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| 1 | Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients显示文摘The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant.However,despite the long use of tacrolimus in clinical practice,the best way to use this agent is still a matter of intense debate.The start of the genomic era has generated new research areas,such as pharmacogenetics,which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body.This variability seems to be correlated with the presence of genetic polymorphisms.Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus;also,unlike phenotypic tests,the genotype is a stable characteristic that needs to be determined only once for any given gene.However,prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication.At present,research has been able to reliably show that the CYP3A5 genotype,but not the CYP3A4 or ABCB1 ones,can modify the pharmacokinetics of tacrolimus.However,it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity.For these reasons,pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing. | Alessio Provenzani Andrew Santeusanio Erin Mathis Monica Notarbartolo Manuela Labbozzetta Paola Poma Ambra Provenzani Carlo Polidori Giovanni Vizzini Piera Polidori Natale D'Alessandro | 2013 | World Journal of Gastroenterology2013，19，48： | 15 |
| 2 | Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis显示文摘AIM: To determine the eff icacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH). METHODS: Retrospectively, clinical parameters, biochemistry and histology were obtained from patient records. RESULTS: Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P = 0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P = 0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P = 0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P = 0.016), while the degree of f ibrosis tended to decrease (P = 0.049). CONCLUSION: The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of f ibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose. | Fin Stolze Larsen Ben Vainer Martin Eefsen Peter Nissen Bjerring Bent Adel Hansen | 2007 | World Journal of Gastroenterology2007，13，23： | 15 |
| 3 | Development of osteomalacia in a post-liver transplant patient receiving adefovir dipivoxil显示文摘We report the case of a patient treated with living donor-related liver transplantation who suffered from osteomalacia during adefovir dipivoxil (ADV)-containing antiviral therapy for lamivudine-resistant hepatitis B virus infection. The patient had generalized bone pain,with severe hypophosphatemia after 20 mo of ADV therapy. Radiographic studies demonstrated the presence of osteomalacia. The peak plasma ADV level was 38 ng/mL after administration of ADV at 10mg/day. It was also found that ADV affected the metabolism of tacrolimus,a calcineurin-inhibitor,and caused an increase in the plasma levels of tacrolimus. The disability was reversed with the withdrawal of ADV and with mineral supplementation. ADV can cause an elevation of plasma tacrolimus levels,which may be associated with renal dysfunction. High levels of ADV and tacrolimus can cause nephrotoxicity and osteomalacia. This case highlights the importance of considering a diagnosis of osteomalacia in liver transplantation recipients treated with both ADV and tacrolimus. | Masami Minemura Yoshiharu Tokimitsu Kazuto Tajiri Yasuhiro Nakayama Kengo Kawai Hiroshi Kudo Katsuharu Hirano Yoshinari Atarashi Yutaka Yata Satoshi Yasumura Terumi Takahara Toshiro Sugiyama | 2010 | World Journal of Hepatology2010，2，12： | 13 |
| 4 | Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review显示文摘BACKGROUND Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease(MS-IBD). This study hypothesized that as a standard of treatment and the primary alternative to biologics, conventional therapy should present robust effectiveness results in IBD outcomes.AIM To investigate the effectiveness of conventional therapy for MS-IBD.METHODS A systematic review with no time limit was conducted in July 2017 through the Cochrane Collaboration, MEDLINE, and LILACS databases. The inclusion criteria encompassed meta-analyses, systematic reviews, randomized clinical trials, observational and case-control studies concerning conventional therapy in adult patients with MS-IBD, including Crohn's disease(CD) and ulcerative colitis(UC). Corticosteroids(prednisone, hydrocortisone, budesonide, prednisolone,dexamethasone), 5-aminosalicylic acid(5-ASA) derivatives(mesalazine and sulfasalazine) and immunosuppressants [azathioprine(AZA), methotrexate(MTX), mycophenolate, cyclosporine, tacrolimus, 6-mercaptopurine(6-MP)] were considered conventional therapy. The exclusion criteria were sample size below50; narrative reviews; specific subpopulations(e.g., pregnant women,comorbidities); studies on postoperative IBD; and languages other than English,Spanish, French or Portuguese. The primary outcome measures were clinical remission(induction or maintenance), clinical response and mucosal healing. As secondary outcomes, fecal calprotectin, hospitalization, death, and surgeries were analyzed. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation criteria.RESULTS The search strategy identified 1995 citations, of which 27 were considered eligible(7 meta-analyses, 20 individual studies). For induction of clinical remission, four meta-analyses were selected(AZA and 6-MP showed no advantage over placebo,MTX or 5-ASA in CD; MTX showed no statistically significant difference versus placebo, 6-MP, or 5-ASA in UC; tacrolimus was superior to placebo for UC in two meta-analyses). Only one meta-analysis evaluated clinical remission maintenance, showing no statistically significant difference between MTX and placebo, 5-ASA, or 6-MP in UC. AZA and 6-MP had no advantage over placebo in induction of clinical response in CD. Three meta-analyses showed the superiority of tacrolimus vs placebo for induction of clinical response in UC. The clinical response rates for cyclosporine were 41.7% in randomized controlled trials(RCTs) and 55.4% in non-RCTs for UC. For induction of mucosal healing,one meta-analysis showed a favorable rate with tacrolimus versus placebo for UC. For secondary outcomes, no meta-analyses specifically evaluated fecal calprotectin, hospitalization or death. Two meta-analyses were retrieved evaluating colectomy rates for tacrolimus and cyclosporine in UC. Most of the twenty individual studies retrieved contained a low or very low quality of evidence.CONCLUSION High-quality evidence assessing conventional therapy in MS-IBD treatment is scarce, especially for remission maintenance, mucosal healing and fecal calprotectin. | Adérson Omar Mourao Cintra Damiao Matheus Freitas Cardoso de Azevedo Alexandre de Sousa Carlos Marcela Yumi Wada Taciana Valéria Marcolino Silva Flávio de Castro Feitosa | 2019 | World Journal of Gastroenterology2019，25，9： | 13 |
| 5 | Minimizing tacrolimus decreases the risk of new-onset diabetes mellitus after liver transplantation显示文摘AbstractAIM: To investigate the impact of minimum tacrolimus(TAC) on new-onset diabetes mellitus (NODM) afterliver transplantation (LT).METHODS: We retrospectively analyzed the data of973 liver transplant recipients between March 1999and September 2014 in West China Hospital LiverTransplantation Center. Following the exclusion ofineligible recipients, 528 recipients with a TAC-dominantregimen were included in our study. We calculatedand determined the mean trough concentration ofTAC (cTAC) in the year of diabetes diagnosis in NODMrecipients or in the last year of the follow-up in non-NODM recipients. A cutoff of mean cTAC value forpredicting NODM 6 mo after LT was identified usinga receptor operating characteristic curve. TAC-relatedcomplications after LT was evaluated by χ^2 test, andthe overall and allograft survival was evaluated usingthe Kaplan-Meier method. Risk factors for NODM afterLT were examined by univariate and multivariate Cox regression.RESULTS: Of the 528 transplant recipients, 131(24.8%) developed NODM after 6 mo after LT, andthe cumulative incidence of NODM progressivelyincreased. The mean cTAC of NODM group recipientswas significantly higher than that of recipients in thenon-NODM group (7.66 ± 3.41 ng/mL vs 4.47 ± 2.22ng/mL, P 〈 0.05). Furthermore, NODM group recipientshad lower 1-, 5-, 10-year overall survival rates (86.7%,71.3%, and 61.1% vs 94.7%, 86.1%, and 83.7%, P 〈0.05) and allograft survival rates (92.8%, 84.6%, and75.7% vs 96.1%, 91%, and 86.1%, P 〈 0.05) thanthe others. The best cutoff of mean cTAC for predictingNODM was 5.89 ng/mL after 6 mo after LT. Multivariateanalysis showed that old age at the time of LT (〉 50years), hypertension pre-LT, and high mean cTAC (≥5.89 ng/mL) after 6 mo after LT were independent riskfactors for developing NODM. Concurrently, recipientswith a low cTAC (〈 5.89 ng/mL) were less likely tobecome obese (21.3% vs 30.2%, P 〈 0.05) or todevelop dyslipidemia (27.5% vs 44.8%, P 〈0.05),chronic kidney dysfunction (14.6% vs 22.7%, P 〈 0.05),and moderate to severe infection (24.7% vs 33.1%, P〈 0.05) after LT than recipients in the high mean cTACgroup. However, the two groups showed no significantdifference in the incidence of acute and chronicrejection, hypertension, cardiovascular events and newonsetmalignancy.CONCLUSION: A minimal TAC regimen can decreasethe risk of long-term NODM after LT. Maintaining a cTACvalue below 5.89 ng/mL after LT is safe and beneficial. | Jiu-Lin Song Wei Gao Yan Zhong Lu-Nan Yan Jia-Yin Yang Tian-Fu Wen Bo Li Wen-Tao Wang Hong Wu Ming-Qing Xu Zhe-Yu Chen Yong-Gang Wei Li Jiang Jian Yang | 2016 | World Journal of Gastroenterology2016，22，6： | 12 |
| 6 | Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation显示文摘Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are widely used immunosuppressive agents for the prevention of post-transplantation rejection and have improved 1-year graft survival rates by up to 90%. However, CNIs can induce severe reactions, such as acute or chronic allograft nephropathy, hypertension, and neurotoxicity. Because CNIs have varied bioavailabilities, narrow therapeutic ranges, and individual propensities for toxic effects, therapeutic drug monitoring is necessary for all CNIs. Identifying the genetic polymorphisms in drug-metabolizing enzymes will help to determine personalized dosage regimens for CNIs, as CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp, MDR1). CNIs are often concomitantly administered with voriconazole or proton pump inhibitors (PPIs), giving rise to drug interaction problems. Voriconazole and PPIs can increase the blood concentrations of CNIs, and both are primarily metabolized by CYP2C19. Thus, it is expected that interactions between CNIs and voriconazole or PPI would be affected by CYP2C19 and CYP3A5 polymorphisms. CNI-induced acute kidney injury (AKI) is a serious complication of transplantations. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are noninvasive urinary biomarkers that are believed to be highly sensitive to CNI-induced AKI. In this article, we review the adverse events and pharmacokinetics of CNIs and the biomarkers related to CNIs, including CYP3A5, CYP2C19, MDR1, NGAL, and KIM-1. We hope that these data will help to identify the optimal biomarkers for monitoring CNI-based immunosuppressive therapy after organ transplantation. | Rao Fu Soichiro Tajima Kimitaka Suetsugu Hiroyuki Watanabe Nobuaki Egashira Satohiro Masuda | 2019 | Acta Pharmacologica Sinica2019，40，2： | 10 |
| 7 | Reversible sinusoidal obstruction syndrome associated with tacrolimus following liver transplantation显示文摘Sinusoidal obstruction syndrome(SOS), previously known as hepatic veno-occlusive disease, is a rare disorder in solid organ transplant patients, and is an uncommon complication after liver transplantation. Severe SOS with hepatic failure causes considerable mortality. Tacrolimus has been reported to be an offending agent, which potentially plays a role in the pathophysiological process of SOS. SOS due to tacrolimus has been reported in lung and pancreatic transplantations, but has never been described in a liver transplant recipient. Herein, we present a case of SOS after liver transplantation, which was possibly related to tacrolimus. A 27-year-old man developed typical symptoms of SOS with painful hepatomegaly, ascites and jaundice after liver transplantation, which regressed following withdrawal of tacrolimus. By excluding other possible predisposing factors, we concluded that tacrolimus was the most likely cause of SOS. | Tian Shen Xiao-Wen Feng Lei Geng Shu-Sen Zheng | 2015 | World Journal of Gastroenterology2015，21，20： | 10 |
| 8 | New-onset diabetes mellitus after kidney transplantation:Current status and future directions显示文摘A diagnosis of new-onset diabetes after transplantation(NODAT) carries with it a threat to the renal allograft,as well as the same short-and long-term implications of type 2 diabetes seen in the general population.NODAT usually occurs early after transplantation,and is usually diagnosed according to general population guidelines.Non-modifiable risk factors for NODAT include advancing age,African American,Hispanic,or South Asian ethnicity,genetic background,a positive family history for diabetes mellitus,polycystic kidney disease,and previously diagnosed glucose intolerance.Modifiable risk factors for NODAT include obesity and the metabolic syndrome,hepatitis C virus and cytomegalovirus infection,corticosteroids,calcineurin inhibitor drugs(especially tacrolimus),and sirolimus.NODAT affects graft and patient survival,and increases the incidence of post-transplant cardiovascular disease.The incidence and impact of NODAT can be minimized through pre-and post-transplant screening to identify patients at higher risk,including by oral glucose tolerance tests,as well as multi-disciplinary care,lifestyle modification,and the use of modified immunosuppressive regimens coupled with glucose-lowering therapies including oral hypoglycemic agents and insulin.Since NODAT is a major cause of post-transplant morbidity and mortality,measures to reduce its incidence and impact have the potential to greatly improve overall transplant success. | Sneha Palepu G V Ramesh Prasad | 2015 | World Journal of Diabetes2015，6，3： | 8 |
| 9 | IL-3 and CTLA4 gene polymorphis.ms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients显示文摘高度可变的 pharmacokinetics 和 tacrolimus (TAC ) 的狭窄的治疗学的窗户妨碍了它的临床的使用。基因多型性可以贡献可变反应,但是证据是不引人注目的,并且解释是不清楚的。在我们试图发现以前未知的基因因素的这研究,那可以影响 TAC 剂量要求。有 TAC 调整剂量的集中(C0/D ) 的 105 小径相关的单个核苷酸多型性(SNP ) 的协会在在 382 中国肾操作以后的 7, 30 和 90 d 被检验移植接受者。在 CYP3A5 non-expressers,带 IL-3 rs181781 AA 遗传型的病人在 30 和 90 d 与 AG 遗传型比那些显示出显著地更高的 TAC logC0/D 操作以后(AA 对 AG, 2.21 吗?? | Mou-ze LIU Hai-yan HE Yue-li ZHANG Yong-fang HU Fa-zhong HE Jian-quan LUO Zhi-ying LUO Xiao-ping CHEN Zhao-qian LIU Hong-hao ZHOU Ming-jie SHAO Ying-zi MING Hua-wen XIN Wei ZHANG | 2017 | Acta Pharmacologica Sinica2017，38，3： | 8 |
| 10 | Post-transplant lymphoproliferative disorder after liver transplantation: Incidence, long-term survival and impact of serum tacrolimus level显示文摘AIM To investigate incidence and survival of post-transplant lymphoproliferative disorder(PTLD) patients after liver transplantation. METHODS A cross-sectional survey was conducted among patients who underwent liver transplantation at Shiraz Transplant Center(Shiraz, Iran) between August 2004 and March 2015. Clinical and laboratory data of patients were collected using a data gathering form. RESULTS There were 40 cases of PTLD in the pediatric age group and 13 cases in the adult group. The incidence of PTLD was 6.25% in pediatric patients and 1.18% in adult liver transplant recipients. The post-PTLD survival of patients at 6 mo was 75.1% ± 6%, at 1 year was 68.9% ± 6.5% and at 5 years was 39.2% ± 14.2%. Higher serum tacrolimus level was associated with lower post-PTLD survival in pediatric patients(OR = 1.07, 95%CI: 1.006-1.15, P = 0.032). A serum tacrolimus level over 11.1 ng/mL was predictive of post PTLD survival(sensitivity = 90%, specificity = 52%, area under the curve = 0.738, P = 0.035). CONCLUSION Incidence of PTLD in our liver transplant patients is comparable to other centers. Transplant physicians may consider adjustment of tacrolimus dose to maintain its serum level below this cutoff point. | Ahad Eshraghian Mohammad Hadi Imanieh Seyed Mohsen Dehghani Saman Nikeghbalian Alireza Shamsaeefar Frouzan Barshans Kourosh Kazemi Bita Geramizadeh Seyed Ali Malek-Hosseini | 2017 | World Journal of Gastroenterology2017，23，7： | 7 |
| 11 | 肾移植术后糖皮质激素和他克莫司的药代动力学相互作用(英文)显示文摘糖皮质激素由于是CYP3A4和P-gp的诱导剂与他克莫司(tacrolimus,TAC)存在相互作用。但是,目前研究中的糖皮质激素剂量均为低剂量而非冲击剂量。本研究回顾性的研究63名肾移植术后患者,根据患者服用的糖皮质激素剂量进行分组:500 mg (术后1–3天), 30 mg (术后4–10天), 25 mg (术后11–17天), 20 mg (术后18–24天), 15 mg (术后25–31天),10 mg (术后32–60天)和10 mg (术后61–90天)。我们每日详细记录患者从手术至术后90天的患者检验和用药信息。研究发现:术后3个月内,不同糖皮质激素剂量下TAC的血药浓度无显著性差异,但是随着糖皮质激素的剂量减低, TAC的平均每日剂量显著性降低。同时,术后1–4天内,TAC每日的剂量没有变化,但是当糖皮质激素的剂量由500mg减为30mg时,TAC的浓度显著降低。本研究验证了低剂量的糖皮质激素对TAC的诱导效应,同时发现高剂量糖皮质激素和他克莫司合用时,糖皮质激素可能起到相关作用,为竞争性底物效果。因此在肾移植术后受者的糖皮质激素剂量发生变化时,监测TAC的血药浓度是有必要的。 | 杨辉 胡小鹏 杨晓勇 刘航 任亮 王玮 刘丽宏 张小东 | 2019 | Journal of Chinese Pharmaceutical Sciences2019，28，4： | 6 |
| 12 | Influence of tacrolimus metabolism rate on renal function after solid organ transplantation显示文摘The calcineurin inhibitor(CNI) tacrolimus(TAC) is an integral part of the immunosuppressive regimen after solid organ transplantation. Although TAC is very effective in prevention of acute rejection episodes, its highly variable pharmacokinetic and narrow therapeutic window require frequent monitoring of drug levels and dose adjustments. TAC can cause CNI nephrotoxicity even at low blood trough levels(4-6 ng/m L). Thus, other factors besides the TAC trough level might contribute to CNI-related kidney injury. Unfortunately, TAC pharmacokinetic is determined by a whole bunch of parameters. However, for daily clinical routine a simple application strategy is needed. To address this problem, we and others have evaluated a simple calculation method in which the TAC blood trough concentration(C) is divided by the daily dose(D). Fast TAC metabolism(C/D ratio < 1.05) was identified as a potential risk factor for an inferior kidney function after transplantation. In this regard, we recently showed a strong association between fast TAC metabolism and CNI nephrotoxicity as well as BKV infection. Therefore, the TAC C/D ratio may assist transplant clinicians in a simple way to individualize the immunosuppressive regimen. | Gerold Th?lking Hans Ulrich Gerth Katharina Schuette-Nuetgen Stefan Reuter | 2017 | World Journal of Transplantation2017，7，1： | 6 |
| 13 | Impact of immunosuppression on incidence of post-transplant diabetes mellitus in solid organ transplant recipients:Systematic review and meta-analysis显示文摘BACKGROUND Solid organ transplantation is a life-saving intervention for end-stage organ disease.Post-transplant diabetes mellitus(PTDM)is a common complication in solid organ transplant recipients,and significantly compromises long-term survival beyond a year.AIM To perform a systematic review and meta-analysis to estimate incidence of PTDM and compare the effects of the 3 major immunosuppressants on incidence of PTDM.METHODS Two hundred and six eligible studies identified 75595 patients on Tacrolimus,51242 on Cyclosporine and 3020 on Sirolimus.Random effects meta-analyses was used to calculate incidence.RESULTS Network meta-analysis estimated the overall risk of developing PTDM was higher with tacrolimus(OR=1.495%CI:1.0–2.0)and sirolimus(OR=1.8;95%CI:1.5–2.2)than with Cyclosporine.The overall incidence of PTDM at years 2-3 was 17%for kidney,19%for liver and 22%for heart.The risk factors for PTDM most frequently identified in the primary studies were age,body mass index,hepatitis C,and African American descent.CONCLUSION Tacrolimus tends to exhibit higher diabetogenicity in the short-term(2-3 years post-transplant),whereas sirolimus exhibits higher diabetogenicity in the longterm(5-10 years post-transplant).This study will aid clinicians in recognition of risk factors for PTDM and encourage careful evaluation of the risk/benefit of different immunosuppressant regimens in transplant recipients. | Sreelakshmi Kotha Bishoy Lawendy Saira Asim Charlene Gomes Jeffrey Yu Ani Orchanian-Cheff George Tomlinson Mamatha Bhat | 2021 | World Journal of Transplantation2021，11，10： | 5 |
| 14 | Optimal immunosuppressor induces stable gut microbiota after liver transplantation显示文摘AIM To study the influence of different doses of tacrolimus(FK506)on gut microbiota after liver transplantation(LT)in rats.METHODS Specific pathogen-free Brown Norway(BN)rats and Lewis rats were separated into five groups:(1)Tolerance group(BN-BN LT,n=8);(2)rejection group(Lewis-BN LT,n=8);(3)high dosage FK506(FK506-H)group(Lewis-BN LT,n=8);(4)middle dosage FK506(FK506-M)group(Lewis-BN LT,n=8);and(5)low dosage FK506(FK506-L)group(LewisBN LT,n=8).FK506 was administered to recipients at a dose of 1.0 mg/kg,0.5 mg/kg,and 0.1 mg/kg body weight for 29 d after LT to the FK506-H,FK506-M,and FK506-L groups,respectively.On the 30^(th) day after LT,all rats were sampled and euthanized.Blood samples were harvested for liver function and plasma endotoxin testing.Hepatic graft and ileocecal tissues were collected for histopathology observation.Ileocecal contents were used for DNA extraction,Real-time quantitative polymerase chain reaction(RT-PCR)and digital processing of denaturing gradient gel electrophoresis(DGGE)profiles and analysis.RESULTS Compared to the FK506-H and FK506-L groups,FK506-M was optimal for maintaining immunosuppression and inducing normal graft function;the FK506-M maintained gut barrier integrity and low plasma endotoxin levels;furthermore,DGGE results showed that FK506-M induced stable gut microbiota.Diversity analysis indicated that FK506-M increased species richness and rare species abundance,and cluster analysis confirmed the stable gut microbiota induced by FK506-M.Phylogenetic tree analysis identified crucial bacteria associated with FK506-M;seven of the nine bacteria that were decreased corresponded to Bacteroidetes,while increased bacteria were of the Bifidobacterium species.FK506-M increased Faecalibacterium prausnitzii and Bifidobacterium spp.and decreased Bacteroides-Prevotella and Enterobacteriaceae,as assessed by RT-PCR,which confirmed the crucial bacterial alterations identified through DGGE.CONCLUSION Compared to the low or high dosage of FK506,an optimal dosage of FK506 induced immunosuppression,normal graft function and stable gut microbiota following LT in rats.The stable gut microbiota presented increased probiotics and decreased potential pathogenic endotoxin-producing bacteria.These findings provide a novel strategy based on gut microbiota for immunosuppressive dosage assessment for recipients following LT. | Jian-Wen Jiang Zhi-Gang Ren Hai-Feng Lu Hua Zhang Ang Li Guang-Ying Cui Jun-Jun Jia Hai-Yang Xie Xin-Hua Chen Yong He Li Jiang Lan-Juan Li | 2018 | World Journal of Gastroenterology2018，24，34： | 5 |
| 15 | 他克莫司治疗膜性肾病进展显示文摘膜性肾病(membranous nephropathy,MN)是肾病综合征的一种常见类型,以肾小球基膜外侧上皮下免疫复合物沉积,基膜增殖致使“钉突”形成和基膜弥漫性增厚为其主要病理特征,病因未明确者称为特发性膜性肾病( idiopathic membranous ne-phropathy,IMN)[1,2]。目前 IMN 的治疗多采用免疫抑制剂,以糖皮质激素联合烷化剂较为经典,但这一方案存在较多的副作用[3]。近年,他克莫司( tacrolimus,TAC)在治疗 MN 中取得了一定的疗效,本文就此综述如下。 | 夏梦迪 谢席胜 艾娜 | 2014 | 中国中西医结合肾病杂志2014，15，10： | 5 |
| 16 | Calcineurin inhibitor sparing strategies in renal transplantation, part one: Late sparing strategies显示文摘Kidney transplantation improves quality of life and reduces the risk of mortality. A majority of the success of kidney transplantation is attributable to the calcineurin inhibitors(CNIs), cyclosporine and tacrolimus, and their ability to reduce acute rejection rates. However, longterm graft survival rates have not improved over time, and although controversial, evidence does suggest a role of chronic CNI toxicity in this failure to improve outcomes. Consequently, there is interest in reducing or removing CNIs from immunosuppressive regimens in an attempt to improve outcomes. Several strategies exist to spare calcineurin inhibitors, including use of agents such as mycophenolate mofetil(MMF), mycophenolate sodium(MPS), sirolimus, everolimus or belatacept to facilitate late calcineurin inhibitor withdrawal, beyond 6 mo post-transplant; or using these agents to plan early withdrawal within 6 mo; or to avoid the CNIs all together using CNI-free regimens. Although numerous reviews have been written on this topic, practice varies significantly between centers. This review organizes thedata based on patient characteristics(i.e., the baseline immunosuppressive regimen) as a means to aid the practicing clinician in caring for their patients, by matching up their situation with the relevant literature. The current review, the first in a series of two, examines the potential of immunosuppressive agents to facilitate late CNI withdrawal beyond 6 mo post-transplant, and has demonstrated that the strongest evidence resides with MMF/MPS. MMF or MPS can be successfully introduced/maintained to facilitate late CNI withdrawal and improve renal function in the setting of graft deterioration, albeit with an increased risk of acute rejection and infection. Additional benefits may include improved blood pressure, lipid profile and serum glucose.Sirolimus has less data directly comparing CNI withdrawal to an active CNI-containing regimen, but modest improvement in short-term renal function is possible, with an increased risk of proteinuria, especially in the setting of baseline renal dysfunction and/or proteinuria. Renal outcomes may be improved when sirolimus is used in combination with MMF. Although data with everolimus is less robust, results appear similar to those observed with sirolimus. | Andrew Scott Mathis Gwen Egloff Hoytin Lee Ghin | 2014 | World Journal of Transplantation2014，4，2： | 5 |
| 17 | Tacrolimus对糖尿病大鼠肾脏巨噬细胞Toll样受体2与4表达的影响显示文摘目的探讨Toll样受体(Toll-like receptor,TLR)2和TLR4在糖尿病大鼠肾脏巨噬细胞的表达水平及tacrolimus对其的调节作用。方法将40只Wistar大鼠随机分为对照组、模型组、tacrolimus(0.5、1.0 mg.kg-1)给药组,通过腹腔注射链脲佐菌素(STZ)诱导糖尿病模型,4周后测大鼠血糖、相对肾质量、尿白蛋白排泄率(UAER),应用免疫组化单染及双染方法检测肾组织ED-1+细胞、NF-κB-p-p65+细胞及ED-1+TLR2+细胞、ED-1+TLR4+细胞的表达。结果 ta-crolimus 1.0 mg.kg-1给药组大鼠相对肾质量明显低于模型组(P<0.05),tacrolimus(0.5、1.0 mg.kg-1)给药组大鼠UAER较模型组明显减少(P<0.05或P<0.01)。免疫组化显示:模型组大鼠肾组织ED-1+、ED-1+TLR2+、ED-1+TLR4+及NF-κB-p-p65+细胞数明显高于对照组(P<0.01),tacrolimus 0.5与1.0 mg.kg-1给药组ED-1+细胞数与模型组比较无差异,而ED-1+TLR2+、ED-1+TLR4+及NF-κB-p-p65+细胞数则明显低于模型组(P<0.05)。结论糖尿病大鼠肾脏巨噬细胞TLR2和TLR4的过度表达与巨噬细胞的活化及由此引发的炎症反应有关,tacrolimus可通过直接或间接作用下调肾脏巨噬细胞TLR2与TLR4表达,从而抑制与TLR-NF-κB信号转导及调控途径有关的炎症反应。 | 陈姗姗 齐向明 张炜 吴永贵 | 2013 | 中国药理学通报2013，29，3： | 4 |
| 18 | Development of tacrolimus-loaded transfersomes for deeper skin penetration enhancement and therapeutic effect improvement in vivo显示文摘The aims of this study were to prepare novel transfersomes(TFs)for tacrolimus to treat atopic dermatitis,and to observe the therapeutic effects on mice atopic dermatitis,as compared to commercial tacrolimus ointment(Protopic)and liposomes-gel.Different kinds of surfactantsdsodium cholate,Tween 80 and Span 80 were investigated to prepare TFs respectively.TFs-Tween 80 was selected as the optimal carrier owing to the best deformability and the highest drug retentions.Entrapment efficiency and diameter were also evaluated.The optimized TFs were further made into gel and in vitro drug release of TFs-gel after 24 h was higher than the commercial ointment.Cumulative drug release from TFs-gel after 12 h in vitro was 37.6%.The optimized TFs-gel illustrated remarkably highest drug skin retentions when compared with liposomes-gel and commercial ointment in vivo skin retention experiments.The amounts of tacrolimus in epidermis and dermis from TFsgel were 3.8 times and 4.2 times respectively as much as ointment,while liposomes-gel was only 1.7 times and 1.4 times respectively as compared to ointment.Topical application of TFs-gel displayed the best therapeutic effect on mice atopic dermatitis induced by repeated topical application of 2,4-dinitrofluorobenzene.Thus TFs displayed superior performance and effective skin target for topical delivery of tacrolimus. | Wei Lei Chuqin Yu Huaqing Lin Xiaoyuan Zhou | 2013 | Asian Journal of Pharmaceutical Sciences2013，8，6： | 4 |
| 19 | Efficacy and safety of tacrolimus and low-dose prednisone in Chinese children with steroid-resistant nephrotic syndrome显示文摘Background Tacrolimus,a calcineurin inhibitor,is recommended by the recent guidelines from the Kidney Disease Improving Global Outcomes Group as the first-line treatment for steroid-resistant nephrotic syndrome(SRNS),but its clinical application in China is still limited.We investigated the efficacy and safety of tacrolimus combined with low-dose corticosteroids in a population of Chinese children with SRNS.Methods In this prospective non-randomized,non-controlled study,Chinese children with SRNS who failed the previous full-dose prednisone treatment were given tacrolimus(0.1 mg/kg/day)and low-dose prednisone(0.25-0.50 mg/kg/day).We compared the overall remission rate(ORR)and adverse events in the follow-up period with this therapeutic regimen.Results A total of 76 children were enrolled into the study with an average follow-up period of 18±6 months(maximum 36 months).ORR achieved by the first,third,and sixth months was 94.7%,94.7%,and 96.0%,respectively.All patients who attained an initial tacrolimus trough concentration(FK506C0)>6 ng/mL(60.3%)achieved remission.The relative risk of relapse at FK506C0<3 ng/mL compared to 3-6 ng/mL,6-9 ng/mL,and 9-12 ng/mL was 2.3,3.2,and 16.9,respectively.During the follow-up period,adverse effects that had been previously reported were rare.Conclusions Combination of tacrolimus and low-dose prednisone was safe and effective for the treatment of children with SRNS,with high remission rates observed as early as the first month.Relapses were infrequent,but tended to increase significantly with decreases in FK506C0. | Hai-Xia Chen Qia Cheng Fang Li Qing-Nan He Yan Cao Zhu-Wen Yi Xiao-Chuan Wu | 2020 | World Journal of Pediatrics2020，16，2： | 4 |
| 20 | Tacrolimus for children with refractory nephrotic syndrome:a one-year prospective,multicenter,and open-label study of Tacrobell®,a generic formula显示文摘Background:Cyclosporine A and tacrolimus(TAC)are often used as a second-line treatment for children with refractory nephrotic syndrome(NS).This study was undertaken to investigate the efficacy and safety of Tacrobell®,a locally produced generic form of TAC.Methods:This study was a one-year prospective,open-label,single-arm,multicenter trial.Fourty-four children with steroid-dependent NS(SDNS)and 33 children with steroid-resistant NS(SRNS)were enrolled.The primary endpoints were defined as the remission rates,whereas the secondary endpoints were recognized as the duration of remission and adverse effects of TAC.Results:After one-year treatment,34(77.3%)of the 44 patients with SDNS were in complete remission,and 6(13.6%)were in partial remission.Nineteen(43.2%)patients did not relapse during the study;for those who did relapse,the mean duration of remission was 4.6±2.9 months.The number of relapse episodes during the study period(0.90 per patient-year)was significantly lower than that in the preceding year(2.8 per patientyear).After treatment for 3 and 6 months,12(36.4%)of the 33 patients with SRNS were in remission,and after treatment for 12 months,the number of patients had increased to 13(39.4%).The mean time to achieve remission was 4.0±3.2 months.After remission(duration,3.7±2.7 months),12(54.5%)of 22 patients relapsed.The fasting blood glucose and blood pressure levels during the therapy were similar to those at the time of study entry.Conclusions:Treatment with Tacrobell®was effective and safe for children with refractory NS.The efficacy of this generic form of TAC was better than that of the original TAC formula. | Eun Mi Yang Sang Taek Lee Hyun Jin Choi Hee Yeon Cho Joo Hoon Lee Hee Gyung Kang Young Seo Park Hae Il Cheong Il-Soo Ha | 2016 | World Journal of Pediatrics2016，12，1： | 4 |
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