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https://www.readbyqxmd.com/read/29779093/pharmacokinetics-of-the-novel-selective-non-steroidal-mineralocorticoid-receptor-antagonist-finerenone-in-healthy-volunteers-results-from-an-absolute-bioavailability-study-and-drug-drug-interaction-studies-in-vitro-and-in-vivo
#1
Roland Heinig, Michael Gerisch, Anna Engelen, Johannes Nagelschmitz, Stephanie Loewen
BACKGROUND AND OBJECTIVES: Finerenone is a selective, non-steroidal mineralocorticoid receptor antagonist. In vivo and in vitro studies were performed to assess absolute bioavailability of finerenone, the effect of metabolic enzyme inhibitors on the pharmacokinetics of finerenone and its metabolites, the quantitative contribution of the involved enzymes cytochrome P450 (CYP) 3A4 and CYP2C8 and the relevance of gut wall versus liver metabolism. METHODS: The pharmacokinetics, safety and tolerability of finerenone (1...
May 19, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29778695/corticosteroids-and-perinatal-hypoxic-ischemic-brain-injury
#2
REVIEW
Katherine R Concepcion, Lubo Zhang
Perinatal hypoxic-ischemic (HI) brain injury is the major cause of neonatal mortality and severe long-term neurological morbidity. Yet, the effective therapeutic interventions currently available are extremely limited. Corticosteroids act on both mineralocorticoid (MR) and glucocorticoid (GR) receptors and modulate inflammation and apoptosis in the brain. Neuroinflammatory response to acute cerebral HI is a major contributor to the pathophysiology of perinatal brain injury. Here, we give an overview of current knowledge of corticosteroid-mediated modulations of inflammation and apoptosis in the neonatal brain, focusing on key regulatory cells of the innate and adaptive immune response...
May 17, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29777284/current-drug-therapy-for-heart-failure-with-reduced-ejection-fraction
#3
D Berliner, M Hallbaum, J Bauersachs
The prevalence of heart failure has been steadily increasing during the past few years, with a further increase predicted in the years to come. Without treatment, the syndrome of heart failure has a very poor prognosis. Advances in drug treatments and the consequent implementation of a guideline-recommended drug therapy have significantly improved the prognosis in heart failure with reduced ejection fraction (HFrEF). Besides angiotensin-converting enzyme (ACE) inhibitors (ACEi) or angiotensin receptor blockers, beta-blockers and diuretics treatment with mineralocorticoid receptor antagonists and ivabradine have become standard in the therapy of symptomatic patients with HFrEF...
May 18, 2018: Herz
https://www.readbyqxmd.com/read/29767448/development-and-validation-of-a-fast-and-sensitive-uhplc-esi-ms-method-for-the-simultaneous-quantification-of-spironolactone-and-its-metabolites-in-ocular-tissues
#4
Naoual Dahmana, Doris Gabriel, Robert Gurny, Yogeshvar N Kalia
Glucocorticoids are a mainstay for the treatment of immune-mediated conditions and inflammatory diseases. However, their chronic use causes numerous side-effects including delays in corneal and cutaneous wound healing. This is attributed to off-target agonism of the mineralocorticoid receptor, which can be reduced by co-administration of a mineralocorticoid receptor antagonist such as spironolactone. The aim of this study was to develop a fast, selective and sensitive UHPLC-ESI-MS method for the simultaneous quantification of spironolactone, its active metabolites - 7α-thiomethylspironolactone and canrenone, the latter's water-soluble prodrug potassium canrenoate, and the synthetic glucocorticoid, dexamethasone, in corneal samples (17α-methyltestosterone served as an internal standard)...
May 16, 2018: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/29764284/role-of-glucocorticoid-negative-feedback-in-the-regulation-of-hpa-axis-pulsatility
#5
Julia K Gjerstad, Stafford L Lightman, Francesca Spiga
The hypothalamic-pituitary-adrenal (HPA) axis is the major neuroendocrine axis regulating homeostasis in mammals. Glucocorticoid hormones are rapidly synthesized and secreted from the adrenal gland in response to stress. In addition, under basal conditions glucocorticoids are released rhythmically with both a circadian and an ultradian (pulsatile) pattern. These rhythms are important not only for normal function of glucocorticoid target organs, but also for the HPA axis responses to stress. Several studies have shown that disruption of glucocorticoid rhythms is associated with disease both in humans and in rodents...
May 15, 2018: Stress: the International Journal on the Biology of Stress
https://www.readbyqxmd.com/read/29763909/cardiac-ablation-of-socs3-aggravates-doca-salt-induced-hypertrophic-remodeling-by-activation-of-gp130-dependent-signaling-in-mice
#6
Shuang Liu, Li-Xin Liu, Yun-Long Zhang, Song Lai, Yun-Peng Xie, Nan-Nan Li, Hong-Xia Wang, Yun-Long Xia, Ying Liu, Hui-Hua Li
BACKGROUND/AIMS: Cardiac remodeling is a critical pathogenetic process leading to heart failure. Suppressor of cytokine signaling-3 (SOCS3) is demonstrated as a key negative regulator of the gp130 receptor to inhibit cardiac hypertrophy. However, the role of SOCS3 in deoxycorticosterone-acetate (DOCA)-salt-induced cardiac remodeling remains unclear. METHODS: Cardiac-specific SOCS3 knockout (SOCS3cKO) and wild-type (WT) C57BL/6J mice were subjected to uninephrectomy and DOCA-salt for 3 weeks...
May 10, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29760244/early-use-of-mineralocorticoid-receptor-antagonists-in-st-elevation-myocardial-infarction-is-it-ever-too-early
#7
EDITORIAL
Kieran F Docherty, Pardeep S Jhund
No abstract text is available yet for this article.
May 14, 2018: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/29758591/mineralocorticoid-receptor-antagonism-prevents-obesity-induced-cerebral-artery-remodeling-and-reduces-white-matter-injury-in-rats
#8
Paulo Wagner Pires, Jonathon Lee McClain, Sebastian F Hayoz, Anne McLaren Dorrance
Midlife obesity is a risk factor for dementia development. Obesity has also been linked to hyperaldosteronism, and this can be modeled in rats by high fat (HF) feeding from weaning. Aldosterone, or activation of the mineralocorticoid receptor (MR) causes cerebrovascular injury in lean hypertensive rats. We hypothesized that rats fed a HF diet would show inward middle cerebral artery (MCA) remodeling that could be prevented by MR antagonism. We further proposed that the cerebral artery remodeling would be associated with white mater injury...
May 14, 2018: Microcirculation: the Official Journal of the Microcirculatory Society, Inc
https://www.readbyqxmd.com/read/29744528/device-therapy-in-heart-failure-with-reduced-ejection-fraction-cardiac-resynchronization-therapy-and-more
#9
D Duncker, C Veltmann
In patients with heart failure with reduced ejection fraction (HFrEF), optimal medical treatment includes beta-blockers, ACE inhibitors/angiotensinreceptor-neprilysin inhibitors (ARNI), mineralocorticoid receptor antagonists, and ivabradine when indicated. In device therapy of HFrEF, implantable cardioverter-defibrillators and cardiac resynchronization therapy (CRT) have been established for many years. CRT is the therapy of choice (class I indication) in symptomatic patients with HFrEF and a broad QRS complex with a left bundle branch block (LBBB) morphology...
May 9, 2018: Herz
https://www.readbyqxmd.com/read/29738736/organic-cation-transporter-3-a-cellular-mechanism-underlying-rapid-non-genomic-glucocorticoid-regulation-of-monoaminergic-neurotransmission-physiology-and-behavior
#10
REVIEW
Paul J Gasser, Christopher A Lowry
Corticosteroid hormones act at intracellular glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) to alter gene expression, leading to diverse physiological and behavioral responses. In addition to these classical genomic effects, corticosteroid hormones also exert rapid actions on physiology and behavior through a variety of non-genomic mechanisms, some of which involve GR or MR, and others of which are independent of these receptors. One such GR-independent mechanism involves corticosteroid-induced inhibition of monoamine transport mediated by "uptake2 " transporters, including organic cation transporter 3 (OCT3), a low-affinity, high-capacity transporter for norepinephrine, epinephrine, dopamine, serotonin and histamine...
May 5, 2018: Hormones and Behavior
https://www.readbyqxmd.com/read/29737520/na-restriction-activates-enac-in-rat-kidney-through-two-mechanisms-and-decreases-distal-na-delivery
#11
Gustavo Frindt, Lei Yang, Krister Bamberg, Lawrence G Palmer
KEY POINTS: Dietary Na restriction, through the mineralocorticoid aldosterone, acts on epithelial Na channels (ENaC) through both fast (24 hrs) and slow (5 to 7 days) mechanisms in the kidney. The fast effect entails increased proteolytic processing and trafficking of channel protein to the apical membrane. It is rapidly reversible by the mineralocorticoid receptor antagonist eplerenone and is largely lost when tubules are studied ex vivo. The slow effect does not require increased processing or surface expression, is refractory to acute eplerenone treatment, and is preserved ex vivo...
May 8, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29733691/corticosteroid-receptors-adopt-distinct-cyclical-transcriptional-signatures
#12
Florian Le Billan, Larbi Amazit, Kevin Bleakley, Qiong-Yao Xue, Eric Pussard, Christophe Lhadj, Peter Kolkhof, Say Viengchareun, Jérôme Fagart, Marc Lombès
Mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) are two closely related hormone-activated transcription factors that regulate major pathophysiologic functions. High homology between these receptors accounts for the crossbinding of their corresponding ligands, MR being activated by both aldosterone and cortisol and GR essentially activated by cortisol. Their coexpression and ability to bind similar DNA motifs highlight the need to investigate their respective contributions to overall corticosteroid signaling...
May 7, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29730238/the-role-of-mineralocorticoid-receptor-antagonists-in-patients-with-acute-myocardial-infarction-is-the-evidence-reflective-of-modern-clinical-practice
#13
REVIEW
Jonathan Hinton, Michael Mahmoudi, Aung Myat, Nick Curzen
No abstract text is available yet for this article.
April 17, 2018: Cardiovascular Revascularization Medicine: Including Molecular Interventions
https://www.readbyqxmd.com/read/29726982/a-real-world-cohort-study-on-the-quality-of-potassium-and-creatinine-monitoring-during-initiation-of-mineralocorticoid-receptor-antagonists-in-patients-with-heart-failure
#14
Erik Nilsson, Pietro De Deco, Marco Trevisan, Rino Bellocco, Bengt Lindholm, Lars H Lund, Josef Coresh, Juan J Carrero
AIMS: Clinical heart failure (HF) guidelines recommend monitoring of creatinine and potassium throughout the initial weeks of mineralocorticoid receptor antagonists (MRAs) therapy. We here assessed the extent to which this occurs in our healthcare. METHODS AND RESULTS: Observational study in 2007-2010 HF patients starting MRA therapy in Stockholm, Sweden. Outcomes included potassium and creatinine laboratory testing before MRA initiation and in the early (days 1-10) and extended (days 11-90) post-initiation periods...
May 2, 2018: European Heart Journal. Quality of Care & Clinical Outcomes
https://www.readbyqxmd.com/read/29724188/the-effect-of-spironolactone-on-calcineurin-inhibitor-induced-nephrotoxicity-a-multicenter-randomized-double-blind-clinical-trial-the-spiren-trial
#15
Line Aas Mortensen, Helle C Thiesson, Birgitte Tougaard, Martin Egfjord, Anne Sophie Lind Fischer, Claus Bistrup
BACKGROUND: Calcineurin inhibitor induced nephrotoxicity contributes to late allograft failure in kidney transplant patients. Evidence points towards aldosterone to play a role in the development of fibrosis in multiple organs. Animal studies have indicated a beneficial effect of mineralocorticoid receptor antagonists preventing calcineurin inhibitor induced nephrotoxicity. Only few studies have explored this effect in humans. The objective of this study is to evaluate the effect of spironolactone on glomerular filtration rate and fibrosis in kidney transplant patients...
May 3, 2018: BMC Nephrology
https://www.readbyqxmd.com/read/29723896/mineralocorticoid-receptor-blockers-and-aldosterone-to-renin-ratio-a-randomized-controlled-trial-and-observational-data
#16
Stefan Pilz, Christian Trummer, Nicolas Verheyen, Verena Schwetz, Marlene Pandis, Felix Aberer, Martin R Grübler, Andreas Meinitzer, Antonia Bachmann, Jakob Voelkl, Ioana Alesutan, Cristiana Catena, Leonardo A Sechi, Winfried März, Barbara Obermayer-Pietsch, Andreas Tomaschitz
Current guidelines recommend to withdraw mineralocorticoid receptor (MR) blocker treatment for at least 4 weeks when measuring the aldosterone to renin ratio (ARR) as a screening test for primary aldosteronism (PA). We aimed to evaluate the effect of MR blocker treatment on ARR and its components, plasma aldosterone concentration (PAC), and direct renin concentration (DRC). First, we performed a post-hoc analysis of the effect of eplerenone on parathyroid hormone levels in primary hyperparathyroidism (EPATH) study, a randomized controlled trial (RCT) in 110 patients with primary hyperparathyroidism (pHPT)...
May 3, 2018: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
https://www.readbyqxmd.com/read/29721801/the-emerging-role-of-aldosterone-mineralocorticoid-receptors-in-the-pathogenesis-of-erectile-dysfunction
#17
REVIEW
Fei Wu, Yun Lin, Qingyong Liu
PURPOSE: Aldosterone is an old hormone that has been discovered for more than fifty years. The clinical application of its receptors' inhibitors, especially spirolactone, has benifited patients for decades worldwide. In this review, we briefly summarized the molecular mechanism of aldosterone/mineralocorticoid receptors (Ald-MRs) signaling in cardiovascular diseases and its emerging role in erectile dysfunction. METHODS: We searched PubMed, Web of Science, and Scopus for manuscripts published prior to December 2017 using key words " aldosterone " AND " erectile dysfunction " OR " cardiovascular disease " OR " mineralocorticoid receptors "...
May 2, 2018: Endocrine
https://www.readbyqxmd.com/read/29717226/aldosterone-impairs-mitochondrial-function-in-human-cardiac-fibroblasts-via-a-kinase-anchor-protein-12
#18
Jaime Ibarrola, Rafael Sadaba, Ernesto Martinez-Martinez, Amaia Garcia-Peña, Vanessa Arrieta, Virginia Alvarez, Amaya Fernández-Celis, Alicia Gainza, Victoria Cachofeiro, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Frederic Jaisser, Natalia Lopez-Andres
Aldosterone (Aldo) contributes to mitochondrial dysfunction and cardiac oxidative stress. Using a proteomic approach, A-kinase anchor protein (AKAP)-12 has been identified as a down-regulated protein by Aldo in human cardiac fibroblasts. We aim to characterize whether AKAP-12 down-regulation could be a deleterious mechanism which induces mitochondrial dysfunction and oxidative stress in cardiac cells. Aldo down-regulated AKAP-12 via its mineralocorticoid receptor, increased oxidative stress and induced mitochondrial dysfunction characterized by decreased mitochondrial-DNA and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expressions in human cardiac fibroblasts...
May 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29709221/corrigendum-to-the-novel-mineralocorticoid-receptor-antagonist-finerenone-in-diabetic-kidney-disease-progress-and-challenges-metabolism-65-2016-1342-1349
#19
Pingping Yang, Tianlun Huang, Gaosi Xu
No abstract text is available yet for this article.
May 2018: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/29704920/hypertension-in-patients-with-type-2-diabetes-mellitus-targets-and-management
#20
REVIEW
Dimitra I Pavlou, Stavroula Α Paschou, Panagiotis Anagnostis, Michael Spartalis, Eleftherios Spartalis, Andromachi Vryonidou, Nicholas Tentolouris, Gerasimos Siasos
Two-thirds of patients with type 2 diabetes mellitus (T2DM) have arterial hypertension. Hypertension increases the incidence of both micro- and macrovascular complications in these patients, while the co-existence of these two major risk factors leads to a four-fold increased risk for cardiovascular disease (CVD) compared with normotensive non-diabetic controls. The aim of this article is to comprehensively review the literature and present updated information on targets for blood pressure (BP) and on the management of hypertension in patients with T2DM...
June 2018: Maturitas
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