Li Jie, Lv Yun-Gang, Pan Li-Hong, Yao Fang-Fang, Peng Tao, Tan Yu-Jun, Zhang Gui-Min, Liu Zhong, Yao Jing-Chun, Ren Yu-Shan
National Engineering Laboratory of High Level Expression in Mammalian Cells, Lunan Pharmaceutical Group Co. Ltd., Linyi, China.
State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, China.
Front Pharmacol. 2019 Oct 16;10:1218. doi: 10.3389/fphar.2019.01218. eCollection 2019.
Our previous studies have investigated the systematic pharmacokinetic characteristics, biological activities, and toxicity of arctigenin. In this research, the potential toxicities of arctigenin in beagle dogs were investigated repeated 28-day subcutaneous injections. Beagle dogs were randomly divided into control, vehicle [polyethylene glycol (PEG)], and arctigenin 6, 20, 60 mg/kg treated groups. The whole experimental period lasted 77 days, including adaptive period (35 days), drug exposure period (animals were treated with saline, PEG, or arctigenin for 28 consecutive days), and recovery period (14 days). Arctigenin injection (60 mg/kg) affected the lymphatic hematopoietic, digestive, urinary, and cardiovascular systems, and all the impact on these tissues resulted in death in five dogs (three female and two male dogs); 20 mg/kg arctigenin injection resulted in toxic reactions of the lymphatic hematopoietic and digestive systems; and 6 mg/kg arctigenin and PEG injection did not lead to significant toxic reactions. Meanwhile, there were no sexual differences of drug exposure and accumulation when dogs underwent different dosages. As stated previously, the toxic target organs of arctigenin administration include lymphatic hematopoietic, digestive (liver and gallbladder), urinary (kidney), and cardiovascular (heart) systems, and the no observed adverse effect level (NOAEL) of arctigenin is less than 6 mg/kg.
我们之前的研究已经探究了牛蒡子苷元的系统药代动力学特征、生物活性和毒性。在本研究中，通过对比格犬进行28天的重复皮下注射，研究了牛蒡子苷元的潜在毒性。比格犬被随机分为对照组、赋形剂[聚乙二醇（PEG）]组以及牛蒡子苷元6、20、60 mg/kg治疗组。整个实验期持续77天，包括适应期（35天）、药物暴露期（动物连续28天接受生理盐水、PEG或牛蒡子苷元治疗）和恢复期（14天）。牛蒡子苷元注射（60 mg/kg）影响了淋巴造血、消化、泌尿和心血管系统，对这些组织的所有影响导致5只犬（3只雌性和2只雄性犬）死亡；20 mg/kg牛蒡子苷元注射导致淋巴造血和消化系统出现毒性反应；6 mg/kg牛蒡子苷元和PEG注射未导致明显的毒性反应。同时，当犬接受不同剂量时，药物暴露和蓄积不存在性别差异。如前所述，牛蒡子苷元给药的毒性靶器官包括淋巴造血、消化（肝脏和胆囊）、泌尿（肾脏）和心血管（心脏）系统，牛蒡子苷元的未观察到不良反应水平（NOAEL）小于6 mg/kg。
