Superior Pyronaridine Single-Dose Pharmacodynamics Compared to Artesunate, Chloroquine, and Amodiaquine in a Murine Malaria Luciferase Model

Abstract

Many previous and 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 single-dose pharmacodynamic properties of artesunate and the 4-aminoquinolines pyronaridine, chloroquine, and amodiaquine in a 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 than artesunate, chloroquine, and amodiaquine during the initial decline in parasites and cure.

Anti-HCV and anti-malaria agent, potential candidates to repurpose for coronavirus infection: Virtual screening, molecular docking, and molecular dynamics simulation study

“…Pyronaridine was synthesized as an antimalarial agent; it has a similar structure to chloroquine but indicates superiority in potency [ 37 ], pharmacokinetic properties, and also less toxicity [ 38 ]. Pyronaridine is effective against acute Chagas disease [ 39 ] and the Ebola virus (EBOV).…”

Efficacy, Safety and Tolerability of Pyronaridine-artesunate in Asymptomatic Malaria-infected Individuals: a Randomized Controlled Trial

“…Single-dose PA had unexpectedly good efficacy in this population. In a murine blood-stage malaria model, single-dose pyronaridine was shown to reduce parasitemia more rapidly and completely than artesunate, chloroquine, or amodiaquine [ 35 ]. This potent effect may have been sufficient to suppress and/or clear parasites after only 1 dose in most individuals with low parasite density.…”

Pyronaridine: a review of its clinical pharmacology in the treatment of malaria

“…The pharmacodynamics (PD) of pyronaridine was further studied using a murine blood-stage malaria model. 80 In mice, a single dose of pyronaridine at 2.5–25 mg/kg presented a dose-dependent killing rate at 24 and 48 h after the initial dose, whereas doses of 50–250 mg/kg exhibited dose-independent parasite reductions of 3.5 logs at 24 h, and 5–6 logs at 48 h after initial dose. 80 A complete cure was achieved at a dose of 10 mg/kg, with no parasite recrudescence within 30 days.…”