Abstract
BackgroundArtemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the “parasite clearance curve”, has been critical for assessing drug efficacy; yet underlying mechanisms remain partly unresolved. The clearance curve may be shaped both by the rate at which drugs kill parasites, and the rate at which drug-affected parasites are removed from circulation.MethodsIn this context, two anti-malarials, SJ733, and an ACT partner drug, pyronaridine were compared against sodium artesunate in mice infected with Plasmodium berghei (strain ANKA). To measure each compound’s capacity for pRBC removal in vivo, flow cytometric monitoring of a single cohort of fluorescently-labelled pRBC was employed, and combined with ex vivo parasite culture to assess parasite maturation and replication.ResultsThese three compounds were found to be similarly efficacious in controlling established infection by reducing overall parasitaemia. While sodium artesunate acted relatively consistently across the life-stages, single-dose SJ733 elicited a biphasic effect, triggering rapid, partly phagocyte-dependent removal of trophozoites and schizonts, followed by arrest of residual ring-stages. In contrast, pyronaridine abrogated maturation of younger parasites, with less pronounced effects on mature parasites, while modestly increasing pRBC removal.ConclusionsAnti-malarials SJ733 and pyronaridine, though similarly efficacious in reducing overall parasitaemia in mice, differed markedly in their capacity to arrest replication and remove pRBC from circulation. Thus, similar parasite clearance curves can result for anti-malarials with distinct capacities to inhibit, kill and clear parasites.
Highlights
Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment
SJ733 and pyronaridine are efficacious at reducing parasitaemia in P. berghei‐infected mice Firstly, it was confirmed that SJ733 and pyronaridine rapidly reduce circulating parasitaemia in mice
SJ733 substantially increases parasitized red blood cells (pRBC) removal Since the decline in parasitaemia is a composite measure of pRBC removal and parasite replication, the established red blood cells (RBC) adoptive transfer approach [6,7,8,9] was used to directly measure whether SJ733 had altered the rate of pRBC removal from circulation
Summary
Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. The kinetics of circulating parasitized red blood cells (pRBC) after anti-malarial drug treatment is commonly referred to as the “parasite clearance curve” (PCC). It has been a useful proxy for determining parasiticidal and clinical efficacy of drug candidates [4]. Ex vivo culture of pRBC from Plasmodium falciparum-infected, artesunate-treated human volunteers has recently been used to demonstrate that parasites are rendered non-viable well before any detectable change in the PCC [5] This revealed a disconnect, and possibly an under-estimation, of anti-malarial drug efficacy when the principal metric is the PCC. The hypothesis here is that two highly effective anti-malarials can reduce total parasite numbers by the same magnitude, yet differentially remove and/or arrest the development of circulating parasites
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