人工神经网络预测肝移植术受者他克莫司血药浓度

建立人工神经网络用于估算他克莫司血药浓度。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,采用遗传算法配合动量法优化网络参数,建立人工神经网络。人工神经网络平均预测误差(MPE)与平均绝对误差(MAE)分别为(0.02±2.40)ng.mL 1和(1.93±1.37)ng.mL 1,84.6%血药浓度数据绝对预测误差≤3.0 ng.mL 1。人工神经网络的准确性及精密度优于多元线性回归。结果表明,人工神经网络预测的相关性、准确性和精密度较好,简便迅捷,可用于预测他克莫司血药浓度。     

肝移植受者他克莫司血药浓度早期预测方案及评估

目的:建立人工神经网络用于估算他克莫司血药浓度。方法:收集36例肝移植受者口服他克莫司的150份稳态全血浓度数据,采用遗传算法配合动量法优化网络参数,建立人工神经网络。结果:人工神经网络平均预测误差(MPE)与平均绝对误差(MAE)分别为0.05±3.01ng·mL-1和2.09±2.12ng·mL-1,78.3%血药浓度数据绝对预测误差≤3.0ng·mL-1。人工神经网络准确性及精密度优于多元线性回归。结论:人工神经网络预测可用于预测他克莫司血药浓度。     

肝移植患者中他克莫司血药浓度影响因素

目的：通过分析服用他克莫司(FK506)肝移植患者的血药浓度监测结果,探讨他克莫司血药浓度的影响因素。方法：根据患者住院号筛选我院2010-2012年接受肝移植的患者,统计患者的性别、年龄、实际住院天数,以及主要诊断及其它诊断、FK506的血药浓度及剂量。分析术后时间、用药剂量、性别、年龄等因素与他克莫司血药浓度的关系。结果：术后14天内与14天后的剂量有明显差异,血药浓度无明显差异(P＜0.05);在同一时间内,性别对他克莫司的血药浓度有一定的影响(p＜0.05);在术后14天内,A组剂量小于B组和C组(p＞0.05),血药浓度C组高于A组和B组(p＜0.05);在大于14天,C组剂量大于A组和B组(p＜0.05),血药浓度C组高于A组和B组(p＜0.05)。结论：他克莫司血药浓度影响因素众多,在使用时应该综合考虑多种因素,以控制血药浓度在理想范围。有利于提高肝移植患者的存活率。     

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.     

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。     

他克莫司在肝移植患者体内的药动学

目的:考察口服他克莫司(FK506)胶囊在肝移植患者体内的药动学特征,为临床调整个体化给药方案提供科学依据.方法:22例肝移植患者,给予FK506为基础的免疫抑制治疗,术后24 h后开始服用FK506,剂量为(0.13±0.04)mg·kg-1·d-1,每12 h服用1次.受试者在服药前(0 h)和服药后0.33,0.66,1,1.5,2,3,4,6,8,10,12 h共12个时间点分别取外周静脉血,用MEIA法进行药物浓度测定,PKBP-N1软件计算药动学参数,并绘制血药浓度-时间曲线.结果:FK506口服后血药浓度一时间曲线为一级吸收二室开放模型,22例肝移植受者在口服FK506后,血药浓度迅速上升达到峰值,然后迅速下降,PK参数分别为t1/2a为(1.2±2.1)h,t1/2β(21.0±10.1)h,Ka(2.2±0.9)·h-1,CLs(0.64±0.3)L·h-1·kg-1,AUG0-12为(136.2±33.7)μg·h·L-1.本实验中和AUC相关性最好的是G、C4、C8,r分别为0.95,0.94,0.91.结论:肝移植患者口服FK506药动学个体差异大,用药应个体化.根据PKBP-N1分析得到的药动学参数,能较好的体现患者的药动学信息,根据单点血药浓度可以比较准确的预测AUC0-12.     

成人肝移植术后他克莫司群体药动学研究

目的：应用非线性混和效应模型考察中国肝移植患者他克莫司群体药动学特征。方法：回顾收集天津市第一中心医院成人肝移患者57例,1 094个他克莫司谷浓度点,验证组患者10例,183个谷浓度点。采用一房室模型,分析处理数据,采用NPDE、Bootstrap和外部验证的方法对模型进行评估。结果：最终模型显示血红蛋白（HGB）和术后时间（POD）为影响清除率的主要因素。药动学参数的群体典型值：清除率（CL/F）估算值为19.8 L·h^-1,表观分布容积估算值为597 L。模型评价显示该模型及所估算参数稳定。结论：本研究所建立的成人肝移植受者口服他克莫司的群体药动学模型能较好地估算患者的个体及群体药动学参数,为今后肝移植患者个体化给药方案的制订提供相关参考。     

调整给药方案对他克莫司低谷浓度肝移植患者的影响

目的:研究他克莫司在低谷浓度肝移植患者的药动学,并在每天总药量不增加的前提下,调整给药方案,使患者的谷浓度达到有效浓度范围。方法:对6例低谷浓度的肝移植患者进行药动学研究,将每12小时给药1次改为每8小时给药。采用微粒子酶免疫分析法(MEIA)测定血药浓度,比较给药方案调整前、后他克莫司谷浓度。结果:调整后的他克莫司平均谷浓度高于调整前的谷浓度(P<0.05),他克莫司的平均谷浓度由调整前的5.8μg.L-1升至调整后的7.8μg.L-1,升高了23.3%。结论:对于他克莫司低谷浓度的肝移植患者,在不增加日给药剂量的前提下,可以通过缩短给药间隔增加谷浓度,使血药浓度更加平稳。     

他克莫司群体药动学在儿童肝移植中的研究进展

他克莫司治疗窗窄，药动学个体差异大，临床难以建立儿童受者的个体化治疗方案。群体药动学（PPK）在个体化给药研究方面有巨大优势。为了实现他克莫司在儿童肝移植受者中的个体化治疗，国内外学者致力于儿童肝移植受者的PPK研究，但各研究的结果存在差异。本文通过检索PubMed、Web of Science及Scopus数据库中的相关文献，着重分析了既往他克莫司PPK在儿童肝移植受者中的研究，总结影响他克莫司PPK参数的主要因素，期望应用PPK方法为构建儿童肝移植受者的个体化治疗方案奠定基础。     

肝移植受者他克莫司治疗窗浓度的初步探讨

目的探讨肝移植受者他克莫司治疗窗浓度参考范围。方法采用化学发光微粒子免疫法(CMIA)监测他克莫司全血谷浓度(C0),结合受者的临床表现及生化指标,对74例肝移植受者的305例次监测结果进行分析。结果肝移植术后前3个月他克莫司C0为(7.0±3.6)ng/ml,3个月后为(5.5±2.3)ng/ml。术后发生急性排斥反应4例次,肝、肾毒性54例次。结论建议将实验室他克莫司治疗窗范围进行调整:肝移植术后前3个月为7～15ng/ml,3个月后为5～10ng/ml,以保证免疫抑制效果,减少排斥反应和肝、肾毒性。     

环孢素A与他克莫司应用于肝移植受者的药物经济学评价

目的评价环孢素A胶囊与他克莫司胶囊治疗肝移植受体排斥的经济性。方法选择在我院接受肝移植,并于2010年1月-2011年12月在门诊继续治疗的患者共60例,比较用药半年后的临床疗效、不良反应及用药成本,运用药物经济学的最小成本分析法对两种药物的经济效果进行评价。结果环孢素A胶囊组总有效率为78%,他克莫司胶囊组为86%,两组比较差异无统计学意义(P>0.05),环孢素A胶囊组的不良反应发生率较他克莫司胶囊组低。成本/效果比(C/E):环孢素A胶囊组为55.81,他克莫司胶囊组为46.19。结论与环孢素A胶囊比较,他克莫司胶囊用于肝移植受者更为经济有效。     

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。     

他克莫司与环孢素肝移植术后疗效对比的 Meta 分析

目的：评价肝移植术后使用免疫抑制剂他克莫司（Tac）和环孢素（CsA）的疗效差异和安全性。方法采用中英文数据库进行文献检索,英文数据库包括 Pubmed、Medline、Embase 和 Cochrane library,中文数据库包括CNkI、VIP、万方。纳入随机对照试验（RCT）,对纳入的文献进行方法学评价和 Meta 分析。结果共纳入17篇 RCTs;Meta 分析结果显示,Tac 对比 CsA,患者生存率差异无统计学意义,移植物存活率和急性排斥反应 Tac 优于 CsA,但他克莫司组的糖尿病发生率较高,差异具有统计学意义。结论肝移植术后 Tac 抗排斥反应治疗效果优于 CsA,但会导致更多患者糖尿病的发生。     

Extrapolation of physiologically based pharmacokinetic model for tacrolimus from renal to liver transplant patients

Physiologically based pharmacokinetic (PBPK) modeling is useful for evaluating differences in drug exposure among special populations, but it has not yet been employed to evaluate the absorption process of tacrolimus. In this study, we developed a minimal PBPK model with a compartmental absorption and transit model for renal transplant patients using available data in the literature and clinical data from our hospital. The effective permeability value of tacrolimus absorption and parameters for the single adjusting compartment were optimized via sensitivity analyses, generating a PBPK model of tacrolimus for renal transplant patients with good predictability. Next, we extrapolated the pharmacokinetics of tacrolimus for liver transplant patients by changing the population demographic parameters of the model. When the physiological parameters of a population with normal liver function were changed to those of a population with impaired hepatic function (Child-Pugh class A) in the constructed renal transplant PBPK model, the predicted tacrolimus concentrations were consistent with the observed concentrations in liver transplant patients. In conclusion, the constructed tacrolimus PBPK model for renal transplant patients could predict the pharmacokinetics in liver transplant patients by slightly reducing the hepatic function, even at three weeks post-transplantation.     

Identification of tolerant recipients following liver transplantation

The need to administer livelong immunosuppressive medication (IS) to transplant recipients to prevent graft rejection often results in severe side effects like infections, malignancies, renal failure and cardiovascular complications. This constitutes one of the major drawbacks of clinical organ transplantation. Therefore, a means to establish medication-independent graft acceptance (tolerance) would be a major breakthrough in the field. Transplantation tolerance can be readily generated in experimental animal models, but so far most efforts to purposely induce this phenomenon in the clinic have failed. Liver transplantation is a unique clinical setting in that up to 20% of recipients can spontaneously withdraw IS without rejecting their grafts and are considered as operationally tolerant. This clinical observation is probably the most extreme manifestation of the well-documented intrinsic tolerogenic properties of the liver. The high rate of spontaneous operational tolerance following liver transplantation and the relative resistance of liver allografts to the effects of cytopathic alloimmune responses make liver transplantation the most suitable clinical transplantation model to test IS withdrawal strategies and tolerance promoting therapies. Liver transplantation constitutes therefore a unique setting to learn the mechanisms underlying allograft tolerance in humans.     

A comparison of the pharmacokinetics of tacrolimus and microemulsified cyclosporin in paediatric renal transplant recipients

Objective Our objective was to identify common factors that determine the dose of tacrolimus and microemulsified cyclosporin in paediatric renal transplant recipients.Methods The concentration profiles of tacrolimus and cyclosporin in blood were determined in 68 children who had received a renal transplant. To avoid disruption of therapy, measurements were made at 2-h intervals over an 8-h period during normal dosing regimens. Direct comparisons of the two drugs were made in 14 of the subjects who were switched from cyclosporin to tacrolimus.Results The ratio of peak to trough levels for tacrolimus was approximately twofold compared with over threefold for cyclosporin. Area under the curve (AUC) for tacrolimus remained relatively constant in each 2-h period of the dosage interval compared with the AUC for cyclosporin, which varied by over twofold in the same time period. In the 14 subjects who received both drugs, there was a poor correlation between C₂/C₀, C₂, t_1/2 and AUC for tacrolimus and cyclosporin in the same individual. In a multivariate analysis, there were no significant associations for tacrolimus concentrations, AUC or C₂/C₀ with age, gender, calcium-channel blocker, quinolone or statin. For cyclosporin, there was some association for AUC with gender and quinolone use and a weak association with calcium-channel blocker or statin use.Conclusions Tacrolimus and microemulsified cyclosporin display a wide intra- and inter-individual variation in pharmacokinetic properties in young subjects. In the case of absorption represented by the peak-trough ratios, the values for tacrolimus are significantly less than those obtained with cyclosporin. The pharmacokinetic parameters obtained for one of these agents is not predictive for the behaviour of the other in young renal transplant recipients.