Dataset Information

LCZ696 (Sacubitril/valsartan) ameliorates oxidative stress, inflammation, fibrosis and improves renal function beyond angiotensin receptor blockade in CKD.

ABSTRACT: Progressive deterioration of kidney function in chronic kidney disease (CKD) is mediated by hypertension, oxidative stress, inflammation, and fibrosis. Renin-angiotensin blockade is commonly used to retard CKD progression. In addition, vasoactive peptides have been shown to reduce blood pressure and exert antioxidant, anti-inflammatory and anti-fibrotic effects. We hypothesized that administration of LCZ696 (sacubitril/valsartan) is more effective than valsartan alone in slowing progression of CKD. Male Sprague Dawley rats underwent sham surgery or 5/6 nephrectomy and after two weeks the CKD animals were randomized to no treatment, valsartan (30 mg/kg), or LCZ696 (60 mg/kg) daily by gavage. Serum, urine and kidney tissue analyses were performed after 8 weeks. The untreated CKD rats exhibited hypertension, proteinuria, tubular and glomerular damage, upregulation of pro-inflammatory, pro-oxidant and pro-fibrotic pathways; reduction in nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its key target products. LCZ696 administration improved renal function and histology and attenuated most of the molecular markers of oxidative stress, inflammation and fibrosis. Furthermore, LCZ696 was more effective than valsartan therapy alone in delaying the progression of kidney disease. Future clinical trials are needed to determine the safety and efficacy of this agent in treatment of patients with CKD.

SUBMITTER: Jing W

PROVIDER: S-EPMC5752897 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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LCZ696 (Sacubitril/valsartan) ameliorates oxidative stress, inflammation, fibrosis and improves renal function beyond angiotensin receptor blockade in CKD.

Jing Wanghui W Vaziri Nosratola D ND Nunes Ane A Suematsu Yasunori Y Farzaneh Ted T Khazaeli Mahyar M Moradi Hamid H

American journal of translational research 20171215 12

Progressive deterioration of kidney function in chronic kidney disease (CKD) is mediated by hypertension, oxidative stress, inflammation, and fibrosis. Renin-angiotensin blockade is commonly used to retard CKD progression. In addition, vasoactive peptides have been shown to reduce blood pressure and exert antioxidant, anti-inflammatory and anti-fibrotic effects. We hypothesized that administration of LCZ696 (sacubitril/valsartan) is more effective than valsartan alone in slowing progression of C ...[more]

PMID: 29312499

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Project description:To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ?35%).A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'.Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.

Project description:ObjectiveTo evaluate the impact of sacubitril/valsartan on blood pressure (BP), ventricular structure, and myocardial fibrosis compared with valsartan in perimenopausal hypertensive women.MethodsThis prospective, randomized, actively controlled, open-label study included 292 women with perimenopausal hypertension. They were randomly divided into two groups: sacubitril/valsartan 200 mg once daily and valsartan 160 mg once daily for 24 weeks. The relevant indicators of ambulatory BP, echocardiography, and myocardial fibrosis regulation were assessed at baseline and at 24 weeks.ResultsThe 24-h mean SBP after 24 weeks of treatment was 120.08 ± 10.47 mmHg in the sacubitril/valsartan group versus 121.00 ± 9.76 mmHg in the valsartan group ( P = 0.457). After 24 weeks of treatment, there was no difference in central SBP between the sacubitril/valsartan and valsartan groups (117.17 ± 11.63 versus 116.38 ± 11.58, P = 0.568). LVMI in the sacubitril/valsartan group was lower than that in the valsartan group at week 24 ( P = 0.009). LVMI decreased by 7.23 g/m 2 from the baseline in the sacubitril/valsartan group and 3.70 g/m 2 in the valsartan group at 24 weeks ( P = 0.000 versus 0.017). A statistically significant difference in LVMI between the two groups was observed at 24 weeks after adjusting for the baseline LVMI ( P = 0.001). The levels of α-smooth muscle actin (α-SMA), connective tissue growth factor (CT-GF) and transforming growth factor-β (TGF-β) were reduced in the sacubitril/valsartan group compared with the baseline ( P = 0.000, 0.005, and 0.000). LVMI between the two groups was statistically significant at 24 weeks after correcting for confounding factors 24-h mean SBP and 24-h mean DBP ( P = 0.005). The LVMI, serum TGF-β, α-SMA, and CT-GF remained statistically significant between the two groups after further correcting the factors of age, BMI, and sex hormone levels ( P < 0.05).ConclusionSacubitril/valsartan could reverse ventricular remodeling more effectively than valsartan. The different effects of these two therapies on ventricular remodeling in perimenopausal hypertensive women might be because of their different effects on the down-regulation of fibrosis-related factors.

Dataset Information

LCZ696 (Sacubitril/valsartan) ameliorates oxidative stress, inflammation, fibrosis and improves renal function beyond angiotensin receptor blockade in CKD.

Publications

LCZ696 (Sacubitril/valsartan) ameliorates oxidative stress, inflammation, fibrosis and improves renal function beyond angiotensin receptor blockade in CKD.

Similar Datasets

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