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https://www.readbyqxmd.com/read/28720639/angioedema-spotlight-a-closer-examination-of-sacubitril-valsartan-safety-results
#1
Ryan E Owens, Carrie S Oliphant
Incorporation of neprilysin inhibition into heart failure pharmacotherapy regimens has recently been recommended by U.S. guidelines, based on results from the PARADIGM-HF trial comparing sacubitril/valsartan to enalapril. While most of the discussion has focused on efficacy, a closer examination of the safety results, particularly the incidence of angioedema during the run-in and double-blind periods, is also warranted. Although no major safety concerns were identified, an angioedema risk comparable to enalapril was found, primarily in the black population...
July 2017: Journal of the American Board of Family Medicine: JABFM
https://www.readbyqxmd.com/read/28719622/characterization-of-plasma-metal-profiles-in-alzheimer-s-disease-using-multivariate-statistical-analysis
#2
Chunmei Guan, Rui Dang, Yu Cui, Liyan Liu, Xiaobei Chen, Xiaoyu Wang, Jingli Zhu, Donggang Li, Junwei Li, Decai Wang
The exact cause of Alzheimer's disease (AD) and the role of metals in its etiology remain unclear. We have used an analytical approach, based on inductively coupled plasma mass spectrometry coupled with multivariate statistical analysis, to study the profiles of a wide range of metals in AD patients and healthy controls. AD cannot be cured and the lack of sensitive biomarkers that can be used in the early stages of the disease may contribute to this treatment failure. In the present study, we measured plasma levels of amyloid-β1-42(0...
2017: PloS One
https://www.readbyqxmd.com/read/28714615/-arni-new-abbreviation-for-a-new-class-of-treatment-of-heart-failure
#3
Soran Karimzadeh, Hazrije Mustafić, Tomoe Stampfli Andres
ARNI (Angiontensin Receptor Neprilysin Inhibitor) are a new class of drug : the angiotensin and neprilysin inhibitors. This combined effect allows an optimisation of the heart failure treatment by acting on both pathways of the renin-angiotensin-aldosterone and of the natriuretic peptides. LCZ696 is a combined molecule of valsartan and sacubitril and is currently the only one on the market. Its efficacy has been shown in a large randomised trial in 2014, and LCZ696 is now part of the last 2016 European Society of Cardiology guidelines for the management of heart failure...
March 1, 2017: Revue Médicale Suisse
https://www.readbyqxmd.com/read/28697571/psd-93-attenuates-amyloid-%C3%AE-mediated-cognitive-dysfunction-by-promoting-the-catabolism-of-amyloid-%C3%AE
#4
Linjie Yu, Yi Liu, Hui Yang, Xiaolei Zhu, Xiang Cao, Jun Gao, Hui Zhao, Yun Xu
Amyloid-β (Aβ) is a key neuropathological hallmark of Alzheimer's disease (AD). Postsynaptic density protein 93 (PSD-93) is a key scaffolding protein enriched at postsynaptic sites. The aim of the present study was to examine whether PSD-93 overexpression could alleviate Aβ-induced cognitive dysfunction in APPswe/PS1dE9 (APP/PS1) mice by reducing Aβ levels in the brain. The level of PSD-93 was significantly decreased in the hippocampus of 6-month-old APP/PS1 mice compared with that in wild-type mice. Following lentivirus-mediated PSD-93 overexpression, cognitive function, synaptic function, and amyloid burden were investigated...
July 1, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28689178/sacubitril-valsartan-beyond-natriuretic-peptides
#5
REVIEW
Jagdeep S S Singh, Louise M Burrell, Myriam Cherif, Iain B Squire, Andrew L Clark, Chim C Lang
Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded as biomarkers in heart failure (HF). However, they are also possible therapeutic agents due to their potentially beneficial physiological effects. The angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin-angiotensin-aldosterone system (RAAS) by blocking the angiotensin II receptor...
July 8, 2017: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/28685579/synthetic-modification-within-the-rprl-region-of-apelin-peptides-impact-on-cardiovascular-activity-and-stability-to-neprilysin-and-plasma-degradation
#6
Shaun M K McKinnie, Wang Wang, Conrad Fischer, Tyler McDonald, Kevin R Kalin, Xavier Iturrioz, Catherine Llorens-Cortes, Gavin Y Oudit, John C Vederas
Apelin is an important mammalian peptide hormone with a range of physiological roles, especially in the cardiovascular system. The apelinergic system is a promising target for treatment of disease, but this remains to be realized due to rapid proteolysis of apelin-derived peptides by proteases, including neprilysin (NEP). The synthetic analogues modified within the NEP degradation site ("RPRL" motif) showed improved in vitro proteolytic stability while maintaining receptor-binding affinities, with three candidate peptides retaining full cardiovascular activities for potential therapeutic application...
July 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28676269/substituted-%C3%AE-mercaptoketones-new-types-of-specific-neprilysin-inhibitors
#7
Hervé Poras, Rémi Patouret, Simon Leiris, Tanja Ouimet, Marie-Claude Fournié-Zaluski, Bernard P Roques
New neprilysin inhibitors containing an α-mercaptoketone HSC(R(1)R(2))CO group, as zinc ligand were designed. Two parameters were explored for potency optimization: the size of the inhibitor which could interact with the S1, S1' or S2' domain of the enzyme and the nature of the substituents R(1), R(2) of the mercaptoketone group. Introduction of a cyclohexyl chain in R(1), R(2) position and a (3-thiophen)benzyl group in position R(3) (compound 12n) yielded to the most potent inhibitor of this series with a Ki value of 2±0...
June 21, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28676030/heart-failure-with-preserved-ejection-fraction-a-dilemma-in-treatment-options
#8
Taylor Bramblett, Mohamed Teleb, Aymen Albaghdadi, Harsh Agrawal, Debabrata Mukherjee
Heart failure with preserved ejection fraction (HFpEF) makes up half of diagnosed heart failure cases and has similar outcomes compared to heart failure with reduced ejection fraction (HFrEF) but a discrepancy in knowledge and approach to treatment. HFpEF is diagnosed using the following criteria: symptoms, preserved ejection fraction (greater than 50%), and evidence of abnormal left ventricular filling or relaxation, or diastolic distensibility or stiffness. Studies conducted to examine the efficacy of angiotensin receptor blockers (irbesartan and candesartan), thiazide diuretics (chlorthalidone), and angiotensin converting enzyme inhibitors (perindopril) in the treatment of HFpEF, showed moderate efficacy but no clear benefit...
July 3, 2017: Cardiovascular & Hematological Disorders Drug Targets
https://www.readbyqxmd.com/read/28674290/elucidating-pathogenic-mechanisms-of-early-onset-alzheimer-s-disease-in-down-syndrome-patients
#9
Masashi Asai, Takashi Kawakubo, Ryotaro Mori, Nobuhisa Iwata
 Down syndrome (DS) patients demonstrate the neuropathology of Alzheimer's disease (AD) characterized by the formation of senile plaques and neurofibrillary tangles by age 40-50 years. It has been considered for a number of years that 1.5-fold expression of the gene for the amyloid precursor protein (APP) located on chromosome 21 leading to overproduction of amyloid-β peptide (Aβ) results in the early onset of AD in adults with DS. However, the mean age of onset of familial AD with the Swedish mutation on APP which has high affinity for β-secretase associated with a dramatic increase in Aβ production is about 55 years...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28662936/angiotensin-receptor-neprilysin-inhibition%C3%A2-in-heart-failure-with-preserved%C3%A2-ejection-fraction-rationale-and-design-of-the-paragon-hf-trial
#10
REVIEW
Scott D Solomon, Adel R Rizkala, Jianjian Gong, Wenyan Wang, Inder S Anand, Junbo Ge, Carolyn S P Lam, Aldo P Maggioni, Felipe Martinez, Milton Packer, Marc A Pfeffer, Burkert Pieske, Margaret M Redfield, Jean L Rouleau, Dirk J Van Veldhuisen, Faiez Zannad, Michael R Zile, Akshay S Desai, Victor C Shi, Martin P Lefkowitz, John J V McMurray
OBJECTIVES: The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial is designed to determine the efficacy and safety of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan compared with valsartan in patients with chronic heart failure and preserved ejection fraction (HFpEF). BACKGROUND: HFpEF is highly prevalent, associated with substantial morbidity and mortality, and in need of effective therapies that improve outcomes...
July 2017: JACC. Heart Failure
https://www.readbyqxmd.com/read/28656517/treatment-of-hyperkalemia-in-heart-failure
#11
REVIEW
Ersilia M DeFilippis, Akshay S Desai
PURPOSE OF REVIEW: The aim of this paper is to discuss strategies for prevention and management of hyperkalemia in patients with heart failure, including the role of novel therapies. RECENT FINDINGS: Renin-angiotensin-aldosterone system (RAAS) antagonists, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA) decrease mortality and morbidity in heart failure but increase the risk of hyperkalemia, especially when used in combination...
June 27, 2017: Current Heart Failure Reports
https://www.readbyqxmd.com/read/28653148/-new-pharmacologic-therapies-for-chronic-heart-failure
#12
REVIEW
T Kempf, U Bavendiek, J Bauersachs
Heart failure is a disease with a high prevalence and incidence. New therapeutic approaches are needed to prevent the onset of heart failure and to reduce the high morbidity and mortality associated with this disease. An optimized therapy of arterial hypertension in patients with risk factors and the use of the SGLT2 inhibitor empagliflozin in type 2 diabetics are proven strategies to prevent heart failure. The therapeutic options in heart failure with preserved ejection fraction are still insufficient. In heart failure with reduced ejection fraction sacubitril/valsartan, the first approved angiotensin receptor-neprilysin inhibitor, is superior to an angiotensin converting enzyme (ACE) inhibitor...
June 26, 2017: Der Internist
https://www.readbyqxmd.com/read/28652105/pharmacokinetic-pharmacodynamic-and-antihypertensive-effects-of-the-neprilysin-inhibitor-lcz-696-sacubitril-valsartan
#13
REVIEW
Steven G Chrysant
LCZ-696, sacubitril/valsartan, is a dual-acting molecule consisting of the angiotensin II (Ang II) receptor blocker valsartan and the neprilysin (neutral endopeptidase) inhibitor AHU-377 with significant beneficial effects in patients with hypertension and heart failure (HF). Several recent studies have demonstrated a higher effectiveness of LCZ-696 compared to valsartan in the treatment of hypertension and HF. The rationale for the development and the Food and Drug Administration approval of LCZ-696 was based on the concept of an additive effect of the Ang II receptor blocker valsartan and the neutral endopeptidase (neprilysin) inhibitor AHU-377 for the treatment of hypertension and HF...
May 25, 2017: Journal of the American Society of Hypertension: JASH
https://www.readbyqxmd.com/read/28623750/lcz696-improves-cardiac-function-via-alleviating-drp1-mediated-mitochondrial-dysfunction-in-mice-with-doxorubicin-induced-dilated-cardiomyopathy
#14
Yan Xia, Zhangwei Chen, Ao Chen, Mingqiang Fu, Zhen Dong, Kai Hu, Xiangdong Yang, Yunzeng Zou, Aijun Sun, Juying Qian, Junbo Ge
AIMS: LCZ696, a novel angiotensin receptor neprilysin inhibitor, is effective in treating heart failure patients. Doxorubicin (DOX) is an effective antitumor medication but the cardiotoxicity limited its clinical use. In this study, we aimed to determine the effect of LCZ696 on DOX-induced cardiomyopathy in mice and in vitro and to explore related mechanisms focusing on fission protein dynamin-related protein 1 (Drp1). METHODS AND RESULTS: In human study, we found that myocardial fission protein Drp1 expression and its ser 616 phosphorylation were significantly increased in dilated cardiomyopathy (DCM) patients...
June 14, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28614052/safety-of-the-neprilysin-renin-angiotensin-system-inhibitor-lcz696
#15
REVIEW
Bo Li, Yunhe Zhao, Bo Yin, Mengfei Helian, Xinmei Wang, Feng Chen, Hongxia Zhang, Hui Sun, Bin Meng, Fengshuang An
OBJECTIVES: The combined neprilysin/rennin-angiotensin system inhibitor sacubitril/valsartan (LCZ696) has shown its superiority over ACEI/ARB therapy. In view of the existing concern of its adverse effects, we aimed to provide evidence of the safety of the new drug. RESULTS: A total of 6 randomized trials with 11,821 subjects were included in this analysis. No significant differences were found in any adverse effects between LCZ696 and ACEI/ARB or placebo groups...
May 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28587858/rebamipide-reduces-amyloid-%C3%AE-1-42-a%C3%AE-42-production-and-ameliorates-a%C3%AE-43-lowered-cell-viability-in-cultured-sh-sy5y-human-neuroblastoma-cells
#16
Kenta Fukui, Kazuma Yachi, Hidemi Yoshida, Kunikazu Tanji, Tomoh Matsumiya, Ryo Hayakari, Kazushi Tsuruga, Hiroshi Tanaka, Tadaatsu Imaizumi
Amyloid-beta (Aβ) peptides, Aβ 1-42 (Aβ42) and Aβ43, in particular, have been implicated in the pathophysiology of neurodegenerative disease such as Alzheimer's disease (AD). Rebamipide (REB), a gastrointestinal protective drug, can cross the blood-brain barrier after oral administration; however, the effects of REB on neuronal cells have not yet been reported. In this study, we investigated the effects of REB on Aβ43-induced cytotoxicity (monomers, 10μM) in cultured SH-SY5Y human neuroblastoma cells...
June 3, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28587583/angiotensin-receptor-neprilysin-inhibition
#17
Ofer Havakuk, Uri Elkayam
The novel combination sacubitril/valsartan represents a new therapeutic approach in the management of heart failure. With the simultaneous blockage of the enzyme neprilysin (by sacubitril) and angiotensin II receptors (by valsartan), this combination reduces the degradation of natriuretic peptides and other counterregulatory peptide systems while avoiding the deleterious effect of angiotensin II receptors activation and thereby encompasses a beneficial impact of 2 important neurohormonal pathways activated in heart failure...
July 2017: Journal of Cardiovascular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28577679/the-effects-of-sacubitril-valsartan-on-coronary-outcomes-in-paradigm-hf
#18
Ulrik M Mogensen, Lars Køber, Søren L Kristensen, Pardeep S Jhund, Jianjian Gong, Martin P Lefkowitz, Adel R Rizkala, Jean L Rouleau, Victor C Shi, Karl Swedberg, Michael R Zile, Scott D Solomon, Milton Packer, John J V McMurray
BACKGROUND: Angiotensin converting enzyme inhibitors (ACE-I), are beneficial both in heart failure with reduced ejection fraction (HF-REF) and after myocardial infarction (MI). We examined the effects of the angiotensin-receptor neprilysin inhibitor sacubitril/valsartan, compared with the ACE-I enalapril, on coronary outcomes in PARADIGM-HF. METHODS AND RESULTS: We examined the effect of sacubitril/valsartan compared with enalapril on the following outcomes: i) the primary composite endpoint of cardiovascular (CV) death or HF hospitalization, ii) a pre-defined broader composite including, in addition, MI, stroke, and resuscitated sudden death, and iii) a post hoc coronary composite of CV-death, non-fatal MI, angina hospitalization or coronary revascularization...
June 2017: American Heart Journal
https://www.readbyqxmd.com/read/28559246/neprilysin-is-required-for-angiotensin-1-7-s-ability-to-enhance-insulin-secretion-via-its-proteolytic-activity-to-generate-angiotensin-1-2
#19
Gurkirat S Brar, Breanne M Barrow, Matthew Watson, Ryan Griesbach, Edwina Choung, Andrew Welch, Bela Ruzsicska, Daniel P Raleigh, Sakeneh Zraika
Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1-7) by angiotensin converting enzyme 2 (ACE2) and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1-7)-mediated GSIS...
May 30, 2017: Diabetes
https://www.readbyqxmd.com/read/28553432/hiv-1-transactivator-protein-induces-zo-1-and-neprilysin-dysfunction-in-brain-endothelial-cells-via-the-ras-signaling-pathway
#20
Wenlin Jiang, Wen Huang, Yanlan Chen, Min Zou, Dingyue Peng, Debing Chen
Amyloid beta (Aβ) deposition is increased in human immunodeficiency virus-1- (HIV-1-) infected brain, but the mechanisms are not fully understood. The aim of the present study was to evaluate the role of Ras signaling in HIV-1 transactivator protein- (Tat-) induced Aβ accumulation in human cerebral microvascular endothelial cells (HBEC-5i). Cell viability assay showed that 1 μg/mL Tat and 20 μmol/L of the Ras inhibitor farnesylthiosalicylic acid (FTS) had no significant effect on HBEC-5i cell viability after 24 h exposure...
2017: Oxidative Medicine and Cellular Longevity
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