BACKGROUND Kidney transplantation is an effective renal replacement therapy for improving survival and quality of life in chronic kidney disease patients.Kidney transplant recipients need lifelong immunosuppression to...BACKGROUND Kidney transplantation is an effective renal replacement therapy for improving survival and quality of life in chronic kidney disease patients.Kidney transplant recipients need lifelong immunosuppression to prevent rejection and allograft dysfunction.Tacrolimus,a calcineurin inhibitor,is metabolized differently based on cytochrome P4503A(CYP3A)5 genetic variations and this impacts the graft outcome.AIM To examine the clinical outcomes in kidney transplant recipients affected by the variable metabolism of tacrolimus due to the CYP3A5 genetic variation,emphasizing personalized immunosuppression strategies to optimize efficacy,minimize toxicity,and enhance long-term graft survival.METHODS A retrospective study was conducted at a tertiary care center in Central India on 95 kidney transplant recipients.Patient demographics,medical history,CYP3A5 polymorphism,post-transplant investigations,graft biopsy results,preexisting comorbidities,history of post–kidney transplant infections,and new onset diabetes after transplantation(NODAT)was collected.Tacrolimus was initiated at 0.1 mg/kg/day for CYP3A5 expressors and 0.05 mg/kg/day for non-expressors,with dose adjustments to maintain target C0 levels of 7-10 ng/mL for first 6 months and 5-7 ng/mL from 6 months to 12 months posttransplant.Patients were followed regularly for one year for glomerular filtration rate(GFR),creatinine,and the tacrolimus trough concentration(ng/mL)/daily tacrolimus dose(mg/kg/day)ratio(C/D).A P value≤0.05 was considered statistically significant.RESULTS Kidney transplant recipients were classified as expressors(CYP3A51 carriers,n=35)and non-expressors(CYP3A5*3*3,n=60).Both groups were comparable for age,sex,and donor characteristics.Tacrolimus dose was comparable post-transplant except at 6 months and 12 months,where expressors required higher doses.Kidney function(creatinine and estimated GFR),NODAT,hypomagnesemia,and infections showed no significant differences between the two groups over 12 months of follow-up.Biopsy-proven acute rejection(BPAR)was found to be more in expressors(22.9%vs 13.3%,P=0.2340)though it was not found to be statistically significant.Nonexpressors had a significantly higher tacrolimus levels and C/D ratio at multiple follow-ups.CONCLUSION CYP3A5 expressors require higher tacrolimus doses to maintain therapeutic levels as compared to non-expressors.BPAR was higher in expressors but the difference was not significant.Graft function,infection rate,and NODAT were comparable irrespective of CYP3A5 expression status,emphasizing the importance of pretransplant CYP3A5 genotyping and therapeutic drug monitoring to guide tacrolimus dosing for individualized immunosuppressive management.展开更多
BACKGROUND Tacrolimus(FK506)is a key calcineurin inhibitor used to prevent organ transplant rejection and is effective in improving graft survival.However,it is linked to hyperglycemia and insulin resistance,contribut...BACKGROUND Tacrolimus(FK506)is a key calcineurin inhibitor used to prevent organ transplant rejection and is effective in improving graft survival.However,it is linked to hyperglycemia and insulin resistance,contributing to new-onset diabetes after transplantation and negatively affecting islet function.AIM To study the effects of tacrolimus on the insulin signaling pathway of hepatocytes.METHODS HL7702 cells were treated with different concentrations of tacrolimus(0.1 mg/L,1 mg/L,5 mg/L)for 24 hours.The proteins involved in insulin signaling were detected by Western blotting.RESULTS Compared with the control group,phosphorylation of insulin receptor substrate(IRS)1 at Ser 307 and Ser 323 were increased significantly when the tacrolimus concentration reached 1 and 5 mg/L.Phosphorylation of IRS1 at Ser 1101 was also increased,although not significantly.However,phosphorylation of Ribosomal protein S6 kinase beta-1 at Thr 389 was decreased significantly.The levels of phosphorylated glycogen synthase kinase 3αSer 21 and Ser 9 were increased.Surprisingly,phosphorylation of glycogen synthase at Ser 641 was increased.There was no significant change in the activity of glycogen phosphorylase.CONCLUSION Tacrolimus has no direct effect on hepatic glucose metabolism,but inhibits IRS1-mediated insulin signaling.This may be one of the underlying mechanisms by which tacrolimus induces insulin resistance.展开更多
Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies a...Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies available to promote nerve regeneration.Tacrolimus accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery.The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure.Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days.Size and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible byproducts.Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic delivery.Given its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.展开更多
Background:The absence of well-established immunosuppressed rabbit models poses a significant hurdle in xenograft experiments.Tacrolimus has been identified as a highly promising immunosuppressive agent for rabbits.Ho...Background:The absence of well-established immunosuppressed rabbit models poses a significant hurdle in xenograft experiments.Tacrolimus has been identified as a highly promising immunosuppressive agent for rabbits.However,determining the optimal dosage and route of administration to minimize toxicity while maintaining efficacy remains challenging.Methods:In this study,we investigated the effect of orally administered tacrolimus in rabbits,with an aim to achieve a whole blood target trough level of 3-10 ng/m L,and looked at signs of tissue rejection after the transplantation of a human nerve conduit to repair a severed fibular nerve.An oral dosage range of 0.25-1.5 mg/kg/d was studied for up to 1 year in 63 New Zealand rabbits.Results:We demonstrated the feasibility of long-term grafting in rabbits while maintaining safe immunosuppression,with side effects mainly limited to diarrhea.Customizing the administered dose proved crucial for graft efficacy and low toxicity,which translated into 100%individual survival.We suggest an oral tacrolimus dose of 1.0-1.5 mg/kg depending on individual heterogeneity and recommend to implement a close therapeutic drug monitoring in the rabbits to maintain a whole blood tacrolimus trough level within the range of 5-12 ng/m L,as levels below 5 ng/m L showed signs of inflammation in the graft.Conclusion:The oral administration of tacrolimus enabled efficient immunosuppression of rabbits over a 1-year period without significant side effects or loss of animals.展开更多
BACKGROUND Tacrolimus(TAC)is metabolized primarily by the CYP3A-encoded enzyme family(CYP3A4,CYP3A5,and CYP3A7).Individuals expressing the CYP3A51 allele are considered fast metabolizers and generally require higher T...BACKGROUND Tacrolimus(TAC)is metabolized primarily by the CYP3A-encoded enzyme family(CYP3A4,CYP3A5,and CYP3A7).Individuals expressing the CYP3A51 allele are considered fast metabolizers and generally require higher TAC doses to reach therapeutic levels.AIM To evaluate the predictive value of the TAC concentration-to-dose(C0/D)ratio for identifying CYP3A5 poly-morphisms in renal transplant recipients.METHODS Eighty-six de novo kidney transplant recipients with TAC-based immunosuppression from the Department of Nephrology and Dialysis at Military Hospital 103(Hanoi,Vietnam)were included in this retrospective study.Blood samples were collected within the first week post-transplantation to monitor TAC levels and to perform genotyping for CYP3A5 genetic polymorphisms.RESULTS The CYP3A53/3 genotype was identified in 37 patients(43%),CYP3A51/3 in 40 patients(46.5%),and CYP3A51/1 in 9 patients(10.5%).Patients carrying the CYP3A51/3 or CYP3A51/1 genotype,classified as fast metabolizers(CYP3A5 expressers),had significantly lower TAC C0 concentrations and C0/D ratios compared to slow meta-bolizers(CYP3A53/3 genotype)at multiple time points during follow-up(all P<0.001).Notably,the TAC C0/D ratio obtained on day 1(0.91)was shown to predict CYP3A5 polymorphism with a sensitivity of 84.6%and a specificity of 84.6%.CONCLUSION This study demonstrates that the TAC C0/D ratio provides a reliable predictive value for CYP3A5 polymorphisms,which can be used to individualize TAC dosing in renal transplant recipients in Vietnam and other low-income countries.展开更多
Tacrolimus(Tac)is a cornerstone immunosuppressant in the treatment regimens for organ transplant recipients.However,its extensive clinical use has brought attention to its associated drug safety concerns.Recent case r...Tacrolimus(Tac)is a cornerstone immunosuppressant in the treatment regimens for organ transplant recipients.However,its extensive clinical use has brought attention to its associated drug safety concerns.Recent case reports highlighting Tac-induced gastrointestinal ulcers have prompted further investigation.In the present study,we analyzed Tac-associated adverse events using data from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)to identify potential adverse event signals.Adverse event reports were collected up to the third quarter(Q3)of 2023,revealing 339 cases of Tac-related gastrointestinal ulcers.A disproportionality analysis was conducted utilizing the Bayesian confidence propagation neural network of information component(IC)and reporting odds ratio(ROR)methods.All statistical analyses were performed using R version 3.6.1.The findings demonstrated a significant signal for gastrointestinal ulcers associated with Tac use,with a ROR1 of 1.87(95%CI:1.68-2.08)and an IC1 of 0.89(95%CI:0.73-1.05)when compared to all other drugs.When compared specifically to cyclosporine,Tac also showed a significant signal(ROR2=1.55,95%CI:1.28-1.86;IC2=0.24,95%CI:0.04-0.44).Further analysis identified age,male gender,and European descent as risk factors for mortality outcomes in patients with Tac-associated gastrointestinal ulcers.These findings highlighted the critical need for clinicians to strengthen the monitoring and early detection of gastrointestinal ulcers in patients undergoing Tac therapy.Enhanced vigilance in this regard is essential to optimize the management and care of transplant patients.展开更多
BACKGROUND Tacrolimus trough levels(TTL)during the first weeks after liver transplantation(LT)have been related with long-term renal function and hepatocellular carcinoma recurrence.Nevertheless,the significance of tr...BACKGROUND Tacrolimus trough levels(TTL)during the first weeks after liver transplantation(LT)have been related with long-term renal function and hepatocellular carcinoma recurrence.Nevertheless,the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debate AIM To evaluate the effect of TTL during the first month on the long-term outcomes after LT.METHODS One hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively studied.Patients with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction therapy.Patients were classified into 2 groups according to their mean TTL within the first month after transplantation:≤10(n=98)and>10 ng/mL(n=57).Multivariate analyses were performed to assess risk factors for patient mortality.RESULTS Mean levels within the first month post-transplant were 7.4±1.7 and 12.6±2.2 ng/mL in the≤10 and>10 groups,respectively.Donor age was higher in the high TTL group 62.9±16.8 years vs 45.7±17.5 years(P=0.002)whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7%vs 15.8%(P=0.02).Recipient features were generally similar across groups.After a median follow-up of 52.8 mo(range 2.8-81.1),no significant differences were observed in:Mean estimated glomerular filtration rate(P=0.69),hepatocellular carcinoma recurrence(P=0.44),de novo tumors(P=0.77),new-onset diabetes(P=0.13),or biopsy-proven acute rejection rate(12.2%and 8.8%,respectively;P=0.50).Eighteen patients died during the follow-up and were evenly distributed across groups(P=0.83).Five-year patient survival was 90.5%and 84.9%,respectively(P=0.44),while 5-year graft survival was 88.2%and 80.8%,respectively(P=0.42).Early TTL was not an independent factor for patient mortality in multivariate analyses.CONCLUSION Differences in tacrolimus levels restricted to the first month after transplant did not result in significant differences in long-term outcomes of LT recipients.展开更多
There is an interaction between tacrolimus(TAC) and glucocorticoids where glucocorticoids is a known CYP3A4 and P-gp inducer.However, the dose of glucocorticoids reported is low but not pulse therapy.We retrospectivel...There is an interaction between tacrolimus(TAC) and glucocorticoids where glucocorticoids is a known CYP3A4 and P-gp inducer.However, the dose of glucocorticoids reported is low but not pulse therapy.We retrospectively studied 63 renal transplant recipients receiving TAC after transplantation.All the patients were classified as 500 mg(POD 1–3), 30 mg(POD 4–10), 25 mg(POD 11–17), 20 mg(POD 18–24), 15 mg(POD 25–31), 10 mg(POD 32–60) and 10 mg(POD 61–90).We recorded daily data for each patient from the day of transplantation until POD 90.There was no difference in TAC blood levels within the 3 months after transplantation in the glucocorticoids groups.However, the average daily dose of TAC was significantly lower by weekly reductions of 5 mg dose.The TAC daily dose was not changed from POD 1–4, but the blood concentrations of TAC were significantly lower after the glucocorticoid dose was changed from 500 mg to 30 mg.We demonstrated the induction effect of low-dose glucocorticoids on TAC in renal transplant recipients, and found that the high-dose of glucocorticoids might play a role in substrate competition.We proposed that monitoring of the blood concentrations of TAC was needed when the glucocorticoid dose was changed in the patient undergoing renal transplantation.展开更多
AIM: To investigate the effect of the ‘‘minimizing tacrolimus' ' strategy on long-term survival of patients after liver transplantation(LT).METHODS: We conducted a retrospective study of 319 patients who rec...AIM: To investigate the effect of the ‘‘minimizing tacrolimus' ' strategy on long-term survival of patients after liver transplantation(LT).METHODS: We conducted a retrospective study of 319 patients who received LT between January 2009 and December 2011 at the First Affiliated Hospital of Zhejiang University School of Medicine. Following elimination of ineligible patients, 235 patients were included in the study. The relationship between early tacrolimus(TAC)exposure and survival period was analyzed by Kaplan Meier curves. Adverse effects related to TAC were eval-uated by the χ2 test. Routine monitoring of blood TAC concentration(TC) was performed using the PRO-TracTM Ⅱ Tacrolimus Elisa Kit(Diasorin, United States). RESULTS: Of 235 subjects enrolled in the study, 124(52.8%) experienced adverse effects due to TAC. When evaluating mean TC, the survival time of patients with a mean TC < 5 ng/mL was significantly shorter than that in the other groups(911.3 ± 131.6 d vs 1381.1 ± 66.1 d, 911.3 ± 131.6 d vs 1327.3 ± 47.8 d, 911.3 ± 131.6 d vs 1343.2 ± 83.1 d, P < 0.05), while the survival times of patients with a mean TC of 5-7, 7-10 and 10-15 ng/mL were comparable. Adverse effects due to TAC in all four groups were not significantly different. When comparing the standard deviation(SD) of TC among the groups, the survival time of patients with a SD of 2-4 was significantly longer than that in the other groups(1388.8 ± 45.4 d vs 1029.6 ± 131.3 d, 1388.8 ± 45.4 d vs 1274.9 ± 57.0 d, P < 0.05), while in patients with a SD < 2 and SD > 4, the survival time was not statistically different. Adverse effects experienced in all three groups were not statistically different. In Cox regression analysis, male patients and those with a primary diagnosis of benign disease, mean TC > 5 ng/mL and TC SD 2-4 had better outcomes.CONCLUSION: The early ‘‘minimizing tacrolimus' ' strategy with a mean TC of 5-10 ng/mL and SD of 2-4 was beneficial in terms of long-term survival after LT.展开更多
AIM： To determine the effects of the calcineurin inhibitors, cyclosporine and tacrolimus, on hepatitis C virus （HCV） replication and activity of recurrent hepatitis C in patients post liver transplantation. METHODS...AIM： To determine the effects of the calcineurin inhibitors, cyclosporine and tacrolimus, on hepatitis C virus （HCV） replication and activity of recurrent hepatitis C in patients post liver transplantation. METHODS： The data of a cohort of 107 patients who received liver transplantation for HCV-associated liver cirrhosis between 1999 and 2003 in our center were retrospectively analyzed. The level of serum HCV-RNA and the activity of recurrent hepatitis were compared between 47 patients who received either cyclosporine or tacrolimus as the primary immunosuppressive agent and an otherwise similar immunosuppressive regimen which did not lead to biliary complications within the first 12 mo after transplantation. RESULTS： HCV-RNA increased within 3 mo after transplantation but the differences between the cyclosporine group and the tacrolimus group were insignificant （P=0.49 at 12 too）. In addition, recurrent hepatitis as determined by serum transarninases and histological grading of portal inflammation and fibrosis showed no significant difference after 12 mo （P= 0.34）.CONCLUSION： Cyclosporine or tacrolimus as a primary immunosuppressive agent does not influence the induction or severity of recurrent hepatitis in HCV- infected patients after liver transplantation.展开更多
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 reci...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.展开更多
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 par...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.展开更多
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...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.展开更多
AIM: Standard immunosuppression after organ transplantation stimulates tumor growth. Sirolimus has a strong antiproliferative and a tumor inhibiting effect. The purpose is to assess the effect on tumor growth of the i...AIM: Standard immunosuppression after organ transplantation stimulates tumor growth. Sirolimus has a strong antiproliferative and a tumor inhibiting effect. The purpose is to assess the effect on tumor growth of the immunosuppressive compounds sirolimus and tacrolimus alone and in combination on cells of human hepatocellular carcinoma.METHODS: We used the human cell lines SK-Hep 1 and Hep 3B derived from hepatocellular carcinoma. Proliferation analyses after treatment with sirolimus, tacrolimus, or the combination of both were performed. FACS analyses were done to reveal cell cycle changes and apoptotic cell death. The expression of apoptosis-related proteins was estimated by Western blots.RESULTS: Sirolimus alone or combined with tacrolimus inhibited the growth of both cell lines after 5 d by up to 35% in SK-Hep 1 cells, and by up to 68% in Hep 3B cells at 25 ng/mL. Tacrolimus alone stimulated the growth by 12% after 5 ng/mL and by 25% after 25 ng/mL in Hep 3B cells. We found an increase of apoptotic Hep 3B cells from 6 to 16%, and a G1-arrest in SK-Hep 1 cells with an increase of cells from 61 to 82%, when sirolimus and tacrolimus were combined. Bcl-2 was down-regulated in Hep 3B, but not in SK-Hep 1 cells after combined treatment.CONCLUSION: Sirolimus appears to inhibit the growth of hepatocellular carcinoma cells alone and in combination with tacrolimus. Sirolimus seems to inhibit the growth stimulation of tacrolimus.展开更多
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 ...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.展开更多
To investigate incidence and survival of post-transplant lymphoproliferative disorder (PTLD) patients after liver transplantation.METHODSA cross-sectional survey was conducted among patients who underwent liver transp...To investigate incidence and survival of post-transplant lymphoproliferative disorder (PTLD) patients after liver transplantation.METHODSA 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.RESULTSThere 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).CONCLUSIONIncidence 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.展开更多
AIM： To investigate the tacrolimus dosage requirements and blood concentrations in adult-to-adult right lobe living donor liver transplantation （AALDLT） recipients with small-for-size （SFS） grafts. METHODS： Duri...AIM： To investigate the tacrolimus dosage requirements and blood concentrations in adult-to-adult right lobe living donor liver transplantation （AALDLT） recipients with small-for-size （SFS） grafts. METHODS： During January 2007 and October 2008, a total of 54 cases of AALDLT with an observation period of 6 mo were enrolled in this study. The 54 patients were divided into two groups according to graftrecipient body weight ratio （GRBW）： SFS grafts group （Group S, GRBW 〈 0.8%, n = 8） and non-SFS grafts group （Group N, GRBW ≥ 0.8%, n = 46）. Tacrolimus 12-hour blood levels and doses were recorded during weeks 1, 2, 3 and 4 and months 2, 3, 4, 5 and 6 in group S and group N. Meanwhile, acute rejection rates, liver and renal function test results, and the number of potentially interacting medications were determined at each interval in the two groups. A comparison of tacrolimus dosage requirements and blood levels were made weekly in the first month post-surgery, and monthly from months 2 to 6. RESULTS： There were no differences in the demo-graphic characteristics, acute rejection rates, liver and renal function test results, or the number of potentially interacting medications administered between the two groups. The tacrolimus dosage requirements in group S were significantly lower than group N at 2 wk （2.8 ± 0.4 mg/d vs 3.6 ± 0.7 mg/d, P = 0.006）, 3 wk （2.9± 0.7 mg/d vs 3.9±0.8 rag/d, P = 0.008）, 4 wk （2.9 ± 0.8 mg/d vs 3.9 ± 1.0 mg/d, P = 0.023） and 2 mo （2.8 ±0.7 mg/d vs 3.8±1.1 mg/d, P = 0.033）. Tacrolimus 12-h trough concentrations were similar between the two groups at all times except for 2 wk post-transplantation, when the concentrations were significantly greater in group S recipients than in group N recipients （11.3 ± 4.8 ng/mL vs 7.0 ± 3.8 ng/mL, P = 0.026）. CONCLUSION： SFS grafts recipients have significantly decreased tacrolimus dosage requirements compared with non-SFS grafts recipients in AALDLT during the first 2 mo post-surgery.展开更多
文摘BACKGROUND Kidney transplantation is an effective renal replacement therapy for improving survival and quality of life in chronic kidney disease patients.Kidney transplant recipients need lifelong immunosuppression to prevent rejection and allograft dysfunction.Tacrolimus,a calcineurin inhibitor,is metabolized differently based on cytochrome P4503A(CYP3A)5 genetic variations and this impacts the graft outcome.AIM To examine the clinical outcomes in kidney transplant recipients affected by the variable metabolism of tacrolimus due to the CYP3A5 genetic variation,emphasizing personalized immunosuppression strategies to optimize efficacy,minimize toxicity,and enhance long-term graft survival.METHODS A retrospective study was conducted at a tertiary care center in Central India on 95 kidney transplant recipients.Patient demographics,medical history,CYP3A5 polymorphism,post-transplant investigations,graft biopsy results,preexisting comorbidities,history of post–kidney transplant infections,and new onset diabetes after transplantation(NODAT)was collected.Tacrolimus was initiated at 0.1 mg/kg/day for CYP3A5 expressors and 0.05 mg/kg/day for non-expressors,with dose adjustments to maintain target C0 levels of 7-10 ng/mL for first 6 months and 5-7 ng/mL from 6 months to 12 months posttransplant.Patients were followed regularly for one year for glomerular filtration rate(GFR),creatinine,and the tacrolimus trough concentration(ng/mL)/daily tacrolimus dose(mg/kg/day)ratio(C/D).A P value≤0.05 was considered statistically significant.RESULTS Kidney transplant recipients were classified as expressors(CYP3A51 carriers,n=35)and non-expressors(CYP3A5*3*3,n=60).Both groups were comparable for age,sex,and donor characteristics.Tacrolimus dose was comparable post-transplant except at 6 months and 12 months,where expressors required higher doses.Kidney function(creatinine and estimated GFR),NODAT,hypomagnesemia,and infections showed no significant differences between the two groups over 12 months of follow-up.Biopsy-proven acute rejection(BPAR)was found to be more in expressors(22.9%vs 13.3%,P=0.2340)though it was not found to be statistically significant.Nonexpressors had a significantly higher tacrolimus levels and C/D ratio at multiple follow-ups.CONCLUSION CYP3A5 expressors require higher tacrolimus doses to maintain therapeutic levels as compared to non-expressors.BPAR was higher in expressors but the difference was not significant.Graft function,infection rate,and NODAT were comparable irrespective of CYP3A5 expression status,emphasizing the importance of pretransplant CYP3A5 genotyping and therapeutic drug monitoring to guide tacrolimus dosing for individualized immunosuppressive management.
文摘BACKGROUND Tacrolimus(FK506)is a key calcineurin inhibitor used to prevent organ transplant rejection and is effective in improving graft survival.However,it is linked to hyperglycemia and insulin resistance,contributing to new-onset diabetes after transplantation and negatively affecting islet function.AIM To study the effects of tacrolimus on the insulin signaling pathway of hepatocytes.METHODS HL7702 cells were treated with different concentrations of tacrolimus(0.1 mg/L,1 mg/L,5 mg/L)for 24 hours.The proteins involved in insulin signaling were detected by Western blotting.RESULTS Compared with the control group,phosphorylation of insulin receptor substrate(IRS)1 at Ser 307 and Ser 323 were increased significantly when the tacrolimus concentration reached 1 and 5 mg/L.Phosphorylation of IRS1 at Ser 1101 was also increased,although not significantly.However,phosphorylation of Ribosomal protein S6 kinase beta-1 at Thr 389 was decreased significantly.The levels of phosphorylated glycogen synthase kinase 3αSer 21 and Ser 9 were increased.Surprisingly,phosphorylation of glycogen synthase at Ser 641 was increased.There was no significant change in the activity of glycogen phosphorylase.CONCLUSION Tacrolimus has no direct effect on hepatic glucose metabolism,but inhibits IRS1-mediated insulin signaling.This may be one of the underlying mechanisms by which tacrolimus induces insulin resistance.
基金supported by the German Research Foundation(DA 2255/1-1to SCD)+4 种基金a SickKids Research Training Competition(RESTRACOMP)Graduate Scholarship(to KJWS)an Ontario Graduate Scholarship(to KJWS)a grant from Natural Sciences and Engineering Research Council of Canada(NSERC)(to KJWS)a Kickstarter grant from the Institute of Biomedical Engineering(BME)at the University of Toronto(to KJWS)the Abe Frank Fund from the Riley’s Children Foundation(GHB)。
文摘Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies available to promote nerve regeneration.Tacrolimus accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery.The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure.Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days.Size and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible byproducts.Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic delivery.Given its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.
基金the Canadian Institutes of Health Research(CIHR),Grant/Award Number:PJT-175016the Fonds de recherche du Québec(FRQ)through the research centre grant for the CHU de Québec-UniversitéLaval Research Center,Grant/Award Number:30641+2 种基金the Quebec Cell,Tissue and Gene Therapy Network—ThéCellthe FRQS,the Fondation du CHU de Québec-UniversitéLavalNeuro Québec。
文摘Background:The absence of well-established immunosuppressed rabbit models poses a significant hurdle in xenograft experiments.Tacrolimus has been identified as a highly promising immunosuppressive agent for rabbits.However,determining the optimal dosage and route of administration to minimize toxicity while maintaining efficacy remains challenging.Methods:In this study,we investigated the effect of orally administered tacrolimus in rabbits,with an aim to achieve a whole blood target trough level of 3-10 ng/m L,and looked at signs of tissue rejection after the transplantation of a human nerve conduit to repair a severed fibular nerve.An oral dosage range of 0.25-1.5 mg/kg/d was studied for up to 1 year in 63 New Zealand rabbits.Results:We demonstrated the feasibility of long-term grafting in rabbits while maintaining safe immunosuppression,with side effects mainly limited to diarrhea.Customizing the administered dose proved crucial for graft efficacy and low toxicity,which translated into 100%individual survival.We suggest an oral tacrolimus dose of 1.0-1.5 mg/kg depending on individual heterogeneity and recommend to implement a close therapeutic drug monitoring in the rabbits to maintain a whole blood tacrolimus trough level within the range of 5-12 ng/m L,as levels below 5 ng/m L showed signs of inflammation in the graft.Conclusion:The oral administration of tacrolimus enabled efficient immunosuppression of rabbits over a 1-year period without significant side effects or loss of animals.
基金Supported by the Vietnam National Foundation for Science and Technology Development,No.NAFOSTED 04/2020/TN.
文摘BACKGROUND Tacrolimus(TAC)is metabolized primarily by the CYP3A-encoded enzyme family(CYP3A4,CYP3A5,and CYP3A7).Individuals expressing the CYP3A51 allele are considered fast metabolizers and generally require higher TAC doses to reach therapeutic levels.AIM To evaluate the predictive value of the TAC concentration-to-dose(C0/D)ratio for identifying CYP3A5 poly-morphisms in renal transplant recipients.METHODS Eighty-six de novo kidney transplant recipients with TAC-based immunosuppression from the Department of Nephrology and Dialysis at Military Hospital 103(Hanoi,Vietnam)were included in this retrospective study.Blood samples were collected within the first week post-transplantation to monitor TAC levels and to perform genotyping for CYP3A5 genetic polymorphisms.RESULTS The CYP3A53/3 genotype was identified in 37 patients(43%),CYP3A51/3 in 40 patients(46.5%),and CYP3A51/1 in 9 patients(10.5%).Patients carrying the CYP3A51/3 or CYP3A51/1 genotype,classified as fast metabolizers(CYP3A5 expressers),had significantly lower TAC C0 concentrations and C0/D ratios compared to slow meta-bolizers(CYP3A53/3 genotype)at multiple time points during follow-up(all P<0.001).Notably,the TAC C0/D ratio obtained on day 1(0.91)was shown to predict CYP3A5 polymorphism with a sensitivity of 84.6%and a specificity of 84.6%.CONCLUSION This study demonstrates that the TAC C0/D ratio provides a reliable predictive value for CYP3A5 polymorphisms,which can be used to individualize TAC dosing in renal transplant recipients in Vietnam and other low-income countries.
文摘Tacrolimus(Tac)is a cornerstone immunosuppressant in the treatment regimens for organ transplant recipients.However,its extensive clinical use has brought attention to its associated drug safety concerns.Recent case reports highlighting Tac-induced gastrointestinal ulcers have prompted further investigation.In the present study,we analyzed Tac-associated adverse events using data from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)to identify potential adverse event signals.Adverse event reports were collected up to the third quarter(Q3)of 2023,revealing 339 cases of Tac-related gastrointestinal ulcers.A disproportionality analysis was conducted utilizing the Bayesian confidence propagation neural network of information component(IC)and reporting odds ratio(ROR)methods.All statistical analyses were performed using R version 3.6.1.The findings demonstrated a significant signal for gastrointestinal ulcers associated with Tac use,with a ROR1 of 1.87(95%CI:1.68-2.08)and an IC1 of 0.89(95%CI:0.73-1.05)when compared to all other drugs.When compared specifically to cyclosporine,Tac also showed a significant signal(ROR2=1.55,95%CI:1.28-1.86;IC2=0.24,95%CI:0.04-0.44).Further analysis identified age,male gender,and European descent as risk factors for mortality outcomes in patients with Tac-associated gastrointestinal ulcers.These findings highlighted the critical need for clinicians to strengthen the monitoring and early detection of gastrointestinal ulcers in patients undergoing Tac therapy.Enhanced vigilance in this regard is essential to optimize the management and care of transplant patients.
文摘BACKGROUND Tacrolimus trough levels(TTL)during the first weeks after liver transplantation(LT)have been related with long-term renal function and hepatocellular carcinoma recurrence.Nevertheless,the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debate AIM To evaluate the effect of TTL during the first month on the long-term outcomes after LT.METHODS One hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively studied.Patients with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction therapy.Patients were classified into 2 groups according to their mean TTL within the first month after transplantation:≤10(n=98)and>10 ng/mL(n=57).Multivariate analyses were performed to assess risk factors for patient mortality.RESULTS Mean levels within the first month post-transplant were 7.4±1.7 and 12.6±2.2 ng/mL in the≤10 and>10 groups,respectively.Donor age was higher in the high TTL group 62.9±16.8 years vs 45.7±17.5 years(P=0.002)whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7%vs 15.8%(P=0.02).Recipient features were generally similar across groups.After a median follow-up of 52.8 mo(range 2.8-81.1),no significant differences were observed in:Mean estimated glomerular filtration rate(P=0.69),hepatocellular carcinoma recurrence(P=0.44),de novo tumors(P=0.77),new-onset diabetes(P=0.13),or biopsy-proven acute rejection rate(12.2%and 8.8%,respectively;P=0.50).Eighteen patients died during the follow-up and were evenly distributed across groups(P=0.83).Five-year patient survival was 90.5%and 84.9%,respectively(P=0.44),while 5-year graft survival was 88.2%and 80.8%,respectively(P=0.42).Early TTL was not an independent factor for patient mortality in multivariate analyses.CONCLUSION Differences in tacrolimus levels restricted to the first month after transplant did not result in significant differences in long-term outcomes of LT recipients.
文摘There is an interaction between tacrolimus(TAC) and glucocorticoids where glucocorticoids is a known CYP3A4 and P-gp inducer.However, the dose of glucocorticoids reported is low but not pulse therapy.We retrospectively studied 63 renal transplant recipients receiving TAC after transplantation.All the patients were classified as 500 mg(POD 1–3), 30 mg(POD 4–10), 25 mg(POD 11–17), 20 mg(POD 18–24), 15 mg(POD 25–31), 10 mg(POD 32–60) and 10 mg(POD 61–90).We recorded daily data for each patient from the day of transplantation until POD 90.There was no difference in TAC blood levels within the 3 months after transplantation in the glucocorticoids groups.However, the average daily dose of TAC was significantly lower by weekly reductions of 5 mg dose.The TAC daily dose was not changed from POD 1–4, but the blood concentrations of TAC were significantly lower after the glucocorticoid dose was changed from 500 mg to 30 mg.We demonstrated the induction effect of low-dose glucocorticoids on TAC in renal transplant recipients, and found that the high-dose of glucocorticoids might play a role in substrate competition.We proposed that monitoring of the blood concentrations of TAC was needed when the glucocorticoid dose was changed in the patient undergoing renal transplantation.
基金Supported by National S and T Major Program,No.2012 ZX10002004National Natural Science Foundation of China,No.81373160 and No.81302074
文摘AIM: To investigate the effect of the ‘‘minimizing tacrolimus' ' strategy on long-term survival of patients after liver transplantation(LT).METHODS: We conducted a retrospective study of 319 patients who received LT between January 2009 and December 2011 at the First Affiliated Hospital of Zhejiang University School of Medicine. Following elimination of ineligible patients, 235 patients were included in the study. The relationship between early tacrolimus(TAC)exposure and survival period was analyzed by Kaplan Meier curves. Adverse effects related to TAC were eval-uated by the χ2 test. Routine monitoring of blood TAC concentration(TC) was performed using the PRO-TracTM Ⅱ Tacrolimus Elisa Kit(Diasorin, United States). RESULTS: Of 235 subjects enrolled in the study, 124(52.8%) experienced adverse effects due to TAC. When evaluating mean TC, the survival time of patients with a mean TC < 5 ng/mL was significantly shorter than that in the other groups(911.3 ± 131.6 d vs 1381.1 ± 66.1 d, 911.3 ± 131.6 d vs 1327.3 ± 47.8 d, 911.3 ± 131.6 d vs 1343.2 ± 83.1 d, P < 0.05), while the survival times of patients with a mean TC of 5-7, 7-10 and 10-15 ng/mL were comparable. Adverse effects due to TAC in all four groups were not significantly different. When comparing the standard deviation(SD) of TC among the groups, the survival time of patients with a SD of 2-4 was significantly longer than that in the other groups(1388.8 ± 45.4 d vs 1029.6 ± 131.3 d, 1388.8 ± 45.4 d vs 1274.9 ± 57.0 d, P < 0.05), while in patients with a SD < 2 and SD > 4, the survival time was not statistically different. Adverse effects experienced in all three groups were not statistically different. In Cox regression analysis, male patients and those with a primary diagnosis of benign disease, mean TC > 5 ng/mL and TC SD 2-4 had better outcomes.CONCLUSION: The early ‘‘minimizing tacrolimus' ' strategy with a mean TC of 5-10 ng/mL and SD of 2-4 was beneficial in terms of long-term survival after LT.
文摘AIM： To determine the effects of the calcineurin inhibitors, cyclosporine and tacrolimus, on hepatitis C virus （HCV） replication and activity of recurrent hepatitis C in patients post liver transplantation. METHODS： The data of a cohort of 107 patients who received liver transplantation for HCV-associated liver cirrhosis between 1999 and 2003 in our center were retrospectively analyzed. The level of serum HCV-RNA and the activity of recurrent hepatitis were compared between 47 patients who received either cyclosporine or tacrolimus as the primary immunosuppressive agent and an otherwise similar immunosuppressive regimen which did not lead to biliary complications within the first 12 mo after transplantation. RESULTS： HCV-RNA increased within 3 mo after transplantation but the differences between the cyclosporine group and the tacrolimus group were insignificant （P=0.49 at 12 too）. In addition, recurrent hepatitis as determined by serum transarninases and histological grading of portal inflammation and fibrosis showed no significant difference after 12 mo （P= 0.34）.CONCLUSION： Cyclosporine or tacrolimus as a primary immunosuppressive agent does not influence the induction or severity of recurrent hepatitis in HCV- infected patients after liver transplantation.
基金Supported by Key Technology Support Program of Sichuan ProvinceNo.2013SZ0023
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.
基金Supported by funding from Rigshospitalet,The Laerdal Foundation for Acute Medicine,Savvaerksejer Jeppe Juhl and wife Ovita Juhls Foundation,The Novo Nordisk Foundation,The AP-Mφller Foundation,and an unrestricted grant from Astellas Inc
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.
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.
文摘AIM: Standard immunosuppression after organ transplantation stimulates tumor growth. Sirolimus has a strong antiproliferative and a tumor inhibiting effect. The purpose is to assess the effect on tumor growth of the immunosuppressive compounds sirolimus and tacrolimus alone and in combination on cells of human hepatocellular carcinoma.METHODS: We used the human cell lines SK-Hep 1 and Hep 3B derived from hepatocellular carcinoma. Proliferation analyses after treatment with sirolimus, tacrolimus, or the combination of both were performed. FACS analyses were done to reveal cell cycle changes and apoptotic cell death. The expression of apoptosis-related proteins was estimated by Western blots.RESULTS: Sirolimus alone or combined with tacrolimus inhibited the growth of both cell lines after 5 d by up to 35% in SK-Hep 1 cells, and by up to 68% in Hep 3B cells at 25 ng/mL. Tacrolimus alone stimulated the growth by 12% after 5 ng/mL and by 25% after 25 ng/mL in Hep 3B cells. We found an increase of apoptotic Hep 3B cells from 6 to 16%, and a G1-arrest in SK-Hep 1 cells with an increase of cells from 61 to 82%, when sirolimus and tacrolimus were combined. Bcl-2 was down-regulated in Hep 3B, but not in SK-Hep 1 cells after combined treatment.CONCLUSION: Sirolimus appears to inhibit the growth of hepatocellular carcinoma cells alone and in combination with tacrolimus. Sirolimus seems to inhibit the growth stimulation of tacrolimus.
基金Supported by National Natural Science Foundation of China,No.81373160
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.
文摘To investigate incidence and survival of post-transplant lymphoproliferative disorder (PTLD) patients after liver transplantation.METHODSA 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.RESULTSThere 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).CONCLUSIONIncidence 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.
文摘AIM： To investigate the tacrolimus dosage requirements and blood concentrations in adult-to-adult right lobe living donor liver transplantation （AALDLT） recipients with small-for-size （SFS） grafts. METHODS： During January 2007 and October 2008, a total of 54 cases of AALDLT with an observation period of 6 mo were enrolled in this study. The 54 patients were divided into two groups according to graftrecipient body weight ratio （GRBW）： SFS grafts group （Group S, GRBW 〈 0.8%, n = 8） and non-SFS grafts group （Group N, GRBW ≥ 0.8%, n = 46）. Tacrolimus 12-hour blood levels and doses were recorded during weeks 1, 2, 3 and 4 and months 2, 3, 4, 5 and 6 in group S and group N. Meanwhile, acute rejection rates, liver and renal function test results, and the number of potentially interacting medications were determined at each interval in the two groups. A comparison of tacrolimus dosage requirements and blood levels were made weekly in the first month post-surgery, and monthly from months 2 to 6. RESULTS： There were no differences in the demo-graphic characteristics, acute rejection rates, liver and renal function test results, or the number of potentially interacting medications administered between the two groups. The tacrolimus dosage requirements in group S were significantly lower than group N at 2 wk （2.8 ± 0.4 mg/d vs 3.6 ± 0.7 mg/d, P = 0.006）, 3 wk （2.9± 0.7 mg/d vs 3.9±0.8 rag/d, P = 0.008）, 4 wk （2.9 ± 0.8 mg/d vs 3.9 ± 1.0 mg/d, P = 0.023） and 2 mo （2.8 ±0.7 mg/d vs 3.8±1.1 mg/d, P = 0.033）. Tacrolimus 12-h trough concentrations were similar between the two groups at all times except for 2 wk post-transplantation, when the concentrations were significantly greater in group S recipients than in group N recipients （11.3 ± 4.8 ng/mL vs 7.0 ± 3.8 ng/mL, P = 0.026）. CONCLUSION： SFS grafts recipients have significantly decreased tacrolimus dosage requirements compared with non-SFS grafts recipients in AALDLT during the first 2 mo post-surgery.
