血药浓度监测回顾性分析硕士学位论文.doc

学位论文Shandong University Master,s Thesis硕 士 学 位 论 文论文20062009年血药浓度监测回顾性分析Retrospectively analysis of blood concentration monitoring of Qilu hospital of Shandong university between 2006 and 2009目 录中文摘要1英文摘要3符号说明6前言7第一部分 四种抗癫痫药物血药浓度监测结果回顾分析1 仪器与试剂92 方法92.1 采集血样92.2 测定方法92.3 血药浓度判断标准93 结果93.1 2006-2009年4种抗癫痫药物各年度血药浓度监测结果103.1.1 2006年4种抗癫痫药物血药浓度监测结果103.1.2 2007年4种抗癫痫药物血药浓度监测结果123.1.3 2008年4种抗癫痫药物血药浓度监测结果143.1.4 2009年4种抗癫痫药物血药浓度监测结果163.2 2006-2009年4种抗癫痫药物各年度汇总分析183.2.1 2006年4种抗癫痫药物监测汇总分析183.2.2 2007年4种抗癫痫药物监测汇总分析193.2.3 2008年4种抗癫痫药物监测汇总分析203.2.4 2009年4种抗癫痫药物监测汇总分析213.3 2006-2009年4种抗癫痫药物监测分析 223.3.1 2006-2009年丙戊酸钠血药浓度测定结果分析 223.3.2 2006-2009年卡马西平血药浓度测定结果分析 233.3.3 2006-2009年苯巴比妥血药浓度测定结果分析 243.3.4 2006-2009年苯妥英钠血药浓度测定结果分析 253.4 2006-2009年4种抗癫痫药物监测人次、年龄和性别汇总分析263.4.1 2006-2009年4种抗癫痫药物监测人次所占比例 263.4.2 2006-2009年4种抗癫痫药物应用患者年龄汇总分析 273.4.3 2006-2009年4种抗癫痫药物在有效浓度范围内男女所占比例汇总分析 283.4.4 2006-2009年4种抗癫痫药物低于浓度范围男女所占比例汇总分析 303.4.5 2006-2009年4种抗癫痫药物高于浓度范围男女所占比例汇总分析 313.5 2006-2009年4种抗癫痫药物测定次数分布情况 334讨论 34第二部分 环孢素血药浓度监测结果回顾分析1 仪器与试剂 362 方法 362.1采集血样 362.2测定方法 362.3血药浓度判断标准 363 结果363.1 20062009年各年度环孢素血药浓度监测分析 373.2 20062009年四年内环孢素血液浓度监测汇总分析 383.3 年龄与环孢素血药浓度监测汇总分析 403.4 不同性别与环孢素血药浓度监测汇总分析 413.5 环孢素监测次数汇总分析 434 讨论 44全文结论45参考文献48致 谢51攻读学位论文期间发表的学术论文52LISTChinese abstract1English abstract3Abbreviations6Introduction7The first part Retrospective analysis of blood concentration monitoring of 4 kind anti-epileptic drugs1 Instruments and reagents92 Methods92.1 Blood sampling92.2 Method for determination92.3 Judgment standard of blood drug concentration93 Results93.1 The results of blood concentration monitoring of 4 kind anti-epileptic drugs in each year from 2006 to 2009103.1.1 The results of blood concentration monitoring of 4 kind anti-epileptic drugs in 2006103.1.2 The results of blood concentration monitoring of 4 kind anti-epileptic drugs in 2007123.1.3 The results of blood concentration monitoring of 4 kind anti-epileptic drugs in 2008143.1.4 The results of blood concentration monitoring of 4 kind anti-epileptic drugs in 2009163.2 Summary analysis of 4 kind anti-epileptic drugs in each year from 2006 to 2009183.2.1 Summary analysis of 4 kind anti-epileptic drugs in 2006183.2.2 Summary analysis of 4 kind anti-epileptic drugs in 2007193.2.3 Summary analysis of 4 kind anti-epileptic drugs in 2008203.2.4 Summary analysis of 4 kind anti-epileptic drugs in 2009213.3 Analysis of blood concentration monitoring of 4 kind anti-epileptic drugs from 2006 to 2009223.3.1 Analysis of blood concentration monitoring of valproic acid sodium from 2006 to 2009223.3.2 Analysis of blood concentration monitoring of carbamazepine from 2006 to 2009233.3.3 Analysis of blood concentration monitoring of phenobarbital from 2006 to 2009243.3.4 Analysis of blood concentration monitoring of phenytoin sodium from 2006 to 2009253.4 Summary analysis of monitoring person-time, age and sex of 4 kind anti-epileptic drugs from 2006 to 2009263.4.1 The ratio of monitoring person-time of 4 kind anti-epileptic drugs from 2006 to 2009263.4.2 The summary analysis of age using 4 kind anti-epileptic drugs from 2006 to 2009273.4.3 The ratio of male and female in effective concentration range of 4 kind anti-epileptic drugs from 2006 to 2009283.4.4 The ratio of male and female lower than effective concentration range of 4 kind anti-epileptic drugs from 2006 to 2009303.4.5 The ratio of male and female more than effective concentration range of 4 kind anti-epileptic drugs from 2006 to 2009313.5 The distribution of determination frequency of 4 kind anti-epileptic drugs from 2006 to 2009334 Discussion34The second part Retrospective analysis of blood concentration monitoring of Cyclosporine1Instruments and reagents362 Methods362.1Blood sampling362.2 Method for determination362.3 Judgment standard of blood drug concentration363 Results363.1 Analysis of blood concentration monitoring of Cyclosporine in each year from 2006 to 2009373.2 Summary analysis of blood concentration monitoring of Cyclosporine in four years from 2006 to 2009383.3 Summary analysis of age and blood concentration monitoring of Cyclosporine403.4 Summary analysis of different sex and blood concentration monitoring of Cyclosporine413.5 Summary analysis of monitoring frequency of Cyclosporine434 Discussion44Conclusion45Reference48Acknowledgment51Articles published during postgraduate period525120062009年山东大学齐鲁医院血药浓度监测回顾性分析2006-2009 qilu hospital of shandong university blood drug concentration monitoring retrospectively中文摘要摘要：目的：回顾性分析2006-2009年所有血药浓度监测情况，以利指导用药。方法：采用回顾性调查分析方法，通过对山东大学齐鲁医院20062009年四种主要抗癫痫药血液浓度监测数据进行分类分析。在不同年龄、性别分别汇总低于有效治疗浓度、有效治疗浓度、高于治疗浓度数据。结果：4种抗癫痫药物中在监测人次上丙戊酸钠所占比例最大（43.41%），其次是卡马西平（32.27%）、苯妥英钠（14.00%）、苯巴比妥（10.33%）；4种抗癫痫药物在03岁和60岁以上监测人次最少，314岁监测人次（436人约占28.55%）最多；4种抗癫痫药物男性达有效治疗浓度（31.14%）的比例要远高于女性（12.17%），低于有效治疗浓度所占比例男性（29.52%）高于女性（16.43%），高于有效治疗浓度所占比例男性（6.33%）高于女性（4.87%）；4种抗癫痫药物监测1次比例最高（94.26%），监测2次比例（4.54%），监测3次以上所占比例极少；4种抗癫痫药物在有效治疗浓度比较：卡马西平最高（57.97%），其次是苯巴比妥（55.26%）、丙戊酸钠（42.11%），苯妥英钠最低（16.41%）。1525例四种抗癫痫药物血药浓度监测结果在有效治疗浓度所占比例为42.94%,低于有效治疗浓度所占比例为46.79%,高于有效治疗浓度所占比例为10.27%。将环孢素的具体监测结果分为6个区段进行比较，结果显示分布于<50g/L，350450g/L和>450g/L的结果仅占总例次的1.2%3.3%,6.6%9.7%和1.8%7.6%；大部分监测结果分布在50150g/L，150250g/L，250350g/L 3个区段，50450g/L有效浓度范围内的占91%，各年度监测结果差别意义不大；4346例环孢素监测人次中男性占3047次（70.18%），女性占1296次（29.82%），男性的有效治疗浓度内（正常值）所占比例（92.64%）略低于女性（94.21%），P>0.05没有差异。5种药物进行5833例次监测,达有效血药浓度的4670例次,占总数80.1%;未达有效血药浓度的1163例次,占总数19.9%;结论：在应用苯妥英钠、卡马西平、苯巴比妥、丙戊酸钠、环孢素时，应全面分析患者的剂量方案、用药史、重要的实验室数据，结合血药浓度监测结果和临床疗效随时调整剂量，真正做到个体化治疗。临床药师和医师应联合,充分利用TDM 技术,建立一个长期有效的治疗方案,最大限度保证患者用药安全、有效、经济。关键词:药物监测;血药浓度;回顾性分析2006-2009 QILU HOSPITAL OF SHANDONG UNIVERSITY BLOOD DRUG CONCENTRATION MONITORING RETROSPECTIVELYABSTRACTAbstract: Objective: The blood concentration monitoring from 2006 to 2009 was analysed retrospectively to direct the use of medicine. Methods: The data as name, age, sex and monitoring results were summarized by analysing the blood concentration monitoring data of main anti-epileptic drugs and cyclosporine which were collected by qilu hospital of shandong university from 2006 to 2009. The data which was lower than effective concentration, equal to effective concentration and more than effective concentration was summarized. Results: Among the monitoring person-time of the 4 kind anti-epileptic drugs, the largest percentage (43.41%) was valproic acid sodium followed by carbamazepine (32.27%), phenytoin sodium (14.00%) and phenobarbital (10.33%). The monitoring person-time of 4 kind anti-epileptic drugs in the age of 03 and 60 years old was lowest, which was most in the age of 314 (436 person). The ratio of male who reached effective concentration of 4 kind anti-epilietic drugs was 31.14%, more than the ratio of female which was 12.17%. The ratio of male whose blood concentration was lower than effective concentration was 29.52%, more than the ratio of female which was 16.43%. The ratio of male whose blood concentration more than effective concentration was 6.33%, more than the ratio of female which was 4.87%. The ratio of monitoring one time was highest which was 94.26%, the ratio of monitoring two times was 4.54%, the ratio of monitoring three times was very low. The ratio of reaching effective concentration of 4 kind anti-epileptic drugs, carbamazepine was highest which was 57.97%, followed by phenobarbital (55.26%), valproic acid sodium (42.11%) and phenytoin sodium (16.41%). Among 1527 patients who were treated with 4 kind anti-epileptic drugs, the ratio of reaching effective concentration was 42.94%, the ratio of lower than effective concentration was 46.79%, and the ratio more than effective concentration was 10.27%. The monitoring results of cyclosporine were divided into 6 ranges.The ratio, which was in the range of lower than 50 g/L, 350450 g/L and more than 450 g/L, was 1.2%3.3%, 6.6%9.7% and 1.8%7.6%. Most monitoring results were in the range of 50150, 150250 and 250350 g/L. The ratio of the range 50450 g/L was 91%. There was no significant difference among the four years. Among the 4346 monitoring patients treated with cyclosporine, the number of male was 3047 (70.18%), and female 1296 (29.82%). The ratio of male who reached effective concentration was 92.64%, which was slightly below female (94.21%). There was no significant difference between male and female (p>0.05). Among 5833 patients treated with 5 kind medicine, the number of reaching effective concentration was 4670, whivh ratio was 80.1%, and the number of lower than effective concentration was 1163, which ratio was 19.9%. Conclusion: When phenytoin sodium, carbamazepine, phenobarbital, valproic acid sodium and cyclosporine were used, the dose scheme, medication history, important laboratory data should be analysed comprehensively, and adjusted the dose momentarily according to the blood concentration results and clinical effects, and individualized therapy can be reached. Clinical physician and pharmacist should be stand together to establish a long-term and effective therapeutic schedule using the therapeutic drug monitoring technology to maximumly assure the medicate safe, effective and economical.Key Words: Drug monitoring; Blood concentration; Retrospective analysis.符号说明TDMTherapeutic drug monitoring药物浓度监测CsACyclosporin环孢素FPIAfluorescence polarization immunoassay荧光偏振免疫法MAFPIAmonoclonal antibodies fluorescence polarization immunoassay特异性单克隆荧光偏振免疫法前 言治疗药物浓度监测(therapeutic drug monitoring，TDM) 是通过测定血液中或其他体液中药物的浓度并利用药动学的原理和公式使给药方案个体化,以提高药物疗效,避免或减少不良反应,同时为药物过量中毒的诊断和处理提供实验依据,是药师对患者进行药学监护的重要手段,对提高临床用药的有效性与安全性具有重要意义1。癫痫(epilepsia)是大脑神经元突发性异常放电，导致短暂的大脑功能障碍的一种慢性疾病。癫痫发作是指脑神经元异常和过度超同步化放电所造成的临床现象。其特征是突然和一过性症状，由于异常放电的神经元在大脑中的部位不同，而有多种多样的表现。可以是运动感觉神经或自主神经的伴有或不伴有意识或警觉程度的变化。人一生中偶发一至数次的机率高达5%，且39% 癫痫患者有自发性缓解倾向，故并非每个癫痫患者都需要用药。而需要用药的患者，由于癫痫及癫痫发作的类型较多，所以应根据癫痫及癫痫发作的类型正确选择用药。正确选择用药70%80% 新诊断癫痫的患者可通过服用一种抗癫痫药物控制癫痫发作，所以治疗初始的药物选择非常关键，正确选择用药，可以增加治疗成功的可能性;如选药不当，则可能导致癫痫发作加重。一般将60年代前合成的抗癫痫药如苯妥英钠、卡马西平、乙琥胺、丙戊酸钠等称为老抗癫痫药，其中苯巴比妥、苯妥英钠、卡马西平、丙戊酸钠是目前广泛应用的一线抗癫痫药。但有些发达国家，由于苯巴比妥、苯妥英钠的一些不良反应，已将其列入二线抗癫痫药。仅将卡马西平、丙戊酸钠列为一线抗癫痫药。患者大发作时可选用苯巴比妥、丙戊酸钠、卡马西平等。复杂部分性发作时可选用苯妥英钠、卡马西平等。失神发作时可选用氯硝安定、安定等。癫痫持续状态时可首选安定。药物剂量从常用量低限开始，逐渐增至发作控制理想而又无严重毒不良反应为宜。给药次数应根据药物特性及发作特点而定。一般不随意更换或间断，癫痫发作完全控制23年后，且脑电图正常，方可逐渐减量停药。应定期药物浓度监测，适时调整药物剂量。环孢素(Cyclosporin,CsA) 是由真菌( Tolypocladium Inflatum Gams) 的代谢产物中提取分离得到的一种亲脂性的含11个氨基酸的环状多肽化合物,是目前用于器官移植中预防排斥反应和治疗自身免疫性疾病的有效免疫抑制药2。但其有明显的肝肠循环和个体差异,治疗窗口窄3。而且CsA 血药浓度水平受药物相互作用、肝胃肠功能、红细胞含量、服药方法、术后时间、性别、年龄、食物以及饮料等众多因素的影响4,5。而且CsA 具有一定的肝、肾毒性。为使CsA 发挥最佳的免疫抑制作用,减少毒副作用,应定期监测CsA 血药浓度。荧光偏振免疫法( FPIA) FPIA法是将荧光偏振原理与竞争性免疫测定相结合形成的高效分析技术。单克隆特异性荧光偏振免疫法(MAFPIA)是目前国内外器官移植中心监测CsA血药浓度选择的主要方法。MAFPIA法测定CsA,反映CsA原型在体内的水平，它不随给药时间、给药途径而变化,对临床鉴别CsA中毒与排异反应具有重要意义。该法具有自动化程度较高,样品需求量少,选择性好，灵敏性好，准确，简便迅速等优点。齐鲁医院开展治疗药物监测，从90年代初起，已成为一项常规工作，其中抗癫痫药和免疫抑制剂环孢素在监测品种和监测人次上均占最大比例。由于这些药物具有服用周期长，安全范围小，有效剂量个体差异大，毒性较强的特点。临床医生凭经验给药，往往难以达到理想的治疗效果。故要获得较好的治疗效果，减少不良反应需要进行血药浓度监测，实现个体化给药方案。本文采用系统回顾性调查的方法，对2006年1月2009年12 月期间山东大学齐鲁医院服用卡马西平、苯巴比妥、苯妥英钠、丙戊酸钠、环孢素5种药物的5000多例患者进行血药浓度监测的结果进行汇总分析，为临床开展个体化用药提供参考。第一部分 四种抗癫痫药物血药浓度监测结果回顾分析1 仪器与试剂XW-80A型旋涡混合器（上海精科实业有限公司），LDZ4-0.8自动平衡微型离心机（美国科俊仪器公司）；CX250H超声清洗器（北京医疗设备二厂）；TDxFLx毒品/血液浓度分析仪，TDxFLx分析用标准曲线盒，试剂盒，质控盒（均为美国雅培公司提供）。2 方法2.1 采集血样根据各种药物给药途径,在用药后的适当时相,抽取稳态或峰、谷时的上肢静脉血1mL2mL 于试管中,分离血清于玻璃试管中,冷冻存放待测。2.2 测定方法所有血样均采用荧光偏振免疫法,按美国雅培公司的标准操作规范，每批次测定样本时，对质控样品进行平行测定，若质控样品超出标识范围内，需校正标准曲线，并于当日内重新测定。2.3 血药浓度判断标准根据文献6,7,8以及齐鲁医院的参考标准,判定药物有效的血液浓度：卡马西平420 g·mL-1，丙戊酸钠50100 g·mL-1，苯妥英钠1020 g·mL-1，苯巴比妥1540 g·mL-1。分析数据均来自山东大学齐鲁医院20062009年血液浓度监测原始数据记录。对姓名、年龄、性别、监测结果分别进行统计、汇总分析，分别汇总低于有效治疗浓度、有效治疗浓度、高于有效治疗浓度数据，剔除数据记录不清晰完整者。抗癫痫药患者共1525例。3 结果2006年1月2009年12月对苯妥英钠、卡马西平、苯巴比妥、丙戊酸钠4种抗癫痫药物共1525人次监测数据进行分析，分析监测结果见下列图表。3.1 2006-2009年4种抗癫痫药物各年度血药浓度监测结果3.1.1 2006年4种抗癫痫药物血药浓度监测结果表1 2006年苯妥英钠血药浓度监测Table1 Blood drug concentration monitoring results of phenytoin sodium in 2006测定结果g·mL-1样本例数(%)女男合计<101020>20总数4(36.36)1(9.09)6(54.55)1114(50.50)8(28.54)6(21.43)2818(46.15)9(23.08)12(30.7)39(100)从表1中可以看出，2006年苯妥英钠测定总人次男性（28人）高于女性（11人），在有效浓度范围内男性所占比例（28.54%）远高于女性（9.09%），合计总人次低于有效浓度所占比例较大（46.15%），达到有效浓度的较少（23.08%），高于有效浓度（30.7%）大于有效浓度.以上各组比较P<0.01有显著性差异。表2 2006年丙戊酸钠血药浓度监测Table 2 Blood drug concentration monitoring results of valproic acid sodium in 2006测定结果g·mL-1样本例数(%)女男合计<5050100>100总数11(37.93)17(58.62)1(3.45)2932(49.23)28(43.08)5(7.69)6543(45.74)45(47.87)6(6.38)94(100)从表2中可以看出，2006年丙戊酸钠血药浓度监测总人次男性（65人）高于女性（29人），在有效浓度范围内女性所占比例（58.62%）高于男性（43.08%），大于有效浓度女性（3.45%）低于男性（7.69%），总例数低于有效浓度所占比例较大（45.74%）和达到有效浓度基本相当（47.8%），高于有效浓度的较少（6.38%）。表3 2006年卡马西平血药浓度监测Table 3 Blood drug concentration monitoring results of carbamazepine in 2006 测定结果g·mL-1样本例数(%)女男合计<4412>12总数4(11.43)21(60.00)10(28.57)3516(26.23)35(57