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Cellular Effects of Everolimus and Sirolimus on Podocytes  [PDF]
Sandra Müller-Krebs, Lena Weber, Julia Tsobaneli, Lars P. Kihm, Jochen Reiser, Martin Zeier, Vedat Schwenger
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080340
Abstract: Everolimus (EVL) and Sirolimus (SRL) are potent immunosuppressant agents belonging to the group of mammalian target of rapamycin (mTOR) inhibitors used to prevent transplant rejection. However, some patients develop proteinuria following a switch from a calcineurin inhibitor regimen to mTOR inhibitors. Whether different mTOR inhibitors show similar effects on podocytes is still unknown. To analyze this, human podocytes were incubated with different doses of EVL and SRL. After incubation with EVL or SRL, podocytes revealed a reduced expression of total mTOR. Phosphorylation of p70S6K and Akt was diminished, whereas pAkt expression was more reduced in the SRL group. In both groups actin cytoskeletal reorganization was increased. Synaptopodin and podocin expression was reduced as well as nephrin protein, particularly in the SRL group. NFκB activation and IL-6 levels were lower in EVL and SRL, and even lower in SRL. Apoptosis was more increased in SRL than in the EVL group. Our data suggests that mTOR inhibitors affect podocyte integrity with respect to podocyte proteins, cytoskeleton, inflammation, and apoptosis. Our study is the first to analyze both mTOR inhibitors, EVL and SRL, in parallel in podocytes. Partially, the impact of EVL and SRL on podocytes differs. Nevertheless, it still remains unclear whether these differences are of relevance regarding to proteinuria in transplant patients.
Everolimus: a review of its pharmacologic properties and use in solid organ transplantation  [cached]
Paul Huiras,Steven Gabardi
Reviews in Health Care , 2011, DOI: 10.7175/rhc.5624229-241
Abstract: The aim of this review article is to review the pharmacology, pharmacokinetics, efficacy and safety of everolimus. Primary literature was obtained via MEDLINE. Studies and abstracts evaluating everolimus in solid organ transplantation were considered for evaluation. English-language studies and abstracts only were selected for inclusion. Everolimus, a proliferation signal inhibitor that prevents growth factor-induced cell proliferation, is effective in reducing the incidence of acute rejection in solid organ transplantation. This agent is also useful in reducing cyclosporine-related nephrotoxicity. Everolimus directly inhibits vascular remodelling and intimal thickening, which are often associated with chronic rejection. Clinical trials have shown that everolimus is generally safe. The most commonly reported adverse events were haematologic effects and hyperlipidaemia. Everolimus is the second proliferation signal inhibitor to be proven effective in preventing acute rejection in solid organ transplant recipients. However, its exact role in the transplant immunosuppressive armamentarium is still unknown.
Everolimus in kidney transplantation
Cooper JE,Christians U,Wiseman AC
Transplant Research and Risk Management , 2011,
Abstract: James E Cooper1, Uwe Christians2, Alexander C Wiseman11Division of Renal Diseases and Hypertension, Transplant Center, 2iC42 Integrated Solutions in Systems Biology for Clinical Research and Development, University of Colorado Denver, Aurora, CO, USAAbstract: Everolimus is a novel target of rapamycin (mTOR)-I analog that has recently been approved in combination with cyclosporine A and steroids for use in the prevention of organ rejection in kidney transplant recipients. Compared with rapamycin, everolimus is characterized by a shorter half-life and improved bioavailability. Prior to US Food and Drug Administration approval, a number of Phase II and III clinical trials were undertaken to evaluate the effectiveness of everolimus in combination with calcineurin inhibitors for preventing acute rejection and promoting allograft survival in kidney transplant recipients. In this report, we review the pharmacokinetic properties of everolimus, the clinical efficacy studies that led to its approval for use in kidney transplantation, as well as reported data on patient safety and tolerability associated with its use.Keywords: mTOR inhibitors, kidney transplantation, everolimus
Everolimus in Heart Transplantation: An Update  [PDF]
Stephan W. Hirt,Christoph Bara,Markus J. Barten,Tobias Deuse,Andreas O. Doesch,Ingo Kaczmarek,Uwe Schulz,J?rg Stypmann,Assad Haneya,Hans B. Lehmkuhl
Journal of Transplantation , 2013, DOI: 10.1155/2013/683964
Abstract: The evidence base relating to the use of everolimus in heart transplantation has expanded considerably in recent years, providing clinically relevant information regarding its use in clinical practice. Unless there are special considerations to take into account, all de novo heart transplant patients can be regarded as potential candidates for immunosuppression with everolimus and reduced-exposure calcineurin inhibitor therapy. Caution about the use of everolimus immediately after transplantation should be exercised in certain patients with the risk of severe proteinuria, with poor wound healing, or with uncontrolled severe hyperlipidemia. Initiation of everolimus in the early phase aftertransplant is not advisable in patients with severe pretransplant end-organ dysfunction or in patients on a left ventricular assist device beforetransplant who are at high risk of infection or of wound healing complications. The most frequent reason for introducing everolimus in maintenance heart transplant patients is to support minimization or withdrawal of calcineurin inhibitor therapy, for example, due to impaired renal function or malignancy. Due to its potential to inhibit the progression of cardiac allograft vasculopathy and to reduce cytomegalovirus infection, everolimus should be initiated as soon as possible after heart transplantation. Immediate and adequate reduction of CNI exposure is mandatory from the start of everolimus therapy. 1. Introduction The mammalian target-of-rapamycin inhibitor (mTOR) everolimus has been licensed in Europe since 2004 for the prevention of organ rejection in adult patients at low to moderate immunological risk receiving an allogeneic kidney, liver or heart transplant. Everolimus is currently the only mTOR inhibitor approved for use in heart transplantation. It was developed to improve the pharmacokinetics of the mTOR inhibitor sirolimus through a stable 2-hydroxyethyl chain substitution at position 40 of the sirolimus molecule [1]. This change confers a shorter half-life, permitting faster reduction or elimination of everolimus exposure and obviating the need for a loading dose. In a pivotal double-blind phase 3 (B253) trial in de novo heart transplant recipients published in 2003, Eisen et al. demonstrated that everolimus provided equivalent immunosuppressive efficacy to azathioprine [2]. Inhibition of vascular smooth muscle cell proliferation by everolimus reduced intimal thickening and lowered the incidence of cardiac allograft vasculopathy (CAV). Based on these findings and early clinical experience in Germany and Austria,
Critical appraisal of the role of everolimus in advanced neuroendocrine tumors of pancreatic origin
Mulet-Margalef N, Capdevila J
Gastrointestinal Cancer: Targets and Therapy , 2012, DOI: http://dx.doi.org/10.2147/GICTT.S24826
Abstract: itical appraisal of the role of everolimus in advanced neuroendocrine tumors of pancreatic origin Review (986) Total Article Views Authors: Mulet-Margalef N, Capdevila J Published Date September 2012 Volume 2012:2 Pages 29 - 37 DOI: http://dx.doi.org/10.2147/GICTT.S24826 Received: 20 June 2012 Accepted: 25 July 2012 Published: 27 September 2012 Núria Mulet-Margalef, Jaume Capdevila Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain Abstract: For many years, the treatment of advanced pancreatic neuroendocrine tumors (pNETs) has been limited almost entirely to somatostatin analogs and streptozocin-based chemotherapy, with modest benefit. Increasing knowledge of the biologic features of pNETs has allowed the design of molecular-based clinical trials, which have taken a step forward in the management of these tumors. In this review, we discuss the molecular rationale for the development of everolimus for patients with advanced pNETs, critically review the clinical data obtained by the main studies in this setting, and discuss essential considerations based on recent findings in pNET biology for future drug development involving the phosphatidylinositol 3' kinase-AKT-mTOR pathway.
Everolimus in kidney transplantation
Cooper JE, Christians U, Wiseman AC
Transplant Research and Risk Management , 2011, DOI: http://dx.doi.org/10.2147/TRRM.S13782
Abstract: olimus in kidney transplantation Review (3358) Total Article Views Authors: Cooper JE, Christians U, Wiseman AC Published Date July 2011 Volume 2011:3 Pages 97 - 112 DOI: http://dx.doi.org/10.2147/TRRM.S13782 James E Cooper1, Uwe Christians2, Alexander C Wiseman1 1Division of Renal Diseases and Hypertension, Transplant Center, 2iC42 Integrated Solutions in Systems Biology for Clinical Research and Development, University of Colorado Denver, Aurora, CO, USA Abstract: Everolimus is a novel target of rapamycin (mTOR)-I analog that has recently been approved in combination with cyclosporine A and steroids for use in the prevention of organ rejection in kidney transplant recipients. Compared with rapamycin, everolimus is characterized by a shorter half-life and improved bioavailability. Prior to US Food and Drug Administration approval, a number of Phase II and III clinical trials were undertaken to evaluate the effectiveness of everolimus in combination with calcineurin inhibitors for preventing acute rejection and promoting allograft survival in kidney transplant recipients. In this report, we review the pharmacokinetic properties of everolimus, the clinical efficacy studies that led to its approval for use in kidney transplantation, as well as reported data on patient safety and tolerability associated with its use.
Critical appraisal of belatacept for prophylaxis of rejection in kidney transplant patients
Martin ST, Tsapepas D, Gabardi S, Chandraker A
Transplant Research and Risk Management , 2011, DOI: http://dx.doi.org/10.2147/TRRM.S11538
Abstract: itical appraisal of belatacept for prophylaxis of rejection in kidney transplant patients Review (3759) Total Article Views Authors: Martin ST, Tsapepas D, Gabardi S, Chandraker A Published Date April 2011 Volume 2011:3 Pages 65 - 75 DOI: http://dx.doi.org/10.2147/TRRM.S11538 Spencer T Martin1, Demetra Tsapepas1, Steven Gabardi2–5, Anil Chandraker2,3 1Department of Pharmacy, New York-Presbyterian Hospital, New York City, NY, USA; 2Harvard Medical School, Boston, MA, USA; 3Renal Division, 4Department of Pharmacy Services, 5Department of Transplant Surgery, Brigham and Women's Hospital, Boston, MA, USA Abstract: Belatacept (LEA29Y) is an intravenous biologic for long-term maintenance immunosuppressive therapy in renal transplant recipients. It is currently being reviewed by the United States Food and Drug Administration (FDA) as a prophylactic therapy against acute cellular rejection (ACR) in de novo renal transplant recipients. To provide an in-depth review of the pharmacology, clinical efficacy, safety, and applications of belatacept, a MEDLINE database search was performed for all English-language articles evaluating the pharmacology and efficacy of belatacept, as well as abstracts from recent scientific meetings. Belatacept is a potent inhibitor of B7 binding to CD28, a potent T-cell co-stimulatory signal. The B7 ligands are found on the surface of antigen-presenting cells, specifically B7-1 (CD80) and B7-2 (CD86). CD80 and CD86 are essential ligands for CD28, a critical component of costimulation in the three-signal transplant model of T-cell activation. Belatacept has proven noninferiority compared with calcineurin-inhibitor (CNI)-based regimens in the incidence of patient and allograft survival. However, the incidence and severity of ACR has been shown to be increased in patients receiving belatacept therapy. Although rates of ACR are increased in patients receiving belatacept, an overall improvement in allograft function has been described with average improvements in glomerular filtration rates of up to 12–15 mL/min higher than CNI-based regimens. The side-effect profile of belatacept has been shown to be similar or improved compared with CNI therapy; however, the risk of malignancy, specifically post-transplant lymphoproliferative disorder is notably higher. Because of the marked increase in the risk of malignancy and ACR, approval of belatacept by the FDA will rely on more robust data from long-term follow-up of currently available data.
Impact of everolimus: update on immunosuppressive therapy strategies and patient outcomes after renal transplantation
Helio Tedesco-Silva Jr,Claudia Rosso Felipe,Tainá Veras de Sandes Freitas,et al
Transplant Research and Risk Management , 2011,
Abstract: Helio Tedesco-Silva Jr, Claudia Rosso Felipe, Tainá Veras de Sandes Freitas, Marina Pontello Cristeli, Carolina Araújo Rodrigues, José Osmar Medina PestanaNephrology Division, Hospital do Rim e Hipertens o, Universidade Federal de S o Paulo, BrazilAbstract: Everolimus is an immunosuppressive agent used for the prophylaxis of acute rejection after kidney transplantation. Everolimus inhibits the activity of the serine/threonine kinase mammalian target of rapamycin (mTOR), a key enzyme that controls cell growth and metabolism, producing cell cycle arrest from the G1 to S phase. As a consequence, everolimus has antiproliferative and antineoplastic effects. Everolimus is a drug with a narrow therapeutic index. The pharmacokinetics of everolimus indicates a need for twice-daily dosing. Intra- and interindividual variability and drug–drug interactions suggest the need for therapeutic drug monitoring to maximize the efficacy/toxicity ratio. The good correlation between exposure (area under the concentration–time curve) and trough concentration indicates that monitoring of everolimus trough concentrations is an adequate strategy after kidney transplantation. Everolimus is indicated for low- to moderate-risk de novo kidney transplant candidates. There are no conclusive studies thus far indicating that everolimus can be used in high-risk patients, such as sensitized patients, retransplants, and African Americans. In de novo kidney transplant recipients, the recommended initial dose of everolimus is 0.75 mg twice daily, adjusted to maintain blood trough concentrations of 3–8 ng/mL, in combination with progressive reduction in blood trough cyclosporine concentrations to 25–50 ng/mL. In combination with reduced trough blood tacrolimus concentrations of 4–7 ng/mL the recommended initial dose of everolimus is 1.5 mg twice daily, adjusted to maintain trough blood concentrations of 3–8 ng/mL. Everolimus can also be used as a conversion strategy, mainly to preserve renal function and to manage patients with malignancy. There is no definition of the ideal strategy for conversion, ie, abrupt or sequential, initial dose of everolimus, or target therapeutic trough blood concentrations. Intensive monitoring is recommended after conversion, especially for acute rejection and proteinuria. Because mTOR is ubiquitous and central to many intracellular processes, an array of adverse reactions may occur, including delayed tissue regeneration, proteinuria, dyslipidemia, diabetes, myelosuppression, infertility, ovarian cysts, and mouth ulcers. Because long-term benefits are the goal of
Critical appraisal of the role of everolimus in advanced neuroendocrine tumors of pancreatic origin  [cached]
Mulet-Margalef N,Capdevila J
Gastrointestinal Cancer: Targets and Therapy , 2012,
Abstract: Núria Mulet-Margalef, Jaume CapdevilaMedical Oncology Department, Vall d'Hebron University Hospital, Barcelona, SpainAbstract: For many years, the treatment of advanced pancreatic neuroendocrine tumors (pNETs) has been limited almost entirely to somatostatin analogs and streptozocin-based chemotherapy, with modest benefit. Increasing knowledge of the biologic features of pNETs has allowed the design of molecular-based clinical trials, which have taken a step forward in the management of these tumors. In this review, we discuss the molecular rationale for the development of everolimus for patients with advanced pNETs, critically review the clinical data obtained by the main studies in this setting, and discuss essential considerations based on recent findings in pNET biology for future drug development involving the phosphatidylinositol 3' kinase-AKT-mTOR pathway.Keywords: pancreatic neuroendocrine tumors, everolimus, targeted therapies
Efficacy and Safety of Low-Dose Cyclosporine with Everolimus and Steroids in de novo Heart Transplant Patients: A Multicentre, Randomized Trial  [PDF]
Andreas Zuckermann,Shoei-Shen Wang,Heather Ross,Maria Frigerio,Howard J. Eisen,Christoph Bara,Daniel Hoefer,Maurizio Cotrufo,Gaohong Dong,Guido Junge,Anne M. Keogh
Journal of Transplantation , 2011, DOI: 10.1155/2011/535983
Abstract: A six-month, multicenter, randomized, open-label study was undertaken to determine whether renal function is improved using reduced-exposure cyclosporine (CsA) versus standard-exposure CsA in 199 de novo heart transplant patients receiving everolimus and steroids ± induction therapy. Mean C2 levels were at the low end of the target range in standard-exposure patients ( ) and exceeded target range in reduced-exposure patients ( ) throughout the study. Mean serum creatinine at Month 6 (the primary endpoint) was ? mol/L in standard-exposure patients versus ? mol/L in reduced-exposure patients ( ). The incidence of biopsy-proven acute rejection ≥3A at Month 6 was 21.0% (21/100) in the standard-exposure group and 16.2% (16/99) in the reduced-exposure group (n.s.). Adverse events and infections were similar between treatment groups. Thus, everolimus with reduced-exposure CsA resulted in comparable efficacy compared to standard-exposure CsA. No renal function benefits were demonstrated; that is possibly related to poor adherence to reduced CsA exposure. 1. Introduction One-year survival following cardiac transplantation has risen to approximately 85%, but long-term graft loss remains a significant problem with life expectancy 12 years after transplantation remaining at only 50% [1]. Late-term complications include renal dysfunction, malignancy, and cardiac allograft vasculopathy (CAV) [1–3]. In a randomized trial of everolimus versus azathioprine with standard-exposure cyclosporine (CsA) and steroids in de novo heart transplant recipients, use of everolimus significantly reduced coronary artery intimal proliferation, assessed by intravascular ultrasound, and the incidence of CAV up to 24 months [4, 5]. While everolimus is not associated with direct renal toxicity [6], it can potentiate CsA-related nephrotoxicity by P450 inhibition of CsA metabolism [7], and serum creatinine levels were higher among patients receiving everolimus in this study. This was found to be due to the use of fixed-dose administration of everolimus, instead of concentration-controlled dosing, and because CsA was given at a standard level of exposure [4]. Accordingly, everolimus dosing is now based on blood concentration and reduced CsA dosing is recommended in the maintenance phase to preserve renal function in cardiac transplant recipients receiving everolimus [8]. The efficacy and safety of everolimus with CNI minimization in maintenance thoracic transplant recipients has been demonstrated in the prospective NOCTET study [9] as well as in a single-arm pilot study [10, 11] and two
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