Abstract
BackgroundThe aim of the present work was to assess the in vitro cross-resistance of pyronaridine with other quinoline drugs, artesunate and several other commonly used anti-malarials and to evaluate whether decreased susceptibility to pyronaridine could be associated with genetic polymorphisms in genes involved in reduced quinoline susceptibility, such as pfcrt, pfmdr1, pfmrp and pfnhe.MethodsThe in vitro chemosusceptibility profiles of 23 strains of Plasmodium falciparum were analysed by the standard 42-hour 3H-hypoxanthine uptake inhibition method for pyronaridine, artesunate, chloroquine, monodesethylamodiaquine, quinine, mefloquine, lumefantrine, atovaquone, pyrimethamine and doxycycline. Genotypes were assessed for pfcrt, pfmdr1, pfnhe-1 and pfmrp genes.ResultsThe IC50 values for pyronaridine ranged from 15 to 49 nM (geometric mean = 23.1 nM). A significant positive correlation was found between responses to pyronaridine and responses to artesunate (r2 = 0.20; P = 0.0317) but too low to suggest cross-resistance. No significant correlation was found between pyronaridine IC50 and responses to other anti-malarials. Significant associations were not found between pyronaridine IC50 and polymorphisms in pfcrt, pfmdr1, pfmrp or pfnhe-1.ConclusionThere was an absence of cross-resistance between pyronaridine and quinolines, and the IC50 values for pyronaridine were found to be unrelated to mutations in the transport protein genes pfcrt, pfmdr1, pfmrp or pfnhe-1, known to be involved in quinoline resistance. These results confirm the interest and the efficacy of the use of a combination of pyronaridine and artesunate in areas in which parasites are resistant to quinolines.
Highlights
The aim of the present work was to assess the in vitro cross-resistance of pyronaridine with other quinoline drugs, artesunate and several other commonly used anti-malarials and to evaluate whether decreased susceptibility to pyronaridine could be associated with genetic polymorphisms in genes involved in reduced quinoline susceptibility, such as pfcrt, pfmdr1, pfmrp and pfnhe
Prior therapy with an amodiaquinecontaining artemisinin-based combination therapy (ACT) has been found to select for a reduced response to monodesethylamodiaquine, suggesting that amodiaquine-containing regimens may rapidly lose efficacy in Africa [16]
The aims of the present work were as follows: i) to assess the in vitro cross-resistance of pyronaridine with other quinoline drugs, including chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, and artesunate, atovaquone, pyrimethamine and doxycycline; and ii) to identify genetic polymorphisms that could be associated with decreased susceptibility to pyronaridine in the genes pfcrt, pfmrp, pfmdr1 and pfnhe-1, which are known to be associated with reduced quinoline susceptibility [21,22,23,24], with the goal of identifying molecular markers of pyronaridine resistance for use in resistance surveillance
Summary
The aim of the present work was to assess the in vitro cross-resistance of pyronaridine with other quinoline drugs, artesunate and several other commonly used anti-malarials and to evaluate whether decreased susceptibility to pyronaridine could be associated with genetic polymorphisms in genes involved in reduced quinoline susceptibility, such as pfcrt, pfmdr, pfmrp and pfnhe. Over the past 20 years, many strains of Plasmodium falciparum have become resistant to chloroquine and other anti-malarial drugs [1]. This development has prompted a search for new effective anti-malarial drugs with minimal side effects. Prior therapy with an amodiaquinecontaining ACT has been found to select for a reduced response to monodesethylamodiaquine, suggesting that amodiaquine-containing regimens may rapidly lose efficacy in Africa [16]. This emergence of parasite resistance to some forms of ACT indicates that novel compounds and combinations must be discovered and developed.
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