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https://www.readbyqxmd.com/read/27892684/angiotensin-receptor-neprilysin-inhibitor-lcz696-pharmacology-pharmacokinetics-and-clinical-development
#1
Yue Hua, Ian Wang, Bin Liu, Darren J Kelly, Christopher Reid, Danny Liew, Yingchun Zhou, Bing H Wang
Heart failure still has a significant disease burden with poor outcomes worldwide despite advances in therapy. The standard therapies have been focused on blockade of renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid antagonists and the sympathetic nervous system with β-blockers. The natriuretic peptide system is a potential counter-regulatory system that promotes vasodilatation and natriuresis. Angiotensin receptor neprilysin inhibitors are a new class drug capable of blocking the renin-angiotensin-aldosterone system and enhancing the natriuretic peptide system to improve neurohormonal balance...
November 28, 2016: Future Cardiology
https://www.readbyqxmd.com/read/27858191/focus-on-the-novel-cardiovascular-drug-lzc696-from-evidence-to-clinical-consideration
#2
L M Lin, Y Wu, M F Wu, J X Lin
LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is comprised of the angiotensin receptor blocker valsartan and the neprilysin inhibitor pro-drug sacubitril (AHU377). After oral administration, AHU377 is rapidly metabolized to the active neprilysin inhibitor LBQ657. LCZ696 exerts its effects of diuresis, natriuresis, vasodilation and aldosterone secretion inhibition through simultaneous renin-angiotensin-aldosterone system (RAAS) blockade and natriuretic peptides system (NPS) enhancement...
November 18, 2016: Cardiovascular Drugs and Therapy
https://www.readbyqxmd.com/read/27853163/long-term-52-week-safety-and-efficacy-of-sacubitril-valsartan-in-asian-patients-with-hypertension
#3
Ouppatham Supasyndh, Ningling Sun, Kazuomi Kario, Kudsia Hafeez, Jack Zhang
Sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor-neprilysin inhibitor, demonstrated significant reductions in office and 24 h ambulatory blood pressure (BP) over 8 weeks in Asian patients with hypertension. This 52-week extension to the 8-week core study was aimed at evaluating the long-term safety, tolerability and efficacy of sacubitril/valsartan. Patients who completed an 8-week randomized study (the core study) were enrolled in this 52-week open-label study and received sacubitril/valsartan 200 mg QD...
November 17, 2016: Hypertension Research: Official Journal of the Japanese Society of Hypertension
https://www.readbyqxmd.com/read/27849566/effects-of-sacubitril-valsartan-lcz696-on-natriuresis-diuresis-blood-pressures-and-nt-probnp-in-salt-sensitive-hypertension
#4
Tzung-Dau Wang, Ru-San Tan, Hae-Young Lee, Sang-Hyun Ihm, Moo-Yong Rhee, Brian Tomlinson, Parasar Pal, Fan Yang, Elizabeth Hirschhorn, Margaret F Prescott, Markus Hinder, Thomas H Langenickel
: Salt-sensitive hypertension (SSH) is characterized by impaired sodium excretion and subnormal vasodilatory response to salt loading. Sacubitril/valsartan (LCZ696) was hypothesized to increase natriuresis and diuresis and result in superior blood pressure control compared with valsartan in Asian patients with SSH. In this randomized, double-blind, crossover study, 72 patients with SSH received sacubitril/valsartan 400 mg and valsartan 320 mg once daily for 4 weeks each. SSH was diagnosed if the mean arterial pressure increased by ≥10% when patients switched from low (50 mmol/d) to high (320 mmol/d) sodium diet...
November 14, 2016: Hypertension
https://www.readbyqxmd.com/read/27837397/from-arb-to-arni-in-cardiovascular-control
#5
REVIEW
Estrellita Uijl, Lodi C W Roksnoer, Ewout J Hoorn, A H Jan Danser
Coexistence of hypertension, diabetes mellitus and chronic kidney disease synergistically aggravates the risk of cardiovascular and renal morbidity and mortality. These high-risk, multi-morbid patient populations benefit less from currently available anti-hypertensive treatment. Simultaneous angiotensin II type 1 receptor blockade and neprilysin inhibition ('ARNI') with valsartan/sacubitril (LCZ696) might potentiate the beneficial effects of renin-angiotensin-aldosterone inhibition by reinforcing its endogenous counterbalance, the natriuretic peptide system...
December 2016: Current Hypertension Reports
https://www.readbyqxmd.com/read/27803793/sacubitril-valsartan-in-heart-failure-latest-evidence-and-place-in-therapy
#6
REVIEW
Edgardo Kaplinsky
Despite significant therapeutic advances, patients with chronic heart failure (HF) remain at high risk for HF progression and death. Sacubitril/valsartan (previously known as LCZ696) is a first-in-class medicine that contains a neprilysin (NEP) inhibitor (sacubitril) and an angiotensin II (Ang-II) receptor blocker (valsartan). NEP is an endopeptidase that metabolizes different vasoactive peptides including natriuretic peptides, bradykinin and Ang-II. In consequence, its inhibition increases mainly the levels of both, natriuretic peptides (promoting diuresis, natriuresis and vasodilatation) and Ang-II whose effects are blocked by the angiotensin receptor blocker, valsartan (reducing vasoconstriction and aldosterone release)...
November 2016: Therapeutic Advances in Chronic Disease
https://www.readbyqxmd.com/read/27754187/sp-04-2-lcz-696-a-new-paradigm-shift-for-the-treatment-of-heart-failure
#7
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
https://www.readbyqxmd.com/read/27754186/sp-04-1-the-role-of-natriuretic-peptides-in-the-pathogenesis-of-cardiovascular-diseases
#8
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
https://www.readbyqxmd.com/read/27747488/angiotensin-neprilysin-inhibition-as-a-paradigm-for-all
#9
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
https://www.readbyqxmd.com/read/27725624/a-treatment-approach-for-patients-with-chronic-systolic-heart-failure
#10
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
https://www.readbyqxmd.com/read/27719743/effect-of-food-on-the-oral-bioavailability-of-the-angiotensin-receptor-neprilysin-inhibitor-sacubitril-valsartan-lcz696-in-healthy-subjects%C3%A2
#11
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...
December 2016: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27643144/sp-04-2-lcz-696-a-new-paradigm-shift-for-the-treatment-of-heart-failure
#12
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
https://www.readbyqxmd.com/read/27643143/sp-04-1-the-role-of-natriuretic-peptides-in-the-pathogenesis-of-cardiovascular-diseases
#13
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
https://www.readbyqxmd.com/read/27636114/-physical-training-in-chronic-heart-failure-pathophysiology-and-clinical-evolution
#14
Eduardo Rivas Estany, Susana Hernández García
Chronic heart failure has become one of the main global health problems; 23 million people suffer from this disease worldwide and age of onset has varied considerably over the past five decades, coinciding with other co-morbidities as longevity in the population increases. Treatment of heart failure has also shown striking variations in recent years. Such is the case of the substitution of sympathomimetic drugs by beta-blocking agents, which primarily means a conceptual change in the pathophysiological interpretation of this syndrome...
2016: Medwave
https://www.readbyqxmd.com/read/27574931/limitations-of-sacubitril-valsartan-in-the-management-of-heart-failure
#15
Srikanth Yandrapalli, Wilbert S Aronow, Pratik Mondal, David R Chabbott
BACKGROUND: The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial was a double-blind trial that randomized 8442 patients with heart failure (HF) with reduced ejection fraction (HFrEF) to receive twice daily dosing of either 200 mg of LCZ696 or 10 mg of enalapril in addition to standard medical therapy for HF. AREAS OF UNCERTAINTY: Limitations of this trial include (1) sacubitril has not been tested by itself in the treatment of HFrEF; (2) the maximum recommended dose of valsartan for the treatment of HFrEF was used in this trial, but the maximum recommended dose of enalapril for the treatment of HFrEF was not used; (3) a run-in phase was used in this trial to test the tolerability of LCZ696, and patients who had adverse effects in this period were excluded from randomization; (4) the percent of blacks enrolled in this trial was only 5%; (5) LCZ696 caused a 14% incidence of hypotension; (6) neprilysin inhibition might favor the development of Alzheimer dementia, which was not assessed in the PARADIGM-HF trial; (7) patients with severe symptomatic HF were underrepresented in this trial; (8) major exclusions from this trial included an acute coronary event in the last 3 months, severe pulmonary disease, hepatic impairment, and an estimated glomerular filtration rate <30 mL per minute per 1...
August 17, 2016: American Journal of Therapeutics
https://www.readbyqxmd.com/read/27542885/improved-insulin-sensitivity-with-angiotensin-receptor-neprilysin-inhibition-in-individuals-with-obesity-and-hypertension
#16
Jens Jordan, Rudi Stinkens, Thomas Jax, Stefan Engeli, Ellen E Blaak, Marcus May, Bas Havekes, Christoph Schindler, Diego Albrecht, Parasar Pal, Tim Heise, Gijs H Goossens, Thomas H Langenickel
Natriuretic peptide (NP) deficiency and sustained renin-angiotensin system activation are associated with impaired oxidative metabolism and predispose to type-2 diabetes. We hypothesized that sacubitril/valsartan (LCZ696), which augments NP through neprilysin inhibition while blocking angiotensin II type-1 (AT1)-receptors improves insulin sensitivity, lipid mobilization, and oxidation. Following 8 weeks of treatment of obese hypertensive patients, sacubitril/valsartan 400 mg QD, but not amlodipine 10 mg QD, was associated with a significant increase from baseline in insulin sensitivity index (hyperinsulinemic-euglycemic clamp), and tended to be higher in patients treated with sacubitril/valsartan compared with amlodipine...
August 20, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27532450/angiotensin-receptor-neprilysin-inhibitor-lcz696-a-novel-targeted-therapy-for-arterial-hypertension
#17
REVIEW
Vasiliki Katsi, Georgios Skalis, Antonis N Pavlidis, Thomas Makris, Petros Nihoyannopoulos, Dimitris Tousoulis, Ioannis Kallikazaros
The need for novel antihypertensive therapies represents a continuous challenge. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that has been shown to enhance endogenous natriuretic peptide (NP) actions on neurohormonal activation. This effect seems to be additive to that of the renin-angiotensin-aldosterone system (RAAS) suppression, as impressively suggested in the PARADIGM HF study. LCZ696 has been shown to be effective in reducing blood pressure in several small studies; however, its effectiveness and safety remain to be proved in larger studies...
October 2015: European Heart Journal. Cardiovascular Pharmacotherapy
https://www.readbyqxmd.com/read/27471351/critical-questions-about-paradigm-hf-and-the-future
#18
REVIEW
Chen-Huan Chen
Cardiovascular (CV) diseases in general and heart failure (HF) in particular are major contributors to death and morbidity and are also recognized as important drivers of health care expenditure. The PARADIGM-HF trial was a pivotal trial designed to compare the long-term effects of LCZ696 with enalapril in patients with symptomatic HF with reduced ejection fraction (HFrEF). This review article presents an in-depth view of the PARADIGM-HF trial and the implications of the results in the management of patients with HF and is based on peer reviewed manuscripts, editorials, perspectives and opinions written about the PARADIGM-HF trial...
July 2016: Acta Cardiologica Sinica
https://www.readbyqxmd.com/read/27422865/early-improvement-of-symptoms-using-lcz696-in-a-patient-with-systolic-heart-failure-and-a-reduced-ejection-fraction-a-case-report
#19
Johannes Kohlmeier, Peter Bramlage
INTRODUCTION: Heart failure is a progressive disease with high mortality and morbidity. LCZ696 is a drug that has recently shown its improved efficacy and safety in patients with systolic heart failure and a reduced ejection fraction. Reports on its impact on the improvement of clinical symptoms are, however, scarce. These are important because they improve a patient's compliance with treatment and their quality of life. CASE PRESENTATION: We report on the case of a 71-year-old patient who had deteriorating symptoms and signs of heart failure (ejection fraction [EF] 34%) in whom we initiated LCZ696 treatment...
July 14, 2016: Perfusion
https://www.readbyqxmd.com/read/27417000/influence-of-sacubitril-valsartan-lcz696-%C3%A2-on%C3%A2-30-day-readmission-after-heart-failure-hospitalization
#20
Akshay S Desai, Brian L Claggett, Milton Packer, Michael R Zile, Jean L Rouleau, Karl Swedberg, Victor Shi, Martin Lefkowitz, Randall Starling, John Teerlink, John J V McMurray, Scott D Solomon
BACKGROUND: Patients with heart failure (HF) are at high risk for hospital readmission in the first 30 days following HF hospitalization. OBJECTIVES: This study sought to determine if treatment with sacubitril/valsartan (LCZ696) reduces rates of hospital readmission at 30-days following HF hospitalization compared with enalapril. METHODS: We assessed the risk of 30-day readmission for any cause following investigator-reported hospitalizations for HF in the PARADIGM-HF trial, which randomized 8,399 participants with HF and reduced ejection fraction to treatment with LCZ696 or enalapril...
July 19, 2016: Journal of the American College of Cardiology
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