冠心宁注射液多次静脉给药对Beagle犬的毒性研究

Study of intravenous injection repeated dose toxicity of Guanxinning injection in Beagle dogs

目的研究冠心宁注射液连续13周静脉注射给予Beagle犬后产生的毒性。方法正常Beagle犬40只,分为对照组和低、中、高剂量实验组。低、中、高剂量实验组分别给予0. 4,0. 8,1. 6 g·kg^(-1)的冠心宁注射液,对照组给予等容积的生理盐水,静脉注射,每天1次,连续注射13周。检测外观体征、体重、临床病理及毒性病理学各项指标,全面评价重复给予Beagle犬后产生的毒性。结果低剂量实验组动物未见任何毒性反应;中剂量实验组动物出现流涎、呕吐、血清谷丙转氨酶(ALT)升高;高剂量实验组动物出现流涎、呕吐、血清ALT、谷草转氨酶(AST)、尿素氮(BUN)升高[ALT (86. 7±17. 2) U·L^(-1),AST(65. 4±11. 5)U·L^(-1),BUN(6. 5±1. 2) mmol·L^(-1))],肝系数增加[(3. 74±0. 56)×10^(-2)],及肝和肾的病理组织学病变。结论冠心宁注射液连续13周静脉注射给予Beagle犬,主要毒性靶器官为肝和肾,其无毒性反应剂量为0. 4 g·kg^(-1)·d^(-1),相当于成人临床用药剂量的6倍左右。

Objective To investigate the repeated dose toxicity of Guanxinning injection in Beagle dogs. Methods Forty Beagle dogs were divided into control group and low,middle,high dose test groups. The dogs in low,middle,high dose test groups were administered intravenously with Guanxinning injection 0. 4,0. 8,1. 6 g·kg^-1 for 13 weeks,control group was given normal saline. The physical signs,body weight,clinicopathology and toxic-pathology were measured for toxicity assessment. Results No toxic reaction was found in low dose test group. Saliva,vomiting and abnormal escalation of the levels of alanine aminotransferase( ALT) were found in middle dose test group. The toxic reactions in high dose test group showed abnormal escalation of the levels of ALT,aspartate aminotransferase( AST), blood urea nitrogen( BUN) [ALT( 86. 7 ± 17. 2) U·L^-1,AST( 65. 4 ± 11. 5) U·L^-1,BUN( 6. 5 ± 1. 2)mmol·L^-1) ] and liver index[( 3. 74 ± 0. 56) × 10^-2]. Pathological changes of kidney and liver was also found by histopathological examination. Conclusion Guanxinning injection administered intravenously has significant toxicity on kidney,liver and drug delivery site. No observed adverse effect level is 0. 4 g·kg^-1·d^-1,which is equivalent to about 6 times the dose of clinical medication in adults.