Objective To summarize the significance of CYP3A5 in individualized immunosuppressive treatment with tacrolimus (FK506) after liver transplantation. Methods Relevant literatures about the effect of CYP3A5 polymorphisms on the pharmacokinetics of tacrolimus in liver transplant recipients, which were published recently domestic and abroad, were reviewed and analyzed. Results Tacrolimus was used effectively to prevent allograft rejection after liver transplantation. Narrow therapeutic range and individual variation in pharmacokinetics made it difficultly to establish a fixed dosage for all patients. Genetic polymorphism in drug metabolizing enzymes and in transporters influenced the plasma concentration of tacrolimus. CYP3A5 genotype had an effect on the tacrolimus dose requirement in liver transplant recipients.Conclusion Genotyping for CYP3A5 may help optimal individualization of immunosuppressive drug therapy for patients undergoing liver transplantation
【摘要】 目的 评价肾移植术后他克莫司（TAC）低剂量对比常规剂量干预的疗效和安全性。 方法 检索MEDLINE、EMbase、SCI、CBM、Cochrane图书馆，纳入肾移植术后TAC低剂量对比常规剂量免疫抑制治疗的随机对照试验（RCT）。检索时间从各个数据库建库至2009年12月，对纳入研究进行方法学质量评价和Meta分析。 结果 纳入3个RCT，其中A级研究2个，B级研究1个。分析结果显示:两组急性排斥反应发生率比较，无统计学意义[RR=1.39， 95%CI(0.64， 3.01)]；肾小球滤过率、受者/移植物生存率和纳入分析的安全性指标差异均无统计学意义。 结论 基于当前临床证据，肾移植术后TAC低剂量与常规剂量干预相比，近期疗效和安全性相似；远期结果尚需进一步研究探讨。【Abstract】 Objective To evaluate the effect and safety of low-dose versus standard-dose tacrolimus immunosuppressive therapy on kidney transplant recipients. Methods MEDLINE, EMbase, SCI, CBM and the Cochrane library were searched and randomized controlled trials (RCT) of low-dose versus standard-dose tacrolimus immunosuppressive therapy in kidney transplant recipients were gathered. The search was updated in December 2009. Quality assessment and meta-analysis were performed. Results A total of three RCT were identified, two of which were graded A and one was graded B. The analysis results indicated that RR (95%CI) value of the acute rejection rate was 1.39 (0.64, 3.01); glomerular filtration rate, patient/graft survival rate, and safety analysis were not significant different between the two groups. Conclusion Based on the evidence currently, compared to standard-dose TAC, Low-dose TAC has the same effect and safety results, but further study are needed to get the long term results.
Objective To evaluate efficacy and safety of topical tacrolimus（FK506）for atopic dermatitis. Methods Randomized controlled trials (RCTs) were identified from specialized trials registered in Cochrane Skin Group (July, 2003), the Cochrane Library (issue 2, 2003), Medline (1996-2003), Embase (1984-2003) and CBM (1978-2003). We handsearched the published and unpublished data and Cochrane Skin Group 8th Annual Meeting. RCTs comparing tacrolimus with placebo or hormone were included. Data were extracted and evaluated by two reviewers independently. Results Eight randomized controlled trials involving 4 122 patients were included, with all trials of high methodological quality. Meta-analysis indicated that 0.03% tacrolimus was more effective than placebo, 1% hydrocortisone acetate and 0.1% hydrocortisone butyrate with odds ratio of 3.03 [95%CI (1.05, 8.73), P=0.04], 0.1% tacrolimus was more effective than placebo, 1% hydrocortisone acetate and 0.1% hydrocortisone butyrate with odds ratio of 3.84 [95%CI (1.43, 10.32), P=0.008], 0.3% tacrolimus was more effective than placebo with odds ratio of 3.20 [95%CI (1.31, 7.79), P=0.01], the odds ratio of 0.1% tacrolimus vs 0.03% tacrolimus was 1.40 [95%CI (1.13, 1.72), P=0.002]. No serious adverse effects were identified. Conclusions Topical tacrolimus for atopic dermatitis is more effective than placebo and 1% hydrocortisone acetate. 0.1% tacrolimus is more effective than 0.03% tacrolimus. No conclusion could be drawn when tacrolimus is compared with 0.1% hydrocortisone butyrate. Tacrolimus tends to improve EASI scores, head and neck scores as well as HRQL scores, but more randomized controlled trials are necessary to draw definite conclusions.
Objective To evaluate the effectiveness of tacrolimus and cyclosporine A on acute rejection, chronic rejection and survival rate of patient and graft after renal transplantation. Methods We searched MEDLINE (1989 to Nov.2004), EMBASE (1989 to Nov.2004), The Chinese Biomedical Database (CBM) (1998 to Nov.2004), Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2004) and handsearched 8 Chinese journals. Trials comparing tacrolimus with cyclosporine A after renal transplantation were included. The quality of included studies such as randomization, blinding, allocation concealment was evaluated and meta-analysis was performed using RevMan 4.2.7 software. Results Eighteen studies involving 3 738 patients were included. Tacrolimus was more effective in decreasing the incidence of acute rejection and chronic rejection than that of cyclosporine A with RR 0.65, 95％CI 0.56 to 0.75 at the end of 6 months; with RR 0.70, 95％CI 0.54 to 0.92 at the end of 12 months for number of patients of acute rejection. The pooled RR was 0.65 (95％CI 0.47 to 0.89) for number of patients of chronic rejection. Tacrolimus could reduce the severity of acute rejection. The relative risks of pathologic grade BanffⅠand Banff (Ⅱ＋Ⅲ) were 1.64 (95％CI 1.08 to 2.49) and 0.75 (95％CI 0.63 to 0.89) respectively. But there was no significant difference on the survival rate of patient and graft within 5 years between the two groups. The relative risk of 6, 12, 24, 36 and 60 months were 1.01 (95％CI 0.99 to 1.02), 1.00 (95％CI 0.99 to 1.02), 1.01 (95％CI 0.97 to 1.05), 1.00 (95％CI 0.97 to 1.03) and 0.97 (95％CI 0.88 to 1.07) respectively for the survival rate of patient and 1.04 (95％CI 1.01 to 1.07), 1.03 (95％CI 1.00 to 1.06), 0.99 (95％CI 0.91 to 1.07), 1.04 (95％CI 0.99 to 1.09) and 1.04 (95％CI 0.90 to 1.21) respectively for the survival rate of grafts. Conclusions On acute rejection and chronic rejection, tacrolimus is more effective than cyclosporine A, but there is no difference in the graft or patient survival rate.
Objective To evaluate the efficacy and safety of glucocorticoids (GC) monotherapy and GC combined with tacrolimus (TAC) therapy in patients with anti-synthetase syndrome-associated interstitial lung disease (ASS-ILD). Methods Through retrospective analysis and propensity score matching (PSM) analysis, the 2-year progression-free survival (PFS) and related side effects of ASS-ILD patients in TAC+GC group and GC monotherapy group were compared. Predictors associated with PFS were analyzed with COX. Results The 2-year PFS rate of TAC+GC group was better than that of GC group [P=0.0163; hazard ratio (HR) 0.347]; Univariate and multivariate analysis of the COX regression model for 2-year PFS in the two groups suggested that creatine kinase level (P=0.0019, HR 1.002) and initial treatment selection [(TAC+GC) vs. GC, P=0.0197, HR 0.207] were independent predictors of PFS; PSM analysis showed that the 2-year PFS rate of TAC+GC group (54.5%) was higher than that of GC group (18.2%) (P=0.0157, HR 0.275). In terms of adverse effect, there was no significant increase in GC+TAC group compared with GC group. Conclusion Compared with GC monotherapy, initial TAC+GC treatment significantly prolonged PFS in ASS-ILD patients and did not increase the incidence of drug-related complications.
Objective To systematically review the correlation between CYP3A5 genotypes and blood levels of tacrolimus (FK506) in renal transplant recipients. Methods Such databases as PubMed (January 1966 to July 2013), Sciverse (January 1823 to July 2013), The Cochrane Library (Issue 7, 2013), CNKI (January 1994 to July 2013), VIP (January 1989 to July 2013), CBM (January 1978 to July 2013) and WanFang Data (January 1995 to July 2013) were electronically searched for studies about the correlation between CYP3A5 genotypes and FK506 (blood concentration/dose-respones relationship) in renal transplant recipients. According to the inclusion and exclusion criteria, literature was screened, data were extracted, and the methodological quality of included studies was also assessed. Then, meta-analysis was performed using RevMan 5.2 software. Results A total of 12 articles involving 956 patients were included. The results of meta-analysis showed that, after renal transplantation, there was a high dose-adjusted concentration of CYP3A5 3/3 carriers on the 7th day (MD= 54.61, 95%CI –67.67 to –41.54, Plt;0.000 01), in the 1st month (MD= –74.84, 95%CI –83.39 to –66.29, Plt;0.000 01), in the 3rd month (MD= –96.09, 95%CI –107.55 to –84.64, Plt;0.000 01), in the 6th month (MD= –107.30, 95%CI –125.65 to –88.95, Plt;0.000 01), and in the 1st year (MD= –78.32, 95%CI –123.02 to –33.61, P=0.000 6). The dose-adjusted concentration of FK506 in CYP3A5 3/3 patients was higher than the other genotypes, while the dose-adjusted concentration of FK506 in CYP3A5 1/1 patients was low. Conclusion The blood concentration as well as dose-respones relationship of FK506 are associated with CYP3A5 genotype in renal transplant recipients. We propose that patients with renal transplantation should receive CYP3A5 genotypes test to determine the use of FK506 as an immunosuppressant, so as to guide its clinical application.
Objective To systematically evaluate the efficacy and safety of tacrolimus and glucocorticoid for oral lichen planus (OLP). Methods The Cochrane review’s method was adopted and computer-based retrieval was performed on The Cochrane Library, MEDLINE, EMbase, CBM, and CNKI (from their establishment to November 2010) to collect randomized controlled trials (RCTs) comparing the clinical efficacy of tacrolimus in treating OLP with that of triamcinolone. The study was selected according to the inclusion and exclusion criteria, the data were collected, and the methodological quality of the included studies was evaluated. The RevMan 5.0.25 software was applied for statistical analyses. Results Four RCTs involving 164 patients were included. Two studies showed that the tacrolimus effectively reduced lesion area and alleviated pain of patients with OLP. The results of meta-analyses showed that the total effective rate of tacrolimus was not higher than that of glucocorticoid (OR=4.38, 95%CI 0.67 to 28.73), and there was no significant difference between the tacrolimus group and the glucocorticoid group in adverse events during the treatment session (OR=3.49, 95%CI 0.49 to 24.84), and there was no significant difference in recurrence rate between those two groups (OR=0.82, 95%CI 0.27 to 2.46). Conclusion Topical tacrolimus can remarkably improve the OLP sign (lesion area) and symptom (pain), which is in line with the findings of other non-RCTs. The current evidence proves that the tacrolimus is similar to glucocorticoid in terms of the total effective rate of treating OLP, the incidence of side reaction during treatment, and the recurrence rate after stopping treatment. Some studies included in this systematic review apply different assessment methods, hence more RCTs with high-quality, multi-center, and therapeutic evaluation indexes with corresponding evaluation methods are required to provide more reliable evidence.
Objective To find out the beneficial and harmful effectiveness of tacrolimus (TAC) compared with cyclosporine A (CSA) for simultaneous pancreas-kidney transplant (SPKT) recipients. Methods Randomized controlled trials (RCTs) of TAC versus CSA for SPKT recipients were collected from The Cochrane Library, MEDLINE, EMbase, SCI, and CBM database. Bias risk assessment and meta-analysis were performed based on the methods recommended by the Cochrane Collaboration. Results Five RCTs including 342 recipients were included. Pooled data of pancreas survival favored TAC (RR=1.15, 95%CI 1.04 to 1.27; RD=0.11, 95%CI 0.03 to 0.19). However, there were no significant differences of acute rejection (RR=0.81, 95%CI 0.58 to 1.12), patient survival (RR=1.00, 95%CI 0.94 to 1.05), kidney survival (RR=1.02, 95%CI 0.95 to 1.09), and infection (RR=1.00, 95%CI 0.83 to 1.20). Conclusion Based on the recent evidence, TAC results in higher episodes of pancreas survival compared with CSA after SPKT. Treating 100 patients with TAC instead of CSA would increase pancreas survival in 11 recipients.
Objective To evaluate the effectiveness and safety of calcineurin inhibitor (CNI) withdrawal from target-of-rapamycin-inhibitor(TOR-I)-based immunosuppression in kidney transplant recipients. Methods We searched MEDLINE, EMbase, SCI, CBM and The Cochrane Library to screen randomized controlled trials (RCT) of calcineurin inhibitor (CNI) withdrawal from target-of-rapamycin-inhibitor-(TOR-I)-based immunosuppression in kidney transplant recipients. The search was updated in Semptember 2009. The quality of the included trials was assessed. RevMan 5.0 software was used for meta-analyses. Results A total of 14 reports from 10 RCTs were identified. Five RCTs were graded A and five graded B. The meta-analyses indicated: RR (95%CI) values of the 1, 2, 4-year acute rejection rates were 1.64 (1.19, 2.27), 1.53 (1.06, 2.22) and 1.21 (0.73, 1.98), respectively; RD (95%CI) values of 1, 2, 4-year patient survival rates were – 0.01 (– 0.02, 0.01), – 0.00 (– 0.03, 0.02) and 0.03 (– 0.01, 0.08), respectively; RD (95%CI) values of 1, 2, 4-year graft survival rates were 0.00 (– 0.02, 0.02), 0.00 (– 0.03, 0.04) and 0.07 (0.01, 0.12), respectively; and glomerular filtration rate WMD was 9.50 and 95%CI 2.96 to 16.03. Conclusion Based on the current evidence, compared to CNI, CNI withdrawal from sirolimus-based immunosuppression in kidney transplantation could be advantageous for renal function. One-year acute rejection rate and 4-year graft survival rate increase. One-year patient/graft survival and fouryear acute rejection rate remain virtually unvariable. The long-term results need further confirmation.