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Nuray Erin, Tümay İpekçi, Bahar Akkaya, İrem Hicran Özbudak, Mehmet Baykara
Calcitonin Gene-related Peptide (CGRP), Vasoactive Intestinal Peptide (VIP) and Substance P (SP) are sensory neuropeptides which may alter cancer growth through modulation of chronic inflammation. We recently reported that SP suppresses breast cancer growth and metastasis through neuroimmune modulation. These neuropeptides are hydrolyzed by Neprilysin (NEP) to bioactive fragments. Decreased activity of NEP was reported in clear cell and chromophobe type renal cell carcinoma (RCC). It is however not known how the levels of neuropeptides hydrolyzed with NEP changes in RCC...
October 19, 2016: Cancer Microenvironment: Official Journal of the International Cancer Microenvironment Society
ByungSu Yoo
Heart failure (HF) represents a significant healthcare issue because of its ever-increasing prevalence, poor prognosis and complex pathophysiology. The cornerstone of modern drug therapy in chronic HF is the inhibition of neurohormonal activation that plays a crucial role in the pathophysiology of HF development and progression and, more specifically, of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. LCZ696 is a first-in-class, angiotensin receptor NEP inhibitor (ARNI) that consists of a supramolecular complex of a molecule of the ARB valsartan in combination with a molecule of the NEP inhibitor prodrug AHU377 (also known as sacubitril)...
September 2016: Journal of Hypertension
Zhanna Kobalava
The burden of cardiovascular diseases (CVD) in general and heart failure (HF) in particular continues to increase worldwide. CVD are major contributors to death and morbidity and recognized as important drivers of healthcare expenditure. Chronic overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in human hypertension and HF pathophysiology. RAAS is fundamental in the overall regulation of cardiovascular homeostasis through the actions of hormones, which regulate vascular tone, and specifically blood pressure through vasoconstriction and renal sodium and water retention...
September 2016: Journal of Hypertension
Sverre Kjeldsen
There is a whole armament of good drugs for treatment of hypertension including diuretics, calcium antagonist, angiotensin receptor antagonists and angiotensin converting enzyme inhibitors. Secondary drugs mostly used for special indications include beta-blockers, alpha-blockers, mineralocorticoid receptor antagonists (aldosterone antagonists), renin-inhibitors, centrally acting drugs, direct vasodilators and others.A variety of new drugs targeting different pressor mechanism exist and have partly been studies experimentally but will unlikely make it to clinical use in human hypertension...
September 2016: Journal of Hypertension
Muthiah Vaduganathan, Akshay S Desai
Composite angiotensin receptor-neprilysin inhibition (ARNi) represents a novel pharmacologic strategy for treatment of heart failure with reduced ejection fraction (HFrEF). In the PARADIGM-HF (Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial of 8399 subjects with HFrEF, treatment with the ARNi LCZ696 (sacubitril/valsartan) was associated with statistically important reductions in cardiovascular death, all-cause mortality, and the composite of cardiovascular death or heart failure hospitalization in comparison with enalapril...
November 2016: Current Cardiology Reports
Melanie Hüttenrauch, Susanne Walter, Margie Kaufmann, Sascha Weggen, Oliver Wirths
The environmental enrichment (EE) paradigm is regarded as a useful tool to create a physical and intellectual stimulation for laboratory rodents and has been used in a variety of Alzheimer disease (AD) mouse models. However, the results of these studies have been conflicting as EE had inconsistent effects on memory performance, Aβ deposition, inflammatory status and other pathological outcomes depending on the AD model. Here, we studied the influence of a lifelong EE on the widely used 5XFAD mouse model, representing the main pathological features of AD...
October 12, 2016: Molecular Neurobiology
Gül Bahtiyar, David Gutterman, Harold Lebovitz
Heart failure (HF) is a major cardiovascular complication of diabetes mellitus (DM). The greatest risk factor for HF is age, and data indicate that 6 to 10 % of individuals over the age of 65 years suffer from HF. Patients with DM have a 2.5-fold increased risk for developing HF than individuals without DM. The 25 to 40 % of patients with HF who have DM have worse outcome (death from cardiovascular disease or hospitalization for worsening HF) than patients without DM. Hyperglycemia is a risk factor for the development of HF with an increase in incidence of HF rising from 10 % at hemoglobin A1c (HbA1c) 8...
November 2016: Current Diabetes Reports
Barry H Greenberg
The treatment of heart failure with reduced ejection (HFrEF) is changing rapidly. Advances over the past several decades have focused on blocking the adverse effects of neurohormonal activation. This approach has resulted in marked improvement in outcomes in the HFrEF population. Despite these advances, however, mortality and morbidity remain high and HFrEF patients have poor quality of life. New approaches to therapy now offer additional benefits. Combined neprilysin inhibition and angiotensin receptor blockade using sacubitril-valsartan (LCZ696) has been shown to be superior to an angiotensin-converting enzyme inhibitor in HFrEF patients...
2016: Reviews in Cardiovascular Medicine
Masashi Asai, Aimi Kinjo, Shoko Kimura, Ryotaro Mori, Takashi Kawakubo, Keiro Shirotani, Sosuke Yagishita, Kei Maruyama, Nobuhisa Iwata
Down syndrome (DS), the most common genetic disorder, is caused by trisomy 21. DS is accompanied by heart defects, hearing and vision problems, obesity, leukemia, and other conditions, including Alzheimer's disease (AD). In comparison, most cancers are rare in people with DS. Overexpression of dual specificity tyrosine-phosphorylation-regulated kinase 1A and a regulator of calcineurin 1 located on chromosome 21 leads to excessive suppression of the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, resulting in reduced expression of a critical angiogenic factor...
2016: Biological & Pharmaceutical Bulletin
Surya Ayalasomayajula, Thomas H Langenickel, Priya Chandra, Edward D Wolfson, Diego Albrecht, Wei Zhou, Parasar Pal, Iris Rajman, Gangadhar Sunkara
OBJECTIVE: Sacubitril/valsartan (LCZ696) provides a novel therapeutic approach of neurohormonal modulation in heart failure via simultaneous inhibition of neprilysin and blockade of the angiotensin II type-1 receptor. This study was conducted to evaluate the effect of food on the oral bioavailability of LCZ696 analytes. MATERIALS AND METHODS: This was an open-label, randomized, 3-period crossover study in healthy subjects. Eligible subjects (N = 36) were randomized to 6 treatment sequences, each comprising 3 treatment periods during which subjects received a single oral dose of 400 mg LCZ696 under fasting condition and following a low- and high-fat meal...
October 10, 2016: International Journal of Clinical Pharmacology and Therapeutics
Douglas L Jennings
Heart failure (HF) continues to afflict millions of Americans, resulting in substantial clinical and economic burden to our society. Recent literature has highlighted the role of 2 novel therapies (an angiotensin receptor blocker/neprilysin inhibitor and ivabradine) in further reducing residual disease in HF. Simultaneously, evidence has mounted suggesting that older therapies like digoxin are not effective in contemporary practice and, in fact, may be harmful. This editorial summarizes the most recently published articles pertaining to both new and old HF therapies and provides a call to action to pharmacists on how to shift patients toward effective drug regimens...
October 3, 2016: Annals of Pharmacotherapy
M Münzner, N Tappenbeck, F Gembardt, R Rülke, J Furkert, M F Melzig, W-E Siems, G A Brockmann, T Walther
BACKGROUND/OBJECTIVE: Consumption of Green Tea has become increasingly popular, particularly because of claimed reduction in body weight. We recently reported that animals with pharmacological inhibition (by candoxatril) or genetic absence of the endopeptidase neprilysin (NEP) develop an obese phenotype. We now investigated the effect of Green Tea extract (in drinking water) on body weight and body composition and the mediating role of NEP. SUBJECTS/METHODS: To elucidate the role of NEP in mediating the beneficial effects of Green Tea extract, 'Berlin fat mice' or NEP-deficient mice and their age-and gender-matched wild-type controls received the extract in two different doses (300 or 600 mg/kg body weight/day) in the drinking water...
October 4, 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Titus W P van den Heuvel, Adam F Cohen, Robert Rissmann
In this article, we consider the new drugs approved for the European market in 2015. We present a summary of the new mechanisms of action introduced and highlight three new mechanisms of action with a potentially high future impact: PCSK9 inhibition (alirocumab (Praluent®) and evolocumab (Repatha®)) for hypercholesterolaemia, neprilysin inhibition (sacubitril in combination with valsartan (Entresto®)) for heart failure, and interleukin-5 inhibition (mepolizumab (Nucala®)) for asthma.
October 2016: Clinical Medicine: Journal of the Royal College of Physicians of London
Anjali Tiku Owens, Susan Brozena, Mariell Jessup
Biologically active natriuretic peptides (NPs) are an integral part of cardiac homeostasis as they help to maintain sodium and fluid balance. When homeostasis is perturbed by neurohormonal activation in heart failure, levels of NPs rise in response. Neprilysin (NEP) is a naturally occuring enzyme that breaks down NPs. Scientists have recently discovered a novel pharmacologic agent that combines a NEP inhibitor and an angiotensin receptor blocker. In a large clinical trial, this new drug was found to reduce hospitalization and mortality in systolic heart failure...
September 21, 2016: Annual Review of Medicine
Muhammad Zahid Khan, Nagina Atlas, Waqas Nawaz
Cognitive deficiency and oxidative stress have been well documented in aging disorders including Alzheimer's disease. The aim of this study was to investigate the therapeutic efficacy of Caralluma tuberculata methanolic extract (CTME) on cognitive impairment in mice induced with d-galactose. In this study we assessed the therapeutic efficacy of CTME on cognitive impairment in mice induced with d-galactose by conduction of behavioral and cognitive performance tests. In order to explore the possible role of CTME against d-galactose-induced oxidative damages, various biochemical indicators were assessed...
September 23, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Loretta Fala
No abstract text is available yet for this article.
March 2016: American Health & Drug Benefits
Erik H Howell, Scott J Cameron
Heart failure (HF) is a manifestation of aberrant vascular responses and remains a public health concern with a worldwide prevalence of around 23 million and a 5-year mortality numerically equivalent to many cancers. Over the last two decades, mortality from HF reached a plateau with current pharmaceutical agents and mechanical cardiac support. In the last several years, various "novel" pharmaceutical agents have been tested in clinical trials and ultimately met with disappointment, showing only incremental benefit in the treatment of HF...
September 26, 2016: Cardiology Journal
Oliver Domenig, Arndt Manzel, Nadja Grobe, Eva Königshausen, Christopher C Kaltenecker, Johannes J Kovarik, Johannes Stegbauer, Susan B Gurley, Dunja van Oyen, Marlies Antlanger, Michael Bader, Daisy Motta-Santos, Robson A Santos, Khalid M Elased, Marcus D Säemann, Ralf A Linker, Marko Poglitsch
Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated...
2016: Scientific Reports
(no author information available yet)
BACKGROUND: Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. METHODS: UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor-neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD...
September 19, 2016: Nephrology, Dialysis, Transplantation
Javier Pacheco-Quinto, Christopher B Eckman, Elizabeth A Eckman
Impaired clearance of amyloid-β peptide (Aβ) has been postulated to significantly contribute to the amyloid accumulation typical of Alzheimer's disease. Among the enzymes known to degrade Aβ in vivo are endothelin-converting enzyme (ECE)-1, ECE-2, and neprilysin (NEP), and evidence suggests that they regulate independent pools of Aβ that may be functionally significant. To better understand the differential regulation of Aβ concentration by its physiological degrading enzymes, we characterized the cell and region-specific expression pattern of ECE-1, ECE-2, and NEP by in situ hybridization and immunohistochemistry in brain areas relevant to Alzheimer's disease...
August 20, 2016: Neurobiology of Aging
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