In vitro assessment of the pharmacodynamic properties of DB75, piperaquine, OZ277 and OZ401 in cultures of Plasmodium falciparum

Abstract

Objectives: Using synchronized cultures of Plasmodium falciparum, the time- and concentration-dependent growth changes of erythrocytic parasite stages to DB75, piperaquine, OZ277 and OZ401 were investigated in vitro over a concentration range of ∼1-100× the IC50 of piperaquine, OZ277 and OZ401 and ∼10-1000 × the IC50 of DB75. Methods: The effects of timed in vitro exposure (1, 6, 12 or 24 h) were monitored by the incorporation of [3H]hypoxanthine into the parasite nucleic acids. Results: After 1 h of exposure to the highest concentration of the compound followed by removal of the compound, the growth of all stages of P. falciparum was reduced to <34% for DB75 and 15% for piperaquine, OZ277 and OZ401 compared with untreated control parasites. At this time point, no stage-specific effects were observed at any of the concentrations. Strong inhibition (≤10% growth) of all parasite stages was observed when the parasites were exposed to 10× or 100× the IC50 of OZ277 and OZ401 for ≥6 h. At the 6 h incubation time point, DB75 was more active against mature parasite stages, with the IC50s of young ring forms elevated up to 7-fold. This trend was observed up to 12 h, but was only statistically significant at the lowest concentration. Interestingly, the stage-specific effect of DB75 on ring forms was not detectable when washing procedures were omitted. This indicates a cytostatic action of DB75 on P. falciparum ring forms. Conclusions: The current study suggests that P. falciparum ring stages are less susceptible to DB75. A milder and often statistically insignificant stage-specific trend was observed for piperaquine, whereas OZ277 and OZ401 were equally active against the erythrocytic parasite stages. © The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.