Early Application of Sacubitril Valsartan Sodium After Acute Myocardial Infarction and its Influence on Ventricular Remodeling and TGF-ß1/Smad3 Signaling Pathway.

Objective: The objective of this study was to investigate the early application of sacubitril valsartan sodium (LCZ696) following acute myocardial infarction (AMI) and its impact on ventricular remodeling and the TGF-ß1/Smad3 signaling pathway in patients. Methods: The clinical data of 73 patients with AMI admitted to the hospital from June 2021 to September 2022 were retrospectively analyzed, and the patients were grouped according to the treatment methods, including 36 cases in the control group (conventional drug treatment) and 37 cases in the observation group (conventional drug + LCZ696 treatment). The clinical efficacy, cardiac function parameters [left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), stroke volume (SV)], cardiac function biochemical indicators [N-terminal pro-B-type natriuretic peptide (NT-proBNP), galectin 3 (Gal-3), amino-terminal peptide of type III procollagen (PIIINP)], ventricular remodeling indicators [left ventricular posterior wall end-diastolic thickness (PWD), posterior wall end-systolic thickness (PWS), ventricular septal end-systolic thickness (IVSS)], ventricular hydrodynamic parameters [left ventricular flow rate in peak ejection (FRPE), flow reversal rate (FRR), flow reversal interval (FRI)], TGF-ß 1/Smad3 signaling pathway-related indicators (TGF-ß1, Smad3), quality of life score (SF-36 Quality of Life Scale) and occurrence of adverse reactions were compared between the two groups. Results: The main findings of the study are as follows: The observation group was significantly better than the control group in many aspects such as overall clinical effectiveness, cardiac function parameters, biochemical indicators, ventricular structure and function, TGF-ß1/Smad3 signaling pathway, and quality of life. Specifically, the observation group showed more significant positive effects in terms of improvement of cardiac function, adjustment of biochemical status, and adjustment of ventricular structure and fluid dynamics parameters. These results provide strong support for the application of new therapeutic approaches in the management of cardiovascular disease. After treatment, the total clinical effective rate in the observation group (89.19%) was significantly higher than that in the control group (69.44%) (P < .05). LVEF and SV in the two groups were significantly increased (P < .05), while LVEDD was significantly decreased (P < .05), and there were statistically significant differences in parameters between the two groups (P < .05). The levels of NT-proBNP, Gal-3 and PIIINP in both groups were significantly reduced (P < .05), and the levels in the observation group were significantly lower than those in the control group (P < .05). The PWD, PWS and IVSS in both groups significantly declined (P < .05), and the indicators in the observation group were significantly lower than those in the control group (P < .05). The FRPE and FRR in the two groups were significantly enhanced (P < .05), while the FRI was significantly reduced (P < .05), and the differences in the above parameters between the two groups were statistically significant (P < .05). The levels of TGF-ß1 and Smad3 in the two groups were significantly declined (P < .05), and the levels in the observation group were significantly lower than those in the control group (P < .05). During the period from before treatment to 6 months of treatment, the quality of life score in the two groups showed a significant downward trend (P < .05), and the score in the observation group after 3 months to 6 months of treatment was significantly lower than that in the control group (P < .05). During treatment, there was no statistical significance in the total incidence rate of adverse reactions between the two groups (P > .05). Conclusion: Early application of LCZ696 after AMI has a significant efficacy, and it can effectively improve the ventricular remodeling, regulate the expression levels of TGF-ß1 and Smad3, inhibit the TGF-ß1/Smad3 signaling pathway, promote the improvements of cardiac function and quality of life, and it has good safety and is worthy of clinical promotion and application. The study's key findings have important clinical implications for understanding and managing acute myocardial infarction (AMI). The observation group showed significant improvements in overall clinical efficacy, cardiac function, biochemical status, ventricular structure and function, etc., providing strong evidence for comprehensive treatment of AMI patients. This treatment method is expected to become an important part of the care and treatment strategy for AMI patients, help reduce cardiovascular risk, improve quality of life, and provide new research directions for future AMI treatment.

Effects of sacubitril/valsartan on exercise capacity: a prognostic improvement that starts during uptitration.

PURPOSE: Sacubitril/valsartan is a mainstay of the treatment of heart failure with reduced ejection fraction (HFrEF); however, its effects on exercise performance yielded conflicting results. Aim of our study was to evaluate the impact of sacubitril/valsartan on exercise parameters and echocardiographic and biomarker changes at different drug doses. METHODS: We prospectively enrolled consecutive HFrEF outpatients eligible to start sacubitril/valsartan. Patients underwent clinical assessment, cardiopulmonary exercise test (CPET), blood sampling, echocardiography, and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Sacubitril/valsartan was introduced at 24/26 mg b.i.d. dose and progressively uptitrated in a standard monthly-based fashion to 97/103 mg b.i.d. or maximum tolerated dose. Study procedures were repeated at each titration visit and 6 months after reaching the maximum tolerated dose. RESULTS: Ninety-six patients completed the study, 73 (75%) reached maximum sacubitril/valsartan dose. We observed a significant improvement in functional capacity across all study steps: oxygen intake increased, at peak exercise (from 15.6 ± 4.5 to 16.5 ± 4.9 mL/min/kg; p trend = 0.001), while minute ventilation/carbon dioxide production relationship reduced in patients with an abnormal value at baseline. Sacubitril/valsartan induced positive left ventricle reverse remodeling (EF from 31 ± 5 to 37 ± 8%; p trend < 0.001), while NT-proBNP reduced from 1179 [610-2757] to 780 [372-1344] pg/ml (p trend < 0.0001). NYHA functional class and the subjective perception of limitation in daily life at KCCQ-12 significantly improved. The Metabolic Exercise Cardiac Kidney Index (MECKI) score progressively improved from 4.35 [2.42-7.71] to 2.35% [1.24-4.96], p = 0.003. CONCLUSIONS: A holistic and progressive HF improvement was observed with sacubitril/valsartan in parallel with quality of life. Likewise, a prognostic enhancement was observed.

[Effect of multi-glycosides of Tripterygium wilfordii on renal injury in diabetic kidney disease rats through NLRP3/caspase-1/GSDMD pyroptosis pathway].

This study investigated the effect of multi-glycosides of Tripterygium wilfordii(GTW) on renal injury in diabetic kidney disease(DKD) rats through Nod-like receptor protein 3(NLRP3)/cysteine-aspartic acid protease-1(caspase-1)/gsdermin D(GSDMD) pyroptosis pathway and the mechanism. To be specific, a total of 40 male SD rats were randomized into the normal group(n=8) and modeling group(n=34). In the modeling group, a high-sugar and high-fat diet and one-time intraperitoneal injection of streptozotocin(STZ) were used to induce DKD in rats. After successful modeling, they were randomly classified into model group, valsartan(Diovan) group, and GTW group. Normal group and model group were given normal saline, and the valsartan group and GTW group received(ig) valsartan and GTW, respectively, for 6 weeks. Blood urea nitrogen(BUN), serum creatinine(Scr), alanine ami-notransferase(ALT), albumin(ALB), and 24 hours urinary total protein(24 h-UTP) were determined by biochemical tests. The pathological changes of renal tissue were observed based on hematoxylin and eosin(HE) staining. Serum levels of interleukin-1ß(IL-1ß) and interleukin-18(IL-18) were detected by enzyme-linked immunosorbent assay(ELISA). Western blot was used to detect the expression of pyroptosis pathway-related proteins in renal tissue, and RT-PCR to determine the expression of pyroptosis pathway-related genes in renal tissue. Compared with the normal group, the model group showed high levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1ß and IL-18(P<0.01), low level of ALB(P<0.01), severe pathological damage to kidney, and high protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01). Compared with the model group, valsartan group and GTW group had low levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1ß and IL-18(P<0.01), high level of ALB(P<0.01), alleviation of the pathological damage to the kidney, and low protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01 or P<0.05). GTW may inhibit pyroptosis by decreasing the expression of NLRP3/caspase-1/GSDMD in renal tissue, thereby relieving the inflammatory response of DKD rats and the pathological injury of kidney.

Qingda granule ameliorates vascular remodeling and phenotypic transformation of adventitial fibroblasts via suppressing the TGF-ß1/Smad2/3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingda granule (QDG) exhibits significant therapeutic effects on high blood pressure, vascular dysfunction, and elevated proliferation of vascular smooth muscle cells by inhibiting multiple pathways. However, the effects and underlying mechanisms of QDG treatment on hypertensive vascular remodeling are unclear. AIM OF THE STUDY: The aim of this study was to determine the role of QDG treatment in hypertensive vascular remodeling in vivo and in vitro. MATERIALS AND METHODS: An ACQUITY UPLC I-Class system coupled with a Xevo XS quadrupole time of flight mass spectrometer was used to characterize the chemical components of QDG. Twenty-five spontaneously hypertensive rats (SHR) were randomly divided into five groups, including SHR (equal volume of double distilled water, ddH2O), SHR + QDG-L (0.45 g/kg/day), SHR + QDG-M (0.9 g/kg/day), SHR + QDG-H (1.8 g/kg/day), and SHR + Valsartan (7.2 mg/kg/day) groups. QDG, Valsartan, and ddH2O were administered intragastrically once a day for 10 weeks. For the control group, ddH2O was intragastrically administered to five Wistar Kyoto rats (WKY group). Vascular function, pathological changes, and collagen deposition in the abdominal aorta were evaluated using animal ultrasound, hematoxylin and eosin and Masson staining, and immunohistochemistry. Isobaric tags for relative and absolute quantification (iTRAQ) was performed to identify differentially expressed proteins (DEPs) in the abdominal aorta, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Cell Counting Kit-8 assays, phalloidin staining, transwell assays, and western-blotting were performed to explore the underlying mechanisms in primary isolated adventitial fibroblasts (AFs) stimulated with transforming growth factor-ß 1 (TGF-ß1) with or without QDG treatment. RESULTS: Twelve compounds were identified from the total ion chromatogram fingerprint of QDG. In the SHR group, QDG treatment significantly attenuated the increased pulse wave velocity, aortic wall thickening, and abdominal aorta pathological changes and decreased Collagen I, Collagen III, and Fibronectin expression. The iTRAQ analysis identified 306 DEPs between SHR and WKY and 147 DEPs between QDG and SHR. GO and KEGG pathway analyses of the DEPs identified multiple pathways and functional processes involving vascular remodeling, including the TGF-ß receptor signaling pathway. QDG treatment significantly attenuated the increased cell migration, actin cytoskeleton remodeling, and Collagen I, Collagen III, and Fibronectin expression in AFs stimulated with TGF-ß1. QDG treatment significantly decreased TGF-ß1 protein expression in abdominal aortic tissues in the SHR group and p-Smad2 and p-Smad3 protein expression in TGF-ß1-stimulated AFs. CONCLUSIONS: QDG treatment attenuated hypertension-induced vascular remodeling of the abdominal aorta and phenotypic transformation of adventitial fibroblasts, at least partly by suppressing TGF-ß1/Smad2/3 signaling.

Effects of Valsartan and Amlodipine Tablets Combined with α-Lipoic Acid on T-AOC, IL-6 and ß2-MG Levels in Patients with Diabetic Nephropathy.

Diabetic nephropathy (DN) is the most important cause of chronic renal and end-stage kidney disease in China. Hypertension (HTN) is highly prevalent in individuals with diabetic nephropathy. Arterial HTN affects two-thirds of people with type 2 diabetes (T2D). In these patients, HTN increased the potential of both micro- and macrovascular complications, and the co-occurrence of 2 such principal causes results in a 4-fold increased risk for cardiovascular disease (CVD) when contrasted with normotensive controls without diabetes. Therefore, the results of valsartan and amlodipine tablets combined with alpha-lipoic acid on total antioxidant capacity (T-AOC) need to be investigated. The aim of this study was to analyze the effects of valsartan (VA) and amlodipine tablets combined with alpha-lipoic acid (α-LA) on T-AOC, IL-6 and ß2-MG levels in patients with DN. We performed statistical analysis including the chi-square test, independent t-test, paired t-test and Analysis of Variance (ANOVA). Our findings indicate that VA, amlodipine and α-LA has a significant effect in patients with DN.

Real-world use patterns of angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) among patients with heart failure within a large integrated health system.

BACKGROUND: Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that is now preferred in guidelines over angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for patients with heart failure with reduced ejection fraction (HFrEF). However, it has not been broadly adopted in clinical practice. OBJECTIVE: To characterize ARNI use within a large diverse real-world population and assess for any racial disparities. METHODS: We conducted a cross-sectional study within Kaiser Permanente Southern California. Adult patients with HFrEF who received ARNIs, ACEIs, or ARBs between January 1, 2014, and November 30, 2020, were identified. The prevalence of ARNI use among the cohort and patient characteristics by ARNIs vs ACEIs/ARBs use were described. Multivariable regression was performed to estimate odds ratios and 95% CIs of receiving ARNI by race and ethnicity. RESULTS: Among 12,250 patients with HFrEF receiving ACEIs, ARBs, or ARNIs, 556 (4.54%) patients received ARNIs. ARNI use among this cohort increased from 0.02% in 2015 to 7.48% in 2020. Patients receiving ARNIs were younger (aged 62 vs 69 years) and had a lower median ejection fraction (27% vs 32%) compared with patients receiving ACEIs/ARBs. They also had higher use of mineralocorticoid antagonists (24.1% vs 19.8%) and automatic implantable cardioverterdefibrillators (17.4% vs 13.3%). There were no significant differences in rate of ARNI use by race and ethnicity. CONCLUSIONS: Within a large diverse integrated health system in Southern California, the rate of ARNI use has risen over time. Patients given ARNIs were younger with fewer comorbidities, while having worse ejection fraction. Racial minorities were no less likely to receive ARNIs compared with White patients. DISCLOSURES: Dr Huang had stock ownership in Gilead and Pfizer. Dr Liang received support for article processing and medical writing.

Anti-inflammatory, anti-oxidant and anti-apoptotic effects of olive leaf extract in cardiac tissue of diabetic rats.

OBJECTIVES: Inflammatory process and apoptosis are involved in the pathogenesis of cardiac injury and oxidative damage caused by diabetes mellitus. The cardioprotective effects of standardized aqueous ethanolic olive leaf extract (OLE), metformin (as a cardiovascular protective agent) and valsartan (as an angiotensin receptor blocker) in the streptozotocin-induced diabetic rats were evaluated. METHODS: Wistar rats divided into control, diabetic, OLE-treated (100, 200 and 400 mg/kg), metformin (300 mg/kg)-treated, valsartan (30 mg/kg)-treated and metformin/valsartan-treated diabetic groups. Biochemical parameters, including malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activates, and the total contents of thiol were measured, and histopathological and gene expression studies were done on cardiac tissues. Fasting blood sugar (FBS) and cardiac injury markers were examined in serum. KEY FINDINGS: FBS; the serum levels of lactate dehydrogenase (LDH), creatine kinase-muscle/brain (CK-MB), aspartate aminotransferase (AST); and heart tissue MDA levels due to diabetes were significantly alleviated by OLE treatment (effect size; ηp2 = 0.934, 0.888, 0.848, 0.888 and 0.879, respectively), and SOD and CAT activity and the thiol content in heart tissue were significantly increased (effect size; ηp2 = 0.770, 0.749 and 0.753, respectively). Interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNF-α) and the number of infiltrating inflammatory cells were reduced in cardiac tissues of OLE-treated groups compared with the diabetic rats (effect size; ηp2 = 0.969 and 0.949, respectively). OLE up-regulated BCL2 gene expression and down-regulated BAX gene expression in cardiac tissue (effect size; ηp2= 0.490 and 0.522, respectively). CONCLUSION: OLE in a dose-dependent manner ameliorates cardiac damage in diabetic cardiomyopathy, perhaps through attenuating inflammation, oxidative stress and apoptosis.

Clinical Effect of Qili Qiangxin Capsule Combined with Sacubitril-Valsartan in Patients with Chronic Heart Failure.

The clinical effect of Qili Qiangxin capsule combined with sacubitril-valsartan on patients with chronic heart failure was studied. We selected 108 patients with chronic heart failure in our hospital from March 2016 to January 2020 and divided them into a control group and a study group according to the random table method, with 54 cases in each. The control group took sacubitril and valsartan orally, and the study group took Qili Qiangxin pill on the basis of sacubitril and valsartan. The course of the treatment for 2 groups is 4 weeks. We compared the total effective rate of the treatment of the 2 groups for 4 weeks, cardiac function (left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF)) before and after 4 weeks of treatment, 6 min walking distance (6MWT), changes in cTnI and NT-proBNP levels, and adverse reactions. The total effective rate in the study group (90.74%) is higher than that in the control group (72.22%) (P＜0.05). After 4 weeks of treatment, the study group LVESV (45.23 ± 2.98 mm) and LVEDV (43.38 ± 4.01 mm) are lower than those of the control group ((49.98 ± 2.56 mm) and (50.75 ± 3.49 mm), respectively), while LVEF (47.38 ± 2.78%) is higher than that in the control group (42.08 ± 3.24%) (P ＜ 0.05). After 4 weeks of treatment, the study group 6MWT (476.58 ± 31.25 m) of patients with chronic heart failure is higher than that of the control group (396.52 ± 24.52 m) (P ＜0.05). After 4 weeks of treatment, the study group serum cTnI (0.36 ± 0.12 µg/L) and NT-proBNP (276.91 ± 30.12 pg/ml) of patients with chronic heart failure are lower than those in the control group (0.87 ± 0.25 µg/L) and (367.48 ± 48.57 pg/ml) (P＜0.05). There is no significant difference between the adverse reactions in the two groups (P ＞ 0.05). Conclusion: Xinbao pills combined with sacubitril and valsartan have a good effect on patients with chronic heart failure, which can improve the heart function and exercise endurance and reduce serum cTnI and NT-proBNP levels.

Shenweifang-containing serum inhibits transforming growth factor-ß1 induced myofibroblast differentiation in normal rat kidney interstitial fibroblast cell.

OBJECTIVE: To investigate the efficacy of Shenweifang (SWF)-containing serum on transforming growth factor (TGF)-ß1-induced fibroblast-myofibroblast transition in normal rat kidney interstitial fibroblast cells (NRK-49F). METHODS: Sprague-Dawley rats were gavaged with one of five solutions: (a) saline; (b) saline plus low-dose SWF; (c) saline plus medium-dose SWF; (d) saline plus highdose SWF; and (e) saline plus valsartan. NRK-49F cells were treated with TGF-ß1 and cultured using serum from the gavaged rats. RESULTS: TGF-ß1 treatment increased the expression of α-smooth muscle actin, proliferating cell nuclear antigen, collagen I, Smad3, mitogen-activated protein kinase (MAPK) 10, and c-Jun N-terminal kinase (JNK) 3 and induced abnormalities in cell morphology, cell cycle progression, and cell proliferation. CONCLUSIONS: SWF- or valsartan-containing serum corrected (or partially corrected) TGF-ß1-induced abnormal changes in this in vitro system. SWF-containing serum reversed abnormalities in morphology, cell cycle progression, and proliferation in TGF-ß1-treated NRK49F cells, probably by blocking the TGF-ß1/Smads and TGF-ß1/MAPK/JNK pathways.

Valsartan-mediated chronotherapy in spontaneously hypertensive rats via targeting clock gene expression in vascular smooth muscle cells.

OBJECTIVE: This study was to investigate the underlying mechanisms of valsartan chronotherapy in regulating blood pressure variability. METHODS: RT-PCR was used to assay clock genes expression rhythm in the hypothalamus, aortic vessels, and target organs after valsartan chronotherapy. WB was used to measure Period 1 (Per1), Period 2 (Per2) protein expression in aortic vessels, as well as to measure phosphorylation of 20-kDa regulatory myosin light chain (MLC20) in VSMCs. RESULTS: Specific clock genes in the hypothalamus, and Per1 and Per2 in aorta abdominalis, exhibited disordered circadian expression in vivo. Valsartan asleep time administration (VSA) restored circadian clock gene expression in a tissue- and gene-specific manner. In vitro, VSA was more efficient in blocking angiotensin II relative to VWA, which led to differential circadian rhythms of Per1 and Per2, ultimately corrected MLC20 phosphorylation. CONCLUSION: VSA may be efficacious in regulating circadian clock genes rhythm, then concomitantly correct circadian blood pressure rhythms.

Sacubitril/Valsartan: A New Dawn has Begun! A Revisited Review.

Heart Failure (HF) is among the major causes of global morbidity as well as mortality. Increased prevalence, frequent and prolonged hospitalization, rehospitalization, long-term consumption of healthcare resources, absenteeism, and death upsurge the economic burden linked to HF. For decades, Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II Receptor Blockers (ARBs), Beta-Blockers (BBs), and mineralocorticoid receptor antagonists (MRA), have remained the mainstay of the standard of care for HF management. Despite their proven efficacy and cost-effectiveness, HF remains a global pandemic and is still increasing in prevalence. Sacubitril/ Valsartan (SAC/VAL) is an Angiotensin Receptor/Neprilysin Inhibitor (ARNI) that proved out to be a game-changer drug in HF treatment. Recent data indicated that SAC/VAL is more efficient and can improve the overall quality of life of HF patients with reduced ejection fraction (HFrEF) with fewer side effects. It is now incorporated in the guidelines as an alternative to ACEIs or ARBs to lower morbidity in addition to mortality in HFrEF patients. This review article will discuss the current guidelines-approved indications and highlight the potential emerging indications, in addition to the currently ongoing clinical trials that will expand the use of SAC/VAL.

Effects of the valsartan/amlodipine combination and nifedipine gastrointestinal therapeutic system monotherapy on brachial pulse pressure and radial augmentation index in hypertensive patients.

OBJECTIVE: In a substudy of a randomized controlled trial, we investigated the effects of the valsartan/amlodipine single-pill combination and nifedipine gastrointestinal therapeutic system (GITS) monotherapy on brachial pulse pressure (bPP) and radial augmentation index (rAI) in patients with previously uncontrolled hypertension. METHODS: We performed measurements of clinic blood pressure (BP) and pulse rate and rAI (n = 63) and ambulatory BP monitoring (n = 42) at baseline and 12-week of follow-up. Analysis of covariance was performed to calculate the least square mean change from baseline and between-group differences [95% confidence interval (CI)]. Correlation analysis was performed to study the interrelationship between the changes in bPP and rAI and in pulse rate. RESULTS: After 12-week treatment, clinic and ambulatory SBP/DBP and pulse rate were not differently changed between the valsartan/amlodipine (n = 29) and nifedipine GITS groups (n = 34, P ≥ 0.06) except daytime SBP (P = 0.01). The reductions in 24-h and daytime ambulatory bPP were significantly greater in the former than the latter group (P ≤ 0.04). rAI increased slightly by 3.5% (P = 0.20) and 5.2% (P = 0.06) in the valsartan/amlodipine and nifedipine groups, respectively, with a between-group difference of -1.7% (95% CI -9.6 to 6.1%, P = 0.66). In the two groups combined, the changes in clinic and ambulatory bPP were not or weakly associated with that in clinic or ambulatory pulse rate (r = -0.14 to 0.36, P = 0.02-0.95), while the changes in rAI were more strongly or significantly associated with that in clinic or ambulatory pulse rate (r = -0.39 to -0.23, P = 0.02-0.16). CONCLUSIONS: Antihypertensive drug-induced changes in rAI but not bPP were dependent on pulse rate.

Valsartan prevents glycerol-induced acute kidney injury in male albino rats by downregulating TLR4 and NF-κB expression.

In this study, the protective effect of valsartan against glycerol-induced acute kidney injury (AKI) in male albino rats was investigated. Valsartan is used to treat high blood pressure and congestive heart failure and can prolong lifespan following a heart attack. The rats were divided into control, AKI, AKI + valsartan 100 mg/kg bw, and AKI + valsartan 200 mg/kg bw groups. Superoxide dismutase, glutathione peroxidase, catalase, lipid peroxidation, and reduced glutathione were assessed, and histopathological, immunohistochemical and western blot analyses were performed. Valsartan supplementation in AKI rats substantially increased superoxide dismutase, catalase, glutathione peroxidase, and glutathione levels but reduced the level of lipid peroxidation. Valsartan significantly reduced the severity of the renal tubular injury, renal lesions, and necrosis. Valsartan decreased NF-κB and TLR4 mRNA expression by >50% and their protein levels by >40%. Therefore, valsartan supplementation inhibited glycerol-induced functional and pathological damage to the kidney in a concentration-dependent manner. We propose that valsartan protects rat kidney tissue by downregulating NF-κB and TLR4 expression.

Cytochrome P450 2C9-natural antiarthritic interactions: Evaluation of inhibition magnitude and prediction from in vitro data.

Many dietary supplements are promoted to patients with osteoarthritis (OA) including the three naturally derived compounds, glucosamine, chondroitin and diacerein. Despite their wide spread use, research on interaction of these antiarthritic compounds with human hepatic cytochrome P450 (CYP) enzymes is limited. This study aimed to examine the modulatory effects of these compounds on CYP2C9, a major CYP isoform, using in vitro biochemical assay and in silico models. Utilizing valsartan hydroxylase assay as probe, all forms of glucosamine and chondroitin exhibited IC50 values beyond 1000 µM, indicating very weak potential in inhibiting CYP2C9. In silico docking postulated no interaction with CYP2C9 for chondroitin and weak bonding for glucosamine. On the other hand, diacerein exhibited mixed-type inhibition with IC50 value of 32.23 µM and Ki value of 30.80 µM, indicating moderately weak inhibition. Diacerein's main metabolite, rhein, demonstrated the same mode of inhibition as diacerein but stronger potency, with IC50 of 6.08 µM and Ki of 1.16 µM. The docking of both compounds acquired lower CDOCKER interaction energy values, with interactions dominated by hydrogen and hydrophobic bondings. The ranking with respect to inhibition potency for the investigated compounds was generally the same in both in vitro enzyme assay and in silico modeling with order of potency being diacerein/rhein > various glucosamine/chondroitin forms. In vitro-in vivo extrapolation of inhibition kinetics (using 1 + [I]/Ki ratio) demonstrated negligible potential of diacerein to cause interaction in vivo, whereas rhein was predicted to cause in vivo interaction, suggesting potential interaction risk with the CYP2C9 drug substrates.

[Shendi granules regulates the balance of T cell subsets and down-regulates podocalyxin in rats with mesangial proliferative glomerulonephritis].

Objective To observe the effect of Shendi granules on T cell subsets and podocyte marker protein in rats with mesangial proliferative glomerulonephritis (MsPGN), and study possible mechanism. Methods Totally 40 SD rats were randomly divided into the model group, valsartan group, Shendi granule group and normal group. The Shendi granule group were given 4 g/(kg.d) of Shendi granule by gavage; the valsartan group were given 10.3 mg/(kg.d) of valsartan by gavage; the model group and normal group were given the same amount of saline per day by gavage. The treatments lasted 12 weeks. Routine biochemical method was used to quantify 24-hour urine protein; the numbers of CD4+ and CD8+ T cells were detected by flow cytometry; the serum levels of interleukin 2 (IL-2), IL-4 and IL-17, the levels of urinary podocalyxin (PCX) and B7-1, the renal calcineurin (CaN) content were determined by ELISA. Results Compared with the normal group, the levels of 24-hour urine protein, CD8+ T cells, serum IL-2 and IL-17, urinary PCX and B7-1, CaN in the model group were higher. The above indexes in the valsartan group and control group were lower than those in the model group, they were lower in the Shendi granule group than in the valsartan group. The whole blood CD4+ T cell number and serum IL-4 level in the model group were lower than those in the normal group, they were higher in the valsartan group and control group than in the model group. Compared with the valsartan group, the Shendi granule group had a better improvement. Conclusion Shendi granule could reduce 24-hour urine protein effectively. The mechanism may be related to the regulation of CD4+ T and CD8+ T cell numbers, the down-regulated expressions of serum IL-2, IL-17, the decreased levels of PCX and B7-1 in urine, CaN in kidney tissue, and the up-regulated level of serum IL-4.

QbD-Oriented Development of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) of Valsartan with Improved Biopharmaceutical Performance.

The objectives of the present studies were to develop the systematically optimized selfnanoemulsifying drug delivery systems (SNEDDS) of valsartan employing the holistic QbD approach. The quality profile target product (QTPP) was defined and critical quality attributes (CQAs) earmarked. Preformulation studies including the equilibrium solubility and pseudoternary phase titration studies facilitated the selection of suitable lipids and emulgents for formulation of SNEDDS. Risk assessment and factor screening studies facilitated the selection of Lauroglycol FCC and Capmul MCM L8 (i.e., lipid), Tween 40 and Tween 80 (i.e., emulgent) as the critical material attributes (CMAs) for SNEDDS prepared using medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs). A central composite design (CCD) was employed for systematic optimization of SNEDDS, taking globule size (Dnm), drug release in 10 min (Q10min) and amount permeated in 45 min (%Perm45min) as the CQAs. Design space was generated using apt mathematical models to embark upon the optimized formulations and validation of the QbD. In situ SPIP studies revealed significant improvement in the absorptivity and permeability parameters of SNEDDS owing to the inhibition of P-gp/MRP2 efflux vis-à-vis the conventional marketed formulation and pure drug. In vivo pharmacokinetic studies corroborated marked enhancement in the oral bioavailability drug from SNEDDS vis-à-vis the marketed formulation. Establishment of various levels of in vitro/in vivo correlations (IVIVC) indicated excellent goodness of fit between the in vitro drug release data with the in vivo absorption parameters. In a nutshell, the present studies report successful QbD-based development of MCT and LCT-SNEDDS of valsartan with improved biopharmaceutical performance.

LCZ696, Angiotensin II Receptor-Neprilysin Inhibitor, Ameliorates High-Salt-Induced Hypertension and Cardiovascular Injury More Than Valsartan Alone.

BACKGROUND: LCZ696, an angiotensin receptor-neprilysin inhibitor, has recently been demonstrated to exert more beneficial effects on hypertensive or heart failure patients than conventional renin-angiotensin system blockers. However, the mechanism underlying the benefit of LCZ696 remains to be understood. The present study was undertaken to examine the effect of LCZ696 compared with valsartan on hypertension and cardiovascular injury. METHODS: (i) Using telemetry, we compared the hypotensive effect of LCZ696 and valsartan in spontaneously hypertensive rats (SHR) that were fed a high-salt diet followed by a low-salt diet. (ii) We also examined the comparative effect of LCZ696 and valsartan on salt loaded SHRcp, a model of metabolic syndrome. RESULTS: (i) LCZ696 exerted a greater blood pressure (BP) lowering effect than valsartan in SHR regardless of high-salt or low-salt intake. Additive BP reduction by LCZ696 was associated with a significant increase in urinary sodium excretion and sympathetic activity suppression. (ii) LCZ696 significantly ameliorated cardiac hypertrophy and inflammation, coronary arterial remodeling, and vascular endothelial dysfunction in high-salt loaded SHRcp compared with valsartan. CONCLUSIONS: LCZ696 caused greater BP reduction than valsartan in SHR regardless of the degree of salt intake, which was associated with a significant enhancement in urinary sodium excretion and sympathetic activity suppression. Furthermore, an additive BP lowering effect of LCZ696 led to greater cardiovascular protection in hypertensive rats.

Different chronotherapeutic effects of valsartan and olmesartan in non-dipper hypertensive patients during valsartan treatment at morning.

This study was undertaken to evaluate the differences in chronotherapeutic effects of angiotensin-II receptor blockers, valsartan and olmesartan in hypertensive patients with non-dipper blood pressure (BP) pattern during valsartan at morning. Ninety four patients were enrolled, and 40 patients were judged to be non-dippers. In these patients, same dose of valsartan was changed to evening (Val-E, n = 12), or olmesartan (equivalent dose of valsartan) was given at morning (Olm-M, n = 13) or evening (Olm-E, n = 15) for 4 months. BP decreased during sleep and increased during waking hours in Val-E group. In Olm-M and Olm-E groups, BP decreased during sleep and waking hours. Percent reduction in BP at night-time compared to BP at waking hours significantly increased after changing the dose regimen in each group. Serum creatinine decreased and estimated glomerular filtration rate (eGFR) elevated in Olm-M and Olm-E, but not Val-E groups. Positive correlation between systolic BP (SBP) during sleep and serum creatinine, and negative correlation between SBP during sleep and eGFR were detected. These data suggest that dipper BP pattern could be obtained by chronotherapeutic approach using valsartan and olmesartan in non-dipper patients with valsartan at morning. Morning and evening olmesartan, but not evening valsartan improved renal function in these patients.