长期灌服细辛水煎剂及其主要马兜铃酸类成分对小鼠主要脏器的影响  

Effect of long-term oral administration of Asari Radix et Rhizoma decoction and its main aristolochic acid analogs to mice main organs

作　　者：刘美婷 孟晶[1] 田婧卓 赵雍[1] 易艳[1] 李春英[1] 柳辰玥 崔爽 张宇实[1] 王连嵋[1] 梁爱华[1] LIU Meiting;MENG Jing;TIAN Jingzhuo;ZHAO Yong;YI Yan;LI Chunying;LIU Chenyue;CUI Shuang;ZHANG Yushi;WANG Lianmei;LIANG Aihua(Institute of Chinses materia medica,China Academy of Chinese Medical Sciences,Beijing 100070,China)

机构地区：[1]中国中医科学院中药研究所,北京100070

出　　处：《中国药物警戒》2024年第10期1087-1094,1102,共9页Chinese Journal of Pharmacovigilance

基　　金：国家自然科学基金资助项目(82174073、82192913);中国中医科学院科技创新工程项目(CI2021B016、CI2021A04801、CI2021A04805);岐黄学者支持项目;中国中医科学院中医药防治流感技术体系项目(ZZ13-035-10)。

摘　　要：目的研究细辛散剂(AHP)及水煎剂(AHD)单次灌胃给药,以及细辛水煎剂、与其等量的主要马兜铃酸类成分(AAs)连续24周反复灌胃给药对小鼠主要脏器的影响,为临床安全用药提供参考。方法急性毒性实验:以细辛散剂(692倍临床剂量,11.54 g·kg^(-1))、水煎剂(500倍临床剂量,25 g·kg^(-1);1000倍临床剂量,50 g·kg^(-1))灌胃小鼠,观察给药后14 d内动物的毒性反应。长期毒性实验:将小鼠随机分为空白对照组,羧甲基纤维素钠溶剂对照组(CMC-Na,0.02%),马兜铃酸-Ⅰ阳性药组(AA-Ⅰ,27.2μg·kg^(-1))、马兜铃酸-Ⅳa组(AA-Ⅳa,27.2μg·kg^(-1))、马兜铃内酰胺-Ⅰ组(AL-Ⅰ,13.5μg·kg^(-1))、细辛低剂量组(10倍临床剂量,0.5 g·kg^(-1))、细辛中剂量组(31.6倍临床剂量,1.6 g·kg^(-1))和细辛高剂量组(100倍临床剂量,5 g·kg^(-1)),分别在连续给药12、24周及停药恢复8周后取其主要脏器称重并进行病理学检查。结果急性毒性实验中小鼠在给予细辛散剂后5~30 min全部死亡,细辛水煎剂单次给药后14 d观察期内未见小鼠死亡及异常情况。长期毒性实验中细辛及其所含主要马兜铃酸类(AA-Ⅳa,AL-Ⅰ)连续给药24周后,小鼠未见死亡及异常情况,主要脏器(心、肺、脾、肾上腺、脑、睾丸)与对照组相比未见因药物引起的病理学改变,停药8周后未见延迟性毒性反应。结论细辛水煎剂相对安全,高剂量细辛水煎剂中所含等量的AA-Ⅳa、AL-Ⅰ在本研究中对小鼠相对安全。但鉴于本研究数据有限,仍不建议细辛水煎剂过量或长期使用。Objective To investigate the toxicological effect of single-dose intragastric administration of Asari Radix et Rhizoma powder and Asari Radix et Rhizoma decoction,and 24-week continuous intragastric administration of Asari Radix et Rhizoma decoction and the equal amount of its major aristolochic acid analogs(AAs)to mice main organs,so as to provide reference for the clinical drug safety application.Methods Acute toxicity experiment:mice were intragastric administrated with Asari Radix et Rhizoma powder(692 times the clinical dose,11.54 g·kg^(-1)),or Asari Radix et Rhizoma decoction(500 times the clinical dose,25 g·kg^(-1);1000 times the clinical dose,50 g·kg^(-1)),then the toxicity to mice were observed within 14 days since administration.Long-term toxicity experiment:Mice were randomly divided into a blank control group,a media control group(0.02%CMC-Na),a positive drug group of aristolochic acid-Ⅰgroup(AA-Ⅰ,27.2μg·kg^(-1)),an aristolochic acid-Ⅳa group(AA-Ⅳa,27.2μg·kg^(-1)),an aristolactam-Ⅰgroup(AL-I,13.5μg·kg^(-1)),a low-dose group of Asari Radix et Rhizoma decoction(10-time the clinical dose,0.5 g·kg^(-1)),a middle-dose group of Asari Radix et Rhizoma decoction(31.6-time the clinical dose,1.6 g·kg^(-1))and a high-dose group of Asari Radix et Rhizoma decoction(100-time the clinical dose,5 g·kg^(-1)).Organs were weighed and pathologically examined at 12,24 weeks and 24 weeks followed by 8 weeks withdraw since drug administration.Results Acute toxicity experiment:All mice died within 5~30 minutes after administration of the Asari Radix et Rhizoma powder.No deaths or abnormalities present in Asari Radix et Rhizoma decoction treated mice during the 14-day observation period.Long-term toxicity experiment:After 24 weeks of continuous administration of Asari Radix et Rhizoma decoction and its major aristolochic acid analogs(AA-Ⅳa,AL-I),mice showed no significant abnormalities in contrast to control cohort.And there were no drug-induced pathological changes in heart,lungs,spleen,adrenal glands

关 键 词：细辛散剂 细辛水煎剂 马兜铃酸类化合物 急性 毒性 长期毒性 小鼠 灌胃 口服 

分 类 号：R969.3[医药卫生—药理学] R994.11[医药卫生—药学]