While thioridazine (Tio) inhibits the antioxidant defenses of Trypanosoma cruzi, the gold standard antitrypanosomal drug benznidazole (Bz) has potent anti-inflammatory and pro-oxidant properties. The combination of these drugs has never been tested to determine the effect on T. cruzi infection. Thus, we compared the impact of Tio and Bz, administered alone and in combination, on the development of skeletal myositis and liver inflammation in T. cruzi-infected mice. Swiss mice were randomized into six groups: uninfected untreated, infected untreated, treated with Tio (80 mg/kg) alone, Bz (50 or 100 mg/kg) alone, or a combination of Tio and Bz. Infected animals were inoculated with a virulent T. cruzi strain (Y) and treated by gavage for 20 days. Mice untreated or treated with Tio alone developed the most intense parasitemia, highest parasitic load, elevated IL-10, IL-17, IFN-γ, and TNF-α plasma levels, increased N-acetylglucosaminidase and myeloperoxidase activity in the liver and skeletal muscle, as well as severe myositis and liver inflammation (P < 0.05). All parameters were markedly attenuated in animals receiving Bz alone (P < 0.05). However, the co-administration of Tio impaired the response to Bz chemotherapy, causing a decrease in parasitological control (parasitemia and parasite load), skeletal muscle and liver inflammation, and increased microstructural damage, when compared to the group receiving Bz alone (P < 0.05). Altogether, our findings indicated that Tio aggravates systemic inflammation, skeletal myositis and hepatic inflammatory damage in T. cruzi-infected mice. By antagonizing the antiparasitic potential of Bz, Tio limits the anti-inflammatory, myoprotectant and hepatoprotective effects of the reference chemotherapy, aggravating the pathological remodeling of both organs. As the interaction of T. cruzi infection, Bz and Tio is potentially toxic to the liver, inducing inflammation and microvesicular steatosis; this drug combination represents a worrying pharmacological risk factor in Chagas disease.

硫代哒嗪（Tio）抑制克氏锥虫的抗氧化防御作用，而金标准抗锥虫药物苯硝唑（Bz）具有有效的抗炎和抗氧化特性。从未测试过这些药物的组合来确定对克氏锥虫感染的作用。因此，我们比较了单独和联合施用的Tio和Bz对克氏锥虫感染小鼠骨骼肌炎的发展和肝脏炎症的影响。瑞士小鼠被随机分为六组：未感染，未治疗，感染，未治疗，单独使用Tio（80 mg / kg），单独使用Bz（50或100 mg / kg）或Tio和Bz的组合治疗。感染的动物接种了强毒的克氏锥虫菌株（Y），并通过管饲法处理20天。未经Tio治疗或仅用Tio治疗的小鼠在肝脏和骨骼肌中出现最强烈的寄生虫血症，最高的寄生虫负荷，IL-10，IL-17，IFN-γ和TNF-α血浆水平升高，N-乙酰氨基葡萄糖苷酶和髓过氧化物酶活性增加以及严重的肌炎和肝炎（P <0.05）。所有参数在单独接受Bz的动物中均显着减弱（P <0.05）。然而，与单独接受Bz的组相比，Tio的共同给药削弱了对Bz化疗的反应，导致了寄生虫学控制（寄生虫血症和寄生虫负荷），骨骼肌和肝脏炎症的降低以及微结构损伤的增加（P < 0.05）。总之，我们的发现表明Tio加剧了全身性炎症，克氏锥虫感染的小鼠。通过拮抗Bz的抗寄生虫潜力，Tio限制了参考化疗的抗炎，抗肌和肝保护作用，加剧了两个器官的病理重塑。由于克鲁斯氏杆菌感染的相互作用，Bz和Tio对肝脏可能具有毒性，从而引起炎症和微囊脂肪变性。这种药物组合代表了恰加斯病中令人担忧的药理危险因素。