注射用牡荆素Beagle犬长期毒性试验研究
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摘要
目的探讨注射用牡荆素的无毒反应剂量。方法选取健康Beagle犬24只,随机分为牡荆素高剂量组[A_1组,50 mg/(kg·d)]、中剂量组[A_2组,20 mg/(kg·d)]、低剂量组[A_3组,8 mg/(kg·d)](均静脉滴注给药)和对照组(B组,静脉滴注等体积0. 9%氯化钠注射液),各6只,用药3个月,给药1. 5个月、3个月(停药次日)和恢复期结束(停药1个月)时检查(及剖检),观察各组犬血液学、血液生化学、尿常规、眼科和心电图各项检测指标的变化,脏器质量及系数、大体观察和组织病理学改变,以及摄食、体质量和体温的改变。结果不同剂量注射用牡荆素对上述指标总体无明显影响,且在犬体内均呈线性方式代谢,暴露量随给药时间延长而有所减小,未见明显毒副反应及中毒靶器官。结论 Beagle犬连续3个月静脉滴注注射用牡荆素较安全,未发现明显毒副反应,安全无毒剂量大于50 mg/(kg·d)。
Objective To investigate the non-toxic response dose of Vitexin for Injection. Methods Totally 24 healthy Beagle dogs were selected and randomly divided into 3 groups: vitexin high dosage group [ group A_1,50 mg/( kg·d) ],vitexin medium dosage group[ group A_2,20 mg/( kg· d) ],vitexin low dosage group [ group A_3,8 mg/( kg·d) ]( the Beagle dogs in the 3 groups were administered intravenously) and the control group( group B,equal votume of 0. 9% Sodium Chloride Injection),6 Beagle dogs in each group,all dogs were given medication for 3 months. The dogs were examined( and dissected) after 1. 5 and 3 months of administration( on the day after discontinuation) and at the end of recovery period( 1 month after drug withdrawal),the changes of hematology,blood biochemistry,urine routine,ophthalmology and electrocardiogram,the organ quality and coefficient,gross observation results and pathological changes of tissues,as well as changes of food intake,body weight and body temperature were observed. Results There was no significant effect of different dosages of Vitexin for Injection on the above indexes,and the drug was metabolized in a linear manner in the dogs. The amount of exposure decreased with the prolongation of administration time,and no obvious toxic side effects or toxic target organs were observed. Conclusion Intravenous drip of Viticetin for Injection in Beagle dogs for 3 consecutive months is safe,and no obvious toxic or side effects are found. The safe and non-toxic dosage is more than 50 mg/( kg·d).
Objective To investigate the non-toxic response dose of Vitexin for Injection. Methods Totally 24 healthy Beagle dogs were selected and randomly divided into 3 groups: vitexin high dosage group [ group A_1,50 mg/( kg·d) ],vitexin medium dosage group[ group A_2,20 mg/( kg· d) ],vitexin low dosage group [ group A_3,8 mg/( kg·d) ]( the Beagle dogs in the 3 groups were administered intravenously) and the control group( group B,equal votume of 0. 9% Sodium Chloride Injection),6 Beagle dogs in each group,all dogs were given medication for 3 months. The dogs were examined( and dissected) after 1. 5 and 3 months of administration( on the day after discontinuation) and at the end of recovery period( 1 month after drug withdrawal),the changes of hematology,blood biochemistry,urine routine,ophthalmology and electrocardiogram,the organ quality and coefficient,gross observation results and pathological changes of tissues,as well as changes of food intake,body weight and body temperature were observed. Results There was no significant effect of different dosages of Vitexin for Injection on the above indexes,and the drug was metabolized in a linear manner in the dogs. The amount of exposure decreased with the prolongation of administration time,and no obvious toxic side effects or toxic target organs were observed. Conclusion Intravenous drip of Viticetin for Injection in Beagle dogs for 3 consecutive months is safe,and no obvious toxic or side effects are found. The safe and non-toxic dosage is more than 50 mg/( kg·d).
引文
[1]牛海军,李晓亮,邵旭,等.注射用牡荆素的冻干工艺参数优化[J].中国药业,2017,26(16):6-8.
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[4]王亚男,彭成凤,甄毅岚,等.注射用牡荆素与葛根素注射液抗大鼠心肌缺血/再灌注损伤量效关系的研究[J].安徽医科大学学报,2015,50(3):314-318.
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[8]邵旭,董六一,李晓亮,等.牡荆素对麻醉犬血流动力学及心肌耗氧量的影响[J].安徽医药,2010,14(9):1001-1004.
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[10]CHE X,WANG X,ZHANG J,et al.Vitexin exerts cardioprotective effect on chronic myocardial ischemia/reperfusion injury in rats via inhibiting myocardial apoptosis and lipid peroxidation[J].Am J Transl Res,2016,8(8):3319-3328.
[11]李晓亮,邵旭,牛海军,等.Beagle犬牡荆素急性毒性实验研究[J].临床合理用药杂志,2017,10(22):56-57.
[12]刘宝峰,唐恒克,刘兆华,等.注射用雷贝拉唑钠Beagle犬的长期毒性[J].毒理学杂志,2007,21(4):314-315.
[13]齐云,蔡润兰,刘彬,等.新药长毒试验动物血液生化测定规范化研究系列之七---Beagle犬血液生化参考值的建立[J].中国比较医学杂志,2006,16(4):201-203.
[14]杨莉,李涛,张弘.血管平滑肌细胞毒物毒理及机制研究进展[J].中国药业,2018,27(3):1-6.
[15]谭乐俊,王萌,朱彦.中药注射剂的不良反应研究进展[J].中国中药杂志,2014,39(20):3889-3898.
[2]DONG LY,CHEN ZW,GUO Y,et al.Mechanisms of vitexin preconditioning effects on cultured neonatal rat cardiomyocytes with anoxia and reoxygenation[J].Am J Chin Med,2008,36(2):385-397.
[3]董六一,范一菲,邵旭,等.牡荆素对大鼠心肌缺血再灌注损伤诱导细胞凋亡的影响[J].中成药,2011,33(6):1041-1044.
[4]王亚男,彭成凤,甄毅岚,等.注射用牡荆素与葛根素注射液抗大鼠心肌缺血/再灌注损伤量效关系的研究[J].安徽医科大学学报,2015,50(3):314-318.
[5]彭成凤.牡荆素对大鼠心肌梗死后再灌注损伤的保护及其机制研究[D].合肥:安徽医科大学,2015.
[6]毛丽娜,朱清,李俊旭.牡荆素的神经保护作用及机制研究进展[J].中国药理学通报,2016,32(10):1353-1356.
[7]李晟,江勤,郭岩,等.牡荆素对实验性心肌缺血的保护作用及机制研究[J].中药药理与临床,2013,29(1):44-47.
[8]邵旭,董六一,李晓亮,等.牡荆素对麻醉犬血流动力学及心肌耗氧量的影响[J].安徽医药,2010,14(9):1001-1004.
[9]DONG L,FAN Y,SHAO X,et al.Vitexin protects against myocardial ischemia/reperfusion injury in Langendorff-perfused rat hearts by attenuating in flammatory response and apoptosis[J].Food Chem Toxicol,2011,49(12):3211-3216.
[10]CHE X,WANG X,ZHANG J,et al.Vitexin exerts cardioprotective effect on chronic myocardial ischemia/reperfusion injury in rats via inhibiting myocardial apoptosis and lipid peroxidation[J].Am J Transl Res,2016,8(8):3319-3328.
[11]李晓亮,邵旭,牛海军,等.Beagle犬牡荆素急性毒性实验研究[J].临床合理用药杂志,2017,10(22):56-57.
[12]刘宝峰,唐恒克,刘兆华,等.注射用雷贝拉唑钠Beagle犬的长期毒性[J].毒理学杂志,2007,21(4):314-315.
[13]齐云,蔡润兰,刘彬,等.新药长毒试验动物血液生化测定规范化研究系列之七---Beagle犬血液生化参考值的建立[J].中国比较医学杂志,2006,16(4):201-203.
[14]杨莉,李涛,张弘.血管平滑肌细胞毒物毒理及机制研究进展[J].中国药业,2018,27(3):1-6.
[15]谭乐俊,王萌,朱彦.中药注射剂的不良反应研究进展[J].中国中药杂志,2014,39(20):3889-3898.