麦考酚酸酯对狼疮性肾炎小鼠肾小球硬化的防治

目的 :研究麦考酚酸酯对实验性狼疮性肾炎肾小球硬化的防治作用。方法 :自发性狼疮模型BWF1小鼠予麦考酚酸酯 10 0mg·kg-1,ig ,qd ,连续 2 0wk。运用考马斯亮蓝法检测 2 4h尿蛋白量 ;ELISA法检测血清抗dsDNA抗体水平 ;免疫组化法检测肾组织中纤维连接蛋白、层黏蛋白、基质金属蛋白酶 1(MMP 1)及基质金属蛋白酶组织抑制剂 1(TIMP 1)的表达 ;逆转录 巢式PCR法检测小鼠肾组织中 (α1)Ⅳ型胶原、转移生长因子 β1(TGF β1)的表达。结果 :在蛋白尿发生前给予麦考酚酸酯治疗可完全抑制小鼠蛋白尿的产生 ,显著降低其血清抗dsDNA抗体水平 ,明显增加肾组织中MMP 1而减少转移生长因子 β1(TGF β1)mRNA、(α1)Ⅳ型胶原mRNA、纤维连接蛋白、层黏蛋白和TIMP 1的表达 ,改善小鼠组织学病变。结论 :麦考酚酸酯对该狼疮模型的肾小球硬化具有明确的保护作用     

霉酚酸酯治疗IV型狼疮性肾炎

目的　观察新型免疫抑制剂霉酚酸酯 (MMF)治疗IV型狼疮性肾炎 (LN)疗效及不良反应并探讨MMF的剂量。方法　对传统剂量激素及免疫抑制剂治疗无效或复发的 10例IV型LN患者予MMF联合小剂量糖皮质激素治疗。MMF剂量 1.5～ 2 .0 g/d ,治疗时间 4～ 10个月 (5 .32± 1.5 )个月。结果　经MMF治疗后 ,5例肾功能不全 (氮质期 3例 ,需透析 2例 )者 4例血清肌肝恢复正常。 8例患者尿蛋白减少一半以上。其中 3例患者尿蛋白转阴。半数患者的血尿消失。血清A -dsDNA均转阴性 ,ANA滴度明显下降 ,血清球蛋白水平明显下降。治疗中 2例并发肺炎 ,1例并发带状疱疹 ,未见白细胞减少及肝功能异常。结论　MMF对传统免疫抑制剂治疗无效的重症、难治性IV型LN有较好的疗效     

霉酚酸酯联合强的松治疗狼疮性肾炎临床研究

目的 观察霉酚酸酯（骁悉）联合强的松治疗LN的临床疗效和不良反应。方法 43例狼疮性肾炎随机分为骁悉联合强的松和环磷酰胺联合强的松治疗组，采用ELISA，间接免疫荧光法，生化法等检测两组病人血清细胞因子IL-6，IL-8，TNF-α水平，自身抗体，补体C3，C4，肝功，肾功和尿蛋白等指标。结果 与环磷酰胺联合强的松治疗相比，病人经骁悉联合强的松治疗后血清IL-6，IL-8，TNF-α水平，抗核抗体，A-dsDNA抗体水平，血尿素氮，肌酐以及尿蛋白水平均明显降低；血C3，C4增高更为明显，且病人无明显的骨髓抑制和肝功能损害。结论 骁悉联合强的松治疗狼疮性肾炎疗效好。安全性高，值得推广应用。     

霉酚酸酯治疗狼疮肾炎肾病综合征的疗效观察

目的　回顾性分析 11例糖皮质激素治疗及 /或环磷酰胺治疗无效 ,或因严重副作用无法治疗的狼疮肾炎肾病综合征患者应用霉酚酸酯 (MMF)联合小剂量激素治疗效果。方法　病理检查证实为狼疮肾炎Ⅳ型患者 11例 ,应用糖皮质激素及环磷酰胺治疗受到限制 ,有中～重度狼疮活动依据 ,改用MMF (1 0～ 2 0 g/d)联合小剂量糖皮质激素治疗 6个月以上 [平均 (8 3± 1 5 )个月 ],同期与继续应用泼尼松及 /或环磷酰胺治疗的狼疮肾炎Ⅳ型患者 8例比较 ,观察尿蛋白、狼疮活动指数及肾功能。结果　经过MMF治疗后 ,尿蛋白由治疗前 (3 9± 0 7)g/d下降到治疗后 (1 4± 0 5 ) g/d ,狼疮活动指数明显下降 (治疗前 13 5± 3 3 ,治疗后 3 8± 1 0 ) ,其中 3例肾功能异常患者肾功能恢复正常 ,与对照组比较尿蛋白、狼疮活动指数恢复差异无显著性。结论　MMF联合应用小剂量糖皮质激素能够有效地抑制狼疮肾炎患者的狼疮活动     

霉酚酸酯治疗狼疮性肾炎

霉酚酸酯（MMF）是霉菌酵解物中分离出的霉酚酸（MPA）半合成衍生物，能选择性抑制次黄嘌呤核苷酸脱氢酶，影响嘌呤核苷酸的合成，从而抑制淋巴细胞增生及抗体的产生，同时抑制内皮细胞黏附分子的表达，MMF治疗狼疮性肾炎（LN）的实验研究及临床应用均表明，MMF可控制狼疮活动，抑制自身抗体的产生，减少蛋白尿，降低血肌酐，改善肾脏病理，很少骨髓抑制及肝脏损害。     

Defining the role of mycophenolate mofetil in the treatment of proliferative lupus nephritis

Systemic lupus erythematosus, which predominantly affects young women, is frequently complicated by renal involvement. The presence of acute glomerulonephritis significantly adds to morbidity and mortality. Cyclophosphamide has become the mainstay of treatment in patients with proliferative forms of lupus nephritis. However, adverse events such as severe infections and infertility have spurred the search for novel treatment regimens and agents. Sequential therapy has significantly reduced adverse events. In several pilot studies, mycophenolate mofetil (MMF) has emerged as a promising therapeutic approach for both the induction and maintenance phase in patients with lupus nephritis, delivering equal efficacy and a better adverse effect profile; however, these studies had a limited power, and a large, multicentre and probably multinational clinical trial will be needed to discern the optimal therapeutic approach. On the basis of the currently available literature, sequential therapy with cyclophosphamide induction followed by azathioprine or MMF maintenance can be recommended for most patients. In selected populations, induction with MMF is a reasonable option to reduce adverse events.     

霉酚酸酯(MMF)联合中药治疗狼疮肾炎临床观察

目的比较霉酚酸酯(mycophenolate mofeti,MMF)和霉酚酸酯加中药自拟方组治疗狼疮肾炎(lupusne-phritis,LN)的近期及远期疗效、不良反应。方法 62例LN患者随机分为两组,对照组31例,治疗组31例,对照组采用MMF联合激素治疗,治疗组采用MMF加中药自拟方治疗,对患者的24 h尿蛋白定量、肝肾功能、副作用进行比较。结果两组治疗LN均能降低蛋白尿,改善肾功能,提高血浆白蛋白,有效地控制LN,两者无显著性差异。但治疗组有效率高于对照组,差异有统计学意义(P<0.05)。且胃肠道症状治疗组显著低于对照组(P<0.05)。结论经MMF加中药自拟方治疗后有效率高于MMF组,而且副作用少,显示MMF加中草药对LN治疗具有一定的优越性。     

霉酚酸酯对狼疮性肾炎患者颈动脉内膜-中膜厚度的影响

目的 探讨霉酚酸酯(MMF)对狼疮性肾炎(LN)患者的动脉粥样硬化指数(AI)及颈动脉内膜-中膜厚度(IMT)的影响.方法 45例LN患者用MMF治疗(MMF组,23例)和环磷酰胺(CTX)治疗(CTX组,22例),比较治疗前后AI、IMT和系统性红斑狼疮疾病活动性指数(SLE-DAI)的变化.结果 两组治疗前后的IMT、AI和SLE-DAI比较差异均无统计学意义(P＞0.05).MMF组和CTX组治疗缓解率分别为81.8％和69.6％ (P＞0.05).缓解病例治疗前后IMT变化值明显小于未缓解病例(P＜0.05).结论 MMF治疗LN的1年疗效与CTX相仿;LN病情控制者的IMT增厚明显减慢.     

Therapeutic drug monitoring of mycophenolate mofetil and enteric-coated mycophenolate sodium in patients with systemic lupus erythematosus

Objective: Mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), is used to treat systemic lupus erythematosus (SLE). MMF and EC-MPS pharmacokinetics were examined to devise guidance for therapeutic drug monitoring (TDM) for SLE patients with normal renal function.

Research design and methods: This observational study included 21 patients receiving MMF (1000 mg twice daily) and 14 taking EC-MPS (720 mg twice daily). MPA AUC between 0 and 12 h (AUC_0–12h), C_max, T_max, and 12-h trough concentrations (C_12h) were determined.

Results: Means of dose-normalized MMF– or EC-MPS–MPA C_max were 64.6 ± 25 and 61.4 ± 27.1 h mg/l, respectively. MPA T_max for EC-MPS was longer and more variable than for MMF. MMF-MPA AUC_0–12h and C_12h were correlated (r = 0.78, p = 0.0001), but EC-MPS–MPA C_max and single concentrations were weakly correlated. A limited-sampling strategy (LSS) combining C_max and C_12h gave satisfactory predictive performance to estimate MPA AUC_0–12h after EC-MPS administration.

Conclusions: For TDM in SLE patients with GFR >?60 ml/min/1.73 m², C_12h after MMF ingestion could predict MPA AUC_0–12h, while an LSS around T_max should be used for patients on EC-MPS.     

霉酚酸酯在系统性红斑狼疮中的应用进展

霉酚酸酯作为一种新型免疫抑制剂，已经成功应用干预防器官移植过程中的急性移植物抗排斥反应．它也应用于治疗多种自身免疫性疾病。对系统性红斑狼疮的治疗主要集中在增殖性狼疮肾炎，目前霉酚酸酯正用于控制狼疮的其他症状，如狼疮病情活动、血液系统症状以及难治性皮肤性狼疮。现综述霉酚酸酯在治疗系统性红斑狼疮中的进展。     

Pharmacokinetics and pharmacodynamics of mycophenolic acid after enteric-coated mycophenolate versus mycophenolate mofetil in patients with progressive IgA nephritis

Mycophenolic acid can be administered orally using mycophenolate mofetil or enteric-coated mycophenolate. In renal transplant patients on immunosuppressant combination therapy, the overall mycophenolic acid exposure after oral dosing with mycophenolate mofetil and enteric-coated mycophenolate is similar. This study compared pharmacokinetics and pharmacodynamics of mycophenolic acid after equivalent doses of enteric-coated mycophenolate (360 mg twice daily) or mycophenolate mofetil (500 mg twice daily) in 7 patients with progressive IgA nephritis (glomerular filtration rate 20-35 mL/min) using a randomized crossover design. The pharmacokinetics of mycophenolic acid concentrations and pharmacodynamics (using inosine 5'-monophosphate dehydrogenase activity as a bio-marker) were sequentially monitored for 12 hours. After enteric-coated mycophenolate treatment, the mycophenolic acid peak concentration (Cmax = 12.8 vs 6.0 microg/mL, P < .05) and the overall exposure were significantly higher (AUC = 60.9 vs 40.7 microg.h/mL, P < .05), and the apparent clearance was significantly lower (CL/F = 7.9 vs 10.7 L/h, P < .05) as compared to that after mycophenolate mofetil. Paradoxically, inosine 5'-monophosphate dehydrogenase activity was not significantly different. In conclusion, the steady-state mycophenolic acid exposure was higher during treatment with enteric-coated mycophenolate as compared to mycophenolate mofetil, which might be explained by more extensive enterohepatic recycling of mycophenolic acid after administration of enteric-coated mycophenolate, whereas inosine 5'-monophosphate dehydrogenase suppression was not different.     

Associations of UDP-glucuronosyltransferases polymorphisms with mycophenolate mofetil pharmacokinetics in Chinese renal transplant patients

Aim:

To evaluate the effects of UDP-glucuronosyltransferases (UGTs) polymorphisms on the pharmacokinetics of the immunosuppressant mycophenolate mofetil (MMF) in Chinese renal transplant recipients.

Methods:

A total of 127 renal transplant patients receiving MMF were genotyped for polymorphisms in UGT1A9 −1818T>C, I399C>T, −118T9/10, −440C>T, −331T>C, UGT2B7 IVS1+985A>G, 211G>T, −900A>G, UGT1A8 518C>G and UGT1A7 622T>C. The plasma concentrations of the MMF active moiety mycophenolic acid (MPA) and main metabolite 7-O-MPA-glucuronide (MPAG) were analyzed using HPLC. Univariate and multivariate analyses were used to assess the effects of UGT-related gene polymorphisms on MPA pharmacokinetics.

Results:

The dose-adjusted MPA AUC_{0–12 h} of the patients with the UGT2B7 IVS1+985AG genotype was 48% higher than that of the patients with the IVS1+985AA genotype, which could explain 11.2% of the inter-individual variation in MPA pharmacokinetics. The dose-adjusted MPAG AUC_{0–12 h} of the patients with the UGT1A7 622CC and UGT1A9 −440CT/−331TC genotypes, respectively, was significantly higher than that of the patients with 622T homozygotes and −440C/−331T homozygotes. Furthermore, the genotypes UGT1A9 −1818T>C and UGT1A8 518C>G were associated with a low dose-adjusted MPAG AUC_{0–12 h}.

Conclusion:

The UGT2B7 11+985A>G genotype is associated with the pharmacokinetics of MPA in Chinese renal transplant patients, which demonstrates the usefulness of this SNP for individualizing MMF dosing.     

吗替麦考酚酯分散片的相对生物利用度及生物等效性

目的:研究吗替麦考酚酯分散片和吗替麦考酚酯胶囊在健康志愿者中的药动学及生物等效性。方法:根据交叉试验方案口服单剂量(1 000mg)两种吗替麦考酚酯制剂,采用高效液相色谱法测定血浆中霉酚酸的浓度。结果:吗替麦考酚酯分散片和吗替麦考酚酯胶囊(对照药)的tmax分别为(0.51±0.29)h和(0.54±0.26)h;Cmax分别为(53.6±22.2)mg.L-1和(52.4±18.3)mg.L-1;AUC0→48分别为(133.7±43.6)mg.h.L-1和(142.8±46.2)mg.h.L-1;分散片相对于胶囊的生物利用度为(96.1±19.7)%。经配对检验,结果表明,两种制剂的主要药动学参数Cmax、AUC0→48的差异无显著性(P>0.05)。结论:吗替麦考酚酯分散片和吗替麦考酚酯胶囊为生物等效制剂。     

Coadministration of tacrolimus and mycophenolate mofetil in stable kidney transplant patients: pharmacokinetics and tolerability

The tolerance and pharmacokinetics (PK) of tacrolimus (T) by the addition of mycophenolate mofetil (MMF) in stable kidney transplant patients (6/group) on long-term tacrolimus-based therapy were investigated. Patients received combination T and MMF therapy at three MMF doses: 1, 1.5, and 2 g/day administered twice daily. A 12-hour blood PK profile for T was obtained prior to MMF dosing; concomitant 12-hour profiles for T, mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG) were obtained after 2 weeks of administration. Tolerance was monitored through 3 months. The intra- and intergroup PK of T were variable. The mean AUC0-12 of T for each group was increased after 2 weeks of concomitant MMF administration, but the increase was not statistically significant. Both drugs were well tolerated. Gastrointestinal events were of interest as such have been attributed to both T and MMF. Events reported were diarrhea, nausea, dyspepsia, and vomiting. Other common adverse events were headache, hypomagnesemia, and tremors. Most were mild, although a few were considered to be moderate. There was no apparent relationship between the incidence of any adverse event and MMF treatment group. In the present study, the coadministration of T and MMF did not significantly alter T pharmacokinetics.     

霉酚酸酯在肾移植患者中的应用

目的：将免疫抑制剂霉酚酸酯（MMF）在预防肾移植术后的排斥反应及肝毒性发生率等指标与硫唑嘌呤（Aza）进行临床对照观察。方法：MMF组（环孢素A＋泼尼松＋MMF）35例,对照组（环孢素A＋泼尼松＋Aza)25例。试验观察期24mo。结果：MMF组移植术后排斥反应及肝毒性发生率明显低于对照组,2组差异有高度统计学意义（P肝＜0．01,P肾＜0．01）;且MMF组肾功能较对照组平稳。结论：MMF与环孢素A及泼尼松三药联用,可降低急慢性排斥反应及肝肾毒性发生率,从而提高了免疫抑制剂应用的安全性和耐受性。     

Early pharmacokinetics of low dosage mycophenolate exposure in Thai kidney transplant recipients

Background The effects of mycophenolic acid exposure in the early period after transplantation on clinical outcomes have been reported; however, mycophenolic acid exposure in the early period after transplantation in Asian kidney transplant recipients who receive 1.5 g/d mycophenolate mofetil has never been investigated. Objective To determine mycophenolic acid exposure on day 3 post-transplantation in kidney transplant recipiens who receive 1.5 g/d mycophenolate mofetil. The effects of the reduced renal function on mycophenolic acid area under the concentration–time curve (AUC) and the achievement of the target AUC on the incidence of biopsy proven acute rejection during the first month post-transplantation were also evaluated. Setting A university hospital Method Blood samples and 24-h urine were collected on day 3 post-transplantation. Main outcome measures The mycophenolic acid AUC was calculated by linear trapezoidal rule and compared with the target of 45 mg*h/L. Results Of 42 Thai kidney transplant recipiens, the mean mycophenolic acid AUC of 45.1 mg*h/L (SD 14.7) was comparable to the AUC target (P?=?0.962). Significant differences of the mycophenolic acid AUC were observed between patients with urine output of?<?2400 mL and those with urine output?≥?2400 mL (35.3?±?6.6 and 47.4?±?15.2, respectively; P?=?0.002), and between patients with 24-h measured CrCl?<?25 mL/min and those with CrCl?≥?25 mL/min (38.0 (29.0, 42.2) and 49.2?±?14.0, respectively; P?=?0.017). Proportions of overall biopsy proven acute rejection among patients with mycophenolic acid AUC of?<?45 and?≥?45 mg*h/L were comparable (20.0% and 23.5%, respectively; P?=?1.000). Conclusions After the starting dosage of 1.5 g/d mycophenolate mofetil, the mean mycophenolic acid AUC on day 3 post-kidney transplantation is comparable with the target of 45 mg*h/L. Severely reduced renal function significantly influences mycophenolic acid exposure.

     

Fludarabine pharmacokinetics after subcutaneous and intravenous administration in patients with lupus nephritis

STUDY OBJECTIVE: To compare the pharmacokinetics of subcutaneous and intravenous fludarabine in patients with lupus nephritis. DESIGN: Open-label, randomized, crossover trial conducted with a phase I-II trial. SETTING: Government research hospital. PATIENTS: Five patients with lupus nephritis. INTERVENTION: Fludarabine 30 mg/m2/day was administered either subcutaneously or as a 0.5-hour intravenous infusion for 3 consecutive days. All patients received oral cyclophosphamide 0.5 g/m2 on the first day of each cycle. MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected before and 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the first dose. Urine was collected at 6-hour intervals for 24 hours. Plasma and urine were analyzed for fluoro-arabinofuranosyladenine (F-ara-A), fludarabine's main metabolite, using high-performance liquid chromatography. Compartmental techniques were used to determine the pharmacokinetics of F-ara-A; a linear two-compartment model best described them. Comparison of the pharmacokinetics between subcutaneous and intravenous administration was done by using a Wilcoxon signed rank test. No significant differences were found between subcutaneous and intravenous administration in median (interquartile range) maximum concentrations of 0.51 (0.38-0.56) and 0.75 (0.52-0.91) mg/L, respectively, or in fitted area under the concentration-time curves from 0-24 hours of 4.65 (4.17-4.98) and 4.55 (3.5-4.94) mg x hour/L, respectively. Bioavailability of F-ara-A after subcutaneous dosing was approximately 105% of the bioavailability after intravenous administration. Differences in renal clearance and percentage of dose excreted in urine for subcutaneous and intravenous administration were nonsignificant. No injection site reactions were seen with subcutaneous dosing. CONCLUSION: Subcutaneous and intravenous administration of fludarabine appear to have similar pharmacokinetics in patients with lupus nephritis. Subcutaneous injection may offer a convenient alternative to intravenous administration.     

吗替麦考酚酯在原发性肾病综合征患者中的群体药动学研究

目的：研究吗替麦考酚酯在原发性肾病综合征患者中的群体药动学模型,为临床个体化用药提供参考。方法选取2011年1月~2014年2月期间我院收治的56例原发性肾病综合征患者作为本组研究的观察对象,所有患者在给予吗替麦考酚酯对症治疗后,采集其血液样本,通过非线性混合效应模型构建出麦考酚酯的群体药动学模型,从而探讨患者的年龄、性别、身高、体重、剂量、血清肌酐、治疗时间等对药动学参数的影响。结果药动学基本模型采用一级吸收和消除的二房室模型最为有效;患者体重与治疗时间是吗替麦考酚酯清除率的主要因素;最终群体药动学模型为：清除率=0.476×体重×(1-e-1.17POD)。结论吗替麦考酚酯在原发性肾病综合征患者中的药动学模型具有明显的代表性,为个体化给药方案的确定提供依据。     

吗替麦考酚酯胶囊含量和有关物质的测定

目的采用反相高效液相色谱法建立吗替麦考酚酯胶囊的有关物质测定法。方法色谱柱symmetry C18150＊4.6mm,流动相为：乙腈-水-三乙胺磷酸缓冲液（取三乙胺10mL,加水990mL,混匀,磷酸调节pH值至5.4±0.1）（40∶40∶20）;流速：1.0mL·min-1,检测波长为249nm;柱温45℃。结果制剂中辅料对主药测定无干扰,吗替麦考酚酯在60.2μg~602.4μg.mL-1浓度范围内,峰面积与浓度线性关系良好,相关系数r=0.99995;平均回收率为99.9%,变异系数为1.4%。溶液在冷藏5℃条件下,4h内稳定,24h降解产物明显增加,因此供试品溶液宜现配现用;麦考酚酸在4.6μg~46.05μg.mL-1范围内R=0.99995;平均回收率为98.5%;精密度测定变异系数为：0.46%。结论本法简便,准确,专属性强,可用于吗替麦考酚酯胶囊的有关物质检查和含量测定。