幼龄SD大鼠自发性病变分析

doi:10.3969/j.issn.1674-5817.2020.02.007

摘要/Abstract

摘要： 目的研究幼龄SPF级SD大鼠自发性病变的发生情况,为药物临床前安全性评价研究特别是儿科药物临床前评价研究提供资料。方法收集近2年幼龄SD大鼠药物重复给药毒性研究试验中出生51 d(PND51)、出生65 d(PND65)、出生111 d(PND111)、出生139 d(PND139)阴性对照组大鼠,制作病理切片,光学显微镜下观察SD大鼠病变的种类及组织形态学特点,并统计其病变发生率。结果分析报告了幼龄SPF级SD大鼠发育不同时间的自发性病变,主要有心脏、肝脏、肾脏等脏器病变,其中肝脏、心脏、肾脏自发性病变发生率及程度随着大鼠的发育有所提高和加深。结论幼龄SPF级SD大鼠发育不同时间的自发性病变及其发生率可为药物重复给药毒性研究提供参考。

关键词: 幼龄动物, SD大鼠, 发育毒性, 自发性疾病, 组织病理学

Abstract: Objective To study the incidence of spontaneous histopathological lesions of young SPF SD rats at different growth and development stages, to provide information for drug nonclinical safety evaluation especially for pediatric drugs. Methods The samples were collected from SD rats in day 51 (PND51), day 65 (PND65), day 111 (PND111) and day 139 (PND139) after born as control groups in safety evaluation studies in recent 2 years. The pathological sections and histomorphological features of SD rats were observed under an optical microscope, and the incidence of pathological changes was also observed. Result The spontaneous lesions of young SPF SD rats at different times were analyzed and reported. The high incidence lesions occurred mainly in heart, liver, kidney and other organ lesions. The incidence and levels of spontaneous histopathological lesions of liver, heart and kidney were increased and developed with the rats growing. Conclusion The spontaneous lesions and their incidence in young SPF SD rats in drug toxicology research can provide some reference for relevant scientist.

Key words: Juvenile animal, SD Rat, Developmental toxicity, Spontaneous lesions, Histopathology

中图分类号:

Q95-33

黄暨生, 吴淑仪, 詹锦河, 倪庆纯. 幼龄SD大鼠自发性病变分析[J]. 实验动物与比较医学, 2020, 40(2): 128-135.

HUANG Jisheng, WU Shuyi, ZHAN Jinhe, NI Qingchun. Analysis of Incidence of Spontaneous Histopathological Lesions in Young SD Rats[J]. Laboratory Animal and Comparative Medicine, 2020, 40(2): 128-135.

参考文献

[1] 孙祖越, 周莉, 韩玲. 儿科用药非临床安全性评价要则及中药评价的特殊性[J]. 中国药理学与毒理学杂志, 2016, 30(1):13-20.
[2] Center for Drug Evaluation of CFDA. 化学药物儿科人群药代动力学研究技术指导原则 [EB/OL]. http://www.cde.org.cn/zdyz.do?method=largePage&id=201.
[3] Center for Drug Evaluation of CFDA. 儿科人群药物临床试验技术指导原则(征求意见稿) [EB/OL]. http://www.cde.org.cn/zdyz.do?method=largePage&id=22207.
[4] Center for Drug Evaluation of CFDA. 儿科用药非临床安全性研究技术指导原则(征求意见稿)[EB/OL]. http://www.cde.org.cn/news.do?method=largeInfo&id=255.
[5] Center for Drug Evaluation of CFDA. 药物重复给药毒性研究技术指导原则 [EB/OL]. http://www.cde.org.cn/zdyz.do?method=largePage&id=192.
[6] FDA. Nonclinical Safety Evaluation of Pediatric Drug Products [EB/OL]. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm079247.pdf.
[7] 黄芳华, 王庆利, JIM Ridings, 等. 幼龄动物毒理学研究:试验设计、实施和结果分析[J]. 中国新药杂志, 2017(2):151-161.
[8] Mann PC, Vahle J, Keenan CM, et al.International harmonization of toxicologic pathology nomenclature: an overview and review of basic principles[J]. Toxicol Pathol, 2012, 40(4 Suppl):7S-13S.
[9] Renne R, Brix A, Harkema J, et al.Proliferative and nonproliferative lesions of the rat and mouse respiratory tract[J]. Toxicol Pathol, 2009, 37(7 Suppl):5S-73S.
[10] Thoolen B, Maronpot RR, Harada T, et al.Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system[J]. Toxicol Pathol, 2010, 38(7 Suppl):5S-81S.
[11] Kaufmann W, Bolon B, Bradley A, et al.Proliferative and nonproliferative lesions of the rat and mouse central and peripheral nervous systems[J]. Toxicol Pathol, 2012, 40(4 Suppl):87S-157S.
[12] Vendemiale G, Grattagliano I, Caraceni P, et al.Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: effect of the nutritional status[J]. Hepatology, 2001, 33(4):808-815.
[13] Rudmann D, Cardiff R, Chouinard L, et al.Proliferative and nonproliferative lesions of the rat and mouse mammary, zymbal’s, preputial, and clitoral glands[J]. Toxicol Pathol, 2012, 40(6 Suppl):7S-39S.
[14] Creasy D, Bube A, de Rijk E, et al. Proliferative and nonproliferative lesions of the rat and mouse male reproductive[J]. Toxicol Pathol, 2012, 40(6 Suppl):40S-121S.
[15] Greaves P, Chouinard L, Ernst H, et al.Proliferative and non-proliferative lesions of the rat and mouse soft tissue, skeletal muscle and mesothelium[J]. J Toxicol Pathol, 2013, 26(3 Suppl):1S-26S.
[16] Mecklenburg L, Kusewitt D, Kolly C, et al.Proliferative and non-proliferative lesions of the rat and mouse integument[J]. J Toxicol Pathol, 2013, 26(3 Suppl):27S-57S.
[17] Dixon D, Alison R, Bach U, et al.Nonproliferative and proliferative lesions of the rat and mouse female reproductive system[J]. J Toxicol Pathol, 2014, 27(3/4 Suppl):1S-107S.
[18] Thomas N, Patricia BW, Charles D, et al.Nonproliferative and proliferative lesions of the gastrointestinal tract, pancreas and salivary glands of the rat and mouse[J]. J Toxicol Pathol, 2016, 29(1 Suppl):1S-125S.
[19] Brian RB, Vasanthi M, Hirofumi N, et al.Nonproliferative and proliferative lesions of the cardiovascular system of the rat and mouse[J]. J Toxicol Pathol, 2016, 29(3 Suppl): 1S-47S.
[20] Fossey S, Vahle J, Long P, et al.Nonproliferative and proliferative lesions of the rat and mouse skeletal tissues (bones, joints, and teeth)[J]. J Toxicol Pathol, 2016, 29(3 Suppl):49S-103S.
[21] Brändli-Baiocco A, Balme E, Bruder M, et al.Nonproliferative and proliferative lesions of the rat and mouse endocrine system[J]. J Toxicol Pathol, 2018, 31(3 Suppl):1S-95S.
[22] Meg FR, Julia B, Elke-Astrid A, et al.Nonproliferative and proliferative lesions of the rat and mouse special sense organs (ocular [eye and glands], olfactory and otic)[J]. J Toxicol Pathol, 2018, 31(3 Suppl):97S-214S.
[23] Willard-Mack CL, Elmore SA, Hall WC, et al.Nonproliferative and proliferative lesions of the rat and mouse hematolymphoid system[J]. J Toxicol Pathol, 2019, 46(6):665-783.
[24] Department of Pathology of Sun Yat-sen University of Medical Science, Tongji Medical University. Surgical P athology[M]. Wuhan: Hubei Science and Technology Press, 1999:651-684.
[25] 朱奎成, 刘娜, 王纯耀, 等. 比格犬自发疾病的病理组织学研究[J]. 实验动物科学, 2011(2):80-81,84.
[26] 赵玺龙, 李学锋, 陈玥, 等. 不同年龄实验恒河猴自然死亡的肝脏病变谱分析[J]. 中国实验动物学报, 2011(3):52-56,103.
[27] 程树军, 黄韧, 秦瑶. 比格犬肝脏自发病变的组织学研究[J]. 上海实验动物科学, 2003, 23(4):200-202.
[28] 秦川. 实验动物学[M]. 北京: 人民卫生出版社, 2010: 99.
[29] 方喜业. 医学实验动物学[M].北京: 人民卫生出版社, 1995:116-125.
[30] 李玉林. 病理学[M]. 北京: 人民卫生出版社, 2010: 5-111.
[31] 魏永杰, 张华. 细胞因子在非酒精性脂肪性肝炎发病机制中的作用[J]. 国际消化病杂志, 2006, 26(1):14-16.
[32] Vendemiale G, Grattagliano I, Caraceni P, et al.Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: Effect of the nutritional status[J]. Hepatology, 2001, 33(4):808-815.
[33] Cornwell GG, Thomas BP.Cardiac fibrosis in the aged germfree and conventional Lobund-Wistar rat[J]. Prog Clin Biol Res, 1989, 287:69-74.
[34] Cornwell GG 3rd, Thomas BP, Snyder DL. Myocardial fibrosis in aging germ-free and conventional Lobund-Wistar rats: the protective effect of diet restriction[J]. J Gerontol, 1991, 46(5):B167-B170.
[35] 今井清, 榎本真, 任进. 图解毒性病理学[M].昆明:云南科学技术出版社, 2006:35.
[36] 汪会玲, 杨华, 于洲, et al.不同品系清洁级8周龄大鼠肾脏常见病理变化及其自发率[J]. 卫生研究, 2006(3):98-99.
[37] Johannsen FR, Levinskas GJ.Comparative chronic toxicity and carcinogenicity of acrylonitrile by drinking water and oral intubation to Spartan Sprague-Dawley rats[J]. Toxicol Lett, 2002, 132(3):197-219.