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neprilysin - Top 30 Publications

Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.

Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a twofold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug-drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum plasma concentration (~2.0-fold) and area under the plasma concentration-time curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the plasma concentration-time curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the plasma concentration-time curves, while the area under the plasma concentration-time curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the plasma concentration-time curves of valsartan and sacubitrilat ~2.1-fold.

Progress in the Presence of Failure: Updates in Chronic Systolic Heart Failure Management.

The therapeutic heart failure armamentarium has evolved from drugs to transplantation to devices through further understanding of its complex pathophysiology and pathogenesis. Current medications capitalize on our evolving understanding of the sympathetic and renin-angiotensin-aldosterone systems that subsequently promote both beneficial and maladaptive responses that ultimately yield a decrease in cardiac function. Despite these advancements, the prevalence of heart failure continues to rise and carries a significant burden on our patients and health care system. This presents a clinical dilemma on how best to care for a growing, complex, and heterogeneous cohort. Ideal treatments should decrease morbidity and mortality while providing an improvement in quality of life and functional capacity. New interventions will continue to become incorporated into everyday practice, but awareness and prevention should remain the mainstay followed by optimization of guideline-directed therapies. It is equally important to individually tailor our therapeutic approach. While strategies to treat heart failure with reduced ejection fraction continue to advance, our understanding of how best to treat specific etiologies remain in question. This review will focus on current and proposed novel interventions for the management of chronic, systolic heart failure including angiotensin receptor-neprilysin inhibitor, If channel antagonist, sodium-glucose cotransporter-2 inhibitors, and oral potassium binders.

First-in-class composite angiotensin receptor-neprilysin inhibitors (ARNI) in practice.

Assessment of the Renin-Angiotensin System in Cellular Organelle: New Arenas for Study in the Mitochondria.

The renin-angiotensin system (RAS) is an important hormonal system composed of various protein and peptide components that contribute to blood pressure regulation. Although originally characterized as a circulating system, there is increasing evidence for the intracellular expression of RAS elements on the nucleus and mitochondria that may function in concert with or independent of the circulating system. The present chapter describes several experimental approaches to quantify the expression of RAS components in isolated mitochondria from the kidney. These approaches are intended to provide a framework to understand the mitochondrial RAS within a cell-free environment.

Sacubitril/valsartan, a new and effective treatment for heart failure with reduced ejection fraction.

Despite significant therapeutic advances, patients with chronic heart failure and reduced ejection fraction (HFrEF) remain at high risk for heart failure progression and death. The PARADIGM-HF study, the largest outcome trial in HFrEF, has shown improved cardiovascular outcomes with sacubitril/valsartan (Entresto®, Novartis), previously known as LCZ696, compared with angiotensin-converting enzyme (ACE) inhibitor therapy, possibly leading us to a new era for heart failure treatment. Sacubitril/valsartan represents a first-in-class drug acting through inhibition of angiotensin receptor and neprilysin, thus modulating the renin-angiotensin-aldosterone system and vasoactive substances such as natriuretic peptides. This approach can be considered a "paradigm shift" from neurohumoral inhibition to neurohumoral modulation. Based on the PARADIGM-HF results, the European Society of Cardiology and the American Heart Association/American College of Cardiology guidelines proposed a substitution of ACE-inhibitor/angiotensin receptor blocker therapy rather than an "add-on" strategy in HFrEF. Sacubitril/valsartan can be considered a milestone in cardiovascular therapy, like aspirin, statins, beta-blockers. Of course there are many questions that arise spontaneously from this trial, three recognized experts can help us to answer them.

Pharmacogenomics of Angiotensin-Receptor/Neprilysin Inhibitor and its Long-Term Side Effects.

The development of the promising agent sacubitril/valsartan, known as an angiotensin receptor blocker-neprilysin inhibitor (ARNI), to improve heart failure (HF) management, may benefit morbidity, mortality, and readmission rates in patients with HF. The PARADIGM-HF trial demonstrated that the ARNI can reduce morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), while ongoing PARAMOUNT and PARAGON-HF trials determined whether the ARNI has morbidity and mortality benefits in patients with heart failure with preserved ejection fraction (HFpEF). However, the risk of long-term side effects of the ARNI such as cognitive dysfunction or Alzheimer's disease (AD) remains unknown. In fact, neprilysin (NEP), encoded by NEP or MME gene, is a principal peptidase involved in the degradation of β-amyloid (Aβ) protein. Several studies have demonstrated that polymorphisms of the NEP gene may be associated with AD and cerebral amyloid angiopathy (CAA). Pharmacogenomics, the study of variability in drug response due to genetic polymorphisms, can potentially explain the variability in the effect of the ARNI and their side effects. Therefore, we have attempted to highlight pharmacogenomic factors and potential long-term side effects of the ARNI. Physicians should carefully monitor elderly patients with genetic risk factors for AD and CAA. In the future, genetic and genomic testing for NEP polymorphisms may play an important role in monitoring long-term side effects in ARNI-treated HF patients. This article is protected by copyright. All rights reserved.

Cardiovascular and Diabetic Medications That Cause Bradykinin-Mediated Angioedema.

Medication-induced angioedema is a bradykinin-mediated process that results from increased production or decreased degradation of bradykinin. These reactions are documented for several cardiac medications including blockers of the renin-angiotensin-aldosterone system (RAAS). Other cardiovascular and diabetes medications further increase the risk of medication-induced angioedema, particularly with concomitant use of RAAS inhibitors. Dipeptidyl peptidase IV inhibitors are a class of oral diabetic agents that affect bradykinin and substance P degradation and therefore can lead to angioedema. Neprilysin inhibitors are a separate class of cardiac medications, which includes sacubitril, and can lead to drug-induced angioedema especially when used in combination with RAAS inhibitors. This article discusses the proposed mechanisms by which these medications cause angioedema and how medication-induced angioedema differs from mast cell-mediated angioedema. It also details how to recognize medication-induced angioedema and the treatment options available.

Neuroprotective Effects of Citrus Fruit-Derived Flavonoids, Nobiletin and Tangeretin in Alzheimer's and Parkinson`s disease.

Neurodegenerative diseases, namely Alzheimer`s disease and Parkinson's disease represent a deleterious impact worldwide. Despite extensive preclinical and clinical research in neurodegenerative disorders, therapeutic strategies aimed at the prevention and chronic treatment of neurodegenerative conditions have not been successfully translated to the clinic. Therefore, the identification of novel pharmacological intervention derived from natural products is warranted. Nobiletin and tangeretin are important citrus flavonoids derived from the peel and other parts of Citrus L. genus, and have been shown to exhibit neuroprotective effects in several in vitro and in vivo studies. Apart from there antioxidant and anti-inflammatory effects, nobiletin and tangeretin have been shown to attenuate cholinergic deficits, reduce the abnormal accumulation of neurotoxic amyloid-beta peptides, reverse N-methyl-D-aspartate (NMDA) receptor hypofunction, ameliorate ischemic injury, inhibit hyperphosphorylation of tau protein, enhance neprilysin levels, modulate several signaling cascades, and protect against 1-methyl-4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Taken together, these naturally occurring phytochemicals may represent beneficial drug candidates for the treatment and prevention of Alzheimer`s and Parkinson's disease.

Sarsasapogenin-AA13 ameliorates Aβ-induced cognitive deficits via improving neuroglial capacity on Aβ clearance and antiinflammation.

Sarsasapogenin has been reported to improve dementia symptoms somehow, probably through modulating the function of cholinergic system, suppressing neurofibrillary tangles, and inhibiting inflammation. However, the role of sarsasapogenin in response to beta-amyloid (Aβ) remains to be delineated. This study aimed to determine the therapeutic effect of sarsasapogenin-13 (AA13, a sarsasapogenin derivative) on learning and memory impairments in Aβ-injected mice, as well as the role of AA13 in neuroglia-mediated antiinflammation and Aβ clearance.

2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.

Heart failure.

Heart failure is common in adults, accounting for substantial morbidity and mortality worldwide. Its prevalence is increasing because of ageing of the population and improved treatment of acute cardiovascular events, despite the efficacy of many therapies for patients with heart failure with reduced ejection fraction, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β blockers, and mineralocorticoid receptor antagonists, and advanced device therapies. Combined angiotensin receptor blocker neprilysin inhibitors (ARNIs) have been associated with improvements in hospital admissions and mortality from heart failure compared with enalapril, and guidelines now recommend substitution of ACE inhibitors or ARBs with ARNIs in appropriate patients. Improved safety of left ventricular assist devices means that these are becoming more commonly used in patients with severe symptoms. Antidiabetic therapies might further improve outcomes in patients with heart failure. New drugs with novel mechanisms of action, such as cardiac myosin activators, are under investigation for patients with heart failure with reduced left ventricular ejection fraction. Heart failure with preserved ejection fraction is a heterogeneous disorder that remains incompletely understood and will continue to increase in prevalence with the ageing population. Although some data suggest that spironolactone might improve outcomes in these patients, no therapy has conclusively shown a significant effect. Hopefully, future studies will address these unmet needs for patients with heart failure. Admissions for acute heart failure continue to increase but, to date, no new therapies have improved clinical outcomes.

Neprilysin inhibitors: A new hope to halt the diabetic cardiovascular and renal complications?

Diabetes is an enormous and ever-growing calamity and a global public health threat of the 21st century. Besides insulin and oral hypoglycaemic drugs, blockage of the renin-angiotensin system (RAS) denotes a key pharmacotherapy for the management of cardiovascular (CVD) and chronic kidney diseases (CKD), which are the leading causes of disability and death among diabetic patients. Neprilysin (NEP) inhibition, auxiliary to RAS blockage increases the bioavailability of natriuretic peptides and benefits the cardio-renal system. Omapatrilat, a dual angiotensin-converting enzyme (ACE) and NEP inhibitor has been reported to show superior anti-hypertensive, anti-atherosclerotic, insulin-sensitizing, cardiovascular and renoprotective effects to ACE inhibitors in experimental animal models for diabetes. In clinical trials on hypertensive subjects Omapatrilat increased the risk of angioedema due to which its further development as anti-hypertensive drug was hampered. This event prompted the development of angiotensin receptor neprilysin inhibitors (ARNi). The first representative of ARNi, LCZ696 (Sacubitril/ Valsartan) halted cardiovascular and renal functional decline and hence protected against CKD and CVD. Recently, LCZ696 was approved by U.S. Food and Drug Administration for the treatment of heart failure. This concise review intends to summarise the currently available reports on NEPi as a therapeutic intervention to treat CVD and CKD associated with diabetes.

Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.

Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a two-fold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug-drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum plasma concentration (~2.0-fold) and area under the plasma concentration-time curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the plasma concentration-time curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the plasma concentration-time curves, while the area under the plasma concentration-time curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the plasma concentration-time curves of valsartan and sacubitrilat ~2.1-fold.

Clinicopathological characteristics and treatment strategies for patients with low-grade endometrial stromal sarcoma.

To investigate and evaluate the clinicopathological characteristics and treatment strategies for patients with low-grade endometrial stromal sarcoma (LG-ESS).The medical records of LG-ESS patients who were treated at 2 cancer referral centers from January 2005 to December 2015 were retrospectively reviewed.Twenty patients with LG-ESS met the inclusion criteria and were included in this analysis. Hysterectomy with bilateral salpingo-oophorectomy was the mainstay of surgery. Lymphadenectomy was performed in 12 (60%) cases, and no positive nodes were identified. CD10 was the most commonly used immunohistochemistry marker, followed by smooth muscle actin (SMA), estrogen receptor (ER), desmin, progesterone receptor (PR), and S-100; the positivity rates of these markers were 88.2%, 66.7%, 75.0%, 16.7%, 88.9%, and 0, respectively. Postoperative chemotherapy, radiotherapy, and hormonal treatment were provided alone or in combination in 10 (50%) patients, 4 (20%) patients, and 1 (5%) patient, respectively. One patient developed lung metastasis at initial diagnosis, and 2 (10%) patients had recurrence with distant metastasis. They all underwent complete or incomplete resection followed by hormonal treatment. The overall survival time of these patients was 66, 89, and 109 months at last contact, respectively. The 5-year and 10-year disease-free survival rates for the entire cohort were 90% and 72%, respectively. No patients died of the disease.CD10/SMA/ER/PR in combination with desmin/S-100 might improve the diagnostic accuracy. Surgical resection is the foremost treatment for LG-ESS patients with recurrence or distant metastasis. Hormonal treatment may be beneficial for unresectable or residual tumors.

The relationship between natriuretic peptides and neprilysin pathways: the clinical simplification against the complexity of biological systems.

A large body of evidence supports the use of natriuretic peptides (brain natriuretic peptide [BNP] and N-terminal proBNP [NT-proBNP]) for the evaluation and management of patients with heart failure over time. Elevated values reflect an enhanced counterregulatory response to hemodynamic stress and are indicative of heart failure severity, thus predicting prognosis. The clinical relevance and result interpretation of natriuretic peptides for monitoring therapy are still debated, and our understanding of their complex nature is still far from being complete. The new data about the clinical efficacy of LCZ696, a combination neprilysin inhibitor and angiotensin receptor blocker recently approved for the treatment of symptomatic chronic heart failure, showed a different susceptibility of BNP and NT-proBNP during therapy. The aim of this article is to discuss the controversial issues concerning the clinical use of cardiac natriuretic peptide measurement, the complex relationship with neprilysin pathways, and the practical implications of LCZ696 therapy for natriuretic peptide testing in clinical practice.

Comparative venom gland transcriptomics of Naja kaouthia (monocled cobra) from Malaysia and Thailand: elucidating geographical venom variation and insights into sequence novelty.

The monocled cobra (Naja kaouthia) is a medically important venomous snake in Southeast Asia. Its venom has been shown to vary geographically in relation to venom composition and neurotoxic activity, indicating vast diversity of the toxin genes within the species. To investigate the polygenic trait of the venom and its locale-specific variation, we profiled and compared the venom gland transcriptomes of N. kaouthia from Malaysia (NK-M) and Thailand (NK-T) applying next-generation sequencing (NGS) technology.

Resetting the neurohormonal balance in heart failure (HF): the relevance of the natriuretic peptide (NP) system to the clinical management of patients with HF.

The natriuretic peptide (NP) system, which includes atrial natriuretic peptide, B-type natriuretic peptide, and C-type natriuretic peptide, has an important role in cardiovascular homeostasis, promoting a number of physiological effects including diuresis, vasodilation, and inhibition of the renin-angiotensin-aldosterone system. Heart failure (HF) is associated with defects in NP processing and synthesis, and there is a strong relationship between NP levels and disease state. NPs are useful biomarkers in HF, and their use in diagnosis and evaluation of prognosis is well established, particularly in patients with HF with reduced ejection fraction (HFrEF). There has also been interest in their use to guide disease management and therapeutic decision making. An understanding of NPs in HF has also resulted in interest in synthetic NPs for the treatment of HF and in treatments that target neprilysin, a protease that degrades NPs. A novel drug, the angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696), which simultaneously inhibits neprilysin and blocks the angiotensin II type I receptor, was shown to have a favorable efficacy and safety profile in patients with HFrEF and has been approved for use in such patients in Europe and the USA. In light of the development of treatments that target neprilysin and of recent data in relation to synthetic NPs, it is timely to review the current understanding of the role of NPs in HF and their use in diagnosis, evaluating prognosis and guiding treatment, as well as their place in HF therapy.

The renal and cardiovascular effects of natriuretic peptides.

The landmark report by de Bold et al. in 1981 signified the heart as one of the endocrine organs involved in fluid and salt balance (de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. Life Sci 28: 89-94, 1981). Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are secreted from cardiomyocytes in response to cardiac stretch as in the case of heart failure, whereas C-type natriuretic peptide (CNP) is secreted from endothelial and renal cells in response to cytokines and endothelium-dependent agonists, such as acetylcholine. Binding ANP or BNP to natriuretic peptide receptor A induces cyclic guanylyl monophosphate as second messenger in the target cells to mediate the following: natriuresis; water diuresis; increasing glomerular filtration rate; decreasing systemic sympathetic activities; plasma volume; cardiac output and blood pressure; and curbing mitoses of heart fibroblasts and hypertrophy of cardiovascular muscle cells. ANP, BNP, and CNP are cleared from the bloodstream by natriuretic peptide receptor C and degraded by an ectoenzyme called neprilysin (NEP). The plasma levels of BNP are typically >100 pg/ml in patients with congestive heart failure. Sacubitril/valsartan is an angiotensin receptor NEP inhibitor that prevents the clinical progression of surviving patients with heart failure more effectively than enalapril, an angiotensin-converting enzyme inhibitor. A thorough understanding of the renal and cardiovascular effects of natriuretic peptides is of major importance for first-year medical students to gain insight into the significance of plasma levels of BNP in patients with heart failure.

Ivabradine: Current and Future Treatment of Heart Failure.

In heart failure (HF), the heart cannot pump blood efficiently and is therefore unable to meet the body's demands of oxygen, and/or there is increased end-diastolic pressure. Current treatments for HF with reduced ejection fraction (HFrEF) include angiotensin-converting enzyme (ACE) inhibitors, angiotension receptor type 1 (AT1 ) antagonists, β-adrenoceptor antagonists, aldosterone receptor antagonists, diuretics, digoxin and a combination drug with AT1 receptor antagonist and neprilysin inhibitor. In HF, the risk of readmission for hospital and mortality is markedly higher with a heart rate (HR) above 70 bpm. Here, we review the evidence regarding the use of ivabradine for lowering HR in HF. Ivabradine is a blocker of an I funny current (I(f)) channel and causes rate-dependent inhibition of the pacemaker activity in the sinoatrial node. In clinical trials of HFrEF, treatment with ivabradine seems to improve clinical outcome, for example improved ejection fraction (EF) and less readmission for hospital, but the effect appears most pronounced in patients with HRs above 70 bpm, while the effect on cardiovascular death appears less consistent. The adverse effects of ivabradine include bradycardia, atrial fibrillation and visual disturbances, but ivabradine avoids the negative inotrope effects observed with β-adrenoceptor antagonists. In conclusion, in patients with stable HFrEF with EF<35% and HR above 70 bpm, ivabradine improves the outcome and might be a first choice of therapy, if beta-adrenoceptor antagonists are not tolerated. Further studies must show whether that can be extended to HF patients with preserved EF.

Early Adoption of Sacubitril/Valsartan for Patients With Heart Failure With Reduced Ejection Fraction: Insights From Get With the Guidelines-Heart Failure (GWTG-HF).

The aim of this study was to assess the prevalence and variation in angiotensin receptor/neprilysin inhibitor (ARNI) prescription among a real-world population with heart failure with reduced ejection fraction (HFrEF).

Current and emerging pharmacologic options for the management of patients with chronic and acute decompensated heart failure.

For many years heart failure (HF) was known as a fatal disease with an ominous prognosis. In the last decades better understanding of the pathophysiological mechanisms underlying HF has resulted in major breakthrough in the management and improvement in the natural history of this clinical syndrome. Areas covered: The review is focused on current and upcoming pharmacological therapies in patients with chronic and acute HF, starting with brief overview of drugs which improve the outcomes in patients with chronic HF with reduced ejection fraction (EF) including neurohormonal antagonists, angiotensin receptor neprilysin inhibitor and If- channel inhibitor, then presenting the summary of symptomatic treatment, the pharmacotherapy in chronic HF with preserved and mid-range EF and in acute HF. Finally, we report the emerging pharmacologic options and ongoing clinical trials and future directions in pharmacotherapy. Expert commentary: The guidelines-recommended therapies in HF with reduced EF need to be widely implemented into the everyday clinical practice. Better clinical characterization of HF with preserved, mid-range EF and acute HF, with better understanding of the underlying pathophysiological mechanisms may ultimately result in a development of effective strategies improving ominous outcomes in these patients.

Paradigm shift from diagnosing patients based on common symptoms to categorizing patients into subtypes with different pathogenic mechanisms to guide treatment for Alzheimer's disease.

Alzheimer's disease (AD) is a major cause of dementia in the elderly, and the number of AD patients is rapidly growing as life expectancy increases. However, disease-modifying drugs are not yet available. According to the amyloid hypothesis, disease onset is triggered by aggregation and accumulation of amyloid-β peptide, followed by the formation of neurofibrillary tangles composed of hyperphosphorylated tau, and synaptic loss/neuronal cell death leading to dementia. Based on this hypothesis, various clinical trials for treatment of AD have been conducted, but most were discontinued due to failure to achieve cognitive improvement or appearance of adverse effects. Here we discuss the reasons for the failure of these trials. We suggest that biomarkers of specific, distinct molecular mechanisms of amyloidogenesis should be developed concomitantly with disease-modifying drugs (the so-called companion diagnosis) to aid the proper design of clinical trials, as well as to enable personalized treatment of individual AD patients.

Efficacy and safety of crystalline valsartan/sacubitril (LCZ696) compared to placebo and combinations of free valsartan and sacubitril in patients with systolic hypertension: the RATIO study.

We compared the systolic blood pressure-lowering efficacy and safety of crystalline valsartan/sacubitril (LCZ696, an angiotensin receptor blocker-neprilysin inhibitor) 400 mg daily against valsartan (320 mg once daily) alone or co-administered with placebo or increasing doses of free sacubitril (50, 100, 200, or 400 mg once daily) in order to identify the optimal antihypertensive combination dose. This multicenter, double-blinded, 7-arm parallel-group study recruited patients with mild-to-moderate systolic hypertension (office systolic BP 150-179 mmHg). Primary dependent variable was change in office systolic BP from baseline to week 8. At entry (n=907), mean age was 61.5 years, sitting office blood pressure (BP) 160/90.2 mmHg, and mean 24-hour ambulatory blood pressure 142/82.1 mmHg; 852 participants completed the study. At week 8, there were greater reductions in sitting office SBP and 24-hour ambulatory systolic BP with LCZ696 400mg than with valsartan 320mg (-5.7 and -3.4 mmHg, respectively, p<0.05 each). The systolic BP reduction with LCZ696 400 daily was similar to co-administered free valsartan 320mg and sacubitril 200mg. Effects were similar in those above and below age 65 and active therapies had adverse event rates similar to placebo. We conclude that crystalline valsartan/sacubitril 400 mg daily: 1) is superior to valsartan 320 mg daily for lowering systolic BP, 2) has similar efficacy to the combination of free valsartan 320 mg plus free sacubitril 200 mg, 3) represents the optimal dosage for systolic hypertension in patients of any age, and 4) is safe and well tolerated.

Systemic administration of sialorphin attenuates experimental colitis in mice via interaction with mu and kappa opioid receptors.

Pharmacological treatment and/or maintenance of remission in inflammatory bowel disease (IBD) is currently one of the biggest challenges in the field of gastroenterology. Here we aimed to assess the anti-inflammatory effect and the mechanism of action of sialorphin, the natural blocker of the endogenous opioid peptide-degrading enzymes neprilysin (NEP) and aminopeptidase N (APN), in the mouse models of IBD and the changes in the expression of these enzymes in IBD patients.

Hypertension up to date: SPRINT to SPYRAL.

Hypertension is the most common chronic cardiovascular condition with increasing prevalence all over the world. Treatment of patients at risk requires a multimodal therapeutic concept to adjust blood pressure, including systematic identification of secondary causes of hypertension or pseudo-resistance, lifestyle modification, polypharmacy, and as well as accompanying risk factors and comorbidities. The present review discusses recent studies on patients with increased cardiovascular risk potentially influencing future treatment strategies. It covers blood pressure targets in patients at risk (SPRINT), novel treatment options such as angiotensin receptor neprilysin inhibitors, discusses the treatment of patients with impaired glucose tolerance, and appreciates novelties in controlling therapy-resistant hypertension by fourth-line pharmacotherapies (PATHWAY), as well as new interventional approaches.

Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial.

Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF.

Analysis of salivary protease spectrum in chronic periodontitis.

This study aimed to investigate the difference in salivary protease expression in patients with chronic periodontitis and normal individuals.

Neprilysin inhibition in heart failure: mechanisms and substrates beyond modulating natriuretic peptides.

The autonomic nervous system, the renin-angiotensin-aldosterone system, and the natriuretic peptide system represent critical regulatory pathways in heart failure and as such have been the major targets of pharmacological development. The introduction and approval of angiotensin receptor neprilysin inhibitors (ARNi) have broadened the available drug treatments of patients with chronic heart failure with reduced ejection fraction. Neprilysin catalyses the degradation of a number of vasodilator peptides, including the natriuretic peptides, bradykinin, substance P, and adrenomedullin, as well as vasoconstrictor peptides, including endothelin-1 and angiotensin I and II. We review the multiple, potentially competing, substrates for neprilysin inhibition, and the resultant composite clinical effects of ARNi therapy. A mechanistic understanding of this novel therapeutic class may provide important insights into the expected on-target and off-target effects when this agent is more widely prescribed.

Degradation paradigm of the Gut Hormone, Pancreatic Polypeptide, by hepatic and renal peptidases.

Pancreatic polypeptide (PP) is a gut hormone that acts on Y4 receptors to reduce appetite. Obese humans display a reduced postprandial rise in PP and remain fully sensitive to the anorectic effects of exogenous PP. The utility of PP as an antiobesity treatment is limited by its short circulating half-life. Insight into the mechanisms by which PP is degraded may aid design of long-acting PP analogues.We aimed to investigate the role of peptidases in PP degradation with a view to determining whether inhibition of these enzymes enhanced PP plasma levels and bioactivity in vivo. DPPIV and neprilysin (NEP) were two peptidase found to cleave PP. Limiting the effect of both peptidases improved the in vivo anorectic effect of PP and PP-based analogues. These studies suggest that inhibiting the degradation of PP using specific inhibitors and/or the design of analogues resistant to cleavage by DPPIV and NEP may be useful in the development of PP as an anti-obesity pharmacotherapy.

Angiotensin receptor neprilysin inhibitor treatment is safe and potentially efficacious in end‑stage hypertrophic cardiomyopathy.