In vitro activity of pyronaridine against Plasmodium falciparum and comparative evaluation of anti-malarial drug susceptibility assays.
BACKGROUND
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 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.


METHODS
In 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.


RESULTS
Pyronaridine 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.


CONCLUSIONS
Pyronaridine is highly active in chloroquine-resistant parasites and seems a promising partner drug for artemisinin-based combination therapy in Africa.
Kurth
Florian
F
Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon. florian.kurth@uniklinikum-dresden.de
Pongratz
Peter
P
Bélard
Sabine
S
Mordmüller
Benjamin
B
Kremsner
Peter G
PG
Ramharter
Michael
M
D000284:Administration, Oral; D000293:Adolescent; D000818:Animals; D000953:Antigens, Protozoan; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use; D000077332:Artesunate; D001681:Biological Assay / Q000379:methods; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005681:Gabon; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology* / Q000627:therapeutic use; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D015800:Protozoan Proteins; D011803:Quinine / Q000494:pharmacology / Q000627:therapeutic use; D012044:Regression Analysis
D000953:Antigens, Protozoan; D000962:Antimalarials; D037621:Artemisinins; C514457:HRP-2 antigen, Plasmodium falciparum; D009287:Naphthyridines; D015800:Protozoan Proteins; D000077332:Artesunate; D002738:Chloroquine; D011803:Quinine; C027871:pyronaridine