Abstract

BackgroundMalaria caused by Plasmodium falciparum is the most virulent form of malaria, leading to approximately a half million deaths per year. Chemotherapy continues to be a key approach in malaria prevention and treatment. Due to widespread parasite drug resistance, identification and development of new anti-malarial compounds remains an important task of malarial parasitology. The semi-synthetic drug amitozyn, obtained through alkylation of major celandine (Chelidonium majus) alkaloids with N,N′N′-triethylenethiophosphoramide (ThioTEPA), is a widely used Eastern European folk medicine for the treatment of various tumours. However, its anti-malarial effect has never been studied.MethodsThe anti-malarial effects of amitozyn alone and in combination with chloroquine, pyrimethamine and artemisinin on the blood stages of P. falciparum were analysed. The cytostatic effects of amitozyn on parasites and various cancerous and non-cancerous human cells were compared and their toxic effects on unparasitized human red blood cells were analysed.ResultsObtained results demonstrate that amitozyn effectively inhibits the growth of blood-stage parasites with IC50 9.6 ± 2, 11.3 ± 2.8 and 10.8 ± 1.8 μg/mL using CS2, 3G8 and NF54 parasite lines, respectively. The median IC50 for 14 tested human cell lines was 33–152 μg/mL. Treatment of uninfected red blood cells with a high dose of amitozyn (500 μg/mL) did not change cell morphology, demonstrating its non-toxicity for erythrocytes. The synergistic impact of the amitozyn/chloroquine combination was observed at growth inhibition levels of 10–80 %, while demonstrating a nearly additive effect at a growth inhibition level of 90 %. The combination of amitozyn with pyrimethamine has a synergistic effect at growth inhibition levels of 10–70 % and a nearly additive effect at a growth inhibition level of 90 %. The synergistic anti-malarial effect of the amitozyn/artemisinin combination was observed at growth inhibition levels of 10–40 % and a nearly additive effect at growth inhibition levels of 50–90 %.ConclusionsThese in vitro results suggest that the semi-synthetic drug amitozyn, typically used for the treatment of tumours, is a potential anti-malarial candidate and warrants more detailed laboratory and pre-clinical investigations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0952-4) contains supplementary material, which is available to authorized users.

Highlights

  • Malaria caused by Plasmodium falciparum is the most virulent form of malaria, leading to approximately a half million deaths per year

  • Amitozyn inhibits the growth of Plasmodium falciparum cultures in vitro The susceptibility assay in vitro was performed against P. falciparum (CS2, 3G8 and NF 54 parasite lines) in order to analyse the antiparasitic effect of amitozyn

  • These results show that the type of antiparasitic effect of amitozyn depends on the drug concentration and length of treatment

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Summary

Introduction

Malaria caused by Plasmodium falciparum is the most virulent form of malaria, leading to approximately a half million deaths per year. Due to widespread parasite drug resistance, identification and development of new anti-malarial compounds remains an important task of malarial parasitology. Malaria is caused by five species: Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, and Plasmodium knowlesi [1, 2]. Appearance of CQ-resistant strains led to the discovery of the new potent anti-malarial drug artemisinin (ART) in the 1970s. This natural sesquiterpene endoperoxide is currently one of the major anti-malarial drugs used around the world. At present ART derivatives are commonly used in drug combinations with lumefantrine, amodiaquine, mefloquine, sulfadoxine-pyrimethamine and antibiotics to treat uncomplicated P. falciparum malaria and P. vivax in areas of CQ resistance [8, 9]

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