Xu Wenxiu, Chen Dan, Zhang Zehan, Liu Shuling, Chen Congai, Sun Chunyan, Ni Wenchao, Kang Xiangdong, Shang Guojiao, Wang Xueqian, Cheng Fafeng, Wang Qingguo
School of Traditional Chinese Medicine Department, Beijing University of Chinese Medicine, Beijing, China.
Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
Front Pharmacol. 2022 Aug 25;13:987997. doi: 10.3389/fphar.2022.987997. eCollection 2022.
Qinzhi Zhudan Formula (QZZD), optimized from Angong Niuhuang Wan, consists of , and . We had investigated the neuroprotective effects of QZZD and its active components, and demonstrated that it could treat cerebral ischemia and dementia through multiple pathways and mechanisms. Nevertheless, toxicological data on this formula still remains limited. In the study, we sought to examine the toxicological effects of QZZD during the treatment and recovery periods. We investigated potential toxicities of QZZD in Sprague-Dawley (SD) rats 28-day gavage administration. SD rats were randomly divided into control group and treatment groups of A (0.5 g/kg/d QZZD), B (1.5 g/kg/d QZZD), and C (5.0 g/kg/d QZZD). The 56-day course includes treatment period (administration with water or QZZD once a day for 28 consecutive days) and recovery period (28 days). The rats received daily monitoring of general signs of toxicity and mortality, as well as weekly determination of body weight and food consumption. Moreover, the complete blood cell count, biochemistry, coagulation, and urine indicators, organ weights, and histopathological report were analyzed respectively at the end of the treatment and recovery periods. There was no death related to the active pharmaceutical ingredients of QZZD during the treatment period. The maximum no observed adverse effect level (NOAEL) was 0.5 g/kg/d, which is approximately 16.7 times of the equivalent dose of clinical dose in rats. In group TB (1.5 g/kg/d QZZD) and TC (5.0 g/kg/d QZZD), there were adverse effects of blue coloring of tail skin, weight loss, a significant increase of total bilirubin (TBIL), blackening of liver and kidney in gross examination, hyperplasia of bile duct and karyomegaly of hepatocytes in histopathological examination. Besides, in females rats, the food consumption was reduced, while in male rats, there was decrease in triglycerides (TG) and slight increase in white blood cell (WBC) count and neutrophils. In group TC (5.0 g/kg/d QZZD), the indicators of red blood cell (RBC) count, hemoglobin (HGB) and hematocrit (HCT) were decreased slightly, while the platelet count (PLT) was increased. However, these changes were not considered to be toxicologically significant because they resolved during the recovery period. Overall, QZZD exhibited a good safety profile. The maximum no observed adverse effect level was 0.5 g/kg/d, and no target organs toxicity were identified. The present findings might confirm the safety of QZZD in clinical practices.
清开灵滴丸（QZZD）由安宫牛黄丸优化而来，由[具体成分未给出]组成。我们已经研究了QZZD及其活性成分的神经保护作用，并证明其可通过多种途径和机制治疗脑缺血和痴呆。然而，关于该方剂的毒理学数据仍然有限。在本研究中，我们试图研究QZZD在治疗期和恢复期的毒理学作用。我们通过对Sprague-Dawley（SD）大鼠进行28天的灌胃给药来研究QZZD的潜在毒性。SD大鼠被随机分为对照组和A（0.5 g/kg/d QZZD）、B（1.5 g/kg/d QZZD）、C（5.0 g/kg/d QZZD）治疗组。56天的实验过程包括治疗期（连续28天每天用水或QZZD给药一次）和恢复期（28天）。每天监测大鼠的一般毒性体征和死亡率，每周测定体重和食物摄入量。此外，在治疗期和恢复期结束时分别分析全血细胞计数、生化指标、凝血指标、尿液指标、器官重量和组织病理学报告。治疗期间未出现与QZZD活性药物成分相关的死亡。最大无观察到不良反应水平（NOAEL）为0.5 g/kg/d，约为大鼠临床等效剂量的16.7倍。在TB组（1.5 g/kg/d QZZD）和TC组（5.0 g/kg/d QZZD）中，出现了尾部皮肤变蓝、体重减轻、总胆红素（TBIL）显著升高、大体检查肝脏和肾脏变黑、组织病理学检查胆管增生和肝细胞肿大等不良反应。此外，雌性大鼠食物摄入量减少，而雄性大鼠甘油三酯（TG）降低，白细胞（WBC）计数略有增加，中性粒细胞增多。在TC组（5.0 g/kg/d QZZD）中，红细胞（RBC）计数、血红蛋白（HGB）和血细胞比容（HCT）指标略有下降，而血小板计数（PLT）增加。然而，这些变化在恢复期消失，因此不被认为具有毒理学意义。总体而言，QZZD表现出良好的安全性。最大无观察到不良反应水平为0.5 g/kg/d，未发现靶器官毒性。本研究结果可能证实了QZZD在临床应用中的安全性。
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