初步探讨他克莫司(FK506)对肝移植受者的治疗窗浓度及其与年龄、性别的关系

目的:探讨适合我国肝移植受者他克莫司理想治疗窗浓度范围及其与年龄、性别的关系.方法:应用微粒子酶免分析法测定75例不同年龄、性别肝移植受者口服他克莫司后12h的血药谷浓度,并观察排斥反应的发生及药物不良反应.结果:他克莫司的血药浓度,术后第1个月为11.3～15.5 ngmL-1,第2、3个月为7.8～10.7 ngmL-1,3个月后为5.3～7.8 ngmL-1,比较不同时期全血他克莫司的谷浓度,均有显著差异(P<0.01).术后发生排斥反应64例次,不良反应73例次.结论:建议他克莫司治疗窗浓度范围改为:术后第1个月为10～15 ngmL-1,第2,3个月为7.0～11 ngmL-1,3月后为5.0～8.0 ngmL-1维持;此浓度范围既能达到满意的免疫抑制效果,又能减少他克莫司的不良反应,并观察到其浓度与年龄、性别有一定的相关性.     

肝移植受者他克莫司治疗窗浓度的初步确定

目的寻求适合国人肝移植受者他克莫司理想治疗窗浓度范围.方法应用微粒子酶免分析法测定69例肝移植患者口服他克莫司后12 h的血药谷浓度,并观察排斥反应的发生及药物的不良反应.结果他克莫司的血药浓度,术后第1个月为(13.1±2.0)μg*L-1,第2,3个月为(9.2±1.7)μg*L-1,3个月后为(6.3±1.2)μg*L-1,比较各时期全血他克莫司谷浓度,差异均有极显著性(P＜0.01).术后发生排斥反应64例次,不良反应73例次.结论他克莫司治疗窗浓度范围术后第1个月为10～15 μg*L-1,第2、3个月为7.0～11 μg*L-1,3个月后为5.0～8.0 μg*L-1维持,此浓度范围既能达到满意的免疫抑制效果,又能减少他克莫司的不良反应.     

最优子集回归模型在预测肝移植受者他克莫司血药浓度中的应用

目的：建立肝移植受者他克莫司血药浓度简易估算方法。方法：收集37例肝移植受者口服他克莫司的176份稳态全血浓度数据,采用最优子集回归法建立他克莫司稳态血药浓度简易估算公式。结果：以浓度测定前4日他克莫司累积剂量预测他克莫司血药浓度的准确性及精密度较好,平均预测误差（0.04±2.5）ng/ml,平均绝对误差（2.00±1.45）ng/ml,80.8%的血药浓度数据绝对预测误差≤3.0ng/ml。结论：本方法预测他克莫司血药浓度准确性和精密度较好,简便迅捷。     

他克莫司血药浓度监测在异基因干细胞移植患者中的应用

目的:探讨异基因外周血干细胞移植(Allo-HSCT)患者他克莫司血药浓度监测结果与疗效、毒副反应及联合用药等的相关性,为他克莫司临床合理应用提供参考。方法:采用酶扩大免疫分析法对16例Allo-HSCT患者住院期间Allo-HSCT 3个月后他克莫司血药浓度进行监测,对移植物抗宿主病(GVHD)出现的情况、不良反应、联合用药情况加以分析讨论。结果:他克莫司血药浓度个体差异较大。当<8 ng/ml时,GVHD发生几率增加;>20 ng/ml时,患者出现糖尿、肾脏毒性等不良反应的几率增加。他克莫司对于预防和治疗GVHD的作用较好,与其他药物联用可产生相互作用。结论:他克莫司血药浓度监测在Allo-HSCT患者术后预防和治疗GVHD及减少毒副反应方面有重要的作用。Allo-HSCT 3个月后,其血药浓度维持在8~20 ng/ml之间,GVHD和不良反应出现的几率较小。     

CYP3A5和MDR1基因型对尿毒症患者肾移植术后早期他克莫司血药浓度和肌酐水平的影响

目的 评价真实临床实践中CYP3A5(CYP3A5*3,6986A>G)及MDR1(C3435>T,G2677>T/A,C1236>T)基因多态性对尿毒症患者接受肾移植术后早期他克莫司血药浓度的影响及其最佳治疗浓度。方法 以入选2013～2017年单中心的131例首次肾移植术且术后以他克莫司为基础进行三联免疫治疗的患者为对象,开展回顾性研究,考察患者基因多态性对他克莫司的日剂量、血药浓度、血药浓度/剂量比值和肌酐水平的影响。结果 在维持他克莫司靶浓度（10～15 ng/ml）的前提下,肾移植术后4周内基因型为CYP3A5*3/*3(GG)肾移植受者的给药剂量低于基因型CYP3A5*1/*1(AA)和CYP3A5*1/*3(AG)。患者血药浓度在10～13 ng/ml内时,其血肌酐水平最接近正常值。结论 CYP3A5基因多态性影响肾移植受者他克莫司的血药浓度,未发现MDR1基因多态性对他克莫司血药浓度的影响。早期肾移植血药浓度控制在10～13 ng/ml时,患者移植肾功能最接近正常人肾功能水平。     

ELISA法监测肝移植患者他克莫司全血浓度

目的通过监测肝移植患者他克莫司全血浓度,观察并建立他克莫司在三联免疫抑制用药方案中的理想治疗窗,为临床合理应用提供参考。方法用ELISA法测定他克莫司全血浓度,对138例患者的1190例次监测结果进行比较分析。结果他克莫司全血浓度随移植后时间延长而逐渐下降。肝移植后1个月内、第2~3个月、第4~6个月和>6个月时,用ELISA法监测他克莫司全血谷浓度的推荐治疗窗范围应分别为8~15、6~12、5~10、3~8μg·L-1,较为适宜。结论常规监测他克莫司全血浓度,参考推荐治疗窗范围调整给药方案,可获得满意的免疫抑制治疗效果。     

糖尿病肾病肾移植受者术后血环孢素A浓度的特点分析

目的探讨糖尿病肾病肾移植受者术后血环孢素A(CsA)浓度的特点。方法采用酶增强免疫分析法(Emit),对34例(糖尿病肾病17例)肾移植受者全血中CsA的谷浓度(C0)和服药后2 h的峰浓度(C2)进行监测,筛除出现肝、肾毒性或排斥反应的数据,并按术后时间进行分组对比分析。结果糖尿病与非糖尿病肾病肾移植术后第1、2月CsA的C0值分别为(214±84)、(175±46)和(251±85)、(209±74)ng/ml,C2值分别为(1087±471)、(963±326)和(1570±600)、(1543±401)ng/ml,2组间差异有统计学意义(P<0.05)。其余月份2组间C0和C2差异无统计学意义(P>0.05)。结论糖尿病肾病肾移植受者术后1～2个月内C0和C2宜控制在(120～250)ng/ml和(550～1500)ng/ml范围内,并随术后时间的延长而逐渐下降,避免毒性和排异反应。     

99例肝移植患者的FK506血药浓度分析

目的：探讨FK506（他克莫司）在肝移植患者血药浓度的控制情况及其出现不良反应的情况。方法：应用TAE法检测99例肝移植患者362例次FK506全血浓度,观察他克莫司理想的治疗窗并分析异常血药浓度形成的原因,为临床合理应用提供参考。结果：我院肝移植患者术后一个月内检测107例血样,FK506血药浓度为（8．6±3．0）ng·mL^-1,术后2—3个月血药浓度为（10．4±4．0）ng·mL^-1。以后血药浓度逐渐减低。与参考值相比,52.2％的患者血药浓度在参考值范围内,27．3％的患者血药浓度低于参考值,20．4％的患者血药浓度高于参考值。血药浓度的异常可能与合并用药及患者用药依从性有关,FK506不良反应的发生率相对少见,主要有感染、肾毒性和神经系统毒性等。结论：我院肝移植患者术后FK506血药浓度基本维持在推荐参考值范围低限,发生不良反应较少,可达到满意的免疫抑制治疗作用。     

35例肾移植患者他克莫司血药浓度监测分析

目的：分析肾移植患者不同时期他克莫司血药浓度与用药量的关系,为他克莫司的使用提供参考。方法对我院2013年4月～2014年3月35例肾移植患者进行长期血药浓度监测,统计分析术后时间、用药剂量等因素与他克莫司血药浓度的关系。结果35例肾移植患者血药浓度监测共计195次,血药浓度个体差异较大。肾移植手术1个月后,他克莫司用药剂量、血药浓度较高,超过1个月后血药浓度控制在4～8ng/mL较为理想。结论他克莫司治疗窗较窄,建议服药期间进行他克莫司血药浓度监测。     

肾移植患者全血他克莫司浓度监测结果分析

目的：探讨肾移植患者全血他克莫司浓度的治疗窗及对血常规和肝肾功能的影响。方法：MEIA法监测全血他克莫司谷浓度。对近4年来390例次肾移植患者全血他克莫司浓度，及他克莫司对血常规和肝肾功能的影响进行分析。结果：390例次全血他克莫司浓度中377例次（80．8％）在3～15μg·L^-1的范围内。移植后6个月内，全血他克莫司浓度差异较大。随着移植时间延长，全血他克莫司浓度逐步降低。在治疗剂量内，他克莫司对肾移植受者的血常规和肝肾功能无明显影响。结论：全血他克莫司谷浓度的治疗窗：术后1～3月为5～15·L^-1，第4～6月为5～10·L^-1，〉6个月为3～10·L^-1。他克莫司对肾移植受者的血常规和肝肾功能无明显影响。     

肾移植受者环孢素A治疗窗浓度研究

目的 :寻找环孢素A(CsA )在肾移植受者三联免疫抑制用药方案中的理想治疗窗浓度。方法 :用特异性荧光偏振免疫法测定268例患者全血CsA谷值浓度 ,并按术后时间及临床诊断分组比较。结果 :CsA理想治疗窗浓度为 :术后1mo内300～400μg/L ,2mo～3mo内250～350μg/L ,4mo～6mo内150～250μg/L ,7mo～12mo内100～200μg/L ,12mo以后100～150μg/L。结论 :CsA在理想治疗窗浓度内 ,既能达到满意的免疫抑制效果 ,又能减少CsA毒性反应和排斥反应     

80例肾移植患者他克莫司血药浓度数据分析

目的探讨肾移植患者他克莫司血药浓度与效应关系,定性分析影响他克莫司血药浓度的各种因素。方法收集我院2000年～2001年80例肾移植患者他克莫司血药浓度达稳态后谷浓度数据,并作回顾性分析。结果与结论他克莫司有效血药浓度与疗程有关,肾移植术后2wk内,他克莫司血药浓度宜为12～15ng/ml,2wk以后应为8～15ng/ml。     

Clinical outcomes of renal transplantation using liquid chromatographic monitoring of tacrolimus

It is suggested that specific methods of Tacrolimus monitoring rather than immunoassays which over-estimate Tacrolimus levels, should be used in transplant recipients. There is limited data, however, comparing clinical outcomes of renal transplantation using each of these techniques. In this study, 40 renal transplant recipients with Tacrolimus monitoring by Microparticle Enzyme Immunoassay (MEIA; target trough level 10-15 ng/ml) were compared with 40 patients monitored by High Performance Liquid Chromatography with Tandem Mass Spectrometry (HPLC-MS; target trough level 8-13 ng/ml). All received anti CD25 antibody induction and Mycophenolate Mofetil in a steroid sparing protocol. No demographic differences were seen between MEIA and HPLC-MS groups. All patients were followed for 6 months. Patient survival was 100% in both groups; graft survival was 100% in the MEIA group and 97.5% in the HPLC-MS group. The groups did not differ in the number of dose changes required in the first 6 months or in the number of patients displaying Tacrolimus levels within target range at three and six months. Delayed graft function occurred in 14 patients in the MEIA group and 12 patients in the HPLC-MS group (P = NS). Biopsy-proven acute rejection occurred in 4 patients in the MEIA group and 1 patient in the HPLC-MS group (P = 0.17). Biopsy proven acute Tacrolimus nephrotoxicity occurred in 6 patients in the MEIA group, and 7 in the HPLC-MS group (P = NS). No difference was seen in serum creatinine or estimated creatinine clearance at 3 or 6 months. No difference between groups was seen in systolic or diastolic blood pressure, or total cholesterol at 3 or 6 months. 2 patients in the MEIA group developed CMV disease and 1 developed posttransplantation diabetes mellitus. CMV and posttransplantation diabetes were not seen in the HPLC-MS group. 2 patients in each group developed reversible tremor. This study suggests that renal transplantation with HPLC-MS monitoring of Tacrolimus is safe and effective.     

Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient

Tacrolimus is a calcineurin inhibitor that has been widely used to prevent allograft rejection after transplantation. We report a case of a living-donor liver transplant recipient experiencing a considerable increase in the trough blood concentration of tacrolimus after concomitant ingestion of grapefruit juice (250 mL) 4 times for 3 days. The trough blood concentrations of tacrolimus were not changed during or immediate after the repeated intake of grapefruit juice. However, almost 1 week after the final ingestion, the blood concentration of tacrolimus markedly increased to as much as 47.4 ng/mL from 4.7 ng/mL before the ingestion, resulting in a profound reduction of calcineurin phosphatase activity in peripheral blood mononuclear cells. Furthermore, headache and nausea, but not nephrotoxicity or hyperglycemia, took place throughout the period of the elevated blood concentrations. Grapefruit juice may have a clinically significant effect on the pharmacokinetics and pharmacodynamics of tacrolimus. It is recommended to avoid the consumption of grapefruit juice in transplant recipients treated with tacrolimus.     

Tacrolimus whole blood concentrations correlate closely to side-effects in renal transplant recipients

AIMS: To evaluate the relationship between tacrolimus whole blood concentrations and side-effects and rejections in 14 renal transplant recipients. METHODS: Tacrolimus was measured by MEIA in whole blood in samples collected repeatedly during the first year after transplantation. Retrospectively, tacrolimus trough concentrations on the days with adverse events (n=172) or rejection (n=28) were related to the total distribution of the concentration values (n=656). RESULTS: Side-effects (one or more) were noted in connection with 76% of tacrolimus concentrations above 30 ng ml-1, with 41% of concentrations within the interval of 20-30 ng ml-1, with 26% of the concentrations within the interval of 10-20 ng ml-1 and with only 5.3% on the concentrations lower than 10 ng ml-1. No relation to the tacrolimus concentration was seen for rejection episodes. CONCLUSIONS: We conclude that therapeutic drug monitoring may be helpful in the management of tacrolimus therapy and that tacrolimus whole blood trough concentrations (MEIA) should preferably be kept below 20 ng ml-1 to avoid side-effects, such as nephro-and neurotoxicity and infections. The lower limit of the therapeutic range has yet to be defined.     

肾移植术后不同时期环孢素A的血浓范围

目的:确定长期存活的肾移植术后患者环孢素 A(CsA)的治疗窗.方法:将已存活4a以上的39例肾移植患者763个血浓谷值按术后时间分为7组,按肝肾功能指标分为3组进行比较分析.结果:肾移植患者的全血CsA谷值(多克隆)维持浓度随着术后时间的延长而降低,肾移植患者各个时期CsA较适宜的治疗窗为:450～600ng/ml(0～6mo),400～550 ng/ml(6～12mo),350～500 ng/ml(1～3a),300～450ng/ml(3～5a),250～40Ong/ml(5～7a).结论:肾移植患者的全血CsA谷值维持浓度随术后时间延长而降低.     

普乐可复在肝脏移植术后的免疫治疗与监测

目的：观察肝脏移植术后应用普乐可复（FK506）免疫治疗的临床效果。方法：回顾性分析我院69例患者肝脏移植术后使用以FK506为基础的三联免疫治疗方案的临床资料，即FK506＋霉酚酸酯（MMF）＋皮质激素。结果：69例中发生急性排斥反应8例（11．6％），经调整药物剂量后逆转。FK506的副作用主要有精神及神经系统紊乱（20．3％）、高血压（11．6％）、血糖升高（20．3％）及肝肾功能异常（8.7％）等。结论：FK506是一种安全、强效的免疫抑制药物，用药剂量应根据药物谷值浓度及个体差异进行调整。     

Cyclosporine Trough Concentrations in Predicting Allograft Rejection and Renal Toxicity up to 12 Months after Renal Transplantation

Study Objective . To evaluate the utility of cyclosporine (CsA) trough concentrations as a monitoring tool for acute graft rejections and CsA nephrotoxicity. Design . Retrospective chart review. Setting . University-affiliated teaching hospital. Patients . One hundred thirty-seven adults who had undergone kidney transplantation. Measurements and Main Results . Clinical data extracted from the charts were CsA dosage, CsA trough levels (whole blood, HPLC method), biopsy findings to confirm acute rejections, and serum creatine to determine clearance by the Jelliffe method. Data were collected at up to 1 month, between 1 month and 3 months, and between 3 and 12 months after transplantation. For each time period, receiver's operating characteristics curves were generated to identify the optimum CsA concentration for avoiding acute rejection and CsA nephrotoxicity. At up to 1 month, the CsA therapeutic response threshold was 182 ng/ml (sensitivity 69%, specificity 84%, p < 0.0001) and toxicity threshold for CsA nephrotoxicity was 204 ng/ml (sensitivity 89%, specificity 56%, p < 0.0001). Between 1 month and 3 months, the respective figures were 175 ng/ml (sensitivity 58%, specificity 89%, p < 0.0002) and 189 ng/ml (sensitivity 87%, specificity 65%, p < 0.0001). Between 3 and 12 months, the CsA therapeutic response threshold decreased to 135 ng/ml (sensitivity 56%, specificity 40%, p > 0.1) and the toxicity threshold for CsA nephrotoxicity remained relatively static at 204 ng/ml (sensitivity 100%, specificity 14%, p < 0.0001). Conclusion . Early in CsA therapy it is essential to prevent graft rejection. Drug concentrations exceeding approximately 182 ng/ml threshold accomplish this goal. Later, successful therapy demands that CsA nephrotoxicity be avoided. This goal is accomplished by not exceeding a CsA concentration of 204 ng/ml.     

他克莫司基因组学在肝移植的应用及其研究进展

他克莫司是一种新型强效免疫抑制剂,在临床广泛应用于肝移植等器官移植术后的抗排异治疗。在肝移植人群中,他克莫司的药代动力学及血药浓度存在个体差异,其用药的个体差异与细胞色素P450酶系CYP3A5和P糖蛋白的基因多态性之间存在较密切联系。本文对他克莫司的药效学、药代动力学、血药浓度范围及其药物基因组学的研究进展进行了综述。