肾移植后霉酚酸酯所致白细胞减少的临床分析

目的 探讨肾移植后应用霉酚酸酯(MMF)所致白细胞减少的发生机理及治疗策略。方法对应用MMF后发生白细胞减少、须停药的25例肾移植患者的资料进行回顾性分析。结果MMF所致白细胞减少的发生率为4％(25／632)，其中重度及危重度患者13例，中度减少12例，暂停或永久停用MMF，重度及危重度患者应用重组人粒细胞集落刺激因子(rhG—CSF)治疗的有效率为92％(12／13)；患者停用MMF期间加用百令胶囊6．0～9．0g／d。结论 肾移植后应用MMF所致须停药的白细胞减少并不少见，其发生可能与体内血中游离的霉酚酸浓度较高有关；严重者可用rhG～CSF治疗，大多数可逆；肾功能不全者应适当减少MMF的用量。     

Elective withdrawal of mycophenolate mofetil in renal transplant recipients treated with mycophenolate mofetil, cyclosporine, and prednisone

In a retrospective study we investigated the risk of acute rejection after the withdrawal of mycophenolate mofetil (MMF) in 39 adult patients treated with cyclosporine (CyA), prednisone, and MMF for at least 6 months following renal transplantation. After reaching a stable renal graft function, MMF was withdrawn and CyA and prednisone were continued. Preceding the withdrawal of MMF, four patients experienced an acute rejection. During a median follow-up of 38 months after discontinuing MMF, no acute rejection occurred. The mean serum creatinine level did not change during the first 6 months after withdrawal of MMF. We conclude that elective withdrawal of MMF in stable renal transplant recipients at 6 months after transplantation bears no important risk of an occurrence of acute rejection. Received: 24 November 1999 Revised: 11 May 2000 Accepted: 18 December 2000     

霉酚酸酯对糖尿病肾组织炎性因子表达的抑制作用

目的探讨霉酚酸酯（MMF）在糖尿病肾组织中发挥抗炎作用及其机制。方法MMF治疗2型糖尿病大鼠，观察肾组织单核／巨噬细胞浸润，及转录因子（NF）-KBp65、神经生长因子表达的变化；不同浓度的霉酚酸干预高糖环境下培养的肾小球系膜细胞，测定细胞间粘附分子（ICAM）-1、单核细胞趋化蛋白（MCP）-1及神经生长因子（NGF）表达的变化。结果MMF治疗能显著改善糖尿病大鼠肾功能，伴肾小球NF-KBp65活性明显下降，NGF表达水平明显降低，单核／巨噬细胞浸润显著减轻。霉酚酸对高糖诱导的肾小球系膜细胞ICAM-1、MCP-1和NGF高表达有显著的抑制作用。结论MMF很可能通过降低NF-KB活性，间接抑制炎性因子表达、炎症细胞浸润。霉酚酸对高糖环境下肾小球系膜细胞ICAM-1、MCP-1和NGF的高表达有显著抑制作用。     

依那普利联合霉酚酸酯对大鼠糖尿病肾脏协同保护作用及机制

目的 探讨依那普利联合霉酚酸酯(MMF)对大鼠糖尿病肾脏协同保护作用及其机制&#65377; 方法 建立STZ诱导的大鼠单侧肾切除糖尿病模型, 随机分5组:对照组&#65380; 模型组&#65380;依那普利组&#65380; MMF组及依那普利与MMF联合给药组&#65377;8周后观察尿白蛋白排泄率(AER)&#65380; 肾组织病理及丙二醛(MDA)含量与超氧化物歧化酶(SOD)&#65380; 过氧化氢酶(CAT)&#65380; 谷胱苷肽过氧化物酶(GSH-PX)活性变化&#65377;免疫组化或Western 印迹检测肾组织ED-1&#65380;ICAM-1与TGF-β1蛋白表达&#65377;结果 (1) 各给药组均可抑制糖尿病大鼠AER增加及肾小球病理损害(P < 0.05, 0.01); 联合给药组可明显减轻糖尿病肾小管间质损伤指数(P < 0.05)&#65377;(2)对糖尿病肾组织MDA含量增加及SOD&#65380; CAT与GSH-PX活性降低的改善作用,联合组优于单给药组(P < 0.05, P < 0.01)&#65377;(3)模型组肾小球与肾小管间质ED-1阳性细胞数与ICAM-1表达明显高于对照组(P < 0.01); 各给药组ED-1阳性细胞数明显低于模型组(P < 0.05, P < 0.01); 依那普利给药组肾组织ICAM-1表达与模型组相比差异无统计学意义, MMF与联合组ICAM-1表达明显低于模型组(P < 0.05)&#65377; (4)Western印迹显示糖尿病肾组织TGF-β1表达较对照组增加1.79倍,各给药组肾组织TGF-β1表达较模型组分别下降39.72%,44.80%与55.09%&#65377;结论 依那普利与MMF联合给药对糖尿病肾脏保护作用优于单种药物治疗,其机制部分与其对肾组织氧化应激增加&#65380;炎症细胞浸润及TGFβ1表达有协同抑制作用有关&#65377;     

他克莫司联合霉酚酸酯应用于胰肾联合移植的初步经验

目的 总结他克莫司(FK506)联合霉酚酸酯(MMF)应用于胰液膀胱引流式胰肾联合移植受者的初步经验. 方法 胰肾联合移植患者14例,术后应用FK506 0.07～0.15mg·kg-1·d-1加MMF 1.0～1.5 g/d加泼尼松25 mg/d三联免疫抑制治疗方案.采用微粒子酶免疫分析法每周测定口服FK506后全血峰谷浓度,依此调整剂量维持最初3个月内FK506全血浓度峰值10～20 μg/L,谷值5～15μg/L.并观察排斥反应的发生及药物的肝肾毒性. 结果 9例患者术后胰肾功能恢复良好,早期无排斥反应发生,血糖及肌酐水平恢复正常.随访18～70个月,平均34个月.存活1～3年者3例,3年～者1例,4年～者1例,>5年者4例,胰肾功能良好,血糖正常,均未使用降糖药.1例因超急性排斥反应术后第2天切除移植胰腺,随访2年肾功能良好.4例死亡,死因分别为术后急性右心功能衰竭、呼吸骤停、急性排斥反应及十二指肠瘘.胰肾联合移植术后各时期FK506全血峰、谷浓度差异均有统计学意义(P<0.05).术后共发生肾脏急性排斥反应4例次,肾毒性2例次,肝毒性1例次. 结论 FK506与MMF在药效上有协同作用,联合应用于胰肾联合移植具有良好的免疫抑制效果,能有效降低排斥反应发生率和提高移植物长期存活率.     

霉酚酸酯抑制大鼠肾间质纤维化的研究

目的：研究霉酚酸酯（MMF）在单侧输尿管梗阻（UUO）大鼠模型中，能否减少肾小管间质肌成纤维细胞（MyoF)的浸润、增殖及I、Ⅲ型胶原（Col I、ColⅢ）的沉积。方法：将54只大鼠中的36只行左输尿管结扎术，另外18只行假手术。结扎后的大鼠分为模型组和MMF组。术后第5、10及15天分别处死各组中的6只大鼠，用免疫组化方法测定增殖细胞核抗原（PCNA）、α－平滑肌肌动蛋白（α-SMA）及Col I、Col Ⅲ的表达情况。行HE和Masson染色，动态观察肾脏病理学变化。结果：MMF能显著减少肾组织处于增殖状态下的细胞数目和肾小管间质区MyoF的浸润，减轻了Col I、Col Ⅲ的沉积，并有效改善了肾脏的病理学改变。结论：MMF可减少输尿管梗阻后MyoF的浸润并抑制其增殖，从而改善UUO所致的肾脏损伤，提示MMF有潜在的延缓慢性肾功能衰竭进程的作用。     

霉酚酸酯及缬沙坦对糖尿病大鼠足细胞的保护机制研究

目的探讨霉酚酸酯、缬沙坦及2者联合应用对糖尿病。肾病（DN）大鼠足细胞损伤的保护作用。方法雄性Wistar大鼠行右肾切除后，腹腔注射链脲佐菌素（STZ，65mg／kg）建立糖尿病模型。将实验动物随机分为右。肾切除对照组（NC）、糖尿病组（DM）、霉酚酸酯治疗组（M）、缬沙坦治疗组（V）、缬沙坦和霉酚酸酯联合治疗组（V＋M）。治疗组分别给予霉酚酸酯15mg·kg^-1·d^-1，缬沙坦40mg·kg^-1·d^-1；联合治疗组为上述两组之和。检测各组8周末的左肾质量／体质量比值、尿蛋白量（24h）、血糖（Glu）、Scr。光镜及电镜观察肾组织形态学变化。免疫组化检测肾组织中nephrin、结蛋白（desmin）及单核细胞趋化因子1（MCP-1）蛋白表达。实时PCR测定肾组织中nephrin及MCP-1mRNA表达。结果与NC组相比，DM组大鼠血糖、尿蛋白量及左肾质量／体质量比值均显著上升（P〈0．01）；肾小球硬化指数（GSI）及肾间质损害加重（P〈0．01）；肾组织内MCP-1、desmin蛋白表达均显著上调（P〈0．01）。与DM组比较，M组、V组及V＋M组上述指标除Glu、Scr外，均明显改善（P〈0．05或P〈0．01）。与NC组（100％）相比，DM组nephrinmRNA表达下调（78％，P〈0.05）；各治疗组nephrinmRNA表达增加，以M组增加最明显（134％，P〈0．01）。与NC组（100％）相比，DM组MCP-1mRNA表达明显上调（251％，P〈0.05）；各治疗组明显降低，以M组最显著（126％，P〈0．01）。nephrinmRNA与MCP-1mRNA表达呈负相关（r=-0，86。P〈0．01）。尿蛋白量（24h）与MCP-1mRNA呈正相关fr=0．82，P〈0．01）；与nephrinmRNA呈负相关（r=-0．78，P〈0．01）。结论霉酚酸酯及缬沙坦均能下调糖尿病大鼠肾组织中desmin及MCP-1基因及蛋白的表达，上调nephrin基因及蛋白表达，降低尿蛋白量，预防肾损伤。联合治疗不优于单一治疗。霉酚酸酯可能通过抗炎性反应减轻足细胞损伤，减少蛋白尿，对早期DN大鼠具有明显的肾保护作用。     

霉酚酸酯对局灶节段性肾小球硬化大鼠肾脏的保护作用

目的观察霉酚酸酯对局灶节段性肾小球硬化大鼠残肾的保护作用。方法给予局灶节段性肾小球硬化大鼠霉酚酸酯（MMF）50mg·kg^-1·d^-1、雷公藤20mg·kg^-1·d^-1。8周后观察大鼠24h尿蛋白定量、血尿素氮（BUN）、血肌酐（SCr）、血浆白蛋白（Alb）的含量以及肾脏病理改变。结果两药均能减少尿蛋白,降低BUN。在肾脏病理上,局灶节段性肾小球硬化大鼠出现局灶性肾间质纤维化,肾小球硬化,用药后病变减轻,以MMF减轻更为显著。结论MMF能抑制局灶节段性肾小球硬化大鼠肾脏中细胞的异常增殖,减少间质纤维化及肾小球硬化,减少蛋白尿,减轻肾脏的损害。     

吗替麦考酚酯与麦考酚钠肠溶片对肾移植受体血药浓度的影响

目的  探讨吗替麦考酚酯（MMF）与麦考酚钠肠溶片（EC-MPS）在同等生物效应剂量下对肾移植受体麦考酚酸（MPA）血药浓度和不良反应的影响。方法  回顾性分析106例活体供肾移植受体的临床资料。按肾移植术后服用不同药物分为两组,MMF组（M1组,62例）和EC-MPS组（M2组,44例）。两组受体的免疫抑制方案分别为M1组用他克莫司（FK506）+MMF+泼尼松,M2组用FK506+EC-MPS+泼尼松。分析两组受体服药后1、2、3周和1、2、3个月MPA血药浓度的变化情况、不良反应发生情况及服用药物所花费用。结果  采取同等生物效应给药,服药后第1、2、3周,第1、2、3个月时M1组MPA血药谷浓度比M2组低,各个时间点两组间比较,差异均有统计学意义（均为P < 0.05）。与M1组比较,M2组术后不良反应的发生率较低且症状较轻。采用同等生物学效应给药,M1组服用MMF所花费用1 710元/月,M2组服用EC-MPS所花费用2 736元/月,但M1组因治疗药物不良反应所产生费用远高于M2组。结论  同等的生物效应剂量下服用EC-MPS的患者相对服用MMF的患者能维持更高的MPA血药浓度并且不良反应更少。     

霉酚酸酯对肾大部切除大鼠肾脏的保护作用

目的 观察霉酚酸酯在肾大部切除大鼠模型中对残肾的保护作用并探讨其可能的机制。方法 采用5/6肾大部切除模型,分别给予霉酚酸酯(MMF,15 mg·kg-1·d-1),福辛普利(25mg·kg-1·d-1)及两药合用。8周后观察大鼠24 h尿蛋白、BUN、Scr以及肾脏病理改变。并用免疫组化观察了胶原Ⅳ、纤连蛋白(FN)、增殖细胞核抗原(PCNA)和巨噬细胞趋化蛋白1(MCP-1)。用RT-PCR的方法测定了肾皮质中转化生长因子β1(TGF-β1)和组织性金属蛋白酶抑制剂1(TIMP-1)mRNA的表达。结果 两药均能减少尿蛋白,降低BUN和Scr,合用组减少最为明显。病理上,肾大部切除组可见基质增生,肾小球硬化,用药后病变减轻。其中应用MMF者可见PCNA和MCP-1明显减少。结论 在5/6肾大部切除模型中,MMF能通过抑制肾脏中的异常增殖、减少MCP-1的表达,下调TGF-β1和TIMP-1,减少细胞外基质,减少尿蛋白,从而明显减轻肾脏的损害。     

霉酚酸酯对糖尿病大鼠肾组织T细胞浸润的影响

目的 探讨霉酚酸酯(MMF)对链脲佐菌素(STZ)诱导的糖尿病大鼠T淋巴细胞在肾脏组织浸润的影响.方法 30只雄性Wistar大鼠(鼠龄2～3个月),随机分为正常对照组、糖尿病模型组和MMF治疗组[15mg·(kg·d)-1].观察16周后,检测大鼠血糖(BG)、血尿素氮(BUN)、血肌酐(Scr)、肾肥大指数(肾重KW/体重BW)和24h尿蛋白定量(24Upro).用流式细胞仪方法检测肾组织中CD3+、CD4+T淋巴细胞以及细胞因子TNF-α、IFN-y的含量,免疫组化法测肾组织中CD4+、CD8+T细胞的表达.结果 与对照组相比,糖尿病(DM)组大鼠BG、BUN、Scr、Kw/Bw、24Upro等指标均显著升高,差异有统计学意义(P＜0.01).通过流式细胞仪检测,糖尿病大鼠肾脏内CD3+、CD4+T细胞以及由CD4+T细胞产生IFN-γ、TNF-α均显著上调(P＜0.01),通过免疫组化肾脏内CD4+、CD8+T细胞均显著升高(P＜0.01).除血糖、肾肥大指数外,治疗组上述指标均比糖尿病组低,差异有统计学意义(P＜0.05).结论 霉酚酸酯通过抑制T淋巴细胞在糖尿病大鼠肾脏组织中的浸润从而下调炎症因子的表达发挥肾脏保护作用.     

Efficacy of mycophenolate mofetil in pediatric patients with steroid-dependent nephrotic syndrome

Most patients with minimal change nephrotic syndrome are steroid responsive and tolerate this medication. However, a substantial number of patients relapse frequently and become steroid dependent. These patients often require treatment with alternative immunosuppressive drugs to maintain remission and minimize steroid toxicity. Previous studies have suggested that mycophenolate mofetil is effective in treating these patients. However, there are limited data on the effectiveness of this agent in pediatric patients, specifically those with steroid-dependent nephrotic syndrome. The purpose of this study was to assess the efficacy and safety of mycophenolate mofetil therapy in children and adolescents with steroid-dependent nephrotic syndrome who failed other treatments. A retrospective chart review was performed on all patients with steroid-dependent nephrotic syndrome. Clinical characteristics, laboratory data and the relapse rate were assessed prior to and during mycophenolate mofetil treatment. Twenty-one patients, ages 2–17 years, with steroid-dependent nephrotic syndrome who were treated with mycophenolate mofetil between 2001–2005 were included in this review. The indication for mycophenolate mofetil use was steroid dependence in 17 and steroid toxicity in 4 patients. The mean duration of treatment was 1.0±0.5 years (range: 0.2–2.0 years). Patients treated with mycophenolate mofetil had a reduction in relapse rate from 0.80±0.41 to 0.47±0.43 relapses per month ( P <0.02). Side effects were mild and mostly gastrointestinal in nature. In 1 child, mycophenolate mofetil was discontinued due to varicella infection and not restarted. The findings indicate that mycophenolate mofetil is a useful adjunctive therapy in the treatment of patients with steroid-dependent nephrotic syndrome. It lowers the relapse rate by 40% and is well tolerated by patients with steroid-dependent nephrotic syndrome.     

肾移植后远期吗替麦考酚酯相关慢性腹泻的药物转换效果观察

目的 探讨肾移植后远期发生吗替麦考酚酯(MMF)相关慢性腹泻时将MMF转换为麦考酚钠肠溶片( EC- MPS)后腹泻的改善情况及对受者机体内环境的影响.方法 26例肾移植受者术后6.2年发生MMF相关的慢性腹泻.确诊后首先将MMF减至最低用量,腹泻仍未减轻,将MMF转换为EC-MPS,360 mg/d.观察转换2周时腹泻的改善状况,若症状无改善,则停用EC-MPS,改用非麦考酚酸类抗排斥反应药物;若症状明显减轻或消失,则第3周时将EC-MPS的用量提高到720 mg/d.提高剂量后再观察2周,若腹泻症状未加重,则维持此剂量,继续观察3个月;若提高剂量后腹泻加重,则重新减量至360 mg/d.药物转换期间观察腹泻症状改善状况以及转换后不同时间的血白细胞计数、血红素、血清丙氨酸转氨酶(ALT)、血肌酐、C-反应蛋白、血钾、血钠、血总二氧化碳(TCO2)及24 h尿蛋白定量等指标.结果 19例于转换药物后2周内腹泻停止,2例腹泻明显减轻,总有效率为80.8％(21/26);另5例转换后腹泻仍较重,停用麦考酚酸类药物;转换药物后,受者的内环境紊乱得到明显改善,血钾、血钠及血TCO2均恢复至正常水平,尤其重要的是,转换前24 h尿蛋白定量为(0.76±0.48)g,转换第3个月为(0.46±0.53)g,明显低于转换前(P＜0.05).结论 移植后晚期发生MMF相关慢性腹泻时将MMF转换为EC-MPS,可使腹泻减轻,并由此改善机体内环境.     

霉酚酸酯与环磷酰胺冲击治疗狼疮性肾炎临床疗效的比较

目的 比较霉酚酸酯（ＭＭＦ）与间断性环磷酚胺静脉冲击疗法（ＣＴＸ）治疗狼疮肾炎（ＬＮ）的近期及远期疗效、不良反应及安全性。方法Ａ组：间断性环磷酞胺冲击疗法治疗３０例ＬＮ患者，平均随访（１８６５±６．１０）（６～２４）月． Ｂ组：ＭＭＦ联合激素治疗ＬＮ患者，平均随访（２１.８９±７. ４８）（６～４８）月．两组患者的病理类型、病情基本相似，但 Ｂ组（ＭＭＦ）绝大部分为皮质激素联合 ＣＴＸ治疗无效者，Ｂ组患者病程明显较Ａ组长。结果ＣＴＸ组、ＭＭＦ组治疗ＬＮ均能降低蛋白尿和血尿，改善肾功能及免疫指标，两组间差异无显著性意义。ＭＭＦ组患者的平均疗程较ＣＴＸ组明显延长，而疗效却基本相同 ．不良反应：ＭＭＦ组无肝功能受累、性腺抑制副反应，感染率为 １３．３％。ＣＴＸ组感染率为 ２３．３％．肝功能受累为 ２３.３％，性腺抑制为 ２８％．结论 ＣＴＸ、ＭＭＦ都能有效的控制狼疮肾炎，改善肾功能，两者无显著性差异．对病程长、激素联合ＣＴＸ无效及病情迁延者，经ＭＭＦ治疗后达到与ＣＴＸ组同样效果，而且副作用少，提示ＭＭＦ具有一定的优越性。     

Steatorrhoea complicating post-infectious diarrhoea in a renal transplant patient on mycophenolate mofetil therapy

Mycophenolate mofetil (MMF) is licensed as a prophylaxis in combination therapy to prevent renal transplant rejection. Gastrointestinal side effects are fairly common and include diarrhoea, abdominal discomfort, nausea, vomiting, gastritis and constipation. This drug has recently been described as causing villous atrophy, nutrient malabsorption and colonic mucosal changes. We present a case of reversible steatorrhoea occurring in a patient treated with MMF following an episode of infections diarrhoea.     

Effects of mycophenolate mofetil and glucocorticoid on Henoch-Schonlein purpura nephritis in children

Objective To explore the effect and safety of mycophenolate mofetil (MMF) and glucocorticoid on Henoch-Schonlein purpura nephritis in children and compared with cyclophosphamide (CTX). Methods The data of 48 patients diagnosed as Henoch-Schonlein purpura by renal biopsy were retrospectively analyzed. Median follow-up time was 22(7, 48) months. The subjects were divided into 2 groups. 34 cases were in the MMF group: MMF (15-20 mg?kg-1?d-1 or 800-1200 mg/m2)+ prednisone, and 14 cases in the CTX group: CTX (8 - 12 mg?kg-1?d-1)+prednisone. Clinical and laboratory data were collected at baseline and 1, 3, 6 months after treatment. During follow - up, cumulative retreatment rate and adverse reactions after treatment were recorded. Results In two groups after treatment for 1, 3, 6 months, 24 hours urinary protein quantitative was significantly lower than the baseline value, serum albumin (sAlb) was significantly higher than the baseline value, and serum creatinine (Scr) indicated no statistically significant difference during the follow-up period. After the treatment of 1 month, the efficient rate of MMF group was higher than the CTX group (MMF 73.5 % vs 42.9%, P=0.046), the effective treatment of 3, 6 months at the end of the follow-up, no statistically significant difference were observed in the accumulative remission rate. The total rate of retreatment was 10.4% (5/48), where MMF group was lower that of the than CTX group (3.0% vs 28.6%, P＜ 0.001). The retreatment often occurred after discontinuation of prednisone and CTX, MMF reduction process. Eleven children received IMPDH2 gene polymorphisms test in MMF group, 9 AA children had shorter time for drugs to be effective than that of the AG and GG children. The incidence of adverse reactions of MMF group was obviously lower than CTX group at the end of the follow-up (8.8% vs 35.7%, P=0.025), where two groups developed fungal infection. Conclusions The short-term effect of both groups are the same, but the recurrent rate and incidence of adverse reactions of MMF group are lower than those of the CTX group. The preliminary study shows that IMPDH2 gene polymorphisms is associated with MMF curative effect and adverse reactions.     

Mycophenolate mofetil pharmacokinetics in renal transplant recipients on peritoneal dialysis

We prospectively studied the impact of peritoneal dialysis (PD) on the pharmacokinetics of mycophenolic acid (MPA) in five patients following renal transplantation. Three patients had a glomerular filtration rate (GFR) of less than 10 ml/min and two had a GFR of more than 40 ml/min. Pharmacokinetics of MPA and of its main metabolite, mycophenolic acid glucuronide (MPAG), were studied during two consecutive 12-h periods (with and without PD). After initiation of PD in patients with severe renal impairment (GFR < 10 ml/min), MPA-area-under-the-concentration-curve (AUC) decreased up to 59 % and MPAG-AUC decreased up to 26 %. We did not observe any substantial changes in the MPA-AUC or MPAG-AUC of either patient with a GFR above 40 ml/min. Patients with a reduced GFR had much higher MPAG values than patients with a GFR above 40 ml/l; yet, we did not observe any differences in the MPA values. We found a significant inverse correlation between GFR and MPA-AUC (r = 0.81, P < 0.05) and between GFR and MPAG-AUC (r = 0.94, P < 0.01). While MPA was found only in traces in the peritoneal ultrafiltrate, the cumulative amount of MPAG removed by PD reached up to 2 g/12 h, representing 1.2 g of MPA. This is the first report describing a reduction in MPA-AUC and MPAG-AUC during PD. Further studies are needed to completely understand the pharmacokinetics of mycophenolate mofetil during PD. Received: 20 June 1997 Accepted: 26 August 1997     

The use of mycophenolate mofetil suspension in pediatric renal allograft recipients

Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m² b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m² b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC_0–12) of 27.2 μg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m² b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients. Received: 7 May 2001 / Revised: 16 July 2001 / Accepted: 16 July 2001     

Pharmacokinetics and tolerance of mycophenolate mofetil in renal transplant children

Mycophenolate mofetil (MMF) is a prodrug that is hydrolyzed to the active immunosuppressant mycophenolic acid (MPA). The drug is now widely prescribed for adult renal transplant recipients and its use has been extended to pediatric patients, although pharmacological data in this age group are limited. Nine pediatric renal transplant recipients received MMF with corticosteroids and either cyclosporine or tacrolimus a median of 55 months (range 7.5–124 months) months after transplantation. The pharmacokinetic parameters of MPA and MPA glucuronide (MPAG) were determined at steady state by high-performance liquid chromatography after administration of MMF at the oral dose of 494±142 mg/m² twice daily. MPA was rapidly absorbed, with a peak concentration at 1.4 h. The mean plasma concentration of MPA at steady state was 4.7±1.3 μg/ml. The areas under the plasma concentration-time curves (AUCs) over 12 h (between two administrations) were 57.0±15.3 μg.h/ml for MPA and 1,515±722 μg.h/ml for MPAG, and the apparent oral clearance was 11.7±7.0 and 0.5±0.4 l/h for MPA and MPAG, respectively. Assuming that the pharmacokinetics of MPA was dose dependent, the mean concentration at steady state and the AUC for MPA were calculated for the recommended dosage schedule of 600 mg/m² every 12 h and were 6.3±2.7 μg/ml and 75.2±32.9 μg.h/ml, respectively. The tolerance of MMF was studied prospectively with a follow-up of 1.1±0.2 years. Gastrointestinal disorders requiring dosage reduction or discontinuation of therapy, observed in five of nine patients, occurred at an incidence higher than expected from adult data. Our results suggest that the dose of 600 mg/m² every 12 h extrapolated from adult data for use in pediatric patients would be associated with plasma levels and AUCs higher than expected and may be associated with a higher incidence of side-effects, primarily gastrointestinal. Received: 3 August 1998 / Revised: 19 January 1999 / Accepted: 19 January 1999     

霉酚酸酯与雷帕霉素合用预防及逆转大鼠心脏移植排斥反应

目的 评价霉酚酸酯（ＭＭＦ）与雷帕霉素（ＲＡＰＱ）合用预防及逆转大鼠心脏移植后排斥反应的作用。方法 将实验动物随机分为４组：（１）对照组;（２）单用ＭＭＦ组;（３）单用ＲＡＰＡ组;（４）ＭＭＦ与ＲＡＰＡ合用组。结果 单用ＭＭＦ和单用ＲＡＰＡ组与对照组比较均显著延长移植心脏存活时间,ＭＭＦ与ＲＡＰＡ合用组与对照组比较非常显著地延长移植心脏存活时间,并且心脏存活时间明显长于同剂量两药的单用组。