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Calcineurin inhibitors

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https://www.readbyqxmd.com/read/28432716/deciphering-tacrolimus-induced-toxicity-in-pancreatic-%C3%AE-cells
#1
J Triñanes, A E Rodriguez-Rodriguez, Y Brito, A Wagner, A P J De Vries, G Cuesto, A Acebes, E Salido, A Torres, E Porrini
β-cell transcription factors like: FoxO1, MafA, PDX-1, NeuroD, are dysfunctional in type 2 diabetes (T2DM). PTDM resembles T2DM and reflects interaction between pre-transplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors. We evaluated the effect of tacrolimus, cyclosporine-A and metabolic stressors (glucose+palmitate) on insulinoma β-cells (INS-1) in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for five days with 100μM palmitate and 22mM glucose; cyclosporin-A (250ng/mL) or tacrolimus (15ng/mL) were added the last 48h...
April 22, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28430812/nacl-cotransporter-abundance-in-urinary-vesicles-is-increased-by-calcineurin-inhibitors-and-predicts-thiazide-sensitivity
#2
Omar A Z Tutakhel, Arthur D Moes, Marco A Valdez-Flores, Marleen L A Kortenoeven, Mathijs V D Vrie, Sabina Jeleń, Robert A Fenton, Robert Zietse, Joost G J Hoenderop, Ewout J Hoorn, Luuk Hilbrands, René J M Bindels
Animal studies have shown that the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus can activate the thiazide-sensitive NaCl cotransporter (NCC). A common side effect of CNIs is hypertension. Renal salt transporters such as NCC are excreted in urinary extracellular vesicles (uEVs) after internalization into multivesicular bodies. Human studies indicate that CNIs also increase NCC abundance in uEVs, but results are conflicting and no relationship with NCC function has been shown. Therefore, we investigated the effects of CsA and Tac on the abundance of both total NCC (tNCC) and phosphorylated NCC at Thr60 phosphorylation site (pNCC) in uEVs, and assessed whether NCC abundance in uEVs predicts the blood pressure response to thiazide diuretics...
2017: PloS One
https://www.readbyqxmd.com/read/28429555/management-of-mineral-and-bone-disorders-in-renal-transplant-recipients
#3
Matthew J Damasiewicz, Peter R Ebeling
The management of post-transplantation bone disease is a complex problem that remains under-appreciated in clinical practice. In these patients, pre-existing metabolic bone disorder is further impacted by the use of immunosuppressive medications (glucocorticoids and calcineurin-inhibitors), variable post-transplantation renal allograft function and post-transplantation diabetes mellitus. The treatment of post-transplantation bone loss should begin pre-transplantation. All patients active on transplant waiting lists should be screened for bone disease...
March 2017: Nephrology
https://www.readbyqxmd.com/read/28426152/donor-specific-alloreactive-t-cells-can-be-quantified-from-whole-blood-and-may-predict-cellular-rejection-after-renal-transplantation
#4
Michaela Fischer, Sarah Leyking, Marco Schäfer, Julia Elsäßer, Martin Janssen, Janine Mihm, Kai van Bentum, Danilo Fliser, Martina Sester, Urban Sester
Preformed cellular alloreactivity can exist prior to transplantation and may contribute to rejection. Here, we used a rapid flow-cytometric whole-blood assay to characterize the extent of alloreactive T cells among 1491 stimulatory reactions from 61 renal transplant candidates and 75 controls. The role of preformed donor-specific alloreactive T cells in cellular rejection was prospectively analyzed in 21 renal transplant recipients. Alloreactive CD8(+) T cells were more frequent than respective CD4(+) T cells, and these levels were stable over time...
April 20, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28425200/high-dose-calcineurin-inhibitor-free-everolimus-as-a-maintenance-regimen-for-heart-transplantation-may-be-a-risk-factor-for%C3%A2-pneumocystis-pneumonia
#5
Yu-Ning Hu, Nan-Yao Lee, Jun-Neng Roan, Chi-Hsin Hsu, Chwan-Yao Luo
BACKGROUND: Everolimus reduces the incidence of cardiac-allograft vasculopathy (CAV) and is less renally toxic than are calcineurin inhibitors (CNIs). We evaluated the safety of CNI-free everolimus for post-heart transplant (HTx) patients. METHODS: We retrospectively reviewed the records of 36 consecutive patients who had undergone an HTx between January 2006 and December 2013 in National Cheng Kung University Hospital. All patients initially had been treated with the standard tacrolimus regimen...
April 20, 2017: Transplant Infectious Disease: An Official Journal of the Transplantation Society
https://www.readbyqxmd.com/read/28422926/targeting-high-calcineurin-inhibitor-levels-after-acute-rejection-with-less-tremor-a-new-strategy
#6
Tarek Alhamad, Karthikeyan Venkatachalam, Reem Daloul, Daniel Brennan, Andrew Malone
No abstract text is available yet for this article.
April 18, 2017: Transplantation
https://www.readbyqxmd.com/read/28418433/capsaicin-presynaptically-inhibits-glutamate-release-through-the-activation-of-trpv1-and-calcineurin-in-the-hippocampus-of-rats
#7
Cheng Wei Lu, Tzu Yu Lin, Ting Yang Hsie, Shu Kuei Huang, Su Jane Wang
Capsaicin is the major ingredient in hot peppers of the plant Capsicum genus with neuroprotective effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus using isolated nerve terminals (synaptosomes) and brain slices. In a synaptosomal preparation, capsaicin dose-dependently reduced 4-aminopyridine-evoked Ca(2+)-dependent glutamate release, with an IC50 of approximately 11 μM. This inhibition was blocked by capsazepin, an antagonist of TRPV1, which was found to be colocalized with the vesicle marker protein synaptophysin in synaptosomes using double immunostaining...
April 18, 2017: Food & Function
https://www.readbyqxmd.com/read/28418012/cyp3a4-is-a-crosslink-between-vitamin-d-and-calcineurin-inhibitors-in-solid-organ-transplant-recipients-implications-for-bone-health
#8
REVIEW
A Prytuła, K Cransberg, A Raes
The use of calcineurin inhibitors (CNIs) and vitamin D deficiency may contribute to the pathogenesis of post-transplant bone disease. CNIs and 1,25-dihydroxyvitamin D₃ (1,25(OH)2D3) are substrates of the drug-metabolizing enzyme CYP3A4. This review summarizes the indications for the use of activated vitamin D analogs in post-transplant care and the current knowledge on the impact of CNIs on bone. We searched for clinical evidence of the interaction between CNIs and 1,25(OH)2D3. We also provide an overview of the literature on the interplay between vitamin D metabolism and CYP3A4 in experimental and clinical settings and discuss its possible implications for solid organ transplant recipients...
April 18, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28417553/calcineurin-inhibitor-free-strategies-for-prophylaxis-and-treatment-of-gvhd-in-children-with-posterior-reversible-encephalopathy-syndrome-after-stem-cell-transplantation
#9
Vered Shkalim-Zemer, Osnat Konen, Yoel Levinsky, Orli Michaeli, Anat Yahel, Aviva Krauss, Isaac Yaniv, Jerry Stein
BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a distinct clinico-radiologic entity that can occur following allogeneic hematopoietic stem cell transplantation, often in the context of treatment with calcineurin inhibitors (CNIs). PROCEDURE: We describe the results of CNI-free management of 14 children with PRES and review the clinical and radiologic manifestations of their presentation. RESULTS: Discontinuation of CNIs usually resulted in remission of PRES, but patients with established graft versus host disease (GVHD) at the time when treatment was changed often experienced progressive GVHD despite administration of immune suppressive and modulating treatments...
April 18, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28414804/cyclosporine-a-alters-expression-of-renal-micrornas-new-insights-into-calcineurin-inhibitor-nephrotoxicity
#10
Jennifer L Gooch, Clayton King, Cynthia E Francis, Paul S Garcia, Yun Bai
Calcineurin inhibitors are powerful immunosuppressants that revolutionized organ transplantation. However, non-immune effects of the calcineurin inhibitor, such as cyclosporine A (CsA), have significantly hindered their use. Specifically, nephrotoxicity, which is associated with tubulointerstitial fibrosis, inflammation, and podocyte damage, affects up to half of all transplant patients. Calcineurin is involved in many aspects of kidney development and function; therefore, mechanisms of CsA-induced nephrotoxicity are complex and not yet fully understood...
2017: PloS One
https://www.readbyqxmd.com/read/28414795/negative-feedback-loop-of-bone-resorption-by-nfatc1-dependent-induction-of-cadm1
#11
Shinya Nakamura, Takuma Koyama, Naohiro Izawa, Seitaro Nomura, Takanori Fujita, Yasunori Omata, Takashi Minami, Morio Matsumoto, Masaya Nakamura, Eriko Fujita-Jimbo, Takashi Momoi, Takeshi Miyamoto, Hiroyuki Aburatani, Sakae Tanaka
Trimethylation of histone H3 lysine 4 and lysine 27 (H3K4me3 and H3K27me3) at gene promoter regions critically regulates gene expression. Key developmental genes tend to exhibit changes in histone modification patterns from the H3K4me3/H3K27me3 bivalent pattern to the H3K4me3 monovalent pattern. Using comprehensive chromatin immunoprecipitation followed by sequencing in bone marrow-derived macrophages (BMMs) and mature osteoclasts, we found that cell surface adhesion molecule 1 (Cadm1) is a direct target of nuclear factor of activated T cells 1 (NFATc1) and exhibits a bivalent histone pattern in BMMs and a monovalent pattern in osteoclasts...
2017: PloS One
https://www.readbyqxmd.com/read/28412754/efficacy-and-safety-of-a-reduced-calcineurin-inhibitor-dose-combined-with-mycophenolate-mofetil-in-liver-transplant-patients-with-chronic-renal-dysfunction
#12
Pusen Wang, Weitao Que, Hao Li, Lvnan Yan, Zhiren Fu, Qifa Ye, Guihua Chen, Kefeng Dou, Shichun Lu, Zhanyu Yang, Zhijun Zhu, Zhihai Peng, Lin Zhong
Calcineurin inhibitors (CNIs) are frequently given at a reduced dose in combination with mycophenolate mofetil (MMF) to avoid nephrotoxicity, but the optimal reduction in CNI dose has not been established. In this prospective, open-label, multicenter study, liver transplant recipients with chronic renal dysfunction who were administered a CNI-based immunosuppressive regimen were included in the intent-to-treat (ITT) population. The primary endpoint was declination in renal function, which was defined as a ≥ 20% decrease in the glomerular filtration rate during the year following regimen adjustment...
February 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28412204/a-calcineurin-antifungal-strategy-with-analogs-of-fk506
#13
Mitchell Nambu, Jonathan A Covel, Mili Kapoor, Xiaoming Li, Molly K Moloney, Mehdi M Numa, Quinlyn A Soltow, Michael Trzoss, Peter Webb, Robert R Webb, Mitchell Mutz
A novel antifungal strategy targeting the inhibition of calcineurin is described. To develop a calcineurin based inhibitor of pathogenic fungi, analogs of FK506 were synthesized that were able to permeate mammalian but not fungal cells. Antagonists in combination with FK506 were not immunosuppressive and retained antifungal activity in A. fumigatus. To reduce the dosage burden of the antagonist, murine oral PK was improved an order of magnitude relative to previous FK506 antagonists.
April 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28407449/drug-interactions-and-safety-profiles-with-concomitant-use-of-caspofungin-and-calcineurin-inhibitors-in-allogeneic-hematopoietic-cell-transplantation
#14
Mitsutaka Nishimoto, Hideo Koh, Atsushi Tokuwame, Yousuke Makuuchi, Masatomo Kuno, Teruhito Takakuwa, Hiroshi Okamura, Shiro Koh, Takuro Yoshimura, Satoru Nanno, Mika Nakamae, Asao Hirose, Yasuhiro Nakashima, Takahiko Nakane, Masayuki Hino, Hirohisa Nakamae
AIM: Small-scale clinical studies have reported on drug interactions between caspofungin (CPFG) and calcineurin inhibitors in healthy subjects; however, little is known about these interactions in allogeneic hematopoietic cell transplantation (allo-HCT) patients. METHODS: We retrospectively assessed the drug interactions and safety profiles in allo-HCT recipients treated concomitantly with CPFG and calcineurin inhibitors. RESULTS: Ninety-one consecutive cases were evaluated...
April 13, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28405602/cognitive-evaluation-in-liver-transplant-patients-under-calcineurin-inhibitor-maintenance-therapy
#15
Nils Heits, Dalibor Keserovic, Niclas Mund, Nicola Ehmke, Alexander Bernsmeier, Alexander Hendricks, Rainer Gunther, Karsten Witt, Thomas Becker, Felix Braun
BACKGROUND: Neurological disorders due to calcineurin inhibitor (CNI) treatment pose a well-known problem after liver transplantation (LTx). In this study, the impact of CNIs on cognitive functioning during maintenance therapy was analyzed. A possible improvement of cognitive functioning, compliance and health-related quality of life (HRQoL) after conversion to a once-daily tacrolimus formulation was prospectively assessed. METHODS: In a cross-section analysis cognitive functioning of living donors (LD), waiting list patients and LTx patients was tested using a 4 times trail making test (4-TTMT)...
April 2017: Transplantation Direct
https://www.readbyqxmd.com/read/28403127/a-randomized-controlled-clinical-trial-comparing-belatacept-with-tacrolimus-after-de-novo-kidney-transplantation
#16
Gretchen de Graav, Carla C Baan, Marian C Clahsen-van Groningen, Rens Kraaijeveld, Marjolein Dieterich, Wenda Verschoor, Jan H von der Thusen, Dave L Roelen, Monique Cadogan, Jacqueline van de Wetering, Joost van Rosmalen, Wilem Weimar, Dennis A Hesselink
BACKGROUND: Belatacept, an inhibitor of the CD28-CD80/86 co-stimulatory pathway, allows for calcineurin-inhibitor free immunosuppressive therapy in kidney transplantation but is associated with a higher acute rejection risk than ciclosporin. Thus, no biomarker for belatacept-resistant rejection has been validated. In this randomized controlled trial, acute rejection-rate was compared between belatacept- and tacrolimus-treated patients and immunological biomarkers for acute rejection were investigated...
April 11, 2017: Transplantation
https://www.readbyqxmd.com/read/28391333/clinical-trials-in-minimal-change-disease
#17
Pietro Ravani, Enrica Bertelli, Simardeep Gill, Gian Marco Ghiggeri
Minimal change disease (MCD) is a pathological condition characterized by subtle glomerular lesions causing massive and reversible proteinuria that is usually steroid sensitive. Recurrence of symptoms of active disease following successful treatment (including proteinuria, oedema and oliguria) and steroid toxicity requires the use of other drugs to attain or maintain remission. Unresolved MCD is considered the initial step in the pathological pathway leading to focal and segmental glomerulosclerosis (FSGS)...
January 1, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28386128/g-protein-coupled-receptor-15-mediates-angiogenesis-and-cytoprotective-function-of-thrombomodulin
#18
Bin Pan, Xiangmin Wang, Chie Nishioka, Goichi Honda, Akihito Yokoyama, Lingyu Zeng, Kailin Xu, Takayuki Ikezoe
Thrombomodulin (TM) stimulates angiogenesis and protects vascular endothelial cells (ECs) via its fifth epidermal growth factor-like region (TME5); however, the cell surface receptor that mediates the pro-survival signaling activated by TM has remained unknown. We applied pull-down assay followed by MALDI-TOF MS and western blot analysis, and identified G-protein coupled receptor 15 (GPR15) as a binding partner of TME5. TME5 rescued growth inhibition and apoptosis caused by calcineurin inhibitor FK506 in vascular ECs isolated from wild type (WT) C57BL/6 mice...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28383548/mir-146a-facilitates-osteoarthritis-by-regulating-cartilage-homeostasis-via-targeting-camk2d-and-ppp3r2
#19
Xudong Zhang, Chuandong Wang, Jingyu Zhao, Jiajia Xu, Yiyun Geng, Liming Dai, Yan Huang, Sai-Chuen Fu, Kerong Dai, Xiaoling Zhang
Osteoarthritis (OA), characterized by insufficient extracellular matrix synthesis and cartilage degeneration, is known as an incurable disease because its pathogenesis is poorly elucidated. Thus far, limited information is available regarding the pathophysiological role of microRNAs (miRNAs) in OA. In this study, we investigated the specific function of miR-146a in OA pathophysiology using mouse OA models. We found that the articular cartilage degeneration of miR-146a knockout (KO) mice was alleviated compared with that of the wild-type (WT) mice in spontaneous and instability-induced OA models...
April 6, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28382751/treatment-of-hcv-infection-in-liver-transplant-recipients-with-ledipasvir-and-sofosbuvir-without-ribavirin
#20
A A Pillai, R Maheshwari, R Vora, J P Norvell, R Ford, S Parekh, N Cheng, A Patel, N Young, J R Spivey, O Mgbemena, J P Wedd
BACKGROUND: Ledipasvir and Sofosbuvir is a well-tolerated regimen with high sustained virological response (SVR) rates in pre-liver transplant patients infected with chronic hepatitis C virus (HCV), but data in liver transplant recipients outside of clinical trials is limited. AIMS: To address this knowledge gap and assess SVR rates without the use of ribavirin in liver transplant recipients METHODS: This is a retrospective study examining the treatment of 75 post-liver transplant recipients with ledipasvir and sofosbuvir without ribavirin...
April 6, 2017: Alimentary Pharmacology & Therapeutics
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