Combination therapy has been proposed as an ideal strategy to reduce drug toxicity and improve treatment efficacy in Chagas disease. Previously, we demonstrated potent in vivo anti-Trypanosoma cruzi activity of voriconazole. In this work, we aimed to study the synergistic effect of voriconazole (VCZ) and benznidazole (BZ) both in vitro and in vivo models of T. cruzi infection using the Tulahuen strain. Combining VCZ and BZ at fixed concentrations, the inhibitory concentration 50% (IC₅₀) on amastigotes was lower than the obtained IC₅₀ for BZ alone and the Fractional Inhibitory Concentration Index (∑FIC) suggested an in vitro additive effect on T. cruzi amastigotes inhibition at concentrations devoid of cytotoxic effects. Treatment response in the in vivo model was evaluated by comparing behavior and physical aspects, parasitemia and mortality of mice infected with Tulahuen strain. VCZ and BZ treatments alone or in combination were well tolerated. All treated animals displayed significantly lower mean peak parasitemia and mortality compared to infected non-treated controls (p< 0.05). However, VCZ + BZ combination elicited no additional benefits over BZ monotherapy. VCZ efficacy was not enhanced by combination therapy with BZ at the doses studied, requiring further and astringent non-clinical studies to establish the VCZ efficacy and eventually moving forward to clinical trials.

已经提出组合疗法作为减少南美锥虫病的药物毒性和提高治疗功效的理想策略。以前，我们证明了伏立康唑在体内具有很强的抗T型克鲁氏锥虫活性。在这项工作中，我们旨在研究伏立康唑（VCZ）和苯并硝唑（BZ）在Tulahuen菌株的克氏锥虫感染的体外和体内模型中的协同作用。固定浓度的VCZ和BZ结合使用时，对amastigotes的抑制浓度50％（IC ₅₀）低于单独获得的BZ的IC ₅₀，并且分数抑制浓度指数（∑FIC）建议在体外在没有细胞毒性作用的浓度下，对克氏锥虫变形杆菌抑制有累加作用。通过比较感染图拉胡恩（Tulahuen）品系的小鼠的行为和生理状况，寄生虫血症和死亡率评估了体内模型中的治疗反应。单独或组合使用VCZ和BZ治疗的耐受性良好。与未经治疗的对照组相比，所有经过治疗的动物均显示出较低的平均峰值寄生虫血症和死亡率（p<0.05）。但是，VCZ + BZ组合比BZ单药疗法没有其他好处。在所研究的剂量下与BZ联合治疗并不能提高VCZ的疗效，因此需要进一步的涩味非临床研究来确定VCZ的疗效，并最终进入临床试验。