Eflornithine Potentiates The Action Of Benznidazole In Two Strains Of Trypanosoma cruzi

AGUERO, FERNAN; MARTINEZ SANTIAGO JOSE; ROMANO, PATRICIA SILVIA; RODRIGUEZ, MATÍAS

Buenos Aires

Congreso; 4th Scientific Meeting of the Research Network Natural Products against Neglected Diseases; 2018

Facultad de Farmacia y Bioquímica

Introduction: finding an effective treatment against Chagas disease is our main priority today. Up to date, the only drugs approved against T. cruzi are Benznidazole (BNZ) and Nifurtimox (NTX), which have positive results for the acute phase, but with relative efficacy in the chronic phase of the disease. Aims: our strategy consists to combine BNZ with other drug to achieve a synergism that increase the effectiveness and, at the same time, reduce the doses of BNZ to decrease the adverse effects that often become intolerant the treatment in the chronic phase. We propose the incorporation of Eflornithine (DFMO) to the current treatment with BNZ. Methods: we performed in vitro experiments at increasing concentrations of BNZ and DFMO ([1, 2, 5, 10, 25, 50, 75, 100M] and [1, 2, 5, 10, 10mM]) respectively, together and separately in epimastigote phase with 72h of treatment and intracellular amastigote with 24h of infection and 48hs of treatment in both strains. We also perform infections in different cell lines to measure infection percentage for 72h. Results: the results showed significant differences comparing Ic50 obtained on in vitro tests in the epimastigote phase and also in the intracellular replication of amastigotes in H9C2 cells (rat myocardium) in the two different DTUs (discrete typing units) TcII and TcV. For the epimastigote phase the values of Ic50 were TcII = 36.97 ± 1.4M for BNZ and 12.03 ± 0.68M for the combination BNZ + DFMO, whereas TcV = 9.71 ± 0.46M for BNZ and 4.61 ± 0.53M for the combination. The intracellular amastigote phase displayed the following values; TcII = 21.9 ± 0.97M (BNZ) and 12.03 ± 0.68M (BNZ + DFMO); and TcV = 13.1 ± 0.91M (BNZ) and 8.44 ± 1.18M for the combination. Discussion: both strains displayed significant differences in the susceptibility to BNZ and also significant differences for each strain with the combined treatment. In addition, the infections in different cell cultures showed to us a remarkable cellular tropism of the TcV strain for cells from muscular tissues (H9C2 and HSkM). Conclusion: we conclude that these two strains of T. cruzi have different cell tropism and different susceptibilities to BNZ, being TcII more resistant than TcV. We highlight the positive effect of DFMO as a possible adjuvant drug for the Chagas disease therapy.