Elsevier

Parasitology International

Volume 48, Issue 4, 8 February 2000, Pages 275-280
Parasitology International

Gametocytocidal activity of pyronaridine and DNA topoisomerase II inhibitors against multidrug-resistant Plasmodium falciparum in vitro

https://doi.org/10.1016/S1383-5769(99)00028-8Get rights and content

Abstract

Gametocytocidal activities of pyronaridine and DNA topoisomerase II inhibitors against two isolates of multidrug-resistant Plasmodium falciparum, KT1 and KT3 were determined. After sorbitol treatment, pure gametocyte cultures of Plasmodium falciparum containing mostly young gametocytes (stage II and III) obtained on day 11 were exposed to the drugs for 48 h. The effect of the drugs on gametocyte development was assessed by counting gametocytes on day 15 of culture. Pyronaridine was the most effective gametocytocidal drug against P. falciparum isolates KT1 and KT3 with 50% inhibitory concentration of 6 and 20 nM, respectively. Moreover, the 50% inhibitory concentration of pyronaridine was lower than that of primaquine which is the only drug used to treat malaria patients harboring gametocytes. Prokaryotic (norfloxacin) and eukaryotic (amsacrine and etoposide) DNA topoisomerase II inhibitors were only effective against asexual but not sexual stages of the malaria parasites. Pyronaridine has both schizontocidal and gametocytocidal activities against the human malaria parasite, P. falciparum.

Introduction

Malaria still remains one of the major health problems in tropical countries, and among the four species of malaria parasites infecting humans, Plasmodium falciparum is the most virulent. Chemotherapy has played a major role in alleviating suffering and in reducing mortality caused by P. falciparum infection. Unfortunately, resistance to most currently used antimalarials has appeared in P. falciparum and continues to increase in many parts of the world [1]. Most of the currently used antimalarial drugs affect only the asexual stage of the parasite, except primaquine which can also act as a gametocytocidal drug.

Pyronaridine, a 9-anilino-aza-acridine synthesized in the 1970s, has been developed primarily from Chinese research efforts and has been used in China for more than 15 years [2], [3]. It is highly effective against chloroquine-sensitive and -resistant strains of P. falciparum [4], [5] and good antimalarial activity has also been reported in Thailand [6]. Pyronaridine is a highly active blood schizontocide and has already undergone extensive trials in human against both P. falciparum and P. vivax [7], [8]. Although an effect of pyronaridine on the ultrastructure of malaria parasite has been reported [9], [10] and our previous study showed that decatenation activity of P. falciparum DNA topoisomerase II was inhibited by pyronaridine [11], the mechanism of action of pyronaridine is still not known.

Since inhibition of P. falciparum sexual stage should not be overlooked, and only one drug, primaquine, is currently used to combat P. falciparum gametocytes, a search for new gametocytocidal drugs is urgently needed. Therefore, in this study, in vitro gametocytocidal activities of pyronaridine and a number of DNA topoisomerase II inhibitors were determined against two isolates of gametocyte-producing P. falciparum from Thailand.

Section snippets

Parasites

Gametocyte-producing isolates, KT1 and KT3, of Plasmodium falciparum were collected from two infected patients at Thong Pha Phum District, Kanchanaburi Province, Thailand. Multi-drug resistant K1 strain originally taken from this province [12] was used as a control parasite for determination of drug resistance. KT1 and KT3 isolates were successfully cultured in our laboratory for at least 3 years and continuously produced gametocytes under our culture conditions [13], [14]. Morphological and

In vitro antimalarial drug sensitivity of the asexual stage of P. falciparum KT1 and KT3 isolates

Asexual parasites were cultured in the presence of five known antimalarials for 48 h and IC50s of these drugs against P. falciparum KT1 and KT3 isolates were determined by measuring uptake of [3H]hypoxanthine compared with K1 strain. Both P. falciparum isolates were resistant to chloroquine, pyrimethamine and cycloguanil, but were still sensitive to mefloquine compared with K1 strain (Table 1). The IC50s of the drugs against KT1 isolates were not significantly different from those of KT3 except

Discussion

Gametocyte-producing P. falciparum KT1 and KT3 isolates used in this study can be looked upon as multidrug-resistant parasites because of their resistance to chloroquine, pyrimethamine and cycloguanil. Both isolates were still sensitive to mefloquine.

The study of topoisomerases has expanded into the realm of pharmacology and clinical medicine through identification of bacterial topoisomerase II (DNA gyrase) as a target of antibitotics and toxins and of eukaryotic DNA topoisomerase II as a

Acknowledgements

We are grateful to Ms Somsri Kajorndechakait and Mr Saiyud Incheng for technical assistance. This work was supported by a grant (RSA/3/2538) from The Thailand Research Fund. P.W. is a Senior Research Scholar of The Thailand Research Fund.

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