In vitro assessment of the pharmacodynamic properties of DB75, piperaquine, OZ277 and OZ401 in cultures of Plasmodium falciparum.
OBJECTIVE
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 approximately 1-100x the IC(50) of piperaquine, OZ277 and OZ401 and approximately 10-1000x the IC(50) of DB75.


METHODS
The effects of timed in vitro exposure (1, 6, 12 or 24 h) were monitored by the incorporation of [(3)H]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 (< or = 10% growth) of all parasite stages was observed when the parasites were exposed to 10x or 100x the IC(50) of OZ277 and OZ401 for > or = 6 h. At the 6 h incubation time point, DB75 was more active against mature parasite stages, with the IC(50)s 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.
Hofer
Sandra
S
Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland.
Brun
Reto
R
Maerki
Sonja
S
Matile
Hugues
H
Scheurer
Christian
C
Wittlin
Sergio
S
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001550:Benzamidines / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D010545:Peroxides / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013997:Time Factors; D010879:Piperazines
D000962:Antimalarials; D001550:Benzamidines; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D010545:Peroxides; D011804:Quinolines; D013141:Spiro Compounds; C489136:arterolane; C033286:furamidine; C034759:piperaquine; D010879:Piperazines