利用中效原理评价虎杖苷与大黄素配伍对高尿酸血症模型大鼠的保护作用

Protective Effect of Polydatin Complicated with Emodin on Hyperuricemia Model Rats with Median Effect Principle

目的:研究虎杖苷与大黄素配伍对高尿酸血症(HUA)模型大鼠的保护作用,筛选两者最优配伍比例,并探讨其可能机制。方法:将SD大鼠随机分为正常对照组、模型组、苯溴马隆组(阳性对照,8 mg/kg)、虎杖苷单用组、大黄素单用组和两药合用A、B、C组,每组各剂量均设置5只大鼠。正常对照组和模型组大鼠均灌胃等体积0.3%羧甲基纤维素钠溶液,各给药组大鼠灌胃相应药物,灌胃体积均为0.1 m L/10 g,每日1次,连续7 d。除正常对照组外,其余各组大鼠均于末次给药1 h前单次腹腔注射氧嗪酸钾(300 mg/kg)以复制HUA模型。末次给药1 h后,检测正常对照组、模型组、苯溴马隆组以及虎杖苷单用组、大黄素单用组(剂量均分别为0.625、1.25、2.5、5、10 mg/kg)和合用A组[虎杖苷+大黄素剂量分别为(0.625+0.625)、(1.25+1.25)、(2.5+2.5)、(5+5)、(10+10)mg/kg]大鼠血清中尿酸的含量;利用中效原理计算上述单用组和合用组的效应(Fa)和联合指数(CI),绘制两成分单用及合用的量效关系曲线以及经模拟后的Fa-CI曲线,评价两药的合用效果。同法检测单用组和合用B、C组[虎杖苷+大黄素剂量分别为(0.625+0.625)、(0.625+1.25)、(0.625+2.5)、(0.625+5)、(0.625+10)mg/kg和(0.625+0.625)、(1.25+0.625)、(2.5+0.625)、(5+0.625)、(10+0.625)mg/kg]大鼠血清中尿酸的含量并计算Fa值,筛选两药的最佳配伍比例。检测正常对照组、模型组、苯溴马隆组以及虎杖苷、大黄素单用组(剂量均为10 mg/kg)和最佳配伍比例合用组大鼠血清中黄嘌呤氧化酶(XOD)的含量,初步分析其作用机制。结果:与正常对照组比较,模型组大鼠尿酸含量显著升高(P<0.01)。与模型组比较,除虎杖苷单用0.625 mg/kg组外,其余各给药组大鼠尿酸含量均显著降低(P<0.05或P<0.01)。两药单用及合用时,其Fa值均与药物剂量成正相关(截距>0,相关系数>0.9),且合用组的Fa值高于任一药物单用组;当模拟Fa值>15%时,其对应CI值<1,两药合用可表现出协同作用。当虎杖苷与大黄素的配伍比例为1∶4时,其Fa值(53.10)与合用A组(53.73)相当,且药物剂量更小[(0.625+2.5)mg/(kg·d)vs.(2.5+2.5)mg/(kg·d)]。与正常对照组比较,模型组大鼠血清XOD含量显著升高(P<0.01);与模型组比较,各给药组大鼠血清XOD含量均显著降低,且最佳比例配伍组显著低于虎杖苷、大黄素单用组(P<0.05或P<0.01)。结论:虎杖苷和大黄素单用或合用均可一定程度地通过抑制XOD的生成来降低HUA模型大鼠血清中尿酸的含量;两者具有一定的协同作用,其最佳配伍比例为1∶4。

OBJECTIVE:To study the protective effect of polydatin complicated with emodin on hyperuricemia(HUA)model rats,and to screen the optimal complication proportion and investigate the potential mechanism.METHODS:SD rats were randomly divided into normal control group,model group,benzbromarone group(positive control,8 mg/kg),polydatin alone group,emodin alone group and drug combination group A,B,C,with 5 rats in each group of each dosage.Normal control group and model group were given constant volume of 0.3%CMC-Na solution,administration groups were given relevant medicine intragastrically.Each group was given 0.1 m L/10 g intragastrically once a day,for consecutive 7 d.Expect for normal control group,other groups were given intraperitoneal injection of potassium oxonate 300 mg/kg 1 h before last medication to induce HUA model.One hour after last medication,the serum contents of uric acid(UA)were determined in normal control group,model group,benzbromarone group,polydatin/alone group(0.625,1.25,2.5,5,10 mg/kg)and drug combination group A[the dose of polydatin+emodin were(0.625+0.625),(1.25+1.25),(2.5+2.5),(5+5),(10+10)mg/kg].The effect(Fa)and combination index(CI)of above single drug groups and combination groups were calculated by the median effect principle.The dose-effect relationship curves of two components alone or combination were drawn;Fa-CI curves after simulation were also drawn to evaluate the effect of two-drug combination.Serum contents of UA in rats were determined and Fa value was calculated in single drug groups and drug combination group B,C[the dose of polydatin+emodin were(0.625+0.625),(0.625+1.25),(0.625+2.5),(0.625+5),(0.625+10)mg/kg and(0.625+0.625),(1.25+0.625),(2.5+0.625),(5+0.625),(10+0.625)mg/kg].The optimal complication proportion of two drugs were screened.The serum contents of xanthine oxidase(XOD)in rats were determined in normal control group,model group,benzbromarone group,polydatin/emodin alone group(10 mg/kg)and the optimal complication proportion groups.The mechanism was analyzed primarily.RESULTS:Compared with normal control group,the content of UA in model group was increased significantly(P<0.01).Compared with model group,except for 0.625 mg/kg polydatin alone group,the content of UA in other administration groups were decreased significantly(P<0.05 or P<0.01).When the two drugs were used alone or in combination,Fa value was positively correlated with drug dose(intercept>0,correlation coefficient>0.9),and Fa value of the combination group was higher than that of any single drug group;when the simulated Fa value was more than 15%,the corresponding CI value was less than 1,two-drug combination showed synergistic effect.When the complication proportion of polydatin and emodin was 1∶4,the Fa value(53.10)was similar to that of drug combination group A(53.73),and the dose of them were less[(0.625+2.5)mg/(kg·d)vs.(2.5+2.5)mg/(kg·d)].Compared with normal control group,serum content of XOD in model group was increased significantly(P<0.01);compared with model group,serum content of XOD in administration groups were decreased significantly,and the optimal complication proportion group was significantly lower than polydatin alone group and emodin alone group(P<0.05 or P<0.01).CONCLUSIONS:The polydatin and emodin used alone or in combination can reduce the serum content of UA in HUA model rats by inhibiting the generation of XOD.They have a certain synergistic effect,and the optimal complication proportion is 1∶4.