厚朴三物配方颗粒促进腹腔镜胆囊切除术后肠功能恢复的适应证候和量效关系研究
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摘要
1.理论研究部分
在中药适应证候研究中,首先对中医证候内涵进行了概述：证候具有诊断学指标特点,证候属综合性指标,证候动态变化。适应证侯指标包括中药的效应指标与证侯的属性指标,设计目的为临床对症用药,并对适应证侯评价进行了研究。关于中药剂量概念,众说纷纭,在中药量效关系研究中,量其实质应该理解成药物应用于机体产生的特定效应的量,即实际利用量。中药剂量选择的依据为药性、病情、患者体质。临床应用中中药剂量存在的问题有药量不精确、药量和药物的实际利用量界限不清。同时,中药临床疗效的特点有：临床疗效的多重性、双向调节的临床作用、临床疗效起效缓慢。剂量对中药临床疗效起关键作用。中药剂量对临床疗效的影响可分为4种情况：(1)中药剂量增加,但临床疗效并不相应的增强,和剂量的增减无相关性。(2)在一定范围内,中药临床疗效随着剂量的增加而增加,呈正相关。(3)超出一定的剂量范围,临床疗效随着剂量的增加反而降低,甚至产生毒副作用。(4)中药剂量改变,临床疗效表现为全或无,或剂量改变,临床疗效完全不同,甚至产生相反的作用,发生质的变化,并举例说明。其他影响中药临床疗效的因素有：中药材质量、中药炮制方式、中药制剂类型、煎煮方法、给药途径、服药时间和服药频率,组方配伍等。其中,通过配伍,可起到扩大治疗范围、增强原有药效、减弱原有疗效、缓解药物毒性、增强药物毒性的作用。并对不同药味配伍、相同药味不同比例配伍对临床疗效的影响进行举例说明。证候对中药量效的影响包括：证候不同,达到相同疗效所需剂量不同；证候不同,相同剂量疗效差异。体质差异是影响中药量效关系的另一个重要因素。体质不同,相同病因治法不同；体质不同,对方药的反应性不同；体质不同,对方药的耐受性不同；体质不同,转归预后不同。最后通过研究历代文献资料对中药量效关系进行了源流追溯,并从基础研究、临床研究、方法学研究角度对现代中药量效关系研究的现状进行了概述。
根据已有的厚朴三物汤临床效应和临床研究资料以及中药量效关系影响因素分析,提出以下假说：假说1,腹胀、腹痛、便秘是厚朴三物配方颗粒的适应证候；假说2,厚朴三物配方颗粒具有量效关系；假说3,证候、体质属性影响厚朴三物配方颗粒的量效关系。
在本课题开展之前,对方案设计中目标适应人群、目标适应症、药物、效应指标、效应评价等方面进行了初步研究。
2.临床研究部分
研究目的
主要目的：探索厚朴三物配方颗粒促进腹腔镜胆囊切除术后肠功能恢复的适应证候
次要目的：评价厚朴三物配方颗粒对腹腔镜胆囊切除术后肠功能恢复作用的量效关系
研究设计类型：区组随机,非盲法,平行对照,优效性检验。
试验用药
低剂量组：相当于经方剂量的1／2,厚朴2g,制大黄1g,枳实0.5g
高剂量组：与经方剂量等量,厚朴4g,制大黄2g,枳实1g
对照组：空白对照
试验步骤
入组受试者随机分成3组,手术前进行辨证分型。药物治疗组于手术后6小时口服厚朴三物配方颗粒,观察3组受试者肠鸣音恢复时间,首次排气、排便时间,探索厚朴三物配方颗粒的适应证候,评价临床疗效和剂量的关系。
疗效指标：手术后患者首次肠鸣音恢复正常(>3次／min)的时间和手术后患者首次肛门排气、排便的时间
统计方法：描述性统计分析,定性指标以频数表、百分率或构成比描述；定量指标以均数,标准差,或中位数,下四分位数(Q1),上四分位数(Q3),最小值,最大值描述。三组对比分析,定性资料采用卡方检验,行×列精确概率法,CMHχ2检验,WLS协方差。定量资料符合正态分布用t检验,方差分析(组间进行方差齐性检验,以0.1作为检验水准,方差不齐时选用Satterthwaite方法进行校正的t检验),不符合正态分布用Wilcoxon秩和检验,Wilcoxon符号秩和检验；GLM协方差。假设检验统一使用双侧检验,给出检验统计量及其对应的P值,以P≤0.05、P≤0.01作为有统计学意义。
研究结果：三组基线特征比较结果为三组性别、年龄、身高、体重、体温、脉搏、呼吸、收缩压、舒张压的差别无统计学意义(P>0.05),基线均衡。三组入组前诊断指标资料研究前用药、有无合并症、体质分型、中医辨证分型、病程的差别无统计学意义(P>0.05)。西医诊断比较有统计学意义(P<0.05),但不会影响用药后临床疗效指标的评价。受试者在研究过程中均无合并用药、不良事件发生,三组无差别。三组手术及手术后有关资料比较表明,三组在手术(麻醉)时间、首次下床间隔时间、首次进食时间的差别无统计学意义(P>0.05)。在厚朴三物配方颗粒治疗腹腔镜胆囊切除术后肠功能恢复作用的适应证候分析中,口苦口臭、口干咽燥为适应证候,腹胀、嗳气为非适应证候。按体质分类,分析体质指标不同厚朴三物配方颗粒临床疗效的差异,结果表明,体质指标不同临床疗效指标肠鸣音恢复时间、首次排气时间、首次排便时间无明显差异(P>0.05)。在厚朴三物配方颗粒治疗腹腔镜胆囊切除术后肠功能恢复作用的量效关系分析中,临床量效线呈斜线,b(斜率)=-0.84,呈现统计学意义趋势,量效关系成立。
结论：(1)厚朴三物配方颗粒改善腹腔镜胆囊切除术后患者肠功能恢复的适应证候为中焦湿热证,证见口苦口臭、口干咽燥者。(2)厚朴三物配方颗粒促进腹腔镜胆囊切除术后肠功能恢复作用有量效关系。(3)本研究未能证明患者证候、体质因素影响厚朴三物配方颗粒的量效关系。
1. Part of theoretical research
In the study of adaptive symptoms, connotation of TCM syndromes is summarized:TCM syndromes has the characteristics of diagnostical and comprehensive index,ant it changes dynamically. Adaptive symptoms includes effect index and attribute index,and it was designed in order to guide the drug usage.The evaluation of daptive symptoms is also studied. Among the various concepts of Chinese Herbs dose,the true concept should be the actual available amount that used in the body when we study the dose-effect relationship. The dose is chosen according to the resistance of the drugs,the disease state and physique of patients..The Chinese Herbs dosage has many questions in clinical application such as the imprecision and confusion of dose and actual available amount. At the same time,in the paper, I also studies the clinical efficacy characteristics of Chinese Herbs which are multiplicity, bidirectional regulation and slow effect onset. It is the dose that influences the clinical efficacy critically. There are four situations of the influence:(1)the clinical efficacy dosen't enhance simultaneously with the dose increase of herbs.They have no correlation; (2)the clinical efficacy enhances with the dose increase of herbs in some range.They have positive correlation; (3)the clinical efficacy decreases and even side effect takes place with the increase dose of herbs when the dose exceeds some range.They have negative correlation; (4)the clinical efficacy shows wholly or nothing when the dose changes. Next, some samples are given.Other influencing factors are those the drug quality, the modes of processing, the types of preparation, decoction methods, administration route, the time and frequency of medicine taking,Compatibility etc.The Chinese Herbs can widen the therapeutic range, reinforce or weaken original efficacy, relieve or aggravate the drug toxicity by the compatibility. Examples were also given about the influence of the compatibility on the clinical efficacy. Syndrome of TCM can influence the dose-effect relationship of Chinese Herbs as the same. For example, the different dose is needed if the syndrome is different,although the disease is same,or the efficacy is different at the same dose if the syndrome is different.There are still other influencing factors such as the constitution.The different constitution,the different therapeutic method at the same etiology.The different constitution,the different reactivity and tolerability at the herbs. At the same time, the different constitution,the different prognosis. Then, origin on the dose-effect relationship of Chinese Herbs is traced back by studying ancient medical classics. Then, the general situation of Chinese Herbs and dose-effect relationship study are summarized through the classification of basic research,clinical research and methodological study.
In the following, three hypotheses are put forward according to the above study:Abdominal distension,abdominal pain and constipation are the adaptive symptoms of Houpusanwu Dispensing Granule; Houpusanwu Dispensing Granule has the dose-effect relationship with its clinical effect; the TCM syndrome and physical attributes may influend the dose-effect relationship.Before the dose-effect relationship study of the Chinese Herbs is carried out,something is studied preliminarily such as the choice of target adpted Population,the target indication,the drugs,the effect indicators,the efficacy evaluation.
2. Part of clinical research
Objective:
Main Objective:To explore the adaptive symptoms of Houpusanwu Dispensing Granule Promoting the Gastrointestinal Motility Recovery after Biliary Selective Operation
Secondary objective:To estimate the dose-effect relationship of Houpusanwu Dispensing Granule Promoting the Gastrointestinal Motility Recovery after Biliary Selective Operation.
Research method:
Research design type:randomized block, non-blind, parallel control, superiority test
Study drug:low dose group equivalent to 1/2 dosage of Classical Prescriptions as follows: Magnolia officinalis 2g, Rhubarblg, citrus aurantium0.5g; high dose group equivalent to the same dosage of Classical Prescriptions as follows:Magnolia officinalis 4g, Rhubarb 2g, citrus aurantium 1g; blank control
Test procedure:Subjects entering the group are divided into 3 groups randomly, and syndrome differentiation is established before the operation. Subjects of the treatment group take Houpusanwu Dispensing Granule orally 6 hours after the operation. Then I begin to explore the adaptive symptoms of Houpusanwu Dispensing Granule and observe the time of intestinal sound recovery,first exhaust and defecation,and estimate the relationship between the clinical efficacy and dosage.
Indexes for therapeutic effects:the time of intestinal sound recovery,first exhaust and defecation.
Statistical method:The data which reflect character is shown by frequency,percent or structure ratio.The data which reflect numerical value is shown by mean value,standard error or median.Comparison of three group:The data which reflect character is verified withχ2 test,R×C Fisher test,Wilcoxon test or CMHχ2 test.The data which reflect numerical value is verified with t test which accord with normal school,other wise we choose Wilcoxon test.All the suppose test we choose two-side test which offer all the Stat number and the P corresponded. There is statistical value if P≤0.05 or P≤0.01.
Result:
The difference of age,height,weight,temperature,pulse,respiratory,systolic blood pressure and diastolic blood pressure has no statistical value (P>0.05).The difference of diagnostic index data(like drugs that used before, the condition of the complication, classification of constitution and syndrome), and the difference of operation time(anaesthesia time),the interval time between the first bed-off, intake time and operation time have no statistical value (P>0.05). Diagnosis has the remarkably statistical value (P<0.05),which would not influence the evaluation of clinical efficacy. All the patients in these three groups have no combined medication and adverse events.
When analyzing the adaptive symptoms,Ⅰconclude that bitter taste and halitosis, dry mouth and dry throat are the adaptive symptoms, abdominal distension, preference for sighing and eructation are the inadaptative symptoms, which is held within the patients that are operated by biliary resection because of the acute and chronic cholecystitis, bile duct stone, gallbladder polyps.
When analyzing the difference of clinical effect with different constitution,the result is that the time of intestinal sound recovery,first exhaust and defecation have no statistical value (P>0.05)
When analyzing the dose-effect relationship of Houpusanwu Dispensing Granule, the clinical dose-effect line is oblique, b (slope)=-0.84, showing statistically significant trends in the establishment of dose-effect relationship.
Conclusion:
(1)The adaptative symptoms of Houpusanwu Dispensing Granule Promoting the Gastrointestinal Motility Recovery after Biliary Selective Operation is middle-jiao damp-heat which has the symptoms of bitter taste and halitosis, dry mouth and dry throa. (2) Houpusanwu Dispensing Granule has the dose-effect relationship.(3) The TCM syndrome and physical attributes may not influend the dose-effect relationship.
在中药适应证候研究中,首先对中医证候内涵进行了概述：证候具有诊断学指标特点,证候属综合性指标,证候动态变化。适应证侯指标包括中药的效应指标与证侯的属性指标,设计目的为临床对症用药,并对适应证侯评价进行了研究。关于中药剂量概念,众说纷纭,在中药量效关系研究中,量其实质应该理解成药物应用于机体产生的特定效应的量,即实际利用量。中药剂量选择的依据为药性、病情、患者体质。临床应用中中药剂量存在的问题有药量不精确、药量和药物的实际利用量界限不清。同时,中药临床疗效的特点有：临床疗效的多重性、双向调节的临床作用、临床疗效起效缓慢。剂量对中药临床疗效起关键作用。中药剂量对临床疗效的影响可分为4种情况：(1)中药剂量增加,但临床疗效并不相应的增强,和剂量的增减无相关性。(2)在一定范围内,中药临床疗效随着剂量的增加而增加,呈正相关。(3)超出一定的剂量范围,临床疗效随着剂量的增加反而降低,甚至产生毒副作用。(4)中药剂量改变,临床疗效表现为全或无,或剂量改变,临床疗效完全不同,甚至产生相反的作用,发生质的变化,并举例说明。其他影响中药临床疗效的因素有：中药材质量、中药炮制方式、中药制剂类型、煎煮方法、给药途径、服药时间和服药频率,组方配伍等。其中,通过配伍,可起到扩大治疗范围、增强原有药效、减弱原有疗效、缓解药物毒性、增强药物毒性的作用。并对不同药味配伍、相同药味不同比例配伍对临床疗效的影响进行举例说明。证候对中药量效的影响包括：证候不同,达到相同疗效所需剂量不同；证候不同,相同剂量疗效差异。体质差异是影响中药量效关系的另一个重要因素。体质不同,相同病因治法不同；体质不同,对方药的反应性不同；体质不同,对方药的耐受性不同；体质不同,转归预后不同。最后通过研究历代文献资料对中药量效关系进行了源流追溯,并从基础研究、临床研究、方法学研究角度对现代中药量效关系研究的现状进行了概述。
根据已有的厚朴三物汤临床效应和临床研究资料以及中药量效关系影响因素分析,提出以下假说：假说1,腹胀、腹痛、便秘是厚朴三物配方颗粒的适应证候；假说2,厚朴三物配方颗粒具有量效关系；假说3,证候、体质属性影响厚朴三物配方颗粒的量效关系。
在本课题开展之前,对方案设计中目标适应人群、目标适应症、药物、效应指标、效应评价等方面进行了初步研究。
2.临床研究部分
研究目的
主要目的：探索厚朴三物配方颗粒促进腹腔镜胆囊切除术后肠功能恢复的适应证候
次要目的：评价厚朴三物配方颗粒对腹腔镜胆囊切除术后肠功能恢复作用的量效关系
研究设计类型：区组随机,非盲法,平行对照,优效性检验。
试验用药
低剂量组：相当于经方剂量的1／2,厚朴2g,制大黄1g,枳实0.5g
高剂量组：与经方剂量等量,厚朴4g,制大黄2g,枳实1g
对照组：空白对照
试验步骤
入组受试者随机分成3组,手术前进行辨证分型。药物治疗组于手术后6小时口服厚朴三物配方颗粒,观察3组受试者肠鸣音恢复时间,首次排气、排便时间,探索厚朴三物配方颗粒的适应证候,评价临床疗效和剂量的关系。
疗效指标：手术后患者首次肠鸣音恢复正常(>3次／min)的时间和手术后患者首次肛门排气、排便的时间
统计方法：描述性统计分析,定性指标以频数表、百分率或构成比描述；定量指标以均数,标准差,或中位数,下四分位数(Q1),上四分位数(Q3),最小值,最大值描述。三组对比分析,定性资料采用卡方检验,行×列精确概率法,CMHχ2检验,WLS协方差。定量资料符合正态分布用t检验,方差分析(组间进行方差齐性检验,以0.1作为检验水准,方差不齐时选用Satterthwaite方法进行校正的t检验),不符合正态分布用Wilcoxon秩和检验,Wilcoxon符号秩和检验；GLM协方差。假设检验统一使用双侧检验,给出检验统计量及其对应的P值,以P≤0.05、P≤0.01作为有统计学意义。
研究结果：三组基线特征比较结果为三组性别、年龄、身高、体重、体温、脉搏、呼吸、收缩压、舒张压的差别无统计学意义(P>0.05),基线均衡。三组入组前诊断指标资料研究前用药、有无合并症、体质分型、中医辨证分型、病程的差别无统计学意义(P>0.05)。西医诊断比较有统计学意义(P<0.05),但不会影响用药后临床疗效指标的评价。受试者在研究过程中均无合并用药、不良事件发生,三组无差别。三组手术及手术后有关资料比较表明,三组在手术(麻醉)时间、首次下床间隔时间、首次进食时间的差别无统计学意义(P>0.05)。在厚朴三物配方颗粒治疗腹腔镜胆囊切除术后肠功能恢复作用的适应证候分析中,口苦口臭、口干咽燥为适应证候,腹胀、嗳气为非适应证候。按体质分类,分析体质指标不同厚朴三物配方颗粒临床疗效的差异,结果表明,体质指标不同临床疗效指标肠鸣音恢复时间、首次排气时间、首次排便时间无明显差异(P>0.05)。在厚朴三物配方颗粒治疗腹腔镜胆囊切除术后肠功能恢复作用的量效关系分析中,临床量效线呈斜线,b(斜率)=-0.84,呈现统计学意义趋势,量效关系成立。
结论：(1)厚朴三物配方颗粒改善腹腔镜胆囊切除术后患者肠功能恢复的适应证候为中焦湿热证,证见口苦口臭、口干咽燥者。(2)厚朴三物配方颗粒促进腹腔镜胆囊切除术后肠功能恢复作用有量效关系。(3)本研究未能证明患者证候、体质因素影响厚朴三物配方颗粒的量效关系。
1. Part of theoretical research
In the study of adaptive symptoms, connotation of TCM syndromes is summarized:TCM syndromes has the characteristics of diagnostical and comprehensive index,ant it changes dynamically. Adaptive symptoms includes effect index and attribute index,and it was designed in order to guide the drug usage.The evaluation of daptive symptoms is also studied. Among the various concepts of Chinese Herbs dose,the true concept should be the actual available amount that used in the body when we study the dose-effect relationship. The dose is chosen according to the resistance of the drugs,the disease state and physique of patients..The Chinese Herbs dosage has many questions in clinical application such as the imprecision and confusion of dose and actual available amount. At the same time,in the paper, I also studies the clinical efficacy characteristics of Chinese Herbs which are multiplicity, bidirectional regulation and slow effect onset. It is the dose that influences the clinical efficacy critically. There are four situations of the influence:(1)the clinical efficacy dosen't enhance simultaneously with the dose increase of herbs.They have no correlation; (2)the clinical efficacy enhances with the dose increase of herbs in some range.They have positive correlation; (3)the clinical efficacy decreases and even side effect takes place with the increase dose of herbs when the dose exceeds some range.They have negative correlation; (4)the clinical efficacy shows wholly or nothing when the dose changes. Next, some samples are given.Other influencing factors are those the drug quality, the modes of processing, the types of preparation, decoction methods, administration route, the time and frequency of medicine taking,Compatibility etc.The Chinese Herbs can widen the therapeutic range, reinforce or weaken original efficacy, relieve or aggravate the drug toxicity by the compatibility. Examples were also given about the influence of the compatibility on the clinical efficacy. Syndrome of TCM can influence the dose-effect relationship of Chinese Herbs as the same. For example, the different dose is needed if the syndrome is different,although the disease is same,or the efficacy is different at the same dose if the syndrome is different.There are still other influencing factors such as the constitution.The different constitution,the different therapeutic method at the same etiology.The different constitution,the different reactivity and tolerability at the herbs. At the same time, the different constitution,the different prognosis. Then, origin on the dose-effect relationship of Chinese Herbs is traced back by studying ancient medical classics. Then, the general situation of Chinese Herbs and dose-effect relationship study are summarized through the classification of basic research,clinical research and methodological study.
In the following, three hypotheses are put forward according to the above study:Abdominal distension,abdominal pain and constipation are the adaptive symptoms of Houpusanwu Dispensing Granule; Houpusanwu Dispensing Granule has the dose-effect relationship with its clinical effect; the TCM syndrome and physical attributes may influend the dose-effect relationship.Before the dose-effect relationship study of the Chinese Herbs is carried out,something is studied preliminarily such as the choice of target adpted Population,the target indication,the drugs,the effect indicators,the efficacy evaluation.
2. Part of clinical research
Objective:
Main Objective:To explore the adaptive symptoms of Houpusanwu Dispensing Granule Promoting the Gastrointestinal Motility Recovery after Biliary Selective Operation
Secondary objective:To estimate the dose-effect relationship of Houpusanwu Dispensing Granule Promoting the Gastrointestinal Motility Recovery after Biliary Selective Operation.
Research method:
Research design type:randomized block, non-blind, parallel control, superiority test
Study drug:low dose group equivalent to 1/2 dosage of Classical Prescriptions as follows: Magnolia officinalis 2g, Rhubarblg, citrus aurantium0.5g; high dose group equivalent to the same dosage of Classical Prescriptions as follows:Magnolia officinalis 4g, Rhubarb 2g, citrus aurantium 1g; blank control
Test procedure:Subjects entering the group are divided into 3 groups randomly, and syndrome differentiation is established before the operation. Subjects of the treatment group take Houpusanwu Dispensing Granule orally 6 hours after the operation. Then I begin to explore the adaptive symptoms of Houpusanwu Dispensing Granule and observe the time of intestinal sound recovery,first exhaust and defecation,and estimate the relationship between the clinical efficacy and dosage.
Indexes for therapeutic effects:the time of intestinal sound recovery,first exhaust and defecation.
Statistical method:The data which reflect character is shown by frequency,percent or structure ratio.The data which reflect numerical value is shown by mean value,standard error or median.Comparison of three group:The data which reflect character is verified withχ2 test,R×C Fisher test,Wilcoxon test or CMHχ2 test.The data which reflect numerical value is verified with t test which accord with normal school,other wise we choose Wilcoxon test.All the suppose test we choose two-side test which offer all the Stat number and the P corresponded. There is statistical value if P≤0.05 or P≤0.01.
Result:
The difference of age,height,weight,temperature,pulse,respiratory,systolic blood pressure and diastolic blood pressure has no statistical value (P>0.05).The difference of diagnostic index data(like drugs that used before, the condition of the complication, classification of constitution and syndrome), and the difference of operation time(anaesthesia time),the interval time between the first bed-off, intake time and operation time have no statistical value (P>0.05). Diagnosis has the remarkably statistical value (P<0.05),which would not influence the evaluation of clinical efficacy. All the patients in these three groups have no combined medication and adverse events.
When analyzing the adaptive symptoms,Ⅰconclude that bitter taste and halitosis, dry mouth and dry throat are the adaptive symptoms, abdominal distension, preference for sighing and eructation are the inadaptative symptoms, which is held within the patients that are operated by biliary resection because of the acute and chronic cholecystitis, bile duct stone, gallbladder polyps.
When analyzing the difference of clinical effect with different constitution,the result is that the time of intestinal sound recovery,first exhaust and defecation have no statistical value (P>0.05)
When analyzing the dose-effect relationship of Houpusanwu Dispensing Granule, the clinical dose-effect line is oblique, b (slope)=-0.84, showing statistically significant trends in the establishment of dose-effect relationship.
Conclusion:
(1)The adaptative symptoms of Houpusanwu Dispensing Granule Promoting the Gastrointestinal Motility Recovery after Biliary Selective Operation is middle-jiao damp-heat which has the symptoms of bitter taste and halitosis, dry mouth and dry throa. (2) Houpusanwu Dispensing Granule has the dose-effect relationship.(3) The TCM syndrome and physical attributes may not influend the dose-effect relationship.
引文
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