不同剂量雷公藤对小鼠抗炎作用的效-毒关联评价

Assessment of efficacy-toxicity correlation based on the anti-inflammatory of different doses of Tripterygium wilfordii on mice

目的：研究不同剂量雷公藤水煎液对小鼠急性炎症的影响,明晰药效和毒副作用的剂量范围、毒副作用种类和程度,为雷公藤＂效-毒＂关联评价提供剂量范围依据。方法：给小鼠灌胃不同剂量雷公藤水煎液,连续3天,建立巴豆油混合致炎液致小鼠耳肿胀模型,观察药物的抗炎作用和产生的毒副作用,末次给药后,取血检测血中前列腺素E2（PGE2）、肿瘤坏死因子-α（TNF-α）、白介素-2（IL-2）等药效学指标和谷丙转氨酶（ALT）、谷草转氨酶（AST）、前白蛋白（PA）、总胆汁酸（TBA）、总胆红素（TBIL）等肝功能指标的变化,称取并计算心、肝、脾、肾等脏器和体重的比值,根据抗炎程度计算半数有效量（ED50）和产生毒副作用的剂量范围。结果：雷公藤水煎液对小鼠耳肿胀有良好的抑制作用,其ED50及95%可信限为0.37（0.17~0.49）g/kg。小鼠血中PGE2、TNF-α、IL-2含量降低,呈良好的量效关系。雷公藤水煎液可引起小鼠血中ALT、AST、TBA、TBIL活性升高,PA含量降低;体重增长缓慢,脏体比值增加;大剂量可致肝细胞水肿、浸润。结论：雷公藤水煎液有效抑制巴豆油混合致炎液致小鼠急性炎症的剂量范围为0.29~1.17 g/kg,其机制与减少炎性介质释放有关。在0.585~1.17 g/kg范围内雷公藤水煎液发挥抗炎作用同时,还产生一定的肝毒性,2.34~4.68 g/kg范围内引起肝脏实质性病变,因此,雷公藤＂功效-毒性＂依赖于剂量而密切相关,雷公藤毒性的认知和表征可为临床安全用药和毒副作用预防提供理论支撑。

Objective： The influence of efficacy and toxicity and side effects from different doses of Tripterygium wilfordii on acute inflammation by mixture of compound croton oil in mice was researched. The dose range, types and degree of efficacy and toxicity and side effects were cleared to provide dose range basis for the ＂dose- efficacy- toxicity＂ associated research. Methods： Mice were respectively given different doses of water decoction of Tripterygium Wilfordii for 3 consecutive days by gavage. The model of ear swelling by, mixture of compound croton oil was made. Then the effects of drugs on the ear swelling degree of inhibition and the toxicity and side effects of a performance were observed. The levels of PGE2, TNF-α, IL-2 related to pharmacodynamics and the activities of ALT, AST, PA, TBA, TBIL related to bepatotoxicity in serum were detected while the ratio of heart, liver, spleen and kidney to body was measured. The ED50 value and toxicity and side effects of dose range were calculated according to the degree of anti-inflammatory. Results： The inflammation of ear sweUing could be inhibited by multiple intragastric administration of water decoction of Tripterygium wilfordii. ED50 and its 95% confidence limits for 0.37 （0.17 - 0.49） g/ kg. The contents of PGE2, TNF-α, IL-2 in serum were decreased and showed a well ＂dose-effect＂ relationship. The activities of serum ALT, AST, TBA, TBIL and the ratio of liver to body increased while the content of PA decreased and the weight gained slowly. And the high dose could cause liver cell edema and infiltration. Conclusion： Acute inflammation caused by mixture of compound croton oil can be significantly inhibited by water extract in the dose range from 0.29 to 1.17 g/kg and it shows an obvious ＂dose- efficacy＂ relationship. The mechanism of anti-inflammatory effect is related to the decreasing of inflammatory medium release. While Side effects of different degree can be caused to liver after administration of the extract in the dose range from 0. 585 to 1.17 g/kg. Substantial lesion in the liver is caused in the dose range from 2.34 to 4.68 g/kg. Therefore the relationship of efficacy- toxicity is closely related to the dose of Tripterygium wilfordii. The clinical safe medication and the toxicity and side effects to be prevented will be provided with theoretical support by the cognition and characterization of the toxicity of Tripterygium wilfordii.