他克莫司治疗难治性狼疮肾炎的疗效和安全性

目的 前瞻性研究环磷酰胺治疗无效的难治性狼疮肾炎患者应用他克莫司(FK506)治疗的临床效果和安全性.方法 收集2009年1月至2010年12月门诊或住院的16～60岁的狼疮肾炎患者.入选患者均符合美国风湿病学会(ACR) 1997年修订的系统性红斑狼疮(SLE)分类标准;尿蛋白定量(24h)≥1.5 g;应用环磷酰胺半年累计剂量超过8 g无效.他克莫司起始剂量2～3 mg/d(体质量≥60 kg,3 mg/d;体质量＜60 kg,2 mg/d),2个月后临床症状无好转,可逐渐调整剂量至4 mg/d,监测血药浓度,观察期为6个月.疗效评价分为完全缓解、部分缓解和无效,达到完全缓解或部分缓解为有效.统计学处理采用单因素方差分析和Pearson相关分析.结果 收集环磷酰胺治疗无效的狼疮肾炎患者14例,其中男性2例,女性12例,平均年龄(30±9)岁,SLE的平均病程(4±3)年;狼疮肾炎的平均病程(2.7±1.9)年.5例患者尿蛋白定量(24 h)1.5～2.9 g,9例患者尿蛋白定量(24 h)≥3.0 g;9例患者有活动性尿沉渣.应用他克莫司的治疗过程中,尿蛋白定量(24h)水平显著下降,从基线(6.2±5.1)g降至6个月(1.1±0.9)g,差异有统计学意义(F=16.21,P＜0.01);血清白蛋白水平呈逐渐上升趋势,从基线(27.9±9.7) g/L升至6个月(37.8±2.2) g/L,差异有统计学意义(F=16.71,P＜0.01).在治疗的第1个月末,8例无效,6例部分缓解;在治疗的第2个月末,3例无效,11例部分缓解;在治疗的第4个月末,2例无效,9例部分缓解,3例完全缓解;在研究6个月时,2例无效,5例完全缓解,7例部分缓解,共12例有效,有效率达86％.他克莫司的起效时间平均(1.7±0.9)个月,其中6例患者1个月内有效,5例患者2个月内有效,1例患者4个月内有效.12例有效患者他克莫司的平均剂量为0.03～0.06 mg/kg,所有他克莫司有效患者的药物浓度均低于3 ng/ml,完全缓解、部分缓解和无效的他克莫司的平均血药浓度分别为(1.6±0.4),(2.0±0.6)和(2.2±1.1)ng/ml,他克莫司的疗效和血药浓度之间无相关性.14例患者仅有1例出现新发高血压,1例出现脱发,观察期间未出现其他不良反应.结论 他克莫司联合糖皮质激素治疗环磷酰胺无效的狼疮肾炎有效,6个月有效率达86％,是一种快速有效的缓解狼疮肾炎的治疗方法,血药浓度3n/ml以下即可有效,其治疗狼疮肾炎的最佳剂量可能为0.03～0.06 mg·kg-1·d-1.     

他克莫司治疗Alport综合征的近期疗效

目的:观察他克莫司(tacrolimus,FK506)治疗Alport综合征(Alport syndrome,AS)的近期疗效.方法:前瞻性观察5例接受FK506治疗的AS患者的近期临床疗效与不良反应.5例患者均经肾活检确诊,男4例,女1例,年龄8～42岁,其中X连锁遗传患者4例,常染色体隐性遗传患者1例.起始FK506治疗剂量为0.15mg/(kg·d),8周后减至0.1 mg/(kg·d),目标血药浓度5～8 ng/dl.随访中每2～4周监测一次FK506的不良反应.4例患者行CYP3A5基因型检测,一例基因型为CYP3A5-* 1/* 1的患者FK506谷浓度始终未达到目标范围.结果:治疗2～4周5例患者蛋白尿明显减少,血清白蛋白升高,但随治疗时间延长,蛋白尿未进一步减少,甚至再次增多.2例延长治疗时间至36周和40周,血清白蛋白维持在33～35g/L,尿蛋白波动于0.5～2.5g/L.2例出现肾毒性和(或)糖代谢异常,FK506减量后不良反应消失,1例未达到目标血药浓度者治疗无效.结论:小样本临床观察显示短期FK506治疗能改善AS患者的蛋白尿及低白蛋白血症,其长期疗效有待进一步观察.     

环孢素A切换成他克莫司对慢性移植肾肾病患者血脂的影响

目的:探讨以他克莫司(FK506)切换环孢素A(CsA)对慢性移植肾肾病(CAN)患者血脂和移植肾功能的影响。　方法:选择我院接受尸肾移植、移植时间在 1年以上,经临床和移植肾活检证实为CAN的患者 50例,男 41例,女 9例,平均年龄(36 .7±12 .7)岁,均采用CsA 硫唑嘌呤 (Aza)或霉酚酸酯 (MMF) 强的松免疫抑制方案治疗。根据是否将CsA切换为FK506将入选病例分为两组:一组继续采用原方案治疗 (CsA组,n=28);另一组切换为FK506 Aza/MMF 强的松方案治疗(FK506组,n=22)。观察两组 12个月时的血脂 [包括总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白(LDL)、高密度脂蛋白 (HDL) ]和肾功能的变化。　结果:观察 12个月时:①FK506组血TC、TG、LDL均显著低于CsA组[分别为 (5 ..2±0 75)mmol/Lvs(6 .6±1 .4)mmol/L,P<0 01; (1. 9±0 .86)mmol/Lvs(3. 0±1 .4 )mmol/L,P<0 .01; ( 3 .0±0 .72 ) mmol/Lvs( 3. 7±0. 93 ) mmol/L,P<0 01 ];②FK506组平均血肌酐水平显著低于CsA组 [ ( 210 .2 ± 65. 02 )μmol/Lvs( 150. 8 ± 54. 56 )μmol/L,P<0. 01 ],FK506的移植肾失功率显著低于CsA组(P<0 .05);③FK506组尿蛋白水平显著低于CsA组 [ (0. 9±0. 6)g/24hvs(1 1±0. 8)g/24h,P<0 .01) ],血清白蛋白水平高于CsA组[ (49±10 .2)g/Lvs(     

他克莫司联合激素治疗Ⅴ型狼疮性肾炎的疗效

目的:前瞻性观察他克莫司(FK506)治疗Ⅴ型狼疮性肾炎(LN)的临床疗效及安全性.方法:利用FK506治疗11例尿蛋白＞2.0g/24h、肾功能正常、并经肾活检确诊的Ⅴ型LN患者.FK506起始剂量为0.1mg/(kg·d),同时口服强的松0.6 mg/(kg·d).疗效分为完全缓解(CR,指尿蛋白＜0.4g/24h,无活动性尿沉渣,血清白蛋白≥35g/L,SCr正常),部分缓解(PR,指尿蛋白定量0.4～2 g/24 h且尿蛋白下降超过基础值的50%,血清白蛋白≥30g/L,SCr正常)及无效(NR,指尿蛋白定量≥2 g/24 h;或血清白蛋白＜30g/L;或SCr升高超过基础值50%;或重复肾活检病理类型转为Ⅳ型LN).结果:11例患者接受FK506治疗3～15个月,无一例退出治疗.治疗3个月时2例(18.2%)患者获得完全缓解、5例(45.5%)获部分缓解.治疗6个月以上的10例患者中获得完全及部分缓解者均为4例(40%).达到完全或部分缓解的中位数治疗时间为3个月(1～7个月).FK506治疗3个月时,2例尿蛋白降至正常,5例降至＜2.0g/24h治疗6个月以上的10例患者中尿蛋白完全、部分缓解者均为4例.10例低蛋白血症患者在治疗3个月后即有7例血清白蛋白升至正常.血清抗核抗体及抗dsDNA抗体转阴或滴度显著下降,同时血清补体水平明显升高.治疗6个月后,8例患者行重复肾活检,肾组织狼疮活动性指数由4.8±2.38降至2.25±1.28(P＜0.05),肾小管-间质纤维化无明显加重.6例患者在治疗初期出现血肌酐可逆性升高,各有1例并发带状疱疹、腹泻和血压升高.结论:FK506联合小剂量强的松能有效降低Ⅴ型LN的蛋白尿、升高血清白蛋白.     

心脏移植术后播散性隐球菌感染一例并文献复习

患者女,62岁.因"低热、头痛、咳嗽、咳痰1个月"入院.患者于1年前因扩张性心肌病行原位心脏移植术,术后持续免疫抑制治疗[泼尼松10 mg/d;马替麦考酚酯1.5 g/d;他克莫司(FK506)1.5 mg/d];发病前曾清理鸽粪.     

他克莫司治疗特发性膜性肾病的临床疗效观察

目的 观察他克莫司(Tacrolimus)治疗有肾病综合征表现的特发性膜性肾病的临床疗效和安全性,并与来氟米特(LEF)进行比较.方法 将表现为肾病综合征的特发性膜性肾病患者20例随机分为他克莫司治疗组(n=10)和LEF治疗组(n=10),分别给予他克莫司及LEF联合强的松治疗6个月,观察各组的疗效、不良反应以及他克莫司的浓度变化.结果 他克莫司治疗组治疗6个月后5例完全缓解,24h尿蛋白量和血清白蛋白的水平完全恢复到正常范围,占50%;4例部分缓解,24 h尿蛋白量在0.4-3.0 g之间,血清白蛋白＞30 g/L,占40%;1例无效,24 h尿蛋白定量＞3.0 g,占10%;治疗期间他克莫司的平均药物浓度保持在5～7 ng/ml的水平.LEF治疗组在疗程结束时,有2例病人获得完全缓解,占20%;3例获得部分缓解,占30%;5例无效,占50%.结论 与LEF相比,他克莫司治疗特发性膜性肾病,可明显缓解病情,不良反应少.     

他克莫司替换环孢素A治疗肾移植后肝、肾功能损害的临床观察

19例用环孢素A(CsA)并相继出现肝和(或)肾功能损害的肾移植患者，用他克莫司(FK506)替换CsA治疗，取得了明显疗效，平均随访观察6个月，疗效稳定。     

他克莫司联合小剂量激素治疗特发性膜性肾病的疗效观察

目的 观察不同疗程中他克莫司治疗有肾病综合征表现的特发性膜性肾病的疗效和安全性.方法 将2004年3月至2007年8月吉林大学第二医院收治的表现为肾病综合征的特发性膜性肾病患者20例随机分为短疗程组10例和长疗程组10例,短疗程组给予他克莫司联合口服泼尼松治疗6个月,长疗程组治疗24个月,观察各组的疗效、他克莫司的浓度变化及复发等情况.结果 短疗程组治疗6个月后5例完全缓解,4倒部分缓解,1例无效;治疗期间他克莫司的平均血药浓度保持在5～7μg/L;治疗结束后,6例复发.长疗程组治疗24个月后6例患者获得完全缓解,3例获得部分缓解,1例无效;长疗程组他克莫司的浓度在6个月内波动于5～8μg/L,12个月时保持在3.38～4.36μg/L;疗程结束时,无复发.结论 短疗程和长疗程他克莫司治疗特发性膜性肾病,均可明显缓解病情;长疗程组可以用较低浓度的他克莫司使病情得到持续缓解,且复发率低.     

他克莫司在移植肾功能延迟恢复患者中的临床应用

目的:探讨他克莫司(FK506)在移植肾功能延迟恢复(DGF)患者中的临床应用价值与合理用药方案.方法:17例DGF患者临床结合移植肾病理确立诊断.肾移植术后早期均接受三联(FK506 MMF Pred)免疫抑制药物治疗至少3个月.不用任何生物制剂诱导治疗,观察临床疗效及副作用.结果:17例患者无一例死亡或摘除移植肾.15例在术后第2～3天开始血液透析(HD)/连续性血液净化(CBP)治疗,2例在术后第5天开始HD/CBP.HD/CBP治疗2～15次后,10例在术后7天内停止,7例在术后7天后仍需CBP治疗,最长1例在术后第18天停止透析.FK506治疗后8～17天患者尿量开始明显增多,SCr开始明显下降.17例患者诊断DGF时SCr水平在489～1028μmol/L,14例在治疗后8～17天降至＜200μmol/L,另3例中2例SCr分别在术后第24天,28天降至＜200μmol/L.副作用主要是腹泻(3例),血糖升高(1例)及手颤,肢体麻木(4例),但未出现CMV等严重感染病例.结论:FK506 MMF Pred三联免疫抑制治疗方案治疗肾移植DGF安全有效,可作为肾移植术后DGF患者的过渡治疗方法之一.     

他克莫司治疗移植肾慢性排斥的初步临床观察

目的：探讨他克莫司（FK506）、环孢素A（CsA)治疗移植肾慢性排斥（CR)的可行性及安全性。方法：40例同种异体肾移植患者肾功能减退经病理证实为CR，随机分为CsA切我为FK506组20例、继续使用CsA组20例。观察各组移植肾功能、肾小球滤过率、蛋白尿、血压、血脂变化及急性排斥（AR）发生率，治疗后随访12个月。结果：追踪12个月，FK506组16例移植肾功能稳定（80％）；3例行血液透析治疗，1例死亡，人存活率95％。CsA组15例移植肾功能稳定，3例行血液透析治疗，逆转成功率75％；2例死亡，人存活率90％。结论：FK506可以延缓慢性移植物失功。FK506的使用是安全和有效的。     

肾移植受者FK506治疗窗浓度的临床观察

目的：寻求适合国人肾移植受者ＦＫ５０６理想治疗窗浓度范围。方法：应用ＥＬＩＡ法测定口服ＦＫ５０６ １２ｈ后全血谷浓度。结果：统计资料显示，术后第１个月应为１２～１８μｇ／Ｌ，第２～３个月为８～１３μｇ／Ｌ；第４个月后为５～８μｇ／Ｌ。结论：此浓度范围既能达到满意的免疫抑制效果，又有减少排斥反应和ＦＫ５０６肾毒性。     

肾移植术后抗排斥药FK506的临床应用

目的研究FK506预防肾移植术后排斥反应的效果和安全性。方法肾移植患者22例,其中18例为始用组,4例为切换组。FK506起始用0.2me／(kg·d),以后逐步减量,3个月后维持血浓度于3～12μg/L水平。切换组于停用CsA24h后应用FK506,剂量和血浓度与始用组相同。同时合并应用MMF0.5g,每日3次口服,以及术后前10天大剂量甲基强的松龙静滴,第11天改强的松口服并减量,6个月后维持强的松15mg／d。所有病例均严密观察并行血尿等生化分析。结果始用组移植肾功能好,平均血肌酐水平l02μmol／L,无一例出现排斥反应。切换组中2例异常的肝功能好转;肾功能进行性减退的2例切换后,血肌酐相对稳定。有血糖升高4例和高血压5例,用药后能控制,其他副反应有上呼吸道和下尿路感染、胸痛、恶心、呕吐、腹泻、腹部不适等。结论FK506是肾移植术后有确切疗效的基础抗排斥药,与MMF、皮质醇合用能有效地预防急性排斥的发生,并可控制慢性排斥的进展。应用剂量适当,无明显的肝、肾毒副作用,但有血糖升高及高血压副作用,药物可以控制。其它呼吸道、尿路、消化道和神经系统副反应轻,不妨碍临床用药。     

Successful Treatment of Tacrolimus (FK506)-Related Leukoencephalopathy with Cerebral Hemorrhage in a Patient Who Underwent Nonmyeloablative Stem Cell Transplantation

A 46-year-old woman with Hodgkin's disease who underwent nonmyeloablative allogeneic stem cell transplantation developed cortical blindness, seizures, and left hemiparesis on day 100 while receiving tacrolimus (FK506) and prednisone for the treatment of graft-versus-host disease (GVHD). Magnetic resonance imaging revealed multiple changes, mainly in the bilateral occipital lobes, suggesting FK506-related leukoencephalopathy. These abnormalities improved after discontinuation of FK506. However, 3 days after the episode, cerebral hemorrhage in the left occipital lobe with perforation to the left subdural space occurred. Although FK506-induced leukoencephalopathy with cerebral hemorrhage is considered the more severe form of such leukoencephalopathy, the patient's neurological symptoms almost completely resolved and radiographic findings improved after discontinuation of FK506, tapering of methylprednisolone, and initiation of mycophenolate mofetil. FK506-related leukoencephalopathy is a rare complication after allogeneic stem cell transplantation. Although the symptoms usually subside after discontinuation of FK506, therapeutic intervention in many cases may result in severe complications, including GVHD and vascular disease. We consider it important to use immunosuppressive agents without vascular endothelial toxicity for preventing the development of fatal GVHD after discontinuation of FK506.     

Microangiopathic hemolytic anemia complicating FK506 (tacrolimus) therapy

We describe 3 episodes of microangiopathic hemolytic anemia (MAHA) in 2 solid organ recipients under FK506 (tacrolimus) therapy. In both cases, discontinuation of FK506 and treatment with plasma exchange, fresh frozen plasma replacement, corticosteroids, aspirin, and dipyridamole led to resolution of MAHA. In one patient, reintroduction of FK506 led to rapid recurrence of MAHA. FK506-associated MAHA is probably rare but physicians must be aware of this severe complication. In our experience and according to the literature, FK506 does not seem to cross-react with cyclosporin A (CyA), an immuno-suppressive drug already known to induce MAHA. © 1996 Wiley-Liss, Inc.     

Bone marrow hypoplasia complicating tacrolimus (FK506) therapy

Tacrolimus (FK506)-induced hematological toxicity, which has rarely been reported in transplant recipients, may result in anemia episodes, reported mainly in kidney and heart transplant recipients, sporadic cases of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, red cell aplasia (4 reported cases), and generalized bone marrow suppression (only 1 reported case). We describe a case of a liver transplant recipient with pancytopenia that appeared during immunosuppressive therapy with tacrolimus. This patient suffered from progressive anemia, leukopenia with severe neutropenia, and mild thrombocytopenia; bone marrow biopsy showed hypoplasia (20% of cellularity) without dysplasia. Bone marrow recovery was made possible by suspending tacrolimus and changing to immunosuppression with cyclosporine A, despite the two drugs being very similar in their mechanism of immunosuppression. Contrary to previously reported cases (pure red cell aplasia and bone marrow hypoplasia), the recovery of hemoglobin and neutrophil values was slow after tacrolimus suspension, even though in the first month transfusions were no longer necessary.     

Tacrolimus (FK506) in the treatment of severe, refractory rheumatoid arthritis: initial experience in 12 patients.

OBJECTIVE: To determine if tacrolimus (FK506) has potential as a therapeutic agent in patients with severe and/or refractory rheumatoid arthritis (RA). METHODS: Twelve patients with RA who had severe and active disease and had failed an average of 5.3 disease modifying antirheumatic drugs (DMARD) were treated with tacrolimus 2-6 mg/day in an open label study. Patients were assessed monthly with respect to RA outcomes and drug related toxicities. RESULTS: Of the 12 patients, 7 were able to complete 6 months of treatment. In these 7 patients, significant improvements were seen in tender joint count (from 26.4 +/- 4.2 to 11.7 +/- 3.2; p = 0.007), swollen joint count (from 17.7 +/- 2.5 to 4.1 +/- 1.3; p = 0.001), and other RA outcomes. All 7 patients achieved the 20% response criteria of the American College of Rheumatology (ACR), and 5 of 7 patients met the ACR 50% response criteria. The other 5 patients withdrew in the first 3 months of treatment due to gastrointestinal symptoms (3), chest pain (1), and neuropathic pain (1). Serum creatinine levels were unchanged in all patients, and hypertension was not seen. CONCLUSION: Tacrolimus was tolerated by only 7 of 12 patients, but in 5 of these 7 patients with severe and refractory disease, the clinical responses were very good.     

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??Abstract??Objective To evaluate the value of serum procalcitonin (PCT) in differentiating pathogens in bloodstream infection patients.Methods Data of septic patients with positive blood cultures who received treatment from January 2011 to December 2013 in the ICU of the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively.Based on the culture findings??patients were assigned into 3 groups??Gram-positive group(G??+ group)??Gram-negative group (G??- group) and fungal group.The levels of serum PCT and the White Blood Cell (WBC) count were compared among the 3 groups.Results One hundred and forty two patients were enrolled??including 51 cases in the G??+ group (35.9%)??75 cases in the G??- group (52.8%) and 16 cases in the fungal group (11.3%).The level of serum PCT (65.32±49.23)μg/L in G??- group was significantly higher than that of the G??+ group(5.36±4.37)μg/L and that of the fungal group (1.59±1.22)μg/L.However??no significant difference in WBC counts was found in 3 groups (P=0.62).ROC curve was drawn to evaluate the value of the level of serum PCT to distinguish the G??- bacteria from the non-G-bacteria.The area under curve was 0.973 (95%CI was 0.953-0.993).The diagnostic threshold was >17 μg/L with the specificity of 95% and the sensitivity of 84%.We also drew a ROC curve to evaluate the value of the level of serum PCT to distinguish the acinetobacter baumannii from other pathogens.The area under curve was 0.965 (95%CI was 0.941-0.990).PCT for cut off >42 μg/L with the specificity of 92% and the sensitivity of 85%.In addition??the ROC curve was drawn to evaluate the value of the level of serum PCT to distinguish fungi from other pathogens.The area under curve was 0.965 (95%CI was 0.934-0.996).PCT for cut off <2.1 μg/L with the specificity of 82% and the sensitivity of 95%.     

Differential effects of FK506 and methotrexate on inflammatory cytokine levels in rat adjuvant-induced arthritis

OBJECTIVE: To investigate the effects of prophylactic and therapeutic treatments with FK506 (tacrolimus), an immunosuppressive drug that specifically inhibits T cell activation, and methotrexate (MTX) on inflammatory cytokines, tumor necrosis factor (TNF)-a, interleukin (IL)-1beta, and IL-6 levels in rat adjuvant-induced arthritis (AIA). METHODS: AIA was induced in female Lewis rats. Arthritis was assessed by hindpaw swelling. TNF-a, IL-1beta, and IL-6 levels in paw extracts were determined by ELISA. To assess the effects on cytokine levels, rats were treated prophylactically with FK506 (3 mg/kg) or MTX (0.1 mg/kg) from day 1 to day 17, and therapeutically with FK506 (5 mg/kg) or MTX (1 mg/kg) from day 15 to day 17 (3-day treatment) or day 15 to 20 (6-day treatment) by oral administration. RESULTS: TNF-a, IL-1beta, and IL-6 levels in paw tissue were found to significantly increase between day 15 and day 21 after adjuvant injection, when the arthritis was in a developed stage. Prophylactic treatment with FK506 and MTX suppressed arthritis and reduced the levels of those inflammatory cytokines. FK506 caused a marked reduction of TNF-a and IL-1beta levels in paw tissue even in short-term (3-day) therapeutic treatment. It reduced all levels of TNF-a, IL-1beta, and IL-6 in paws in 6-day therapeutic treatment. In contrast, therapeutic treatment with MTX affected neither TNF-a or IL-6 levels in paws. MTX reduced IL-1beta levels only in the 6-day treatment. CONCLUSION: FK506 is more effective than MTX in reducing elevated levels of inflammatory cytokines TNF-a, IL-1beta, and IL-6 in established stages of AIA. Our findings suggest that inhibition of T cell activation results in a rapid reduction of inflammatory cytokine levels even after the arthritis is established in AIA.