中药临床试验肝肾功能指标异常值的分析与评价

  本文关键词：中药临床试验肝肾功能指标异常值的分析与评价，由笔耕文化传播整理发布。

        目的：建立药物临床试验肝肾功能指标异常值不良反应数据库，通过对中药临床试验肝肾功能指标异常值的分析与评价，研究中药新药临床试验中指标异常意义的判定与解释存在的问题及肝肾功能异常与药物的相关性。方法：通过查询、收集2005-2010年辽宁省中医院国家药物临床试验机构保存的72项新药临床试验总结报告，收录报告中安全性评价内容中肝肾指标异常的试验病例，建立包含录入、查询等功能的药物临床试验不良反应数据库，对异常状态判定与进行回顾性研究与统计分析。结果：1.不良反应数据库收录临床试验项目的基本情况数据库中共收录新药临床试验项目涉及48个国家食品药品监督管理局药物临床试验机构，430个次临床试验参加单位，总病例24535例，异常肝肾功能病例有2051例。不良反应数据库收录的项目涉及9大系统72个项目，包含神经精神系统疾病、心血管系统疾病、内分泌系统疾病、妇科系统疾病、泌尿系统疾病、骨科疾病、呼吸系统疾病、五官系统疾病、风湿免疫系统疾病等，数据库收录项目的用药主要包括口服给药、注射给药及局部用药三大类，收录剂型最多的为胶囊剂、颗粒剂、片剂和注射液。2.临床试验肝肾功能异常值临床意义判定情况通过查询肝肾功能指标异常值数据库，临床试验疗前肝肾功能异常值中有141例临床判定为有意义，占疗前异常病例总数的26.9%，而383例临床判定为无意义，占疗前异常病例总数的73.1%，在疗后肝肾功能异常值中有349例临床判定为有意义，占疗后异常病例总数的22.9%，而1178例临床判定为无意义，占疗后异常病例总数的77.1%。在肝功能指标异常值数据库中，ALT异常数据总计1050例，治疗前ALT在40-60U/L、60-80U/L范围内判定为有临床意义的病例数为18例、17例，分别占ALT异常病例总数的1.7%、1.6%，治疗后ALT在40-60U/L、60-80U/L范围内判定为有临床意义的病例数为34例、25例，分别占ALT异常病例总数的3.2%、2.4%，ALT在40-60U/L、60-80U/L范围内判定为有临床意义的病例分别占ALT异常病例总数的4.9%和4.0%；治疗前ALT在40-60U/L、60-80U/L范围内判定为无临床意义的病例数为158例、57例，分别占ALT异常病例总数的15.0%、5.4%，治疗后ALT在40-60U/L、60-80U/L范围内判定为无临床意义的病例数为452例、133例，分别占ALT异常病例总数的43.0%、12.7%，ALT在40-60U/L、60-80U/L范围内判定为无临床意义的病例分别占ALT异常病例总数的58%和17.7%。在肝功能指标异常值数据库中，AST异常数据总计207例，治疗前AST在40-60U/L、60-80U/L范围内判定为有临床意义的病例数为4例、1例，分别占AST异常病例总数的1.9%、0.4%，治疗后AST在40-60U/L、60-80U/L范围内判定为有临床意义的病例数为16例、11例，分别占AST异常病例总数的7.7%、5.3%，AST在40-60U/L、60-80U/L范围内判定为有临床意义的病例分别占AST异常病例总数的9.6%和5.7%；治疗前AST在40-60U/L、60-80U/L范围内判定为无临床意义的病例数为30例、5例，分别占AST异常病例总数的14.5%、2.4%，治疗后AST在40-60U/L、60-80U/L范围内判定为无临床意义的病例数为106例、19例，分别占AST异常病例总数的51.2%、9.2%，AST在40-60U/L、60-80U/L范围内判定为无临床意义的病例分别占AST异常病例总数的65.7%和11.6%。在肾功能BUN异常值数据库中，BUN异常病例总计811例，治疗前BUN在6.4-10.5mmol/L、10.5-21mmol/L范围内判定为有临床意义的病例数为13例、5例，分别占BUN异常病例总数的1.6%、0.6%，治疗后BUN在6.4-10.5mmol/L范围内判定为有临床意义的病例数为21例、8例，分别占BUN异常病例总数的2.6%，0.9%，BUN在6.4-10.5mmol/L、10.5-21mmol/L范围内判定为有临床意义的病例分别占BUN异常病例总数的4.2%和1.5%；治疗前BUN在6.4-10.5mmol/L、10.5-21mmol/L范围内判定为无临床意义的病例数为66例、8例，分别占BUN异常病例总数的8.1%、1.0%，治疗后BUN在6.4-10.5mmol/L范围内判定为无临床意义的病例数为360例，分别占BUN异常病例总数的44.4%，BUN在6.4-10.5mmol/L、10.5-21mmol/L范围内判定为无临床意义的病例分别占BUN异常病例总数的52.5%和1.0%。在肾功能CR异常值数据库中，CR异常病例共计188例，治疗前CR在110-140umol/l、140-180umol/l范围内判定为有临床意义的病例数为13例、8例，分别占CR异常病例总数的6.9%、4.2%，治疗后CR在110-140umol/l、140-180umol/l范围内判定为有临床意义的病例数为25例、12例，分别占CR异常病例总数的13.3%、6.4%，而治疗前CR在110-140umol/l、140-180umol/l范围内判定为无临床意义的病例数分别为4例、13例，分别占CR异常病例总数的2.1%、6.9%，治疗后CR在110-140umol/l、140-180umol/l范围内判定为无临床意义的病例分别为4例、13例，分别占CR异常病例总数的2.1%、6.9%。（1）临床试验中疗前及疗后肝功能异常病例原因解释临床试验肝功能ALT异常有临床意义病例解释中，肝功能数值在40-60U/L范围内共计54例，异常原因判定为脂肪肝的为33例，合并用药者2例，饮酒或饮食1例，其他原因8例，未判定原因者5例，分别占该异常值范围病例的61.1%、3.7%、1.9%、14.8%、9.3%；肝功能数值在60-80U/L范围内共计46例，异常原因判定为脂肪肝或酗酒的为25例，其他原因3例，合并用药者1例，未判定原因者17例，分别占该异常值范围病例的54.3%、6.5%、2.2%、37.0%；肝功能数值在80-120U/L范围内共计42例，异常原因判定为脂肪肝的为10例，合并用药及饮酒者8例，其他原因7例，未判定原因者17例，分别占该异常值范围病例的23.8%、19.0%、16.7%、40.5%。临床试验肝功能ALT异常无临床意义病例解释中，肝功能数值在40-60U/L范围内共计611例，异常原因判定为脂肪肝等为151例，饮酒或饮食等14例，未判定原因者446例，分别占该异常值范围病例的24.7%、2.3%、73.0%；肝功能数值在60-80U/L范围内共计192例，异常原因判定为脂肪肝的为69例，饮酒或饮食等6例，未判定原因者117例，分别占该异常值范围病例的35.9%、3.1%、60.9%；肝功能数值在80-120U/L范围内共计32例，异常原因判定为脂肪肝或酒精肝为17例，饮酒者3例，未判定原因者13例，分别占该异常值范围病例的53.1%、9.3%、40.6%。临床试验肝功能AST异常有临床意义病例解释中，全部肝功能异常数值均进行了异常原因解释，临床试验疗后肝功能AST异常有临床意义病例解释中，肝功能数值在40-60U/L范围内共计16例，异常原因判定为脂肪肝的为6例，未判定原因者10例，分别占该异常值范围病例的37.5%、62.5%；肝功能数值在60-80U/L范围内共计11例，异常原因判定为脂肪肝的为6例，未判定原因者5例，分别占该异常值范围病例的54.5%、45.4%。临床试验肝功能AST异常无临床意义病例解释中，肝功能数值在40-60U/L范围内共计136例，异常原因判定为脂肪肝及饮酒为22例，未判定原因者114例，分别占该异常值范围病例的16.2%、83.8%；肝功能数值在60-80U/L范围内共计24例，其中8例进行了异常原因判定，其余16例未判定原因，分别占该异常值范围病例的33.3%、66.7%。（2）临床试验中疗前及疗后肾功能异常病例原因解释临床试验肾功能BUN异常有临床意义病例解释中，BUN数值在6.4-10.5mmol/L范围内共计34例，异常原因判定为痛风性肾病等为7例，未判定原因者25例，分别占该异常值范围病例的20.6%、73.5%；BUN数值在10.5-21mmol/L范围内共计13例，异常原因判定为痛风性肾病等为6例，未判定原因者7例，分别占该异常值范围病例的46.2%、53.8%。临床试验肾功能BUN异常无临床意义病例解释中，BUN数值在6.4-10.5mmol/L范围内共计378例，异常原因判定为饮食等为80例，未判定原因者298例，分别占该异常值范围病例的21.2%、78.8%；BUN数值在10.5-21mmol/L范围内共计8例，异常原因判定为糖尿病肾病等为1例，其余7例未判定原因。临床试验疗前肾功能CR异常有临床意义病例解释中，CR数值在70-110umol/l范围内共计7例，异常原因判定为痛风性肾病、慢性肾功能不全为2例，未判定原因者5例；CR数值在110-140umol/l范围内共计37例，异常原因判定为痛风性肾病等为19例，未判定原因者19例；CR数值在140-180umol/l范围内共计12例，异常原因判定为痛风性肾病等为3例，未判定原因者9例；CR数值在≥180umol/l范围内共计4例，有3例进行了异常原因解释。临床试验疗后肾功能CR异常无临床意义病例解释中，CR数值在70-110umol/l范围内共计54例，异常原因判定为糖尿病肾病等为8例，未判定原因者46例，分别占该异常值范围总病例的14.8%、85.2%；CR数值在110-140umol/l范围内共计15例，异常原因判定为痛风性肾病等为3例，未判定原因者12例，分别占该异常值范围总病例的20%、80%；CR数值在140-180umol/l范围内共计1例，，异常原因判定未判定。3.临床试验肝肾功能异常原因分析及与试验药物相关性判断通过对肝肾功能指标异常值数据库中的数据分析，引起肝肾功能异常最常见的原因依次为饮酒、脂肪肝、饮食，而使各临床试验中肝肾功指标结果影响最主要的原因依次为脂肪肝、其它疾病、饮酒、饮食及合用它药。在肝肾功能指标异常值数据库中，疗后肝肾功能异常值与药物关系判定为可能有关的为3例，可疑26例，占全部疗后异常病例的1.5%，其余异常病例均判断为与试验药物无关。结论：1、临床试验中研究人员对于安全性评价指标异常数值的评价存在疏漏，对新药临床试验药物安全性的警戒意识和专业知识欠缺。关于临床试验肝肾功指标异常值数据库中的数据，对于治疗前数据多数研究者能给予足够的重视，而对于药物治疗结束出组时的安全性评价指标异常值研究者对异常原因未进行充分的解释和评价，无法（难以）正确评价试验药物的用药安全性。2、临床试验中对安全性评价重视不够。对Ⅱ/Ⅲ期临床试验安全性的观察和总结重视不够,包括不良事件的描述不详细、临床意义判定得出的结论缺乏正确的分析,甚至是“不良事件与药物无关”的结论,影响了对新药安全性的全面评价和认识。3、研究者对于肝肾功能异常无临床意义的判定缺少可靠依据。存在肝肾功能异常无临床意义者解释原因的缺失比例要远大于肝肾功能异常有临床意义者，一是说明研究者对于这部分无临床意义数值的判定存在一定的困惑，缺少可靠的判定依据，另一方面可能是研究者对于肝功能异常无临床意义病例未给予足够的重视，忽视其在新药临床安全性评价中的重要作用，这些判定的差异性严重影响着临床试验质量的控制，影响了研究结果的可靠性，不能真实反映临床试验目的。

    Objective:To establish a database of clinical trials of drug liver and kidney functionindicators outliers adverse reactions, analysis and evaluation of the value ofChinese medicine clinical trials liver and kidney function abnormalities, studyChinese medicine clinical trials indicators unusual significance determinationand interpretation problems in liver renal dysfunction drug relevance.Methods：By querying and collecting72clinical trials of new drugs summary reportsof Liaoning Provincial Hospital of national clinical trial from2005to2010,included in the safety evaluation report content indicators of liver and kidneyabnormalities test cases to establish entry containing the query functions indrug clinical trial database of adverse reactions, undertakeing retrospectivestudies and statistical analysis of the abnormal state.Results:First the basic situation of the clinical trial program,in the adversereaction database.Database were included in clinical trials of new drugs project involves48countries of the Food and Drug Administration for clinical test,430clinicaltrial participants in total cases,24,535cases,2051cases of abnormal liverand kidney function. The adverse reactions Indexed project involves nine system 72projects, including neuropsychiatric diseases, diseases of thecardiovascular system, endocrine system diseases, gynecological diseases,urinary system diseases, orthopedic diseases, respiratory diseases, facialsystem diseases, rheumatological The system diseases Indexed medicationincluding oral administration, injection and topical application threecategories, RECORDING formulations Maximum capsules, granules, tablets andinjection.Second, the whole situation of clinical significance of dysfunction liverand kidney value in clinical trialsOutliers database by querying the indicators of liver and kidney function,liver and kidney function abnormal values in clinical trials before treatmentin141cases judged meaningful, accounting for26.9%of the total number ofabnormal cases before treatment, and383cases determined to be meaningless,accounting treatment73.1%of the total number of abnormal cases,349casesjudged to be meaningful, accounting for22.9%of the total number of abnormalcases after treatment in the treatment of liver and kidney function abnormalvalues, and1178cases of clinical judgment as meaningless, accounting for thetreatment of abnormal cases77.1%of the total.Abnormal liver function values database, ALT abnormal data a total of1050cases, treatment of ALT in40-60U/L,60-80U/L range judged to be clinicallysignificant number of cases to18cases,17cases, accounting for ALT abnormalcases the total number of1.7%,1.6%, ALT determined within the range of40-60U /L,60-80U/L after treatment for clinically significant number of cases,34cases,25cases, respectively, of the total number of cases of abnormal ALT3.2%,2.4%, ALT clinically significant cases accounted for4.9%and4.0%of the totalnumber of cases of abnormal ALT determined within the range of40-60U/L,60-80U/L; pretreatment ALT in40-60U/L60-80U/L range determination is notclinically significant number of cases to158cases,57cases, accounting for15.0%of the total number of cases of abnormal ALT,5.4%, after treatment ALT40-60U/L,60-80U/L, determine the number of cases of no clinical significanceof452cases,133cases, accounting for the the abnormal ALT total number ofcases of43.0%,12.7%, ALT within the range of40-60U/L,60-80U/L judgedas clinical The significance of the cases accounted for58%and17.7%of thetotal number of cases of abnormal ALT.Abnormal liver function values database, AST abnormal data a total of207cases, treatment the former AST in40-60U/L,60-80U/L range judged to beclinically significant number of cases in4cases,1case, respectively, of ASTabnormal cases the total number of1.9%,0.4%, AST within the range of40-60U/L,60-80U/L after treatment determine the clinical significance of the numberof cases to16cases,11cases, respectively, of the total number of cases ofabnormal AST7.7%,5.3%, AST clinically significant cases accounted for9.6%and5.7%of the total number of cases of abnormal AST is determined within therange of40-60U/L,60-80U/L; pre-treatment AST40-60U/L60-80U/L rangedetermination is not clinically significant number of cases,30cases,5cases, accounting for14.5%of the total number of cases of abnormal AST,2.4%, ASTafter treatment in the40-60U/L,60-80U/L within the judgment is not clinicallysignificant number of cases to106cases,19cases, respectively, of the totalnumber of cases of abnormal AST51.2%,9.2%, AST within the range of40-60U/L,60-80U/L judged as clinical The significance of the cases accounted for65.7%and11.6%of the total number of cases of abnormal AST.In renal BUN outliers database, BUN abnormal cases totaled811cases,6.4-10.5mmol/L,10.5-21mmol/L within the pre-treatment BUN judged to beclinically significant number of cases to13cases,5cases, respectively.accounted for1.6%of the total number of cases of abnormal BUN,0.6%, treatmentBUN6.4-10.5mmol/L range judged to be clinically significant number of cases,21cases,8cases, accounting for2.6%of the total number of cases of BUN abnormal,0.9%, BUN6.4-10.5mmol/L,10.5-21mmol/L range judged to be clinicallysignificant cases accounted for4.2%and1.5%of the total number of BUN abnormalcases; pre-treatment BUN6.4-10.5mmol/L,10.5-21mmol/L range judged to benot clinically significant number of cases,66cases,8cases, accounting for8.1%of the total number of BUN abnormal cases,1.0%, after treatment BUN judgedas6.4-10.5mmol/L within the clinical The significance of the number of casesto360cases, accounting for BUN of44.4%of the total number of cases of abnormalBUN6.4-10.5mmol/L,10.5-21mmol/L within the range determined to be noclinically significant cases accounted for52.5%of the total number of casesof BUN abnormal and1.0%, respectively. Renal CR outliers database CR abnormal cases amounted to188cases, thetreatment of former CR in the the110-140umol/l,140-180umol/l range judgedto be clinically significant number of cases to13cases,8cases, respectively,of CR abnormal cases the total number of6.9%,4.2%, after treatment CR in thethe110-140umol/l,140-180umol/l within the scope determined to be clinicallysignificant number of cases to25cases,12cases, respectively, of the totalnumber of cases of CR abnormal13.3%,6.4%, and treatment before the CR in the110-140umol/l,140-180umol/l range judged to be not clinically significantnumber of cases were4cases,13cases, accounting for2.1%of the total numberof cases of CR abnormal,6.9%, CR is determined within the range of110-140umol/l,140-180umol/l after treatment for cases of no clinical significance were4cases,13cases, accounting for2.1%of the CR exception of the total cases,6.9%.(1) explanations of abnormal liver function cases in clinical trials beforetreatment and after treatment.Clinical trials liver function abnormal ALT interpretation of clinicalsignificance cases, liver function values in the range of40-60U/L, total54cases, the reason for the exception determination of fatty liver in33cases,combination therapy in2cases, drinking or eating one cases,8cases of otherreasons, did not determine the cause of five cases, respectively accounting for61.1%of the cases of abnormal values range,3.7%,1.9%,14.8%,9.3%; liverfunction values in the range of60-80U/L total of46cases, the reason for the exception is determined as fatty liver or alcohol for25cases,3cases ofother reasons, combination therapy, not determine reasons in17cases,accounting for54.3%of the cases the exception value range,6.5%,2.2%,37.0%; liver function values in the range of80-120U/L, a total of42cases, thereason for the exception determination of fatty liver for10cases, concomitantmedications and drinker eight cases, seven cases of other reasons, did notdetermine the cause in17cases, accounting for the range of values of theexception cases23.8%,19.0%,16.7%,40.5%.Interpretation of clinical trials liver function abnormal ALT cases ofclinical significance, liver function values in the range of40-60U/L, a totalof611cases, the reason for the exception is determined that the fatty liverand other151cases, drinking or eating14cases, did not determine the cause446cases, accounting for24.7%of the cases of the outliers range,2.3%,73.0%;liver function values in the range of60-80U/L, a total of192cases, the reasonfor the exception determination of fatty liver was69cases, drinking or eating6cases, did not determine the reason for117cases, respectively accountingfor35.9%of the cases the outliers range,3.1%,60.9%; liver function valuesin the range of80-120U/L, a total of32cases, the reason for the exceptionis determined that fatty liver or alcohol liver in17cases, three cases of thedrinker, did not determine the cause in13cases, accounting for53.1%of thecases of abnormal values range,9.3%,40.6%.Clinical trials liver function abnormal AST interpretation of clinical significance cases, abnormal liver function values are abnormal reasons toexplain the clinical trials after treatment cases the interpretation of theclinical significance of abnormal liver function AST, liver function valuesin40-60U/L range within a total of16cases, the reason for the exceptionjudged to fatty liver in6cases, did not determine the cause in10cases,accounting for37.5%of the cases of abnormal values range,62.5%; liver functionvalues in the range of60-80U/L11For example, the reason for the exceptiondetermination for fatty liver in6cases, not determined the reasons in5patients,respectively, accounted for54.5%of the cases of abnormal values range45.4%.A total of136cases, the reason for the exception judged to fatty liverand drinking22cases,114cases not determined by reason, interpretation ofclinical trials liver function abnormal AST case of no clinical significance,liver function values in the range of40-60U/L respectively of the totaloutliers range of cases16.2%,83.8%; liver function values in the range of60-80U/L total of24cases,8cases determine the reason for the exception, theremaining16patients did not determine the cause of the abnormal cases of therange of values33.3%,66.7%.(2) clinical trials before treatment and after treatment of renaldysfunction cases explanationsAbnormal clinical trials of renal BUN interpretation of cases of clinicalsignificance, BUN values in the6.4-10.5mmol/L within the total34cases, thereason for the exception determination gouty nephropathy7cases not determine the reason there were25cases respectively of the total outliers range of20.6%of the cases,73.5%; BUN value in the10.5-21mmol/L range, a total of13cases,the reason for the exception is determined to gouty nephropathy in6cases, didnot determine the cause in7cases, accounting for the outliers range46.2%ofthe cases,53.8%.Abnormal clinical trials of renal BUN no cases of clinical significanceinterpretation, BUN values in the6.4-10.5mmol/L within the scope of a totalof378cases, the reason for the exception is determined that diet and other80cases not determine the reason there were298cases, accounting for theoutliers cases in the range of21.2%,78.8%; the BUN value1.05-21mmol/L withinthe scope of a total of eight cases, the reason for the exception determinationdiabetic nephropathy in1case, the remaining seven patients did not determinethe cause.Clinical trials before treatment cases the interpretation of the clinicalsignificance of the CR value in the the70-110umol/l within the total of7cases, the reason for the exception determination gouty nephropathy, chronicrenal insufficiency in2cases, did not determine the cause abnormal renal CRcases; CR value in the the110-140umol/l within the total37cases, abnormaldetermine the reason for the gouty nephropathy in19cases, not determine thereason there were19cases; CR values the140-180umol/l within the scope ofa total of12cases, abnormal judged to gouty nephropathy as3cases, did notdetermine the cause in9cases; CR values of≥180umol/l within the scope of a total of4cases,3cases explain the cause of the exception.Clinical trials after treatment, abnormal renal function CR no clinicalsignificance in the case explained the CR value in the the70-110umol/l withinthe total54cases, the reason for the exception determination as diabeticnephropathy and other8cases, did not determine the cause in46casesrespectively of the total the total cases of abnormal values range14.8%,85.2%;CR value in the range of the110-140umol/l, a total of15cases, the reasonfor the exception is determined to gouty nephropathy in3cases, did not determinethe cause in12cases, accounting for the outliers range of20%of the cases,80%; CR value in the the140-180umol/l within the total cases, the reason forthe exception determination not determined.Third，clinical trials, liver and kidney dysfunction reason analysis andcorrelation with the test drug judgmentThe data in the database of liver and kidney function abnormalities value,causing liver and kidney dysfunction the most common causes were drinking, fattyliver, diet, leaving the indicators of liver and kidney function results inclinical trials of the main reason is as follows fatty liver, other diseases,alcohol consumption, diet and combination drug.In liver and kidney function indicators outliers database, liver and kidneydysfunction after treatment with the drug judged as may be relevant for the3cases, suspicious in26cases, accounting for1.5%of all after treatment ofabnormal cases, the rest of the abnormal cases were judged independent of the test drug.Conclusions:Firstly, clinical trials researchers are omissions in the evaluation of thesafety evaluation indicators of abnormal values, lack of awareness andexpertise of clinical trials of new drugs drug safety alertion. The data in thedatabase of clinical trials and kidney function indicators outliers, for thepre-treatment data most researchers can give adequate attention, but forsecurity evaluation for the end of the drug treatment researchers is not in fullinterpretation and evaluation can not be correctly evaluated for drug safetyof the test drug.Secondly, insufficient attention should be paid to the safety evaluationof clinical trials. safety observation and summary of clinical trials of PhaseII/III was given inadequate attention, including a description of the adverseevents detailed clinical significance determination concluded lack of properanalysis, even "adverse events has nothing to do with drugs," the conclusion,affecting a comprehensive evaluation of new drug safety and awareness.Thirdly, researchers lack of reliable basis for liver and kidney dysfunctionwithout clinical significance of determination. Explanation of loss ratio ofdysfunction of liver and kidney without clinical significance is much greaterthan the liver and kidney dysfunction which has clinical implications, on onehand the researcher has certain confusion for those parts which has no clinicalsignificance value judgement, on the other hand researchers might not give enough attention for the cases of abnormal liver function without clinical significance,neglecting its important role in new drug clinical safety evaluation, theseseriously affected the quality control of clinical trial, for the results can’treflect the real clinical trial purpose.

中药临床试验肝肾功能指标异常值的分析与评价

摘要4-9Abstract9-19前言20-22文献综述22-361. 资料与方法362. 结果与分析36-68分析讨论68-78结论78-79参考文献79-84致谢84-85个人简历85

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