中国汉族人群中CYP3AP1基因型与CYP3A活性的相关性研究

目的:研究中国汉族人群中CYP3AP1基因型的分布特征及其与CYP3A活性的相关性.方法:以口服7.5mg咪哒唑仑后1小时血浆中1′-羟化咪哒唑仑与咪哒唑仑的比值作为CYP3A活性的衡量指标,测定191名中国汉族健康受试者的CYP3A活性,并利用多聚酶链式反应-限制性片段长度多态性(PCR-RFLP)方法对已知CYR3A活性受试者的DNA进行CYP3AP1基因分型.结果:CYP3AP1不同基因型个体的CYR3A活性存在显著差异(P<0.05).A_(-44)等位基因纯合子个体的CYP3A活性低于A_(-44)G杂合子,而G_(44)等位基因纯合子个体的CYP3A活性最高.结论:CYP3AP1基因型与体内CYP3A活性的增加存在相关性.     

肾移植免疫抑制治疗方案的决策树分析

目的:评价肾移植应用免疫抑制剂维持治疗方案。方法:采用药物经济学决策树模型分析方法,选择期望成本最小治疗方案来评价免疫抑制维持的效果。结果:每治疗1例肾移植,霉酚酸酯治疗方案与硫唑嘌呤治疗方案的例均移植治疗费用分别为4．59万元和4．63万元;但期望治疗成本霉酚酸酯方案为6．28万元,硫唑嘌呤方案为7．22万元。结论:霉酚酸酯方案对于肾移植长期治疗者是一个较好的方案。     

肾移植术后环孢素A治疗窗浓度的临床研究

目的：探讨肾移植（RT）术后患者在不同时期环孢素A（CsA）的血药浓度与临床的关系，寻找适合国人肾移植受者理想的CsA治疗窗浓度范围。方法：采用荧光偏振免疫（FPIA）法，对30例肾移植受者进行常规CsA血药浓度检测，并结合患者临床症状进行归纳，分析，统计。结果：CsA式肾移植后＜1月，1月－＜3月，3月－＜6月，6月－＜12月，1年以上理想治疗窗应分别为：250－450。250－400，180－350，150－300，100－250μg.L^-1。结论：根据患者的实际情况具体分析，将CsA血药浓度调整到治疗窗内，避免毒性反应和排异反应的发生。     

肾移植术后免疫抑制治疗药物的经济性评价研究综述

近年,已有众多研究人员对免疫抑制剂用于肾移植术后治疗的经济性进行评价。本文通过系统综述的方法,以了解国内外针对肾移植术后免疫抑制治疗药物的经济性研究方法和结果,从而了解该领域的经济学评价方法和结果的进展,以期为我国免疫抑制剂的临床合理使用及今后开展类似的经济性评价研究提供借鉴。     

不同免疫抑制治疗方案对肾移植的成本效用分析

随着越来越多的免疫抑制药物进入临床应用,肾移植术后发生急性排斥反应率明显降低,而且患者生存率和器官存活率也明显增加[1]。本研究旨在探讨肾移植治疗方案的综合效果,既充分提高患者的健康水平,又有效利用有限的卫生资源。1研究对象与方法资料来源于1999-09—2003-09,本院移植中心接受的同种异体肾移植患者249例。进入MMF方案有117例,男57例,女114例,年龄为(43±12.2)岁;进入Aza方案有78例,男26例,女52例,年龄为(46.1±11.9)岁。药物霉酚酸酯胶囊,为上海罗氏制药公司生产($770/包);硫唑嘌呤,为葛兰素-威康公司生产($272/瓶)。治疗MMF…     

肾移植患者的免疫抑制治疗药物

对于许多慢性肾功能不全或晚期肾衰竭的患者 ,肾移植是一种替代治疗方法 ,但其花费昂贵 ,且为了预防同种移植发生的排斥反应需要持续进行免疫抑制治疗 ,尤其是抗基底膜抗体阳性的患者术后免疫抑制治疗常持续６周～８周［１］。排斥反应的类型主要有两种 :(１)超急性反应发生于肾移植术后数小时内 ,因术前进行ＨＬＡ组织配型和血型交叉配型测试 ,其发生率极低。急性反应常发生于术后几个月内 ,约５０ %在术后３个月内发生。血清肌酸酐值突然增高预示急性反应有可能发生 ;此外 ,患者反应时还可能出现血压升高、尿排出量减少、肾区疼痛 ,此时可…     

两组免疫抑制方案用于肾移植术后的对比研究

目的 比较肾移植患者术后应用他克莫司(FK506)或环孢素A(CsA)为基础的2种免疫抑制方案的疗效和安全性.方法 .肾移植患者57例分成2组,FK506组为25例,CsA组为32例.观察肾移植后1年内两组的急性排斥发生率、药物性肝肾损害发生率、血糖异常及感染的发生情况.结果 两组免疫抑制方案在肝肾损害发生率、感染发生率以及对血糖的影响方而差异无统计学意义.结论 两种免疫抑制方案在肾移植术后具有同样的临床应用价值.     

细胞色素P450的工具药选择及种属差异的研究进展

药物对代谢酶的影响以及代谢产生的药物相互作用与药物安全性密切相关。细胞色素P450(CYP)是参与内、外源性化合物I相代谢反应的重要超家族酶系。特异性探针、诱导剂、抑制剂以及实验动物模型广泛应用于CYP介导的代谢途径以及药物相互作用研究。已知CYP底物存在明显重叠性,且表达调控机制种属差异显著,故研究中选择适当的实验动物以及特异性的探针、诱导剂和抑制剂,成为影响数据外推的关键问题。本文简要综述了CYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP3A4/5的常用体内外探针、诱导剂、抑制剂以及动物种属表达调控的差异。     

细胞色素P450—3A4相关的药物相互作用

目的：综述与细胞色素P4503A4相关的药物相互作用。方法：检索Medline和中国药学文摘。结果：发现多种由CYP3A4催化代谢的药物之间可以竞争药物代谢酶,引起药物相互作用,CYP3A4的抑制剂和诱导剂均可以抑制或诱导CYP3A4催化代谢的药物代谢。导致有益或不良的药物相互作用。结论：CYP3A4催化代谢的药物联合使用,特别是CYP3A4抑制剂与底物联合使用时,可能因为抑制了药物的代谢而导致严重的药物不良反应。     

撤除激素的肾移植免疫抑制方案研究

目的观察在应用巴利昔单抗的基础上,早期撤除激素的免疫抑制剂方案临床效果。方法21例肾移植患者在应用巴利昔单抗的同时联合他克莫司(FK506)和霉酚酸酯(MMF),早期撤除激素,随访观察急性排斥发生情况,以及对血糖血脂代谢的影响等。结果巴利昔单抗联合FK506和MMF,早期撤除激素,使急性排斥发生率明显降低同时,也降低高血糖、高血脂等代谢紊乱发生率。结论应用巴利昔单抗同时联合强有力的免疫抑制剂FK506和MMF,调整药物FK506浓度于治疗窗范围,早期撤除激素,是安全有效的方案。     

狼疮性肾炎免疫抑制治疗研究进展

狼疮性肾炎（Lupus nephritis,LN）是系统性红斑狼疮（systemic lupus erythematosus,SLE）最常见且最严重的并发症,是造成SLE患者死亡的主要原因。随着社会工业化,环境污染加重,LN已成为我国最常见的继发性肾小球疾病之一。 LN的治疗原则包括免疫抑制治疗和支持治疗,治疗的最终目的是防止狼疮性肾炎的进展及复发,保护肾功能,防止治疗带来的损伤,提高患者的生活质量和生存率。经过几十年的探索,LN的免疫抑制治疗已经取得了一定的进展。该文就LN的免疫抑制治疗方案以及研究进展进行了综述。     

他克莫司免疫抑制方案改善儿童肝移植术后的研究进展

肝移植作为一种有效的治疗手段广泛地应用于儿童终末期肝病的治疗。为了预防可能发生的排斥反应,患儿需要长期服用免疫抑制剂。他克莫司是一种具有强效免疫抑制特性的大环内酯类药物,以他克莫司为主的免疫抑制方案可以减少排斥反应和激素抵抗型排斥反应的发生率。探讨了基因多态性、减少剂量或撤药、不同剂型之间转换以及免疫抑制剂短期、长期生存结果对儿童肝移植术后的影响,以期优化他克莫司的给药方案,为器官移植患儿的他克莫司药物监测和剂量调整提供参考。     

Inflammatory bowel disease after liver transplantation: the effect of different immunosuppressive regimens

BACKGROUND: Seemingly conflicting results have been reported on the prevalence and severity of inflammatory bowel disease after liver transplantation. Regimens with different combinations of drugs can be used for immunosuppression after transplantation. AIM: To study retrospectively the prevalence of inflammatory bowel disease after liver transplantation, and the possible relationship with maintenance immunosuppressive regimens. METHODS: All 78 patients with end-stage primary sclerosing cholangitis (48 patients) or autoimmune cirrhosis (30 patients), transplanted between 1979 and July 2001, and with a follow-up of at least 1 year, were eligible for this study. In addition to patient and transplant characteristics, data on inflammatory bowel disease and immunosuppression before and after transplantation were collected. The Kaplan-Meier method was used for survival analysis. Possible risk factors for inflammatory bowel disease after transplantation were analysed by Cox univariate and multivariate regression. RESULTS: The median follow-up after transplantation was 7.2 years (range, 1.1-22.3 years). Nine of 25 patients with pre-transplant inflammatory bowel disease experienced flare-ups after transplantation. Six of 53 patients without pre-transplant inflammatory bowel disease developed de novo inflammatory bowel disease after transplantation. The cumulative risks (standard errors in parentheses) for inflammatory bowel disease were 6% (3%), 12% (4%) and 20% (5%) at 1, 3 and 5 years after transplantation, respectively. The inflammatory bowel disease-free survival was significantly higher in patients not receiving tacrolimus vs. those receiving tacrolimus, in patients receiving azathioprine vs. those not receiving azathioprine and in patients taking the regimen prednisolone-azathioprine-ciclosporin A vs. those taking tacrolimus-prednisolone. Pre-transplant inflammatory bowel disease and the use of tacrolimus were found to be independent predictors for inflammatory bowel disease after transplantation. CONCLUSIONS: The prevalence of inflammatory bowel disease after liver transplantation is affected by the immunosuppression used. Azathioprine seems to have a protective effect and tacrolimus a promoting effect.     

Model-informed precision dosing to optimise immunosuppressive therapy in renal transplantation

Immunosuppressive therapy is pivotal for sustained allograft and patient survival after renal transplantation. However, optimally balanced immunosuppressive therapy is challenged by between-patient and within-patient pharmacokinetic (PK) variability. This could warrant the application of personalised dosing strategies to optimise individual patient outcomes. Pharmacometrics, the science that investigates the xenobiotic–biotic interplay using computer-aided mathematical modelling, provides options to describe and quantify this PK variability and enables identification of patient characteristics affecting immunosuppressant PK and treatment outcomes. Here, we review and critically appraise the available pharmacometric model-informed dosing solutions for the typical immunosuppressants in modern renal transplantation, to guide their initial and subsequent dosing.     

Combating chronic renal allograft dysfunction : optimal immunosuppressive regimens

Kidney transplantation is the best treatment for patients with end-stage renal disease, both in terms of survival benefit and quality of life. The major limitation is the continuing shortage of kidneys suitable for transplantation, reinforcing the need to maximise graft survival. After the first year of transplantation, chronic renal allograft dysfunction (CRAD) is the first cause of late graft deterioration and failure. CRAD has been defined as a progressive renal dysfunction, independent of acute rejection, drug toxicity and recurrent or de novo nephropathy, with features on biopsy of chronic allograft nephropathy (CAN) characterised by vascular intimal hyperplasia, tubular atrophy, interstitial fibrosis and chronic transplant glomerulopathy. Protocol biopsy-based studies have demonstrated a high and early prevalence of CAN lesions during the first year in patients with normal and stable renal function. Beyond 1 year, the injuries associated with calcineurin inhibitors (CNIs) appear to be very common. The physiopathology of CRAD is complex and multifactorial. Both alloantigen-dependent factors (acute rejection, HLA matching, donor-specific antibodies, inadequate immunosuppression) and alloantigen-independent factors (donor age, brain death, ischaemia/reperfusion injuries, hypertension, hyperlipidaemia, cytomegalovirus, CNI-related nephrotoxicity) are involved. Consequently, CRAD appears as a dynamic process, evolving with time, and immunosuppressive regimens need to be modulated in order to provide the most suitable treatment at the different phases of its natural history. On the basis of this scheme, the new paradigm would be the use of a CNI-based regimen during the period of maximal risk of (subclinical) acute rejection, followed by a conversion to a CNI-free regimen in order to avoid the long-term consequences of nephrotoxicity. Fortunately, new agents are being introduced in clinical practice providing a large range of combinations and allowing individualisation of immunosuppressive regimens. Large, prospective, multicentre trials are warranted, and the challenge is to define new endpoints of CRAD and to determine the best therapeutic strategy.     

Current immunosuppressive treatment after kidney transplantation

Introduction: Since 1995, several immunosuppressive drugs have entered the field of organ transplantation: tacrolimus, mycophenolate and the mTOR-inhibitors. Now treating physicians have a choice.

Areas covered: The authors review the important studies on immunosuppressive drugs used at present after kidney transplantation, published in the last three decades. This review also discusses the available evidence for selecting one of the calcineurin inhibitors, antiproliferative agents and induction therapy. Interesting new drugs are discussed briefly.

Expert opinion: Calcineurin inhibitors (CNIs) are considered, especially in de novo transplantation, to be the most effective maintenance drugs to prevent acute rejection. Combining CNI with mycophenolate or an mTOR-inhibitor has made it possible to reduce CNI dose and diminish nephrotoxicity. Uniform treatment regimes according to guidelines are useful but should leave room for adjustment to the needs of individual patients. Longer follow-up studies are needed to decide on the optimal maintenance treatment.     

IL-2, IL-6 and IL-8 levels remain unaltered in the course of immunosuppressive therapy after renal transplantation

Cytokines regulate the immune reactions elicited by renal transplantation (RT). This study was designed to investigate the blood serum levels of IL-2, IL-6, IL-8 in 25 RT patients (10 female and 15 male, mean 5.4±2.7 yrs after RT) three times over a six-month period during standard immunosuppressive therapy with cyclosporine A, azathioprine and prednisolone. The levels of IL-2, IL-6 and IL-8 were tested with ELISA Quantikine Human Interleukin Immunoassay (R&D Systems, detection level 7,0.7 and 10 pg/cm³, respectively). There was no significant alternation of blood serum levels of IL-2, IL-6 and IL-8 in the study patients.     

Current immunosuppressive treatment after kidney transplantation

INTRODUCTION: Since 1995, several immunosuppressive drugs have entered the field of organ transplantation: tacrolimus, mycophenolate and the mTOR-inhibitors. Now treating physicians have a choice. AREAS COVERED: The authors review the important studies on immunosuppressive drugs used at present after kidney transplantation, published in the last three decades. This review also discusses the available evidence for selecting one of the calcineurin inhibitors, antiproliferative agents and induction therapy. Interesting new drugs are discussed briefly. EXPERT OPINION: Calcineurin inhibitors (CNIs) are considered, especially in de novo transplantation, to be the most effective maintenance drugs to prevent acute rejection. Combining CNI with mycophenolate or an mTOR-inhibitor has made it possible to reduce CNI dose and diminish nephrotoxicity. Uniform treatment regimes according to guidelines are useful but should leave room for adjustment to the needs of individual patients. Longer follow-up studies are needed to decide on the optimal maintenance treatment.     

Current and future immunosuppressive strategies in renal transplantation

The past decade has witnessed the introduction of several new immunosuppressive agents. The availability of these new pharmacologic offerings has not diminished the challenge of achieving a balance of adequate graft protection while minimizing the consequences of excessive immunosuppression. For renal transplant recipients, maintenance immunosuppression generally consists of a calcineurin inhibitor in combination with an antiproliferative agent and a corticosteroid; more recently, mammalian target of rapamycin inhibitors have been used. Excellent results have been achieved at many transplant centers with combinations of these agents in a variety of protocols. Regimens designed to limit or eliminate calcineurin inhibitor and/or corticosteroid therapy are actively being pursued in the transplant community. Allograft tolerance and xenotransplantation are being studied, and the knowledge gained from the effort may help in the development of innovative strategies and new immunosuppressive agents.