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
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.
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.
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.
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 評價腎移植術后他克莫司（TAC）低劑量對比常規劑量干預的療效和安全性。 方法 檢索MEDLINE、EMbase、SCI、CBM、Cochrane圖書館，納入腎移植術后TAC低劑量對比常規劑量免疫抑制治療的隨機對照試驗（RCT）。檢索時間從各個數據庫建庫至2009年12月，對納入研究進行方法學質量評價和Meta分析。 結果 納入3個RCT，其中A級研究2個，B級研究1個。分析結果顯示:兩組急性排斥反應發生率比較，無統計學意義[RR=1.39， 95%CI(0.64， 3.01)]；腎小球濾過率、受者/移植物生存率和納入分析的安全性指標差異均無統計學意義。 結論 基于當前臨床證據，腎移植術后TAC低劑量與常規劑量干預相比，近期療效和安全性相似；遠期結果尚需進一步研究探討。【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 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.
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.