Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation.

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.

A 1-year randomized controlled study of everolimus versus mycophenolate mofetil with reduced-dose cyclosporine in maintenance heart transplant recipients.

BACKGROUND: The aim of this study was to demonstrate noninferiority of everolimus with reduced cyclosporine (CsA) vs mycophenolate mofetil (MMF) with reduced CsA in improving renal function. METHODS: In this 1-year randomized, open-label, noninferiority study in maintenance heart transplant recipients with impaired renal function 70 patients received everolimus (n = 36) or MMF (n = 34) in combination with reduced CsA. The planned sample size was not reached as the study was prematurely discontinued due to slow recruitment. RESULTS: Noninferiority of the everolimus regimen could not be shown: In the total population MMF seemed to be favorable on renal function assessed by serum creatinine and filtration rates, but not in the subset of patients who reached the intended reduced CsA level. Incidence rates of rejection episodes were significantly higher under MMF at month 6 (P = .0332). CONCLUSIONS: Overall, the results of this trial using reduced CsA in combination with either everolimus or MMF show that there is evidence to reduce the CsA level when everolimus is given concomitantly and that the benefit of MMF with reduced CsA levels is limited due to insufficient immunosuppression.

A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation--PROTECT.

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal-sparing alternative. In this randomized 1-year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post-LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft-Gault formula (-2.9 mL/min in favor of EVR, 95%-CI: [-10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (-7.8 mL/min, 95%-CI: [-14.366; -1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy-proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI-based to EVR-based immunosuppression proved to be a safe alternative post-LTx that deserves further investigation in terms of nephroprotection.

Enteric-coated mycophenolate-sodium in heart transplantation: efficacy, safety, and pharmacokinetic compared with mycophenolate mofetil.

Mycophenolic acid (MPA) is an effective immunosuppressive treatment for renal transplant recipients, but its effective use and best practice are not established in cardiac transplantation. This multicenter, single-blind, randomized, parallel group clinical trial prospectively evaluated the therapeutic equivalence of enteric-coated mycophenolate-sodium (EC-MPS) versus mycophenolate mofetil (MMF) in combination with cyclosporine (CyA) and steroids as determined by the primary objective of treatment efficacy during the first 6 months of treatment in 154 de novo heart transplant recipients. Both groups received equivalent doses of MPA, either 720 mg b.i.d EC-MPS or 1000 mg b.i.d MMF. EC-MPS showed a comparable efficacy and safety profile compared with MMF with significantly less dose reduction. Treatment failure occurred in 57.7% and 60.5% with EC-MPS and MMF, respectively, EC-MPS was therapeutically equivalent to MMF in cardiac transplantation.

C2 therapeutic drug monitoring of cyclosporine is a safe and feasible method in de novo heart transplant patients.

BACKGROUND: The narrow therapeutic window of cyclosporine (CsA) requires close therapeutic drug monitoring (TDM). While C2-TDM has been established after renal and liver transplantations, clinical experience is limited for patients after de novo heart transplantation (HTX). PATIENTS AND METHODS: In a retrospective study, we investigated 40 patients undergoing HTX; 34 patients received induction therapy using antithymocyte globulin (ATG Mérieux). Immunosuppression was administered with CsA (Sandimmun-Optoral), with dosages adjusted according to C2 levels (800-1100 ng/mL during the first 6 months and reduced to 400-600 ng/mL from the beginning of the first year). At different times TI (months 1-3). TII (months 12-14) TIII (months 24-26), and TIV (months 34-36), we obtained measures of acute cellular rejections (ARs), cytomegalovirus (CMV) infections, creatinine, and safety laboratory parameters. RESULTS: The cumulative survival was 95% after 1 year, and 88% after 3.8 years. Eight ARs were diagnosed at a mean of 7.6 months after HTX in 7 patients. Twenty-four CMV infections/reactivations were verified. In 10 cases, treatment was started because of clinical symptoms. The mean creatinine values significantly rose in the early postoperative phase (TI: 1.23+/-0.47 mg/dL, TII: 1.49+/-0.41 mg/dL; P<.0001). Thereafter the creatinine values declined; however, this was not statistically significant (TIII: 1.38+/-0.57 mg/dL, TIV: 1.15+/-0.30 mg/dL). All other safety parameters showed no significant changes. CONCLUSIONS: C2 allows individualization of immunosuppression with reduced CsA toxicity, but without loss in safety among de novo patients after HTX. We obtained freedom from severe AR, a low number of CMV infections, and excellent patient survival.

Effect of tropisetron on circulating catecholamines and other putative biochemical markers in serum of patients with fibromyalgia.

OBJECTIVE: The aim of the study was to assess the influence of the 5HT3-receptor antagonist tropisetron on circulating catecholamines as biochemical markers of the activity of the sympathoadrenal system in fibromyalgia. Moreover, serum concentrations of serotonin, somatomedin C, oxytocin, calcitonin-gene-related-peptide, calcitonin and cholecystokinin were assayed as putative markers in pain-related disorders like primary fibromyalgia. METHODS: In 96 patients, who met the ACR classification criteria for fibromyalgia, and in 20 sex and age matched controls concentrations of dopamine, noradrenaline, adrenaline, serotonin and tropisetron were assayed in serum by HPLC with electrochemical detection. All other transmitters were determined by ELISA. RESULTS: There was with the exception of tropisetron, calcitonin and dopamine, no correlation between doses of tropisetron 5, 10, 15 mg respectively and significant changes in circulating transmitters or other transmitters as putative biochemicals markers in primary fibromyalgia. Regarding the prediction of pain reduction to tropisetron, patients with elevated dopamine and/or reduced plasma 5-HT concentrations tended to show a higher response rate. CONCLUSION: Despite these partly disappointing results another prospective pilot study with selected patients vs. age and sex matched controls, double blind and with comparison of other 5HT3-receptor antagonists e.g. dolasetron and granisetron e.g. after i.v. bolus injection is suggested. Still the data obtained in this preliminary paper provide some evidence regarding the present discussion on subgroups of patients with primary fibromyalgia.