Modulating Agents in Resistant Malaria

Modulating agents in combination with major chemotherapeutics have been proposed for restoring drug effectiveness in cellular or parasite resistance. Verapamil was the first in vitro modulating agent reported for resistant malaria followed by psychoactive drugs, natural products and other diverse structural compounds. However, conflicting results for in vitro and in vivo assays and in clinical tests have been reported following the use of modulating agents in combination with antimalarial drugs, mainly, chloroquine. We, herein, demonstrated the failure of modulating agents to restore the in vitro sensibility of Brazilian chloroquine-resistant P. falciparum isolates. In contrast, a significant intrinsic antiplasmodial effect, which was not dependent on the chloroquine combination, was observed. Nevertheless, it is currently recognized that the effectiveness or failure of modulating agents depends on genotypic characteristics, the observed intrinsic activity may be hypothesized based on the common biological or antiplasmodial effect. This may occur due to the structural similarities of chloroquine and the modulating agents. Similar features have also been observed in the new lead modulating agents. In this paper, an overview of the evaluation, use and perspectives of modulating agents against drug and multidrug-resistant malaria is presented.