肾移植术后监测环孢素A血药浓度峰值(C2)的临床意义

目的 探讨肾移植术后早期监测环孢素血药浓度峰值(C2)的临床意义.方法 回顾性分析28例肾移植受者,采用单抗免疫荧光偏振法(TDX)同步监测CsA全血谷浓度(C0)和峰浓度(C2),比较研究C0和C2的监测在预测肾移植术后早期急性排异反应、药物性肝损害以及肾毒性中的价值.结果 8例患者发生急性排异反应,6例发生药物性肝损害,6例发生肾中毒.术后各时间段发生急性排异患者CsA谷浓度C0与未发生的相比无统计学差异(P﹥0.05),而发生急性排斥反应患者CsA峰浓度C2明显低于正常组C2(P<0.05).结论 监测CsA峰值浓度(C2)能有效预测肾移植术后急性排异反应的发生.     

P-选择蛋白用于诊断肾移植术后排异的可行性探讨

目的：寻找一个比环孢素A（CsA）更加灵敏的、经济的、用于诊断肾移植（RT）术后排异反应的特异性指标。方法：采用酶联免疫吸附法（ELISA）测定血浆P-选择蛋白水平，采用单克隆抗体荧光偏振免疫分析法（FPIA）测定CsA谷浓度，分析了P-选择蛋白的变化与CsA谷浓度、疗效三者之间的相关性，并对二者诊断RT术后的准确性进行了比较，探讨了P-选择蛋白用于诊断RT术后排异的可行性。结果：当移植肾有发生排异的趋势时，血浆P-选择蛋白会有显著增高，且其用于诊断RT术后排异的准确率明显大于CsA（P〈0．05）。结论：P-选择蛋白可以作为一个更加灵敏的、用于诊断排异反应的特异性指标。     

肾移植术后环孢素A全血谷浓度研究

目的:探索肾移植术后接受环孢素A(CsA)进行免疫抑制治疗的患者,采用环孢素、强的松和硫唑嘌呤三联免疫抑制治疗方案的稳定治疗浓度范围.方法:采用特异性荧光偏振免疫法测定肾移植术后患者CsA全血谷浓度,结合临床疗效统计分析,分组比较测定结果.结果:肾移植术后CsA免疫抑制治疗的推荐治疗浓度范围:术后<30d:250～450ng/ml; 30～90d:250～400ng/ml;90～180d:180～400ng/ml; 180～360d:150～300ng/ml,1年以上:l00～250ng/ml.CsA血药浓度调整到推荐治疗浓度范围内的中毒反应发生率为14.5%,移植排斥反应发生率为4%.结论:在推荐治疗浓度范围内,能减少CsA毒性反应和排异反应,达到较为理想的治疗效果.     

肾移植术后环孢素A血药浓度监测与临床疗效关系

目的:研究肾移植(RT)术后环孢素A(CsA)浓度与临床疗效之间的关系。方法:将RT患者分成3组:正常组、中毒组、排异组。应用荧光偏振免疫(FPIA)法,对921例次RT术后患者进行常规CsA血药浓度监测,同时观察疗效。结果:平均血浓度正常组为256.10±47.52ng/ml;排异组为142.25±44.71ng/ml;中毒组为432.96±107.99ng/ml。正常组分别与中毒组、排异组之间血药浓度的显著性差异(P<0.001)。结论:CsA血药浓度监测可以指导临床合理用药,避免或减少不良反应。     

肾移植术后环孢素A血药浓度的监测

目的 :探讨肾移植术后患者常规应用环孢素A(CsA)抗排异 ,服药后 2hCsA血药浓度 (C2 )监测的合理性及临床意义。方法 :采用荧光免疫偏振法 (FPIA)测定CsA血药浓度。结果 :C2 与CsA血药浓度 时间曲线下面积 (AUC)显著相关 (r =0 .94 9) ,且离散程度最大标准差为± 5 76 .4 0 ;CsA谷浓度 (C0 )与AUC相关不显著。结论 :肾移植术后患者以C2 为监测点预防排异反应和调整给药剂量比C0 更具有科学性和敏感性。     

特异性荧光偏振免疫法监测521例肾移植后环孢素A全血浓度3275次

目的通过监测肾移植后病人环孢素A(CsA)全血浓度 ,提出CsA在三联免疫抑制用药方案中的理想治疗窗。方法用特异性荧光偏振免疫法测定CsA全血浓度 ,对521例病人监测3275次 ,按术后时间及临床表现分组比较。结果肾移植后<1 ,、1～3、3～6、6～12个月、1～2和>2年的CsA全血谷浓度的理想治疗窗应分别为250～450、200～400、150～300、100～250、100～200和100～180μg/L。结论CsA全血浓度在上述范围内 ,中毒反应和排异反应明显减少     

环孢素对肾移植术后病人血胆固醇和甘油三脂的影响

目的 :观察环孢素浓度和肾移植手术本身对血胆固醇及甘油三脂水平的影响。方法 :在 50名肾移植术后病人 ,同时测定病人的环孢素、胆固醇及甘油三脂水平 ,按不同的环孢素峰、谷浓度将患者分组。并将术前和术后的水平进行比较。用t检验进行统计学处理。结果 :在肾移植前后 ,胆固醇水平有显著差异 (P <0 .0 0 1 ) ;在肾移植术后 ,环孢素峰、谷水平过高或过低时 ,甘油三脂浓度有显著升高 (P <0 .0 0 1 )。结论 :服用环孢素可能是胆固醇升高的原因之一 ,不能排除肾移植手术或其它药物如强的松、硫唑嘌呤对胆固醇的影响 ;环孢素浓度过高或过低可引起甘油三脂的波动可能是环孢素中毒或移植肾排斥影响到甘油三脂水平     

特异性荧光偏振免疫法监测521例肾移植后环孢素A全血浓度3275次

目的 通过监测肾移植后病人环孢素A（CsA)全血浓度，提出CsA在三联免疫抑制用药方案中的理想治疗窗。方法 用特异性荧光偏振免疫法测定CsA全血浓度，对521例病人监测3275次，按术后时间及临床表现分组比较。结果 肾移植后＜1、1－3、3－6、6－12个月、1－2和＞2年的CsA全血谷浓度的理想治疗窗应分别为250－450、200－400、150－300、100－250、100－200和100－180μg/L。结论 CsA全血浓度在上述范围内，中毒反应和排异反应明显减少。     

肾移植患者环孢素A的药效学研究

目的:分析肾移植患者术后环孢素A(CsA)血药浓度与剂量、疗效的关系。方法:采用荧光偏振免疫法(FPIA)对70例肾移植患者进行251次CsA全血药物浓度测定。结果:肾移植术后不同时间段CsA血药谷浓度0～3个月时为(336.99±224.89)ng/mL,3～6个月为(252.07±113.71)ng/mL,6～12个月为(195.83±105.11)ng/mL,1～2年为(179.64±85.48)ng/mL,2年以上则为(144.95±55.68)ng/mL。结论:CsA药物浓度的跟踪检测对观察肾移植术后的排异反应、减少药物不良反应具有重要的临床意义。     

197例肾移植患者环孢素A血药浓度监测数据分析

目的　探讨肾移植患者环孢素A(CsA)血药浓度与效应关系 ,定性分析影响CsA血药浓度的各种因素。方法　收集中山大学附属第一医院 1999～ 2 0 0 1年 197例肾移植患者服用CsA 3d以上血药浓度达稳态后谷浓度数据 ,并作回顾性分析。结果　CsA血药浓度 3 0 0～ 40 0ng ml组的平均肌酐清除率与 10 0～ 3 0 0ng ml组有显著性差异 (P <0 .0 5 )。患者性别、年龄、体质量对CsA血药浓度有影响。结论　不能单纯依赖血清肌酐浓度判断治疗效果 ,肾移植术后第 1m ,CsA血药浓度不宜低于 3 0 0ng ml,以免影响疗效。     

Trough levels of mycophenolic acid and its glucuronidated metabolite in renal transplant recipients

OBJECTIVE: The prophylactic use of the immunosuppressant prodrug, mycophenolate mofetil (MMF) to prevent graft rejection in renal transplant patients is continuing to increase. We measured trough levels of the active metabolite, mycophenolic acid (MPA) and its inactive glucuronide (MPAG) in renal recipients with the aim of characterizing individual variability and of ascertaining factors influencing trough levels, in particular the effect of differences in renal function and the effect of drugs given concurrently. METHODS: Laboratory and clinical data obtained in 35 renal recipients treated with triple therapy (MMF, cyclosporin A (CsA), steroids) were included in this retrospective study. Trough levels of MPA and MPAG were obtained after transplantation and up to 16 months post transplantation where the mean observation period was 5.7 months. Plasma levels were measured using a validated HPLC assay. RESULTS: A total of 212 plasma concentrations of MPA and 209 of MPAG were measured. There was considerable intra- and interindividual variability in MPA and MPAG trough levels especially in the early post-transplantation phase. At a fixed dose of 2 g/d MMF, the mean MPA level during the first 30 days averaged 1.46 +/- 1.31 microg/ml vs. 1.87 +/- 0.89 microg/ml after 30 days and later (p = 0.130) and the mean MPAG concentration averaged 188.1 = 142.8 [microg/ml vs. 98.09 +/- 52.4 microlg/ml (p 0.003). The MPAG levels were positively correlated with the serum creatinine concentrations (r = 0.815, p < 0.001), and in the case of MPA there was a correlation with the serum protein concentrations (r = 0.258, p = 0.001). Concomitant drug treatment using CsA, steroids and furosemide were without effect of the measured plasma concentrations, but in the case of xipamide (+) and diltiazem (-) an effect on MPA and MPAG levels and a co-effect depending on the serum creatinine could not be excluded. Neither CsA trough levels nor hemoglobin levels were related to MPA and MPAG trough levels. CONCLUSIONS: The data of this study demonstrate that there is substantial individual variability in the trough levels of MPA and MPAG after renal transplantation which may be associated with the functional status of the graft and the serum protein level. Whether comedication with xipamide and diltiazem affects the plasma levels of MPA and MPAG remains to be clarified in further investigations.     

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.     

Cyclosporin C2hour monitoring after renal transplantation

Therapeutic drug monitoring of cyclosporin A (CsA) is essential because of its variable pharmacokinetics in individual patients and its narrow therapeutic window. In the past, standard trough level (C0) monitoring has been used, and although this method is currently the routine strategy, it has been shown that a single blood concentration measurement 2 hours after CsA administration (C2hour) is a significantly more accurate predictor of drug exposure and clinical events than trough concentrations. The CsA absorption profiling, in particular the measurement of C2hour, is a much more sensitive approach to assessing the pharmacokinetics and predicting the clinical effect in the individual patient. However, there are limited prospective data available examining the risks and benefits of C2hour monitoring in renal transplant recipients. Most studies focus on the early post-transplant phase, but there is little experience with C2hour monitoring in maintenance patients. Our experience in 127 stable long-term renal allograft recipients suggests that the therapeutic window for C2hour levels in patients during maintenance is lower than previously anticipated. Repeat determinations of both C0 and C2hour levels in 46 patients to determine precision of C2hour monitoring showed a high intrapatient variability. We observed only a slightly better coefficient of variation for C2hour than for C0 in repeat determinations. This suggests that drug monitoring using C2hour levels in transplant patients may provide a more accurate and reliable measure of drug exposure in the individual patient. However, CsA absorption showed only a weak correlation with dose during repeated measurements, suggesting high variability in absorption in these stable patients. We conclude that an adequate C2hour level soon after transplantation is associated with a reduced risk of acute rejection in adult renal transplant recipients. It is important to identify slow and poor absorbers in the initial phase after transplantation in order to avoid inappropriate increases in CsA dose. In maintenance patients, C2hour values between 500 and 600 ng/ml are effective and safe for providing effective rejection prophylaxis. Although mean C2hour levels do not seem to identify patients at risk of rejection, they may help to identify excessive immunosuppression and to improve long-term survival by reducing CsA toxicity.     

Relationship between erythrocyte-to-plasma distribution ratio of cyclosporin and lymphocyte proliferation in renal transplant patients

Objective: The aim of this study was to examine the relationship between erythrocyte-to-plasma distribution ratio of cyclosporin (CsA-EP) and lymphocyte proliferation as an indicator of immunosuppressive activity in renal transplant patients. Methods: A total of 113 whole blood samples obtained from 6 inpatients with renal transplantation were analysed. CsA concentrations in blood and plasma at trough were measured by fluorescence polarization immunoassay using monoclonal antibody, lymphocyte proliferation in response to phytohaemagglutinin was evaluated by the fluorimetric derivatization method using ethidium bromide and the stimulation index (SI) was calculated. Results: There was no correlation between CsA dose and trough levels (vs blood CsA, r ² = 0.052; vs plasma CsA, r ² = 0.054, n = 113). A significant negative correlation between the SI and the CsA-EP was found in individual or all samples (r ² = 0.224, p < 0.0001, n = 113), whereas CsA trough levels in blood or plasma had no correlation with the SI. Conclusion: Although the degree of contribution of CsA-EP to the SI was 22%, the CsA-EP is a more useful predictor of changes in immunosuppressive response than CsA concentration in blood or plasma. The adoption of the CsA-EP as a monitoring index could be helpful in assessing the appropriateness of CsA immunosuppressive therapy. Accepted: 4 November 1996     

骨髓移植受者环孢素A血药浓度监测结果分析

目的:探讨骨髓移植患者术后环孢素A(CsA)有效血药浓度临床治疗的有效性与安全性。方法:采用免疫分析法,对14例骨髓移植患者术后1～466 d全血谷浓度进行监测,共216例/次,并对监测结果进行分析。结果:慢性粒细胞性白血病、急性非淋巴细胞白血病、急性淋巴细胞白血病、地中海贫血、全血细胞减少症患者术后CsA的有效血药浓度范围分别为50～450、100～450、100～350、200～500、250～500 ng·mL~(-1)。骨髓移植术后7例出现排斥反应,其谷浓度为67.4～189.34 ng·mL~(-1)(平均125.44±39.56 ng·mL~(-1));3例发生不良反应,其谷浓度为412.5～548.62 ng·mL~(-1)(平均481.39±68.08 ng·mL~(-1))。结论:及时监测患者的CsA血药浓度,调整用药方案,可避免排斥反应和不良反应的发生,对确保患者用药安全、有效具有重要意义。     

Pharmacokinetic monitoring of mycophenolate mofetil in kidney transplanted patients

Mycophenolate mofetil (MMF) is a new immunosuppressant drug used in association with cyclosporin and oral corticosteroids to prevent acute rejection following renal allograft transplantation. MMF is an ester pro-drug of mycophenolic acid (MFA), the true active species, into which it is completely transformed after oral administration. The recommended initial dose to prevent kidney transplant rejection is 2 g/day irrespective of body weight, 1 g twice daily. The goal of this study was to correlate dosage (fixed or by body weight) and toxic effects to some non-compartmental values such as peak level (Cmax), time to peak level (Tmax) and trough level (Cmin). In a small number of patients who had already reached the plasma steady state, we found a large inter-patient variability, while the same qualitative pharmacokinetic profile (as Tmax) was conserved. At plasma trough level > 4 microg/ml some serious toxic effects were observed, whereas at Cmin < 2 microg/ml, there were some cases of interstitial rejection. There was also a negative correlation between dosage and body weight, suggesting that dosages related to body weight might be better than fixed ones. Finally, monitoring plasma level of drug from transplantation to at least 12 months after surgery, at fixed MFA dosage, a small but significant decline of MFA plasma levels was found.     

骨髓移植患者术后环孢素血药浓度监测

目的:探讨异基因骨髓移植患者术后环孢素(CsA)的血药浓度与移植物抗宿主病(GVHD)和药物相关毒性之间的关系。方法:采用荧光偏振免疫分析法(FPIA),对28例骨髓移植患者术后全血谷浓度进行监测,共252例次,并对监测结果进行分析。结果:28例骨髓移植患者252例次监测结果提示,有效浓度为100～400μg.L-1。当浓度>400μg.L-1时,药品不良反应(ADR)发生率增加为16.28%;当浓度<100μg.L-1时,GVHD率增加为27.27%。结论:及时监测CsA浓度,根据动态监测结果制订个体化给药方案,才能减少GVHD以及ADR的发生,提高移植后的成功率。     

Cyclosporin A absorption profiles in pediatric renal transplant recipients predict the risk of acute rejection

The current focus of cyclosporin A (CsA) monitoring in adult transplantation for optimized immunosuppression is on the early portion of the CsA area under the concentration-time curve (AUC), particularly in the first 4 hours postdose, designated as AUC(0-4), and on the blood concentration 2 hours postdose (C2) as a highly predictive marker for AUC(0-4). Because data in pediatric patients are scarce, full-time (12 hours) and absorption profiles of CsA were analyzed in relation to CsA effectiveness in 61 pediatric renal transplant recipients aged 3.2 to 17.4 years on an immunosuppressive triple regimen with CsA, mycophenolate mofetil, and methylprednisolone. CsA dosing was based on body surface area and adjusted to CsA trough levels. Pharmacokinetic (PK) profiles were obtained 1 and 3 weeks (initial period) and 3 and 6 months posttransplant (stable period). Patients with an AUC(0-4) < 4400 microg x h/L at both PK sampling periods in the first 3 weeks posttransplant had an adjusted relative risk of 48.4% to suffer an acute rejection episode (ARE), whereas in patients with at least 1 AUC0-4 above this threshold, the adjusted relative risk for an ARE was only 13.1% (P < 0.02). The single PK parameters C0 or C2 did not discriminate between patients with and without acute rejection. The PK parameters C1.25 (r2 = 0.64) or C2 (r2 = 0.60) showed a stronger relationship to the absorption profile (AUC(0-4)) than C0 (r2 = 0.15). An abbreviated profile consisting of the PK variables C(0.5;2) or C(0;0.5;2) showed the closest correlation to the absorption profile (r2 = 0.89) and the lowest percentage prediction error. These data indicate that absorption profiling in pediatric renal transplant recipients has the potential to optimize immunosuppressive therapy with CsA.     

NIDDM患者血浆GMP-140的变化及其临床意义

采用放射免疫法测定了64例非胰岛素依赖型糖尿病患者(NIDDM)及36例健康对照的血浆中血小板α颗粒膜蛋白(GMP-140)的水平。结果表明NIDDM患者血浆GMP-140显著高于对照组(P<0.001)。NIDDM组中有血管并发症者血浆GMP-140较无血管并发症者高(P<0.001)。且随病程延长而升高。提示GMP-140可能参与了糖尿病血管病变的发生发展过程。     

肾移植患者血浆可溶性白介素－2受体水平的监测及临床意义

以荧光偏振免疫法和ＥＬＩＳＡ分别测定肾移植患者全血环孢素（Ｃ＿ｓＡ）浓度和血浆可溶性白介素－２受体（＿ｓＩＬ－２Ｒ）水平。稳定移植组、排斥反应组和Ｃ＿ｓＡ毒性组的＿ｓＩＬ－２Ｒ均与正常对照组者有明显差异（Ｐ＜０．０１）；稳定移植组与排斥反应组差异显著（Ｐ＜０．０１），而与Ｃ＿ｓＡ毒性组无明显差异（Ｐ＞０．０５）。全血Ｃ＿ｓＡ浓度与＿ｓＩＬ－２Ｒ，水平无明显相关关系。提示＿ｓＩＬ－２Ｒ是鉴别肾移植患者排斥反应或Ｃ＿ｓＡ毒性的重要指标，对Ｃ＿ｓＡ合理用药有重要意义。