他克莫司胶囊和缓释胶囊预防肝移植急性排斥反应的效果和安全性

Objective To evaluate the efficacy and safety of tacrolimus exposure in stable liver transplant recipients converted from FK506 twice a day to Advagraf (tacrolimus extended-release capsules) once daily. Methods This was an open-label, random, control and multi-center study.Eligible patients were 19 to 70 years of age, 6 months post-transplant with stable renal and hepatic function and receiving stable doses of tacrolimus twice a day for 2 weeks prior to enrollment. There were 86 patients in the experimental group and the control group, separately. The average age of experimental group and control group was 46 ± 10 and 49 ± 9, respectively. Patients in experimental group received Advagraf, once daily, and the dose was adjusted according to the drug concentration,and the drug concentration was between 2 to 10 μg/L. The control group given tacrolimus, twice daily, and the drug concentration was between 2 to 10 μg/L. Results The incidence of acute rejection reaction was 1.20 % and 1.18 % respectively in experimental group and control group, and the 95 %confidence interval was -3.25% ～3.31 % and -3.26% ～ 3.34 %, individually. There was 1 case of acute rejection reaction in experimental group and control group, respectively. The patient and organ survival rate was 100%. Sixteen adverse events occurred in 15 patients (17.65 %) of the experimental group, and 10 adverse events occurred in 10 patients (11.63 %) of control group. Severe adverse events relating to the test drug in experimental group occurred in 4 patients (4. 71 %). and 2 patients (2. 33) in control group.Conclision Clinical trials indicated that Advagraf has efficacy and safety profiles similar to those of tacrolimus. The drug is safe and may improve patient compliance.     

他克莫司胶囊和缓释胶囊预防肝移植急性排斥反应的效果和安全性

Objective To evaluate the efficacy and safety of tacrolimus exposure in stable liver transplant recipients converted from FK506 twice a day to Advagraf (tacrolimus extended-release capsules) once daily. Methods This was an open-label, random, control and multi-center study.Eligible patients were 19 to 70 years of age, 6 months post-transplant with stable renal and hepatic function and receiving stable doses of tacrolimus twice a day for 2 weeks prior to enrollment. There were 86 patients in the experimental group and the control group, separately. The average age of experimental group and control group was 46 ± 10 and 49 ± 9, respectively. Patients in experimental group received Advagraf, once daily, and the dose was adjusted according to the drug concentration,and the drug concentration was between 2 to 10 μg/L. The control group given tacrolimus, twice daily, and the drug concentration was between 2 to 10 μg/L. Results The incidence of acute rejection reaction was 1.20 % and 1.18 % respectively in experimental group and control group, and the 95 %confidence interval was -3.25% ～3.31 % and -3.26% ～ 3.34 %, individually. There was 1 case of acute rejection reaction in experimental group and control group, respectively. The patient and organ survival rate was 100%. Sixteen adverse events occurred in 15 patients (17.65 %) of the experimental group, and 10 adverse events occurred in 10 patients (11.63 %) of control group. Severe adverse events relating to the test drug in experimental group occurred in 4 patients (4. 71 %). and 2 patients (2. 33) in control group.Conclision Clinical trials indicated that Advagraf has efficacy and safety profiles similar to those of tacrolimus. The drug is safe and may improve patient compliance.     

他克莫司胶囊和缓释胶囊预防肝移植急性排斥反应的效果和安全性

Objective To evaluate the efficacy and safety of tacrolimus exposure in stable liver transplant recipients converted from FK506 twice a day to Advagraf (tacrolimus extended-release capsules) once daily. Methods This was an open-label, random, control and multi-center study.Eligible patients were 19 to 70 years of age, 6 months post-transplant with stable renal and hepatic function and receiving stable doses of tacrolimus twice a day for 2 weeks prior to enrollment. There were 86 patients in the experimental group and the control group, separately. The average age of experimental group and control group was 46 ± 10 and 49 ± 9, respectively. Patients in experimental group received Advagraf, once daily, and the dose was adjusted according to the drug concentration,and the drug concentration was between 2 to 10 μg/L. The control group given tacrolimus, twice daily, and the drug concentration was between 2 to 10 μg/L. Results The incidence of acute rejection reaction was 1.20 % and 1.18 % respectively in experimental group and control group, and the 95 %confidence interval was -3.25% ～3.31 % and -3.26% ～ 3.34 %, individually. There was 1 case of acute rejection reaction in experimental group and control group, respectively. The patient and organ survival rate was 100%. Sixteen adverse events occurred in 15 patients (17.65 %) of the experimental group, and 10 adverse events occurred in 10 patients (11.63 %) of control group. Severe adverse events relating to the test drug in experimental group occurred in 4 patients (4. 71 %). and 2 patients (2. 33) in control group.Conclision Clinical trials indicated that Advagraf has efficacy and safety profiles similar to those of tacrolimus. The drug is safe and may improve patient compliance.     

他克莫司缓释胶囊与他克莫司胶囊的临床对照试验

目的 比较和评价首次肾移植受者使用他克莫司缓释胶囊和他克莫司胶囊治疗的安全性和有效性.方法 11家中心的241例肾移植受者随机分配为试验组(应用他克莫司缓释胶囊+吗替麦考酚酯+皮质激素)和对照组(应用他克莫司胶囊+吗替麦考酚酯+皮质激素),观察时间从移植当天至术后12周.试验组受试者每天上午一次性服用他克莫司缓释胶囊,对照组受试者每天早晚分2次服用他克莫司胶囊.两组试验药物的起始剂量均为0.1～0.15 mg·kg-1·d-1.分别在治疗前和治疗后第1、3、7、14、28、56和84 d各随访1次.对两组受者用药的有效性、安全性、依从性以及不良反应进行对比分析.结果 进入符合方案分析集者共223例,其中试验组111例,对照组112例.两组受者的平均年龄、性别、原发病的差异均无统计学意义,各有12例发生急性排斥反应.对照组和试验组分别有36例(32.1%)和37例(33.3%)发生与试验药物相关的不良反应.无受者连续3 d未按照方案服用药物.两组治疗后期较治疗前期的服药量均减少,且组内差异有统计学意义(P<0.05).治疗早期两组血他克莫司浓度较接近,从28 d开始,试验组血药浓度低于对照组,但差异无统计学意义.结论 从药物安全性、药物治疗的有效性、相关不良反应以及受者依从性各方面分析显示,每天1次的他可莫司缓释胶囊均非劣效于每天2次的他克莫司胶囊,在临床应用中,用他克莫司缓释胶囊代替他克莫司胶囊是切实可行的.

Abstract：

Objective To compare the efficacy and safety of twice-daily tacrolimus (Tacrolimus BID; Prograf) vs once-daily prolonged release tacrolimus (Tacrolimus QD; Advagraf), combined with steroids and mycophenolate mofetil in preventing acute rejection in De Novo renal transplantation patients. Methods 241 patients from 11 centers were randomized into two groups with 3 months observation period post-transplantation. Advagraf was administered as a single oral dose in the morning (initially 0. 1-0. 15 mg/kg every day) and Prograf was administered in two equal oral doses 12h apart (initially 0. 1-0. 15 mg/kg). Study visits were scheduled for days 1, 3, 7, 14, 28, 56, 84post-transplantion. The efficacy, safety, compliance and adverse effects were compared between two groups. Results Totally 223 patients completed the study. The two groups were comparable in age,gender and primary disease. There were 12 episodes of acute rejection in each group. There was no graft loss or patient death in both groups. The incidence of drug related adverse events was 32. 1 %and 33. 3% respectively in the control and experimental groups. Dosage was decreased in both groups and there was significant difference in each group. The trough level was similar at the initiate period.Twenty-eight days post-transplantation the trough level in the Advagraf group was lower than in the Prograf group. Conclusion Advagraf has the same efficacy, safety and drug related adverse effects as Prograf. It is practical and feasible for Advagraf substitute for Prograf in clinical practice.     

他克莫司缓释胶囊对肝移植术后稳定期受者安全性和临床疗效评估

目的通过他克莫司缓释胶囊（MR4）的Ⅲ期临床试验（MR4LTxCN02）评价MR4在肝移植术后稳定期受者中的安全性和临床疗效。方法受试者随机分配入MR4或他克莫司（FK506）组,MR4组药物剂量按1：1进行药物转换,每日口服1次;FK506组维持每12h服药1次至试验结束。在为期3个月的临床试验阶段,随访了受试者生命体征、不良事件、血常规、尿常规、肝功能、血糖、血脂及FK506的谷值浓度。随访结果采用SAS8．0统计软件进行了Fisher精确卡方检验及t检验分析。结果MR4组按1：1药物转换后与FK506组具有同等的安全性和临床疗效。与FK506组比较,MR4组具有感冒、上呼吸道感染症状减少倾向,没有增加不良事件或不良反应的发生率。转换药物后的剂量和血药浓度与换药前未发生显著变化;药代动力学检测结果表明,MR4具备缓释剂型的药代动力学特征,并与FK506具有良好的生物等效性。结论MR4与FK506具有同等的安全性和临床疗效,同时简化了服药次数,在提高受者长期依从性以及术后生活质量方面具有较大的优势。     

肝移植患者将他克莫司替换为环孢素A的临床分析

目的分析肝移植后需用环孢素A（CsA）替换他克莫司（FK506）的原因和结果。方法317例肝移植患者术后采用巴昔利单抗、FK506、霉酚酸酯及肾上腺皮质激素预防排斥反应，血FK506浓度谷值，术后0～30d维持在10～15μg／L，30-90d维持在8～12μg／L，90～180d维持在5～8μg／L。术后随访6个月。结果317例患者中，有16例（5．05％）需要将FK506替换为CsA，其中5例（31．25％）主要因为FK506的神经系统不良反应，2例（12．50％）因为血液系统不良反应，1例（6．25％）因为胃肠道不良反应，3例（18．75％）因血FK506浓度始终达不到治疗窗范围，2例（12．50％）因为顽固性高血糖，另有3例（18．75％）因为经济原因。除2例患者因药物替换后发生肾功能损害而再次恢复应用FK506方案外，其余14例患者的不良反应大多在替换为CsA后明显好转，无因换药而死亡的病例，也无与替换药物相关的不良反应。结论肝移植后，当发生FK506的不良反应时，将FK506替换为CsA是安全、有效的。     

心脏移植后他克莫司预防急性排斥效果的研究

目的探讨以他克莫司为基础的免疫抑制治疗方案在心脏移植中的应用。方法回顾性分析2014年3月-2016年12月天津市第一中心医院25例终末期心脏病患者的临床资料。患者行同种异体心脏移植术,免疫抑制方案为巴利昔单抗诱导,他克莫司、吗替麦考酚酯联合糖皮质激素的三联免疫抑制方案。术后监测他克莫司谷值浓度、术后重症感染发生率及排斥反应发生率等,随访患者的心功能情况。结果共纳入25例心脏移植手术,男性24例,女性1例;平均年龄48.7岁;其中缺血性心肌病4例,扩张性心肌病19例,瓣膜病2例;心功能分级均为Ⅳ级。手术顺利,术后均安返监护室,1例患者术后1个月出现真菌感染;1例术后出现双侧膈神经麻痹;3例术后出现急性肾功能衰竭。术后早期无急性排斥反应发生,1个月以内病死率为4%,3个月内存活率为88%,1年存活率为84%,末次随访平均他克莫司用量为(2.89±0.85)mg/d。随访至39个月时,所有患者均未出现明显排斥反应。结论采用以他克莫司为基础的免疫抑制剂方案可有效预防心脏移植术后排斥反应的发生。     

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     

他克莫司缓释胶囊在儿童肾移植受者中的应用分析

目的 总结儿童肾移植受者术后应用他克莫司缓释胶囊应用的体会,为儿童肾移植的免疫抑制剂的应用和临床决策提供参考.方法 回顾性分析2014年4月1日—2020年3月31日期间,西安交通大学第一附属医院22例初始(或转换)应用他克莫司缓释胶囊的儿童肾移植受者的临床资料、临床事件、生化指标、全血中他克莫司谷浓度变化等情况进行总...     

他克莫司撤药诱发大鼠肝移植急性排斥反应的病理学观察与分析

目的建立大鼠肝移植急性排斥反应动物模型,观察大鼠肝移植术后他克莫司撤药诱发受体急性排斥反应的肝脏动态病理学变化,为临床肝移植术后他克莫司停药或者用药不规律所致急性排斥反应的预测和评估提供理论依据。方法通过Kamada二袖套法,建立雄性DA大鼠至Lewis大鼠的原位肝移植模型60例。受体大鼠术前1 d和术后7 d内饲喂治疗剂量的他克莫司,之后半量递减至停药。分别于术后7、14、21及28 d处死部分受体大鼠,获取肝组织标本,观察受体大鼠肝脏大体和镜下的动态病理学改变,并进行排斥活动指数评分,同时观察受体大鼠的术后生存时间。结果受体大鼠术后7 d内由于受他克莫司的保护,肝脏未出现典型的急性排斥反应表现,至术后14 d由于他克莫司的减量及撤出,迅速发生肝脏的急性排斥反应,术后14、21及28 d排斥活动指数评分分别为(3.7±0.9)分(、6.3±0.9)分和(8.1±0.7)分。受体术后生存时间为(20.85±0.71)d,中位生存期为21 d。结论通过围手术期短期饲喂治疗剂量他克莫司并逐渐减量至撤药诱发肝移植大鼠急性排斥反应模型术后的急性排斥反应,动态观察该实验条件下排斥反应发生的时限和严重程度,对临床肝移植术后类似情况下所发生的急性排斥反应具有一定的预测价值和严重程度评估价值。     

他克莫司与环孢素A在尸肾移植中应用的长期疗效和安全性比较

目的　比较他克莫司 (FK5 0 6 )和环孢素A(CsA)在尸肾移植中应用的长期疗效和安全性。方法　 2 10例尸肾移植患者分为FK5 0 6组和CsA组 ,随访 12～ 32个月 ,观察两个组血药浓度变化、急性排斥和慢性排斥反应发生率、人 /肾 1年存活率、血肌酐、肝功能、血糖及血脂水平、药物不良反应、感染发生率以及FK5 0 6逆转顽固性急性排斥反应的效果。结果　血中FK5 0 6和CsA浓度谷值的变化趋势基本相同。FK5 0 6组与CsA组相比 ,急、慢性排斥反应发生率明显降低 (P <0 .0 5 ) ;肝功能异常发生率、高脂血症和牙龈增生发生率以及术后 3个月血肌酐水平均明显降低 (P <0 .0 5 ) ;高血糖和震颤发生率明显升高 (P <0 .0 5 ) ;感染发生率及人 /肾 1年存活率的差异无显著性。结论　与CsA相比 ,FK5 0 6是一种更高效的免疫抑制剂 ,长期使用可以有效降低肾移植后急、慢性排斥反应的发生率 ,有利于移植肾功能的恢复。     

Efficacy and safety of oral low-dose tacrolimus treatment in liver transplantation

Abstract Eighty-four adult patients were recruited from four centres in Spain to evaluate the efficacy and safety of low-dose (0.1 mg/kg per day) oral tacrolimus plus corticosteroid immunosuppression in liver transplantation. The median daily dose of tacrolimus was increased during the first 3 weeks of therapy from an initial dose of 0.1 mg/kg per day to a maximum of 0.145 mg/kg per day and was subsequently decreased gradually to a minimum of 0.076 mg/kg per day at 1 year. At 7 days posttransplantation, 87.7 % of patients had trough whole blood levels of tacrolimus within the therapeutic range (5–20 ng/ml), and the median levels remained fairly constant during the rest of the year (10.1–11.8 ng/ml). None of the patients required intravenous administration of tacrolimus. At 1 year, Kaplan-Meier estimates showed that 73.8 % of the patients were receiving tacrolimus monotherapy without the need for corticosteroids. One-year patient and graft survival were 75.9 % and 72.3 %, respectively. The incidence of acute rejection was 51.2 %; 9.5 % of cases resolved spontaneously without antirejection therapy and 10.7 % were corticosteroid resistant. Only 1 patient (1.2 %) developed chronic rejection. The most important adverse events were hypertension (45.2%), tremor (44.0%), diabetes mellitus (33.3%), diarrhoea (31 %) and nephrotoxicity (29.8%). Severe neurotoxicity-like convulsions (4.8%), dysarthria (9.5 %), delirium (1.2%), coma (1.2 %) and the need for haemodialysis (3 patients) were uncommon. In conclusion, low-dose oral tacrolimus immunosuppression is associated with low toxicity without compromising efficacy.     

西罗莫司在肝移植术后免疫抑制中的效果及安全性

目的 探讨肝移植术后应用西罗莫司(SRL)的免疫抑制效果和安全性.方法 对21例以SRL作为免疫抑制维持治疗的肝移植受者进行了观察.其中术后直接应用SRL者6例(术前肾功能不全者2例、原发病为肿瘤者4例);因他克莫司(Tac)药物相关性因素替换为SRL者15例(Tac肾毒性4例、高度可疑Tae肝毒性8例、Tac用量过大仍不能达到预期血药浓度者3例).术后对21例受者平均随访25.4个月(6～42个月),评估SRL的临床免疫抑制效果及安全性.结果 随访期间,2例受者因药物副反应停药,药物耐受率为90.5%.发生急性排斥反应1例次,经治疗后痊愈,其余患者均获得良好的免疫抑制效果.Tac肾毒性患者肾功能改善3例;Tac肝毒性患者肝功能显著好转6例.结论 SRL作为受者肝移植术后的免疫抑制维持治疗是安全有效的.术后早期及时用SRL替换Tac可有效逆转后者所致的肝、肾毒性损害.     

肝移植中应用巴利昔单抗诱导治疗的免疫抑制方案的疗效

目的 探讨肝移植中应用巴利昔单抗诱导治疗的免疫抑制方案的疗效。方法 2007年8月至2009年7月间139例成人肝移植受者接受含巴利昔单抗诱导的免疫抑制方案（诱导组）。以2006年1月至2006年12月间接受常规免疫抑制方案的106肝移植受者为对照组。术后随访12个月,记录两组受者排斥反应、代谢并发症的发生情况,以及患者的存活情况。结果 诱导组术后1个月内急性排斥反应、糖尿病、高血压及感染的发生率分别为7.9％、33.8％、21.6％和22.3％,对照组分别为15.1％、72.6％、40.6％和43.4％,差异有统计学意义(P＜0.05)。术后12个月内,诱导组急性排斥反应、移植后新发糖尿病、高血压以及高脂血症的发生率分别为10.8％、5.0％、4.3％和7.9％,而对照组分别为19.8％、9.4％、8.5％和14.2％,差异有统计学意义(P＜0.05)。诱导组和对照组术后1年的存活率分别为92.1％和88.7％(P＞0.05)。结论 免疫抑制方案中应用巴利昔单抗诱导治疗可以早期撤除皮质激素,并可降低急性排斥反应的发生率及减少使用皮质激素引起的不良反应。