两种克班宁长循环纳米粒的急性毒性与抗心律失常作用研究  

Study on the Acute Toxicity and Antiarrhythmic Effects of Two Kinds of Long-Circulating Crebanine Nanoparticles

作　　者：崔利利 孔淑君 程欣 金文彬 徐颖 张景莲 王丽 马云淑 CUI Lili;KONG Shujun;CHENG Xin;JIN Wenbin;XU Ying;ZHANG Jinglian;WANG Li;MA Yunshu(College of Chinese Material Medica,Yunnan University of Traditional Chinese Medicine,Kunming 650500 Yunnan,China;Yunnan Key Laboratory of External Drug Delivery System and Preparation Technology in Universities,Kunming 650500 Yunnan,China;Disha Pharmaceutical Group Co.Led.,Weihai 264200 Shandong,China;Yunnan Key Laboratory of Dai and Yi Medicine,Kunming 650500 Yunnan,China;Engineering Research Center for Medicine and Homologous Beverage of Yunnan Province,Yunnan University of Traditional Chinese Medicine,Kunming 650500 Yunnan,China)

机构地区：[1]云南中医药大学中药学院,云南昆明650500 [2]云南省高校外用给药系统与制剂技术重点实验室,云南昆明650500 [3]迪沙药业集团有限公司,山东威海264200 [4]云南省傣医药与彝医药重点实验室,云南昆明650500 [5]云南省药食同源饮品工程研究中心,云南昆明650500

出　　处：《中药新药与临床药理》2024年第4期500-505,共6页Traditional Chinese Drug Research and Clinical Pharmacology

基　　金：国家自然科学基金项目(82060723)。

摘　　要：目的对两种经PEG修饰载体材料(PELGE、PLGA)制备的克班宁(Crebanine,Cre)长循环纳米粒(PELGE-Cre-NPs、PLGA-Cre-NPs)进行急性毒性试验与抗心律失常作用研究,探讨其增效减毒的效果。方法采用Bliss法对PELGE-Cre-NPs与PLGA-Cre-NPs进行小鼠急性毒性试验,求半数致死量(LD_(50));采用氯仿诱发小鼠心室纤颤模型、氯化钡(BaCl_(2))及乌头碱致心律失常大鼠模型对两种纳米粒进行药效作用考察。结果PLGA-Cre-NPs与PELGE-Cre-NPs静脉注射的LD_(50)分别为13.619 mg·kg^(-1)与14.839 mg·kg^(-1),均比克班宁静脉注射的LD_(50)(9.382 mg·kg^(-1))明显增加。与模型对照组比较,两种纳米粒均能明显对抗氯仿诱发的小鼠心室纤颤、对抗氯化钡诱导的大鼠心律失常,明显提高乌头碱诱发大鼠室性早搏(VPB)、室性心动过速(VT)、心室纤颤(VF)及心脏停搏(CA)的阈剂量(P<0.05,P<0.01,P<0.001)。与克班宁(5 mg·kg^(-1))实验组比较,PELGE-Cre-NPs高剂量(5 mg·kg^(-1))组恢复窦性心律维持时间≥5 min的鼠数量明显增多(P<0.05),心脏停搏乌头碱阈剂量明显提高(P<0.05)。结论两种材料纳米粒PLGA-Cre-NPs与PELGE-Cre-NPs的毒性较克班宁小,并具有较明显的抗心律失常活性,且作用效果强于游离克班宁,达到增效减毒作用。To compare the acute toxicity and antiarrhythmic effect of the two kinds of long-circulating Crebanine(Cre)nanoparticles(PELGE-Cre-NPs,PLGA-Cre-NPs)prepared from two PEG-modified carrier materials(PELGE,PLGA),and to explore their synergistic and attenuated effects.Methods The acute toxicity test of PLGA-Cre-NPs and PELGE-Cre-NPs in mice were conducted by using Bliss method,and LD_(50)values were calculated by using of statistical software.The effect of PLGA-Cre-NPs and PELGE-Cre-NPs on ventricular fibrillation caused by trichloromethane in mice,ventricular arrhythmia caused by BaCl_(2)in rats and arrhythmia caused by aconitine in rats was observed.Results The LD_(50)of PLGA-Cre-NPs and PELGE-Cre-NPs after intravenous injection were 13.619 mg·kg^(-1)and 14.839 mg·kg^(-1),respectively,which showed an obvious increase in LD_(50)compared to that of Cre(LD_(50),9.382 mg·kg^(-1)).Compared with the model control group,both nanoparticles significantly inhibited chloroform-induced ventricular fibrillation in mice and barium chloride-induced arrhythmia in rats,and significantly increased the threshold dose of aconitine induced ventricular premature beat(VPB),ventricular tachycardia(VT),ventricular fibrillation(VF)and cardiac arrest(CA)in rats(P<0.05,P<0.01,P<0.001).Compared with Cre(5 mg·kg^(-1))group,the number of mice with high-dose of PELGE-Cre-NPs(5 mg·kg^(-1))restored sinus rhythm for≥5 minutes was significantly increased(P<0.05).The threshold dose of aconitine in cardiac arrest was significantly increased(P<0.05).Conclusion The toxicity of PLGA-Cre-NPs and PELGE-Cre-NPs were lower than that of Cre,and they had significant antiarrhythmic activity.Moreover,nanoparticles displayed stronger effect than Cre,and they can reduce toxicity of Cre.

关 键 词：克班宁 长循环纳米粒 PELGE-Cre-NPs PLGA-Cre-NPs 急性毒性 抗心律失常作用 大鼠 小鼠 

分 类 号：R285.5[医药卫生—中药学]