In vitro and in vivo evaluation of new drugs and combination therapies for Chagas disease

GULIN, JEN; ROCCO, DM; BISIO, M; ALTCHEH, J; SOLANA, ME; GARCÍA BOURNISSEN, F

Campinas

Workshop; São Paulo School of Advanced Science on Neglected Diseases Drug Discovery ? focus on Kinetoplastids; 2015

Centro Nacional de Pesquisa em Energia e Materiais (CNPEM).

Current research project focuses on systematic in vitro and in vivo evaluation of drugs and drug combinations potentially actives against T. cruzi which could be repurposed for Chagas disease treatment. Eligible drug candidates must meet certain criteria, such as previous approval for human use, pharmacokinetics studies in adults and, desirably, in children, good absorption by PO route, lowrate of adverse effects reported, among others. Reported activity against related protozoan parasites is an ideal condition but not limited. For in vitro assays, VERO cells are infected with trypomastigotes for 24 hs and treated with different concentrations of drug candidates. If IC50 is similar or higher thanBenznidazole (Bz) IC50 (positive control), the compound continues to a stringent evaluation in an acute murine model. BALB/c mice are infected with VD strain trypomastigotes and treatment with compound (or combination) starts at parasitaemia onset, for 20 consecutive days. Surviving animals are submittedto immunosuppression cycle. Finally, parasitological response is determined with qPCR from blood and target organs. At present, several drugs have been evaluated, including voriconazole (monotherapy and in combination with Bz), lumefantrine (alone and in combinations) and dihydroartemisinin. Mostdrugs tested so far proved to be inferior to Bz alone, but more potent drugs are currently being studied.