心脏移植受者FK506治疗窗的临床初探

目的 寻求适合中国人心脏移植受者FK506理想治疗窗谷浓度范围。方法 应用微粒子酶免疫分析法（MEIA）测定6例心脏移植受者口服FK506后全血谷浓度,以FK506谷浓度结合病人临床疗效及不良反应的情况,总结FK506在心脏移植术后的治疗窗。结果 术后1年病人的FK506谷浓度控制在5-25ng/ml,未出现严重的排异反应和肾毒性,但术后早期曾出现头痛和震颤等不良反应。结论 FK506具有良好的免疫抑制效果,其治疗窗谷浓度范围,术后第1个月内为：15-20ng/ml,第2-3个月10-15ng/ml,第4-6个月8-12ng/ml,6个月后5-8ng/ml。此浓度范围即可有满意的免疫抑制效果。又可减少FK506的肾毒性。     

FK506研究进展

FK_(506)是1984年日本Fujasawa药物公司从土壤真菌(Streptomyces tsukubaensis)的发酵肉汤中分离出的大环酯类抗生素,分子量为822kd,化学分子式为C_(44)H_(69)NO_(12)H_(12)。不溶于水,易溶于甲醇、乙醇、丙酮等有机溶剂。在体内广泛分布于各种组织,主要通过肝脏代谢。口服吸收情况与Cy相似,但不依赖于胆汁。半衰期为3.5～40.5小时,个体差异大。影响半衰期的主要因素是肝功能。肝功能异常时,FK_(506)半衰期明显延长。     

FK506对小鼠移植心脏中白细胞介素12mRNA的抑制作用

用反转多聚酶链反应（ＲＴ－ＰＣＲ）方法检测白细胞介素１２（ＩＬ－１２）及白细胞介素２（ＩＬ－２）ｍＲＮＡ在移植心脏及宿主脾脏中的变化。结果在移植物和宿主脾脏中ＩＬ－１２及ＩＬ－２ｍＲＮＡ呈增加调节，ＩＬ－１２及ＩＬ－２在移植心脏中的增加均被ＦＫ５０６抑制，而宿主脾脏中的ＩＬ－１２ｍＲＮＡ不受ＦＫ５０６的影响。认为ＦＫ５０６在抑制排斥反应的同时不影响宿主对肿瘤和病毒感染的防御。     

FK506与心脏移植

ＦＫ５０６与心脏移植孟旭综述陈宝田审校作者单位：１０００２９首都医科大学附属安贞医院心外科ＦＫ５０６是土壤链霉菌属提取的抗霉素代谢物。日本学者〔１，２〕首先做了基础研究报道；多项体外实验表明ＦＫ５０６有良好的免疫抑制效应，其免疫抑制有效浓度（ＩＣ５０...     

异体肢体移植应用 FK506 免疫抑制治疗的临床观察

目的探讨以“小剂量”FK506为基础的联合免疫抑制治疗方案在异体肢体移植中的可行性和疗效。方法2例异体肢体移植术后应用以FK506为基础的联合免疫抑制治疗方案,即口服FK5061mg,1次/d;骁悉500mg,2次/d;强的松80mg,1次/d,以后每周减5～10mg,至10mg/d维持量。结果经术后一年临床观察,移植肢体未出现明显排斥反应和常见的毒副作用,移植左手、右拇指血循环、皮肤温度、颜色与正常对侧相同,感觉恢复到指尖,功能恢复满意。结论FK506是一种安全高效的免疫抑制剂,经初步临床观察,以“小剂量”FK506为基础的联合免疫抑制治疗方案在异体肢体移植中是可行的,且毒副作用少。     

FK—506的免疫抑制作用

据文献报道,新型免疫抑制剂FK-506的免疫抑制作用是环孢素的100倍。其作用机理类似环孢素,能抑制白介素Ⅱ的产生和受体的表达;副作用远较其它同类药物小。本文介绍FK-506的发现、结构、理化性质、免疫抑制作用及其机理和毒性作用。     

FK506和抗淋巴细胞血清诱导兔异体膝关节移植耐受的实验研究

目的　探讨短期使用FK5 0 6和抗淋巴细胞血清 (ALS)诱导兔同种异体膝关节移植嵌合耐受的作用。　方法　雄性大耳白兔作为供体 ,雌性新西兰白兔作为受体 ,施行同种异体异位膝关节移植 ,设单独使用ALS( 1ml/kg)组、单独使用FK5 0 6( 0 5mg/kg)组、联合使用FK5 0 6和ALS组及对照组。FK5 0 6和ALS在移植术前 1d开始使用 ,ALS连续使用 3d ,FK5 0 6连续使用 15d。观察移植物的存活时间 ,检测受体内供体血细胞嵌合率 ,进行组织切片检查。　结果　对照组平均存活 ( 13 6± 0 8)d ,单独使用ALS组为 ( 17 4± 1 8)d ,单独使用FK5 0 6组为 ( 2 3 8± 1 5 )d ,联合使用FK5 0 6和ALS组为 ( 4 0 4±2 9)d。联合使用FK5 0 6和ALS组的供体血细胞嵌合率停药后 3周稳定在 10 %以上。　结论　短期使用FK5 0 6和ALS可显著延长兔同种异体膝关节移植的存活时间 ,可维持 3周的嵌合耐受。     

免疫抑制剂FK506对雪旺细胞的影响

周围神经损伤后，雪旺细胞对周围神经再生过程中的形态和功能的修复起着至关重要的作用。其增殖速度的提高可大大改善神经移植桥接体的存活率，但免疫排斥反应仍是影响异体组织工程化神经移植成败的关键所在。迄今为止，已经有很多免疫抑制剂应用于临床。免疫抑制剂FK506能有效地抑制周围神经同种异体和异种移植中的排斥反应。本综述从免疫抑制剂FK506的理化性质和作用机制及其对雪旺细胞增殖的影响因素入手，阐述免疫抑制剂FK506对雪旺细胞的增殖作用，为FK506进一步的深入研究和临床应用提供理论依据。     

不同血药浓度FK506在肝移植术后应用的比较

目的总结肝脏移植术后应用免疫抑制药他克莫司(FK506)的经验。方法回顾性分析52例乙肝后肝硬化失代偿期肝移植患者的临床资料,依据术后应用FK506的浓度分为两组,观察其两组的术后存活率、移植肝功能及并发症发生情况。结果术后1年人/肝存活率、急性排斥反应及HBV再感染发生率,两组差异无统计学意义,肝功能在术后3、6个月两组之间差异有统计学意义,其余时间点差异无统计学意义,而术后肺部感染、新发糖尿病及高血脂发生率情况,两组差异有统计学意义。结论肝移植术后应用低剂量FK506更安全有效,术后一些并发症的发生和该药物的浓度有一定的相关性。     

FK506 conversion for intractable rejection of the liver allograft

Twenty-seven liver transplant recipients with intractable, biopsy-proven, acute or chronic rejection (defined as vanishing bile duct syndrome) were conerted from cyclosporin to FK506. Successful conversion was achieved in 9 of 15 patients with acute rejection and in 6 of 12 patients with vanishing bile duct syndrome. A normal bilirubin was achieved more quickly in those with acute rejection (within 1 moth) than in those with chronic rejection (within 3 months). A preconversion total bilirubin of less than 12 mg/dl was considered significant with regard to a successful outcome (P=0.002). Graft survival was 66.7% and patient survival 73% in the case of acute rejection, and 50% and 66.7%, respectively, in the case of chronic rejection. Nephrotoxicity, neurotoxicity, and gastroitestinal side effects were the most serious complications of FK506 conversion. Six of ten patients had a drop in GFR that was 50% or greater a minimum of 1 month of FK506 exposure. The mean maintenance dose of FK506 to maintain FK506 serum levels of 0.5–1.5 ng/ml was 0.07 mg/kg per 12 h for adults (half the recommended dose), compared to 0.15 mg/kg per 12 h for pediatric patients. This study demonstrates that FK506 can be used successfully to convert patients with intractable acute and chronic rejection. Careful adjustments of FK506 dosages and levels are required to minimize side effects.     

A comparative study of FK506 granules and capsules in renal transplant recipients

Nine renal transplant recipients in stable systemic condition on FK506 capsules were converted to FK506 granules in order to investigate the safety, efficacy, and pharmacokinetics of the granular formulation of FK506. The study period for the administration of FK506 granules was 4 weeks, and in principle, the oral dose was the same as that of the FK506 capsules. Renal graft function remained stable and no rejection signs were noticed while the patients were taking the granules. The area under the blood concentration-time curve (AUC), the maximum blood level (C_max), and the time to reach C_max (T_max) after FK506 capsules and FK506 granules were, respectively, 93.1 ± 66.4 and 97.0 ± 89.1 ng · h/ml (P = 0.81), 12.7 ± 7.1 and 15.2 ± 11.7 ng/ml (P = 0.39), and 2.0 ± 1.7 and 1.3 ± 0.6 h (P = 0.29). The mean trough blood level during FK506 medication was 4.25 ± 3.42 and 4.02 ± 3.83 ng/ml, respectively, for the capsules and the granules. FK506 granules, a new formulation, showed an efficacy comparable to that of the FK506 capsular formulation. Received: 28 July 1997 Received after revision: 25 November 1997 Accepted: 14 January 1998     

FK506 Nephrotoxicity

Tacolimus (FK506) is a potent immunosuppressive agent with significant nephrotoxic properties. FK506 is completed with an intracellular binding protein FKBP-12. Both the immunosuppressive and nephrotoxic effects may be linked to the inhibitory effect of this complex on calcineurin. The initial phase of FK506 nephrotoxicity is associated with a reduction in renal blood flow and glomerular filtration rate. More significant microvascular injury may follow with endothelial damage. Tubular epithelial cell vacuolation, atrophy and micocalcification may be associated with the development of irreversible interstitial fibrosis. At times, mesangial cell proliferation adds to the glomerular abnormalities.

These effects may be mediated by the inhibitory effect on calcineurin and its role in regulating cellular calcium channels. FK506 stimulates several inflammatory cytokines, such as transforming growth factor-beta, with potential deleterious effects. Also abnormalities in the reninangiotensin system, endothelin, renal prostaglandins, adrenergic receptors may all play a role in the nephrotoxic effects.     

Sensitivity of baboon lymphocytes to cyclosporin A and FK 506: relative resistance of alloactivated cells to CyA

The interspecies differences in CyA pharmacokinetics necessitate the establishment of optimal immunosuppressive doses in the baboon, especially as its use as host for preclinical xenografts is anticipated. We assessed the immunosuppressive effects of CyA and FK 506 on lymphocytes from charma baboons, using human cells for comparison. At concentrations up to 100 mol/l, neither drug was toxic to lymphocytes. FK 506 inhibited baboon and human lymphocyte proliferation and IL-2 synthesis equally. In contrast, approximately four times higher doses of CyA were needed to inhibit baboon lymphocytes responding to alloantigens. This may explain the inadequate immunosuppression of baboon graft recipients treated with clinically acceptable doses of CyA. We propose that CyA whole blood target levels of ±1500 ng/ml should be used in this species and we provide evidence that chacma baboons are able to tolerate such doses without nephroxicity.     

普乐可复在肾移植中的临床应用

目的 研究普乐可复（ＦＫ５０６）对肾移植患者免疫抑制的疗效与安全性。方法 肾移植术后应用ＦＫ５０６免疫抑制治疗８２例,分为临床验证组４２例和切换治疗组４０例。结果 临床验证组有４０例（９５．２％）肾功能在１４ｄ内恢复正常,１例（２．４％）发生急性排斥反应,经治疗逆转。切换治疗组有２４例肝功能正常;３例移植肾发生急性肾小管坏死（ＡＴＮ）伴急性排斥反应,６例发生慢性排斥反应,４例发生难治性排斥反应,均     

Low-dose tacrolimus (FK506)-based immunosuppressive protocol in living donor renal transplantation

Abstract In order to avoid the side effects of tacrolimus (FK506), a low-dose FK506-based regimen was started from 1 June 1991. The dose was adjusted to maintain the FK506 whole blood trough level at 15–20 ng/ml for 7 days postoperatively, at 10–15 ng/ml for 2 months, and under 10 ng/ml thereafter. The graft survival rates at 3 years and 5 years were 87.8 and 82.3 % (FK506) vs 86.8 and 86.8% [cy-closporine (CyA)]. The incidence of acute rejection within the first 90 days was 31.6% in the FK506 group which was lower than the 57.1% of the CyA group ( P - 0.0585). Grades of acute rejection episodes over IIA in the FK506 group were 20 %, which was lower than the 37 % in the CyA group. The mean oral dosages of FK506 were 0.061 and 0.04 mg/kg per day at 3 and 5 years, respectively. The incidence of new onset diabetes was 27.8% in the FK506 group and 17.1 % in the CyA group. However, insulin therapy was withdrawn in all patients of the FK506 group within 5 months. The percentage of patients who required an antihypertensive agent was 28.6 % and 40 % in the FK506 group and 73.2% and 88 % in the CyA group at 1 and 3 years, respectively ( P < 0.05). Nephrotoxicity was seen in 20% of the FK506 group and 14.3 % of the CyA group. Hypercholesterolemia was less frequent in the FK506 group than the CyA group. The FK506-based regimen described here is a protocol with the potential to reduce its adverse effects. The whole blood concentration of FK506 should be monitored and blood levels maintained in the range of 5–10 ng/ml after 90 postoperative days for optimal efficacy and minimal toxicity.     

FK506对离体肝再灌注后TNF-α mRNA表达的影响

目的探讨 FK506 对肝脏保存再灌注中TNF-α mRNA表达的影响 .方法建立离体大鼠肝脏再灌注模型,应用RT-PCR方法检测TNF-α mRNA的表达,观察FK506对不同时间保存的肝脏TNF-α mRNA表达的影响. 结果 FK506组保存16,24和32h 再灌注,TNF-α mRNA表达分别为0.83±0.07,0.91±0.06和1.32±0.08, 明显低于对照组的0.98±0.05,1.42±0.09和1.86±0.16. 结论 FK506能抑制肝脏保存再灌注中TNF-α mRNA的表达,对离体肝的再灌注损伤可能具有保护作用.     

T细胞疫苗联合FK506抑制异种神经移植排斥的实验研究

目的 研究T细胞疫苗接种联合应用FK506对大鼠异种神经移植排斥反应的抑制作用. 方法 利用BABL/c小鼠的脾细胞免疫SD大鼠,取后者脾细胞活化所制备的T细胞疫苗对异种神经移植受体的SD大鼠进行免疫,移植后联合应用FK506.以异种神经移植后混合淋巴细胞培养、微量细胞毒测定、移植神经的组织学观察和胫前肌湿重测定等,对该方法抗大鼠异种神经移植排斥反应的作用加以分析. 结果 和对照组相比较,T细胞疫苗接种联合FK506使神经移植大鼠胫前肌湿重明显增加(P＜0.05),淋巴细胞转化率等排斥反应指标差异也具有统计学意义(P＜0.05). 结论 T细胞疫苗接种联合应用FK506能显著抑制大鼠异种神经移植的免疫排斥反应.