【作者】 熊玮；

【导师】 李虹；

【作者基本信息】 四川大学 ， 外科学， 2007， 博士

【副题名】随机对照临床试验Meta分析和实验研究的证据

【摘要】 目的输尿管结石是泌尿外科的常见疾病之一，其治疗方法较多，但药物排石一直受到关注。近年，α1肾上腺素受体阻滞剂用于输尿管结石排石治疗的数个临床研究报告发表，提示其有效性。本文拟研究α1肾上腺素受体阻滞剂治疗输尿管结石的效果，并探讨α1肾上腺素受体亚型在输尿管各段的分布及mRNA表达。方法系统检索PubMed、MEDLINE、EMBASE、BIOSIS、International Pharmaceutical Abstracts(IPA)、Cochrane图书馆、中国期刊全文数据库(1995年—2006年9月)电子数据库及重要学术会议论文集，收集坦索罗辛治疗输尿管结石的随机对照临床试验报告；由2名评价者共同评价纳入研究质量并提取资料，合并同质研究进行Meta分析，采用STATA9.0完成定量资料合并。收集外科手术切除标本的输尿管各段(上中下段和膀胱壁间段)，采用石蜡包埋、苏木素-伊红染色和免疫组织化学方法，结合图像分析方法，检测α1肾上腺素受体亚型(α1A-AR、α1B-AR、α1D-AR)在输尿管各段平滑肌的分布；并采用人α1肾上腺素受体亚型的序列特异性引物和逆转录聚合酶链式反应检测α1肾上腺素受体亚型在输尿管各段的mRNA表达差异，数据分析采用SPSS11.0完成。结果1、共纳入16个随机对照临床研究，1521例输尿管下段结石患者。(1)坦索罗辛组比仅使用饮水和镇痛药的保守疗法结石排出率高[RR1.50，95％CI(1.20，1.87)]，排石时间短[SMD-1.29，95％CI(-2.27，-0.31)]并可降低后期ESWL或输尿管镜治疗率[RR0.40，95％CI(0.27，0.59)]。(2)坦索罗辛／地夫可特联用组比保守疗法排石率高[RR1.59，95％CI(1.31，1.93)]，缩短排石时间[SMD-0.8，95％CI(-1.18，-0.421)]，明显减少后期ESWL或输尿管镜治疗率[RR0.13，95％CI(0.06，0.31)]。(3)坦索罗辛／地夫可特联用组比单用坦索罗辛在结石排出率方面仅有稍微优势[RR1.20，95％CI(1.07，1.35)，P=0.002]，但明显减少镇痛药剂量和后期输尿管镜治疗率[RR0.09，95％CI(0.02，0.47)，P=0.004]。(4)坦索罗辛／地夫可特联用组比硝苯地平／地夫可特联用组结石排出率高，而排石时间和后期ESWL或输尿管镜治疗率无差异。(5)以坦索罗辛为主的干预组和保守疗法在药物副作用方面没有差异。2、α1肾上腺素受体亚型特异性的单克隆抗体免疫组织化学方法证明α1肾上腺素受体亚型α1A-AR、α1B-AR、α1D-AR在输尿管上中下段和膀胱壁间段均有表达，且主要分布于纵行平滑肌束。3、输尿管各段α1-AR亚型mRNA上中段以α1A-AR和α1D-AR为主，而下段和膀胱壁间段则为以α1A-AR和α1B-AR为主。而相对丰度则是：输尿管膀胱壁段＞输尿管下段＞输尿管中段＞输尿管上段。4、对各段组织的M1、M2受体、NPYY1mRNA亦采用RT-PCR法进行检测，无阳性发现。结论1、目前的证据支持：坦索罗辛对输尿管下段和膀胱壁段结石具有较高的促排石率，缩短排石时间和降低后期侵入性治疗率。每日0.4毫克坦索罗辛对下段输尿管结石治疗安全有效。有限证据支持坦索罗辛同地夫可特联用有助于提高排石率，但需要大样本的研究结果予以支持。2、人体输尿管各段以纵行平滑肌束为主；α1肾上腺素受体亚型α1A-AR、α1B-AR、α1D-AR在输尿管上中下段和膀胱壁间段均有表达，且主要分布于纵行平滑肌束。3、α1肾上腺素受体亚型mRNA在输尿管各段均表达，而相对丰度：输尿管膀胱壁段＞输尿管下段＞输尿管中段＞输尿管上段。4、各段组织M1、M2受体mRNA未获得阳性结果，提示：α1-ARs可能是参与输尿管神经调节的主要神经递质受体。更多还原

【Abstract】 Objectives Although enthusiasm is growing for theα1adrenoreceptor antagonist tamsulosin treatment for ureteral calculi, there areconflicting data regarding their effectiveness and no agreement on theregimen of the tamsulosin based medical expulsive therapy. We assessed theefficacy of medical expulsive therapy for ureteral calculi with tamsulosin bymeta-analysis method, and explored the distribution and mRNA expressionof alphal adrenoreeeptor subtypes in different segments of human ureter.Methods The PubMed, MEDLINE, EMBASE, BIOSIS,International Pharmaceutical Abstracts(IPA) databases, Cochrane Libraryand Chinese Journal Full-text Database from 1995 to September of 2006and the urological scientific conferences from 2000 to 2006 were retrieved. The randomized controlled clinical trials which compared the effectivenessbetween tamsulosin and other therapies for ureteral calculi among adultswere included. Data was extracted by two reviewers independently andsynthesized by STATA9.0 version.Harvesting the healthy ureteral segments including proximal/media/distaland ureterovesical segments from the surgical samples following operation.And measure the thickness of longitudinal coursing muscle of ureteralsegments in HE dying and the alphal adrenoreceptor subtypes expressionwas examined in different ureteral segments by immunocytochemistry. Thealphal adrenoreceptor subtypes mRNA expression in different ureteralsegments was examined using different gene specific primers as primers forsemi-quantitative reverse transcription-polymerase chain reaction.Results 16 studies involving 1521 patients with distal orjuxtavesical ureteral calculi were identified. Compared to conservativetherapy receiving oral hydration(2 liters daily)and analgesics giving ondemand, tamsulosin and combination therapy of tamsulosin plus deflazacortshowed higher expulsion rate with pooled relative ratio of 1.50(95％CI, 1.20to 1.87, P＜0.0001) and 1.59 (95％CI, 1.31 to 1.93, P＜0.00001), respectively,with reduction of expulsion time with standardized mean difference of-1.29(95％CI, -2.27 to -0.31, P＜0.00001) and -0.8(95％CI, -1.18 to -0.42,P＜0.00001), and later ESWL or ureteroscopy with pooled relative ratio of0.40(95％CI, 0.27 to 0.59, P＜0.0001) and 0.13 (95％CI, 0.06 to 0.31,P＜0.00001), Compared to nifedipine plus deflazacort, the tamsulosin plus deflazacort therapy had a higher expulsion rate with pooled relative ratio of1.20 (95％CI, 1.07 to 1.35, P=0.002). There was no statistical difference inexpulsion rate between tamsulosin plus deflazacort therapy and tamsulosinmonotherapy, but the combination therapy had a lower rate of later ESWLor ureteroscopy with pooled relative ratio 0.09 (95％CI, 0.02 to 0.47,P=-0.004). But the included studies had variable quality and there was a mildrisk of publication bias.The mierostructure of human ureter from proximal segment to juxtavesicalsegments shows the muscle bundles are so arranged that morphologicallydistinct longitudinal and circular layers cannot be clearly distinguished. Andour immunocytochemistry shows that theα1 adrenoreceptor subtypesα1A-AR,α1B-AR,α1D-AR mainly locate at the longitudinal musclebundles and the relative expression density ofα1 adrenoreceptors arejuxtavesical segment＞distal segment＞media segment＞proximal segmentby usingα1 adrenoreceptor subtypes specific monoclonal antibodies.Theα1 adrenoreceptor mRNA ofα1A-AR andα1D-AR subtypes dominatein every segments and the density ofα1 adrenoreceptors mRNA arejuxtavesical segment＞distal segment＞media segment＞proximal segment.The mRNA of muscarinicacetylcholine receptor 1 and 2, neuropeptide Yreceptors was measured by RT-PCR but not detected.Conclusions The meta-analysis results demonstrates: tamsulosinhas a beneficial effect on expulsion of ureteral calculi, especially for distal and juxtavesical ureteral calculi. The tamsulosin based medical expulsivetherapy with 0.4mg daily is an effective and safe dose for patients withdistal ureteral calculi. The validity of different regimen, such as combinationof tamsulosin plus deflazacort requires larger studies.Our data suggests that the longitudinal muscle bundles dominate in humanureter. And theα1 adrenoreceptor subtypesα1A-AR,α1B-AR,α1D-ARmainly locate at the longitudinal muscle bundles of the ureter and therelative expression density ofα1 adrenoreceptors are juxtavesical segment＞distal segment＞media segment＞proximal segment.Theα1 adrenoreceptor mRNA ofα1A-AR andα1D-AR subtypes dominatein every segments and the density ofα1 adrenoreceptor mRNA arejuxtavesical segment＞distal segment＞media segment＞proximal segment.The mRNA of muscarinicacetyicholine receptor 1 and 2, neuropeptide Y receptorswas measured by RT-PCR but not detected and suggests theα1-ARs play acritical role in regulating the tension of the ureter.更多还原