Nifurtimox has been an important treatment for trypanosomiasis for many years, but new research indicates that the drug may also be an effective therapy for malignant neuroblastoma. However, there have been few published reports evaluating the toxicity of nifurtimox in different species. Therefore, to further understand its toxicity and toxicokinetic profiles, Sprague Dawley rats and beagle dogs were orally administered nifurtimox at 0, 25, 75 and 150 mg kg-1 day-1, and 0, 30, 60 and 120 mg kg-1 day-1, respectively, for 28 days, which was followed by a 28-day recovery period. Significant decreases in the body weight and food consumption were observed in rats given 75 and 150 mg kg-1 day-1, but no significant difference was observed in either body weight or food consumption in dogs. No notable gender difference was observed in the rats in our study. The mean Cmax and AUC0-t increased with the exposure time in rats, and systemic exposure on day 28 was notably higher than that on day 1 for each dosing group. In contrast, in dogs the mean Cmax and AUC0-t increased significantly in the 120 mg kg-1 day-1 group only. Other findings in rats included a dose-dependent increase in total bilirubin and urea, a significant increase in the kidney organ coefficient, a decrease in heart and thymus weights, and a decrease in the weight of testes and epididymides tissue in males administered 75 and 150 mg kg-1 day-1, with dead sperms observed in the epididymides and a loss of necrotic cells. Furthermore, the brains of rats administered 150 mg kg-1 day-1 nifurtimox revealed cerebral tissue softening. In dogs there were no treatment-related changes in organ weights during the dosing period. However, deciduous spermatoblasts were observed in the seminiferous tubules and there was a lack of long sperms in the epididymides. The findings from this study demonstrate inter-species differences in nifurtimox toxicity and toxicokinetics. These results are relevant to the evaluation of the wider clinical applications of this drug.

中文翻译：

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大鼠和狗二十八天重复剂量口服硝呋莫司后的毒性和毒代动力学比较。


硝呋替莫多年来一直是锥虫病的重要治疗方法，但新的研究表明该药物也可能是治疗恶性神经母细胞瘤的有效方法。然而，评估硝呋莫司在不同物种中毒性的报道很少。因此，为了进一步了解其毒性和毒代动力学特征，Sprague Dawley大鼠和比格犬口服硝呋莫司0、25、75和150 mg kg-1 day-1，以及0、30、60和120 mg kg-1 day。 -1，分别持续 28 天，随后是 28 天的恢复期。在给予 75 和 150 mg kg-1 day-1 的大鼠中，观察到体重和食物消耗量显着下降，但在狗中，体重或食物消耗量没有观察到显着差异。在我们的研究中，大鼠中没有观察到显着的性别差异。大鼠中平均Cmax和AUC0-t随着暴露时间的延长而增加，并且每个给药组在第28天的全身暴露显着高于第1天。相比之下，在狗中，仅 120 mg kg-1 day-1 组的平均 Cmax 和 AUC0-t 显着增加。在大鼠中的其他发现包括总胆红素和尿素的剂量依赖性增加、肾器官系数的显着增加、心脏和胸腺重量的减少以及给予75和150的雄性的睾丸和附睾组织重量的减少mg kg-1 day-1，在附睾中观察到死亡精子和坏死细胞的损失。此外，给予 150 mg kg-1 day-1 硝呋莫司的大鼠大脑显示脑组织软化。在狗身上，在给药期间没有出现与治疗相关的器官重量变化。 然而，在生精小管中观察到乳汁精母细胞，而附睾中缺乏长精子。这项研究的结果证明了硝呋莫司毒性和毒代动力学的种间差异。这些结果与该药物更广泛的临床应用的评估相关。