Superior pyronaridine single-dose pharmacodynamics compared to artesunate, chloroquine, and amodiaquine in a murine malaria luciferase model

Winter A. Okoth, Elijah J. Dukes, David J Sullivan

Research output: Contribution to journalArticle

Abstract

Many 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.

Original languageEnglish (US)
Article numbere00394-18
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number9
DOIs
StatePublished - Sep 1 2018

Fingerprint

Chloroquine
Luciferases
Malaria
Parasites
Amodiaquine
Pharmaceutical Preparations
pyronaridine
artesunate drug combination amodiaquine
Plasmodium berghei
Parasitemia
Green Fluorescent Proteins
Body Weight
artesunate

Keywords

  • Antimalarial agents
  • Chemotherapy
  • Malaria
  • Pharmacodynamics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Superior pyronaridine single-dose pharmacodynamics compared to artesunate, chloroquine, and amodiaquine in a murine malaria luciferase model. / Okoth, Winter A.; Dukes, Elijah J.; Sullivan, David J.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 9, e00394-18, 01.09.2018.

Research output: Contribution to journalArticle

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