理气散结浸膏灌胃给予大鼠的长期毒性研究
|
摘要
目的:研究大鼠灌胃理气散结浸膏后的长期毒性,为其临床前安全性评价提供参考。方法:将160只大鼠随机分为对照组(生理盐水)和理气散结浸膏低、中、高剂量组(7.828 0、15.656 0、31.312 0 g/kg,以生药量计),每组40只。每天灌胃给药1次,每周一至周六连续给药6 d,实验周期为120 d,实验结束后的30 d为恢复期。观察各个时期大鼠的一般状况,并每周测定大鼠体质量和饲料消耗量1次。在给药第61天、给药结束及恢复期结束后,各组分别取10、20、10只大鼠,观察其血液学、血液生化学、脏器系数和组织病理学变化。结果:在给药第61～120天,理气散结浸膏高剂量组大鼠有脱毛和竖毛现象,停药后恢复正常。在给药期间,理气散结浸膏低、中剂量组大鼠的体质量增长较对照组变快,而理气散结浸膏高剂量组大鼠体质量增长较对照组变慢;理气散结浸膏低剂量组大鼠的饲料消耗量较对照组增加,理气散结浸膏中、高剂量组大鼠的饲料消耗量较对照组减少,停药后基本恢复。在给药第61天及给药结束后,给药组大鼠部分血液学指标、血液生化学指标以及脏器系数较对照组均有明显变化(P<0.05或P<0.01)。恢复期结束后,大鼠血液学、血液生化学和脏器系数基本恢复正常,但理气散结浸膏低剂量组大鼠血液中的红细胞数、红细胞比积、红细胞宽度标准差、白蛋白、白球比和钾离子(K~+)水平较对照组仍明显降低(P<0.05或P<0.01);理气散结浸膏中剂量组大鼠血液中的中间细胞绝对值较对照组仍明显升高(P<0.05),血液中平均血红蛋白浓度、K~+和子宫系数较对照组仍明显降低(P<0.05);理气散结浸膏高剂量组大鼠血液中白细胞数、淋巴细胞绝对值、中间细胞绝对值、中间细胞百分比、凝血酶原时间以及脾系数较对照组仍明显升高(P<0.05或P<0.01),平均血红蛋白浓度、粒细胞百分比、白蛋白、碱性磷酸酶和K~+较对照组仍明显降低(P<0.05或P<0.01)。大鼠经系统尸解和组织病理学检查,均未发现异常。结论:大鼠长期灌胃理气散结浸膏会产生一定毒性反应,但低剂量理气散结浸膏的毒性反应较少、较轻,且停药后能自动恢复,可为临床安全剂量的确定提供参考。
OBJECTIVE:To study the long-term toxicity of Liqi sanjie extractum in rats after intragastric administration,and to provide reference for safety evaluation before clinical practice. METHODS:A total of 160 rats were randomly divided into control group(normal saline)and Liqi sanjie extractum low-dose,medium-dose and high-dose groups(7.828 0,15.656 0,31.312 0g/kg,calculated by crude drug),with 40 rats in each group. They were given relevant medicine intragastrically once a day from Monday to Saturday. The experimental period was 120 days,and the recovery period was 30 days after the end of the experiment.General information of rats was observed,and body weight and feed consumption of rats were measured once a week. At the 61 st day of administration,the end of administration and the end of recovery period,10,20 and 10 rats were collected from each group to observe their hematology,blood biochemistry,organ coefficient and histopathology changes. RESULTS:From 61 st day to 120 th day of administration,the rats of Liqi sanjie extractum high-dose group had hair loss and erection,and recovered after withdrawal of medicine. During medication,the body weight of mice in Liqi sanjie extractum low-dose and medium-dose groups increased faster than control group,while the body weight of rats in Liqi sanjie extractum high-dose group increased slower than control group. Compared with control group,the feed consumption of Liqi sanjie extractum low-dose group increased,while those of Liqi sanjie extractum medium-dose and high-dose groups decreased;the rats were recovered after drug withdrawal. On the 61 st day of administration and after the end of administration,some hematological indexes,blood biochemical indexes and organ coefficients of rats in administration group were significantly different from those of control group(P<0.05 or P<0.01). The hematology,blood biochemistry and organ coefficients of rats were basically recovered after the end of the recovery period. The number of erythrocyte,hematocrit,standard deviation of erythrocyte width,albumin,globulin ratio and potassium K~+levels in Liqi sanjie extractum low-dose group were significantly lower than those in control group(P<0.05 or P<0.01). The absolute value of intermediate cells in blood of rats in Liqi sanjie extractum medium-dose group was significantly higher than that of control group(P<0.05),and the mean hemoglobin concentration,K~+and uterine coefficient in blood were significantly lower than those of control group(P<0.05). The number of white blood cells,absolute value of lymphocyte,absolute value of intermediate cells,the percentage of intermediate cells, prothrombin time and spleen coefficient in Liqi sanjie extractum high-dose group were significantly higher than those in the control group(P<0.05 or P<0.01). Mean hemoglobin concentration, granulocyte percentage,albumin,alkaline phosphatase and K~+were significantly lower than those in the control group(P<0.05 or P<0.01).No abnormalities in systemic autopsy and histopathology were noticed in rats. CONCLUSIONS: Long-term intragastric administration of Liqi sanjie extractum can cause certain toxic reactions in rats,and low dose of Liqi sanjie extractum causes less and lighter toxic reactions which can be automatically recovered after drug withdrawal. It can provide reference for the determination of clinical safe dose.
OBJECTIVE:To study the long-term toxicity of Liqi sanjie extractum in rats after intragastric administration,and to provide reference for safety evaluation before clinical practice. METHODS:A total of 160 rats were randomly divided into control group(normal saline)and Liqi sanjie extractum low-dose,medium-dose and high-dose groups(7.828 0,15.656 0,31.312 0g/kg,calculated by crude drug),with 40 rats in each group. They were given relevant medicine intragastrically once a day from Monday to Saturday. The experimental period was 120 days,and the recovery period was 30 days after the end of the experiment.General information of rats was observed,and body weight and feed consumption of rats were measured once a week. At the 61 st day of administration,the end of administration and the end of recovery period,10,20 and 10 rats were collected from each group to observe their hematology,blood biochemistry,organ coefficient and histopathology changes. RESULTS:From 61 st day to 120 th day of administration,the rats of Liqi sanjie extractum high-dose group had hair loss and erection,and recovered after withdrawal of medicine. During medication,the body weight of mice in Liqi sanjie extractum low-dose and medium-dose groups increased faster than control group,while the body weight of rats in Liqi sanjie extractum high-dose group increased slower than control group. Compared with control group,the feed consumption of Liqi sanjie extractum low-dose group increased,while those of Liqi sanjie extractum medium-dose and high-dose groups decreased;the rats were recovered after drug withdrawal. On the 61 st day of administration and after the end of administration,some hematological indexes,blood biochemical indexes and organ coefficients of rats in administration group were significantly different from those of control group(P<0.05 or P<0.01). The hematology,blood biochemistry and organ coefficients of rats were basically recovered after the end of the recovery period. The number of erythrocyte,hematocrit,standard deviation of erythrocyte width,albumin,globulin ratio and potassium K~+levels in Liqi sanjie extractum low-dose group were significantly lower than those in control group(P<0.05 or P<0.01). The absolute value of intermediate cells in blood of rats in Liqi sanjie extractum medium-dose group was significantly higher than that of control group(P<0.05),and the mean hemoglobin concentration,K~+and uterine coefficient in blood were significantly lower than those of control group(P<0.05). The number of white blood cells,absolute value of lymphocyte,absolute value of intermediate cells,the percentage of intermediate cells, prothrombin time and spleen coefficient in Liqi sanjie extractum high-dose group were significantly higher than those in the control group(P<0.05 or P<0.01). Mean hemoglobin concentration, granulocyte percentage,albumin,alkaline phosphatase and K~+were significantly lower than those in the control group(P<0.05 or P<0.01).No abnormalities in systemic autopsy and histopathology were noticed in rats. CONCLUSIONS: Long-term intragastric administration of Liqi sanjie extractum can cause certain toxic reactions in rats,and low dose of Liqi sanjie extractum causes less and lighter toxic reactions which can be automatically recovered after drug withdrawal. It can provide reference for the determination of clinical safe dose.
引文
[1]郭广成,李林,段馨,等.消结安胶囊联合他莫昔芬治疗乳腺增生症的临床研究[J].现代药物与临床,2018,33(7):1763-1766.
[2]郭宇飞,王书勤,赵素贞,等.岩鹿乳康胶囊对乳腺增生大鼠血清雌孕激素的影响[J].世界中医药,2018,13(6):1521-1524.
[3]谷丽艳,易佳丽,樊延宏,等.中医药疗法治疗乳腺增生研究进展[J].辽宁中医药大学学报,2014,16(1):173-176.
[4]国家药典委员会.中华人民共和国药典:一部[S].2015年版.北京:中国医药科技出版社,2015:32-33、357-358.
[5]彭平建,殷永和.几类有毒中药的毒性成分及炮制解毒:下[J].基层中药杂志,1995,9(1):18-19.
[6]祁公任,陈涛.同名异物中药毒性辨[J].江苏中医,1998,19(1):34-36.
[7]李仪奎,金若敏,王钦茂.中药药理实验方法学[M].2版.上海:上海科学技术出版社,2006:1008-1017.
[8]《中药、天然药物长期毒性研究技术指导原则》课题研究组.中药、天然药物长期毒性研究技术指导原则[S].北京:国家食品药品监督管理局,2013:1-12.
[9]《中药、天然药物急性毒性研究技术指导原则》课题研究组.中药、天然药物急性毒性研究技术指导原则[S].北京:国家食品药品监督管理局药品审评中心,2005:2-8.
[10]袁伯俊,廖明阳,李波.药物毒理学实验方法与技术[M].北京:化学工业出版社,2007:212-231.
[11]魏伟,吴希美,李元建.药理实验方法学[M].4版.北京:人民卫生出版社,2010:393-406.
[12]陈奇.中药药理研究方法学[M].3版.北京:人民卫生出版社,2011:121-132.
[13]魏谭军,胡凤娇,王张,等.理气散结浸膏对小鼠和大鼠急性毒性研究[J].中药与临床,2018,9(3):41-45.
[14]梁源,胡凤娇,王张,等.大鼠乳腺增生模型造模要素及中医药防治数据挖掘研究[J].中药与临床,2018,9(2):36-42.
[2]郭宇飞,王书勤,赵素贞,等.岩鹿乳康胶囊对乳腺增生大鼠血清雌孕激素的影响[J].世界中医药,2018,13(6):1521-1524.
[3]谷丽艳,易佳丽,樊延宏,等.中医药疗法治疗乳腺增生研究进展[J].辽宁中医药大学学报,2014,16(1):173-176.
[4]国家药典委员会.中华人民共和国药典:一部[S].2015年版.北京:中国医药科技出版社,2015:32-33、357-358.
[5]彭平建,殷永和.几类有毒中药的毒性成分及炮制解毒:下[J].基层中药杂志,1995,9(1):18-19.
[6]祁公任,陈涛.同名异物中药毒性辨[J].江苏中医,1998,19(1):34-36.
[7]李仪奎,金若敏,王钦茂.中药药理实验方法学[M].2版.上海:上海科学技术出版社,2006:1008-1017.
[8]《中药、天然药物长期毒性研究技术指导原则》课题研究组.中药、天然药物长期毒性研究技术指导原则[S].北京:国家食品药品监督管理局,2013:1-12.
[9]《中药、天然药物急性毒性研究技术指导原则》课题研究组.中药、天然药物急性毒性研究技术指导原则[S].北京:国家食品药品监督管理局药品审评中心,2005:2-8.
[10]袁伯俊,廖明阳,李波.药物毒理学实验方法与技术[M].北京:化学工业出版社,2007:212-231.
[11]魏伟,吴希美,李元建.药理实验方法学[M].4版.北京:人民卫生出版社,2010:393-406.
[12]陈奇.中药药理研究方法学[M].3版.北京:人民卫生出版社,2011:121-132.
[13]魏谭军,胡凤娇,王张,等.理气散结浸膏对小鼠和大鼠急性毒性研究[J].中药与临床,2018,9(3):41-45.
[14]梁源,胡凤娇,王张,等.大鼠乳腺增生模型造模要素及中医药防治数据挖掘研究[J].中药与临床,2018,9(2):36-42.