基于临床药效剂量下的吴茱萸镇痛及伴随毒副作用研究

Study on analgesic and accompanying toxic and side effects of Euodiae Fructus based on clinical efficacy dose

目的:对吴茱萸水提组分发挥镇痛药效剂量下出现的伴随毒副作用及其机制进行观察与研究,为阐明其"功效-毒性"相关性提供实验依据。方法:小鼠按体重随机分为5组,即正常对照组、扶他林组、吴茱萸水提组分高、中、低剂量组,连续给药7 d,末次药后90 min采用小鼠腹腔注射醋酸致痛法及小鼠热板法疼痛模型,观察其在发挥药效作用时的伴随毒副作用;除观察小鼠毒性症状外,检测血清和肝脏组织谷丙转氨酶(ALT)、谷草转氨酶(AST)活性,以及血清尿素氮(BUN)、肌酐(Cr)含量,计算肝、肾脏器指数;另取一部分血清检测前列腺素E2(PGE2)水平、丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性、一氧化氮(NO)、一氧化氮合酶(NOS)、谷胱甘肽(GSH)和谷胱甘肽过氧化物酶(GSH-PX)的含量和活性。结果:连续多次给小鼠灌胃药效剂量下的吴茱萸水提组分,可显著减少小鼠扭体反应次数和明显提高小鼠热板痛阈值,且呈现良好的"量-效"关系;给药期间,小鼠出现腹泻、怠动、烦躁、体重增长缓慢等毒性症状;给药7 d后,血清和肝组织内ALT,AST活性均升高,肝体比值明显增大,血清BUN,Cr含量无明显变化,肾体比值只有高剂量组出现增大;血中PGE2,SOD,GSH,GSH-PX含量和活性明显下降,MDA,NO,NOS含量和活性明显升高。上述变化随剂量的增加而逐渐加重,与对照组比较有明显差异,呈现一定的量-毒关系。结论:连续给小鼠灌服一定剂量的吴茱萸水提组分,其在发挥镇痛药效的同时会对肝脏产生一定的毒副作用,并呈现一定的剂量依赖关系;其镇痛机制与降低血中PGE2含量有关,其毒性机制与氧化损伤有一定相关性。

Objective： To observe and study the toxic and side effects of water extracts from Euodiae Fructus accompanied with its efficacy analgesic dose and its mechanism, in order to provide experimental basis for the correlation between its ＂efficacy-toxicity＂. Method： Mice were randomly divided into 5 groups according to weight, namely the normal group, the voharen group, and Euodiae Fructus water extracts high, middle and low dose groups. Mice were administered with drugs for consecutively seven days, abdominally injected with acetic acid at 90 min and treated with hot plates after the last administration to establish the pain model, in order to the toxic and side effects accompanied with the efficacy. Besides toxic symptoms in mice, activities of ALT and AST, and content of BUN and Cr in serum were detected to calculate indexes in livers and kidneys. The other part of serum was collected to detect the content and activities of PGE2, MDA, SOD, NO, NOS, GSH and GSH-PX in serum. Result： Continuous oral administration of water extracts from Euodiae Fructus of efficacy dose could significantly decrease the frequency of writhe in mice and increase the hot plate pain thresh- old, with good dose-efficacy relationship. During the administration, mice showed such toxic symptoms as diarrhoea, idle move, dys- phoria and slow growth of weight. The activities of both ALT and AST in serum and hepatic tissues were remarkably increased and the liver size remarkably increased, without notable chance in content of BUN and CR in serum. Kidney size increased in only the high dose group. The content and activities of PGE2, SOD, GSH, GSH-PX in serum notably decreased, where the content and activities of MDA, NO, NOS in serum increased. The above-mentioned changes gradually aggravated with the rise in dose. There was significant difference compared with the model group, showing ＇dose-toxicity＇ relationship to certain extent. Conclusion： Continuous oral adminis- tration of certain dose of water extracts from Euodiae Fructus to mice can generate the toxic and side effects in liver accompanying with the analgesic effect, and show dose-dependence relationship to some extent. Its analgesic mechanism is related to the reduction of PGE2 content in blood, while its toxic mechanism is related to oxidative injury to some extent.