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

目的 研究稳定期的肝移植受者分别服用他克莫司缓释胶囊和他克莫司胶囊在预防急性排斥反应的效果和安全性方面的差异.方法 采用多中心、随机、开放、对照的研究方法.试验组和对照组入组的稳定期肝移植受者各86例.试验组受试者的年龄为(46±10)岁;对照组受试者的年龄为(49±9)岁.试验组口服他克莫司缓释胶囊,每天1次,根据血药浓度谷值调整药量,维持血药浓度谷值为2～10 μg/L;对照组口服他克莫司胶囊,每天2次,维持血药浓度谷值为2～10 μg/L.结果 试验组和对照组分别有1.20%和1.18%的受试者发生急性排斥反应,两组的95%可信区间分别为-3.25%～3.31%和-3.26%～3.34%,可信区间上限均低于10%的非劣效标准.试验组和对照组急性排斥反应的发生率分别为1.20%和1.18%,两组患者发生急性排斥反应的次数均为1次,患者及移植物的存活率均为100%,以上指标两组间的差异均无统计学意义(P＞0.05).试验组有15例(占17.65%)共发生16次与试验药物相关的不良反应,对照组有10例(11.63%)共发生10次与试验药物相关的不良反应;试验药物有关严重不良反应中,试验组有4例(占4.71%)共发生4次,对照组有2例(占2.33%)共发生2次.两组不良反应发生率的差异均无统计学意义.结论 稳定期肝移植受者服用他克莫司缓释胶囊和他克莫司胶囊在预防急性排斥反应的疗效和安全性方面无明显差异.

Abstract：

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。     

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。     

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。     

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...     

肝移植后采用巴利昔单抗进行免疫诱导治疗

目的 探讨肝移植后采用巴利昔单抗进行免疫诱导治疗预防急性排斥反应的有效性和安全性.方法 160例肝移植患者中,47例术后给予两剂巴利昔单抗(20 mg/剂)进行免疫诱导治疗(研究组),另外113例为对照组,不使用巴利昔单抗.所有患者术后均采用他克莫司、霉酚酸酯和糖皮质激素预防排斥反应.结果 术后1年内,研究组的急性排斥反应发生率为8.5%(4/47),对照组为22.1%(25/113),二者间的差异有统计学意义(P＜0.05);研究组排斥反应活动指数平均为4,对照组为6,两组间的差异无统计学意义(P＞0.05).研究组术后感染发生率为31.9 %(15/47),对照组为26.5%(30/113),两组间的差异无统计学意义(P＞0.05).研究组患者及移植肝1年存活率分别为95.7%和95.7%,对照组分别为96.5%和94.7%,两组间的差异均无统计学意义(P＞0.05).两组间其它不良反应发生率的差异也无统计学意义.结论 在以他克莫司为基础的免疫抑制治疗方案中,采用巴利昔单抗进行诱导治疗可明显降低肝移植后急性排斥反应发生率,且不增加感染和其它不良反应发生率.     

移植肝内C4d沉积在肝移植急性和慢性排斥反应诊断和治疗中的意义

目的 观察移植肝组织中补体C4的裂解片断CAd沉积情况,探讨其与排斥反应的关系,为临床诊断和治疗排斥反应提供思路和依据.方法 25例肝移植患者术后共行移植肝穿刺36次,取34次肝脏穿刺样本入组研究.穿刺时间为移植后7 d至25个月,所有供肝移植前均留取样本.穿刺所得移植肝组织进行HE染色和免疫组织化学染色,观察CAd的沉积情况.结果 34次病理检查中,诊断为急性排斥反应16次,慢性排斥反应9次,非排斥反应9次(包括胆道并发症3次,药物性肝损害5次,乙型肝炎复发1次).移植前供肝组织中均未见CAd沉积.发生急性排斥反应者中,9例(9/16)移植肝组织中可见到C4d沉积,发生慢性排斥反应者中,5例(5/9)移植肝组织中可见到CAd沉积,非排斥反应者中,仅1例(1/9)非吻合口胆管狭窄患者的肝组织中有CAd沉积.排斥者和非排斥者的CAd沉积部位无明显差异.急性排斥反应者和慢性排斥反应者的C4d阳性率均高于非排斥反应者(P<0.05,P<0.05);CAd阳性率与肝损伤程度无明显相关性.CAd阳性者激素冲击有效率为35.7%(5/14),远低于CAd阴性者的63.6%(7/11).结论 CAd沉积可提示体液性排斥反应,可作为肝移植后肝损害时病理检查的常规免疫组织化学项目,有利于监测和预警体液性排斥反应的发生.并为选择冲击治疗方案提供依据.     

氯化钆抑制大鼠肝移植急性排斥反应的机理

目的　探讨氯化钆抑制大鼠肝移植急性排斥反应的机理。方法分别采用健康雄性Wistar和SD大鼠作为供、受者。随机分为A组(假手术对照):SD大鼠10只,开腹后不作任何处理,关腹结束手术;B组(氯化钆预处理 肝移植):受者1 5只,供者在移植前进行氯化钆预处理2 d,再获取供肝移植给受者;C组(生理盐水预处理 肝移植):受者15只,供者用生理盐水代替氯化钆预处理,其余处理同B组。分别检测各组的术后生存率、肝功能、肝脏病理组织学、肝组织和胆汁中细胞因子表达、枯否氏细胞核转录因子κB(NF-κB)以及细胞膜表面分子的表达情况。结果(1)B组术后1个月生存率明显高于C组(P<0.01)。(2)B组术后肝功能逐渐恢复正常,C组肝功能进行性恶化;B组肝组织病理学改变轻微,C组出现典型急性排斥改变。(3)B组肝组织和胆汁中γ-干扰素(IFN-γ)和白细胞介素2 (IL-2)较A组明显降低(P<0.05),IL-10较A组明显升高(P<0.05),IL-4无明显变化;C组出现与之相反的变化。(4)C组枯否氏细胞NF-κB活性明显高于A、B两组(P<0.01)。(5)B组枯否氏细胞膜表面主要组织相容性抗原复合物(MHC)、CD80、CD86分子明显低于A组(P<0.05),C组高表达上述膜表面分子。结论氯化钆能够有效地抑制枯否氏细胞的免疫活性,从而抑制大鼠同种肝移植后急性排斥反应的发生。     

Induction of cyclo-oxygenase-2 by acute liver allograft rejection and cytomegalovirus infection in the rat

Cytomegalovirus (CMV) infection has been shown to increase inflammation in rat liver allografts. In-vitro CMV has been shown to transactivate cyclo-oxygenase-2 (COX-2), while COX-2 plays a role in the CMV replication cycle. Our aim was to investigate the expression of COX-2 in liver allograft rejection and concomitant CMV infection. Expression of COX-2 was studied immunohistologically in rat liver allografts with or without rat CMV infection, in isografts, and in normal rat liver. There were small amounts of COX-2-positive mononuclear inflammatory cells in the normal liver and isografts. Acute rejection increased the amount of COX-2-expressing cells in the portal areas only, whereas concomitant CMV infection did this also in the sinusoid area. COX-2 may play a role in CMV infection in vivo as well. The possible role of COX-2 in the association between CMV infection and allograft rejection warrants further study.     

A randomized trial comparing two corticosteroid regimens combined with mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection

INTRODUCTION: The launching of mycophenolate mofetil (MMF) has reduced the incidence of acute rejection episodes. We sought to evaluate the efficacy of decreasing the steroid dose. MATERIALS AND METHODS: This was a quasiexperimental, randomized, prospective trial. We enrolled 150 patients who received de novo renal transplantations from living or cadaveric donors, fulfilling the screening criteria. Patients were randomized to one of the following two arms: (A) MMF at a 2 g/d dose, cyclosporine (CsA) at a dose necessary to achieve target levels, and corticosteroids at the usual doses; (B) MMF at a 2 g/d dose, CsA at a dose necessary to achieve target levels, and corticosteroids at doses 50% lower than those of group A. RESULTS: Group A included 72 (48%) and group B, 78 patients (52%). There were no differences among the variables: leukopenia occurred in 11 patients in group A, and five patients in group B. Complications occurred in 67.4% (56) of group A, but only 32.6% (27) were related to infections. One case of urinary infection occurred in group B, while six occurred in group A. There was one case of acute rejection in group A, and none in group B. One graft loss occurred in group A. There were no differences in the remaining variables under study. DISCUSSION: The results showed an increased complication rate related to receiving usual steroid doses. There was no increase in acute rejection episodes among patients receiving 50% of the usual steroid dose.