Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model

 

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dc.contributor.author Abay, Efrem en_ZA
dc.contributor.author van der Westuizen, Jan en_ZA
dc.contributor.author Swart, Kenneth en_ZA
dc.contributor.author Gibhard, Liezl en_ZA
dc.contributor.author Lawrence, Nina en_ZA
dc.contributor.author Dambuza, Ntokozo en_ZA
dc.contributor.author Wilhelm, Anke en_ZA
dc.contributor.author Pravin, Kendrekar en_ZA
dc.contributor.author Wiesner, Lubbe en_ZA
dc.date.accessioned 2015-11-27T09:33:09Z
dc.date.available 2015-11-27T09:33:09Z
dc.date.issued 2015 en_ZA
dc.identifier.citation Abay, E. T., van der Westuizen, J. H., Swart, K. J., Gibhard, L., Lawrence, N., Dambuza, N., ... & Wiesner, L. (2014). Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model. Malaria journal, 14(1), 8-8. en_ZA
dc.identifier.uri http://hdl.handle.net/11427/15393
dc.identifier.uri http://dx.doi.org/10.1186/1475-2875-14-8
dc.description.abstract BACKGROUND: Even though malaria is a completely preventable and treatable disease, it remains a threat to human life and a burden to the global economy due to the emergence of multiple-drug resistant malaria parasites. According to the World Malaria Report 2013, in 2012 there were an estimated 207 million malaria cases and 627,000 deaths. Thus, the discovery and development of new, effective anti-malarial drugs are required. To achieve this goal, the Department of Chemistry at the University of the Free State has synthesized a number of novel amino-alkylated chalcones and analogues, which showed in vitro anti-malarial activity against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. The lead compound (NP046) was selected for a comprehensive pharmacokinetic (PK) and in vivo efficacy evaluation in a mouse model. METHODS: In vivo efficacy: Water solutions of NP046 were administered orally at 50 and 10mg/kg using oral gavage and IV at 5 and 1mg/kg via the dorsal penile vein to Plasmodium berghei (ANKA strain) infected male C57BL/6 mice (n=5), once a day for four days. Blood samples were collected via tail bleeding in tubes containing phosphate buffer saline (PBS) on day five to determine the % parasitaemia by flow cytometry.In vivo PK: NP046 solutions in water were administered orally (50 and 10mg/kg) and IV (5mg/kg) to male C57BL/6 mice (n=5). Blood samples were collected via tail bleeding into heparinized tubes and analysed using a validated LC-MS/MS assay. Data obtained from the concentration-time profile was evaluated using Summit PK software to determine the PK parameters of NP046. RESULTS: NP046 inhibited parasite growth for the oral and IV groups. Better parasite growth inhibition was observed for the IV group. The PK evaluation of NP046 showed low oral bioavailability (3.2% and 6% at 50mg/kg and 10mg/kg dose, respectively and a moderate mean half-life ranging from 3.1 to 4.4hours. CONCLUSION: Even though the oral bioavailability of NP046 is low, its percentage parasite growth inhibition is promising, but in order to improve the oral bioavailability, structure-activity-relationship (SAR) optimization studies are currently being conducted. 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/4.0. 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 Drug development en_ZA
dc.subject.other Pharmacokinetics en_ZA
dc.subject.other in vivo efficacy en_ZA
dc.title Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model en_ZA
dc.type Journal Article en_ZA
dc.rights.holder 2015 Abay et al.; licensee BioMed Central. 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