以FK506为基础的四联免疫抑制方案应用于肝移植的研究

目的 探索以FK506为基础的四联免疫抑制方案在肝移植患者中的应用.方法 2001年2月到2004年7月间40例成人尸体肝移植患者接受以FK506为基础的四联免疫抑制方案,比较高浓度（QH）组与低浓度（QL）组在术后6个月时的有效性与安全性.结果 两组在急性排斥反应率、人/肝存活率、高血压、高血糖、感染的发生率差异均无统计学意义;QL组的手震颤发生率显著低于QH组（χ^2=5.105,P=0.624）,术后15 d、3个月血肌酐水平在QL组显著低于QH组（t15天=2.10,P15天=0.042;t3月=2.45,P3月=0.019）,术后3个月、6个月血胆固醇水平在QL组显著低于QH组（t3月=2.35,P3月=0.024;t6月=2.11,P6月=0.042）.结论 QL组使用四联免疫抑制的安全性较好.用四联方案在术后6个月内FK506的血药浓度可控制在5～8 ng/ml.血胆固醇、血肌酐水平、手震颤的发生率与FK506的血药浓度呈正相关.     

肝移植后他克莫司的用量及血药浓度的变化规律

目的　探讨肝移植后口服他克莫司 (FK5 0 6 )剂量与其全血浓度谷值的关系及浓度随时间而变化的规律。方法　回顾性分析肝移植后存活超过 1年、以FK5 0 6和糖皮质激素预防排斥反应的 2 0例患者的临床资料。结果　FK5 0 6初始口服剂量为 0 .15mg·kg-1·d-1时 ,术后第 1周内有5 3.4 %的血FK5 0 6浓度谷值高于理想治疗窗的 15 μg/L ,2 3.3%在 10～ 15 μg/L的理想范围内 ,2 3.3%低于 10 μg/L ;术后FK5 0 6的浓度 /剂量比值逐渐增高 ,第 2个月为高峰 (2 17.2± 136 .6 ) ,与第3、4、5、6、7、8和 11个月相比 ,差异有显著性 (P <0 .0 5 ) ,全组患者的浓度 /剂量比值总平均数为 190 .3±75 .4 ;维持术后第 1周内FK5 0 6浓度谷值在 10～ 15 μg/L的理想治疗范围内需要的剂量为(0 .10 137± 0 .0 2 6 10 )mg·kg-1·d-1,至 1年时维持浓度谷值为 5～ 7μg/L时需要的剂量为 (0 .0 6 4 6 6± 0 .0 2 797)mg·kg-1·d-1。结论　我国人肝移植后FK5 0 6口服剂量宜从 0 .1mg·kg-1·d-1左右开始 ,术后前 2个月内的血FK5 0 6浓度 /剂量比值高于其后各月的平均值。     

不同血药浓度FK506对亲体肝移植患者安全性的临床观察：附46例临床报告

目的 探讨亲体肝移植术后使用不同血药浓度的免疫抑制剂(FK506)对肝移植患者安全性的影响. 方法 回顾性分析近5年间完成的46例亲体肝移植术患者的临床资料,比较FK506低浓度(3～5 ng/mL, 1年后1～2 ng/mL)组和常规浓度组(10～15 ng/mL, 1年后5～8 ng/mL)在术后1个月的免疫相关并发症的发生率及随访1年移植肝的存活情况和并发症,比较两者的安全性.结果 两组在术后1个月急性排斥发生率、高血压、高血糖发生率和肝功能无显著性差异(P＞0.05),术后感染、肾功能损害低浓度组发生率显著低于正常浓度组(P＜0.05).1年移植肝存活率两者相同,血肌酐水平、感染发生率、黄疸发生率低浓度组显著低于常规组(P＜0.05).结论 低浓度的FK506在围手术期和远期均有较好的安全性.术后感染率,肾功能损害发生率与免疫抑制剂浓度呈正相关.     

他克莫司的20例肝移植中的应用

目的 探讨他克莫司（ＦＫ５０６）在肝移植中的应用方法。方法 ３０例肝移植患者随机分为ＦＫ５０６高浓度组、ＦＫ５０６中浓度组、ＣｓＡ转换为ＦＫ５０６组、ＦＫ５０６转移为ＣｓＡ组。观察各组临床表现、药物副作用病理学变化。结果 ＦＫ５０６高浓度组容易出现感染、药物性肝损害等不良表现，ＦＫ５０６中浓度组叶也出现多种并发站，但易于处理。结论 ＦＫ５０６是一种高效免疫抑制剂，ＦＫ５０６血药中浓度是一种较理想的     

他克莫司延缓移植肾功能衰竭进程的临床研究

目的　观察他克莫司 (FK5 0 6 )延缓慢性移植肾功能衰竭进程的有效性及安全性。方法　选择肾移植术后肾功能异常 ,并经病理证实为慢性排斥反应者 ,将原先以环孢素A (CsA)为基础的免疫抑制方案切换成FK5 0 6为主的免疫抑制方案 ,FK5 0 6起始剂量为 0 .15mg·kg-1·d-1。结果　 10例肾移植受者在换用FK5 0 6治疗后 ,血胆固醇水平和血压明显降低 ,用于控制高血压的药物明显减少 ,血肌酐水平明显降低 ,肾小球滤过率得到明显改善。结论　FK5 0 6对延缓移植肾慢性排斥引起的肾功能衰竭的进程是安全有效的。     

环孢素A与他克莫司对阿霉素治疗肝癌影响的实验研究

20世纪80年代以来，肝移植技术发展迅速，已成为肝脏终末期疾病的重要治疗手段。环孢素A（CsA）与他克莫司（FK506）为目前肝移植术后基本抗免疫排斥药。阿霉素为肝癌的常用的有效化疗药物，CsA、FK506等免疫抑制剂与阿霉素联合应用是否会增加肝癌复发一直困扰着移植外科医师。我们对此进行了深入研究。     

常规剂量他克莫司导致肝移植患者免疫抑制过度一例

他克莫司 (ＦＫ50 6)是一种新型免疫抑制剂 ,临床使用推荐剂量一般为 0 .0 6～ 0 .4ｍｇ·ｋｇ- 1 ·ｄ- 1 ,围手术期维持血药浓度在 5～ 1 5μｇ/Ｌ[1 ] 。我们有 1例肝移植患者在使用上述剂量的ＦＫ50 6后发生免疫抑制过度 ,并发感染 ,报道如下。患者为男性 ,34岁 ,体重 40ｋｇ。因乙型肝炎、肝硬化于2 0 0 1年 7月 2 4日接受肝移植术 ,术后恢复顺利 ,1个月后进普通饮食 ,肝功能正常 ,ＦＫ50 6的用量为 4ｍｇ/ｄ ,同时服用泼尼松 1 0ｍｇ/ｄ ,抗生素及抗真菌药停用 ,血ＦＫ50 6的浓度为9.55μｇ/Ｌ(放射免疫法 )。Ｔ淋巴细胞亚群测定 :Ｃ…     

肝移植术后长期存活慢性肾功能损害受者的免疫抑制方案个体化应用

目的探讨肝移植术后长期存活慢性肾功能损害受者应用个体化免疫抑制方案的疗效。方法选择18岁以上、肝移植术后2年以上、入组前采用以他克莫司(FK506)为基础免疫抑制方案、肝功能正常而肾功能损害的受者,共32例。根据免疫功能评分和白细胞计数制定个体化免疫抑制方案,以FK06用量最小化为原则,转换为麦考酚吗乙酯(MMF)或西罗莫司,并调整其用量。调整后至少每个月随访1次,进行肝功能、肾功能、血常规检查和免疫功能评估。结果 32例受者经个体化免疫抑制方案治疗,随访(24.3±7.6)个月,个体化治疗后各时段的肾小球滤过率(GFR)均较此前有明显提高(均为P<0.01),以调整用药后1个月最明显。无发生排斥反应。结论根据免疫功能评分和白细胞计数制定个体化免疫方案,使FK506用量最小化,可以有效改善肝移植术后长期存活的受者的肾功能,并不增加排斥反应的发生率。     

两剂激素联合两剂达利珠单抗及他克莫司的免疫抑制方案在肝移植中的应用

目的 探讨两剂激素联合两剂达利珠单抗及他克莫司(FK506)的免疫抑制方案在肝移植中应用的安全性及有效性.方法 中山大学附属第一医院器官移植中心2006年9月至2008年3月共实施成人肝移植74例,排除3例血型不合、4例围手术期死亡外,余67例纳人本研究,其中男性54例,女性13例,年龄28～66岁,平均(46.9±8.7)岁.将67例成人肝移植患者随机分为两组:传统免疫抑制方案(激素3个月撤离)组(n=35)和两剂激素免疫抑制方案组(n=32),比较两组术后代谢并发症、感染(含细菌、真菌及巨细胞病毒感染)及排斥反应的发生率的差异.结果 两组患者的术后早期高血糖发生率,高血糖患者使用胰岛素的平均剂量,随访期内糖尿病、高血压及感染的发生率的差异有统计学意义(P<0.05);术后早期高血压发生率及随访期内排斥反应的发生率和高脂血症发生率无明显差异(P0.05).结论 两剂激素的免疫抑制方案是安全有效的,其不增加急性排斥反应的发生率,并可显著减少长期使用激素引起的各种不良反应及并发症的发生.     

肝硬化或肝癌伴银屑病患者肝移植术后治疗经验

目的  总结患有银屑病的肝移植受者免疫抑制治疗的临床经验。 方法 以5例肝硬化或肝细胞癌(肝癌)伴银屑病的肝移植受者为研究对象,其乙型肝炎病毒(HBV)血清标志物均阳性。术前采用诱导方案,术后早期采用他克莫司(FK506)+吗替麦考酚酯(MMF)+肾上腺皮质激素(激素)三联免疫抑制方案,1周内停用激素。3例乙型病毒性肝炎(乙肝)后肝硬化合并肝癌肝移植患者1个月内逐步转换为西罗莫司替代治疗;2例乙肝后肝硬化肝移植受者患者一直采用FK506加或不加MMF方案。全部患者均予抗HBV治疗。分析其基本情况、银屑病皮损面积和严重性指数(PASI)评分变化及术后免疫抑制剂治疗方案的调整情况。结果 5例患者肝移植术后至投稿日随访(8.3±1.5)年,均存活。与术前相比,患者术后6个月PASI评分明显降低(P＜0.05)。2例乙肝后肝硬化肝移植受者患者在术后2年后出现银屑病复发,PASI评分显著升高,改为西罗莫司替代FK506的治疗方案后逐步下降,术后3年开始维持在稳定状态,无进展;3例乙肝后肝硬化合并肝癌肝移植受者无复发。 结论 以西罗莫司为主的免疫抑制治疗方案可有效控制肝移植受者的银屑病病情,对HBV阳性患者应同时进行抗HBV治疗。      

Long-term use of FK 506 in living related liver transplantation

Abstract FK 506 (Tacrolimus) was used with steroids to treat 61 pediatric patients who received living related partial liver transplantation. Fifty-two recipients survived and 9 died between 6 months and 3 years after transplantation. In the surviving patients, oral doses of Tacrolimus were tapered from 0.298 ± 0.277 mg/kg daily at 1 month after transplantation to 0.078 ± 0.054 at 24 months after transplantation. The 12 h trough levels of Tacrolimus were 12.6 ± 7.1 ng/ml and 4.1 ± 2.4 at 1 and 24 months after transplantation, respectively. The percentage of recipients free from steroids was 77%, 97%, and 94% at 6, 12, and 24 months after transplantation, respectively. Liver allograft rejection was encountered in seven recipients, five of whom were treated by steroid pulse therapy and a dose increase of Tacrolimus; the remaining two required OKT3. However, there was no episode of rejection that required retransplantation. Infectious complications encountered in 34 patients included 12 bacterial, 3 fungal, and 19 viral infections. Two recipients died one of fungal pneumonia and one of Epstein-Barr virus-associated lymphoproliferative disorder. Regarding adverse reactions of Tacrolimus, hypertension was observed in 28 patients, diabetes mellitus in 3, pancreatitis in 3, convulsion in 1, tremor in 12, itching in 5, and pigmentation in the oral mucosa in 2. Slightly increased values of creatinine were observed in most of the patients; however, an abnormal increase of serum of serum creatinine (> 1.0 mg/dl) was confined to the complicated cases. Improvement of somatic growth was observed in 21 patients (62%) and 13 (75%) at 12 and 24 months after transplantation, respectively. The long-term use of Tacrolimus is highly effective in terms of its immunosuppressive potential and reduced adverse reaction. Steady growth development can be expected in pediatric recipients free from steroids.     

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     

Conversion from cyclosporin to FK 506 after liver transplantation

Thirty-seven liver-grafted patients with steroid-resistant acute or chronic graft rejection or with cyclosporin-related complications were converted from CyA to FK 506. The clinical outcome of the patients primarily depended on the degree of liver dysfunction present at initiation of FK 506 treatment. In patients switched to FK 506 for treatment of acute or early chronic graft rejection, CyA nephrotoxicity, or CyA malabsorption, the FK 506 therapy was associated with a clear improvement in the clinical course. In contrast, in patients with advanced chronic graft rejection, a lower response rate to the conversion in immunosuppression was observed. The lower response rate was associated with a higher patient mortality. These studies demonstrate that FK 506 represents a valuable alternative immunosuppressant for liver-grafted patients. The conversion from CyA to FK 506 should take place before serious — and potentially irreversible — disturbances in liver function are observed.     

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。     

Comparison of short and long-term renal function in liver transplant patients receiving cyclosporin or FK 506

Abstract Long-term renal function was compared in 49 liver recipients [25 patients received cyclosporin (CyA) and 24 patients received FK 5061 followed for a period of 1 year. Creatinine (CR) and glome-rular filtration rate (GFR) pre-transplantation (pre-Tx) and at 1, 3, 5, and 12 months post-Tx were recorded, as well as incidences of hyperkalemia, post-Tx hypertension, and insulin-dependent diabetes mellitus (IDDM) in the two groups. At 1 year post-Tx, the mean Cr had risen from baseline by 56% and 60% in the FK and CyA groups, respectively; the mean GFR had dropped by 32% in FK patients and by 27 % in CyA patients. Acute nephrotoxicity occurred in 1/25 CyA patients (217 required dialysis) and 9/26 FK patients (7/9 required dialysis; 211 were switched to CyA). None remained on dialysis at 3 months. Renal insufficiency persisted at 1 year in 7/16 patients with early toxicity (CyA, 4; FK, 3) and in 3 of the remaining 36 pts ( P < 0.001). Hyperkalemia occurred in 4/25 CyA, and in 12/24 FK patients ( P < 0.025), post-Tx hypertension occurred in 15 CyA, and 7 FK patients ( P < 0.05), and IDDM occurred in 4 CyA and 7 FK patients ( P = ns). FK 506 and CyA, thus, exerted similar chronic renal effects. Although acute renal insufficiency improved upon dose reduction, renal impairment was permanent in some cases.     

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.     

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     

Neurological examinations after liver transplantation concerning patients under corticosteroid immunosuppression and either FK 506 or cyclosporin

Abstract To study the neurological sequelae in liver transplanted recipients, 25 patients were followed up between 5 and 30 months after transplantation and another 14 patients were seen before and after transplantation. Physical examination took special note of tremor and polyneuropathy; additionally, patients estimated concentration and memory, tremor, paraesthesias and sleep disturbances on a self-rating scale. Tremor was reported to be preexistent in 50% of the later FK 506 and cyclosporin group and only temporarily rose afterwards. Twenty-eight percent complained of tremor and 20 % said that it interfered mildly with daily activity. Only 2 of 39 patients showed new signs of polyneuropathy. Concentration and memory improved significantly after transplantation. In the second group of patients, MRI, EEG, lumbar puncture and neuropsychological tests were done just before and routinely after transplantation, revealing numerous preexisting neurological deficits with only singular changes afterwards.     

Corticosteroids and concomitant medication in the European multicentre study of FK 506 and cyclosporin in primary liver transplantation

Abstract The steroid-paring effect and the use of concomitant medication during the treatment of liver transplant patients with the novel immunosuppressant FK 506 were evaluated within the European multicentre, randomized, parallel-group study in liver transplantation. Patients undergoing primary liver transplantation were randomized to treatment with FK 506 ( n = 267) or with a cyclosporin-based immunosuppressive regimen ( n = 273). The total cumulative steroid usage was significantly reduced in the FK 506 treatment group, which is likely to have resulted from the lower incidence of acute rejection in these patients. The number of patients receiving antidiabetic, diuretic and antihypertensive therapy did not differ between the two treatment groups, even though the incidence of diabetes mellitus and oliguria was significantly higher in the FK 506 group. It can, therefore, be assumed that in a number of such cases the severity of these events was very mild necessitating no specific therapy.     

Japanese study of FK 506 on kidney transplantation: 2. Follow-up study of FK 506-treated patients

Thirty-seven primary renal transplant patients were enrolled in the early phase II study on kidney transplantation. All grafts survived during the follow-up period. However, 10 of the 37 patients were changed from FK 506 to conventional drugs, and 3 were treated concomitantly with azathioprine (AZA) or mizoribine (MZR) in the 3-month period of observation. After 3 months posttransplantation, an additional 10 patients were treated continuously with AZA or MZR. In addition, 3 were converted from FK 506 to conventional drugs. No additional conversion was observed after 4 months. Trough level monitoring was effective enough to regulate the FK 506 dosage. Nephrotoxicity and hyperglycemia were associated with a high trough level of FK 506 (whole blood, > 20 ng/ml).