艾叶不同组分对小鼠镇痛及伴随毒副作用研究

Study on the Toxicity and Side-effects Accompanied with Analgesic Effect of Different Components from Folium Artemisiae Argyi in Mice

目的明确艾叶发挥镇痛作用的物质基础、有效剂量范围、时间范围及产生伴随毒副作用的剂量和时间点,锁定毒性靶器官,为临床安全用药提供实验数据。方法采用热板法、扭体法,考察艾叶挥发油、水提组分高、中、低剂量组小鼠在1、3、7天的镇痛作用。通过一般症状观察、肝/体比值、肾/体比值分析、血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、尿素氮(BUN)、肌酐(Cr)水平检测来考察其伴随的毒副作用。结果艾叶挥发油、水提组分不同剂量组在给药后1、3、7天,均可提高小鼠热板痛阈,延长扭体潜伏期,减少扭体次数,其镇痛效果呈现一定的时间和剂量依赖关系,与空白对照组比较呈现不同程度的显著性差异,且水提组分镇痛效果优于挥发油。血生化指标检测显示,艾叶水提组分和挥发油各剂量组对小鼠血ALT、AST、Cr、BUN水平和肝体比值、肾体比值均有不同程度地升高作用,其升高程度呈现一定的时间和剂量依赖关系,与空白对照组比较呈现不同程度的显著性差异,且挥发油毒副作用强于水提组分。结论艾叶挥发油、水提组分在给药1、3、7天中均有较好的镇痛作用,其镇痛有效剂量范围分别为(34.5 g.kg-1-138 g.kg-1)、(1.17 g.kg-1-4.68 g.kg-1),且呈现一定的依赖剂量和时间的量效和时效变化,按折合生药量计算,镇痛作用强度上水提组分强于挥发油;其伴随毒副作用表现主要为肝功、肾功和脏体比值,其中以肝脏的毒副作用为甚,挥发油、水提组分产生肝脏毒副作用的剂量范围分别为(34.5 g.kg-1-138 g.kg-1)、(2.34 g.kg-1-4.68 g.kg-1),且呈现一定的依赖剂量和时间的量毒和时毒变化;肾脏毒副作用的剂量范围分别为(69.0 g.kg-1-138g.kg-1)、(2.34 g.kg-1-4.68 g.kg-1)且呈现一定的依赖剂量和时间的量毒和时毒变化;目前药典推荐人日用量3-9g,按相当于人日用量9g时的动物折算剂量在给药7天就出现了肝脏、肾脏毒副作用,更应引起临床应用的注意。

Objective To determine the material basis of the volatile oil and water extracts from Folium Artemisia Argyi, the effective dose range and time range as well as the dose range and the time window occurred with side effects, to lock the target organ of toxicity, in order to provide the experimental data for clinical safety. Methods Analgesic effect of the volatile oil and water extracts from Folium Artem/sia Argy/ were investigated by hot plate test and acetic acid writhing test in mice. The symptoms of mice were observed, the ratios of liver and kidney were calculated, and the levels of ALT, AST, BUN and Cr in blood were detected, for the purpose of inspecting the side effects of the volatile oil and water extracts. Results There were significant differences in the value of hot-plate pain threshold and frequency of the writhing test of each dose group after 1,3 、7 days administration to mice, and there were certain time and dosage dependence relationships, and the analgesic effect of water extracts components was stronger than volatile oil. The indexes detection in serum showed that different dosage group had different increase in the level of ALT,AST,Cr BUN and the ratio of liver and kidney, and there were certain time and dosage dependence relationships, and the toxicity of volatile oil was stronger than water extracts components. Conclusion The volatile oil and water extracts from Folitwn Artemisia Argyi showed certain effect of analgesia, the effective range of analgesia were respectively（34.5 g·kg-l-138 g·kg-1） and （1.17 g·kg-14.68 g·kg-1）, and showed certain dose-effect and time-effect relationship, and calculated by equivalent amount of crude drug, the, analgesic effect of volatile oil was stronger than water extracts components. The side-effects accompanied with analgesic effect were liver function, renal function and viscera indexs, the hepatotoxical injury in particular. The dose ranges of the volatile oil and water extracts produced liver toxicity were （34.5 g·kg-1 138 g·kg-1） and （2.34 g·kg-14.68 g·kg-1）, it showed certain dose-dependent and time-dependent relationship; while the dose ranges of the volatile oil and water extraction component produced kidney toxicity were（69.0 g· kg-1-138 g·kg-1） and （2.34 g·kg-1-4.68 g· kg-1）. At present the Pharmacopoeia recommends that the amount of Folium Artemisia Argyi is 3-9g; as there has been hepatotoxicity and renaltoxicity when the animals were administrated for 7 days, which should be attended in clinical application.