锝[~(99m)Tc]喷替酸盐注射液单次给药毒性和局部毒性研究
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摘要
目的探讨锝[~(99m)Tc]喷替酸盐注射液临床前安全性,为后续放射性药物安全性研究提供参考。方法选取ICR小鼠、新西兰兔和豚鼠,分别开展尾静脉注射单次给药毒性实验(对照组、5 550 MBq·kg~(-1)组和925 MBq·kg~(-1)组),血管刺激、肌肉刺激和主动全身过敏试验。实验期间观察动物状态,测定动物体重、饲料消耗量并进行组织病理学检查,其中单次给药实验检测血液学指标,对死亡动物及观察期结束后仍存活动物进行大体解剖检查,摘取胸腺、脾脏、肾脏、睾丸称重,计算脏器系数。结果单次给药实验5 550 MBq·kg~(-1)组动物给药后均眼睑下垂,静卧少动,给药后约10 min有1只雄性动物死亡;925 MBq·kg~(-1)组动物未见明显异常。血管刺激、肌肉刺激和主动全身过敏试验给药组均未见明显异常。结论本实验条件下未发现与药物有关的明显毒性反应,为其临床安全应用提供了参考信息。
Objective To study the preclinical safety of technetium[~(99m)Tc] pentetate acid injection, so as to provide a reference for the safety study of radiopharmaceuticals. Methods ICR mice, New Zealand rabbits and guinea pigs were used respectively to carry out the single dose toxicity test of tail intravenous injection(control group, 5 550 MBq·kg~(-1) group and 925 MBq·kg~(-1) group), vein irritating test, muscle irritating test and active systemic anaphylaxis test. The general symptoms were observed, while the weight changes of the animals and the feed consumption were determined during tests. Histopathological examination was performed, in which hematological indexes were detected by single dose toxicity, gross anatomy examination was performed on dead animals and animals still alive after the end of observationperiod, thymus, spleen, kidney and testicles were extracted for weighing, and viscera coefficients were calculated.Results All the mice in the 5 550 MBq·kg~(-1) group had drooping eyelids and little movement after administration,and one male animal died about 10 min after administration. No obvious abnormality was found in animals in the925 MBq·kg~(-1) group. Vein irritating, muscle irritating and active systemic anaphylaxis group showed no obvious abnormalities. Conclusion No obvious toxic reaction related to the drug was found under the conditions of this experiment, suggesting that it provides reference information for its clinical safe application.
Objective To study the preclinical safety of technetium[~(99m)Tc] pentetate acid injection, so as to provide a reference for the safety study of radiopharmaceuticals. Methods ICR mice, New Zealand rabbits and guinea pigs were used respectively to carry out the single dose toxicity test of tail intravenous injection(control group, 5 550 MBq·kg~(-1) group and 925 MBq·kg~(-1) group), vein irritating test, muscle irritating test and active systemic anaphylaxis test. The general symptoms were observed, while the weight changes of the animals and the feed consumption were determined during tests. Histopathological examination was performed, in which hematological indexes were detected by single dose toxicity, gross anatomy examination was performed on dead animals and animals still alive after the end of observationperiod, thymus, spleen, kidney and testicles were extracted for weighing, and viscera coefficients were calculated.Results All the mice in the 5 550 MBq·kg~(-1) group had drooping eyelids and little movement after administration,and one male animal died about 10 min after administration. No obvious abnormality was found in animals in the925 MBq·kg~(-1) group. Vein irritating, muscle irritating and active systemic anaphylaxis group showed no obvious abnormalities. Conclusion No obvious toxic reaction related to the drug was found under the conditions of this experiment, suggesting that it provides reference information for its clinical safe application.
引文
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[2]FDA.Developing Medical Imaging Drug and Biological Products:Part 1:Conducting Safety Assessments[EB/OL].(2004)[2018-12-20].http://www.fda.gov/CDER/GUIDANCE/5742prt2.
[3]CFDA.药物单次给药毒性研究技术指导原则[EB/OL].(2014-05-13)[2018-12-20].http://www.cde.org.cn/zdyz.do?method=largePage&id=189.
[4]CFDA.药品非临床研究质量管理规范[EB/OL].(2003-08-06)[2018-12-20].http://samr.cfda.gov.cn/WS01/CL1031/24472.html.
[5]国家药典委员会.中华人民共和国药典(四部)[M].北京:中国医药科技出版社,2015:410-411.
[6]CFDA.药物刺激性、过敏性和溶血性研究技术指导原则[EB/OL].(2014-05-13)[2018-12-20].http://www.cde.org.cn/zdyz.do?method=largePage&id=188.
[7]袁伯俊,廖明阳,李波,等.药物毒理学实验方法与技术[M].北京:化学工业出版社,2007.
[8]Orsal E,Seven B,Subasi I D,et al.Vesicoureteral reflux in a nonfunctioning kidney detected by 99mTc-DTPA study[J].Japanese Journal of Radiology,2013,31(12):823-825.
[9]李晶,程文俊,郝永哲,等.99mTc-DTPA肾动态显像在老年高血压早期肾损害中的诊断价值[J].实用医学杂志,2018,34(8):1372-1375.
[10]邵小南,张玮.核素肾动态显像评价肾癌患者术前肾功能的意义[J].实用医学杂志,2011,27,(10):1792-1794.
[11]聂红洲,朱娴.99mTc-DTPA肾动态显像在慢性肾脏疾病诊断中的应用[J].临床合理用药杂志,2018,11(4):42-43.
[12]董放,王刚,关薇,等.我国医疗器械不良事件信息管理机制研究[J].中国药物警戒,2016,13(3):148-153.
[13]孙宇昕,魏芬芳,杨悦.美国药物临床试验法律责任研究[J].中国药物警戒,2017,14(7):424-429.