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。     

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.     

Pharmacokinetic study of tacrolimus in cystic fibrosis and non-cystic fibrosis lung transplant patients and design of Bayesian estimators using limited sampling strategies

OBJECTIVES: To: (i) test different pharmacokinetic models to fit full tacrolimus concentration-time profiles; (ii) estimate the tacrolimus pharmacokinetic characteristics in stable lung transplant patients with or without cystic fibrosis (CF); (iii) compare the pharmacokinetic parameters between these two patient groups; and (iv) design maximum a posteriori Bayesian estimators (MAP-BE) for pharmacokinetic forecasting in these patients using a limited sampling strategy. METHODS: Tacrolimus blood concentration-time profiles obtained on three occasions within a 5-day period in 22 adult lung transplant recipients (11 with CF and 11 without CF) were retrospectively studied. Three different one-compartment models with first-order elimination were tested to fit the data: one with first-order absorption, one convoluted with a gamma distribution to describe the absorption phase, and one convoluted with a double gamma distribution able to describe secondary concentration peaks. Finally, Bayesian estimation using the best model and a limited sampling strategy was tested in the two groups of patients for its ability to provide accurate estimates of the main tacrolimus pharmacokinetic parameters and exposure indices. RESULTS: The one-compartment model with first-order elimination convoluted with a double gamma distribution gave the best results in both CF and non-CF lung transplant recipients. The patients with CF required higher doses of tacrolimus than those without CF to achieve similar drug exposure, and population modelling had to be performed in CF and non-CF patients separately. Accurate Bayesian estimates of area under the blood concentration-time curve from 0 to 12 hours (AUC12), AUC from 0 to 4 hours, peak blood concentration (Cmax) and time to reach Cmax were obtained using three blood samples collected at 0, 1 and 3 hours in non-CF patients (correlation coefficient between observed and estimated AUC12, R2 = 0.96), and at 0, 1.5 and 4 hours in CF patients (R2 = 0.91). CONCLUSION: A particular pharmacokinetic model was designed to fit the complex and highly variable tacrolimus blood concentration-time profiles. Moreover, MAP-BE allowing tacrolimus therapeutic drug monitoring based on AUC12 were developed.     

霉酚酸酯对红斑狼疮患者疗效及细胞凋亡影响的相关研究

目的 探讨霉酚酸酯(MMF)治疗红斑狼疮患者的临床疗效及对肾细胞凋亡情况的影响.方法 选取2011年1月至2016年1月来我院治疗的135例红斑狼疮患者,完全随机分为两组,其中一组患者采用激素联合MMF治疗,简称为MMF组;另一组采用激素联合环磷酰胺(CTX)治疗,简称为CTX组.观察比较治疗前及治疗后6个月两组患者SLEDAI评分、血红蛋白、血小板、尿蛋白、血清白蛋白、SCr、C3、ANA(+)、抗-dsDNA(+)及aCL(+)、血清转氨酶等指标的变化情况及治疗过程中不良反应发生情况.采用肾活检及原位末端标记法检测两组患者肾细胞凋亡情况,并比较分析.结果 ①与治疗前比较,两组患者治疗后各指标均有显著改善,差异有统计学意义(P＜0.05);治疗后,MMF组在血红蛋白、血小板、尿蛋白、抗-dsDNA(+)方面较CTX组有显著改善,且差异有统计学意义(P＜0.05).②MMF组患者治疗过程中不良反应发生率显著低于CTX组,差异有统计学意义(P＜0.05).③MMF组患者肾小管上皮细胞、肾小球及肾间质细胞凋亡数量分别为(29.0±8.9)个、(1.0±0.5)个及(1.4±0.9)个,均显著少于CTX组的(51.5±10.8)个、(4.5±1.5)个及(5.5±1.5)个,差异均有统计学意义(P＜0.05).结论 MMF在治疗红斑狼疮患者过程中临床效果好,安全性高,且具有阻碍肾细胞凋亡的效果,值得进一步在临床中推广应用.     

Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients

AIMS

Pharmacokinetic (PK) and pharmacodynamic (PD) monitoring strategies and clinical outcome were evaluated in enteric-coated mycophenolate sodium (EC-MPS)-treated renal allograft recipients.

METHODS

PK [mycophenolic acid (MPA)] and PD [inosine monophosphate dehydrogenase (IMPDH) activity] data were analysed in 66 EC-MPS and ciclosporin A (CsA)-treated renal allograft recipients. Adverse events were considered in a follow-up period of 12 weeks.

RESULTS

Analyses confirmed a limited sampling strategy (LSS) consisting of PK and PD data at predose, 1, 2, 3 and 4 h after oral intake as an appropriate sampling method (MPA r²= 0.812; IMPDH r²= 0.833). MPA AUC_0–12 of patients with early biopsy-proven acute rejection was significantly lower compared with patients without a rejection (median MPA AUC_0–12 28 µg*h ml⁻¹ (7–45) vs. 40 µg*h ml⁻¹ (16–130), P < 0.01), MPA AUC_0–12 of patients with recurrent infections was significantly higher compared with patients without infections (median MPA AUC_0–12 65 µg*h ml⁻¹ (range 37–130) vs. 37 µg*h ml⁻¹ (range 7–120), P < 0.005). Low 12-h IMPDH enzyme activity curve (AEC_0–12) was associated with an increased frequency of gastrointestinal side-effects (median IMPDH AEC_0–12 43 nmol*h mg⁻¹ protein h⁻¹[range 12–67) vs. 75 nmol*h mg⁻¹ protein h⁻¹ (range 15–371), P < 0.01].

CONCLUSIONS

Despite highly variable absorption data, an appropriate LSS might be estimated by MPA AUC_0–4 and IMPDH AEC_0–4 in renal transplant patients treated with EC-MPS and CsA. Regarding adverse events, the suggested MPA-target AUC_0–12 from 30 to 60 µg*h ml⁻¹ seems to be appropriate in renal allograft recipients.     

甲泼尼龙合用吗替麦考酚酯诱发系统性红斑狼疮患者肺孢子虫肺炎

1例60岁系统性红斑狼疮女性患者,初始服用甲泼尼龙40mg,1次/d,用甲泼尼龙治疗45d后加用吗替麦考酚酯0.75g,2次/d,用药38d后出现发热、胸闷、低氧血症。X线胸片示双肺纹理增多模糊,双肺野呈磨玻璃样。给予哌拉西林-三唑巴坦钠和莫西沙星抗感染治疗,效果欠佳。实验室检测示CD4＋T淋巴细胞亚群计数为103/mm3,支气管肺泡灌洗液检出伊氏肺孢子菌,确诊为肺孢子虫肺炎。遂将吗替麦考酚酯减量至0.5g,并给予卡泊芬净50mg/d,联磺甲氧苄胺2片,4次/d,用药第5天患者胸闷、呼吸困难好转。     

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。     

Pharmacokinetic monitoring of mycophenolate mofetil in kidney transplanted patients

Mycophenolate mofetil (MMF) is a new immunosuppressant drug used in association with cyclosporin and oral corticosteroids to prevent acute rejection following renal allograft transplantation. MMF is an ester pro-drug of mycophenolic acid (MFA), the true active species, into which it is completely transformed after oral administration. The recommended initial dose to prevent kidney transplant rejection is 2 g/day irrespective of body weight, 1 g twice daily. The goal of this study was to correlate dosage (fixed or by body weight) and toxic effects to some non-compartmental values such as peak level (Cmax), time to peak level (Tmax) and trough level (Cmin). In a small number of patients who had already reached the plasma steady state, we found a large inter-patient variability, while the same qualitative pharmacokinetic profile (as Tmax) was conserved. At plasma trough level > 4 microg/ml some serious toxic effects were observed, whereas at Cmin < 2 microg/ml, there were some cases of interstitial rejection. There was also a negative correlation between dosage and body weight, suggesting that dosages related to body weight might be better than fixed ones. Finally, monitoring plasma level of drug from transplantation to at least 12 months after surgery, at fixed MFA dosage, a small but significant decline of MFA plasma levels was found.     

Evaluation of limited sampling strategies for mycophenolic acid after mycophenolate mofetil intake in adult kidney transplant recipients

Multiple limited sampling strategies (LSSs) have been proposed for estimation of mycophenolic acid (MPA) area under the concentration-time curve from 0 to 12 hours postdose (AUC 0-12) after mycophenolate mofetil intake. The aim of this study was to provide summary information on all published LSSs for MPA and to evaluate their predictive performance in an independent population of kidney transplant recipients. Seventy-eight LSSs for MPA were identified. Sixty-nine full AUC profiles were collected from 45 subjects (25 cotreated with cyclosporine and 20 with tacrolimus). Predicted MPA AUC 0-12, calculated by applying the relevant concentration measurements within the LSS equations, was compared with full AUC calculated by using all concentration measurements in the linear trapezoidal rule. Four error indices (median prediction error, median percentage prediction error [MPPE], root median squared prediction error, and median absolute percentage prediction error [MAPE]) were used to evaluate bias and imprecision. Twelve of the 25 LSSs for cyclosporine-cotreated recipients and one of the 53 LSSs for tacrolimus-cotreated recipients displayed acceptable (less than 15%) bias and imprecision. In the cyclosporine group, two equations demonstrated the highest predictive power, one that used four time points in the first 6 hours postdose (r2 = 0.84, MPPE 1.6%, MAPE 7.8%) and one that used four time points in the first 4 hours postdose (r2 = 0.76, MPPE -0.8%, MAPE 10.2%). In the tacrolimus group, an equation that used two time points in the first 4 hours postdose was superior (r2 = 0.80, MPPE -3.0%, MAPE 13.6%). Application of the LSSs most appropriate for cyclosporine-cotreated patients to the tacrolimus-cotreated group resulted in clinically unacceptable bias and imprecision and vice versa. High variability in performance of LSSs highlights the importance of validating any LSS before applying it to an alternative population. Attention to comedication use is of particular relevance when choosing a LSS.     

Pharmacokinetic modeling of therapies for systemic lupus erythematosus

With the increasing use of different types of therapies in treating autoimmune diseases such as systemic lupus erythematosus (SLE), there is a need to utilize pharmacokinetic (PK) strategies to optimize the clinical outcome of these treatments. Various PK analysis approaches, including population PK modeling and physiologically based PK modeling, have been used to evaluate drug PK characteristics and population variability or to predict drug PK profiles in a mechanistic manner. This review outlines the PK modeling of major SLE therapies including immunosuppressants (methotrexate, azathioprine, mycophenolate and cyclophosphamide, among others) and immunomodulators (intravenous immunoglobulin). It summarizes the population PK modeling, physiologically based PK modeling and model-based individualized dosing strategies to improve the therapeutic outcomes in SLE patients.     

系统性红斑狼疮合并心血管疾病的临床研究

目的探讨系统性红斑狼疮合并心血管疾病患者的临床及实验室指标特点及其临床意义。方法回顾性分析144例SLE患者的临床及实验室指标,及其与心血管疾病发生的相关性。结果 144例SLE患者中,60例(41.6%)合并心血管疾病。心脏损害组与心脏未受损害组比较,两组间年龄、病程差异具有统计学意义;且心脏损害组的SLE患者的血红蛋白明显低于心脏未损害组,而C反应蛋白明显高于未损害组(P<0.05)。结论病程长、贫血及CRP增高可能会增加SLE患者合并心血管疾病的发生率,可以作为患者病情判断、预后评估的指标。     

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     

系统性红斑狼疮患者支原体感染的研究

目的　探讨支原体感染与系统性红斑狼疮 (SLE)的相关性。方法　收集 1 0 2例SLE患者 (SLE组 )及 2 6例正常对照者 (对照组 ) ,应用套式聚合酶链反应 (nPCR)检测血清及眼、咽、尿道分泌物中的人型支原体 (Mh)及解尿尿原体 (Uu)DNA ,并对阳性产物进行DNA序列测定。结果　SLE组阳性 66例 ,阴性 36例。正常对照组阳性 8例 ,阴性 1 8例。SLE患者支原体感染明显高于正常对照组 (P <0 0 0 5) ,SLE活动期明显高于稳定期 (P <0 0 0 5)。结论　支原体感染为诱发SLE活动的一个重要诱因 ,亦可能参与SLE的发病机制     

系统性红斑狼疮患者免疫功能变化的初步研究

目的：通过观察系统性红斑狼疮（SLE）患者免疫球蛋白、补体以及细胞因子的变化,探讨狼疮细胞和体液免疫功能对SLE的诊断、治疗和预后评估意义。方法2013年2月至2014年2月分别采用免疫散射比浊法及酶联免疫吸附试验（ELISA）法检测25例SLE、12例非SLE自身免疫性疾病（AID）患者以及20例健康对照者血清中免疫球蛋白、补体及细胞因子[白介素6（IL-6）、肿瘤坏死因子α（TNF-α）]水平,初步了解SLE患者体液免疫变化情况。结果 SLE组血清免疫球蛋白G（IgG）和TNF-α水平[（13.94±5.99）g/L、（42.00±20.77）pg/L]较健康对照组[（11.26±1.35）g/L、（16.54±5.45）pg/L]明显升高,补体 C3、C4水平[（0.69±0.22）、（0.15±0.11）g/L]较健康对照组[（0.97±0.20）、（0.30±0.02）g/L]、非SLE AID组[（1.16±0.22）、（0.28±0.05）g/L]明显降低,差异均有统计学意义（P<0.05）,而血清IgM、IgA及IL-6水平较健康对照组, IgM、IL-6、TNF-α水平较非SLE AID组升高不明显,差异均无统计学意义（P>0.05）。结论 SLE患者存在免疫球蛋白升高及补体水平降低等体液免疫紊乱,对临床诊断和治疗有一定辅助意义。     

Acetylation genotype and phenotype in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting various tissues and organs. In the studies on SLE etiopathogenesis, a potential role of genetically determined impairment of xenobiotic metabolism has been emphasized. N-acetyltransferase 2 enzyme (NAT2) exhibits gene polymorphism and the acetylation rate with NAT2 involvement varies from person to person. The study on acetylation phenotype was carried out using isonicotinic acid hydrazide (isoniazid) as a model drug, while NAT2 alleles were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. Among patients with SLE, NAT2*4/NAT2*6 and NAT2*5/NAT2*5 genotypes occurred most frequently, while NAT2*4/NAT2*6 and NAT2*5/NAT2*6 prevailed in the control group. The concordance of 96.8% was achieved between acetylation phenotype and NAT2 genotype in the group of SLE patients studied. Conclusion: Acetylation polymorphism appears not to be an important risk factor in SLE.     

Pharmacokinetic variability of mycophenolic acid and its glucuronide in systemic lupus erythematosus patients in remission maintenance phase

The aim of this study was to identify factors affecting the pharmacokinetics of mycophenolic acid (MPA) and its 7-O-glucuronide (MPAG) in systemic lupus erythematosus (SLE) patients. Thirty-one SLE patients in remission maintenance phase treated with mycophenolate mofetil (median 1500 mg/d) and prednisolone and followed-up for up to 56 months (median 13 months) were enrolled. Creatinine clearance and metal medication were significant predictors accounting for interindividual variability in the dose-normalized predose plasma concentration (C?) of MPA (adjusted R2=0.305, p=0.01) in a multivariate analysis. Dose-normalized MPAG C? was significantly correlated with only creatinine clearance (adjusted R2=0.135, p=0.03). The free fraction of MPA was significantly correlated with only serum albumin (adjusted R2=0.700, p<0.01). The free fraction of MPAG was significantly correlated with serum albumin, metal medication, and age (adjusted R2=0.598, p=0.02). In conclusion, renal function and co-administered metal influenced the pharmacokinetics of MPA and MPAG in SLE patients in remission maintenance phase.