This study describes the synergistic interaction of two calcium channel 
blockers, verapamil (VR) and SR33557 or fantofarone (SR), in reversing 
chloroquine resistance in Plasmodium falciparum, the causative agent of human 
malaria. The two calcium channel blockers exhibited an intrinsic antimalarial 
activity at 10 and 1 microM for verapamil and fantofarone, respectively. 
Isobolograms revealed that chloroquine and verapamil, and chloroquine and 
fantofarone, acted synergistically against chloroquine-resistant strains of P. 
falciparum. When used at subinhibitory concentrations, verapamil appeared 2 to 3 
times more potent than fantofarone in reversing chloroquine resistance. Indeed, 
verapamil completely reversed the chloroquine resistance in P. falciparum, while 
fantofarone did so only partially. In the highly chloroquine-resistant strain 
FcB1, VR and SR acted synergistically to reverse CQ resistance, and the 
concentrations of VR used in these combinations could be reduced 10- or 100-fold 
(e.g. 100 nM and 10 nM) those required when this drug was used alone. In the 
moderately chloroquine-resistant strain K1, a combination of VR and SR for CQ 
resistance reversal allowed us to reduce the concentration of these 
chemosensitizers 1000- and 100-fold, respectively. The maximum tolerable plasma 
level beyond which side-effects occurred when using verapamil is 2.5 microM. 
Thus, the approach described, which allowed us to lower the doses of 
chemosensitizers, could well prevent toxic effects in humans and enlighten the 
advantages of polychemotherapy.