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 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 We handsearched the published and unpublished data and Cochrane Skin Group 8th Annual Meeting.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 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 investigate effect of intravitreal injection of FK506 on the survival of human retinal pigment epithelial (RPE) cells heter oplastically transplanted into the subretinal space of rabbits.Methods The immortalized human RPE cells were genetically labeled by retrovirus vector carrying a green fluorescent protein (GFP). A total of 50 μl RPE cells suspension with 4×103 cells/μl which expressed GFP were injected into the subretinal space of both eyes of 18 white rabbits and 10 gray rabbits. The left eyes of all of the rabbits were injected of 5 μl FK506 (5 μg/μl) intravitreally once a week during the first 5 weeks, then once every other week until the 20th week and the right eyes were as the control. The histological sections of heteroplastic RPE cells were observed by epifluorescent microscope.Results GFP-expressing cells could be seen after 1 week, 2, 3, 4, 6, 10, 11, 14, 18, 20, 23, 24, 25, 26, 33, and 54 weeks in white rabbits and after 4 , 5, 6, 7, 14, 18, 20, and 26 weeks in gray rabbits. The configuration and integrality of the RPE-GFP cells in the left eyes which had been intravitreally injected of FK506 1-14 weeks after transplantation were better than those in the right eyes without injection. After 18 weeks, the condition of heteroplastic cells with few difference in both eyes in 7 white and 3 gray rabbits were found. After 1-6 weeks, focal and disseminated lymphocytes around the choroidal small vessles of right eyes in 6 white and 3 gray rabbits could be seen while the infiltration of the lymphocytes in the left eyes was much reduced.Conclusion Intravitreal injection of a small amount of FK506 at the first 3 months after transplantation may significantly improve the survival of heteroplastic RPE cells in the subretinal space of rabbits. (Chin J Ocul Fundus Dis，2003，19：333-404)
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 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 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.
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 observe the dynamic histopathologic changes of acute rejection in rat orthotopic liver transplantation (OLT) model after tacrolimus discontinued and provide some prediction and evaluation data for clinical acute rejection after liver transplantation. Methods Kamada two-cuff technique was used to establish 60 rat OLT model， and male DA rats, male Lewis rats were used as donors and recipients respectively. Therapeutic amount of tacrolimus (0.05 mg/kg, twice per day, continued for 8 d, 1 d before operation and 7 d after operation, intragastric administrated) was administrated to recipients, then continuously half dose was decreased every day beginning from day 8 after operation and tacrolimus administration was stopped on day 13. Liver tissues were collected on day 7, 14, 21, and 28 after liver transplantation. Histopathologic changes and rejection activity index (RAI) of liver tissues were observed, survival time of recipients was calculated. Results Owing to protection effects of tacrolimus, liver tissues displayed no significant histopathologic changes of acute rejection in 7 d after OLT, while typical acute rejection histopathologic changes began to be observed on day 14 after OLT due to tacrolimus discontinuation. On day 14, 21, and 28, RAI were 3.7±0.9, 6.3±0.9, and 8.1±0.7 respectively. Survival time of recipients was (20.85±0.71) d with a median of 21 d. Conclusion Acute rejection could be induced in rat OLT model after tacrolimus discontinuation, and data collected from this model shows some extent of predictive value and assessment value for clinical liver acute rejection.