Abstract
BackgroundPyronaridine, a Mannich base anti-malarial with high efficacy against drug resistant Plasmodium falciparum, is currently evaluated as a fixed dose combination with artesunate for the treatment of uncomplicated malaria. In this study, the in vitro activity of pyronaridine against clinical isolates of P. falciparum from Lambaréné, Gabon, was assessed in order to obtain baseline data on its activity prior to its future use in routine therapy. Moreover, follow-up assessment on the in vitro activity of chloroquine, artesunate and quinine was performed.MethodsIn vitro response of field isolates of P. falciparum to pyronaridine, chloroquine, artesunate and quinine was assessed using the traditional WHO microtest. In addition, the histidine-rich protein 2 (HRP-2) assay was performed and evaluated for its future implementation for follow-up of drug susceptibility testing.ResultsPyronaridine exhibited a high in vitro activity against P. falciparum, with a geometric mean cut-off concentration of 9.3 nmol/l. Fifty percent effective concentrations were 1.9 nmol/l and 2.0 nmol/l in the WHO microtest and HRP-2 assay, respectively. Results matched closely in vivo findings from a recent clinical trial on pyronaridine-artesunate treatment. One isolate showed diminished sensitivity to artesunate. For chloroquine and quinine resistance levels were comparable to prior studies from Lambaréné. Results from the novel HRP-2 assay corresponded well to those obtained by the WHO microtest.ConclusionPyronaridine is highly active in chloroquine-resistant parasites and seems a promising partner drug for artemisinin-based combination therapy in Africa.
Highlights
Pyronaridine, a Mannich base anti-malarial with high efficacy against drug resistant Plasmodium falciparum, is currently evaluated as a fixed dose combination with artesunate for the treatment of uncomplicated malaria
In addition to assessing the activity of common antimalarials against Plasmodium falciparum in routine surveys, the evaluation of new compounds against field isolates is of major importance for drug development
Twenty-five isolates fulfilled the criteria for successful parasite-culture in the histidine-rich protein 2 (HRP-2) assay and 15, 16, 12 and 14 were successfully employed for drug sensitivity testing, respectively
Summary
Pyronaridine, a Mannich base anti-malarial with high efficacy against drug resistant Plasmodium falciparum, is currently evaluated as a fixed dose combination with artesunate for the treatment of uncomplicated malaria. In addition to assessing the activity of common antimalarials against Plasmodium falciparum in routine surveys, the evaluation of new compounds against field isolates is of major importance for drug development. Novel methods in drug susceptibility testing have been developed, such as the histidinerich protein II (HRP-2) assay [7] This method, based on HRP-2 measurement in an enzyme-linked immunosorbent assay (ELISA), is simple to implement, but considerably less labour intensive compared with the WHO microtest. Due to these advantages, the WHO microtest will be replaced for standard drug susceptibility monitoring in Lambaréné in the future by the novel HRP2 assay. Previous findings from laboratory adapted clones and from different geographical regions suggest that results obtained by the HRP-2 assay be comparable with those obtained by the WHO microtest [7]
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