JAC Advance Access originally published online on July 30, 2008
Journal of Antimicrobial Chemotherapy 2008 62(5):1061-1064; doi:10.1093/jac/dkn315
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Original research |
In vitro assessment of the pharmacodynamic properties of DB75, piperaquine, OZ277 and OZ401 in cultures of Plasmodium falciparum
1 Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland 2 F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel, Switzerland 3 Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, PO Box 61, CH-3010 Bern, Switzerland
Received 16 April 2008; returned 16 June 2008; revised 7 July 2008; accepted 10 July 2008
* Correspondence address. Swiss Tropical Institute, Socinstrasse 57, PO Box, CH-4002 Basel, Switzerland. Tel: +41-61-284-81-36; Fax: +41-61-284-81-01; E-mail: sergio.wittlin{at}unibas.ch
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 
1–100x the IC50 of piperaquine, OZ277 and OZ401 and 10–1000x 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 10x or 100x 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.
Keywords: speed of antimalarial drug action , stage specificity , [3H]hypoxanthine