Cheng Bowen, Zhang Huarui, Zhao Wenjin, Jiang Shaofeng, Wu Zhijun, Li Huiling, Liu Shuai, Zhang Hongshun
State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing 400038, China.
State Key Laboratory of Trauma and Chemical Poisoning, National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China.
Heliyon. 2024 Oct 19;10(20):e39620. doi: 10.1016/j.heliyon.2024.e39620. eCollection 2024 Oct 30.
Maduramicin (MAD) is an anticoccidial veterinary drug, but it frequently causes fatal poisonings in poultry, livestock, or humans. However, there is no specific antidote or guidance on first aid for MAD poisoning.
The aim of the present study is to evaluate the acute toxicity and toxicokinetics of MAD after oral exposure, so as to make a foundation for developing diagnostic and therapeutic protocols for human intoxication.
Five groups of rats (eight-to-nine-week-old male Wistar rats) were orally administered MAD via gavage at doses of 0, 4.64, 10.0, 21.5, or 46.4 mg/kg bw for only one time. The survival rates of the rats were observed over the following 14 days to assess acute toxicity. To evaluate the toxic effects of MAD, two doses (4.8 mg/kg bw and 10 mg/kg bw) were orally administered via gavage. Biochemical parameters including creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, urea, creatinine, serum myoglobin, and urinary myoglobin were measured. Liver, kidney, heart, and hind limb skeletal muscle samples from severely poisoned rats were obtained for pathological examination. For toxicokinetic analysis, samples of serum, urine, and feces from the 4.8 mg/kg bw dose group were analyzed using high-performance liquid chromatography-tandem mass spectrometry.
The LD50 of MAD in male Wistar rats was determined to be 6.81 mg/kg bw. In the 10 mg/kg bw group, elevated serum urea levels and increased myoglobin levels in both serum and urine indicated renal injury and potential muscle damage. Toxicokinetics in serum revealed that following oral administration of 4.8 mg/kg bw MAD, peak serum concentration of 59.8 ± 8.9 μg/L was achieved at 30.0 ± 13.9 h. MAD exhibited a slow elimination from the blood with an elimination half-life of 72.9 ± 36.8 h and a mean residence time of 79.6 ± 25.5 h. Additionally, fecal excretion of MAD was found to be greater than urinary excretion.
MAD is a highly toxic veterinary drug which requires careful handling. The primary effects of poisoning include kidney injury and suspected rhabdomyolysis. It is excreted very slowly after oral administration. Promoting toxin excretion in individuals poisoned by MAD could potentially serve as an effective treatment method until a specific antidote is identified.
马杜霉素（MAD）是一种抗球虫兽药，但它经常在家禽、家畜或人类中导致致命中毒。然而，对于MAD中毒没有特效解毒剂或急救指导。
本研究的目的是评估口服暴露后MAD的急性毒性和毒代动力学，以便为制定人类中毒的诊断和治疗方案奠定基础。
将五组大鼠（8至9周龄雄性Wistar大鼠）通过灌胃一次性给予剂量为0、4.64、10.0、21.5或46.4mg/kg体重的MAD。在接下来的14天观察大鼠的存活率以评估急性毒性。为了评估MAD的毒性作用，通过灌胃口服给予两个剂量（4.8mg/kg体重和10mg/kg体重）。测量包括肌酸激酶、乳酸脱氢酶、天冬氨酸转氨酶、丙氨酸转氨酶、尿素、肌酐、血清肌红蛋白和尿肌红蛋白在内的生化参数。从严重中毒的大鼠获取肝脏、肾脏、心脏和后肢骨骼肌样本进行病理检查。对于毒代动力学分析，使用高效液相色谱 - 串联质谱法分析4.8mg/kg体重剂量组的血清、尿液和粪便样本。
雄性Wistar大鼠中MAD的半数致死剂量（LD50）确定为6.81mg/kg体重。在10mg/kg体重组中，血清尿素水平升高以及血清和尿液中肌红蛋白水平增加表明肾脏损伤和潜在的肌肉损伤。血清中的毒代动力学显示，口服4.8mg/kg体重的MAD后，在30.0±13.9小时达到血清峰值浓度59.8±8.9μg/L。MAD从血液中消除缓慢，消除半衰期为72.9±36.8小时，平均驻留时间为79.6±25.5小时。此外，发现MAD的粪便排泄量大于尿液排泄量。
MAD是一种高毒性兽药，需要谨慎处理。中毒的主要影响包括肾脏损伤和疑似横纹肌溶解。口服给药后其排泄非常缓慢。在确定特效解毒剂之前，促进MAD中毒个体的毒素排泄可能是一种有效的治疗方法。
