去甲斑蝥素控释微球的肝动脉栓塞作用和急性毒性实验

Effect of Norcantharidin Controlled Release Microspheres on Embolization of Hepatic Artery and Experiment of Acute Toxicity

目的评价去甲斑蝥素-海藻酸/聚酸酐微球(NA/PMs)的肝动脉栓塞作用及其安全性。方法在DSA下对新西兰大白兔行肝动脉造影注入NA/PMs,观察NA/PMs对兔肝动脉栓塞作用;进行NA/PMs小鼠急性毒性试验和大鼠肝动脉介入实验,评价NA/PMs对两种动物的毒性作用。结果兔肝动脉栓塞前,肝脏血管造影清晰,栓塞后10 min造影,远端微血管消逝,肝动脉增粗、迂曲,3 d时可见肝脏轻微肿胀,7 d后肿胀明显减轻,14 d出现小片状梗死灶。急性毒性实验显示,NA/PMs组小鼠的死亡率和肾毒性明显低于去甲斑蝥素组(P<0.05),且无其它明显的脏器损害。大鼠肝动脉介入给药后,病理切片显示NA/PMs栓塞于肝窦前小动脉,且栓塞后出现一过性肝功能损害,AST,ALT均在栓塞后1 d达峰值,以后逐渐下降,7 d左右恢复正常水平(P>0.05)。栓塞后白细胞出现一过性升高,第3天达峰值,第7天接近正常水平(P>0.05)。结论去甲斑蝥素-海藻酸/聚酸酐微球具有良好的肝动脉末梢栓塞作用,且微球制剂能明显降低去甲斑蝥素的体内毒副作用。

Objective To evaluate the effect of Norcantharidin Alginate/PLGA Microspheres on embolization of hepatic artery and it＇s safety. Methods Under digital subtracted angiography（ DSA）, hepatic angiographies were performed in New Zealand white rabbits with injection of norcantharadin microspheres via hepatic artery, to observe the effect of NA/PMs on embolization of rabbit hepatic artery. Meanwhile, to perform acute toxicity experiment on mouse and intervention experiment on rat hepatic artery of NA/ PMs, then to evaluate it＇s safety on two animals. Results Before hepatic embolization, the angiographic images showed clear delineation of hepatic vessels. The disappearance of distal microvessels with thicker and twisted hepatic arteries occurred at 10 min after the emblization. Little swelling of liver after was appeared on 3rd day, lightened obviously on 7th day, and infarct focus in fragmentis was presented on 14th day. Acute toxicity experiment exhibited that mortality and nephrotoxicity of the NA/PMs group is lower than NCTD group obviously（ P 〈 0.05 ）, and havent conspicuous other organ damage. After interventional administration via hepatic artery to rat, the pathological analysis revealed that the microspheres were mainly present in presinusoidal arterioles after the embolization. The transient liver function damage occurred after embolization with both AST and ALT, reaching the peak levels on the 1 st day. which decreased gradually and then returned to normal on 7th day （P 〉 0.05）. Simultaneously, the transient elevation of white blood cells occurred, approaching the peak level on 3rd day and back to the normal on 7th day （P 〉 0.05）. Conclusion NA/PMs possesses a better embolitic action on the terminad hepatic arteries,and it＇s microsphere praeparatum could degrade internal toxicity.