药学学报, 2021, 56(10): 2797-2801
引用本文:
张鹏, 田毅, 马高亭, 董超然, 王明超, 周建明, 曹亮, 朱海波. 比格犬急性血栓性颅内大血管闭塞药物溶栓再通评价方法[J]. 药学学报, 2021, 56(10): 2797-2801.
ZHANG Peng, TIAN Yi, MA Gao-ting, DONG Chao-ran, WANG Ming-chao, ZHOU Jian-ming, CAO Liang, ZHU Hai-bo. A new evaluation method of reperfusion after thrombolysis in beagle dogs with acute thrombotic cerebral vessel occlusion[J]. Acta Pharmaceutica Sinica, 2021, 56(10): 2797-2801.

比格犬急性血栓性颅内大血管闭塞药物溶栓再通评价方法
张鹏1, 田毅2, 马高亭3, 董超然1, 王明超1, 周建明4, 曹亮4, 朱海波1*
1. 中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 新药作用机制研究与药效学评价北京市重点实验室, 北京 100050;
2. 首都医科大学附属北京安贞医院, 北京 100029;
3. 首都医科大学附属北京天坛医院, 北京 100070;
4. 江苏康缘药业股份有限公司, 江苏 连云港 222067
摘要:
本文根据脑血管造影评价再灌注程度,提出了比格犬颅内血栓性大血管闭塞药物溶栓评价方法。采用自体血栓经颈内动脉推入方法,建立比格犬颅内大血管闭塞模型,以血管数字减影技术(DSA)进行血管显影,并将血流再灌注程度分为0级、Ⅰ级、Ⅱa级、Ⅱb级和Ⅲ级5个等级,并进行相应评分:0级代表无灌注(1分);Ⅰ级为极微量灌注(2分);Ⅱa级为小于二分之一灌注(3分);Ⅱb级为大于二分之一灌注(4分);Ⅲ级为完全灌注(5分)。以阿替普酶溶栓药物对方法量化指标进行验证。结果显示,模型组100%达到Ⅰ级及以下水平;阿替普酶组83%达到Ⅱa及以上水平。秩和检验分析结果表明,阿替普酶显著促进闭塞脑血管灌注再通。该动物实验已经通过中国医学科学院药物研究所实验动物管理与动物福利委员会批准。通过以上方式建立犬血栓性颅内大血管闭塞药物溶栓药效评价方法,为溶栓药物临床前药效评价提供技术支持。
关键词:    比格犬      急性血栓性颅大血管闭塞      药物溶栓      脑缺血-再灌注损伤      临床前药效学评价方法     
A new evaluation method of reperfusion after thrombolysis in beagle dogs with acute thrombotic cerebral vessel occlusion
ZHANG Peng1, TIAN Yi2, MA Gao-ting3, DONG Chao-ran1, WANG Ming-chao1, ZHOU Jian-ming4, CAO Liang4, ZHU Hai-bo1*
1. State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
2. Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China;
3. Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China;
4. Jiangsu Kanion Pharmaceutical Company, Lianyungang 222067, China
Abstract:
We provide a new preclinical pharmacodynamic evaluation method of cerebral thrombolytics using beagle dogs with acute thrombotic cerebrovascular occlusion. An intracranial large vessel occlusion animal model was generated by pushing an autologous thrombus to the left carotid artery under X-ray angiography. The experiments were approved by the Animal Care and Welfare Committee Institute of Materia Medica, China Academy of Medical Sciences (CAMS), Peking Union Medical College. According to the degrees of cerebral blood flow reperfusion, the new method has 0, Ⅰ, Ⅱ (Ⅱa and Ⅱb), Ⅲ levels. Respectively, 0 level represents no blood flow through the area of vascular occlusion; Ⅰ level has low perfusion; Ⅱa level is less than half the infusion; Ⅱb level is more than half perfusion; Ⅲ level is completely recanalization perfusion. Alteplase was used as a positive drug to verify the accuracy of the method. Our results suggest that 100% of dogs reached the level of grade I and below in the model group, while 83% reached the level of grade IIa and above in the alteplase group. Results of a rank sum test showed that alteplase significantly improved the reperfusion of occluded cerebral vessels. We propose a method to evaluate the efficacy of thrombolytic drugs on dogs with middle cerebral artery occlusion.
Key words:    beagle dog    acute thrombotic cerebral vessel occlusion    thrombolytic drug    ischemia reperfusion injury    preclinical evaluation method   
收稿日期: 2021-02-04
DOI: 10.16438/j.0513-4870.2021-0193
基金项目: 国家“十三五重大新药创制”科技重大专项(2018ZX09711001-003-01).
通讯作者: 朱海波,Tel:86-10-63188132,E-mail:zhuhaibo@imm.ac.cn
Email: zhuhaibo@imm.ac.cn
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