罗哌卡因乳酸羟乙基乙酸共聚物微球在小鼠体内的药效及毒性学研究

摘要] 目的 研究局麻药缓释制剂罗哌卡因乳酸羟乙基乙酸共聚物微球（ROP-PLGA-MS）在小鼠坐骨神经阻滞的药效学及对局部组织、神经及全身主要脏器的组织毒性。方法 昆明小鼠25只，双侧坐骨神经旁分别植入罗哌卡因乳酸羟乙基乙酸共聚物微球和乳酸羟乙基乙酸共聚物微球空白微球（PLAC-MS）建立动物模型（每侧植药量为400 mg/kg）。按微球植入后4,10,18,30,48 h 5个时间点随机分5组(n=5)，进行局麻药效学测定。每组小鼠按设定时间点比较双侧肢体感觉运动的阻滞情况（以空白微球植入侧为对照）。感觉阻滞评估采用热踏板法以撤腿潜伏时间为小鼠对热疼痛的反应时间；运动阻滞评估按小鼠后爪的屈伸能力进行4-point scale评分。同时观察小鼠全身及植入部位情况，1周后观察小鼠植入侧坐骨神经、周围组织及全身主要脏器的病理学变化。结果 微球植入后4,10,18,30 h小鼠ROP-PLGA-MS植入侧肢体热踏板撤腿潜伏时间明显较空白球植入侧长（P=0.015，0.000，0.002，0.013）。运动阻滞结果表明各小鼠空白球植入侧肢体均未受阻滞，评分均为1分，ROP-PLGA-MS植入侧在药物植入后4～30 h评分为1～3分，运动阻滞轻微(P<0.05)。48 h后感觉运动阻滞恢复（P>0.05）。ROP-PLGA-MS植入部位神经及附近组织病理切片仅见轻微炎症反应，全身主要脏器无病理学改变。结论 罗哌卡因乳酸羟乙基乙酸共聚物微球组织毒性小，在小鼠体内具有缓释、延长镇痛时间的作用。 关键词] 镇痛 小鼠 罗哌卡因乳酸羟乙基乙酸共聚物微球 植入 坐骨神经 神经阻滞 毒性

Evaluation the pharmacodynamics and the toxicity of ropivacaine loading poly(lactide-co-glycolide) microspheres in mice

ABSTRACT OBJECTIVE:Objective To evaluate the efficacy and toxicity of a newformulation of ropivacaine loaded in an fatty acid based biodegradable polymer poly(lactide-co-glycolide) (PLGA) when implant near the sciatic nerve of mice.MOTHOLD:Twenty-five Kunming mice were implanted with the Polymer–ropivacaine microspheres 400mg.kg-1 and the placebo microspheres 400mg.kg-1 nearby the two sciatic nerves respectively,and were randomly divided into five grouds by the time point after implanted the microspheres(4h、10h、18h、30h、48h),n=5.The efficacy of the polymer–drug combination was determined by measure the sensory and motor nerve blockade for 48h.Sensory tests were performed at each time point using the YLS-6B hot plate,the latency to withdraw the hide paw from the hot plate used as the respond tim to the thermal nociception.Motor tests were performed to examine the hind paw’s ability to splay and flex by 4-point scale. While monitoring the animal general health and the injection site.After one week,sacrifice the disposed mice,Microscopic examination of the main internal organs and the tissues of implanted sites. RESULTS: The time point 4h、10h、18h and30h after implanted the microspheres in mice,the withdrawal latency of the Polymer–ropivacaine microspheres sides were longer than the the placebo microspheres sides(P=0.015,0.000,0.002,0.013). The 4-point scale of motor tests show that 4-30h,the Polymer–ropivacaine microspheres sides were 1-3,the placebo microspheres sides were 1, the sensory and motor nerve blockade were recover after 48h (P>0.05). Microscopic examination of the implanted sites revealed only mild infiltration in examined tissues with no pathological findings for internal organs were found.CONCLUSION: Polymer–ropivacaine microspheres have sustained release effect in mice and can prolonged analgesia of ropivacaine,and have no toxicity on mice.