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 day, and 0, 30, 60 and 120 mg kg day, 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 day, 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 and AUC 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 and AUC increased significantly in the 120 mg kg day 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 day, with dead sperms observed in the epididymides and a loss of necrotic cells. Furthermore, the brains of rats administered 150 mg kg day 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.
-β, β-dimethylacrylalkannin is a major active chemical component extracted from Lithospermum erythrorhizon, a traditional Chinese medicine that exhibits strong antimicrobial, anti-cancer and anti-inflammatory activities. However, its potential toxicity has not been rigorously studied. To confirm its safety, the oral toxicity of β, β-dimethylacrylalkannin was evaluated in vivo. An acute oral toxicity study in mice demonstrated that β, β-dimethylacrylalkannin was practically nontoxic based on its high median lethal dose (LD 50 > 10 g/kg). No deaths or abnormal responses were observed in the acute toxicity test using Wistar rats, suggesting that the maximum tolerated dose of β, β-dimethylacrylalkannin was greater than 10 g/kg. Chronic toxicity studies also revealed an absence of mortality and clinical symptoms, and no treatment-related adverse effects were detected by hematology, blood biochemistry and urinalysis examinations in all rats treated with 10-160 mg/kg/day β, β-dimethylacrylalkannin during a 6-month period. Increases in the relative organ weight of the lungs of females and the liver of males were observed at 160 mg/kg. Histopathological analyses revealed brown pigmentation in renal tubular epithelial cells at the middle and high doses (40-160 mg/kg/day). The no-observed-adverse-effect level (NOAEL) of β, β-dimethylacrylalkannin is 10 mg/kg/day. These results suggest that β, β-dimethylacrylalkannin is potentially safe for further development as a therapeutic agent in humans.
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