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sirolimus to tacrolimus

Lucy Chen, Lisa Liberatore, Tom Chin, Scott Walker, Helen Fanous, Michelle M Nash, Lindita Rapi, Jennie Huckle, Jeffrey S Zaltzman, G V Ramesh Prasad
BACKGROUND: Ensuring reliable gastrointestinal drug absorption of orally-administered immunosuppressive medications posttransplant is critical to ensuring graft survival. METHODS: A 66 year old man of East Asian origin with a previous total gastrectomy was evaluated for living donor kidney transplantation. Pretransplant pharmacokinetic testing was performed to determine the most appropriate posttransplant medication strategy. The Gastrointestinal Quality of Life Index and Gastrointestinal Rating Scale questionnaires were administered to gauge immunosuppressive medication-related side effects in the absence of a stomach...
September 29, 2016: Transplantation
Jian Jin, Sun Woo Lim, Long Jin, Ji Hyun Yu, Hyun Seon Kim, Byung Ha Chung, Chul Woo Yang
Background/Aims: Metformin (MET) is a first-line drug for type 2 diabetes mellitus (DM); its effect on new-onset diabetes after transplantation caused by immunosuppressant therapy is unclear. We compared the effects of MET on DM caused by tacrolimus (TAC) or sirolimus (SRL). Methods: DM was induced by injection of TAC (1.5 mg/kg) or SRL (0.3 mg/kg) for 2 weeks in rats, and MET (200 mg/kg) was injected for 2 more weeks. The effects of MET on DM caused by TAC or SRL were evaluated using an intraperitoneal glucose tolerance test (IPGTT) and by measuring plasma insulin concentration, islet size, and glucose-stimulated insulin secretion (GSIS)...
September 30, 2016: Korean Journal of Internal Medicine
Johan Törlén, Olle Ringdén, Karin Garming-Legert, Per Ljungman, Jacek Winiarski, Kari Remes, Maija Itälä-Remes, Mats Remberger, Jonas Mattsson
Improvement of graft-versus-host disease prophylaxis remains an important goal in allogeneic hematopoietic stem cell transplantation. Based on reports of possibly preferential properties of sirolimus, we compared the standard regimen of cyclosporine and methotrexate (n=106) with a combination of tacrolimus and sirolimus (n=103) as graft-versus host disease prophylaxis after allogeneic hematopoietic stem cell transplantation in a prospective, open, randomized trial. The hypothesis was that the tacrolimus/sirolimus regimen would lead to less acute graft-versus-host disease and reduced transplant-related mortality...
August 4, 2016: Haematologica
Vikas R Dharnidharka, Mark A Schnitzler, Jiajing Chen, Daniel C Brennan, David Axelrod, Dorry L Segev, Kenneth B Schechtman, Jie Zheng, Krista L Lentine
We examined integrated national transplant registry, pharmacy fill and medical claims data for Medicare-insured kidney transplant recipients in 2000-2011 (n=45,164) from the United States Renal Data System to assess efficacy and safety endpoints associated with 7 early (first 90 days) immunosuppression (ISx) regimens. Risks of clinical complications over 3 years according to IS regimens were assessed with multivariate regression, including adjustment for covariates and propensity for receipt of a non-reference ISx regimen...
August 26, 2016: Transplant International: Official Journal of the European Society for Organ Transplantation
Elena Navarro-Villarán, José Tinoco, Granada Jiménez, Sheila Pereira, Jize Wang, Sara Aliseda, María A Rodríguez-Hernández, Raúl González, Luís M Marín-Gómez, Miguel A Gómez-Bravo, Francisco J Padillo, José M Álamo-Martínez, Jordi Muntané
Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with potential portal hypertension and/or bilirubinemia, but without vascular-associated diseases. The patients are receiving immunosuppressive therapy to reduce graft rejection, but differential side effects have been related to calcineurin and mTOR inhibitor administration regarding tumor recurrence and nephrotoxicity. The in vitro studies showed that Tacrolimus exerted a more potent pro-apoptotic effect than Everolimus (Huh 7>Hep 3B>HepG2), being sirolimus only active in Hep3B cell line...
2016: PloS One
Helio Tedesco-Silva, V Ram Peddi, Ana Sánchez-Fructuoso, Brad A Marder, Graeme R Russ, Fritz Diekmann, Alison Flynn, Carolyn M Hahn, Huihua Li, Michael A Tortorici, Seth L Schulman
UNLABELLED: Calcineurin inhibitor-associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients. METHODS: This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus...
April 2016: Transplantation Direct
Suleiman Al-Hammadi, Saeeda Almarzooqi, Alia Albawardi, Abdul-Kader Souid
BACKGROUND: Blocking mTOR (molecular target of rapamycin) by sirolimus has been shown to suppress cellular respiration. The bearing of this impaired cellular bioenergetics on the mode-of-action of mTOR inhibitors has yet to be illustrated. METHODS: This study investigated in vitro effects of several molecularly-targeted therapies on O2 consumption in thymic fragments from C57BL/6 mice. RESULTS: Thymocyte respiration (µM O2 min(-1) mg(-1)) was reduced by sirolimus and everolimus (p ≤ 0...
2015: Experimental Hematology & Oncology
Anton Pohanka, Staffan Rosenborg, Jonatan D Lindh, Olof Beck
A liquid chromatography-tandem mass spectrometry method is presented that was applied for over five years for routine measurement of the immunosuppressant drugs ciclosporin, everolimus, sirolimus and tacrolimus in blood. The method has been used for analysis of 142 thousand unknowns and has been running 7days a week without a single day shutdown during the entire time. The measuring ranges were 10-1500ng/mL for ciclosporin and 1-50ng/mL for everolimus, sirolimus and tacrolimus. The method validation showed performance meeting the EMA validation guideline requirements and acceptable performance in a proficiency control program...
September 2016: Clinical Biochemistry
Andrei Alexandru Constantinescu, Malak Abbas, Mohamad Kassem, Céline Gleizes, Guillaume Kreutter, Valerie Schini-Kerth, Ioan Liviu Mitrea, Florence Toti, Laurence Kessler
To examine and compare the mitochondria-related cellular mechanisms by which tacrolimus (TAC) or sirolimus (SIR) immunosuppressive drugs alter the pancreatic exocrine and endocrine β-cell fate. Human exocrine PANC-1 and rat endocrine insulin-secreting RIN-m5F cells and isolated rat islets were submitted to 1-100 nM TAC or SIR. In cultures, insulin secretion was measured as endocrine cell function marker. Apoptosis was quantified by annexin 5 and propidium iodide staining. Cleaved caspase-3, Bax apoptosis indicators, and p53, p21 cell cycle regulators were detected by Western blot...
July 2016: Molecular and Cellular Biochemistry
Chie Emoto, Alexander A Vinks, Tsuyoshi Fukuda
BACKGROUND: Sirolimus is a mammalian target of rapamycin inhibitor that is being used to prevent organ rejection in kidney transplant patients often in combination with calcineurin inhibitors (CNIs; cyclosporine and tacrolimus). All 3 drugs are metabolized primarily by CYP3As. Clinical drug-drug interaction (DDI) studies of cyclosporine on sirolimus pharmacokinetics have been reported; however, there are a few clinical DDI data related to tacrolimus. METHODS: In vitro inhibition assay with sirolimus were conducted using recombinant CYP3As and human microsomes in the presence and absence of CNIs...
October 2016: Therapeutic Drug Monitoring
Helio Tedesco Silva, Claudia Rosso Felipe, Jose Osmar Medina Pestana
Here, we review 15 years of clinical use of sirolimus in our transplant center, in context with the developing immunosuppressive strategies use worldwide. The majority of studies were conducted in de novo kidney transplant recipients, using sirolimus (SRL) in combination with calcineurin inhibitors (CNIs). We also explored steroid (ST) or CNI-sparing therapies, including CNI minimization, elimination, or conversion strategies in combination with mycophenolate (MMF/MPS). Pooled long-term outcomes were comparable with those obtained with CNI and antimetabolite combination...
2015: Transplantation Research
Josh Levitsky, Joshua Miller, Xuemei Huang, Lorenzo Gallon, Joseph R Leventhal, James M Mathew
Everolimus (EVL) is a novel mTOR-inhibitor similar to sirolimus (SRL) that is used in organ transplant recipients, often in combination with tacrolimus (TAC) or mycophenolate (MPA). The current study aims to determine its effects on regulatory T cells. Increasing concentrations of EVL, MPA and TAC alone or in combination were added to MLRs of healthy volunteers. Lymphoproliferation by 3H-TdR incorporation and the percentage of newly generated CD4+CD127-CD25+FOXP3+ (total Treg) and CD4+CD127-CD25HighFOXP3+ (natural Treg) in CFSE labeled responder cells were assessed by flow cytometry...
2016: PloS One
Nazmi Mutlu Karakas, Ilkay Erdogan, Beril Ozdemir, Atilla Sezgin
For patients with late congenital heart diseases and advanced heart failure, heart transplant is the one of the most effective known treatment methods. With the development of immunosuppressive medicines, it is possible to prevent and treat rejection, and survival after organ transplant has increased rapidly. Calcineurin inhibitors (tacrolimus and cyclosporine), mycophenolate mofetil, and corticosteroids are used together in many centers as immunosuppressive medications. Although the use of calcineurin inhibitors is essential, therapy is switched to sirolimus in some specific cases and when significant adverse effects occur...
May 17, 2016: Experimental and Clinical Transplantation
Fernando Bril, Veronica Castro, Ignacio G Centurion, Jeronimo Espinosa, Guillermo A Keller, Claudio D Gonzalez, Maria C Soler Riera, Cristian L Saubidet, Guillermo Di Girolamo, Gervasio S Pujol, Paulino A Alvarez
AIM: Renal transplant patients are frequently subject to polypharmacy and drug-drug interactions. However, no previous study has systematically assessed the risk of drug interactions and Adverse Drug Reactions (ADRs) in this population. METHODS: A total of 138 consecutive adult kidney transplant recipients admitted to our hospital between August 2010 and February 2012 were prospectively and systematically assessed by our pharmacovigilance team, within 24 hours of admission, to identify potential drug-drug interactions and probable ADRs...
2016: Current Drug Safety
Jie Zhou, Zhenhua Hu, Qijun Zhang, Zhiwei Li, Jie Xiang, Sheng Yan, Jian Wu, Min Zhang, Shusen Zheng
BACKGROUND: De novo malignancies occur after liver transplantation because of immunosuppression and improved long-term survival. But the spectrums and associated risk factors remain unclear. AIMS: To describe the overall pattern of de novo cancers in liver transplant recipients. METHODS: Data from Scientific Registry of Transplant Recipients from October 1987 to December 2009 were analyzed. The spectrum of de novo cancer was analyzed and logistic-regression was used to identify predictors of do novo malignancies...
2016: PloS One
E J Lim, R Chin, U Nachbur, J Silke, Z Jia, P W Angus, J Torresi
In recurrent hepatitis C (HCV) post-liver transplantation (OLT), the combination of immunosuppressants and HCV is postulated to increase hepatocyte apoptosis and liver fibrosis. We evaluated hepatocyte apoptosis within the liver tissue of patients with postOLT HCV recurrence compared to HCV-negative individuals and correlated these findings with the effects of immunosuppressants on HCV-induced cell death and its inhibition in primary mouse hepatocytes (PMoH). Liver biopsies from patients with and without HCV were evaluated by immunohistochemistry for markers of apoptosis M30 CytoDEATH (M30) and cleaved PARP (clPARP)...
September 2016: Journal of Viral Hepatitis
J A García-Bello, E G Romo-Del Río, E Mendoza-Gómez, P A Camarena-Arias, M Santos-Caballero
BACKGROUND: Cardiovascular disease (CVD) is the second major cause of death in kidney-transplanted children. Cardiovascular risk factors (CVRF) prevalence after transplant may increase. The effect of immunosuppressive therapy has not been fully studied in children. The objective of the study was to measure and compare CVRF prevalence in kidney-transplanted children, depending of immunosuppressive therapy. METHODS: The study was an observational, transversal, retrospective, comparative study of pediatric patients transplanted at UMAE Hospital General Centro Medico La Raza...
March 2016: Transplantation Proceedings
Guillaume Deslandes, Matthieu Grégoire, Christian Renaud, Catherine Monteil-Ganière, Claudine Azoulay, Alain Pineau, Pascale Jolliet, Eric Dailly
BACKGROUND: The whole blood extraction for liquid chromatography tandem mass spectrometry (LC-MS/MS) of simultaneous quantification of cyclosporine A (Cys A), tacrolimus (Tacrs), sirolimus (Siros), and everolimus (Evers) is still performed manually in many laboratories. The analytical results obtained with an automated method using a liquid handler versus a classical manual preparation were compared. METHODS: Cys A (n = 36), Tacrs (n = 50), Siros (n = 34), Evers (n = 38) whole blood samples of patients were analyzed by LC-MS/MS assay after manual preparation and automated process using a liquid handling platform including a centrifugation step...
April 18, 2016: Journal of Clinical Laboratory Analysis
Thomas Jouve, Lionel Rostaing, Paolo Malvezzi
CONTEXT: BK virus (BKV) viremia and BKV-associated nephropathy (BKVAN) have become a serious nuisance to kidney transplant (KT) patients since the mid-nineties, when the incidence of this disease has increased significantly. EVIDENCE ACQUISITION: Directory of open access journals (DOAJ), EMBASE, Google Scholar, PubMed, EBSCO, and Web of Science have been searched. RESULTS: Many hypothesis have been made as to why this phenomenon has developed; it is of general opinion that a more potent immunosuppression is at the core of the problem...
January 2016: Journal of Nephropathology
Ibrahim Aldoss, Ni-Chun Tsai, Marilyn L Slovak, Joycelynne Palmer, Joseph Alvarnas, Guido Marcucci, Stephen J Forman, Vinod Pullarkat
The prognostic relevance of cytogenetics at diagnosis on the outcome of allogeneic hematopoietic stem cell transplantation (alloHCT) for adult acute lymphoblastic leukemia (ALL) remains unclear. We retrospectively analyzed outcomes of 333 adult ALL patients who underwent alloHCT at our institution over a 10-year period. Patients were classified according to disease status at transplantation (complete response [CR] 1 [n = 202] or > CR1) and according to cytogenetic risk, defined as good (2%), intermediate (42%), poor (46%), or unknown (10%) based on available outcome data for each of the cytogenetic abnormalities...
July 2016: Biology of Blood and Marrow Transplantation
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