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

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dc.contributor.authorAbay, Efremen_ZA
dc.contributor.authorvan der Westuizen, Janen_ZA
dc.contributor.authorSwart, Kennethen_ZA
dc.contributor.authorGibhard, Liezlen_ZA
dc.contributor.authorLawrence, Ninaen_ZA
dc.contributor.authorDambuza, Ntokozoen_ZA
dc.contributor.authorWilhelm, Ankeen_ZA
dc.contributor.authorPravin, Kendrekaren_ZA
dc.contributor.authorWiesner, Lubbeen_ZA
dc.date.accessioned2015-11-27T09:33:09Z
dc.date.available2015-11-27T09:33:09Z
dc.date.issued2015en_ZA
dc.description.abstractBACKGROUND: 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.identifier.apacitationAbay, E., van der Westuizen, J., Swart, K., Gibhard, L., Lawrence, N., Dambuza, N., ... Wiesner, L. (2015). Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model. <i>Malaria Journal</i>, http://hdl.handle.net/11427/15393en_ZA
dc.identifier.chicagocitationAbay, Efrem, Jan van der Westuizen, Kenneth Swart, Liezl Gibhard, Nina Lawrence, Ntokozo Dambuza, Anke Wilhelm, Kendrekar Pravin, and Lubbe Wiesner "Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model." <i>Malaria Journal</i> (2015) http://hdl.handle.net/11427/15393en_ZA
dc.identifier.citationAbay, 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.ris TY - Journal Article AU - Abay, Efrem AU - van der Westuizen, Jan AU - Swart, Kenneth AU - Gibhard, Liezl AU - Lawrence, Nina AU - Dambuza, Ntokozo AU - Wilhelm, Anke AU - Pravin, Kendrekar AU - Wiesner, Lubbe AB - 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. DA - 2015 DB - OpenUCT DO - 10.1186/1475-2875-14-8 DP - University of Cape Town J1 - Malaria Journal LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model TI - Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model UR - http://hdl.handle.net/11427/15393 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/15393
dc.identifier.urihttp://dx.doi.org/10.1186/1475-2875-14-8
dc.identifier.vancouvercitationAbay E, van der Westuizen J, Swart K, Gibhard L, Lawrence N, Dambuza N, et al. Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model. Malaria Journal. 2015; http://hdl.handle.net/11427/15393.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.holder2015 Abay et al.; licensee BioMed Central.en_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0.en_ZA
dc.sourceMalaria Journalen_ZA
dc.source.urihttp://www.malariajournal.com/en_ZA
dc.subject.otherMalariaen_ZA
dc.subject.otherDrug developmenten_ZA
dc.subject.otherPharmacokineticsen_ZA
dc.subject.otherin vivo efficacyen_ZA
dc.titleEfficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse modelen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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