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
ObjectivesTo systematically review the efficacy and safety of tacrolimus (TAC) and cyclosporine A (CsA) for patients after renal transplantation.MethodsPubMed, EMbase, Web of Science, The Cochrane Library, CBM, WanFang Data and CNKI databases were electronically searched to collect randomized controlled trials (RCTs) on the efficacy and safety of TAC vs. CsA after renal transplantation from inception to December, 2018. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, meta-analysis was performed by using RevMan 5.3 software.ResultsA total of 12 RCTs involving 3 130 patients were included. The results of meta-analysis showed that: compared with CsA, the TAC had lower incidence of acute rejection at 6 months after renal transplantation (RR=0.61, 95%CI 0.50 to 0.74, P<0.000 01), and had higher glomerular filtration rate (GFR) (MD=4.20, 95%CI 1.07 to 7.34, P=0.009), lower incidence of dyslipidemia (RR=0.46, 95%CI 0.27 to 0.80, P<0.006), higher incidence of diabetes (RR=1.36, 95%CI 1.12 to 1.65, P=0.002) at 12 months after renal transplantation. There was no significant difference between two groups in the incidence of hypertension after renal transplantation (RR=0.90, 95%CI 0.69 to 1.17,P=0.43).ConclusionsCurrent evidence shows that, compared with CsA, TAC can significantly improve renal function, reduce the risk of acute rejection and dyslipidemia, but it can increase the risk of diabetes. Due to limited quality and quantity of the included studies, more high-quality studies are needed to verify above conclusions.
【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.
ObjectiveTo investigate the relationship between the CYP3A5 genotyping and the drug metabolism of tacrolimus after operation in adult liver transplantation.MethodsNinety-eight adult patients with liver transplantation in Tianjin First Center Hospital were selected as subjects. The blood samples of liver transplantation recipients and donor were collected before operation, and then tested the CYP3A5 genotyping by PCR method. The weekly body mass, tacrolimus dose, and drug valley concentration of the patients were monitored in 1, 2, 3, and 4 weeks after operation, to calculate the tacrolimus concentration/dose ratio. And then compared the effects of different genotyping of donor and receptors on tacrolimus concentration/dose ratio.ResultsIn the CYP3A5 genotyping of 98 patients with liver transplantation and the corresponding donors, GG type was the most and AA type was the least, the distribution of alleles was in accordance with the genetic law, and the difference was not statistically significant (P>0.05). According to the donor genotype, the results showed that there was a significant correlation between tacrolimus concentration/dose ratio and donor or recipients CYP3A5 genotype at 1, 2, 3, and 4 weeks after liver transplantation, and there was significant difference among the three groups (P<0.05): GG>AG>AA. According to the combined grouping of donor and receptor genotype, the results showed that there was significant difference in tacrolimus concentration/dose ratio among A*/A*, A*/GG, GG/A*, and GG/GG group (P<0.05), while there was significant difference in tacrolimus concentration/dose ratio between GG/GG and A*/A* group (P<0.01), the tacrolimus concentration/dose ratio was highest in GG/GG group and lowest in A*/A* group.ConclusionsThe CYP3A5 genotyping of the recipient and donor can affect the blood concentration of tacrolimus after liver transplantation, and the CYP3A5 GG genotype is more likely to reach the target plasma concentration than the other genotypes, that the detection of donor and recipient CYP3A5 genotype in patients with liver transplantation can provide a reference for individualized treatment of tacrolimus after liver transplantation.
ObjectiveTo compare tacrolumus (FK506) with cyclosporine A (CsA) in clinical application to organ transplantation.MethodsThe literature in recent years has been reviewed and compared. ResultsFK506 was a powerful immunosuppression with a mechanism of action similar to that of CsA, but significantly superiori to CsA in terms of prophylaxis and treatment of allograft acute rejection, delay of chronic rejection, and withdrawal of steroid in early period. The cardiovascular mortality and chronic graft nephropathy (CGN),such as hypertension and hyperlipidemia were less frequently seen in FK506treated patients and FK506 also had an acceptable safety profile, including a low incidence of hypertrichosis,gingival hyperplasia and infections.However, CsA had been showed a better result in prevention of posttransplantation diabetes mellitus (PTDM ) and more economic agent than FK506. Pharmacokinetic studies showed CsA in the form of Sandimmun Neoral showed less inter an intrapatient variability than FK506.Meanwhile, the combination of MMF and FK506 or CsA has been proved effectively with excellent graft and patients survival. Conclusion FK506 and CsA are safe and effective long term maintenance immunosuppressive agents in organ transplantation with wonderful prospect.
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 assess the efficacy and safety of tacrolimus and pimecrolimus ointment for treating Vitiligo. Methods We searched the MEDLINE (1966 to June 2008), Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2008), OVID (1978 to June 2008), EMbase (1980 to June 2008), CBM (1978 to June 2008), and CNKI (1979 to June 2008) to collect randomized controlled trials (RCTs). We also handsearched relevant journals and conference proceedings. The language was confined to English and Chinese. We screened the retrieved studies according to the predefined inclusion and exclusion criteria, evaluated the quality of included studies, and performed meta-analyses using the Cochrane Collaboration’s RevMan 4.2 software. Results Fourteen trials involving 414 patients in 11 self-control trials and 182 patients in other 3 trials were included and assessed. The rate of 75% repigmentation induced by combination of topical tacrolimus with monochromatic excimer light was higher than that of control [RR= – 2.28, 95%CI (1.02, 5.10)]. The efficacy rate of combination treatment was also obviously higher than that of control [RR= 1.24, 95%CI (1.13, 1.37)]. The irradiation number of initial repigmentation induced by combination of topical pimecrolimus with monochromatic excimer light was less than that of control [WMD= – 3.00, 95%CI (– 3.22, – 2.78)], and the repigmentationrate of facial lesions in the combination group was higher than that of control. The efficacy rate of topical tacrolimus combination with Fufang Kaliziran Ding was significantly higher than that of control [RR= 1.83, 95% (1.14, 2.94)]. No significant difference was seen between topical tacrolimus combination with the NB-UVB group and the control group, or between the topical tacrolimus or pimecrolimus alone group with the control group. The side effects were limited and brief. Conclusion The limited evidence indicats that the combination of topical tacrolimus with monochromatic excimer light or Fufang Kaliziran Ding could improve the efficacy rate of treating vitiligo leukoplakia. The combination of topical pimecrolimuswith monochromatic excimer light shortens the irradiation number of initial repigmentation and works better on facial lesions.
ObjectiveTo illustrate the role of epidermal growth factor (EGF) secreted by astrocytes in the process of tacrolimus (FK506) in promoting neurite outgrowth. MethodsThe spinal cord astrocytes and neuronal cells were isolated respectively from 2-day-old Sprague Dawley (SD) rats and 15-day SD pregnant rats, and cultured in vitro and identified by immunofluorescence staining. The spinal cord astrocytes were cultured with 20 μmol/L FK506 medium in the experimental group, and with FK506 free medium in the control group. The supernatant was collected after 24 hours for preparing conditioned medium, and astrocytes were collected. EGF proteins in the conditioned medium were detected with ELISA, and EGF gene expressions of astrocytes were detected with real-time quantitative PCR (RT-qPCR). The spinal cord neurons were cultured respectively with conditioned medium from the experimental group (FK506-CM) and the control group (C-CM) in group A and group B, also with neutralized C-CM and neutralized FK506-CM with anti-EGF neutralizing antibodies in group C and group D. Both the total neurite length and the longest neurite length were measured and compared among groups. ResultsBoth astrocytes and neurons were confirmed by immunofluorescence staining. The EGF content of experimental group (0.241±0.044) was significantly higher than that of the control group (0.166±0.014) (t=3.93, P=0.01); EGF gene expression of the experimental group (1.12±0.25) was significantly higher than that of the control group (0.46±0.11) (t=5.78, P=0.00). The neurite length measurement displayed that the total neurite length and the longest neurite length of groups C and D were significantly shorter than those of groups A and B (P<0.05). Both the total and longest neurite length of group A were significantly longer than those of group B (P<0.05), but no significant difference was shown between groups C and D (P>0.05). ConclusionThe EGF secreted by spinal cord astrocytes can promote the neurite outgrowth. So spinal cord astrocytes can be used as an important intermediary target of FK506 to promote the recovery of neurological function.
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.