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 |