In vitro and in vivo efficacy of miltefosine in experimental Trypanosoma cruzi infection

BISIO MMC; GARCIA BOURNISSEN, F; GULIN, JULIÁN ERNESTO NICOLÁS; ROCCO D; ALTCHEH J; SOLANA ME

Varadero

Congreso; International Workshop Animal Models and Preclinical Research; 2019

Committed to the animal welfare

Treatment options for Chagas disease are limited to benznidazole (BZ) and nifurtimox (NFX). Alternative treatments are not currently available, in part due to the high cost of developing new active molecules. Drug repurposing is a cost-effective strategy to fulfill current needs for better and safer therapy. Initially developed for visceral leishmaniasis, miltefosine (MLT) arose as a drug candidate with potential activity against T. cruzi. With this aim, MLT activity was initially assayed both on trypomastigotes and intracellular amastigotes from VD strain. Trypomastigotes lysis and amastigote development inhibition was evaluated after being exposed to serial MLT or BZ dilutions (160-0.156 μM). For in vivo treatment, six weeks-old BALB/c female mice were infected with 500 trypomastigotes by intraperitoneal (ip) route. At parasitemia onset, groups were randomly assigned to: Non-treated (NT); BZ 100 mg/kg; NFX 100 mg/kg; MLT 25, 50, 75 or 100 mg/kg. Treatment was administered by oral route during 20 consecutive days. Parasitemia parameters, mortality and parasitemia rebound after immunosuppression with cyclophosphamide (CYP, 200 mg/kg, ip) were recorded. Drug concentration that resulted in 50% trypomastigotes viability reduction (LC50) for MLT was 30.85 μM (vs. 9.432 μM for BZ) while the concentration that inhibited 50% of amastigotes development (IC50) was 0.513 μM (vs. 0.726 μM for BZ). In the murine model, MLT treatment decreased parasitemia levels in a dose-response manner, with 100% mice survival in the 50 to 100 mg/kg dosing groups. Parasitemia rebound after CYP immunosuppression was observed in all MLT-treated and BZ-treated mice, as well as in 57% of animals in the NFX group. MLT exhibited potent in vitro parasiticidal effect, especially against amastigotes, but in vivo parasitostatic activity. Further studies on combined therapies with BZ or NFX are needed.