摘要
药物的量效关系即是在一定的剂量范围内,药物的效应强度随着给药剂量的增加而增加,当效应强度达到最大效能时,则剂量增大,效应不会进一步增大。方药剂量是关乎临床疗效的关键科学问题之一。在传统中医药理论体系中,对方药量-效关系只有散在的认识,科学内涵模糊,缺乏能够指导临床的系统科学的方药剂量理论。中医方药剂量理论的形成对指导临床用药,提高临床疗效意义重大均有重要意义。
本实验依据中医理论体系的整体观特点,以葛根芩连汤、麻杏石甘汤为研究对象,对相应的模型动物采用变换剂量的方法,分别研究葛根芩连汤、麻杏石甘汤整方不同剂量对相应的疾病模型：2型糖尿病、溃疡性结肠炎及咳、热、喘动物模型疗效的变化特征和趋势,为中药方剂量效关系规律的发现提供实验依据。
实验共分五个部分,分别研究葛根芩连汤及麻杏石甘汤对相应疾病模型疗效的量效特征。
1、葛根芩连汤整方对2型糖尿病模型大鼠疗效量效特征研究
目的：
研究葛根芩连汤整方剂量变化对2型糖尿病的大鼠体重、脏器指数、血糖浓度、胰岛素水平、胰岛素抵抗指数、糖化血红蛋白水平、糖化血清蛋白浓度、血清肌酐、血清尿素氮等生理生化指标的量效关系,阐述相应的量效关系数据。
方法：
通过建立较为符合临床2型糖尿病的大鼠模型,雄性SD大鼠(120～150g)适应性喂养后,除正常组大鼠进行正常饲料喂养外,其余各组给予高脂饲料喂养4周,达到如下肥胖标准者可用于造模：高脂饲料喂养的大鼠体重超过正常饲料喂养的大鼠体重的20%或者高脂饲料喂养大鼠的体质量指数BMI(体重／体长2)与正常喂养大鼠有统计学差异。大鼠按30mg/kg尾静脉注射柠檬酸缓冲液新鲜配制的STZ(链脲佐菌素)诱导糖尿病大鼠模型,正常对照组注射同等剂量的柠檬酸盐缓冲液。大鼠自由饮水进食,给药72小时后和一周后测定大鼠尾尖空腹血糖值,两次血糖均大于11.1mmol/L为2型糖尿病大鼠造模成功。实验分组：正常对照组、2型糖尿病模型对照组、阳性药物对照组(二甲双胍200mg/kg)、葛根芩连汤整方剂量变化的9个剂量给药组(分别为1.65、4.95、8.25、11.55、14.85、18.15、21.45、24.75、28.05g饮片/kg),每组15只。观察的主要药效指标：体重、脏器指数(肝脏、肾脏、脾脏)、血糖、胰岛素水平、糖化血红蛋白水平、糖化血清蛋白浓度、血肌酐、尿素氮等。
结果：
给药10周后,葛根芩连汤整方剂量变化对于2型糖尿病大鼠血清中的血糖、胰岛素水平、糖化血清蛋白浓度、糖化血红蛋白水平、血肌酐、尿素氮等指标存在着一定的量效关系,依据血糖水平计算其对糖尿病模型大鼠降糖作用的量效参数分别为剂量范围：[D]0.8-[D]0.2=27.01-1.09g/kg；[D]0.8/[D]0.2=7；中位剂量：[D]0.5=3.81g/kg OR24.30g/kg；剂量阈：[D]0.2=1.09g/kg；在一定剂量范围内,随着葛根芩连汤整方剂量的增大,药效增强。
结论：
葛根芩连汤整方剂量变化对2型糖尿病大鼠的生理生化指标具有良好的量一效关系特征。
2、葛根芩连汤对溃疡性结肠炎模型大鼠疗效的量效关系研究
目的：通过对不同剂量的葛根芩连汤对溃疡性结肠炎模型动物治疗效果的实验研究,探讨其量效关系,为临床用药提供科学依据。
方法：随机抽取10只大鼠为空白组,以5%TNBS原液(100mg/kg)与50%乙醇造溃疡性结肠炎大鼠模型,确定造模成功后,以MPO含量、隐血及体重为依据,筛选出110只溃疡性结肠炎模型大鼠。将造模成功大鼠按体重随机分为模型组,阳性药物组及剂量1-剂量9组,每组10只。第三天开始给药,阳性药每天按照0.5g/kg剂量灌胃,剂量1-剂量9组按实验设计剂量,1次/天,给药5天。检测大鼠MPO,MDA及DAI指数等指标。
结果：DAI指数、MDA、MPO、NO、SOD经SPSS和GraphPad软件拟合结果分析,SPSS拟合后,曲线方程R2由大到小排序为：MPO(0.89)>SOD(0.887)>DAI指数(0.502)> MDA (0.413)> NO (0.378);经GraphPad拟合后,R2由大到小排序为：MPO (0.8218)> SOD(0.377)> DAI指数(0.119)>MDA(0.0726)> NO(0.0349)。
结论：MPO指标所得的结果比较好,与模型相似度较高,以MPO为指标求得葛根芩连汤质量溃疡性结肠炎模型大鼠的剂量阈参数为：有效剂量范围：[D]20～[D]80=(15.39～17.11)g/kg,中位剂量：[D]50=16.25g/kg,阈剂量：[D]20=15.39g／kg。
3、麻杏石甘汤整方对发热模型大鼠治疗作用的量效关系研究
目的：
通过对不同剂量的麻杏石甘汤解热功效的实验研究,探讨其量效关系,为临床用药提供科学依据。
方法：
采用尾静脉注射内毒素脂多糖(LPS)造模,灌胃给药9个剂量麻杏石甘汤,分别设为正常对照组、模型对照组、麻杏石甘汤剂量1-剂量9组,造模后每0.5h记录一次体温,统计结果并计算出TRI6.0值；在6.0h时将大鼠处死心脏取血采用ELISA法测血浆PGE2含量；
以代谢组学方法研究麻杏石甘汤实验剂量对大鼠内源性物质整体状态的影响,通过内源性物质状态分析麻杏石甘汤的解热作用的量效关系及其量效参数。
结果：
与模型组相比,剂量1-9组发热程度明显降低(P<0.05或P<0.01)；体温反应指数(TRI)除剂量3与剂量6外,均明显下降(P<0.05或P<0.01)；剂量1、2、4、5组血浆PGE2含量与模型组相比显著降低(P<0.05或P<0.01),且与空白对照组相比无统计学差异(P>0.05)。
相应临床用低、中、高剂量对LPS致大鼠发热模型具有较好的解热作用。低剂量对发热温度的降温作用优于中剂量与高剂量,但相应三个剂量间无统计学差异；而TRI6.0值随剂量增大而增大,解热效应降低；中剂量的血浆PGE2含量低于低剂量与高剂量。
代谢组学结果显示麻杏石甘汤对发热大鼠内源性物质状态整体影响具有明显的量效特征,量效剂量范围：[D]0.8-[D]0.2=4.0935g/kg～4.1543g/kg；[D]0.8/[D]0.2=1.015；中位剂量：[D]0.5=4.124g/kg；剂量阈：[D]0.2=4.0935g/kg。
结论：
麻杏石甘汤对内毒素致大鼠发热模型有良好的解热效应,通过减少机体PGE2合成可能不是其解热的主要作用途径。临床相应剂量麻杏石甘汤对大鼠内毒素致热模型具有较好的解热作用,但其量效关系的相关性仅为临床用药提供参考。代谢组学的研究结果显示基于整体效应的研究方法可能是麻杏石甘汤量效关系的有效方法。
4、麻杏石甘汤整方对咳嗽模型大鼠治疗作用的量效关系研究
目的：研究麻杏石甘汤整方对咳嗽模型大鼠治疗作用的量效特征,
方法：用超声雾化器喷入浓度为0.4mol/L的枸橼酸溶液,雾化速率为15L/min,雾化1min,观察并记录5min内豚鼠咳嗽次数,筛选选咳嗽次数多于10次的豚鼠为模型动物。模型豚鼠120只,按体重随机分组,分空白对照组、模型对照组、阳性对照组、麻杏石甘汤剂量1-剂量9组,共计12组,每组10只,雌雄各半。空白对照组灌胃给予等容量生理盐水(NS),阳性对照组灌胃给予等容量磷酸可待因(8.5mg/kg),剂量1-剂量9组按10ml/kg/只灌胃给与药麻杏石甘汤,连续给药15天。测咳当天天禁食不禁水12小时后,给药1小时后测量观测,记录10min内豚鼠的咳嗽次数,用秒表记录咳嗽潜伏期,生物信号采集系统同步记录咳嗽幅度的变化。同时用声音放大器放大并录制气咳嗽声音。然后心脏取血,支气管及其肺组织等,血液离心取其血清待测CAT、H202、MDA、SOD等生化指标。
结果：
临床低、中剂量的麻杏石甘汤均具有明显治疗咳嗽的效果,且从1.44g生药/kg体重到4.286g生药/kg间存在随剂量增加效应增强的趋势。高剂量区域无效且效应增强。
结论：麻杏石甘汤整方治疗咳嗽在一定范围内,具有量-效关系,呈多波折现象,一定范围内随剂量增加效应增加趋势。
5、麻杏石甘汤整方对哮喘模型大鼠治疗作用的量效关系研究
目的：
对不同剂量的麻杏石甘汤整方组和君药配比组平喘功效进行实验研究,探讨其相应的量效关系及可能的作用机制,为临床规范其合理用量提供客观科学的依据。
方法：
采用磷酸组胺和乙酰胆碱的等体积混合液进行喷雾造模,整方剂量组和君药配比剂量组均设为正常组、模型对照组、阳性对照组、麻杏石甘汤剂量1-剂量9共12个组。除正常组和模型对照组灌胃生理盐水外,9个剂量组灌胃给药麻杏石甘汤,末次给药后1小时测定豚鼠的引喘潜伏期和哮喘持续时间,统计结果并比较差异,做出量效关系图；麻杏石甘汤君药配比剂量组豚鼠测完指标后麻醉取血应用ELISA法测血清HIS、LTB4、IL-4、IFN-γ含量,SPSS进行统计分析,支气管和肺组织做病理切片检查；计算平静波和哮喘波的振幅变化率,判定哮喘标准.
结果：
豚鼠三种哮喘模型造模结果表明速发型哮喘模型和迟发型哮喘模型与正常对照组相比有极显著性差异(P<0.01),重复致敏迟发型哮喘模型组与正常对照组相比无统计学差异(P>0.05)。
以振幅变化率≥1000%的抽搐波首次出现的时间为标准判定哮喘潜伏期、振幅变化率≥100%的抽搐波末次出现的时间为标准判定哮喘持续时间。
代谢组学结果显示麻杏石甘汤对哮喘模型大鼠内源性物质状态整体影响具有明显的量效特征,量效剂量范围：[D]0.2～[D]0.8=1.3311g/kg～1.3415g/kg,其比值[D]0.8/[D]0.2=1.008；中位剂量：[D]0.5=1.336g/kg;剂量阈：[D]0.2=1.3311g/kg.
结论：
麻杏石甘汤对乙酰胆碱和磷酸组胺致豚鼠哮喘模型有良好的平喘作用。临床中剂量或小剂量可能为其最佳剂量,其相应的量效关系在一定程度上可为临床用药提供参考。代谢组学的研究结果显示基于整体效应的研究方法可能是麻杏石甘汤平喘量效关系的有效方法。
The definition of the dose-effect relationship of drug is the intensity changes of drug effect with the dose in certain dosage range, when the strength of effect reached the maximum, the dose increased but effect did not change. The formula dose is one of the key scientific issues and relates to clinical therapeutic effect. In the theoretical system of traditional Chinese medicine, the knowledge about the dose-effect relationship is sporadic and different to build system science theory of the clinical prescription dose. The theory of formula is important to guide clinical medication and improve the clinical level.
According to the TCM holistic theory, Gegen Qinlian decoction (GQD) and Maxing Shigan decoction (MSD) were used as the study models. The dose-effect relationship of GOD and MSD on related animal models was investigated on the disease models include type2diabetes, ulcerative colitis, fever, cough and asthma.
The experiment is divided into five parts. The corresponding dose-response characteristics of GQD and MSD were investigated in the models of different disease.
1> Study on the dose-effect relationship of Gengen Qinlian Decoction in type2diabetes rats
[Objective]
To investigate the effects of Gengen Qinlian Decoction (GQD) in type2diabetes rats, body weight, organ index, blood glucose levels, insulin levels, insulin resistance (IR) index, glycosylated hemoglobin(GHb) levels, glycosylated serum protein (GSP) concentration, serum creatinine, serum urea nitrogen and other indicators of impact were investigated to obtain relative dose-effect relationship.
[Methods]
The rat model of type2diabetes was built. After the male SD rats (120-150g) were adaptively feed, they were feed by high fat food for4weeks to obtain the rat model of type2diabetes whereas the normal control rats were normal feed. Body weight of the rats from high fat treatment is more than120%body weight of the rats from normal control or physique quantum BMI (body weight/length of body square) of rats have statistics difference normally comparing the normal group. The rats were injected with30mg/kg streptozotocin (STZ) citric acid buffer solution by tail intravenous injection to induce the rat model of diabetes, the normal control group were injected the same level dosage the citrate buffer solution. After rats were treated for72hours and one week, empty stomach blood sugar value of the rats tail point were determined, Both of blood sugars level are more than11.1mmol/L so that the model of type2diabetes rats were built successfully. Experimental groups were divided as normal control group, type2diabetes mellitus model control group, positive control group (metformin hydrochloride200mg/kg) and GQD dose group (9of the dose change of the whole party were1.65、4.95、8.25、11.55、14.85、18.15、21.45、24.75、28.05g Pieces/kg)(n=15). Efficacy indicators were observed such as weight, organ indices (liver, kidney, spleen), blood glucose, insulin levels, glycated hemoglobin levels, and glycosylated serum protein concentration, serum creatinine, blood urea nitrogen etc.
[Results]
After oral administration for10weeks, serum glucose, insulin levels, and glycosylated serum protein concentration, glycosylated hemoglobin level, serum creatinine, blood urea nitrogen of type2diabetic rat were changed by GQD in the dose-effect relationship, and other indicators were demonstrated for dose-effect relationship. Based on level of blood glucose, the dose-effect relationship parameters of GQD on diabetic model rats were as follows:dose range:[D]0.8～[D]0.2=27.01～1.09g/kg;[D]0.8/[D]0.2=7; median dose:[D]0.5=3.81g/kg; dose threshold:0.2=1.09g/kg. Certain dose range with GQD was demonstrated that dose increases, drug efficacy enhancement.
[Conclusion]
Fine dose-effect relationship was confirmed by GQD treatment of type2diabetes.
2、The study of dose-effect relationship of Gegenqinlian decoction for the treatment of ulcerative colitis rats
[Objective] To study the dose-effect relationship for the treatment of UC rats caused by dose change of Gegenqinlian decoction (GQD), and explore the dose parameters.
[Methods]10SD rats was selected as control group,110SD rats were used to make ulcerative colitis (UC) model by the mixed liquid of5%TNBS an ethanol, then divided into11groups randomly, the MPO, MDA, NO, SOD content in plasma were detected, the SPSS and GraphPad software were used to fit dose-response curve, evaluate the dose-effect relationship, and calculate dose parameters.
[Results] Take MPO content as the indicator, the fitting equation model similarity is high, and dose-response curves showed a reverse "S" shape, the calculated dose threshold parameters are as follows:[D]20～[D]80-(15.39～17.11)g/kg, median dose:[D]50=16.25g/kg, and the threshold dose:[D]20=15.39g/kg.
[Conclusion] The dose-response curves for the GQD treatment rendered reverse "S" shape, suggesting that the effective range of treatment is the medium dose, roughly in (15.39～17.11)g/kg.
3、Study on the Dose-effect Relationship of Maxing Shigan Decoction (MSD) on the Treatment of Fever
[Objective] To study the effect of Maxing Shigan decoction (MSD) with different dose on the treatment of the fever, and explore the dose-effect relationship to provide the scientific basis for the clinical application.
[Methods]:The SD rats were grouped into11groups randomly:normal group, modeling group, and MSD dose-1group to dose-9group, set the fever model by inject lippolysaccharide (LPS) through the tail vein of rats. The temperatures of rats a time every0.5hour were recorded, and TRI6.0was calculated. After6.0hours treatment, after modeling, the concentration of PGE2in the plasma of the rats was detected. Metabolomics was used to observe the effects of MSD by the overall state of endogenous substances
[Results]:The optimum LPS dose of fever model was20μg/kg. Compared with modeling group, dose-1group to dose-9group reduced temperature significantly (P <0.05,or P<0.01); the thermal response index (TRI) were dramatically decreased except dose-3group and dose-6group (P<0.05, or P<0.01); the level of PGE2in the plasma were lower than the modeling group(P<0.05, or P<0.01), and were not different from the control group (P>0.05).
Three clinical relevant doses have effect on treating the fever of modeling rats. Low-dose group (LDG) could were reduced the temperature more than middle-dose group (MDG) and high-dose group (HDG), but the difference between three dosages was not significant. The TRI6.0increased with the dosage, but the antipyretic effect was decreased; and the PGE2level in the plasma of MDG was lower than LDG and MDG.
From the results of metabonomics, there is an obvious dose-effect characteristic by the overall effect of endogenous substance state in fever model rats on the treatment of MSD. The dose-effect relationship parameters of MSD on fever model rats were as follows:dose range:[D]0.8-[D]0.2=4.0935g/kg-4.1543g/kg;[D]0.8/[D]0.2=1.015; median dose:[D]0.5=4.124g/kg; dose threshold:0.2=4.0935g/kg;
[Conclusion]:MSD have antipyretic effect on rats which are set by LPS, but the mechanism of MSD treatment may not mainly by decreasing the synthesis of PGE2. The clinical dosages also have antipyretic effect on the rat models, and the dose-effect relationship can provide a reference to the clinical application.
4, The dose-effect relationship investigation of Maxing Shigan Decoction (MSD) on cough model of rats
[Objective] To investigate the dose-effect relationship characteristics of MSD on the cough model of rats.
[Methods] The guinea pigs were chosen as trail animal and modeled to cough by the citric acid solution with0.4mol/L. the solution was atomizated by ultrasonic atomizer with atomization rate of15L/min for1min. After that, the cough frequency was recorded for5min, the guinea pig with cough frequency beyond10times was selected as a model animal. In this way,120guinea pigs were selected as model animal and were randomly divided into12groups, named respectively by model group, positive group and dose1to dose9group. What is more, control group was settled. As a result, there are a total of12groups,10guinea pigs in1group.
Control group were gavaged with NS, positive were gavaged with codeine phosphate (8.5mg/kg), dose1to dose9groups were gavaged with MSD for continuous administration for15days according to10ml/kg. After oral administration, cough frequency were recorded every10min in one hour, latent period with a stopwatch, variations of the amplitude of synchronous were recorded by biological signal acquisition system. At the same time, gas cough sound were with the sound amplifier, bronchial and lung tissue, blood centrifuged serum tested CAT, H2O2, MDA, SOD and other biochemical indexes.
[Results] MSD has an obvious therapeutic effect in the clinical low and medium dose. Moreover, result showed that the therapeutic effect increased from1.44g/kg to4.286g/kg but high dose is invalid.
[Conclusion] MSD has the effect on the treatment of cough. In a certain range, dose-effect curve is more twists and turns, the therapeutic effect increased with the gavaged dose.
5、Study of the Dose-effect Relationship of Maxing Shigan Decoction (MSD) on the treatment of Antiasthmatic
[Objective] To study the antiasthmatic efficacy of MSD which exists as different doses of the whole prescription and different ratio of monarch drug and investigate the dose-effect relationship, provide an objective scientific basis for its reasonable amount of Clinical Practice.
[Methods] Guinea pig experimental animal model was built by spraying volumetric mixture of histamine phosphate and acetylcholine. Both the whole prescription group and different drug ratio group are divided into12groups including the blank group, the model group, the positive control group and9MSD groups with different concentrations. Among every group, except the blank group and the model group lavaging physiological saline, we measure the asthma latency and asthma duration one hour after the last time lavaging with different concentrations of MSD. Results from relative groups were analyzed, and the chart of dose effect relationship was made. ELISA (enzyme linked immunosorbent assay) was applied for measuring the concentrations of HIS、LTB4、IL-4、IFN-y from the serum of anaesthetic guinea pigs, statistical analysis was performed by the software SPSS. The histopathologic examination of bronchial and lung tissue was performed. The amplitude change rate of asthma waves and calm waves were calculated and the criteria of asthma was set. Changes in tension of tracheal smooth muscle by the treatment with different concentrations of MSD were detected by isolated organ tester.
[Results] Compared with the blank group, rapid onset asthma model group and late onset asthma model, it appear extremely significant difference according to the result of the three guinea pig asthma models (P<0.01), the repeated sensitizing late-onset asthma model group has no significant difference with the blank group (P>0.05)
We took the time when the tic wave (changing rate≥1000%) appeared for the first time as standard so that to determining the incubation period of asthma and the time when the tic wave(changing rate≥100%) appeared for the last time as standard to assess the asthma duration.
The medium dose group (3.24g/kg) and the fourth ratio dose group had good anti-asthmatic effects on the asthmatic model of guinea pig, which had extremely significant difference between the model group (P<0.01),and no significant difference between the positive control group (P>0.05)
From the results of metabonomics, there is an obvious dose-effect characteristic by the overall effect of endogenous substance state in asthma model rats with the treatment of MSD. The parameter of dose-effect relationship of MSD on asthma model rats were as follows:dose range:[D]0.8-[D]0.2=1.3311g/kg～1.3415g/kg;[D]0.8/[D]0.2=1.008; median dose:[D]0.5=1.336g/kg; dose threshold [D]0.2=1.3311g/kg.
[Conclusion] MSD has positive effects on the asthmatic guinea pig models which are sensitized by histamine phosphate and acetylcholine. The medium dose or small dose may be the optimal dose for clinical treatment of asthma. The dose-effect relationship of MSD may be helpful to clinical medication.
引文
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