Effects of Artesunate on Parasite Recrudescence and Dormancy in the Rodent Malaria Model Plasmodium vinckei

Abstract

Artemisinin (ART) is the recommended first line therapy for treating uncomplicated and drug-resistant Plasmodium falciparum, the most pathogenic form of malaria. However, treatment failure following ART monotherapy is not uncommon and resistance to this rapidly acting drug has been reported in the Thai-Cambodian border. Recent in vitro studies have shown that following treatment with dihydroartemisinin (DHA), the development of ring-stage parasites is arrested for up to 20 days. These arrested (i.e. dormant) rings could be responsible for the recrudescence of infection that is observed following ART monotherapy. To develop a better understanding of the stage-specific effects of ART and determine if dormancy occurs in vivo, the ART derivative artesunate (AS) was used to treat mice infected with the synchronous rodent malaria parasites P. vinckei petteri (non-lethal) and P. v. vinckei (lethal). Results show that in both the non-lethal and lethal strains, ring-stage parasites are the least susceptible to treatment with AS and that the day of treatment has more of an impact on recrudescence than the total dose administered. Additionally, 24 hrs post-treatment with AS, dormant forms similar in morphology to those seen in vitro were observed. Finally, rate of recrudescence studies suggest that there is a positive correlation between the number of dormant parasites present and when recrudescence occurs in the vertebrate host. Collectively, these data suggest that dormancy occurs in vivo and contributes to recrudescence that is observed following AS treatment. It is possible that this may represent a novel mechanism of parasite survival following treatment with AS.

Antiplasmodial activity of aqueous extract ofBerberis aristataroots againstPlasmodium berghei-infected BALB/c mice

“…This problem is observed during the long-term treatment of malaria (Lacrue et al, 2011). Moreover, similar antiplasmodial studies suggested that follow-up of mice for at least 1 month becomes necessary in order to monitor the efficacy of any antimalarial drug (Rajendran et al, 2014).…”

Reprint of “Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin”

“…Meanwhile, there remains an urgent need to develop new antimalarials [6]. However, the behaviour of current artemisinins is still not fully understood; debate remains concerning their mechanism of action [7,8] and stage-specific effects [9]. One theory is that artemisinins decompose when activated by iron that has accumulated in malaria infected red blood cells, forming free radicals which then damage the parasites [10].…”

“…This recrudescence may be attributed to either resistant or arrested/dormant parasites, or the drug concentrations in blood falling below their effective levels, but such issues have not yet been fully characterised [9].…”

Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin

“…Artemisinin and its derivatives have been used as antimalarials with increasing frequency since the 1990s [3]. They are the most rapidly acting drugs out of the currently available anti-malarials [4], reducing the parasite biomass ∼10, 000-fold However, the behaviour of current artemisinins is still not fully understood; debate remains concerning their mechanism of action [7,8] and stage-specific effects [9]. One theory is that artemisinins decompose when activated by iron that has accumulated in malaria infected red blood cells, forming free radicals which then damage the parasites [10].…”

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