Determination of the mitigating effect of colon-specific bioreversible codrugs of mycophenolic acid and aminosugars in an experimental colitis model in Wistar rats

AIM To design colon-targeted codrugs of mycophenolic acid(MPA) and aminosugars as a safer option to mycophenolate mofetil(MMF) in the management of inflammatory bowel disease. METHODS Codrugs were synthesized by coupling MPA with aminosugars(D-glucosamine and D-galactosamine) using EDCI coupling. The structures were confirmed by infrared radiation, nuclear magnetic resonance, mass spectroscopy and elemental analysis. The release profile of codrugs was extensively studied in aqueous buffers, upper gastrointestinal homogenates, faecal matter and caecal homogenates(in vitro) and rat blood(in vitro). Anti-colitic activity was assessed in 2,4,6-trinitrobezenesulfonic acid-induced colitis in Wistar rats by the estimation of various demarcating parameters. Statistical evaluation was performed by applying one-way and two-way ANOVA when compared with the disease control.RESULTS The prodrugs resisted activation in HCl buffer(pH 1.2) and stomach homogenates of rats with negligible hydrolysis in phosphate buffer(p H 7.4) and intestinal homogenates. Incubation with colon homogenates(in vitro) produced 76% to 89% release of MPA emphasizing colon-specific activation of codrugs and the release of MPA and aminosugars at the site of action. In the in vitro studies, the prodrug of MPA with D-glucosamine(MGLS) was selected which resulted in 68% release of MPA in blood. in vitro studies on MGLS revealed its colon-specific activation after a lag time of 8 h which could be ascribed to the hydrolytic action of N-acyl amidases found in the colon. The synthesized codrugs markedly diminished disease activity score and revived the disrupted architecture of the colon that was comparable to MMF but superior to MPA. CONCLUSION The significant attenuating effect of prodrugs and individual aminosugars on colonic inflammation proved that the rationale of the codrug approach is valid.     

Autoimmune hepatitis treatment in the elderly: A systematic review

BACKGROUND Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease with a high risk of progression to liver cirrhosis. The initial treatment for AIH usually includes a steroid, with or without azathioprine. AIH can present at any age;however, the most effective and safe induction treatment for AIH in the elderly remains unclear. AIM To systematically review available data on both effectiveness and safety of AIH treatments in elderly subjects. METHODS To identify studies on AIH induction treatment in elderly patients (≥ 60 years of age), an electronic research was performed (PubMed, EMBASE and Cochrane Library databases) until February 2019. Eligible studies were selected through screening of titles and abstracts, followed by full-text critical evaluation. After risk of bias assessment, data on study designs, interventions, and outcomes were extracted and reviewed. RESULTS Among the 1736 retrieved papers, 15 studies were selected. Out of them, eight studies were excluded because of a critical risk of bias. The remaining seven studies included 789 patients and out of them 239 subjects were elders. First-line treatment was a steroid either alone or in combination with azathioprine in most patients (87.6%) and only one study investigated the effect of combined steroid and mycophenolate mofetil therapy. Standard therapy was effective in inducing remission in the elderly. Moreover, treatment failure and relapses occurred less often in the elderly compared to younger people.CONCLUSION Treatment of AIH is challenging in elderly patients. This systematic review confirms the efficacy and safety of standard induction treatment for AIH in the elderly. Available evidence is insufficient to draw any conclusion on the effect of novel AIH treatments in elderly subjects.     

环孢素A与吗替麦考酚酯治疗难治性肾病综合征疗效对比

目的：通过检测临床指标的变化,观察对比环孢素A和吗替麦考酚酯治疗难治性肾病综合征的疗效差异。方法：将本院自2008年1月以来收治的56例原发性难治性肾病综合征患者随机分为CsA、MMF两组,在口服泼尼松0.5mg.kg-1.d-1治疗的基础上,CsA组口服环孢素4mg·kg-1.d-1,MMF组口服吗替麦考酚酯0.75mg2/d,进行1年的随访,在治疗前、治疗3、6、12个月分别记录尿常规、24h尿蛋白定量、肝功能（AST、ALT、Alb）、肾功能（CRE,UA,GLU）、血脂以及环孢素血药浓度等指标的变化,并记录不良反应。结果：从治疗1个月开始,部分患者的尿蛋白定量减轻,血浆白蛋白水平开始有所恢复,前后结果差异有统计学意义（P〈0.05）,两组患者之间差异无统计学意义（P〉0.05）。结论：环孢素A、吗替麦考酚酯均可以有效的治疗难治性肾病综合征,治疗同期两者差异不明显。     

Pancreas transplantation: The Wake Forest experience in the new millennium

AIM: To investigate the Wake Forest experience with pancreas transplantation in the new millennium with attention to surgical techniques and immunosuppression.METHODS: A monocentric, retrospective review of outcomes in simultaneous kidney-pancreas transplant (SKPT) and solitary pancreas transplant (SPT) recipients was performed. All patients underwent pancreas transplantation as intent-to-treat with portal venous and enteric exocrine drainage and received depleting antibody induction; maintenance therapy included tapered steroids or early steroid elimination with mycophenolate and tacrolimus. Recipient selection was based on clinical judgment whether or not the patient exhibited measureable levels of C-peptide.RESULTS: Over an 11.25 year period, 202 pancreas transplants were performed in 192 patients including 162 SKPTs and 40 SPTs. A total of 186 (92%) were primary and 16 (8%) pancreas retransplants; portal-enteric drainage was performed in 179 cases. A total of 39 pancreas transplants were performed in African American (AA) patients; of the 162 SKPTs, 30 were performed in patients with pretransplant C-peptide levels > 2.0 ng/mL. In addition, from 2005-2008, 46 SKPT patients were enrolled in a prospective study of single dose alemtuzumab vs 3-5 doses of rabbit anti-thymocyte globulin induction therapy. With a mean follow-up of 5.7 in SKPT vs 7.7 years in SPT recipients, overall patient (86% SKPT vs 87% SPT) and kidney (74% SKPT vs 80% SPT) graft survival rates as well as insulin-free rates (both 65%) were similar (P = NS). Although mortality rates were nearly identical in SKPT compared to SPT recipients, patterns and timing of death were different as no early mortality occurred in SPT recipients whereas the rates of mortality following SKPT were 4%, 9% and 12%, at 1-, 3- and 5-years follow-up, respectively (P < 0.05). The primary cause of graft loss in SKPT recipients was death with a functioning graft whereas the major cause of graft loss following SPT was acute and chronic rejection. The overall incidence of acute rejection was 29% in SKPT and 27.5% in SPT recipients (P = NS). Lower rates of acute rejection and major infection were evidenced in SKPT patients receiving alemtuzumab induction therapy. Comparable kidney and pancreas graft survival rates were observed in AA and non-AA recipients despite a higher prevalence of a “type 2 diabetes” phenotype in AA. Results comparable to those achieved in insulinopenic diabetics were found in the transplantation of type 2 diabetics with detectable C-peptide levels.CONCLUSION: In the new millennium, acceptable medium-term outcomes can be achieved in SKPT and SPTs as nearly 2/3rds of patients are insulin independent following pancreas transplantation.     

麦考酚酸酯治疗幼年特发性关节炎全身型的疗效分析

目的：评价麦考酚酸酯（mycophenolate mofetil, MMF）治疗幼年特发性关节炎全身型（system onset juvenile idiopathic arthritis, SoJIA）的临床疗效。方法：35例确诊为SoJIA并初次接受治疗的患儿随机分为3组,即传统治疗方案组（对照组）,15例;MMF 1 组：传统治疗方案治疗2周后,病情无缓解,加用MMF治疗,7例;MMF 2 组：采用非甾体抗炎药+泼尼松+MMF治疗方案,13例。观察3组患儿治疗后2、4、12周的症状、体征、实验室指标及不良反应,并随访3~6个月。结果：治疗前MMF2组病程显著长于对照组,差异有统计学意义（P<0.05）。治疗2周后,与对照组相比,MMF1组和MMF2组的泼尼松用量明显减少,ESR明显减低（P<0.05）;MMF1组患儿体温高于另两组（P<0.05）。治疗4周时,与对照组比较,MMF1组泼尼松用量减少（P<0.05）,ESR降低（P<0.05）;MMF2组泼尼松用量减少,体温下降并恢复至正常,WBC值降低,ESR降低,铁蛋白降低,差异均具有统计学意义（P<0.05）;MMF1和MMF2组相比,MMF2组体温更低（P<0.05）。MMF治疗组均未出现MMF用药的副作用。结论：MMF联合治疗能更好地控制SoJIA患儿病情,更快缓解其临床症状,减少联合应用的糖皮质激素药物的剂量,并有良好的安全性。     

Use of mycophenolate mofetil in inflammatory bowel disease

AIM： To assess the efficacy and safety of mycophenolate mofetil （MMF） prospectively in inflammatory bowel disease （IBD） patients intolerant or refractory to conventional medical therapy.
METHODS： Crohn＇s disease （CD） or ulcerative colitis/ IBD unclassified （UC/IBDU） patients intolerant or refractory to conventional medical therapy received MMF （500-2000 mg bid）. Clinical response was assessed by the Harvey Bradshaw index （HBI） or colitis activity index （CAI） after 2, 6 and 12 mo of therapy, as were steroid usage and adverse effects.
RESULTS： Fourteen patients （9 CD/5 UC/IBDU; 8M/6F; mean age 50.4 years, range 28-67 years） were treated and prospectively assessed for their response to oral MMF. Of the 11 patients who were not in remission on commencing MMF, 7/11 （63.6%） achieved remission by 8 wk. All 3 patients in remission on commencing MMF maintained their remission. Ten patients were still on MMF at 6 mo with 9/14 （64.3%） in remission, while of 12 patients followed for 12 mo, 8 were in remission without dose escalation （66.7%）. Three patients were withdrawn from the MMF due to drug intolerance. There were no serious adverse events attributed due to the medication.
CONCLUSION： MMF demonstrated efficacy in the management of difficult IBD. MMF appeared safe, well tolerated and efficacious for both short and long-term therapy, without the need for dose escalation. Further evaluation of MMF comparing it to conventional immunosuppressants is required.     

霉酚酸酯对高糖所致大鼠肾小球系膜细胞增殖的影响

目的：观察霉酚酸酯(mycophenolate mofetil MMF)对高糖环境大鼠肾小球系膜细胞(mesangial cells MCs)增殖及Ⅳ型胶原的影响。方法：以30?mmol/L葡萄糖刺激体外培养的大鼠MCs增殖,加入不同浓度的MMF,采用MTT比色法观察6、12、24、48?h系膜细胞的增殖情况;放射免疫法测定细胞上清液中Ⅳ型胶原的含量。结果：葡萄糖对系膜细胞的增殖效应呈浓度和时间依赖性,反应最佳浓度为30?mmol/L,最佳时点为24?h。MMF有抑制高糖所致MCs增殖、减少细胞外基质的作用,并呈剂量时间依赖性。结论：高糖在一定浓度和一定时段内有刺激大鼠系膜细胞增殖的效应,MMF对高糖所致MCs增殖具有抑制作用,且随MMF剂量增大,作用时间的延长,抑制作用增强。     

缬沙坦联合泼尼松、吗替麦考酚酯治疗小儿难治性肾病综合征的近期疗效观察

目的:了解缬沙坦联合泼尼松、吗替麦考酚酯(MMF)治疗小儿难治性肾病综合征的疗效。方法:54例符合难治性肾病综合征诊断标准的患儿,随机选取36例为治疗组,采用缬沙坦联合泼尼松、吗替麦考酚酯(MMF)治疗12周,对照组18例,仅使用泼尼松、吗替麦考酚酯联合治疗,定期复查尿常规、24 h尿蛋白定量、肝、肾功能等,观察两组近期疗效。结果:治疗组治疗3个月后总有效率为94.5%,对照组为83.3%,两组疗效比较差异有统计学意义(P0.05)。结论:缬沙坦联合泼尼松、MMF治疗小儿难治性肾病综合征具有更好的疗效。     

麦考酚醐旨联合甲基强的松龙治疗大鼠急性脊髓损伤的研究

目的观察联合应用麦考酚酸酯（MMF）和甲基强的松龙（MP）对大鼠急性脊髓损伤的治疗效果。方法采用Allen的重物坠落法（WD法）建立大鼠的SCI模型。72只致伤大鼠随机分成4组。MP组：MP30mg／kg;MMF组：MMF20mg／kg;对照组：5mL生理盐水。MMF＋MP组：MP30mg／kg＋MMF20mg／kg。上述药物均于伤后0．5h腹腔注射。分别在伤后4h、24h、10d处死动物,观察受损部位脊髓的脂质过氧化水平及病理形态,其中10d组记录10d的运动功能评分和斜板试验。结果MP、MMF及联合组治疗大鼠急性脊髓损伤,在抗脂质过氧化进程、Gales评分、斜板试验及病理形态上与生理盐水组相比都有很大的改善,两个治疗组以及联合组在上述方面治疗效果相当。结论麦考酚酸酯、甲基强的松龙及两药联合组对大鼠急性脊髓损伤的治疗作用无显著性差异。