Hydroxymethylnitrofurazone (NFOH) decreases parasitaemia, parasitism and tissue lesion caused by infection with the Bolivia Trypanosoma cruzi type I strain in Swiss and C57BL/6 mice

Abstract The chemical hydroxymethylation of the antimicrobial nitrofurazone leads to the prodrug NFOH, also increases the anti-T. cruzi activities (in vitro and in vivo), as well as showed non-genotoxic (Ames and micronucleus assays). In the present study, we assessed the anti-T. cruzi effect of the NFOH In vivo - in acute Swiss and C57Bl/6 experimental Chagas models. The treatment started at 5 days post-infection during 20 consecutive days (orally, once day, 150mg/kg), and the parasitaemia as well as histopathology analysis were performed. In both experimental murine models, NFOH was able to reduce parasitemia blood avoiding parasitic reactivation, during immunosuppression period (dexamethasone 5mg/kg, 14 days), in 100% of the mice, and decrease tissue parasite nests, demonstrating absence of amastigote forms in all organs (100%) analyzed, data similar to benznidazole (BZN). Therefore, the results shown here pointing to the NFOH as promising compound for further preclinical studies, being a high potential drug to effective and safe chemotherapy to Chagas disease.

摘要 对抗菌剂呋喃西林（nitrofurazone）进行化学羟甲基化（hydroxymethylation）修饰可得到前体药物（prodrug）NFOH，同时增强其抗克氏锥虫（Trypanosoma cruzi）的体外与体内活性，且经埃姆斯试验（Ames assay）与微核试验（micronucleus assay）检测未表现出遗传毒性。本研究旨在评估NFOH在急性瑞士小鼠及C57Bl/6小鼠恰加斯病（Chagas disease）实验模型中的体内抗克氏锥虫效果。治疗于感染后第5天启动，连续给药20天，经口给药，每日1次，剂量为150mg/kg；随后开展小鼠血液寄生虫血症检测与组织病理学分析。在两种实验小鼠模型中，经地塞米松（dexamethasone，5mg/kg，连续给药14天）免疫抑制期间，NFOH可降低小鼠血液寄生虫血症水平，使100%受试小鼠避免寄生虫复发，同时减少组织内的寄生虫病灶，所有检测器官中均未检出锥虫无鞭毛体（amastigote），该实验数据与苄硝唑（benznidazole，BZN）的结果一致。综上，本研究结果表明NFOH是一种极具应用前景的化合物，可用于后续恰加斯病治疗的临床前研究（preclinical studies），有望开发成为治疗恰加斯病的高效安全化学治疗药物。