Repurposing drugs against Leishmania donovani: in vitro efficacy of loratadine and cyproheptadine and their liposomal formulations

Abstract

In a previous study, we identified the trypanocidal drugs loratadine (LTD) and cyproheptadine (CPH). Both compounds are antihistamines already approved for clinical use. The aim of this work was to evaluate the effectiveness of LTD and CPH for drug repurposing against another protozoan parasite, Leishmania donovani, the causative agent of visceral leishmaniasis. LTD and CPH inhibited promastigote proliferation and amastigote growth in murine peritoneal macrophages. Furthermore, with the aim of improving their leishmanicidal activity, we also formulated liposomes of LTD and CPH, composed of phosphatidylcholine and stearylamine. The liposomal formulations significantly enhanced the efficacy against both promastigotes and intracellular amastigotes, reducing the IC50 values by 5-fold and 2.5-fold, respectively, compared to the free drugs. The reference drug amphotericin B presented a higher effect against these parasites but it remains a second-line drug to treat leishmaniasis because of its high toxicity. The results obtained demonstrate that LTD and CPH liposomes formulations are promising antileishmanial agents, with great potential to be repurposed against L. donovani. Both drugs are approved for human use, which could reduce significantly the requirements for their possible application in the treatment of this neglected disease.