Over the last decade,neprilysin inhibition has been established as the cornerstone of therapy in heart failure(HF).Patients with chronic kidney disease(CKD)and end-stage kidney disease(ESKD)have a high prevalence of H...Over the last decade,neprilysin inhibition has been established as the cornerstone of therapy in heart failure(HF).Patients with chronic kidney disease(CKD)and end-stage kidney disease(ESKD)have a high prevalence of HF;the concomitant presence of HF and CKD or ESKD,conventionally termed chronic cardiorenal syndrome,is associated with a higher rate of adverse outcomes,including increased hospitalizations and mortality.The use of this novel class of medications in patients with advanced CKD or ESKD has been limited due to uncertainty about their efficacy and safety.Herein,we provide an overview of the available evidence on the use of neprilysin inhibition in HF and discuss how those concepts would apply to patients with concomitant CKD or ESKD.展开更多
Neurodegenerative brain disorders are a major burden in our society,such as Alzheimer´s disease.In order to repair or prevent such diseases,drugs are designed which enter the brain,but the blood-brain barrier lim...Neurodegenerative brain disorders are a major burden in our society,such as Alzheimer´s disease.In order to repair or prevent such diseases,drugs are designed which enter the brain,but the blood-brain barrier limits their entry and the search for alternative pathways is important.Recently,we reported that intranasal delivery of the amyloid-beta degrading enzyme neprilysin eliminated amyloid-beta plaques in transgenic Alzheimer´s disease mice.This review describes the anatomical structure of the intranasal pathway,explains the intranasal delivery of pure neprilysin,cell-loaded neprilysin(platelets)and collagen-embedded neprilysin to destruct amyloid-beta plaques in Alzheimer´s disease in transgenic APP_SweDI mice and hypothesizes why this may cause compensation and why the amyloid-beta cascade hypothesis may fail.展开更多
Heart failure(HF)is a clinical syndrome that results from a structural or functional cardiac disorder that reduces the ability of the ventricle of the heart to fill with,or eject,blood.It is a multifaceted clinical co...Heart failure(HF)is a clinical syndrome that results from a structural or functional cardiac disorder that reduces the ability of the ventricle of the heart to fill with,or eject,blood.It is a multifaceted clinical condition that affects up to 2%of the population in the developed world,and is linked to significant morbidity and mortality;it is therefore considered a major concern for public health.Regarding the mechanism of HF,three neurohumoral factors-the reninangiotensin-aldosterone system,the sympathetic nervous system,and natriuretic peptides—are related to the pathology of chronic HF(CHF),and the targets of treatment.Angiotensin receptor blocker and neprilysin inhibitor(angiotensinreceptor neprilysin inhibitor),namely sacubitril/valsartan(SAC/VAL),has been introduced as a treatment for CHF.SAC/VAL is an efficacious,safe,and costeffective therapy that improves quality of life and longevity in patients with HF with reduced ejection fraction(HFrEF),and reduces hospital admissions.An inhospital initiation strategy offers a potential new avenue to improve the clinical uptake of SAC/VAL.In the last five years,SAC/VAL has been established as a cornerstone component of comprehensive disease-modifying medical therapy in the management of chronic HFrEF.On the other hand,further work,with carefully designed and controlled preclinical studies,is necessary for understanding the molecular mechanisms,effects,and confirmation of issues such as long-term safety in both human and animal models.展开更多
Background: Heart failure with reduced ejection fraction has a significant association with considerable morbidity and mortality, but there is still inadequacy in appropriate treatment to prevent this condition. We ob...Background: Heart failure with reduced ejection fraction has a significant association with considerable morbidity and mortality, but there is still inadequacy in appropriate treatment to prevent this condition. We observed the effect of angiotensin receptor neprilysin inhibitor (ARNi) with such disorder compared to valsartan. Methods: In this single-blind trial, the patients were enrolled with chronic HF aged on or above 40 years, symptomatic NYHA class II - IV, an elevated NT-proBNP above 400 pg/ml level and a reduced LVEF of 40% or less. The patients were randomly assigned 1:1 to the treatment arms either ARNi (50 mg titrated to 100 mg twice a day) or valsartan (40 mg titrated to 80 mg twice a day) and followed for a median of 88 days. The primary outcome was mode of cardiovascular death and re-hospitalization for heart failure. Changes in the level of NT-proBNP and rate of ejection fraction were also measured. Results: Cardiovascular deaths occurred 4 (8%) in the ARNi treatment arm, while 11 (22%) in the valsartan treatment arm with significant hazard ratio in the ARNi group [Hazard Ratio = 0.37;95% CI: 0.34, 0.64;p = 0.042] during a median of 88 days of follow up period and 2 (4%) of the patients from the ARNi treatment arm were hospitalized due to HF, while in the valsartan treatment arm, 10 (20%) patients were hospitalized due to HF followed by receiving treatment respectively with hazard ratio in the ARNi group [Hazard Ratio = 0.80;95% CI: 0.57, 0.92;p Conclusion: Chronic treatment with the angiotensin receptor neprilysin inhibitor (ARNi) strongly decreases the NT-proBNP as well as morbidity and mortality and increases LVEF in patients with heart failure compared to valsartan.展开更多
Objective:To investigate the effect of Angiotensin Receptor Neprilysin Inhibitor(ARNI)on ventricular remodeling after AMI in rats.Methods:Sixty male SD rats were randomly divided into Control group,AMI group,AMI-valsa...Objective:To investigate the effect of Angiotensin Receptor Neprilysin Inhibitor(ARNI)on ventricular remodeling after AMI in rats.Methods:Sixty male SD rats were randomly divided into Control group,AMI group,AMI-valsartan group,AMI-ARNI group,15 rats in each group,ligating the left coronary anterior descending artery to establish the rat model of AMI.Valsartan group and ARNI group were treated with valsartan(34mg/kg/day)and ARNi(68mg/kg/day)for 6 weeks,the Control group and AMI group were given the same amount of normal saline.LVIDd,LVIDs,EF were measured by color doppler echocardiography before and 6 weeks after treatment.After 6 weeks,the rats were sacrificed,the hearts were weighed,then myocardial tissue Masson staining was performed to calculate the collagen volume fraction(CVF).Results:compared with the control group,LVIDs increased significantly with the reduction of EF in the AMI group,valsartan group and ARNI group(P<0.05).After 6 weeks of treatment,compared with the AMI group,LVIDd and LVIDs both reduced significantly with the increase of EF in the ARNI group(P<0.05).Compared with the control group,the left ventricular weight,right ventricular weight and atrial weight all increased significantly in the AMI group,valsartan group,and ARNI group(P<0.05);compared with the AMI group,the left ventricular weight,right ventricular weight,atrial weight and CVF reduced significantly in the valsartan group and ARNI group(P<0.05);compared with the valsartan group,the left ventricular weight and CVF further reduced in the ARNI group.(P<0.05).Conclusions:ARNI has the effect of reversing ventricular remodeling after AMI in rats,which can reduce left ventricular volume,increase myocardial contractility,and inhibit myocardial cell hypertrophy and fibrosis.展开更多
BACKGROUND Sacubitril/valsartan is a first-in-class angiotensin receptor neprilysin inhibitor(ARNI)which combines an angiotensin receptor blocker(valsartan)with sacubitril,an inhibitor of the enzyme neprilysin.By virt...BACKGROUND Sacubitril/valsartan is a first-in-class angiotensin receptor neprilysin inhibitor(ARNI)which combines an angiotensin receptor blocker(valsartan)with sacubitril,an inhibitor of the enzyme neprilysin.By virtue of combined effect of blocking the action of angiotensin-II and inhibiting the breakdown of natriuretic peptides,ARNIs have beneficial role in heart failure(HF).AIM To evaluate the effect of sacubitril/valsartan on N-terminal pro-B-type natriuretic peptide(NT-pro BNP),inflammatory marker[high-sensitivity C-reactive protein(hs-CRP)],and quality of life when given as add-on to standard therapy in patients with HF.METHODS Sacubitril/valsartan as add-on therapy for improvement in HF study was a randomised controlled trial conducted from July 2023 to November 2024 in a public tertiary care hospital in India.Eligible patients were randomised in 1:1 ratio to either of the 2 study arms:(1)Group A(sacubitril/valsartan+standard treatment);and(2)Group B(standard treatment)for 12 weeks.Primary end point was change in NT-pro BNP levels at 12 weeks from baseline.Secondary endpoints included(1)Change in hs-CRP levels;(2)Change in World Health Organisation Quality of Life Questionnaire(WHOQOL-BREF)score;and(3)Incidence of treatment-related adverse events or worsening HF.Statistical analysis was done using Statistical Package for the Social Sciences trial version 29.0 and P<0.05 was considered significant.RESULTS Out of 124 patients screened,80 were enrolled of which 25 patients in each group were available for per-protocol analysis.At baseline,both the groups were comparable.Sacubitril/valsartan group exhibited a statistically significant greater reduction in NT-pro BNP(-35.91±28.01 vs 24.68±31.86;P<0.0001)and hs-CRP(-2.87±3.22 vs 0.76±1.60;P<0.0001)levels at 12 weeks compared to standard treatment group.There was also a greater improvement in quality of life with sacubitril/valsartan group(overall change in WHOQOL-BREF:13.16±8.73 in sacubitril/valsartan vs-4.12±6.25 in standard treatment arm).No major adverse events were reported in two groups.CONCLUSION Sacubitril/valsartan demonstrated significant improvements in HF biomarkers,inflammation,and quality of life without compromising safety supporting its role as an effective addition to standard HF therapy.Further research is needed to evaluate its long-term benefits on mortality and cardiac remodeling.展开更多
文摘Over the last decade,neprilysin inhibition has been established as the cornerstone of therapy in heart failure(HF).Patients with chronic kidney disease(CKD)and end-stage kidney disease(ESKD)have a high prevalence of HF;the concomitant presence of HF and CKD or ESKD,conventionally termed chronic cardiorenal syndrome,is associated with a higher rate of adverse outcomes,including increased hospitalizations and mortality.The use of this novel class of medications in patients with advanced CKD or ESKD has been limited due to uncertainty about their efficacy and safety.Herein,we provide an overview of the available evidence on the use of neprilysin inhibition in HF and discuss how those concepts would apply to patients with concomitant CKD or ESKD.
文摘Neurodegenerative brain disorders are a major burden in our society,such as Alzheimer´s disease.In order to repair or prevent such diseases,drugs are designed which enter the brain,but the blood-brain barrier limits their entry and the search for alternative pathways is important.Recently,we reported that intranasal delivery of the amyloid-beta degrading enzyme neprilysin eliminated amyloid-beta plaques in transgenic Alzheimer´s disease mice.This review describes the anatomical structure of the intranasal pathway,explains the intranasal delivery of pure neprilysin,cell-loaded neprilysin(platelets)and collagen-embedded neprilysin to destruct amyloid-beta plaques in Alzheimer´s disease in transgenic APP_SweDI mice and hypothesizes why this may cause compensation and why the amyloid-beta cascade hypothesis may fail.
文摘Heart failure(HF)is a clinical syndrome that results from a structural or functional cardiac disorder that reduces the ability of the ventricle of the heart to fill with,or eject,blood.It is a multifaceted clinical condition that affects up to 2%of the population in the developed world,and is linked to significant morbidity and mortality;it is therefore considered a major concern for public health.Regarding the mechanism of HF,three neurohumoral factors-the reninangiotensin-aldosterone system,the sympathetic nervous system,and natriuretic peptides—are related to the pathology of chronic HF(CHF),and the targets of treatment.Angiotensin receptor blocker and neprilysin inhibitor(angiotensinreceptor neprilysin inhibitor),namely sacubitril/valsartan(SAC/VAL),has been introduced as a treatment for CHF.SAC/VAL is an efficacious,safe,and costeffective therapy that improves quality of life and longevity in patients with HF with reduced ejection fraction(HFrEF),and reduces hospital admissions.An inhospital initiation strategy offers a potential new avenue to improve the clinical uptake of SAC/VAL.In the last five years,SAC/VAL has been established as a cornerstone component of comprehensive disease-modifying medical therapy in the management of chronic HFrEF.On the other hand,further work,with carefully designed and controlled preclinical studies,is necessary for understanding the molecular mechanisms,effects,and confirmation of issues such as long-term safety in both human and animal models.
文摘Background: Heart failure with reduced ejection fraction has a significant association with considerable morbidity and mortality, but there is still inadequacy in appropriate treatment to prevent this condition. We observed the effect of angiotensin receptor neprilysin inhibitor (ARNi) with such disorder compared to valsartan. Methods: In this single-blind trial, the patients were enrolled with chronic HF aged on or above 40 years, symptomatic NYHA class II - IV, an elevated NT-proBNP above 400 pg/ml level and a reduced LVEF of 40% or less. The patients were randomly assigned 1:1 to the treatment arms either ARNi (50 mg titrated to 100 mg twice a day) or valsartan (40 mg titrated to 80 mg twice a day) and followed for a median of 88 days. The primary outcome was mode of cardiovascular death and re-hospitalization for heart failure. Changes in the level of NT-proBNP and rate of ejection fraction were also measured. Results: Cardiovascular deaths occurred 4 (8%) in the ARNi treatment arm, while 11 (22%) in the valsartan treatment arm with significant hazard ratio in the ARNi group [Hazard Ratio = 0.37;95% CI: 0.34, 0.64;p = 0.042] during a median of 88 days of follow up period and 2 (4%) of the patients from the ARNi treatment arm were hospitalized due to HF, while in the valsartan treatment arm, 10 (20%) patients were hospitalized due to HF followed by receiving treatment respectively with hazard ratio in the ARNi group [Hazard Ratio = 0.80;95% CI: 0.57, 0.92;p Conclusion: Chronic treatment with the angiotensin receptor neprilysin inhibitor (ARNi) strongly decreases the NT-proBNP as well as morbidity and mortality and increases LVEF in patients with heart failure compared to valsartan.
基金The application of basic research project of Shanxi provincial department of science and technology(No.201901D111445)
文摘Objective:To investigate the effect of Angiotensin Receptor Neprilysin Inhibitor(ARNI)on ventricular remodeling after AMI in rats.Methods:Sixty male SD rats were randomly divided into Control group,AMI group,AMI-valsartan group,AMI-ARNI group,15 rats in each group,ligating the left coronary anterior descending artery to establish the rat model of AMI.Valsartan group and ARNI group were treated with valsartan(34mg/kg/day)and ARNi(68mg/kg/day)for 6 weeks,the Control group and AMI group were given the same amount of normal saline.LVIDd,LVIDs,EF were measured by color doppler echocardiography before and 6 weeks after treatment.After 6 weeks,the rats were sacrificed,the hearts were weighed,then myocardial tissue Masson staining was performed to calculate the collagen volume fraction(CVF).Results:compared with the control group,LVIDs increased significantly with the reduction of EF in the AMI group,valsartan group and ARNI group(P<0.05).After 6 weeks of treatment,compared with the AMI group,LVIDd and LVIDs both reduced significantly with the increase of EF in the ARNI group(P<0.05).Compared with the control group,the left ventricular weight,right ventricular weight and atrial weight all increased significantly in the AMI group,valsartan group,and ARNI group(P<0.05);compared with the AMI group,the left ventricular weight,right ventricular weight,atrial weight and CVF reduced significantly in the valsartan group and ARNI group(P<0.05);compared with the valsartan group,the left ventricular weight and CVF further reduced in the ARNI group.(P<0.05).Conclusions:ARNI has the effect of reversing ventricular remodeling after AMI in rats,which can reduce left ventricular volume,increase myocardial contractility,and inhibit myocardial cell hypertrophy and fibrosis.
文摘BACKGROUND Sacubitril/valsartan is a first-in-class angiotensin receptor neprilysin inhibitor(ARNI)which combines an angiotensin receptor blocker(valsartan)with sacubitril,an inhibitor of the enzyme neprilysin.By virtue of combined effect of blocking the action of angiotensin-II and inhibiting the breakdown of natriuretic peptides,ARNIs have beneficial role in heart failure(HF).AIM To evaluate the effect of sacubitril/valsartan on N-terminal pro-B-type natriuretic peptide(NT-pro BNP),inflammatory marker[high-sensitivity C-reactive protein(hs-CRP)],and quality of life when given as add-on to standard therapy in patients with HF.METHODS Sacubitril/valsartan as add-on therapy for improvement in HF study was a randomised controlled trial conducted from July 2023 to November 2024 in a public tertiary care hospital in India.Eligible patients were randomised in 1:1 ratio to either of the 2 study arms:(1)Group A(sacubitril/valsartan+standard treatment);and(2)Group B(standard treatment)for 12 weeks.Primary end point was change in NT-pro BNP levels at 12 weeks from baseline.Secondary endpoints included(1)Change in hs-CRP levels;(2)Change in World Health Organisation Quality of Life Questionnaire(WHOQOL-BREF)score;and(3)Incidence of treatment-related adverse events or worsening HF.Statistical analysis was done using Statistical Package for the Social Sciences trial version 29.0 and P<0.05 was considered significant.RESULTS Out of 124 patients screened,80 were enrolled of which 25 patients in each group were available for per-protocol analysis.At baseline,both the groups were comparable.Sacubitril/valsartan group exhibited a statistically significant greater reduction in NT-pro BNP(-35.91±28.01 vs 24.68±31.86;P<0.0001)and hs-CRP(-2.87±3.22 vs 0.76±1.60;P<0.0001)levels at 12 weeks compared to standard treatment group.There was also a greater improvement in quality of life with sacubitril/valsartan group(overall change in WHOQOL-BREF:13.16±8.73 in sacubitril/valsartan vs-4.12±6.25 in standard treatment arm).No major adverse events were reported in two groups.CONCLUSION Sacubitril/valsartan demonstrated significant improvements in HF biomarkers,inflammation,and quality of life without compromising safety supporting its role as an effective addition to standard HF therapy.Further research is needed to evaluate its long-term benefits on mortality and cardiac remodeling.
