李勇,曾菊芳,陈祥燕,谢晓娟,万峰.氢溴酸樟柳碱注射液大鼠单次和重复给药毒性试验研究[J].药物评价研究,2019,42(8):1523-1530
氢溴酸樟柳碱注射液大鼠单次和重复给药毒性试验研究
Single dose and repeat doses toxicity studies of Anisodine Hydrobromide Injection in rats
投稿时间:2019-03-04  
DOI:10.7501/j.issn.1674-6376.2019.08.007
中文关键词:  氢溴酸樟柳碱;大鼠;单次给药毒性试验;重复给药毒性试验
英文关键词:anisodine hydrobromide;rats;single dose toxicity study;repeat doses toxicity study
基金项目:四川省科技支撑项目(2016sz0027)
作者单位
李勇 四川省医学科学院·
四川省人民医院实验动物研究所, 四川 成都 610212 
曾菊芳 四川省医学科学院·
四川省人民医院实验动物研究所, 四川 成都 610212 
陈祥燕 四川省医学科学院·
四川省人民医院实验动物研究所, 四川 成都 610212 
谢晓娟 四川省医学科学院·
四川省人民医院实验动物研究所, 四川 成都 610212 
万峰 成都第一制药有限公司, 四川 成都 611930 
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中文摘要:
      目的 通过SD大鼠的单次和重复静脉给药毒性试验,评价氢溴酸樟柳碱注射液的安全性。方法 单次给药毒性试验采用最大耐受量法,观察大鼠的死亡情况和毒性反应。重复给药毒性试验:将大鼠随机分为溶媒对照组和氢溴酸樟柳碱10、50、200 mg/kg剂量组,每组30只,尾iv给药,连续13周,停药恢复4周。进行各项毒理学指标检测。结果 急性毒性试验:氢溴酸樟柳碱注射液在364.5~504.5 mg/kg对大鼠产生明显毒性,症状有给药时尖叫、俯卧、后肢无力、颤抖、抽搐、惊厥、瞳孔散大、尾部发绀等,甚至造成个别动物死亡。重复给药毒性试验:50、200 mg/kg剂量组出现体质量增长减缓,摄食下降,给药后尖叫,鼻端、眼周异常分泌物增多,皮肤脱毛、结痂,耳廓溃疡、缺损,瞳孔散大,尾部发绀,血红蛋白(HGB)、红细胞压积(HCT)、Cl-浓度升高等症状,200 mg/kg剂量组还出现给药后肌张力减退、颤抖、抽搐、呼吸困难、皮下炎性包块等表现。溶媒对照组和200 mg/kg剂量组动物注射部位均出现静脉炎及静脉周围炎,严重程度无差异,停药4周后病变减轻。结论 氢溴酸樟柳碱注射液SD大鼠静脉单次给药的最大耐受量(MTD)为428.8 mg/kg,约相当于临床剂量的2 573倍;重复给药毒性试验未见明显毒性反应剂量(NOAEL)为10 mg/kg,约相当于临床剂量的60倍。
英文摘要:
      Objective To evaluate the safety of anisodine hydrobromide injection for SD rats by single and repeat administration toxicity studies. Methods In single dose toxicity study, maximum tolerance dose (MTD) method was applied to observe the death and toxic reaction of rats. In repeat doses toxicity study, rats were randomly divided into vehicle control, anisodine hydrobromide injection 10, 50 and 200 mg/kg groups, and each group had 30 rats. All animals were intravenously given vehicle or anisodine hydrobromide injection for 13 weeks followed by 4-week recovery. Toxicology parameters were determined. Results In single dose toxicity study, anisodine hydrobromide injection induced obvious toxicity in rats at 364.5-504.5 mg/kg, such as screaming during administration, face lying, muscular hypotonus of hindlimb, tremor, spasm, convulsion, mydriasis, tail cyanosis, even some rats died. In repeat doses toxicity study, following adverse effects were observed in rats at 50 and 200 mg/kg groups:body weight increasing slowly, food consumption decreasing, screaming during administration, abnormal secretions increasing at the end of nose and around eyes, depilation and scab of skin, ulcer and defect of auricle, mydriasis, tail cyanosis, HGB, HCT and Cl-increasing. At 200 mg/kg group, muscular hypotonus, tremor, spasm, dyspnea, subcutaneous inflammatory lumps were also observed. Phlebitis and periphlebitis were found at injection site in rats at both vehicle control and 200mg/kg groups, with no obvious difference between the two groups, and alleviated after 4-week recovery. Conclusion The maximum tolerance dose (MTD) of anisodine hydrobromide injection in SD rats by single dose intravenous injection was 428.8 mg/kg, about 2573 times of clinical dose. The no observed adverse effect level (NOAEL) in repeat doses toxicity study was 10 mg/kg, about 60 times of clinical dose.
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