Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C is the most common cause of end-stage liver disease leading to liver transplant. The disease can recur after transplant, resulting in clinical hepatitis in up to 75% of patients and severe disease in approximately 7%. Treatment of rejection with steroid boluses and treatment of steroid-resistant rejection with OKT3 have both been shown to increase the incidence of recurrent hepatitis C. The use of OKT3 for steroid-resistant rejection is reportedly associated with more severe recurrence. The calcineurin inhibitors tacrolimus and cyclosporine have not been conclusively associated with different rates or severity of recurrence. Viral levels rise 10- to 15-fold after transplant and appear to be associated with the use of immunosuppression. Studies suggest that high viral levels, either pretransplant or early after transplant, may be associated with severe recurrent disease. Although the role of genotype is still unclear, genotype 1b is known to be associated with a poorer prognosis in nontransplanted patients and a lesser response to treatment than other genotypes. Furthermore, some reports suggest that after transplant, recurrent disease may progress more rapidly in patients with genotype 1. Treatment options after recurrence remain poor. Neither interferon nor ribavirin alone provides any true benefit. Combination therapy appears to have a better short-term outcome but may be poorly tolerated, and long-term benefits are unknown. Prophylaxis with combination therapy may be a better option but requires further study. Finally, retransplantation for recurrent hepatitis C is complicated not by rapid recurrence of disease in the new allograft but by high perioperative mortality that may be predicted by the presence of renal failure or sepsis preretransplant.
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PMID:Hepatitis C after liver transplantation. 1094 24

Hepatic graft rejection is a common complication after liver transplantation (LT), with a maximum incidence within the first weeks. The identification of high-risk patients for early acute rejection (EAR) might be useful for clinicians. A series of 133 liver graft recipients treated with calcineurin inhibitors was retrospectively assessed to identify predisposing factors for EAR and develop a mathematical model to predict the individual risk of each patient. The incidence of EAR (< or =45 days after LT) was 35.3%. Multivariate analysis showed that recipient age, underlying liver disease, and Child's class before LT were independently associated with the development of EAR. Combining these 3 variables, the following risk score for the development of EAR was obtained: EAR score [F(x)] = 2.44 + (1.14 x hepatitis C virus cirrhosis) + (2.78 x immunologic cirrhosis) + (2.51 x metabolic cirrhosis)--(0.08 x recipient age in years) + (1.65 x Child's class A) [corrected]. Risk for rejection = e(F(x))/1 + e(F(x)). The combination of age, cause of liver disease, and Child's class may allow us to predict the risk for EAR.
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PMID:Prognostic model for early acute rejection after liver transplantation. 1124 67

During the last two decades, owing to advances in immunosuppressive pharmacotherapy, liver transplantation has been increasingly accepted by the medical community as an effective treatment for patients with end-stage liver disease. Successful transplantation of the liver, however, requires frequent monitoring. Most of the serious infectious complications and allograft dysfunction occur during the early post-transplantation period (i.e., first six months). Blood levels of cyclosporine or tacrolimus, the two major calcineurin inhibitors currently in use, need to be frequently checked. Drug dosage is adjusted in order to maintain target serum concentrations and the patients free of side-effects. In the time, the risk of acute allograft rejection decreases considerably, whereas the proportion of patients with fibrosis or cirrhosis increases, particularly among hepatitis C virus carriers. Graft loss may occur, secondary to recurrent disease or chronic rejection. Patients with well-functioning grafts may still be affected by significant comorbidities, such as hypertension, diabetes, obesity, hyperlipidemia and osteoporosis, which appear to be related to long-term immunosuppression. The incidence of lymphoma, skin and colorectal cancers in liver transplantation recipients exceeds those found in the general population and requires early detection. The principles of the management of medical problems after liver transplantation are a careful clinical assessment of the patient and a judicious use of laboratory tests, radiological evaluation and liver biopsy.
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PMID:[Periodic clinical monitoring after liver transplantation]. 1141 96

The pathogenesis of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is poorly understood, but the cellular immune response is likely to have a major role. Daclizumab, an interleukin-2 receptor (IL-2R) antibody that blunts T-cell activation, leading to a decreased risk for cellular rejection, is used frequently in transplant recipients. The aim of this study is to evaluate the effect of daclizumab therapy on the incidence and severity of recurrent HCV. Forty-one liver transplant recipients (21 patients, HCV positive; 20 patients, HCV negative) at high risk for neurological or renal complications of calcineurin inhibitors were administered daclizumab, mycophenolate mofetil (MMF), and steroids in the early post-LT period, followed by tacrolimus and a steroid taper. All patients were followed up prospectively for graft function and disease recurrence with protocol liver biopsies day 7, month 4, and yearly. Compared with patients without HCV, patients with HCV administered daclizumab had greater 4-month serum alkaline phosphatase, total bilirubin, and alanine aminotransferase (ALT) levels. These biochemical differences resolved by 12 months, except for persistent elevation of ALT levels. Compared with a well-matched HCV control population, patients with HCV administered daclizumab were more likely to have an earlier onset of hepatitis, jaundice, and greater histological activity. Recurrent hepatitis progressed more rapidly in the daclizumab group; 45% developed advanced disease within 1 year. HCV viral load in the daclizumab group was significantly greater at both 4 months and 1 year. Results of this study suggest that the use of adjuvant IL-2R antibodies in combination with MMF in the early peritransplantation period may be associated with early recurrence of hepatitis C and more rapid histological progression of disease.
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PMID:Anti-interleukin-2 receptor therapy in combination with mycophenolate mofetil is associated with more severe hepatitis C recurrence after liver transplantation. 1175 8

Posttransplant diabetes mellitus (PTDM) remains a common complication of immunosuppression. Although multiple risk factors have been implicated, none have been clearly identified as predisposing to the increased PTDM frequency observed in patients on tacrolimus. Hepatitis C virus (HCV) has been associated with diabetes and is a significant renal transplant comorbidity. In this study, records of 427 kidney recipients who had no known diabetes before transplantation were retrospectively examined. A multivariate logistic regression model was fit with covariates that had unadjusted relationships with PTDM to examine the independent relationship of HCV and the odds of development of PTDM by 12 mo posttransplant. A potential interaction between HCV and the use of tacrolimus as maintenance therapy on the odds of the development of PTDM was examined. Overall, PTDM occurred more frequently in HCV(+) than HCV(-) patients (39.4% versus 9.8%; P = 0.0005). By multivariate logistic regression, HCV (adjusted odds ratio [OR], 5.58; 95% confidence interval [CI], 2.63 to 11.83; P = 0.0001), weight at transplantation (adjusted OR 1.028; 95% CI, 1.00 to 1.05; P = 0.001), and tacrolimus (adjusted OR, 2.85; 95% CI, 1.01 to 5.28; P = 0.047) were associated with PTDM. A significant interaction (P = 0.0001) was detected between HCV status and tacrolimus use for the odds of PTDM. Among the HCV(+) cohort, PTDM occurred more often in tacrolimus-treated than cyclosporine A-treated patients (57.8% versus 7.7%; P < 0.0001). PTDM rates in HCV(-) patients were similar between the two calcineurin inhibitors (10.0% versus 9.4%; P = 0.521, tacrolimus versus cyclosporine A). In conclusion, HCV is strongly associated with PTDM in renal transplant recipients and appears to account for the increased diabetogenicity observed with tacrolimus.
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PMID:Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus. 1196 Oct 26

Strategies for dealing with the exponential growth of the waiting lists for solid organ transplants were the hottest clinical topics in 2002, and dominated the abstracts presented at ATC 2002. Other clinical topics that were prominent in the 2002 literature and received the highest scores at ATC 2002 included: the development of immunosuppressive regimens minimizing calcineurin inhibitors and eliminating steroids; the increasing frequency and severity of hepatitis C recurrence following transplantation; the safety and efficacy of solid organ transplantation in HIV-positive recipients; the induction of tolerance with donor stem cell infusion and recipient preconditioning; the increasing incidence of BK virus; and beta-cell replacement for the treatment of diabetes mellitus.
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PMID:The year in review--ATC 2002. 1269 58

This article highlights the currently available immunosuppressive medications that are used to prevent or treat hepatic allograft rejection. Currently-available immunosuppressive medications are highly effective in prevention of allograft rejection, graft loss, and patient death. However, side effects of medications are common, usually dose-related, and specific to the administered drug. Maintenance immunosuppression which has been primarily based upon calcineurin inhibitors (Cyclosporine, CsA, or tacrolimus, Tac) is commonly modified to reduce metabolic complications of therapy. Toxic consequences of steroids may be ameliorated by steroid withdrawal without risk of acute rejection or immunologic graft loss. Calcineurin-sparing regimens may include use of mycophenolate mofetil (MMF) or sirolimus, and allow reduction in doses and plasma levels of CsA and Tac. Recurrence of hepatitis C is universal after liver transplantation and progresses rapidly, compared to its natural history in non-immunocompromised patients. Unfortunately, no single immunosuppressive agent or strategy has yet been shown to convincingly modify the course of post-transplant recurrence. Most centers manage recurrenc hepatitis C by either steroid avoidance, reduction in immunosuppression, or institution of antiviral therapy. Ongoing advances in immunosuppressive and antiviral medications will allow tailoring of the immunosuppressive prescription, which undoubtedly will benefit current and future liver recipients.
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PMID:Immunosuppression in liver transplantation. 1460 51

Over the last 20 years, immunosuppression protocols in liver transplant patients have been based on calcineurin inhibitors, such as cyclosporine (CsA). Currently, there are three outstanding clinical issues related to the use of CsA in the liver transplant setting that merit further attention: (1) dose adjustment according to 2-hour postdose (instead of trough) concentrations to improve efficacy and safety, (2) possible synergistic effect between CsA and antiviral treatments for recurrent posttransplant hepatitis C infection, and (3) preliminary results showing favorable outcomes after liver transplantation in HIV-positive patients receiving antiviral therapy.
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PMID:Impact of cyclosporine on the development of immunosuppressive therapy in liver transplantation. 1504 55

Therapeutic drug monitoring of CsA has evolved since the introduction of CsA microemulsion. The purpose of the present review is to summarize the history of CsA concentration 2 hours postdose (C2) monitoring in heart and liver transplantation. C2 has been shown to be the best single time point that correlates with the area-under-the-curve, with a correlation coefficient (r2) ranging between .83 and.93. C2 monitoring (300 to 600 ng/mL) has resulted in a significant clinical benefit in long-term heart and liver transplant patients compared to trough level (C0) monitoring. Moreover, a C2 range of 300 to 600 ng/mL resulted in a similar calcineurin inhibition compared to a C2 range of 700 to 1000 ng/mL or a C0 range of 100 to 200 ng/mL while being less injurious to renal function. In de novo liver transplant patients not receiving induction therapy, the achievement of a target C2 of 850 to 1400 ng/mL by postoperative day 3 has resulted in a low acute rejection rate. Furthermore, C2 monitoring has been associated with a lower rejection rate in hepatitis C virus (HCV)-negative patients and with an overall lesser severity of acute rejection compared to C0 monitoring. In de novo heart transplant patients who receive antithymocyte globulin induction, a lower C2 range may be sufficient to prevent rejection and renal dysfunction. Future studies should help to fine-tune the optimal C2 range in heart or liver transplant patients receiving induction therapy and different maintenance immunosuppressive combinations.
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PMID:History of C2 monitoring in heart and liver transplant patients treated with cyclosporine microemulsion. 1504 83

The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients. Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates. Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 'acceptable' ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immunosuppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.
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PMID:Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. 1524 95


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