基于改善脑缺血效应的混合均匀设计法优化加味佛手散的处方研究

Study on Prescription Optimization of Jiawei Foshou San Based on Mixed Uniform Design to Improve Cerebral Ischemia Effect

目的筛选改善脑缺血的加味佛手散复方,确定处方组成和最佳剂量。方法运用数据挖掘方法筛选治疗高血压性脑出血(HICH)常用中药,进行聚类分析,获得加味佛手散复方;按混合均匀设计U_(14)(4^(2)×3^(3)×2^(2)),采用小鼠耳廓动脉扩张实验和饱和氯化镁致小鼠急性脑缺血实验分别观察小鼠耳廓动脉指数和存活时间,评价各组方改善脑缺血的药理效应,在药效学直观分析的基础上进行逐步多元回归分析,用回归方程计算加味佛手散处方组成及剂量,对优化的处方采用小鼠急性脑缺血实验验证。结果经数据挖掘筛选出治疗HICH的方剂共51首,包含103味中药,总频次535次;混合均匀设计U_(14)(4^(2)×3^(3)×2^(2))试验显示,加味佛手散各组方小鼠耳廓动脉指数均有不同程度增加,处方4、8、12、13组间差异显著(P<0.05),处方3、7、9、11、14组间差异极显著(P<0.01);处方2-14组小鼠急性脑缺血存活时间均有延长,与空白组相比差异有统计学意义(P<0.01),根据回归方程确定新加味佛手散处方为黄芪60 g、当归60 g、川芎24 g、赤芍15 g、地龙9 g;验证结果显示,新加味佛手散高、中剂量均能延长小鼠急性脑缺血的呼吸时间,增加呼吸次数,延长常压耐缺氧时间(P<0.01,P<0.05)。结论混合均匀设计结合脑缺血效应指标能确定加味佛手散的处方组成和最佳剂量,新加味佛手散具有改善脑缺血的作用。

Objective Screening of modified Foshou San to improve cerebral ischemia,determine the best prescription composition and the proper dose.Methods Using data mining method,the traditional Chinese medicine for hypertensive intracerebral hemorrhage(HICH)were screened,and cluster analysis was carried out to obtain Jiawei Foshou San combinations;According to the mixed uniform design U_(14)(4^(2)×3^(3)×2^(2)),the auricular artery dilatation experiment and acute cerebral ischemia induced by saturated magnesium chloride in mice were used to observe the auricular artery dilatation index and survival time of mice,and the pharmacological effects of each prescription to improve cerebral ischemia were evaluated.On the basis of visual analysis of pharmacodynamics,stepwise multiple regression analysis was carried out,and the regression equation was used to calculate the best prescription composition and dose of Jiawei Foshou San.The optimized prescription was verified by acute cerebral ischemia experiment in mice.Results A total of 51 prescriptions that may be used for the treatment of HICH were selected by data mining,including 103 Chinese herbs,with a total frequency of 535 times.The results of mixed uniform design U_(14)(4^(2)×3^(3)×2^(2))test showed that the auricular artery index of mice in each prescription group of Jiawei Foshou San increased to varying degrees.The differences between prescription 4,8,12 and 13 were significant(P<0.05),and the differences between prescription 3,7,9,11 and 14 were extremely significant(P<0.01).The survival time of acute cerebral ischemia in mice was prolonged to varying degrees in each group of Jiawei Foshou San,and the difference between prescription 2-14 groups and the blank group was statistically significant(P<0.01).The prescription of the new Jiawei Foshou San was determined as 60 g of Astragalus membranaceus,60 g of Angelica sinensis,24 g of Ligusticum chuanxiong,15 g of Paeonia lactiflora and 9 g of Dilong from the intuitive analysis.The validation results showed that the high and middle dosage of the new Jiawei Foshou San could significantly prolong the breathing time,increase the number of breaths,and prolong the time of normal pressure hypoxia tolerance in mice with acute cerebral ischemia(P<0.01,P<0.05).Conclusion Using mixed uniform design combined with improving cerebral ischemia effect index can determine the best prescription composition and the best dose of Jiawei Foshou San,and the effect of improving cerebral ischemia is certain.