The artemiside-artemisox-artemisone-m1 tetrad : efficacies against blood stage p. falciparum parasites, dmpk properties, and the case for artemiside

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dc.contributor.author Gibhard, Liezl
dc.contributor.author Coertzen, Dina
dc.contributor.author Reader, Janette
dc.contributor.author Van der Watt, Mariette Elizabeth
dc.contributor.author Birkholtz, Lyn-Marie
dc.contributor.author Wong, Ho Ning
dc.contributor.author Batty, Kevin T.
dc.contributor.author Haynes, Richard K.
dc.contributor.author Wiesner, Lubbe
dc.date.accessioned 2022-10-06T05:27:20Z
dc.date.available 2022-10-06T05:27:20Z
dc.date.issued 2021-12-03
dc.description Supplementary Material 1: S1 Efficacy of artemisox, dose response curves against asexual, and gametocyte blood stage parasites: Figure S1a–e; S2 Efficacy of M1, dose response curves against asexual, and gametocyte blood stage parasites: Figure S2a–d; S3 Pharmacokinetics and metabolism, circulating concentrations of artemiside, artemisox, and artemisone: Table S3a–f, LC-MS/MS chromatograms of M1 Figure S3a–c; S4 In vitro efficacy data— previously published data for artemiside, artemisone, M1: Table S4a–c; S5 In vivo efficacy data— previously published data for artemiside, artemisone: Table S5; S6 Neurotoxicity data–previously published neurotoxicity data for DHA, artesunate, artemiside, artemisone: Table S6. en_US
dc.description Supplementary Material 2: PDF copy of reference [37]. en_US
dc.description.abstract Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf ) blood stage parasites (IC50 1.5–2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies. en_US
dc.description.department Biochemistry en_US
dc.description.department Genetics en_US
dc.description.department Microbiology and Plant Pathology en_US
dc.description.department UP Centre for Sustainable Malaria Control (UP CSMC) en_US
dc.description.librarian am2022 en_US
dc.description.sponsorship The South African Medical Research Council (MRC) Flagship Project MALTB-Redox with funds from the National Treasury under its Economic Competitiveness and Support Package, a South African National Research Foundation (SA NRF) grant, and by a South African MRC Strategic Health Innovation Partnership (SHIP) grant, a South African MRC Collaborative Centre for Malaria Research grant and the Department of Science and Innovation and SA NRF South African Research Chairs Initiative (SARChI) Grant. en_US
dc.description.uri https://www.mdpi.com/journal/pharmaceutics en_US
dc.identifier.citation Gibhard, L.; Coertzen, D.; Reader, J.; van derWatt, M.E.; Birkholtz, L.-M.;Wong, H.N.; Batty, K.T.; Haynes, R.K.;Wiesner, L. The Artemiside-Artemisox-Artemisone- M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside. Pharmaceutics 2021, 13, 2066. https://DOI.org/10.3390/pharmaceutics13122066. en_US
dc.identifier.issn 1424-8247 (online)
dc.identifier.other 10.3390/pharmaceutics13122066
dc.identifier.uri https://repository.up.ac.za/handle/2263/87541
dc.language.iso en en_US
dc.publisher MDPI en_US
dc.rights © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. en_US
dc.subject Antimalarial drugs en_US
dc.subject Artemisinins en_US
dc.subject Resistance en_US
dc.subject Amino-artemisinins en_US
dc.subject Pharmacokinetics en_US
dc.subject Metabolism en_US
dc.subject Cmax en_US
dc.subject Drug efficacy en_US
dc.subject Artemisinin-based combination therapies (ACTs) en_US
dc.subject Triple artemisinin-based combination therapies (TACTs) en_US
dc.title The artemiside-artemisox-artemisone-m1 tetrad : efficacies against blood stage p. falciparum parasites, dmpk properties, and the case for artemiside en_US
dc.type Article en_US


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