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dc.contributor.authorOkoth, Winter A
dc.contributor.authorDukes, Elijah J
dc.contributor.authorSullivan, David J
dc.date.accessioned2020-02-26T03:04:47Z
dc.date.available2020-02-26T03:04:47Z
dc.date.issued2018
dc.identifier.issn0066-4804
dc.identifier.doi10.1128/AAC.00394-18
dc.identifier.urihttp://hdl.handle.net/10072/391923
dc.description.abstractMany previous in vitro and in vivo preclinical malaria drug studies have relied on low-parasite-number drug inhibition numerically compared to the untreated controls. In contrast, human malaria drug studies measure the high-parasite-density killing near 100 million/ml. Here we compared the in vivo single-dose pharmacodynamic properties of artesunate and the 4-aminoquinolines pyronaridine, chloroquine, and amodiaquine in a Plasmodium berghei ANKA-green fluorescent protein GFP-luciferase-based murine malaria blood-stage model. Pyronaridine exhibited dose-dependent killing, achieving parasite reductions near 5 to 6 logs at 48 h, with complete cure at 10 mg/kg of body weight compared to artesunate, which exhibited a 48-h dose-dependent killing with a 2-log drop at the noncurative 250-mg/kg dose. Chloroquine, which was noncurative, and amodiaquine, which was partially curative, had nearly the same initial dose-independent killing, with a lag phase of minimal parasite reduction at all doses between 6 and 24 h, followed by a 2.5-log reduction at 48 h. In experiments with drug-treated, washed infected blood transfer to naive mice, chloroquine and amodiaquine showed fewer viable parasites at the 24-h transfer than at the 8-h transfer, measured by a prolonged return to parasitemia, despite a similar parasite log reduction at these time points, in contrast to the correlation of the parasite log reduction to viable parasites with artesunate and pyronaridine. Artesunate in combination with pyronaridine exhibited an initial parasite reduction similar to that achieved with pyronaridine, while with chloroquine or amodiaquine, the reduction was similar to that achieved with artesunate. Single-oral-dose pyronaridine was much more potent in vivo than artesunate, chloroquine, and amodiaquine during the initial decline in parasites and cure.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Society for Microbiology
dc.relation.ispartofissue9
dc.relation.ispartofjournalAntimicrobial Agents and Chemotherapy
dc.relation.ispartofvolume62
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchMedical Microbiology
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.subject.fieldofresearchcode0605
dc.subject.fieldofresearchcode1108
dc.subject.fieldofresearchcode1115
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsPharmacology & Pharmacy
dc.subject.keywordsantimalarial agents
dc.titleSuperior Pyronaridine Single-Dose Pharmacodynamics Compared to Artesunate, Chloroquine, and Amodiaquine in a Murine Malaria Luciferase Model
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationOkoth, WA; Dukes, EJ; Sullivan, DJ, Superior Pyronaridine Single-Dose Pharmacodynamics Compared to Artesunate, Chloroquine, and Amodiaquine in a Murine Malaria Luciferase Model, Antimicrobial Agents and Chemotherapy, 2018, 62 (9)
dcterms.dateAccepted2018-06-15
dc.date.updated2020-02-26T03:01:24Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2018 American Society for Microbiology. The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
gro.hasfulltextFull Text
gro.griffith.authorOkoth, Winter A.


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