Therapeutic combinations in Visceral Leishmaniasis: the antileishmanial potential of calcium channel blockers

Abstract

Leishmaniasis is a disease caused by Leishmania parasites, found in 88 countries and with 12 million infected people. Despite the incidence and high lethality, Visceral Leishmaniasis (VL) is considered by the World Health Organization one of the most important diseases. The treatment makes use of drugs with high toxicity as the pentavalent antimonials, amphotericin B and pentamidine, demonstrating a restricted therapeutic arsenal, surpassed by resistance cases. With a high necessity for novel drugs, the chemotherapeutic swithching or "piggy-back" therapy represents one of the most promising forms for the introduction of new active compounds. Moreover, the study of combinatorial therapy is fundamental in the prevention of resistance and in the reduction of the time and toxicity of the treatment. Based in these data, our group have been studying the antileishmanial activity of calcium channel blockers clinically used for another diseases, and have recently found for the first time, the antileishmanial activity of nimodipine (in press data). The goal of this project is the in vitro and in vivo evaluation of the antileishmanial activity of clinically used calcium channel blockers for the pharmacological screening of novel drug candidates against VL. Furthermore, it will also be studied the therapeutical combinations of this class of drugs with drugs clinically used in the treatment of VL and the in vitro and in vivo evaluation of the synergic or antagonistic potential of these combinations. Transmission electron microscopy studies will be conducted with active drugs in order to evaluate the ultrastructural modifications of Leishmania (L.) chagasi. Considering the previous antileishmanial activity of nimodipine, as for other calcium antagonists as amlodipine and lacidipine, the study of the therapeutical combinations could contribute for the discovery of new alternatives for the treatment of VL, resulting in a considerable reduction of costs and time of the research for the development of a novel drug.