsen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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